Bukas Emergencies in Dermatology 2013 PDF

Buka’s Emergencies in Dermatology
Bobby Buka Annemarie Uliasz

●
Karthik Krishnamurthy
Editors
Buka’s Emergencies
in Dermatology
Editors
Bobby Buka, MD JD Annemarie Uliasz, MD
Private Practice Private Practice
Section Chief Clinical Instructor
Department of Dermatology Department of Dermatology
Mount Sinai School of Medicine Mount Sinai School of Medicine
New York, NY, USA New York, NY, USA
Karthik Krishnamurthy, DO
Dermatology, Jacobi Medical Center
Cosmetic Dermatology Clinic
Montefiore Medical Center
Albert Einstien College of Medicine
Bronx, NY, USA
ISBN 978-1-4614-5030-6 ISBN 978-1-4614-5031-3 (eBook)

DOI 10.1007/978-1-4614-5031-3
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Preface
“A thick skin is a gift from God.”

—Konrad Adenauer (1876–1976), German statesman
As dermatology residents, long before we are asked to discern papu-

losquamous from eczematous, mentors ask the much simpler question, “dan-
gerous” or “benign?” It seemed so rudimentary at the time, but the response
to this basic query dictates every other aspect of the patient encounter to fol-
low. How quickly to act? How varied is the differential diagnosis? What treat-
ments to offer and which would present an acceptable risk:benefit analysis?
When must we swiftly enjoin additional subspecialists? The entire algorithm
of care stems from this first, most critical element: “Is this a crisis?”
Buka’s Emergencies in Dermatology is designed to address this pivotal
question for medical students, residents, emergency personnel, and commu-
nity and attending physicians alike. We begin with an overview of critical
care—how to manage patients with a severely compromised skin structure
and function. Next, we focus on the pediatric population and special consid-
erations for emergency care therein. Our remaining 14 chapters serve as a
reference resource, each devoted to urgent care for the 14 classes of specific
dermatologic emergency. We hope to equip readers with a more complete
appreciation for the early recognition and treatment for those skin disorders
that offer a grave risk of morbidity or mortality.
Thankfully, the field of dermatology offers very few critical presentations;
this is precisely the reason we must endeavor to recognize these early and
respond thoroughly.
New York, NY, USA Robert L. Buka

Bobby Buka, MD JD
v
Acknowledgements
To Mom, whose support turned every challenge into an opportunity for

greatness.
To Uncles Steve and Dave and their spirit of mischief.
To Bari who showed me how to be a doctor first and a physician second.
To Bogi who taught me the periscope has two ends.
and
To Matt, my older and dearest friend.
vii
Contents
1 Neonatal and Pediatric Dermatologic Emergencies ................ 1

Dawn X. Zhang, Ted W. Farrand, Maryam Afshar, Lucia Diaz,
Tina Chen, Michael Caglia, and Lawrence F. Eichenfield
2 Infectious Emergencies in Dermatology ................................... 19
Emily Stamell and Karthik Krishnamurthy
3 Drug Eruptions............................................................................ 43
Rita V. Patel and Gary Goldenberg
4 Histamine-Mediated Emergencies ............................................. 57
Alyx Rosen, Sarit Itenberg, and Adam Friedman
5 Cutaneous Emergencies in the HIV-Positive Patient ............... 83
Markus Boos, Karolyn Wanat, and James Treat
6 Graft-Versus-Host Disease ......................................................... 103
David Pompei, Kathryn J. Russell, and Frederick A. Pereira
7 Erythroderma .............................................................................. 133
Gillian Heinecke and Mark Lebwohl
8 Vesiculobullous Dermatoses ....................................................... 147
Michael W. Cashman, Daven Doshi, and Karthik Krishnamurthy
9 Vasculitis ...................................................................................... 175
Larissa Chismar, Sara Wildstein, and Karthik Krishnamurthy
10 Skin Manifestations of Internal Disease ................................... 193
Daniel Behroozan and Hana Jeon
11 Cutaneous Findings of Collagen Vascular Disease
and Related Emergent Complications ...................................... 207
Aneesa Krishnamurthy, Diana H. Lee, and Aegean Chan
12 Burn and Other Exposure Injuries ........................................... 235
Alexander M. Sailon and Peter J. Taub
13 Dermatological Emergencies: Skin Manifestations
of Abuse........................................................................................ 247
Rachel Nazarian, Joy Checa, and Orit Markowitz
ix
x Contents
14 Dermatologic Surgery Complications ....................................... 259

Amylynne J. Frankel and Ellen S. Marmur
15 Bites and Stings ........................................................................... 271
Annemarie Uliasz
Index ..................................................................................................... 287

Contributors
Maryam Afshar, MD Division of Dermatology, Department of Medicine,

University of California, San Diego, CA, USA
Daniel Behroozan, MD Dermatology Institute of Southern California, Santa
Monica, CA, USA
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Markus Boos, MD, PhD Department of Dermatology, Perelman School of
Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Bobby Buka, MD JD Private Practice, Section Chief, Department of
Dermatology, Mount Sinai School of Medicine, New York, NY, USA
Michael Caglia, MD Pediatric and Adolescent Dermatology, Rady Children’s
Hospital/University of California, San Diego, San Diego, CA, USA
Michael W. Cashman, MD Einstein Division of Dermatology, Montefiore
Medical Center, Bronx, NY, USA
Aegean Chan, MD Department of Dermatology, Albert Einstein College of
Medicine, Montefiore Medical Center, Bronx, NY, USA
Joy Checa, BA American University of the Caribbean School of Medicine,
Coral Springs, FL, USA
Tina Chen, MD Pediatric & Adolescent Dermatology, Rady Children’s
Hospital/University of California, San Diego, CA, USA
Larissa Chismar, MD Division of Dermatology, Montefiore Medical
Center, Bronx, NY, USA
Lucia Diaz, MD Department of Dermatology, University of Texas Medical
School at Houston, Houston, TX, USA
Daven Doshi, MD Department of Dermatology, Albert Einstein College of
Medicine, Bronx, NY, USA
xi
xii Contributors
Lawrence F. Eichenfield, MD Pediatric & Adolescent Dermatology, Rady

Children’s Hospital/University of California, San Diego, CA, USA
Ted W. Farrand, BSE Pediatric & Adolescent Dermatology, Rady
Children’s Hospital/University of California, San Diego, CA, USA
Amylynne J. Frankel, MD Department of Dermatology, Mt. Sinai School
of Medicine, New York, NY, USA
Mount Sinai Medical Center, New York, NY, USA
Adam Friedman, MD, FAAD Division of Dermatology, Department of
Medicine, Montefiore Medical Center, Albert Einstein College of Medicine,
Bronx, NY, USA
Gary Goldenberg, MD Department of Dermatolgoy, Mount Sinai School
Gillian Heinecke, BS Department of Dermatolgy, Mt. Sinai School of Medicine,
New York, NY, USA
Sarit Itenberg, DO Division of Dermatology, Department of Medicine,
Albert Einstein College of Medicine, Bronx, NY, USA
Hana Jeon, MD David Geffen School of Medicine at UCLA, Los Angeles,
CA, USA
Mark Lebwohl, MD Department of Dermatology, Mt. Sinai School of
Medicine, New York, NY, USA
Diana H. Lee, MD, PhD Department of Dermatology, Albert Einstein
College of Medicine, Montefiore Medical Center, Bronx, NY, USA
Aneesa Krishnamurthy, DO Preferred Health Partners, Brooklyn, NY, USA
Karthik Krishnamurthy, DO Dermatology, Jacobi Medical Center,
Cosmetic Dermatology Clinic, Montefiore Medical Center, Albert Einstein
College of Medicine, Bronx, NY, USA
Orit Markowitz, MD Department of Dermatology, Mt. Sinai Hospital,
New York, NY, USA
Faculty Practice Associates-Dermatology, New York, NY, USA
Ellen S. Marmur, MD Department of Dermatology, The Mount Sinai
Medical Center, New York, NY, USA
Department of Genetics and Genomic Research, The Mount Sinai Medical
Center, New York, NY, USA
Cosmetic & Surgical Dermatology, The Mount Sinai Medical Center, New York,
NY, USA
Procedural Dermatology, The Mount Sinai Medical Center, New York, NY, USA
Cosmetic Dermatology, The Mount Sinai Medical Center, New York, NY, USA
Contributors xiii
Rachel Nazarian, MD Department of Dermatology, Mt. Sinai Hospital,

New York, NY, USA
Rita V. Patel, MD Department of Dermatolgoy, Mount Sinai School of
Frederick A. Pereira, MD Department of Dermatology, Mount Sinai School
Department of Dermatology, New York Medical College, New York, NY, USA
David Pompei, Pharm D Einstein-Montefiore Division of Dermatology,
Montefiore Medical Center, Bronx, NY, USA
Alyx Rosen, BSE Albert Einstein College of Medicine, New York, NY, USA
Kathryn J. Russell, MD Department of Dermatology, New York Medical
College, New York, NY, USA
Alexander M. Sailon, MD Division of Plastic and Reconstructive Surgery,
Department of Surgery, Mount Sinai School of Medicine, New York, NY, USA
Emily Stamell, MD Department of Medicine, Division of Dermatology,
Albert Einstein College of Medicine, Bronx, NY, USA
Peter J. Taub, MD, FACS, FAAP Division of Plastic and Reconstructive
Surgery, Department of Surgery and Pediatrics, Mount Sinai School of
James Treat, MD Pediatrics and Dermatology, Perelman School of Medicine
at the University of Pennsylvania, USA
Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia,
PA, USA
Karolyn Wanat, MD Department of Dermatology, Perelman School of
Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Sara Wildstein, BA Albert Einstein College of Medicine, Bronx, NY, USA
Annemarie Uliasz, MD Spring Street Dermatology, New York, NY, USA
Department of Dermatology, Mount Sinai School of Medicine, New York
City, NY, USA
Dawn X. Zhang, BS Department of Cellular & Molecular Medicine,
Neonatal and Pediatric
Dermatologic Emergencies 1
Dawn X. Zhang, Ted W. Farrand, Maryam Afshar,
Lucia Diaz, Tina Chen, Michael Caglia,
and Lawrence F. Eichenfield
potentially resulting in death. It is therefore

1.1 Introduction
important that these entities be rapidly identified
and addressed. The following pages present a
A wide variety of neonatal and childhood derma- limited collection of some of the most important
tologic conditions can be emergencies. These emergency situations.
may arise from genetic disorders, including those
causing skin structural protein and keratin dys-
function, vascular birthmarks with systemic 1.2 Neonatal Emergencies
associations, autoimmune disorders, and infec-
tions. If left untreated, these conditions can There are broad sets of neonatal dermatologic
lead to systemic effects or may increase the conditions that are true emergencies. Vesicles,
risk of developing secondary complications, pustules, and denuded skin at birth or in the neo-
natal period may be localized lesions without
consequence, such as sucking blisters, or signs of
a life-threatening genetic mechanobullous disor-
der such as epidermolysis bullosa. Herpes sim-
D.X. Zhang, B.S. plex virus (HSV) and opportunistic infections
Department of Cellular & Molecular Medicine,
can be dermatologic emergencies, requiring
e-mail: daz001@ucsd.edu prompt recognition, diagnosis, and initiation of
therapy. Vascular tumors, including port-wine
M. Afshar, M.D.
Division of Dermatology, Department of Medicine, stains (PWS) and hemangiomas, may require
University of California, San Diego, CA, USA urgent management including diagnostic workup,
L. Diaz, M.D. referral for specialty evaluation, and/or early
Department of Dermatology, University of Texas introduction of therapy. The conditions discussed
Medical School at Houston, Houston, TX, USA below are only a select subset of neonatal derma-
L.F. Eichenfield, M.D. (*) • T.W. Farrand, B.S.E. tologic issues that may be considered emergen-
• T. Chen, M.D. • M. Caglia, M.D. cies. Other resources more extensively discuss
Pediatric and Adolescent Dermatology,
other neonatal dermatologic conditions (e.g.,
Rady Children’s Hospital/University of California,
8010 Frost Street, Ste 602, San Diego, CA 92130, USA Neonatal Dermatology, 2nd Edition. Eichenfield,
e-mail: leichenfield@rchsd.org Frieden and Esterly, Saunders/Elsevier).
B. Buka et al. (eds.), Buka’s Emergencies in Dermatology, 1

DOI 10.1007/978-1-4614-5031-3_1, © Springer Science+Business Media, LLC 2013
2 D.X. Zhang et al.
level exhibiting the plane of separation. Specific

1.3 Epidermolysis Bullosa
genetic testing may be utilized as well.
Epidermolysis bullosa (EB) is a group of con-

genital disorders characterized by the pro-
found susceptibility of skin and mucosa to 1.3.1 Epidermolysis Bullosa Simplex
separate from underlying tissues following
mechanical trauma. EB generally presents at EBS, the mildest and most common type of EB, is
birth or in the first few weeks of life with characterized by the lysis of basal keratinocytes
denuded skin, vesicles, or bullae. Milder forms above the basement membrane zone [1]. Most
may present later in life. EB is caused by subtypes of EBS are autosomal dominant muta-
mutations in structural proteins in the skin, tions in Keratin 5 or 14 (such as Weber–Cockayne,
and is generally categorized by the level of Koebner, and Dowling–Meara); however, auto-
blistering and the target proteins: EB simplex somal recessive mutations and mutations in other
(EBS) (epidermolytic), junctional EB (JEB) genes have been reported. Keratin 5 and 14 func-
(lysis in the lamina lucida, or “lucidolytic”), tion in the adhesion of cells to the hemidesmo-
dystrophic (dermolytic), and Kindler syn- some through plectin, another EBS-associated
drome (mixed blistering levels) [1]. protein [2]. Most EBS children experience an
EB has an incidence of 1 in every 50,000 increased tendency to blister as temperature
births, consisting mostly of the milder EBS increases; however, their overall prognosis is
type [2]. Of the three types of EB, EBS and excellent with normal life expectancy and
JEB generally heal without scarring. In con- decreased tendency to blister with time. The
trast, healing with milia suggests Dystrophic Weber–Cockayne (WC) EBS subtype is the mild-
EB (DEB), but has been reported in other types. est, most common subtype of EBS where the bul-
Some children exhibit a congenital localized lae, though temperature sensitive, are confined
absence of skin (Bart syndrome) at birth, which predominantly to the hands and feet. In Koebner
is characterized by large ulcers usually in the (K) EBS, patients experience generalized blister-
lower extremities [3]. Oral erosions are most ing with little to no mucosal involvement. 20% of
commonly found in JEB and DEB, and are patients experience nail involvement; however,
rarely found in EBS. Extensive blistering can all symptoms improve with advancing age.
lead to fluid and electrolyte abnormalities, Dowling-Meara (DM) EBS is most severe in the
temperature dysregulation, as well as sepsis; neonate and infant, and can be fatal in the neona-
supportive measures are essential in the treat- tal period. Large generalized blistering predomi-
ment plan. nates; however, blisters do decrease with age.
The differential diagnosis of erosions, blis- DM children experience profound mucosal
ters, or denuded skin includes infections (e.g., involvement, as well as nail involvement and
HSV) and other blistering diseases. To diag- mild acral blistering. Unlike other major EBS
nose EB, a biopsy should be taken from unaf- disorders, EBS with muscular dystrophy is char-
fected skin. The area to be biopsied may be acterized by an autosomal recessive mutation in
rubbed for 1 min, generally with a pencil eraser, the gene coding plectin. These patients experi-
to induce cutaneous blistering; after a 5–10- ence early-onset generalized blistering with
min wait, a shave, or punch biopsy is taken [2]. laryngeal and mucosal involvement, as well as
Evaluation can include light microscopy, progressive muscular dystrophy. Finally, EBS
immunofluorescence antigen mapping for with mottled pigmentation is a rare autosomal
absent or attenuated antigens diagnostic for the dominant subtype characterized by mechanically
EB subtype, or transmission electron micros- induced blistering, unaffected mucosa, and a mix-
copy, which may visualize the ultrastructural ture of hyper- and hypopigmented macules [4].
1 Neonatal and Pediatric Dermatologic Emergencies 3
1.3.2 Junctional Epidermolysis

Bullosa
JEB (Fig. 1.1), characterized by mechanically

induced blistering occurring within the base-
ment membrane at the lamina lucida [1], is the
least common form of EB, showing poor out-
come in infancy. JEB is caused by autosomal
recessive mutations in genes coding components
of the hemidesmosome-anchoring complex crit-
ical for dermal–epidermal adhesion. The Herlitz
and non-Herlitz subtypes of JEB are character-
ized by mutations in laminin 5, which is essen-
tial for the adhesion of keratin intermediate
filaments to the basement membrane. In the Fig. 1.1 Junctional epidermolysis bullosa. Erosions,
most common form, the Herlitz subtype, there is blisters, and denudation on the hands
significant mortality (approximately 50%) by 2
years of age [2]. This subtype is characterized
by exuberant granulation tissue within ulcers 1.3.3 Dystrophic Epidermolysis
especially in the ocular and perioral region with Bullosa
sparing of the lips. Affected individuals experi-
ence dental enamel dysplasia, severe blistering DEB is characterized by blistering below the
of the periungual and finger pad regions, and lamina densa of the basement membrane zone,
erosions of the laryngeal and respiratory epithe- causing lysis of the dermis [1]. DEB is caused by
lium, resulting in hoarseness. Blisters heal with autosomal dominant and recessive mutations in
atrophy but not milia. The amount of blistering type VII collagen, a major component of anchor-
is often not predictive of prognosis. Common ing fibrils, thus resulting in defective attachment
complications include anemia of chronic dis- of the basement membrane to the underlying der-
ease and growth retardation. In severe cases, mis [2]. There exists a profound variation in the
death may be due to severe sepsis and failure to prognosis of DEB patients due to the spectrum of
thrive. In contrast, the non-Herlitz subtypes are presenting symptoms. Dominant DEB is a much
characterized by less severe but similar manifes- milder subtype with an onset from birth to early
tations to the Herlitz type including dental, nail, infancy. Blistering predominates on elbows,
and laryngeal involvement; however, patients knees, lower legs, and the dorsum of hands; 80%
experience less mucosal involvement and of children experience nail dystrophy [3]. Milia
improved prognosis. Finally, JEB with pyloric are associated with scarring, which was once
atresia is a rare subtype characterized by a muta- thought to be pathognomonic for DEB, and some
tion in a6b4 integrin and sometimes a mutation patients develop scar-like lesions on the trunk. In
in the plectin gene. Patients present at birth with contrast, Recessive DEB is present at birth and
upper gastrointestinal obstruction, most often characterized by widespread blistering, scarring,
affecting the pyloric region. There is variable and milia. Patients experience deformities due to
skin involvement; however, the ocular, respira- scarring such as digital fusion and joint contrac-
tory, and urogenital epithelium are almost tions. There may be severe involvement of the
always affected. Prenatal signs include polyhy- nails and mucous membranes of the gastrointesti-
dramnios and abdominal masses. Corrective nal tract, ocular mucosa, and genitourinary system.
surgery is necessary. The prognosis is often poor In severe cases, failure to thrive may result from
due to failure to thrive, fluid and electrolyte chronic wound healing, poor nutrition, infection,
imbalances, and sepsis [3]. and blood loss from erosions. Children and
4 D.X. Zhang et al.
adolescents often experience growth retardation thyotic conditions, early recognition, therapy,
and are greatly predisposed later in life to squamous and monitoring will be required to prevent infec-
cell carcinoma in heavily scarred areas [4]. tion or fluid and electrolyte imbalance.
Emergent evaluation of a neonate with pos-
sible EB includes skin biopsy and institution of
aggressive supportive measures, including 1.4.1 Collodion Baby
excellent skin care. Fluids and electrolytes must
be closely monitored, and the temperature must The collodion infant presents at birth encased in
be kept moderate since heat can induce blister- a shiny, thickened, variably erythematous, cello-
ing. Care must be taken to minimize new blis- phane-like membrane [5]. This presentation is
ters and erosions through gentle handling and associated with several disorders, including non-
the use of nonadhesive bandages especially for bullous congenital ichthyosiform erythroderma
the first layer of bandaging. The skin care regi- (NCIE), lamellar ichthyosis, and self-healing col-
men must promote wound healing through daily lodion baby. Less commonly encountered condi-
bathing and vigilant inspection of blisters. tions that may present with collodion membranes
A topical or systemic antimicrobial can be used include Sjögren–Larsson syndrome, Conradi–
to prevent infection, though use must be bal- Hünermann syndrome, trichothiodystrophy, and
anced by the potential for selection of resistant neonatal Gaucher’s disease [3].
microbes. Topical antibiotics may be rotated Despite the markedly thickened stratum cor-
and the use of such products should be discon- neum in collodion infants, the membrane acts as
tinued when the wound is clean [2]. Nonsteroidal a poor barrier due to cracking and fissuring. This
anti-inflammatory drugs or opiates can be results in increased water and electrolyte loss
administered to decrease pain during bandaging leading to a hypovolemic hypernatremic state,
and other procedures. Intact blisters must be heat loss, and an increased risk of developing
incised on the dependent side using a sterile cutaneous infections and sepsis. Infants are also
needle to prevent lesion extension. It is impor- at risk for developing pneumonia from aspiration
tant to properly diagnose the EB type and sub- of squamous material in utero, and have difficulty
type, as well as counsel and educate parents on closing their eyes due to the thickened skin and
prognosis and future therapy. Referral for ectropion [3].
genetic counseling is appropriate. In-hospital Treatment of an infant with a collodion mem-
care may be appropriate until the infant is feed- brane is primarily supportive. The babies should
ing well and gaining weight with stable skin be placed in a high-humidity, neutrally thermal
involvement, and the family has adequate train- environment with the application of bland emol-
ing in skin care management. lients such as petrolatum ointment to prevent
dehydration. Serum electrolytes and fluids should
be monitored. Surgical debridement is contrain-
1.4 Disorders of Keratinization dicated and the use of keratolytics in the neonatal
(Ichthyosis) period through the first 6 months of life is not
recommended due to the increased risk of toxic-
There are several ichthyotic conditions that mani- ity from excessive absorption through permeable
fest during the neonatal period as either collodion skin [5].
baby or scaling erythroderma. These disorders The management of these infants should
encompass a wide range of genetic conditions include a dermatological consultation to help
with molecular defects affecting the epidermis [3]. identify the ichthyotic disorder and tailor their
At birth and up to the first day of life, desquama- treatment. A skin biopsy evaluating the histologic
tion of the skin is abnormal and the differential appearance of lesional skin and the use of elec-
diagnosis includes congenital ichthyosis, intra- tron microscopy and/or specific genetic testing
uterine stress, and postmaturity [5]. For most ich- may confirm the etiologic diagnosis. Because
involvement of the face may result in ectropion CNS disease, which represents 30% of neonatal
formation, ophthalmologic consultation is appro- HSV cases, generally presents in full-term infants
priate [5]. after 16–19 days of life [10]. Skin lesions are only
present in 60% of infants. Encephalitis can result
from retrograde neuronal spread of mucosal
1.5 Herpes Simplex Virus lesions [8]. HSV encephalitis or meningoencepha-
litis can cause irritability, lethargy, poor feeding,
HSV is a DNA virus that can cause acute skin seizures, coma, and death. Prompt initiation of
infections and serious illness in neonates and acyclovir therapy substantially improves outcome;
infants, ranking as one of the most significant prolonged therapy has been associated with better
dermatologic emergencies in the first year of life. outcomes. A significant number of neonates with
HSV-2 causes 70–85% of neonatal HSV infec- HSV-2 CNS infections may have neurologic prob-
tions, with HSV-1 associated with the remainder lems at 1 year, including developmental delay, epi-
of cases. The rate of neonatal HSV disease in the lepsy, blindness, and cognitive disabilities [10].
United States is approximately 1 per 10,000 Disseminated disease occurs in 25% of neo-
births [6], roughly 1,500 cases per year. nates, and is the most common presentation of
HSV infection of the neonate can occur during HSV in premature infants. Clinical manifesta-
the intrauterine (5%), peripartum (85%), or post- tions appear after 1–2 weeks of life. Skin or
partum (10%) periods [7]. Most neonatal HSV mucosal lesions are present in 60% of cases [8].
infections are acquired by contact with asymp- Disseminated disease commonly involves the
tomatic primary or recurrent genital HSV infec- lung, liver, and brain, resulting in shock, dissemi-
tion during delivery [8]; the risk of transmission nated intravascular coagulation, and multiple
is substantially reduced by caesarean section. organ system failure [10]. Mortality is 75% in
Transmission risk is increased by prolonged rup- untreated neonates and can be as high as 30%
ture of the membranes, as well as vacuum or for- despite treatment.
ceps delivery and placement of fetal scalp The presence of a vesicular rash in a febrile
monitors, which breach the integrity of the muco- neonate, with or without lethargy, seizures, or sys-
cutaneous barrier and may serve as an inocula- temic findings should raise suspicion for HSV
tion site for HSV. disease [9]. Early consideration and diagnosis of
HSV infections occur with three distinct clini- HSV infection allow initiation of therapy, thus
cal presentations: (1) disease limited to the skin, minimizing significant viral replication and dis-
eyes, and/or mouth (SEM disease), (2) central semination [10]. HSV infection in neonates may
nervous system (CNS) disease, with or without present as eroded or denuded skin. However, since
skin lesions, and (3) disseminated disease involv- vesicular rashes and erosions may be absent in
ing multiple visceral organs, including the lungs, HSV infection, neonates with CNS infection or
liver, adrenal glands, skin, eyes, and brain [8]. sepsis should prompt consideration of HSV.
SEM disease accounts for 45% of neonatal A complete workup should include cultures of the
HSV cases. Skin is involved in 80–85% of cases CSF, blood, mouth, nasopharynx, conjunctivae,
[8]. Isolated or grouped vesicles on an erythema- rectum, and skin vesicles. Histologic examination
tous base appear 1–2 weeks following inoculation. of scrapings from the base of a vesicle or mucosal
Within 1–3 days, vesicles progress to coalescing ulceration, for the presence of multinucleated
crusted papules and plaques. The lesions may giant cells and eosinophilic intranuclear inclu-
erode or ulcerate [9]. Systemic therapy is required; sions typical of HSV (i.e., with Tzanck test), has
otherwise, dissemination of the infection may low sensitivity. Direct fluorescence antibody
occur. With treatment, the long-term developmen- staining of vesicle scrapings allows for rapid diag-
tal outcome of SEM disease is good. Neonates nosis. Polymerase chain reaction (PCR) assay of
with SEM disease often have recurrent cutaneous CSF to detect HSV DNA is currently the diagnos-
herpes during early childhood [10]. tic method of choice for CNS disease. A complete
6 D.X. Zhang et al.
blood count and comprehensive metabolic panel, structures may be dangerous and even life-threat-
including liver transaminases, should be per- ening. Of particular concern are IHs in the perior-
formed to assess systemic involvement [8]. bital, perioral, deep subcutaneous, and perineal
High-dose parenteral acyclovir is the treat- regions. Facial and perineal hemangiomas should
ment of choice for neonatal HSV infections. raise consideration of associated structural anom-
Acyclovir (generally given as 60 mg/kg/day given alies such as the PHACES and PELVIS/SACRAL
in three divided doses over 21 days) improves syndromes, as these may be associated with
both mortality and morbidity from neonatal dis- significant medical risks.
seminated and CNS HSV. Similar dosing for a IHs found periocularly may permanently
shorter duration is recommended for SEM dis- affect vision; unless the lesion is both superficial
ease, and for asymptomatic infants born to women and small in size, an ophthalmologist should be
acquiring HSV infection near term [8, 10]. consulted. For lesions that may partially or fully
A recent multicenter observational study of neo- obstruct vision, systemic therapy is usually indi-
nates with HSV infection determined that delayed cated. The contralateral eye may be patched for
initiation of acyclovir therapy is associated with a several hours each day to promote opening of the
higher rate of in-hospital death [11]. Thus, it is affected eye. Systemic therapy, such as propra-
reasonable to consider empiric acyclovir therapy nolol or prednisone, should be instituted early
in ill neonates where HSV is being considered in by a specialist with expertise in treating IHs.
the differential diagnosis while awaiting diagnos- Occasionally, intralesional corticosteroids are
tic testing results. Pediatric infectious disease utilized for periocular lesions, although there
consultation is reasonable in established cases of have been rare reports of ipsilateral and even con-
CNS or disseminated infection [10]. Transient tralateral blindness after such procedures.
neutropenia may occur in up to 20% of neonates Perioral IHs not only risk deformation of the
treated with high-dose acyclovir, but may not lip cosmetically but may be also associated with
result in clinically significant adverse outcomes. pharyngeal or tracheal lesions, potentially caus-
ing airway obstruction and stridor. In patients
with large mandibular IHs, especially involving
1.6 Vascular Birthmarks multiple areas of the perioral, chin, and bilateral
jawline segments, imaging of the airway by direct
1.6.1 Hemangiomas visualization, CT, or MRI should be considered.
Systemic therapy should also be instituted in
Infantile hemangiomas (IHs) are the most com- cases involving airway obstruction. In more
mon vascular tumor, affecting 4–10% of all severe cases, an otolaryngologist may utilize
infants born in the United States. IHs are benign laser or other surgically destructive techniques.
tumors that may not be present at birth, but pres- Deep IHs are more difficult to monitor, as the
ent within the first few weeks of life. Precursor exact size is less clinically discernible. CT or
lesions are common but often subtle; early signs MRI imaging can aid in determining the extent of
include pallor, telangiectases, a bruise-like involvement as well as elucidate proximity to
appearance, or, rarely, skin ulceration. IHs typi- organs and vascular structures, such as the carotid
cally proliferate, with rapid growth of the tumor artery and vein, which are at risk for compression
in the first several months of life. This phase is during the proliferative stage. Deep IHs that are
followed by an involution stage, with slow, spon- in close proximity to vascular structures need to
taneous diminishment of the lesion over several be monitored very closely during the prolifera-
years. Following involution of the vascular com- tive stage; systemic therapy should also be initi-
ponent, there is sometimes a residual fibro-fatty ated to minimize functional impact and potential
mass. deformation.
Occasionally, IHs may require emergent atten- IHs in the perineal region need special consid-
tion and therapy [12]. IHs that are near vital eration, since these lesions can affect genitouri-
Fig. 1.2 PHACES. Infant with large segmental heman-

gioma of the face, one of the diagnostic criteria for
PHACE syndrome
Fig. 1.3 Port Wine Stain. Infant with port wine stain involv-
nary and gastrointestinal functions. CT or MRI
ing the ophthalmic branch (V1) of the trigeminal nerve
imaging may be helpful in delineating the extent
of involvement, and systemic therapy may also
be required. arterial anomalies, and Renal anomalies), and
PHACE syndrome (Fig. 1.2), a constellation SACRAL syndrome are all used to refer to the simi-
of clinical findings associated with IHs, refers lar findings associated with larger IHs in the ano-
to Posterior fossa brain abnormalities, Heman- genital region. There are no published guidelines
giomas, Arterial malformations, Coarctation of regarding the appropriate threshold for performing
the aorta and other cardiac defects, and Eye imaging and workup to look for associated anoma-
abnormalities. Diagnostic criteria for PHACE lies. Further studies are needed to establish both the
syndrome and possible PHACE syndrome include size and location of perineal IHs of concern.
major and minor findings such as cerebrovas- Functionally significant or potentially deforming
cular, cardiovascular, ocular, brain, and ventral or hemangiomas warrant early referral to specialists
midline defects [13]. An IH of at least 5 cm in with expertise in workup and management.
size found on the head and neck region should
undergo a workup to rule out underlying abnor-
malities that may be life-threatening. An MRI 1.6.2 Port-Wine Stains
and MRA of the soft tissues of the head and neck,
as well as of the brain, should be performed. An PWS (Fig. 1.3) are non-palpable vascular malfor-
ECHO and EKG may identify cardiac anomalies, mations composed of capillary venules present at
and an eye exam should be performed. Despite birth, which may be isolated cutaneous findings or
their benign appearance, facial IHs may portend associated with syndromic features. PWS on the
serious underlying malformations. face, primarily involving the ophthalmic branch of
Large, segmental hemangiomas in the anogeni- the trigeminal nerve (V1), may be associated with
tal region have also been found to be associated Sturge–Weber Syndrome (SWS) [14]. SWS may
with underlying anomalies. The acronyms PELVIS manifest with seizures and developmental delay,
syndrome (Perineal hemangioma, External genita- and/or glaucoma. PWS may also be associated
lia malformations, Lipomyelomeningocele, with more complex vascular malformations.
Vesicorenal abnormalities, Imperforate anus, and Management in the neonatal period should
Skin tag), LUMBAR syndrome (Lower body include consideration of the differential diagno-
hemangioma and other cutaneous defects, sis (PWS, hemangioma, complex malformation)
Urogenital anomalies, ulceration, Myelopathy, and evaluation for possible syndromic features
Bony deformities, Anorectal malformations, that may require emergent measures. Facial PWS
8 D.X. Zhang et al.
overlying the V1 distribution require urgent Stevens–Johnson Syndrome (SJS) and toxic
evaluation for possible glaucoma [14]. Evaluations epidermolysis, acute infectious complications of
for CNS manifestations may be considered, but atopic dermatitis, and some primary infections
need not be performed as a part of emergency due to bacteria, viruses, and fungi.
management.
1.9 Drug Eruptions and Drug

1.7 Opportunistic Fungal Hypersensitivity
Infections
1.9.1 Urticaria
Due to their immature skin barrier, premature
neonates are at risk for cutaneous fungal infec- Urticaria is characterized by pruritic, well-
tions. These infections can manifest as pustules, circumscribed, pink, edematous papules or
vesicles, plaques, indurations, ecchymoses, plaques (wheals) usually associated with allergic
crusts, erosions, and necrotic lesions often ini- responses or infections. The lesions may be local-
tially appearing at sites of skin trauma [15]. ized or generalized, and usually last less than
Opportunistic fungi can easily disseminate, and 24 h; however, associated angioedema can last
even with treatment are associated with high hours to days. Systemic symptoms may include
mortality rates. diarrhea, breathing difficulties, fever, fatigue, or
An aggressive workup is necessary given the arthralgias.
very broad differential diagnosis (intrauterine Acute urticaria is caused by viral infection in
epidermal necrosis, HSV, Behçet’s disease, lupus, 80% of children as well as by foods and drugs in
etc.) [15]. The infant’s maternal, family, perina- most teenagers. Penicillins, sulfonamides, cepha-
tal, and neonatal histories should be evaluated. losporins, aspirin, NSAIDs, anticonvulsants, tet-
A CBC with differential, coagulation studies, and racyclines, opiates, and radiocontrast are common
antibody studies, if cutaneous lupus is being con- causes of urticaria [16]. Milk, eggs, nuts, shellfish,
sidered (anti-SSA/Ro, SSB/La, U1RNP, ANA) and wheat are examples of food triggers. Contact,
are recommended. Tissue cultures, blood cul- pressure, aquagenic, cholinergic, and cold urti-
tures, biopsies, and appropriate rapid diagnostic caria are further considerations. The differential
testing (e.g., HSV direct fluorescent antibodies, diagnosis includes arthropod bites, contact der-
PCR) should be performed and are critical for matitis, erythema multiforme, mastocytosis,
identifying causative organisms. dermatographism, serum sickness-like reaction
Treatment consists of excision or debridement (SSLR), and urticarial vasculitis.
along with systemic antifungals [15]. The anti- The diagnosis is made clinically. In contrast to
fungal therapy of choice is dependent on the erythema multiforme, lesions of annular urticaria
identity of the organism, and infectious disease usually lack a dusky center. However, in younger
specialists should advise its selection. children, bruising may occur secondary to urti-
caria that can be confused with erythema multi-
forme. For atypical lesions with purpura or those
1.8 Childhood Emergencies lasting longer than 24 h, a biopsy should be
performed to rule out urticarial vasculitis.
Emergency dermatologic conditions in children Urticaria is usually self-limited once the incit-
are extensive in number and scope. While many ing agent is removed, and lesions usually disap-
conditions are discussed elsewhere in this book, pear in a few days. If urticarial lesions persist for
this section emphasizes several conditions that more than 6 weeks, an infectious workup may be
may commonly be considered in the differential warranted, although without specific signs or
diagnosis of emergent conditions in childhood, symptoms it may be difficult to make a causative
including urticarial eruptions, drug eruptions, diagnosis. Approximately 80% of patients respond
to oral therapy with twice-daily dosing of second- sary. Oral antihistamines such as diphenhydramine,
generation antihistamines such as cetirizine, lor- cetirizine, or hydroxyzine, bland emollients, or topi-
atadine, levocetirizine, or fexofenadine [16]. cal corticosteroids may be administered for pruritus
These agents should be tapered over several weeks [16]. After 1–2 weeks, the eruption usually desqua-
after the urticaria resolves. Severe outbreaks or mates leaving a temporary hyperpigmentation.
pruritus can be treated with first-generation anti-
histamines such as hydroxyzine or diphenhy-
dramine, doxepin, or even H2 blockers such as
ranitidine or cimetidine. Oral corticosteroids 1.9.3 Serum Sickness-Like Reaction
should be reserved for nonresponsive cases in
order to avoid potential side effects and rebound. SSLR is characterized by fever, an urticaria-like
Epinephrine can be used for anaphylaxis and an eruption, and arthralgias that occur 1–3 weeks
epinephrine pen should be considered in patients after a drug exposure. The eruption can be fixed
at risk for severe allergic responses. and may become purpuric. Unlike true serum
sickness, this type of eruption is not associated
with immune complexes, vasculitis, hypocom-
1.9.2 Exanthematous Reaction plementemia, or renal involvement.
Cephalosporins, penicillins, minocycline, sul-
Exanthematous or morbilliform drug reactions fonamides, and bupropion are the main causes,
are the most common type of drug eruptions. with cefaclor being the most common [15]. The
Classic findings are pruritic, pink macules, or differential diagnosis includes viral or drug exan-
papules coalescing into patches or plaques begin- thems, rheumatoid arthritis, urticarial vasculitis,
ning at 1–2 weeks after starting a medication. urticaria, drug vasculitis, and post-viral synovitis.
The eruption is symmetric and usually appears Management includes discontinuing the
on the trunk before generalized dissemination. offending medication; antihistamines and topical
A coexisting viral infection can increase the inci- corticosteroids can be administered for pruritus.
dence and severity of a morbilliform reaction as If fever or arthralgias are severe, a short course of
seen when amoxicillin is prescribed during an oral corticosteroids (1–2 mg/kg/day) may be
Epstein–Barr Virus infection. prescribed. Since cefaclor rarely cross-reacts
Penicillins, sulfonamides, cephalosporins, and with other beta-lactam antibiotics, other cepha-
anticonvulsants are common causes of exan- losporins are usually tolerated.
thematous reactions [16]. The differential diag-
nosis includes viral exanthems, pityriasis rosea,
acute graft versus host disease, allergic contact 1.9.4 Fixed Drug Eruption
dermatitis, scarlet fever, and eczema. In contrast
to viral exanthems, a drug exanthem is more A fixed drug eruption is characterized by a few
likely to be pruritic. well-circumscribed, oval, erythematous, or
Usually, the diagnosis is made on clinical hyperpigmented plaques that recur at the same
grounds. Occasionally, a skin biopsy may be sites with repeat drug administration. Lesions
helpful, especially in differentiating from other favor the lips, extremities, upper trunk, and
conditions, such as graft versus host disease. It is genitalia. The eruption occurs 1–2 weeks after
important to assess if drug reactions are isolated drug exposure and tends to be asymptomatic.
to the skin, or affect other organ systems, as Barbiturates, sulfonamides, acetaminophen, ibu-
occurs with Drug Reaction with Eosinophilia and profen, aspirin, tetracyclines, pseudoephedrine,
Systemic Symptoms (DRESS) syndrome, which lamotrigine, and phenolphthalein are the typical
affects hematologic, lymphatic, hepatic, renal, triggers [16]. The differential diagnosis includes
and pulmonary systems. The offending drug arthropod bites, contact dermatitis, eczema,
should be discontinued if not completely neces- cellulitis, urticaria, and erythema multiforme.
10 D.X. Zhang et al.
To confirm the diagnosis, a skin biopsy or

drug rechallenge may be performed. Histolog-
ically, a fixed drug eruption resembles erythema
multiforme with additional evidence of chronic-
ity. Identifying and removing the offending drug
are essential. Other treatments are usually not
necessary, but topical corticosteroids may be used
for pruritus.
1.9.5 Erythema Multiforme

Fig. 1.4 Erythema multiforme. Targetoid plaques with
Erythema multiforme (EM) is a type of hypersen- central crusting on the leg
sitivity that occurs in response to infections,
medications, or other illnesses. The eruption con-
sists of symmetric, targetoid, erythematous 1.9.6 Stevens–Johnson Syndrome and
plaques on the skin and sometimes in the oral Toxic Epidermal Necrolysis
cavity (Fig. 1.4). Epidermal detachment is not a
hallmark finding. Lesions may appear anywhere, SJS and toxic epidermal necrolysis (TEN) are
with a preference for the palms and soles, exten- life-threatening skin conditions defined by the
sor extremities, and the backs of hands and feet. percentage of epidermal detachment. Epidermal
Local symptoms include pruritus or burning. detachment of less than 10% of the total body
Fever, fatigue, arthralgias, or other viral-like surface is considered to be SJS, while 10–30% is
symptoms may be present. The majority of EM SJS/TEN overlap, and >30% is TEN. These erup-
cases in children are caused by infections, mostly tions are immune-mediated hypersensitivity reac-
from an HSV, followed by mycoplasma. Less tions involving the skin and membranes, which
commonly, NSAIDs, sulfonamides, penicillins, may include eyes, nose, mouth, respiratory tract,
allopurinol, or anticonvulsants may cause this and gastrointestinal, genital, and urethral mucosa.
eruption [16]. The differential diagnosis includes Prior to the rash, patients have prodromal symp-
bullous diseases, fixed drug eruption, subacute toms such as malaise, fever, cough, headache,
lupus erythematosus, polymorphous light erup- and anorexia. SJS and TEN are characterized by
tion, vasculitis, urticaria, and tinea corporis. confluent targetoid lesions, erythroderma, or bul-
The diagnosis of EM is mainly clinical, but a lae, requiring involvement of at least 2 mucous
biopsy should be considered if lupus erythemato- membranes, with patients demonstrating the
sus, vasculitis, or another condition is suspected. Nikolsky sign. Lesions usually start on the face
Herpes or mycoplasma cultures and antibody and upper trunk, but can spread to other areas,
titers may be performed if appropriate. Most often involving the palms and soles.
cases of EM resolve within 2–3 weeks. In contrast to EM, SJS or TEN is most com-
Symptomatic treatment with oral antihistamines, monly caused by drugs, mainly sulfonamides,
emollients, and topical corticosteroids may be NSAIDs, allopurinol, penicillins, and anticonvul-
administered for pruritus [16]. For recurrent epi- sants [17]. Infections have also been associated
sodes associated with HSV, prophylactic acyclo- with SJS and TEN. The differential diagnosis
vir should be considered; however, treatment includes erythema multiforme, Kawasaki dis-
with acyclovir during each EM episode is usually ease, Staphylococcal scalded skin syndrome
not effective. In most cases, oral corticosteroids (SSSS), pemphigus, and bullous lupus erythema-
can result in longer and more frequent recur- tosus. SSSS presents with a more superficial
rences, but are sometimes prescribed for severe exfoliation pattern with crusting, and primarily
symptoms. affects periorificial and flexural areas.
Mortality estimates for SJS and TEN are as may be useful. Topical corticosteroids and anti-
high as 1–5% and 25–35%, respectively [17]. histamines can be prescribed for pruritus.
Withdrawing the offending drug is essential. If Symptoms and labs may initially improve and
epidermal detachment is extensive, patients then flare after a few weeks. Thyroid testing
should be transferred to an ICU or burn unit to should be repeated 2–3 months after treatment to
optimize wound care, prevent infections, and test for autoimmune thyroiditis, even if the results
attend to hydration and nutrition. Ophthalmology are normal at baseline.
should be consulted for ocular involvement. The
administration of systemic corticosteroids is con-
troversial and is advocated by some for treatment 1.10 Selected Pediatric Systemic
during the first few days of the eruption. A longer Diseases
course may increase morbidity due to increased
risk of infections. Furthermore, IVIG (2.5–3 mg/ 1.10.1 Juvenile Dermatomyositis
kg/day) over 3–5 days has been advocated as
another treatment option. Additionally, there Juvenile Dermatomyositis (JD), a humoral and
have been reports of improvement with cellular immune-mediated chronic inflammatory
cyclosporine, plasmapheresis, and cyclophosph- condition characterized by generalized capillary
amide. Of importance, aromatic anticonvulsants vasculopathy, results in a pronounced erythema-
(phenobarbital, phenytoin, and carbamazepine) tous rash of the face or extremities and symmetri-
may cross-react and should not be substituted for cal muscle weakness. JD has an incidence of 3
one another. per million children per year [2]. Specific HLA
and cytokine polymorphisms, as well as environ-
mental triggers such as group A hemolytic strep-
1.9.7 Drug Rash with Eosinophilia tococci and other microbial infections have been
and Systemic Symptoms implicated in disease pathogenesis. JD should be
considered when a child presents with character-
DRESS is a life-threatening condition that devel- istic rashes (a violaceous rash of the periocular
ops 1–8 weeks after drug exposure. Patients usu- area, pink-red papules of the dorsal fingers,
ally present with a morbilliform eruption, as well photosensitive dermatitis) and two or more of the
as edema, cervical lymphadenopathy, fever, and following: progressive symmetrical proximal
internal organ involvement (hepatitis, pneumoni- muscle weakness, inflammatory and atrophic
tis, interstitial nephritis, encephalitis, myocardi- muscle histopathology, elevated muscle-derived
tis, and thyroiditis). Drugs implicated in DRESS enzymes, and EMG changes or MRI appearance
include aromatic anticonvulsants, dapsone, of inflammatory myopathy. Fifty percent of
allopurinol, minocycline, sulfonamides, lam- patients report a progressive onset characterized
otrigine, and terbinafine. Furthermore, the differ- by weakness, anorexia, malaise, abdominal pain,
ential diagnosis consists of bacterial or viral and a violaceous rash that precedes or follows
infections, lymphoma, and idiopathic hypereo- muscle weakness. Thirty percent have fulminant
sinophilic syndrome. A new rash associated with onset of fever, weakness, and multisystem
unexplained eosinophilia, atypical lymphocyto- involvement [3].
sis, and elevated transaminases may be indicative Cutaneous signs include photosensitive skin
of DRESS. Hepatic transaminases, a CBC, uri- changes of the hands and knuckles, “Gottron’s
nalysis, serum creatinine, and thyroid testing sign,” cutaneous ulceration at pressure points,
should be ordered at baseline and followed. heliotrope rash of the face, periungal changes
A skin biopsy is usually nonspecific. (telangiectasia, cuticular overgrowth), and less
Management includes immediate removal of commonly calcinosis. Nondestructive, nonde-
the offending drug. In cases of visceral involve- forming arthritis of the knee can occur in parallel
ment, systemic corticosteroids (1–2 mg/kg/day) with proximal muscle weakness, resulting in an
inability to rise from the floor. Currently, there than skin usually involves joints, the gastrointes-
has been no association with malignancy in chil- tinal tract, and/or kidneys. Skin lesions can begin
dren; however, myositis and muscle weakness as urticarial macules or papules that may become
can result in decreased esophageal motility, reflux purpuric, bullous, or necrotic. Although 80%
with ulceration or aspiration pneumonia, and of cases have joint and skin involvement, in 25% of
decreased respiratory capacity. Vasculitis of mes- cases, non-migratory oligoarthritis may be the
enteric vessels, the retina and eyelid, and renal only presenting sign [3]. Gastrointestinal symp-
ischemia leading to renal failure are further com- toms range from colicky abdominal pain and
plications that must be considered [4]. positive fecal occult blood to serious complica-
Prompt evaluation by a specialist is warranted, tions such as intussusception, acute pancreatitis,
as earlier diagnosis and initiation of therapy may bowel perforation, and protein-losing enteropa-
improve overall prognosis. Workup may include thy. Renal complications include transient micro-
CBC, CPK, LDH, Aldolase, antibody screens, scopic hematuria, proteinuria, gross hematuria,
and MRI. nephrotic syndrome, acute nephritis, and, in the
First-line treatment includes high-dose oral long-term, end-stage renal disease; however, most
corticosteroid therapy (1–2 mg/kg/day) or intra- renal cases have excellent prognosis with com-
venous methylprednisone (3-day pulses of 30 mg/ plete resolution. In rare cases, neurological symp-
kg) when there is multisystem involvement. toms such as headache, intracerebral bleeds, and
Methotrexate can be administered as second-line seizures have been reported.
therapy, and has been shown to improve muscu- Often the diagnosis is straightforward in chil-
lar strength as well as other signs of disease activ- dren presenting with purpura of the buttocks
ity; evolving use of biologics should be and lower extremities, and with other associated
considered. Patients should be counseled in sun systemic findings [4]. A differential diagnosis
protection and referred to physiotherapy follow- of hypersensitivity vasculitis can be excluded by
ing resolution of the acute phase of the disease. a careful diagnostic workup including patient
history detailing recent infections and medica-
tions, and relevant laboratory investigations,
1.10.2 Henoch–Schönlein Purpura including metabolic panels, blood cell counts,
coagulation studies, radiographic studies, stool
Henoch–Schönlein Purpura (HSP), an acute non- guaiac testing, urinalysis, abdominal ultrasonog-
granulomatous vasculitis of small blood vessels, raphy for GI symptoms, and kidney biopsy
is the most common childhood vasculitis [2]. with IgA immunofluorescence. A skin biopsy
HSP affects predominantly male children aged with IgA immunofluorescence is unnecessary
two and older, and is characterized by the differ- unless the child presents with atypical symp-
ential regulation of pro- and anti-inflammatory toms such as hemorrhagic bullous purpura.
cytokines in response to IgA immune complex Treatment includes supportive hydration, bed
deposition. Although several HLA alleles have rest, and symptomatic pain relief such as non-
been linked to this disease, in more than half the steroidal anti-inflammatory drugs for joint pain.
cases, HSP is preceded by upper respiratory tract Systematic corticosteroids may be administered
infections of viral or bacterial nature. for severe GI, joint, and renal complications, as
Noninfectious triggers include antibiotics, non- well as hemorrhagic bullous purpura, but may
steroidal anti-inflammatory drugs, vaccinations, not prevent long-term renal impairment. Most
immune response modifiers, and insect bites. cases of HSP resolve spontaneously within 4
HSP usually presents with characteristic non- weeks; however, patients must be educated
blanching palpable purpura or petechiae due to regarding recurrent attacks. Furthermore, patients
edema and extravasation of erythrocytes, with with renal abnormalities require laboratory
lower leg predominance. Organ involvement other monitoring and subsequent follow-up.
1.10.3 Kawasaki Disease bility or lethargy, urethritis and sterile pyuria,

and anterior uveitis [2, 4].
Kawasaki disease (KD, mucocutaneous lymph KD should be considered in the differential
node syndrome) is an acute febrile systemic diagnosis of children with prolonged fever and
inflammatory illness with vasculitis primarily rash. Management of KD is focused on the reduc-
occurring in young children. It has a proclivity to tion of systemic and coronary artery inflammation
involve the coronary arteries, and is therefore a [18]. Treatment during the early, acute stage is
leading cause of acquired heart disease in the usually IVIG plus high doses of aspirin until the
pediatric population [2]. fever is controlled or until day 14 of the disease,
The disease typically manifests as a fever last- followed by low doses of aspirin until blood
ing at least 5 days that is unresponsive to anti- counts and echocardiograms normalize (usually
pyretics, with at least four of the five following 2–3 months after onset). If symptoms persist
findings: (1) non-exudative bilateral conjunctival (often signaled by a rising or elevated CRP), a
injection (Fig. 1.5); (2) peripheral extremity second course of IVIG is often effective [2, 4].
changes including erythema, edema, and periun- Other therapies for refractory KD include corti-
gual desquamation; (3) oropharyngeal changes costeroids, pentoxifylline, methotrexate, TNF
including erythematous or fissured lips, straw- inhibitors, cyclophosphamide, ulinastatin, plas-
berry tongue, and pharyngeal injection; (4) poly- mapheresis, and cyclosporine.
morphous rash; and (5) acute non-purulent
cervical adenopathy. Other findings can include
cardiac manifestations (arrhythmia, myocarditis, 1.11 Atopic Dermatitis
pericardial effusion), CNS manifestations (aseptic
meningitis, mononuclear CSF pleocytosis, facial Atopic Dermatitis is the most common eczema-
palsy, hearing loss), gastrointestinal manifes- tous eruption. It presents as a chronic pruritic
tations (diarrhea, abdominal pain, jaundice, eruption, commonly in the first few years of life.
enlarged gallbladder, enlarged liver), musculosk- Severe atopic dermatitis may be considered a
eletal manifestations (arthritis, arthralgia), irrita- medical emergency if associated with significant
infection and/or erythroderma.
1.11.1 Eczema Herpeticum
Eczema Herpeticum (EH, Kaposi’s varicelliform

eruption) is a cutaneous HSV infection in patients
with atopic dermatitis. The herpes virus can dis-
seminate, leading to further complications.
Patients usually present with clustered vesicles,
pustules, crusts, and punched-out lesions often in
areas of active dermatitis (Fig. 1.6). Direct
fluorescent assay, viral culture, Tzanck tests, or
HSV genomic probes can verify the diagnosis,
although these techniques are not standardized
for skin use [4]. Antiviral treatment should be ini-
tiated with acyclovir or similar antivirals intrave-
nously or orally depending on disease severity.
Additional supportive treatments include anti-
Fig. 1.5 Kawasaki’s Disease. Non-exudative conjuncti- pyretics, analgesics, topical corticosteroids, skin
val injection with limbal sparing care, and antibiotics. The consideration of con-
Fig. 1.6 Eczema Herpeticum. Clustered “punched-out”

vesicles and erosions in areas of dermatitis indicative of
eczema herpeticum
current bacterial infection with staphylococcus or

streptococcus species is appropriate.
Fig. 1.7 Erythroderma. Infant with generalized erythema
and scaling
1.11.2 Bacterial Superinfection
sepsis. Treatment for systemic infection and
Staphylococcus aureus superinfections are very intensive skin care are appropriate.
common in patients with atopic dermatitis. They
can manifest as honey-colored crusted lesions,
impetigo, pustules, abscesses, and cellulitis. 1.12 Primary Infections
Active superinfected atopic dermatitis may be
associated with systemic findings and can there- 1.12.1 Staphylococcal Scalded
fore be considered a dermatologic emergency. Skin Syndrome
Management should include antibiotic therapy
with coverage for methicillin-sensitive S. aureus SSSS is a superficial desquamative condition that
[4]. In the case of a more significant or life- usually presents with fever and tender skin. The
threatening infection, broader antibiotic coverage exfoliative toxin-producing S. aureus phage
including methicillin-resistant S. aureus (MRSA) group II, with hematogenous transport of the
antibiotics is appropriate. exotoxin to the skin, causes characteristic ery-
thema and widespread sloughing of the superficial
epidermis. SSSS predominately affects children
1.11.3 Erythroderma less than 5 years old, who have not yet developed
protective antibodies against the staphylococcal
Erythroderma is a generalized erythema of essen- toxins and have reduced renal clearance of exfo-
tially all skin surfaces (Fig. 1.7) with inflammation liatins, leading to their accumulation in the body.
and scaling, most commonly secondary to atopic Transmission occurs by asymptomatic carriers,
dermatitis and psoriasis. The differential diagno- such as nursery attendants and parents [19].
sis includes other conditions such as cutaneous SSSS begins as fever, malaise, and general-
lymphoma, malignancy, drug hypersensitivity, ized, tender, macular erythema that rapidly
and metabolic diseases. Erythroderma in children evolves into a scarlatiniform eruption. Over 2–5
is generally an emergency that warrants evalua- days, flaky desquamation of the entire skin occurs
tion for underlying diagnosis as well as acute [3]. In severe cases, after the erythrodermic
skin management, and may be complicated by phase, diffuse, sterile, flaccid blisters develop
with bullous desquamation of large sheets of monly isolated organism in children with
skin. At this stage, the epidermis may separate necrotizing fasciitis [22]. Pediatric risk factors
upon gentle shear force (Nikolsky’s sign) result- include chronic illness, trauma, surgery, and
ing in a scalded appearance. Mucous membranes recent infection with varicella [23].
are spared, distinguishing SSSS from toxic epi- Necrotizing fasciitis commonly presents with
dermal necrolysis. localized pain and erythema [22]. Within hours to
Cultures of blood, cerebrospinal fluid, urine, days the infection can progress to a large area of
nasopharynx, umbilicus, etc. should be obtained necrosis, ulceration, and bullae, as well as septic
to identify the primary infection site [3]. However, shock [3]. Imaging studies may aid in the diagno-
skin cultures are classically negative, since cuta- sis of necrotizing fasciitis. However, imaging
neous findings are due to a systemic toxin, not should not delay surgical inspection to identify
local infection. Histopathological examination of and debride deep soft tissue infection, as well as
a biopsy of the roof of a blister demonstrating to obtain surgical specimens for Gram culture
intraepidermal acantholysis within the stratum and stain. Delay in surgical debridement is a
granulosum confirms the diagnosis. significant modifiable contributor to increased
In older literature, childhood mortality was mortality. Currently, pediatric mortality rates are
cited as approximately 11% and usually occurred as high as 5.4% [22].
in conjunction with extensive exfoliation, over- If necrotizing fasciitis is suspected, immediate
whelming sepsis and the resulting electrolyte management should be in an intensive care set-
imbalance [20]. Improved recognition and diag- ting involving surgical consultation, antibiotic
nosis have markedly decreased mortality. coverage, and fluid resuscitation. The priority is
Treatment with intravenous antibiotics, such as a early surgical debridement to remove all affected,
beta-lactamase-resistant anti-staphylococcal anti- necrotic tissue. GAS infections should be treated
biotics or, if MRSA is suspected, vancomycin, is with intravenous penicillin and clindamycin
appropriate. Alternatively, clindamycin may be while treatment for non-GAS infections should
prescribed if the Staphylococcus aureus strain is include intravenous broad spectrum antibiotics
found to be susceptible to this agent. Management with aerobic, anaerobic, and MRSA coverage.
also consists of analgesia, sterile dressings, tem-
perature regulation, and fluid replacement. The
skin usually heals without scarring. 1.12.3 Herpes Simplex Virus
Gingivostomatitis is the most common clinical

1.12.2 Necrotizing Fasciitis manifestation of primary HSV infection in child-
hood [8]. HSV-1 causes 90% of the cases.
Necrotizing fasciitis is a bacterial infection of the Gingivostomatitis is characterized by multiple
superficial fascia and subcutaneous cellular tis- crops of vesicles on any oral mucosal surface. An
sue, and is considered an acute emergency with intensely erythematous, edematous, and ulcer-
high morbidity and mortality. Type 1 infections ated gingiva may be accompanied by fever, mal-
are polymicrobial, commonly with streptococcus, aise, headache, dysphagia, salivation, regional
staphylococcus, bacteroides, and gram-negative lymphadenitis, and even life-threatening enceph-
enterobacteriaceae. Type 2 are monomicrobial alitis. Treatment includes adequate hydration,
infections, classically caused by group A nutrition, analgesia, and antipyretics. While there
Streptococcus (GAS) either alone or in associa- is insufficient evidence that oral acyclovir is
tion with Staphylococcus aureus. Recently, com- effective in decreasing symptoms, many experts
munity-acquired MRSA has been identified as a treat severe cases [9, 24].
cause of necrotizing fasciitis in up to 39% of A less common presentation of HSV is her-
cases, with 93% of these cases monomicrobial in petic whitlow (herpetic paronychia). In children,
nature [21]. GAS is reportedly the most com- this may be the result of digital/oral contact; in
adolescents, digital/genital contact is more com-

mon, making HSV-2 the principal infectious
agent. Herpetic whitlow usually manifests with
local swelling, erythema, and one or more small,
tender, ulcerated vesicles on the pulp of the distal
phalanx of the hand. Fever and malaise may be
present, especially in infants. Oral antiviral medi-
cations may be used in extensive disease [9].
1.12.4 Fungal Infections
Cutaneous fungal infections, which include der-

matophyte infections of hair, skin, and nails, are
not generally pediatric emergencies. However, Fig. 1.8 Aspergillosis. Erythematous plaque with
superficial scale
there are some fungal infections that are associ-
ated with a more severe clinical picture, and
these may be life-threatening in immune-com-
promised patients. Risk factors for cutaneous References
fungal infections include immunosuppression,
1. Fine JD, Eady RA, Bauer EA, et al. The classification
long-term hospital stays, prolonged broad-spec- of inherited epidermolysis bullosa (EB): report of the
trum antibiotic use, parenteral feeding, and Third International Consensus Meeting on Diagnosis
long-term intravascular catheters [25]. Some of and Classification of EB. J Am Acad Dermatol.
the most important and/or dangerous of these 2008;58:931–50.
2. Irvine AD, Hoeger PH, Yan AC, editors. Harper’s
life-threatening cutaneous fungal infections are textbook of pediatric dermatology. 3rd ed. Chichester:
systemic candidiasis, Paracoccidioidomycosis, Wiley-Blackwell; 2011.
sporotrichosis, zygomycosis, and histoplasmo- 3. Eichenfiled LF, Frieden IJ, Esterly NB, editors.
sis and should be included in the differential Neonatal dermatology. 2nd ed. Philadelphia: Elsevier
Saunders; 2008.
diagnosis of atypical cutaneous rashes and viral 4. Paller AS, Mancini AJ. Hurwitz clinical pediatric der-
drug reactions. matology. 3rd ed. Philadelphia: Elsevier Saunders;
Candida and Aspergillus species are the lead- 2006.
ing causes of invasive fungal infections in pediat- 5. Cohen BA. Pediatric dermatology. 3rd ed.
Philadelphia: Elsevier Mosby; 2005.
ric patients [26]. Dermatologic manifestations of 6. Flagg EW, Weinstock H. Incidence of neonatal herpes
systemic candidiasis affect 13–36% of patients. simplex virus infections in the United States.
Cutaneous findings in systemic candidiasis are Pediatrics. 2011;127(1):e1–8.
typically erythematous or purpuric plaques, mac- 7. Anzivino E, Fioriti D, Mischitelli M, et al. Herpes
simplex virus infection in pregnancy and in neonate:
ules, or nodules, sometimes with central pale status of art of epidemiology, diagnosis, therapy and
vesicular or pustular centers. The rash may be prevention. Virol J. 2009;6(1):1–11.
generalized or localized to the extremities. 8. Herpes Simplex. Red Book. 2009;2009(1):363-73.
Pediatric invasive Aspergillus (Fig. 1.8) cases 9. Chayavichitsilp P, Buckwalter JV, Krakowski AC,
Friedlander SF. Herpes Simplex. Pediatr Rev.
have cutaneous involvement in 14–41%. In a 2009;30(4):119–30.
large multicenter pediatric study, 53% of chil- 10. Corey L, Wald A. Maternal and neonatal herpes sim-
dren with cutaneous manifestations presented plex virus infections. N Engl J Med.
with disease strictly localized to the skin [27]. 2009;361:1376–85.
11. Shah SS, Aronson PL, Mohamad Z, Lorch SA.
Cutaneous findings are typically tender, ery- Delayed acyclovir therapy and death among neonates
thematous macules, or vesicles, which frequently with herpes simplex virus infection. Pediatrics.
progress to necrotic eschars. 2011;128:1153–60.
12. Maguiness SM, Frieden IJ. Management of difficult Skin Syndrome in Germany. J Investig Dermatol.
infantile haemangiomas. Arch Dis Child. 2012;97: 2005;124(4):700–3.
266–71. 21. Miller LG, Perdreau-Remington F, Rieg G, et al.
13. Metry D, Heyer G, Hess C, et al. Consensus statement Necrotizing fasciitis caused by community-associated
on diagnostic criteria for PHACE syndrom. Pediatrics. methicillin-resitant staphylococcus aureus in Los
2009;124:1447–56. Angeles. New England Joural of Medicine.
14. Melancon JM, Dohil MA, Eichenfield LF. Facial port- 2005;352(14):1445–53.
wine stain: when to worry? Pediatr Dermatol. 22. Eneli I, Davies HD. Epidemiology and outcome of
2012;29:131–3. necrotizing fasciitis in children: an active surveillance
15. Hook KP, Eichenfield LF. Approach to the neonate study of the Canadian Paediatric Surveillance
with ecchymoses and crusts. Dermatol Ther. Program. J Pediatr. 2007;151:79–84.
2011;24:240–8. 23. Laupland KB, Davies HD, Low DE, Schwartz B,
16. Lansang P, Wienstein M, Shear N. Drug reactions. In: Green K, McGeer A. Invasive group A streptococcal
Shahner LA, Hanson RC, editors. Pediatric disease in children and association with varicella-
Dermatology. 4th ed. China: Elsevier; 2011. p. zoster virus infection. Pediatrics. 2000;105(5):e60.
1698–711. 24. Nasser M, Fedorowicz Z, Khoshnevisan MH, Shahiri
17. Levi N, Bastuji-Garin S, Mockenhaupt M, et al. Tabarestani M. Acyclovir for treating primary her-
Medications as risk factors of Stevens-Johnson syn- petic gingivostomatitis. Cochrane Database Syst Rev.
drome and toxic epidermal necrolysis in children: a 2008;(4):CD006700.
pooled analysis. Pediatrics. 2009;123:e297–304. 25. Hacimustafaoglu M, Celebi S. Candida infections in
18. Kushner HI, Bastian JF, Turner CL, Burns JC. The non-neutropenic children after the neonatal period.
two emergencies of Kawasaki syndrome and the Expert Rev Anti Infect Ther. 2011;9(10):923–40.
implications for the developing world. Pediatr Infect 26. Katragkou A, Roilides E. Best practice in treating
Dis J. 2008;27:377–83. infants and children with proven, probable or sus-
19. Hoeger PH, Elsner P. Staphylococcal scalded skin pected invasive fungal infections. Curr Opin Infect
syndrome: transmission of exfoliatin-producing Dis. 2011;24(3):225–9.
Staphylococcus aureus by an asymptomatic carrier. 27. Burgos A, Zaoutis TE, Dvorak CC, et al. Pediatric
Pediatr Infect Dis J. 1988;7:340–2. invasive aspergillosis: a multicenter retrospective
20. Mockenhaupt M, Idzko M, Grosber M, Schopf E, analysis of 139 contemporary cases. Pediatrics.
Norgauer J. Epidemiology of Staphylococcal Scalded 2008;121(5):e1286–94.
Infectious Emergencies
in Dermatology 2
Emily Stamell and Karthik Krishnamurthy
2.1 Introduction 2.2 Bacterial Infections
While most infections with dermatological mani- 2.2.1 Necrotizing Fasciitis

festations are self-limited, there are clinical sce-
narios when infectious cutaneous diseases are Necrotizing fasciitis is characterized by rapidly
associated with life-threatening systemic symp- progressive necrosis of subcutaneous fat and fas-
toms. These diseases may be difficult to diagnose, cia. In many cases, no identifiable cause is found;
but a dermatologist can use visual cues to create a however, patients often have a history of trauma
differential. The majority of infectious emergen- [1]. Most patients have preexisting conditions
cies in dermatology are due to a bacterial patho- increasing their susceptibility to infection, includ-
gen; however, select viruses, fungi, and parasites ing immunosuppression, diabetes, chronic dis-
can also cause severe disease. This chapter focuses ease, drugs (e.g., steroids), malnutrition, age
on cutaneous infections where prompt diagnosis greater than 60, intravenous drug misuse, periph-
and initiation of treatment are paramount. We eral vascular disease, renal failure, underlying
highlight the main cutaneous patterns, individuals malignancy, or obesity [2].
at risk, diagnostic modalities applicable to the Necrotizing fasciitis can be divided into three
dermatologist, and treatment options for each categories based on etiologic agent. Type I is poly-
infectious emergency in dermatology. microbial and can include Group A β-hemolytic
Streptococcus Streptococcus pyogenes or GAS),
Staphylococcus aureus, Klebsiella species,
Enterococci, Escherichia coli, as well as Clostridium
and Bacteroides species. Type II is caused by GAS
only and Type III is associated with Vibrio
vulnificus, which is introduced into the subcutane-
E. Stamell, M.D. (*)
ous tissue by puncture wounds from fish or marine
Department of Medicine, Division of Dermatology,
Albert Einstein College of Medicine, Bronx, creatures [3].
NY, USA The initial clinical features may be nonspecific,
e-mail: estamell@gmail.com often leading to misdiagnosis. Early findings
K. Krishnamurthy, D.O include pain, cellulitis, fever, tachycardia, swelling,
Dermatology, Jacobi Medical Center, induration, and skin anesthesia. As the infection
Cosmetic Dermatology Clinic, Montefiore Medical
progresses, severe pain out of proportion with the
Center, Albert Einstien College of Medicine, Bronx,
NY, USA skin examination, purple or black skin discoloration,
e-mail: kkderm@gmail.com blistering, hemorrhagic bullae, crepitus, discharge

20 E. Stamell and K. Krishnamurthy
Table 2.1 Antimicrobial regimens for necrotizing fasciitis [3]

Organism First-line therapy
Mixed Infections Ampicllin–sulbactam intravenous 1.5–3 g every 6 h
or
Piperacillin–tazobactam intravenous (dose based on creatinine clearance)
+
Clindamycin intravenous 450–900 mg every 8 h
+
Ciprofloxacin intravenous 400 mg every 12 h
or
Meropenem 500 mg every 8 h/cefotaxime 1–2 g every 8–12 h
+
Metronidazole 500 mg every 8 h/Clindamycin intravenous 450–900 mg every 8 h
GAS Penicillin intravenous 1–2 million units every 6 h
+
S. aureus Nafcillin intravenous 1–2 g every 4–6 h
or
Oxacillin intravenous 1–1.5 g every 4–6 h
or
Cefazolin intravenous 1–2 g every 6–8 h
or
MRSA Vancomycin intravenous 1 g every 12 h (doses adjusted based on creatinine clearance
and vancomycin troughs)
Clostridium Penicillin intravenous 1–2 million units every 6 h
+
P. aeruginosa Ceftazidime intravenous 2 g every 8 h
of “dishwater,” or murky, grayish, fluid, severe sep- pain, rapidly spreading tense edema, hemor-
sis, systemic inflammatory response syndrome, or rhagic bullae formation, gray-blue discoloration,
multiorgan failure can develop [2]. The infection and foul-smelling discharge [5].
rapidly evolves over hours or days. The mainstay of effective treatment is exten-
The pathognomonic finding of crepitus and sive surgical debridement in conjunction with
soft tissue air on plain radiograph is only seen in broad-spectrum antibiotics. Gram stain can guide
37% and 57% of patients, respectively. Crepitus appropriate antimicrobial therapy, but should not
results from anaerobic tissue metabolism, which be delayed while awaiting results. Initial ther-
produces hydrogen and nitrogen, insoluble apy should include a b-lactam/b-lactamase inhib-
gases, that accumulate in the subcutaneous tis- itor combined with broad-spectrum coverage
sues. Other common laboratory findings include against Gram-negative bacilli, Staphylococci,
elevated white cell count, increased concentra- Streptococci, and anaerobes. Antibiotics can be
tions of serum glucose, urea, and creatinine, tailored depending on the isolated organism(s).
hypoalbuminemia, acidosis, and altered coagu- Table 2.1 outlines the antimicrobial algorithm for
lation profile [4]. However, given the nonspecific necrotizing fasciitis [3]. Hyperbaric oxygen has
nature of these studies, the diagnosis is clinical. been postulated to decrease the number of debri-
Clinical signs that favor necrotizing fasciitis dements and mortality; however, no large study
over cellulitis include presence of cutaneous has confirmed this theory [6]. Intravenous immu-
anesthesia as it suggests a deeper component to noglobulin (IVIG) has been used as an adjuvant
the infection affecting sensory nerves, severe therapy primarily in patients with GAS necrotizing
2 Infectious Emergencies in Dermatology 21
fasciitis. Studies have showed varying success, S. aureus or GAS, whereas preseptal cellulitis
and it should not replace the gold standard of due to primary bacteremia is usually due to
debridement and antimicrobial therapy [7, 8]. Streptococcus pneumoniae. Orbital cellulitis may
Mortality rates range from 20 to 40% [5]. One be polymicrobial and is caused by pathogens
retrospective study identified eight independent responsible for sinusitis, including S. pneumo-
predictors of mortality for necrotizing fasciitis: niae, non-typable Haemophilus influenzae,
liver cirrhosis, soft tissue air, Aeromonas infec- Moraxella catarrhalis, GAS, S. aureus, and/or
tion, a gram-negative facultative anaerobic rod, anaerobes [10].
age over 60 years, band polymorphonuclear neu- Consultation with ophthalmology and otolar-
trophils greater than 10%, activated partial thro- yngology should be obtained immediately with
moplastin time of greater than 60 s, and serum concomitant initiation of antimicrobials against
creatinine greater than 2 mg/dL [9]. the common pathogens. Preseptal cellulitis is man-
aged with oral antibiotics whereas orbital cellulitis
requires intravenous antimicrobials. Surgical inter-
2.2.2 Preseptal and Orbital Cellulitis vention, such as abscess drainage, has a role in the
management of patients with orbital cellulitis. A
Bacterial infections involving the orbit poten- recent national perspective study found that older
tially cause severe damage to the eye, cavernous patients, those with diplopia, and hospital admis-
sinus thrombosis, and death. Preseptal cellulitis sion via the emergency room were predictors of
is an infection of the eyelids and surrounding surgery [12]. With prompt initiation of antimi-
skin anterior to the orbital septum whereas orbital crobials, prognosis is very good. When treatment
cellulitis is an infection posterior to the septum. is inadequate or delayed, however, complications
Preseptal cellulitis is usually secondary to trauma include blindness, cranial nerve palsies, brain
or bacteremia and the average age of patients is abscesses, and death [13].
21 months of age. On the other hand, orbital (also
known as post-septal) cellulitis is a complication
of sinusitis, with average incident age of 12 years 2.2.3 Malignant Otitis Externa
[10]. It is imperative to distinguish orbital celluli-
tis from preseptal cellulitis as the former is a Malignant otitis externa is a severe form of otitis
more severe infection, threatening permanent externa most commonly seen in elderly diabetic
vision damage, requiring hospitalization, and patients. Patients often report failure of local
intravenous antibiotics [3]. therapy. Clinically, they have severe tenderness
Clinical signs can be useful in characterizing around the auricle, persistent drainage, and gran-
preseptal and orbital cellulitis. Patients with ulation tissue at the junction of the osseous and
either form of cellulitis complain of pain, con- cartilaginous portions of the external ear canal.
junctivitis, epiphora (insufficient tear film drain- Almost all cases are due to P. aeruginosa and
age from the eyes), and blurred vision. Physical antimicrobial treatment should be directed against
exam will reveal periorbital erythema and edema. this pathogen. While the treatment of choice was
However, patients with orbital cellulitis may also previously oral ciprofloxacin 750 mg twice daily
display ophthalmoplegia, pain on eye motion, with or without rifampin, as mentioned previ-
proptosis, vision loss, abnormal papillary reflexes, ously, increasing pseudomonal resistance to
and/or disk edema [10]. If clinical evaluation is fluoroquinolones now necessitates hospitaliza-
unequivocal, computed tomography (CT) with tion and intravenous antibiotics with a third-gen-
intravenous contrast can distinguish the two con- eration cephalosporin, such as ceftazidime 2 g
ditions [11]. every 8 h. Complications include osteomyelitis
The pathogenesis of the infection usually dic- of the skull, nerve palsies, mastoiditis, sepsis,
tates the causative organism. The pathogen in sigmoid sinus thrombosis, and a mortality rate of
preseptal cellulitis due to trauma is most likely around 20% [5, 14].
2.2.4 Meningococcemia
Meningococcemia is a serious medical emer-

gency that is frequently diagnosed by dermatolo-
gists due to the presence of a classic petechial
eruption seen in one-third to one-half of patients.
The causative pathogen is Neisseria meningitidis,
an aerobic Gram-negative diplococcus, and pri-
marily affects young children and young adults
with a male predominance [15]. The incidence of
endemic disease is up to 5 cases per 100,000 pop-
ulation per year worldwide [16]. Epidemic rates Fig. 2.1 Meningococcemia
of disease are seen in sub-Saharan Africa [17].
The most common serogroups are A, B, C, Y, and charide vaccine has been available in the United
W-135. Worldwide, the majority of cases are due States since 1982. This vaccine is effective
to serogroups A and C; however, in the United against serogroups A, C, Y, and W-135 and
States, serogroups B and C predominate [15]. induces serotype-specific antibodies in older
Transmission is via respiratory droplets and children and adults, but is not immunogenic in
there is an average incubation period of 3–4 days young children. While this vaccine was approved
[18]. Although not all N. meningitidis infections for individuals older than 2 years of age, it was
result in septicemia, when they do, a petechial only recommended to control outbreaks, to pro-
eruption precedes the development of ecchy- tect immunocompromised individuals, for people
moses and ischemic necrosis (Fig. 2.1). Other traveling to epidemic areas, or for individuals liv-
occasional skin findings include bullous hemor- ing in close quarters. Recommendations have
rhagic lesions and a transient blanchable morbil- more recently changed with the development of a
liform eruption. The rash of meningococcemia quadrivalent A, C, Y, and W-135 conjugate vac-
can be accompanied by systemic symptoms cine. This vaccine provides long-term protection
including fever, chills, hypotension, meningitis, as it induces immunologic memory [20]. Current
meningoencephalitis, pneumonia, arthritis, peri- vaccination recommendations released by the
ardititis, myocarditits, and disseminated intravas- Centers for Disease Control and Prevention
cular coagulation (DIC) [5]. (CDC) include routine vaccination of adolescents
Prompt diagnosis and initiation of treatment at age 11–12 years, unvaccinated adolescents at
with intravenous antibiotics are paramount. entry to high school or age 15 (whichever comes
Diagnosis is confi rmed through detection of first), all college freshman residing in dormito-
N. meningitidis in blood or cerebral spinal fluid ries, military personnel, and high-risk groups
cultures. Polymerase chain reaction analysis has [16]. It is important to note that neither vaccine
been developed for rapid detection of specific protects against serogroup B, one of the most
serogroups of N. meningitidis, but is not commer- commonly isolated types in the United States.
cially available in many countries [18].
Appropriate antibiotics include penicillin G
500,000 U/kg/day in six divided doses, ceftriax- 2.2.5 Rocky Mountain Spotted Fever
one 100 mg/kg/day in one or two divided doses,
or cefotaxime 200 mg/kg/day in three divided Rocky Mountain spotted fever (RMSF) is the
doses. Close contacts should receive prophylactic most common rickettsial disease in the United
antibiotic treatment with rifampin [16, 19]. States and is characterized by the history of a tick
Hearing loss, limb amputation, and a mortality bite, fever, and rash [21]. Rickettsia rickettsii, a
rate of 10% are among the complications of small gram-negative bacteria, is transmitted into
meningococcemia [20]. A quadrivalent polysac- the dermis by a tick bite and replicates in the
endothelial cells, subsequently causing vasculi- diagnosis is rendered as treatment with doxycy-
tis, hypoperfusion, and end-organ damage. In the cline 100 mg twice daily for adults or 2.2 mg/kg
United States, the vector is the American dog twice daily for children under 45 kg for 7–14 days
tick, Dermacentor variabilis, and the Rocky should not be delayed for diagnostic confirmation
Mountain wood tick, Dermacentor andersoni [21]. Chloramphenicol 50 mg/kg is an alternative
[22]. RMSF has been reported in the United treatment for patients younger than 9 years of age
States, Western Canada, Western and Central or pregnant women [18]. Of 100 individuals
Mexico, Panama, Costa Rica, Northwestern infected, 5–10 of those will die and many others
Argentina, Brazil, and Colombia. In the United will suffer amputation, deafness, or permanent
States, RMSF has occurred in every state except learning disability from hypoperfusion [22]. As
for Vermont and Maine, with half the cases found there are no current vaccines to prevent rickettsial
in Oklahoma, Tennessee, Arkansas, Maryland, diseases, preventative measures have been empha-
Virginia, and the Carolinas [23]. Up to 1,200 sized. General recommendations for prevention
cases annually have been reported in the United of RMSF include avoidance of tick habitats,
States, but there are likely a number of unreported implementation of personal protective measures
cases each year [24]. The highest incidence of to limit possibility of tick exposure, frequent
disease has been seen in children less than 10 examination of oneself to identify any attached
years of age and adults between 40 and 64 years ticks, and proper removal of attached ticks to
old as well as men and Caucasians [23]. reduce transmission [23, 26]. A minimum of
The diagnosis is primarily clinical. The triad 4–6-h period of attachment is required for
of fever, headache, and rash in an individual with transmission of R. rickettsii. Therefore, early and
the history of a tick bite or exposure to ticks proper removal techniques are emphasized to
should raise suspicion for RMSF; however, this is decrease the risk of transmission. These include
only seen in 3% of patients with RMSF [25]. wearing protective gloves, grasping the tick with
Fever often accompanied by headache and myal- fine forceps close to the point of attachment and
gia precedes the rash by 3–6 days. Other early pulling straight outward, avoiding jerking, twist-
symptoms include nausea, vomiting, and abdom- ing, or squeezing the tick, and disinfecting the
inal pain. The patient may eventually develop bite wound after tick removal [27]. Both the use
hypotension, thrombocytopenia, and acute renal of Tick repellent (N,N-diethyl-meta-toluamide,
failure followed by hypotensive shock and acute DEET) on exposed skin and application of an aca-
respiratory failure. The rash begins as small mac- ricide (e.g.,disease is caused permethrin) on cloth-
ules around the wrists and ankles, eventually ing can be helpful [23, 28].
involving the majority of the body, but spares the
face. Red-pink macules and papules are seen on
the palms and soles later in the course of disease. 2.2.6 Lyme Disease
Petechiae develop within the macules or papules
due to severe vascular injury. The petechiae even- Lyme disease, also known as Lyme borreliosis, is
tually evolve to cutaneous necrosis [5, 19, 21]. the most common tick-borne infectious disease
Definitive diagnosis can be made by in North America [29]. The disease is caused by
immunofluorescence or immunohistochemistry in the spirochete Borrelia burgdorferi sensu lato
a biopsy specimen of an eschar, macule, papule, complex and is transmitted by Ixodes ticks. In the
or petechial lesion. Serologic diagnosis cannot be United States, Lyme borreliosis is caused
utilized at the time of diagnosis as antibodies do not specifically by B. burgdorferi sensu stricto and
develop until at least 7 days after the onset of the Ixodes scapularis serves as the primary vector.
illness. Acute and convalescent-phase serum sam- Small mammals, such as white-footed mouse,
ples can be used for indirect immunofluorescence, white-tailed deer, and raccoons, and are the reser-
latex agglutination, and enzyme immunoassay to voir for the disease. Lyme disease is transmitted
detect anti-rickettsial antibodies. Often a clinical through the saliva of the Ixodes ticks, and a
feeding period of more than 36 h is usually IgM and IgG immunoblots are performed. Of
required for transmission [30]. Disease transmission note, IgG levels are positive after at least 4 weeks
is most common between June and August [29]. of symptoms [36].
Erythema migrans is the most common clini- Treatment is required to prevent disseminated
cal manifestation of localized disease and has disease and the development of delayed compli-
been seen in as many as 89% of patients in one cations. A single dose of doxycycline 200 mg
case series [31]. Clinically, an expanding red orally can be administered within 72 h of removal
annular patch with or without central clearing is of an Ixodes scapularis as a chemoprophylactic
appreciated at the site of the tick bite. Borrelial measure except to children less than 8 years of
lymphocytoma, a painless bluish-red nodule or age and pregnant women [39]. Doxycycline
plaque usually on the ear lobe, ear helix, nipple, 100 mg twice daily and amoxicillin 500 mg twice
or scrotum, is a rare cutaneous lesion that also daily are both indicated in the treatment of Lyme
occurs at the site of a tick bite during the early disease. Cefuroxime axetil 500 mg twice daily is
disseminated stage of Lyme disease. Early dis- considered second line due to cost and intrave-
seminated disease is characterized by one of the nous penicillin is now limited to cases with neu-
following: two or more erythema migrans lesions, rologic involvement. The length of treatment
Lyme neuroborreliosis (meningo-radiculitis, varies based on the clinical manifestations of the
meningitis, or peripheral facial palsy), or Lyme disease. A 14-day course of antibiotics is indi-
carditis (acute onset of atrioventricular conduc- cated in patients with neurologic involvement or
tion delays, rhythm disturbances, myocarditis, or borrelial lymphocytoma. A 28-day course of
pericarditis). Late Lyme disease manifests as antibiotics, on the other hand, is required in
arthritis, which is characterized by recurrent patients with late neuroborreliosis, recurrent
attacks or persistent swelling in one or more large arthritis after one course of oral treatment, and
joints, or acrodermatitis chronica atrophicans acrodermatitis chronica atrophicans [29, 37].
(chronic erythematous plaques on the extensor Prevention of infection is vital in decreasing
surfaces of the extremities, which eventually the incidence of infections and the development
become atrophic) [32]. Late Lyme neuroborrelio- of late complications. Repellents are the most
sis is uncommon and presents as slowly progress- effective modality to prevent tick attachment, and
ing encephalomyelitis [33]. the most frequent agent used is DEET [38].
Diagnosis of Lyme disease can be made clini- Repellents combined with protective clothing
cally by the presence of erythema migrans as have been shown to reduce the incidence of Lyme
serologic studies early in the disease are gener- disease infections [40]. Permethrin can be applied
ally negative [29]. Serologic evaluation is pur- to clothing, shoes, bed nets, or other outdoor
sued in patients without erythema migrans. equipment, but has limited utility as a topical
Samples are first screened with an enzyme-linked agent [38]. If a tick is found attached to an indi-
immunosorbent assay (ELISA). IgM antibodies vidual, care should be taken to remove the tick
appear 2–6 weeks after exposure and IgG titers appropriately. Both the World Health Organization
can be detected 3–4 weeks thereafter [34]. The and the CDC recommend using fine-tipped for-
utility of the ELISA varies depending on disease ceps to grasp the tick closest to the point of entry
prevalence. The positive predictive value is much to the skin, and the body of the tick should not be
lower, ranging from 8 to 28% depending on the compressed [34].
sensitivity and specificity, in a region with low
prevalence of disease whereas the positive pre-
dictive value is as high as 83% in a region with a 2.2.7 Anthrax
high prevalence of disease. The false negative
rate is low for the ELISA with the negative pre- Anthrax is caused by Bacillus anthracis, an aerobic
dictive value of the test ranging from 95 to 99% Gram-positive rod, and results in three different
[35]. If the ELISA is positive or equivocal, then clinical syndromes depending on the mode of
transmission: cutaneous anthrax via inoculation, systemic complications. However, in the other
pulmonary anthrax via inhalation, and gastroin- 10% of cases, edema of the head and neck result-
testinal anthrax via ingestion. B. anthracis pro- ing in respiratory compromise or toxic shock
duces three polypeptides that comprise anthrax from overwhelming septicemia can occur [45].
toxin: protective antigen (PA), lethal factor (LF, a Diagnosis of anthrax must be confirmed with
protease), and edema factor (EF, an adenyl serology or polymerase chain reaction assay via
cyclase). The PA binds to cellular receptors, is the CDC; however, these tests can take several
cleaved by cellular furin, oligomerizes, and trans- days. Treatment should not be delayed for
ports LF and EF into cells. Edema toxin (ET, the confirmation. In uncomplicated cases of cutaneous
combination of PA and EF) is a calcium- and anthrax, oral ciprofloxacin 500 mg twice daily or
calmodulin-dependent adenylate cyclase that doxycycline 100 mg twice daily is indicated for
increases the intracellular level of cyclic AMP adults. For children, oral ciprofloxacin 10–15 mg/
(cAMP), and ultimately leads to impaired water kg twice daily, not to exceed 1 g/d, or doxycycline
homeostasis and cellular edema. Lethal toxin 100 mg twice daily should be used. The CDC
(LT, the combination of PA and LF) is a zinc- currently advocates for a 60-day course of antibi-
dependent endoprotease. It cleaves the N-terminus otics given increased likelihood of reexposure.
of mitogen-activated protein kinase kinases Intravenous ciprofloxacin 400 mg every 12 h or
(MAPKK) and thus inhibits the MAPKKs. As such, doxycycline 100 mg every 12 h are indicated for
lethal toxin promotes macrophage apoptosis and complicated cases of cutaneous anthrax [3]. The
release of tumor necrosis factor alpha (TNF-a) mortality rate in untreated cutaneous anthrax is
and interleukin-1 beta (IL-1b) [41]. ET and LT as high as 20%. However, with appropriate treat-
are responsible for the clinical symptoms of ment, the mortality rate is less than 1% [46].
anthrax infection.
In cutaneous anthrax, the most common form,
spores gain access to the skin via trauma and ger- 2.2.8 Tularemia
minate within macrophages locally. The result is
edema and necrosis from toxins and a Tularemia, a bacterial infection caused by
hyperinflammatory response. Although the Francisella tularenis, a Gram-negative, nonmo-
majority of cases remain localized, up to 10% of tile coccobacillus, can present as six distinct syn-
untreated cutaneous anthrax may disseminate. In dromes according to the mode of transmission
this situation, macrophages carry the spores to and clinical presentation: ulceroglandular, glan-
regional lymph nodes where they germinate and dular, oculoglandular, oropharyngeal/gastroin-
the bacteria rapidly multiply. It subsequently dis- testinal, typhoidal/septicemic, and pneumonic
seminates through the blood, causing hemor- [5]. Tularemia is an arthropod-borne disease and
rhagic lymphadenitis and possible death from is transmitted by the ticks, Amblyomma america-
septicemia and toxemia [42]. num (lone-start tick), Dermacenter andersoni
Cutaneous anthrax starts as a painless pru- (Rocky Mountain wood tick), and Dermacenter
ritic papule approximately 1–12 days after inoc- variabilis (American dog tick) as well as the
ulation. The papule enlarges and develops a deerfly, Chrysops discalis. F. tularensis can also
central vesicle or bulla with surrounding edema be transmitted by handling infected mammals,
within 48 h. The vesicle becomes hemorrhagic such as rabbits, muskrats, prairie dogs, and other
with the subsequent development of necrosis rodents, or by contaminated food or water [47].
and ulceration. The classic black eschar (thick Ulceroglandular tularemia is the most com-
crust) develops over the ulcer with edema and mon type and accounts for 80% of cases of tula-
erythema remaining a prominent feature [43]. remia. A painful erythematous papule develops
Associated symptoms include fever, headache, at the inoculation site and can be solitary or mul-
malaise, and regional lymphadenopathy [44]. In tiple depending on the mode of transmission. The
90% of cases, the eschar disengages and heals papule(s) develop first into a pustule and then a
without scarring over 1–2 weeks without punched-out ulcer with raised ragged edges and a
gray-to-red necrotic base [48]. A necrotic eschar 2.2.9 Staphyloccocal Scalded Skin
is seen at the site of the ulcer and tender regional Syndrome
lymphadenopathy follows. In contrast to cutane-
ous anthrax, the eschar heals with scarring after Staphylococcal scalded skin syndrome (SSSS),
several weeks to months [48]. Sudden onset of also known as Ritter’s disease or pemphigus
flu-like symptoms develops on average 4–5 days neonatorum, is caused by S. aureus exfoliative
after inoculation. Hematogenous spread to the (also known as epidermolytic) toxins (ETs), pri-
spleen, liver, lungs, kidneys, intestine, central marily A and B. The toxins are directed against
nervous system, and skeletal muscles can occur desmoglein-1, a desmosomal adhesion molecule,
[47]. Tularemids, or secondary eruptions, may which causes an intraepidermal split through the
occur following hematogenous dissemination granular layer [51]. As a toxin-mediated disease,
and presents as macular, morbilliform, nodular, the bacterial infection usually lies at a distant
acneiform, papulovesicular, or plaque-like erup- focus, most commonly the conjunctiva, nasophar-
tions [48]. ynx, ear, urinary tract, or skin, and no organism
Oculoglandular tularemia occurs in less than is recovered from lesional skin, yielding nega-
1% of cases of tularemia and can present with tive tissue cultures [18]. SSSS primarily affects
conjunctivitis, periorbital edema and erythema, children and rarely adults with renal disease, as
lymphadenopathy, and lymphadenitis [49]. The the exfoliative toxins are excreted by the kid-
other forms of tularemia do not present with cuta- neys, or immunocompromise [19, 52, 53].
neous findings. The initial signs of SSSS are abrupt onset of
Diagnosis is made by fluorescent antibody fever, skin tenderness, and toxic erythema. The
testing. First-line treatment is streptomycin 1 g erythema first appears on the head and general-
intramuscularly every 12 h for 10 days, but intra- izes in 48 h, but sparing the palms, sole, and
venous gentamicin 1.5–2 mg/kg loading dose fol- mucous membranes. Flaccid bullae may develop,
lowed by 1–1.7 mg/kg every 8 h or 5–7 mg/kg and the Nikolsky sign is positive [19]. Within 1–2
every 24 h, ciprofloxacin 500–750 mg twice a days, the skin sloughs, usually starting in the
day for 10 days, or levofloxacin 500 mg daily for flexural areas. Scaling and desquamation occur
14 days have also proven efficacious in the treat- for the next 3–5 days, and re-epithelialization is
ment of tularemia. Doxycycline 100 mg oral or seen 10–14 days after the initial signs [5]
intravenous for 14–21 days has also demonstrated (Fig. 2.2). Of note, the absence of mucosal
efficacy, but is associated with higher risk of involvement is helpful in clinical differentiation
relapse [5, 50]. of SSSS from Stevens–Johnson Syndrome and
Fig. 2.2 Ritter’s disease

toxic epidermal necrolysis (TEN), as desmog- desquamation does not occur until 10–21 days
lein-1 is not expressed in mucosal epithelium. In after the onset of disease [54]. In contrast, the
addition, the diagnosis can be distinguished from desquamation in TEN is full thickness and
TEN by histologic examination of the roof of a occurs hours to days from the first signs of the
blister, as TEN shows full thickness epidermal disease [5]. The source of infection in staphylo-
necrosis, whereas SSSS only affects the upper coccal TSS is not always clear and is not identified
layers of the epidermis. in a large number of patients. S. aureus is rarely
Both immediate initiation of appropriate cultured from the blood, but instead is found in
antimicrobials and supportive care are crucial the focus of infection if one is identified. In
[19]. Antimicrobial regimens for SSSS include contrast to staphylococcal TSS, which occurs
dicloxacillin 2 g every 6 h or cefazolin 1 g every in the setting of menstruation or nosocomial
8 h. If MRSA is suspected, then vancomycin infections, streptococcal TSS usually arises
1 g every 12 h, with doses adjusted based on from deep invasive soft-tissue infections [57].
creatinine clearance and vancomycin troughs, The illness is similar, although more than 60%
is indicated [54]. Prognosis is good in children, of cases have positive blood cultures and the
but mortality in adults approaches 50%. In source of infection is usually easy to identify
adults with underlying disease, mortality is [57, 61]. In addition, mortality rate is much
almost 100% [55]. higher in streptococcal TSS [62].
Supportive management, source control, and
appropriate antimicrobial coverage are the most
2.2.10 Toxic Shock Syndrome important immediate steps in treatment. However,
it is important to recognize that treatment must
Toxic shock syndrome (TSS) results from the both reduce organism load and exotoxin produc-
release of bacterial antigens, known as superanti- tion [57]. Antimicrobial regimens are tailored to
gens, from S. aureus, GAS, and group C strepto- the specific organisms responsible for TSS.
coccus. The superantigen causes leaking Table 2.2 outlines first- and second-line therapies
capillaries, which clinically results in fever, exan- for GAS, MSSA, and MRSA infections
them, mucositis, “strawberry” tongue, hypoten- (Table 2.2). It is important to mention that the
sion, multiorgan dysfunction, and convalescent role of clindamycin or linezolid in the antimicro-
desquamation [56]. Superantigens have the abil- bial regimen is to inhibit toxin production by both
ity to bypass MHC-limited antigen processing, S. aureus and GAS [57].
and instead bind unprocessed directly to MHC IVIG has been used as an adjuvant therapy in
class II molecules and activate T-cells [57]. the treatment of TSS as it has been shown to
TSS can be divided into two categories: men- block T-cell activation by staphylococcal and
strual and non-menstrual. Menstrual TSS is sec- streptococcal superantigens [63]. A Canadian
ondary to strains of S. aureus that produce toxic comparative observational study found that there
shock syndrome toxin-1 (TSST-1) and histori- was an improved 30-day survival in 21 patients
cally has been linked to superabsorbent tampons who received IVIG compared to the 32 patents
[58]. Non-menstrual TSS is associated with any who did not [7]. Subsequently, a multicenter ran-
staphylococcal infection that produces TSST-1, domized placebo control trial attempted to exam-
staphylococcal enterotoxin (SE) serotype B, and ine the efficacy of IVIG in streptococcal TSS;
SE serotype C in addition to 11 different strepto- however, the trial only enrolled 21 patients and
coccal superantigens [59, 60]. was terminated due to low recruitment. The study
Staphylococcal TSS has an abrupt onset did analyze the 21 patients and found that there
with flu-like symptoms followed by confusion, was a higher mortality rate in the placebo group
lethargy, and agitation. Rash is common early at 28 days, although it did not meet statistical
in the illness; however, the characteristic significance [8].
Table 2.2 Antimicrobial regimens for TSS [3, 57]

Organism First-line therapy Second-line therapy
GAS Penicillin G 3–4 million units every 4 h Macrolide or fluorquinolone
+ +
Clindamycin 600–900 mg every 8 h Clindamycin 600–900 mg every 8 h
S. aureus (MSSA) Cloxacillin 500 mg PO every 6 h Clarithromycin 250–500 mg PO
or +
Nafcillin 1–2 g IV every 4–6 h Clindamycin 600–900 mg every 8 h
or
Cefazolin 500–1,000 mg every 6–8 h
+
Clindamycin 600–900 mg every 8 h
S. aureas (MRSA) Vancomycin 1 g every 12 h (adjusted for creatinine
clearance)
+
Clindamycin 600–900 mg every 8 h
or
Linezolid 600 mg IV/PO every 12 h
2.2.11 Purpura Fulminans
Purpura fulminans is seen in three clinical set-

tings: hereditary deficiency of protein C or S;
acute infectious purpura fulminans; and idio-
pathic purpura fulminans [64]. The acute infec-
tious purpura fulminans is the most common
form and is discussed in this section [19]. A num-
ber of infections induce this syndrome, but the
two most common are Neisseria meningitidis and
streptococcal infections [65].
Infectious purpura fulminans begins with der-
mal discomfort that progresses within hours to
petechiae that then coalesce to form purple ecchy-
moses [66] (Fig. 2.3). The ecchymoses evolve
into hemorrhagic bullae with subsequent necrosis Fig. 2.3 Purpura fulminans
and gangrene [67]. The affected areas are initially
sterile, but can develop secondary infections. The
pathology in purpura fulminans is not limited to 2.2.12 Ecthyma Gangrenosum
the skin, and as a result, there can be multiorgan
failure [68]. Other associated findings include Ecthyma gangrenosum is an uncommon cutane-
fever, DIC, and flu-like symptoms [67]. ous variant of impetigo most commonly associated
If recognized at the initial stage prior to devel- with P. aeruginosa septicemia, but may occur
opment of necrosis, the syndrome may be com- without bacteremia. It occurs in up to 2.8% of
pletely reversed [67]. The primary treatment is patients with P. aeruginosa bacteremia. The mor-
supportive in conjunction with appropriate anti- tality rate in individuals with ecthyma gangrenosum
microbials to treat the underlying infection. due to Pseudomonas septicemia can approach
Vasopressors may actually contribute to poor 77% compared to the 15% mortality rate in those
peripheral circulation and peripheral tissue dam- without bacteremia [69]. The most common risk
age and should be avoided [19, 67]. factor is neutropenia usually due to underlying
malignancy or immunosuppressive therapy. the neonate during the intrauterine (5%),

Ecthyma gangrenosum may occur more fre- intrapartum (85%), or postpartum (10%) periods
quently in infections associated with primary [3]. In comparison with primary genital herpes,
immunodeficiencies, including hypogammaglob- recurrent genital herpes is more common during
ulinemia, dysfunctional neutrophils, and chronic pregnancy. However, women with primary geni-
granulomatous disease [69, 70]. Occasionally, tal HSV disease are at the highest risk of trans-
ecthyma gangrenosum may occur in healthy indi- mitting HSV to the baby [75]. Approximately
viduals without any predisposing factors; how- two-thirds of women who acquire genital herpes
ever, underlying risk factors should be sought out during pregnancy are asymptomatic, and in
[69, 71]. accordance with this number, 60–80% of women
Ecthyma is a vasculitis affecting the media who deliver an HSV-infected infant have no evi-
and adventitia of blood vessels due to hematoge- dence of genital HSV at delivery [76, 77]. Infants
nous spread of a pathogen or direct inoculation who acquire HSV in utero typically have a triad
via the skin [69]. The eruption begins as ery- of cutaneous manifestations, ophthalmologic
thematous or purpuric macules usually in the findings, and neurologic involvement. Cutaneous
anogenital area or on an extremity. The lesions manifestations include scarring, active vesicular
evolve into hemorrhagic vesicles or bullae which lesions, hypo- and hyperpigmentation, aplasia
rupture to form a gangrenous ulcer with a central cutis, and an erythematous macular exanthem
gray-black eschar [72]. The lesions develop over [75]. HSV can manifest as three different types of
12 h and may exist in different stages on the same infections in neonates: involvement limited to the
individual [69]. On histology, lesions show necro- skin, eyes, or mouth, central nervous system, and
tizing hemorrhagic vasculitis, and Gram-negative disseminated multiorgan infections [3].
rods may be visible in the medial and adventitial Disseminated disease occurs in approximately
walls of deeper vessels [72]. 25% of neonatal HSV infections with approxi-
In addition to blood and urine cultures, biopsy mately 80% of these cases presenting with a
of a lesion for tissue culture should be performed vesicular eruption [78]. Complications include
with immediate administration of anti- encephalitis in 60–75% of cases, severe coagul-
pseudomonal antimicrobials [73]. Due to opathy, liver dysfunction, pulmonary involvement,
pseudomonal resistance, intravenous antibiotics and a high mortality rate [75, 79]. Neonatal HSV
with a third-generation cephalosporin with anti- infection should be treated with intravenous acy-
pseudomonas activity, such as ceftazidime 2 g clovir 10–20 mg/kg every 8 h for 10–21 days.
every 8 h, are indicated. Immunosuppressed patients are at risk of
developing fulminant herpes infections. Vesicles
enlarge to form hemorrhagic blisters and deep
2.3 Viral Infections ulcers [80] (Fig. 2.4). Death is often secondary
to visceral involvement and despite early treat-
2.3.1 Herpes Simplex Virus ment with intravenous acyclovir 10 mg/kg ideal
body weight every 8 h for 7–14 days, herpes
Herpes simplex virus (HSV) is generally associ- encephalitis carries significant morbidity and
ated with self-limiting infections. However, there mortality [81].
are a few circumstances where HSV is a Eczema herpeticum (also known as Kaposi’s
dermatological emergency and those clinical sce- varicelliform eruption) is a herpetic superinfec-
narios are covered in this section: neonatal HSV, tion of a preexisting skin disease, such as atopic
in the setting of immunosuppression, and eczema dermatitis, cutaneous burns, or skin compromise
herpeticum. The mainstay of treatment of HSV in sustained during cosmetic procedures. Clinically,
emergency situations is intravenous acyclovir. there is an acute onset of monomorphic vesicles
Neonatal HSV occurs in approximately 1 in and pustules that coalesce into large superficial
3,200 deliveries [74]. HSV may be transmitted to erosions that are susceptible to superinfection
Fig. 2.4 Herpes simplex virus
Fig. 2.6 Varicella virus
an erythematous base resembling “dew drops on

a rose petal” (Fig. 2.6). The vesicles quickly
evolve into pustules that form a crust. The lesions
may occur in crops, and the presence of lesions in
various stages of development is a characteristic
Fig. 2.5 Kaposi varicelliform eruption of this condition. Mucosal surfaces may develop
aphthous-like ulcers [80]. Both varicella and her-
pes zoster are usually self-limited diseases, but
[82] (Fig. 2.5). Patients may experience constitu- similar to HSV infection, there are specific cir-
tional symptoms. In eczema herpeticum, herpetic cumstances where VZV infections are dermato-
lesions bypass the nerve endings and ganglions logical emergencies.
and directly spread to a diseased cutaneous region Neonatal varicella is seen in two clinical set-
[83]. Rapid initiation of intravenous acyclovir tings: primary VZV infection during pregnancy
5–10 mg/kg ideal body weight every 8 h for 5–7 that is transmitted across the placenta or primary
days is crucial as HSV may completely dissemi- VZV infection during the perinatal period. The
nate and lead to possible death [84]. former can occur at any point during gestation and
results in either congenital varicella syndrome
and/or fetal death. It is worth mentioning that not
2.3.2 Varicella Zoster Virus all primary VZV infections during pregnancy
result in transplacental infection. Congenital vari-
cella syndrome most commonly occurs with
transplacental VZV infection between 13 and 20
2.4 Varicella weeks of gestation [85]. Affected babies develop
cicatricial skin lesions that may be depressed and
Varicella zoster virus (VZV) presents as varicella hyper- or hypopigmented in a dermatomal distri-
(chickenpox) as a primary infection and herpes bution. Other affected organ systems include ocular
zoster (shingles) when the virus is reactivated. (chorioretinitis, microphthalmia, nystagmus, and
Clinically, varicella lesions start as small ery- Horner’s syndrome, which is the triad of miosis,
thematous papules, which evolve into vesicles on ptosis, and anhidrosis), musculoskeletal (hypoplasia
of bones and muscles and malformed digits), central

nervous system (cortical atrophy, seizures, mental 2.5 Herpes Zoster
retardation, and microcephaly), and autonomic
nervous system (neurogenic bladder, hydroureter, Herpes zoster, the latent reactivation of previous
esophageal dilation, and reflux). Prognosis is poor VZV, is rarely life-threatening; however, dissem-
and death during infancy results from gastroe- inated disease can be associated with increased
sophageal reflux, aspiration pneumonia, or morbidity and mortality [80]. Herpes zoster
respiratory failure [86]. infection is heralded by paresthesias or stabbing
The second form of neonatal varicella is peri- pain. Shortly thereafter, an eruption of small ves-
natal varicella, which occurs when there is icles in the same distribution as the pain appears
maternal disease 5 days before delivery to 2 days and crusts over during the next 15 days [80]
after delivery. Infants develop the classic skin (Fig. 2.7). Generally, herpes zoster appears in a
vesicles on an erythematous base; however, dis- dermatomal distribution; however, in immuno-
semination may result in pneumonia, hepatitis, suppressed patients, disseminated disease may
encephalitis, and severe coagulopathy [86]. occur, defined as more than 20 vesicles outside
Infants exposed to maternal infection should be the area of the primary or adjacent dermatome
given VZIG if available or IVIG at birth or as [5]. Common complications of disseminated dis-
soon as maternal symptoms develop [87]. Despite ease include pneumonia, encephalitis, and hepa-
VZIG or IVIG, varicella can still develop and titis. The mortality rate has been reduced due to
acyclovir should be administered if there are any antiviral therapy.
signs of illness [86]. Herpes zoster often begins with a prodrome of
Varicella infections can be life-threatening in intense pain associated with pruritus, tingling, or
a few other circumstances. Immunocompromised hyperesthesia. If severe enough, the pain can be
individuals with varicella or herpes zoster have misdiagnosed as an acute abdomen or myocar-
an increased risk for systemic complications dial infarction, depending on the dermatome
including pneumonitis, central nervous system involved. Patients usually present with tingling
involvement, pneumonia, thrombocytopenia, and and paresthesia in the dermatome where cutane-
liver function impairment [80]. Although less ous lesions eventually develop. Diagnosis is often
than 5% of varicella cases occur in immunocom- delayed as the cutaneous lesions are not present
petent adults, 55% of deaths due to varicella at the onset of disease and mortality rate remains
occur in adults. Adults with varicella infection high despite initiation of antiviral therapy [91].
are at increased risk of pneumonitis and most Immunocompromised patients are at an
commonly expire secondary to pneumonia with increased risk not only for uncomplicated herpes
respiratory failure [88]. zoster infections but also for complications of
A live attenuated varicella vaccine was
approved for use in children in the United States
in 1995 [89]. The vaccine is indicated for chil-
dren 12 months to 12 years of age in addition to
individuals greater than 13 years old who have no
evidence of immunity. Finally, the vaccine should
be offered to high-risk adults without immunity,
including health care providers, household contacts
of immunocompromised individuals, nonpreg-
nant women of childbearing age, individuals who
work in places where chickenpox transmission
may occur, and international travelers [90]. It is
noteworthy that the varicella vaccine may reduce
the incidence and severity of herpes zoster [5]. Fig. 2.7 Zoster virus
zoster. Patients with AIDS or other conditions zoster [99]. Early complications include residual
with depressed cellular immunity are at risk for ptosis, lid scarring, deep scalp pitting, entropion,
chronic VZV encephalitis which may occur ectropion, pigmentary changes, and lid necrosis
months after an episode of herpes zoster. Patients [97]. Glaucoma, optic neuritis, encephalitis,
have a subacute clinical presentation with head- hemiplegia, and acute retinal necrosis are more
ache, fever, mental status changes, seizures, and severe long-term complications, the risk of which
focal neurologic defects [91]. Cerebrospinal fluid may be reduced by half with prompt initiation of
analysis reveals VZV DNA by polymerase chain antiviral therapy [19]. If herpes zoster ophthal-
reaction [92]. Death often results, although case micus is suspected, ophthalmology should be
reports have shown that high-dose intravenous consulted immediately.
acyclovir therapy may be efficacious [91]. While uncomplicated zoster may be adequately
Ramsay Hunt syndrome, also known as herpes treated with oral antivirals, such as valacyclovir
zoster oticus, is a herpetic infection of the inner, 1 g every 8 h for 7 days, disseminated and severe
middle, and external ear. It is a reactivation of infections require intravenous acyclovir 10 mg/kg
latent VZV virus in the geniculate ganglion, the ideal body weight every 8 h for 7–14 days.
sensory ganglion of the facial nerve; however, Although corticosteroids may be added as an
reactivation affects both the facial nerve (cranial adjuvant therapy in herpes zoster infections due to
nerve VII) and the vestibulocochlear nerve (cra- their anti-inflammatory properties, studies have
nial nerve VIII) due to their close proximity [93]. failed to show a beneficial effect on acute pain and
The incidence is about 5 cases per 100,000 of the in some instances had adverse effects, including
US population annually and occurs more fre- gastrointestinal symptoms, edema, and granulo-
quently in individuals over the age of 60 years cytosis. However, in Ramsay Hunt syndrome,
[94]. Patients present with severe ear pain, small steroids may be added to antiviral therapy if
vesicles on the pinna or oral mucosa, and facial there are no contraindications [100].
palsy [95]. Prompt diagnosis is paramount as ini- Zostavax is a live attenuated vaccine indicated
tiation of antiviral therapy within 72 h of the for the prevention of herpes zoster and post-her-
onset of symptoms leads to resolution of the petic neuralgia in individuals greater than 50
facial palsy in as many as 75% of cases [94]. years of age [101]. The vaccine has been shown
Herpes zoster ophthalmicus, the second most to reduce the incidence of herpes zoster by 51%,
common presentation of herpes zoster, involves reduce the incidence of post-herpetic neuralgia
the ophthalmic division of the trigeminal nerve by 67%, and reduce the herpes zoster-related bur-
and occurs in up to 20% of patients with herpes den of illness by 61% [102]. Gabapentin has been
zoster [96, 97]. The ophthalmic division divides approved since 2002 by the US Food and Drug
into the nasociliary, frontal, and lacrimal branches. Administration (FDA) for the treatment of post-
The nasociliary nerve innervates the anterior and herpetic neuralgia [103].
posterior ethmoidal sinuses, conjunctiva, sclera,
cornea, iris, choroid, and the skin of the eyelids
and tip of the nose [96]. Hutchinson’s sign, first 2.5.1 Cytomegalovirus
described in 1864, is the appearance of a herpes
zoster lesion on the tip or side of the nose and Cytomegalovirus (CMV) or human herpesvirus-5
serves as a useful prognostic factor in the ensuing (HHV-5), a large double-stranded DNA virus of
ocular inflammation [98]. Uveitis followed by the viral family herpesviruses, is acquired by expo-
keratitis are the most common forms of ocular sure to infected children, sexual transmission, and
involvement [19]. Clinically, patients develop transfusion of CMV-infected blood products. Up
lesions on the margin of the eyelid occasionally to 80% of adults are infected with CMV [19].
associated with periorbital edema and ptosis. CMV causes a mild form of infectious mononu-
Chronic disease due to neurologic damage occurs cleosis in most affected immunocompetent indi-
in up to 30% of patients with this form of herpes viduals; however, in rare cases, fatal massive
hepatic necrosis can occur. Immunocompromised spots, bluish gray areas on the tonsils, and
individuals, including those with HIV, malignancy, Koplik’s spots, punctate blue-white lesions
or post-organ transplant patients, may have severe, surrounded by an erythematous ring on the buc-
complicated CMV infections [3]. cal mucosa, appear [80]. Complications of mea-
CMV infection in immunocompromised indi- sles include encephalitis, subacute sclerosing
viduals can either directly induce death or disable panencephalitis, and fetal death if infection
the patient’s immune system, making them even occurs during pregnancy [107].
more susceptible to secondary infections [104]. Vaccination is the gold standard for prevent-
CMV can be a fatal disease in newborns. When a ing infection. The measles, mumps, rubella
primary CMV infection is sustained during preg- (MMR) or MMR plus varicella (MMRV) is a live
nancy, transplacental transmission may occur and attenuated vaccine and as a result cannot be used
severely affect the fetus [80]. Nonimmune preg- in immuncompromised patients [3]. Although no
nant women, especially those working in health- antivirals have been effective in treating measles
care settings or daycare facilities, should take infection, vitamin A supplementation may reduce
precautions, primarily proper hand washing. deaths from measles by 50% as vitamin A
Cutaneous manifestations of congenital CMV deficiency has been shown to increase morbidity
include jaundice, petechiae, and purpura, referred and mortality [108].
to as “blueberry muffin” lesions and complications
include hearing loss and mental retardation [3].
Antiviral therapy should be given to affected 2.5.3 German Measles (Rubella)
immunocompromised patients in addition to pas-
sive immunization of CMV with hyperimmune Rubella is a viral infection caused by the rubella
globulin (HIG). Women who develop primary virus, an RNA virus in the Togaviridae family. It
CMV infections during pregnancy may prevent is associated with mild constitutional symptoms
transmission to the fetus with CMV HIG. that are more severe in adults compared to chil-
Ganciclovir is not approved for pregnant women, dren. Following a 2-week incubation period, a
but is safe for newborns [3]. pale erythematous eruption appears on the head
and spreads to the feet, lasting approximately 3
days. Forchheimer’s spots, macular petechiae, can
2.5.2 Measles (Rubeola) be identified on the soft palate. Often there is
coexistent tender lymphadenopathy, especially of
Measles, due to the morbillivirus, an RNA virus the occipital, posterior auricular, and cervical
in the Paramyxoviridae family, has markedly chains. Rubella is generally self-limiting, but
decreased in incidence since the development of severe complications may occur. Children are
vaccination against the virus. However, it remains more susceptible to thrombocytopenia, vasculitis,
an active disease in both developed and develop- orchitis, neuronitis, and progressive panencepha-
ing countries [105]. Generally, affected individu- litis [80]. Neonatal infections in the first trimester
als are unvaccinated children less than 5 years of can result in congenital defects, fetal death, spon-
age or vaccinated school-age children who failed taneous abortion, or premature delivery.
to develop immunity to the vaccine [106]. Prevention is via vaccination, and, as previously
The virus is transmitted via respiratory secre- stated, is contraindicated in immunocompromised
tions. Following an asymptomatic incubation of patients. Treatment of infection is supportive [3].
10–11 days, a high fever develops with subse-
quent rapid defervescence. Coryza, conjuncti-
vitis, and a barking cough are characteristic. 2.5.4 Parvovirus B19
Additionally, an eruption begins on the head with
erythematous macules and papules that coalesce Parvovirus B19 is a small, single-stranded DNA-
and spread distally involving the palms and soles. containing virus causing a wide range of diseases
One to two days prior to the exanthem, Herman’s varying from asymptomatic infections to fetal
demise. The most common form of infection is weeks gestation. Most fetal losses occur between
erythema infectiosum, or “fifth disease.” In gen- 20 and 28 weeks gestation [110].
eral, regardless of the clinical presentation, the The mainstay of treatment is supportive.
virus is self-limited with the exception of a few However, there are treatment modalities that have
circumstances [80]. The peak incidence of infec- been used. High-dose IVIG have been shown to
tion occurs in the winter and spring. It is trans- eliminate parvovirus B19 from the bone marrow.
mitted through respiratory secretions, blood Intrauterine transfusions can reverse fetal anemia
products, or vertically during pregnancy. and reduce fetal demise. Prevention and measures
Although parvovirus B19 is more common in to avoid susceptible people are often difficult as
children, infection does occur in adults with vary- once the rash appears and is recognized as parvovi-
ing clinical presentation. The seroprevalance of rus B19, patients are no longer contagious [3, 111].
parvovirus B19 antibodies increases with age—
up to 15% of children 1–5 years of age are
affected versus up to 80% of adults [5]. 2.6 Fungal Infections
Erythema infectiosum occurs after a 4–14-
day incubation period. Individuals develop the 2.6.1 Systemic Candidiasis
classic “slapped-cheek” facial erythema that
spares the nasal bridge and circumoral regions. Candida species are the most common cause of
One to four days later, erythematous macules fungal infections. While Candida albicans is the
and papules appear which progress to form a most common pathogen in oropharyngeal and
lacy, reticulate pattern most commonly cutaneous candidiasis, other species of Candida
observed on the extremities, lasting 1–3 weeks. have been isolated in a rising number of infec-
Once cutaneous signs appear, the individual is tions in both invasive and vaginal candidiasis
no longer contagious [5, 80]. Arthralgia or [112]. Systemic candidiasis is a fatal infection
arthritis, seen in up to 10% of patients with that is increasing in incidence, especially in
erythema infectiosum, is more common in immunocompromised patients. Risk factors
female adults and may occur in up to 60% of include chemotherapy, hematological diseases,
those infected [109]. and prolonged use of broad-spectrum antibiotics
Both children and adults may develop a dis- [113, 114].
tinct syndrome known as papular purpuric glove Cutaneous lesions occur in a minority of
and socks syndrome which is also secondary to patients, but when present can aid in early diag-
parvovirus B19. Clinically, patients have edema nosis and rapid initiation of appropriate treat-
and erythema of the palms and soles with pete- ment, especially since there is no specific
chiae and purpura associated with burning and diagnostic tool for systemic candidiasis [113].
pruritus [5]. Clinically, cutaneous lesions in systemic candidi-
Parvovirus B19 can cause complications in asis begin as macules that develop into papules,
three situations: immunosuppression, pregnancy, pustules, or nodules with a surrounding ery-
and underlying hematologic disease. Patients with thematous halo. The lesions are common on the
hematologic disease, such as sickle cell anemia or trunk and extremities. Purpura can be seen in
hereditary spherocytosis, who become infected patients with or without thrombocytopenia [113].
with parvovirus B19 are at risk of developing Tissue culture may isolate the fungi.
severe transient aplastic anemia. In general, recov- Antifungal medications should be started once
ery is usually spontaneous, but heart failure and systemic candidiasis is suspected. Fluconazole is
death may occur. Thrombocytopenia is another the treatment of choice for C. albicans; however,
less common complication. Fetal infection with other species of Candida require amphotericin B
parvovirus B19 can result in miscarriage or non- deoxycholate [113, 115]. The mortality rate asso-
immune hydrops fetalis [80]. The greatest risk to ciated with systemic candidiasis ranges from 46
the fetus is when infection is acquired before 20 to 75% [116].
2.6.2 Mucormycosis with cerebral, cutaneous, or pulmonary mucormy-

cosis [119].
Mucormycosis, previously encompassed by the Diagnosis of cutaneous lesions can be confirmed
now obsolete term zygomycosis, is a potentially by histopathologic examination, revealing wide-
life-threatening fungal infection [117]. angled branching fungal hyphae. Potassium hydrox-
Mucormycosis is caused by fungi in the order ide preparations can be used to identify the hyphae
Mucorales and the family Mucoraceae. The genus from bronchoalveolar lavage samples. Blood cul-
contains over 3,000 species; however, not all tures are often negative, even when the diagnosis is
cause disease in humans. The most commonly confirmed with hyphae on histology [3].
isolated genera include Rhizopus, Mucor, It is important to be aware of risk factors for
Rhizomucor, and Absidia [118]. Disease can be the development of mucormycosis as treatment
classified as rhino-orbital-cerebral, pulmonary, includes reversal of these underlying risk factors
cutaneous, gastrointestinal, or disseminated if present. Risk factors include long-term
forms, and the host influences which form of dis- neutropenia, high-dose glucocorticoid therapy,
ease develops. Immunocompromised individuals hyperglycemia, diabetes with or without
are most susceptible to mucormycosis. Diabetics ketoacidosis, iron overload, and use of defoxam-
commonly present with the rhino-orbital-cerebral ine treatment [117]. Early diagnosis is required
form. Those individuals receiving deferoxamine for successful treatment of mucormycosis with
are more susceptible to pulmonary, followed by prompt administration of antifungal therapy and
rhinocerebral, and finally disseminated disease. surgical debridement in select patients [123]. One
Ferric complex of deferoxamine stimulates iron study found that a greater than 6-day delay in
uptake and growth of Rhizopus. [119, 120]. treatment with intravenous amphotericin-B
Cerebral disease is most commonly seen in 0.5–1 mg/kg/day after diagnosis led to a doubled
intravenous drug users, and solid-organ trans- mortality rate at 12 weeks [124].
plant patients may develop pulmonary or rhino-
orbital-cerebral disease [119, 121]. Recently
Apophysomyces elegans, a pathogen causing 2.6.3 Histoplasmosis
mucormycosis, has led to primary cutaneous and
rhino-orbital-cerebral disease in immunocompe- Histoplasmosis, caused by the dimorphic fungus
tent patients [122]. This section covers the rhino- Histoplasma capsulatum var. capsulatum, is a
orbital-cerebral, cutaneous, and disseminated common infection in Southeastern and Central
forms of disease. United States. Birds and bats serve as reservoirs
Rhino-orbital-cerebral disease can present as for histoplasmosis, and their feces contain the
rhinosinusitis, sinusitis, rhino-orbital, or rhinoc- organism. Individuals acquire the disease either
erebral disease. Clinically, rapid development of through inhalation or, less commonly, by direct
tissue necrosis is seen in invasive mucormycosis cutaneous inoculation of the fungus. While
due to vascular invasion and thrombosis [117]. immunocompromised individuals are at a higher
Progressive disease is seen with necrosis or eschar risk for disseminated histoplasmosis, immuno-
formation in the nasal cavity or on the palate. competent hosts can become infected if the expo-
Patients can also develop trigeminal and facial sure is significant [3].
cranial nerve palsy, ophthalmoplegia, epidural or Clinical presentations range from primary cuta-
subdural abscesses, and cavernous or sagittal neous to pulmonary to disseminated histoplasmo-
sinus thrombosis [117]. sis. The latter is covered in this section as it is the
Cutaneous mucormycosis develops after direct only clinical presentation of histoplasmosis that
spore inoculation in a wound. Initially, patients would constitute a dermatologic emergency. Most
develop erythema and induration of the skin, patients infected with histoplasmosis experience
which progresses to necrosis with a black eschar asymptomatic hematogenous dissemination through
[117]. Disseminated disease develops in patients macrophages infected with the parasite [125]. Risk
factors for developing disseminated disease include and Panstronglus megistus [130]. Transmission
young age, AIDS, hematologic malignancies, solid occurs when a prior wound or an intact mucous
organ transplant, hematopoietic stem cell transplant, membrane is inoculated with the feces of an
immunosuppressive agents, and congenital T-cell infected bug [131].
deficiencies [126]. Patients often have fever, mal- Chagas disease occurs in two main phases:
aise, anorexia, and weight loss. Cutaneous findings the acute and chronic phases [132]. Acute Chagas
in disseminated histoplasmosis are nonspecific. disease develops after a 1–2-week incubation
They vary from mucocutaneous oral ulcers or ero- period and begins with a macular or papulonodu-
sions to erythematous or molluscum-like papules or lar, erythematous to violet, hard, painless lesion
nodules [3, 127]. The most common extracutaneous at the inoculation site [3]. Inoculation through
sites for disseminated involvement are the lung, the conjunctiva results in nonpainful, unilateral
spleen, lymph nodes, bone marrow, and liver; how- edema of the upper and lower eyelid for several
ever, any organ system can be involved. Severe dis- weeks, known as Romaña’s sign [131]. The
seminated disease can present as sepsis with lesion may ulcerate, but usually regresses in 3
hypotension, disseminated intravascular coagula- weeks. A maculopapular, morbilliform, or urti-
tion, renal failure, and acute respiratory distress carial eruption may also be seen. Associated
[126]. Uncommonly, patients can develop endo- signs of acute infection include satellite lymph-
carditis, central nervous system infection, or adenitis, fever, myalgia, and hepatosplenomeg-
Addison’s disease when there is destruction of bilat- aly [3]. The acute phase lasts for 4–8 weeks
eral adrenal glands by the fungus [126, 128]. [131].
Laboratory abnormalities are nonspecific, but Without successful treatment, the patient can
will often include elevated alkaline phosphatase go on to develop chronic Chagas disease [131].
levels, pancytopenia, an increased sedimentation The chronic form is characterized by cardiac and
rate, elevated C-reactive protein levels, high lac- gastrointestinal manifestations. Early cardiac
tate dehydrogenase levels, hypercalcemia, and findings include conduction-system abnormalities
increased ferritin expression [125, 126]. The and ventricular wall-motion abnormalities [130].
fungi can be cultured in the blood, but the diag- After time, patients progress to high-degree heart
nosis of disseminated histoplasmosis can be block, sustained and nonsustained ventricular
obtained by tissue biopsy of any involved site, tachycardia, sinus-node dysfunction, apical aneu-
revealing intracellular yeast forms surrounded by rysm, embolic phenomena, and progressive
a rim of clearing [3, 129]. dilated cardiomyopathy [133]. With these findings,
Treatment is not indicated in self-limited there is a high risk of sudden death [134].
infections. However, disseminated histoplasmo- Gastrointestinal Chagas disease involves the
sis requires systemic antifungal therapy (ampho- esophagus, colon, or both. Uncommon findings
tericin B 0.7–1 mg/kg/day or itraconazole are megaesophagus and megacolon [135].
200–400 mg daily) [3]. Diagnosis during the acute phase is made by
direct examination of Giemsa-stained blood
smears, touch preps, or lymph-node biopsy. In
2.7 Parasitic Infections the chronic phase, direct immunofluorescence
and PCR for anti-T. cruzi immunoglobulin M
2.7.1 American Trypanosomiasis antibodies can be diagnostic [132].
(Chagas Disease) Treatment with benznidazole 5 mg/kg/day
or nifurtimox 8–10 mg/kg/day in 3–4 doses
Chagas disease, also known as American try- has been shown to reduce the severity of symp-
panosomiasis, is caused by the parasite tom and shorten the clinical course during the
Trypanosoma cruzi, which is found in tropical acute infection. The cure rate during the acute
zones of the Americas. The parasite is transmitted phase is between 60 and 85% [130]. The
by the reduviid bug, which constitutes three main efficacy of treatment for chronic infection is
species: Triatoma infestans, Rhodnius prolixus, unclear [136].
2.7.2 Mucocutaneous Leishmaniasis
Leishmaniasis, caused by protozoa in the genus

Leishmania, encompasses three clinical forms:
cutaneous, mucocutaneous, and visceral leishma-
niasis. Although leishmaniasis is endemic in
Southern Europe, Central and South America,
Africa, the Middle East, and South Asia, it is
increasingly seen in non-endemic regions in the
setting of travel to endemic countries [137].
Leishmania, an intracellular parasite that targets
macrophages, dendritic cells, and neutrophils, is Fig. 2.8 Mucocutaneous leishmaniasis
transmitted via the bite of an infected female sand
fly, primarily Phlebotomus (Old World) and of intracellular amastigotes, but often specimens
Lutzomyia (New World) [138, 139]. will show granulomas [141]. When suspicion is
While cutaneous leishmaniasis is generally high and biopsy only shows granulomas, PCR
benign and self-limiting, mucocutaneous leish- may be used to isolate Leishmania DNA [142].
maniasis is a potentially life-threatening infec- Pentavalent antimony is first-line therapy fol-
tion that requires treatment [138]. The progression lowed by amphotericin B 0.5–1 mg/kg/day [143].
to mucosal disease depends on the virulence of All photographs used in this chapter are with
the parasite as well as the individual cell-mediated permission and courtesy of Michael Fisher, M.D.
immunity. Only 1–10% of infected patients
will develop mucosal involvement [140].
Immunodeficiency is not necessarily a predispos- References
ing factor [141].
Patients with mucocutaneous leishmaniasis 1. Singh G, Sinha SK, Adhikary S, Babu KS, Ray P,
Khanna SK. Necrotising infections of soft tissues—a
will often have a history of cutaneous leishmani-
clinical profile. Eur J Surg. 2002;168(6):366–71.
asis starting 1–5 years prior to the mucosal 2. Hasham S, Matteucci P, Stanley PR, Hart NB.
involvement. The primary cutaneous lesion is Necrotising fasciitis. BMJ. 2005;330(7495):830–3.
generally ulcerative and can be solitary or multi- 3. Wolf R, Davidovici BB, Parish JL, Parish LC.
Emergency dermatology. New York: Cambridge
ple [140]. Persistent nasal congestion is the most
University Press; 2010.
common presenting symptom [141]. As the dis- 4. Elliott DC, Kufera JA, Myers RA. Necrotizing soft tis-
ease progresses, patients develop erythema, ero- sue infections. Risk factors for mortality and strategies
sions, and ulcers around the nares and lips for management. Ann Surg. 1996;224(5):672–83.
5. Bolognia J, Jorizzo JL, Rapini RP. Dermatology. St.
followed by lesions on the oropharynx, and occa-
Louis, MO: Mosby Elsevier; 2008.
sionally widespread cutaneous disease [137] 6. Jallali N, Withey S, Butler PE. Hyperbaric oxygen as
(Fig. 2.8). Later in the disease course, patients adjuvant therapy in the management of necrotizing
can have nasal septal perforation and palatal fasciitis. Am J Surg. 2005;189(4):462–6.
7. Kaul R, McGeer A, Norrby-Teglund A, Kotb M,
ulceration with eventual destruction of the orona-
Schwartz B, O’Rourke K, Talbot J, Low DE.
sopharyngeal mucosa and cartilaginous facial Intravenous immunoglobulin therapy for streptococ-
and upper airway structures [137, 138]. Other cal toxic shock syndrome—a comparative observa-
findings include lymphadenopathy, fever, and tional study. The Canadian Streptococcal Study
Group. Clin Infect Dis. 1999;28(4):800–7.
hepatomegaly [137].
8. Darenberg J, Ihendyane N, Sjolin J, Aufwerber E,
Histopathology and touch preparations are Haidl S, Follin P, Andersson J, Norrby-Teglund A.
diagnostic in cutaneous leishmaniasis; however, Intravenous immunoglobulin G therapy in strepto-
biopsy is necessary in mucocutaneous disease coccal toxic shock syndrome: a European random-
ized, double-blind, placebo-controlled trial. Clin
as there are very few parasites in the nasal
Infect Dis. 2003;37(3):333–40.
mucosa. Diagnosis is confirmed by the presence
9. Huang KF, Hung MH, Lin YS, Lu CL, Liu C, Chen 28. Lacz NL, Schwartz RA, Kapila R. Rocky Mountain
CC, Lee YH. Independent predictors of mortality for spotted fever. J Eur Acad Dermatol Venereol.
necrotizing fasciitis: a retrospective analysis in a 2006;20(4):411–7.
single institution. J Trauma. 2011;71(2):467–73. 29. Stanek G, Wormser GP, Gray J, Strle F. Lyme bor-
10. Givner LB. Periorbital versus orbital cellulitis. reliosis. Lancet. 2011;379(9814):461–73.
Pediatr Infect Dis J. 2002;21(12):1157–8. 30. des Vignes F, Piesman J, Heffernan R, Schulze TL,
11. Rudloe TF, Harper MB, Prabhu SP, Rahbar R, Stafford 3rd KC, Fish D. Effect of tick removal on
Vanderveen D, Kimia AA. Acute periorbital infec- transmission of Borrelia burgdorferi and Ehrlichia
tions: who needs emergent imaging? Pediatrics. phagocytophila by Ixodes scapularis nymphs.
2010;125(4):e719–26. J Infect Dis. 2001;183(5):773–8.
12. Mahalingam-Dhingra A, Lander L, Preciado DA, 31. Huppertz HI, Bohme M, Standaert SM, Karch H,
Taylormoore J, Shah RK. Orbital and periorbital Plotkin SA. Incidence of Lyme borreliosis in the
infections: a national perspective. Arch Otolaryngol Wurzburg region of Germany. Eur J Clin Microbiol
Head Neck Surg. 2011;137(8):769–73. Infect Dis. 1999;18(10):697–703.
13. Hasanee K, Sharma S. Ophthaproblem. Orbital cel- 32. Stanek G, Fingerle V, Hunfeld KP, Jaulhac B, Kaiser
lulitis. Can Fam Physician. 2004;50(359):365–7. R, Krause A, Kristoferitsch W, O’Connell S, Ornstein
14. Carfrae MJ, Kesser BW. Malignant otitis externa. K, Strle F, Gray J. Lyme borreliosis: clinical case
Otolaryngol Clin North Am. 2008;41(3):537–49. definitions for diagnosis and management in Europe.
viii–ix. Clin Microbiol Infect. 2011;17(1):69–79.
15. Rosenstein NE, Perkins BA, Stephens DS, Popovic 33. Halperin JJ. Nervous system Lyme disease. Infect
T, Hughes JM. Meningococcal disease. N Engl J Dis Clin North Am. 2008;22(2):261–74. vi.
Med. 2001;344(18):1378–88. 34. Bhate C, Schwartz RA. Lyme disease: Part II.
16. Milonovich LM. Meningococcemia: epidemiology, Management and prevention. J Am Acad Dermatol.
pathophysiology, and management. J Pediatr Health 2011;64(4):639–53. quiz 654, 653.
Care. 2007;21(2):75–80. 35. Brown SL, Hansen SL, Langone JJ. Role of serology
17. Sexton K, Lennon D, Oster P, Aaberge I, Martin D, in the diagnosis of Lyme disease. JAMA.
Reid S, Wong S, O’Hallahan J. Proceedings of the 1999;282(1):62–6.
Meningococcal Vaccine Strategy World Health 36. Branda JA, Aguero-Rosenfeld ME, Ferraro MJ,
Organization satellite meeting, 10 March 2004, Johnson BJ, Wormser GP, Steere AC. 2-tiered anti-
Auckland, New Zealand. N Z Med J. body testing for early and late Lyme disease using
2004;117(1200):1. p preceding U1027. only an immunoglobulin G blot with the addition of
18. Ramos-e-Silva M, Pereira AL. Life-threatening a VlsE band as the second-tier test. Clin Infect Dis.
eruptions due to infectious agents. Clin Dermatol. 2010;50(1):20–6.
2005;23(2):148–56. 37. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin
19. James WD, Elston DM, Berger TG, Andrews GC. JJ, Steere AC, Klempner MS, Krause PJ, Bakken JS,
Andrews’ diseases of the skin: clinical dermatology. Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS,
London: Saunders Elsevier; 2011. Nadelman RB. The clinical assessment, treatment,
20. Healy CM, Baker CJ. The future of meningococcal and prevention of lyme disease, human granulocytic
vaccines. Pediatr Infect Dis J. 2005;24(2):175–6. anaplasmosis, and babesiosis: clinical practice
21. Usatine RP, Sandy N. Dermatologic emergencies. guidelines by the Infectious Diseases Society of
Am Fam Physician. 2010;82(7):773–80. America. Clin Infect Dis. 2006;43(9):1089–134.
22. Dumler JS, Walker DH. Rocky Mountain spotted 38. Katz TM, Miller JH, Hebert AA. Insect repellents:
fever–changing ecology and persisting virulence. historical perspectives and new developments. J Am
N Engl J Med. 2005;353(6):551–3. Acad Dermatol. 2008;58(5):865–71.
23. Dantas-Torres F. Rocky Mountain spotted fever. 39. Nadelman RB, Nowakowski J, Fish D, Falco RC,
Lancet Infect Dis. 2007;7(11):724–32. Freeman K, McKenna D, Welch P, Marcus R,
24. Spach DH, Liles WC, Campbell GL, Quick RE, Aguero-Rosenfeld ME, Dennis DT, Wormser GP.
Anderson Jr DE, Fritsche TR. Tick-borne diseases in Prophylaxis with single-dose doxycycline for the
the United States. N Engl J Med. prevention of Lyme disease after an Ixodes scapu-
1993;329(13):936–47. laris tick bite. N Engl J Med. 2001;345(2):79–84.
25. Helmick CG, Bernard KW, D’Angelo LJ. Rocky 40. Vazquez M, Muehlenbein C, Cartter M, Hayes EB,
Mountain spotted fever: clinical, laboratory, and epi- Ertel S, Shapiro ED. Effectiveness of personal pro-
demiological features of 262 cases. J Infect Dis. tective measures to prevent Lyme disease. Emerg
1984;150(4):480–8. Infect Dis. 2008;14(2):210–6.
26. Parola P, Paddock CD, Raoult D. Tick-borne rick- 41. Moayeri M, Leppla SH. The roles of anthrax toxin in
ettsioses around the world: emerging diseases chal- pathogenesis. Curr Opin Microbiol. 2004;7(1):19–24.
lenging old concepts. Clin Microbiol Rev. 42. Wenner KA, Kenner JR. Anthrax. Dermatol Clin.
2005;18(4):719–56. 2004;22(3):247–56. v.
27. Gammons M, Salam G. Tick removal. Am Fam 43. Swartz MN. Recognition and management of anthrax–
Physician. 2002;66(4):643–5. an update. N Engl J Med. 2001;345(22): 1621–6.
44. Inglesby TV, O’Toole T, Henderson DA, Bartlett JG, 61. Stevens DL. Streptococcal toxic shock syndrome.
Ascher MS, Eitzen E, Friedlander AM, Gerberding Clin Microbiol Infect. 2002;8(3):133–6.
J, Hauer J, Hughes J, McDade J, Osterholm MT, 62. McCormick JK, Yarwood JM, Schlievert PM. Toxic
Parker G, Perl TM, Russell PK, Tonat K. Anthrax as shock syndrome and bacterial superantigens: an
a biological weapon, 2002: updated recommenda- update. Annu Rev Microbiol. 2001;55:77–104.
tions for management. JAMA. 63. Kato K, Sakamoto T, Ito K. Gamma-globulin inhib-
2002;287(17):2236–52. its superantigen-induced lymphocyte proliferation
45. Dixon TC, Meselson M, Guillemin J, Hanna PC. and cytokine production. Allergol Int. 2007;56(4):
Anthrax. N Engl J Med. 1999;341(11):815–26. 439–44.
46. Inglesby TV, Henderson DA, Bartlett JG, Ascher 64. Adcock DM, Brozna J, Marlar RA. Proposed
MS, Eitzen E, Friedlander AM, Hauer J, McDade J, classification and pathologic mechanisms of purpura
Osterholm MT, O’Toole T, Parker G, Perl TM, fulminans and skin necrosis. Semin Thromb Hemost.
Russell PK, Tonat K. Anthrax as a biological 1990;16(4):333–40.
weapon: medical and public health management. 65. Carpenter CT, Kaiser AB. Purpura fulminans in
Working Group on Civilian Biodefense. JAMA. pneumococcal sepsis: case report and review. Scand
1999;281(18):1735–45. J Infect Dis. 1997;29(5):479–83.
47. Evans ME, Gregory DW, Schaffner W, McGee ZA. 66. Adcock DM, Hicks MJ. Dermatopathology of skin
Tularemia: a 30-year experience with 88 cases. necrosis associated with purpura fulminans. Semin
Medicine (Baltimore). 1985;64(4):251–69. Thromb Hemost. 1990;16(4):283–92.
48. McGinley-Smith DE, Tsao SS. Dermatoses from 67. Betrosian AP, Berlet T, Agarwal B. Purpura fulmin-
ticks. J Am Acad Dermatol. 2003;49(3):363–92. ans in sepsis. Am J Med Sci. 2006;332(6):339–45.
quiz 393–6. 68. Varon J, Chen K, Sternbach GL. Rupert Waterhouse
49. Choi E. Tularemia and Q fever. Med Clin North Am. and Carl Friderichsen: adrenal apoplexy. J Emerg
2002;86(2):393–416. Med. 1998;16(4):643–7.
50. Dana AN. Diagnosis and treatment of tick infesta- 69. Zomorrodi A, Wald ER. Ecthyma gangrenosum:
tion and tick-borne diseases with cutaneous manifes- considerations in a previously healthy child. Pediatr
tations. Dermatol Ther. 2009;22(4):293–326. Infect Dis J. 2002;21(12):1161–4.
51. Amagai M, Matsuyoshi N, Wang ZH, Andl C, 70. Baro M, Marin MA, Ruiz-Contreras J, de Miguel SF,
Stanley JR. Toxin in bullous impetigo and staphylo- Sanchez-Diaz I. Pseudomonas aeruginosa sepsis and
coccal scalded-skin syndrome targets desmoglein 1. ecthyma gangrenosum as initial manifestations of primary
Nat Med. 2000;6(11):1275–7. immunodeficiency. Eur J Pediatr. 2004;163(3):173–4.
52. Odom RB, James WD, Berger TG. Andrews’ dis- 71. Wong SN, Tam AY, Yung RW, Kwan EY, Tsoi NN.
eases of the skin: clinical dermatology. St. Louis, Pseudomonas septicaemia in apparently healthy
MO: Mosby; 2000. children. Acta Paediatr Scand. 1991;80(5):515–20.
53. Cribier B, Piemont Y, Grosshans E. Staphylococcal 72. Bettens S, Delaere B, Glupczynski Y, Schoevaerdts
scalded skin syndrome in adults. A clinical review D, Swine C. Ecthyma gangrenosum in a non-neutro-
illustrated with a new case. J Am Acad Dermatol. paenic, elderly patient: case report and review of the
1994;30(2 Pt 2):319–24. literature. Acta Clin Belg. 2008;63(6):394–7.
54. Murray RJ. Recognition and management of 73. Gucluer H, Ergun T, Demircay Z. Ecthyma gan-
Staphylococcus aureus toxin-mediated disease. grenosum. Int J Dermatol. 1999;38(4):299–302.
Intern Med J. 2005;35 Suppl 2:S106–19. 74. Brown ZA, Wald A, Morrow RA, Selke S, Zeh J,
55. Gemmell CG. Staphylococcal scalded skin syn- Corey L. Effect of serologic status and cesarean deliv-
drome. J Med Microbiol. 1995;43(5):318–27. ery on transmission rates of herpes simplex virus from
56. Macias ES, Pereira FA, Rietkerk W, Safai B. mother to infant. JAMA. 2003;289(2): 203–9.
Superantigens in dermatology. J Am Acad Dermatol. 75. Kimberlin DW. Neonatal herpes simplex infection.
2011;64(3):455–72. quiz 473–4. Clin Microbiol Rev. 2004;17(1):1–13.
57. Lappin E, Ferguson AJ. Gram-positive toxic shock 76. Yeager AS, Arvin AM. Reasons for the absence of a
syndromes. Lancet Infect Dis. 2009;9(5):281–90. history of recurrent genital infections in mothers of
58. Schlievert PM, Blomster DA. Production of staphy- neonates infected with herpes simplex virus.
lococcal pyrogenic exotoxin type C: influence of Pediatrics. 1984;73(2):188–93.
physical and chemical factors. J Infect Dis. 77. Brown ZA, Selke S, Zeh J, Kopelman J, Maslow A,
1983;147(2):236–42. Ashley RL, Watts DH, Berry S, Herd M, Corey L.
59. Bohach GA, Fast DJ, Nelson RD, Schlievert PM. The acquisition of herpes simplex virus during preg-
Staphylococcal and streptococcal pyrogenic toxins nancy. N Engl J Med. 1997;337(8):509–15.
involved in toxic shock syndrome and related ill- 78. Whitley RJ, Corey L, Arvin A, Lakeman FD, Sumaya
nesses. Crit Rev Microbiol. 1990;17(4):251–72. CV, Wright PF, Dunkle LM, Steele RW, Soong SJ,
60. Fraser JD, Proft T. The bacterial superantigen and Nahmias AJ, et al. Changing presentation of herpes
superantigen-like proteins. Immunol Rev. simplex virus infection in neonates. J Infect Dis.
2008;225:226–43. 1988;158(1):109–16.
79. Arvin AM, Yeager AS, Bruhn FW, Grossman M. 97. Liesegang TJ. Herpes zoster ophthalmicus natural
Neonatal herpes simplex infection in the absence of history, risk factors, clinical presentation, and mor-
mucocutaneous lesions. J Pediatr. 1982;100(5):715–21. bidity. Ophthalmology. 2008;115(2 Suppl):S3–12.
80. Rebora A. Life-threatening cutaneous viral diseases. 98. Zaal MJ, Volker-Dieben HJ, D’Amaro J. Prognostic
Clin Dermatol. 2005;23(2):157–63. value of Hutchinson’s sign in acute herpes zoster
81. Kusuhara T, Nakajima M, Inoue H, Takahashi M, ophthalmicus. Graefes Arch Clin Exp Ophthalmol.
Yamada T. Parainfectious encephalomyeloradiculitis 2003;241(3):187–91.
associated with herpes simplex virus 1 DNA in cere- 99. Harding SP. Management of ophthalmic zoster.
brospinal fluid. Clin Infect Dis. 2002;34(9): J Med Virol. 1993;(Suppl 1):97–101.
1199–205. 100. Dworkin RH, Johnson RW, Breuer J, Gnann JW,
82. Fatahzadeh M, Schwartz RA. Human herpes sim- Levin MJ, Backonja M, Betts RF, Gershon AA,
plex virus infections: epidemiology, pathogenesis, Haanpaa ML, McKendrick MW, Nurmikko TJ,
symptomatology, diagnosis, and management. J Am Oaklander AL, Oxman MN, Pavan-Langston D,
Acad Dermatol. 2007;57(5):737–63. quiz 764–6. Petersen KL, Rowbotham MC, Schmader KE, Stacey
83. Marcus B, Lipozencic J, Matz H, Orion E, Wolf R. BR, Tyring SK, van Wijck AJ, Wallace MS, Wassilew
Herpes simplex: autoinoculation versus dissemination. SW, Whitley RJ. Recommendations for the manage-
Acta Dermatovenerol Croat. 2005;13(4): 237–41. ment of herpes zoster. Clin Infect Dis. 2007;44 Suppl
84. Sanderson IR, Brueton LA, Savage MO, Harper JI. 1:S1–26.
Eczema herpeticum: a potentially fatal disease. Br 101. Arnou R, Fiquet A, Thomas S, Sadorge C.
Med J (Clin Res Ed). 1987;294(6573):693–4. Immunogenicity and safety of ZOSTAVAX(R)
85. Enders G, Miller E, Cradock-Watson J, Bolley I, approaching expiry potency in individuals aged
Ridehalgh M. Consequences of varicella and herpes >/=50 years. Hum Vaccin. 2011;7(10):1060–5.
zoster in pregnancy: prospective study of 1739 cases. 102. Sanford M, Keating GM. Zoster vaccine (Zostavax):
Lancet. 1994;343(8912):1548–51. a review of its use in preventing herpes zoster and
86. Smith CK, Arvin AM. Varicella in the fetus and new- postherpetic neuralgia in older adults. Drugs Aging.
born. Semin Fetal Neonatal Med. 2009;14(4): 2010;27(2):159–76.
209–17. 103. Thomas B, Farquhar-Smith P. Extended-release
87. Chapman SJ. Varicella in pregnancy. Semin gabapentin in post-herpetic neuralgia. Expert Opin
Perinatol. 1998;22(4):339–46. Pharmacother. 2011;12(16):2565–71.
88. Selleger C. [Fatal varicella pneumonia in adults. 104. Adler SP, Marshall B. Cytomegalovirus infections.
Report of two cases and review of literature (author’s Pediatr Rev. 2007;28(3):92–100.
transl)]. Rev Fr Mal Respir. 1979;7(1):9–18. 105. Cutts FT, Henao-Restrepo A, Olive JM. Measles
89. Grose C. Varicella vaccination of children in the elimination: progress and challenges. Vaccine.
United States: assessment after the first decade 1999;17 Suppl 3:S47–52.
1995–2005. J Clin Virol. 2005;33(2):89–95. discus- 106. Epidemiology of measles—United States, 2001–
sion 96–8. 2003. MMWR Morb Mortal Wkly Rep.
90. Marin M, Meissner HC, Seward JF. Varicella pre- 2004;53(31):713–716.
vention in the United States: a review of successes 107. Scott LA, Stone MS. Viral exanthems. Dermatol
and challenges. Pediatrics. 2008;122(3):e744–51. Online J. 2003;9(3):4.
91. Gnann Jr JW. Varicella-zoster virus: atypical presen- 108. Hussey GD, Klein M. A randomized, controlled trial
tations and unusual complications. J Infect Dis. of vitamin A in children with severe measles. N Engl
2002;186 Suppl 1:S91–8. J Med. 1990;323(3):160–4.
92. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia 109. Balkhy HH, Sabella C, Goldfarb J. Parvovirus: a
JJ, Mahalingam R, Cohrs RJ. Neurologic complica- review. Bull Rheum Dis. 1998;47(3):4–9.
tions of the reactivation of varicella-zoster virus. N 110. Norbeck O, Papadogiannakis N, Petersson K, Hirbod
Engl J Med. 2000;342(9):635–45. T, Broliden K, Tolfvenstam T. Revised clinical pre-
93. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J sentation of parvovirus B19-associated intrauterine
Neurol Neurosurg Psychiatry. 2001;71(2):149–54. fetal death. Clin Infect Dis. 2002;35(9):1032–8.
94. Murakami S, Hato N, Horiuchi J, Honda N, Gyo K, 111. Katta R. Parvovirus B19: a review. Dermatol Clin.
Yanagihara N. Treatment of Ramsay Hunt syndrome 2002;20(2):333–42.
with acyclovir-prednisone: significance of early 112. Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG,
diagnosis and treatment. Ann Neurol. 1997;41(3): Dismukes WE, Edwards JE. Practice guidelines for
353–7. the treatment of candidiasis. Infectious Diseases
95. Uscategui T, Doree C, Chamberlain IJ, Burton MJ. Society of America. Clin Infect Dis. 2000;30(4):
Corticosteroids as adjuvant to antiviral treatment in 662–78.
Ramsay Hunt syndrome (herpes zoster oticus with 113. Pedraz J, Delgado-Jimenez Y, Perez-Gala S, Nam-
facial palsy) in adults. Cochrane Database Syst Cha S, Fernandez-Herrera J, Garcia-Diez A.
Rev.2008;CD006852. Cutaneous expression of systemic candidiasis. Clin
96. Sanjay S, Huang P, Lavanya R. Herpes zoster oph- Exp Dermatol. 2009;34(1):106–10.
thalmicus. Curr Treat Options Neurol. 114. Pagano L, Mele L, Fianchi L, Melillo L, Martino B,
2011;13(1):79–91. D’Antonio D, Tosti ME, Posteraro B, Sanguinetti M,
Trape G, Equitani F, Carotenuto M, Leone G. 128. Smith JW, Utz JP. Progressive disseminated histo-
Chronic disseminated candidiasis in patients with plasmosis. A prospective study of 26 patients. Ann
hematologic malignancies. Clinical features and out- Intern Med. 1972;76(4):557–65.
come of 29 episodes. Haematologica. 2002;87(5): 129. Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW,
535–41. McKinsey DS, Loyd JE, Kauffman CA. Clinical
115. Ratip S, Odabasi Z, Karti S, Cetiner M, Yegen C, practice guidelines for the management of patients
Cerikcioglu N, Bayik M, Korten V. Clinical micro- with histoplasmosis: 2007 update by the Infectious
biological case: chronic disseminated candidiasis Diseases Society of America. Clin Infect Dis.
unresponsive to treatment. Clin Microbiol Infect. 2007;45(7):807–25.
2002;8(7):435–6. 442–34. 130. Rassi Jr A, Rassi A, Marin-Neto JA. Chagas disease.
116. Uzun O, Ascioglu S, Anaissie EJ, Rex JH. Risk fac- Lancet. 2010;375(9723):1388–402.
tors and predictors of outcome in patients with can- 131. Bern C. Antitrypanosomal therapy for chronic
cer and breakthrough candidemia. Clin Infect Dis. Chagas’ disease. N Engl J Med. 2011;364(26):
2001;32(12):1713–7. 2527–34.
117. Sun HY, Singh N. Mucormycosis: its contemporary 132. Lescure FX, Le Loup G, Freilij H, Develoux M,
face and management strategies. Lancet Infect Dis. Paris L, Brutus L, Pialoux G. Chagas disease:
2011;11(4):301–11. changes in knowledge and management. Lancet
118. Reyes HM, Tingle EJ, Fenves AZ, Spiegel J, Burton Infect Dis. 2010;10(8):556–70.
EC. Pulmonary invasive mucormycosis in a patient 133. Rassi Jr A, Rassi A, Little WC. Chagas’ heart dis-
with secondary iron overload following deferoxam- ease. Clin Cardiol. 2000;23(12):883–9.
ine therapy. Proc (Bayl Univ Med Cent). 134. Rassi Jr A, Rassi SG, Rassi A. Sudden death in
2008;21(4):378–81. Chagas’ disease. Arq Bras Cardiol. 2001;76(1):
119. Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, 75–96.
Sarkisova TA, Schaufele RL, Sein M, Sein T, Chiou 135. de Oliveira RB, Troncon LE, Dantas RO,
CC, Chu JH, Kontoyiannis DP, Walsh TJ. Epidemiology Menghelli UG. Gastrointestinal manifestations of
and outcome of zygomycosis: a review of 929 reported Chagas’ disease. Am J Gastroenterol. 1998;93(6):
cases. Clin Infect Dis. 2005;41(5):634–53. 884–9.
120. Van Cutsem J, Boelaert JR. Effects of deferoxamine, 136. Marin-Neto JA, Rassi Jr A, Avezum Jr A, Mattos
feroxamine and iron on experimental mucormycosis AC, Rassi A, Morillo CA, Sosa-Estani S, Yusuf S.
(zygomycosis). Kidney Int. 1989;36(6):1061–8. The BENEFIT trial: testing the hypothesis that try-
121. Almyroudis NG, Sutton DA, Linden P, Rinaldi MG, panocidal therapy is beneficial for patients with
Fung J, Kusne S. Zygomycosis in solid organ trans- chronic Chagas heart disease. Mem Inst Oswaldo
plant recipients in a tertiary transplant center and Cruz. 2009;104 Suppl 1:319–24.
review of the literature. Am J Transplant. 137. David CV, Craft N. Cutaneous and mucocutaneous
2006;6(10):2365–74. leishmaniasis. Dermatol Ther. 2009;22(6):491–502.
122. Liang KP, Tleyjeh IM, Wilson WR, Roberts GD, 138. Murray HW, Berman JD, Davies CR, Saravia NG.
Temesgen Z. Rhino-orbitocerebral mucormycosis Advances in leishmaniasis. Lancet. 2005;366(9496):
caused by Apophysomyces elegans. J Clin Microbiol. 1561–77.
2006;44(3):892–8. 139. Solbach W, Laskay T. The host response to
123. Spellberg B, Walsh TJ, Kontoyiannis DP, Edwards Jr Leishmania infection. Adv Immunol. 2000;74:
J, Ibrahim AS. Recent advances in the management 275–317.
of mucormycosis: from bench to bedside. Clin Infect 140. Weigle K, Saravia NG. Natural history, clinical evo-
Dis. 2009;48(12):1743–51. lution, and the host-parasite interaction in New
124. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying World cutaneous Leishmaniasis. Clin Dermatol.
amphotericin B-based frontline therapy significantly 1996;14(5):433–50.
increases mortality among patients with hematologic 141. Ahluwalia S, Lawn SD, Kanagalingam J, Grant
malignancy who have zygomycosis. Clin Infect Dis. H, Lockwood DN. Mucocutaneous leishmaniasis:
2008;47(4):503–9. an imported infection among travellers to central
125. Goodwin Jr RA, Shapiro JL, Thurman GH, Thurman and South America. BMJ. 2004;329(7470):
SS, Des Prez RM. Disseminated histoplasmosis: 842–4.
clinical and pathologic correlations. Medicine 142. Scope A, Trau H, Bakon M, Yarom N, Nasereddin A,
(Baltimore). 1980;59(1):1–33. Schwartz E. Imported mucosal leishmaniasis in a
126. Kauffman CA. Histoplasmosis: a clinical and labora- traveler. Clin Infect Dis. 2003;37(6):e83–7.
tory update. Clin Microbiol Rev. 2007;20(1): 115–32. 143. Amato VS, Tuon FF, Siqueira AM, Nicodemo AC,
127. Reddy P, Gorelick DF, Brasher CA, Larsh H. Neto VA. Treatment of mucosal leishmaniasis in
Progressive disseminated histoplasmosis as seen in Latin America: systematic review. Am J Trop Med
adults. Am J Med. 1970;48(5):629–36. Hyg. 2007;77(2):266–74.
Drug Eruptions
3
Rita V. Patel and Gary Goldenberg
(AGEP). Due to the evolving definition, the true

3.1 Introduction
incidence of SCARs is difficult to ascertain.
However, in one study conducted in Singapore in
Cutaneous reactions are the most frequently 2002, analysis of an inpatient network-based
occurring adverse reactions to drugs. These reac- electronic drug allergy notification system
tions can range from mild (two-thirds of cases) to showed that in over 90,000 admissions, 210 drug
life-threatening (one-third of cases) in the hospital allergy cases were verified by an allergist.
setting [1, 2]. Distinguishing a mild versus a life- Cutaneous manifestations were the most com-
threatening reaction is challenging, yet critical, in mon clinical presentation (96%) with SCARs
the management of drug allergies. Cutaneous occurring in 5% of patients. The most common
manifestations are frequently the earliest signs of causative drugs were antimicrobials and antiepi-
a systemic drug allergy and can provide informa- leptic drugs [8].
tion on the severity and prognosis of an allergic
reaction [3]. Numerous risk factors predispose
patients to severe cutaneous drug reactions, 3.2 Stevens–Johnson Syndrome
including immunosuppression (especially infec- and Toxic Epidermal Necrolysis
tion with human immunodeficiency virus [4] or
mononucleosis) [5], female gender [6], number of SJS and TEN are severe reactions commonly
drugs being taken, and elderly age [7]. triggered by medications. They are chiefly distin-
Cutaneous reactions are considered severe guished by the severity and percentage of body
when they result in serious skin compromise or surface involvement. Blistering and skin loss
involve multiple organs. Severe cutaneous between 1 and 10% of the body surface area
adverse reactions (SCARs) include Stevens– (BSA) is known as SJS, whereas skin detachment
Johnson syndrome (SJS), toxic epidermal necrol- greater than 30% is known as TEN (Table 3.1).
ysis (TEN), and drug rash with eosinophilia and SJS/TEN overlap syndrome describes patients
systemic symptoms (DRESS). Recently, the with involvement of greater than 10% but less
SCARs definition was reclassified to include than 30% BSA [9]. SJS was first described in the
acute generalized exanthematous pustulosis 1920s as an acute mucocutaneous syndrome
characterized by severe purulent conjunctivitis,
severe stomatitis with extensive mucosal necro-
R.V. Patel, M.D. • G. Goldenberg, M.D. (*) sis, and purpuric macules and was thought to
Department of Dermatolgoy, Mount Sinai
have an infectious etiology at the time. First
School of Medicine, 5 East 98th Street, Box 1048,
New York, NY 10029, USA reported in the 1950s,TEN was believed to be
e-mail: garygoldenberg@gmail.com triggered by drugs as reports accumulated.

44 R.V. Patel and G. Goldenberg
Table 3.1 Clinical features distinguishing SJS, SJS/TEN overlap, and TEN [9]
Clinical entity SJS SJS/TEN overlap TEN
Primary Lesions Dusky red lesions Dusky red lesions Poorly delineated erythematous
Flat atypical targets Flat atypical targets plaques with desquamation
Dusky red lesions
Flat atypical targets
Distribution Isolated lesions Isolated lesions Isolated lesions (rare)
Confluence (+) of face Confluence (++) of face Confluence (+++) of face and trunk
and trunk and trunk
Mucosal Yes Yes Yes
Involvement
Systemic Usually Always Always
Symptoms
% BSA <10 10–30 >30
Detachment
In absolute numbers, SJS and TEN are rare

diseases with the incidence of severe exfoliative
skin reactions estimated at 1–7 cases per million
person-years for SJS and 0.4–1.5 cases per mil-
lion person-years for TEN [10–13]. In children,
TEN affects both genders equally. In adults,
women are more frequently affected by a ratio of
3:2. Additionally, the elderly seem to be at
increased risk of developing TEN [14]. Patients
with HIV infection have been reported to be at
three times increased risk for SJS/TEN. The rea-
sons for this susceptibility are not fully under-
stood, although exposure to multiple medications
(including sulfonamide antibiotics), “slow acety- Fig. 3.1 Toxic Epidermal Necrolysis (Courtesy of Jason
Emer, MD). Widespread patchy erythema with confluence
lation” status, immune dysregulation, and pres- and darkening at sites of epidermal detachment (flaccid
ence of concomitant infections may contribute. blisters) of the posterior chest
There is support for genetic susceptibility as well,
for instance, an increased incidence of HLA-B12 thema multiforme (EM), a condition with similar
has been seen in pathogenesis studies of TEN. presentation that is commonly associated with
Certain drugs show a genetic predisposition to infections, particularly herpes simplex virus and
cause SJS or TEN in association with certain mycoplasma pneumonia [16, 17]. EM, the least
alleles. Allopurinol and HLA-B*580 in the Han severe of the disorders, is characterized by targe-
Chinese population as well as HLA-B*150 and toid, edematous papules, and/or plaques. In EM,
carbamazepine have been reported in the same less than 10% of cases are drug induced and
population [15]. In patients with HIV, the annual patients typically present with a prodrome of flu-
incidence of TEN is 1,000-fold higher than in the like symptoms prior to the skin eruption which
general population, with approximately 1 case classically affects the hands, feet, and limbs.
per 1,000 patient years. The estimated mortality Characteristic EM lesions can be erythematous
from SJS is 10%, SJS/TEN overlap 30%, and macules or wheals and are usually 1–2 cm in
TEN is almost 50%. diameter (Fig. 3.1). They are usually darker in the
There are differing opinions about the degree center and paler peripherally; sometimes larger
to which SJS and TEN overlap with severe ery- lesions exhibit concentric rings, or the so-called
3 Drug Eruptions 45
Table 3.2 Commonly associated culprit drugs

SJS/TEN Allopurinol, sulfon-
amides >> penicillins > cepha-
losporins, carbamazepine, dilantin,
lamotrigine, and phenobarbital,
piroxicam, acetaminophen
DRESS Aromatic anticonvulsants, lamotrig-
ine, valproic acid, NSAIDs,
allopurinol, dapsone, sulfonamides,
minocycline, abacavir, nevirapine
AGEP Penicillins, macrolides, quinolones,
hydroxychloroquine, terbinafine, and
diltiazem
Serum Sickness Antithymocyte globulin, infliximab,
and rituximab
target lesions. There is often some systemic dis-

turbance including fever, malaise, and organ dys-
function. It has been hypothesized that SJS and
TEN are varying degrees of the same process,
different in the extent of involvement. However,
unifying this concept has not been universally
accepted as some cite subtle histologic differ-
ences between EM and SJS or TEN [1, 18].
The pathogenesis of SJS and TEN is not com- Fig. 3.2 Stevens-Johnson syndrome (Courtesy of Jason
Emer, MD). Large flaccid blister on the back of a patient
pletely understood, but the etiology is hypothe- with epidermal detachment
sized to be immune mediated. Various groups
contend that the ligand FasL and the cognate The initial prodromic symptoms can be
receptor, Fas, permit signaling that triggers the nonspecific; however, symptoms can include
apoptosis of keratinocytes [19]. Gene expression fever, stinging eyes, and discomfort when swal-
analysis of blister fluid from patients with SJS lowing. TEN often displays temperatures that
and TEN has also recently identified secretory are higher than SJS, often exceeding 39°C.
granulysin protein, a key molecule responsible Within days, early sites of cutaneous involve-
for the induction of keratinocyte death [20]. ment typically occur on the presternal trunk,
The majority of SJS and TEN cases are caused face, and palms and soles. Skin lesions manifest
by drug exposure (Table 3.2). Anti-gout agents as generalized macules with purpuric centers
(allopurinol), antibiotics (sulfonamides > > peni- which progress to large confluent blisters with
cillins > cephalosporins), antipsychotics and anti- subsequent epidermal detachment (Figs. 3.1 and
eplileptics (carbamazepine, dilantin, lamotrigine, 3.2). A positive Nikolsky sign may be elicited in
and phenobarbital), and analgesics or NSAIDs which light lateral pressure applied with the
(piroxicam) [21–24]. A survey of TEN in chil- index finger results in the detachment of the full-
dren identified similar drugs to those in adults, thickness epidermis. Erythema and erosions of
additionally implicating acetaminophen [25]. the buccal, genital, or ocular mucosa occur in
However, pediatric infections with Mycoplasma greater than 90% of patients, and occasionally
pneumonia and herpes virus, rather than drug the respiratory or gastrointestinal tracts are
ingestion, represent a greater proportion of pedi- affected at the same time. In the following 3–5
atric cases of SJS [26]. days, separation of the epidermis advances lead-
SJS/TEN typically presents 1–3 weeks after ing to large denuded areas associated with
the administration of the responsible drug. extreme pain, bleeding, massive fluid loss, hypo-
Clinically, both SJS and TEN present similarly. thermia, and infection [27–29].
Table 3.3 SCORETEN assessment of the severity of TEN [32]

SCORETEN
SCORETEN parameter Individual score (sum of individual scores) Predicted mortality (%)
Age > 40 years Yes = 1, No = 0 0–1 3.2
Malignancy Yes = 1, No = 0 2 12.1
Tachycardia (>120/min) Yes = 1, No = 0 3 35.8
Initial surface of epidermal Yes = 1, No = 0 4 58.3
detachment >10%
Serum urea >10 mmol/l Yes = 1, No = 0 >5 90
Serum glucose >14 mmol/l Yes = 1, No = 0
Bicarbonate >20 mmol/l Yes = 1, No = 0
SJS, TEN, and SJS/TEN overlap syndrome severity-of-illness score for TEN (SCORTEN
are clinical diagnoses supported by compatible [Table 3.3]) [32]. Experts advocate admission to
histologic findings. Currently, there are no uni- an intensive care unit, when the score is 2. Once
versally accepted diagnostic criteria and histo- the SCORTEN reaches 3 the predicted mortality
logic findings are neither specific nor diagnostic. is 35% [1].
Despite these limitations, the diagnosis of SJS or Garcia-Doval and colleagues demonstrated
TEN would be appropriate in a patient with a his- better prognosis with early withdrawal of the
tory of antecedent drug exposure or illness, a pro- causative agent, and exposure to agents with long
drome of acute-onset febrile illness with malaise, half-lives carried higher mortality [33]. Oplatek
diffuse erythema which progresses to vesicles or et al. [34] showed that early referral to a special-
bullae, or necrosis with sloughing of the epider- ized ICU, along with supportive care, correlated
mis. Rapid supportive evidence of SJS or TEN with increased survival rates.
should be obtained by submitting a frozen sec- Patients with SJS or TEN are at high risk of
tion of the already peeling layer of skin, which infection which can enter through the compro-
can help the clinician institute treatment as soon mised skin barrier. Sepsis remains a prominent
as possible. The histology of skin lesions com- cause of mortality; however, prophylactic sys-
monly reveals a subepidermal bullae with temic antibiotics are not employed by the major-
full-thickness necrosis of the epidermis. ity of burn units. Topical antibiotics are commonly
Histopathologic analysis of the skin biopsy is used such as silver nitrate and newer silver-
critical in ruling out other diagnoses such as auto- imbued nanocrystalline gauze materials [35].
immune blistering diseases, bullous fixed drug Supportive care is comparable to that in those
eruptions, AGEP, and, although uncommon in with severe burns, focusing on correcting hypov-
adults, staphylococcal scalded skin syndrome olemia, electrolyte imbalance, renal insufficiency,
[30]. Extent of skin involvement is a major prog- and sepsis. Daily wound care and nutritional/
nostic factor and when evaluating BSA coverage, hydrational support most commonly take place in
only necrotic skin which is already detached an intensive care setting. A dermatologic consult
should be included in the evaluation [31]. Various is warranted for cutaneous care. For the face and
appropriate cultures should be performed on sera, isotonic sterile sodium chloride solution
blood, wounds, and mucosal lesions to evaluate should be used to wash sites, an antibiotic oint-
for the presence of staphylococcal species, in ment should be applied to orifices, and silicone
particular. In children, serologies for Mycoplasma dressings are used to cover denuded areas. An
pneumoniae infection should also be sought out. ocular examination by an opthamologist should
As soon as the diagnosis of SJS or TEN has be carried out regularly as well [15].
been established, the severity, prognosis, and The use of systemic corticosteroids in SJS/TEN
management plan can be determined via the remainscontroversial.Theoretically,glucocorticoids
3 Drug Eruptions 47
increase the risk of sepsis, increase protein catabo- ondary to corneal inflammation also occurs in
lism, and decrease the rate of epithelialization. those without initial infection of the eye and is
Studies have found that administration of systemic considered to be the most severe long-term com-
glucocorticoids was associated with increased mor- plication in SJS/TEN survivors [47, 48]. Long-
bidity and mortality, particularly if patients had term mucosal complications including xerostomia
TEN and received glucocorticoids for prolonged or keratoconjunctivitis have also been reported in
periods of time [36]. As a consequence of the dis- small clinical studies [49].
covery of the anti-Fas potential of pooled human Hematologic abnormalities, particularly ane-
intravenous immunoglobulins (IVIG) in vitro, mia and lymphopenia, are common in TEN.
IVIG (1 g/kg/day for 3 consecutive days) has been Eosinophilia is unusual despite the strong associa-
tested for the treatment of TEN. To date the major- tion of TEN with drug ingestion. Neutropenia is
ity of studies confirm the mortality benefit, excel- noted in approximately one-third of patients and
lent tolerability, and low toxic potential of IVIG. correlates with poor prognosis. Glucocorticoids
However, caution should be exercised in those with can cause demarginalization and mobilization of
renal or cardiac insufficiency and thromboembolic neutrophils in the circulation, giving a falsely ele-
risk. Use of IVIG is contraindicated in those with vated white blood count. This must be considered
IgA antibodies or IgA deficiency [37–41]. In one in patients who received these agents prior to test-
phase II trial, although not statistically significant, ing, as this may obscure neutropenia [13, 50].
cyclosporine was administered orally (3 mg/kg/day The time course of SJS/TEN from prodrome
for 10days) and resulted in no deaths, whereas the to hospital discharge in the absence of significant
prognostic score predicted 2.75 deaths amongst the complications is typically 2–4 weeks.
29 patients with SJS, SJS/TEN, or TEN included in Reepithelialization may begin after several days
the trial [42]. Other anti-inflammatory therapies, and typically requires 2–3 weeks.
like tumor necrosis factor-alpha (TNF-a) antago-
nists, have been published in case reports; however
the published data is insufficient to draw a conclu- 3.3 Drug Rash with Eosinophilia
sion on the therapeutic potential of TNF-a antago- and Systemic Symptoms
nists in TEN [43].
Rechallenge with culprit drugs is not recom- DRESS is a severe and potentially fatal adverse
mended in the patient with SJS/TEN; however, drug reaction characterized by fever, skin erup-
the current focus of allergy testing lies more on tion, hematologic abnormalities (prominent
ex vivo/in vitro tests such as the lymphocyte eosinophilia or atypical lymphoctytes), and
transformation test (LTT) which measures the multi-organ involvement which may affect the
proliferation of T cells to a drug in vitro by gen- liver, kidneys, heart, and/or lungs [51, 52]. Also
erating T-lymphocyte cell lines and clones. known as the drug-induced hypersensitivity syn-
Pichler and Tilch report a sensitivity of 60–70% drome, DRESS has other noteworthy features
for those allergic to beta-lactam antibiotics in the including a delayed onset, usually 2–6 weeks
classic exanthematic drug rash [44]. However, after initiation of drug therapy, and the possible
the sensitivity of LTT is still very low in SJS/ persistence or aggravation of symptoms despite
TEN. To improve the sensitivity in SJS and TEN, the discontinuation of the culprit drug [17].
LTT should be done within 1 week after onset of The estimated incidence of this syndrome
the disease to get the highest sensitivity [45]. ranges from 1 in 1,000 to 1 in 10,000 drug expo-
Studies have shown TEN to commonly pro- sures [53]. The incidence may be higher in African
duce sequelae including hypo- and hyperpigmen- Americans and patients from the Caribbean.
tation (63%), nail dystrophies (38%), and ocular DRESS is considered to be a Gell and Coombs
complications [46]. Chronic ophthalmic compli- type IV reaction (Table 3.4). Type IV drug reac-
cations occur more frequently in patients with tions involve the activation of T cells and in some
initial ocular involvement, but loss of vision sec- cases other cell types (macrophages, eosinophils,
Table 3.4 Gell and Coombs classification of immunologic reactions [54]

Type Description Mechanism Clinical features
I (Immediate IgE-mediated Antigen exposure causes IgE-mediated Anaphylaxis
reaction, immediate-type activation of mast cells and basophils, Angioedema
within 1 h) hypersensitivity with release of vasoactive substances such Bronchospasm
as histamine, prostaglandins, and leukotrienes Urticaria
II Antibody-dependent Antigen or hapten that is intimately associated Hemolytic anemia
cytotoxicity with a cell binds to antibody, leading to cell or Thrombocytopenia
tissue injury Neutropenia
III Immune complex Damage is caused by formation and deposition Serum sickness
disease of antigen–antibody complexes in vessels/tissue.
Deposition of immune complexes causes
complement activation and/or recruitment of
neutrophils by interaction of immune complexes
with Fc IgG receptors
IV Cell-mediated Antigen exposure activates T cells, which SJS/TEN
or delayed then mediate tissue injury. Depending upon the AGEP
hypersensitivity type of T cell activation and the type of DRESS
T cell activation and the other effector Contact dermatitis
cells recruited, different subtypes can be Some morbilliform
differentiated (i.e., Types IVa–IVd) reactions
or neutrophils). Clinically, those reactions involving Herpes viruses have been shown to reactivate in a
T cells have prominent cutaneous findings, because certain order with the cascade of reactivation ini-
the skin is a repository for T cells. Many cutaneous tiated by Epstein–Barr virus (EBV), human her-
T cells are primed memory-effector cells, which pes virus-6 (HHV-6), HHV-7, and then
react rapidly if immunogenic agents penetrate the cytomegalovirus (CMV) [58]. In one study,
skin barrier or diffuse into the skin from the circu- HHV-6 was detected via PCR in six of seven
lation [54, 55]. patients with DRESS [58]. It has been hypothe-
In Type IV reactions, onset of clinical presen- sized that certain drugs have intrinsic properties
tation is usually delayed by at least 48–72 h and to induce an immunosuppression that reactivates
sometimes by days to weeks following exposure herpes viruses. Subsequent antiviral T cell activa-
to culprit drug. Upon rechallenge with the sus- tion leads to a cross-reaction with drug antigens,
pect drug, symptoms can appear within 24 h. and, as a consequence, DRESS develops.
Onset of symptoms depends partly upon the Although this could suggest a key role for the
number of T cells activated by the drug. These viral infection in the development of an immuno-
responses are polyclonal in nature, and symptoms logic reaction, it could just represent nonspecific
appear rapidly if the drug stimulates a large num- activation of a ubiquitous virus [59].
ber of different T cell clones. In contrast, a drug Clinically, this hypersensitivity syndrome
that activates just a few clones may not cause develops 2–6 weeks after the culprit drug is initi-
clinical symptoms until these T cells have prolif- ated, which is of later onset compared to most
erated for a longer period of time, such as weeks. other immunologically mediated skin reactions.
In DRESS, patients may suddenly develop signs Fever and a morbilliform eruption are the most
and symptoms of a fulminant immune reaction. common symptoms seen in 85 and 75% of cases,
This reaction results from uncontrolled expan- respectively. The face, upper trunk, and extremi-
sion of oligoclonal T cells that have been mas- ties are usual sites of involvement (Fig. 3.3).
sively stimulated by the culprit drug, reminiscent Vesicles, tense bullae, pustules, erythroderma,
of superantigen-like stimulation [56]. and purpuric lesions can also be seen. In one
Detection of herpes viruses has been recently study by Chen et al. [60] involving DRESS sub-
proposed as a diagnostic marker of DRESS [57]. jects close to half of all patients were reported to
3 Drug Eruptions 49
Table 3.5 Inclusion criteria for potential cases of DRESS

published by RegiSCAR [64]
Hospitalization
Reaction suspected to be drug related
Acute rash
Fever >38 C
Enlarged lymph nodes at a minimum of two sites
Involvement of at least one internal organ
Blood count abnormalities
Lymphocytes above or below normal limits
Eosinophils above the laboratory limits
Platelets below laboratory limits
*Three of these four criteria are required for diagnosis
roic acid, allopurinol, NSAIDs, and minocycline

have also been associated with this clinical entity
(Table 3.2) [36]. Certain medications may cause
inflammation affecting a specific organ. For
example, anticonvulsant-induced DRESS fre-
quently involves hepatitis, allopurinol can cause
nephritis, and abacavir can cause pneumonitis
[62]. Some DRESS reactions occur more fre-
Fig. 3.3 (Courtesy of Jason Emer, MD). Drug rash with
quently in those with certain HLA types, a phe-
eosinophilia and systemic symptoms. Diffuse erythema-
tous patches of the chest nomenon also seen in SJS/TEN [63]. For instance,
DRESS secondary to allopurinol is associated
with HLA-B*5801.
have lesions involving at least one mucosal area, DRESS can be difficult to distinguish from
always affecting the oral mucosa. The liver is the serum sickness or vasculitis on clinical grounds.
most common visceral organ involved with a ful- The diverse presentations and varied organ
minant hepatitis being the major cause of death in involvement highlight the need for a set of diag-
this syndrome. Myocarditis, interstitial pneu- nostic criteria that are easily applicable in the
monitis, interstitial nephritis, thyroiditis, and clinical setting. The RegiSCAR group (Table 3.5)
infiltration of the brain may be observed. has suggested a series of criteria in which hospi-
Cutaneous and visceral symptoms can last for talized patients with a drug rash must have at
weeks even after drug withdrawal. For this rea- least three of four systemic features (fever,
son, liver function tests should be conducted peri- lymphadenopathy, internal organ involvement,
odically after drug withdrawal. On skin biopsy, hematological abnormalities). To qualify for a
specimens showed various degrees of basal vacu- diagnosis of DRESS, abnormalities must include
olization, dyskeratosis, lymphocyte exocytosis, either eosinophilia or atypical lymphocytes as
dermal edema, and superficial perivascular well as changes reflective of hepatic or renal dys-
inflammation, resulting in a pathologic diagnosis function [64].
of EM [60]. Because thyroiditis has been reported Systemic steroid therapy is the first line for
to develop in a small subset of patients, thyroid- DRESS, starting with a moderate dose followed
stimulating hormone levels should also be mea- by a gradual taper. Topical steroids can be uti-
sured and repeated after 2–3 months [61]. lized for skin manifestations. It is not uncommon
Anticonvulsants (phenytoin, phenobarbital, for the reaction to flare up again with abrupt dis-
carbamazepine) are the most common causes of continuation of steroid therapy [65]. Cross-
DRESS. Other drugs such as lamotrigine, valp- sensitivity among phenytoin, cabamazepine, and
phenobarbital has been reported in 40–80% of

patients with anticonvulsant hypersensitivity syn-
drome. Therefore, afflicted patients should not be
treated with any aromatic anticonvulsants and
should inform family members that they too may
be at a higher risk for severe adverse reactions to
these medications, since susceptibility is believed
to be partially genetic [66].
3.4 Acute Generalized

Exanthematous Pustulosis
AGEP is characterized by fever above 38°C and a

cutaneous eruption with nonfollicular sterile pus-
tules on an edematous erythematous background.
The interval between drug administration and
onset of eruption can vary from 24 h to 3 weeks. Fig. 3.4 (Courtesy of Jason Emer, MD). Acute general-
ized erythematous pustulosis Edematous, erythematous
A long interval probably indicates primary sensi-
plaques of the face and neck dotted with pustules
tization and the shorter interval may be related to
an unintentional reexposure [67]. Neutrophil
counts are elevated and there is usually no vis- psoriasis, perhaps more frequently than expected
ceral involvement. Spontaneous healing typically by chance. Nevertheless, skin pathology can help
occurs in 10–15 days. Similarly to TEN/SJS and to differentiate the two pustular eruptions. While
DRESS, AGEP is considered to be a type IV drug both entities are characterized by subcorneal
reaction involving the activation of T cells spongiform pustules, AGEP is characterized by
(Table 3.4). edema in the superficial dermis, vasculitis, exocy-
The eruption begins on the face or intertrigi- tosis of eosinophils, and single-cell necrosis of
nous area and disseminates within a few hours. keratinocytes, while psoriasiform hyperplasia is
Subcorneal aseptic pustules are characteristic and suggestive of PP. The acute onset of AGEP in
easily recognized. Edema of the face also may association with a recent intake of pharmaceuti-
occur along with targetoid skin lesions, purpura, cals is the cornerstone of its identification [69].
and vesicles (Fig. 3.4). Mild, non-erosive lesions Antibiotics are thought to play a role in 80% of
occur in the mouth and tongue in about 20% of AGEP cases with penicillins and macrolides being
cases [68]. Occasionally the pustules coalesce to the most common offenders (Table 3.2). A large,
produce extensive superficial detachment and a multinational case–control study also found qui-
positive Nikolsky sign which may be confused nolones, hydroxychloroquine, terbinafine, and
with TEN [69]. The syndrome is generally self- diltiazem to be highly associated with AGEP.
limited, resolving spontaneously in approxi- Additional drugs with weaker associations include
mately 2 weeks, although fatalities are reported glucocorticoids, NSAIDs, and antiepileptics [71].
in about 5% of cases [70]. Infection is a less common cause of AGEP.
The clinical presentation of AGEP is very simi- However, reports of viruses such as enterovirus,
lar to that of acute pustular psoriasis (PP). However, parvovirus B19, adenovirus, EBV, CMV, and hep-
in PP, the initial stage is less acute, the fever is atitis B have been implicated in causing AGEP.
lower, and the duration of eruption is usually lon- AGEP usually spontaneously regresses upon
ger than 3 weeks. A history of plaque psoriasis on removal of the culprit drug. Topical steroids, anti-
the palms and soles is frequent in those with dis- pyretics, and emollients are usually required to
seminated PP. AGEP also occurs in those with assist with the healing process [68].
3 Drug Eruptions 51
3.5 Serum Sickness and Serum

Sickness-Like Reactions
While not an official part of the SCAR definition,

serum sickness and serum sickness-like reactions
(SSLRs) are integral members of the family of
emergent drug eruptions as afflicted patients can
appear severely ill during this self-limited disease.
In 1905, von Pirquet and Schick provided the first
detailed description of serum sickness in humans.
Eight to twelve days after subcutaneous injections
of horse serum was injected in children who were
being treated with serum containing diphtheria Fig. 3.5 Urticarial reaction. Small erythematous papules
antitoxin, a clinical syndrome characterized by
fever, lymphadenopathy, cutaneous eruptions, and
arthralgias was reported to occur. Proteinuria weeks after drug initiation [77]. Other findings
without evidence of glomerulonepthritis was also such as lymphadenopathy and eosinophilia may
observed. A delay was noted between the admin- also be present; however, immune complexes,
istration of the horse serum and the development hypocomplementemia, vasculitis, and renal
of symptoms. The delay was shortened if the involvement are absent [78]. Drugs, particularly
serum was re-administered [72]. antibiotics, are the leading cause of SSLRs.
Serum sickness is the prototypic example of Penicillin, amoxicillin, cefaclor, and trimethop-
Gell and Coombs type III or immune complex- rim-sulfamethoxazole are most commonly impli-
mediated hypersensitivity reaction (Table 3.4). cated, although many drugs have been associated
The reaction requires the presence of antibodies with these reactions. In children, SSLRs are about
directed against an antigen which subsequently 15-fold more likely with cefaclor than with other
form immune complexes. These complexes are cephalosporins or amoxicillin [79]. In one study
normally cleared by the mononuclear phagocyte of children under the age of five, cefaclor-associ-
system; however, if this system is not functioning ated SSLRs were reported to occur in 0.2% with
well or becomes saturated, excess immune com- about 50% of these patients requiring hospital-
plexes deposit in tissues or directly develop ization [80]. SSLRs also occur following infec-
within involved tissues. Immune complexes react tions (especially streptococcal and some viral
with the Fc IgG receptors on neutrophils, mast infections) and a variety of vaccines [79].
cells, and phagocytes and trigger an inflammatory Historically, serum sickness has been described
response releasing cytokines, histamine, and following the administration of antitoxin or anti-
other inflammatory mediators (activating the venom. More recently, serum sickness has been
complement cascade) [73, 74]. Resolution of ill- reported in patients receiving biologic immuno-
ness occurs when the antigen is completely therapy with agents such as antithymocyte globu-
cleared from the serum. Recurrence can develop lin, infliximab, and rituximab (Table 3.2) [81–85].
more rapidly if a previously immunized patient Risk factors for serum sickness include increas-
becomes reexposed to the culprit antigen. The ing dose and duration, nature of the heterologous
subsequent amnestic IgG response to a recall protein, and age less than 16 years old.
antigen initiates a more acute, severe response The cutaneous manifestations of serum sick-
within 12–36 h [75, 76]. ness are variable. Almost all develop a pruritic
In contrast, SSLRs are defined by the presence rash, which is often the earliest clinical feature
of fever, urticaria, and arthralgias occurring 1 to 3 (Fig. 3.5). The rash often starts in the region
around the injection site if a drug was adminis- diagnosis in patients of any age includes viral
tered locally by intramuscular or subcutaneous exanthems, urticarial vasculitis, acute rheumatic
injection. Skin changes may be prominent at the fever, and disseminated gonococcemia or
lateral aspect of the feet and the hands, at the meningococcemia.
junction of the sole and side of the foot, or at the Randomized controlled trial data concerning
border between the palm and dorsal skin of the the treatment of serum sickness or SSLRs is lack-
fingers or hands. Mucus membranes are spared. ing; however, one published retrospective chart
Virtually all patients develop fever which usually review of the management of children with
peaks 38.5°C, and arthralgias appear in approxi- SSLRs caused by cefaclor showed that discon-
mately two-thirds of patients with metacarpopha- tinuation of the culprit drug in combination with
langeal joints, knees, wrists, and ankles most antihistamines and glucocorticoids provides the
commonly involved [73, 74]. most symptomatic relief [87].
Neutropenia, mild thrombocytopenia, and
eosinophlia can be present, and mild proteinuria
occurs in about 50% of patients. During severe 3.6 Conclusion
episodes, complement measurements including
C3, C4, and total hemolytic complement are All patients who experience a drug eruption
depressed reflecting complement consumption. should be instructed to avoid the culprit drug and
Histologically, mild perivascular infiltrates con- any other closely related drugs with suspicion of
sisting of lymphocytes and histiocytes in the cross-reactivity. In the future as the laboratory
absence of vessel necrosis are observed in skin technology for drug allergy testing develops,
biopsies of those who develop serum sickness there may be an additional means to confirm the
from equine antithymocyte globulin [86]. clinical diagnosis of a drug eruption. Considering
Diagnosis of serum sickness and SSLRs is the diagnostic similarities and overlapping mor-
made clinically after exposure to a potential phological features of the various forms of drug
offending agent. Complete blood count with dif- eruptions, biopsies should always be used to help
ferential, urinalysis, serum chemistries, and com- make a definitive diagnosis (Table 3.6).
plement studies often aid in diagnosis. Skin Additionally, physicians should always err on the
biopsies are rarely used in confirmation of diag- side of caution when dealing with any subject
nosis as findings are variable. The differential with a possible drug eruption.
Table 3.6 Clinical features of drug eruptions

SJS/TEN DRESS AGEP Serum sickness
Symptoms Fever, cough, Fever, cutaneous Fever, cutaneous Fever, lymphadenopathy,
malaise, macular eruption, multi-organ eruption, facial edema arthralgias, cutaneous
exanthema, failure eruptions
mucosal
involvement
Laboratory Anemia, Atypical lymphocytosis Leukocytosis Neutropenia, mild
Abnormalities lymphopenia, (CD8+) w/prominent with elevated thrombocytopenia,
neutropenia eosinophilia; lab neutrophil count eosinophilia,
abnormalities dependent and esoinophilia complement depletion,
on the organ involved proteinuria
Onset 2–8 weeks 2–8 weeks 24 h to 3 weeks 1–2 weeks
of Symptoms
3 Drug Eruptions 53
18. Lee A. Drug induced skin reactions. London:

References Pharmaceutical Press; 2006.
19. Murata J, Abe R, Shimizu H. Increased soluble Fas
1. Ardern-Jones MR, Friedmann PS. Skin manifesta- ligand levels in patients with Stevens-Johnson syn-
tions of drug allergy. Br J Clin Pharmacol. 2011;71(5): drome and toxic epidermal necrolysis preceding skin
672–83. detachment. J Allergy Clin Immunol.
2. Bigby M, et al. Drug-induced cutaneous reactions. 2008;122(5):992–1000.
A report from the Boston Collaborative Drug 20. Chung WH, et al. Granulysin is a key mediator for
Surveillance Program on 15,438 consecutive inpa- disseminated keratinocyte death in Stevens-Johnson
tients, 1975 to 1982. JAMA. 1986;256(24):3358–63. syndrome and toxic epidermal necrolysis. Nat Med.
3. Lubart R, et al. A novel explanation for the healing 2008;14(12):1343–50.
effect of the Er:YAG laser during skin rejuvenation. 21. Schopf E, et al. Toxic epidermal necrolysis and Stevens-
J Cosmet Laser Ther. 2011;13(1):33–4. Johnson syndrome. An epidemiologic study from West
4. Battegay M, et al. Rash with amoxycillin-clavulanate Germany. Arch Dermatol. 1991;127(6): 839–42.
therapy in HIV-infected patients. Lancet. 22. Mockenhaupt M, et al. The risk of Stevens-Johnson
1989;2(8671): 1100. syndrome and toxic epidermal necrolysis associated
5. Patel BM. Skin rash with infectious mononucleosis with nonsteroidal antiinflammatory drugs: a multina-
and ampicillin. Pediatrics. 1967;40(5):910–1. tional perspective. J Rheumatol. 2003;30(10):
6. Naldi L, et al. Cutaneous reactions to drugs. An analy- 2234–40.
sis of spontaneous reports in four Italian regions. Br J 23. Devi K, et al. Carbamazepine–the commonest cause
Clin Pharmacol. 1999;48(6):839–46. of toxic epidermal necrolysis and Stevens-Johnson
7. Ibia EO, Schwartz RH, Wiedermann BL. Antibiotic syndrome: a study of 7 years. Indian J Dermatol
rashes in children: a survey in a private practice set- Venereol Leprol. 2005;71(5):325–8.
ting. Arch Dermatol. 2000;136(7):849–54. 24. Mockenhaupt M, et al. Stevens-Johnson syndrome
8. Thong BY, et al. Drug allergy in a general hospital: and toxic epidermal necrolysis: assessment of medi-
Results of a novel prospective inpatient reporting sys- cation risks with emphasis on recently marketed
tem. Ann Allergy Asthma Immunol. 2003;90(3): drugs. The EuroSCAR-study. J Invest Dermatol.
342–7. 2008;128(1):35–44.
9. Bastuji-Garin S, et al. Clinical classification of cases 25. Levi N, et al. Medications as risk factors of Stevens-
of toxic epidermal necrolysis, Stevens-Johnson syn- Johnson syndrome and toxic epidermal necrolysis in
drome, and erythema multiforme. Arch Dermatol. children: a pooled analysis. Pediatrics. 2009;123(2):
1993;129(1):92–6. e297–304.
10. Chan HL, et al. The incidence of erythema multiforme, 26. Wetter DA, Camilleri MJ. Clinical, etiologic, and his-
Stevens-Johnson syndrome, and toxic epidermal topathologic features of Stevens-Johnson syndrome
necrolysis. A population-based study with particular during an 8-year period at Mayo Clinic. Mayo Clin
reference to reactions caused by drugs among outpa- Proc. 2010;85(2):131–8.
tients. Arch Dermatol. 1990;126(1): 43–7. 27. Lebargy F, et al. Pulmonary complications in toxic
11. Strom BL, et al. A population-based study of Stevens- epidermal necrolysis: a prospective clinical study.
Johnson syndrome. Incidence and antecedent drug Intensive Care Med. 1997;23(12):1237–44.
exposures. Arch Dermatol. 1991;127(6):831–8. 28. Revuz J, et al. Toxic epidermal necrolysis. Clinical
12. Naldi L, et al. Incidence of toxic epidermal necrolysis findings and prognosis factors in 87 patients. Arch
in Italy. Arch Dermatol. 1990;126(8):1103–4. Dermatol. 1987;123(9):1160–5.
13. Roujeau JC, et al. Toxic epidermal necrolysis (Lyell 29. Wong KC, Kennedy PJ, Lee S. Clinical manifesta-
syndrome). Incidence and drug etiology in France, tions and outcomes in 17 cases of Stevens-Johnson
1981–1985. Arch Dermatol. 1990;126(1):37–42. syndrome and toxic epidermal necrolysis. Australas J
14. Prendiville JS, et al. Management of Stevens-Johnson Dermatol. 1999;40(3):131–4.
syndrome and toxic epidermal necrolysis in children. 30. Harr T, French LE. Toxic epidermal necrolysis and
J Pediatr. 1989;115(6):881–7. Stevens-Johnson syndrome. Orphanet J Rare Dis.
15. French LA, Prins C. Erythema multiforme, Stevens- 2010;5:39.
Johnson syndrome and toxic epidermal necrolysis. In: 31. Gerull R, Nelle M, Schaible T. Toxic epidermal
Bologina JL, Jorizzo JL, Rapini R, editors. Urticarias, necrolysis and Stevens-Johnson syndrome: a review.
erythemas, and pupuras. 2nd ed. Philadelphia, PA: Crit Care Med. 2011;39(6):1521–32.
Elsevier; 2008. 32. Bastuji-Garin S, et al. SCORTEN: a severity-of-ill-
16. Wolkenstein PE, Roujeau JC, Revuz J. Drug-induced ness score for toxic epidermal necrolysis. J Invest
toxic epidermal necrolysis. Clin Dermatol. 1998;16(3): Dermatol. 2000;115(2):149–53.
399–408. 33. Garcia-Doval I, et al. Toxic epidermal necrolysis and
17. Roujeau JC, Stern RS. Severe adverse cutaneous Stevens-Johnson syndrome: does early withdrawal of
reactions to drugs. N Engl J Med. 1994;331(19): causative drugs decrease the risk of death? Arch
1272–85. Dermatol. 2000;136(3):323–7.
34. Oplatek A, et al. Long-term follow-up of patients dilemma of classification. Clin Dermatol.
treated for toxic epidermal necrolysis. J Burn Care 2005;23(3):311–4.
Res. 2006;27(1):26–33. 52. Descamps V, et al. Association of human herpesvirus
35. Dunn K, Edwards-Jones V. The role of acticoat with 6 infection with drug reaction with eosinophilia and
nanocrystalline silver in the management of burns. systemic symptoms. Arch Dermatol. 2001;137(3):
Burns. 2004;30 Suppl 1:S1–9. 301–4.
36. Wolf R, et al. Life-threatening acute adverse cutane- 53. Fiszenson-Albala F, et al. A 6-month prospective sur-
ous drug reactions. Clin Dermatol. 2005;23(2): vey of cutaneous drug reactions in a hospital setting.
171–81. Br J Dermatol. 2003;149(5):1018–22.
37. Brown KM, et al. Toxic epidermal necrolysis: does 54. Clark RA, et al. The vast majority of CLA + T cells are
immunoglobulin make a difference? J Burn Care resident in normal skin. J Immunol. 2006;176(7):
Rehabil. 2004;25(1):81–8. 4431–9.
38. Prins C, Gelfand EW, French LE. Intravenous immu- 55. Schaerli P, et al. A skin-selective homing mechanism
noglobulin: properties, mode of action and practical for human immune surveillance T cells. J Exp Med.
use in dermatology. Acta Derm Venereol. 2007;87(3): 2004;199(9):1265–75.
206–18. 56. Pichler WJ. Pharmacological interaction of drugs with
39. Campione E, et al. High-dose intravenous immuno- antigen-specific immune receptors: the p-i concept.
globulin for severe drug reactions: efficacy in toxic Curr Opin Allergy Clin Immunol. 2002;2(4):301–5.
epidermal necrolysis. Acta Derm Venereol. 57. Picard D, et al. Drug reaction with eosinophilia and
2003;83(6):430–2. systemic symptoms (DRESS): a multiorgan antiviral
40. Prins C, et al. Treatment of toxic epidermal necrolysis T cell response. Sci Transl Med. 2010;2(46):46ra62.
with high-dose intravenous immunoglobulins: multi- 58. Eshki M, et al. Twelve-year analysis of severe cases
center retrospective analysis of 48 consecutive cases. of drug reaction with eosinophilia and systemic symp-
Arch Dermatol. 2003;139(1):26–32. toms: a cause of unpredictable multiorgan failure.
41. Shortt R, et al. Intravenous immunoglobulin does not Arch Dermatol. 2009;145(1):67–72.
improve outcome in toxic epidermal necrolysis. 59. Saida S, et al. A case of drug-induced hypersensitivity
J Burn Care Rehabil. 2004;25(3):246–55. syndrome-like symptoms following HHV-6 encephal-
42. Valeyrie-Allanore L, et al. Open trial of ciclosporin opathy. Allergol Int. 2010;59(1):83–6.
treatment for Stevens-Johnson syndrome and toxic 60. Chen YC, Chiu HC, Chu CY. Drug reaction with
epidermal necrolysis. Br J Dermatol. 2010;163(4): eosinophilia and systemic symptoms: a retrospective
847–53. study of 60 cases. Arch Dermatol. 2010;146(12):
43. Harr T, French LE. Severe cutaneous adverse reac- 1373–9.
tions: acute generalized exanthematous pustulosis, 61. Gupta A, et al. Drug-induced hypothyroidism: the
toxic epidermal necrolysis and Stevens-Johnson syn- thyroid as a target organ in hypersensitivity reactions
drome. Med Clin North Am. 2010;94(4):727–42. x. to anticonvulsants and sulfonamides. Clin Pharmacol
44. Pichler WJ, Tilch J. The lymphocyte transformation Ther. 1992;51(1):56–67.
test in the diagnosis of drug hypersensitivity. Allergy. 62. Spanou Z, et al. Involvement of drug-specific T cells
2004;59(8):809–20. in acute drug-induced interstitial nephritis. J Am Soc
45. Kano Y, et al. Utility of the lymphocyte transforma- Nephrol. 2006;17(10):2919–27.
tion test in the diagnosis of drug sensitivity: depen- 63. Chung WH, et al. Medical genetics: a marker for
dence on its timing and the type of drug eruption. Stevens-Johnson syndrome. Nature.
Allergy. 2007;62(12):1439–44. 2004;428(6982):486.
46. Magina S, et al. Dermatological and ophthalmologi- 64. Walsh SA, Creamer D. Drug reaction with eosino-
cal sequels in toxic epidermal necrolysis. Dermatology. philia and systemic symptoms (DRESS): a clinical
2003;207(1):33–6. update and review of current thinking. Clin Exp
47. Gueudry J, et al. Risk factors for the development of Dermatol. 2011;36(1):6–11.
ocular complications of Stevens-Johnson syndrome 65. Mockenhaupt M. Severe drug-induced skin reactions:
and toxic epidermal necrolysis. Arch Dermatol. clinical pattern, diagnostics and therapy. J Dtsch
2009;145(2):157–62. Dermatol Ges. 2009;7(2):142–60. quiz 161-2.
48. Power WJ, et al. Analysis of the acute ophthalmic 66. Bohan KH, Mansuri TF, Wilson NM. Anticonvulsant
manifestations of the erythema multiforme/Stevens- hypersensitivity syndrome: implications for pharma-
Johnson syndrome/toxic epidermal necrolysis disease ceutical care. Pharmacotherapy. 2007;27(10):
spectrum. Ophthalmology. 1995;102(11):1669–76. 1425–39.
49. Roujeau JC, et al. Reporting adverse drug reactions. 67. Beltraminelli HS, et al. Acute generalized exanthema-
Lancet. 1985;2(8466):1244. tous pustulosis induced by the antifungal terbinafine:
50. Westly ED, Wechsler HL. Toxic epidermal necrolysis. case report and review of the literature. Br J Dermatol.
Granulocytic leukopenia as a prognostic indicator. 2005;152(4):780–3.
Arch Dermatol. 1984;120(6):721–6. 68. Halevy S. Acute generalized exanthematous pustulo-
51. Wolf R, et al. Drug rash with eosinophilia and sys- sis. Curr Opin Allergy Clin Immunol. 2009;9(4):
temic symptoms vs toxic epidermal necrolysis: the 322–8.
3 Drug Eruptions 55
69. Bachot N, Roujeau JC. Differential diagnosis of 79. Brucculeri M, Charlton M, Serur D. Serum sickness-
severe cutaneous drug eruptions. Am J Clin Dermatol. like reaction associated with cefazolin. BMC Clin
2003;4(8):561–72. Pharmacol. 2006;6:3.
70. Roujeau JC. Clinical heterogeneity of drug hypersen- 80. Vial T, et al. Cefaclor-associated serum sickness-like
sitivity. Toxicology. 2005;209(2):123–9. disease: eight cases and review of the literature. Ann
71. Sidoroff A, et al. Risk factors for acute generalized Pharmacother. 1992;26(7–8):910–4.
exanthematous pustulosis (AGEP)-results of a multi- 81. Molldrem JJ, et al. Antithymocyte globulin for
national case–control study (EuroSCAR). Br J patients with myelodysplastic syndrome. Br J
Dermatol. 2007;157(5):989–96. Haematol. 1997;99(3):699–705.
72. Pirquet SV. Serum sickness. Baltimore: Wilkins; 82. Hommes DW, van Deventer SJ. Infliximab therapy in
1951. Crohn’s disease: safety issues. Neth J Med.
73. Lawley TJ, et al. A prospective clinical and immuno- 2003;61(4):100–4.
logic analysis of patients with serum sickness. N Engl 83. D’Arcy CA, Mannik M. Serum sickness secondary to
J Med. 1984;311(22):1407–13. treatment with the murine-human chimeric antibody
74. Vincent C, Revillard JP. Antibody response to horse IDEC-C2B8 (rituximab). Arthritis Rheum.
gamma-globulin in recipients of renal allografts: rela- 2001;44(7):1717–8.
tionship with transplant crises and transplant survival. 84. Todd DJ, Helfgott SM. Serum sickness following
Transplantation. 1977;24(2):141–7. treatment with rituximab. J Rheumatol.
75. Clark BM, et al. Severe serum sickness reaction to 2007;34(2):430–3.
oral and intramuscular penicillin. Pharmacotherapy. 85. Lundquist AL, et al. Serum sickness following rabbit
2006;26(5):705–8. antithymocyte-globulin induction in a liver transplant
76. Wilson CB, Dixon FJ. Quantitation of acute and recipient: case report and literature review. Liver
chronic serum sickness in the rabbit. J Exp Med. Transpl. 2007;13(5):647–50.
1971;134(3):7–18. 86. Bielory L, et al. Cutaneous manifestations of serum
77. King BA, Geelhoed GC. Adverse skin and joint reac- sickness in patients receiving antithymocyte globulin.
tions associated with oral antibiotics in children: the J Am Acad Dermatol. 1985;13(3):411–7.
role of cefaclor in serum sickness-like reactions. 87. Joubert GI, et al. Selection of treatment of cefaclor-
J Paediatr Child Health. 2003;39(9):677–81. associated urticarial, serum sickness-like reactions
78. Knowles SR, Shear NH. Recognition and manage- and erythema multiforme by emergency pediatricians:
ment of severe cutaneous drug reactions. Dermatol lack of a uniform standard of care. Can J Clin
Clin. 2007;25(2):245–53. viii. Pharmacol. 1999;6(4):197–201.
Histamine-Mediated Emergencies
4
Alyx Rosen, Sarit Itenberg, and Adam Friedman
gencies in order to implement timely and directed

4.1 Introduction
therapy that could be potentially lifesaving.
In this chapter, we review the pathophysiology
The wheel and flare of urticaria is the pathogno- of histamine-mediated disease, the clinical mani-
monic feature of histamine-mediated cutaneous festations, and targeted therapies. Subjects that
lesions. In fact, urticaria is one of the most are discussed in detail include urticaria, angioe-
common chief complaints encountered by dema, anaphylaxis and their many etiologies
dermatologists. Fortunately, their life-threatening including foods, medications, blood products,
sequelae, namely, anaphylaxis and shock, are latex, arthropod assaults, as well as the many
exceedingly rare. Understanding the mechanisms physical urticarias and their triggers. We con-
through which histamine release occurs and its clude with a brief review of cutaneous and sys-
subsequent physiologic and potentially patho- temic mastocytosis and their potential to be
logic impact is vital to our ability to triage and life-threatening.
treat appropriately. All dermatologists should be
proficient at recognizing and diagnosing both
common and unusual histamine-mediated emer- 4.2 Histamine
Histamine is an organic nitrogen compound that

has potent physiologic activity. Several life-
threatening emergencies are mediated by hista-
mine, most of which have associated dermatologic
A. Rosen, B.S.E. (*) manifestations.
Albert Einstein College of Medicine, New York, Histamine was first discovered in 1910 as a
NY, USA
critical mediator of hypersensitivity. About 20
e-mail: Alyx.rosen@med.einstein.yu.edu
years later, it was identified as a mediator of life-
S. Itenberg, D.O.
threatening anaphylactic reactions. Histamine
Division of Dermatology, Department of Medicine,
Albert Einstein College of Medicine, belongs to a group of biogenic amines and is syn-
111 E 210th Street, Bronx, NY 10467, USA thesized from the amino acid histidine [1]. This
e-mail: sarit.itenberg@gmail.com process occurs most notably in mast cells and
A. Friedman, M.D., F.A.A.D. basophils, but also in platelets, histaminergic
Division of Dermatology, Department of Medicine, neurons, and enterochromaffin cells. Histamine
Montefiore Medical Center, Albert Einstein College
is stored intracellularly within vesicles and
of Medicine, 111 E 210th Street,
Bronx, NY 10467, USA released upon stimulation. Histamine has a rapid
e-mail: ajf0424@yahoo.com onset of action, able to achieve its maximum

58 A. Rosen et al.
Table 4.1 Histamine receptors

Receptor Location Function
H1 Smooth muscle, vascular endothelium, Constriction of bronchial smooth muscle, systemic
heart, CNS vasodilation pruritus, symptoms of allergic rhinitis
H2 Gastric parietal cells, vascular smooth Vasodilation gastric acid secretion
muscle, heart, CNS
H3 CNS > PNS Autoreceptor in presynaptic histaminergic neurons;
Decreases release of histamine, acetylcholine,
norepinephrine, serotonin
H4 Bone marrow, WBCs, thymus, small Mediates cellular chemotaxis.
intestine, spleen, colon, liver, lung, testes,
tonsils, trachea
CNS central nervous system, PNS peripheral nervous system, WBCs white blood cells
productivity quite efficiently. Notably, once Though histamine is the principle mediator of
released into circulation, histamine is elevated hypersensitivity reactions and anaphylaxis, it is
for only 30–60 min, making it a poor marker for not the only one. Research has shown that other
mast cell and basophil activation [2]. However, a granule-associated preformed mediators
metabolite of histamine, methylhistamine, is (tryptase, chymase, and heparin), newly formed
present in the urine for up to 24 h after peak mediators (prostaglandins, leukotrienes, and
plasma histamine levels [2], and may be used as a platelet activating factor), and numerous cytok-
diagnostic tool. ines and chemokines are released during the
Histamine exerts specific actions by binding degranulation cascade (Fig. 4.2).
to one of four known human histamine recep- Release of mediators can occur within several
tors designated H1–H4 (Table 4.1). Its effects, minutes of the inciting event. The release of
however, are potentiated mainly through the inflammatory cytokines, however, can take several
H 1 and H 2 receptors and include vasodilation hours, thereby mainly contributing to late phase
(seen as erythema, flushing, and hypotension), reactions [2]. Late phase reactions occur within
increased vascular permeability by separation 2–24 h of exposure to the inciting event and are
of endothelial cells (seen as angioedema), due to the migration of leukocytes to the skin,
smooth muscle contraction (seen as stomach respiratory tract, or gastrointestinal tract. Cytokines
cramps and diarrhea), increased cardiac con- may also contribute to protracted reactions that
traction (leading to tachycardia and arrhyth- can last hours to days without a clear resolution of
mias), and increased glandular secretion symptoms. This is not to be confused with bipha-
(allergic rhinitis, dyspnea, and bronchocon- sic reactions. Biphasic reactions are characterized
striction) [1, 2]. Finally, histamine stimulates by initial symptoms of a uniphasic anaphylactic
the release of cyclic adenine monophosphate response that resolve spontaneously or with treat-
(cAMP), leading to increased production of ment, followed by an asymptomatic period
mast cells in the bone marrow. Activation of (1–72 h), and then a recurrence of symptoms with-
the H3 receptor in the peripheral and central out further exposure to antigen [3–5]. The second
nervous system leads to increased neurotrans- response in biphasic reactions may be less severe,
mitter release causing vertigo, nausea, and similar to, or more severe than the original epi-
vomiting (Fig. 4.1). The numerous effects of sode, and can be fatal. Biphasic reactions can
histamine explain why the clinical signs and occur in patients of any age. The mechanism of
symptoms of urticaria, angioedema, bronchos- biphasic reactions is not completely understood.
pasm, hypotension, and gastrointestinal symp- There are also no consistently reported risk factors,
toms can occur rapidly after mast cell and which creates a clinical dilemma for clinicians
basophil activation [2]. treating patients for anaphylaxis [4].
4 Histamine-Mediated Emergencies 59
Fig. 4.1 Systemic effects of histamine. Adapted from: Maintz L et al. Dtsch Artzebl 2006;103:A3477–83
Fig. 4.2 Mediators released by dermal mast cell degranulation. Adapated from Bolognia, Jean, Joseph L. Jorizzo, and
Ronald P. Rapini. “Dermatology.” 2nd ed. St. Louis, Mo.: Mosby/Elsevier, 2008. Figure 19.4
mon classification of hypersensitivity reactions is

4.3 Hypersensitivity Reactions
that of Gel and Coombs (Table 4.2). Histamine
release from mast cell and basophil activation
Hypersensitivity, or allergic, reactions are “over- occurs mainly through immunogolublin E (IgE)-
reactions” of the immune system to innocuous mediated immune reactions, which are type I
environmental antigens in susceptible, pre-sensitized hypersensitivity reactions. In brief, soluble
individuals. These reactions can range from antigen and IgE activation of mast cells and
localized tissue injury to death. The most com- basophils causes degranulation and release of
60
Table 4.2 Hypersensitivity reactions

Reaction type Immune mechanism Examples Pathologic lesions
Type I (immediate) Soluble antigen/IgE activation of mast Angioedema, systemic anaphylaxis, Vascular dilation, edema, smooth muscle
hypersensitivity cells causing vasodilation, vascular allergic rhinitis, asthma, urticaria contraction, mucus production, tissue
leakage, smooth muscle spasm injury, inflammation
(immediate reaction) and recruitment
of inflammatory cells (late phase)
Type II (antibody-mediated) IgG/IgM bind to antigen on target Autoimmune hemolytic anemia, Phagocytosis and lysis of cells;
hypersensitivity cell or tissue resulting in phagocytosis Goodpasture syndrome, certain drug inflammation; in some diseases, functional
or lysis of target cell by activated reactions and reactions to incompatible derangements without cell or tissue injury
complement or Fc receptors; recruitment blood transfusions
of leukocytes
Type III (immune complex- Antigen–antibody complexes deposit Systemic lupus erythematosus, some Inflammation, vasculitis
mediated) hypersensitivity in tissues → complement activation forms of glomerulonephritis, serum
→ recruitment of leukocytes by sickness, subacute bacterial endocarditis,
complement products and Fc arthus reaction
receptors → release of enzymes and
other toxic molecules
Type IV (T-cell-mediated) Soluble antigen activates CD4+ T-cells Contact dermatitis, multiple sclerosis, Perivascular cellular infiltrates, edema,
hypersensitivity causing the release of cytokines and thus type I diabetes, rheumatoid arthritis, granuloma formation, cell destruction
inflammation and macrophage and inflammatory bowel disease, tuberculosis
eosinophil activation Contact dermatitis (e.g., poison ivy),
Cell-associated antigen activates CD8+ reactions to certain virus-infected cells,
T-cells causing direct T-cell-mediated some instances of graft rejection
cytotoxicity
A. Rosen et al.
mediators leading to vasodilation, vascular leak- Anaphylaxis is commonly defined as a

age, smooth muscle spasm, and the recruitment life-threatening IgE-mediated type I hypersensi-
of inflammatory cells. These physiological mech- tivity reaction that is rapid in onset and involves
anisms result clinically in urticaria, asthma, multiple organ systems [9, 10]. It occurs when
allergic rhinitis, angioedema, and anaphylaxis. an immunologic reaction to an allergen in a sen-
sitized individual causes a life-threatening event
[11]. Anaphylactic reactions usually occur
4.4 Urticaria, Angioedema, within 30 min of exposure to the antigen and
and Anaphylaxis rarely last beyond 2 h. Delayed presentations as
well as biphasic anaphylactic reactions have
4.4.1 Definitions been described in patients up to 72 h after expo-
sure [12]. Histamine is the principal mediator of
Urticaria has been recognized since the begin- allergic hypersensitivity reactions, including
ning of medicine during the times of Hippocrates. anaphylaxis. Manifestations of anaphylaxis
The name dates back to the 18th century, when include diffuse erythema, urticaria, and angioe-
the burning and swelling of skin was likened to dema initially, followed by bronchospasm,
that caused by contact with nettles (Urtica dioica). laryngeal edema, increased gastrointestinal
Urticaria, or “hives,” is a vascular inflammatory motility, increased mucosal secretions, hypoten-
reaction of the papillary dermis [6]. The lesions sion, and cardiac arrhythmias [6].
appear as superficial wheals typically sur-
rounded by an erythematous, often pruritic, ring,
or flare with central clearing. Mast cells and 4.4.2 Epidemiology
basophils are the primary effectors of urticarial
reactions. They release inflammatory mediators Approximately 15–25% of individuals will expe-
that cause an increase in capillary permeability, rience at least one episode of urticaria at some
the most important of which is histamine [6]. point during their lives. Many people suffer from
Acute urticaria, by definition, occurs over a mild symptoms and fail to recognize it as urti-
period of less than 6 weeks. It typically involves caria. This leads to tremendous under reporting.
isolated, self-limited lesions that rarely last The majority of these cases are acute urticarial
longer than 24 h, are often migratory, and can episodes that do not recur; however, up to 30% of
recur for indefinite periods of time. Rarely, cases can advance to chronic urticaria. Urticaria
postinflammatory pigment alteration is noted is present in higher proportions in patients with
following resolution. Contact urticaria is defined atopic dermatitis. One study found that of patients
as the development of acute urticarial lesions at with acute urticaria, half also suffered from hay
the site where an external agent contacts the skin fever, allergic asthma, or atopic dermatitis [13].
or mucosa; these lesions are not migratory [7]. Acute urticaria is also more common in children
In contrast, chronic urticaria requires episodes and adolescents, while chronic urticaria is seen
at least 2 days per week lasting more than 6 more frequently in adults.
weeks duration [8]. While patients with chronic The epidemiology of anaphylaxis is difficult
urticaria are observed for IgE-mediated causes, to quantify, but it is estimated that there are
only 10–20% of patients with chronic urticaria around 84,000 cases of anaphylaxis each year in
have an identifiable trigger. the USA. Anywhere from 500 to 1000 of these
Angioedema is caused by the same pathophys- cases are fatal [14]. Based on reports by the
iologic mechanism as urticaria but occurs deeper, American College of Allergy, Asthma and
typically in the subcutaneous, and submucosal Immunology Epidemiology of Anaphylaxis
tissues. Thus, although swelling is appreciated in Working Group in 2006, the estimated lifetime
angioedema, erythema is typically absent. prevalence is approximately 0.05–2.0% with the
62 A. Rosen et al.
largest number of incident cases among children capable allergens. While up to 50% of chronic
and adolescents [15]. However, accurate reporting urticaria cases are thought to be idiopathic, recent
is complicated by factors such as under diagnosis, studies show that approximately 35–45% of
under reporting, and a prior lack of a universal patients with idiopathic chronic urticaria in fact
definition for anaphylaxis, making a true estimate have an IgG autoantibody directed against mast
of exact cases difficult to measure [16]. cell or basophil surface-bound IgE. Thus, an
autoimmune process may actually cause many
cases of chronic urticaria.
4.4.3 Pathophysiology Mast cells reside in the skin and in connective
tissue near blood vessels in the lower respiratory
Acute urticaria and angioedema are caused by tract, bronchial lumen, central nervous system,
allergic IgE-mediated, non-IgE-mediated, and bone marrow, and gastrointestinal tract mucosa
nonimmunologic mechanisms. In allergic IgE- [14, 18]. Basophils are polymorphonuclear
mediated urticaria, the body views an antigen and leukocytes found circulating in the blood. They
produces specific IgE antibodies against this anti- constitute 0.1–2.0% of peripheral blood leuko-
gen [17]. The Fc portion of IgE has a strong cytes and are rarely found in tissues [18]. When
affinity for the Fce receptor-1 (FceR1) proteins on these cells are activated, preformed and newly
the surface of mast cells and basophils. Once the formed mediators are released; the most impor-
IgE binds to these receptors, a person is consid- tant is histamine.
ered “sensitized” to the IgE-specific antigen. As Similar to urticaria and angioedema described
many as half a million molecules of IgE can fix to above, anaphylaxis is caused by allergic IgE-
a single mast cell or basophil [18]. The body can mediated, non-IgE-mediated, and nonimmuno-
be exposed to an antigen through the skin, mucous logic mechanisms. It too is a result of mast cell
membranes, respiratory tract, or the gastrointesti- and basophil activation and subsequent release of
nal tract. histamine and other small molecules. The wide
Upon reintroduction, the antigen binds to sev- and variable distribution of mast cells and baso-
eral IgE antibodies already bound to mast cells or phils throughout the body may explain why sys-
basophils, causing cross-linking of the IgE anti- temic features seen in anaphylaxis are not present
bodies, thus activating the inflammatory cascade during the activation of cutaneous mast cells in
that clinically presents as urticaria and/or angioe- patients who present with urticaria or angioe-
dema (Fig. 4.3). Cross-linkage of IgE antibodies dema. The effects of the released chemical medi-
may also occur from anti-IgE antibodies or other ators include smooth muscle contraction,
Fig. 4.3 Mast cell/basophil degranulation. Adapted from Alberts, Bruce. Molecular Biology of the Cell. 4th ed. 1 vols.
New York: Garland Science, 2002. Print. Figure 24–27
especially in the pulmonary and gastrointestinal Thus, IgE-dependent reactions occur only
systems, coronary artery vasoconstriction, after the patient has been previously exposed at
increased vascular permeability and capillary least once to the antigen and is sensitized.
leakage. Extravasation of fluid and protein from Conversely, non-IgE mediated reactions can
blood vessels leads to a decrease in plasma vol- occur following a single, first time exposure to
ume, reduction in venous return, and circulatory certain agents in non-sensitized individuals.
collapse [11, 18]. Because immunologic reactions produce the
Anaphylactic shock is reserved for cases of same clinical manifestations, regardless of the
circulatory collapse that occur during anaphylac- method of histamine release, treatment is uniform
tic reactions. There are four broad classifications [24]. Nonimmunologic triggers induce mast cell
of shock (hypovolemic, cardiogenic, distributive, and basophil activation without evidence of
and obstructive). Anaphylactic shock may be a involvement of IgE, IgG, or immune complexes,
combination of hypovolemic shock due to capil- and are elaborated on later in this chapter.
lary leakage, distributive shock secondary to
vasodilation, and cardiogenic shock because of
decreased cardiac contractility [19]. Half of all 4.4.4 Clinical Features
deaths due to anaphylaxis result from circulatory
collapse and shock. The other half are from air- The lesions of acute urticaria appear as erythema-
way obstruction [20]. tous wheals (Fig. 4.4). They are pruritic and blanch-
Aside from the classic immunologic IgE- able and generally resolve within 12–24 h without
mediated hypersensitivity reactions, clinically
identical presentations can occur via immuno-
logic non-IgE mediated or nonimmunologic
mechanisms. Immunologic non-IgE mediated
reactions occur through activation of the comple-
ment system via immune complexes, and genera-
tion of kallikrein and bradykinin. Certain
byproducts of the complement cascade, includ-
ing plasma-activated complement 3 (C3a),
plasma-activated complement 4 (C4a), and
plasma-activated complement 5 (C5a), are called
anaphylotoxins and can cause mast cell or baso-
phil activation without IgE involvement [21].
Nonimmunologic reactions are a result of physi-
cal factors or antigens acting directly on mast
cells and basophils to cause degranulation and
histamine release, and not via an antigen–anti-
body interaction [14]. With regards to immuno-
logic contact urticaria, the pathophysiology is
similar to what was described above for allergic
IgE-mediated urticaria. In contrast, nonimmuno-
logic contact urticaria is thought to occur inde-
pendent of histamine and rather through
prostaglandin release from the epidermis. This is
based on the beneficial response in such cases to
acetylsalicylic acid (ASA) and nonsteroidal anti-
Fig. 4.4 Urticaria. Photo courtesy of Dr. Douglas I.
inflammatory drugs (NSAIDs) versus antihista- Rosen, Assistant Clinical Professor of Medicine, Division
mines [22, 23]. of Dermatology, Montefiore Medical Center
64 A. Rosen et al.
complication or residual skin findings. Wheals medical attention. Finally, it is important to

may be small or large, single or multiple. In the remember that anaphylactic reactions can occur
case of physical urticaria, the distribution pattern without any dermatologic manifestations.
and morphology can be helpful in separating the
different clinical types. Allergens that are only
locally absorbed, as in contact urticaria, usually 4.4.5 Risk Factors for Severe
result in confined symptoms of burning, itching, Hypersensitivity Reactions
tingling, and wheals developing at the site of
exposure [25]. Angioedema is also often present. Several important factors can increase the likeli-
In cases of immunologic contact urticaria, how- hood of a severe hypersensitivity reaction. These
ever, skin or mucosal contact with an inciting anti- include very young or old age, pregnancy, comor-
gen in a sensitized patient can also lead to bidities (e.g., asthma, atopy, or cardiovascular or
extracutaneous symptoms such as rhinoconjuncti- respiratory disease), and use of certain concurrent
vitis, orolaryngeal and gastrointestinal dysfunction, medications like angiotensin converting enzyme
or even progress to anaphylaxis [22]. Allergens that (ACE) inhibitors or b-blockers, which sometimes
disseminate systemically through ingestants or hinder the treatment of anaphylaxis [28].
inhalants can result in diffuse urticaria. Small retrospective case series and large
In contrast to the erythematous pruritic lesions patient databases have demonstrated that an
of urticaria, angioedema typically has no corre- underlying history of asthma is a major risk factor
sponding visible erythema, rather patients com- for fatal or near fatal anaphylactic reactions to
plain of pain at the involved site. Angioedema food with up to a 3.3 relative risk of anaphylaxis
typically involves the extremities, head, neck, in patients with severe asthma [12, 29]. In addi-
face, and, in men, and the genitalia in men, and tion, severe allergic rhinitis and severe eczema
may last for several days. Most importantly, if it increase the risk of life-threatening anaphylaxis
occurs in the soft tissues of the larynx and upper [21]. Atopy also appears to be a risk factor.
airway it can lead to life-threatening airway com- However, it is not as specific for food-induced
promise and death [26]. Urticaria and angioe- anaphylaxis, as patients with atopy may also have
dema may occur in any location together or an increased incidence of anaphylactic reactions
separately. Urticaria occurs in association with to latex, exercise, and radiocontrast media [14].
angioedema in up to 50% of patients [27]. More severe and immediate reactions to medi-
Approximately 10% of cases will exhibit angioe- cations occur when drugs are delivered parenter-
dema in the absence of urticaria and 40% involve ally versus orally. In patients with allergies to
urticaria alone [25]. hymenoptera stings, elevated baseline tryptase
The classic clinical picture of anaphylaxis levels demonstrate a higher risk for severe sys-
begins with scalp pruritus, urticaria, and angioe- temic reactions. Therefore baseline tryptase levels
dema, and ends with bronchospasm, hypotension, in patients with systemic reactions should be
and gastrointestinal symptoms. Urticaria and measured [30].
angioedema are the most common symptoms in Finally, patients with subclinical or clinical
anaphylaxis and are seen in 88% of patients [2]. mastocytosis who have a history of a serious
In nonlethal cases, hypotension often causes hypersensitivity reaction to a known allergen,
symptoms of nausea, vomiting, dyspnea, dizzi- have a significantly increased risk for future life-
ness, and diaphoresis [19]. However, systemic threatening reactions [14, 31].
hypotension and profound shock are clinical
emergencies and may rapidly lead to cardiopul-
monary arrest within 5–15 min after reaction 4.4.6 Etiologies
onset [17, 20]. Patients who experience severe
anaphylaxis should be observed for an extended Many of the same causes of urticaria and angioe-
timeframe of up to 72 h to eliminate the risk of a dema can lead to anaphylaxis. Triggers can func-
severe biphasic reaction occurring without tion via three different mechanisms: immunologic
Table 4.3 Common causes of type I hypersensitivity reactions

Immunologic IgE-mediated Immunologic non-IgE-mediated Nonimmunologically mediated
Food IVIg Medications causing direct mast cell
degranulation (e.g., opioids, tartrazine,
polymyxin B, benzoate, vancomycin,
NSAIDs)
Medications (Acetylsalicylic acid, Animal antiserum Complement factors (i.e., C3a and C5a)
NSAIDS)
Insect bites/stings Autoimmune Cytokines
Parasitic infections Febrile illness (viral, bacterial, fungal) Radiocontrast material
Contact allergens (latex) Acetylsalicylic acid
Physical stimuli
Exercise
Biologic agents (vaccines, mAbs,
hormones)
Radiocontrast material
IgE-mediated, immunologic non-IgE-mediated, recovery rates for children with non-IgE-mediated

and nonimmunologic (Table 4.3). This section allergies. While fewer studies have been con-
focuses on life-threatening causes of hypersensi- ducted in children with allergies to egg and wheat,
tivity reactions. a significant percentage of these allergies are also
lost by school age [32].
4.4.6 A Food Shellfish allergy is typically an IgE-mediated
Food allergy is still considered the most common process with shrimp, crab, and lobster responsi-
cause of anaphylaxis. It is also one of the most ble for the majority of reported allergic reactions
common causes of immunologic IgE-mediated [33]. Allergy in these patients is typically thought
contact urticaria. Up to 2% of the US population to be lifelong.
may be affected by food allergies with 4–8% of Scombroid poisoning or histamine fish poi-
children and 1–3% of adults with food allergy soning can mimic food-induced anaphylaxis, but
confirmed by skin prick testing [32]. The contri- results from the consumption of mishandled
bution of foods differ by age with children most scombridae fish including tuna, mackerel, and
often affected by peanuts, tree nuts, milk, and bonito as well as other (non-scombroid) fish spe-
eggs, and adults with increased rates of allergy to cies such as mahi mahi or sardines [34]. Bacteria
shellfish, fish, and peanuts. Food additives (e.g., in spoiled fish produces enzymes capable of
spices, vegetable gums, colorants (e.g., carmine), decarboxylating histadine to produce biogenic
sodium benzoate, nitrates, and papain), food con- amines like histamine and cis-urocanic acid,
taminants, and food parasites (e.g., Anisakis sim- which are also capable of mast cell degranulation
plex) have also rarely been associated with and further histamine release. While there are
anaphylaxis [14, 28]. numerous other proposed mechanisms of toxic-
Cow’s milk protein is often the first allergen to ity, scombroid poisoning caused by elevated his-
which infants react, with symptoms presenting in tamine levels in seafood is the most widely
the first week that formula feeds are introduced understood [34]. Common symptoms are similar
into the diet. The majority of children will out- to those seen in patients with food allergies.
grow their allergy. This reaction can be either Rarely are serious cardiac and respiratory com-
IgE- or non-IgE-mediated with slightly better plications reported and even more infrequently
66 A. Rosen et al.
do patients require hospitalization. One way to protective doses, which may protect many high-risk
help differentiate between fish poisoning and a patients against accidental ingestion reactions [40].
seafood allergy is that most people eating the However, until larger randomized trials are con-
same meal will demonstrate a response to scom- ducted to further evaluate the benefit-risk ratio of
brotoxic fish versus only those with a specific fish OIT versus avoidance, which is the current main-
allergy are expected to experience symptoms stay of management, OIT cannot be considered for
[35]. Regardless of the mechanism of toxicity, routine clinical practice [40, 41].
scombroid poisoning is treated in a similar man-
ner to food allergy. 4.4.6 B Medications and Blood Products
Peanut allergy remains the most common Drug allergy is considered a type of adverse drug
cause of food-induced anaphylaxis. It typically reaction and there is tremendous overlap between
starts in early childhood but a late-onset cohort of drugs that lead to urticaria, angioedema, and life-
patients can also be seen. The incidence of child- threatening anaphylaxis. Medications can trigger
hood peanut allergy is increasing and exceeds a anaphylaxis through immunologic IgE-dependent,
prevalence of 1% in the US [36]. In contrast to immunologic non-IgE-mediated, or nonimmuno-
children with milk, egg, and wheat allergies, only logic mechanisms. Several medications can also
a small proportion outgrow peanut allergy [37], act through multiple different mechanisms.
and vigilant lifelong avoidance is necessary. Antibiotics are the most common cause of IgE-
Signs and symptoms of anaphylaxis typically dependent reactions, especially beta-lactams such
develop within 30 min of food ingestion but can as penicillins and cephalosporins, and less fre-
also occur within 5 min and rarely up to 2 h later. quently, sulfonamides and tetracyclines [42].
The skin and respiratory systems are involved in Biologic agents including vaccines and hormones,
up to 76% and 80% of patients, respectively, and as well as radiocontrast dye and certain monoclo-
gastrointestinal symptoms are seen frequently in nal antibodies, also act through IgE-dependent
cases of food-induced anaphylaxis [38, 39]. pathways; however, the majority of hypersensi-
Respiratory collapse is the cause of death in most tivity reactions to radiocontrast media are nonim-
fatal cases of food-induced anaphylaxis. Shock is munologic. Radiocontrast media may also act via
a rare physiologic component and almost never complement activation that subsequently leads to
seen without respiratory compromise [32]. mast cell activation [28]. As the use of monoclo-
Several recent studies have assessed the efficacy, nal antibodies in various clinical settings contin-
safety, and feasibility of oral immunotherapy (OIT) ues to increase, there is also a rise in incidence of
for high-risk patients with severe peanut allergies. hypersensitivity reactions. Many of these reac-
One study was conducted in 23 children, ages 3–14 tions are seen with the first dose of therapy, impli-
years, with confirmed IgE-mediated peanut aller- cating a nonimmunologic mechanism of action.
gies. They received OIT following a rush protocol However, many patients also experience IgE-
with roasted peanut for 7 days or, if protective doses dependent reactions or even delayed reactions,
of 0.5 g (0.16 teaspoons) of peanut were not achieved with symptoms developing after several future
during the rush protocol, long-term buildup with doses [5]. Systemic infusion reactions related to
biweekly dose increases up to 0.5 g of peanut was the rate of monoclonal antibody drug infusion
performed. Twenty-two of 23 patients continued also occur.
with the long-term protocol and 14 reached the Opioids cause mainly nonimmunologic
0.5 g protective dose after a median of 7 months. hypersensitivity reactions while ASA classi-
Subsequently, these patients were able to tolerate a cally acts via a non-IgE-mediated immunologic
median of 1 g of peanut, in comparison to 0.19 g of pathway. NSAIDs produce mainly nonimmu-
peanut before OIT. Therefore, it was determined nologic and rarely IgE-dependent immunologic
that for long-term buildup, but not rush, OIT was reactions [28] and are responsible for up to 25%
safe and effective in reaching clinically relevant of all adverse drug reactions. After taking ASA
or other NSAIDs, one-third of patients with deficiency. Up to 40% of patients with IgA
controlled underlying chronic urticaria and up deficiency produce IgG or IgE anti-IgA antibodies.
to two-thirds of patients with active chronic During blood transfusions, the IgG or IgE anti-IgA
urticaria will have exacerbations of urticaria or antibodies attack the IgA proteins in the donor
angioedema [43, 44]. blood. Two ways to prevent or minimize a serious
Vancomycin, a glycopeptide antibiotic, can anaphylactic reaction could be to use washed red
cause two different hypersensitivity reactions: blood cells or blood from another IgA deficient
(1) nonimmunologic mast cell and basophil individual. In cases when IgA levels are not readily
degranulation causing “Red Man Syndrome” available, patients may be pretreated with antihis-
and (2) IgE-mediated anaphylaxis. “Red Man tamines prior to emergent therapy.
Syndrome” is far more common and is caused by The most severe cases of drug allergies can
a rapid infusion of vancomycin [45]. It typically occur immediately or hours to days following
presents with flushing, erythema, and pruritus of drug administration. Factors including prior
the face and upper torso but can also progress to sensitization, route of administration, drug
angioedema, hypotension, and, rarely, cardio- metabolism, drug interactions and concomitant
vascular depression [46]. While there is a corre- food intake play a modifying role [48] and affect
lation with the peak plasma histamine the rate of symptom development. Anaphylaxis
concentration during infusion and severity of the secondary to cutaneous injections or topical
reaction, elevated histamine levels may also be applications has only rarely been reported.
seen in patients treated with slower infusion rates
who do not experience “Red Man Syndrome” 4.4.6 C Latex
[47]. Other antibiotics have rarely been associ- Food and latex (natural rubber) are two of the
ated with “Red Man Syndrome.” most common causes of immunologic IgE-
Urticaria and angioedema can occur together mediated contact urticaria. In the 1980s, when
or independent of each other. In the case of universal precautions were implemented and the
angioedema without urticaria, it is important to use of latex gloves increased, so too did the inci-
consider an underlying complement system dence of type-I hypersensitivity reactions pre-
enzyme deficiency, such as hereditary or dominantly in healthcare settings. Typically,
acquired C1-esterase inhibitor deficiency. On reactions from a latex allergy occur within 30
the other hand, all patients treated with ACE min of exposure and include the development of
inhibitors, a type of antihypertensive, can expe- pruritus and urticaria to the localized area of con-
rience side effects related to increased bradyki- tact [49]. Generalized urticaria can occur and
nin, including angioedema without urticaria. often results from dissemination of the allergen
Therefore, special consideration should be taken (antigen) after direct contact with mucosal sur-
when prescribing ACE inhibitors in patients faces. Serious, life-threatening latex induced
who may have an underlying enzyme deficiency anaphylactic reactions can also occur.
due to their predisposition for angioedema. Latex allergy may be a source of morbidity for
Furthermore, it should be noted that symptoms patients in their work place, in particular medical
of angioedema secondary to an underlying workers and people in occupations where they
enzyme deficiency may be delayed up to a year are regularly exposed to or use latex gloves.
after beginning treatment with ACE inhibitors Individuals can also be exposed in their homes
and may be mistaken as a side effect of the with common latex items including balloons,
drug only. latex contraceptives, rubber bands, and much
Life-threatening reactions to the administration more. The latex-fruit syndrome refers to the
of human IgG are rare in clinical practice. The cross-reaction of latex allergens with many plant-
most common blood transfusion related anaphy- derived food allergens, which results from struc-
lactic reaction occurs in patients with IgA tural similarities between several latex and plant
68 A. Rosen et al.
antigenic proteins. The most commonly involved are based on clinical history of systemic reac-
fruits include kiwi, banana, avocado, passion tions, positive skin test, and knowledge of the
fruit, and chestnut. In this situation, it is difficult history and risk factors for a severe reaction to
to determine if the patients were first sensitized to treatment [21, 31].
latex or to fruit, which would help provide more
evidence-based prophylaxis [49]. It is highly 4.4.6 E Idiopathic
advised that when visiting a doctor patients make Idiopathic reactions are responsible for up to one-
their latex allergy known in order to help prevent third of all type I hypersensitivity reactions. The
life-threatening reactions. diagnosis is one of exclusion after a complete
medical history, skin prick testing, serum specific
4.4.6 D Hymenoptera Stings IgE levels, radioallergosorbent test (RAST), and
Venom from insects of the order Hymenoptera, other lab testing reveal no recognizable external
which includes ants, bees, hornets, wasps, and trigger. Similarly, any other diseases that could
yellow jackets, or saliva from biting insects mimic the anaphylactic hypersensitivity reaction
such as flies, mosquitoes, ticks, kissing bugs, picture should be ruled out. Patients should also
and caterpillars, can cause severe anaphylactic be evaluated for mastocytosis or clonal mast cell
reactions [ 50 ] . Insect stings as a cause of disorders [28]. Serum tryptase can be very useful
anaphylaxis can be seen all around the world in differentiating anaphylaxis from many condi-
with varying geographic areas affected more tions that can masquerade as anaphylaxis [53].
commonly by different families of Hymenoptera. The attack rate is variable and fatalities can occur.
Similarly, occupational hazards lend to Patients typically present with symptoms identi-
increased risks of specific allergies. An obvious cal to those of other type I hypersensitivity
example is seen with the bee venom allergy, reactions and individual patients tend to have
which is found in higher proportions in bee- the same physical manifestations on repeated
keepers [30]. Population-based studies have episodes.
difficulty calculating the overall prevalence of
Hymenoptera sting allergies, which may be 4.4.6 F Less Common Etiologies
responsible for up to 34.1% of all-cause Physical urticaria is an eruption in response to
anaphylaxis [31]. Severe systemic reactions are physical stimuli. Several defined subtypes of this
seen more frequently in adults and may present phenomenon include dermatographic (Fig. 4.5),
with all the same features of anaphylaxis with cold, heat, adrenergic, cholinergic, aquagenic,
hypotension being the most dominant feature
[30]. Baseline serum tryptase levels are the best
predictor of the severity of anaphylaxis in insect
sting-allergic patients [51, 52]. Understanding
the classification of the various insect stings
and bites that can lead to life-threatening hyper-
sensitivity reactions is helpful in patient man-
agement and future preventive therapy [50].
Specific venom immunotherapy (VIT) can pre-
vent morbidity and mortality in patients with
severe hymenoptera sting allergies. A 3–5 year
course of subcutaneous injections significantly
reduces the risk of anaphylaxis in up to 98% of
Fig. 4.5 Physical urticaria: dermatographism. Photo
children and is even effective and safe in high- courtesy of Dr. Douglas I. Rosen, Assistant Clinical
risk patients with mastocytosis. Indications and Professor of Medicine, Division of Dermatology,
recommendations for VIT differ by country and Montefiore Medical Center
solar, pressure, vibratory, and exercise-induced/ ogy, location, and duration of cutaneous signs of
food and exercise-induced (Table 4.4) [54]. histamine release, in particular urticaria and
Severe life-threatening responses to physical angioedema, should also be undertaken. Specific
stimuli are exceedingly rare. Of all the physical testing should be based on information provided
urticarias, exercise-induced and food-exercise- in the history and physical and may include blood
induced urticaria/anaphylaxis, and primary cold tests, skin biopsies of notable lesions in patients
urticaria have the highest incidence of associated with lesions lasting more than 24 h, food chal-
anaphylaxis. lenges, skin testing for allergens, and tests
Viral infections, while not a primary cause of designed to look for functional autoantibodies
urticaria, have also been known to exacerbate against IgE or the high-affinity receptor (FceR1)
urticarial reactions. It is thought that the up regu- of dermal mast cells and basophils.
lation of cytokines during acute phases of illness A measurement of serum and urine histamine
may lead to an enhanced state of mediator release and histamine metabolites and serum tryptase
from mast cells. can be done to demonstrate mast cell or basophil
activation. Serum histamine levels remain ele-
vated for only 30–60 min after the onset of symp-
4.4.7 Differential Diagnosis toms; therefore normal serum histamine levels
cannot rule out a serious histamine-mediated
The differential diagnosis of histamine-mediated reaction. A 24-h urine study of methylhistamine
emergencies in dermatology is extensive. Because is more accurate and should be initiated as soon
cutaneous signs such as urticaria are frequently as possible after symptoms begin. Tryptase is a
the earliest signs of life-threatening events, con- proteinase specific to mast cells and levels remain
ditions with an urticarial component must be elevated for up to 5 h after mast cell activation. In
ruled out. These include insect bite reactions, cases of anaphylaxis, levels are expected to
Sweets’ syndrome (acute febrile neutrophilic exceed 10 ng/mL and can increase greater than
dermatosis), the urticarial stage of bullous pem- 100 ng/mL in anaphylaxis from hymenoptera
phigoid, acute contact dermatitis of the face, urti- stings or medications [12].
carial drug reactions, and urtication caused by Allergen-specific skin testing or radioallergo-
rubbing of the lesions of urticaria pigmentosa. sorbent (RAST) testing can be used to identify
The prolonged duration of the individual urticar- certain causes of immunologic IgE-mediated
ial lesions in these conditions helps to differenti- reactions to food, latex, stinging insects, and
ate them from true urticaria, lesions of which other environmental allergens. These reactions
typically last for less than 24 h. can manifest as acute urticaria, angioedema, con-
tact urticaria, or anaphylaxis. The recent National
Institute for Health and Clinical Excellence
4.4.8 Diagnosis guidelines recommend that all children with a
clinically suspected immediate-type hypersensi-
4.4.8 A Urticaria and Angioedema tivity reaction, based on an allergy focused clini-
A comprehensive history and physical examina- cal history, undergo skin prick testing or specific
tion are essential in the diagnosis of a suspected IgE blood tests, in order to confirm the diagnosis.
histamine-mediated emergency. The sequential Additionally, these tests should only be per-
exposure to an agent with the development of formed where facilities are available to quickly
signs and symptoms, along with details of dis- manage and treat an anaphylactic reaction [55].
ease duration, known allergens, occupation, his- Patients with severe chronic urticaria should be
tory and frequency of similar episodes, duration tested for thyroid autoantibodies as well as have
of previous episodes, and any previously success- thyroid function tests performed if clinically rel-
ful or unsuccessful therapies should be reviewed. evant. Patients with chronic urticaria have a
A thorough physical exam assessing morphol- higher incidence of thyroid autoantibodies, which
70
Table 4.4 Physical urticarias: characteristics, diagnostic features, and treatment

Physical urticaria Features Eliciting stimulus Treatment
Symptomatic Linear wheals at sites of scratching or Stroking or rubbing Non-sedating H1 blocker
dermatographism friction (Most common physical urticaria); Can be
delayed by more than 30 min
Cholinergic urticaria Multiple small (1–5 mm) pruritic wheals Rise in core temperature Non-sedating H1 blocker
surrounded by a flare, “fried-egg” appearance; and sweating (exercise, hot baths,
Symmetric, initially most prominent spicy food, and stress)
on upper half of the body but can become
generalized; Angioedema can be present
Cold urticaria (primary) Urticarial eruption and edema localized to areas of Ice-cube test-positive; Non-sedating H1 blocker; Doxepin 25 mg at
cold exposures, usually the face and hands; Rarely Rewarming of skin after cooling bedtime up to 50 mg bid
respiratory and cardiovascular compromise occur; can worsen symptoms
Can be fatal if a person goes swimming or showers (localized or systemic)
in cold water; Begins in adulthood
Delayed pressure urticaria Superficial and deep erythematous swellings Sustained perpendicular Non-sedating H1 blocker
at sites of sustained pressure to the skin; swellings pressure
can be painful or pruritic or both; Can have systemic
features such as malaise or arthralgias; Diagnosis
can be difficult if swelling is over joints
Solar urticaria Eruption from exposure to ultraviolet light; Key finding Ultraviolet or visible solar Non-sedating H1 blocker; Avoidance of trigger
is the limitation of physical findings to radiation
areas of body exposed to direct sunlight; Prolonged
exposure leads to wheals; Anaphylaxis is possible if
exposed body surface area is large enough, >80%
Localized heat urticaria Formation of wheals when a warm stimulus comes Local heat contact Non-sedating H1 blocker; Tolerance induction;
into direct contact with the skin Hydroxychloroquine
Adrenergic urticaria Small (1–5 mm) red macules and papules with Emotional stress Beta-adrenoreceptor-blocker (e.g., propranolol)
surrounding pallor
Aquagenic urticaria Multiple small (1–5 mm) pruritic wheals Local water contact at any Non-sedating H1 blocker; Avoidance of trigger
surrounded by a flare, “fried-egg” temperature
appearance
A. Rosen et al.
Physical urticaria Features Eliciting stimulus Treatment 4
Exercise-induced anaphylaxis Wheals tend to be larger than cholinergic wheals Exercise, not secondary to rise in Non-sedating H1 and H2 blocker prior to
(EIA) and EIA can also occur without wheals; Additional core temperature like in hot baths exercise; Self-injectable epinephrine kits in
manifestations of mast cell degranulation can occur patients with a history of anaphylactic episodes
including bronchospasm or cardiovascular collapse and respiratory symptoms
and anaphylaxis
Food and EIA Angioedema or anaphylaxis occur within minutes Exercise following a heavy food Non-sedating H1 blocker prior to exercise and
of exercise in patients who have ingested specific load or eating specific foods avoidance of certain foods or large meals prior
foods up to several hours prior to exercising; to exercise; Self-injectable epinephrine kits in
Some patients may experience food-dependent, patients with a history of anaphylactic episodes
EIA with the consumption of any solid food or large and respiratory symptoms
meals prior to exercising
Vibratory angioedema Erythema and swelling in response to vibratory Vibration (jogging, using a Avoidance of vibratory stimuli
stimuli; Familial form is autosomal dominant; lawnmower, or riding a
Histamine-Mediated Emergencies
Acquired form is milder motorcycle)

71
72 A. Rosen et al.
may indicate an autoimmune etiology of the also highly likely if at least two of the following
patient’s urticaria. Limitations exist in confirming signs and symptoms are present: involvement of
the presence of functional serum autoantibodies. the skin or mucosa; respiratory compromise;
Immunoassays for anti-FceRI and anti-IgE may hypotension; or persistent gastrointestinal symp-
not be completely accurate as patients may have toms. Finally, criteria for diagnosing anaphylaxis
nonfunctional as well as functional autoantibod- can be completely based on a patient’s reduced
ies. Autologous serum skin tests (ASSTs) can be blood pressure after exposure to a known aller-
a helpful screening tool. They involve intrader- gen. In adults, a systolic blood pressure of less
mal injections of autologous serum versus saline than 90 mm Hg or a 30% or greater decrease from
controls with positive results demonstrated by a baseline is considered significant [10].
pink wheal response at 30 min that is 1.5 mm
greater in diameter than the control. Further
research is necessary to find accurate means to 4.4.9 Treatment
diagnose patients with functional autoantibodies
and an autoimmune etiology of anaphylaxis. 4.4.9 A Urticaria and Angioedema
Urticaria is often idiopathic, infrequently associ-
4.4.8 B Physical Urticaria ated with a known allergen, and rarely results in
Several different standards have been proposed to life-threatening conditions. The treatment is not a
aid in the diagnosis of the numerous physical clear-cut science and often requires a patient
urticarias. Table 4 provides a basic elicitation specific regimen. All patients who suffer from
strategy for each physical urticaria. Eliciting for a urticaria should be given information on common
physical urticaria along with antihistamine- precipitants. Antihistamines, topical antipruritic
responsive symptoms may be all that is required preparations, and the avoidance of known trig-
for diagnosis. However, some patients may prove gers are often a successful initial approach. Some
more difficult to accurately diagnose. Important patients, however, will need additional interven-
to remember is that patients may have severe tions, including systemic steroids.
reactions upon eliciting a physical urticaria and First line therapy for treatment of urticaria is
testing must be performed in a safe, controlled accomplished with antihistamines, which are
setting. most effective when taken on a daily basis rather
than as-needed symptomatic relief. Classic sedat-
4.4.8 C Anaphylaxis ing H1-antihistamines include chlorpheniramine,
Although anaphylaxis was first described over hydroxyzine, and diphenhydramine. While effec-
100 years ago, and is broadly understood as tive in controlling symptoms of urticaria, their
described above (see Urticaria, Angioedema, and potent sedative effects are a drawback, and they
Anaphylaxis: Definitions), there is still no univer- are not more efficient than the modern, non-sedating
sally accepted definition. In 2006, the second H1-antihistamines. Additionally, newer H1-
National Institute of Allergy and Infectious antihistamines and their derivatives have less
Disease/Food Allergy and Anaphylaxis Network anticholinergic effects; therefore, patients experi-
symposium on the definition and management of ence less dry mouth, visual disturbances, tachy-
anaphylaxis was held to determine the necessary cardia, or urinary retention. Examples include
clinical criteria for diagnosing anaphylaxis. loratadine, desloratadine, cetirizine, levocetiriz-
Anaphylaxis is considered highly likely when ine, terfenadine, fexofenadine, and mizolastine
there is acute onset of illness (within minutes to (Table 4.5). H2-antihistamines, such as cimeti-
hours) with involvement of the skin, mucosal tis- dine and ranitidine, have no beneficial effect on
sue, or both AND either respiratory compromise histamine-induced pruritus, and should therefore
or evidence of end organ dysfunction (i.e., not be used as monotherapy for urticaria.
decreased blood pressure, incontinence, syncope). If symptoms are not improved after 2 weeks of
After exposure to a likely allergen, anaphylaxis is treatment with a non-sedating H1-antihistamine,
Table 4.5 Treatment algorithm for urticaria and angioedema modified from international treatment recommendations
Treatment level Intervention Examples
First level Non-sedating H1-antihistamine Cetirizine
Newer non-sedating H1-antihistamine Loratadine
Terfenadine
Mizolastine
Levocetirizine
Desloratadine
Fexofenadine
Second level Increase dose of non-sedating H1-antihistamine up to 4 times
Third level Continue non-sedating H1-antihistamine and add a leukotriene antagonist Zafrilukast
Or, try changing H1-antihistamine Montelukast
Or, continue non-sedating H1-antihistamine and add Doxepin
Corticosteroidsa for severe exacerbations of acute urticaria or resistant cases Prednisone
of chronic urticaria. Short course (3–7 days) Prednisolone
Fourth level Add one of the following to H1-antihistamine
Cyclosporine
H2-antihistamine Cimetidine
Dapsone Ranitidine
Omalizumab
a
Pediatric prescribing manuals should be referenced for details on doses on children
Adapted from: Zuberbier, T. et al. Allergy 2009: 64: 1427–1443
increasing the dosage up to 4 times may provide antihistamine acitivity, may also be beneficial for
relief. Patients with chronic urticaria have patients unresponsive to antihistamine therapy.
demonstrated increased symptomatic relief from Dosing begins at 10–25 mg at night, and can be
doses of antihistamines up to 4 times higher than increased to up to 75 mg nightly [62]. Side effects
conventional doses without a compromise in may include sedation and weight gain.
safety [56]. Patients with frequent episodes of A short course (3–7 days) of high-dose corti-
idiopathic anaphylaxis may also benefit from the costeroids (prednisone or prednisolone 30–60 mg/
use of daily prophylactic H1-antihistamine. day) may be effective in antihistamine resistant
Patients should wait between 1 and 4 weeks cases of chronic urticaria or severe episodes of
before considering switching to alternative thera- acute urticaria when a rapid clinical response is
pies to allow for the full effectiveness of antihis- needed [63]. Longer treatments with steroids
tamine therapy. Patients should also try switching beyond 7–14 days are not recommended, but if
to a different H1-antihistamine before adding on necessary, should be carried out under the care of
additional medications [57]. a specialty clinic. Long-term use of systemic cor-
Second line therapies should be initiated if ticosteroids is associated with substantial adverse
symptomatic relief is not accomplished with anti- effects. Patients may be at increased risk for
histamines alone. The addition of a leukotriene developing diabetes mellitus, hypertension,
antagonist, such as zafirlukast or montelukast, osteoporosis, adrenal insufficiency, or gastroin-
may provide some patients relief from symptoms, testinal bleeding [64]. Patients who suffer from
especially patients with symptoms aggravated by chronic urticaria or known severe allergies to
NSAIDs and food additives [58, 59]. While evi- certain foods, medications, or insect bites
dence is limited for the use of lipoxygenase (zile- should carry a self-injectable epinephrine pen
uton) and cyclooxygenase (rofecoxib) inhibitors, (e.g., EpiPen) and be adequately trained in its use
these medications may also be effective for and administration.
chronic urticaria [60, 61]. Doxepin, a tricyclic If symptomatic relief is still not achieved, the
antidepressant with potent H1- and H2- addition of cyclosporine, H2-antihistamines,
74 A. Rosen et al.
dapsone, or omalizumab are recommended as unknown [75]. Rituximab is a chimeric murine/

fourth level treatment by the current interna- human recombinant mAb that binds to CD20,
tional guidelines for management of urticaria which is found on B-cells. This binding leads to
(Table 4.5) [57]. Low-dose cyclosporine has B-cell depletion and possibly decreased produc-
shown in several randomized and non-random- tion of IgG autoantibodies. Rituximab is being
ized trials to be safe and effective in decreasing investigated for the treatment of non-IgE autoan-
urticarial symptoms in patients with chronic tibody-mediated forms of chronic autoimmune
idiopathic urticaria [65–67]. Additionally, cyclo- urticaria, but further research is needed in this
sporine inhibits the release of preformed hista- patient population [72].
mine and de novo mediators from human skin In summary, the treatment of urticaria and
mast cells and basophils [68]. The combined angioedema first requires the avoidance of known
use of H1- and H2-antihistamines may improve allergens such as food, drugs, latex, or other
symptoms in some patients with difficult contact allergens. Symptomatic relief is often
chronic urticaria [69]. Dapsone has been shown achieved with oral antihistamines. A short course
to achieve better long-term complete resolution of oral corticosteroids may be necessary for
of urticaria when used in combination with severe protracted episodes and to prevent a late-
antihistamines as compared to treatment with phase response, though it takes up to 4 hours for
antihistamines alone [70, 71]. However, the the effects of oral corticosteroids to be seen.
efficacy of dapsone longer than 3 months after Finally, epinephrine should be considered only in
withdrawal has not been well studied. the acute intervention of severe and life-threatening
Omalizumab is a recombinant humanized attacks.
monoclonal antibody (mAb) that binds to the C3
domain of the IgE antibody, the site where IgE 4.4.9 B Anaphylaxis
binds to the FceR1, thereby blocking the binding Despite efforts to avoid known or common trig-
of IgE to the FceR1 on the surface of mast cells gers of anaphylaxis, there is still no way to abso-
and basophils. Therefore, it can reduce levels of lutely prevent exposures. Therefore, it is crucial
circulating IgE autoantibodies and inhibit binding that at-risk patients and caregivers be able to rec-
of IgE to high-affinity FceR1 resulting in FceR1 ognize early signs and symptoms of anaphylaxis
down regulation [72, 73]. Studies have demon- and have knowledge of emergent, life-saving
strated that a fixed subcutaneous dose of omali- measures. The treatment of anaphylaxis requires
zumab added to a stable dose of H1-antihistamine implementing standard principles for emergency
may be effective in patients with refractory chronic resuscitation, including an initial assessment of
idiopathic urticaria or a small subpopulation of the patient’s airway, breathing, circulation, and
chronic urticaria patients who exhibit IgE autoan- vital signs, before proceeding with any further
tibodies against thyroperoxidase [73, 74]. management.
Since the recognition that some patients with Epinephrine is considered an essential com-
chronic urticaria may have an autoimmune component of anaphylaxis treatment by the World
ponent to their disease, research is ongoing in the Health Organization and World Allergy
use of other immunomodulatory therapies. Organization [76]. Epinephrine should be
These include low-dose methotrexate, rituximab, administered at the first sign of anaphylaxis
mycophenolate mofetil, cyclosporine, cyclo- since delayed administration of epinephrine,
phosphamide, plasmapheresis, intravenous especially in the pediatric population, leads to
immunoglobulin therapy, azathioprine, and oral an increased risk of biphasic reactions, hypoxic-
tacrolimus. Methotrexate is an antimetabolite ischemic encephalopathy, and mortality. The
that has demonstrated efficacy in patients with most important life-saving effects of epineph-
chronic urticaria nonresponsive to conventional rine occur through the alpha-1 adrenergic
therapies. The mechanism of methotrexate in receptors. These include vasoconstriction of
treating chronic urticaria, however, remains small arterioles and precapillary sphincters
with resultant decreased mucosal edema, injection into the postero-lateral calf muscle
reduction in angioedema and hives, and relief (gastrocnemius/soleus), with little overlying
of upper airway obstruction, hypotension, and subcutaneous fat and no endangered superficial
shock. Additional benefit from epinephrine arteries or nerves, may provide an effective
follows from the effects on alpha-2 (decreased alternative [79]. Otherwise, varying length nee-
insulin release), beta-1 (increased heart rate dles on preloaded syringes provide another
and force of cardiac contractions), and beta-2 option, although with reduced shelf life of the
(bronchodilation and decreased release of epinephrine.
mediators from mast cells and basophils) Up to 20% of patients require a second or
adrenergic receptors [76]. multiple injections due to persistent symptoms
In an emergency, epinephrine administered or a biphasic reaction. Maximum doses may be
intramuscularly or subcutaneously is the treat- repeated every 5–15 min as needed in the absence
ment of choice; however, intramuscular injec- of a response to epinephrine [21]. Posture may
tions have been shown to reach peak plasma also affect mortality in anaphylaxis and thus
epinephrine levels more rapidly than subcutane- patients should be kept lying down with raised
ous injections with an auto-injector in children at legs to maintain the vena cava as the lowest part of
risk of anaphylaxis [77]. The first-aid dose of the body. This helps blood flow return to the right
epinephrine is 0.5 mg for adults and 0.3 mg for side of the heart and ensures adequate myocardial
children [78]. Auto-injector formulations of perfusion [83]. Patients and caretakers must be
epinephrine include the EpiPen (Dey LP, Napa, properly instructed on the importance of and how
California, USA), Adrenaclick and Twinject to use emergency epinephrine auto-injectors so
(Sciele, Division of Shionogi, Japan), and the as to avoid injury from unintentional injections
Anapen (Lincoln Medical, Salisbury, Wiltshire, and to make sure epinephrine is delivered to the
UK; not available in the USA), and in most coun- individual experiencing an anaphylactic episode.
tries they are available in two fixed epinephrine Epinephrine auto-injectors, or any self-inject-
doses per injection, 0.3 mg (e.g., EpiPen) and able devices when auto-injectors are unavailable,
0.15 mg (e.g., EpiPen Jr.). The Twinject and the should be prescribed for individuals who have
Adrenaclick are similar devices but the Twinject already experienced anaphylaxis involving respi-
contains two doses of epinephrine where the ratory symptoms, hypotension, or shock, patients
Adrenaclick contains only one. In some coun- with known triggers that are commonly encoun-
tries, the Anapen is also available in a 0.5 mg tered in the community, including foods, insect
fixed epinephrine dose. The injections should be stings, or physical urticarias, and patients with a
administered intramuscularly in the lateral thigh history of idiopathic anaphylaxis [84]. Clinical
to control symptoms and maintain normal blood judgment should be used when prescribing an
pressures. The 0.3 mg and the 0.15 mg injectable epinephrine auto-injector for patients with a
doses are appropriate for pediatric patients over history of moderate to severe urticarial reactions
30 kg and between 15 and 30 kg, respectively. after exposure to a known inciting allergen but no
However, allergy specialists should be involved history of anaphylaxis. There are no contraindi-
in the treatment of children below 15 kg requir- cations to using epinephrine in anaphylaxis and
ing first-aid treatment with epinephrine for thus the threshold for prescribing should be low
anaphylaxis for which the 0.15 mg dose may be [78]. When multiple repeat intramuscular doses
too high [79]. of epinephrine are required, patients may benefit
With increasing rates of obesity in the USA from intravenous epinephrine in the form of bolus
[80], physicians must be aware that auto-injector epinephrine or a continuous infusion. However,
needles might not achieve appropriate depths for intravenous administration of epinephrine should
intramuscular injection, even in pediatric patients only be performed by a trained and experienced
[81, 82]. It has been proposed that in such patients, specialist [85].
76 A. Rosen et al.
Side effects of epinephrine include tachycardia, often absent in more advanced forms of sys-
anxiety, and headache, and caution should be temic disease [87]. Cutaneous mastocytosis is
applied for use in patients with hypertension, more common in children than in adults, with
ischemic heart disease, cerebrovascular disease, 55% of patients noted to have onset before 2
and diabetes mellitus. Additionally, side effects years of age and an additional 10% of patients
of epinephrine may mimic signs of anaphylaxis with disease onset before the age of 15 [88]. In
and care must be taken not to administer extrane- childhood disease, the skin is almost exclusively
ous doses. Oxygen therapy and placing the patient involved and skin lesions typically improve or
in the supine position with lower extremity eleva- resolve by late adolescence [89]. In contrast,
tion should also be maintained. Additional thera- adult-onset disease occurs between the ages of
pies depend on the severity of the anaphylactic 20 and 40 years, [89, 90] is more frequently
episode and include intravenous fluids, antihista- systemic, and disease persists throughout a
mines, vasopressors, corticosteroids, glucagon, patient’s lifetime. Although cutaneous mastocy-
atropine, and nebulized albuterol. Monitoring tosis is less commonly seen in the adult popula-
patients for several hours after an anaphylactic epi- tion, patients with systemic mastocytosis and
sode is extremely important, as is providing instruc- skin involvement are frequently diagnosed based
tions on how best to avoid future reactions based on their cutaneous lesions.
on the inciting antigen. The arrhythmogenicity of
epinephrine may be augmented by certain medi-
cations, including tricyclic antidepressants, drugs 4.5.2 WHO Categorization
such as cocaine, or underlying cardiac arrhythmias
[79]. Therefore, the benefits must be weighed The WHO classification of mastocytosis is an
against the potential side effects when prescrib- accepted clinical approach to help distinguish
ing epinephrine auto-injectors for patients. cutaneous mastocytosis, systemic mastocytosis,
Finally, efforts should be made to treat any under- and their subvariants [91]. The major types of
lying medical conditions since certain diseases, cutaneous mastocytosis include urticaria pigmen-
such as asthma or cardiovascular disease, can tosa, diffuse cutaneous mastocytosis, solitary
increase a patient’s risk for a severe anaphylactic mastocytoma, and telangiectasia macularis erup-
episode [78, 86]. tiva perstans. The majority of pediatric cases of
cutaneous mastocytosis show a good prognosis
with gradual resolution of both symptoms and
4.5 Mastocytosis skin lesions [92].
In children, systemic involvement is rare and
4.5.1 Definition and Epidemiology disease may regress spontaneously in puberty or
early adolescence. In adults, disease does not
Mastocytosis represents a collection of hetero- regress but rather has an indolent clinical course
geneous disorders characterized by the abnor- [87]. Survival in patients with indolent systemic
mal growth and accumulation of mast cells mastocytosis is not statistically different from the
and the aberrant release of mast cell mediators, general population. Prognoses for aggressive
predominantly histamine, in various organ systemic mastocytosis and mast cell leukemia,
systems. Mastocytosis can be broadly divided however, are poor, and median survival is around
into cutaneous mastocytosis, characterized by 41 months and 2 months, respectively [93].
the presence of one or more lesions limited to
the skin; and systemic mastocytosis, defined by
lesions affecting various internal organs, com- 4.5.3 Pathophysiology
monly the bone marrow, gastrointestinal tract,
liver, and spleen. Systemic mastocytosis may or In most patients with mastocytosis disease is
may not involve the skin. Cutaneous involve- caused by a gain of function mutation in KIT, the
ment is more common in indolent forms and mast/stem cell growth factor receptor that is
responsible for the differentiation and growth of

mast cells. Mutation results in activation with
subsequent accumulation and increased survival
of mast cells, although a second “hit” is neces-
sary in the pathogenesis, as the same mutations
have been found independent of mastocytosis.
Specifically, the D816V point mutation is found
in 95% of adult patients with systemic mastocy-
tosis [51]. As the pathogenesis of mastocytosis
has become better understood it is known that the
mechanisms of disease in the pediatric and adult
populations may differ, and the frequency and Fig. 4.6 Nodular mastocytoma. Photo courtesy of Dr.
significance of mutations in pediatric cases of Douglas I. Rosen, Assistant Clinical Professor of Medicine,
mastocytosis is controversial [51, 87]. Division of Dermatology, Montefiore Medical Center
4.5.4 Clinical Features
For some patients, the cosmesis of urticaria pig-

mentosa lesions is the only complaint and the
majority of patients with mastocytosis are com-
pletely asymptomatic. When present, cutaneous
and systemic symptoms are caused by IgE-
dependent and non-IgE-mediated degranulation
of mast cells and release of histamine and other
mediators, including tryptase, from the patho-
genic mast cells. The pathophysiology of symp-
tom development in mastocytosis is identical to
that described for urticaria, angioedema, and ana-
phylaxis, and can be precipitated by the same
mast cell stimulators as detailed above and out-
lined in Table 4.3. Symptoms of mastocytosis
may be exacerbated by physical stimuli
(Table 4.4), alcohol, narcotics, salicylates and
other NSAIDs, polymyxin B, or anticholinergic
medications.
Childhood cutaneous mastocytosis often
presents with a solitary tan or pink to brown
plaque or nodule (mastocytoma) (Fig. 4.6) or
anywhere from 10 to 1,000 tan to brown macules
or papules (urticaria pigmentosa) (Fig. 4.7). Fig. 4.7 Urticaria pigmentosa. Photo courtesy of Dr.
Erythema, swelling, and blister formation can Douglas I. Rosen, Assistant Clinical Professor of Medicine,
occur after stroking or rubbing the lesions [94]. Division of Dermatology, Montefiore Medical Center
Darier’s sign, the development of urticaria after
stroking the lesions of mastocytosis, is not
always present and correlates with the concen- but lesions can also occur on the face, palms,
tration of mast cells in the lesion. The trunk and soles, and scalp. Of note, the extent of cutaneous
extremities are the most common sites involved, involvement is not directly associated with
78 A. Rosen et al.
symptoms and is also not predictive of systemic The cumulative prevalence of anaphylaxis in
disease [89]. Diffuse cutaneous mastocytosis children with mastocytosis is between 6% and
(DCM) is a rare severe form seen predominantly 9% and in adults is between 22% and 49%.
in infants. The skin is infiltrated by mast cells in Patients with systemic disease are at increased
a generalized and diffuse pattern. The skin is risk of anaphylaxis compared to patients with
thickened and appears doughy with a yellow dis- solely cutaneous disease [51]. Severe anaphylac-
coloration and accentuated folds. In areas of tic reactions with shock or cardiopulmonary
increased mast cell accumulation, nodules or arrest are more common in patients with sys-
plaques are present. Additionally, edema may temic mastocytosis, especially individuals with
result from the mast cell infiltration and degran- hymenoptera allergies. Deaths associated with
ulation in the skin [92]. Life-threatening hypoten- extensive mast cell mediator release are rare but
sive episodes are common complications of have been documented in both the pediatric and
DCM and occur due to the extent of lesions, adult populations. Overall, the spectrum of cuta-
which can involve the entire skin, and the large neous subtypes of mastocytosis has a good prog-
amount of mast cell mediator release locally and nosis in comparison to systemic disease.
systemically during severe episodes [94]. Bullous
eruptions with hemorrhage is a subvariant of
DCM seen predominantly in neonates with blis- 4.5.5 Diagnosis
ters erupting spontaneously or from a stimulus.
Patients may present at birth (congenital) or in The diagnosis of cutaneous mastocytosis requires
early infancy, but blistering typically resolves by a high index of suspicion in patients with skin
3–5 years of age [92]. Mild symptoms such as lesions with or without mast cell mediator-related
cutaneous flushing, blistering, or pruritus, or symptoms. These include flushing spells, pruri-
more severe symptoms such as shortness of tus, redness, swelling, respiratory symptoms,
breath, asthma exacerbations, hypotension, and including asthma exacerbations and shortness of
gastrointestinal symptoms, occur more com- breath, and gastrointestinal symptoms, including
monly in patients with systemic disease, but may peptic ulcer disease and diarrhea. The lesions of
also be seen in patients with severe cutaneous childhood and adult mastocytosis are very char-
disease, in particular DCM, due to the higher acteristic and may rarely be confused with other
concentrations of mast cells [89]. skin disorders. Demonstration of a positive
When cutaneous lesions are present in adults Darier’s sign, seen most commonly in patients
they appear different from the typical lesions with mastocytomas, is helpful in the diagnosis.
seen in children. They are 2–5 mm brown-reddish A negative sign, however, does not rule out
macules or papules. Telangiectasia macularis mastocytosis. Most diagnoses are based on
eruptiva perstans is seen in <1% of patients and clinical findings and results of skin biopsies.
exclusively in adults. The lesions appear as tan- Demonstration of increased mast cells in either
to-brown macules with patchy erythema and the blister fluid or skin biopsy of the mastocytosis
telangiectasias. patient may establish the correct diagnosis.
Evolution of a childhood cutaneous form of Special stains that recognize tryptase and KIT
mastocytosis to a systemic form is seen infre- (CD117) aid in the identification of tissue mast
quently. The signs and symptoms of systemic cells [96]. Analysis of KIT-receptor mutations,
mastocytosis reflect the infiltration of mast cells specifically the D816V mutation, within skin
into the involved tissues. Patients may present with mast cells is recommended. Serum tryptase
constitutional signs, skin lesions, mediator-related levels can also be an indicator of mast cell load,
findings (flushing, syncope, diarrhea, hypotension, but are more likely to be increased in patients
headache, and/or abdominal pain), and musculo- with systemic mastocytosis.
skeletal disease, with an increased risk of severe Systemic mastocytosis often requires more
osteoporosis [95]. invasive diagnostic measures. A workup should
be performed in children when there is suspicion mutation in codon 816 in blood, bone marrow, or
of progression to a systemic adult form, severe other lesional tissue; (3) Mast cells in the bone
recurrent systemic mast cell mediator-related marrow, blood, or other lesional tissue express
symptoms, organomegaly, or skin lesions that fail CD25 or CD2; (4) Baseline total tryptase level is
to resolve. In adults, a careful workup is neces- persistently >20 mg/mL [51]. Further criteria are
sary to accurately diagnose and stage patients used to subcategorize patients based on the sever-
with systemic disease. Initial laboratory testing ity of their disease.
includes a complete blood count with differen-
tials, a chemistry panel, liver enzymes, and
tryptase levels [92]. Bone marrow examination 4.5.6 Treatment
with biopsies is also often indicated in adult
patients. There are no definitive effective treatments for
In most patients, histologic evaluation of bone patients with cutaneous mastocytosis or indolent
marrow biopsies and mast cell identification systemic mastocytosis, and aggressive forms of
allow for the most efficient diagnosis of sys- therapy in these patients are not indicated. In gen-
temic mastocytosis, as the bone marrow is almost eral, treatment of patients with mastocytosis is
always involved. Just as molecular detection of directed towards alleviating symptoms. Patients
KIT mutations are performed in skin biopsies, should be advised to avoid triggers and medica-
they can be performed on fresh bone marrow tions that induce mast cell degranulation, as well
aspirate, clot sections, bone marrow biopsy as heat and friction, which can induce local or
sections, and even peripheral blood if there are systemic symptoms. Local and systemic thera-
circulating mast cells. An immunohistochemistry pies should target symptoms related to mast cell
panel consisting of CD117, tryptase, and CD25, mediator release and symptomatic skin lesions.
with the latter not present in normal or reac- Patients with more severe disease, and especially
tive mast cells, can also detect neoplastic mast those with underlying asthma, respiratory condi-
cells [95]. tions, or known severe allergies (i.e., hymenoptera
Additional laboratory and radiographic stud- allergy), who are at increased risk of anaphylaxis,
ies may be indicated for patients with additional should be directed to carry an emergency kit with
signs of systemic involvement. Patients with self-injectable epinephrine, antihistamines, and
complaints of bone pain should have an X-ray corticosteroids at all times. Similar treatments as
evaluation to look for skeletal involvement. those described for urticaria, angioedema, and
However, in children with cutaneous mastocyto- anaphylaxis are also utilized in the treatment of
sis and no evidence of systemic disease, positive mastocytosis. First-line therapy is non-sedating
X-ray findings may falsely convey signs of sys- H1-anithistamines. For patients with recurrent
temic disease [97]. The liver, spleen, lymph episodes of anaphylaxis or persistent pruritus,
nodes, gastrointestinal tract, and any other organ prophylaxis with daily antihistamines is recom-
may also be involved, and require further imag- mended. Additionally, management of pruritus
ing or workup for diagnosis. and gastric hypersecretion may be accomplished
Ultimately, the diagnosis of systemic masto- with proton pump inhibitors, anticholinergics,
cytosis is based on World Health Organization cromolyn sodium (which inhibits mast cell
criteria, with one major and one minor, or three degranulation), or leukotriene antagonists.
minor criteria required. The major criterion is the Omalizumab (anti-IgE mAb) has also been
presence of multifocal dense infiltrates of mast successful in mastocytosis patients with multiple
cells in bone marrow and/or other extracutaneous episodes of anaphylaxis. Topical corticosteroids
tissues. The minor criteria include: (1) More than are effective for localized treatment, such as
25% of the mast cells in bone marrow smears or mastocytomas, and lifelong allergen-specific
tissue biopsy sections are spindle shaped or dis- venom immunotherapy (VIT) is recommended
play atypical morphology; (2) Detection of a c-kit for patients with mastocytosis and hymenoptera
80 A. Rosen et al.
venom allergy [51]. Finally, emergency manage- 8. Gober LM, Saini SS. Allergic urticaria. In: Tyring SK,
ment of anaphylaxis begins with an initial assess- Gaspari AA, editors. Clinical and basic immunoder-
matology. London: Springer; 2008. p. 459–77.
ment of the patient’s airway, breathing, circulation, 9. Sampson HA, et al. Symposium on the definition and
and vital signs, and then rapid administration of management of anaphylaxis: summary report.
epinephrine. J Allergy Clin Immunol. 2005;115(3):584–91.
10. Sampson HA, et al. Second symposium on the
definition and management of anaphylaxis: summary
report–Second National Institute of Allergy and
4.6 Conclusion Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. J Allergy Clin Immunol.
Emergencies in dermatology are infrequent, and 2006;117(2):391–7.
11. Kanji S, Chant C. Allergic and hypersensitivity reactions
histamine-mediated emergencies are even more in the intensive care unit. Crit Care Med. 2010;38:S162–
rare. As a very powerful mediator of hypersensi- 8. doi:10.1097/CCM.0b013e3181de0c99.
tivity reactions, histamine can result in classic 12. Sampson HA, Mendelson L, Rosen JP. Fatal and near-
clinical signs and symptoms that should not be fatal anaphylactic reactions to food in children and
Adolescents. N Engl J Med. 1992;327(6):380–4.
overlooked as they could very quickly evolve into 13. Zuberbier T. Urticaria. Allergy. 2003;58(12):
life-threatening entities. Immediate diagnosis and 1224–34.
appropriate intervention could be lifesaving. 14. Volcheck, G.W. Anaphylaxis and anaphylactoid reac-
Urticaria, angioedema, and mastocytosis are the tions, in clinical allergy: diagnosis and Management.
Humana Press; 2009. p. 433–63.
most important histamine-mediated entities car- 15. Lieberman P, et al. Epidemiology of anaphylaxis:
rying the risk of anaphylaxis, shock, and possibly findings of the American College of Allergy, Asthma
death. It is of paramount importance to perform a and Immunology Epidemiology of Anaphylaxis
complete history (including possible triggers, Working Group. Ann Allergy Asthma Immunol.
2006;97(5):596–602.
individual risk factors, and medications) and a 16. Clark S, Camargo Jr CA. Epidemiology of anaphy-
thorough physical examination. Any case of urti- laxis. Immunol Allergy Clin North Am. 2007;27(2):
caria should prompt a vigilant interaction between 145–63. v.
clinician and patient. 17. Wolf R. Emergency dermatology. Cambridge:
Cambridge University Press; 2010. p. 178–83. xi,
363.
18. Hall JE, Guyton AC. Guyton and Hall textbook of
References medical physiology. Philadelphia, PA: Saunders/
Elsevier; 2011. p. xix, 1091 p.
1. Maintz L, Novak N. Histamine and histamine intoler- 19. Brown SG. The pathophysiology of shock in anaphy-
ance. Am J Clin Nutr. 2007;85(5):1185–96. laxis. Immunol Allergy Clin North Am.
2. Ogawa Y, Grant JA. Mediators of anaphylaxis. 2007;27(2):165–75. v.
Immunol Allergy Clin North Am. 2007;27(2):249–60. 20. Pumphrey RS. Lessons for management of anaphy-
vii. laxis from a study of fatal reactions. Clin Exp Allergy.
3. Lieberman P. Clinical aspects and diagnosis of ana- 2000;30(8):1144–50.
phylaxis. In: Pawankar R, Holgate ST, Rosenwasser 21. Simons FE. Anaphylaxis. J Allergy Clin Immunol.
LJ, editors. Allergy frontiers: diagnosis and health 2010;125(2 Suppl 2):S161–81.
economics. Springer: Tokyo; 2009. p. 319–33. 22. Bhatia R, Alikhan A, Maibach HI. Contact urticaria:
4. Tole JW, Lieberman P. Biphasic anaphylaxis: review present scenario. Indian J Dermatol. 2009;54(3):
of incidence, clinical predictors, and observation rec- 264–8.
ommendations. Immunol Allergy Clin North Am. 23. Novembre E, et al. Urticaria and urticaria related skin
2007;27(2):309–26. viii. condition/disease in children. Eur Ann Allergy Clin
5. Viale PH, Yamamoto DS. Biphasic and delayed Immunol. 2008;40(1):5–13.
hypersensitivity reactions: implications for oncol- 24. Finn AA. Urticaria and angioedema. In: Lieberman P,
ogy nursing. Clin J Oncol Nurs. 2010;14(3): Anderson JA, editors. Allergic diseases. London:
347–56. Humana Press; 2007. p. 199–215.
6. James WD, et al. Andrews’ diseases of the skin clini- 25. Yang MS, et al. Epidemiologic and clinical features of
cal dermatology. London: Saunders Elsevier; 2011. p. anaphylaxis in Korea. Annals of allergy, asthma &
138–54. immunology: official publication of the American
7. Fisher AA. Contact dermatitis. Philadelphia: Lea and College of Allergy, Asthma, & Immunology.
Febiger; 1973. 2008;100(1):31–6.
26. Frigas E, Park MA. Acute urticaria and angioedema: 47. Bircher AJ, Scherer K. Delayed cutaneous manifesta-
diagnostic and treatment considerations. Am J Clin tions of drug hypersensitivity. Med Clin North Am.
Dermatol. 2009;10(4):239–50. 2010;94(4):711–25. x.
27. Simons FER. Anaphylaxis pathogenesis and treat- 48. Shah D, Chowdhury MM. Rubber allergy. Clin
ment. Allergy. 2011;66:31–4. Dermatol. 2011;29(3):278–86.
28. Gonzalez-Perez A, et al. Anaphylaxis epidemiology 49. Freeman TM. Clinical practice. Hypersensitivity to
in patients with and patients without asthma: a United hymenoptera stings. N Engl J Med. 2004;351(19):
Kingdom database review. J Allergy Clin Immunol. 1978–84.
2010;125(5):1098.e1–104. 50. Brockow K, Ring J. Update on Diagnosis and
29. Krishna MT, et al. Diagnosis and management of Treatment of Mastocytosis. Curr Allergy Asthma
hymenoptera venom allergy: British Society for Rep. 2011;11(4):292–9.
Allergy and Clinical Immunology (BSACI) guide- 51. Rueff F, et al. Predictors of severe systemic anaphy-
lines. Clin Exp Allergy. 2011;41(9):1201–20. lactic reactions in patients with Hymenoptera venom
30. Bilò MB. Anaphylaxis caused by Hymenoptera stings: allergy: importance of baseline serum tryptase-a study
from epidemiology to treatment. Allergy. 2011;66: of the European Academy of Allergology and Clinical
35–7. Immunology Interest Group on Insect Venom
31. Keet CA, Wood RA. Food allergy and anaphylaxis. Hypersensitivity. J Allergy Clin Immunol.
Immunol Allergy Clin North Am. 2007;27(2):193– 2009;124(5):1047–54.
212. vi. 52. Tanus T, et al. Serum tryptase in idiopathic anaphy-
32. Ayuso R. Update on the diagnosis and treatment of laxis: a case report and review of the literature. Ann
shellfish allergy. Curr Allergy Asthma Rep. Emerg Med. 1994;24(1):104–7.
2011;11(4):309–16. 53. Dice JP. Physical urticaria. Immunol Allergy Clin
33. Hungerford JM. Scombroid poisoning: A review. North Am. 2004;24(2):225–46. vi.
Toxicon. 2010;56(2):231–43. 54. Sackeyfio A, et al. Diagnosis and assessment of food
34. Taylor SL, Stratton JE, Nordlee JA. Histamine poi- allergy in children and young people: summary of
soning (scombroid fish poisoning): an allergy-like NICE guidance. BMJ. 2011;342:d747.
intoxication. J Toxicol Clin Toxicol. 55. Staevska M, et al. The effectiveness of levocetirizine
1989;27(4–5):225–40. and desloratadine in up to 4 times conventional doses
35. Sicherer SH, Leung DYM. Advances in allergic skin in difficult-to-treat urticaria. J Allergy Clin Immunol.
disease, anaphylaxis, and hypersensitivity reactions to 2010;125(3):676–82.
foods, drugs, and insects in 2010. J Allergy Clin 56. Zuberbier T, et al. EAACI/GA(2)LEN/EDF/WAO
Immunol. 2011;127(2):326–35. guideline: management of urticaria. Allergy.
36. Venter C, Arshad SH. Epidemiology of food allergy. 2009;64(10):1427–43.
Pediatr Clin North Am. 2011;58(2):327–49. ix. 57. Erbagci Z. The leukotriene receptor antagonist mon-
37. Bochner BS, Lichtenstein LM. Anaphylaxis. N Engl J telukast in the treatment of chronic idiopathic urti-
Med. 1991;324(25):1785–90. caria: a single-blind, placebo-controlled, crossover
38. Novembre E, et al. Anaphylaxis in children: clinical clinical study. J Allergy Clin Immunol. 2002;110(3):
and allergologic features. Pediatrics. 1998;101(4):E8. 484–8.
39. Blumchen K, et al. Oral peanut immunotherapy in 58. Kosnik M, Subic T. Add-on montelukast in antihista-
children with peanut anaphylaxis. J Allergy Clin mine-resistant chronic idiopathic urticaria. Respir
Immunol. 2010;126(1):83.e1–91. Med. 2011;105 Suppl 1:S84–8.
40. Thyagarajan A, et al. Peanut oral immunotherapy is 59. Anand MK, Nelson HS, Dreskin SC. A possible role
not ready for clinical use. J Allergy Clin Immunol. for cyclooxygenase 2 inhibitors in the treatment of
2010;126(1):31–2. chronic urticaria. J Allergy Clin Immunol.
41. Khan DA, Solensky R. Drug allergy. J Allergy Clin 2003;111(5):1133–6.
Immunol. 2010;125(2 Suppl 2):S126–37. 60. Spector S, Tan RA. Antileukotrienes in chronic
42. Doeglas HM. Reactions to aspirin and food additives urticaria. J Allergy Clin Immunol. 1998;101(4 Pt
in patients with chronic urticaria, including the physi- 1):572.
cal urticarias. Br J Dermatol. 1975;93(2):135–44. 61. Smith PF, Corelli RL. Doxepin in the management of
43. Sanchez-Borges M. NSAID hypersensitivity (respira- pruritus associated with allergic cutaneous reactions.
tory, cutaneous, and generalized anaphylactic symp- Ann Pharmacother. 1997;31(5):633–5.
toms). Med Clin North Am. 2010;94(4):853–64. xiii. 62. Asero R, Tedeschi A. Usefulness of a short course of
44. An SY, et al. Vancomycin-associated spontaneous oral prednisone in antihistamine-resistant chronic
cutaneous adverse drug reactions. Allergy Asthma urticaria: a retrospective analysis. J Investig Allergol
Immunol Res. 2011;3(3):194–8. Clin Immunol. 2010;20(5):386–90.
45 Polk RE, et al. Vancomycin and the red-man syn- 63. Buchman AL. Side effects of corticosteroid therapy.
drome: pharmacodynamics of histamine release. J Clin Gastroenterol. 2001;33(4):289–94.
J Infect Dis. 1988;157(3):502–7. 64. Di Leo E, et al. Cyclosporin-A efficacy in chronic
46. Renz C, et al. Histamine release during rapid vancomy- idiopathic urticaria. Int J Immunopathol Pharmacol.
cin administration. Inflamm Res. 1998;47(13):69–70. 2011;24(1):195–200.
82 A. Rosen et al.
65. Grattan CE, et al. Randomized double-blind study of to the intramuscular tissues. Ann Allergy Asthma
cyclosporin in chronic ‘idiopathic’ urticaria. Br J Immunol. 2005;94(5):539–42.
Dermatol. 2000;143(2):365–72. 81. Stecher D, et al. Epinephrine auto-injectors: is needle
66. Vena GA, et al. Cyclosporine in chronic idiopathic length adequate for delivery of epinephrine intramus-
urticaria: a double-blind, randomized, placebo-con- cularly? Pediatrics. 2009;124(1):65–70.
trolled trial. J Am Acad Dermatol. 2006;55(4):705–9. 82. Pumphrey RS. Fatal posture in anaphylactic shock.
67. Stellato C, et al. Anti-inflammatory effect of J Allergy Clin Immunol. 2003;112(2):451–2.
cyclosporin A on human skin mast cells. J Invest 83 Sicherer SH, Simons FE. Quandaries in prescribing
Dermatol. 1992;98(5):800–4. an emergency action plan and self-injectable epineph-
68. Harvey RP, Wegs J, Schocket AL. A controlled trial of rine for first-aid management of anaphylaxis in the
therapy in chronic urticaria. J Allergy Clin Immunol. community. J Allergy Clin Immunol. 2005;115(3):
1981;68(4):262–6. 575–83.
69. Cassano N, et al. Low-dose dapsone in chronic idio- 84. Soar J, et al. Emergency treatment of anaphylactic
pathic urticaria: preliminary results of an open study. reactions–guidelines for healthcare providers.
Acta Derm Venereol. 2005;85(3):254–5. Resuscitation. 2008;77(2):157–69.
70. Engin B, Ozdemir M. Prospective randomized non- 85. Mueller UR. Cardiovascular disease and anaphylaxis.
blinded clinical trial on the use of dapsone plus anti- Curr Opin Allergy Clin Immunol. 2007;7(4):337–41.
histamine vs. antihistamine in patients with chronic 86. Arock M, Valent P. Pathogenesis, classification and
idiopathic urticaria. J Eur Acad Dermatol Venereol. treatment of mastocytosis: state of the art in 2010
2008;22(4):481–6. and future perspectives. Expert Rev Hematol.
71. Chakravarty SD, Yee AF, Paget SA. Rituximab suc- 2010;3(4):497–516.
cessfully treats refractory chronic autoimmune urti- 87. Tharp MD. Mastocytosis. In: Bolognia J, Jorizzo JL,
caria caused by IgE receptor autoantibodies. J Allergy Rapini RP, editors. Dermatology. St. Louis, Mo:
Clin Immunol. 2011;128(6):1354–5. Mosby; 2008.
72. Maurer M, et al. Efficacy and safety of omalizumab in 88. Wedi B, Frieri M. Mastocytosis. In: Mahmoudi M,
patients with chronic urticaria who exhibit IgE against editor. Challenging cases in allergy and immunology.
thyroperoxidase. J Allergy Clin Immunol. London: Humana Press; 2009. p. 193–212.
2011;128(1):202.e5–9. 89. Valent P, et al. Standards and standardization in mas-
73. Saini S, et al. A randomized, placebo-controlled, tocytosis: consensus statements on diagnostics, treat-
dose-ranging study of single-dose omalizumab in ment recommendations and response criteria. Eur
patients with H1-antihistamine-refractory chronic J Clin Invest. 2007;37(6):435–53.
idiopathic urticaria. J Allergy Clin Immunol. 90. Valent P, et al. Diagnosis and classification of mast
2011;128(3):567.e1–73. cell proliferative disorders: delineation from immuno-
74. Sagi L, et al. Evidence for methotrexate as a useful logic diseases and non-mast cell hematopoietic neo-
treatment for steroid-dependent chronic urticaria. plasms. J Allergy Clin Immunol. 2004;114(1):3–11.
Acta Derm Venereol. 2011;91(3):303–6. quiz 12.
75. Kemp SF, Lockey RF, Simons FE. Epinephrine: the 91. Briley LD, Phillips CM. Cutaneous mastocytosis: a
drug of choice for anaphylaxis. A statement of the review focusing on the pediatric population. Clin
World Allergy Organization. Allergy. 2008;63(8): Pediatr. 2008;47(8):757–61.
1061–70. 92. Lim KH, et al. Systemic mastocytosis in 342 consecu-
76. Simons FE, et al. Epinephrine absorption in children tive adults: survival studies and prognostic factors.
with a history of anaphylaxis. J Allergy Clin Immunol. Blood. 2009;113(23):5727–36.
1998;101(1 Pt 1):33–7. 93. Castells M, Metcalfe DD, Escribano L. Diagnosis and
77. Simons KJ, Simons FE. Epinephrine and its use in treatment of cutaneous mastocytosis in children: prac-
anaphylaxis: current issues. Curr Opin Allergy Clin tical recommendations. Am J Clin Dermatol.
Immunol. 2010;10(4):354–61. 2011;12(4):259–70.
78. Pumphrey R. When should self-injectible epinephrine 94. George TI, Horny HP. Systemic mastocytosis.
be prescribed for food allergy and when should it be Hematol Oncol Clin North Am. 2011;25(5):
used? Curr Opin Allergy Clin Immunol. 1067–83.
2008;8(3):254–60. 95. Longley Jr BJ, et al. Activating and dominant inacti-
79. Ogden CL, Carroll MD, Flegal KM. High body mass vating c-KIT catalytic domain mutations in distinct
index for age among US children and adolescents, clinical forms of human mastocytosis. Proc Natl Acad
2003–2006. JAMA. 2008;299(20):2401–5. Sci USA. 1999;96(4):1609–14.
80. Song TT, et al. Adequacy of the epinephrine 96. Heide R, Tank B, Oranje AP. Mastocytosis in child-
autoinjector needle length in delivering epinephrine hood. Pediatr Dermatol. 2002;19(5):375–81.
Cutaneous Emergencies in the
HIV-Positive Patient 5
Markus Boos, Karolyn Wanat, and James Treat
present on the surface of HIV particles [2, 3].

5.1 Overview Binding of gp120 to CD4 on the surface of T
helper (TH) lymphocytes, monocyte-derived mac-
The Human Immunodeficiency Virus (HIV) is a rophages (including tissue-specific macrophages
member of the retrovirus family of enveloped such as brain microglia), and dendritic cells
RNA viruses. Retroviruses rely on an RNA- (including Langerhans cells of the skin) results in
dependent DNA polymerase (reverse tran- a conformational change in gp120 that facilitates
scriptase) for their replication [1]. HIV is the binding to the chemokine co-receptors CCR5 and
causative organism in the development of CXCR4 and exposes the HIV gp41 envelope pro-
acquired immune deficiency syndrome (AIDS). tein, allowing membrane fusion and viral entry
Although a complete review of the pathogenesis into a given cell [3]. Once it has entered a host
of HIV is beyond the scope of this text, a basic cell, HIV initiates the synthesis of a double-
comprehension of the mechanism of HIV infec- stranded DNA molecule from its original RNA
tion is helpful in understanding its resultant clini- genome via reverse transcriptase activity; this
cal manifestations. Briefly, HIV initiates infection may result in direct cellular lysis or altered activ-
of cells bearing the CD4 receptor through the ity of host cells, causing immune dysregulation
interaction of the gp120 envelope glycoprotein and subsequent release of HIV virions into the
bloodstream [4]. Alternatively, viral DNA may
be integrated into the host genome, where it can
remain latent in cellular reservoirs (most com-
monly macrophages). When a host cell infected
with latent virus receives subsequent signals to
M. Boos, M.D., Ph.D. • K. Wanat, M.D. proliferate, this concomitantly activates tran-
Department of Dermatology, Perelman School
scription of the original RNA virus, allowing for
of Medicine at the University of Pennsylvania,
3400 Spruce Street, 2 Maloney Building, Philadelphia, continued viral dissemination [4]. Of note, fol-
PA 19104, USA lowing primary infection there is a rapid rise in
e-mail: Markus.boos@uphs.upenn.edu; HIV viral counts that typically precedes the pro-
karolyn.wanat@uphs.upenn.edu
duction of HIV-specific antibodies between 1 and
J. Treat, M.D. (*) 3 months post infection; it is these antibodies that
Pediatrics and Dermatology, Perelman School
are detected by HIV screening tests [2, 5, 6]. As
of Medicine at the University of Pennsylvania, USA
a result of their viremia, individuals newly
Department of Pediatrics, Children’s Hospital
infected with HIV are more infectious and are at
of Philadelphia, 3550 Market Street,
2nd floor Dermatology, Philadelphia, PA 19104, USA increased risk of transmitting the virus to others
e-mail: treat@email.chop.edu before being identified as seropositive [5, 7].

84 M. Boos et al.
The worldwide morbidity and mortality asso- Table 5.1 Constellation of symptoms associated with
ciated with the AIDS epidemic are substantial, acute HIV infection
and as such, a significant public health effort has Constitutional Fever, fatigue, headache, night
been initiated to control both the spread of HIV sweats
and the progression of disease within infected Dermatologic Morbilliform eruption of upper
trunk composed of pink-red
individuals. HIV is transmitted through contact macules
with blood, vaginal secretions, or semen of an Mucocutaneous change: Anal,
infected individual. Transmission most often gential, oropharyngeal ulcers
occurs through sexual intercourse (including oral Gastrointestinal Sore throat, nausea, vomiting,
sex), IV drug use, or via vertical mother-to-child diarrhea
transmission in the womb or during the perinatal Musculoskeletal Arthralgias, myalgias
period [2, 8]. HIV can also be transmitted via Hematologic Lymphadenopathy, lymphopenia,
thrombocytopenia
blood transfusion, though improved screening
Additionally, patients should have a history of probable
measures make this mode of transmission increas-
antecedent exposure in the preceding 2–4 weeks: either
ingly rare. risky sexual behavior or IV drug use
5.2 Primary HIV Infection The eruption may resemble a primary roseola exan-
thema. The macules that compose this rash are typi-
The acute manifestations of primary HIV infec- cally non-confluent, range in size from 4 to 10 mm,
tion are nonspecific, and a high degree of suspi- and are pink or red in color [10, 13]. Notably, the
cion is required to establish the proper diagnosis. exanthem is not painful, rarely pruritic, and usually
Since early diagnosis and treatment of HIV can disappears within 1–2 weeks, occasionally inducing
help prevent serious sequelae in the source patient a fine desquamation as it resolves [5, 10, 12, 13].
and further dissemination of HIV to sexual con- The histologic features of the rash are also
tacts, it is considered here as an emergency. nonspecific and mimic various viral and drug reac-
Symptomatic primary HIV infection has been tions; an absence of epidermal change and a sparse
described as “mononucleosis-like” and most dermal perivascular infiltrate composed mainly of
often presents with fever, fatigue, and rash lymphocytes and histiocytes is seen. Other skin
between 2 and 4 weeks after exposure [9–11]. findings that have been reported in association with
Additionally, symptoms such as sore throat, primary HIV infection include a papulopustular and
lymphadenopathy, headache, arthralgias, myal- vesicular exanthem, urticaria, and desquamation of
gias, night sweats, nausea, vomiting, and diarrhea the palms and soles [7, 11, 15].
are not uncommon [2, 9–11]. Hematologic abnor- In addition to its characteristic rash, the der-
malities including lymphopenia and thrombocy- matologic findings common to primary HIV
topenia are frequently seen on laboratory infection include mucocutaneous change.
evaluation (Table 5.1) [2, 5, 12]. Any patient who Specifically, anal and genital ulcers, as well as
presents with this constellation of signs and ulceration of the esophagus, buccal mucosa, pal-
symptoms therefore warrants a detailed sexual ate, and gingiva, have been reported in the absence
and drug use history, as well as a thorough physi- of any other infectious causes [10, 12]. These
cal exam to assist in the early diagnosis of new characteristic ulcers have been described as
HIV infection. 5–10 mm, round to oval in shape, with a white
The most common cutaneous manifestation of base surrounded by a red rim [10]. Enanthema of
primary HIV infection (estimated to occur in up the soft and hard palates have also been noted
to 80% of new infections) is a macular or morbilli- [10, 12, 14]. Lymphadenopathy is another visible
form eruption that is localized primarily on the early manifestation of acute HIV infection; it
upper trunk, but may also include the neck, face, appears most prominently during resolution of
extremities, scalp, palms, and soles [2, 8, 10, 13, 14]. the acute syndrome [2, 9].
5 Cutaneous Emergencies in the HIV-Positive Patient 85
5.2.1 Diagnosis morbidity and mortality. This is achieved by

restoring normal immune function via a reduc-
Early diagnosis of HIV infection is of paramount tion of viral load and a concomitant increase in
importance, as recognition of new infections CD4 T cell count. The most recent recommenda-
helps to prevent inadvertent transmission. tions of the International AIDS Society—USA
Traditionally, the diagnosis of HIV infection is Panel include beginning HAART at a CD4 cell
made via a screening enzyme-linked count of less than or equal to 500/mL; patients
immunosorbent assay (ELISA) followed by a who wait until they have a CD4 count below 350
confirmatory Western blot for antibodies against or become symptomatic typically have worse
the p24 nucleocapsid antigen, and the gp120 outcomes. Other indications to initiate HAART
and gp41 envelope proteins. For populations of include a high viral load (>100,000) or a rapid
patients in remote locations or who infrequently decrease in CD4 cell count (>100 cells/mL per
or reluctantly visit healthcare practitioners, year), age greater than 60, or coinfection with
however, a rapid antibody test may be preferred hepatitis B or C [17].
because, although it can be more user depen- Importantly, HAART is also recommended
dent (the presence or absence of a line must be for symptomatic primary HIV infection to limit
interpreted and proper controls must be used), viremia or a rapid decline in CD4 cell count, as
at least the answer can be given immediately well as to preserve immune function and pre-
without having to worry that the patient will not vent further transmission. The panel also rec-
be able to be located. One limitation of the tra- ommends considering HAART in asymptomatic
ditional ELISA is that it is unable to identify a patients with a primary infection irrespective
new HIV infection when the immune system of CD4 count, though deferring treatment
has yet to mount an appreciable antibody remains an option in those patients with a CD4
response (the so-called window of infectivity) cell count of >500/mL. A large, multinational
[5, 6]. As a result, alternate tests are needed to cohort study has shown that HAART improves
establish a diagnosis of HIV when it is sus- survival rates in all patients with HIV, arguing
pected in the acute phase before a screening for initiation of HAART in all patients; how-
ELISA becomes positive. Two tests are cur- ever, the reduction in mortality is less for
rently used to diagnosis acute HIV infection: patients who have a higher CD4 count at diag-
the p24 antigen test and a quantitative HIV nosis [17].
RNA test. Of these two, evaluation of HIV RNA The decision of what antiretroviral medica-
appears to have greater sensitivity but also has tions to begin should be based on HIV resistance
a lower specificity and is more expensive; p24 patterns, adverse side effects of medication, a
antigen detection may therefore be a more prac- patient’s individual comorbidities, and the ease
tical test in a setting of limited resources [5, of dosing. Usually two nucleoside reverse tran-
16]. Whether p24 or HIV RNA assay is per- scriptase inhibitors (NRTIs) and a third agent
formed, an ELISA should be performed simul- (a protease inhibitor, non-nucleoside reverse
taneously to establish the chronicity of infection. transcriptase inhibitor or an integrase inhibi-
These tests should all be performed in consulta- tor) are suggested; fixed dose or once-a-day
tion with an infectious disease specialist. regimens are preferred. The goal of therapy is
to induce a viral load of less than 50 copies/mL
as evaluated by polymerase chain reaction
5.2.2 Treatment (PCR) at 24 weeks. Initiating therapy, monitor-
ing a patient’s immune status, and the decision
The rationale for using highly active antiretrovi- to change a given regimen secondary to resis-
ral therapy (HAART) for HIV is not to cure the tance, toxicity, or convenience should be per-
patient, but rather to reduce the incidence of formed in consultation with an infectious
AIDS defining illnesses and their associated disease specialist [17].
86 M. Boos et al.
nying arthritis. Interestingly, spontaneous reso-

5.3 HIV-Associated Dermatoses
lution of psoriasis in patients with end-stage
AIDS is also recognized [24].
HIV infection is associated with the development Though HIV-associated psoriasis of varying
of atypical and uncommon dermatoses, as well as severity can manifest at any CD4 T cell count, it
irregular or exuberant presentations of more com- often presents later in the course of disease
mon cutaneous disease. Two such conditions that when CD4 numbers decrease to below 100–350
may require prompt medical intervention, psoria- [21, 25]. This paradoxical worsening of a disease
sis and eosinophilic folliculitis, are discussed driven by T cells is thought to be secondary to a
below. decrease in the CD4:CD8 T cell ratio late in
advanced HIV infection. Specifically, elevated
CD8+ T cell counts and the absence of CD4+ T
5.3.1 Psoriasis cells (including suppressor cells) may allow for
unrestrained pro-inflammatory activity and the
Psoriasis is an inflammatory dermatitis with development of psoriasis even in the face of
multiple clinical manifestations, but classic pso- decreasing absolute T cell numbers [19].
riasis vulgaris is characterized by well-circum- Furthermore, staphylococcal and streptococcal
scribed, erythematous plaques with a thick silver infections in these immunocompromised hosts
scale commonly located on the extensor surfaces may induce flares of psoriasis [20]. Diagnosis of
of the arms and legs. In immunocompetent psoriasis can typically be done clinically, but his-
patients, the pathogenesis of psoriasis is thought tologic evaluation reveals proliferation of basal
to be secondary to localized inflammation sec- keratinocytes, acanthosis, and desquamation of
ondary to unrestrained activity of Th1 and Th17 the stratum corneum. In HIV+ patients, there is a
subsets of helper T lymphocytes. Interestingly, predominance of plasma cells, and the pres-
though psoriasis is thought to occur in HIV+ ence of T cells and dyskeratotic keratinocytes is
patients at approximately the same frequency as uncommon [18, 19]. The discovery of plasma
in the immuncompetent population (between 1 cells on biopsy should therefore raise the suspi-
and 3 %), its clinical features vary [18]. Notably, cion of an associated HIV infection in patients
psoriasis in HIV+ patients often follows an with new-onset or abruptly worsening psoriasis.
explosive course: preexisting psoriasis can flare Therapy for psoriasis in HIV+ patients is chal-
with new HIV infection or clinical progression lenging as immunomodulating drugs—a main-
to AIDS, and abrupt onset of severe psoriasis stay of psoriasis therapy—may expose the patient
often occurs with HIV-associated immune dys- to increased risk of opportunistic malignancy and
function, requiring emergent intervention. infection. As a result, topical therapies including
Though psoriasis vulgaris is also the most com- calcipotriene, corticosteroids, tazarotene, and
mon form of psoriasis in HIV+ patients, inverse, calcipotriol/betamethasone are considered first
erythrodermic, guttate, rupioid, pustular (includ- line for mild to moderate disease [25]. Ultraviolet
ing keratoderma blennorrhagicum), and sebop- (UV) therapy and antiretrovirals are also thought
soriatic variants are not uncommon [19, 20]. In to be safe and effective options for this subgroup
particular, inverse and palmoplantar forms occur of psoriatic patients. Second-line treatment
more frequently in patients who develop psoria- consists of oral retinoids such as acitretin.
sis after contracting HIV. Furthermore, multiple Immunomodulating agents such as methotrexate,
morphologies can often be simultaneously pres- cyclosporine, and biologic agents are reserved
ent on the skin of the same patient, and an exten- for the most severe and recalcitrant cases [25].
sive amount of body surface area can be involved These instances should be considered on a case-
[19, 21–23]. HIV+ patients with psoriasis also by-case basis, and close monitoring, as well as insti-
appear to be more prone to developing accompa- tution of antiretroviral therapy and prophylaxis
against infection, should be initiated when pressed although typically scabies, even in severely
beginning immunosuppressant therapy. immunosuppressed patients, spares the face.
The pathogenesis of EF remains unknown,
though it is thought to occur secondary to the
5.3.2 Eosinophilic Folliculitis skewing of the immune system toward a Th2
phenotype in the context of extreme immunosup-
Eosinophilic folliculitis (EF) is an extremely pru- pression and immune dysregulation. Many com-
ritic, follicular-based eruption of erythematous mon environmental antigens, including skin flora
papules that is most commonly seen in HIV+ and medications, have been suggested to potenti-
patients with low CD4 counts [26–28]. It has ate a hypersensitivity reaction that leads to the
been reported as the primary presentation of HIV clinical appearance of EF.
but more commonly serves to identify patients at Treatment of EF is challenging, and no con-
risk for severe opportunistic infections. The pres- sensus exists on the optimal treatment for this
ence of EF therefore indicates that urgent inter- condition. Of foremost importance is the initia-
vention is required to identify and/or treat an tion of HAART, which, though it may potentiate
associated HIV infection [29]. The characteristic EF when initiated in those with low CD4 cell
lesions of EF are 3–5 mm papules located pri- counts, ultimately helps resolve the condition by
marily on the upper trunk, head, neck, and proxi- restoring normal immune system function [27,
mal extremities that are often excoriated or 30, 32]. Among other therapeutic modalities,
crusted as a result of associated pruritus [27–29]. UVB therapy two to three times per week appears
Rarely, EF can present as erythematous plaques to most reliably provide improvement within 3–6
or urticaria [30]. A relative peripheral eosino- weeks, though weekly maintenance treatments
philia and elevated IgE levels may also be noted are usually required [32]. High-potency topical
on laboratory studies [28]. The condition has a steroids applied twice daily may also be effective,
stark male predominance and has rarely been but given their side effects of skin atrophy, hypop-
reported in women [27–29]. Interestingly, EF is igmentation, and telangiectasias, an effective
associated with CD4 cell counts less than 250/mL; alternative topical therapy such as tacrolimus may
however, the initiation of HAART also appears to be a better option [28, 33]. Systemic therapies
be a trigger of EF in these same patients [26, 27]. including itraconazole (begun at 200 mg/day),
This tends to occur between 3 and 6 months after metronidazole (250 mg three times per day), and
initiating HAART [27]. isotretinoin (0.3–1 mg/kg/day) have also been
The differential diagnosis for EF includes used to treat EF, with varying degrees of success
multiple pruritic dermatoses such as scabies, [32]. Symptomatic control of pruritus can be
papular urticaria, dermatitis herpetiformis, achieved by using antihistamines such as cetiriz-
arthropod assault, and bacterial folliculitis [31]. ine or doxepin, as well as through the application
In order to establish a diagnosis, skin biopsy of a of topical lotions containing menthol [31, 32].
papule is often helpful, though care must be taken
to section the specimen appropriately so that an
involved follicle can be evaluated. Histologic 5.4 Infectious Complications
examination reveals a mixed perivascular or peri- of HIV Infection
follicular infiltrate of eosinophils and lympho-
cytes with occasional neutrophils, often with Given the global immunosuppression associated
rupture of the associated sebaceous gland [26, with HIV infection and the depletion of CD4+ T
28, 30]. Notably, infectious organisms are absent helper cells, patients who are HIV+ are at an
on both H&E and special stain examinations. increased risk of both common and opportunistic
A scabies preparation is also helpful to exclude infections. The most common and life-threatening
this condition in patients who are immunosup- infections are discussed below.
88 M. Boos et al.
importantly, physicians must simply be alert to

5.5 Tuberculosis and Other
the possible diagnosis of disseminated cutaneous
Mycobacterial Infections
TB in any HIV+ individual who presents with
multiple nonspecific skin lesions [37].
Coinfection with HIV and Mycobacterium tuber- Treatment of tuberculosis includes quadruple
culosis is a significant public health issue, as therapy with isoniazid, rifampicin, pyrazinamide,
these two organisms have synergistically detri- and ethambutol, though sensitivities should be
mental effects on individuals afflicted with both. performed given increasing TB drug resistance;
Namely, weakening of the immune system by alternative medications may be required. HAART
HIV allows latent M. tuberculosis infection to is also indicated in these patients, but there is
become active. In turn, tuberculosis (TB), which considerable interaction between antituberculo-
has become increasingly resistant to a greater sis and antiretroviral medications; therefore treat-
number of pharmacologic therapies, is a leading ment should be undertaken with an infectious
infectious cause of death worldwide in HIV+ disease specialist [35, 38].
individuals [34–36]. HIV infection often prevents Infection with other non-tuberculosis myco-
timely diagnosis of TB because of the atypical bacteria can also produce cutaneous findings. M.
presentation of active TB in the immunosup- kansasii, M. haemophilum, and M. avium/M.
pressed; HIV also promotes immune anergy and intracellulare (the MAI complex) rarely cause
makes tests such as the tuberculin skin test less cutaneous disease but are more likely to do so in
sensitive for diagnosis [34, 35]. immunocompromised hosts, including those with
Although cutaneous TB is rare, it appears to be HIV. The clinical manifestations of these assorted
more common in patients co-infected with HIV mycobacteria are variable, and include firm red
and therefore deserves special mention [37]. While nodules, erythematous papules, pustules, ulcers,
scrofuloderma (suppurative, subcutaneous nodules abscesses, sinus tracts, verrucous lesions, and
of TB originating from an underlying nidus of firm annular plaques [40, 41]. It is therefore
infection such as a lymph node) can be seen in the important for physicians to consider these atypi-
context of immunosuppression, the more common cal infections as a potential cause of persistent,
appearance of cutaneous TB in patients with HIV/ nonspecific skin lesions in patients with HIV.
AIDS, particularly with CD4 cell counts <100/mL, Importantly, in the context of an unclear clinical
is the disseminated miliary form, a.k.a. tuberculo- diagnosis, biopsy sections should be cultured
sis cutis miliaris acuta generalisata [36, 37]. broadly and evaluated with special AFB stains so
Cutaneous miliary TB typically appears as mac- as not to miss the diagnosis of a mycobacterial
ules, papules, and crusted ulcers, but papulovesi- infection [42]. As with tuberculosis, therapy and
cles, pustules, purpura, and subcutaneous nodules management should be performed in consultation
are also possible manifestations [36–39]. The dis- with an infectious disease specialist, and evi-
tribution of these multiple lesions most often dence of a disseminated infection should be
includes the buttocks, trunk, thighs, and extensor sought and managed as necessary.
extremities. Other clinical signs of TB include
fever, weight loss, and productive cough.
Diagnosis of cutaneous TB can be made via 5.6 Fungal Infections
scraping of a lesion and visualizing acid-fast
bacilli (AFB) under microscopy after Ziehl– 5.6.1 Candidiasis
Neelsen staining. Biopsy may be necessary, and
reveals a superficial dermal infiltrate of neutro- Candida species, in particular Candida albicans,
phils, histiocytes, and/or lymphocytes, though are the most frequent cause of fungal disease in
granuloma formation is uncommon given patients with HIV [43]. Typically, candidal disease
patients’ weakened immune response. Special presents as infection of the oropharynx, esopha-
stains are often necessary to visualize AFB. Most gus, or anogenital region, though intertriginous
involvement of the skin is not uncommon [43, 44]. tory cases or for esophageal involvement when
Disseminated infections are rare in HIV-associated systemic therapy is indicated [43–45]. Cutaneous
Candida in part due to a relatively more functional candidiasis is typically responsive to Nystatin or
humoral immune system [43]. Candida infections topical azoles including ketoconazole or clotri-
present at moderate-to-advanced stages of HIV mazole [43].
infection (with CD4 cell counts <200–300/mL),
and often signify progressive disease and poor
clinical outcomes [17, 43, 45]. 5.6.2 Cryptococcus and Other Invasive
There are four main manifestations of oropha- Fungal Infections
ryngeal candidiasis: pseudomembranous, ery-
thematous/atrophic and hyperplastic forms, as Infection with the encapsulated yeast Cryptococcus
well as angular cheilitis [43]. Pseudomembranous neoformans is a common occurrence in patients
oral candidiasis (OC) presents as creamy white with AIDS, occurring in between 6 and 13 % of
plaques present on multiple oropharyngeal sur- patients, typically with CD4 cell counts below
faces, including the tongue, palate, and buccal 200/mL [4, 47]. Cryptococcal infection occurs fol-
mucosa; these lesions can be easily scraped away. lowing inhalation of the organism, which is found
Erythematous and atrophic lesions are common in in soil or grass contaminated with pigeon drop-
older patients with HIV and present as red ulcers pings; from this primary pulmonary focus, the
and erosions; they can often be found under oral organism can disseminate hematogenously [47,
accessories such as dentures [45]. The hyperplas- 48]. Most often this dissemination manifests as
tic form and angular cheilitis are far less common meningitis associated with central nervous system
and appear as thick yellow plaques or erythema involvement, but cutaneous involvement occurs in
and painful fissuring at the angles of the mouth, approximately 6–20 % of patients with dissemi-
respectively. Patients with active oral Candida nated disease, as well [4, 47]. Primary cutaneous
infections may note altered taste, and complaints disease secondary to external inoculation is over-
of pain on swallowing should alert the physician whelmingly rare [47].
to potential esophageal involvement, as well [45]. The primary lesions of cutaneous cryptococ-
Vulvovaginitis, enteritis, and gastritis are also cal disease are protean in appearance, but most
possible mucocutaneous manifestations of often present as umbilicated papules and nodules,
Candida infection [43]. Cutaneous candidiasis is often with a central hemorrhagic crust [4, 49].
marked by pink-red, thin plaques and patches Other potential morphologies include violaceous
with surrounding satellite pustules, found most and crusted papules, plaques and nodules, scaly
commonly in skin folds, including the groin, plaques, and less commonly ulcers or draining
inframammary, and axillary regions [43]. sinuses [4, 47]. These lesions occur primarily on
The diagnosis of candidiasis is often a clinical the face and neck, though involvement of the
one, though KOH preparations demonstrating extremities and trunk also occurs at a reduced
budding yeast and pseudohyphae, fungal culture, frequency [4]. The differential diagnosis of these
and biochemical tests can aid in diagnosis when lesions includes molluscum contagiosum,
uncertainty exists [43, 45]. In adults, treatment of Kaposi’s sarcoma, basal cell carcinoma, and
oral candidiasis can be achieved by administering nummular eczema [4, 47]. Identification of an
oral fluconazole at a dose of 100–200 mg/day antecedent flu-like illness or symptoms indicat-
until the patient has remained asymptomatic for ing multi-organ system involvement, such as
1–2 weeks; alternatively, a single dose of 750 mg neurologic changes or pulmonary symptoms,
can be given [46]. Clotrimazole troches and nys- may assist the astute dermatologist in making the
tatin solution are other topical alternatives for correct diagnosis of cryptococcal infection.
treatment of oral candidiasis, while itraconazole, Diagnosis can easily be established on biopsy
voriconazole, or posaconazole can be used as with routine histology. Two primary histopathologic
alternatives to fluconazole in unusually refrac- appearances manifest in the case of cryptococcal
90 M. Boos et al.
infection: granulomatous or gelatinous, though and rosacea, and even ulcers have all been
individual biopsy specimens can also exhibit an reported in association with histoplasmosis [51].
overlap of these two patterns. In the granulomatous Oral manifestations are also common, presenting
form, multiple histiocytes can be seen phagocytiz- most often as painful ulcerations or granuloma-
ing budding yeast that are surrounded by clear halos. tous lesions [52]. Blastomycosis can also present
The gelatinous form exhibits fungal organisms sur- in a variety of forms, including papules, pustules,
rounded by a pool of mucin. These organisms can ulcers, and granulomatous masses [53, 54].
be found in a variety of distributions, from subepi- Similarly, cutaneous coccidiomycosis manifests
dermal foci to involvement of the entire dermis [4]. typically on the face as papules, pustules, or nod-
PAS stains may aid in identification of encapsulated ules. If given time to expand and coalesce, these
yeast organisms. In instances where the diagnosis lesions can eventually transform into abscesses,
remains in question despite biopsy, other methods ulcers, and verrucous or scarred plaques [51].
of identification can be used including culture on Given the nonspecific nature of these cutaneous
Sabouraud dextrose agar or identification of crypto- findings and the considerable overlap in presenta-
coccal capsular polysaccharide antigen in serum tion between the various fungal organisms, these
[47, 49]. Microscopic or serologic examination of species must always be considered in HIV+
cerebrospinal fluid may also help in establishing the patients who present with any of the aforemen-
diagnosis in patients with concomitant meningitis tioned cutaneous findings. Biopsy and serologic
or neurologic symptoms [49]. testing are indicated to quickly establish the
Treatment of disseminated cryptococcal infec- appropriate diagnosis [50]. Treatment of all of
tion in immunocompromised patients includes these organisms should be guided by an infec-
intravenous amphotericin B; adjunct therapy with tious disease specialist but typically begins with
fluconazole or flucytosine is often administered. amphotericin B, with azole therapy (typically
Lifelong prophylactic therapy is subsequently with itraconazole or fluconazole) initiated after
indicated, most often with daily oral fluconazole. clinical stabilization. Patients subsequently require
Although less common, infection with other lifelong prophylaxis to prevent recurrence [48, 50].
invasive fungi such as Histoplasma capsulatum
(histoplasmosis), Blastomyces dermatitidis (blas-
tomycosis), and Coccidioides immitis (coccidio- 5.6.3 Cutaneous Bacterial Infections
mycosis) must also be considered in HIV+ that Can Be Emergencies
patients with cutaneous manifestations, espe-
cially those who live in or have recently traveled 5.6.3.1 Staphylococcus aureus
to endemic areas. Methicillin-resistant Staphylococcus aureus
Histoplasmosis is found primarily in the Ohio (MRSA) is a rapidly emerging pathogen that has
and Mississippi River valleys, blastomycosis in a higher prevalence of both colonization and skin
the Midwest and southeastern United States, and and soft tissue infection in people infected with
coccidiomycosis is most common in the south- HIV. MRSA colonization is more highly associ-
western United States [50]. For all of these dis- ated with HIV-infected patients who have low
eases, infection occurs primarily after inhalation CD4 counts, are intravenous drug users, and in
and by entry through the lungs; cutaneous mani- men who have sex with men [55–58].
festation therefore represents disseminated disease Staphylococcus aureus presents in the skin most
in the majority of patients, as primary cutaneous frequently with folliculitis or furunculosis and
disease secondary to inoculation is rare [48, 50]. can lead to more severe systemic infection.
Like Cryptococcus, cutaneous histoplasmosis Although folliculitis and furunculosis are rarely
often presents on the face, and has a protean emergencies, given the risk of bacteremia and
appearance. Red macules, necrotic papules, nod- internal abscesses, it is important to identify and
ules and pustules, eruptions reminiscent of acne treat cutaneous MRSA infections in HIV patients.
Antibacterial washes such as 4 % chlorhexidine Tetracyclines are often used as a second-line

can be used to decolonize the skin and treat mild agent, again for 2 months [61].
folliculitis. When indicated, antibiotic therapy
for cutaneous bacterial infections should be 5.6.3.3 Syphilis
guided by cultures to assure the proper antibiotic Syphilis is a bacterial infection caused by
choice. Furuncles and abscesses should be Treponema pallidum, which is most often sexu-
drained when possible. Antibiotic choices should ally transmitted. The initial cutaneous manifesta-
be based on regional differences in susceptibili- tion of syphilis is the primary chancre that is
ties. Since MRSA presents commonly with commonly found in the perineum. In immuno-
furunculosis, proper MRSA coverage (typically suppressed HIV patients, the primary chancre
trimethoprim-sulfamethoxazole, a tetracycline, may be deeper and longer lasting and there may
or clindamycin) should be started empirically be multiple chancres [62]. In addition, syphilis
while waiting for cultures if antibiotics are to be may predispose to easier transmission of HIV
used. Dosing guidelines for skin and soft tissue due to the chronic open wound with HIV shed-
infections should be followed, and patients should ding from the wound [63, 64].
be monitored closely for clinical resolution as Secondary syphilis is usually characterized by
they may need more extended duration due to scaling papules and plaques on the trunk, palms,
immunodeficiency. and soles but can include scattered ulcerations
and condyloma lata. Later findings of cutaneous
5.6.3.2 Bacillary Angiomatosis syphilis include large ulcerations (gummas). The
Bacillary angiomatosis (BA) is a bacterial infec- risk of transition to neurosyphylis may be higher
tion caused by Bartonella henselae or Bartonella in patients with HIV, and therefore promptly rec-
quintana. BA is nearly exclusively a manifesta- ognizing and treating syphilis in HIV patients is
tion of immunosuppression [59]. BA presents vital [65]. Non-treponemal tests such as rapid
with papules and nodules that grow slowly in the plasma reagin (RPR) and venereal disease refer-
skin and often ulcerate. The skin lesions often ence laboratory (VDRL) can be falsely positive
look distinctly vascular and can be mistaken for or negative in patients with HIV but are still the
multiple pyogenic granulomas or Kaposi sar- preferred first-line tests. Biopsies of skin lesions
coma. A high index of suspicion is vital, espe- with special stains as well as dark field examina-
cially if an ulceration is cultured with conventional tion and specific treponemal tests can help
swab and does not yield a typical staphylococcal confirm the diagnosis [66].
infection. Since BA can be an emergency with
fever, fatigue, and disseminated lesions involving 5.6.3.4 Cancrum Oris (Noma)
the liver, spleen, bone, and CNS, it is important to Noma is a gangrenous infection of the oral cavity
be able to recognize BA in the skin. BA is typi- that typically affects young children. The infection
cally seen in patients with a CD4 count below typically starts with an ulceration on the gingiva
100 cells/mL [59]. Therefore, a diagnosis of BA which spreads to involve the mucosal and cutane-
should prompt a thorough workup for other ous lips. Noma is thought to be caused by a com-
diseases of extreme immunodeficiency such as bination of poor nutrition and immunosuppression
Pneumocystis carinii pneumonia. Diagnosis of such as HIV. It is often polymicrobial and very
BA can be made with histology showing a vas- challenging to treat. Noma can lead to significant
cular proliferation with protuberant cuboidal morbidity and mortality due to the inability to eat
cells and positive staining of organisms with and drink. Therapy is based on augmenting nutri-
Warthin-Starry or Silver stains. PCR and immu- tional status and targeted therapy toward HIV as
noglobulin M detection can also be done where well as treating the infection based on cultures
available [60]. Therapy is typically with erythro- with antibiotics. Reconstructive surgery is also very
mycin (500 mg every 6 h typically for 2 months). important once the infection has been treated [67].
92 M. Boos et al.
5.6.3.5 Viral Infections

Cutaneous viral infections are common and can
manifest as typical self-limited infections in
patients with HIV, especially if they have a nor-
mal CD4 count. This section reviews the atypical
manifestations in patients with HIV and lowered
immunity. Viral infections in immunosuppressed
patients often present as more severe, dissemi-
nated, or chronic infections than in immunocom-
petent patients.
5.6.3.6 Herpetic Infections

Herpes simplex virus (HSV) typically affects
mucous membranes including the mouth, eyes,
perianal areas, perineum, and penis. This is
because these areas are most likely to have micro-
abrasions that can serve as portals of entry for the
virus. HSV typically presents clinically with
grouped vesicles that progress to grouped crusts
and erosions as the vesicles rupture. In HIV
patients with lowered immunity, the lesions will
often be long standing or never fully resolve
without therapy [68]. The resultant lesion is a Fig. 5.1 Grouped vesicles involving the left cheek, ear,
and ear canal consistent with herpes zoster infection
non-healing ulcer, often in a typical location for
HSV (perianal, perioral). These lesions can also
become vegetative and exophytic requiring a high immunity, VZV may start as a typical reactivation
index of suspicion to diagnose. within a dermatome (shingles) (Fig. 5.1). However,
HSV can present in an emergent fashion when due to the lowered immunity, the cutaneous
cutaneous lesions disseminate hematogenously. manifestations can be exuberant, last longer than
Disseminated HSV can lead to widespread cuta- the typical 1–2 weeks, or widely disseminate.
neous erosions that can lead to secondary bacte- Disseminated VZV is defined by having many
rial infection and sepsis. HSV can also disseminate lesions outside of the original dermatome or
widely (especially to the central nervous system multiple noncontiguous dermatomes due to
or liver) leading to significant morbidity and pos- hematogenous spread. Disseminated VZV can
sible mortality in severely immunosuppressed lead to significant morbidity and mortality espe-
patients [69]. Diagnosis is typically with viral cially with involvement of the CNS, liver, or lungs
culture or more rapid tests such as PCR and direct [70]. Therefore disseminated VZV in a previously
fluorescent antibody. Therapy is based on the vaccinated or infected individual should prompt
extent of involvement. a workup for immunosuppression including
Varicella zoster virus (VZV) can be the first HIV testing.
manifestation of new HIV infection. VZV is typi- Cytomegalovirus (CMV) is another type of
cally a self-limited widespread infection charac- herpes virus that is typically self-limited in a nor-
terized by vesicles on an erythematous base mal host. In immunosuppressed HIV-positive
(“dew drops on a rose petal”), especially in non- patients, CMV can present as chronic ulcers
immunized people. In immunized patients or (often oral or perianal) that are rarely emergent.
those with prior infection, widespread or exuberant Rarely digital necrosis has been reported in HIV-
VZV is rare. Instead, these patients may present positive patients associated with CMV infection
with viral reactivation in one or two contiguous but the role of the CMV is not fully understood
dermatomes. In HIV patients with lowered [71]. CMV is usually treated with gancyclovir
but should be guided by an experienced infec- Table 5.2 Medications reported to cause a serious drug
tious disease specialist. reaction in the setting of HIV
Abacavir
5.6.3.7 Molluscum Contagiosum Amprenavir
Molluscum contagiosum is caused by a DNA Atazanavir
pox virus and most typically manifests as small Didanosine
flesh colored papules with central umbilica- Indinavir
Isoniazid/rifampin combination therapy
tion. Although molluscum is not a life-threat-
Nevirapine
ening infection, the virus can overgrow
Ritonavir-boosted darunavir
extensively in HIV patients. This overgrowth
Trimethoprim-sulfamethoxazole (TMP-SMX)
can lead to nodular lesions which can obstruct
Zidovudine
vision and become purulent and disfiguring
[72]. Exuberant molluscum inflammation can
also be a manifestation of immune reconstitu- epidermal necrolysis (TEN), drug hypersensitiv-
tion inflammatory syndrome (IRIS, discussed ity syndrome (DHS) or drug reaction with eosino-
later in this chapter). philia and systemic symptoms (DRESS), and
Viral infections can also be a precursor lesion acute generalized exanthematous pustulosis
to carcinomatous change. Chronic infection with (AGEP). There are a few clinical signs and symp-
human papillomavirus (HPV) infection that is toms which can alert the clinician that one of
recalcitrant to therapy and exuberant should raise these serious drug reactions might be occurring:
suspicion for transition to verrucous carcinoma. high fever, skin pain, mucous membrane involve-
Biopsy should be performed in immunosup- ment, facial swelling, and internal organ involve-
pressed patients with especially recalcitrant ment suggested by laboratory abnormalities.
warts, especially around the perineum. Table 5.2 provides a list of common medications
used in the setting of HIV that may cause a seri-
ous drug reaction, including antiretrovirals and
5.6.4 Drug Reactions antibiotic regimens.
Many medications used for the treatment of HIV

and for AIDS-associated opportunistic infections 5.6.5 Drug Hypersensitivity Syndrome
are associated with cutaneous toxicities and can
cause serious reactions, many of which are emer- DHS has also been named Drug Reaction with
gencies. Although the majority of cutaneous drug Eosinophilia and Systemic Symptoms or DRESS.
reactions are morbilliform, urticarial, or nonspe- DHS is characterized by the triad of fever, skin
cific reactions, clinicians need to be aware of the eruption, and internal organ involvement in the
concerning features associated with more serious setting of exposure to a medication [75]. Patients
drug reactions. Patients with HIV have allergic typically have a high fever (38–40 °C), malaise,
reactions at a higher rate than the general popula- facial edema, and lymphadenopathy. If suspected,
tion. Allergic reactions in HIV patients are likely laboratory testing should be performed to eval-
to be multifactorial, and severe drug reactions need uate for internal organ involvement and should
to be caught early to minimize morbidity and include a complete blood count (CBC) with
mortality [73, 74]. This is potentially difficult differential looking for atypical lymphocytosis
because of the multiple medications or combina- and eosinophilia; evaluation of liver abnormali-
tion regimens that are used to treat these patients ties with special attention to transaminases, alka-
making it difficult to identify the culprit medication. line phosphatase, prothrombin time, and bilirubin;
The serious drug reactions that can occur evaluation of kidney function with urinalysis and
include Stevens–Johnson syndrome (SJS), toxic BUN and creatinine; and fecal occult blood test
94 M. Boos et al.
to look for inflammatory colitis if gastrointestinal

symptoms are present. Liver abnormalities are
present in about 50 % of patients, and severe
hepatitis and liver failure can occur [76]. Skin
biopsy results in these situations are generally
nonspecific but may allow the clinician to
evaluate for underlying vasculitis, if suspected.
In addition, because autoimmune thyroiditis
occurring within 2 months of the onset of symp-
toms may result in hypothyroidism, thyroid func-
tion tests should be performed [76]. Fig. 5.2 Intact vesicles and target lesions on the plantar
feet in a patient with SJS
In the setting of HIV, abacavir hypersensitiv-
ity is a well-described, serious, and potentially
fatal drug hypersensitivity reaction that can occur and sloughing of the skin (Fig. 5.2) and mucous
in both children and adults and affected approxi- membranes with mortality rates ranging from 5
mately 5–8 % of people [77, 78]. It typically to 30 % (typically depending on the amount of
starts within the first 8 weeks of therapy and is body surface area involved and time to treatment)
characterized by two of the following: morbilli- [82–84]. These drug reactions are discussed in
form rash, lymphadenopathy, fever, malaise, detail in other chapters.
myalgias, gastrointestinal symptoms, and respi- Many HIV medications have increased risk of
ratory symptoms. Upon rechallenge, patients inducing SJS/TEN. Nevirapine is a non-nucleo-
may experience hypotension and similar but side reverse transcriptase inhibitor for which
worsened symptoms within hours which can severe life-threatening cutaneous rashes have
result in death; because of this severity, hypersen- been reported at a rate of 0.5–1 % [85–87]. Severe
sitivity to abacavir is considered an absolute con- hepatotoxicity has been associated with the
traindication to future use [79]. Testing for severe drug reactions and should be monitored
HLA-B*5701 is recommended as positivity sug- for regularly. A review of the literature identified
gests a strong genetic predisposition for this several antiretrovirals as potential culprit medica-
hypersensitivity reaction [80]. Treatment of this tions, which are included in Table 5.1 [88].
syndrome includes prompt discontinuation of the In addition to antiretroviral medications,
medication. The use of systemic steroids also is serious drug reactions can occur with the use
recommended, at a dose of 1–2 mg/kg/day if of sulfonamides as antibiotic therapy or for
symptoms are severe and should be used until Pneumocystis jiroveci prophylaxis. The incidence
laboratory abnormalities resolve. First-degree of TEN due to trimethoprim-sulfamethoxazole
relatives should also be counseled to avoid these was about fourfold compared to the general pop-
medications because of the increased risk to ulation and was 8.4 cases per 100,000 exposures
them. There are many other medications impli- [89]. Similarly, tuberculosis drugs can play a role
cated in DHS including medications commonly in serious drug reactions as concomitant infec-
used in HIV such as trimethoprim-sulfamethox- tion is not rare in this population [90].
azole, dapsone, and nevirapine [81]. SJS and TEN are most often caused by medi-
cations in HIV-positive patients, but severe forms
of erythema multiforme and SJS have been
5.6.6 Stevens–Johnson Syndrome and described in association with infections including
Toxic Epidermal Necrolysis HSV and Mycoplasma pneumoniae, especially in
pediatric populations, and should be considered
SJS and TEN are other forms of severe hypersen- if an inciting medication is not apparent [91–97].
sitivity reactions that occur in the setting of HIV Mycoplasma PCR and evaluation of HSV via
and are characterized by widespread blistering PCR, direct-fluorescence antibody, or viral
culture can be performed if the timing of the drug In summary, it is important for clinicians to
reaction (patient has been on a medication for have a high index of suspicion when HIV-positive
several years) or clinical scenario of mucosal pre- patients present with cutaneous drug eruptions.
dominant involvement, preceding cough and Clues to a potentially serious underlying drug
shortness of breath, or other information suggests reaction include high fever, skin pain, facial
an alternate diagnosis [91, 92, 98]. Treatment of swelling and lymphadenopathy, and mucous
SJS/TEN is discussed in detail in other chapters. membrane involvement. General laboratory tests
should be obtained to evaluate for underlying
internal organ involvement. If a serious drug
5.6.7 Acute Generalized reaction is suspected, immediate cessation of the
Exanthematous Pustulosis culprit medication is essential.
AGEP is a rare severe drug reaction characterized

by a fever above 38 °C and a cutaneous reaction 5.6.8 Malignancies
with non-follicular sterile pustules on an edema-
tous and erythematous base. The onset of the Malignancies are an increasingly recognized
reaction after drug administration can vary from complication of HIV infection in all settings.
2 days to 3 weeks, depending on prior sensitiza- There were five traditional AIDS-defining can-
tion. The onset is typically extremely abrupt, cers including Kaposi sarcoma, cervical cancer,
starting on the face and extending to the trunk and three types of non-Hodgkin’s lymphoma
and then to the lower limbs. In addition, patients related to infection with the Epstein–Barr virus,
may have petechial purpura [101]. Laboratory including primary central nervous system lym-
studies should be performed and will reflect neu- phoma, immunoblastic lymphoma, and Burkitt
trophilia. Liver and kidney function should also lymphoma [108–110]. These are common and
be evaluated due to possible involvement in these seen often, although some controversy about cer-
organs. In the setting of HIV infection, the anti- vical cancer being AIDS-defining exists because
retrovirals reported to cause this condition are the it also can be commonly seen in HIV-negative
protease inhibitors, ritonavir-boosted darunavir individuals. Interestingly, all five of these tumors
and atazanavir. Protease inhibitors have also been are associated with chronic oncogenic viral infec-
reported to be culprit medications when used for tion. There also are a wide variety of cancers that
postexposure prophylaxis [102–104]. As overlap have been found to be more common in the set-
between AGEP and SJS/TEN or DRESS has been ting of HIV, which have been termed non-AIDS-
reported, clinicians should have a high index of defining cancers including Hodgkin’s lymphoma,
suspicion when the constellation of symptoms lung cancer, and hepatocellular carcinoma [110].
with high fever and internal organ involvement is Many of these malignancies are chronic and
present, especially when a higher risk medication overall indolent, but some of them present as
is used [105]. emergencies with cutaneous features as their pre-
It also is important to note that a subgroup of senting signs.
patients with very low CD4+ counts (less than HIV-associated Kaposi sarcoma (KS) is
50) also may exhibit drug reactions to every drug caused by human herpes virus 8 and is primarily
they are provided, which can pose a significant a disease of men who have sex with men. It clas-
problem because these patients are on multiple sically presents as asymptomatic red-purple to
new medications [106]. To help prevent these brown papules, plaques, or tumors involving the
reactions, some of which are dangerous as out- head, neck, palate, chest, and extremities
lined above, and enable the use of medications, a (Fig. 5.3) [111]. In children, prominent lymph-
slow prednisone taper over 12 weeks while indi- adenopathy often is the presenting sign, and tis-
vidual medications are added individually can sue pathology is essential to establish diagnosis
help [107]. and rule out infection or lymphoma [112]. Skin
96 M. Boos et al.
ease at presentation. Digital squamous cell

carcinoma, also related to underlying HPV infec-
tion, can lead to amputation, which has significant
morbidity [120]. Metastatic disease also can ulti-
mately lead to death.
5.6.9 Immune Reconstitution

Inflammatory Syndrome
IRIS is a condition that is characterized by para-

doxical clinical deterioration in patients with
HIV days to months after starting HAART and is
Fig. 5.3 Infiltrated red-purple papules and plaques of
Kaposi sarcoma on the arm due to the restoration of pathogen-specific
immune responses [121, 122]. Opportunistic
pathogens may grow unchecked in immuno-
biopsy may be necessary to differentiate KS from suppressed patients. When the immune system
other vascular proliferations such as bacillary recovers there may be an exuberant inflammatory
angiomatosis or lymphoma/leukemia cutis, and response to these previously silent infections
typically reveals a spindle cell proliferation with [123, 124]. Approximately 10–25% of individuals
slit-like vascular spaces and increased red blood who start HAART experience this syndrome, and
cell extravasation. Immunohistochemical stains the skin is the most common organ system
with HHV8 will confirm the diagnosis. In involved with 52–78% of manifestations involv-
advanced stages, there may be associated lym- ing the skin [123]. The presenting symptoms and
phedema, as well as aerodigestive tract, pulmo- dermatologic manifestations can be variable and
nary, or gastrointestinal involvement. Internal include entities such as seborrheic dermatitis,
involvement can be a poor prognostic factor psoriasis, acne vulgaris, folliculitis, molluscum
indicative of rapid decompensation [113, 114]. contagiosum, and tinea versicolor or tinea capi-
The cornerstone of treatment and avoidance of tis. More serious presentations can occur when
this emergency is early detection and antiretrovi- there is a significant opportunistic infection or
ral therapy [111, 115, 116]. In some advanced or coinfection, and the inflammatory response can
emergent cases, collaboration with oncology and be detrimental. Frequently, differentiating this
administration of doxorubicin/danorubicin che- reaction from a medication reaction can be
motherapy may be important. difficult. The opportunistic diseases most com-
Cervical and anal cancer related to underlying monly associated with IRIS include mycobacte-
human papilloma viral infection also is an AIDS- rial diseases, including tuberculosis,
defining malignancy. Invasive cervical cancer Mycobacterium avium complex disease, leprosy,
was included as an AIDS-defining illness in 1993, and a wide range of other nontuberculous myco-
and there is now good evidence that precursor bacterial diseases; deep fungal infections, espe-
lesions also are increased in women with HIV cially cryptococcal meningitis; herpes viruses,
[109, 110, 117–119]. Although these changes can including CMV retinitis, herpes zoster and her-
be slow-growing and chronic in nature, the extent pes simplex; Kaposi Sarcoma (KS); and progres-
of disease can become emergent as it interferes sive multifocal leukoencephalopathy (PML) [41,
with underlying bowel and bladder dysfunction 72, 125–135]. The diverse clinical manifestations
or metastasis. In most clinical situations, treat- and clinical sequelae of IRIS have been well
ment of these diseases is the same as in immuno- documented. Early identification of HIV and
competent women, although HIV-positive women institution of HAART may help prevent both
and men often present with more advanced dis- the unmasking and worsening of preexisting
opportunistic infections by IRIS. For less 10. Lapins J, Gaines H, Lindback S, Lidbrink P,
dangerous dermatologic manifestations, general Emtestam L. Skin and mucosal characteristics of
symptomatic primary HIV-1 infection. AIDS Patient
treatment guidelines as previously outlined in Care STDS. 1997;11(2):67–70.
this chapter can be used. 11. Cooper DA, Gold J, Maclean P, et al. Acute AIDS
retrovirus infection. Definition of a clinical illness
associated with seroconversion. Lancet.
1985;1(8428):537–40.
5.7 Summary 12. Hulsebosch HJ, Claessen FA, van Ginkel CJ, Kuiters
GR, Goudsmit J, Lange JM. Human immunodeficiency
In conclusion, there are many cutaneous manifes- virus exanthem. J Am Acad Dermatol. 1990;23(3 Pt
tations of HIV and AIDS. Clinicians should be 1):483–6.
13. Balslev E, Thomsen HK, Weismann K.
able to recognize and treat HIV early to prevent Histopathology of acute human immunodeficiency
both serious illnesses and transmission. The cuta- virus exanthema. J Clin Pathol. 1990;43(3):201–2.
neous manifestations of HIV are often the most 14. Wantzin GR, Lindhardt BO, Weismann K, Ulrich K.
clinically evident since they can be seen easily. Acute HTLV III infection associated with exan-
thema, diagnosed by seroconversion. Br J Dermatol.
This chapter has reviewed the appearance of the 1986;115(5):601–6.
initial eruption, dermatoses, infections, malig- 15. Calabrese LH, Proffitt MR, Levin KH, Yen-
nancies, and inflammatory reactions that should Lieberman B, Starkey C. Acute infection with the
alert the clinician to recognize undiagnosed HIV human immunodeficiency virus (HIV) associated
with acute brachial neuritis and exanthematous rash.
as well as provide appropriate management in Ann Intern Med. 1987;107(6):849–51.
patients with known infection. 16. Daar ES, Little S, Pitt J, et al. Diagnosis of primary
HIV-1 infection. Los Angeles County Primary HIV
Infection Recruitment Network. Ann Intern Med.
2001;134(1):25–9.
References 17. Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral
treatment of adult HIV infection: 2010 recommen-
1. Murray PR, Rosenthal KS, Pfaller MA. Medical dations of the International AIDS Society-USA
microbiology. 6th ed. Philadelphia: Mosby/Elsevier; panel. JAMA. 2010;304(3):321–33.
2009. 18. Mallon E, Bunker CB. HIV-associated psoriasis.
2. Kahn JO, Walker BD. Acute human immunodeficiency AIDS Patient Care STDS. 2000;14(5):239–46.
virus type 1 infection. N Engl J Med. 19. Morar N, Willis-Owen SA, Maurer T, Bunker CB.
1998;339(1):33–9. HIV-associated psoriasis: pathogenesis, clinical fea-
3. Gorry PR, Ancuta P. Coreceptors and HIV-1 patho- tures, and management. Lancet Infect Dis.
genesis. Curr HIV/AIDS Rep. 2011;8(1):45–53. 2010;10(7):470–8.
4. Murakawa GJ, Kerschmann R, Berger T. Cutaneous 20. Duvic M, Johnson TM, Rapini RP, Freese T, Brewton
Cryptococcus infection and AIDS. Report of 12 G, Rios A. Acquired immunodeficiency syndrome-
cases and review of the literature. Arch Dermatol. associated psoriasis and Reiter’s syndrome. Arch
1996;132(5):545–8. Dermatol. 1987;123(12):1622–32.
5. Quinn TC, Brookmeyer R, Kline R, et al. Feasibility 21. Obuch ML, Maurer TA, Becker B, Berger TG.
of pooling sera for HIV-1 viral RNA to diagnose Psoriasis and human immunodeficiency virus infec-
acute primary HIV-1 infection and estimate HIV tion. J Am Acad Dermatol. 1992;27(5 Pt 1):667–73.
incidence. AIDS. 2000;14(17):2751–7. 22. Wolfer LU, Djemadji-Oudjiel N, Hiletework M,
6. Horsburgh Jr CR, Ou CY, Jason J, et al. Duration of et al. HIV-associated psoriasis. Clinical and histo-
human immunodeficiency virus infection before logical observations in 36 patients. Hautarzt.
detection of antibody. Lancet. 1989;2(8664): 637–40. 1998;49(3):197–202.
7. Ho DD, Sarngadharan MG, Resnick L, 23. Reveille JD, Conant MA, Duvic M. Human
Dimarzoveronese F, Rota TR, Hirsch MS. Primary immunodeficiency virus-associated psoriasis, psori-
human T-lymphotropic virus type III infection. Ann atic arthritis, and Reiter’s syndrome: a disease con-
Intern Med. 1985;103(6 Pt 1):880–3. tinuum? Arthritis Rheum. 1990;33(10):1574–8.
8. Schacker T, Collier AC, Hughes J, Shea T, Corey L. 24. Colebunders R, Blot K, Mertens V, Dockx P.
Clinical and epidemiologic features of primary HIV Psoriasis regression in terminal AIDS. Lancet.
infection. Ann Intern Med. 1996;125(4):257–64. 1992;339(8801):1110.
9. Tindall B, Barker S, Donovan B, et al. Characterization 25. Menon K, Van Voorhees AS, Bebo Jr BF, et al.
of the acute clinical illness associated with human Psoriasis in patients with HIV infection: from the
immunodeficiency virus infection. Arch Intern Med. medical board of the National Psoriasis Foundation.
1988;148(4):945–9. J Am Acad Dermatol. 2010;62(2):291–9.
98 M. Boos et al.
26. Nervi SJ, Schwartz RA, Dmochowski M. 42. Taylor CR, Bailey EM. Red nodule on the forearm of
Eosinophilic pustular folliculitis: a 40 year retro- an HIV-positive man. Isolated cutaneous
spect. J Am Acad Dermatol. 2006;55(2):285–9. Mycobacterium avium-intracellulare infection. Arch
27. Rajendran PM, Dolev JC, Heaphy Jr MR, Maurer T. Dermatol. 1998;134(10):1279–80. 1282-1273.
Eosinophilic folliculitis: before and after the intro- 43. Durden FM, Elewski B. Fungal infections in HIV-
duction of antiretroviral therapy. Arch Dermatol. infected patients. Semin Cutan Med Surg.
2005;141(10):1227–31. 1997;16(3):200–12.
28. Rosenthal D, LeBoit PE, Klumpp L, Berger TG. 44. Johnson NW. The mouth in HIV/AIDS: markers of
Human immunodeficiency virus-associated eosino- disease status and management challenges for the den-
philic folliculitis. A unique dermatosis associated tal profession. Aust Dent J. 2010;55 Suppl 1:85–102.
with advanced human immunodeficiency virus 45. Thompson 3rd GR, Patel PK, Kirkpatrick WR, et al.
infection. Arch Dermatol. 1991;127(2):206–9. Oropharyngeal candidiasis in the era of antiretroviral
29. Basarab T, Russell Jones R. HIV-associated eosino- therapy. Oral Surg Oral Med Oral Pathol Oral Radiol
philic folliculitis: case report and review of the liter- Endod. 2010;109(4):488–95.
ature. Br J Dermatol. 1996;134(3):499–503. 46. Single-Dose Fluconazole versus Standard 2-Week
30. Fearfield LA, Rowe A, Francis N, Bunker CB, Therapy for Oropharyngeal Candidiasis in HIV-
Staughton RC. Itchy folliculitis and human Infected Patients: A Randomized, Double-Blind,
immunodeficiency virus infection: clinicopathologi- Double-Dummy Trial Clin Infect Dis. 2008;47(10):
cal and immunological features, pathogenesis and 1270–6.
treatment. Br J Dermatol. 1999;141(1):3–11. 47. Dharmshale SN, Patil SA, Gohil A, Chowdhary A,
31. Porras B, Costner M, Friedman-Kien AE, Cockerell Oberoi C. Disseminated crytococcosis with exten-
CJ. Update on cutaneous manifestations of HIV infec- sive cutaneous involvement in AIDS. Indian J Med
tion. Med Clin North Am. 1998;82(5):1033–80. v. Microbiol. 2006;24(3):228–30.
32. Ellis E, Scheinfeld N. Eosinophilic pustular follicu- 48. Ampel NM. Emerging disease issues and fungal
litis: a comprehensive review of treatment options. pathogens associated with HIV infection. Emerg
Am J Clin Dermatol. 2004;5(3):189–97. Infect Dis. 1996;2(2):109–16.
33. Toutous-Trellu L, Abraham S, Pechere M, et al. Topical 49. Tuerlinckx D, Bodart E, Garrino MG, Weemaes G,
tacrolimus for effective treatment of eosinophilic folli- de Bilderling G. Cutaneous lesions of disseminated
culitis associated with human immunodeficiency virus cryptococcosis as the presenting manifestation of
infection. Arch Dermatol. 2005;141(10):1203–8. human immunodeficiency virus infection in a twen-
34. Pimpin L, Drumright LN, Kruijshaar ME, et al. ty-two-month-old child. Pediatr Infect Dis J.
Tuberculosis and HIV co-infection in European 2001;20(4):463–4.
Union and European Economic Area countries. Eur 50. Sarosi GA, Davies DA. Endemic mycosis compli-
Respir J. 2011;38(6):1382–92. cating human immunodeficiency virus infection.
35. Elston JW, Thaker HK. Co-infection with human West J Med. 1996;164(4):335–40.
immunodeficiency virus and tuberculosis. Indian J 51. Dover JS, Johnson RA. Cutaneous manifestations of
Dermatol Venereol Leprol. 2008;74(3):194–9. human immunodeficiency virus infection. Part II.
36. High WA, Evans CC, Hoang MP. Cutaneous miliary Arch Dermatol. 1991;127(10):1549–58.
tuberculosis in two patients with HIV infection. J 52. Economopoulou P, Laskaris G, Kittas C. Oral histo-
Am Acad Dermatol. 2004;50(5 Suppl):S110–3. plasmosis as an indicator of HIV infection. Oral
37. Oliva SM, Redini L, Bases OM, et al. Cutaneous Surg Oral Med Oral Pathol Oral Radiol Endod.
tuberculosis in patients with AIDS. AIDS Patient 1998;86(2):203–6.
Care STDS. 1997;11(6):443–9. 53. Witzig RS, Hoadley DJ, Greer DL, Abriola KP,
38. Regnier S, Ouagari Z, Perez ZL, Veziris N, Bricaire Hernandez RL. Blastomycosis and human
F, Caumes E. Cutaneous miliary resistant tuberculo- immunodeficiency virus: three new cases and review.
sis in a patient infected with human immunodeficiency South Med J. 1994;87(7):715–9.
virus: case report and literature review. Clin Exp 54. Pappas PG, Pottage JC, Powderly WG, et al.
Dermatol. 2009;34(8):e690–2. Blastomycosis in patients with the acquired
39. Farina MC, Gegundez MI, Pique E, et al. Cutaneous immunodeficiency syndrome. Ann Intern Med.
tuberculosis: a clinical, histopathologic, and bacte- 1992;116(10):847–53.
riologic study. J Am Acad Dermatol. 1995;33(3): 55. Imaz A, Pujol M, Barragan P, Dominguez MA,
433–40. Tiraboschi JM, Podzamczer D. Community associ-
40. Friedli A, Krischer J, Hirschel B, Saurat JH, Pechere ated methicillin-resistant Staphylococcus aureus in
M. An annular plaque due to Mycobacterium hae- HIV-infected patients. AIDS Rev.
mophilum infection in a patient with AIDS. J Am 2010;12(3):153–63.
Acad Dermatol. 2000;43(5 Pt 2):913–5. 56. Shastry L, Rahimian J, Lascher S. Community-
41. Mitha M, Naicker P, Taljaard J. Cutaneous associated methicillin-resistant Staphylococcus
Mycobacterium kansasii infection in a patient with aureus skin and soft tissue infections in men who
AIDS post initiation of antiretroviral therapy. J Infect have sex with men in New York City. Arch Intern
Dev Ctries. 2011;5(7):553–5. Med. 2007;167(8):854–7.
57. Sztramko R, Katz K, Antoniou T, et al. Community- 70. Chilek K, Routhouska S, Tamburro J. Disseminated
associated methicillin-resistant Staphylococcus varicella zoster virus in an immunized child as the
aureus infections in men who have sex with men: acquired immunodeficiency syndrome-defining ill-
A case series. Can J Infect Dis Med Microbiol. ness. Pediatr Dermatol. 2010;27(2):192–4.
2007;18(4):257–61. 71. Smith KJ, Skelton HG, Yeager J, Wagner KF.
58. Hidron AI, Kourbatova EV, Halvosa JS, et al. Risk Cutaneous thrombosis in human immunodeficiency
factors for colonization with methicillin-resistant virus type 1-positive patients and cytomegalovirus
Staphylococcus aureus (MRSA) in patients admitted viremia. Arch Dermatol. 1995;131(3):357–8.
to an urban hospital: emergence of community-asso- 72. Pereira B, Fernandes C, Nachiambo E, Catarino MC,
ciated MRSA nasal carriage. Clin Infect Dis. Rodrigues A, Cardoso J. Exuberant molluscum con-
2005;41(2):159–66. tagiosum as a manifestation of the immune reconsti-
59. Plettenberg A, Lorenzen T, Burtsche BT, et al. tution inflammatory syndrome. Dermatol Online J.
Bacillary angiomatosis in HIV-infected patients—an 2007;13(2):6.
epidemiological and clinical study. Dermatology. 73. Pirmohamed M, Park BK. HIV and drug allergy.
2000;201(4):326–31. Curr Opin Allergy Clin Immunol. 2001;1(4):311–6.
60. Hoey JG, Valois-Cruz F, Goldenberg H, et al. 74. Roujeau JC. Drug eruptions in HIV infection. Presse
Development of an immunoglobulin M capture- Med. 1994;23(3):111–2.
based enzyme-linked immunosorbent assay for diag- 75. Roujeau JC, Stern RS. Severe adverse cutaneous reac-
nosis of acute infections with Bartonella henselae. tions to drugs. N Engl J Med. 1994;331(19):1272–85.
Clin Vaccine Immunol. 2009;16(2):282–4. 76. Cacoub P, Musette P, Descamps V, et al. The DRESS
61. Biswas S, Rolain JM. Bartonella infection: treatment syndrome: a literature review. Am J Med.
and drug resistance. Future Microbiol. 2011;124(7):588–97.
2010;5(11):1719–31. 77. Cutrell AG, Hernandez JE, Fleming JW, et al.
62. Rompalo AM, Joesoef MR, O’Donnell JA, et al. Updated clinical risk factor analysis of suspected
Clinical manifestations of early syphilis by HIV sta- hypersensitivity reactions to abacavir. Ann
tus and gender: results of the syphilis and HIV study. Pharmacother. 2004;38(12):2171–2.
Sex Transm Dis. 2001;28(3):158–65. 78. Symonds W, Cutrell A, Edwards M, et al. Risk factor
63. Telzak EE, Chiasson MA, Bevier PJ, Stoneburner analysis of hypersensitivity reactions to abacavir.
RL, Castro KG, Jaffe HW. HIV-1 seroconversion in Clin Ther. 2002;24(4):565–73.
patients with and without genital ulcer disease. 79. Escaut L, Liotier JY, Albengres E, Cheminot N,
A prospective study. Ann Intern Med. Vittecoq D. Abacavir rechallenge has to be avoided
1993;119(12):1181–6. in case of hypersensitivity reaction. AIDS.
64. Plummer FA, Wainberg MA, Plourde P, et al. 1999;13(11):1419–20.
Detection of human immunodeficiency virus type 1 80. Chirouze C, Hustache-Mathieu L, Rougeot C, et al.
(HIV-1) in genital ulcer exudate of HIV-1-infected Risk factors for Abacavir-induced hypersensibility
men by culture and gene amplification. J Infect Dis. syndrome in the “real world”. Pathol Biol (Paris).
1990;161(4):810–1. 2004;52(9):529–33.
65. Lukehart SA, Hook 3rd EW, Baker-Zander SA, 81. Shearer WT. HIV infection and AIDS. Prim Care.
Collier AC, Critchlow CW, Handsfield HH. Invasion 1998;25(4):759–74.
of the central nervous system by Treponema pal- 82. Roujeau JC, Revuz J. Toxic epidermal necrolysis: an
lidum: implications for diagnosis and treatment. Ann expanding field of knowledge. J Am Acad Dermatol.
Intern Med. 1988;109(11):855–62. 1994;31(2 Pt 1):301–2.
66. Zellan J, Augenbraun M. Syphilis in the HIV- 83. French LE. Toxic epidermal necrolysis and Stevens
infected patient: an update on epidemiology, diagno- Johnson syndrome: our current understanding.
sis, and management. Curr HIV/AIDS Rep. Allergol Int. 2006;55(1):9–16.
2004;1(3):142–7. 84. Roujeau JC. The spectrum of Stevens-Johnson syn-
67. Chidzonga MM, Mahomva L. Recurrent noma (can- drome and toxic epidermal necrolysis: a clinical
crum oris) in human immunodeficiency virus infec- classification. J Invest Dermatol. 1994;102(6):
tion and acquired immunodeficiency syndrome (HIV 28S–30.
and AIDS): report of a case. J Oral Maxillofac Surg. 85. Saiag P, Caumes E, Chosidow O, Revuz J, Roujeau
2008;66(8):1726–30. JC. Drug-induced toxic epidermal necrolysis (Lyell
68. Siegal FP, Lopez C, Hammer GS, et al. Severe syndrome) in patients infected with the human
acquired immunodeficiency in male homosexuals, immunodeficiency virus. J Am Acad Dermatol.
manifested by chronic perianal ulcerative herpes sim- 1992;26(4):567–74.
plex lesions. N Engl J Med. 1981;305(24): 1439–44. 86. Knobel H, Miro JM, Domingo P, et al. Failure of a
69. Stewart JA, Reef SE, Pellett PE, Corey L, Whitley short-term prednisone regimen to prevent nevirap-
RJ. Herpesvirus infections in persons infected with ine-associated rash: a double-blind placebo-con-
human immunodeficiency virus. Clin Infect Dis. trolled trial: the GESIDA 09/99 study. J Acquir
1995;21 Suppl 1:S114–20. Immune Defic Syndr. 2001;28(1):14–8.
100 M. Boos et al.
87. Knobel H, Miro JM, Mahillo B, et al. Failure of ceti- patient. J Antimicrob Chemother. 2011;66(9):
rizine to prevent nevirapine-associated rash: a dou- 2188–9.
ble-blind placebo-controlled trial for the GESIDA 101. Ghosn J, Duvivier C, Tubiana R, Katlama C, Caumes
26/01 Study. J Acquir Immune Defic Syndr. E. Acute generalized exanthematous pustulosis
2004;37(2):1276–81. induced by HIV postexposure prophylaxis with lopi-
88. Rotunda A, Hirsch RJ, Scheinfeld N, Weinberg JM. navir-ritonavir. Clin Infect Dis. 2005;41(9):1360–1.
Severe cutaneous reactions associated with the use 102. Aquilina C, Viraben R, Roueire A. Acute general-
of human immunodeficiency virus medications. Acta ized exanthematous pustulosis: a cutaneous adverse
Derm Venereol. 2003;83(1):1–9. effect due to prophylactic antiviral therapy with pro-
89. Gimnig JE, MacArthur JR. M’Bang’ombe M, et al. tease inhibitor. Arch Intern Med.
Severe cutaneous reactions to sulfadoxine- 1998;158(19):2160–1.
pyrimethamine and trimethoprim-sulfamethoxazole 103. Harr T, French LE. Severe cutaneous adverse reac-
in Blantyre District, Malawi. Am J Trop Med Hyg. tions: acute generalized exanthematous pustulosis,
2006;74(5):738–43. toxic epidermal necrolysis and Stevens-Johnson
90. Kouassi B, Horo K, Vilasco B, et al. Lyell’s syn- syndrome. Med Clin North Am. 2010;94(4):
drome occurring in three HIV-positive patients 727–42. x.
undergoing anti-tuberculous therapy. Rev Mal 104. Chaponda M, Pirmohamed M. Hypersensitivity
Respir. 2010;27(3):247–50. reactions to HIV therapy. Br J Clin Pharmacol.
91. Ravin KA, Rappaport LD, Zuckerbraun NS, 2011;71(5):659–71.
Wadowsky RM, Wald ER, Michaels MM. 105. Dolev J, Reyter I, Maurer T. Treatment of recurring
Mycoplasma pneumoniae and atypical Stevens- cutaneous drug reactions in patients with human
Johnson syndrome: a case series. Pediatrics. immunodeficiency virus 1 infection: a series of 3
2007;119(4):e1002–5. cases. Arch Dermatol. 2004;140(9):1051–3.
92. Meyer Sauteur PM, Gansser-Kalin U, Lautenschlager 106. Spagnuolo V, Galli L, Salpietro S, et al. Ten-year
S, Goetschel P. Fuchs syndrome associated with survival among HIV-1 infected subjects with AIDS-
Mycoplasma pneumoniae (Stevens-Johnson syn- or non-AIDS-defining malignancies. Int J Cancer.
drome without skin lesions). Pediatr Dermatol. 2012;130(12):2990–6.
2011;28(4):474–6. 107. Wilkins K, Dolev JC, Turner R, LeBoit PE, Berger
93. Tsai V, Oman J. Stevens-Johnson syndrome after TG, Maurer TA. Approach to the treatment of cuta-
Mycoplasma pneumoniae infection. J Emerg Med. neous malignancy in HIV-infected patients. Dermatol
2011;40(3):324–7. Ther. 2005;18(1):77–86.
94. Strom J. Herpes simplex virus as a cause of allergic 108. Casper C. The increasing burden of HIV-associated
mucocutaneous reactions (ectodermosis erosiva malignancies in resource-limited regions. Annu Rev
pluriorificialis, Stevens-Johnson’s syndrome, etc.) Med. 2011;62:157–70.
and generalized infection. Scand J Infect Dis. 109. Martellotta F, Berretta M, Vaccher E, Schioppa O,
1969;1(1):3–10. Zanet E, Tirelli U. AIDS-related Kaposi’s sarcoma:
95. Detjen PF, Patterson R, Noskin GA, Phair JP, Loyd state of the art and therapeutic strategies. Curr HIV
SO. Herpes simplex virus associated with recurrent Res. 2009;7(6):634–8.
Stevens-Johnson syndrome. A management strategy. 110. Arkin LM, Cox CM, Kovarik CL. Kaposi’s sarcoma
Arch Intern Med. 1992;152(7):1513–6. in the pediatric population: the critical need for a tis-
96. Golden HE. Stevens-Johnson syndrome associated sue diagnosis. Pediatr Infect Dis J.
with herpes simplex virus. Arch Intern Med. 2009;28(5):426–8.
1993;153(11):1396. 111. Mesri EA, Cesarman E, Boshoff C. Kaposi’s sar-
97. Cheriyan S, Patterson R. Recurrent Stevens-Johnson coma and its associated herpesvirus. Nat Rev Cancer.
syndrome secondary to herpes simplex: a follow up 2010;10(10):707–19.
on a successful management program. Allergy 112. Stebbing J, Mazhar D, Lewis R, et al. The presenta-
Asthma Proc. 1996;17(2):71–3. tion and survival of patients with non-cutaneous
98. Manwani NS, Balasubramanian S, Dhanalakshmi K, AIDS-associated Kaposi’s sarcoma. Ann Oncol.
Sumanth A. Stevens Johnson Syndrome in 2006;17(3):503–6.
Association with Mycoplasma Pneumonia. Indian J 113. Clayton G, Omasta-Martin A, Bower M. The effects
Pediatr. 2011. of HAART on AIDS-related Kaposi’s sarcoma and
99. Peermohamed AR, Shafar J. Sustained azathioprine- non-Hodgkin’s lymphoma. J HIV Ther.
induced remission in Wegener’s granulomatosis. Br 2006;11(3):51–3.
Med J. 1969;4(5683):600–1. 114. Nasti G, Martellotta F, Berretta M, et al. Impact of
100. Bourkia M, Charles L, Lambotte O, Orostegui-Giron highly active antiretroviral therapy on the presenting
L, Goujard C, Ghosn J. Life-threatening acute gener- features and outcome of patients with acquired
alized exanthematous pustulosis induced by two dif- immunodeficiency syndrome-related Kaposi sar-
ferent protease inhibitors in an HIV-1-infected coma. Cancer. 2003;98(11):2440–6.
115. Gormley RH, Kovarik CL. Dermatologic manifesta- 125. Couppie P, Abel S, Voinchet H, et al. Immune
tions of HPV in HIV-infected individuals. Curr HIV/ reconstitution inflammatory syndrome associated
AIDS Rep. 2009;6(3):130–8. with HIV and leprosy. Arch Dermatol. 2004;140(8):
116. Schwartz JJ, Dias BM, Safai B. HIV-related malig- 997–1000.
nancies. Dermatol Clin. 1991;9(3):503–15. 126. Connick E, Kane MA, White IE, Ryder J, Campbell
117. Bower M, Palmieri C, Dhillon T. AIDS-related TB. Immune reconstitution inflammatory syndrome
malignancies: changing epidemiology and the associated with Kaposi sarcoma during potent anti-
impact of highly active antiretroviral therapy. Curr retroviral therapy. Clin Infect Dis.
Opin Infect Dis. 2006;19(1):14–9. 2004;39(12):1852–5.
118. Gormley RH, Groft CM, Miller CJ, Kovarik CL. 127. Breton G, Duval X, Estellat C, et al. Determinants of
Digital squamous cell carcinoma and association immune reconstitution inflammatory syndrome in
with diverse high-risk human papillomavirus types. J HIV type 1-infected patients with tuberculosis after
Am Acad Dermatol. 2011;64(5):981–5. initiation of antiretroviral therapy. Clin Infect Dis.
119. Shelburne 3rd SA, Hamill RJ. The immune reconsti- 2004;39(11):1709–12.
tution inflammatory syndrome. AIDS Rev. 128. Richardson D, Rubinstein L, Ross E, et al. Cystic
2003;5(2):67–79. lung lesions as an immune reconstitution
120. Shelburne 3rd SA, Hamill RJ, Rodriguez-Barradas inflammatory syndrome (IRIS) in HIV-TB co-infec-
MC, et al. Immune reconstitution inflammatory syn- tion? Thorax. 2005;60(10):884.
drome: emergence of a unique syndrome during 129. Pires A, Nelson M, Pozniak AL, et al. Mycobacterial
highly active antiretroviral therapy. Medicine immune reconstitution inflammatory syndrome in
(Baltimore). 2002;81(3):213–27. HIV-1 infection after antiretroviral therapy is associ-
121. Huiras E, Preda V, Maurer T, Whitfeld M. Cutaneous ated with deregulated specific T-cell responses:
manifestations of immune reconstitution beneficial effect of IL-2 and GM-CSF immunother-
inflammatory syndrome. Curr Opin HIV AIDS. apy. J Immune Based Ther Vaccines. 2005;3:7.
2008;3(4):453–60. 130. Reddy V, Luzzi GA. Chronic vulval ulceration–
122. Ratnam I, Chiu C, Kandala NB, Easterbrook PJ. another immune reconstitution inflammatory syn-
Incidence and risk factors for immune reconstitution drome? Int J STD AIDS. 2005;16(6):454–5.
inflammatory syndrome in an ethnically diverse HIV 131. Breton G, Adle-Biassette H, Therby A, et al. Immune
type 1-infected cohort. Clin Infect Dis. reconstitution inflammatory syndrome in HIV-
2006;42(3):418–27. infected patients with disseminated histoplasmosis.
123. da Cunha Colombo ER, Mora DJ, Silva-Vergara ML. AIDS. 2006;20(1):119–21.
Immune reconstitution inflammatory syndrome (IRIS) 132. Imamura E, Yamashita H, Fukuhara T, et al. Case of
associated with Cryptococcus neoformans infection highly active anti-retroviral therapy-induced immune
in AIDS patients. Mycoses. 2011;54(4):e178–82. reconstitution inflammatory syndrome in AIDS-
124. Achenbach CJ, Harrington RD, Dhanireddy S, Crane related progressive multifocal leukoencephalopathy.
HM, Casper C, Kitahata MM. Paradoxical Immune Rinsho Shinkeigaku. 2007;47(10):650–6.
Reconstitution Inflammatory Syndrome in HIV-Infected 133. Ueno T, Mitsuishi T, Kimura Y, et al. Immune recon-
Patients Treated With Combination Antiretroviral stitution inflammatory syndrome associated with
Therapy After AIDS-Defining Opportunistic Infection. Kaposi’s sarcoma: successful treatment with inter-
Clin Infect Dis. 2012;54(3): 424–33. feron-alpha. Eur J Dermatol. 2007;17(6):539–40.
Graft-Versus-Host Disease
6
David Pompei, Kathryn J. Russell,
and Frederick A. Pereira
Graft-versus-host disease (GVHD) is a multisys- [1]. Animal research demonstrated that HSCT
tem disorder combining features of both autoim- was able to replace radiation-damaged host cells
munity and immunodeficiency. It is a common with healthy, transplanted donor cells. This pre-
and serious complication of hematopoietic stem clinical data provided impetus for future studies
cell transplantation (HSCT), and rarely solid investigating HSCT following chemoradiother-
organ transplantation, transfusion, and donor apy in leukemic patients. The use of transplanted
lymphocyte infusion. Because of its complex cells as a treatment option has driven research
pathophysiology and diverse clinical manifesta- into stem cell graft types (autologous, syngeneic,
tions, management of this challenging disease and allogeneic) and graft sources (bone marrow,
requires a multidisciplinary approach. Skin peripheral blood, and umbilical cord blood).
findings are the most common presenting sign, Improvements in treatment have led to increased
and they found in all forms of GVHD; therefore, use of HSCT for a wide variety of disease
the dermatologist plays an important role in diag- (Table 6.1). Unfortunately, despite these improve-
nosis and therapy. ments and research advances, GVHD remains a
Research into HSCT began in the years fol- serious complication of this procedure.
lowing World War II in an effort to address fears
over the deleterious effects of radiation exposure
6.1 Overview of HSCT
D. Pompei, Pharm.D. (*) The process of bone marrow ablation is termed

Einstein-Montefiore Division of Dermatology, “conditioning.” Conditioning reduces tumor bur-
Montefiore Medical Center, 3411 Wayne Avenue,
den, creating a physical space into which trans-
2nd Floor, Bronx, NY 10467, USA
e-mail: Davepompei@gmail.com planted cells can migrate and proliferate, and it
induces a state of immunosuppression so donor
K.J. Russell, M.D.
Department of Dermatology, New York Medical College, stem cells will not be rejected. Myeloablative
1901 First Avenue, Room 1208, New York, conditioning consists of total body irradiation
NY 10029, USA and/or chemotherapy. Specific conditioning reg-
e-mail: Katyrussell@gmail.com
imens depend upon center protocols and the dis-
F.A. Pereira, M.D. ease being treated. Myeloablative conditioning
Department of Dermatology, Mount Sinai School
is associated with significant organ toxicity and
of Medicine, One Gustave L. Levy Place,
Box 1047, New York, NY 10029, USA is usually used in patients under 60 with good
performance status. Non-myeloablative, mini-
Department of Dermatology, New York Medical College,
New York, NY, USA mally toxic conditioning regimens have been
e-mail: PereiraF@aol.com developed for use in older patients or those with

104 D. Pompei et al.
Table 6.1 Indications for hematopoietic stem cell transplantation

Malignant disorders Congenital disorders Other disorders
· Multiple myeloma · Severe combined immunodeficiency · Aplastic anemia
· Non-Hodgkin lymphoma · Hemophagocytic lymphohistiocytosis · Primary Amyloidosis
· Hodgkin disease · Hemoglobinopathies, i.e., · Autoimmune disorders, i.e.,
· Acute myeloid leukemia o Sickle cell anemia o Multiple sclerosis
· Acute lymphoblastic o Thalassemia major o Systemic sclerosis
leukemia · Inborn errors of metabolism, i.e., o Systemic lupus erythematosus
· Chronic myeloid leukemia o Porphyrias o Crohn’s disease
· Juvenile Chronic Myeloid o Hunter’s Syndrome o Type I diabetes
Leukemia · Congenital bone marrow failure syndromes, i.e., o Rheumatoid arthritis
· Myelodysplastic syndromes o Fanconi anemia o Juvenile idiopathic arthritis
· Other myeloproliferative o Blackfan–Diamond anemia o Hematologic immune
disorders o Shwachman–Diamond syndrome cytopenias
· Medulloblastoma · Epidermolysis Bullosa, i.e., o Pemphigus vulgaris
· Germ-cell tumors o Recessive Dystrophic o Scleromyxedema
· Ovarian cancer o Junctional Variant
· Neuroblastoma · Dyskeratosis congenita
· Cutaneous T-cell lymphoma/ · Bloom syndrome
Sézary syndrome · Paroxysmal noctural hemoglobinuria
· Wiskott-Aldrich syndrome
· POEMs syndromea
· Osteopetrosis
· Griscelli syndrome
a
POEMS syndrome- Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes
significant comorbidities [2]. Conditioning usu- cells (RBCs) are reinfused back into the donor.
ally takes 7–10 days. Stem cells can be frozen for prolonged periods
After completion of conditioning, stem cells without damaging their function or viability.
are infused intravenously, usually through a cen- Peripheral blood contains more T cells than bone
tral venous line. Stem cells can be derived from marrow, thus increasing the risk of graft-versus-
bone marrow, peripheral blood or umbilical cord host disease (GVHD) [4, 5]. With umbilical cord
blood. If the patient himself provides stem cells, blood, there is a lower incidence of GVHD, and a
the transplant is said to be autologous. An alloge- much lower risk of infection by latent viruses
neic (allos means other in Greek) transplant such as Epstein Barr (EB) or cytomegalovirus
means that stem cells are derived from another (CMV). One or two HLA disparities can be toler-
individual. If the other individual is an identical ated by the recipient, and cord blood is easily
twin, the transplant is “syngeneic.” banked, typed and stored. The main disadvantage
Extraction of bone marrow is usually done is that it contains low numbers of stem cells, and
under general anesthesia as significant amounts there may be failure of engraftment. Cord blood
of marrow (>70 ml) are obtained from the iliac is mainly used in children [6–8] (Table 6.2).
crests. Extraction of stem cells from peripheral Following infusion, stem cells migrate to the
blood is logistically easier, and it avoids the risks bone marrow. In the range of 2–4 weeks, they
of general anesthesia. Peripheral blood is the will “engraft” and start producing normal blood
most common source of allogeneic stem cells in cells. The day of engraftment is defined as the
adult recipients (>20 years old), and bone mar- first of three consecutive days in which the neu-
row the most common in recipients under 20. trophil count is greater than 0.5 × 10(9)/l. If
Overall, peripheral blood is the most common engraftment does not occur by day 30, the graft is
source of stem cells [3]. The donor is primed with considered failed [9]. Hematopoietic function
granulocyte-macrophage stimulating factor normalizes in a matter of weeks; however,
(GMSF), peripheral blood is removed, white immune function takes months, or even years to
blood cells (WBCs) are separated, and red blood normalize [10]. From the start of conditioning to
6 Graft-Versus-Host Disease 105
Table 6.2 Characteristics of stem cell sources

Stem cell content Engraftment time Risk of aGVHD Risk of cGVHD
Bone marrow Moderate Moderate Moderate Moderate
Peripheral blood High Fastest Moderate Highest
Cord blood Low Slowest Lowest Lowest
the time of engraftment, the patient is in a state of GVHD to occur [21]. One, the graft must contain
pancytopenia and profound immunosuppression. immunologically active cells, now known to be
The risk of lethal viral, bacterial or fungal infec- alloreactive T cells. Two, the recipient must
tion is high. Infection can come about from exter- express tissue antigens foreign to the donor.
nal sources, from endogenous flora of the skin Three, the recipient must be incapable of mount-
and gut, or through reactivation of latent viruses, ing an immunological response against the donor
particularly CMV [11]. Prophylactic antibiotics cells. The incidence and severity of aGVHD
and careful supportive care are critical during this relate to the extent of mismatch of HLA proteins
period. Mucositis can be severe during the pancy- [19]. Ideally, there will be high resolution match-
topenic phase, and total parenteral nutrition ing for HLA-A, B, C and DR B1 between donor
(TPN) may be necessary [12–14]. Following and recipient (“8/8 match”) [19]. However, even
engraftment, there is recovery from pancytopenia if the donor is an identical twin, GVHD can still
and healing of mucositis; however, at this early occur because of mismatch of minor histocom-
stage the immune system remains weakened and patibility antigens (mHA) [22, 23].
dysregulated. Every human being is genetically unique, and
HSCT is a debilitating, emotionally taxing, this uniqueness also applies to monozygotic twins
high-risk procedure associated with significant in whom subtle, but medically significant genetic
treatment-related morbidity and mortality [15, differences exist. For example, single nucleotide
16]. In the months to years it takes for the engrafted polymorphisms (SNPs) in the thiopurine methyl-
stem cells to differentiate, proliferate and give rise transferase gene have been identified in identical
to a functional immune system, patients suffer twins. These polymorphisms result in differences
infections, fatigue and psychological debility. in metabolizing capacity between the twins.
Children and young adults are most likely to expe- These genetic differences come about because of
rience complete immune reconstitution; however, somatic mutations that occur in utero, meiotic
complete immune recovery may never take place and mitotic recombination, and biased gene con-
in older adults, particularly in patients who versions. Genes and genomes are in a state of
develop chronic GVHD (cGVHD) [17, 18]. constant evolution [22, 24].
Following HSCT, donor-derived, immunologi- Minor HAs are immunogenic peptides derived
cally active cells are confronted with infection, from genes outside the MHC. They arise through
residual malignant cells, and a variety of foreign polymorphisms in homologous genes between
proteins. Acute GVHD (aGVHD) results from recipient and donor [25]. Polymorphisms in
this confrontation and is a major cause of morbi- recipient genes result in different amino acid
dity and mortality following HSCT [19]. sequences, which are recognized by donor T cells
aGVHD occurs when donor T cells react as non-self [19]. Approximately 30 mHAs have
against recipient HLA antigens and minor histo- thus far been identified in humans [22]. For
compatibility antigens (mHA). It occurs in example, males express several H-Y antigens
60–80% of patients in which there is an HLA encoded on the Y chromosome. These antigens
mismatch, and in 20–50% of patients who receive are recognized as foreign by lymphocytes from
stem cells from an HLA identical sibling donor female donors, and aGVHD will result from gen-
[20]. In 1966, Rupert Billingham identified three der mismatch [26]. Multiple other mHAs exist,
preconditions that need to be met in order for all of which can trigger aGVHD [27]. Minor HAs
may play an important role in graft-versus-leuke- 100 days. This temporal division has been
mia (GVL) effect because some of these antigens superseded by a new classification developed
are only expressed on hematopoietic cells [28]. by experts in an NIH Consensus Development
The success of HSCT in leukemia is due in part Project on Criteria for clinical trials in cGVHD
to GVL effect mediated by donor immune cells [29] (Table 6.3). In the new classification, the two
[25, 28]. The relapse rate of leukemia is lower in main categories remain, but each has two subcat-
patients who develop GVHD compared to those egories. aGVHD is subclassified into “classic”
who do not. It is also lower in patients receiving aGVHD occurring before day 100 following the
allogeneic versus syngeneic transplants because transplant, or persistent, recurrent or late aGVHD
the former are more likely to develop GVHD occurring after day 100. cGVHD is subclassified
than the latter. into classic cGVHD, and an overlap syndrome in
which features of aGVHD and cGVHD occur
together. In the new classification system, clinical
6.1.1 Acute GVHD and pathologic manifestations take priority over
time of onset.
GVHD has traditionally been divided into two Ferrara and associates have identified three
forms, acute and chronic. aGVHD classically distinct phases in the pathogenesis of aGVHD
referred to disease that occurred in the first 100 [19, 30, 31] (Fig. 6.1). Phase one involves induc-
days, and chronic, after day 100. This classification tion of host cytokines and activation of host
has proven inadequate because aGVHD can antigen presenting cells (APCs). Infections, con-
occur after day 100, particularly in patients who ditioning regimens and underlying disease all
have undergone reduced intensity conditioning, cause cellular damage and release of pro-
and features of cGVHD are common in the first inflammatory cytokines such as TNF-a, IL-1,
Table 6.3 NIH criteria for clinical trials in chronic graft-versus-host disease
Classic acute Persistent, recurrent or late Classic chronic Overlap syndrome
acute GVHD
Days post transplant £100 >100 N/A N/A
Symptoms Maculopapular Maculopapular rash, At least one Features of both
rash, nausea, nausea, vomiting, anorexia, diagnostic clinical acute and chronic
vomiting, anorexia, diarrhea, ileus, choestatic sign or manifesta- GVHD
diarrhea, ileus, hepatitis tion confirmed by
choestatic hepatitis biopsy or other
testing (see
Table 6.3)
Fig. 6.1 Pathogenesis of acute GVHD

and IL-6. Increased serum levels of these cytok- causes tissue damage by inducing apoptosis of
ines upregulate adhesion molecules, MHC mole- target cells after activation of the TNF-Fas activa-
cules and mHAs on APCs [30]. In addition, tion pathway [36]. NO, produced by macrophages,
damage to the GI tract from conditioning results inhibits proliferation of epithelial stem cells and
in translocation of immunostimulatory molecules thereby inhibits repair of target tissue [35]. Damage
such as lipopolysaccharide (LPS) and other bac- to the GI tract occurring during phase three causes
terial products into the systemic circulation [32, more release of bacterial LPS, which further
33]. Macrophages and other cells of the innate upregulates innate immune function. A feedback
immune system recognize pathogen associated loop is created that enhances antigen presentation
molecular patterns, and they secrete cytokines, and activation of alloreactive donor T cells [30].
chemokines, adhesion molecules and costimula- Natural killer (NK) cells appear to modulate
tory molecules. The innate immune system is aGVHD. NK cells are the first lymphocytes to
“primed.” MHC molecules are upregulated, lead- recover to normal numbers after HSCT, and they
ing to enhanced antigen presentation by antigen- play a role in both innate and adaptive immunity.
presenting cells [34]. Decontamination of the Early animal models demonstrated that NK cells
gastrointestinal tract has been associated with were not crucial for the development of GVHD
reduced incidence of aGVHD both clinically and and their role in GVHD was incompletely under-
in animal models, and in some centers, gut decon- stood [37]. More recently, NK cells have been
tamination is standard procedure [34]. shown to decrease GVHD severity by inhibiting
Phase two consists of antigen presentation to immature dendritic cells and suppressing alloanti-
donor T cells. This occurs in recipient lymphoid gen-driven proliferation of donor CD4+ T cells
tissue. In direct presentation, donor T cells [38, 39]. In addition, they can work in concert
recognize peptides bound to allogeneic MHC with T regulatory (Treg) cells to prevent cGVHD
molecules on recipient APCs, or they recognize [39]. NK cell function may be more important in
and react to the allogeneic MHC molecule itself unrelated donor HSCTs compared to related
without peptide [35]. In indirect presentation, donors as polymorphisms in NK cell receptor and
donor APCs will degrade allogeneic MHC mole- ligand complexes have been linked to differences
cules into peptides, which are presented on the in GVHD and relapse rates. Patients undergoing
cell surface by donor-MHC molecules and recog- unrelated HSCT with a graft containing high
nized by donor T cells. In response to antigen pre- numbers of NK cells (CD56+) had a significantly
sentation, activated donor T cells proliferate and reduced incidence of severe aGVHD compared to
differentiate. They then exit lymphoid tissue and patients receiving grafts with lower numbers of
traffic to target organs. Activated T cells secrete NK cells [40]. This effect was not seen with
cytokines, in particular IL-2 and IFN-g, both of related donors and did not seem to influence the
which are important mediators of aGVHD. These graft-versus-leukemia (GVL) effect.
cytokines trigger cytotoxic T lymphocyte (CTL) aGVHD can involve many organs; however,
responses to alloantigens, and they also induce skin, intestine, and liver are the main targets [20].
monocytes and macrophages to produce Skin is usually the first organ involved with rashes
proinflammatory cytokines IL-1 and TNF-a [35]. occurring in at least 80% of patients [20]. Hepatic
During phase three, the effector stage, actual and intestinal manifestations appear a few days
target organ damage takes place [30, 35]. CTLs are after the rash [41]. Extensive rashes are common
the predominant cellular effectors of aGVHD, and in the post-transplant period, and these can
they cause tissue damage via the Fas/FasL and the include drug reactions, chemotherapy related
perforin/granzyme pathway. TNF-a, IL-1, and toxicity, viral exanthems, toxin-mediated ery-
nitric oxide (NO) are the main inflammatory themas, engraftment syndrome, and intrinsic
cytokine effectors. TNF-a activates APCs, it inflammatory skin diseases not related to the
enhances alloantigen recognition, and it recruits HSCT. These pathologic processes may occur
effecter cells to target organs [19]. It also directly simultaneously.
Dermatologists play a key role in sorting out more likely drug reactions, reactions to condi-
post-transplant rashes. Diagnosis of aGVHD is tioning, or infections rather than aGVHD. Acute
based on clinical and histopathologic features. cutaneous GVHD is heralded by a pruritic, some-
The main histopathologic features of cutaneous times painful “maculopapular” rash that tends to
aGVHD include a lymphocytic interface derma- be acrally distributed (Figs. 6.4, 6.5, and 6.6).
titis, vacuolar degeneration of the basal cell layer, Involvement of the palms, soles, pinnae, and
and necrotic keratinocytes [42]. Histopathologic cheeks is common [45]. Involvement of the face,
grading is based on the extent of keratinocyte palms and soles together is strongly predictive of
necrosis, which ranges from subtle vacuolar aGVHD rather than drug reaction [46]. The rash
alteration to complete epidermal necrosis [42] of aGVHD commonly affects the upper, sun-
(Table 6.4). A skin biopsy can yield valuable exposed areas of the body such as the face, arms
diagnostic information with minimal risk to the and shoulders [43, 47]. Exanthematous drug
patient (Figs. 6.2 and 6.3). In contrast, invasive reactions usually begin centrally and often do not
endoscopic procedures and biopsies of intestine involve the palms and soles. A follicular localiza-
and liver carry significant procedural risks, par- tion is also typical of aGVHD and an important
ticularly with respect to bleeding and infection clue to diagnosis [20, 48–50]. Atypical and severe
post-transplant [23, 43, 44]. skin manifestations of aGVHD may occur [51].
aGVHD usually manifests 2–6 weeks after Acute grade IV cutaneous GVHD resembles SJS/
transplantation. As a rough rule of thumb, rashes TEN, and mucositis consisting of oral and lip
occurring in the first 20 days post-transplant are erosions occurs in approximately 60% of these
patients [51]. However, in milder forms of
Table 6.4 Grading of the histopathological findings of aGVHD, mucositis is not a prominent clinical
cutaneous aGVHD feature [47]. Other mucosal manifestations of
Grade Skin changes aGVHD include erythema and lichenoid lesions.
1 Vacuolar degeneration of The liver is a common target organ in aGVHD.
epidermal basal cells Abnormal liver functions and jaundice secondary
2 Vacuolar change with spongiosis
to cholestasis comprise the typical clinical picture.
and dyskeratosis
3 Epidermolysis and bulla
Biliary epithelial cells are the primary target of
formation alloreactive donor T cells recognizing foreign
4 Total loss of epidermis HLA antigens and minor HAs on the surface of
Fig. 6.2 Lymphocytic infiltration

with necrotic keratinocytes (100×)
(Photo Courtesy of Dr. Paul Chu,
M.D.)
Fig. 6.3 Lymphocytic infiltration

with necrotic keratinocytes (200×)
(Photo Courtesy of Dr. Paul Chu,
M.D.)
Fig. 6.4 A woman with acute GVHD showing erythema- Fig. 6.5 A woman with acute GVHD with extensive ery-
tous macules and papules on the palms (Photo courtesy of thematous follicular macules coalescing into dusky
Gil Cortes, M.D.) patches on the thighs (same patient as in Fig. 6.4) (Photo
courtesy of Gil Cortes, M.D.)
these cells [52]. Histologically, there is lympho- chronic hepatic GVHD, and only 30% of patients
cytic infiltration of small bile ducts, nuclear pleo- with acute hepatic GVHD will experience com-
morphism, and apoptosis of epithelial cells [53]. plete resolution of liver abnormalities after initial
Untreated, acute hepatic GVHD can lead to loss of immunosuppressive treatment [52]. The differen-
bile ducts and worsening jaundice. A rising or per- tial diagnosis of liver abnormalities in the post-
sistent elevation of the bilirubin portends a poor transplant patient is complex and includes
prognosis. In some patients aGVHD can present sinusoidal obstruction syndrome (SOS), acute
with a hepatitis-like picture with elevation of ami- viral hepatitis and other infections, biliary obstruc-
notransferase enzymes [52, 53]. Fifty percent of tion, drug induced liver injury, TPN hepatotoxic-
patients with acute hepatic GVHD will develop ity, and numerous other conditions [53, 54]. Acute
In the post transplant period, a disorder known

as engraftment syndrome (ES) can occur. ES shares
some clinical features with classic aGVHD, and
some authorities consider ES a variant of aGVHD.
ES occurs after allogeneic or autologous HSCT at
the time of neutrophil recovery [56]. Major features
consist of generalized maculopapular rash, fever,
and noncardiogenic pulmonary edema associated
with hypoxemia. The clinical picture can be accom-
panied by diarrhea, weight gain secondary to fluid
retention, hepatic or renal dysfunction, transient
Fig. 6.6 An 11-month-old child presents 2 months post- encephalopathy and keratitis [57, 58]. The reported
HSCT with hemophagocytic lymphohistiocytosis and an incidence of ES varies from 7 to 59%. The wide
overlap syndrome of acute and chronic GVHD. Note a disparity in numbers probably reflects differences
lichenoid dermatitis with discrete and confluent viola-
ceous papules involving palm and extending onto forearm
in definition. In one large series of 328 patients
(Photo courtesy of Jason Emer, M.D.) undergoing peripheral blood autologous HSCT, the
incidence was 12.8% [57].
hepatic GVHD usually does not occur in isolation, ES is thought to result from release of
and other stigmata of aGVHD such as rash and GI proinflammatory cytokines and products of
abnormalities are part of the total clinical picture. degranulation and oxidative metabolism of neu-
Timing is also an important consideration. If trophils [59]. This results in systemic endothelial
signs of liver damage occur in the first 20 days cell damage [57, 59]. ES responds well to corti-
post-transplant, causes other than aGVHD are costeroids when given in a timely fashion and in
likely, especially SOS. SOS occurs following adequate amounts; however, if treatment is
damage to the hepatic sinusoids from myeloabla- delayed or inadequate, ES can progress to multi-
tive conditioning, especially regimens containing organ failure and death [60]. Patients with ES
cyclophosphamide, the metabolites of which are have a 21% greater likelihood of non-relapse
toxic to sinusoidal endothelial cells [52]. The mortality in 5 years compared to those without
condition is characterized by varying degrees of ES. Steroid treatment does not reduce this
hepatomegaly, fluid retention, jaundice and bio- increased mortality [60].
chemical abnormalities. Severe cases can be fatal. Autologous GVHD (autoGVHD) was first
The predominant clinical sign of acute intesti- reported by Hood et al. in 1987 [61]. Seven
nal GVHD is diarrhea. Vomiting, anorexia, patients receiving autologous bone marrow trans-
abdominal pain and ileus may also be present. plantations developed cutaneous eruptions
Diarrhea in the first 20 days after HSCT is usu- compatible both clinically and histologically with
ally associated with conditioning toxicity. From grade II aGVHD. Also known as the “auto-
day 20 to day 100, aGVHD is most likely, and aggression” syndrome, autoGVHD tends to be
after day 100, an enteric infection should be con- milder than aGVHD following allogeneic HSCT.
sidered [44]. Biopsy of intestinal mucosa in acute It usually involves skin alone and is generally
intestinal GVHD will show inflammatory changes self-limited; however, more severe forms involv-
associated with epithelial cell apoptosis, the pres- ing the liver and intestine can occur. AutoGVHD
ence of which is necessary for histopathologic is thought to result from loss of self-tolerance
diagnosis [44]. The rectosigmoid area is the opti- because of loss of regulatory T cells (Treg) and
mum site for biopsy. In comparison to other sites damage to the thymus from conditioning [62].
in the GI tract such as stomach or duodenum, rec- Treg cells are a subset of T cells that prevent self-
tosigmoid mucosal biopsies have a sensitivity of reactive T cells that have escaped thymic deletion
95.6% and a specificity of 100% [55]. from reacting to self antigens. Treg cells establish
tolerance to both allo- and self-MHC antigens Despite the large number of passenger
[63]. Myeloablative conditioning causes deple- lymphocytes, the incidence of GVHD is low. An
tion of Treg cells [64]. In addition, cyclosporine important reason is that a high percentage of
(CSA) and other medications administered post- hepatic T cells express gd receptors, 7–54% ver-
transplant interfere with the functional capacity sus <6% in peripheral blood. These cells produce
of the thymus to delete T cells bearing autoreac- Th2 cytokines, which downregulate Th1 responses
tive TCRs. This effect has been demonstrated in and suppress aGVHD [70]. In addition, patients
rodents, which are considered accurate models of receiving OLTs are immunosuppressed, not
human aGVHD [64, 65]. In the setting of autolo- immunoablated. Donor T cells are rejected by a
gous HSCT, loss of central tolerance coupled partially functioning immune system.
with the absence of peripheral Treg cells creates Skin rash is the major clinical sign associated
a permissive environment in which autoreactive with OLT-associated aGVHD [71]. Lesions erupt
T cells damage host tissue [62]. 1–8 weeks after transplantation. Skin lesions usu-
Although aGVHD causes considerable mor- ally begin distally on the palms and soles and rap-
bidity and mortality, it is associated with significant idly generalize [70]. Rapid progression to the GI
anti-tumor effects. It has been observed repeat- tract and bone marrow follow [70]. Fever in asso-
edly that patients with aGVHD have lower dis- ciation with the rash is a poor prognostic sign.
ease relapse rates than those without. Because aGVHD associated with OLT differs from
autoGVHD tends to be mild and limited to skin, aGVHD following HSCT in several respects. The
investigations have been undertaken to harness transplanted liver itself is not a target organ
graft-versus-tumor (GVT) effect by artificially because alloreactive lymphocytes recognize trans-
inducing autoGVHD by post-transplant adminis- planted liver tissue as self. On the other hand,
tration of CSA alone, or CSA plus IFNg or IL-2. bone marrow involvement manifesting as pancy-
Unfortunately, no clear-cut anti-cancer benefit has topenia is a common and serious development
thus far been shown in clinical trials [64, 66]. [70]. Neutropenia can be a presenting sign of
GVHD following OLT [70, 71]. Because of high
mortality, and immunologic rejection of donor T
6.2 Acute GVHD Following Solid cells, cGVHD following OLT is unusual [70].
Organ Transplantation, A risk factor for aGVHD in the setting of OLT
Transfusion, and Donor is HLA compatibility [68]. The more well-
Lymphocyte Infusion matched the graft, the greater the likelihood of
aGVHD. If alloreactive hepatic T lymphocytes
aGVHD after solid organ transplantation is an express shared HLA determinants with the recip-
uncommon, but serious complication with high ient, they are less likely to be destroyed by the
mortality. It can occur with transplantation of any recipient immune system [70]. Age greater than
solid organ, but it is most likely to occur after 65, and large disparity in age between a young
small intestine transplant (5–10% incidence) or donor and an older recipient are also risk factors
orthotopic liver transplant (OLT) (1–2% inci- for the development of aGVHD following OLT.
dence) [67]. (“Orthotopic” means the donor organ Given the rarity of aGVHD following solid
is transplanted into the same place as the patient’s organ transplantation, diagnosis can be challeng-
original organ.) OLTs are performed much more ing. The usual presenting sign is rash, sometimes
commonly than intestinal transplants, so aGVHD associated with fever. The differential diagnosis
associated with solid organ transplants generally includes viral exanthem or other infection, drug
refers to OLT [68]. Alloreactive lymphocytes are eruption, and aGVHD [72]. A skin biopsy show-
transplanted along with the organ, and liver and ing interface dermatitis, vacuolar degeneration of
intestine contain the largest numbers. In fact, the basal cells and necrotic epidermal cells is highly
number of lymphocytes transferred in an OLT is suggestive of GVHD [70]. Donor cell chimerism
roughly equivalent to that in a bone marrow trans- is also an important feature of GVHD associated
plant [69]. with solid organ transplantation. Chimerism
refers to the presence of a mixed population of exceeds 90% [74]. Prevention is the best and
donor and recipient lymphocytes in tissue or most effective management strategy. Prevention
peripheral blood. Although important, chimerism consists of identifying those at risk. Once
is not absolutely diagnostic. It is not present in all identified, these patients should only receive
patients with solid organ aGVHD, and it is a fre- blood and blood components that have been irra-
quent finding immediately after OLT [73]. diated with 2,000 cGy or higher [74, 75].
Clinical response to treatment correlates with Irradiation of blood and blood products blocks
decrease or disappearance chimerism [69]. alloreactive lymphocyte proliferation, but it does
Transfusion associated aGVHD (TA-GVHD) not interfere with the function of RBCs, WBCs
occurs when transfused donor lymphocytes or platelets. Although some leakage of potassium
engraft in an immunocompromised host, or has been observed in irradiated blood, there is no
when the donor is homozygous for an HLA clinical evidence that irradiated blood is harmful
class 1 haplotype of the recipient, which allows to patients [74, 78].
donor lymphocytes to escape immunologic rec- Should leukemia relapse after HSCT, infu-
ognition by the recipient [74]. This sometimes sion of lymphocytes from the original donor can
happens when blood relatives donate blood to be used as a salvage treatment. Donor lympho-
immunocompetent recipients [74–76]. Certain cyte infusion (DLI) relies on graft-versus-leuke-
clinical situations are also high risk. Granulocyte mia effect, and it has proven quite effective in
transfusions contain large numbers of lympho- certain forms of leukemia, particularly in
cytes, and patients receiving them are usually relapsed chronic myelogenous leukemia (CML)
neutropenic and immunocompromised. Infants [79]. Complete molecular and cytogenetic remis-
receiving exchange transfusions for erythroblas- sions have been achieved using this modality in
tosis fetalis receive a large volume of blood and a substantial proportion of treated patients [80].
cells, and their immune systems are immature. aGVHD and cGVHD can complicate DLI; how-
Patients with Hodgkin’s disease, non-Hodgkin ever, GVHD following DLI tends to be mild to
lymphoma (NHL), congenital immunodeficiency moderate, it is more responsive to treatment with
diseases, persons undergoing HSCT, and per- immunosuppressive therapy, and the onset tends
sons treated with purine analogues such as to occur later than GVHD following HSCT [79].
cytarabine are at risk for TA-aGVHD [74, 75, The reason is that the tissue damage and
77]. Patients with solid malignancies, hemato- “cytokine storm” resulting from conditioning,
logic malignancy other than Hodgkin’s disease/ infection and underlying disease are generally
NHL, and patients with AIDS are not consid- not present in the setting of DLI. However, the
ered to be at high risk [74]. presence of either aGVHD or cGVHD following
TA-aGVHD begins abruptly with fever 3–30 DLI is associated with a 2.3-fold risk of death in
days after the transfusion. Fever is followed by a comparison to patients without GVHD [81].
generalized maculopapular rash, which can prog- cGVHD develops in 33–61% of patients follow-
ress to erythroderma and bulla formation. Profuse ing DLI [82].
diarrhea, vomiting, anorexia, right upper quad-
rant pain, jaundice, elevated liver enzymes, and
pancytopenia complete the clinical picture [75]. 6.3 Staging and Grading of Acute
The overall tempo of TA-aGVHD is more rapid GVHD
than in HSCT-associated aGVHD [75]. Diagnosis
is made by clinical signs and symptoms, the dem- Stratification of aGVHD severity is important in
onstration of chimerism in blood and tissue, and determining prognosis. It is also useful in deter-
skin biopsy findings of interface dermatitis, basal mining entry into clinical trials and assessment of
cell vacuolization, and epidermal cell necrosis. outcomes to particular regimens. In 1974,
Unfortunately, treatment for TA-GVHD is Glucksberg proposed a grading system for
generally ineffective, and the overall mortality aGVHD severity [83]. The Glucksberg system is
intuitive, easy to apply, and has been in common but stage 3 skin involvement had significantly
use ever since. Severity of skin, liver and intesti- higher risk of death than patients with grade II
nal tract involvement is measured and assigned Glucksberg with stage 0–2 skin involvement [85].
stages from one to four. To determine grade, the The IBMTR severity index assigns letter grades
stages of the three organ systems, and a subjective from A to D. The assigned grade is based on the
one to four assessment of overall performance maximum involvement in an individual organ
status are tabulated. The patient is then assigned a regardless of involvement of other organ systems
grade of severity from one to four. In the [85]. It relies only on objective measurement of
Glucksberg system there are 125 possible combi- organ involvement, thereby reducing inter-ob-
nations when three organs plus performance sta- server variability (Table 6.6). Thus, in the exam-
tus are staged one to four [84] (Table 6.5). ple above, a patient with stage three skin
The International Bone Marrow Transplant involvement would be assigned to level C even if
Registry (IBMTR) severity index was created liver and intestinal tract were stage one. In addi-
after it was noted that patients with the same tion, the IBMTR severity index eliminates sub-
Glucksberg grade but with different patterns of jective assessment of performance status.
organ involvement had different outcomes [85]. In a mixed retrospective and prospective study
For example, patients with grade II Glucksberg, of 114 patients, Martino et al. found the IBMTR
Table 6.5 Glucksberg clinical stage and grade of aGVHD

Stage Skin Liver (Bilirubin mg/dl) Intestinal tract
1 Maculopapular rash <25% BSA 2–3 >500 ml diarrhea/day
2 Maculopapular rash 25–50% BSA 3–6 >1000 ml diarrhea/day
3 Generalized erythroderma 6–15 >1500 ml diarrhoea/day
4 Generalized erythroderma with bullous formation >15 Severe abdominal pain,
and desquamation with or without ileus
Grade Degree of organ involvement
I Stage 1–2 skin rash; no gut involvement; no liver involvement; no decrease in clinical performance
II Stage 1–3 skin rash; stage 1 gut involvement or stage 1 liver involvement (or both); mild decrease in
clinical performance
III Stage 2–3 skin rash; stage 2–3 gut involvement or 2–4 liver involvement (or both); marked decrease in
clinical performance
IV Similar to Grade III with stage 2–4 organ involvement and extreme decrease in clinical performance
Reproduced with permission from Wolters Kluwer Health and Glucksberg et al. 1974 [83]
Table 6.6 Criteria for IBMTR severity index for aGVHD

Skin involvement Liver involvement Gastrointestinal involvement
Index (based on maximum Extent of Stage Total bilirubin Volume of diarrhea
involvement of any organ) Stage (max) rash (BSA) (max) (mg/dl) Stage (max) (ml/dl)
A 1 <25 % 0 2–3 0 <500
B 2 25–50 % 1–2 3–6 1–2 550–1500
C 3 >50 % 3 6–15 3 >1500
D 4 Bullae 4 >15 4 Severe pain and ileus
Reproduced with permission from John Wiley and Sons and Rowlings et al. 1997 [85]
index superior to the Glucksberg grading system agents, anti-CD3, anti-IL2 receptor, denileukin
in predicting transplant related mortality and fail- difitox, sirolimus, antithymocyte globulin, pen-
ure [86]. However, in a prospective study of 607 tostatin, and visilizumab, an anti CD-3 monoclo-
patients evaluating the two systems, Cahn et al. nal antibody [23, 27, 30, 87]. Corticosteroid
observed strong agreement between the two sys- nonresponders have a poor prognosis.
tems and no clear-cut advantage of one over the
other [84].
6.5 Conclusion
6.4 Prophylaxis and Treatment HSCT ranks as one of the most radical interven-
of Acute GVHD tions in the whole of medicine. The patient is
given nothing less than an entirely new immune
Risk factors for the development of aGVHD system, and he is potentially cured of hitherto
include histoincompatibility of MHC antigens untreatable, fatal diseases. New indications for
(particularly class II antigens), older age of donor HSCT are constantly arising, and the procedure
and recipient, gender mismatch (particularly is being performed with greater frequency. As
female donor with male recipient), presence of with all drastic interventions, HSCT comes with
infection, underlying disease stage and intensity a high cost: aGVHD. At high severity grades,
of conditioning [9, 26]. To the extent possible, aGVHD is a direct threat to life. Even with the
these risk factors should be modified. In addition, best of care, mortality is high. Lower severity
use of cord blood and decontamination of the gut grades are associated with considerable morbid-
are associated with lower incidence of aGVHD ity, and there is a high chance of evolution into
[6, 32]. cGVHD. cGVHD in its own right is a serious,
GVHD prophylaxis usually consists of a com- devastating disease associated with a huge pano-
bination of calcineurin inhibitor (CNI) plus ply of medical and psychological problems.
methotrexate or mycophenolate mofetil (MMF) On the other hand, aGVHD is associated with
[23]. The purpose of prophylaxis is to inhibit the GVT effect. A consistent observation is that
activity of alloreactive T cells. Without prophy- patients with GVHD have a lower rate of leuke-
laxis the incidence of aGVHD approaches 100% mia and cancer relapse than those who do not.
[27]. Tacrolimus appears to be somewhat supe- Thus far, all interventions that ameliorate or pre-
rior to cyclosporine, and is less toxic [27]. MMF vent GVHD lessen GVT effect. The “holy grail”
is associated with less mucositis than methotrex- of treatment is to separate the two by targeting
ate. Antithymocyte globulin and anti-CD52 GVHD while preserving GVT. This remains an
monoclonal antibody (alemtuzumab) have also area of intensive, ongoing research.
been used for prophylaxis. Ex vivo depletion of T
cells in the donor graft is associated with
decreased incidence of aGVHD; however, this 6.6 Chronic Graft-Versus-Host
technique is associated with increased incidence Disease
of malignant disease relapse [27].
First line treatment of aGVHD consists of cor- cGVHD can arise during or directly after an epi-
ticosteroids [23, 27, 30]. Patients are usually sode of aGVHD (progressive onset cGVHD),
started on methylprednisolone 2 mg/kg/day, and after a disease-free interval (quiescent cGVHD),
the dose is slowly tapered depending on clinical or it can present de novo [88]. The condition usu-
response. Roughly 25% of patients will experi- ally occurs within 3 years after transplant, with
ence a complete response, and 50% a partial an average onset of 5 months [89]. cGVHD is a
response. For corticosteroid nonresponders, a multisystem disorder of immune dysregulation
wide variety of therapies has been tried including combining features of autoimmunity and
PUVA, extracorporeal photophoresis, anti-TNF immunodeficiency. It can affect virtually any
organ, and serious infection and secondary malig- The reported incidence of cGVHD following
nancy are constant threats. cGVHD profoundly allogeneic HSCT varies, but the overall incidence
damages quality of life, and patients with the is in the range of 50–70% [90, 91]. Incidence
condition suffer a variety of disabilities and depends on multiple predisposing factors includ-
impairments. cGVHD is associated with grafting prior aGVHD, older recipient age, intensity of
versus-tumor (GVT) effect, a phenomenon in conditioning, hematopoietic stem cell source
which alloreactive T cells attack host cancer cells (peripheral blood > bone marrow > umbilical cord
in addition to normal tissue. Because of GVT blood), mismatched or unrelated donor, female
effect, the incidence of cancer relapse is lower in donors with male recipients, graft manipulation
patients who experience cGVHD. Ideally, treat- (T-cell depletion), GVHD prophylaxis regimen
ment regimens for malignant disease aim to pre- and use of post-transplantation donor lymphocyte
serve GVT effect while preventing GVHD. infusions [29, 89, 92]. In a multi-center cohort
As previously stated, a 2005 NIH consensus analyzing 5,343 HSCT recipients with cGVHD,
conference established new guidelines for the the probability of overall survival was 72% at 1
diagnosis and staging of GVHD [29]. The new year and 55% at 5 years with a non-relapse mortal-
guidelines emphasized that clinical manifesta- ity (death unrelated to the original cancer) of 21%
tions rather than time are the major criteria by and 31% at 1 and 5 years, respectively [89]. Using
which cGVHD is distinguished from late aGVHD multivariate analysis of overall survival and non-
(Table 6.3). The clinical manifestations of relapse mortality, the study further classified
cGVHD are classified into four categories: diag- patients into risk categories and found several vari-
nostic, distinctive, common and other (Table 6.7). ables associated with a poorer outcome (Table 6.8).
Diagnostic features are considered pathogno- A prospective study comparing outcomes of
monic for the disease, and when present they patients with “overlap” GVHD versus those with
establish the diagnosis without any further test- classic cGVHD showed that overlap patients had
ing. Diagnostic skin findings include poikilo- greater functional impairment, higher symptom
derma, lichen planus-like eruption, deep sclerotic burden and increased non-relapse mortality [93].
lesions, morphea-like lesions, and lichen sclero- cGVHD most commonly affects skin, mucosal
sus-like lesions. Distinctive lesions are those surfaces, eyes, musculoskeletal system, gastroin-
commonly seen in cGVHD, but not sufficiently testinal tract, lungs, liver, and bone marrow.
unique to be considered diagnostic. These Clinical findings often mimic autoimmune dis-
include depigmentation, sweat impairment, pru- eases, particularly scleroderma, systemic lupus
ritus, maculopapular rash, and erythema. erythematosus, and Sjögren’s syndrome.
Distinctive features require further testing such Sclerodermoid, lichenoid lesions and lichen-scle-
as skin biopsy, or demonstration of cGVHD in rosus-like lesions are the characteristic skin man-
another organ system. Common features are ifestations of advanced cGVHD; however, subtle
those that occur in both aGVHD and cGVHD and nonspecific skin changes such as xerosis,
and include maculopapular rash, pruritus, and maculopapular rash, and ichthyosis can charac-
erythema. Other features such as keratoses terize early disease.
pilaris, hyperpigmentation and ichthyosis are Sclerotic variants range from superficial mor-
nonspecific and cannot be used to establish the phea or lichen-sclerosus-like lesions to deep, dif-
diagnosis. The diagnosis of cGVHD requires at fuse indurated plaques resembling scleroderma.
least one diagnostic clinical sign, or one distinc- An association exists between exposure to total
tive clinical sign plus a positive diagnostic test, body irradiation and the development of sclerotic
and the exclusion of other possible diagnoses, cGVHD [94]. All forms of sclerotic GVHD can
particularly late-onset aGVHD, malignancy, progress to disfigurement and impairment.
drug reaction and infection. An “overlap” sub- Sclerosis of underlying subcutaneous tissues can
type encompasses features of both aGVHD and lead to edema, joint stiffness, decreased range of
cGVHD. motion, and contracture. Lichenoid cGVHD
116
Table 6.7 Signs and symptoms of chronic GVHD

Organ or site Diagnostic (sufficient to establish Distinctive (seen in chronic GVHD, Other featuresc Common (seen with both acute
the diagnosis of chronic GVHD) but insufficient alone to establish a and chronic GVHD)
diagnosis of chronic GVHD)
Skin Poikiloderma Depigmentation Sweat impairment Erythema
Lichen planus-like features Ichthyosis Maculopapular rash
Sclerotic features Keratosis pilaris Pruritus
Morphea-like features Hypopigmentation
Lichen sclerosus-like features Hyperpigmentation
Nails Dystrophy
Longitudinal ridging, splitting, or
brittle features
Onycholysis
Pterygium unguis
Nail loss (usually symmetric; affects
most nails)a
Scalp and body hair New onset of scarring or nonscarring Thinning scalp hair, typically patchy,
scalp alopecia (after recovery from coarse, or dull (not explained by
chemoradiotherapy) endocrine or other causes)
Scaling, papulosquamous lesions
Premature gray hair
Mouth Lichen-type features Xerostomia Gingivitis
Hyperkeratotic plaques Mucocele Mucositis
Restriction of mouth opening from Mucosal atrophy Erythema
sclerosis Pseudomembranesa Pain
Ulcersa
Eyes New onset dry, gritty, or painful eyesb Photophobia
Cicatricial conjunctivitis Periorbital hyperpigmentation
Keratoconjunctivitis siccab
Confluent areas of punctate
keratopathy
Blepharitis (erythema of the eyelids
with edema)
Genitalia Lichen planus-like features Erosionsa
D. Pompei et al.
6
Vaginal scarring or stenosis Fissuresa
Ulcersa
GI tract Esophageal web Exocrine pancreatic insufficiency Anorexia
Strictures or stenosis in the upper to Nausea
mid third of the esophagusa Vomiting
Diarrhea
Graft-Versus-Host Disease
Weight loss
Failure to thrive (infants and
children)
Liver Total bilirubin, alkaline
phosphatase >2 × upper limit
of normala
ALT or AST >2× upper limit
of normala
Lung Bronchiolitis obliterans diagnosed Bronchiolitis obliterans diagnosed BOOP
with lung biopsy with PFTs and radiologyb
Muscles, fascia, Fasciitis Myositis or polymyositisb Edema
joints Joint stiffness or contractures Muscle cramps
secondary to sclerosis Arthralgia or arthritis
Hematopoietic and Thrombocytopenia
immune
Eosinophilia
Lymphopenia
Hypo- or hypergammaglobulinemia
Autoantibodies (AIHA and ITP)
Other Pericardial or pleural effusions
(continued)
117
Table 6.7 (continued)
118
Other Ascites
Peripheral neuropathy
Nephrotic syndrome
Myasthenia gravis
Cardiac conduction abnormality or
cardiomyopathy
Reproduced with permission from Elsevier and the NIH consensus development project on criteria for clinical trials in chronic GVHD, 2005 [29]
GVHD graft-versus-host disease, ALT alanine aminotransferase, AST aspartate aminotransferase, BOOP bronchiolitis obliterans-organizing pneumonia, PFTs pulmonary func-
tion tests, AIHA autoimmune hemolytic anemia, ITP idiopathic thrombocytopenic purpura
a
In all cases, infection, drug effects, malignancy, or other causes must be excluded
b
Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes)
c
Can be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is confirmed
D. Pompei et al.
Table 6.8 Factors associated with a higher risk of hyperkeratosis with follicular plugging and
mortality in chronic GVHD edema coupled with homogenization of the upper
Variable Comment dermis. All three chronic cutaneous GVHD
Increasing recipient >30 years old variants closely resemble both clinically and
age histologically their respective dermatologic
Presence of prior acute Increased risk with higher
conditions.
GVHD grade
Early onset of chronic Onset prior to 5 months
Oral and genital disease occurs in up to 80%
GVHD patients [97]. Lichen planus-like lacy white
Elevated serum >2 mg/dl plaques, ulceration, and scarring occur on the oral
bilirubin and genital mucosa of both women and men;
Lower Karnofsky <80 (Functional Status Score however, genital lesions cause more functional
performance status 0–100) impairment and more severe symptoms in women.
Thrombocytopenia Platelet count of <100 × 109/L
Vulvovaginal lesions cause dyspareunia and inter-
Transplant from a HLA Versus transplant from
mismatched unrelated HLA-identical sibling donor
ference with sexual function. Genital lesions are
or related donor usually associated with concurrent oral involve-
Intermediate or Versus early disease ment [98]. cGVHD commonly affects salivary
advanced disease status glands with resultant xerostomia [99, 100].
GVHD prophylaxis Better outcome with Ocular manifestations of cGVHD include
regimen CSA + MTX ± other vs.
xerophthalmia, blepharitis, corneal ulcer, cica-
Tacrolimus ± MTX ± other
Gender mismatch Female donor to male
tricial conjunctivitis, scleritis, glaucoma, and
recipient versus male donor to infections. Xerophthalmia is the most common
male recipient problem. Diagnosis is based on an abnormal
Schirmer test and slit-lamp demonstration of
keratoconjunctivitis sicca. Chronic ocular
presents with violaceous papules and plaques on GVHD rarely affects visual acuity, and it is gen-
extensor surfaces. The clinical presentation is erally accompanied by other systemic findings
virtually identical to that of idiopathic lichen [29, 101].
planus. Other skin changes associated with Nail changes are present in up to 50% of
cGVHD include depigmentation, poikiloderma, patients, and longitudinal ridging is the most
hypohidrosis with heat intolerance, erythema, common finding [102]. Periungual erythema,
and pruritus [95]. Pigment abnormalities can brittle nails, Beau’s lines, pterygium, and com-
cause severe cosmetic disfigurement. Chronic plete nail loss are also features of cGVHD.
cutaneous GVHD can be associated with an iso- Dermatoscopy reveals abnormalities in nailbed
morphic or isotopic response. Sclerotic cGVHD capillaries of patients with sclerodermoid
often appears in areas of minor skin trauma (iso- cGVHD, but not in patients with lichenoid
morphic response, or Koebner phenomenon), and cGVHD. These abnormalities include enlarged
lichenoid cGVHD sometimes follows another capillaries, neovascularization, avascular areas
skin disease such as herpes zoster (isotopic and hemorrhage [103]. Both scarring and non-
response) [95, 96]. scarring alopecia occur in cGVHD, and poliosis
The main histopathologic features of lichenoid is common. Hair abnormalities associated with
cGVHD lesions consist of hyperkeratosis, focal cGVHD should be distinguished from chemo-
hypergranulosis, vacuolar degeneration of the therapy or radiation effects.
basal cell layer, and a band-like infiltrate of lym- Systemic cGVHD often involves the GI tract,
phoid cells. Sclerodermatous lesions show epi- liver, lungs and immune system. Nausea, vomit-
dermal atrophy and sclerosis of the dermis. The ing, diarrhea, anorexia, weight loss, and abdomi-
sclerosis can involve the dermis alone, or it can nal pain are typical manifestations of
also involve subcutaneous fat and muscle. Lichen- gastrointestinal cGHVD. Endoscopic biopsy and
sclerosis like lesions show epidermal atrophy, characteristic radiographic findings confirm the
diagnosis. Chronic hepatic GVHD is usually tor forkhead box P3 (FoxP3). In cGVHD, the
associated with cholestasis, elevated bilirubin numbers of CD4+ CD25+ FoxP3+ Treg cells are
and elevated alkaline phosphatase. Definitive diminished [109, 110]. Strategies to increase
diagnosis requires positive liver biopsy findings numbers of Treg cells such as extracorporeal
plus a distinctive cGVHD manifestation in photophoresis and low dose IL-2 are associated
another organ system. with clinical improvement [91, 111].
Pulmonary signs and symptoms include B cell homeostasis is disturbed in cGVHD,
cough, wheezing, and dyspnea on exertion. These and both host-derived and donor-derived B cells
result from bronchiolitis obliterans (BO), an appear to play a role in pathogenesis [109, 112,
airway disorder in which bronchioles become 113]. The importance of B cells in cGVHD is
obstructed by fibrous granulation tissue. BO is a evidenced by significant clinical improvement
diagnostic pulmonary manifestation of cGVHD, following use of rituximab, an anti-CD20 mono-
and diagnosis of BO is confirmed by biopsy and clonal antibody causing B cell depletion. Several
abnormal pulmonary function tests [29]. Lung case series of patients treated with rituximab for
dysfunction is serious, and its presence is invari- cGVHD have shown improvement with response
ably associated with the highest severity grades rates varying from 43 to 80%. Manifestations of
of cGVHD [104]. skin, mucosal and musculoskeletal cGVHD
Thrombocytopenia and other cytopenias are respond best [90, 114]. B cells perform multiple
harbingers of decreased survival [105]. immunologic functions other than antibody pro-
Eosinophilia is common in cGVHD. Once duction. B cells present antigen, produce cytok-
thought to be a favorable predictor, reports now ines and chemokines, and regulate immune
show no correlation between eosinophilia and reactivity [88, 90]. Autoreactive B cells in
outcome [106]. The effect of cGVHD on immu- cGVHD secrete proinflammatory cytokines
nity can be devastating, and infection is a com- including IL-6, TNF-a, and IFN-g that activate T
mon cause of death. Immunosuppressant and cells, macrophages and NK cells [90]. The net
immunomodulating medications worsen suscep- result is potentiation of the inflammatory cas-
tibility to infection. cade. Antigen presentation by autoreactive B
The pathophysiology of cGVHD is complex cells promotes autoimmune tissue damage inde-
and current knowledge remains incomplete. pendent of antibody production [90]. Patients
A primary reason is the lack of animal models with cGVHD have a higher frequency of autoan-
that recapitulate human disease as completely in tibodies, including antinuclear antibodies and
cGVHD as they do in aGVHD [107, 108]. Several antibodies to smooth muscle, cardiolipin, dsDNA,
mechanisms have been identified that alone or in and platelet-derived growth factor receptor
concert contribute to pathogenesis [88]. Damage (PDGFR) [115, 116]. It is not entirely clear
to thymic epithelium from conditioning and whether these autoantibodies are directly patho-
aGVHD interfere with thymic deletion of self- genic or merely bystanders. Transfer of autoanti-
reactive T cells, resulting in loss of self-tolerance. bodies from cGVHD mice does not produce
Failure of central tolerance can lead to autoim- disease in normal mice [90]. However, autoanti-
mune phenomena. bodies to PDGFR have a stimulatory effect on
Under physiologic conditions, not all self- fibroblasts and induce production of collagen.
reactive T cells are eliminated in the thymus, and Stimulatory antibodies to PDGFR were found in
some make their way to the periphery. A subset 22 patients with extensive cGVHD, but not in
of T cells, regulatory T cells (Treg), inhibit self- HSCT patients without GVHD or in normal con-
reactive T cells that have escaped thymic deletion trols. Levels were highest in those with general-
from proliferating in response to self-antigens. ized skin involvement and lung fibrosis.
Treg cells exert their effects through several Autoantibodies to PDGFR may contribute to
cytokines including TGF-b and IL-10. Treg cells fibrosis and the scleroderma-like phenotype in
express CD4+ CD25+ and the transcription fac- cGVHD [117].
B cell-activating factor of the TNF family known to develop after localized radiation ther-
(BAFF), also known as B-lymphocyte stimulator, apy [95]. This is thought to represent an isomor-
is a cytokine that provides survival signals to B phic (Koebner) phenomenon. Similarly, Martires
cells and prevents apoptosis [90, 113]. High lev- et al. showed an association between condition-
els are present in autoimmune diseases such as ing with total body irradiation and the develop-
SLE, and a monoclonal antibody against BAFF ment of sclerotic type cGVHD [94].
(belimumab) is used in treatment of active lupus Patients with cGVHD should practice strict
[90]. High levels of BAFF are also present in sun avoidance because of immunosuppression
cGVHD. cGVHD is associated with low numbers and a propensity to develop skin cancer. The inci-
of naïve B cells and high levels of activated, dence of cutaneous squamous cell carcinoma and
autoantibody-producing CD27+ B cells [118]. melanoma is elevated in cGVHD, particularly in
The high levels of BAFF enhance survival of acti- males and in those who have received total body
vated alloreactive and autoreactive B cells, thus irradiation [124]. Patients taking voriconazole, a
causing perpetuation of disease. systemic antifungal medication, are at especially
cGVHD in humans and in murine models is high risk. Voriconazole is a potent photosensi-
associated with expansion of Th2 CD4 lympho- tizer and a strong exacerbating factor for devel-
cytes and polarization to a Th2 cytokine profile opment of squamous cell carcinoma and
[88, 108, 109]. aGVHD is thought to be a Th1 melanoma [125–127]. Squamous cell carcinoma
mediated disease with elevation of TNF-a and associated with voriconazole can be aggressive
IFN-g, whereas cGVHD is considered a Th2 and multifocal, with high metastatic potential
mediated disease [45, 119, 120]. Fibrosis and [128–130].
chronic inflammation are the hallmarks of Frequent skin and mucosal examinations
cGVHD, whereas necrosis in target organs is the should be performed to detect cancer, ulcers, or
predominant finding in aGVHD [108]. In murine new areas of sclerosis. Serial photography is
models, transforming growth factor beta (TGF-b) helpful in this regard. cGVHD patients with a
plays an important role in the development of history of skin cancer should be examined every
fibrosis. CD4+ T cells home to target tissue and 6 months [131]. The incidence of oral cancer is
secrete IL-13, a Th2 cytokine that stimulates also increased, and examination of mucosal sur-
macrophages. Activated macrophages produce faces should be part of routine cancer surveil-
TGF-b, which binds to receptors on fibroblasts lance [124]. Mucosal and cutaneous erosions
causing collagen synthesis and fibrosis [108]. In must be treated promptly to prevent adhesions
patients with cGVHD, serum levels of TGF-b are and infection [131]. The skin of cGVHD patients
significantly increased [121]. IL-13 itself can tends to be xerotic, and generous use of emol-
bind to fibroblast receptors and directly stimulate lients is recommended. Treatment of chronic
collagen synthesis. IL-4 (another Th2 cytokine) ocular GVHD consists of liberal and frequent use
similarly binds to fibroblast receptors and stimu- of preservative-free artificial tears [132].
lates collagen synthesis [122]. Thus, the fibrotic If sclerodermoid change or faciitis are detected,
changes seen in cGVHD may be accounted for physiotherapy is advised. Physiotherapy, which
by a Th2 cytokine profile and by the presence of includes stretching, heat, and edema management,
autoantibodies to PDGFR. is considered a very important component of gen-
aGVHD is a strong predictor of subsequent eral cGVHD management. It should be started
cGVHD [123]. Therefore, steps to decrease the early to prevent contracture, reduced range of
risk of aGVHD, such as ex vivo T cell depletion motion and disability. Fasciitis occurs in approxi-
in the graft and optimization of HLA match, are mately 1% of patients and is characterized by
undertaken. In addition, minimizing toxicity of rock-hard, subcutaneous induration. Fasciitis is
conditioning reduces tissue damage, which can progressive and can lead to serious functional
later become a target for cGVHD. For example, impairment [131]. Myositis presents with muscle
lesions of sclerotic, cutaneous cGVHD have been pain and weakness, usually in association with
skin findings. Evaluation includes electromyogra- band ultraviolet B (UVB) are all treatment
phy, determination of creatine kinase and aldolase options. Higher response rates to phototherapy
activity, and muscle biopsy [112, 133]. Cases of have been observed in lichenoid disease as com-
myocarditis with electrocardiographic abnormali- pared to sclerodermoid cGVHD [139]. Although
ties have been described [134]. PUVA is effective, UVA and UVB without a
Patients with cGVHD are immunosuppressed, photosensitizer have the significant advantage of
and infection is a major cause of morbidity and avoiding psoralen-related side effects [140, 141].
mortality. Prophylactic antibiotics are an impor- In addition, the risk of skin cancer in long-term
tant adjunctive treatment [132]. Patients are at treatment is lower in UVB than in PUVA [142].
increased risk of infection by Pneumocystis In a small case series, Brazzelli et al. used
jirovecii and by encapsulated organisms such as narrow-band UVB to treat ten children with
S. pneumonia, H. influenzae and N. meningitides. steroid-refractory cutaneous cGVHD. Eight
Those at high risk for fungal or viral infections had a complete response with resolution of
should also be treated prophylactically with anti- skin lesions, while the other two showed a
fungal and antiviral medications. Patients lose partial response [143]. Given its wide safety
protective immunity after HSCT, and vaccination margin, phototherapy is an excellent choice for
should be instituted six months post-transplant patients with solitary cutaneous involvement or
[135]. However, patients and close contacts persistent skin lesions unresponsive to systemic
should avoid live vaccines until full immunocom- immunosuppression.
petency is achieved.
6.6.2 Systemic Therapies

6.6.1 Specific Treatments
If internal organs are affected, systemic treatment
Treatment of cGVHD is complex and multifac- is required. Systemic corticosteroids alone or in
eted, and a multidisciplinary team consisting of combination with a CNI are first line therapy,
oncologists, dermatologists, ophthalmologists, with starting doses of prednisone at 1 mg/kg/day.
physical therapists, plastic surgeons and others Some groups recommend maintaining this dose
with expertise in the disorder best serves the for 2 weeks, after which a slow taper is begun
patient. For mild disease limited to skin, topical [144, 145]. Approximately 50% of cGVHD
corticosteroids (TCS) and emollients alone will patients will respond, but long-term side effects
suffice. The lowest potency and frequency of are a concern. The addition of a CNI does not
application should be used to avoid local adverse necessarily reduce mortality, but it may reduce
cutaneous effects. Because immunosuppressive treatment-related morbidity. In a randomized trial
effects are minimal, topical therapy is particu- of low-risk cGVHD patients without thrombocy-
larly advantageous in patients at high risk of topenia, combination therapy with prednisone
malignancy relapse. Topical calcineurin inhibi- and a CNI did not significantly reduce transplan-
tors (CNI) are useful for sensitive areas such as tation-related mortality compared to prednisone
the face and groin [136, 137]. For oral mucosal alone. Combination therapy did however reduce
involvement, TCS are also the mainstay of ther- the incidence of steroid-related toxicities such as
apy. One study showed that the combination of osteonecrosis [146]. Patients with cGVHD at
topical dexamethasone and topical tacrolimus high risk for adverse corticosteroid side effects
was particularly effective in reducing symptoms may therefore benefit from the addition of a CNI
attributable to oral cGVHD [138]. to the initial regimen [146]. In another study of
Phototherapy has antiproliferative and immu- high-risk cGVHD patients with thrombocytope-
nomodulatory effects, and it is effective in cuta- nia, the combination of a CNI and prednisone as
neous cGVHD. Ultraviolet A (UVA), psoralen first-line therapy conferred a distinct survival
with UVA (PUVA), and both narrow and broad advantage [145, 147].
More than one third of cGVHD patients do methotrexate [159, 160], azathioprine [161, 162],
not respond to corticosteroid therapy [148]. pentostatin, rituximab, and imatinib.
Steroid refractory and steroid dependent disease Mycophenolate may be associated with a risk of
are typically defined by progression of cGVHD thrombocytopenia, recurrent malignancy, infec-
on prednisone ³1 mg/kg/day for 2 weeks, stable tion, and gastrointestinal discomfort [163, 164].
disease on ³0.5 mg/kg/day for 4–8 weeks or Methotrexate is a reasonable option. It is effec-
inability to taper the dose to £0.5 mg/kg/day. If a tive, and side effects are predictable and manage-
patient cannot be weaned from corticosteroids able [159, 160]. Azathioprine is not often used
after 3 months, adjuvant therapies need to be con- because one study showed increased nonrelapse
sidered; however, there is no established second- mortality when azathioprine plus prednisone was
line treatment [91]. compared to prednisone alone [161]. Pentostatin
Inhibitors of the mammalian target of rapamy- inhibits adenosine deaminase resulting in apopto-
cin (mTOR), sirolimus and everolimus, block sis of dividing lymphocytes, and two phase II tri-
response to interleukin-2 (IL-2) and prevent acti- als demonstrated response rates of about 50%
vation and proliferation of T and B lymphocytes. [149, 165]. Side effects of pentostatin, however,
In addition, they may promote the generation of are severe: serious infection, leukoencephalopa-
Treg cells [149]. Treatments of cGVHD with the thy, anemia, and gastrointestinal symptoms
combination of an mTOR inhibitor and predni- caused a 25% drop out rate in the trials. Rituximab
sone have shown response rates of 60–70% [150, has shown benefit in the treatment of cGVHD,
151]. This combination is well tolerated and and it may also be helpful in prevention [90, 108,
effective for patients with sclerodermatous 166]. A meta-analysis of 111 patients with
cGVHD [151]. However, the addition of an cGVHD showed a combined response rate that
mTOR inhibitor to a CNI appears to increase the approached 70% [167]. The most notable
risk of thrombotic microangiopathy [151, 152]. responses were seen with the cutaneous and
Extracorporeal photophoresis (ECP) is a pro- musculocutaneous manifestations [168]. Imatinib
cedure wherein peripheral blood mononuclear mesylate is a tyrosine kinase inhibitor with activ-
cells are collected from the patient, treated with ity against BCR-ABL-positive malignancies. It is
8-methoxypsoralen, irradiated with UVA, and also an inhibitor of PDGF and TGF-b signaling
then reinfused back into the patient [153]. The pathways. Several case reports and small series
net result is that ECP causes apoptosis of donor have shown usefulness in sclerodermatous
effector lymphocytes while increasing donor cGVHD [149, 165, 169–172].
Treg cells [154]. ECP is considered an immuno-
modulating treatment, not an immunosuppressive
treatment [155]. It is effective for some cases of 6.7 Emerging Therapies
steroid dependent or refectory cGVHD, and one
study showed lower non-relapse mortality in ECP Interleukin-2 (IL-2) is a cytokine necessary for
responders [156]. Another study showed that the development, expansion and function of T
most patients were able to achieve 50% improve- cells, including Treg cells, which suppress
ment in cutaneous cGVHD lesions with bimonthly autoreactivity and maintain tolerance to self-
ECP sessions, and over 75% of the patients were antigens. Treg cells are reduced in cGVHD and
able to reduce doses of systemic immunosup- other autoimmune diseases [109, 110]. Koreth
pressive medication after six months [157]. et al. treated 29 patients with glucocorticoid
Sclerodermatous lesions responded better than refractory cGVHD with daily low-dose subcu-
lichenoid lesions. Given its excellent safety taneous IL-2 [91]. Of 23 patients available for
profile, ECP is a valuable adjunctive therapy. analysis, 12 had major responses in several
Numerous other medications have been used sites, including skin, and 3 patients had partial
in the treatment of steroid-refractory cGVHD. responses. All treated patients experienced a
These include mycophenolate mofetil [149, 158], marked increase in Treg cells compared to
baseline values. None of the patients experi- patients treated with MSCs. Four patients achieved
enced recurrent malignancy, and several who a complete response and ten a partial response
continued this treatment were able to lower [148]. Moreover, 9 of the 14 patients were able to
their glucocorticoid dose. The most common reduce or discontinue immunosuppressive therapy
adverse effect was a dose-dependent flu-like completely, and the 2-year survival approached
syndrome. Serious adverse effects included 80%. Likewise, Zhou et al. treated four patients
renal dysfunction, thrombocytopenia, throm- with sclerodermatous cGVHD by direct injection
botic microangiopathy, and infection. Daily of MSCs into bone marrow. Following the injec-
low-dose IL-2 may prove to be an effective tion, Th1 cells increased and Th2 cells decreased
treatment, but safety and adverse side effects in all four patients. The reversal of Th1/Th2 ratio
remain a concern [91]. was accompanied by significant improvement in
Mesenchymal stem cells (MSCs) also show skin lesions and joint mobility. None of the
potential value for treatment of both aGVHD and patients showed evidence of cancer recurrence
cGVHD. MSCs are pluripotent bone marrow after 14 months [180]. Although MSCs appear
progenitor cells capable of developing into mul- promising, more clinical trials are needed to assess
tiple mesenchymal cell lineages including osteo- effectiveness and safety.
blasts, chondrocytes, adipocytes, cardiomyocytes,
neurons, and endothelial cells [173]. They can
repair various tissues by homing to damaged sites 6.8 Conclusion
and differentiating into cells of that tissue [174].
They are also immunomodulators, and they cGVHD is a major source of disability and
inhibit T cell responses to create an immunosup- impairment following HSCT, and it can have a
pressive local microenvironment [175, 176]. profoundly negative impact on quality of life.
MSCs inhibit B lymphocytes, NK cells, and den- Fibrosis is a hallmark feature and a significant
dritic cells, but they increase Treg cell numbers cause of impairment. The immunosuppression
[176]. MSCs are obtained from bone marrow, accompanying cGVHD renders the patient sus-
umbilical cord blood, adipose tissue, and muscle. ceptible to infection and cancer, the main causes
They exhibit immunomodulatory effects while of death in this condition. The pathogenesis of
maintaining low immunogenicity. Several studies cGVHD is being elucidated, and promising new
have shown that they are safe to infuse intrave- treatments are on the horizon.
nously, and HLA-compatibility between MSC
donor and recipient does not appear to be impor-
tant. MSCs are hypoimmunogenic, and they References
avoid allorecognition.
Investigations have been undertaken to deter- 1. Mathe G, Amiel JL, Schwarzenberg L, Cattan A,
Schneider M. Adoptive immunotherapy of acute leu-
mine whether MSCs can prevent GVHD. In an
kemia: experimental and clinical results. Cancer Res.
open-label, randomized clinical trial, Ning et al. 1965;25:1525–31.
co-administered an allograft and MSCs at the 2. Sorror ML, Sandmaier BM, Storer BE, Franke GN,
time of HSCT [177]. Although co-administration Laport GG, Chauncey TR, et al. Long-term outcomes
among older patients following nonmyeloablative
decreased the incidence of both aGVHD and
conditioning and allogeneic hematopoietic cell trans-
cGVHD, it increased the risk of primary disease plantation for advanced hematologic malignancies.
relapse [177]. However, other investigators sug- JAMA. 2011;306:1874–83.
gest that co-administration of MSCs and allograft 3. Ahmed SO, Ghavamzadeh A, Zaidi SZ, Baldomero
H, Pasquini MC, Hussain F, et al. Trends of hematopoi-
during HSCT is safe and may actually speed the
etic stem cell transplantation in the Eastern
engraftment process [178, 179]. Mediterranean region, 1984–2007. Biol Blood
MSCs are also being explored for treatment of Marrow Transplant. 2011;17:1352–61.
established cGVHD. Weng et al. reported good 4. Zhang H, Chen J, Que W. Allogeneic peripheral blood
stem cell and bone marrow transplantation for hema-
response in 14 of 19 steroid-refractory cGVHD
tologic malignancies: meta-analysis of randomized 19. Choi SW, Levine JE, Ferrara JL. Pathogenesis and
controlled trials. Leuk Res. 2011;36(4):431–7. management of graft-versus-host disease. Immunol
5. Bensinger WI. Allogeneic transplantation: peripheral Allergy Clin North Am. 2010;30:75–101.
blood vs. bone marrow. Curr Opin Oncol. 2011;24(2): 20. Penas PF, Zaman S. Many faces of graft-versus-
191–6. host disease. Australas J Dermatol. 2010;51:1–10.
6. Rocha V, Gluckman E. Clinical use of umbilical cord quiz 1.
blood hematopoietic stem cells. Biol Blood Marrow 21. Billingham RE. The biology of graft-versus-host reac-
Transplant. 2006;12:34–41. tions. Harvey Lect. 1966;62:21–78.
7. Cohen Y, Nagler A. Umbilical cord blood transplanta- 22. Spencer CT, Gilchuk P, Dragovic SM, Joyce S. Minor
tion–how, when and for whom? Blood Rev. histocompatibility antigens: presentation principles,
2004;18:167–79. recognition logic and the potential for a healing hand.
8. Bertaina A, Bernardo ME, Caniglia M, Vinti L, Curr Opin Organ Transplant. 2010;15:512–25.
Giorgiani G, Locatelli F. Cord blood transplantation 23. Jacobsohn DA, Vogelsang GB. Acute graft versus
in children with haematological malignancies. Best host disease. Orphanet J Rare Dis. 2007;2:35.
Pract Res Clin Haematol. 2010;23:189–96. 24. Duret L, Galtier N. Biased gene conversion and the
9. Saliba RM, de Lima M, Giralt S, Andersson B, Khouri evolution of mammalian genomic landscapes. Annu
IF, Hosing C, et al. Hyperacute GVHD: risk factors, Rev Genomics Hum Genet. 2009;10:285–311.
outcomes, and clinical implications. Blood. 2007; 25. Bleakley M, Riddell SR. Exploiting T cells specific
109:2751–8. for human minor histocompatibility antigens for ther-
10. Peggs KS, Aviva K, Mackall CL. Clinical implica- apy of leukemia. Immunol Cell Biol. 2011;89:
tions of immune reconstitution following hematopoi- 396–407.
etic stem cell transplantation. In: Bishop MR, editor. 26. Gratwohl A, Hermans J, Niederwieser D, van Biezen
Hematopoietic stem cell transplantation. New York: A, van Houwelingen HC, Apperley J. Female donors
Springer; 2009. p. xv. 589 p. influence transplant-related mortality and relapse
11. Jang JE, Hyun SY, Kim YD, Yoon SH, Hwang DY, incidence in male recipients of sibling blood and mar-
Kim SJ, et al. Risk factors for progression from cyto- row transplants. Hematol J. 2001;2:363–70.
megalovirus viremia to cytomegalovirus disease after 27. Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-
allogeneic hematopoietic stem cell transplantation. host disease: pathobiology and management. Exp
Biol Blood Marrow Transplant. 2011;18(6):881–6. Hematol. 2001;29:259–77.
12. Kashiwazaki H, Matsushita T, Sugita J, Shigematsu 28. Bleakley M, Riddell SR. Molecules and mechanisms
A, Kasashi K, Yamazaki Y, et al. A comparison of oral of the graft-versus-leukaemia effect. Nat Rev Cancer.
mucositis in allogeneic hematopoietic stem cell trans- 2004;4:371–80.
plantation between conventional and reduced-inten- 29. Filipovich AH, Weisdorf D, Pavletic S, Socie G,
sity regimens. Support Care Cancer. 2011;20(5): Wingard JR, Lee SJ, et al. National Institutes of Health
933–9. consensus development project on criteria for clinical
13. McDiarmid S. Nutritional support of the patient trials in chronic graft-versus-host disease: I. Diagnosis
receiving high-dose therapy with hematopoietic stem and staging working group report. Biol Blood Marrow
cell support. Can Oncol Nurs J. 2002;12:102–15. Transplant. 2005;11:945–56.
14. Arfons LM, Lazarus HM. Total parenteral nutrition and 30. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-
hematopoietic stem cell transplantation: an expensive versus-host disease. Lancet. 2009;373:1550–61.
placebo? Bone Marrow Transplant. 2005;36:281–8. 31. Ferrara JL, Levine JE. Graft-versus-host disease in the
15. McNeer JL, Kletzel M, Rademaker A, Alford K, 21st century: new perspectives on an old problem.
O’Day K, Schaefer C, et al. Early elevation of Semin Hematol. 2006;43:1–2.
C-reactive protein correlates with severe infection and 32. Cooke KR, Olkiewicz K, Erickson N, Ferrara JL. The
nonrelapse mortality in children undergoing alloge- role of endotoxin and the innate immune response in
neic stem cell transplantation. Biol Blood Marrow the pathophysiology of acute graft versus host dis-
Transplant. 2010;16:350–7. ease. J Endotoxin Res. 2002;8:441–8.
16. Agarwal S, O’Donoghue S, Gowardman J, Kennedy 33. Liu D, Yan C, Xu L, Wang Y, Han W, Zhang X, et al.
G, Bandeshe H, Boots R. Intensive care unit experi- Diarrhea during the conditioning regimen is corre-
ence of hematopoietic stem cell transplant patients. lated with the occurrence of severe acute graft-versus-
Intern Med J. 2011;42(7):748–54. host disease through systemic release of inflammatory
17. Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cytokines. Biol Blood Marrow Transplant.
cell transplantation: an overview of infection risks and 2010;16:1567–75.
epidemiology. Infect Dis Clin North Am. 2010;24: 34. Penack O, Holler E, van den Brink MR. Graft-versus-host
257–72. disease: regulation by microbe-associated molecules and
18. Cavazzana-Calvo M, Andre-Schmutz I, Dal Cortivo innate immune receptors. Blood. 2010;115:1865–72.
L, Neven B, Hacein-Bey-Abina S, Fischer A. Immune 35. Reddy P, Ferrara JLM. Pathophysiology of graft-ver-
reconstitution after haematopoietic stem cell trans- sus-host disease. In: Soiffer RJ, editor. Hematopoietic
plantation: obstacles and anticipated progress. Curr stem cell transplantation. Totowa, NJ: Humana,
Opin Immunol. 2009;21:544–8. Springer distributor; 2008. p. xvi. 736 p.
36. Washington K, Jagasia M. Pathology of graft-versus- 54. Levitsky J, Sorrell MF. Hepatic complications of
host disease in the gastrointestinal tract. Hum Pathol. hematopoietic cell transplantation. Curr Gastroenterol
2009;40:909–17. Rep. 2007;9:60–5.
37. Varkila K, Hurme M. Natural killer (NK) cells and 55. Ross WA, Ghosh S, Dekovich AA, Liu S, Ayers GD,
graft-versus-host disease (GVHD): no correlation Cleary KR, et al. Endoscopic biopsy diagnosis of
between the NK cell levels and GVHD in the murine acute gastrointestinal graft-versus-host disease: recto-
P––F1 model. Immunology. 1985;54:121–6. sigmoid biopsies are more sensitive than upper gastro-
38. Olson JA, Leveson-Gower DB, Gill S, Baker J, Beilhack intestinal biopsies. Am J Gastroenterol.
A, Negrin RS. NK cells mediate reduction of GVHD 2008;103:982–9.
by inhibiting activated, alloreactive T cells while retain- 56. Nishio N, Yagasaki H, Takahashi Y, Hama A, Muramatsu
ing GVT effects. Blood. 2010;115:4293–301. H, Tanaka M, et al. Engraftment syndrome following
39. Noval Rivas M, Hazzan M, Weatherly K, Gaudray F, allogeneic hematopoietic stem cell transplantation in
Salmon I, Braun MY. NK cell regulation of CD4 T children. Pediatr Transplant. 2009;13:831–7.
cell-mediated graft-versus-host disease. J Immunol. 57. Carreras E, Fernandez-Aviles F, Silva L, Guerrero M,
2010;184:6790–8. Fernandez de Larrea C, Martinez C, et al. Engraftment
40. Tanaka M, Kobayashi S, Numata A, Tachibana T, syndrome after auto-SCT: analysis of diagnostic crite-
Takasaki H, Maruta A, et al. The impact of the dose of ria and risk factors in a large series from a single cen-
natural killer cells in the graft on severe acute graft- ter. Bone Marrow Transplant. 2010;45:1417–22.
versus-host disease after unrelated bone marrow 58. Dai E, Couriel D, Kim SK. Bilateral marginal keratitis
transplantation. Leuk Res. 2011;36(6):699–703. associated with engraftment syndrome after hematopoi-
41. Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, etic stem cell transplantation. Cornea. 2007;26:756–8.
Neiman PE, et al. Bone-marrow transplantation (sec- 59. Schmid I, Stachel D, Pagel P, Albert MH. Incidence,
ond of two parts). N Engl J Med. 1975;292:895–902. predisposing factors, and outcome of engraftment syn-
42. Rapini RP. Practical dermatopathology. St. Louis, drome in pediatric allogeneic stem cell transplant recipi-
MO: Elsevier Mosby; 2005. ents. Biol Blood Marrow Transplant. 2008;14:438–44.
43. Deeg HJ, Antin JH. The clinical spectrum of acute graft- 60. Koreth J, Biernacki M, Aldridge J, Kim HT, Alyea III
versus-host disease. Semin Hematol. 2006;43:24–31. EP, Armand P, et al. Syngeneic donor hematopoietic
44. Ross WA, Couriel D. Colonic graft-versus-host dis- stem cell transplantation is associated with high rates
ease. Curr Opin Gastroenterol. 2005;21:64–9. of engraftment syndrome. Biol Blood Marrow
45. Hausermann P, Walter RB, Halter J, Biedermann BC, Transplant. 2011;17:421–8.
Tichelli A, Itin P, et al. Cutaneous graft-versus-host 61. Hood AF, Vogelsang GB, Black LP, Farmer ER,
disease: a guide for the dermatologist. Dermatology. Santos GW. Acute graft-vs-host disease. Development
2008;216:287–304. following autologous and syngeneic bone marrow
46. Byun HJ, Yang JI, Kim BK, Cho KH. Clinical differ- transplantation. Arch Dermatol. 1987;123:745–50.
entiation of acute cutaneous graft-versus-host disease 62. Hess AD. Autologous graft-versus-host disease. J
from drug hypersensitivity reactions. J Am Acad Hematother Stem Cell Res. 2000;9:297.
Dermatol. 2011;65:726–32. 63. Hess AD. Modulation of graft-versus-host disease:
47. Benesch M, Deeg HJ. Pathophysiology of graft-ver- role of regulatory T lymphocytes. Biol Blood Marrow
sus-host disease. In: Soiffer RJ, editor. Hematopoietic Transplant. 2006;12:13–21.
stem cell transplantation. Totowa, NJ: Humana; 64. Kline J, Subbiah S, Lazarus HM, van Besien K.
Springer distributor; 2008. p. xvi. 736 p. Autologous graft-versus-host disease: harnessing
48. Tani M, Adachi A. Acute follicular graft-versus-host anti-tumor immunity through impaired self-tolerance.
disease. Dermatology. 1992;185:281–3. Bone Marrow Transplant. 2008;41:505–13.
49. Friedman KJ, LeBoit PE, Farmer ER. Acute follicular 65. Jenkins MK, Schwartz RH, Pardoll DM. Effects of
graft-vs-host reaction. A distinct clinicopathologic cyclosporine A on T cell development and clonal
presentation. Arch Dermatol. 1988;124:688–91. deletion. Science. 1988;241:1655–8.
50. Chaudhuri SP, Smoller BR. Acute cutaneous graft 66. Bolanos-Meade J, Garrett-Mayer E, Luznik L, Anders
versus host disease: a clinicopathologic and immuno- V, Webb J, Fuchs EJ, et al. Induction of autologous graft-
phenotypic study. Int J Dermatol. 1992;31:270–2. versus-host disease: results of a randomized prospective
51. Goiriz R, Penas P, Perez-Gala S, Delgado-Jimenez Y, clinical trial in patients with poor risk lymphoma. Biol
Aragues M, Garcia-Diez A, et al. Stage IV cutaneous Blood Marrow Transplant. 2007;13:1185–91.
acute graft-versus-host disease. Clinical and histo- 67. Zhang Y, Ruiz P. Solid organ transplant-associated
logical study of 15 cases. J Eur Acad Dermatol acute graft-versus-host disease. Arch Pathol Lab Med.
Venereol. 2009;23:1398–404. 2010;134:1220–4.
52. McDonald GB. Review article: management of 68. Kohler S, Pascher A, Junge G, Sauer IM, Nagy M,
hepatic disease following haematopoietic cell trans- Schonemann C, et al. Graft versus host disease after
plant. Aliment Pharmacol Ther. 2006;24:441–52. liver transplantation—a single center experience and
53. McDonald GB. Hepatobiliary complications of review of literature. Transpl Int. 2008;21:441–51.
hematopoietic cell transplantation, 40 years on. 69. Shin CR, Nathan J, Alonso M, Yazigi N, Kocoshis S,
Hepatology. 2010;51:1450–60. Tiao G, et al. Incidence of acute and chronic graft-
versus-host disease and donor T-cell chimerism after Francaise de Greffe de Moelle et Therapie Cellulaire
small bowel or combined organ transplantation. J (SFGM-TC), Dana Farber Cancer Institute (DFCI),
Pediatr Surg. 2011;46:1732–8. and International Bone Marrow Transplant Registry
70. Taylor AL, Gibbs P, Bradley JA. Acute graft versus (IBMTR) prospective study. Blood.
host disease following liver transplantation: the enemy 2005;106:1495–500.
within. Am J Transplant. 2004;4:466–74. 85. Rowlings PA, Przepiorka D, Klein JP, Gale RP,
71. Assi MA, Pulido JS, Peters SG, McCannel CA, Passweg JR, Henslee-Downey PJ, et al. IBMTR
Razonable RR. Graft-vs.-host disease in lung and Severity Index for grading acute graft-versus-host dis-
other solid organ transplant recipients. Clin Transplant. ease: retrospective comparison with Glucksberg
2007;21:1–6. grade. Br J Haematol. 1997;97:855–64.
72. Walling HW, Voigt MD, Stone MS. Lichenoid graft 86. Martino R, Romero P, Subira M, Bellido M, Altes A,
vs. host disease following liver transplantation. J Sureda A, et al. Comparison of the classic Glucksberg
Cutan Pathol. 2004;31:179–84. criteria and the IBMTR Severity Index for grading
73. Schrager JJ, Vnencak-Jones CL, Graber SE, Neff AT, acute graft-versus-host disease following HLA-
Chari RS, Wright Jr KJ, et al. Use of short tandem identical sibling stem cell transplantation. International
repeats for DNA fingerprinting to rapidly diagnose Bone Marrow Transplant Registry. Bone Marrow
graft-versus-host disease in solid organ transplant Transplant. 1999;24:283–7.
patients. Transplantation. 2006;81:21–5. 87. Carpenter PA, Lowder J, Johnston L, Frangoul H,
74. Ruhl H, Bein G, Sachs UJ. Transfusion-associated Khoury H, Parker P, et al. A phase II multicenter
graft-versus-host disease. Transfus Med Rev. study of visilizumab, humanized anti-CD3 antibody,
2009;23:62–71. to treat steroid-refractory acute graft-versus-host dis-
75. Linden JV, Pisciotto PT. Transfusion-associated graft- ease. Biol Blood Marrow Transplant.
versus-host disease and blood irradiation. Transfus 2005;11:465–71.
Med Rev. 1992;6:116–23. 88. Min CK. The pathophysiology of chronic graft-ver-
76. Agbaht K, Altintas ND, Topeli A, Gokoz O, Ozcebe sus-host disease: the unveiling of an enigma. Korean J
O. Transfusion-associated graft-versus-host disease in Hematol. 2011;46:80–7.
immunocompetent patients: case series and review of 89. Arora M, Klein JP, Weisdorf DJ, Hassebroek A, Flowers
the literature. Transfusion. 2007;47:1405–11. ME, Cutler CS, et al. Chronic GVHD risk score: a
77. Parshuram C, Doyle J, Lau W, Shemie SD. Center for International Blood and Marrow Transplant
Transfusion-associated graft versus host disease. Research analysis. Blood. 2011;117:6714–20.
Pediatr Crit Care Med. 2002;3:57–62. 90. Shimabukuro-Vornhagen A, Hallek MJ, Storb RF,
78. Bashir S, Naik F, Cardigan R, Thomas S. Effect of von Bergwelt-Baildon MS. The role of B cells in the
X-irradiation on the quality of red cell concentrates. pathogenesis of graft-versus-host disease. Blood.
Vox Sang. 2011;101:200–7. 2009;114:4919–27.
79. Frey NV, Porter DL. Graft-versus-host disease after 91. Koreth J, Matsuoka K, Kim HT, McDonough SM,
donor leukocyte infusions: presentation and manage- Bindra B, Alyea III EP, et al. Interleukin-2 and regula-
ment. Best Pract Res Clin Haematol. tory T cells in graft-versus-host disease. N Engl J
2008;21:205–22. Med. 2011;365:2055–66.
80. Porter D, Hexner EO, Cooley S, Miller JS. Cellular 92. Carlens S, Ringden O, Remberger M, Lonnqvist B,
adoptive immunotherapy after autologous and alloge- Hagglund H, Klaesson S, et al. Risk factors for chronic
neic hematopoietic stem cell transplantation. In: graft-versus-host disease after bone marrow trans-
Bishop MR, editor. Hematopoietic stem cell transplantation: a retrospective single centre analysis. Bone
plantation. New York: Springer; 2008. Marrow Transplant. 1998;22:755–61.
81. Chalandon Y, Passweg JR, Schmid C, Olavarria E, 93. Pidala J, Vogelsang G, Martin P, Chai X, Storer B,
Dazzi F, Simula MP, et al. Outcome of patients Pavletic S, et al. Overlap subtype of chronic graft vs.
developing GVHD after DLI given to treat CML host disease is associated with adverse prognosis,
relapse: a study by the Chronic Leukemia Working functional impairment, and inferior patient reported
Party of the EBMT. Bone Marrow Transplant. outcomes: a chronic graft vs. host disease Consortium
2010;45:558–64. study. Haematologica. 2012;97:451–8.
82. Porter D, Levine JE. Graft-versus-host disease and 94. Martires KJ, Baird K, Steinberg SM, Grkovic L, Joe
graft-versus-leukemia after donor leukocyte infusion. GO, Williams KM, et al. Sclerotic-type chronic GVHD
Semin Hematol. 2006;43:53–61. of the skin: clinical risk factors, laboratory markers,
83. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman and burden of disease. Blood. 2011;118:4250–7.
PE, Clift RA, et al. Clinical manifestations of graft- 95. Martires KJ, Baird K, Citrin DE, Hakim FT, Pavletic
versus-host disease in human recipients of marrow SZ, Cowen EW. Localization of sclerotic-type chronic
from HL-A-matched sibling donors. Transplantation. graft-vs-host disease to sites of skin injury: potential
1974;18:295–304. insight into the mechanism of isomorphic and isotopic
84. Cahn JY, Klein JP, Lee SJ, Milpied N, Blaise D, Antin responses. Arch Dermatol. 2011;147:1081–6.
JH, et al. Prospective evaluation of 2 acute graft-ver- 96. Mehra T, Metzler G, Bauer J, Koberle M, Garbe C.
sus-host (GVHD) grading systems: a joint Societe Isotopic response of graft versus host disease following
Herpes Zoster infection: case report and review of the positive regulatory T-cell (Treg) content is associated
literature. Acta Derm Venereol. 2012;92(4):383–4. with a low risk of GVHD following HLA-matched
97. Aractingi S, Chosidow O. Cutaneous graft-versus- allogeneic SCT. Blood. 2006;108:1291–7.
host disease. Arch Dermatol. 1998;134:602–12. 111. Heshmati F. Extra corporeal photo chemotherapy
98. Kfoury HK, Alghonaim M, AlSuwaida AK, Zaidi (ECP) in acute and chronic GVHD. Transfus Apher
SN, Arafah M. Nasopharyngeal T-cell monomorphic Sci. 2010;43:211–5.
posttransplant lymphoproliferative disorders and 112. Perruche S, Marandin A, Kleinclauss F, Angonin R,
combined IgA nephropathy and membranous glom- Fresnay S, Baron MH, et al. Association of mixed
erulonephritis in a patient with renal transplantation: hematopoietic chimerism with elevated circulating
a case report with literature review. Transplant Proc. autoantibodies and chronic graft-versus-host disease
2010;42:4653–7. occurrence. Transplantation. 2006;81:573–82.
99. Resende RG, de Fatima Correia-Silva J, Arao TC, 113. Socie G. Chronic GVHD: B cells come of age.
Brito JA, Bittencourt H, Gomez RS, et al. Oral Blood. 2011;117:2086–7.
cGVHD screening tests in the diagnosis of systemic 114. Kharfan-Dabaja MA, Cutler CS. Rituximab for pre-
chronic graft-versus-host disease. Clin Oral Investig. vention and treatment of graft-versus-host disease.
2012;16(2):565–70. Int J Hematol. 2011;93:578–85.
100. Nagler R, Marmary Y, Krausz Y, Chisin R, Markitziu 115. Rozmus J, Schultz KR. Biomarkers in chronic graft-
A, Nagler A. Major salivary gland dysfunction in versus-host disease. Expert Rev Hematol.
human acute and chronic graft-versus-host disease 2011;4:329–42.
(GVHD). Bone Marrow Transplant. 1996;17:219–24. 116. Fujii H, Cuvelier G, She K, Aslanian S, Shimizu H,
101. Koch KR, Joussen AM, Huber KK. Ocular involve- Kariminia A, et al. Biomarkers in newly diagnosed
ment in chronic graft-versus-host disease: therapeu- pediatric-extensive chronic graft-versus-host dis-
tic approaches to complicated courses. Cornea. ease: a report from the Children’s Oncology Group.
2011;30:107–13. Blood. 2008;111:3276–85.
102. Sanli H, Arat M, Oskay T, Gurman G. Evaluation of 117. Svegliati S, Olivieri A, Campelli N, Luchetti M,
nail involvement in patients with chronic cutaneous Poloni A, Trappolini S, et al. Stimulatory autoanti-
graft versus host disease: a single-center study from bodies to PDGF receptor in patients with extensive
Turkey. Int J Dermatol. 2004;43:176–80. chronic graft-versus-host disease. Blood.
103. Akay BN, Sanli H, Topcuoglu P, Arat M, Akyol A. 2007;110:237–41.
Nailfold capillary abnormalities are prevalent in 118. Kim SJ, Won JH. B cell homeostasis and the devel-
sclerodermoid graft-versus-host disease and readily opment of chronic graft-versus-host disease: impli-
detected with dermatoscopy. Br J Dermatol. cations for B cell-depleting therapy. Leuk Lymphoma.
2010;162:1076–82. 2012;53:19–25.
104. Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler 119. Skert C, Damiani D, Michelutti A, Patriarca F,
C, et al. Global and organ-specific chronic graft- Arpinati M, Fili C, et al. Kinetics of Th1/Th2 cytok-
versus-host disease severity according to the 2005 ines and lymphocyte subsets to predict chronic
NIH Consensus Criteria. Blood. 2011;118:4242–9. GVHD after allo-SCT: results of a prospective study.
105. Kuzmina Z, Eder S, Bohm A, Pernicka E, Vormittag Bone Marrow Transplant. 2009;44:729–37.
L, Kalhs P, et al. Significantly worse survival of 120. Kansu E. The pathophysiology of chronic graft-ver-
patients with NIH-defined chronic graft-versus-host sus-host disease. Int J Hematol. 2004;79:209–15.
disease and thrombocytopenia or progressive onset 121. Liem LM, Fibbe WE, van Houwelingen HC, Goulmy
type: results of a prospective study. Leukemia. E. Serum transforming growth factor-beta1 levels in
2011;26(4):746–56. bone marrow transplant recipients correlate with
106. Ahmad I, Labbe AC, Chagnon M, Busque L, Cohen blood cell counts and chronic graft-versus-host dis-
S, Kiss T, et al. Incidence and prognostic value of ease. Transplantation. 1999;67:59–65.
eosinophilia in chronic graft-versus-host disease after 122. Murata T, Husain SR, Mohri H, Puri RK. Two differ-
nonmyeloablative hematopoietic cell transplantation. ent IL-13 receptor chains are expressed in normal
Biol Blood Marrow Transplant. 2011;17:1673–8. human skin fibroblasts, and IL-4 and IL-13 mediate
107. Schroeder MA, DiPersio JF. Mouse models of graft- signal transduction through a common pathway. Int
versus-host disease: advances and limitations. Dis Immunol. 1998;10:1103–10.
Model Mech. 2011;4:318–33. 123. Atkinson K, Horowitz MM, Gale RP, van Bekkum
108. Chu YW, Gress RE. Murine models of chronic graft- DW, Gluckman E, Good RA, et al. Risk factors for
versus-host disease: insights and unresolved issues. chronic graft-versus-host disease after HLA-identical
Biol Blood Marrow Transplant. 2008;14:365–78. sibling bone marrow transplantation. Blood.
109. Zhang C, Todorov I, Zhang Z, Liu Y, Kandeel F, Forman 1990;75:2459–64.
S, et al. Donor CD4+ T and B cells in transplants induce 124. Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie
chronic graft-versus-host disease with autoimmune G, Travis LB, et al. Solid cancers after bone marrow
manifestations. Blood. 2006;107:2993–3001. transplantation. N Engl J Med. 1997;336:897–904.
110. Rezvani K, Mielke S, Ahmadzadeh M, Kilical Y, 125. Epaulard O, Leccia MT, Blanche S, Chosidow O,
Savani BN, Zeilah J, et al. High donor FOXP3- Mamzer-Bruneel MF, Ravaud P, et al. Phototoxicity
and photocarcinogenesis associated with voricon- 139. Penas PF, Fernandez-Herrera J, Garcia-Diez A.
azole. Med Mal Infect. 2011;41:639–45. Dermatologic treatment of cutaneous graft versus
126. Clancy CJ, Nguyen MH. Long-term voriconazole host disease. Am J Clin Dermatol. 2004;5:403–16.
and skin cancer: is there cause for concern? Curr 140. Leiter U, Kaskel P, Krahn G, Gottlober P, Bunjes D,
Infect Dis Rep. 2011;13:536–43. Peter RU, et al. Psoralen plus ultraviolet-A-bath pho-
127. Vadnerkar A, Nguyen MH, Mitsani D, Crespo M, tochemotherapy as an adjunct treatment modality in
Pilewski J, Toyoda Y, et al. Voriconazole exposure cutaneous chronic graft versus host disease.
and geographic location are independent risk factors Photodermatol Photoimmunol Photomed. 2002;18:
for squamous cell carcinoma of the skin among lung 183–90.
transplant recipients. J Heart Lung Transplant. 141. Vogelsang GB, Wolff D, Altomonte V, Farmer E,
2010;29:1240–4. Morison WL, Corio R, et al. Treatment of chronic
128. Ibrahim SF, Singer JP, Arron ST. Catastrophic graft-versus-host disease with ultraviolet irradiation
squamous cell carcinoma in lung transplant patients and psoralen (PUVA). Bone Marrow Transplant.
treated with voriconazole. Dermatol Surg. 1996;17:1061–7.
2010;36:1752–5. 142. Hearn RM, Kerr AC, Rahim KF, Ferguson J, Dawe
129. Vanacker A, Fabre G, Van Dorpe J, Peetermans WE, RS. Incidence of skin cancers in 3867 patients treated
Maes B. Aggressive cutaneous squamous cell carci- with narrow-band ultraviolet B phototherapy. Br J
noma associated with prolonged voriconazole ther- Dermatol. 2008;159:931–5.
apy in a renal transplant patient. Am J Transplant. 143. Brazzelli V, Grasso V, Muzio F, Moggio E, Zecca M,
2008;8:877–80. Locatelli F, et al. Narrowband ultraviolet B photo-
130. McCarthy KL, Playford EG, Looke DF, Whitby M. therapy in the treatment of cutaneous graft-versus-
Severe photosensitivity causing multifocal squamous host disease in oncohaematological paediatric
cell carcinomas secondary to prolonged voricon- patients. Br J Dermatol. 2010;162:404–9.
azole therapy. Clin Infect Dis. 2007;44:e55–6. 144. Lee SJ, Flowers ME. Recognizing and managing
131. Marks C, Stadler M, Hausermann P, Wolff D, chronic graft-versus-host disease. Hematology Am
Buchholz S, Stary G, et al. German-Austrian-Swiss Soc Hematol Educ Program 2008:134–41.
Consensus Conference on clinical practice in chronic 145. Wolff D, Gerbitz A, Ayuk F, Kiani A, Hildebrandt GC,
graft-versus-host disease (GVHD): guidance for Vogelsang GB, et al. Consensus conference on clinical
supportive therapy of chronic cutaneous and muscu- practice in chronic graft-versus-host disease (GVHD):
loskeletal GVHD. Br J Dermatol. 2011;165:18–29. first-line and topical treatment of chronic GVHD. Biol
132. Couriel DR. Ancillary and supportive care in chronic Blood Marrow Transplant. 2010;16:1611–28.
graft-versus-host disease. Best Pract Res Clin 146. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg
Haematol. 2008;21:291–307. HJ, Nash RA, et al. Therapy for chronic graft-ver-
133. Couriel DR, Beguelin GZ, Giralt S, De Lima M, sus-host disease: a randomized trial comparing
Hosing C, Kharfan-Dabaja MA, et al. Chronic graft- cyclosporine plus prednisone versus prednisone
versus-host disease manifesting as polymyositis: an alone. Blood. 2002;100:48–51.
uncommon presentation. Bone Marrow Transplant. 147. Sullivan KM, Witherspoon RP, Storb R, Deeg HJ,
2002;30:543–6. Dahlberg S, Sanders JE, et al. Alternating-day
134. Ahn JS, Cho SH, Kim YK, Yang DH, Bae WK, cyclosporine and prednisone for treatment of high-
Shim HJ, et al. Polymyositis and myocarditis after risk chronic graft-v-host disease. Blood. 1988;72:
donor lymphocyte infusion. Int J Hematol. 555–61.
2009;90:113–6. 148. Weng JY, Du X, Geng SX, Peng YW, Wang Z, Lu
135. Hilgendorf I, Freund M, Jilg W, Einsele H, Gea- ZS, et al. Mesenchymal stem cell as salvage treat-
Banacloche J, Greinix H, et al. Vaccination of allo- ment for refractory chronic GVHD. Bone Marrow
geneic haematopoietic stem cell transplant recipients: Transplant. 2010;45:1732–40.
report from the international consensus conference 149. Wolff D, Schleuning M, von Harsdorf S, Bacher U,
on clinical practice in chronic GVHD. Vaccine. Gerbitz A, Stadler M, et al. Consensus conference
2011;29:2825–33. on clinical practice in chronic GVHD: second-line
136. Ziemer M, Gruhn B, Thiele JJ, Elsner P. Treatment treatment of chronic graft-versus-host disease. Biol
of extensive chronic cutaneous graft-versus-host dis- Blood Marrow Transplant. 2011;17:1–17.
ease in an infant with topical pimecrolimus. J Am 150. Couriel DR, Saliba R, Escalon MP, Hsu Y, Ghosh S,
Acad Dermatol. 2004;50:946–8. Ippoliti C, et al. Sirolimus in combination with tac-
137. Schmook T, Kraft J, Benninghoff B, Nindl I, Roewert rolimus and corticosteroids for the treatment of
J, Ulrich C, et al. Treatment of cutaneous chronic resistant chronic graft-versus-host disease. Br J
graft-versus-host disease with topical pimecrolimus. Haematol. 2005;130:409–17.
Bone Marrow Transplant. 2005;36:87–8. 151. Jedlickova Z, Burlakova I, Bug G, Baurmann H,
138. Mawardi H, Stevenson K, Gokani B, Soiffer R, Schwerdtfeger R, Schleuning M. Therapy of sclero-
Treister N. Combined topical dexamethasone/tac- dermatous chronic graft-versus-host disease with
rolimus therapy for management of oral chronic mammalian target of rapamycin inhibitors. Biol
GVHD. Bone Marrow Transplant. 2010;45:1062–7. Blood Marrow Transplant. 2011;17:657–63.
152. Ponticelli C. De novo thrombotic microangiopathy. phenolate mofetil for initial treatment of chronic
An underrated complication of renal transplantation. graft-versus-host disease. Blood. 2009;113:5074–82.
Clin Nephrol. 2007;67:335–40. 164. Furlong T, Martin P, Flowers ME, Carnevale-
153. Goussetis E, Varela I, Tsirigotis P. Update on the Schianca F, Yatscoff R, Chauncey T, et al. Therapy
mechanism of action and on clinical efficacy of with mycophenolate mofetil for refractory acute and
extracorporeal photopheresis in the treatment of chronic GVHD. Bone Marrow Transplant.
acute and chronic graft versus host disease in chil- 2009;44:739–48.
dren. Transfus Apher Sci. 2012;46(2):203–9. 165. Inamoto Y, Flowers ME. Treatment of chronic graft-
154. Gatza E, Rogers CE, Clouthier SG, Lowler KP, versus-host disease in 2011. Curr Opin Hematol.
Tawara I, Liu C, et al. Extracorporeal photopheresis 2011;18:414–20.
reverses experimental graft-versus-host disease 166. Ratanatharathorn V, Ayash L, Reynolds C, Silver S,
through regulatory T cells. Blood. 2008;112: Reddy P, Becker M, et al. Treatment of chronic graft-
1515–21. versus-host disease with anti-CD20 chimeric mono-
155. Tsirigotis P, Kapsimalli V, Baltadakis I, Kaloyannidis clonal antibody. Biol Blood Marrow Transplant.
P, Karakasis D, Papalexandri A, et al. Extracorporeal 2003;9:505–11.
photopheresis in refractory chronic graft-versus-host 167. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B,
disease: the influence on peripheral blood T cell sub- Cutler C, Mohty M, Kumar A. Efficacy of rituximab in
populations. A study by the Hellenic Association of the setting of steroid-refractory chronic graft-versus-
Hematology. Transfus Apher Sci. 2012;46(2): host disease: a systematic review and meta-analysis.
181–8. Biol Blood Marrow Transplant. 2009;15:1005–13.
156. Tsirigotis P, Kaloyannidis P, Papalexandri A, 168. Cutler C, Miklos D, Kim HT, Treister N, Woo SB,
Baltadakis I, Karakasis D, Batsis I, et al. Bienfang D, et al. Rituximab for steroid-refractory
Extracorporeal photopheresis in the treatment of chronic graft-versus-host disease. Blood.
chronic graft-versus-host disease. The Hellenic expe- 2006;108:756–62.
rience: a study by the Hellenic association of hema- 169. Olivieri J, Coluzzi S, Attolico I, Olivieri A. Tirosin
tology. Transfus Apher Sci. 2012;46(2):173–80. kinase inhibitors in chronic graft versus host disease:
157. Dignan FL, Greenblatt D, Cox M, Cavenagh J, from bench to bedside. ScientificWorldJournal.
Oakervee H, Apperley JF, et al. Efficacy of bimonthly 2011;11:1908–31.
extracorporeal photopheresis in refractory chronic 170. Sanchez-Ortega I, Servitje O, Arnan M, Orti G,
mucocutaneous GVHD. Bone Marrow Transplant. Peralta T, Manresa F, et al. Dasatinib as salvage ther-
2012;47(6):824–30. apy for steroid refractory and imatinib resistant or
158. Takami A, Mochizuki K, Okumura H, Ito S, Suga Y, intolerant sclerotic chronic graft-versus-host disease.
Yamazaki H, et al. Mycophenolate mofetil is effec- Biol Blood Marrow Transplant. 2012;18:318–23.
tive and well tolerated in the treatment of refractory 171. Chen GL, Arai S, Flowers ME, Otani JM, Qiu J,
acute and chronic graft-versus-host disease. Int J Cheng EC, et al. A phase 1 study of imatinib for
Hematol. 2006;83:80–5. corticosteroid-dependent/refractory chronic graft-
159. Wang Y, Xu LP, Liu DH, Chen H, Chen YH, Han W, versus-host disease: response does not correlate with
et al. First-line therapy for chronic graft-versus-host anti-PDGFRA antibodies. Blood. 2011;118:4070–8.
disease that includes low-dose methotrexate is asso- 172. Lazar J, Poonawalla T, Teng JM. A case of sclero-
ciated with a high response rate. Biol Blood Marrow dermatous graft-versus-host disease responsive to
Transplant. 2009;15:505–11. imatinib therapy. Pediatr Dermatol. 2011;28:172–5.
160. Inagaki J, Nagatoshi Y, Hatano M, Isomura N, 173. Wang S, Qu X, Zhao RC. Mesenchymal stem cells
Sakiyama M, Okamura J. Low-dose MTX for the hold promise for regenerative medicine. Front Med.
treatment of acute and chronic graft-versus-host dis- 2011;5:372–8.
ease in children. Bone Marrow Transplant. 2008;41: 174. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom
571–7. C, Hassan M, Uzunel M, et al. Treatment of severe
161. Sullivan KM, Witherspoon RP, Storb R, Weiden P, acute graft-versus-host disease with third party hap-
Flournoy N, Dahlberg S, et al. Prednisone and azathio- loidentical mesenchymal stem cells. Lancet.
prine compared with prednisone and placebo for treat- 2004;363:1439–41.
ment of chronic graft-v-host disease: prognostic 175. Ryan JM, Barry FP, Murphy JM, Mahon BP.
influence of prolonged thrombocytopenia after alloge- Mesenchymal stem cells avoid allogeneic rejection.
neic marrow transplantation. Blood. 1988;72:546–54. J Inflamm (Lond). 2005;2:8.
162. Curtis RE, Metayer C, Rizzo JD, Socie G, Sobocinski 176. Aggarwal S, Pittenger MF. Human mesenchymal
KA, Flowers ME, et al. Impact of chronic GVHD stem cells modulate allogeneic immune cell
therapy on the development of squamous-cell can- responses. Blood. 2005;105:1815–22.
cers after hematopoietic stem-cell transplantation: 177. Ning H, Yang F, Jiang M, Hu L, Feng K, Zhang J,
an international case-control study. Blood. et al. The correlation between cotransplantation of
2005;105:3802–11. mesenchymal stem cells and higher recurrence rate
163. Martin PJ, Storer BE, Rowley SD, Flowers ME, in hematologic malignancy patients: outcome of a
Lee SJ, Carpenter PA, et al. Evaluation of myco- pilot clinical study. Leukemia. 2008;22:593–9.
178. Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz sus-tumor effects after HLA-mismatched allogeneic
RT, Holland HK, et al. Cotransplantation of HLA- transplantation following nonmyeloablative condi-
identical sibling culture-expanded mesenchymal tioning. Biol Blood Marrow Transplant. 2010;16:
stem cells and hematopoietic stem cells in hemato- 838–47.
logic malignancy patients. Biol Blood Marrow 180. Zhou H, Guo M, Bian C, Sun Z, Yang Z, Zeng Y,
Transplant. 2005;11:389–98. et al. Efficacy of bone marrow-derived mesenchymal
179. Baron F, Lechanteur C, Willems E, Bruck F, Baudoux stem cells in the treatment of sclerodermatous
E, Seidel L, et al. Cotransplantation of mesenchymal chronic graft-versus-host disease: clinical report.
stem cells might prevent death from graft-versus- Biol Blood Marrow Transplant. 2010;16:403–12.
host disease (GVHD) without abrogating graft-ver-
Erythroderma
7
Gillian Heinecke and Mark Lebwohl
of age and a mean age of onset of 55 years, although

7.1 Introduction it should be noted that most studies exclude pediatric
cases of erythroderma [5]. Approximately 50% of
Erythroderma (exfoliative dermatitis) is a clinical cases are exacerbations of preexisting dermatoses
syndrome characterized by extensive erythema such as psoriasis, atopic dermatitis, or pityriasis
involving greater than 90% of the skin surface. It rubra pilaris. Other causative factors include
may be the result of many different dermatologi- drug reactions (20%), malignancies (11%), and
cal conditions including preexisting dermatoses, idiopathic (17%) [3, 4, 8–15].
drug reactions, and malignancy. Hospitalization
may be required for initial evaluation and treat-
ment since many of these patients are elderly and 7.3 Etiology
the skin involvement is extensive leading to
significant mortality risk. Patients need to be A wide range of cutaneous and systemic diseases
monitored to ensure that temperature, water, pro- can cause erythroderma. It is important to estab-
tein, and electrolyte homeostasis are maintained. lish the correct diagnosis whenever possible
Erythroderma accounts for 1% of all dermato- because specific therapy other than corticosteroids
logic hospital admissions [1]. or anti-inflammatory treatments may be necessary
to improve the patient’s condition [6]. Table 7.1
provides an overview of the major etiologies
7.2 Epidemiology responsible for erythroderma [3, 4, 8–15].
Erythroderma is a rare skin disorder with an esti-

mated annual incidence of 1–2 patients per 100,000 7.3.1 Dermatoses
population [2]. It is more common in males with a
male to female ratio of 2:1 to 4:1 [2–4]. Erythroderma occurring secondary to a preexist-
Erythroderma occurs more commonly in older ing skin condition is the most common etiology.
adults, with affected patients usually over 45 years The underlying skin condition is commonly known
prior to onset of the erythroderma; however, some
may initially present with erythroderma. In ana-
G. Heinecke, B.S. • M. Lebwohl, M.D. (*) lyzing the combined data from the studies listed in
Department of Dermatolgy, Mt. Sinai School of Table 7.1 [3, 4, 8–15], psoriasis was the most com-
Medicine, One Gustave L. Levy Place, 5 East 98th St.
mon (23.1%) followed by atopic dermatitis/
5th floor, New York, NY 10029, USA
e-mail: Gillian.Heinecke@mssm.edu; mark.lebwohl@ eczema (9.5%), pityriasis rubra pilaris (3.4%),
mountsinai.org; Lebwohl@aol.com contact dermatitis (3.2%), actinic dermatitis

134 G. Heinecke and M. Lebwohl
Table 7.1 Major etiologies for erythroderma from ten series

Number Drug-induced
Series (year) of patients Dermatoses (%) reaction (%) Malignancy (%) Idiopathic (%)
Abrahams (1963) [11] 101 35 11 8 47
Nicolis (1973) [8] 135 27 40 21 12
King (1986) [12] 82 30 34 20 16
Sehgal (1986) [14] 80 53 25 0 23
Botella-Estrada (1994) [4] 56 63 16 13 9
Sigurdsson (1996) [9] 102 53 5 16 26
Pal (1998) [13] 90 74 6 6 15
Akhyani (2005) [3] 97 60 22 11 7
Rym (2005) [15] 80 72 11 9 8
Yuan (2010) [10] 82 72 17 5 6
Total 905 52 20 11 17
Table 7.2 Dermatoses known to cause erythroderma

Actinic dermatitis Norwegian scabies
Bullous pemphigoid [17] Pemphigus foliaceus
Candidiasis [18] Perforating folliculitis [23]
Contact dermatitis Phytophotodermatitis
Dermatophytosis Pityriasis Rubra Pilaris
Eczema/atopic dermatitis Psoriasis
Erythema gyratum repens Radiation recall dermatitis
[19] [24]
Hailey-Hailey [20] Seborrheric dermatitis
Icthyosiform dermatitis Senile xerosis
Impetigo herpetiformis Staphylococcal scalded
[21] skin syndrome
Lichen planus Stasis dermatitis
Mastocytosis [22] Subacute cutaneous lupus
erythematosus [25]
remaining cases. Table 7.2 lists the inflammatory

dermatoses associated with erythroderma. It is
important to consider other possible etiologies
even in patients with clear preexisting dermatoses.
Eugster et al. described that five out of seven
patients with malignancy-induced erythroderma
had a history of a preexisting dermatosis [16].
Fig. 7.1 Erythroderma secondary to congenital icthyosi-
form dermatitis. Courtesy of Mount Sinai Dermatology
collection 7.3.2 Psoriasis
(2.7%), and seborrheric dermatitis (2.5%). Erythrodermic psoriasis is a rare and severe form
Additionally, pemphigus foliaceus, lichen planus, of psoriasis occurring in 1–2.25% of patients with
icthyosiform dermatitis (Fig. 7.1), phytophotoder- psoriasis [26, 27]. It typically occurs in patients
matitis, stasis dermatitis, extensive dermatophytosis, with established psoriasis with an average of 14
Norwegian scabies, senile xerosis, and staphylo- years between the onset of psoriasis and the first
coccal scalded skin syndrome account for the erythrodermic episode [26], although in some
7 Erythroderma 135
cases, it can be the patient’s initial presentation of may also be seen in psoriasis, cutaneous T-cell
psoriasis. Erythrodermic psoriasis may present lymphoma and sarcoidosis [6]. Patients with PRP
acutely or may run a chronic course with frequent may also have underlying follicular papules and
relapses [26]. There are a variety of medical and keratoderma of palms and soles.
social conditions that may trigger outbreaks of
erythroderma in previously localized psoriasis
including systemic illness such as HIV infection, 7.3.4 Drug Hypersensitivity Reactions
discontinuation of medications (including oral
corticosteroids, potent topical steroids, methotrex- Both topical and systemic drugs are notorious for
ate or biologics), emotional stress, UV burn, topi- precipitating erythroderma, accounting for 20% of
cal tar, and alcoholism [26, 28]. The classic plaques cases. While this list is constantly expanding, many
of psoriasis may be present in the early and remit- of the implicated drugs come from single case
ting stages of erythroderma. The patient may also reports. The most commonly implicated drugs
have the classical nail changes and arthritis associ- include allopurinol, arsenicals, aspirin, carbam-
ated with psoriasis [29]. azepine, captopril, gold, hydantoins, mercurials,
penicillin, phenothiazines, phenylbutazone, quina-
crine, and sulfonamides. Additionally homeo-
7.3.3 Pityriasis Rubra Pilaris pathic, unani, ayurvedic, herbal, and home remedies
have also been reported to cause erythroderma
Pityriasis rubra pilaris (PRP) may initially resem- [14]. Interestingly, while carbamazepine is known
ble a seborrheic dermatitis-like eruption of the to induce erythroderma, Smith et al. reported a case
scalp that then progresses into erythroderma over where the carbamazepine successfully cleared
weeks to years. A similar picture of eruption on erythrodermic psoriasis [30, 31] (Table 7.3).
the scalp, with additional involvement of butterfly Drug-induced erythroderma typically occurs
regions of the face and upper trunk can also be rapid and resolves quickly—on average 2–6 weeks
seen in early erythrodermic pemphigus foliaceus after discontinuation of the drug. Drug eruptions
[6]. The erythroderma in PRP classically appears that initially began as morbilliform, lichen planus-
as generalized salmon-colored erythema with like or urticarial may evolve into erythroderma [8].
islands of sparing (Fig. 7.2). Islands of sparing Nicolis et al. reported that erythroderma caused by
sulfonamides, penicillins, antimalarials, barbitu-
rates, arsenicals, and mercurials tended to have a
more severe clinical course. Fever appears to be
prominent in these cases, and moderate to severe
liver degeneration can occur [8]. Drug-induced
erythroderma due to dapsone or antileprosy agents
can mimic the clinical and histolopathologic fea-
tures of cutaneous T-cell lymphoma. In this situa-
tion, the erythroderma resolves with withdrawal of
offending drugs [7].
7.3.5 Malignancy
Erythroderma may be a clinical expression of both

hematological and internal malignancies, account-
ing for approximately 11% of cases. Cutaneous
T-cell lymphoma is the most common etiology,
Fig. 7.2 Patient with erythroderma secondary to PRP
with characteristic islands of sparing. Courtesy of Mount accounting for 74% of the malignancy-induced
Sinai Dermatology collection erythroderma and 7.8% of all cases of erythroderma.
Table 7.3 Drugs reported to cause erythroderma Table 7.3 (continued)

Antibacterial agents Cardiovascular agents Cisplatin [65] Heavy metals
Amoxicillin [10] Amiodarone [29] Fluorouracil [29] Arsenic [8]
Aztreonam [29] Captopril [5, 29] Interleukin 2 [66] Gold [9, 11]
Cefoxitin [32, 33] Diltiazem [50] Thalidomide [67, 68] Mercury [8]
Clofazimine [34] Epoprostenol [51]
Dapsone [35, 36] Isosorbide dinitrate
[12] Table 7.4 Malignancies associated with erythroderma
Doxycycline [37] Mexiletine [29]
Hematologic malignancies Internal malignancies
Gentamicin [38] Nifedipine [52]
Cutaneous T-cell leukemia • Prostate [8, 76]
Isoniazide [12, 14] Quinidine [9]
• Sezary Syndrome • Lung [8, 9, 76]
Minocycline [29] • Mycosis fungoides • Thyroid [8]
Neomycin [29] Diuretic agents Leukemias • Liver [8, 77]
Penicillin [3, 4, 8, 10, 12, 15, Thiazides [12] • Acute myelomonocytic • Breast [76]
39] leukemia [69] • Ovary [76]
Ribostamycin [40] • Adult T-cell leukemia [70] • Fallopian tube [78]
• Chronic lymphocytic • Rectum [76]
Rifampin [39] Antiepileptic agents
leukemia [12] • Esophagus [79]
Streptomycin [14] Bupropion [53] • Stomach [9, 10, 80]
• Chronic eosinophilic
Sulfonamides [3, 8, 11, 12, Carbamazepine [3, 4, leukemia [71] • Melanoma [65, 76,
14] 9, 15, 39] 81]
Lymphoma
Teicoplanin [41] Lamotrigine [54] • Hodgkin’s lymphoma [8, • Buschke-
Thiacetazone [14] Phenobarbital [3, 15] 12, 13, 72] Loewenstein tumor
Vancomycin [3] Phenytoin [3, 9, 12] • B-cell lymphoma [73] [82]
Antifungal agents Psychotropic agents • Anaplastic large cell
Terbinafine [42] Chlorpromazine [39] lymphoma [74]
Clonazepam [39] Miscellaneous
• Reticulum cell sarcoma
Antiparasitic agents Diazepam [39]
[11]
Chloroquine [11] Etumine [4] • Myelodysplasia [75]
Quinacrine [8, 12] Lithium [3]
Antiviral agents Miscellaneous
Didanosine [43] Allopurinol [4, 9, 12, Other malignancies include Hodgkin’s lymphoma
39] (11%), internal malignancy (8.5%), leukemia
Indinavir [44] Bromodeoxyuridine (4.2%), and non-CTCL, non-Hodgkin’s lymphoma
[55]
(2.1%). Table 7.4 lists the specific hematologic,
Zidovudine [45] Chlorpropamide [29]
and internal malignancies implicated in erythro-
Cimetidine [56]
derma. Malignancy should be considered in the
Analgesic and anti- Ephedrine [57]
inflammatory agents differential diagnosis for erythroderma, especially
Acetaminophen [15] Erythropoietin [58] when the disease is insidious, debilitating, or pro-
Aspirin [39] Fluidione [59] gressive in course, when the patient has no history
Celecoxib [46] Iodine [8] of preexisting dermatoses, or when the erythro-
Codeine [8] Isotretinoin [60] derma is refractory to treatment [5].
Diflunisal [47] Omeprazole [61]
Indomethacin [10] Pseudoephedrine [62]
Metamizole [48] Rantidine [29] 7.3.6 Cutaneous T-Cell Lymphoma
Phenylbutazone [14] Tar [14]
Piroxicam [49] Terbutaline [12] Cutaneous T-cell lymphoma (CTCL), also known
Timolol eyedrops [63]
as mycosis fungoides, is the most frequently
Chemotherapeutic
identified malignancy to cause erythroderma,
Carboplatin [64]
and Sézary syndrome is the most common pre-
(continued) sentation associated with erythroderma. Sézary
7 Erythroderma 137
syndrome is characterized by peripheral blood groups. These disorders include graft-versus-host

involvement of Sézary cells. The Sézary cell is disease (GVHD), hepatitis, irradiation, reactive
an atypical lymphocyte with the characteristic arthritis (formerly known as Reiter’s syndrome),
morphology of a cerebriform nucleus and ample sarcoidosis, acquired immunodeficiency, con-
cytoplasm with vacuoles [83]. It is controversial genital immunodeficiency syndrome, and dis-
how many Sézary cells are needed to define seminated histoplasmosis [6, 87, 88]. Japanese
Sézary syndrome. The original NCI classification patients have been reported to develop a poten-
used the criterion of greater than 5%, but current tially fatal postoperative erythroderma caused by
practice at mycosis fungoides referral centers a unique form of transfusion-related GVHD and
prefer greater than 20% or an absolute count of this can be prevented by the use of irradiated
at least 100/mm3 Sézary cells [84]. In both blood for transfusions [89]. The clinical findings
Sézary syndrome and non-Sézary mycosis fun- in erythroderma caused by reactive arthritis may
goides, erythroderma may be accompanied by mimic the appearance of erythrodermic pustular
poikiloderma or frank tumors [84]. Patients also psoriasis. Important distinguishing features of
have intense pruritus which may be so severe as reactive arthritis include recent history of gastro-
to interfere with daily activities. The diagnosis enteritis, cervicitis in women or urethritis in men,
should be considered in all cases of erythroderma mouth ulcers, or iridocyclitis [6]. The erythro-
when the patient has infiltration of the skin, derma that can occur secondary to progressive
marked or asymmetric lymphadenopathy or disseminated Histoplasma capsulatum infection
splenomegaly. In severe cases of Sézary syn- can closely resemble CTCL. The diagnosis of
drome, patients may have leonine facies and Histoplasma should be suspected when chronic
hyperkeratosis of palms and soles with painful ulcers with an indurated base occur on the skin or
fissuring [85]. Erythroderma may be the first oral mucosa or if characteristic chorioretinal
sign of CTCL, and its clinical and histological lesions occur in the eyes [6].
appearance may be identical to that of benign
erythroderma [7]. In these cases, flow cytometry
immunophenotyping of lymphocytes and T-cell 7.4 Pathogenesis
receptor gene analysis are useful in identifying
CTCL [86]. Sézary syndrome has a poorer prog- One intriguing aspect of erythroderma is the
nosis than mycosis fungoides with a median sur- fact that clinically distinct skin diseases can
vival of 2.5–5 years [85]. progress into erythroderma with a relatively
uniform clinical picture. The pathogenesis of
erythroderma is not completely understood and
7.3.7 Internal Malignancy it is still unclear whether the underlying mecha-
nisms leading to erythroderma are the same or
Internal malignancies are implicated in 1% of all different depending on the underlying disease
cases of non-CTCL-related erythroderma. [90]. The development of erythroderma is
Frequently, the malignancy is occult at the initial thought to be secondary to a complex interac-
presentation of erythroderma. The common types tion of cytokines and cellular adhesion mole-
of causative malignancies cited in the literature cules including interleukins (IL)-1, -2, -4, -5,
include carcinoma of the lung, prostate, thyroid, and -10, tumor necrosis factor (TNF), interferon
rectum, stomach, and liver [8–10, 76]. (IFN)-g, intercellular adhesion molecule-I
(ICAM-1), vascular cell adhesion molecule 1
(VCAM-1), selectin-E and -P [87, 90, 91].
7.3.8 Miscellaneous Diseases Siggurdsson et al. found that while all types of
erythroderma have a predominately CD4+ T-cell
Erythroderma is also associated with several dis- lymphocytic infiltrate in the skin, Sézary syn-
orders that do not fit into the aforementioned drome tends to have CD4+ T-cells that secrete
IL-4, consistent with the Th2 subset of T-helper

(Th) cells while benign forms of erythroderma
such as atopic dermatitis and psoriasis have a
cytokine profile characterized by IFN-g secre-
tion, consistent with the Th1 subset [91].
Siggurdsson et al. also found that atopic derma-
titis-induced erythroderma, CTCL-induced
erythroderma, and idiopathic erythroderma all
had increased levels of circulating adhesion
molecules, and the types of adhesion molecules
expressed were not significant between the dif-
ferent causes [90].
These molecular, cellular, and immunologic
changes lead to increased mitotic rate and
increased number of germ skin cells, resulting
in a dramatic increase in the epidermal turn-
Fig. 7.3 Erythrodermic Psoriasis patient: This patient
over rate. This increased turnover rate leads to has the extensive erythema and scaling characteristic of
greater loss of viable cellular material such as erythroderma. Courtesy of Mount Sinai Dermatology
nucleic acids, amino acids, protein, and folic collection
acid [5, 92, 93]. Erythroderma may increase
daily protein loss through loss of keratinocytes The size of the scale also varies with the duration
and scaling by 25–30% in psoriatic erythro- of symptoms, with larger scale in acute cases and
derma and by 10–15% in other causes of eryth- smaller scale in chronic [5]. Secondary bacterial
roderma [92]. infections are a frequent complication and can
cause crusting, impetigo, or folliculitis [6].
Nail examination in erythrodermic patients
7.5 Clinical Manifestations frequently reveals dystrophy, especially in
patients whose erythroderma is secondary to pso-
Erythroderma is defined as generalized erythema riasis. The nail plate is often thickened and luster-
and scaling of at least 90% of the patient’s skin less with horizontal depressions (Beau’s lines)
surface as seen in Fig. 7.3. The condition typically [6]. Subungual hyperkeratosis, the accumulation
begins as patches of erythema accompanied by of keratinaceous material under the nail plate,
pruritus. These patches then enlarge and coalesce, may occur leading to distal onchycholysis, sepa-
eventually resulting in involvement of most of, or ration of the nail plate from the nail bed. The
in some cases all of, the skin surface area. The entire nail plate may be shed in severe cases [6]
palms, soles, and mucous membranes are gener- (Fig. 7.4). Additionally, the patient’s hair may
ally spared [8]; however, erythroderma that is also be affected. Alopecia occurs in 25% of
secondary to cutaneous T-cell lymphoma or pityr- patients and more often develops in patients with
iasis rubra pilaris may involve the palms and soles severe forms of exfoliation [8].
[29]. The character of erythema varies with the Most patients complain of pruritus, which
duration of the disorder with sudden-onset lesions may be mild to severe. Some patients also experi-
typically bright red and more chronic lesions ence pain or a burning sensation of the skin [6].
generally deeper, dusky red [6]. In darker-skinned Constitutional symptoms such as fever, chills,
patients, the erythema is darker from the onset. and malaise are common. Both hyperthermia and
The degree of scaling can vary greatly between hypothermia may be observed. Heat loss is a
cases from virtually none to extensive. The scaling major concern secondary to the defective skin
usually begins within several days of the onset of barrier. There is loss of normal vasoconstrictive
erythema, classically beginning in the flexures. function of the dermis, decreased sensitivity of
7 Erythroderma 139
deficiency, and a chronic inflammatory state [31].

More severe anemia is unusual [12]. Leukocytosis
of greater than 20,000 leukocytes/mm3 is seen in
both benign and malignant forms of erythroderma
[8]. Eosinophilia and increased IgE are frequently
observed findings in erythroderma secondary to
atopic dermatitis and drug reactions but are not
diagnostic for these conditions [4, 8, 9, 14].
Griffiths et al. observed transient CD4+ T-cell
lymphocytopenia in HIV negative patients with
acute erythroderma as a consequence of T-cell
Fig. 7.4 Erythrodermic psoriasis patient showing char- sequestration in the skin [5, 94].
acteristic nail involvement. The rapid keratinocyte turn- For the diagnosis of Sézary syndrome, Sézary
over rate has lead to accumulation of keratinaceous cell count analysis can be useful. In current prac-
material on the nail bed resulting subungual hyperkerato-
tice, greater than 20% or absolute count of at
sis. Courtesy of Mount Sinai Dermatology collection
least 100/mm3 circulating Sézary cells is diag-
nostic for Sézary syndrome [84]. Less than 10%
the shivering reflex and increased heat loss from circulating Sézary cells is nonspecific and is seen
evaporation of weeping fluids from the skin. in a variety of benign dermatoses including con-
These processes can lead to increased basal met- tact dermatitis, atopic dermatitis, psoriasis, lichen
abolic rate and a catabolic state resulting in planus, discoid lupus, and parapsoriasis [83].
significant weight loss [7]. Patients may develop Differentiating Sézary syndrome from erythro-
either regional or generalized lymphadenopathy. dermic actinic reticuloid can be difficult since the
Axillary and inguinal lymphodenopathy is more two diseases can have similar clinical presenta-
common than cervical lymphodenopathy [8]. tions and high levels of circulating Sézary cells in
Generalized lymphadenopathy is more common the peripheral blood [95, 96]. However, immuno-
in patients whose erythroderma is secondary to phenotyping and nuclear contour index (NCI) of
malignancy. Mild hepatomegaly may occur in up blood lymphocytes can help differentiate the two
to 20% of cases regardless of etiology; however, since actinic reticuloid has increased CD8+ T
splenomegaly is usually only seen in patients cells and decreased NCI compared to Sézary syn-
with underlying malignancy, sarcoidosis, histo- drome [29, 95]. Additionally, actinic reticuloid
plasmosis, or severe hypersensitivity reactions. patients are photosensitive. Looking for clonal
Other nonspecific clinical findings include T-cell populations in peripheral blood smears
peripheral edema, gynecomastia, and high output through T-cell receptor gene analysis can help to
cardiac failure, which results from peripheral distinguish CTCL from benign erythroderma [96,
vasodilation [6]. 97]. This technique can also be applied to skin
biopsies [98].
7.6 Laboratory Findings

7.7 Histopathology
The laboratory findings are often not helpful in
uncovering the underlying cause of erythroderma. Skin biopsy is an important diagnostic tool for
Common abnormalities include mild anemia, identifying the etiology of the erythroderma, but
leukocytosis, elevated sedimentation rate, hyper- interpretations of these specimens may be difficult.
uricemia, hyperglobulinemia, hypoalbuminemia, This difficulty is due to the fact that the histopatho-
and eosinophilia [4, 5, 8, 9, 12–14]. Mild anemia, logical expression of the underlying disorder tends
with hematocrit values between 35 and 38% [12], to be more subtle in the setting of erythroderma
is thought to be due to folic deficiency, iron than in the conventional disease form [99]. Multiple
Fig. 7.5 Epidermis shows

minimal acathosis, slight
intercellular edema
(spongiosis), and foci of
parakeratosis characteristic
of erythroderma secondary
to dermatitis. Courtesy of
Mount Sinai Dermatology
collection
Fig. 7.6 Histopathology

consistent with
Erythrodermic psoriasis.
The typical features of
erythrodermic psoriasis
includes suprapapillary
thinning, exocytosis of
neutrophils, subcorneal
pustules, and edema of
papillary dermis [90].
Courtesy of Mount Sinai
Dermatology collection
skin biopsies submitted simultaneously can It is especially important to differentiate benign

increase the accuracy of histopathological diagno- inflammatory erythroderma from Sézary syndrome
sis, as the histopathological manifestations of the given the aggressive course of this lymphoma.
underlying disease are often heterogeneously dis- Ram-Wolff et al. found that this distinction could
tributed in the affected skin [99]. Studies compar- be made with certainty in 57% of cases [100].
ing “blinded” microscopic diagnosis with final Distinguishing histopathological features of Sézary
diagnosis found a 31–66% correlation [99–101]. syndrome include Pautrier microabcesses, atypical
Walsh et al. found that the correct pathological lymphocytes (Fig. 7.7), basilar lymphocytes, and
diagnosis is reached more often in patients with dense dermal infiltrate [100]. The basal lympho-
dermatitis (Fig. 7.5), CTCL, and psoriasis (Fig. 7.6) cytes seen in CTCL can be difficult to distinguish
than in patients with drug eruptions or PRP [99]. from the interface (dermal–epidermal) inflammation
7 Erythroderma 141
Fig. 7.7 Epidermal and

dermal infiltrate of atypical
T cells characteristic of
CTCL. Courtesy of Mount
Sinai Dermatology
collection
seen in drug eruptions [99]. Identification of numer- tored if used to avoid nephrotoxicity in an
ous dilated blood vessels favors a diagnosis of erythrodermic patient [103]. Sedating oral anti-
benign inflammatory erythroderma [100]. histamines can enhance this effect and relieve
anxiety [5]. Patients require a warm and
humidified environment to increase comfort,
7.8 Treatment prevent hypothermia, and increase moisture to
the skin [29]. Diuretics may be needed to treat
All cases of erythroderma are considered a der- edema, and systemic antibiotics may be required
matological emergency, and hospitalization for secondary bacterial infections.
should be considered if fluid and electrolyte Patients who are refractory to topical therapy
imbalance or cardiovascular or respiratory should receive systemic therapy directed at the
comprise occur. Regardless of the underlying underlying etiology. First-line treatment for
etiology, the initial therapy for an erythrodermic erythrodermic psoriasis includes cyclosporine,
patient should focus on fluid, electrolyte, and infliximab, acitretin, and methotrexate with
nutritional management as well as gentle skin cyclosporine and infliximab being more rapidly
care measures. If a drug reaction has not been acting agents [104]. While systemic corticoster-
ruled out, all nonessential medications should oids should be avoided in patients with suspected
be discontinued if possible. Oatmeal baths and underlying psoriasis because of the potential to
wet dressings to weeping or crusted sites fol- induce a rebound flare, they are helpful in treat-
lowed by bland emollients and low-potency ing drug-induced and atopic dermatitis-related
topical corticosteroids can help to reduce erythroderma. Pityriasis rubra pilaris-induced
inflammation and pruritus [29]. High potency disease responds well to retinoids and methotrex-
corticosteroids should be avoided due to ate [5]. The best treatment regimen for Sézary
increased systemic absorption from the exten- syndrome depends on a variety of patient factors
sive surface area involvement and increased per- including burden of disease, impact on quality of
meability of erythrodermic skin [102]. Topical life, and rate of disease progression. Systemic
tacrolimus has also been shown to be systemi- therapies such as extracorporeal photopheresis,
cally absorbed and blood levels should be moni- interferon-a, bexarotene, low-dose methotrexate,
and denileukin diftitox can be used alone, or

combined with skin-directed therapies such as
References
phototherapy, topical nitrogen mustard, and total 1. Bruno TF, Grewal P. Erythroderma: a dermatologic
skin electron beam radiation [105]. emergency. CJEM. 2009;11:244–6.
When the etiology of erythroderma remains 2. Hasan T, Jansen CT. Erythroderma: a follow up of
unknown, patients can be treated with empiric fifty cases. J Am Acad Dermatol. 1983;8:836–40.
3. Akhyani M, Ghodsi ZS, Toosi S, Dabbaghian H.
therapy which includes systemic corticosteroids, Erythroderma: a clinical study of 97 cases. BMC
methotrexate, cyclosporine, mycophenolate Dermatol. 2005;5:5.
mofetil, and actretin. Until CTCL has been ruled 4. Botella-Estrada R, Sanmartin O, Oliver V, Febrer I,
out by up-to-date laboratory testing, immuno- Aliaga A. Erythroderma: a clinicopathical study of 56
cases. Arch Dermatol. 1994;130:1503–7.
suppressive agents should be avoided [29]. 5. Sehgal V, Srivastava G, Sardana K. Erthroderma/
exfoliative dermatitis: a synopsis. Int J Dermatol.
2004;43:39–47.
7.9 Complications 6. Vonderheid E. Chronic generalized erythroderm.
In: Lebwohl M, editor. Difficult diagnoses in der-
matology. London: Churchill Livingstone; 1988.
Patients with erythroderma can suffer from a p. 89–100.
variety of serious complications including sec- 7. Karakayli G, Backham G, Orengo I, Rosen T. Exfoliative
ondary infection, dehydration and electrolyte dermatitis. Am Fam Physician. 1999;59:625–30.
8. Nicolis GD, Helwig EB. Exoliative dermatitis. A clin-
abnormalities, edema and high output cardiac icopathologic study of 135 cases. Arch Dermatol.
failure. Patients with erythroderma have increased 1973;108:788–97.
skin colonization of Staphylococcus aureus when 9. Sigurdsson V, Toonstra J, Hezemans-Boer M, van
compared to healthy controls [106]. This coloni- Vloten W. Erythroderma: a clinical and follow-up
study of 102 patients with special emphasis on sur-
zation may explain the high incidence of staphy- vival. J Am Acad Dermatol. 1996;35:53–7.
lococcal septicemia in patients with erythrodermic 10. Yuan X, Guo Y, Dang Y, Qiao L, Liu W. Erythroderma:
psoriasis and CTCL [107, 108]. The rapid turn- a clinical-etiological study of 82 cases. Eur J Dermatol.
over of the epidermis leads to increased daily 2010;20:373–7.
11. Abrahams I, McCarthy JT, Sanders SL. 101 cases of
protein loss of 25–30% in psoriatic erythroderma exfoliative dermatitis. Arch Dermatol. 1963;87:96–101.
and 10–15% in other causes of erythroderma 12. King Jr LE, Dufresne Jr RG, Lovett GL, Rosin MA.
which can lead to a net negative nitrogen balance Erythroderma: review of 82 cases. South Med J.
as seen by muscle wasting, hypoalbuminemia, 1986;79:1210–5.
13. Pal S, Haroon TS. Erythroderma: a clinico-etiologic
and edema [92]. Increased cardiac output has study of 90 cases. Int J Dermatol. 1998;37:104–7.
been demonstrated in patients with erythroderma 14. Sehgal VN, Srivastava G. Exfoliative dermatitis. A
secondary to dilation of cutaneous blood vessels prospective study of 80 patients. Dermatologica.
in the diseased skin which can lead to heart fail- 1986;173:278–84.
15. Rym BM, Mourad M, Bechir Z, et al. Erythroderma in
ure especially in patients with underlying cardiac adults: a report of 80 cases. Int J Dermatol.
disease or the elderly [109]. 2005;44:731–5.
16. Eugster R, Kissling S, Brand CU. Clinical aspects and
etiology of erythroderma: an analysis of 64 cases.
Schweiz Rundsch Med Prax. 2001;90:1449–54.
7.10 Prognosis 17. Alonso-Llamazares J, Dietrich SM, Gibson LE.
Bullous pemphigoid presenting as exfoliative erythro-
The prognosis of erythroderma depends on the derma. J Am Acad Dermatol. 1998;39:827–30.
underlying disease. Drug-induced erythroderma 18. Glassman BD, Muglia JJ. Widespread erythroderma
and desquamation in a neonate. Congenital cutaneous
often resolves quickly once the offending agent is candidiasis. Arch Dermatol. 1993;129:902.
removed, while CTCL often has a chronic and 19. Muller CS, Lorenz MT, Tigen W, Rass K. Primary
refractory course [29]. While older series report manifestation of erythema gyratum repens as a tran-
high mortality from erythroderma ranging from 5 sient erythroderma in a patient with bronchial carci-
noma. Int J Dermatol. 2010;49:676–8.
to 64% [4, 8, 11, 12], this mortality has been likely 20. Marsch WC, Stuttgen G. Generalized Hailey-Hailey
reduced due to advances in diagnosis and therapy. disease. Br J Dermatol. 1978;9:553–60.
7 Erythroderma 143
21. Arslanpence I, Dede FS, Gokcu M, Gelisen O. 41. Paul C, Janier M, Carlet J, et al. Erythroderma induced by
Impetigo herpetiformis unresponsive to therapy in a teicoplanin. Ann Dermatol Venereol. 1992;119:667–9.
pregnant adolescent. J Pediatr Adolesc Gynecol. 42. Gupta AK, Lynde CW, Lauzon GJ, et al. Cutaneous
2003;16:129–32. adverse effects associated with terbinafine therapy: 10
22. Tebbe B, Stavropoulos PG, Krasagakis K, Orfanos case reports and review of the literature. Br J Dermatol.
CE. Cutaneous mastocytosis in adults. Evaluation of 1998;138:529–32.
14 patients with respect to systemic disease manifes- 43. Just M, Carrascosa JM, Ribera M, Bielsa I, Ferrandiz C.
tations. Dermatology. 1998;197:101–8. Dideoxyinosine-associated Ofuji papuloerythroderma in
23. Zachariae H, Sogaard H. Progressive generalized per- an HIV-infected patient. Dermatology. 1997;195:410–1.
forating folliculitis. Dermatological. 1984;168:131–7. 44. Rietsema WJ. Fever, erythroderma, abdominal pain,
24. Kodym E, Kalinska R, Ehringfeld C, Sterbik-Lamina and renal failure following initiation of indinavir ther-
A, Kodym R, Hohenberg G. Frequency of radiation apy. Clin Infect Dis. 1997;25:1268–9.
recall dermatitis in adult cancer patients. Onkologie. 45. Duque S, de la Puente J, Rodriguez F, Fernandez
2005;28:18–21. Pellon L, Maquiera E, Jerez J. Ziovudine-related
25. Mutasim DF. Severe subacute cutaneous lupus ery- erythroderma and successful desensitization: a case
thematosus presenting with generalized erythroderma report. J Allergy Clin Immunol. 1996;98:234–5.
and bullae. J Am Acad Dermatol. 2003;48:947–9. 46. Friedman B, Orlet HK, Still JM, Law E. Toxic epider-
26. Boyd AS, Menter A. Erythrodermic psoriasis. mal necrolysis due to administration of celecoxib
Precipitating factors, course and prognosis in 50 (Celebrex). South Med J. 2002;95:1213–4.
patients. J Am Acad Dermatol. 1989;21:985–91. 47. Chan LK, Winearls CG, Oliver DO, Dunnill MS.
27. Goeckerman WH, O’Leary PA. Erythroderma psoriati- Acute interstitial nephritis and erythroderma associ-
cum. A review of 22 cases. JAMA. 1932;99:2102–5. ated with diflunisal. Br Med J. 1980;280:84–5.
28. Gaylor ML, Duvic M. Generalized pustular psoriasis 48. Bernedo N, Audicana MT, Uriel O, et al. Metamizol
following withdrawal of efalizsumab. J Drugs as a cause of postoperative erythroderma. Contact
Dermatol. 2004;3:77–9. Dermatitis. 2004;50:317–8.
29. Rothe MJ, Bernstein ML, Grant-Kels J. Life- 49. Stern RS, Bigby M. An expanded profile of cutaneous
threatening erythroderma: diagnosing and treating the reactions to nonsteroidal anti-inflammatory drugs. Reports
“red man”. Clin Dermatol. 2005;23:206–17. to a specialty-bases system for spontaneous reporting of
30. Smith KJ, Decker C, Yeager J, Skelton HG, Baskin S. adverse reactions to drugs. JAMA. 1984;252:1433–7.
Therapeutic efficacy of carbamazepine in a HIV-1 50. Wittal RA, Fischer GO, Georgouras KE, Baird PJ.
positive patient with psoriatic erythroderma. J Am Skin reactions to diltiazem. Australas J Dermatol.
Acad Dermatol. 1997;37:851–4. 1992;33:11–8.
31. Shuster S, Marks J. Dermatopathic anaemia. Br J 51. Ahearn GS, Selim MA, Tapson VF. Severe erythro-
Dermatol. 1967;79:393–7. derma as a complication of continuous epoprostenol
32. Kannangara DW, Smith B, Cohen K. Exfoliative der- therapy. Chest. 2002;122:379–80.
matitis during cefoxitin therapy. Arch Intern Med. 52. Reynolds NJ, Jones SK, Crossley J, Harman RR.
1982;142:1031–2. Exfoliative dermatitis due to nifedipine. Br J Dermatol.
33. Tietze KJ, Gaska JA. Cefoxitin-associated exfoliative 1989;121:401–4.
dermatitis. Clin Pharm. 1983;2:582–4. 53. Cox NH, Gordon PM, Dodd H. Generalized pustular
34. Pavithran K. Exfoliative dermatitis after clofazimine. and erythrodermic psoriasis associated with bupro-
Int J Lepr Other Mycobact Dis. 1985;53:645–6. pion treatment. Br J Dermatol. 2002;146:1061–3.
35. Patki AH, Menta JM. Dapsone-induced erythroderma 54. Hurley SC. Lamotrigine update and its use in mood
with Beau’s line. Lepr Rev. 1989;60:274–7. disorders. Ann Pharmacother. 2002;36:860–72.
36. Rao PN, Lakshmi TS. Increased in the incidence of 55. Fine JD, Breathnach SM. Distinctive eruption charac-
dapsone hypersensitivity syndrome—an appraisal. terized by linear supravenous papules and erythro-
Lepr Rev. 2001;72:57–62. derma following broxuridine (bromodeoxyuridine)
37. Batinac T, Zamolo G, Jonjic N, et al. therapy and radiotherapy. Arch Dermatol. 1986;122:
Angioimmunoblastic lymphodenopathy with dyspro- 199–200.
teinemia following doxycycline administration. 56. Yantis PL, Bridges ME, Pittman FE. Cimetidine-
Tumori. 2003;89:91–5. induced exfoliative dermatitis. Dig Dis Sci.
38. Guin JD, Phillips D. Erythroderma from systemic 1980;25:73–4.
contact dermatitis: a complication of systemic gen- 57. Catlin DH, Sekera M, Adelman DC. Erythroderma
tamicin in a patient with contact allergy to neomycin. associated with ingestion of an herbal product. West I
Cutis. 1989;43:564–7. Med. 1993;159:491–3.
39. Khaled A, Sellami A, Fazaa B, Kharfi M, Zeglaoui F, 58. Cuxart M, Just M, Sans R. Generalized exfoliative
Kamoun MR. Acquired erythroderma in adults: a dermatitis caused by erythropoietin. Med Clin (Barc).
clinical and prognostic study. J Eur Acad Dermatol 2000;115:158.
Venereol. 2010;24:781–8. 59. Sparsa A, Bedane C, Benazahary H, et al. Drug hyper-
40. Puig LL, Abadia M, Alomar A. Erythroderma due to sensitive syndrome caused by fluidione. Ann Dermatol
ribostamycin. Contact Dermatitis. 1989;21:79–82. Venereol. 2001;128:1014–8.
60. Wantzin GL, Thomsen K. A new cutaneous side effect low up of 38 patients. J Am Acad Dermatol. 1988;
of isotretinoin. J Am Acad Dermatol. 1985;13:665. 18:1307–12.
61. Rebuck JA, Rybak MJ, Ramos DP, Weingarten CM. 77. Nishijima S. Papuloerythroderma associated with hepa-
Omeprazole-induced exfoliative dermatitis. tocellular carcinoma. Br J Dermatol. 1998;139:1115–6.
Pharmotherapy. 1998;18:877–9. 78. Axelrod JH, Herbold DR, Freel JH, Palmer SM.
62. Gonzalo-Garijo MA, Perez-Calderon R, de Argila D, Exfoliative dermatitis: a presenting sign of fallopian
Rodriguez-Nevado I. Erythroderma to pseudoephed- tube carcinoma. Obstet Gynecol. 1988;71:1045–7.
rine in a patient with contact allergy to phenylephrine. 79. Deffer TA, Overton-Keary PP, Goette DK.
Allergol Immunopathol. 2002;30:239–42. Erythroderma secondary to esophageal carcinoma. J
63. Shelley WB, Shelley ED. Chronic erythroderma Am Acad Dermatol. 1985;13:311–3.
induce by ®(beta)-blocker (timolol maleate) eye- 80. Harper TG, Latuska RF, Sperling HV. An unusual
drops. J Am Acad Dermatol. 1997;37:799–800. association between erythroderma and an occult gas-
64. Polyzos A, Tsavaris N, Kosmas C, et al. tric carcinoma. Am J Gastroenterol. 1984;79:921–3.
Hypersensitivity reactions to carboplatin administra- 81. Thami GP, Sharma NL, Sharma A, Sharma RC.
tion are common but not always severe: a 10-year Exfoliative dermatitis and malignant melanoma: coin-
experience. Oncology. 2001;61:129–33. cidence or association. Int J Dermatol. 1996;35:682.
65. Lee TC, Hook CC, Long HJ. Severe exfoliative der- 82. Antony FC, Ardern-Jones M, Evans AV, Rosenbaum
matitis associated with hand ischemia during cisplatin T, Russell-Jones R. Giant condyloma of Buschke-
therapy. Mayo Clin Proc. 1994;69:80–2. Loewenstein in association with erythroderma. Clin
66. Asnis LA, Gaspari AA. Cutaneous reactions to recom- Exp Dermatol. 2003;28:46–9.
binant cytokine therapy. J Am Acad Dermatol. 83. Duncan SC, Winkelmann RK. Circulating Sézary
1995;33:393–410. cells in hospitalized dermatology patients. Br J
67. Bielsa I, Teixido J, Ribera M, Ferrandiz C. Dermatol. 1978;99:171–8.
Erythroderma due to thalidomide: report of two cases. 84. Zinzani PL, Ferreri AJ, Cerroni L. Mycosis fungoides.
Dermatology. 1994;189:179–81. Crit Rev Oncol Hematol. 2008;65:172–82.
68. Hall VC, El-Azhary RA, Bouwhuls S, Rajkumar SV. 85. Wieselthier JS, Kohn HK. Sézary syndrome: diagno-
Dermatologicside effects of thalidomide in patients sis, prognosis, and critical review of treatment options.
with multiple myeloma. J Am Acad Dermatol. J Am Acad Dermatol. 1990;22:381–401.
2003;48:548–52. 86. Vonderheld EC, Bernengo MG, Burg G, et al. Update
69. De Coninck A, De Hou MF, Peters O, Van Camp B, on erythrodermic cutaneous T-cell lymphoma: Report
De Roseeuw DI. Aleukemic leukemia cutis. An of the international society for cutaneous lymphomas.
ususual presentation of acute myelomonocytic leuke- J Am Acad Dermatol. 2002;46:95–106.
mia. Dermatologica. 1986;172:272–5. 87. Wilson DC, Jester JD, King LE. Erythroderma and
70. Hashizume H, Nakayama F, Oku T, Takigawa M. exfoliative dermatitis. Clin Dermatol. 1993;11:67–72.
Adult T-cell leukemia with regression of erythroderma 88. Satoh H, Yamashita YT, Ohtsuka M, Sekizawa K. Post-
and simultaneous emergence of leukemia. J Am Acad irradiation erythroderma. Clin Oncol. 2000;12:336.
Dermatol. 1992;27:846–9. 89. Ito K, Fujita M, Norioka M, et al. Postoperative eryth-
71. Granjo E, Lima M, Lopes JM, et al. Chronic eosino- roderma with change of HLA phenotypes from
philic leukaemia presenting with Erythroderma, mild heterozygotes to homozygotes: a report of two cases.
eosinophilia and hyper-IgE: clinical, immunological Eur J Haematol. 1991;46:217–22.
and cytogenetic features and therapeutic approach. A 90. Sigurdsson V, de Vries IJ, Toonstra J, et al. Expression
case report. Acta Haematol. 2002;107:108–12. of VCAM-1, ICAM-1, E-selectin, and P-selectin on
72. Artia K, Akiyama M, Sakai T, Shimizu H. Severely endothelium in situ in patients with erythroderma,
hyperkeratotic erythroderma associated with Hodgkin’s mycosis fungoides and atopic dermatitis. J Cutan
disease: does a high serum level of granulocyte-colony Pathol. 2000;27:436–40.
stimulating factor contribute to formation of skin 91. Sigurdsson V, Toonstra J, Bihari IC, Bruijnzeel-
lesions? J Am Acad Dermatol. 2003;49:772–3. Koomen CA, van Vloten WA, Thepen T. Interleukin 4
73. Leong AS, Cowled PA, Zalewski PD, Burry JN, and interferon-gamma expression of the dermal
Meredith DJ, Forbes IJ. Erythroderma, an unusual infiltrate in patients with erythroderma and mycosis
manifestation of B cell lymphoma. Br J Dermatol. fungoides. A immuno-histochemical study. J Cutan
1978;99(1):99–106. Pathol. 2000;27:429–35.
74. Denton K, Wilson CL, Venning VA. Primary cutane- 92. Kanthraj GR, Srinivas CR, Devi PU, et al. Quantitative
ous anaplastic large-cell lymphoma with a prolonged estimation and recommendations for supplementa-
erythrodermic prodrome. Br J Dermatol. 1992;126: tion of protein lost through scaling in exfoliative der-
297–300. matitis. Int J Dermatol. 1999;38:91–5.
75. Chu P, Aitchison R, Jones PA. Myelodysplasia present- 93. Hild DH. Folate losses from the skin in exfoliative
ing as erythroderma. Postgrad Med J. 1987;63:481–2. dermatitis. Arch Intern Med. 1969;123:51–7.
76. Thestrup-Pedersen K, Halkier-Sorensen L, Sogaard 94. Griffiths TW, Stevens SR, Cooper KD. Acute erythro-
H, Zachariae H. The red man syndrome. Exfoliative derma as an exclusion criterion for idiopathic CD4+ T
dermatitis of unknown etiology: a description and fol- lymphocytopenia. Arch Dermatol. 1994;130:1530–3.
7 Erythroderma 145
95. Preesman AH, Schrooyen SJ, Toonstra J, et al. The 102. Aatlo-Korte K, Turpeinen M. Quantifying systemic
diagnostic value of morphometry on blood absorption of topical hydrocortisone in erythro-
lymphocytes in erythrodermic actinic reticuloid. derma. Br J Dermatol. 1995;133:403–8.
Arch Dermatol. 1995;131:1298–303. 103. Teshima D, Ikesue H, Itoh Y, Urabe K, Furue M,
96. Bakels V, van Oostveen JW, Preesman AH, Meijer Oishi R. Increased topical tacrolimus absorption in
CJ, Willemze R. Differentiation between actinic generalized leukemic erythroderma. Ann
reticuloid and cutaneous T cell lymphoma by T cell Pharmacother. 2003;37:1444–7.
receptor gamma gene rearrangement analysis and 104. Rosenbach M, Hsu S, Korman NJ, et al. Treatment
immunophenotyping. J Clin Pathol. 1998;51:154–8. of erythrodermic psoriasis: from the medical board
97. Fraser-Andrews EA, Russell-Jones R, Woolford AJ, of the National Psoriasis Foundation. J Am Acad
Wolstencroft RA, Dean AJ, Whitttaker SJ. Diagnostic Dermatol. 2010;62:655–62.
and prognostic importance of T-cell receptor gene 105. Olsen EA, Rook AH, Zic J, et al. Sézary syndrome:
analysis in patients with Sézary syndrome. Cancer. immunopathogenesis, literature review of therapeu-
2001;92:1745–52. tic option and recommendations for therapy by the
98. Cherny S, Mraz S, Su L, Harvell J, Kohler S. United States Cutaneous Lymphoma Consortium
Heteroduplex analysis of T-cell receptor gamma (USCLC). J Am Acad Dermatol. 2011;64:352–404.
gene rearrangement as an adjuvant diagnostic tool in 106. Tomi NS, Kranke B, Aberer E. Staphylococcal tox-
skin biopsies for erythroderma. J Cutan Pathol. ins in patients with psoriasis, atopic dermatitis and
2001;28:351–5. erythroderma and in healthy control subjects. J Am
99. Walsh NM, Prokopetz R, Tron VA, et al. Histopathology Acad Dermatol. 2005;53:67–72.
in erythroderma: review of a series of cases by multiple 107. Green MS, Prystowsky JH, Cohen SR, Cohen JI,
observers. J Cutan Pathol. 1994;21:419–23. Lebwohl MG. Infectious complications of erythro-
100. Ram-Wolff C, Martin-Garcia N, Bensussan A, Bagot dermic psoriasis. J Am Acad Dermatol. 1996;34:
M, Ortonne N. Histopathologic diagnosis of lym- 911–4.
phomatous versus inflammatory erythroderma: a 108. Posner LE, Fossieck Jr BE, Eddy JL, Bunn Jr PA.
morphologic and phenotypic study on 47 skin biop- Septicemic complications of cutaneous T-cell lym-
sies. Am J Dermatopathol. 2010;32:755–63. phomas. Am J Med. 1981;71:210–6.
101. Zip C, Murray S, Walsh NM. The specificity of his- 109. Voigt GC, Kronthal HL, Crounse RG. Cardiac out-
topathology in erythroderma. J Cutan Pathol. 1993; put in erythrodermic skin disease. Am Heart J.
2:393–8. 1966;72:615–20.
Vesiculobullous Dermatoses
8
Michael W. Cashman, Daven Doshi,
and Karthik Krishnamurthy
insignificant trauma or traction to the skin. The

8.1 Introduction term “acantholysis” refers to intraepidermal
pathology, whereas “blister” is traditionally used
The vesicobullous diseases in dermatology are to delineate subepidermal disease. Whether
numerous and quite distinct from one another; acquired or inherited, vesicobullous diseases are
the unifying feature, intuitively, is the histologic a major source of patient morbidity and mortality
feature of separation either intraepidermally or in dermatology, either due to inherent disease
subepidermally. Vesicobullous diseases can be processes or from therapeutic complications.
mediated through infections, allergic causes, Several clinical characteristics including age
physical insults, or may occur as a result of auto- of onset, family history, exposure history, and
immune and hereditary disorders. The majority known systemic or other dermatologic disease
of vesicobullous diseases are acquired, wherein can provide clues as to the etiology of a blistering
autoantibodies target specific cellular adhesion disease [1]. Advanced clinical recognition of
molecules resulting in separation of keratino- vesicobullous diseases takes lesion morphology,
cytes. In contrast, inherited vesicobullous dis- distribution, evolution, and presence of Nikolsky
eases due to genetic loss of either adhesion sign into consideration; however, diagnosis
molecules or basic structural proteins, lead to strictly relies on histological and immunologic
loss of cell–cell adhesion following minor or criteria through application of specialized immu-
nohistologic techniques [2, 3]. Despite this clini-
cal armamentarium, blistering diseases are often
misdiagnosed and delay in diagnosis or institu-
tion of appropriate treatment can sometimes
result in death [4].
M.W. Cashman, M.D.
Einstein Division of Dermatology, Montefiore Medical
Center, Bronx, NY, USA 8.2 Intraepidermal Blistering
e-mail: mcashman@gwmail.gwu.edu Diseases
D. Doshi, M.D.
Department of Dermatology, Albert Einstein College Intraepidermal blistering diseases include the
of Medicine, Bronx, NY, USA
acquired pemphigus family and the inherited
K. Krishnamurthy, D.O. (*) epidermolysis bullosa simplex. Pemphigus is a
Dermatology, Jacobi Medical Center, Cosmetic
group of rare, life-threatening autoimmune
Dermatology Clinic, Montefiore Medical Center,
Albert Einstien College of Medicine, Bronx, NY, USA blistering diseases characterized by widespread
e-mail: kkderm@gmail.com bullae and erosions of the skin and mucous mem-

148 M.W. Cashman et al.
branes. The pemphigus family can be divided is 2:1, whereas the majority of all cases (73%) are
into three major forms: pemphigus vulgaris, pem- due to vulgaris in France where the incidence is
phigus foliaceus, and paraneoplastic pemphigus. 1.7 cases per million per year [9].
Other pemphigus subtypes exist such as pemphi- The exact etiology of PV remains unknown;
gus vegetans and Fogo selvagem, all of which however, the interaction between environmental
will be reviewed in this chapter. Dysfunctional factors and genetic background is thought to con-
desmosomal proteins leading to acantholysis tribute to its development. Predisposition to PV is
within the epidermis with subsequent flaccid linked to genetic factors. For example, certain
blister formation characterize the pemphigus major histocompatibility complex (MHC) class
family of disorders. Epidermolysis bullosa is a II molecules, specifically the alleles of human
spectrum of inherited and acquired blistering dis- leukocyte antigen DR4 and DRw6, are more
eases; heritable keratin defects found in common in patients with PV [10–15]. Despite
Epidermalysis Bullosa Simplex lead to acanthol- this, predisposing genetic factors alone may not
ysis and will be discussed in this section, whereas be sufficient to trigger the autoimmune response
the remainder lead to subepidermal disease and seen [16]. Clinical evidence supports the role of
will be discussed later in this chapter. dietary factors in the exacerbation of pemphigus
[17, 18]. Suspected culprits capable of inducing
PV as reported in the literature include thiol com-
8.3 Pemphigus pounds (garlic, leek, chives) and phycocyanins
(Spirulina platensis alga) [18, 19]. Another cause
Before the advent of corticosteroids, pemphigus of pemphigus reported in the literature is medica-
was associated with a high mortality rate. Today, tions including thiol drugs, phenol drugs, and
pemphigus remains a possible dermatologic emer- nonthiol nonphenol drugs. The thiol drugs known
gency; however, with new therapeutics, mortality to cause pemphigus include captopril, pen-
rates have decreased, yet it still conveys significant icillamine, and gold. The phenol group includes
morbidity. The most classic form of pemphigus is culprits such as aspirin, rifampin, levodopa, and
pemphigus vulgaris (PV). PV is also known as heroin, while nonsteroidal anti-inflammatory
“deep” pemphigus, as blisters develop in the drugs (NSAIDs), angiotensin converting enzyme
deeper portion of the epidermis just above the (ACE) inhibitors, calcium channel blockers, and
basal cell layer. Of the entire pemphigus family dipyrone are examples of nonthiol nonphenol
PV is the most potentially life threatening [5]. medications known to induce pemphigus [20].
The prevalence of pemphigus vulgaris in men In PV, blister formation is associated with IgG
and women is nearly equal and the mean age of antibodies against desmoglein 3 and 1, key adhe-
onset is 50–60 years, although the range is broad sion proteins found in both the skin and mucous
and disease arising in the elderly and children has membranes [20]. Patients with active disease have
been described [6]. Available data is limited in circulating and tissue-bound autoantibodies of
regards to the incidence of PV, although one both the immunoglobulin G1 (IgG1) and immuno-
review cited an annual incidence of 0.42 per globulin G4 (IgG4) subclasses [21, 22].
100,000 [7]. In the general population, the inci- Autoantibody binding directly interferes with cell–
dence ranges from 0.76 to 5 new cases per mil- cell adhesion, leading to suprabasilar acantholysis.
lion per year. However, the incidence is much The target antigen affected—desmoglein 1 or 3
higher in people of Mediterranean, South Asian, (Dsg1 or Dsg3)—dictates the clinical phenotype
and Jewish ancestry, reported at 16–32 cases per seen in pemphigus. For example, individuals with
million per year [8]. PV is more common than the mucosal-dominant type of PV have only anti-
other forms of pemphigus such as pemphigus Dsg3 IgG autoantibodies, whereas patients with
foliaceus. In Japan with an incidence of 3.5 cases the mucocutaneous type of PV have both anti-
per million per year, the ratio of vulgaris to foliaceus Dsg1 and anti-Dsg3 IgG autoantibodies [23].
8 Vesiculobullous Dermatoses 149
Fig. 8.1 Mucosal lesions in pemphigus vulgaris seen on

Fig. 8.2 Pemphigus vulgaris. Coalescing epidermal ero-
the mucosal lips, tongue, and buccal mucosa
sions on the trunk. Crust reminiscent of the flaccid blister
All patients with PV have mucosal membrane substrate. An intercellular “fishnet” pattern of
erosions, and in 50–70% of patients, the disease IgG antibody and C3 deposition is virtually diag-
begins with the development of oral lesions [24]. nostic (Fig. 8.3). An indirect immunofluorescence
In acute PV, patients often present to the ER or (IIF) is not necessary for diagnosis; however, a
their primary care physician complaining of baseline is useful before therapy is initiated [25].
severe dysphagia. On physical exam, there are Antibody titer usually parallels disease activity in
usually ill-defined erosions of the lips, tongue, PV and can be used to track therapeutic response
buccal mucosa, gingiva, or hard/soft palate [28]. In the past 10 years, serum enzyme-linked
(Fig. 8.1) [25]. Those unfamiliar with PV may immunosorbent assay (ELISA) testing has
diagnose the patient with herpes gingivostomati- become widely available for PV and has been
tis, apthous stomatitis, oral lichen planus, shown to be more sensitive than convential IIF
Stevens-Johnson syndrome, or traumatic ulcer- [29]. Similar to IIF titers, ELISA values may be
ation. In misdiagnosed and therefore untreated used to track disease activity [30].
PV, the oral erosions show little or no tendency to As previously mentioned, the diagnosis of PV
heal. This leads to hypoalimentation secondary to can be missed, as there are simulators of this dis-
patient fear of pain with eating and subsequent ease. The differential diagnosis for pemphigus
malnutrition and unintended weight loss. Other vulgaris includes distinguishing it from other
mucous membranes can be involved including variants of pemphigus including pemphigus foli-
the conjunctivae, nasal mucosa, esophagus, aceus and paraneoplastic pemphigus. Additionally,
vagina, penis, and anus [26]. More than half of all the differential can be divided into two main cat-
patients will also have cutaneous erosions and/or egories—only oral lesions present versus both
flaccid bullae. Common cutaneous locations oral and cutaneous lesions present. The list of
include the head, upper torso, and intertriginous diseases on the former includes aphthous stoma-
areas (Fig. 8.2) [25, 27]. titis, erythema multiforme, herpes simplex, ero-
In patients with suspected pemphigus vulgaris, sive lichen planus, and cicatricial pemphigoid,
a biopsy specimen for routine histology should while the latter differential includes Stevens-
be obtained from lesional skin. Histology findings Johnson syndrome/toxic epidermal necrolysis,
in PV include suprabasilar blister formation, bullous pemphigoid, linear IgA dermatitis, and
acantholysis, and minimal inflammation [25]. In epidermolysis bullosa acquisita.
addition to routine histology, a direct Before the advent of corticosteroids in the
immunofluorescence (DIF) of perilesional skin 1950s, pemphigus vulgaris had been a deadly
should be obtained against monkey esophagus disease with mortality rates between 90 and
Fig. 8.3 (a) Low power H&E view of Pemphigus Vulgaris showing suprabasilar acantholysis. (b) High power view
showing “tombstoning” of basilar keratinocytes. (c) Direct Immunofluorescence
100% of affected patients within 2 years of dis- abstention from food or drink for 30 min thereaf-
ease onset. Death largely resulted from sepsis ter. It should also be noted that patient should be
secondary to loss of skin barrier, leading to loss aware that these topical therapies are used off-
of body fluids or serving as a nidus for secondary label and products often claim “for external use
bacterial infections [31]. PV is almost universally only” [26]. A prosthetic device such as a dental
fatal in the absence of therapy, and studies dem- tray that fits over the teeth and gingiva can be
onstrate higher mortality among the elderly; fashioned by a dentist to make application of a
therefore, early intervention is essential [25]. topical corticosteroid preparation easier. When
With the vast array of treatment options available these topical medicines are applied under a den-
today including systemic glucocorticoids, non- tal tray their potency is increased [34]. There are
steroidal systemic immunosuppressives, biolog- few recognized adverse effects associated with
ics, and immunomodulatory procedures, mortality the use of topical corticosteroids in the oral cav-
is now less than 10% [32]. ity including oral candidiasis and reactivation of
If the disease appears nonprogressive and herpes simplex virus (HSV). The former can be
restricted to one body area such as the mouth, treated with antifungal agents such as clotrima-
topical therapy alone may be adequate [26]. zole lozenges five times per day for 1 week, nys-
Corticosteroid gels or ointments such as tatin swish and swallow four times per day until
fluocinonide, desoximetasone, or clobetasol can the patient is asymptomatic for 48 h, or oral
be initially used two to three times per day [33]. fluconazole dosed twice weekly. When HSV
Gels are often more easily applied and better tol- reactivation occurs, treatment with topical acy-
erated when used within the oral cavity. It should clovir six times per day for 1 week is appropriate
be advised that daily applications should initially with lesions limited to the oral cavity; however, if
occur two to three times per day when symptoms life-threatening HSV reactivation occurs intrave-
are severe and gradually tapered once relative nous acyclovir may be necessary. Intralesional
improvements are seen. Q-tip or fingertip appli- corticosteroid injections can be used in the treat-
cation is recommended, rubbing the gel or ointment of PV with some success using triamcino-
ment onto the affected areas gently for 30 s with lone 5–10 mg/mL every 2–4 weeks [26].
Excellent oral care is integral in patients with tation for osteoporosis prophylaxis. Other adverse
PV. Such care includes gently brushing the teeth events to consider include steroid-induced glau-
twice daily using a soft-bristle toothbrush, daily coma or elevated intraocular pressure (IOP) and
flossing, and professional teeth cleaning every osteonecrosis. While an every other day dosing
3–6 months [26]. Ahmed et al. have recom- schedule mitigates the occurrence of several ste-
mended gentle debridement of necrotic mucosal roid-induced side effects, it only decreases the risk
tissue to prevent infection [35]. Therefore, it is of cataract development without fully eliminating
important to have a dentist involved in those the risk, and does not affect the risk of osteoporo-
patients with PV. Topical analgesics or anesthet- sis/osteonecrosis at all [38].
ics and antiseptic mouthwashes are recommended A rapid response is usually noted once sys-
as further treatment. Various elixirs containing temic glucocorticoids are initiated; however, pro-
combinations of viscous lidcaine, diphenhy- longed therapy is often required to achieve
dramine, and antacids can be used as an oral rinse clearance. With a long course comes many side
to decrease mouth pain [35, 36]. Oral trauma can effects and the elderly are particularly susceptible
easily lead to new erosions and should be avoided to these adverse effects. As such, the manage-
as much as possible. Poorly fitted dentures, dry ment of elderly patients mandates the lowest
crackers, and hard candies have all been impli- effective dose of corticosteroids with early initia-
cated in giving rise to trauma of the oral mucosal tion of adjuvant therapy. Examples of adjuvant
surface [26]. therapies include immunosuppressive agents
Systemic corticosteroids are the mainstay of such as azathioprine and mycophenolate mofetil,
therapy and often first-line for PV, while immuno- and antibiotics such as dapsone. Such agents
suppressive agents are used to aid in disease remis- allow for a decreased dose of systemic corticos-
sion and decrease the need for long-term systemic teroid needed to achieve disease control and their
steroids. The goal of therapy is to control the dis- expedited tapering [26].
ease with the lowest possible dose of corticoster- Prior to initiating any systemic immunosup-
oids. Systemic corticosteroid therapy usually in pressive, a complete physical examination and
the form of oral prednisone is standard treatment. age-appropriate malignancy screening should be
Therapeutic effects are assessed by the number of performed. Baseline laboratory data may be help-
new blisters per day, and their rate of healing with ful in selecting a steroid-sparing agent. Monitoring
gradual tapering of prednisone. Once clinical for potential adverse effects include a complete
remission is obtained, changes in the titer of circu- blood count (CBC) with differential, serum
lating autoantibodies are helpful in estimating the chemistry, liver function tests (LFT), fasting lipid
dose of prednisone [37]. Should the disease flare at profile, urinalysis, tuberculin skin test, hepatitis
any point during the attempted taper, patients panel, glucose-6-phosphate dehydrogenase
should return to the steroid dose prior to the dis- (G6PD) enzyme level (for dapsone), and thiopu-
ease flare and be maintained at that dose for 4 rine methyltransferase (TPMT) enzyme level (for
weeks before attempting another taper. Patients azathioprine) [26]. Bone densitometry is indi-
with PV often require several months of high-dose cated for those patients on a daily dose of predni-
corticosteroid therapy before a taper can be sone 5 mg or more for longer than 6 months [38].
attempted, irrespective of whether adjuvant ther- Blood pressure, blood glucose, and stool guaiac
apy is administered. Therefore, patients should be should also be monitored [39]. Prophylaxis for
counseled at length on the adverse effects of sys- Pneumocystis carinii pneumonia (PCP) should
temic corticosteroids. Treating physicians should be considered in patients on long-term oral corti-
protect against recognized sequelae of prolonged costeroids or other immunosuppressives with the
corticosteroid treatment [26]. Such precautions exception of dapsone [40]. However, recent data
include use of an H2-blocker or proton pump has shown that routine prophylaxis for PCP may
inhibitor for ulcer prophylaxis, as well as a bispho- not be necessary, recommending physicians who
sphonate and calcium with vitamin D supplemen- prescribe immunosuppressants for dermatologic
indications to consider it on a case-by-case basis decreases greater than 2 g may require

[41]. Regardless, patients should be monitored discontinuation [26]. Baseline CBC including
closely for signs and symptoms of infection or reticulocyte count should be obtained prior to ini-
malignancy in general, and if either occurs, tiation then frequently checked thereafter in order
appropriate treatment should be instituted early to monitor for this potential complication in addi-
and aggressively [26]. tion to screen for agranulocytosis, which affects 1
Tetracycline along with nicotinamide has been in 400 patients and most often occurs after 8–12
used with some success in patients with mild weeks of therapy. Any significant rise in reticulo-
pemphigus vulgaris, using tetracycline 2 g daily cyte count (i.e., 5% higher than baseline) may
along with nicotinamide 1,500 mg daily [39]. warrant discontinuation of the drug [43, 44].
This antibiotic regimen has a minimal side effect Dapsone hypersensitivity syndrome is an idio-
profile and is ideally suited for elderly patients. syncratic reaction characterized by fever, gener-
Side effects of tetracycline include gastrointesti- alized eruption, hepatitis, and peripheral
nal upset and phototoxicity; administration eosinophilia, typically occurring 8 weeks after
should be avoided in patients with renal impair- drug initiation. When this occurs, discontinuation
ment. The main adverse effects of nicotinamide of the offending agent is required [26]. Dapsone
include flushing and pruritus. Although this regi- can also cause a distal motor peripheral neuropa-
men is particularly useful in the elderly, it should thy, which is usually reversible upon discontinu-
be avoided in patients with renal impairment and ation. Therefore, patients should be monitored
in children less than 9 years old, as tetracyclines for hand and/or leg weakness or muscle atrophy
are associated with permanent tooth discoloration throughout treatment duration [33].
in the pediatric population [26]. Numerous immunosuppressive agents have
Dapsone, historically used as a therapy for been used as adjunctive therapy, particularly
leprosy, is another antibiotic that can be used as when there is severe disease or when disease
adjuvant therapy for PV. Although some studies extends beyond the oral cavity. Such agents
have shown no statistically significant difference include azathioprine, mycophenolate mofetil,
in remission when dapsone was compared to pla- cyclophosphamide, methotrexate, and
cebo, dapsone has been documented to be cyclosporine with monotherapy of the chosen
extremely useful in controlling mild to moderate immunosuppressive agent as the eventual goal
PV if introduced early in disease evolution [26]. [26]. The use of azathioprine when combined
Dapsone is contraindicated in patients with low with corticosteroids may result in gaining early
G6PD levels. In patients with normal levels, the control of disease and increased percentage of
degree of hemolytic anemia and associated symp- clinical remissions [4, 45]. Remission rates of
toms may be avoided by gradually increasing the 28–45% and mortality rates of 1.4–7% have been
dose of dapsone. The drug can be started at reported when azathioprine and systemic corti-
25–50 mg/day and increased every third day by costeroids are used [26]. Azathioprine has been
25 mg until 100 mg is reached. Dapsone 100 mg used alone; however, its long latency of onset (up
should be taken for 1 week before increasing to a to 8 weeks) limits its use as initial monotherapy
target maintenance dose of 125–150 mg daily [45, 46]. The main adverse effects include hepa-
[42]. This gradual titration allows for the bone totoxicity, hypersensitivity syndrome, and neu-
marrow to adapt to the hemolytic insult. tropenia. Patients with low TPMT levels are at
Other important adverse effects of dapsone greater risk of neutropenia. Therefore dosing
include methemoglobinemia, agranulocytosis, should be individualized based on the patient’s
and hypersensitivity syndrome. Patients should TPMT enzyme activity level [39]. Individuals
be counseled to expect a 1–2 g drop in hemoglo- with high TPMT enzyme activity levels require
bin. Most patients can tolerate such a mild ane- higher doses to achieve clinical effect [47].
mia, and this often does not necessitate Regular laboratory monitoring should include
discontinuation of the medication; however, LFTs and CBC with differential. Azathioprine
should not be prescribed in patients who take final adjunctive immunosuppressive cyclosporine
allopurinol unless unavoidable, since allopurinol is used concomitantly with prednisone in the
interferes with the metabolism of azathioprine treatment of pemphigus vulgaris [52]. Known
increasing plasma levels of 6-mercaptopurine, adverse effects include hypertension, nephrotox-
which may result in potentially fatal blood icity, hepatitis, and neurologic changes. With
dyscrasias. such a toxicity profile, cyclosporine should be
Mycophenolate mofetil is another adjuvant not considered first-line adjuvant therapy, but
immunosuppressive used to treat PV [26, 48]. may be used to achieve rapid initial control.
Similar to azathioprine, therapeutic effect takes Two final medications used to treat pemphigus
approximately 6–8 weeks; however, mycopheno- vulgaris—one more recently debuted, the other
late mofetil has less hepatotoxicity and myelo- more historic—are rituximab and gold. The for-
suppression, but more gastrointestinal toxicity mer has activity against tumor necrosis factor
than azathioprine [49]. Laboratory parameters alpha (TNF-a), and recently emerged as a choice
including CBC with differential and LFTs should for refractory cases to more standard immuno-
be checked regularly. Both azathioprine and suppressive therapy because of its ability to target
mycophenolate mofetil can be used in conjunc- plasma cell precursors responsible for antibody
tion with dapsone should the latter provide only production [25, 53]. Most patients respond within
partial control. 3 months after starting rituximab; however,
Cyclophosphamide is another adjunctive delayed response after a year of treatment has
immunosuppressive agent used to treat pemphi- been reported [54]. Its use is limited by cost, infu-
gus vulgaris. Its combination with systemic corti- sion route of delivery, and potential for serious
costeroids may result in gaining early control of immunosuppression and infection. Other biolog-
disease and increased percentage of clinical ics such as etanercept and infliximab have been
remissions [4, 50]. Although cyclophosphamide investigated in treating PV; however, results are
is still typically used in combination with sys- variable [25]. Gold has been used to treat mild to
temic corticosteroids, numerous case series have moderate cases of PV as monotherapy or with
reported utilizing it as monotherapy with clinical oral glucocorticoids [26]. Two early studies
effect in acute disease at doses of 50–200 mg/day reported complete remission in 15–44% in a total
[26]. Cyclophosphamide has a higher incidence of 44 PV patients; however, it was considered
of adverse effects including hemorrhagic cystitis, ineffective in 15–28% of patients, while 17–35%
infertility, and bladder cancer when compared to discontinued the due to side effects [55, 56]. Gold
azathioprine or mycophenolate mofetil [26]. is rarely used today because of its delayed onset
Regular laboratory monitoring includes CBC of action, side effect profile, and relative ineffec-
with differential and urianalysis. Given its poten- tiveness compared to other treatments available.
tial risk of toxicity, it should only be used as Immunomodulatory procedures such as intra-
short-term therapy with transition to an alterna- venous immunoglobulin (IVIg), plasmapheresis
tive adjuvant once disease activity is controlled and extracorporeal photopheresis have all been
[51]. Furthermore, intravenous administration is employed in the management of pemphigus vul-
available in those patients who cannot tolerate garis. High-dose IVIg (2 g/kg per cycle) may be
oral intake. necessary in patients with rapidly progressive,
Methotrexate should be considered in patients extensive, or treatment resistant PV [26, 57].
where other adjuvant medications have failed or IVIg has a very rapid onset of action, and has
are contraindicated. The major adverse effect of been used with oral corticosteroids and an immu-
methotrexate is total cumulative dose-dependent nosuppressant drug in patients with refractory
hepatotoxicity. Additional side effects include PV; however, consensus on its efficacy remains
anemia, leukopenia, pulmonary toxicity, mucosi- controversial, as well as duration of treatment
tis, and nausea. Doses ranging from 10 to 17.5 mg [26]. Plasmapheresis plays a limited role in the
once weekly are typically used to treat PV. The management of PV, but can be considered in
difficult cases. Plasmapheresis is useful for steroids with longer remissions [59]. As such,
quickly reducing very high titers of autoantibod- morbidity and mortality is similar to PV for the
ies and should be considered in severe presen- Neumann subtype.
tations if unresponsive to a combination of
immunosuppressants and corticosteroids [32, 51].
Extracorporeal photopheresis has been used in 8.5 Pemphigus Foliaceus
patients with PV; however, clinical efficacy is
variable [26]. One final medication with cytokine- Like pemphigus vulgaris, pemphigus foliaceus
modulating effects recently reported in treating (PF) is one of the originally characterized classic
PV is thalidomide. The report showed it to be a forms of pemphigus. PF is generally a more
very effective treatment option deserving further benign variant; however, localized lesions tend to
evaluation. The recommendation was to consider persist for months to years carrying a significant
the use of this drug for patients in whom standard amount of morbidity for some patients. Although
therapy, IVIg, and rituximab have all failed [58]. PF is not often associated with considerable mor-
Table 8.1 outlines therapeutic options in the treat- tality, the disease can progress to erythroderma
ment of most autoimmune blistering diseases. (see Chap. 7) representing a true dermatological
emergency. These patients require prompt hospi-
talization to prevent serious and sometimes fatal
8.4 Pemphigus Vegetans complications from high output cardiac failure
and metabolic instability [62].
Pemphigus vegetans, a rare clinical variant of Sporadic PF is a rare disease accounting for
pemphigus vulgaris affecting 1–2% of patients, is 20–30% of pemphigus cases. Its incidence in the
thought to represent a reactive pattern of the skin USA and Europe is estimated at less than 1 case
to the autoimmune insult of PV. Pemphigus veg- per million inhabitants per year [61]. The preva-
etans is characterized by the occurrence of hyper- lence of PF is approximately equal between men
trophic, papillomatous, or verrucous vegetating and women affecting all races and ethnicities
skin lesions predominately involving the inter- with an average age of onset between 40 and 60
triginous areas [59, 60]. In general, flaccid blis- years old [62]. The epidemiologic statistics
ters become erosions with subsequent formation exhibit considerable variation when examining
of fungating vegetative plaques (Fig. 8.4). the endemic forms of PF as discussed later. The
Two clinical subtypes of pemphigus vegetans exact cause of sporadic PF remains unknown;
are recognized: the Neumann type and the however, extensive UV exposure, burns, and vari-
Hallopeau type. The former is more severe with ous drugs have all been implicated in its develop-
longstanding and refractory erosions that trans- ment. Penicillamine and captopril are the two
form into vegetating lesions, while the latter is a medications in particular that are associated with
milder presentation characterized by the initial PF, and in patients receiving penicillamine, PF is
appearance of pustules and rapid evolution to seen more commonly than PV with a ratio of
verrucous vegetative plaques with persistent approximately 4:1 [20]. Similar to PV, one dietary
peripheral pustules. Diagnosis may be difficult in factor has also been reported in giving rise to PF
patients with chronic vegetations, but the DIF seen in a patient taking herbal supplements with
staining is identical to that seen in classic PV phycocyanin [63]. An overlap syndrome exists
[61]. As in PV, systemic corticosteroids are the that exhibits characteristics of both PF and sys-
principal treatment for pemphigus vegetans. temic lupus erythematosus called Senear-Usher
Patients with the Neumann subtype have a simi- Syndrome or pemphigus erythematosus. The
lar disease course to PV, mandating higher ste- name was used to describe patients with overlap-
roid doses with multiple remissions and relapses, ping immunologic features of both diseases (IgG
while patients with the Hallopeau subtype have a and C3 deposition and circulating antinuclear
benign disease course, only needing low doses of antibodies); however, only a few patients have
8
Table 8.1 Therapies used in bullous dermatoses

Therapy Use Standard dose Notes
Topical corticosteroids (e.g., PV, PF, BP, PG, MMP 0.05% gel or ointment -Useful in mild, localized cases including disease
fluocinonide, clobetasol) in the oral cavity
Nicotinamide with tetracycline PV, BP, MMP 1.5–2 g/day for both Useful in mild cases
Higher doses of nicotinamide required in MMP
(3 g/day)
Not for pediatric use
Vesiculobullous Dermatoses
Dapsone PV, PF, BP, MMP, LABD 125–150 mg/day Useful in mild cases
Start 25–50 mg/day and titrate slowly
100 mg/day is mean dose for disease control in
LABD but may need higher dose of 300 mg/day
Watch for G6PD deficiency, hemolysis, and
methemoglobinemia
Systemic corticosteroids (e.g., PV, PF, BP, PNP, PG, MMP, 0.75–1 mg/kg/day Usually initial therapy
prednisone) LABD Maintenance use in moderate to severe cases
Lower dose in PG and LABD at 0.5 mg/kg/day
Azathioprine PV, PF, BP, MMP 2–4 mg/kg/day Useful in severe cases
Steroid-sparing adjuvant
First-line adjuvant in MMP
Check TPMT levels
Care with concomitant use of Allopurinol
Cyclophosphamide PV, PF, BP, MMP 1–3 mg/kg/day Useful in severe cases
Steroid-sparing adjuvant;
Consider use in very aggressive cases as efficacy
achieved faster compared to other adjuvants
Risk of infertility and GU malignancy
Mycophenolate mofetil PV, PF, BP, MMP 2–3 g/day in two divided doses Useful in severe cases
Less hepatotoxic
Methotrexate PV, BP, MMP 7.5–20 mg/week Not commonly used but helpful in some patients
Cyclosporine PV, MMP 5 mg/kg/day Useful in severe cases
Topical formulation used in ocular MMP
155
(continued)
Table 8.1 (continued)
156
Therapy Use Standard dose Notes

IVIG PV, BP, MMP 400 mg/kg/day for five consecutive days Used in refractory cases
May need to repeat dose
Especially helpful in progressive ocular MMP
Controversial efficacy in PV
Plasmapheresis PV, BP, MMP 1–2 times per week Short bridging therapy to decrease autoantibody
levels in extremely difficult cases
Extracorporeal photopheresis PV 2 days per month Useful in refractory or treatment resistant cases
Variable outcomes
Rituximab PV, PNP, BP, MMP 375 mg/m2 IV once weekly for 4 weeks Useful in patients resistant or intolerant to
1,000 mg IV at day 0 and day 14 standard therapies (e.g., systemic steroids and
adjuvants)
After induction, long-term therapy with infusions
every 4–12 weeks may be continued
Etanercept MMP 25 mg SQ twice weekly Reported success in case reports and small case
series
Infliximab MMP 5 mg/kg Reported success in case reports and small case
series
Infusions are given at 0, 2, and 6 weeks and then
every 8 weeks thereafter
Gold PV 50 mg IM once weekly Used in mild to moderate cases of PV either alone
or with glucocorticoids
Thalidomide MMP 100 mg/day Reported success in a single case of refractory
MMP
Subconjunctival mitomycin C MMP 0.02 mg per injection Last resort in rapidly progressive ocular MMP
unresponsive to oral agents
No more than 1–3 injections
IVIG = intravenous immunoglobulin; PV = pemphigus vulgaris; PF = pemphigus foliaceus; BP = bullous pemphigoid; PNP = paraneoplastic pemphigus; PG = pemphigoid gesta-
tionis; MMP = mucous membrane pemphigoid; LABD = linear IgA bullous dermatosis; g = gram; mg = milligram; kg = kilogram; SQ = subcutaneous; IM = intramuscular;
G6PD = glucose-6-phosphate dehydrogenase; TPMT = thiopurine methyltransferase
M.W. Cashman et al.
Fig. 8.4 Pemphigus Vegetans. Verrucous and eroded

plaques in the axilla
been reported to actually have the two diseases

concurrently [64].
In pemphigus foliaceus, blister formation is
associated with IgG antibodies against desmog-
lein 1 only, which is essential to keratinocyte
cohesion only in the most superficial layer of the
epidermis [25]. DIF is similar to that in PV, but a
Fig. 8.5 Pemphigus Foliaceus. Eroded and crusted
stronger staining has been described in the upper plaques. Vesicles are transient and are rarely seen due to
epidermal portion. IIF shows mainly IgG4 anti- superficial nature of blisters
bodies best detected using guinea pig esophagus
[25]. Anti-desmoglein 1 antibodies are frequently present with active and widespread disease. Such
detected with ELISA assays on serum of PF extensive cases may require adjuvant immuno-
patients in more than 90% of cases. Desmoglein suppresants such as systemic corticosteroids,
1 values parallel the course of the disease [61]. azathioprine, cyclophosphamide, or mycopheno-
Antibodies directed against desmoglein 3 are not late mofetil [67, 68]. In some patients with PF,
detected as it has been clearly demonstrated that disease activity may remain localized for many
autoantibody reactivity is restricted to desmog- years and topical high potency corticosteroids
lein 1 in PF [61, 65]. may provide sufficient control [69]. Dapsone
Clinically, the primary lesions seen in pem- might be considered when neutrophils are domi-
phigus foliaceus are flaccid superficial vesicles nant histologically [70].
and bullae confined to the skin. Such lesions may
not necessarily be seen at time of presentation
since they are both transient and fragile. Therefore, 8.6 Fogo Selvagem
secondary lesions are more often seen including
shallow erosions with extensive crusting [62]. Fogo selvagem (FS) is an endemic subtype of
Lesions are typically well demarcated and have a pemphigus foliaceus. Endemic PF differs from
seborrheic distribution favoring the face, scalp, the sporadic form of the disease in its geographic
upper trunk, and back (Fig. 8.5) [25]. distribution, high familial incidence, and younger
Therapy for pemphigus foliaceus is usually age of onset [71]. Patients are clinically, histo-
less aggressive than that of PV because of lower logically, and immunopathologically similar to
morbidity and mortality rates [66]. In general, the patients with sporadic PF; however, a higher inci-
treatment is similar to PV when patients with PF dence of more severe, generalized exfoliative
dermatitis is related to a higher morbidity and Hyperkeratosis on the soles and palms is also fre-
mortality seen in FS [62]. quently observed [61]. Therapeutics are similar
Fogo selvagem occurs with a high frequency in to those used in PF.
Central and Southwestern Brazil where as many
as 50 cases per million per year are seen. Some
endemic regions of Brazil exhibit a prevalence 8.7 Paraneoplastic Pemphigus
equal to 3% of the population, where the ratio of
FS to PV is 17:1 [72]. FS affects a larger number Of the entire pemphigus family, paraneoplastic
of children and young adults without sex predilec- pemphigus (PNP) is the most severe [76]. PNP
tion as symptoms usually begin during the second carries significant morbidity and mortality, par-
or third decade of life [62]. Another focus of tially due to development in the setting of malig-
endemic PF exists in the northern part of Columbia. nancy and also the associated often extensive
The prevalence of Columbian PF is close to 5% mucosal involvement. When PNP is associated
and greater than 95% of those affected are men with malignancy, mortality is estimated at 93%
[61]. A third focus of endemic PF has also been usually from sepsis, bronchiolitis obliterans, or
described in Tunisia. There, the overall incidence progression of the underlying malignancy [25].
is 6–7 cases per million per year; however, the Epidemiological data on the prevalence and
incidence dramatically increases up to 20 cases incidence of PNP is scarce. One review reported
per million per year in some areas in south Tunisia, approximately 150 cases in the literature 10 years
particularly affecting young adult women from 25 ago. The age range for PNP is from 7 to 83 years,
to 34 years old as evidenced by a female to male although the majority of patients are between the
ratio of 4:1 [61, 62]. ages of 45 and 70 years [77]. The mean age at onset
The exact cause of fogo selvagem is unknown. is 60 years without predilection of sex or race. PNP
FS frequently occurs in genetically related family occurs in the setting of malignancy including, in
members, and more than 50% of normal individ- decreasing order of frequency, non-Hodgkin lym-
uals in certain areas of Brazil have antidesmog- phoma, chronic lymphocytic leukemia, Castleman
lein 1 IgG autoantibodies [73]. In addition to disease, thymoma, Waldenstrom macroglobuline-
genetic propensity, FS is thought to be triggered mia, and spindle-cell sarcomas [25].
by the bite of an insect, where antibodies pro- PNP patients display autoantibodies to des-
duced against this unidentified antigen may moglein 1 and 3, as well as desmosomal proteins
cross-react with desmoglein 1 in genetically sus- of the plakin family including desmoplakin I and
ceptible individuals, leading to the development II, envoplakin, periplakin, plectin, BP antigen
of FS [62]. More recent research has focused on 230, and a 170-kDa protein that has not been fur-
the study of a protein transmitted from the saliva ther identified [25, 78]. DIF reveals IgG, C3, or
of Simulium nigrimanum, a type of black fly both in an intercellular pattern like PV, but in
[74]. Dietary factors have also been implicated as addition, linear/granular IgG or C3 may be pres-
increased amounts of tannins dissolved in the ent at the basement membrane zone. Results of
water systems directly serving Amazonian natives IIF are similar to PV but autoantibodies may also
could explain the occurrence of FS in Amazonian demonstrate binding to simple or transitional epi-
Brazil [75]. thelium substrates like rodent bladder, which is
The target antigen in fogo selvagem is des- considered unique and diagnostic of PNP [25].
moglein 1 with similar DIF and IIF staining pat- Severe involvement of multiple mucous mem-
terns as seen in PF. Clinically, patients with FS branes is the major clinical feature and hallmark of
exhibit the same characteristics as patients with this disease. The most constant clinical feature is
PF. Some patients with chronic disease may severe and intractable stomatitis consisting of
develop verrucous plaques on the trunk and erosions and ulcerations that affects all surfaces of
extremities, which have also been described in the oropharynx, characteristically extending to
patients with Columbian endemic pemphigus. the vermilion lip (Fig. 8.6) [25, 77]. Mucosal
8.8 Epidermolysis Bullosa Simplex
Epidermolysis bullosa simplex is one of three

major forms of inherited epidermolysis bullosa
(EB), which is the prototypic mechanobullous
disease, characterized by the development of
blisters after trivial trauma to the skin. Most epi-
demiologic data is derived from the work of the
National EB Registry stating that 50 EB cases
occur per million live births and approximately
92% are classified as EB simplex [80]. EB sim-
plex is mostly transmitted in an autosomal domi-
Fig. 8.6 Paraneoplastic pemphigus presented as intrac-
table mucosal ulcerations nant fashion and appears to be the result of
mutations within the gene for either keratin 5
(K5) or keratin 14 (K14), which are present pri-
involvement may also include the conjunctiva, marily within the basal layer of the epidermis
genitalia, or tracheobronchial tree [25]. Such exten- [81]. Transmission electron microscopy (TEM)
sive mucosal involvement is a considerable source distinguishes among the three major EB types by
of morbidity in PNP patients as the conjunctival the identification of the ultrastructural level of
fornices may become scarred and obliterated lead- cutaneous blister formation. TEM can also be
ing to synblepharon, while esophageal ulceration used to quantitatively and qualitatively assess
may lead to hypoalimentation and malnourish- specific structures such as basilar tonofilaments,
ment. The cutaneous findings are by definition hemidesmosomes, subbasal dense plates, anchor-
polymorphous and may present as erythematous ing filaments, and anchoring fibrils [80].
macules, flaccid blisters and erosions resembling EB simplex is characterized by mechanically
PV, tense blisters resembling bullous pemphigoid, fragile skin, tense fluid-filled blisters, erosions,
erythema multiforme, or lichenoid dermatitis [25]. and crusts with subsequent atrophic scarring
Treatment is aimed at the underlying malig- (Fig. 8.7). These features are seen beginning at
nancy, but the course of PNP does not correlate birth or soon after. The more severe subtype of
with the course of the underlying neoplasm [25]. EB simplex known as EB simplex herpetiformis,
Patients with benign tumors such as a thymoma or Dowling-Meara, is characterized by grouped
or localized Castleman’s disease should have blisters often in an arcuate or polycyclic array,
them surgically excised, as the majority of these and also associated with the most significant
patients will significantly improve [79]. There is mucosal membrane involvement and increased
no consensus on a standard effective therapeutic mortality. Morbidity and mortality of EB simplex
regimen for patients with malignant tumors. relates to the consequences of repeated damage,
Cutaneous lesions respond more rapidly to ther- ulceration, and poor healing of the skin.
apy in contrast to the stomatitis, which is gener- Malnutrition and growth stunting is consistently
ally refractory to most treatment measures. seen in patients with EB simplex [16]. This may
Aggressive combinations of immunosuppres- be due to oral blistering and ulcerations, diges-
sants including systemic corticosteroids, ritux- tion and absorption problems, or loss of blood
imab, and others have been used but are frequently and protein through open skin blisters [82–84].
unsuccessful [25]. Yet another source of morbid- Although more common over a decade ago, bac-
ity in these patients with PNP is the susceptibility terial sepsis and subsequent death is now rela-
to infection caused by the loss of skin integrity, tively rare; however, it can still occur in the EB
exacerbated by the potent immunosuppressants simplex Dowling-Meara subtype, and hyperme-
used to treat the condition. tabolism resulting in increased heat loss and
villus sampling as early as 8–10 weeks or amnio-

centesis in the second trimester are both used to
aid in diagnosis.
8.9 Subepidermal Blistering

Diseases
Subepidermal blistering diseases often requiring

emergent attention include bullous pemphigoid,
gestational pemphigoid, cicatricial pemphigoid,
linear IgA bullous dermatosis, and epidermolysis
Fig. 8.7 Mechanicobulla seen in Epidermolysis Bullosa bullosa acquisita in addition to two heritable dis-
Simplex
orders known as junctional epidermolysis bullosa
and epidermolysis bullosa dystrophica. All the
protein turnover is especially common in the set- acquired disorders are characterized by circulat-
ting of skin infections [85]. ing and tissue-bound autoantibodies against vari-
There are no FDA approved therapies for any ous components of the dermo-epidermal
form of inherited EB, but two clinical trials involv- anchoring complex (hemidesmosome), whereas
ing molecular therapy are currently underway and the inherited disorders result from various defects
specific treatment may become a reality for at least in these hemidesmosomal proteins [88].
some types or subtypes of EB in the near future.
One clinical trial is investigating bone marrow
transplantation and immunosuppression to deliver 8.10 Bullous Pemphigoid
corrective skin cells in the patient, while the other
clinical trial is examining retroviral-mediated type Bullous pemphigoid (BP) is the most commonly
VII collagen gene transfer. For now, daily manage- encountered autoimmune, subepidermal blister-
ment revolves around the prevention of both ing disease of the skin, most commonly affecting
mechanical trauma through the use of padded ban- the elderly. Elderly individuals are more likely to
dages and loose-fitting garments, in addition to the have comorbid conditions, and the presence of
prevention of infection via mild, broad-spectrum such conditions complicates the selection of and
topical antibiotic ointments or creams. Experience effect of therapy and may also dramatically
in a few patients suggests that systemic tetracy- influence both prognosis and outcome [89, 90].
cline might be of clinical benefit in EB simplex Elderly patients also frequently have suboptimal
[86]. Most of the extracutaneous complications of nutritional states that can adversely affect prog-
EB can be surgically or medically managed. In nosis and further complicate care [91]. The mor-
patients with significant malnutrition, aggressive bidity and mortality in BP is also influenced by
nutritional supplementation facilitated by place- its chronicity with periodic remissions and exac-
ment of a gastrostomy tube can be performed erbations with a profound impact on quality of
when necessary [87]. Genetic counseling should life. Among studies of patients with BP published
be considered as genetic information from muta- in the past two decades, 1-year mortality rates
tion analyses on epidermolysis bullosa candidate ranged from 15 to 41% [92].
genes provides an immediate benefit to families of Previously published case series have docu-
patients with the disease. Prenatal diagnosis of mented an age of onset range from 68 to 82 years
epidermolysis bullosa in affected families is a [25]. The annual incidence of BP is estimated to
genetic-based protocol, providing that the patient be at least 6–7 new cases per million per year with
identified as the original proband has had a rapid increase after the age of 60 years, and
identification of the defective gene, and chorionic expected to rise given the advancing age of the
population. The relative risk for patients over 90

years of age appears to be about 300-fold higher
than for those 60 years of age or younger with an
apparent predominance in men. Certain HLA
class II alleles are more prevalent in patients with
BP than in the general population including DQB1
in Caucasians and DRB1 in Japanese [93].
Most cases of BP occur sporadically without
any obvious precipitating factors; however, sev-
eral reports have implicated various triggers such
as UV light, radiation therapy, percutaneous
endoscopic gastrostomy, thermal burn, amputa-
tion stump, and adhesive dressings [94–97]. BP
Fig. 8.8 Urticarial papules and plaques on the lower
has also been reported to develop in associated abdomen in early Bullous Pemphigoid. Overlying scale
with other autoimmune diseases like diabetes suggests early blister formation
mellitus and pernicious anemia, chronic
inflammatory skin diseases such as lichen planus The clinical presentation of BP is highly vari-
and psoriasis, and various malignancies [98]. able. Patients may seek medical attention during
Despite the various case reports of BP associated the initial nonbullous phase, which is often a
with renal cell carcinoma, gallbladder malig- simple complaint of pruritus or urticarial patches,
nancy, and colon and breast cancers, large popu- plaques and erythema with no evidence of bullae
lation studies have reported conflicting evidence. (Fig. 8.8). When blisters eventually develop,
Therefore, the relationship between BP and they are classically 1–4 cm in size, tense, bilat-
malignancy is still a matter of debate. Medications eral, and symmetric with predilection for the
associated with bullous pemphigoid include furo- flexural proximal extremities and trunk (Fig. 8.9).
semide, ibuprofen and other NSAIDs, captopril, Pruritus is common and mucosal involvement
penicillamine, and antibiotics [98]. can occur in a minority of patients and often lim-
The target antigens in BP are components of ited to the oral cavity [25]. Several variants of
the hemidesmosome in cutaneous basal cells. BP exist, and many carry unique morbidity and
Most BP patients have bound and circulating IgG mortality characteristics. For example, dys-
antibodies directed towards the extracellular hidrosiform pemphigoid—a localized variant of
noncollagenous domain of collagen type 17, a BP often presenting with recurrent, painful vesi-
transmembrane protein in basal cells also known cles, and bullae of the palms and/or soles—can
as BP180 (BPAg2). Patients with BP also exhibit lead to significant functional impairment,
autoreactivity to a cytoplasmic plakin family pro- whereas erythrodermic pemphigoid tends to
tein known as BP230 (BPAg1), which is also a induce a high output cardiac failure placing
structural part of the hemidesmosome [25]. DIF patients at risk for sepsis and subsequent death.
studies are generally considered more sensitive Interestingly, the overall trend in mortality over a
than IIF because circulating antibodies may not 24-year period was found to increase in pemphi-
be detectable in a small but significant portion of goid but decrease in pemphigus, while mortality
patients; however, if the DIF does not display the in the black population was significantly higher
characteristic pattern (i.e., deposition of IgG and/ for every bullous disorder [30].
or C3 at the basement membrane zone), serum Systemic corticosteroids are the most effec-
for IIF on salt-split skin and/or BP180 ELISA tive therapy for BP, and prednisone given at doses
may be necessary to differentiate BP from the ranging from 0.5 to 0.75 mg/kg/day is generally
inflammatory variant of epidermolysis bullosa sufficient for disease control [100]. More recent
acquisita, bullous systemic lupus erythematosus, reports have been published in regards to the
and mucus membrane pemphigoid (MMP) [99]. efficacy of topical corticosteroids in the treatment
gestationis and subsequent development of

choriocarcinoma [103, 104]. The mother is also
at increased risk for enduring the same eruption
with subsequent pregnancies. Fetal morbidity
and mortality includes low birth weight for gesta-
tional age and prematurity. In addition to the pos-
sibility of fetal adrenal insufficiency and transient
neonatal pemphigoid exist from transplacental
antibody transfer exist, although much less com-
mon [102].
The incidence of pemphigoid gestationis is
estimated to be 1 in 50,000 pregnancies in North
America [105]. Only 14% of cases develop in the
postpartum period [106]. An increased risk for
the development of this disease has been delin-
eated in patients with HLA-DR3 and HLA-DR4
alleles. Those patients with this same haplotype
also have a higher relative prevalence of other
autoimmune diseases including Hashimoto thy-
roiditis, Graves disease, and pernicious anemia
[102]. Pemphigoid gestationis appears to be
caused by an anti-basement membrane zone
(BMZ) serum factor that induces C3 deposition
along the dermal–epidermal junction. The major-
Fig. 8.9 Tense blisters on the lower extremities in ity of patients also have antibodies to BP180 (as
Bullous Pemphigoid seen in BP patients) of the IgG1 subclass. The
gold standard in diagnosing pemphigoid gestatio-
of BP; however, it is still unclear whether topical nis is DIF on perilesional skin, which shows a
steroids are unequivocally better than systemic bright linear deposition of C3 along the BMZ in
regimens [25]. Additional therapies for BP with 100% of cases, an immunopathologic hallmark
documented efficacy include azathioprine, meth- [102]. IIF shows circulating IgG antibodies in
otrexate, and tetracycline with nicotinamide 30–100% of cases, and in salt-split skin, staining
[101]. In treatment resistant cases, IVIg, plasma remains with the epidermal fragment as seen in
exchange, or rituximab are all potential options, patients with BP [107].
discussed more extensively in the pemphigus The initial clinical findings of pemphigoid ges-
vulgaris section. tationis are characterized by the presence of severe
pruritus and erythematous urticarial papules,
which coalesce into plaques. The typical localiza-
8.11 Pemphigoid Gestationis tion of the lesions is on the abdomen and exclu-
sively within or proximate to the umbilicus. In
Pemphigoid gestationis is one of the dermatoses atypical cases, the lesions tend to cluster over the
of pregnancy that places both mother and fetus at limbs, palms, or soles [102]. Lesions spare
risk, and emergent diagnosis and treatment is abdominal striae unlike the lesions in pruritic urti-
paramount in order to prevent any significant carial papules and plaques of pregnancy (PUPPP)
morbidity to either. It is intensely pruritic and that have a predilection of involving abdominal
generally develops in the third trimester or the striae. As lesions progress over the course of days
immediate postpartum period [102]. Case reports to weeks, tense blisters develop, and a generalized
have documented an association with pemphigoid pemphigoid pattern of eruption becomes evident.
The bullae are similar to those found in BP—tense to 66 years [25, 109]. However, MMP has also
with serous fluid and often leaving widespread been reported in children [26]. The incidence of
erosions. The entire skin surface can be involved, MMP is estimated to be between 1 in 12,000 and
but the face, palms, soles, and mucous membranes 1 in 20,000 in the general population. Although
are usually spared [108]. Systemic corticosteroids no geographic or racial predilection has been
are the cornerstone of therapy and most patients described, several studies have demonstrated an
respond to prednisone 0.5 mg/kg/day. Maintenance increased risk in patients with an HLA-DQw7
therapy is generally held at a lower dose and may haplotype [109]. No specific diseases or predis-
not even be required throughout gestation depend- posing factors have been noted in association
ing on response. Interestingly, many patients will with MMP, with the exception of colon cancer in
experience spontaneous disease regression during patients with antilaminin 5 (epiligrin) MMP [101].
the third trimester, only to experience a flare dur- Laboratory evidence suggests that the autoan-
ing childbirth [102]. tibodies in MMP can target multiple different
Many pregnant women become concerned structural components of the extracellular por-
with the risks of systemic steroids on fetal well- tions of the hemidesmosomal adhesion complex
being, and these apprehensions should be appro- in the skin and mucosal surfaces [25]. The vari-
priately addressed. There is an increased ous target antigens can include BP180, BP230,
inclination to develop fetal risks such as small for laminin 5, laminin 6, and integrin alpha-6/beta-4
gestational age and prematurity suggesting a low- subunit [25, 26]. Patients with antibodies against
grade placental insufficiency; however, it has the integrin subunits predominantly exhibit ocu-
recently been shown that these risks seem to be lar disease. Patients with antibodies against lami-
more associated with antibodies binding to the nin 5 have no specific phenotype, and whereas
placenta rather than the effect of systemic ste- those with BP180 autoantibodies can exhibit
roids. The other potential risk to consider is adre- cutaneous involvement [25].
nal insufficiency, especially in those women Similar to BP, immunofluorescence studies are
treated with systemic steroids over longer periods the gold standard for diagnosis. Biopsy for DIF is
of time; however, the maternal–fetal gradient of best obtained from perilesional uninvolved
prednisone is only 10:1 and fetal adrenal sup- mucosa such as the lower labial mucosa which is
pression is only a rare consequence [102]. easily accessible [25]. In general, MMP is charac-
terized by the linear deposition of IgG, IgA, and/
or C3 along the epidermal BMZ in mucosal and/
8.12 Mucous Membrane (Cicatricial) or cutaneous biopsy specimens [26]. IIF is posi-
Pemphigoid tive in approximately 20–30% of cases in contrast
to the much higher detection rate seen in BP [25].
Mucous membrane pemphigoid (MMP) is a Given the lower detection rate with IIF on human
chronic inflammatory subepidermal blistering split skin, western blotting, immunoprecipitation,
disease. MMP is characterized by the presence of and ELISA using various cell-derived and recom-
antibodies targeting subepidermal BMZ struc- binant proteins are pivotal diagnostic tools for
tural components of mucosal surfaces. The mor- MMP. Despite a low detection rate, laminin 5
bidity and mortality for this disease are significant, detected on the dermal side of salt split skin dif-
and serious sequelae can develop including scar- ferentiates it from all other pemphigoids [65].
ring and fibrosis of the involved mucous mem- The diagnosis of MMP should be entertained in
branes [25]. The disease course is often slow and patients with erosive or blistering mucosal lesions,
progressive interrupted with periods of explosive especially if evidence of scarring is present.
inflammatory activity. Erythema multiforme, erosive lichen planus, and
MMP is rare but most often affects elderly PV should be considered and can be differentiated
individuals with a 2:1 female preponderance aged by histology and immunofluorescence studies. BP,
60–80 years, and an average age ranging from 62 epidermolysis bullosa acquisita, and linear IgA
MMP carries signi fi cant morbidity and

mortality often resulting from severe conse-
quences arising from untreated disease. Chronic
and progressive ocular inflammation can lead to
scar formation, ultimately resulting in blindness.
Laryngeal webs may develop causing sore throat,
hoarseness, and possible loss of speech.
Supraglottic stenosis secondary to erosions, scar
formation, and edema may necessitate a tracheo-
stomy as the airway becomes progressively com-
promised. Esophageal strictures can result in
dysphagia, odynophagia, hypoalimentation, mal-
nourishment, and subsequent weight loss [25,
Fig. 8.10 Erosive blisters on the floor of the mouth in a
Cicatrical Pemphigoid (MMP) 26]. And finally, involvement of the anogenital
mucosa may lead to urinary stricture and sexual
dysfunction [110].
Several treatment modalities exist, and most
patients with extensive disease will require long-
term therapy. Excellent oral and ocular care
should be emphasized in patients diagnosed with
MMP. Therefore, patient care should coordinate
the services of both an ophthalmologist and
dentist (see Sect. 8.3 for more information on
oral care). In regards to ocular care, frequent
lubrication with artificial tears to prevent dryness
is recommended, and topical cyclosporine can be
considered for extreme dryness although burning
may limit compliance. Placement of lacrimal
Fig. 8.11 Scarring blistering dermatosis on the scalp in punctal plugs is recommended if patients do not
Cicatrical Pemphigoid
already have occluded puncta secondary to scar-
ring. It is also important to clean debris and
bullous dermatosis should also be included in the exudate that accumulates in order to prevent
differential diagnosis [25]. secondary infection. Cleaning can also be
The most common sites of MMP involvement achieved with artificial tears, but buffered pre-
are the oral mucosa and conjunctival mucosa, but served saline solutions are also available for
the nasopharynx, esophagus, larynx, and anogen- patients that need an extra cleanse [26].
ital mucosa can also be affected (Fig. 8.10) [25, For MMP localized to the oral cavity with or
26]. Approximately 25% of patients will display without cutaneous involvement, the first-line
cutaneous involvement, typically scalp (Fig. 8.11), therapy has been topical corticosteroids such as
but mucosal disease predominates in true cases dexamethasone swish [25]. Other vehicles have
of MMP. Any part of the mouth can be affected been used such as corticosteroid gels, which are
including the attached gingiva, hard palate, and more easily applied and better tolerated within
buccal mucosa. A common clinical presentation the oral cavity. There are few recognized adverse
is that of a painful, erosive gingivitis, and intact effects associated with steroid use in the oral
blisters are usually not apparent. Symptoms and cavity including oral candidiasis and herpes
clinical findings in early ocular MMP are often simplex virus reactivation [26]. Topical corti-
nonspecific, and patients may complain of burn- costeroids should not be used alone and are not
ing, pain, or foreign body sensation [25]. effective in controlling disease progression in
ocular MMP [111]. Although corticosteroid

injections have been used for ocular MMP, it 8.13 Linear Iga Bullous Dermatosis
only achieves short-term results and carries a
risk of cataract formation. Subconjunctival Linear IgA bullous dermatosis (LABD) is an
injections should only be performed by an oph- autoimmune subepidermal blistering disease with
thalmologist, but are rarely used in clinical a heterogenous clinical presentation often idio-
practice [26]. pathic or drug induced affecting both adults and
Dapsone can be used as first-line therapy in children. The morbidity and mortality of this dis-
localized MMP or slowly progressing, extensive ease largely rests on whether mucous membranes
disease as it can take 10–12 weeks before pro- as these lesions will tend to heal with scarring.
ducing benefit [42]. Systemic corticosteroids are Desquamative gingivitis may secondarily dam-
the first-line therapy for treatment of extensive age teeth, while ocular involvement can poten-
MMP, rapidly progressive MMP, or in patients tially lead to blindness as seen in MMP [122].
with ocular, laryngeal, esophageal, severe ano- Adults often deal with higher morbidity rates as
genital, or severe gingival involvement causing the disease course is prolonged as compared to
loosening of teeth [33]. However, systemic corti- children.
costeroids alone are frequently inadequate for The true incidence of LABD is unknown, but
disease control and adjuvant immunosuppres- the incidence in southern England has been esti-
sants are often required [25]. Azathioprine is the mated to be 1 in 250,000 per year [122]. Incidence
first choice of adjuvant therapy in MMP, pro- in the USA has not been reported. LABD can
vided the disease is not rapidly progressive and occur at any age, but there are two peaks of onset:
threatening vision [33]. Mycophenolate mofetil an average age of onset at 60 years in adults, and
has also demonstrated efficacy as an adjuvant an average age of 4.5 years in children [123–125].
therapy; however, cyclophosphamide is used in Many drugs have been reported in association
aggressive MMP, as it achieves efficacy sooner with LABD, but nearly half the cases are due to
than either azathioprine or mycophenolate vancomycin [25]. Other important inducers of
mofetil [110]. LABD include captopril, penicillins, cepha-
Other treatment modalities include the use of losporins, and nonsteroidal anti-inflammatory
IVIg, which has a very rapid onset of action and agents [126]. Another factor affecting the mor-
found to be especially helpful in patients with bidity and mortality of LABD includes the docu-
progressive ocular MMP suffering from active mented association with malignancy seen in
deterioration of vision [112, 113]. There has B-cell lymphoma, chronic lymphocytic leuke-
been reported success using etanercept and mia, and carcinoma of the bladder, thyroid and
infliximab in the management of MMP [114– esophagus [122, 127].
116]. Rituximab has been reported to be success- Linear IgA disease antigen-1 (LAD-1), the
ful in three cases of recalcitrant MMP [117–119]. 120-kDa cell-derived soluble ectodomain of
A single case of thalidomide use in refractory BP180 is the major target antigen of IgA autoan-
MMP has been reported, which may be consid- tibodies in patients with linear IgA disease.
ered in patients that are not responding to con- BP230 is an additional target antigen in the dis-
ventional therapies [120]. Subconjunctival ease [65]. The diagnosis of LABD is based on
mitomycin C injections have been used by oph- histology, which invariably shows a subepider-
thalmologists in the treatment of ocular MMP mal blister with a superficial dermal infiltrate of
and reserved as an option of last resort [121]. neutrophils. DIF is confirmatory with homoge-
Despite the numerous treatment options avail- nous, linear IgA deposits at the BMZ. Rarely,
able, decisions must be heavily weighed against weak deposits of IgG and C3 at the BMZ may
the potential adverse effects of therapy, and par- also be present [25]. IIF can be either negative or
ticularly in elderly patients with multiple comor- detect low levels of IgA BMZ autoantibodies that
bidities [25]. would react with the epidermal, dermal, or both
8.14 Epidermolysis Bullosa

Acquisita
Epidermolysis bullosa acquisita (EBA) is an

extremely rare, acquired subepidermal blistering
disorder, associated with significant morbidity
resulting from involvement of various skin and
mucosal surfaces including similar irreversible
complications as seen in MMP such as blindness
and esophageal strictures. Tracheal involvement
and upper airway obstruction requiring tracheos-
tomy has been described. Indeed, more aggres-
Fig. 8.12 Annular arrangement of bullae (“cluster of
jewels” sign) on the trunk in Linear IgA Bullous sive cases of EBA are often difficult to control
Dermatosis and associated with a significant mortality rate.
EBA is a chronic disease that is difficult to treat
and for which there is no cure [131].
sides of the blister when tested on salt-split skin The exact incidence and prevalence of EBA is
substrate [128]. unknown, but it seems rare overall. Few available
As previously mentioned, LABD can vary in studies showed an incidence of 0.22 cases per
its clinical presentation; however, patients classi- million per year in Germany, 0.26 per million per
cally present with symmetric, grouped, annular year in France, 0.23 per million per year in
vesicles, and bullae on the trunk and extensors Kuwait, and a slightly higher incidence of 0.5 per
that are usually pruritic and often excoriated. million per year in Singapore [132–134]. EBA
Annular arrangement at the periphery showing a may occur in patients of any age with an average
tendency to heal in the center is a characteristic age at onset of 40 years, and unlike BP does not
feature of LABD known as the “cluster of jew- exhibit a predilection for the elderly [25]. The
els” sign (Fig. 8.12) [25]. Atypical presentations disease does seem to be slightly more common in
of LABD have been described including forms women and black patients [135]. The cause is
that resemble erythema multiforme, toxic epider- unknown, but genetic predisposition is likely
mal necrolysis, and a morbilliform eruption given its association with specific haplotypes
[129]. Mucosal involvement can occur, but is less HLA-DR2 and HLA-DRB1 [136]. A number of
commonly seen in drug-induced LABD, which disorders have been anecdotally reported with
appears within 7–14 days of starting the offend- EBA including systemic lupus erythematosus,
ing agent [25]. amyloidosis, autoimmune thyroiditis, diabetes
The majority of LABD cases will respond to mellitus, and multiple endocrinopathy syndromes
either oral dapsone or sulfapyridine therapy, [137]. The most frequent association is with
and most patients have a clinical response inflammatory bowel disease [25].
within 48–72 h. The average dose of dapsone EBA is characterized by IgG autoantibodies
needed for disease control is 100 mg daily, targeting type VII collagen, which is unique to
however, doses as high as 300 mg may be stratified squamous epithelium and is the primary
required [130]. On occasion, the addition of component of the anchoring fibril in the BMZ
oral prednisone in doses up to 40 mg daily for connecting the lamina densa to the papillary der-
complete control of the disease may be required mis of skin and mucosa [25, 138]. Two clinical
[128]. The treatment for drug-induced LABD types of EBA exist—the classic form and
involves discontinuation of the suspected caus- inflammatory form. The latter contains varying
ative agent, and improvement is usually evident degrees of inflammation with lymphocytes, neu-
within 3 weeks [25]. trophils, and eosinophils distinguishing it from
the former on histology. Inflammatory EBA is a standard immunosuppressant agents such as cor-
great mimicker of BP; thus, the distinction ticosteroids, azathioprine, and methotrexate have
between the two can only be made with been used with varying success [25]. In addition,
immunofluorescence studies and clinical course. variable efficacy has been reported in using pho-
DIF microscopy reveals linear deposits of IgG topheresis, infliximab, or high-dose IVIg.
along the BMZ, with variable presence of linear
C3, IgA, and IgM. The intensity of IgG is gener-
ally greater than the other substrates [25]. IIF can 8.15 Junctional and Dystrophic
be useful in differentiating EBA from BP since Epidermolysis Bullosa
circulating IgG antibodies along the dermal side
of salt-split skin can only be detected in 10–30% Junctional epidermolysis bullosa (JEB) and dys-
of cases of EBA [25, 139]. Furthermore, a more trophic epidermolysis bullosa represent the two
sensitive ELISA for the detection of antibodies other major types of inherited EB. The main
against type VII collagen is also available [129]. focus will include the JEB-Herlitz subtype and
The differential diagnosis of classic EBA the recessive dystrophic EB (RDEB) subtype in
includes variants of porphyria, pseudoporphyria, particular. According to a National Epidermolysis
and hereditary forms of epidermolysis bullosa, Bullosa Registry report, 50 EB cases occur per
while inflammatory EBA must be distinguished one million live births, and of these cases 5% are
from BP, LABD, MMP, bullous drug eruptions, classified as dystrophic while only 1% are
and bullous lupus [25]. Disruption of type VII classified as junctional [141]. All subtypes of
collagen function results in the clinical manifes- JEB are transmitted in an autosomal recessive
tations seen with this disease and also found dis- manner, while dystrophic EB is transmitted in
rupted in bullous lupus, although the latter often either an autosomal dominant or autosomal
presents with a known history or other signs or recessive manner. Evidently, RDEB is transmit-
symptoms of systemic lupus erythematosus. ted in an autosomal recessive fashion. The most
Patients with classic EBA present with blisters, severe subtype of JEB is JEB-Herlitz, which
arising in areas of the skin where frequent and leads to a mutation in the protein subunits of
minor trauma can occur on noninflammed skin laminin 5, a key component of the lamina lucida
including the dorsum of the hands, knuckles, of the dermo-epidermal junction [142]. RDEB
elbows, knees, sacral area, and feet. Healing usually results in a mutation within the type VII
results in scarring and milia formation [25]. collagen gene [143].
Approximately half of all patients present with Similar to the clinical features seen in EB sim-
inflammatory EBA, which constitutes a vesicu- plex, JEB and RDEB also exhibit mechanically
lobullous eruption most prominent over the trunk fragile skin tense fluid-filled blisters, erosions,
and flexural skin. As opposed to classic EBA, and crusts at birth with subsequent atrophic scar-
skin fragility is not a characteristic feature of ring (Fig. 8.13). A unique characteristic of JEB-
inflammatory EBA with minimal to absent scar Herlitz includes excessive granulation tissue
and milia formation. Mucous membrane involve- usually in a symmetric distribution involving
ment can occur either exclusively or with cutane- periorifacial skin, axillary vaults, and the upper
ous lesions, making it very difficult to clinically back and nape of the neck [144]. It is practically
distinguish from MMP [25, 140]. impossible to make a strict clinical diagnosis
Treatment of EBA is both challenging and comparing the several entities of epidermolysis
often unsatisfactory, as no clear therapeutic lad- bullosa; therefore, TEM is also used to aid in the
ders have been established. Prevention of blister diagnosis of JEB and RDEB as seen in EB sim-
formation through avoidance of trauma and plex. An exact diagnosis is preferred because
prompt attention to ulcerations is extremely each entity of epidermolysis bullosa carries dif-
important in order to reduce the possibility of ferent prognoses, unique morbidities, and specific
secondary infection. Dapsone, colchicine, and management strategies.
scan. A few patients with severe RDEB have

developed a cardiomyopathy, and it has been
suggested that this may be due to selenium
deficiency [148]. Finally, failure to thrive is com-
mon among infants with JEB and may lead to
death, and another major cause of death in JEB
during the first 6 years of life is acute airway
obstruction secondary to blisters within the tra-
chea [149]. A major complication of RDEB is
the development of multiple cutaneous squamous
cell carcinomas, which arise in chronic non-
healing wounds or hyperkeratotic lesions. The
risk of cutaneous malignancy is not solely lim-
Fig. 8.13 Infant with Dystrophic Epidermolysis Bullosa ited to patient with RDEB, and an increased risk
exhibiting blisters on legs of skin cancer exists for all individuals with any
chronic blistering disorder. Melanoma has also
arisen in a small number of children with RDEB
Morbidity and mortality of JEB and RDEB with a cumulative risk of 1.5% by the age of 12
relates to the consequences of repeated damage, years [150].
ulceration, and poor healing of the skin in addi- Similar to EB simplex, no specific treatment
tion to extracutaneous complications. options are currently available. For now, the daily
Malnutrition and growth stunting is consistently precautions should be taken with careful avoid-
seen in patients with JEB and RDEB but even ance to prevent trauma and careful surveillance
more severely than in patients with EB simplex for and prevention of infection. Other treatment
[16]. This may be due to oral blistering and modalities have been used historically as well
ulcerations, digestion and absorption problems, including systemic phenytoin administration in
or loss of blood and protein through open skin patients with dystrophic EB or JEB [151, 152].
blisters [82–84]. In addition vitamin and min- Interestingly, systemic retinoids in low doses
eral deficiencies have been reported more read- may very well have a role in effectively treating
ily in patients with JEB and RDEB including patients with RDEB, although little data exists on
low iron levels, zinc deficiency, deficiencies in this issue [153, 154]. Aggressive nutritional sup-
selenium and carnitine, and vitamins A, C, D, plementation should be considered in patients
and E [16]. Although more common over a with JEB or RDEB who are severely malnour-
decade ago, bacterial sepsis and subsequent ished. In addition, esophageal and urethral stric-
death is now relatively rare; however, it can still tures may be successfully dilated through
occur in the either JEB or RDEB, and hyperme- appropriate procedures. Since the risk of acute
tabolism resulting in increased heat loss and life-threatening airway obstruction is practically
protein turnover is especially common in the guaranteed in JEB, tracheostomy is considered
setting of skin infections [85, 145]. standard of care in such patients. Finally,
More unique characteristics of morbidity and squamous cell carcinomas should be treated with
mortality also arise in either JEB or RDEB. For conventional wide excision in those patients with
example, enamel hypoplasia is a characteristic RDEB who are at increased risk for developing
feature of JEB, and if left untreated, teeth are lost such lesions [155].
during childhood as a result of excessive caries All photographs used in this chapter are with
[145, 146]. Pseudosyndactyly can occur in permission and courtesy of Michael Fisher, M.D.,
RDEB, although it may also occur in JEB [147]. Melinda Mohr, M.D., Christopher D’Angelis,
Osteoporosis is a common finding in both RDEB M.D., Marc Meulener, M.D., and Karthik
and JEB, which is readily detectable on DEXA Krishnamurthy, D.O.
18. Chorzelski TPHT, Jablonska S, et al. Can pemphigus

References vulgaris be induced by nutritional factors? Eur J
Dermatol. 1996;6:284–6.
1. Powell AM, Black M. A stepwise approach to the 19. Lee AN, Werth VP. Activation of autoimmunity fol-
diagnosis of blisters in the clinic. Clin Dermatol. lowing use of immunostimulatory herbal supple-
2001;19:598–606. ments. Arch Dermatol. 2004;140:723–7.
2. Harman KE. New laboratory techniques for the 20. Brenner S, Goldberg I. Drug-induced pemphigus.
assessment of acquired immunobullous disorders. Clin Dermatol. 2011;29(4):455–7.
Clin Exp Dermatol. 2002;27:40–6. 21. Bhol K, Mohimen A, Ahmed AR. Correlation of sub-
3. Mihai S, Sitaru C. Immunopathology and molecular classes of IgG with disease activity in pemphigus vul-
diagnosis of autoimmune bullous diseases. J Cell Mol garis. Dermatology. 1994;189 Suppl 1:85–9.
Med. 2007;11:462–81. 22. Wilson CL, Wojnarowska F, Dean D, Pasricha JS. IgG
4. Fine JD. Management of acquired bullous skin dis- subclasses in pemphigus in Indian and UK popula-
eases. N Engl J Med. 1995;30:1475–84. tions. Clin Exp Dermatol. 1993;18(3):226–30.
5. Browne BJ, Edwards B, Rogers RL. Dermatologic 23. Amagai M, Tsunoda K, Zillikens D, et al. The clinical
emergencies. Prim Care Clin Office Pract. 2006;33: phenotype of pemphigus is defined by the anti-des-
685–95. moglein autoantibody profile. J Am Acad Dermatol.
6. Fuertes I, Guilabert A, Mascaro JM, et al. Rituximab 1999;40:167–70.
in childhood pemphigus vulgaris: a long-term follow- 24. Keehn CA, Morgan MB. Clinicopathologic attributes
up case and review of the literature. Dermatology. of common geriatric dermatologic entities. Dermatol
2010;221:13–6. Clin. 2004;22(1):115–23 [vii.].
7. Yeh SW, Sami N, Ahmed RA. Treatment of pemphi- 25. Parker SRS, MacKelfresh J. Autoimmune blistering
gus vulgaris: current and emerging options. Am J Clin diseases in the elderly. Clin Dermatol. 2011;29:
Dermatol. 2005;6(5):327–42. 69–79.
8. Black M, Mignogna MD, Scully C. Number II. 26. Knudson RM, Kalaaji AN, Bruce AJ. The manage-
Pemphigus vulgaris. Oral Dis. 2005;11(3):119–30. ment of mucous membrane pemphigoid and pemphi-
9. Bastuji-Garin S, Souissi R, Blum L, et al. Comparative gus. Dermatol Ther. 2010;23:268–80.
epidemiology of pemphigus in Tunisia and France: 27. Mahoney MG, Wang Z, Rothenberger K, et al.
unusual incidence of pemphigus foliaceus in young Explanations for the clinical and microscopic local-
Tunisian women. J Invest Dermatol. 1995;104: ization of lesions in pemphigus foliaceus and vulgaris.
302–5. J Clin Invest. 1999;103:461–8.
10. Firooz A, Mazhar A, Ahmed AR. Prevalence of auto- 28. Ide A, Hashimoto T, Amagai M, et al. Detection of
immune diseases in the family members of patients autoantibodies against bullous pemphigoid and pem-
with pemphigus vulgaris. J Am Acad Dermatol. phigus antigens by an enzyme-linked immunosorbent
1994;31(3):434–7. assay using the bacterial recombinant proteins. Exp
11. Ahmed AR, Wagner R, Khatri K, et al. Major histo- Dermatol. 1995;4:112–6.
compatibility complex haplotypes and class II genes 29. Ishii K, Amagai M, et al. Detection of autoantibodies
in non-Jewish patients with pemphigus vulgaris. Proc against bullous pemphigoid and pemphigus antigens
Natl Acad Sci U S A. 1991;88(11):5056–60. by an enzyme-linked immunosorbent assay using the
12. Lombardi ML, Mercuro O, Ruocco V, et al. Common bacterial recombinant proteins. Exp Dermatol.
human leukocyte antigen alleles in pemphigus vul- 1995;4:112–6.
garis and pemphigus foliaceus Italian patients. J Invest 30. Risser J, Lewis K. Weinstock MA Mortality of bullous
Dermatol. 1999;113(1):107–10. skin disorders from 1979 through 2002 in the United
13. Szafer F, Brautbar C, Tzfoni E, et al. Detection of States. Arch Dermatol. 2009;145(9):1005–8.
disease-specific restriction fragment length polymor- 31. Seidenbaum M, David M, Sandbank M. The course
phisms in pemphigus vulgaris linked to the DQw1 and prognosis of pemphigus. A review of 115 patients.
and DQw3 alleles of the HLA-D region. Proc Natl Int J Dermatol. 1988;27:580–4.
Acad Sci U S A. 1987;84(18):6542–5. 32. Bystryn JC, Steinman NM. The adjuvant therapy
14. Matzner Y, Erlich HA, Brautbar C, et al. Identical of pemphigus. An update. Arch Dermatol. 1996;132:
HLA class II alleles predispose to drug-triggered and 203–12.
idiopathic pemphigus vulgaris. Acta Derm Venereol. 33. Fleming TE, Korman NJ. Cicatricial pemphigoid. J
1995;75(1):12–4. Am Acad Dermatol. 2000;43:571–91.
15. Sinha AA, Brautbar C, Szafer F, et al. A newly char- 34. Lee MS, Wakefield PE, Lonzelman JL, James WD.
acterized HLA DQ beta allele associated with pem- Oral insertable prosthetic device as an aid in treating
phigus vulgaris. Science. 1988;239(4843):1026–9. oral ulcers. Arch Dermatol. 1991;127:479–80.
16. Fedeles F, Murphy M, Rothe MJ, et al. Nutrition 35. Ahmed AR, Kurgis BS, Rogers RS. Cicatricial pem-
and bullous skin diseases. Clin Dermatol. 2010;28: phigoid. J Am Acad Dermatol. 1991;24:987–1001.
627–43. 36. Muzyka BC, Greenberg MS, Glick MG. Management
17. Ruocco V, Brenner S, Lombardi ML. A case of diet- of oral manifestations of mucous membrane pemphi-
related pemphigus. Dermatology. 1996;192:373–4. goid. J Geriatr Dermatol. 1994;2:105–9.
37. Amagai M, Komai A, Hashimoto T, et al. Usefulness 54. Niedermeier A. Delayed response of oral pemphigus
of enzyme-linked immunosorbent assay (ELISA) vulgaris to rituximab treatment. Eur J Dermatol.
using recombinant esmogleins 1 and 3 for serodiagno- 2006;16:266–70.
sis of pemphigus. Br J Dermatol. 1999;140:351–7. 55. Pandya AG, Dyke C. Treatment of pemphigus with
38. Khan YK, Kalaaji AN, Clarke BL. Prevention and gold. Arch Dermatol. 1998;134:1104–7.
treatment of glucocorticoid-induced osteoporosis in 56. Penneys NS, Eaglstein WH, Frost P. Management of
dermatologic practice: a review. J Drugs Dermatol. pemphigus with gold compounds. A long-term fol-
2008;7:2–8. low-up report. Arch Dermatol. 1976;112:185–7.
39. Toth GG, Jonkman MF. Therapy of pemphigus. Clin 57. Jolles S. A review of high-dose intravenous immuno-
Dermatol. 2001;19:761–7. globulin (hdIVIg) in the treatment of the autoimmune
40. Gerhart J, Kalaaji A. Development of Pneumocystis blistering disorders. Clin Exp Dermatol. 2001;26:
carinii pneumonia in patients with immunobullous 127–31.
and connective tissue disease receiving immunosup- 58. Lee F. Longterm clinical remission of oral and cutane-
pressive medications. J Am Acad Dermatol. 2010; ous pemphigus with thalidomide. Int J Dermatol.
62(6):957–61. 2011;50:1120–3.
41. Lehman JS, Kalaaji AN. Role of primary prophy- 59. Ahmed AR, Blose DA. Pemphigus vegetans. Neumann
laxis for pneumocystis pneumonia in patients treated type and Hallopeau type. Int J Dermatol. 1984;23:
with systemic corticosteroids or other immunosup- 135–41.
pressive agents for immune-mediated dermatologic 60. Becker BA, Gaspari AA. Pemphigus vulgaris and
conditions. J Am Acad Dermatol. 2010;63(5): vegetans. Dermatol Clin. 1993;11:429–52.
815–23. 61. Joly P, Litrowski N. Pemphigus group (vulgaris, veg-
42. Rogers RS, Mehregan DA. Dapsone therapy of cica- etans, foliaceus, herpetiformis, brasiliensis). Clin
tricial pemphigoid. Semin Dermatol. 1988;7:201–5. Dermatol. 2011;29:432–6.
43. Hornsten P, Keisu M, Wiholm B. The incidence of 62. James KA, Culton DA, Diaz LA. Diagnosis and clini-
agranulocytosis during treatment of dermatitis herpe- cal features of pemphigus foliaceus. Dermatol Clin.
tiformis with dapsone as reported in Sweden, 1972 2011;29(3):405–12.
through 1988. Arch Dermatol. 1990;126:919–22. 63. Kraigher O, Wohl Y, Gat A, Brenner S. A mixed
44. Raizman MB, Fay AM, Weiss JS. Dapsone-induced immunoblistering disorder exhibiting features of
neutropenia in patients treated for ocular cicatricial bullous pemphigoid and pemphigus foliaceus associ-
pemphigoid. Ophthalmology. 1994;101:1805–7. ated with Spirulina algae intake. Int J Dermatol.
45. Aberer W, Wolff SE, Stingl G, Wolff K. Azathioprine 2008;47:61–3.
in the treatment of pemphigus vulgaris. A long-term 64. Steffen C, Thomas D. The men behind the eponym:
follow-up. J Am Acad Dermatol. 1987;16:527–33. Francis E. Senear, Barney Usher, and the Senear-
46. Roenigk HH, Deodar S. Pemphigus treatment with Usher syndrome. Am J Dermatopathol. 2003;25(5):
azathioprine. Arch Dermatol. 1973;107:353–7. 432–6.
47. Nousari HC, Anhalt GJ. The role of mycophenolate 65. Schmidt E. Zillikens D Modern diagnosis of autoim-
mofetil in the management of pemphigus. J Am Acad mune blistering skin diseases. Autoimmun Rev.
Dermatol. 1999;135:853–4. 2010;10:84–9.
48. Beissert S, Werfel T, Frieling U, et al. A comparison 66. Grando SA. New approaches to the treatment of pem-
of oral methylprednisolone plus azathioprine or myco- phigus. J Investig Dermatol Symp Proc. 2004;9(1):
phenolate mofetil for the treatment of pemphigus. 84–91.
Arch Dermatol. 2006;142:1447–54. 67. Gupta R. Prolonged remission of pemphigus induced
49. Kirtschig G, Khumalo NP. Management of bullous by dexamethasone-cyclophosphamide pulse therapy.
pemphigoid: recommendations for immunomodula- Indian J Dermatol Venereol Leprol. 2007;73(2):
tory treatments. Am J Clin Dermatol. 2004;5:319–26. 121–2.
50. Fellner MJ, Katz JM, McCabe JB. Successful use of 68. Katz KH, Marks Jr JG, Helm KF. Pemphigus folia-
cyclophosphamide and prednisone for initial treat- ceus successfully treated with mycophenolate mofetil
ment of pemphigus vulgaris. Arch Dermatol. as a steroid-sparing agent. J Am Acad Dermatol.
1978;114:889–94. 2000;42(3):514–5.
51. Harman KE, Albert S, Black MM. Guidelines for the 69. Dumas V, Roujeau JC, Wolkenstein P, Revuz J,
management of pemphigus vulgaris. Br J Dermatol. Cosnes A. The treatment of mild pemphigus vulgaris
2003;149:926–36. and pemphigus foliaceus with a topical corticosteroid.
52. Ioannides D, Chrysomallis F, Bystryn JC. Br J Dermatol. 1999;140(6):1127–9.
Ineffectiveness of cyclosporine as an adjuvant to cor- 70. Cianchi G, Lembo L, Colonna L, et al. Pemphigus
ticosteroids in the treatment of pemphigus. Arch foliaceus induced by radiotherapy and responsive to
Dermatol. 2000;136:868–72. dapsone. J Dermatolog Treat. 2006;17(4):244–6.
53. El Tal AK, Posner MR, Spigelman Z, Ahmed AR. 71. Friedman H, Campbell I, Rocha-Alvarez R, et al.
Rituximab: a monoclonal antibody to CD20 used in Endemic pemphigus foliaceus (fogo selvagem) in
the treatment of pemphigus vulgaris. J Am Acad native Americans from Brazil. J Am Acad Dermatol.
Dermatol. 2006;55:449–59. 1995;32:949–56.
72. Warren SJ, Lin MS, Giudice GJ, et al. The prevalence 88. Schmidt E, Zillikens D. Autoimmune and inherited
of antibodies against desmoglein 1 in endemic pem- subepidermal blistering diseases: advances in the
phigus foliaceus in Brazil. Cooperative Group on clinic and the laboratory. Adv Dermatol. 2000;16:
Fogo Selvagem Research. N Engl J Med. 2000; 113–57.
343(1):23–30. 89. Hall WH, Ramachandran R, Narayan S, et al. An
73. Li N, Aoki V, Hans-Filho G, et al. The role of intra- electronic application for rapidly calculating Charlson
molecular epitope spreading in the pathogenesis of comorbidity score. BMC Cancer. 2004;4:94.
endemic pemphigus foliaceus (fogo selvagem). J Exp 90. Jassal SV, Chiu E, Hladuewich M. Loss of indepen-
Med. 2003;197:1501–10. dence of patients starting dialysis at 80 years of age
74. Ribeiro JM, Valenzuela JG, Pham VM, et al. An or older. N Engl J Med. 2009;361:1612–3.
insight into the sialotranscriptome of Simulium nigri- 91. Posner BM, Jette AM, Smith KW, et al. Nutrition
manum, a black fly associated with fogo selvagem in and health risks in the elderly: the nutrition screen-
South America. Am J Trop Med Hyg. 2010;82: ing initiative. Am J Public Health. 1993;83:972–8.
1060–75. 92. Marazza G, Pham HC, Scharer L, et al. Incidence of
75. Tur E, Brenner S, Lombardi ML. A case of diet- bullous pemphigoid and pemphigus in Switzerland:
related pemphigus. Dermatology. 1996;192:373–4. a 2-year prospective study. Br J Dermatol.
76. Anhalt GJ, Kim S, Stanley JR, et al. Paraneoplastic 2009;161:861–8.
pemphigus. An autoimmune mucocutaneous disease 93. Delgado JC, Turbay D, Yunis EJ, et al. A common
associated with neoplasia. N Engl J Med. 1990;323: major histocompatibility complex class II allele
1729–35. HLA-DQB1*0301 is present in clinical variants of
77. Kimyal-Asadi A. Jih MH Paraneoplastic pemphigus. pemphigoid. Proc Natl Acad Sci USA. 1996;93:
Int J Dermatol. 2001;40(6):367–72. 8569–71.
78. Amgai M, Nishikawa T, Nousari HC, et al. Antibodies 94. Nozu T, Mita H. Bullous pemphigoid and percutane-
against desmoglein 3 (pemphigus vulgaris antigen) ous endoscopic gastrostomy. Intern Med. 2010;49:
are present in sera from patients with paraneoplastic 971–5.
pemphigus and cause acantholysis in vivo in neonatal 95. Sheerin N, Bourke JF, Holder J, North J, Burns DA.
mice. J Clin Invest. 1998;102:775–82. Bullous pemphigoid following radiotherapy. Clin
79. Anhalt GJ. Paraneoplastic pemphigus. J Invest Exp Dermatol. 1995;20:80–2.
Dermatol Symp Proc. 2004;9:29–33. 96. Balato N, Ayala F, Patruno C, Turco P, Ruocco V.
80. Fine JD, Eady RAJ, Bauer EA, et al. Revised Bullous pemphigoid induced by a thermal burn. Int J
classification system for inherited epidermolysis Dermatol. 1994;33:55–6.
bullosa: report of the Second International Consensus 97. Parslew R, Verbov JL. Bullous pemphigoid at sites
Meeting on diagnosis and classification of epider- of trauma. Br J Dermatol. 1997;137:825–6.
molysis bullosa. J Am Acad Dermatol. 2000;42: 98. Khandpur S, Verma P. Bullous pemphigoid. Indian J
1051–66. Dermatol Venereol Leprol. 2011;77(4):450–5.
81. Fuchs E, Coulombe P, Cheng J, et al. Genetic bases of 99. Barnadas M, Rubiales V, Gonzalez J, et al. Enzyme-
epidermolysis bullosa simplex and epidermolytic linked immunosorbent assay (ELISA) and indirect
hyperkeratosis. J Invest Dermatol. 1994;103(S): immunofluorescence testing in a bullous pemphig-
25–30. oid and pemphigoid gestationis. Int J Dermatol.
82. Haynes L. Nutritional support for children with epi- 2008;47:1245–9.
dermolysis bullosa. Br J Nurs. 2006;15:1097–101. 100. Joly P, Roujeau JC, Benichou J, et al. A comparison of
83. Gruskay DM. Nutritional management in the child oral and topical corticosteroids in the treatment of
with epidermolysis bullosa. Arch Dermatol. patients with bullous pemphigoid: a multicenter ran-
1988;124:760–1. domized study. J Invest Dermatol. 2009;129:1681–7.
84. Fine JD, Johnson LB, Weiner M, et al. Gastrointestinal 101. Egan CA, Lazarova Z, Darling TN, et al. Anti-
complications of inherited epidermolysis bullosa: epiligrin cicatricial pemphigoid and relative risk for
cumulative experience of the National Epidermolysis cancer. Lancet. 2001;357:1850–1.
Bullosa Registry. J Pediatr Gastroenterol Nutr. 102. Roth MM. Pregnancy dermatoses, diagnosis man-
2008;46:147–58. agement and controversies. Am J Clin Dermatol.
85. Gamelli RL. Nutritional problems of the acute and 2011;12(1):25–41.
chronic burn patient. Relevance to epidermolysis 103. Djahansouzi S, Nestle-Kraemling C, Dall P, et al.
bullosa. Arch Dermatol. 1988;124:756–9. Herpes gestationis may present itself as a paraneo-
86. Retief CR, Malkinson FD, Pearson RW. Two familial plastic syndrome of choriocarcinoma-a case report.
cases of epidermolysis bullosa simplex successfully Gynecol Oncol. 2003;89(2):334–7.
treated with tetracycline. Arch Dermatol. 104. do Valle Chiossi MP, Costa RS, Ferreira Roselino
1999;135:997–8. AM. Titration of herpes gestationis factor fixing to C3
87. Fine JD, Eady RAJ. Tetracycline and epidermolysis in pemphigoid herpes gestationis associated with cho-
bullosa simplex-a new indication for one of the oldest riocarcinoma. Arch Dermatol. 2000; 136(1):129-30.
and most widely used drugs in dermatology. Arch 105. Yancey KB. Herpes gestationis. Dermatol Clin.
Dermatol. 1999;135:981–2. 1990;8:727–34.
106. Jenkins RE, Hern S, Black MM. Clinical fea- and immunopathologic overlap. J Am Acad
tures and management of 87 patients with pem- Dermatol. 1988;19(5):792–805.
phigoid gestationis. Clin Exp Dermatol. 123. Esterly NB, Furey NL, Kirschner BS, et al. Chronic
1999;24:255–9. bullous dermatosis of childhood. Arch Dermatol.
107. Paunescu MM, Feier V, Paunescu M. Dermatoses of 1977;113:42–6.
pregnancy. Acta Dermatovenerol Alp Panonica 124. Provost TT, Maize JC, Ahmed AR, et al. Unusual
Adriat. 2008;17(1):4–11. subepidermal bullous diseases with immunologic
108. Shornick JK. Herpes gestationis. J Am Acad features of bullous pemphigoid. Arch Dermatol.
Dermatol. 1987;17:539–56. 1979;115:156–60.
109. Yunis JJ, Mobini N, Yunis EJ, et al. Common major 125. Wojnarowska F, Marsden RA, Bhogal B, et al.
histocompatibility complex class II markers in clini- Childhood cicatricial pemphigoid with linear IgA
cal variants of cicatricial pemphigoid. Proc Natl deposits. Clin Exp Dermatol. 1984;9:407–15.
Acad Sci U S A. 1994;91:7747–51. 126. Kuechle MK, Stegemeir E, Maynard B, et al. Drug-
110. Chan LS, Ahmed AR, Anhalt GF, et al. The first induced linear IgA bullous dermatosis: report of six
international consensus on mucous membrane pem- cases and review of the literature. J Am Acad
phigoid. Arch Dermatol. 2002;43:571–91. Dermatol. 1994;30:187–92.
111. Foster CS. Cicatricial pemphigoid. Trans Am 127. Mobacken H, Kastrup W, Ljundhall K, et al. Linear
Ophthalmol Soc. 1986;85:527–663. IgA dermatosis: a study of ten adult patients. Acta
112. Ahmed AR, Colon JE. Comparison between IVIG Derm Venereol. 1983;63:123–8.
and conventional immunosuppressive therapy regi- 128. Dabrowski J, Chorzelski TP, Jablonska S, et al.
mens in patients with severe oral pemphigoid. Arch Immunoelectron microscopic studies in IgA linear
Dermatol. 2001;137:1181–9. dermatosis. Arch Dermatol Res. 1979;265:289–98.
113. Ahmed AR, Dahl MV. Consensus statement on the 129. Chen M, Chan LS, Cai X, et al. Development of an
use of intravenous immunoglobulin therapy in the ELISA for rapid detection of anti-type VII collagen
treatment of autoimmune mucocutaneous blistering autoantibodies in epidermolysis bullosa acquisita. J
diseases. Arch Dermatol. 2003;139:1051–9. Invest Dermatol. 1997;108:68–72.
114. Canizares MJ, Smith DI, Conners MS, et al. 130. Leonard JN, Haffenden GP, Ring NP, et al. Linear
Successful treatment of mucous membrane pemphi- IgA disease in adults. Br J Dermatol. 1982;107:
goid with etanercept in 3 patients. Arch Dermatol. 301–16.
2006;142:1457–61. 131. Wieme N, Lambert J, Moerman M, et al. Epidermolsis
115. Sacher C, Rubbert A, Konig C, et al. Treatment of bullosa acquisita with combined features of bullous
recalcitrant cicatricial pemphigoid with the tumor pemphigoid and cicatrical pemphigoid. Dermatology.
necrosis factor alpha antagonist etanercept. J Am 1999;198:310–3.
Acad Dermatol. 2022;46:113–5. 132. Zillikens D, Wever S, Roth A, et al. Incidence of
116. Hefferman MP, Bentley DD. Successful treatment of autoimmune subepidermal blistering dermatoses in a
mucous membrane pemphigoid with infliximab. region of central Germany. Arch Dermatol.
Arch Dermatol. 2006;142:1268–70. 1995;131:957–8.
117. Ross A, Jaycock P, Cook S, et al. The use of ritux- 133. Nanda A, Dvorak R, Al-Saeed K, et al. Spectrum of
imab in refractory mucous membrane pemphigoid autoimmune bullous diseases in Kuwait. Int J
with severe ocular involvement. Br J Ophthalmol. Dermatol. 2004;43:876–81.
2009;93:421–2. 134. Wong SN, Chua SH. Spectrum of subepidermal
118. Schumann T, Schmidt E, Booken N, et al. Successful immunobullous disorders seen at the National Skin
treatment of mucous membrane pemphigoid with Centre Singapore: a 2-year review. Br J Dermatol.
the anti-CD20 antibody rituximab. Acta Derm 2002;147:476–80.
Venereol. 2009;89:101–2. 135. Gammon WR. Epidermolysis bullosa acquisita.
119. Taverna JA, Lerner A, Bhawan J, et al. Successful Semin Dermatol. 1988;7:218–24.
adjuvant treatment of recalcitrant mucous membrane 136. Zumelzu C, Le Roux-Villet C, Loiseau P, et al. Black
pemphigoid with anti-CD20 antibody rituximab. J patients of African descent and HLA-DRB1*15:03
Drugs Dermatol. 2007;6:731–2. frequency overrepresented in epidermolysis bullosa
120. Duong DJ, Moxley RT, Kellman RM, et al. acquisita. J Invest Dermatol. 2011;131:2386–93
Thalidomide therapy for cicatricial pemphigoid. J [Epub ahead of print].
Am Acad Dermatol. 2002;47:S193–5. 137. Hallel-Halevy D, Nadelman C, Chen M, et al.
121. Donnenfelt ED, Perry HD, Wallerstein A, et al. Epidermolysis bullosa acquisita update and review.
Subconjunctival mitomycin C for the treatment of Clin Dermatol. 2001;19:712–18.
ocular cicatricial pemphigoid. Ophthalmology. 138. Woodley DT, Briggaman RA, O’Keefe EJ, et al.
1999;106:72–8. Identification of the skin basement membrane
122. Wojnarowska F, Marsden RA, Bhogal B, Black MM. autoantigen in epidermolysis bullosa acquisita. N
Chronic bullous disease of childhood, childhood Engl J Med. 1984;310:1007–13.
cicatricial pemphigoid, and linear IgA disease of 139. Gammon WR, Kowalwski C, Chorzelski TP, et al.
adults. A comparative study demonstrating clinical Direct immunofluorescence studies of sodium
chloride-separated skin in the differential diagnosis 148. Melville C, Atherton D, Burch M, et al. Fatal
of bullous pemphigoid and epidermolysis bullosa cardiomyopathy in dystrophic epidermolysis
aquisita. J Am Acad Dermatol. 1990;22:664–70. bullosa. Br J Dermatol. 1996;135:603–6.
140. Caux F, Kirtschig G, Lemarchand-Venencie F, et al. 149. Fine JD, Johnson LB, Weiner M, Suchindran C.
IgA epidermolysis bullosa aquisita in a child result- Tracheolaryngeal complications of inherited epider-
ing in blindness. Br J Dermatol. 1997;137:270–5. molysis bullosa (EB): experience of the National EB
141. Fine JD, Bauer EA, McGuire J, Moshell A, editors. registry. Laryngoscope. 2007;117(9):1652–60.
Epidermolysis bullosa: clinical, epidemiologic, and 150. Fine JD, Johnson LB, Suchindran C, et al. Cancer
laboratory advances and the findings of the National and inherited epidermolysis bullosa: lifetable analy-
Epidermolysis Bullosa Registry. Baltimore, MD: ses of the National Epidermolysis Bullosa Registry
Johns Hopkins University Press; 1999. study population. In: Fine JD, Bauer EA, McGuire J,
142. Christiano AM, Uitto J. Molecular diagnosis of Moshell A, editors. Epidermolysis bullosa: clinical,
inherited skin diseases: the paradigm of dystrophic epidemiologic, and laboratory advances, and the
epidermolysis bullosa. Adv Dermatol. 1996;11: findings of the national epidermolysis bullosa regis-
199–214. try. Baltimore, MD: Johns Hopkins University Press;
143. Uitto J, Christiano AM. Molecular basis for the dys- 1999. p. 175–92.
trophic forms of epidermolysis bullosa: mutations in 151. Bauer EA, Cooper TW, Tucker DR, Esterly NB.
the type VII collagen gene. Arch Dermatol Res. Phenytoin therapy of recessive dystrophic epidermo-
1994;287:16–22. lysis bullosa. Clinical trial and prposed mechanism
144. Christiano AM, Fine JD, Uitto J. Genetic basis of of action on collagenase. N Engl J Med.
dominantly inherited transient bullous dermolysis of 1980;303:776–81.
the newborn: a splice site mutation in the type VII 152. Fine JD, Johnson L. Efficacy of systemic phenytoin
collagen gene. J Invest Dermatol. 1997;109:811–4. in the treatment of junctional epidermolysis bullosa.
145. Wright JT, Fine JD, Johnson LB. Hereditary epider- Arch Dermatol. 1988;124:1402–6.
molysis bullosa: oral manifestations and dental man- 153. Fritsch P, Klein G, Aubock J, Hintner H. Retinoid
agement. Pediatr Dent. 1993;15:242–8. therapy of recessive dystrophic epidermolysis bullosa
146. Wright JT, Fine JD, Johnson L. Dental caries risk in [Letter]. J Am Acad Dermatol. 1983;9:766–7.
hereditary epidermolysis bullosa. Pediatr Dent. 154. Fine JD, Weiner M, Stein A, et al. Systemic isot-
1994;16:427–32. retinoin and recessive dystrophic epidermolysis
147. Fine JD, Johnson LB, Weiner M, et al. bullosa (RDEB): results of a Phase 1 clinical trial. J
Pseudosyndactyly and musculoskeletal deformities Invest Dermatol. 2001;117:543.
in inherited epidermolysis bullosa (EB): experience 155. Fine JD. Skin bioequivalents and their role in the
of the National Epidermolysis Bullosa Registry, treatment of inherited epidermolysis bullosa
1986-2002. J Hand Surg [Br]. 2005;30:14–22. [Editorial]. Arch Dermatol. 2000;136:1259–60.
Vasculitis
9
Larissa Chismar, Sara Wildstein,
and Karthik Krishnamurthy
9.1 Introduction 9.1.1 Classification
Vasculitis is defined as inflammation of blood Several classification systems have been used.
vessel walls. There are many types of vasculi- One common system is based on vessel size [1]
tis, lending to its variable clinical presenta- (see Table 9.1). Large vessels encompass the
tion, with or without systemic involvement. aorta, as well as its branching large arteries and
The diagnosis of specific vasculitides can be veins that are directed toward major body regions,
difficult, given much overlap in clinical mani- such as the carotid arteries and their branches.
festations, serum laboratory tests, and tissue Giant cell arteritis and Takayasu arteritis mainly
histopathology. In addition, it is essential to involve these vessels. These large arteries are not
differentiate benign, self-limited forms of found in the skin, although skin manifestations
vasculitis from those that may be life- can be seen in these vasculitides [2]. Medium
threatening. vessels are the main visceral (renal, hepatic, cor-
onary, and mesenteric) vessels; these vessels are
implicated in entities such as polyarteritis nodosa
and Kawasaki disease. They may also be involved
in Wegener’s granulomatosis, Churg-Strauss syn-
drome, microscopic polyangitis, and cryoglobu-
linemic vasculitis. Small vessels are arterioles,
venules, and capillaries. These vessels are
involved in many types of vasculitis such as cuta-
neous leukocytoclastic vasculitis, Wegener’s
L. Chismar, M.D.
granulomatosis, Churg-Strauss syndrome, micro-
Division of Dermatology, Montefiore Medical Center,
Bronx, NY, USA scopic polyangitis, Henoch-Schonlein purpura,
e-mail: larissa.chismar@gmail.com and others accounting for the majority of visible
S. Wildstein, B.A. cutaneous disease.
Albert Einstein College of Medicine, Two classification schemes are those of the
Bronx, NY, USA American College of Rheumatology (ACR) and
K. Krishnamurthy, D.O. (*) the Chapel Hill Consensus Conference (CHCC).
Dermatology, Jacobi Medical Center, The ACR criteria of 1990 are a set of clinical
Cosmetic Dermatology Clinic, Montefiore
and histological features that classify vasculiti-
Medical Center, Albert Einstien College of Medicine,
Bronx, NY, USA des (see Table 9.2) [3–10]. The CHCC definitions
e-mail: kkderm@gmail.com of 1992 provide histological definitions for ten

176 L. Chismar et al.
Table 9.1 Size-based classification of vasculitis [1] endothelium and also provides a chemotactic
Vessel size Vasculitides signal for the recruitment of inflammatory cells.
Small Cutaneous small vessel The immune complexes themselves are also
vasculitis thought to activate polymorphonuclear leuko-
Henoch-Schonlein purpura cytes (PMNs) and increase production of tumor
Urticarial vasculitis
necrosis factor-alpha (TNF-alpha), Fas ligand,
Small and medium Cryoglobulinemic vasculitis
Microscopic polyangitis and perforin. Vessel damage may occur during
Wegener’s granulomatosis diapedesis of PMNs from the luminal side of the
Churg-Strauss syndrome vessel wall [14].
Malignancy-associated
In the anti-neutrophil cytoplasmic antibody
vasculitis
Infection-associated vasculitis (ANCA)-associated vasculitides (Wegener’s
Drug-associated vasculitis granulomatosis, Churg-Strauss syndrome, and
Connective tissue disorder- microscopic polyangitis), antibodies directed
associated vasculitis
against myeloperoxidase (MPO) or proteinase 3
Medium Polyarteritis nodosa
(PR3) are present. Anti-MPO antibodies increase
Large Takayasu’s arteritis
Giant cell arteritis leukocyte adhesion to endothelial cells and
migration into renal and pulmonary tissues. These
antibodies also activate MPO; this generates an
oxidative stress which leads to damage of
types of vasculitis (see Table 9.3) [11]. Both of endothelial cells. PR3 bound to the neutrophil
these classification schemes were designed as membrane plays a proinflammatory role, and
research tools. CHCC definitions are based on anti-PR3 antibodies increase the expression of
histology and have limited value for clinical membrane-bound PR3 in neutrophils during cell
diagnosis. The ACR criteria are more amenable adhesion. Anti-PR3 also activates epithelial cells
to clinical diagnosis, but these criteria have a and increases epithelial cell production of
positive predictive value of only 17–29% for the proinflammatory cytokines (interleukin (IL)-6,
diagnosis of specific vasculitides [12]. An expert IL-8, monocyte chemoattractant protein 1, and
group from the European League Against TNF) [14].
Rheumatism (EULAR) has recently suggested Cell-mediated immune responses may also
that new diagnostic and classification criteria play a role in giant cell arteritis, Takayasu’s
should be developed with more consideration arteritis, Wegener’s granulomatosis, and Churg-
given to current diagnostic testing. While this Strauss syndrome. CD4+ T cells are activated by
group did not propose a new classification sys- antigens in vessel walls or in the circulation.
tem, they proposed 17 points to consider in the These cells produce chemotactic cytokines which
development of such a system. These points recruit monocytes. Monocytes mature into mac-
include biopsy, laboratory testing, radiologic rophages which produce lysosomal enzymes that
testing, nosology, definitions, and research damage endothelial cells [14].
agenda [13].
9.1.3 The Emergent Nature

9.1.2 Pathogenesis of Vasculitis
Vasculitis may be caused by a Type III hyper- Vasculitis is an emergency because of systemic
sensitivity reaction which leads to deposition complications which can be life-threatening.
of immune complexes in blood vessel walls. Renal, gastrointestinal, pulmonary, and cardiac
This deposition is an early event in pathogen- complications can be seen with specific vasculiti-
esis and is followed by activation of comple- des. Urgent diagnosis of vasculitis can ensure
ment. Complement may directly damage the prompt initiation of appropriate treatment.
9 Vasculitis 177
Table 9.2 ACR criteria for classification of vasculitis [4–10]

Disease Criteria
Hypersensitivity vasculitis (diagnose with 3/5 1. Age >16 years at disease onset
criteria; three or more criteria with sensitivity of 2. Medication taken at the onset of symptoms that may have
71.0% and specificity of 83.9%) precipitated the event
3. Palpable purpura
4. Maculopapular rash
5. Biopsy including arteriole and venule with granulocytes in
a perivascular or extravascular location
Henoch-Schonlein purpura (diagnose with 2/4 1. Palpable purpura
criteria; two or more criteria with sensitivity of 2. Age less than or equal to 20 years at disease onset
87.1% and specificity of 87.7%) 3. Bowel angina
4. Vessel wall granulocytes on biopsy
Wegener’s granulomatosis (diagnose with 2/4 1. Nasal or oral inflammation
criteria; two or more criteria with sensitivity of 2. Abnormal chest X-ray with nodules, fixed infiltrates, or
88.2% and specificity of 92.0%) cavities
3. Urinary sediment with microscopic hematuria (>5 red
blood cells per high power field) or red cell casts
4. Granulomatous inflammation on biopsy
Churg-Strauss syndrome (diagnose with 4/6 criteria; 1. Asthma
four or more criteria with sensitivity of 85.0% and 2. Eosinophilia (>10%)
specificity of 99.7%) 3. Mononeuropathy or polyneuropathy
4. Nonfixed pulmonary infiltrates
5. Paranasal sinus abnormality
6. Extravascular eosinophils
Polyarteritis nodosa (diagnose with 3/10 criteria; 1. Weight loss greater than or equal to 4 kg
three or more criteria with sensitivity of 82.2% and 2. Livedo reticularis
specificity of 86.6%) 3. Testicular pain or tenderness
4. Myalgias, weakness, or leg tenderness
5. Mononeuropathy or polyneuropathy
6. Hypertension with diastolic blood pressure >90 mmHg
7. Renal impairment with elevated blood urea nitrogen
(>40 mg/dl) or creatinine (>1.5 mg/dl)
8. Hepatitis B Virus
9. Abnormal arteriography
10. Biopsy of small or medium-sized artery containing
polymorphonuclear leukocytes
Takayasu’s arteritis (diagnose with 3/6 criteria; 1. Age at disease onset less than or equal to 40 years
presence of three or more criteria with sensitivity of 2. Claudication of extremities
90.5% and specificity of 97.8%) 3. Decreased brachial artery pulses
4. >10 mmHg difference in systolic blood pressure between
arms
5. Bruit over subclavian artery or aorta
6. Abnormal arteriogram
Giant cell arteritis (diagnose with 3/5 criteria; 1. Age at disease onset greater than or equal to 50 years
presence of three or more criteria with sensitivity of 2. New headache
93.5% and specificity of 91.2%) 3. Temporal artery abnormality (tenderness to palpation or
decreased pulsation)
4. Elevated erythrocyte sedimentation rate (greater than or
equal to 50 mmHg)
5. Abnormal artery biopsy showing vasculitis
Table 9.3 CHCC definitions of vasculitis [11]

Disease Definition
Cutaneous small vessel vasculitis Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or
glomerulonephritis
Henoch-Schonlein purpura Vasculitis with IgA-dominant immune deposits, affecting small vessels (i.e.,
capillaries, venules, or arterioles). Typically involves skin, gut, and glomeruli,
and is associated with arthralgias or arthritis
Cryoglobulinemic vasculitis Vasculitis, with cryoglobulin immune deposits, affecting small vessels (i.e.,
capillaries, venules, or arterioles), and associated with cryoglobulins in serum.
Skin and glomeruli are often involved
Microscopic polyangitis Necrotizing vasculitis, with few or no immune deposits, affecting small vessels
(i.e., capillaries, venules, or arterioles). Necrotizing arteritis involving small and
medium-sized arteries may be present. Necrotizing glomerulonephritis is very
common. Pulmonary capillaritis often occurs
Wegener’s granulomatosis Granulomatous inflammation involving the respiratory tract, and necrotizing
vasculitis affecting small- to medium-sized vessels (e.g., capillaries, venules,
arterioles, and arteries). Necrotizing glomerulonephritis is common
Churg-Strauss syndrome Eosinophil-rich and granulomatous inflammation involving the respiratory tract,
necrotizing vasculitis affecting small- to medium-sized vessels, and associated
with asthma and eosinophilia
Polyarteritis nodosa Necrotizing inflammation of medium-sized or small arteries without glomerulo-
nephritis or vasculitis in arterioles, capillaries, or venules
Kawasaki’s disease Arteritis involving large, medium-sized, and small arteries, and associated with
mucocutaneous lymph node syndrome. Coronary arteries are often involved.
Aorta and veins may be involved. Usually occurs in children
Takayasu’s arteritis Granulomatous inflammation of the aorta and its major branches. Usually occurs
in patients younger than 50
Giant cell arteritis Granulomatous arteritis of the aorta and its major branches, with a predilection
for the extracranial branches of the carotid artery. Often involves the temporal
artery. Usually occurs in patients older than 50 and often is associated with
polymyalgia rheumatica
9.2 Types of Vasculitis 9.2.2 Henoch-Schonlein Purpura
9.2.1 Cutaneous Small Vessel Henoch-Schonlein purpura (HSP) is a small ves-

Vasculitis sel vasculitis that is associated with immuno-
globulin A immune complex deposition. It
Cutaneous small vessel vasculitis, also known as accounts for approximately 10% of cases of
cutaneous leukocytoclastic angiitis, is caused by small vessel vasculitis [16]. HSP is the most
inflammation in post-capillary venules. Lesions common type of vasculitis in children. It classi-
often occur in crops on the lower extremities. cally occurs in boys 4–8 years of age. Peak inci-
Palpable purpura is the classic clinical finding, but dence is in winter months, and patients often
macules, urticarial lesions, and vesicles can also be have an upper respiratory tract infection 1–2
seen (Fig. 9.1). Once mature, these lesions do not weeks prior to the development of symptoms
blanch with diascopy. Patients may develop fever, [17]. A recent study by Weiss et al. has shown
malaise, arthralgia, and myalgia. Underlying causes temporal association between hospitalizations
include infections, medications, foods (gluten, milk for Group A beta-hemolytic streptococcus,
proteins), chemical exposure (petroleum products, Staphylococcus aureus, and Parainfluenza and
insecticides), autoimmune disease, and malignancy. hospitalization for HSP. Despite this temporal
Despite the numerous causes, no specific etiologic association, a causal role for these organisms has
factor is identified in up to 60% of patients [15]. not yet been established [18].
9 Vasculitis 179
Fig. 9.1 Early purpura on the ankle Fig. 9.2 Symmetrically distributed palpable purpura on
the lower extremities due to Henoch-Schonlein purpura
The classic tetrad of HSP includes palpable

purpura, arthritis, nephritis, and gastrointestinal effective in decreasing the intensity of abdominal
tract involvement with abdominal pain or bleed- pain and joint pain in this study [24]. A more
ing. All patients with HSP have skin involvement. recent study from these authors compared the
In a study of 100 children with HSP, 83% had outcomes of patients 8 years after treatment with
arthritis, 63% had abdominal pain, 33% had gas- prednisone or placebo at disease onset. This study
trointestinal bleeding, and 40% developed nephri- found no beneficial effect from early prednisone
tis [19]. Adults commonly present with joint or treatment, and the authors concluded that predni-
kidney involvement, but gastrointestinal manifes- sone should not be routinely used [25].
tations are less common. Adults may be more
refractory to treatment than children [20, 21].
Palpable purpura is the classic cutaneous 9.2.3 Urticarial Vasculitis
finding. Lesions may begin as macular erythema
or urticaria that develops into nonblanching ery- Urticarial vasculitis is a small vessel vasculitis that
thematous macules and papules. Lesions are is seen in 1–10% of patients with chronic urticaria
symmetrically distributed, and dependent areas [26]. It has a predilection for women and is most
such as the lower extremities and buttocks are the common in the fourth or fifth decades [27].
most common sites of involvement (Fig. 9.2). Patients with urticarial vasculitis have wheals
Individual lesions generally resolve within 10–14 and erythematous plaques that persist in the same
days [17]. While this condition is self-limited in location for more than 24 h. Patients often com-
most patients, the physician must take care to plain of burning pain in these lesions. These fea-
evaluate for renal involvement. Long-term renal tures contrast with the evanescent pruritic lesions
impairment is seen in 1.8% of all children with seen in classic, allergic urticaria, which is IgE-
HSP and in 19.5% of children who develop mediated. Lesions of urticarial vasculitis favor
nephritic or nephrotic syndrome [22]. In a study the proximal trunk and extremities. Petechiae or
by Coppo et al., end stage renal disease was seen purpura are often seen, and lesions frequently
in 15.8% of adults and 7% of children with HSP resolve with postinflammatory pigmentary alter-
nephritis [23]. The use of systemic therapy to ation (Fig. 9.3) [28].
decrease the likelihood of renal complications Normocomplementemic urticarial vasculitis
remains controversial. In one study by Ronkainen tends to be limited to the skin. It is often self-
et al., prednisone did not prevent renal disease limited and may be regarded as a subset of cuta-
from occurring although it led to faster resolution neous small vessel vasculitis [17]. Low
of disease once it occurred. Prednisone was also complement levels are seen in 18–32% of patients
commonly shows a neutrophilic leukocytosis,

while SLE may have neutropenia and positive
antinuclear antibody (ANA). Schnitzler syn-
drome is benign in most patients although there is
a risk of development of lymphoproliferative dis-
orders [32].
9.2.4 Cryoglobulinemic Vasculitis
Cryoglobulinemic vasculitis affects both small-

and medium-sized vessels. Cryoglobulins are
immunoglobulin molecules that precipitate in
Fig. 9.3 Residual hyperpigmentation after resolved urti-
carial vasculitis. The post-inflammatory changes and cold temperatures. This precipitation occurs
duration of lesions help distinguish this from allergic in vitro and may be due to intrinsic characteris-
urticaria tics of the immunoglobulin components [33].
Type I cryoglobulins are monoclonal immuno-
with urticarial vasculitis [27]. Patients with hypo- globulin (Ig) M and less commonly IgG. These
complementemic urticarial vasculitis have more cryoglobulins are associated with hematologic
severe disease with involvement of the joints conditions such as multiple myeloma or
(50% of patients), the gastrointestinal tract (20% Waldenstrom’s macroglobulinemia. Type I cryo-
of patients), and the airways with asthma and globulins are associated with cold-induced vas-
obstructive airways disease (20% of patients) culopathy but are not associated with vasculitis.
[29]. Some patients with severe disease may be Vasculopathy refers to vascular occlusion with-
considered to have hypocomplementemic urti- out blood vessel wall inflammation. The cryo-
carial vasculitis syndrome (HUVS). Patients with globulins associated with vasculitis, types II and
this syndrome may have renal involvement with III (the mixed cryoglobulins), are monoclonal
glomerulonephritis or ophthalmologic involve- IgM directed against polyclonal IgG and poly-
ment with uveitis or episcleritis in addition to the clonal IgM directed against polyclonal IgG,
above symptoms [30]. All patients with this syn- respectively. Fifteen percent of patients with
drome have anti-C1q precipitins, and 24% may cryoglobulins have cryoglobulinemic vasculitis.
have anti-double stranded deoxyribonucleic acid This vasculitis results from deposition of immune
(dsDNA) antibodies [17]. There are overlapping complexes in blood vessel walls with subsequent
features of HUVS and systemic lupus erythema- complement activation and inflammation [17].
tosis (SLE). Fifty percent of patients with HUVS In a study of 443 patients with cryoglobuline-
are subsequently diagnosed with SLE; HUVS is mia, underlying infection was seen in 75%, auto-
seen in 7–8% of patients with SLE [31]. Another immune disease in 24%, and hematologic disease
syndrome associated with urticarial vasculitis is in 7% [34]. Hepatitis C virus is the most common
Schnitzler syndrome. This syndrome is charac- infection associated with cryoglobulinemia [33].
terized by urticarial vasculitis, immunoglobulin Hepatitis B and human immunodeficiency virus
M monoclonal gammopathy, fever, lymphade- are less frequently associated. Associated autoim-
nopathy, arthralgia, bone pain, hepatosplenom- mune diseases include Sjögren’s syndrome, sys-
egaly, elevated erythrocyte sedimentation rate, temic sclerosis, SLE, rheumatoid arthritis (RA),
leukocytosis, and abnormal bone radiology stud- and primary antiphospholipid syndrome.
ies. This syndrome also has overlapping features Hematologic associations include non-Hodgkin’s
with SLE. Urticarial lesions in SLE may be more lymphoma, Hodgkin’s lymphoma, chronic lym-
pruritic and difficult to control than those of phocytic leukemia, chronic myeloid leukemia,
Schnitzler syndrome. Schnitzler syndrome also multiple myeloma, and myelodysplasia [34].
9 Vasculitis 181
9.2.5 Microscopic Polyangitis
Microscopic polyangitis is a necrotizing vascu-

litis that affects small- and medium-sized ves-
sels. It is most frequently associated with
perinuclear-antineutrophil cytoplasmic antibody
(pANCA; anti-myeloperoxidase antibody),
although cytoplasmic-antineutrophil cytoplas-
mic antibody (c-ANCA; anti-proteinase 3 anti-
body) is less frequently seen [17]. p-ANCA
has a sensitivity of 58% and specificity of 81%
in the diagnosis of microscopic polyangitis;
c-ANCA has a sensitivity of 23% [36]. It may
Fig. 9.4 Purpuric ulcers on the lower extremity due to
cryoglobulin deposition be slightly more common in men, and the aver-
age age of onset is 57 [37].
The first symptoms of microscopic polyangi-
Cryoglobulinemic vasculitis often presents tis are typically fever, weight loss, arthralgia,
with palpable purpura localized to the lower and/or myalgia which may begin months to years
extremities. Other cutaneous manifestations before other disease manifestations. Palpable
include erythematous papules, dermal nodules, purpura is the most common cutaneous manifes-
ecchymoses, skin necrosis, bullae, urticarial tation and is seen in 45% of patients at diagnosis
lesions, ulcers, and livedo reticularis (Fig. 9.4). In [38]. Other skin findings include splinter hemor-
contrast to the vasculopathy associated with type I rhages, nodules, livedo reticularis, and palmar
cryoglobulins, cold temperatures induce lesions in erythema [27]. Renal involvement, seen in
only 10–30% of cases [17]. Common extracutane- 79–90% of patients, manifests as a focal segmen-
ous manifestations include joint involvement, tal necrotizing glomerulonephritis. Pulmonary
peripheral neuropathy, and renal involvement. involvement occurs in 25–50% of patients, and
Patients may also have weakness, fever, lymph- pulmonary hemorrhage is seen in 12–29% of
adenopathy, central nervous system, pulmonary, patients [17].
and gastrointestinal tract involvement. Central ner- Microscopic polyangitis must be differenti-
vous system involvement may lead to devastating ated from other causes of pulmonary-renal syn-
complications such as cerebral ischemia, spinal drome which include the other ANCA-associated
cord complications, or cranial nerve palsy [34]. vasculitides (Wegener’s granulomatosis, Churg-
Detection of cryoglobulins requires careful Strauss syndrome), Goodpasture syndrome
handling of specimens. Two red-topped tubes (a clinical condition in which patients develop
(without anticoagulant) must be drawn and trans- diffuse pulmonary hemorrhage and rapidly pro-
ported to the laboratory at 37°C. This may be gressive glomerulonephritis), and SLE. Serology
achieved by submerging the tubes in warm water may be helpful in this endeavor; ANCA will be
or carrying the specimen in the axilla. The sam- positive in the ANCA-associated vasculitides,
ple is allowed to clot at 37°C for 1 h prior to cen- while anti-basement membrane antibody is seen
trifugation. Type I cryoglobulins may precipitate in Goodpasture syndrome. Microscopic polyan-
within 24 h, but it may take several days for pre- gitis may be differentiated from Wegener’s
cipitation of mixed cryoglobulins. Many labs granulomatosis by the lower incidence of severe
observe specimens for up to 7 days [35]. upper respiratory tract and ocular disease as
Rheumatoid factor can serve as a surrogate well as lack of granulomatous inflammation.
marker for Type II and III cryoglobulins because Unlike Churg-Strauss syndrome, microscopic
this test looks for IgM directed against IgG in the polyangitis is not associated with asthma or
blood. eosinophilia.
patients with Wegener’s granulomatosis, and

cutaneous manifestations may be the initial
finding in 10% of patients [17]. Systemic disease
in Wegener’s granulomatosis can be severe. The
upper and lower respiratory tracts are frequently
involved at the time of diagnosis. Upper respira-
tory tract involvement can manifest as epistaxis,
ulcerations of mucosa, nasal septal perforation, or
saddle nose deformity; symptoms of lower respi-
ratory tract involvement include cough, hemopty-
sis, dyspnea, and pleuritis. Glomerulonephritis is
less common at presentation, although it may
develop in up to 77% of patients [40]. Causes of
death include rapidly progressive renal disease
and pulmonary disease with hemorrhage [17].
Other less common systemic findings include
ocular (proptosis, optic nerve ischemia leading to
loss of vision, entrapment of extraocular muscles),
musculoskeletal (myalgia, arthralgia, arthritis),
nervous system (mononeuritis multiplex, cerebro-
vascular accident, cranial nerve palsies), and car-
diac (pericarditis, cardiac muscle or vessel
involvement) manifestations [40].
Fig. 9.5 Papulonecrotic lesions in Wegener’s
granulomatosis
9.2.7 Churg-Strauss Syndrome
9.2.6 Wegener’s Granulomatosis
Churg-Strauss syndrome, also known as allergic
Wegener’s granulomatosis is a triad of necrotiz- granulomatosis, is a necrotizing granulomatous
ing vasculitis of small vessels, necrotizing granu- vasculitis of small- and medium-sized vessels. It is
lomatous inflammation of the upper and lower classically associated with asthma and peripheral
respiratory tract, and pauci-immune glomerulo- blood eosinophilia. It is associated with p-ANCA
nephritis. It is associated with c-ANCA in in 55–60% of patients and c-ANCA in 10–15% of
75–80% of patients; those who are negative for patients [17]. It is slightly more common in women
this antibody are more likely to have a better and has an average age of onset of 35 [1].
prognosis with more localized disease. p-ANCA Churg-Strauss syndrome often occurs in three
is seen in only 10–15% of patients [17]. c-ANCA phases. In the first phase, patients have symptoms
has a sensitivity of 64% and specificity of 95% in of allergic rhinitis and asthma. This phase may last
the diagnosis of Wegener’s granulomatosis; for years to decades [17]. In the second phase,
p-ANCA has a sensitivity of 21% in this disease peripheral eosinophilia develops with eosinophilic
[36]. Wegener’s granulomatosis is slightly more infiltration of tissues, and in the third phase, patients
common in women. Ninety-eight percent of develop vasculitis [41]. There is often a long delay
patients in one study were Caucasians, and the between phase one and phase three; the average
peak age of onset is from 45 to 65 years [39]. length of the delay is 3 years, but in some patients
Palpable purpura and oral ulcers are common this delay may be as long as 30 years [17].
cutaneous manifestations of Wegener’s granulo- Symptoms may develop following the use of leu-
matosis. Other skin findings include subcutaneous kotriene inhibitors, abrupt discontinuation of ste-
nodules, ulcers, or papulonecrotic lesions roids, or vaccinations such as hepatitis B vaccine
(Fig. 9.5). The skin is involved in 46–66% of [17, 42]. It is unclear whether leukotriene inhibitors
9 Vasculitis 183
directly cause Churg-Strauss syndrome. The use of

these agents in the treatment of asthma may allow
for tapering of corticosteroid doses with subsequent
unmasking of Churg-Strauss symptoms [43].
Dermatologic manifestations occur in 40–70%
of patients. Common lesions include palpable and
retiform purpura, petechiae, ecchymoses, hemor-
rhagic bullae, subcutaneous nodules often located
on the scalp or extremities, urticaria, and livedo
reticularis (Fig. 9.6) [27]. Pulmonary, cardiac,
neurologic, renal, gastrointestinal, and rarely uro-
logic systems can be involved. Renal involvement
may take the form of focal segmental glomerulo-
Fig. 9.6 Retiform purpura in a patient with Churg-
nephritis. It is seen in 16–49% of patients with Strauss syndrome. Similar lesions may be seen in other
Churg-Strauss syndrome. Peripheral neuropathy, small- to medium-sized vessel vasculitides and other
usually mononeuritis multiplex, is very common entities
and occurs in 53–75% of patients. Potentially
fatal cardiovascular complications result from
granulomatous infiltration of the myocardium and
coronary vessel vasculitis [44]. Cardiovascular
manifestations include cardiac arrest, myocardial
infarction, valvular heart disease, congestive heart
failure, pericardial effusion, and constrictive peri-
carditis [41].
9.2.8 Malignancy-Associated
Vasculitis
Vasculitis may occur in the setting of malignancy,

and metastases may mimic vasculitis (Fig. 9.7). It is
more common with hematologic malignancies, Fig. 9.7 Metastatic bowel cancer mimicking cutaneous
although it can also occur with solid tumors. vasculitis
Malignancies that have been associated with vascu-
litis include hairy cell leukemia, leukemia, multiple
myeloma, non-Hodgkin’s lymphoma, Hodgkin’s
lymphoma, sarcomas, malignant histiocytosis, lung
cancer, cervical cancer, melanoma, breast cancer,
prostate cancer, and renal cancer. Therapy for can-
cer may also result in vasculitis; chemotherapy
agents, radiation, and bone marrow transplantation
have all been associated with vasculitis [45].
9.2.9 Infection-Associated Vasculitis
Vasculitis may occur secondary to bacterial, viral,

fungal, or parasitic infection (Fig. 9.8). Causative
organisms include Group A beta-hemolytic Fig. 9.8 Acral or septic vasculitis
Streptococcus, Staphylococcus aureus,

Mycobacterium, hepatitis A virus, hepatitis B
virus, hepatitis C virus, herpes simplex virus,
influenza virus, Candida albicans, Plasmodium
malariae, Schistosoma mansoni, Schistosoma
haematobium, and Onchocerca volvulus [15].
9.2.10 Drug-Associated Vasculitis
Numerous drugs have been implicated as causal

agents in vasculitis. The timing of the onset of
vasculitis is variable, and cases may occur hours
to years after the initial drug exposure. It often
develops following increases in dose or following
rechallenge with a given medication [46].
Drugs that induce ANCA-negative vasculitis
include methotrexate, isotretinoin, and colony
stimulating factors. ANCA-negative drug-associ-
ated vasculitis is often limited to the skin and
typically presents a few days to weeks after ini- Fig. 9.9 Necrotic purpura in a cocaine abuser. Note the
earlobe involvement
tial drug exposure. Other drugs induce an ANCA-
associated vasculitis; common examples are
propylthiouracil, allopurinol, hydralazine, mino- Sjögren’s syndrome. Vasculitis can also occur
cycline, penicillamine, and phenytoin. Retiform secondary to systemic sclerosis, Behçet’s disease,
purpura and visceral involvement with severe dermatomyositis, mixed connective tissue disease,
systemic complications may be seen with these relapsing polychondritis, and antiphospholipid
medications [27]. antibody syndrome. The presence of vasculitis
Levamisole-adulterated cocaine has also been correlates with increased activity of the under-
shown to cause an ANCA-associated vasculitis lying connective tissue disease and suggests a
which typically presents with purpuric lesions on poorer prognosis [51].
the face in a reticular, retiform, or stellate pattern
(Fig. 9.9). In one study, 50% of patients presented
with a rash on their earlobes [47]. Similarly, 9.2.12 Polyarteritis Nodosa
patients treated with levamisole for nephritic syn-
drome presented with a rash on their earlobes Polyarteritis nodosa is a necrotizing vasculitis of
[48–50]. Patients should immediately discontinue medium-sized blood vessels. It is more common in
cocaine use in order to accelerate the healing pro- men and most frequently occurs in patients 40–60
cess; in some cases this may be sufficient treat- years of age [17]. Systemic polyarteritis nodosa
ment. It is unclear whether steroids are useful in has been associated with hepatitis B virus [44].
this type of vasculitis [47]. Cutaneous polyarteritis nodosa has been associ-
ated with Group A beta-hemolytic Streptococcus,
Parvovirus B19, hepatitis B virus, hepatitis C virus,
9.2.11 Connective Tissue Disorder- and Mycobacterium tuberculosis. It can also be
Associated Vasculitis seen in association with inflammatory bowel dis-
ease (IBD) or minocycline use [52].
The most common connective tissue disorders In the systemic variant, livedo reticularis,
associated with vasculitis are RA, SLE, and ulcers with a “punched-out” appearance, and
9 Vasculitis 185
tender erythematous subcutaneous nodules are

seen [17]. Systemic findings include fever, weight
loss, malaise, fatigue, arthralgias, and myalgias.
Renal involvement may present with proteinuria,
renal failure, or hypertension. Gastrointestinal
involvement may lead to abdominal pain, nausea,
vomiting, or bleeding. Mononeuritis monoplex is
a typical neurologic manifestation. The heart,
testicles, and eyes may also be involved [53].
Orchitis is particularly common in patients with
polyarteritis nodosa secondary to hepatitis B
virus. Of note, there is no respiratory involve-
ment in classic polyarteritis nodosa [17].
In cutaneous polyarteritis nodosa, livedo retic- Fig. 9.10 Late desquamation of the palms in a child with
Kawasaki disease
ularis, subcutaneous nodules, and ulcers are seen.
A burst pattern of livedo reticularis surrounding
an ulcer is very suggestive of cutaneous polyar- four of these criteria may be diagnosed with
teritis nodosa. Painful subcutaneous ulcers are atypical Kawasaki disease if coronary artery
more common than in the systemic form. Systemic abnormalities are present [55].
symptoms are limited to constitutional symptoms, The exanthem of Kawasaki disease occurs in
arthralgias, myalgias, and neuropathy [52]. over 90% of patients. It may manifest as a scarla-
tiniform rash, generalized erythema, papules,
acral pustules, or erythema multiforme-like
9.2.13 Kawasaki Disease lesions. This rash may be noted at the onset of
fever, and it typically persists throughout the acute
Kawasaki disease is a vasculitis that is commonly stage of the illness. As mentioned above, other
seen in children. Most cases occur in children cutaneous manifestations of Kawasaki disease
between 6 months and 5 years, and the peak inci- include erythema and induration of the palms and
dence is from 13 to 24 months. It is most com- soles with fusiform swelling of the digits, desqua-
mon in Japanese, Korean, and Asian-American mation of digits beginning at the fingertips
children [54]. It is slightly more common in boys (Fig. 9.10), perineal rash with erythema and
with a male:female ratio of 1.4:1. It is most com- desquamation, strawberry tongue, and fissured
mon in the late winter and spring which has led erythematous lips [55].
some to propose an infectious etiology. An alter- Kawasaki disease is thought to proceed
native theory suggests that superantigens may through four stages. In the first stage (days 1–9) a
play an etiological role [55]. small vessel vasculitis is present along with inti-
The diagnosis of Kawasaki disease requires a mal inflammation in larger blood vessels. The
fever that lasts at least 5 days and four of the fol- second stage (days 12–25) is characterized by
lowing: polymorphic exanthem; peripheral thrombosis with inflammation of the coronary
extremity manifestations including erythema, arteries. In the third stage (days 28–31) the
edema, and induration in the acute phase and inflammation regresses, and in the fourth stage
desquamation in the convalescent phase; bilat- (day 40 to 4 years after the onset of illness) scar
eral nonexudative conjunctival injection; oropha- formation and reorganization of thrombi occur.
ryngeal manifestations including marked Death may occur in the first and second stages
erythema of lips, fissuring of lips, and strawberry from cardiac arrhythmias, myocarditis, acute
tongue; and nonsuppurative cervical lymphade- myocardial thrombosis, or rupture of coronary
nopathy with at least one lymph node greater artery aneurysms. In the third and fourth stages
than 1.5 cm in diameter. Patients with fewer than death may occur from sudden myocardial
infarction. Because of the risk of cardiovascular and exertional dyspnea. Patients develop syncope,
complications, echocardiography and electrocar- congestive heart failure, angina, hypertension,
diography (ECG) are recommended for all Raynaud’s phenomenon, and claudication of the
patients. Coronary arteriography may be pursued upper or lower extremities in the pulseless phase.
in those patients with persistent ECG changes or Physical exam may reveal arterial bruits and ten-
symptoms of cardiac ischemia [55]. Kawasaki derness over the sites of large arteries [61].
disease may have cardiac effects even years after Skin manifestations are seen in 8–28% of
the acute illness. Adults with history of Kawasaki patients. Cutaneous findings include erythema
disease may have increased risk of endothelial nodosum, erythema induratum, and pyoderma
dysfunction and premature atherosclerosis, and gangrenosum. These manifestations are typically
thus long-term follow-up may be warranted in localized to the lower extremities [62].
these patients [56].
Treatment with intravenous immunoglobulin
(IVIG) has been associated with improved out- 9.2.15 Giant Cell Arteritis
comes in this condition [55]. Treatment with
aspirin is somewhat controversial. Aspirin has Giant cell arteritis (temporal arteritis) is a form
been used because of its anti-inflammatory and of large vessel vasculitis that involves the aorta
antithrombotic effects. Typical regimens use high and its major branches. It is most common in
doses of 80–100 mg/kg/day during the acute individuals older than 50 years. It occurs most
febrile phase and a maintenance dose of 3–5 mg/ frequently in women and Caucasian individuals
kg/day once the fever subsides [55]. A retrospec- of Northern European descent [63].
tive study by Hsieh et al. found that treatment Giant cell arteritis can present with temporal
without aspirin had no effect on fever duration, headache, claudication of the jaw, and visual
response to IVIG, or incidence of coronary artery changes including visual loss. Nonspecific symp-
aneurysms in patients with acute Kawasaki dis- toms such as fever, malaise, night sweats,
ease who were treated with high-dose IVIG (2 g/ anorexia, and weight loss may also be present. It
kg) [57]. A Cochrane review from 2006 found can result in serious complications such as per-
that there was insufficient evidence to determine manent visual loss, aortic aneurysm, stroke, and
whether or not children should continue to receive limb claudication, and thus early detection is
aspirin in the treatment of Kawasaki disease [58]. essential [64]. Cutaneous findings include scalp
Studies have shown that corticosteroids may be tenderness, blanching of the temporal scalp, cord-
added to IVIG with improved clinical and cardiac like thickening of the temporal artery, and
outcomes [59]. Such improved outcomes are decreased or absent temporal arterial pulse [27].
especially seen in patients who are at high risk to
be IVIG nonresponders [60].
9.3 Clinical Evaluation
9.2.14 Takayasu’s Arteritis 9.3.1 History
Takayasu’s arteritis, also known as pulseless dis- A detailed history is essential in the diagnosis of
ease, is a vasculitis that affects large arteries. It is vasculitis, and a thorough review of systems
typically a disease of young women with peak should be performed. Symptoms suggestive of
incidence between 10 and 24 years of age. It is systemic involvement include fever, malaise,
most common in Asia [61]. weight loss, arthritis, arthralgia, myalgia, hemop-
Clinical manifestations are typically divided tysis, cough, shortness of breath, sinusitis,
into pre-pulseless and pulseless phases. In the pre- abdominal pain, melena, hematochezia, hematu-
pulseless phase patients may experience fever, ria, and paresthesias [17]. One should also
fatigue, weight loss, headache, myalgia, arthralgia, consider possible causes of vasculitis. Patients
9 Vasculitis 187
should be asked about preceding illnesses, medi- 9.3.3 Pathologic Evaluation

cations, vaccines, chemical exposures, and symp-
toms of connective tissue disease or malignancy. Biopsy confirms the diagnosis of vasculitis and
identifies the size of the involved vessel. In order
to obtain the most information, the most purpuric,
9.3.2 Physical Exam erythematous, and tender skin should be biopsied.
It is also important to biopsy lesions that are less
Palpable purpura is pathognomonic for vasculi- than 48 h old; after 48 h lymphocytes and mac-
tis. Palpable purpura consists of elevated, non- rophages replace initial inflammatory cells regard-
blanching erythematous lesions. Not all vasculitis less of the underlying type of vasculitis. This is
presents with palpable purpura, however, and a also true for direct immunofluorescence speci-
variety of dermatologic lesions may be seen mens as the likelihood of finding immunoglobu-
including macules, papules, wheals, vesicles, lins decreases after 48–72 h [68]. One must also
bullae, and ulcers [65]. Specific clinical manifes- take care when deciding on the type of biopsy
tations reflect the size of the involved vessels. to perform. The subcutaneous tissue must be
Small vessel vasculitis commonly presents with included if a medium-sized vessel vasculitis is
purpura, erythema, urticaria, vesiculobullous suspected. A deep biopsy of the central white area
lesions, superficial ulcers, and splinter hemor- should be performed for livedo reticularis. In
rhages. Medium-vessel vasculitis can present cases in which ulcers are present, one should
with subcutaneous nodules, erythematous nod- attempt to biopsy nonulcerated sites or the edge
ules, deep ulcers, livedo reticularis, pitted palmar of a superficial ulcer. In cases in which deep ulcers
scars, gangrene of the digits, or infarcts. Review are present, biopsy of the subcutaneous tissue
of vital signs may show hypertension if there is can be taken from the central portion of the ulcer.
renal artery involvement, and thorough neuro- In addition to hematoxylin and eosin staining, a
logic exam may reveal deficits consistent with sample may be sent for direct immunofluorescence
mononeuritis. Large vessel vasculitis often has [27]. See Table 9.4 for histologic findings in
no skin manifestations; common findings on specific types of vasculitis [61, 63, 69].
physical exam include asymmetric blood pres-
sure, absence of pulses, and bruits [27].
The important finding of retiform purpura 9.3.4 Laboratory and Radiologic
deserves special mention. Retiform purpura con- Evaluation
sists of nonblanching erythematous lesions in a
reticulate, branching, serpentine, or stellate pat- Thorough laboratory evaluation is required in
tern. Retiform purpura is caused by complete patients with systemic disease or chronic vasculi-
loss of blood flow in the dermal and subcutane- tis. Laboratory evaluation should include com-
ous blood vessels. It may be caused by vasculiti- plete blood count with differential, blood urea
des such as cryoglobulinemic vasculitis, nitrogen and creatinine, liver function tests, hepa-
connective tissue disorder-associated vasculitis, titis B and C serologies, ANCA, ANA, rheuma-
polyarteritis nodosa, microscopic polyangitis, toid factor, immunoglobulin levels, complement
Wegener’s granulomatosis, and Churg-Strauss levels, antiphospholipid antibodies, cryoglobu-
syndrome. It may also be caused by vasculopa- lins, urinalysis, and stool for occult blood [27]. In
thies. The differential diagnosis includes patients with fever and/or a heart murmur, blood
antiphospholipid antibody syndrome, protein C cultures and echocardiography may be warranted.
or S deficiencies, disseminated intravascular Anti-streptolysin O titers can also be checked
coagulation, coumadin necrosis, heparin necro- and may be particularly useful in children. The
sis, cholesterol embolization, calciphylaxis, and physician must be aware of the possibility of
type I cryoglobulinemia [66, 67]. false-negative test results, particularly with
Table 9.4 Histologic findings in specific vasculitides [59, 61, 67]

Vasculitis Histologic findings on H&E Direct immunofluorescence
Cutaneous small vessel Small vessel neutrophilic vasculitis affecting the Typically small granular deposits
vasculitis superficial dermal plexus (see disruption of vessels by of IgM, IgG, and C3 in vessel
inflammatory cells, deposition of fibrin in vessel walls walls
or lumen, and nuclear debris)
Henoch-Schonlein Small vessel neutrophilic vasculitis affecting IgA vascular deposits
purpura superficial dermis; occasionally may have involvement
of whole dermis
Urticarial vasculitis Focal nuclear debris or vascular fibrin deposits, with
or without extravasated red blood cells
Cryoglobulinemic Small vessel neutrophilic vasculitis affecting Vascular immunoglobulins (IgM)
vasculitis superficial dermis and subcutis vessels; some cases and complement
with neutrophilic muscular-vessel vasculitis
Microscopic polyangitis Small vessel neutrophilic vasculitis
Wegener’s Necrotizing vasculitis in small- and medium-sized
granulomatosis vessels
Churg-Strauss syndrome Small vessel eosinophil-rich neutrophilic vasculitis
affecting dermal venules and arterioles; less com-
monly muscular vessel eosinophil-rich arteritis or
histiocyte-rich granulomatous arteritis of the
dermo-subcutaneous junction or subcutis
Infection-associated Small vessel neutrophilic vasculitis affecting Predominant IgA vascular
vasculitis superficial dermis; increased frequency of pustules deposits
(subcorneal, intraepidermal, or subepidermal), tissue
neutrophilia; fewer lymphocytes and eosinophils
Drug-associated vasculitis Superficial dermal small vessel neutrophilic or
lymphocytic vasculitis; tissue eosinophilia
Connective tissue Mixed neutrophilic vasculitis affecting both small and
disorder-associated muscular vessels; may see pathologic findings from
vasculitis underlying disease
Polyarteritis nodosa Muscular vessel neutrophilic vasculitis affecting
arterial branch points at the dermo-subcutaneous
junction or in the subcutis
Takayasu’s arteritis Large vessel vasculitis with granulomatous
inflammation of the vessel wall and infiltration of
inflammatory cells into the adventitia
Giant cell arteritis Large and medium vessel vasculitis with lymphocytic
infiltrate with activated macrophages and multinucle-
ated giant cells
cryoglobulins and complement levels. It is sug- histamines, aspirin, nonsteroidal

gested that these labs be sent on at least three anti-inflammatory drugs (NSAIDS), leg eleva-
separate occasions [17]. tion, ice packs, and avoidance of tight-fitting
clothing may be sufficient. In a study of 95
patients with hypersensitivity vasculitis, 54
9.4 Treatment patients did not require treatment, and another 26
cases resolved with NSAIDS only [70]. It is
Many cases of cutaneous vasculitis will be self- important to note that NSAIDS have limited
limited and short-lived. The first step in treatment value in vasculitides with renal involvement.
is to reverse the underlying cause of the vasculi- These agents cause vasoconstriction of the affer-
tis, if possible. Symptomatic treatment with anti- ent arteriole which decreases renal perfusion and
9 Vasculitis 189
can exacerbate renal failure. In patients with itch- Cyclophosphamide may be associated with
ing or burning or in those with refractory or serious adverse effects such as infection, bone
recurrent skin disease, dapsone (titrated from 25 marrow toxicity, cystitis, transitional cell carci-
to 50 mg daily), colchicine (0.5–0.6 mg twice noma, myelodysplasia, and infertility [72]. An
daily or three times daily), or pentoxifylline important study by Jayne et al. showed that expo-
(400 mg three times daily) may be tried [71]. sure to cyclophosphamide could be safely reduced
Systemic immunosuppression may be required by substitution of azathioprine after remission was
in patients who develop systemic symptoms, achieved. In this study, comparable rates of relapse
extensive disease, or persistent lesions. Agents were seen in patients who continued on cyclophos-
that may be used include prednisone (15–80 mg phamide after remission (13.7%) and those who
daily or 1–1.5 mg/kg daily), methotrexate were switched to azathioprine (15.5%) [75].
(5–20 mg weekly), azathioprine (50–200 mg Methotrexate has been shown to be an alternative
daily or 0.5–2.5 mg/kg daily based on thiopurine to azathioprine in maintenance therapy. A study
methyltransferase (TPMT) level), hydroxychlo- by Pagnoux et al. showed that the two drugs had
roquine (400 mg three times daily), mycopheno- similar rates of adverse events (azathioprine 29/63
late mofetil (2 g daily), cyclosporine (2.5–5 mg/ patients, methotrexate 35/63) and relapse (azathio-
kg daily, divided twice a day), or cyclophosph- prine 23/63, methotrexate 21/63). Of note, 73% of
amide (2 mg/kg daily) [15, 71]. these relapses occurred after the study drugs were
Therapy for the ANCA-associated vasculitides discontinued [76]. Mycophenolate mofetil appears
has been studied in depth. Before the use of cyclo- to be less effective than azathioprine for mainte-
phosphamide, Wegener’s granulomatosis was a nance of remission. In a study of 156 patients,
fatal disease with death typically occurring within relapse was seen in 30/80 patients treated with
5–12 months of disease onset. The introduction of azathioprine and 42/76 patients treated with myco-
cyclophosphamide and corticosteroids increased phenolate mofetil (p = 0.03) [77].
survival to 80% [72]. A randomized controlled Novel biologic therapies targeted against
trial of 149 patients with ANCA-associated vasc- specific components of the immune system may
ulitis showed that pulse cyclophosphamide be used in patients in whom conventional therapy
(15 mg/kg every 2–3 weeks) was as effective as has failed. Agents such as infliximab (chimeric
daily oral cyclophosphamide (2 mg/kg) in induc- antitumor necrosis factor-alpha (TNF-alpha)
ing remission; in addition, fewer cases of leuko- monoclonal antibody), etanercept (fusion protein
penia were seen with the pulse regimen [73]. of the p75 TNF-alpha receptor and IgG1), adali-
In some patients, methotrexate may be an alter- mumab (fully humanized IgG1 anti-TNF-alpha
native to cyclophosphamide for induction of monoclonal antibody), rituximab (chimeric anti-
remission. A randomized trial of 100 patients CD20 monoclonal antibody), anakinra (recombi-
found similar remission rates at 6 months of ther- nant interleukin-1 receptor antagonist), and IVIG
apy (methotrexate 89.8% and cyclophosphamide may be used in refractory disease [78, 79].
93.5%). However, remission was delayed in Prospective studies of infliximab and adalimumab
patients with lower respiratory tract involvement combined with standard therapy of cyclophosph-
or more extensive disease. Patients treated with amide and corticosteroids in patients with ANCA-
methotrexate had a higher rate of relapse (69.5%) associated vasculitis have shown that these agents
than patients treated with cyclophosphamide may reduce corticosteroid requirements. Mean
(46.5%), and relapse occurred sooner in those prednisolone doses decreased from 23.8 mg/day to
treated with methotrexate (13 months) than in 8.8 mg/day at week 14 with infliximab [80]. In
those treated with cyclophosphamide (15 months). patients with ANCA-associated vasculitis and
In this study both treatments were tapered and renal involvement, adalimumab reduced mean
stopped by 12 months; the high rates of relapse prednisolone doses from 37.1 to 8.1 mg/day at
lead the authors to conclude that therapy should week 14 [81]. A randomized controlled trial of
be continued longer than 12 months [74]. 174 patients found that etanercept was not more
effective than placebo in maintenance treatment of 2. Carlson JA, Chen KR. Cutaneous vasculitis update:
Wegener’s granulomatosis. Sustained remission neutrophilic muscular vessel and eosinophilic, granu-
lomatous, and lymphocytic vasculitis syndromes. Am
was seen in 69.7% of patients treated with etaner- J Dermatopathol. 2007;29:32–43.
cept and in 75.3% of patients in the control group 3. Hunder GG, Arend WP, Bloch DA, et al. The
(p = 0.39) [82]. A recent study by the European American College of Rheumatology 1990 criteria for
Vasculitis Study Group found that rituximab and the classification of vasculitis. Introduction. Arthritis
Rheum. 1990;33:1065–7.
cyclophosphamide-based induction regimens for 4. Hunder GG, Bloch DA, Michel BA, et al. The
ANCA-associated renal vasculitides had similar American College of Rheumatology 1990 criteria for
rates of sustained remissions and adverse effects. the classification of giant cell arteritis. Arthritis
Sustained remission was seen in 76% of patients in Rheum. 1990;33:1122–8.
5. Arend WP, Michel BA, Bloch DA, et al. The American
the rituximab group (treated with glucocorticoids, College of Rheumatology 1990 criteria for the
rituximab for 4 weeks, and 2 cyclophosphamide classification of Takayasu arteritis. Arthritis Rheum.
pulses) and in 82% of patients in the control group 1990;33:1129–34.
(treated with glucocorticoids and cyclophosph- 6. Lightfoot RW, Michel BA, Bloch DA, et al. The
American College of Rheumatology 1990 criteria for
amide for 3–6 months followed by azathioprine). the classification of polyarteritis nodosa. Arthritis
Severe adverse effects occurred in 42% of patients Rheum. 1990;33:1088–93.
in the rituximab group and 36% of patients in the 7. Leavitt RY, Fauci AS, Bloch DA, et al. The American
control group; 18% of patients in each group died College of Rheumatology 1990 criteria for the
classification of Wegener’s granulomatosis. Arthritis
[83]. The RAVE-ITN Research Group found that Rheum. 1990;33:1101–7.
rituximab may be superior to cyclophosphamide 8. Masi AT, Hunder GG, Lie JT, et al. The American
for inducing remission in relapsing disease. College of Rheumatology 1990 criteria for the
Disease remission at 6 months (without corticos- classification of Churg-Strauss syndrome (allergic
granulomatosis and angiitis). Arthritis Rheum.
teroids) was seen in 67% of the rituximab group 1990;33:1094–100.
versus 42% of the control group treated with 9. Mills JA, Michel BA, Bloch DA, et al. The American
cyclophosphamide (p = 0.01) [84]. College of Rheumatology 1990 criteria for the
classification of Henoch-Schonlein purpura. Arthritis
Rheum. 1990;33:1114–21.
10. Calabrese LH, Michel BA, Bloch DA, et al. The
9.5 Conclusion American College of Rheumatology 1990 criteria for
the classification of hypersensitivity vasculitis.
The vasculitides are a heterogeneous group of dis- Arthritis Rheum. 1990;33:1108–13.
11. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature
eases. While some forms of vasculitis are limited of systemic vasculitides. Proposal of an international
to the skin, the physician must always consider consensus conference. Arthritis Rheum.
the possibility of systemic involvement. A thor- 1994;37:187–92.
ough history, physical examination, and biopsy 12. Rao JK, Allen NB, Pincus T. Limitations of the 1990
American College of Rheumatology classification cri-
increase the likelihood of making a correct diag- teria in the diagnosis of vasculitis. Ann Intern Med.
nosis. While some forms of vasculitis progress 1998;129:345–52.
slowly, others can lead to fatal complications rap- 13. Basu N, Watts R, Bajema I, et al. EULAR points to
idly; the prompt recognition of vasculitis and consider in the development of classification and
diagnostic criteria in systemic vasculitis. Ann Rheum
determination of extent of disease are crucial so Dis. 2010;69:1744–50.
that appropriate therapy can be initiated. 14. Danila MI, Bridges SL. Update on pathogenic mecha-
nisms of systemic necrotizing vasculitis. Curr
Rheumatol Rep. 2008;10:430–5.
15. Lotti T, Ghersetich I, Comacchi C, Jorizzo JL.
Cutaneous small-vessel vasculitis. J Am Acad
References Dermatol. 1998;39:667–90.
16. Carlson JA, Chen KR. Cutaneous vasculitis update:
1. Chung L, Kea B, Fiorentino DF. Cutaneous vasculitis. small vessel neutrophilic vasculitis syndromes. Am J
In: Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatopathol. 2006;28:486–506.
Dermatology. 2nd ed. Spain: Mosby Elsevier; 2008. 17. Fiorentino DF. Cutaneous vasculitis. J Am Acad
p. 347–67. Dermatol. 2003;48:311–40.
9 Vasculitis 191
18. Weiss PF, Klink AJ, Luan X, Feudtner C. Temporal 36. Beauvillain C, Delneste Y, Renier G, Jeannin P, Subra
association of Streptococcus, Staphylococcus, and JF, Chevailler A. Antineutrophil cytoplasmic antibod-
parainfluenza pediatric hospitalizations and hospital- ies: how should the biologist manage them? Clin Rev
ized cases of Henoch-Schonlein purpura. J Rheumatol. Allergy Immunol. 2008;35:47–58.
2010;37:2587–94. 37. Gonzalez-Gay MA, Garcia-Porrua C. Systemic vasc-
19. Saulsbury FT. Henoch-Schonlein purpura in children. ulitides. Best Pract Res Clin Rheumatol.
Report of 100 patients and review of the literature. 2002;16:833–45.
Medicine. 1999;78:395–409. 38. Burrows NP, Lockwood CM. Antineutrophil cyto-
20. Watts RA, Lane S, Scott DG. What is known about plasmic antibodies and their relevance to the derma-
the epidemiology of the vasculitides? Best Pract Res tologist. Br J Dermatol. 1995;132:173–81.
Clin Rheumatol. 2005;19:191–207. 39. Abdou NI, Kullman GJ, Hoffman GS, et al. Wegener’s
21. Blanco R, Martinez-Taboada VM, Rodriguez- granulomatosis: survey of 701 patients in North
Valverde V, Garcia-Fuentes M, Gonzalez-Gay MA. America. Changes in outcome in the 1990s. J
Henoch–Schonlein purpura in adulthood and child- Rheumatol. 2002;29:309–16.
hood. Arthritis Rheum. 1997;40:859–64. 40. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener’s
22. Narchi H. Risk of long term renal impairment and granulomatosis: an analysis of 158 patients. Ann
duration of follow-up recommended for Henoch- Intern Med. 1992;116:488–98.
Schonlein purpura with normal or minimal urinary 41. Ramakrishna G, Midthun DE. Churg-Strauss syn-
findings: a systematic review. Arch Dis Child. drome. Ann Allergy Asthma Immunol.
2005;90:916–20. 2001;86:603–13.
23. Coppo R, Mazzucco G, Cagnoli L, Lupo A, Schena 42. Vanoli M, Gambini D, Scorza R. A case of Churg-
FP. Long-term prognosis of Henoch-Schonlein nephri- Strauss vasculitis after Hepatitis B vaccination. Ann
tis in adults and children. Nephrol Dial Transplant. Rheum Dis. 1998;57:256–7.
1997;12:2277–83. 43. Jamaleddine G, Diab K, Tabbarah Z, Tawil A, Arayssi
24. Ronkainen J, Koskimies O, Ala-Houhala M, et al. T. Leukotriene antagonists and the Churg-Strauss syn-
Early prednisone therapy in Henoch-Schonlein pur- drome. Semin Arthritis Rheum. 2002;31:218–27.
pura: a randomized, double-blind, placebo controlled 44. Lhote F, Cohen P, Guillevin L. Polyarteritis nodosa,
trial. J Pediatr. 2006;149:241–7. microscopic polyangiitis and Churg-Strauss syn-
25. Jauhola O, Ronkainen J, Koskimies O, et al. Outcome drome. Lupus. 1998;7:238–58.
of Henoch-Schonlein purpura 8 years after treatment 45. Mertz LE, Conn DL. Vasculitis associated with malig-
with a placebo or prednisone at disease onset. Pediatr nancy. Curr Opin Rheumatol. 1992;4:39–46.
Nephrol. 2012;27(6):933–9 [Epub ahead of print]. 46. ten Holder SM, Joy MS, Falk RJ. Cutaneous and sys-
26. Poonawalla T, Kelly B. Urticaria: a review. Am J Clin temic manifestations of drug-induced vasculitis. Ann
Dermatol. 2009;10:9–21. Pharmacother. 2002;36:130–47.
27. Chen KR, Carlson JA. Clinical approach to cutaneous 47. Gross RL, Brucker J, Bahce-Altuntas A, et al. A novel
vasculitis. Am J Clin Dermatol. 2008;9:71–92. cutaneous vasculitis syndrome induced by levamisole-
28. Stone JH, Nousari HC. “Essential” cutaneous vasculitis: contaminated cocaine. Clin Rheumatol. 2011;30:1385
what every rheumatologist should know about vasculitis [Epub ahead of print].
of the skin. Curr Opin Rheumatol. 2001;13:23–34. 48. Menni S, Gianotti R, Ghio L, Edefonti A. Ear lobe
29. Black AK. Urticarial vasculitis. Clin Dermatol. bilateral necrosis by levamisole-induced occlusive
1999;17:565–9. vasculitis in a pediatric patient. Pediatr Dermatol.
30. Jara L, Navarro C, Medina G, Vera-Lastra O, Saavedra 1997;14:477–9.
SA. Hypocomplementemic urticarial vasculitis syn- 49. Rongioletti F, Ghio L, Ginervi F, et al. Purpura of the
drome. Curr Rheumatol Rep. 2009;11:410–5. ears: a distinctive vasculopathy with circulating autoan-
31. Aydogan K, Karadogan SK, Adim SB, Tunali S. tibodies complicating long-term treatment with levami-
Hypocomplementemic urticarial vasculitis syndrome: sole in children. Br J Dermatol. 1999;140:948–51.
a rare presentation of systemic lupus erythematosus. 50. Powell J, Grech H, Holder J. A boy with cutaneous
Int J Dermatol. 2006;45:1057–61. necrosis occurring during treatment with levamisole.
32. Almerigogna F, Giudizi MG, Cappelli F, Romagnani Clin Exp Dermatol. 2002;27:32–3.
F. Schnitzler’s syndrome: what’s new? J Eur Acad 51. Doyle MK. Vasculitis associated with connective tis-
Dermatol Venereol. 2002;16:214–9. sue disorders. Curr Rheumatol Rep. 2006;8:312–6.
33. Ferri C, Zignego AL, Giuggioli D, et al. HCV and 52. Morgan AJ, Schwartz RA. Cutaneous polyarteritis
cryoglobulinemic vasculitis. Cleve Clin J Med. nodosa: a comprehensive review. Int J Dermatol.
2002;69:SII20–3. 2010;49:750–6.
34. Trejo O, Ramos-Casals M, Garcia-Carrasco M, et al. 53. Pettigrew HD, Teuber SS, Gershwin ME. Polyarteritis
Cryoglobulinemia: study of etiologic factors and clin- nodosa. Compr Ther. 2007;33:144–9.
ical and immunologic features in 443 patients from a 54. Gedalia A. Kawasaki disease: an update. Curr
single center. Medicine. 2001;80:252–62. Rheumatol Rep. 2002;4:25–9.
35. Motyckova G, Murali M. Laboratory testing for cryo- 55. Nasr I, Tometzki AJP, Schofield OMV. Kawasaki dis-
globulins. Am J Hematol. 2011;86:500–2. ease: an update. Clin Exp Dermatol. 2001;26:6–12.
56. Noto N, Okada T, Karasawa K, et al. Age-related 71. Carlson JA, Cavaliere LF, Grant-Kels JM. Cutaneous
acceleration of endothelial dysfunction and subclini- vasculitis: diagnosis and management. Clin Dermatol.
cal atherosclerosis in subjects with coronary artery 2006;24:414–29.
lesions after Kawasaki disease. Pediatr Cardiol. 72. Langford CA. Cyclophosphamide as induction ther-
2009;30:262–8. apy for Wegener’s granulomatosis and microscopic
57. Hsieh KS, Weng KP, Lin CC, Huang TC, Lee CL, polyangitis. Clin Exp Immunol. 2011;164 Suppl
Huang SM. Treatment of acute Kawasaki disease: 1:31–4.
aspirin’s role in the febrile stage revisited. Pediatrics. 73. de Groot K, Harper L, Jayne DRW, et al. Pulse versus
2004;114:e689–93. daily oral cyclophosphamide for induction of remis-
58. Baumer JH, Love SJ, Gupta A, Haines LC, Maconochie sion in antineutrophil antibody-associated vasculitis:
I, Dua JS. Salicylate for the treatment of Kawasaki a randomized trial. Ann Intern Med.
disease in children. Cochrane Database Syst Rev. 2009;150:670–80.
2006;4:CD004175. 74. De Groot K, Rasmussen N, Bacon PA, et al.
59. Inoue Y, Okada Y, Shinohara M, et al. A multicenter Randomized trial of cyclophosphamide versus metho-
prospective randomized trial of corticosteroids in pri- trexate for induction of remission in early systemic
mary therapy for Kawasaki disease: clinical course antineutrophil cytoplasmic antibody-associated vasc-
and coronary artery outcome. J Pediatr. ulitis. Arthritis Rheum. 2005;52:2461–9.
2006;149:336–41. 75. Jayne D, Rasmussen N, Andrassy K, et al. A random-
60. Kobayashi T, Inoue Y, Otani T, et al. Risk stratification ized trial of maintenance therapy for vasculitis associ-
in the decision to include prednisolone with intrave- ated with antineutrophil cytoplasmic antibodies. N
nous immunoglobulin in primary therapy of Kawasaki Engl J Med. 2003;349:36–44.
disease. Pediatr Infect Dis J. 2009;28:498–502. 76. Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine
61. Fraga A, Medina F. Takayasu’s arteritis. Curr or methotrexate maintenance for ANCA-associated
Rheumatol Rep. 2002;4:30–8. vasculitis. N Engl J Med. 2008;359:2790–803.
62. Pascual-Lopez M, Hernandez-Nunez A, Aragues- 77. Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate
Montanes M, Dauden E, Farga J, Garcia-Diez A. mofetil vs azathioprine for remission maintenance in
Takayasu’s disease with cutaneous involvement. antineutrophil cytoplasmic antibody-associated vasc-
Dermatology. 2004;208:10–5. ulitis. JAMA. 2010;304:2381–8.
63. Villa-Forte A. Giant cell arteritis: Suspect it, treat it 78. Langford CA. Drug insight: anti-tumor necrosis fac-
promptly. Cleve Clin J Med. 2011;78:265–70. tor therapies for the vasculitic diseases. Nat Clin Pract
64. Direskeneli H, Aydin SZ, Herlyn K, et al. Development Rheumatol. 2008;4:364–70.
of outcome measures for large-vessel vasculitis for 79. Eleftheriou D, Melo M, Marks SD, et al. Biologic
use in clinical trials: opportunities, challenges, and therapy in primary systemic vasculitis of the young.
research agenda. J Rheumatol. 2011;38:1471–9. Rheumatology (Oxford). 2009;48:978–86.
65. De Araujo TS, Kirsner RS. Vasculitis. Wounds. 80. Booth A, Harper L, Hammad T, et al. Prospective
2001;13:99–112. study of TNF-alpha blockade with infliximab in anti-
66. Wysong A, Venkatesan P. An approach to the patient neutrophil cytoplasmic antibody-associated systemic
with retiform purpura. Dermatol Ther. vasculitis. J Am Soc Nephrol. 2004;15:717–21.
2011;24:151–72. 81. Laurino S, Chaudhry A, Booth A, Conte G, Jayne D.
67. Piette W. Purpura: mechanisms and differential diag- Prospective study of TNF-alpha blockade with adali-
nosis. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. mumab in ANCA-associated systemic vasculitis with
Dermatology. 2nd ed. Spain: Mosby Elsevier; 2008. renal involvement. Nephrol Dial Transplant.
p. 321–30. 2010;25:3307–14.
68. Sais G, Vidaller A, Jucgla A, Servetje O, Condom E, 82. The Wegener’s Granulomatosis Etanercept Trial
Peyri J. Prognostic factors in leukocytoclastic vasculi- Research Group. Etanercept plus standard therapy for
tis: a clinicopathologic study of 160 patients. Arch Wegener’s granulomatosis. N Engl J Med.
Dermatol. 1998;134:309–15. 2005;352:351–61.
69. Carlson JA. The histologic assessment of cutaneous 83. Jones RB, Tervaert JWC, Hauser T, et al. Rituximab
vasculitis. Histopathology. 2010;56:3–23. versus cyclophosphamide in ANCA-associated renal
70. Martinez-Taboada VM, Blanco R, Garcia-Fuentes M, vasculitis. N Engl J Med. 2010;363:211–20.
Rodriguez-Valverde V. Clinical features and outcome 84. Stone JH, Merkel PA, Spiera R, et al. Rituximab ver-
of 95 patients with hypersensitivity vasculitis. Am J sus cyclophosphamide for ANCA-associated vasculi-
Med. 1997;102:186–91. tis. N Engl J Med. 2010;363:221–32.
Skin Manifestations of Internal
Disease 10
Daniel Behroozan and Hana Jeon
pregnancy. Xanthomas and xanthelasmas are

10.1 Introduction dermatologic manifestations indicative of a
possible abnormality in lipid metabolism.
As the largest organ in the body, the skin may
reveal the first manifestations of internal disease.
The astute clinician can often use dermatologic 10.2.1 Xanthomas
findings to diagnose an underlying systemic
disease. This chapter outlines some of the most Xanthomas appear as yellowish or pink papules,
important skin manifestations of internal disease. plaques, or nodules. Histologically, dermal accu-
Common yet clinically important systemic dis- mulations of lipid-laden macrophages are charac-
eases will be reviewed, and their most notable teristic. Eruptive xanthomas are small papules
skin findings will be delineated. that appear suddenly on the buttocks, hands, or
extensor surfaces, sometimes accompanied by
pruritus or tenderness [1] (Fig. 10.1). They are
10.2 Hyperlipidemia associated with very high triglyceride levels and
clear rapidly when serum lipid levels are lowered.
Hyperlipidemia is a well-known risk factor for They can also be secondary to uncontrolled
coronary artery disease. Hyperlipidemia may be diabetes. Patients with eruptive xanthomas are at
a primary disorder or secondary to another cause. risk of developing severe pancreatitis and should
Primary hyperlipidemia consists of dyslipidemia be appropriately managed with dietary and
syndromes while secondary hyperlipidemia may pharmacologic interventions such as statins to
be associated with endocrine disorders, renal normalize serum lipid levels [2].
disorders, chronic liver disease, medications, and Tuberous xanthomas tend to be larger and
deeper than eruptive xanthomas and evolve slowly.
They appear on the knees, palms, or extensor sur-
D. Behroozan, M.D. (*) faces of the body. The lesions are painless and due
Dermatology Institute of Southern California, to cholesterol accumulation within the tissues.
2221 Lincoln Blvd., Suite 100 Santa Monica,
Tuberous xanthomas are associated with primary
CA 90405, USA
hyperlipoproteinemias with elevated cholesterol
David Geffen School of Medicine at UCLA,
levels, such as familial hypercholesterolemia and
405 Hilgard Ave. Los Angeles, CA 90095, USA
e-mail: db@dermsurgery.net familial dysbetalipoproteinemia. Tendinous xan-
thomas, which are similar lesions found in exten-
H. Jeon, M.D.
David Geffen School of Medicine at UCLA, sor tendons such as the Achilles tendon, may also
405 Hilgard Ave., Los Angeles, CA 90095, USA be present in these patients. Treating the underlying

194 D. Behroozan and H. Jeon
is a risk factor for mortality from atherosclerotic

disease regardless of cholesterol level. It has also
been reported that patients with xanthelasmas in
the setting of normal levels of cholesterol and trig-
lycerides may have elevated LDL and VLDL and
decreased HDL. Therefore, xanthelasma should
be considered a marker of dyslipidemia, and a full
lipid profile should be considered to identify those
with more subtle lipid abnormalities that are still
associated with increased risk of cardiovascular
disease. Familial hypercholesterolemia or familial
dysbetalipoproteinemia should be considered
especially in those patients who develop xan-
Fig. 10.1 Diffuse yellow papules and small plaques con-
sistent with eruptive xanthomas. Images courtesy of the thelasma at a young age.
Victor D. Newcomer, M.D. collection at UCLA and Xanthelasmas are not known to cause serious
Logical Images, Inc complications expect in rare instances in which
the lesions become large and obstruct vision [5].
condition is essential in conjunction with dietary Although the classic method of treatment is surgi-
changes, exercise, and pharmacologic interven- cal excision, surgical scarring can occur. This has
tion. While eruptive xanthomas can resolve within led to investigations of other methods of treatment
weeks of initiating systemic medical treatment, including trichloroacetic acid peeling, electrodes-
and tuberous xanthomas can resolve after months sication, and laser therapy, all of which result in
of similar treatment, tendinous xanthomas may varying success [6]. Regardless of the mode of
persist for years despite treatment and may even treatment, recurrence of xanthelasma is common,
need surgical intervention to alleviate infrequent especially in cases of familial hyperlipoproteine-
but obvious swelling which can rarely lead to mia where involvement of all four eyelids, or
chronic morbidity. more than one recurrence, is common [7].
10.2.2 Xanthelasma 10.3 Kidney Disease
Xanthelasmas, also known as xanthelasma palpe- 10.3.1 Half-and-Half Nails

brarum, are yellowish plaques that are most com-
monly found on the inner canthi. More common Half-and-half nails (also known as Lindsay’s
in women and older individuals, xanthelasmas nails) are associated with chronic renal failure.
are the most common of all xanthomas [3]. The This nail finding is a result of nail bed edema and
lesions can be soft, semisolid, or calcified, and characterized by apparent leukonychia in the
are characterized by a tendency to be symmetric, proximal half of the nail which fades upon appli-
permanent, progressive, multiple, and coalescent cation of pressure [8]. These nail changes are
[4]. They tend to grow slowly with time, and the thought to be an occasional but very specific
diagnosis can often be made clinically. finding of chronic renal failure, and it is estimated
Histologically, the lesions are composed of that up to 40% of patients with renal insufficiency
foamy, lipid-laden histiocytes that tend to be have the nail changes during the course of their
located in the superficial dermis in perivascular disease [9]. It has been proposed that the distal
and periadnexal locations. dark color is caused by melanin deposition result-
Although roughly 50% of patients with xan- ing from stimulation of nail matrix melanocytes
thelasma have normal serum cholesterol levels, by acidosis and uremia [10]. Others have proposed
studies have shown that the presence of xanthelasma that changes in the nail bed rather than in the nail
10 Skin Manifestations of Internal Disease 195
produced the change, such as an increase in the characteristic lesions help to make the diagnosis.
number of capillaries and a thickening of the cap- To verify the composition of the lesions, scrap-
illary walls in the nail bed [11]. ings can be taken and diluted in normal saline,
and then tested for elevated urea nitrogen levels.
10.3.2 Uremic Pruritus

10.4 Diabetes
While pruritus is infrequent in patients with acute
renal failure, it is a common symptom in patients 10.4.1 Necrobiosis Lipoidica
with chronic renal failure [12]. The pathogenesis
of uremic pruritus is unknown, with various pro- Necrobiosis lipoidica is present in approximately
posed mechanisms including nitric oxide, pruri- 0.3% of patients with diabetes. It may be seen in
togenic cytokines, and altered skin innervations both type I and type II diabetes with about two-
secondary to neuropathy [13]. thirds of cases occurring in type II [16]. Although
Before initiating treatment, a specific diagno- not all patients with necrobiosis lipoidica have dia-
sis should first be made as patients with chronic betes, studies have shown that majority of those
renal failure may experience pruritus secondary to without diabetes had abnormal glucose tolerance
other skin conditions such as infections or contact tests, subsequently developed diabetes, or had a
dermatitis from dialysis catheters. Secondary strong family history of diabetes [17]. Most patients
hyperparathyroidism due to chronic renal failure are females. The pathogenesis remains unknown.
has also been associated with uremic pruritus Proposed mechanisms include vascular abnormali-
(parathyroidectomy in dialysis patients with sec- ties, collagen abnormalities, sweat gland and nerve
ondary hyperparathyroidism has been reported to disturbances, and abnormal leukocyte function.
decrease pruritus), though PTH itself does not Necrobiosis lipoidica initially presents as an
seem to be pruritogenic. Thus, surgery should be oval violaceous patch, most often in the pretibial
considered for pruritus in association with sec- region. It slowly evolves into a larger lesion with
ondary hyperparathyroidism. In cases without a an erythematous advancing border and central
specific cause, treatment includes optimizing dial- epidermal atrophy (Fig. 10.2). Subsequent ulcer-
ysis, as well as the use of emollients and topical ation is common. Histologically, the lesions dem-
analgesics such as pramoxine. Ultraviolet light B onstrate layers of interstitial granulomatous
therapy has also been shown to be effective. inflammation and fibrosis with multinucleated
histiocytes involving the entire dermis. Diagnosis
can often be made clinically.
10.3.3 Uremic Frost At this time, there is no consistently effective
treatment for necrobiosis lipoidica. Treatment
Uremic frost is a rare dermatologi manifestation options include corticosteroids, fibrinolytics,
of severe azotemia which clinically manifests as antiplatelet agents, and surgical treatments (i.e.,
characteristic white, crystalline, and friiable excision and grafting). Diabetic glycemic control
depostis arising in the head and neck area.. The does not seem to result in the resolution of necro-
lesions form as a result of the accumulation of biosis lipoidica.
urea and other nitrogenous waste products in
sweat which then crystallize after evaporation
[14]. Today, this dermatologic finding is rarely 10.4.2 Bullae Diabeticorum
seen in developed countries due to the availabil-
ity of hemodialysis [15]. Uremic frost should be Although most commonly seen in patients with
differentiated from eczema, postinflammatory long-standing diabetes, bullosis diabeticorum
desquamation, and retention keratosis. A history may also occur as the initial presentation of
of severe azotemia as well as the presence of diabetes [18]. The lesions are characterized by
most commonly involving the axillae and/or neck

creases, as well as other intertiginous areas such as
the groin, and less frequently the flexural extremi-
ties, periorally, and periorbitally. High levels of
circulating insulin promote increased liver produc-
tion of insulin-like growth factor, which binds to
epidermal growth factor receptors to produce
thickening of the epidermis and hyperkeratosis
[24]. These lesions are most often asymptomatic,
but can be malodorous or painful. Histologically,
acanthosis nigricans is characterized by hyperker-
atosis, mild acanthosis, and papillomatosis. The
hyperpigmentation results from thickness of the
Fig. 10.2 Erythematous to violaceous atrophic plaques
of the pretibial legs consistent with necrobiosis lipoidica. keratin-containing superficial epithelium rather
Images courtesy of the Victor D. Newcomer, M.D. collec- than a change in melanocytes. Acanthosis nigri-
tion at UCLA and Logical Images, Inc cans is classified either as benign when it occurs in
the context of insulin resistance, or as malignant
the rapid onset of tense, painless blisters on the when it is a paraneoplastic sign of an internal
feet, legs, or hands. They vary in size from 0.5 to malignancy, most commonly gastric adenocarci-
3 cm, can be unilateral or bilateral [19], and usu- noma [25]. Thus, evaluation for an internal malig-
ally heal in 2–4 weeks [20]. The pathogenesis of nancy should be considered if patients with
bullosis diabeticorum is unknown. Proposed acanthosis nigricans are found not to have insulin
mechanisms include nephropathy, immune-medi- resistance. Because obesity is an important cause
ated vasculitis, and disturbed metabolism of cal- of insulin resistance, weight control and dietary
cium, carbohydrates, or magnesium. changes play an important role in therapy. Common
The diagnosis is made clinically as there is no pharmacologic therapies to improve insulin sensi-
specific diagnostic test for bullosis diabeticorum tivity such as metformin or long-term treatment
[21]. Histologically, subepidermal bullae are with octreotide (a synthetic analog of somatosta-
observed, and direct immunofluorescence is usu- tin) to reduce insulin secretion and eventually
ally negative [22]. The differential diagnosis reduce insulin binding to insulin-like growth fac-
includes other blistering disorders such as bullous tor may be helpful. Topical treatment includes
pemphigoid, porphyria cutanea tarda, pseudopor- retinoids, ammonium lactate, and calcipotriene.
phyria, drug-induced bullous eruptions, and fric-
tion/burn blisters.
The goal of treatment is to prevent secondary 10.5 Thyroid Disease
infection and to allow the lesions to heal on their
own [23]. While some clinicians suggest topical 10.5.1 Graves’ Disease
therapies are not necessary, others suggest aspi-
rating the blisters to reduce discomfort and apply- Graves’ disease is an autoimmune hyperthyroid-
ing petroleum jelly or a topical antibiotic ointment ism caused by autoantibodies that bind to thy-
to prevent secondary infection. rotropin (also known as thyroid-stimulating
hormone, TSH) receptors in the thyroid gland
resulting in increased thyroid hormone synthesis.
10.4.3 Acanthosis Nigricans Pretibial myxedema is a specific sign of Graves’
disease, but occurs in only 3–5% of patients with
About 30–50% of patients with diabetes have the disease [26]. It is characterized by indurated
acanthosis nigricans. Acanthosis nigricans is char- tan to brownish-red plaques over the pretibial
acterized by velvety, hyperpigmented plaques areas (Fig. 10.3). Histologically, there is
Fig. 10.3 Indurated waxy plaques of the pretibial leg in a

patient with hyperthyroidism. Images courtesy of the Fig. 10.4 Physical finding and eye changes seen in
Victor D. Newcomer, M.D. collection at UCLA and patients with Graves’ disease. Images courtesy of the
Logical Images, Inc Victor D. Newcomer, M.D. collection at UCLA and
Logical Images, Inc
infiltration by mucopolysaccharides (mucinous
ground substance), thought to be caused by stim- ichthyosis. The loss of the outer third of the eye-
ulation of TSH receptors that are present in the brows is considered a classic hair loss pattern for
pretibial connective tissue. Treating hyperthy- patients with hypothyroidism. Hair may be coarse
roidism does not alter the presence of pretibial and brittle, with slowed growth rate (increase in
myxedema because treatment of Graves’ disease telogen hairs) [28]. In severe hypothyroidism,
treats hyperthyroidism rather than the underlying enlargement of the lips and tongue as well as dif-
autoimmune disease [27]. fuse thickened skin may be observed. The thick-
Graves’ ophthalmopathy (proptosis) may be ened skin, also called myxedema, differs from
the first sign of hyperthyroidism. Associated pretibial myxedema of Graves’ disease; myxedema
symptoms include photophobia, tearing, and sen- of hypothyroidism has a generalized distribution
sation of a foreign material in the eye [28] with smaller quantities of mucin. The skin of hypo-
(Fig. 10.4). It is thought to be caused by infiltration thyroid patients may appear yellow due to impaired
of retrobulbar tissues and extraocular muscles by hepatic conversion of carotene to vitamin A, result-
mononuclear cells and mucopolysaccharides. ing in excess deposition of serum carotene in the
Dermatologic manifestations of hyperthyroid- stratum corneum. There may be cutaneous pallor
ism may generally be characterized by warm, caused by both vasoconstriction and alteration of
moist skin and separation of the nails from the the fraction of incident light, which results from
nail bed (onycholysis). The nail changes are char- increased water and mucopolysaccharide content
acterized by rapid growth, softening, and friabil- in the dermis [28]. About 90% of patients with
ity, and often reverse following successful therapy hypothyroidism have some degree of nail changes.
of hyperthyroidism. Hair caliber may be fine and The nails are brittle, slow growing, and striated
thin; frank alopecia is also seen, though the sever- either longitudinally or horizontally. Onycholysis
ity of alopecia does not correlate with the severity is more common in hyperthyroidism but has been
of hyperthyroidism. reported in association with myxedema.
10.5.2 Hypothyroidism 10.6 Sarcoidosis
Dermatologic manifestations of hypothyroidism Sarcoidosis is a multisystem granulomatous dis-

include dry, scaly, and cold skin. Some patients order of unknown etiology. Skin manifestations
may be severely xerotic and develop an acquired occur in approximately 25% of cases and may be
involvement of T-lymphocytes as well as reactive

oxygen intermediates in producing the tissue
damage and inflammation [32]. Erythema nodo-
sum is typically associated with a subacute tran-
sient course of sarcoidosis. Löfgren’s syndrome
describes an acute form of sarcoidosis associated
with erythema nodosum in the setting of asymp-
tomatic bilateral hilar lymphadenopathy, uveitis,
fever, and arthritis. It most often resolves without
treatment. Erythema nodosum is usually self-lim-
iting or improves with treatment of the underlying
disorder. Symptomatic treatment to relieve the
discomfort associated with the skin lesions can be
Fig. 10.5 Common nonspecific skin findings seen in
Sarcoidosis. Note the annular pattern of lesions. Images achieved with salicylates or nonsteroidial anti-
courtesy of the Victor D. Newcomer, M.D. collection at inflammatory drugs. Although the mechanism is
UCLA and Logical Images, Inc unclear, potassium iodide (400–900 mg daily) has
been reported to be beneficial in refractory cases.
the first sign of sarcoidosis. The lesions are Sarcoidosis is diagnosed by a combination of
classified as either specific or nonspecific, based clinical, radiologic, histopathologic, and labora-
on the presence or absence of non-caseating tory findings. In patients with asymptomatic bilat-
granulomas on histology, respectively. eral hilar lymphadenopathy or Löfgren’s syndrome,
The most common skin findings are small, clinical presentation may be sufficient. Following
smooth dermal papules of varying colors such as diagnosis, patients should be thoroughly assessed
tan, red, violaceous, or brown (Fig. 10.5), though to evaluate the extent of the disease.
in African Americans, they may be hypopig- Approximately 70% of cutaneous sarcoidosis
mented. Lesions are most commonly located resolve without treatment in 1–2 years. For mild
around eyelids, nasal alae, nasolabial folds, and disease, potent topical corticosteroids such as
neck [29]. The papules sometimes enlarge or clobetasol or intralesional corticosteroids may be
coalesce to form annular lesions or plaques [30]. considered. For extensive cutaneous disease,
Uncommon but specific skin lesions of sarcoidosis prednisone is the drug of choice [33]. For refrac-
include subcutaneous nodules, ulcerations, dystro- tory sarcoidosis, methotrexate is most commonly
phic nails, scarring alopecia, verrucous lesions, used as a nonglucocorticoid immunosuppressive
pustular lesions, and rarely erythroderma [29]. agent. Other antimetabolites such as azathioprine
Lupus pernio is a distinct form of cutaneous and leflunomide are also used when patients fail
sarcoidosis presenting as purplish plaques around or cannot tolerate methotrexate. Other options for
the nose, ears, lips, fingers, and face [31]. The patients who fail glucocorticoid treatments
lesions appear insidiously and progress to result include antimalarial drugs with immunomodulat-
in scarring, fibrosis, and deformity. Lupus pernio ing properties (e.g., chloroquine, hydroxychloro-
is associated with the involvement of the upper quine) and tumor necrosis factor alpha (TNFa)
respiratory tract, pulmonary fibrosis, as well as inhibitors (TNFa is thought to play a role in
severe bony disease. Patients with lupus pernio maintenance of granuloma formation in sarcoi-
often have persistent and progressive pulmonary dosis by accelerating the inflammatory process).
manifestations [30].
Erythema nodosum is the most common
nonspecific skin lesion of sarcoidosis. It is charac- 10.7 Cushing’s Syndrome
terized by erythematous and tender subcutaneous
nodules most often located in the pretibial areas. Cushing’s syndrome refers to a state of excess glu-
It is thought to be caused by a delayed cocorticoids and has various dermatologic findings.
hypersensitivity response, and studies have shown Thinning and atrophy of the skin, easy bruising,
Fig. 10.7 Hyper-convexity of the nail consistent with

clubbing. Images courtesy of the Victor D. Newcomer,
M.D. collection at UCLA and Logical Images, Inc
by erythematous papules and pustules uniform in

their stage of development and without come-
dones. They spare the face and appear on the
trunk, arms, and shoulders. Hypertrichosis is also
common most often on the face. Hair tends to be
laguno-like rather than true beard growth [35].
Hypercortisolism could be due to iatrogenic
Fig. 10.6 Characteristic striae and body habitus of a administration of glucocorticosteroids, pituitary
patient with Cushing’s syndrome. Images courtesy of the
Victor D. Newcomer, M.D. collection at UCLA and
or ectopic adrenocorticotropic hormone (ACTH)
Logical Images, Inc production, or adrenal tumors [35]. Although the
most common cause is therapeutic administration
and inhibition of wound healing may be observed. of exogenous systemic glucocorticoids, it has
A reduction in epidermal and dermal components been reported that the use of potent topical corti-
of the skin leads to atrophy; there is decreased col- costeroids can induce similar skin changes [36].
lagen synthesis, elastic fibers, and dermal muco- Some suggest limiting the usage of potent topical
polysaccharides [34]. The epidermis is shiny and glucocorticoids to 50 g/week in adults and 15 g/
may show scaling [35]. High levels of glucocorti- week in children to avoid such adverse reactions
coids impair wound repair and cause easy damage [36]. The skin changes caused by Cushing’s syn-
to the skin with subsequent ulceration and infec- drome are only partially reversible with treatment
tion. Additionally, increased vascular fragility of the underlying disease.
results in petechiae and ecchymoses.
Large, violaceous striae may appear in areas of
stretched skin such as the abdomen and buttocks 10.8 Pulmonary Disease
(Fig. 10.6) due to weak dermal connective tissue
and the failure of normal regenerative capacity of Clubbing is characterized by increased convexity
the skin [35]. The striae of Cushing’s are increased of the nail due to proliferation of the soft tissues
in depth, breath, and intensity of color as com- in the distal phalanx (Fig. 10.7). The emergence
pared to the striae of adolescence or pregnancy. angle of the nail becomes equal to or greater than
Excess deposits of fat in the clavicles, poste- 180° [37]. The nail plate enlarges in size. About
rior neck (buffalo hump), cheeks (moon facies), 80% of nail clubbing is associated with respira-
and abdomen result in the characteristic body tory diseases such as lung cancer, sarcoidosis,
habitus. Patients with Cushing’s syndrome can mesothelioma, empyema, cystic fibrosis, and
also develop steroid-induced acne characterized interstitial lung disease.
Fig. 10.8 Absent lunulae,

absent cuticles, thickening
with curvature to the sides,
and yellowing of nails in a
patient with yellow nail
syndrome. Images courtesy
of the Victor D.
Newcomer, M.D.
collection at UCLA and
Logical Images, Inc
In the evaluation of clubbing, it is important to aeruginosa that may produce green-to-black

verify that the patient has true clubbing rather discoloration of the nail plate. In patients with
than pseudoclubbing, which involves only a sin- paraneoplastic yellow nail syndrome, the nails
gle digit and is usually due to a subungual mass often return to normal when the underlying tumor
[37]. In those with true clubbing, a chest X-ray is treated. The exact pathogenesis of the yellow
should be considered to rule out underlying pul- nail syndrome remains unknown. One possible
monary causes. mechanism is a congenital abnormality of the
Hypertrophic osteoarthropathy is an important lymphatic vessels, which explains the nail pathol-
entity to consider when evaluating nail clubbing. ogy characterized by ectatic lymphatics in the
It is a syndrome that consists of simple clubbing, nail bed as well as matrix dermis [37].
peripheral neurovascular disease, acute bone
pain, muscle weakness, joint pain, and hypertro-
phy of the extremities. The presence of these 10.9 Gastrointestinal
findings is associated with malignant tumors of
the pulmonary system 90% of the time. The syn- 10.9.1 Pyoderma Gangrenosum
drome mostly affects males with a familial
predisposition. Pamindronate may be considered Pyoderma gangrenosum is a severe ulcerative
in treating painful osteoarthropathy [38]. skin condition that is associated with inflammatory
Yellow nail syndrome is also associated with bowel disease and chronic infectious hepatitis, as
pulmonary diseases such as tuberculosis, pulmo- well as other non-gastrointestinal conditions such
nary malignancies, and asthma. The classic triad as rheumatoid arthritis, lupus erythematosus, and
of yellow nail syndrome is lymphedema of the HIV infection. It is estimated that about 5% of
lower extremity, nail changes, and pleural effu- patients with ulcerative colitis develop pyoderma
sion. The nail changes consist of absent lunulae gangrenosum. In some patients, pyoderma gan-
and cuticles, nail thickening with lateral curva- grenosum may develop years before the onset of
ture, and yellowing (Fig. 10.8). The syndrome inflammatory bowel disease.
usually involves all 20 nails. Nail growth is The lesion begins as a small tender pustule,
slowed to less than 0.2 mm/week [39]. Total nail but eventually breaks down and forms an expand-
plate detachment may occur (secondary onycho- ing ulcer. It can grow rapidly and extend to fat,
lysis), as well as colonization by Pseudomonas fascia, and muscle. The ulcers can become very
large before healing with a thin and atrophic scar disease, treatment of which may help to treat the
[40]. While not specific to pyoderma gangreno- skin lesions; the nodules may regress as the level
sum, patients may exhibit pathergy, a phenome- of lipolytic pancreatic enzymes decreases.
non where skin trauma or injury can trigger the
development of skin ulcerations which may be
resistant to healing. Pathergy may also lead to 10.9.3 Dermatitis Herpetiformis
non-healing wounds at sites of surgical incisions.
Facial pydoerma gangrenosum tends to be more Dermatitis herpetiformis, a cutaneous marker of
superficial and less destructive. gluten-sensitive enteropathy, is characterized by
The pathogenesis of pyoderma gangrenosum pruritic grouped papules and vesicles symmetri-
remains largely unknown. It is thought that abnor- cally distributed on the elbows, knees, scalp, but-
mal neutrophil trafficking and immunologic dys- tocks, and extensor forearms [42]. Men are more
function are involved. Pyoderma gangrenosum is often affected than women, and dermatitis herpe-
a diagnosis of exclusion; culture for bacterial, tiformis usually first occurs at a young adult age.
viral, and fungal agents should be done. Therapy Gluten is the main adhesive substance of many
involves treating the associated disease and grains, and gliadin is the most important sensitiz-
administration of systemic steroids (predinoso- ing protein as well as the substrate for tissue glu-
lone 1–2 mg/kg daily with tapering as healing taminase. Autoantibodies against tissue
occurs) and other immunosuppressive agents glutaminase also cross-react with epidermal trans-
such as cyclosporine. However, treatment is often glutaminase leading to the formation of the cuta-
recalcitrant when an underlying systemic condi- neous lesions. There is a strong HLA association
tion cannot be identified and subsequently treated. with 90% of patients possessing HLA-DQ2.
More recently, the use of TNF-a inhibitors, The diagnosis can be made by histologic
specifically infliximab (5 mg/kg infusion at weeks examination of an early blister and direct
0, 2, and 6 and every 8 weeks after that), has also immunofluorescence of non-lesional skin in
been shown to be effective in management of this which IgA is seen in the dermal papillae.
difficult condition. Suppressive therapy using dapsone is the main-
stay of treatment. Dapsone is effective in rapidly
clearing the rash, but relapse upon discontinua-
10.9.2 Pancreatic Panniculitis tion of the medication is also rapid. Therapy
should also include a gluten-free diet, which can
Pancreatic panniculitis has been associated with be difficult, but essential in treating the underly-
both acute and chronic pancreatitis as well as ing disease as well as dermatitis herpetiformis.
pancreatic carcinoma, but overall is a rare associ-
ated finding in patients with pancreatitis.
Pancreatitis results in the outpouring of digestive 10.9.4 Hepatobiliary/Cirrhosis
enzymes, such as pancreatic lipase, phospholi-
pase, trypsin, and amylase, that may migrate into 10.9.4.1 Spider Angiomas
tissue to cause pancreatic panniculitis [41]. The cutaneous signs of liver disease generally
Tender, fluctuant, red subcutaneous nodules correlate with the severity of the disease [43].
develop on the lower legs. Occasionally, the nod- Cirrhosis distorts the normal liver anatomy
ules rupture discharging a thick and oily liquid causing decreased blood flow through the liver
which may be a result of autodigestion of the resulting in portal hypertension. Portal hyperten-
subcutaneous fat by the pancreatic enzymes. sion, in turn, results in ascites, peripheral edema,
Histologically, a mixed lobular and septal pan- and varices. There is also impaired biochemical
niculitis with lipocyte necrosis (“ghost cells”) function; albumin as well as clotting factor syn-
and basophilic saponification may be seen. thesis are decreased. This results in purpura and
Prognosis depends on the underlying pancreatic ecchymoses.
Spider angiomas result from hyperestrinism, and

develop in at least 75% of patients with cirrhosis.
The lesion is characterized by centralized red mac-
ule or papule with outward vascular extensions
resembling a spider web. The center is a coiled cen-
tral arteriole, and the extensions are smaller vessels
radiating outward. Spider angiomas are most often
planar, but can enlarge to form hemangioma-like
masses [43]. They are found on the face, neck,
trunk, and upper extremities. The lesions are usu-
ally associated with chronic liver disease, but may
be associated with pregnancy and oral contracep-
tives, as well. Thus, spider angiomas are not consid-
Fig. 10.9 Periorbital spontaneous purpura in a patient
ered to be pathognomonic of liver disease. with systemic amyloidosis. Images courtesy of the Victor
D. Newcomer, M.D. collection at UCLA and Logical
Images, Inc
10.9.5 Terry’s Nails
teins that can be precursors for amyloid fibril
Terry’s nails occur in patients with liver disease, deposition in the skin: light-chain monoclonal
and are characterized by nails that turn opaque protein, beta-2 microglobulin, serum protein A,
white except for the distal portion which remains prealbumin, and keratin. Amyloidosis can be
pink in color. The discoloration stops suddenly at classified according to the type of amyloid pro-
about 1–2 mm from the distal edge of the nail, tein deposition and clinical presentation.
leaving a reddish brown transverse band [44]. About 30% of patients with primary or
These nail findings are not specific to patients myeloma-related systemic amyloidosis have
with cirrhosis, and may also be found in some cutaneous manifestations. The dermatological
normal women younger than 20 years of age. It is signs of systemic amyloidosis can be helpful in
thought that hypoalbuminemia results in edema diagnosis because these signs may be the only
of the connective tissue in the distal nail bed, con- manifestations before systemic amyloidosis
verting it into a loosely knit rather than highly develops into a late-stage disease [46]. As amy-
compact collagenous structure. This change in loid infiltrates and weakens blood vessels, patients
turn stimulates the organization of the lunula pro- develop purpura, petechiae, or ecchymoses occur-
ducing a white color of the nail. Histologically, ring spontaneously on skin folds (e.g., the eye-
there are changes in vascularity, and specifically lids, axillae, and anogenital area). “Pinch purpura”
distal telangiectasias [44]. The recognition of in which pinching the skin produces purpuric
Terry’s nails may serve as an important clue to lesions may occur. Periorbital pupura may form
early diagnosis of hepatic disease. following coughing or the valsalva maneuver
(Fig. 10.9). When amyloid infiltrates travel to the
dermis, subcutaneous nodules or plaques may
10.10 Amyloidosis form. The lesions appear hemorrhagic, though
they may also appear smooth and waxy.
Amyloidosis refers to a group of conditions char- Lichen amyloidosis, the most common type of
acterized by the extracellular deposition of an localized cutaneous amyloidosis, is characterized
abnormal protein [45]. While most of proteins in by tan to brown pruritic papules which may
humans and other species are synthesized in an coalesce to form plaques [47]. The lesions most
alpha-helical structure, amyloid protein is commonly form on the shins.
synthesized in a much less biodegradable Various stains of a biopsied specimen can be
beta-pleated sheet structure. There are many pro- used to diagnosis amyloidosis. Congo red, for
example, shows doubly refractive and apple green

amyloid when examined in polarized light.
Although treatments are usually ineffective,
topical corticosteroids could be tried as an antipru-
ritic measure. PUVA or systemic retinoids may be
considered as well. In macular amyloidosis, pru-
ritic macular hyperpigmentation occurs in the
interscapular area. Treatment is similar to lichen
amyloidosis. Topical capsaicin once daily for long
periods of time has helped some patients. Both
lichen amyloidosis and macular amyloidosis are
variants of primary localized cutaneous amyloido-
sis and occur most often in patients from Asia, the
Fig. 10.10 Periumbical metastatic tumors consistent
Middle East, and Central and South America. with a diagnosis of Sister Mary Joseph nodule. The diag-
nosis was made by an incisional biopsy. From the per-
sonal collection of Daniel Behroozan, M.D
10.11 Malignancy
10.11.1 Sister Mary Joseph’s Nodule

(Colon Cancer)
Sister Mary Joseph’s nodule is a nodular umbili-

cal metastatic tumor (Fig. 10.10). It was named
after Sister Mary Joseph, the first surgical assis-
tant to Dr. William Mayo and the superintendent
of St. Mary’s Hospital in Rochester, Minnesota,
who noted the association between metastatic
intraabdominal cancer and paraumbilical nodules
[48]. Sister Mary Joseph’s nodule is associated
with cancers of the gastrointestinal tract and
ovary. The most commonly associated malig-
nancy is stomach (20%), followed by large bowel
(14%), ovary (14%), and pancreatic tumors
(11%). In about 20% of patients, the primary site
cannot be identified.
In general, cutaneous metastasis is a poor prog-
nostic sign and may signify widespread internal
metastasis [49]. While the prognosis is dependent
on the primary tumor, a study found that the aver- Fig. 10.11 Diffuse and disseminated blue nodules in two
age life expectancy after developing skin metasta- patients with metastatic melanoma. From the personal
ses was 3 months (Figs. 10.11 and 10.12). collection of Daniel Behroozan, M.D
acanthosis nigricans when there is a sudden onset

10.11.2 Malignant Acanthosis of widespread acanthosis nigricans with weight
Nigricans loss, suggesting an underlying malignancy [50].
About 60% of patients who develop malignant
Acanthosis nigricans (previously discussed acanthosis nigricans have been found to have
under the diabetes section) is called malignant adenocarcinoma of the stomach, and most often
It is characterized by skin lesions, fever, malaise,

and leukocytosis. About 20% of patients have an
associated hematopoietic malignancy. The classic
cutaneous manifestation of Sweet’s syndrome is
sharply demarcated and painful plaque that often
has papulovesicles and pustules on the surface.
The plaques are present on the face, neck, upper
trunk, and extremities. Lesions may be present in
the oral mucous membrane and eyes as well. As
in pyoderma gangrenosum, the phenomenon of
pathergy (hypersensitivity reaction developing at
the site of minor skin trauma) may be seen.
The laboratory abnormalities include leukocy-
tosis (present in 60% of patients), elevated sedi-
mentation rates, anemia, thrombocytopenia, and
increased number of segmented neutrophils.
Sweet’s syndrome responds well to systemic
corticosteroids (e.g., prednisolone 60 mg daily
tapered over two to four weeks), but recurs in
about 25% of cases. Various alternatives such as
potassium iodide, clofazimine, or colchicine may
be considered in recurrent cases.
Fig. 10.12 Diffuse and disseminated blue nodules in two
patients with metastatic melanoma. From the personal
collection of Daniel Behroozan, M.D References
1. Massengale WT, Nesbitt Jr LT. Xanthomas. In:
are at an advanced stage of the disease. “Tripe Bolognia JL et al., editors. Dermatology. New York:
palms,” acanthosis nigricans of the palms, is Mosby; 2003. p. 1448.
2. Naik NS. Eruptive xanthomas. Dermatol Online J.
characterized by a velvety furrowing of the pal- 2001;7:11.
mar surfaces and is also often associated with 3. Cohen P. Xanthelasma palpebrarum. J Gt Houst Dent
internal malignancy. It is thought that acanthosis Soc. 1996;67:10.
nigricans appears due to an epidermal growth 4. Bergman R. The pathogenesis and clinical significance
of xanthelasma palpebrarum. J Am Acad Dermatol.
factor that is secreted by the tumor. The evidence 1994;30:236.
for this has been shown in some cases where suc- 5. Pedace FJ, Winkelmann RK. Xanthelasma palpe-
cessful resection of the adenocarcinoma results brarum. JAMA. 1965;193:893.
in regression of the acanthosis nigricans [50]. 6. Merola JF, Mengden SJ, Soldano A, Rosenman K.
Eruptive xanthomas. Dermatol Online J. 2008;
14(5):10.
7. Park EJ, Youn SH, Cho EB, Lee GS, Hann SK, Kim
10.11.3 Sweet’s Syndrome KH, Kim KJ. Xanthelasma palpebrarum treatment
with a 1,450-nm-diode laser. Dermatol Surg. 2011.
doi 10.1111/j.1524-4725.2011.01945.x. [Epub ahead
Sweet’s syndrome is commonly associated with of print].
hematopoietic malignancies including acute 8. Mendelson BC, Masson JK. Xanthelasma: follow-up
myelogenous leukemia (the most common), on results after surgical excision. Plast Reconstr Surg.
chronic myelogenous leukemia, lymphocytic 1976;58:535.
9. Muehrcke RC. The fingernails in chronic hypoalbu-
leukemia, T- and B-cell lymphomas, and poly- minaemia: a new physical sign. BMJ. 1956;9:1327–8.
cythemia [51]. No clinical or histopathologic dif- 10. Lindsay PG. The half-and-half nail. Arch Intern Med.
ferences exist between patients with and without 1967;119:583–7.
associated malignancy. Sweet’s syndrome most 11. Leyden JJ, Wood MG. The half and half nail: a
uremic onychopathology. Arch Dermatol. 1972;105:
commonly occurs in women 30–60 years of age. 591–2.
12. Kint A, Bussels L, Fernandes M, Ringoir S. Skin and 34. Baughman RP, Lower EE. Newer therapies for cuta-
nail disorders in relation to chronic renal failure. Acta neous sarcoidosis: the role of thalidomide and other
Derm Venerol. 1974;54:137–40. agents. Am J Clin Dermatol. 2004;5:385–94.
13. Goicoechea M, de Sequera P, Ochando A, et al. 35. Feldman SR. Adrenal, androgen-related, and pituitary
Uremic pruritus: an unresolved problem in hemodial- disorders. In: Callen JP et al., editors. Dermatological
ysis patients. Nephron. 1999;82:73–4. signs of internal disease. Philadelphia, PA: W.B.
14. Urbonas A, Schwartz RA, Szepietowski JC. Uremic Saunders; 1995. p. 203–11.
pruritus: an update. Am J Nephrol. 2001;21:343–50. 36. Freinkel RK. Other endocrine diseases. In:
15. Walsh SR, Parada NA. Uremic frost. N Eng J Med. Freedberg IM et al., editors. Fitzpatrick’s dermatol-
2005;352:e13. ogy in general medicine. New York: McGraw-Hill;
16. Kuo CC, Hung JB, Tsai CW, Chen YM. Uremic frost. 1999. p. 1980–1.
CMAJ. 2010;182(17):E800. Epub 2010. 37. Ohnishi T, et al. Erythrodermic psoriasis associated
17. Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am with hyperuricemia and iatrogenic Cushing’s syn-
Acad Dermatol. 1991;25:735. drome due to topical corticosteroid therapy. Int J
18. Muller SAK, Winkelman RK. Necrobiosis lipoidica Dermatol. 1996;35(5):379–80.
diabeticorum: a clinical and pathological investigation 38. Tosti A, Iorizzo M, Piraccini BM, Starace M. The nail
of 171 cases. Arch Dermatol. 1966;93(3):272–81. in systemic diseases. Dermatol Clin. 2006;24:341–7.
19. Suzuki K, Ito Y, Nakamura S, Ochiai J, Aoki K. 39. Martinez-Lavin M, Vargas A, Rivera-Viñas M.
Relationship between serum carotenoids and hyperg- Hypertrophic osteoarthropathy: a palindrome with a
lycemia: a population-based crosssectional study. J pathogenic connotation. Curr Opin Rheumatol.
Epidemiol. 2002;12:357–66. 2008;20:88–91.
20. Huntley AC. Cutaneous manifestations of diabetes 40. Tosti A, Piraccini BM, Iorizzo M. Systemic itracon-
mellitus. Dermatol Clin. 1989;7:531–46. azole in the yellow nail syndrome. Br J Dermatol.
21. Wahid Z, Kanjee A. Cutaneous manifestations of dia- 2002;146(6):1064–7.
betes mellitus. J Pak Med Assoc. 1998;48:304–5. 41. Jorizzo JL, Greer KE, Callen JP. Miscellaneous disor-
22. Lipsky BA, Baker PD, Ahroni JH. Diabetic bullae: 12 ders with prominent features involving the skin and
cases of a purportedly rare cutaneous disorder. Int J the joints. In: Callen JP, Jorizzo JL, Bolognia JL, et al.,
Dermatol. 2000;39:196–200. editors. Dermatologic signs of internal disease. 3rd ed.
23. Aye M, Masson EA. Dermatological care of the dia- Philadelphia, PA: W.B. Saunders; 2003. p. 39–41.
betic foot. Am J Clin Dermatol. 2002;3:463–74. 42. Beltraminelli HS, Buechner SA, Haeusermann P.
24. Bolognia JL, Jorizzo JL, Rapini RP. Other vesicu- Pancreatic panniculitis in a patient with an acinar cell
lobullous diseases. In: Dermatology, 1st ed. cystadenocarcinoma of the pancreas. Dermatology.
Philadelphia, PA: Mosby, 2003. pp 501–8. 2004;208:265–7.
25. Lopez PR, Leicht S, Sigmon JR, Stigall L. Bullosis 43. Nikolas ME, Krause PK, Gibson LE, et al. Dermatits
diabeticorum associated with a prediabetic state. herpetiformis. Int J Dermatol. 2003;42:588–600.
South Med J. 2009;102(6):643–4. 44. Braverman IM. Disease of the gastrointestinal tract.
26. Hermanns-Le T, Scheen A, Pierard GE. Acanthosis Skin signs of systemic disease, 3rd ed. Philadelphia,
nigricans associated with insulin resistance: PA: W.B. Saunders, 1998. pp. 405–37.
pathophysiology and management. Am J Clin 45. Holzberg M, Walker HK. Terry’s nails: revised
Dermatol. 2004;5:199–203. definition and new correlations. Lancet. 1984;1:896–9.
27. Ai J, Leonhardt JM, Heymann WR. Autoimmune thy- 46. Piette WW. Dysproteinemias, plasma cell disorders,
roid diseases: etiology, pathogenesis, and dermatologic and amyloidosis. In: Callen JP et al., editors.
manifestations. J Am Acad Dermatol. 2003;48:641–59. Dermatological signs of internal disease. Philadelphia,
28. Daumerie C, Ludgate M, Costagliola S, Many MC. PA: W.B. Saunders; 1995. p. 137–49.
Evidence of thyrotropin receptor immunoreactivity in 47. Silverstein SR. Primary, systemic amyloidosis and the
pretibial connective tissue from patients with thyroid-asso- dermatologist: where classic skin lesions may provide
ciated dermopathy. Eur J Endocrinol. 2002;146:35–8. the clue for early diagnosis. Dermatol Online J.
29. Rosen T, Kleman GA. Thyroid and the skin. In: Callen JP 2005;11:5.
et al., editors. Dermatological signs of internal disease. 48. Jambrosic J, from L, Hanna W. Lichen amyloidosis:
Philadelphia, PA: W.B. Saunders; 1995. p. 189–95. Ultrastructure and pathogenesis. Am J Dermatopathol.
30. Yanardag H, Pamuk ON, Karayel T. Cutaneous 1984;6:151–8.
involvement in sarcoidosis: analysis of the features in 49. Albano EA, Kanter J. Images in clinical medicine.
170 patients. Respir Med. 2003;97:978–82. Sister Mary Joseph’s nodule. N Engl J Med.
31. Callen JP. Sarcoidosis. In: Callen JP et al., editors. 2005;352(18):1913.
Dermatological signs of internal disease. Philadelphia, 50. Carroll MC, Fleming M, Chitambar CR, Neuburg M.
PA: W.B. Saunders; 1995. p. 293–300. Diagnosis, workup, and prognosis of cutaneous
32. Leonard AL. Sarcoidosis. Dermatol Online J. metastases of unknown primary origin. Dermatol
2003;9:40. Surg. 2002;28:533–5.
33. Kunz M, Beutel S, Brocker E. Leukocyte activation in 51. Mekhail TM, Markman M. Acanthosis nigricans with
erythema nodosum. Clin Exp Dermatol. 1999;24: endometrial carcinoma: case report and review of the
396–401. literature. Gynecol Oncol. 2002;84:332–4.
Cutaneous Findings of Collagen
Vascular Disease and Related 11
Emergent Complications
Aneesa Krishnamurthy, Diana H. Lee,

and Aegean Chan
11.1 Introduction 11.2 Lupus Erythematosus
Collagen vascular diseases are disorders of Lupus erythematosus is a broad term used to
unknown etiology, with features of autoimmu- describe a spectrum of clinical entities ranging
nity, in which the immune system loses the capac- from localized cutaneous manifestations to poten-
ity to distinguish self from nonself. This loss of tially life-threatening, multi-organ systemic
immune tolerance can result in varied and pro- involvement, caused by pathogenic autoantibod-
tean clinical manifestations, ranging from mild ies, leading to immune complex formation in tar-
constitutional symptoms to major organ failure. get tissues.
Skin changes may be the initial manifestation of, Systemic lupus erythematosus (SLE) is diag-
or have pathognomonic features, for specific col- nosed clinically, as proposed by the American
lagen vascular diseases, and are often invaluable College of Rheumatology (ACR) criteria. Patients
to diagnosis. In this chapter we focus on identify- must fulfill 4 of the 11 criteria [1, 2] (Table 11.1).
ing features of collagen vascular diseases, with Constitutional symptoms including fatigue,
an emphasis on cutaneous findings and emergent weight loss, and fever are common during active
complications. lupus. Fatigue may persist even when lupus is
“quiescent” [3, 4].
Arthritis, presenting as joint swelling and
pain, and arthralgias, or joint pain without syno-
vitis, are one of the most common, and early fea-
tures of SLE, and are often present at sometime
during the disease course (Table 11.2), specifically
with a lupus flare [5].
Hematologic manifestations are also common,
A. Krishnamurthy, D.O. (*)
including leukopenia (46%), anemia (42%), and
Preferred Health Partners, 233 Nostrand Avenue,
Brooklyn, NY 11205, USA thrombocytopenia (7–30%) [6, 7]. When leukope-
e-mail: aneesakrish@gmail.com; nia is secondary to active lupus, the WBC rarely
krishnamurthya@brooklyndocs.com decreases to <1,500 and the bone marrow is usu-
D.H. Lee, M.D., Ph.D. • A. Chan, M.D. ally normal, with a greater drop in neutrophil count
Department of Dermatology, Albert Einstein College than lymphocyte count, though isolated lympho-
of Medicine, Montefiore Medical Center,
cytopenia is a more frequent finding. Anemia is
111 East 210th Street, Bronx, NY 10467-2490, USA
e-mail: diana.h.lee@gmail.com; frequent and often multifactorial, usually second-
Aegean.Chan@med.einstein.yu.edu ary to chronic disease or iron deficiency [8, 9].

208 A. Krishnamurthy et al.
Table 11.1 1997 American College of rheumatology revised criteria for classification of systemic lupus
erythematosus
Criterion Definition
Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the
nasolabial folds
Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular
plugging; atrophic scarring may occur in older lesions
Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician
observation
Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician
Arthritis Non-erosive arthritis involving two or more peripheral joints, characterized by
tenderness, swelling, or effusion
Serositis (a) Pleuritis—convincing history of pleuritic pain, rubbing heard by a physician,
or evidence of pleural effusion
OR
(b) Pericarditis—documented by ECG, rub or evidence of pericardial effusion
Renal disorder (a) Persistent proteinuria greater than 0.5 g/day or greater than 3+ if quantitation
not performed
OR
(b) Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed
Neurologic disorder (a) Seizures—in the absence of offending drugs or known metabolic derange-
ments, e.g., uremia, ketoacidosis, or electrolyte imbalance
OR
(b) Psychosis—in the absence of offending drugs or known metabolic derange-
ments, e.g., uremia, ketoacidosis, or electrolyte imbalance
Hematologic disorder (a) Hemolytic anemia with reticulocytosis
OR
(b) Leukopenia—less than 4,000/mm3 total WBC on two or more occasions
OR
(c) Lymphopenia—less than 1,500/mm3 on two or more occasions
OR
(d) Thrombocytopenia—less than 100,000/mm3 in the absence of offending drugs
Immunologic disorder (a) Anti-DNA antibody to native DNA in abnormal titer
OR
(b) Anti-Sm: presence of antibody to Sm nuclear antigen
OR
(c) Positive finding of antiphospholipid antibodies based on (1) an abnormal
serum level of IgG or IgM anticardiolipin antibodies; (2) a positive test result
for lupus anticoagulant using a standard methods; or (3) a false-positive
serologic test for syphilis known to be positive for at least 6 months and
confirmed by Treponema pallidum immobilization or fluorescent treponemal
antibody absorption test (FTA-ABS)
Antinuclear antibody (ANA) An abnormal titer of antinuclear antibody by immunofluorescence (or an
equivalent assay) at any point in time and in the absence of drugs known to be
associated with “drug-induced lupus” syndrome
11.2.1 Emergent Complications includes microangiopathic hemolytic anemia

(suggested by schistocytes on peripheral smear),
Occasionally SLE patients can have severe life- CNS deficits, renal failure, and fever [10].
threatening thrombocytopenia in the setting of a Cardiopulmonary involvement is not infre-
lupus flare, which can be refractory even to quent. Pleuritic chest pain occurs in up to 50% of
aggressive therapy. Thrombocytopenia may be lupus patients at some time during their disease
part of the antiphospholipid syndrome or throm- [11]. Pericarditis is another common cause of
botic thrombocytopenic purpura (TTP), which chest pain in SLE patients, occurring ultimately
11 Cutaneous Findings of Collagen Vascular Disease and Related Emergent Complications 209
Table 11.2 Cumulative prevalence of 16 clinical and lab 11.2.1.1 Cutaneous Lupus
manifestations in 2,000 lupus patients [6]
Cutaneous lupus is seen in 59–85% of SLE
Clinical or lab manifestation Percentage patients [25] and can be classified as LE-specific
Positive ANA 97% skin disease and LE-nonspecific skin disease.
Arthritis, arthralgia, or myalgia 80% LE-specific skin disease has characteristic histo-
Skin changes 71% pathologic changes, including epidermal atrophy,
Low complement 51% hyperkeratosis, liquefactive degeneration of the
Cognitive dysfunction 50%
basal epidermis, and mononuclear cell infiltrate
Fever 48%
[26]. The three main categories of LE-specific
Elevated anti-dsDNA 46%
cutaneous disease are acute cutaneous (ACLE),
Leukopenia 46%
subacute cutaneous (SCLE), and chronic cutane-
Pleuritis 44%
Proteinuria 42%
ous (CCLE).
Anemia 35% LE-nonspecific lesions, such as vasculitis and
Antiphospholipid antibody 35% alopecia, do not have the characteristic LE histo-
Elevated gamma globulin 32% pathological changes, and can found in other
Pleural or pericardial effusion 12% medical conditions besides lupus.
CNS vasculitis 12% It is important to note that not all cutaneous
Adenopathy 10% lupus patients have systemic lupus. Of patients
with discoid lupus erythematosus (DLE) lesions,
only 5–10% will go on to develop SLE.
in 19–48% of patients [12]. Tamponade and Conversely, 25% of patients with systemic lupus
myocardial disease is rare [13]. Clinicians should develop DLE lesions at some point in their dis-
consider pulmonary embolism as the cause of ease course. Of patients with SCLE, about
cardiopulmonary symptoms in patients with 10–15% develop SLE. Presence of acute cutane-
lupus anticoagulant or anticardiolipin antibodies ous lupus lesions usually indicates underlying
[14]. Pulmonary hemorrhage is a rare, yet life- SLE [27, 28].
threatening emergency in SLE, presenting with
marked hypoxia along with abnormal chest
imaging [15]. This complication is usually the 11.2.2 LE-Specific Skin Disease
result of either pneumonitis or pulmonary
embolus and is associated with high mortality in 11.2.2.1 Acute Cutaneous Lupus
the range of 50–90% [16]. Lupus patients are at Erythematosus
higher risk for coronary artery disease, and myo- Acute cutaneous lupus erythematosus (ACLE)
cardial infarction is now the most common cause can present in localized or generalized distribu-
of death in SLE patients in the Western world tions and often occurs in the setting of acutely
[17, 18]. flaring SLE [29]. The most common form of
Kidney involvement is a major cause of mor- ACLE is localized symmetric, confluent ery-
bidity and hospital admissions. The most com- thema and edema over the malar region and the
mon manifestation of lupus nephritis is proteinuria bridge of the nose, sparing the nasolabial folds,
[19, 20]. Nephritic or nephrotic syndrome can be also known as the “butterfly” rash (Fig. 11.1).
observed in 30% of patients. Rapidly progressive The malar butterfly rash is present at time of SLE
glomerulonephritis occurs in less than 5% of diagnosis in 20–60% of patients [25, 30]. The
patients with SLE [21]. eruption fluctuates with disease activity and can
Neuropsychiatric manifestations are seen in be differentiated from acne rosacea or seborrheic
up to 60% of patients. Symptoms include sei- dermatitis by its lack of papules and pustules and
zures, personality changes, and cerebrovascular by its distribution. Painless oral and/or nasal
accidents, and are a major cause of morbidity mucosal ulcerations (Fig. 11.2) frequently accom-
[22–24]. pany lesions of ACLE [31].
Table 11.3 Extra-articular involvement of RA [163, 164, 167]

Ocular Keratoconjunctivitis sicca, scleritis, ulcerative keratitis
Hematologic Anemia of chronic disease, thrombocytosis, lymphadenopathy, Felty syndrome
Renal Mild membranous glomerulonephritis, secondary amyloidosis
Neurologic Cervical myelopathy from atlantoaxial subluxation, mononeuritis multiplex, peripheral neuropathy
Pulmonary Pleural effusions, interstitial lung disease, pulmonary nodules
Cardiac Pericarditis—usually asymptomatic, aortic root dilatation, coronary arteritis from rheumatoid
vasculitis
corneal blindness and laryngoesophageal steno-

sis. Histopathology and immunofluorescence
studies are necessary to delineate bullous SLE
from other blistering diseases in the lupus patient
[29]. A patient presenting with vesiculobullous
lesions should be treated emergently regardless
of etiology (see vesiculobullous diseases and
drug eruptions chapters).
11.2.2.2 Subacute Cutaneous Lupus

Erythematosus
Subacute cutaneous lupus erythematosus (SCLE)
presents as erythematous macules and/or papules
Fig. 11.1 Malar rash of acute cutaneous lupus erythema- that evolve into hyperkeratotic, papulosquamous
tosus (ACLE) also called the “butterfly” rash annular plaques often occurring often over the
neck, shoulders, upper extremities, and trunk
(Fig. 11.4), resembling psoriasis [33]. About
Generalized ACLE presents similar to a viral 70% of SCLE patients have positive anti-Ro/SSA
exanthem or drug eruption, as a widespread mor- antibodies. SCLE patients are, in general, more
billiform eruption, with diffuse edema and ery- likely to progress to SLE than those with chronic
thema of the face, upper trunk, or extremities cutaneous lupus [34]. Severe systemic manifesta-
(Fig. 11.3). The lesions develop rapidly and last tions such as systemic vasculitis, renal disease,
for hours to days. There may be associated and CNS occur in less than 10% of patients with
edema and erythema of the hands over the dorsal SCLE [29]. Risk factors for the development of
and interphalangeal areas, with pathognomonic SLE in a patient with SCLE lesions include papu-
sparing of the skin overlying the knuckles, in losquamous SCLE, leukopenia, and antinuclear
contrast to Gottron’s papules of dermatomyosi- antibody (ANA) titer greater than 1:640 [35].
tis. Generalized ACLE can affect up to a third of SCLE is drug-induced in 12% of cases. It resem-
patients with SLE [29]. Severe forms of general- bles idiopathic SCLE clinically and histopatho-
ized ACLE can present with vesiculobullous logically, but resolves when the offending drug,
skin changes, due to widespread apoptosis of most often an antihypertensive or antifungal
epidermal keratinocytes, clinically resembling agent, is withdrawn [33, 34].
toxic epidermal necrolysis (TEN). However,
unlike TEN, bullous ACLE is photosensitive, 11.2.2.3 Chronic Cutaneous LE
occurring predominantly over sun-exposed areas, The most common form of chronic cutaneous LE
has a more insidious onset, and may or may not (CCLE) is discoid lupus, which begins as red-pur-
involve mucosa [32]. Outside of the skin, there ple macules and papules that evolve into coin-
can be bullous LE involvement of ocular, esoph- shaped, erythematous plaques with scale extending
ageal, or laryngeal tissue, potentially leading to into the openings of dilated hair follicles (Fig. 11.5).
Fig. 11.2 Oral ulcerations

of ACLE
Fig. 11.3 Generalized rash of ACLE, which is typically Fig. 11.5 Discoid lesions of chronic cutaneous lupus
photosensitive, occurring mainly over sun-exposed areas erythematosus
Central scarring, telangiectasias, and hypopig-

mentation are the post-inflammatory hallmarks of
these lesions, most striking on darker skinned
patients, and can be very disfiguring. DLE is com-
monly found on the head and neck and extensor
aspects of the arms, similar to ACLE, but is neither
edematous nor transient. There can be mucosal
DLE involvement of the oral and genital mucosa
and the conjunctiva [36]. The small percentage of
DLE patients that progress to develop SLE are
more likely to do so within the first 5 years of DLE
diagnosis and usually have generalized DLE dis-
tribution (lesions both above and below the neck)
[37]. SLE patients with DLE skin lesions tend to
Fig. 11.4 Subacute cutaneous lupus erythematosus have less severe systemic lupus activity.
Other variants of CCLE are lupus panniculitis,

lupus tumidus, and chilblains lupus. Lupus
panniculitis (or lupus profundus) presents as firm,
depressed nodules, extending into the deep der-
mis, and is seen in 1–3% of CCLE patients
(Fig. 11.6) [38]. About 10–40% of those with LE
panniculitis have mild manifestations of SLE
[39]. Lupus tumidus presents as erythematous,
urticarial plaques with minimal surface change
and no follicular plugging (Fig. 11.7) [40]. Lupus
tumidus patients rarely have clinically evident
SLE and are usually ANA negative. Chilblain
lupus, a rare form of DLE, presents as violaceous
plaques and papules on the tips of fingers and Fig. 11.6 Lupus panniculitis/lupus profundus
toes, exacerbated by cold exposure (Fig. 11.8).
Twenty percent of chilblain lupus patients go on
to develop SLE [41].
11.2.3 LE-Nonspecific Skin Disease
Cutaneous vasculitis is reported to occur in 11%

of SLE patients (Fig. 11.9) [42]. Palpable purpura
is common, often in the lower extremities,
although a generalized or acral distribution can
also be observed [29]. Less-dependent areas of
the skin can exhibit urticarial vasculitis.
Fig. 11.7 Lupus tumidus
Additionally, fingertip gangrene, splinter hemor-
rhages, periungual telangiectasia, and purpuric
lesions of the palm can be seen. Antiphospholipid
syndrome or infective endocarditis should be kept
in the differential when evaluating these patients
[42]. Cutaneous vasculitis may be a predictor of
the future development of LE nephritis [43].
Alopecia is common in lupus patients [44].
Telogen effluvium can occur with systemic flares
and tends to resolve with lupus treatment. Discoid
lupus can cause a scarring alopecia [29]. Non-
scarring alopecia is seen in 24% of patients with
SLE [30].
Cutaneous mucinosis is an unusual nonspecific
presentation of SLE, presenting as asymptomatic
Fig. 11.8 Chilblain lupus
papules and nodules on the trunk and arms, with
increased mucin deposition in the dermis on his-
tology. In one study, this occurred in 1.5% of tive tissue diseases, such as dermatomyositis and
SLE patients. Another study found that 80% of scleroderma [45, 46].
patients with this presentation had underlying Other nonspecific cutaneous findings include
SLE, though it can also be seen in other connec- Senear-Usher syndrome, or pemphigus erythe-
Fig. 11.9 Cutaneous

vasculitis of SLE
matosus, which manifests as pemphigus folia- sive metabolic panel, urinalysis, complement lev-
ceous-like lesions in a seborrheic distribution in els, and autoantibody profile.
the setting of LE, and Rowell syndrome, in which
erythema multiforme-like lesions are seen in
patients with LE [31, 47]. 11.2.5 Treatment
Antimalarials, particularly hydroxychloroquine,

11.2.4 Laboratory Findings are used almost universally in SLE patients,
except in those with intolerance or G6PD enzyme
Whereas ANA may or may not be positive in iso- deficiency [50]. Hydroxychloroquine is safe in
lated cutaneous lupus patients, ANA >1:160 is pregnancy and lactation, prevents and decreases
present in virtually all SLE patients [27]. Anti- severity of lupus flares, and has the added benefit
double-stranded DNA antibodies (dsDNA), seen of increased survival, decreased thrombosis, and
in 70% of patients, and anti-Smith antibodies improved lipid levels in patients who take the
(anti-Sm), seen in 25% of patients, are both highly medication compliantly [51, 52]. Patients on anti-
specific for SLE [25]. Along with falling comple- malarials should be screened for maculopathy and
ment levels, rising anti-dsDNA titers are markers neuromyopathy. Another side effect is increased
for an acute or impending SLE flare. With a lupus blue-gray skin pigmentation with chronic
flare, the CBC may reveal leukopenia, hemolytic hydroxychloroquine ingestion [25, 53, 54].
anemia, and/or thrombocytopenia [7, 25, 48]. Lupus flares are treated according to severity
All lupus patients should be monitored for and risk to major organ function, with glucocorti-
proteinuria and active urinary sediment, such as coids being the cornerstone of treatment. Mild to
cellular casts and hematuria, which are indicative moderate flares, arthritis, and serositis can be
of lupus nephritis [49]. As ACLE often occurs in treated with low-dose prednisone 10–20 mg/day,
the setting of active systemic lupus, these patients while moderate to severe flares require higher
should have thorough evaluation for underlying doses. Steroids are tapered according to patient
disease activity including a history and physical response [55]. For patients who flare with steroid
examination, complete blood count, comprehen- tapering, or have recurrent lupus flares, or severe
organ manifestations, maintenance immunosup-

pression with azathioprine or mycophenolate
mofetil [25, 56], among others, should be consid-
ered. For patients who fail these standard therapies,
the newest FDA-approved medication for moder-
ate to severe SLE, IV Belimumab, a B-lymphocyte
stimulator-specific inhibitor, may be considered.
Most hospitalized patients and those with
severe flares are treated with the equivalent of
prednisone 1 mg/kg/day, or pulse doses of IV
methylprednisolone: 1 g/day for 3 days, particu-
larly for cases of rapidly progressive lupus
nephritis or life/organ-threatening manifesta-
Fig. 11.10 Atrophic plaques of previously acute neona-
tions. For patients with life-threatening organ tal lupus erythematosus
manifestations such as severe lupus nephritis or
neuropsychiatric disease, six monthly doses of
IV cyclophosphamide may be added to high-dose SSA/Ro or SSB/La antibodies and/or U1-RNP
steroids. Due to concern over cyclophosphamide to the fetus [61]. The risk of a baby being born
toxicity, azathioprine can be substituted for with NLE to an SSA/Ro + mother is roughly
milder forms of lupus nephritis, and mycopheno- 20%, and increases to 25% in women who have
late mofetil can be effective in induction treat- previously given birth to an affected child. Unlike
ment for even moderate to severe proliferative classic SCLE, the SCLE-like rash of neonatal
lupus nephritis, especially in African Americans lupus can scar (Fig. 11.10). Congenital heart
and Hispanics [57]. Intravenous immunoglobulin block occurs in 1–3% neonatal lupus, thought to
(IVIG) has shown benefit in autoimmune hemo- result from anti-Ro/La antibodies attacking car-
lytic anemia and thrombocytopenia and can be diac conduction tissue [62]. Congenital heart
used for other severe lupus manifestations, with- block can be diagnosed by fetal echocardiogra-
out increasing risk for secondary infection [58]. phy, usually starting at gestational week 18, and
Because cutaneous lupus is highly photosensi- is treated with IV steroids administered to the
tive, sun protection is paramount, including the mother [61, 63]. Fetal mortality from congenital
use of sunblocks and sunscreens, as well as hats heart block is roughly 20–30%. There is also a
and sun-protective clothing [59]. Initial therapy risk of liver failure secondary to hepatobiliary
usually includes topical glucocorticoids and/or disease and thrombocytopenia. Most deaths
intralesional steroid injection. Antimalarials such occur in utero or within the first 3 months after
as hydroxychloroquine with or without quina- birth [61, 62, 64]. NLE without cardiac involve-
crine are added first as systemic therapy or in ment usually spontaneously resolves within 2–6
combination if topical or local therapy is inade- months, though during that period, maternal
quate [60]. Patients with extensive skin involve- antibodies persist and can precipitate new skin
ment may require oral corticosteroids, and if lesions upon exposure to UV light [65].
needed, azathioprine, methotrexate, mycopheno-
late mofetil, dapsone (particularly for bullous
lesions), or thalidomide can be added [25, 29]. 11.4 Antiphospholipid Syndrome
Antiphospholipid syndrome (APS) is defined by

11.3 Neonatal Lupus persistent serum antiphospholipid antibodies
[anticardiolipin (ACL), lupus anticoagulant
One-third of SLE patients have antibodies to the (LAC), or anti-b2-glycoprotein I antibodies (anti-
SSA/Ro and SSB/La antigens. Neonatal lupus b2GPI)], along with vascular thromboses and/or
(NLE) is caused by placental transfer of either pregnancy morbidity [66]. Primary disease occurs
Fig. 11.11 Livido reticularis Fig. 11.12 Lower extremity ulceration secondary to
thrombosis in acute antiphospholipid antibody syndrome
in 1% of the population [11]. Patients with con- morbidity can manifest as unexplained consecu-
comitant autoimmune disease such as lupus are tive spontaneous abortions before the 10th week
labeled as “secondary APS.” Of lupus patients of gestation, death of a normal fetus beyond the
with antiphospholipid antibodies, 10–15% have 10th week of gestation, or premature birth of a
clinical manifestations of APS [67, 68]. normal neonate prior to 34th week of gestation
Up to 50% of APS patients have nonbacterial due to eclampsia, severe preeclampsia, or pla-
cardiac valvular thickening or vegetations, known cental insufficiency. Those occurring after 10
as marantic or Libman-Sacks endocarditis. weeks of gestation are most associated with aPL.
Though severe cardiac manifestations requiring Patients with a history of previous fetal loss and
valvular replacement are rare, dermatologic man- high titer IgG aCL are at 80% risk for loss of
ifestations are common. Livedo reticularis is seen their current pregnancy. Other obstetric manifes-
in 22–35% of SLE patients [42], particularly tations of APS include premature delivery, oligo-
those with antiphospholipid syndrome hydramnios, and intrauterine growth restriction
(Fig. 11.11). Other nonspecific APS skin mani- [71, 72].
festations include atrophie blanche, painful Catastrophic antiphospholipid syndrome
extremity ulcers that heal as a white atrophic scar (CAPS) is defined as positive antiphospholipid
(Fig. 11.12), and embolic phenomenon leading to antibodies along with three or more organ throm-
acral purpura and gangrene [69]. boses occurring over a short period of time.
Occlusion of small vessels, or thrombotic
microangiopathy, is characteristic. CAPS should
11.4.1 Emergent Complications be distinguished from TTP and disseminated
intravascular coagulation. CAPS is rare, occur-
Thrombosis may occur in large, medium, and ring in only 0.8% of patients with APS, but is
small vessels of the venous and arterial circula- significant due to high mortality rate [73].
tion. Venous thromboses are most common in the
legs, but have been reported in varied sites not
limited to the renal, mesenteric, axillary, and sag- 11.4.2 Laboratory Findings
ittal veins. Arterial events can be the result of
either primary thrombosis or from emboli origi- APS laboratory criteria require at least one of the
nating from valvular vegetations. Transient isch- three following tests, present on two or more
emic attacks are the most frequent manifestation occasions in a period of 12 weeks: lupus antico-
of arterial thrombosis in APS [66, 70]. agulant, IgG, or IgM anticardiolipin antibodies in
APS is a significant cause of recurrent medium-high titers, or IgG, IgM, or anti-®2-GPI
pregnancy loss in lupus patients. Pregnancy antibodies above the 99th percentile [66, 74–76].
Fig. 11.13 Gottron papules of

dermatomyositis (DM)
False-positive tests for syphilis often indicate the CAPS patients are in general very ill, and
presence of underlying antiphospholipid antibodies. require anticoagulation, high-dose steroids and
Besides being associated with autoimmune disease, plasma exchange [83].
APS antibodies and can be drug-induced or infec- Women with APS and recurrent miscarriages
tion related [76]. Medications associated with aPL are treated with low-dose aspirin along with
are hydralazine, procainamide, and phenytoin. either heparin or low molecular weight heparin
Bacterial infections, including syphilis, Lyme dis- (LMWH) during subsequent pregnancies [84].
ease, post-streptococcal rheumatic fever, and viral Anticoagulation is continued for 6 weeks after
infections, such as hepatitis A, B, C, mumps, HIV, delivery [85]. Intravenous immunoglobulin with
varicella zoster, EBV, and parvovirus can all result or without steroids is also being evaluated in clin-
in IgM anticardiolipin in the serum [77]. ical trials for use in preventing pregnancy losses
Other lab abnormalities seen in APS are in women with APL. Pregnant APS patients are
thrombocytopenia (typically mild), and less com- at risk for and should be monitored for preec-
monly, Coombs-positive hemolytic anemia. lampsia. The fetus should be monitored for pla-
Antiphospholipid antibodies with thrombocy- cental insufficiency the last weeks of the third
topenia and autoimmune hemolytic anemia are trimester [85].
known as Evans syndrome [78].
11.5 Dermatomyositis
11.4.3 Treatment
Dermatomyositis (DM) is an inflammatory mus-
Patients with APS and history of thrombosis cle disease associated with characteristic skin
require lifelong anticoagulation at an INR of 2–3 manifestations. The cutaneous findings pathog-
for venous events. There is controversy over nomonic for DM are Gottron’s papules, viola-
whether the INR should be kept at a higher level ceous or pink papules of the dorsal metacarpal
for arterial thrombosis [79]. Some studies sug- and interphalangeal joints (Fig. 11.13), and
gest that APL antibody positive SLE patients Gottron’s sign, macular erythema over extensor
may benefit from prophylactic aspirin therapy surfaces such as the elbows and knees (Fig. 11.14).
[80]. Severe cases of APS-associated thrombocy- Lesions resemble cutaneous lupus in that they are
topenia are treated with steroids, IVIG, or sensitive to UV light and have similar histopatho-
splenectomy if resistant [81, 82]. logic findings. Also frequently occurring are the
laboratory or histologic evidence muscle

involvement for at least 2 years following initial
presentation [88].
11.5.1 Emergent Complications
Interstitial lung disease (ILD) is the most fre-

quent cause of morbidity and mortality in DM
[89, 90] and is usually associated with the pres-
ence of anti-Jo1 antibody. An important subset
of myositis is the antisynthetase syndrome:
inflammatory myositis associated with the
Fig. 11.14 Gottron sign of DM
presence of anti-Jo1 antibody, along with ILD,
fever, Raynaud’s phenomenon, arthritis, and
“mechanics hands” (rough erythema on the
sides of the fingers and palm) [91, 92]. Of amy-
opathic DM patients, up to 25% have ILD and
must be screened with annual pulmonary func-
tion tests [93]. The natural course of ILD is
gradual and progressive, though acute deteriora-
tions can occur [92, 94]. Besides ILD, dyspnea
can be due to weakness of the diaphragm and
thoracic muscles, or from myositis of the stri-
ated esophageal muscles, which can lead to
aspiration pneumonia.
Cardiac myositis, another complication of
DM, is usually subclinical, presenting with mild
rhythm disturbances. Congestive heart failure
from myocarditis or fibrosis is rare. Myocardial
Fig. 11.15 Heliotrope rash of DM
involvement, pharyngeal weakness, malignancy,
ILD, and delayed initiation of steroids are associ-
heliotrope rash, presenting as periorbital viola- ated with poor survival [95, 96]. Several popula-
ceous erythema (Fig. 11.15), and erythema tion-based studies have documented a higher than
extending over the shoulders (the “shawl sign”) expected risk of malignancy in patients with
or the anterior chest (the “V-sign”), which can adult-onset DM [97–99]. Risk of malignancy
later progress to poikiloderma. Nail fold changes increases with age, male gender, and elevated
are also common, including periungual erythema serum creatine kinase levels [100]. The most
and telangiectasias [86]. commonly associated malignancies are ovarian,
DM is most commonly diagnosed using the breast, lung, pancreatic, stomach, colorectal can-
Bohan and Peter Criteria. According to the cri- cer, and non-Hodgkin lymphoma [101]. Risk of
teria, a patient has definite DM if presenting malignancy appears to approach that of the gen-
with a typical DM skin rash, and any three of eral population if no malignancy is discovered
the following: symmetric proximal muscle within the first 2 years of diagnosis [102].
weakness, elevated skeletal muscle enzymes, DM can also occur in the pediatric population,
characteristic electromyogram, or myositis on with a similar rash as adult DM, except with a
muscle biopsy [87]. Amyopathic DM is defined more frequent incidence of soft tissue calcinosis
as a characteristic DM rash, without clinical, and cutaneous or gastrointestinal ulceration and
Fig. 11.16 “Salt and pepper”

appearance of the skin in systemic
sclerosis (SSc)
vasculitis [103]. Unlike adult dermatomyositis, topical steroids, and hydroxychloroquine.

malignancy is rarely associated with juvenile der- Malignancy-associated myositis and DM rash
matomyositis. Up to 15–24% of adult individuals are generally refractory to steroids, resolving
with dermatomyositis are diagnosed with malig- only with treatment of the underlying cancer
nancy either at time of diagnosis of DM or soon [101, 109].
thereafter, in contrast to only 1% of pediatric
patients with juvenile dermatomyositis [104].
11.6 Systemic Sclerosis
11.5.2 Laboratory Findings Systemic sclerosis (SSc), also known as sclero-

derma, is characterized by microvascular injury
Evidence of myositis includes elevated creatine and excessive collagen deposition and fibrosis of
kinase (CK), aldolase, and liver function tests. the skin and internal organs. The extent of skin
CK is most often used for monitoring of disease sclerosis determines whether the patient has a
activity and response to therapy [105]. diffuse or limited systemic sclerosis. Each subset
has unique serologic markers and variable asso-
ciations with underlying organ manifestations.
11.5.3 Treatment Diffuse systemic sclerosis (dSSc) is defined by
skin changes extending from the fingers and toes
Initial pharmacologic therapy for DM consists of proximally to the elbow and knees, often involving
high-dose glucocorticoids, tapered once muscle the chest and abdominal wall. With progressive
enzymes normalize [106]. Steroid sparing agents skin tightening and fibrosis, certain areas of the
may be added, most commonly azathioprine and/ skin may become hypo- or hyperpigmented. Often,
or methotrexate, particularly in patients with pigment is maintained around the hair follicle,
major organ involvement, delayed diagnosis or leading to a “salt and pepper” appearance of the
treatment, or severe myositis. For treatment resis- skin (Fig. 11.16). Disease presentation is usually
tant myositis, IVIG, mycophenolate mofetil, and abrupt, and symmetric hand edema and Raynaud’s
rituximab may provide benefit [107, 108]. phenomenon are closely related to the onset of
The rash of dermatomyositis often responds to sclerosis. While skin sclerosis is the most severe in
myositis treatment, along with sun avoidance, the first 18 months of disease and can subsequently
tension, acute renal failure, and microangiopathic

hemolytic anemia [116].
Nowadays, most disease-related SSc mortality
is from cardiopulmonary involvement: ILD, sub-
sequent pulmonary fibrosis, and pulmonary artery
hypertension (PAH). Patients are monitored for
lung disease with pulmonary function tests and/
or imaging [117]. The greatest decline in lung
function from ILD occurs in the first 4–6 years of
scleroderma onset [118, 119].
Pulmonary arterial hypertension (PAH) can
occur in any subset of scleroderma, but as
mentioned earlier, is more frequent in limited
Fig. 11.17 Taut facial skin yielding a mask-like appear-
ance and small oral aperture of SSc
SSc, usually occurring years after diagnosis.
Patients are monitored for PAH by echocardiog-
raphy, and diagnosis is confirmed by right heart
improve, disease involvement of internal organs catheterization [120].
continues to progress with time [110, 111]. Besides PAH, other cardiac features include
Limited systemic sclerosis (lSSc) presents with pericardial effusions, arrhythmias, and dia-
a more indolent course than dSSc. Patients often stolic dysfunction. Myocardial ischemia,
have a longstanding preexisting history of fibrosis, and myocarditis have been noted as
Raynaud’s phenomenon, later presenting with well [121, 122].
skin thickening and fibrosis distal to the elbows Empiric treatment with a proton pump inhibi-
and knees. Both diffuse and limited SSc can have tor is recommended to prevent SSc gastrointesti-
taut facial skin yielding a mask-like appearance, nal complications, including dysmotility, reflux,
with a small oral aperture (Fig. 11.17). Besides and stricture formation. [123]. SSc patients may
Raynaud’s, other lSSc features include subcuta- have gastrointestinal blood loss from mucosal
neous calcinosis, gastrointestinal reflux and telangiectasias, such as gastric antral vascular
esophageal dysmotility, sclerodactyly, and telang- ectasia (GAVE), described endoscopically as
iectasias, also known as CREST syndrome. One “watermelon stomach” [124]. There is an asso-
percent of cases can develop internal organ ciation between primary biliary cirrhosis (PBC),
involvement without characteristic skin changes which often has an associated anticentromere
[112]. Limited SSc is associated with a higher risk antibody, and limited scleroderma. Without
of pulmonary hypertension, but overall prolonged ursodiol treatment, there can be progression to
survival when compared to dSSc [113, 114]. secondary cirrhosis [125]. Intestinal fibrosis can
Scleroderma can overlap with other autoim- yield dysmotility, giving rise to bacterial over-
mune diseases, including the inflammatory myo- growth, abdominal pain, and bloating.
pathies, SLE, and Sjögren’s syndrome. Finally, Raynaud’s phenomenon of sclero-
derma is typically severe and resistant to treat-
ment, leading to critical digital ischemia,
11.6.1 Emergent Complications ulceration, gangrene, and ultimately, auto-ampu-
tation (Fig. 11.18). Ischemic pain and decreased
Until the development of ACE inhibitors, sclero- capillary refill with or without signs of visible tis-
derma renal crisis (SRC) was the most serious sue damage is a sign of ongoing ischemia and
and lethal complication of SSc [115]. SRC, aris- requires immediate treatment. Care should be
ing from vessel narrowing and ischemic kidney taken to not mistake either digital calcinosis, or
disease, presents almost exclusively during the sores from microtrauma of taut atrophic skin cov-
first 5 years of diffuse SSc, as new-onset hyper- ering joints, for digital ulcerations [126].
Fig. 11.18 Digital ischemia and ulceration in SSc Fig. 11.19 Auricular chondritis of relapsing
polychondritis
11.6.2 Laboratory Findings

phamide has been shown in randomized controlled
Most SSc patients will have a positive ANA. studies to be of benefit in SSc ILD, albeit mod-
A negative ANA should alert the clinician to estly [117, 130]. Corticosteroids play a minimal
consider other diagnoses such as nephrogenic role in the management of scleroderma and are
systemic fibrosis, scleromyxedema, scleredema, used mainly for the treatment of associated
graft versus host disease (GVHD), and toxin- inflammatory arthritis [131].
mediated sclerotic syndromes [127]. The anti- Depending on the severity of PAH, oral
centromere antibody is almost exclusively seen endothelin receptor antagonists, phosphodi-
in lSSc. Anti-Scl antibody is more characteristic esterase inhibitors, inhaled iloprost, or prostacy-
of dSSc, especially those with ILD, and is found clin can be used [132, 133].
in 20–30% of patients. Anti-RNA polymerase
I/III antibodies are linked to SRC [128, 129].
11.7 Relapsing Polychondritis
11.6.3 Treatment Relapsing polychrondritis (RP) is characterized

by painful inflammation of cartilage throughout
Most treatment is directed towards a specific organ the body. Autoantibodies and cell-mediated
and/or symptom. For Raynaud’s, vasodilatation immunity towards extracellular matrix compo-
and increased blood flow to the digits is the goal of nents, including collagen types II, IX, and XI,
treatment and can include any combination of cal- have been implicated in the pathogenesis.
cium channel blockers, angiotensin receptor block- Episodes last days to weeks and can resolve
ers, nitropaste, or even sildenafil and/or bosentan, spontaneously. The classic finding in RP is acute
if resistant secondary ulcers are present. uni- or bilateral auricular chondritis (Fig. 11.19).
Proton pump inhibitors are beneficial for Recurrent attacks of auricular chondritis can
esophageal dysmotility, strictures, and esophagi- result in the floppy “cauliflower ear,” and attacks
tis. Promotility agents such as metoclopramide of nasal cartilage can yield a depressed “saddle
alternating with antibiotics can alleviate symp- nose” deformity. Nasal involvement is common,
toms of bacterial overgrowth. presenting as a tender, warm, and red nasal bridge.
Many immunosuppressant agents have been Up to 12% of patients may present with nonspecific
used as disease modifying treatments in systemic dermatologic findings, including erythema
sclerosis, including mycophenolate mofetil, aza- nodosum, purpura, livedo reticularis, and distal
thioprine, and methotrexate, but only cyclophos- necrosis [134, 135].
11.7.1 Emergent Complications tive in all cases. A positive ANA is seen in

22–66% of patients. In atypical cases, biopsy
Involvement of the cartilaginous rings of the of involved cartilage may be needed to confirm
respiratory tract is a major cause of mortality, diagnosis [133].
and can occur in over 50% of patients [136].
Though there is little correlation between sever-
ity of clinical symptoms and the extent of airway 11.7.3 Treatment
involvement, clinicians should consider laryn-
gotracheal involvement in any RP patient with Initial treatment of relapsing polychondritis con-
respiratory complaints, including hoarseness, sists of low-dose prednisone for mild auricular or
nonproductive cough, wheezing, dyspnea, or nasal chondritis, or arthritis, while more serious
stridor. Flow-volume loop studies should be manifestations such as laryngeotracheal or ocular
obtained for all patients diagnosed with RP and symptoms require higher doses. For steroid
be repeated every 6–12 months to evaluate for dependent or refractory cases, anecdotal evidence
subacute airway strictures and narrowing. During suggests dapsone and colchicine, or if severe,
an acute attack, CT scan may show edema and cyclophosphamide, azathioprine, cyclosporine,
thickening of the trachea. Recurrent pneumonias or mycophenolate mofetil may be helpful.
or bronchiectasis may suggest a collapsed bron- Biologics such as infliximab and the IL-1 recep-
chus [137, 138]. tor antagonist, Anakinra, have been used as well.
Less than 10% of cases have cardiovascular Localized steroid therapy can be used in the form
involvement. Aortic regurgitation secondary to of eye drops, inhaled steroids, or intra-articular or
aortic root dilatation can occur [139]. Other man- intralesional injections [145–148].
ifestations include mitral regurgitation and con-
duction abnormalities [140].
Renal dysfunction is seen in up to one quar- 11.8 Rheumatoid Arthritis
ter of patients, manifesting as IgA nephropathy,
tubulointerstitial nephritis, or segmental necro- Rheumatoid arthritis (RA) is a chronic
tizing crescentic glomerulonephritis [141]. inflammatory polyarthritis, with a predilection
Renal involvement is associated with extra- for the small joints of the hands, feet, and wrists.
renal vasculitis, arthritis, and overall worse The arthritis is commonly symmetric, affecting
prognosis [142]. upper and lower extremity joints, with associated
Ocular inflammation is found in up to 60%. morning stiffness lasting for hours. If left
Episcleritis and scleritis are most frequent, fol- untreated, or suboptimally treated, chronic
lowed by keratoconjunctivitis, sicca, uveitis, and untreated joint inflammation can progress to a
ulcerative keratitis. Although rare, blindness can secondary osteoarthritis and deforming arthritis
result from corneal perforation, retinal vasculitis, with bone erosions on imaging. Among the more
and optic neuritis [143]. common cutaneous findings in RA are rheuma-
There is an association between myelodyspla- toid nodules, seen in 20–30% of patients.
sia and RP, especially in patients who are male, Rheumatoid nodules are painless, firm, flesh-
have dermatologic manifestations and an older colored subcutaneous nodules, occurring over
age at onset of disease [133, 144]. extensor surfaces, believed to occur from small
vessel vasculitis with fibrinoid necrosis.
Rheumatoid nodules portend a more severe dis-
11.7.2 Laboratory Findings ease course and higher risk of developing extraar-
ticular disease. Rheumatoid nodules are more
There is no specific screening autoantibody common in males and rheumatoid factor (RF)
for RP. Anti-collagen antibody tests are not positive patients [149]. Neutrophilic dermatoses
always readily available and may not be posi- can also present in patients with RA, including
pyoderma gangrenosum, Sweet’s syndrome, Felty’s syndrome, consisting of RA, leukopenia

rheumatoid neutrophilic dermatitis, erythema and splenomegaly, occurs in 1%of RA patients,
elevatum diutinum, and palisading neutrophilic mainly those with long-standing, seropositive,
and granulomatous dermatitis [150, 151]. erosive, and deforming RA [158]. Patients with
Bywater’s lesions are small brown to purpuric Felty’s syndrome frequently have lower extremity
painless lesions on the nail fold, nail edge, or ulcers as well as an increased risk of melanoma,
digital pulp that represent nail fold infarctions, lymphomas, and leukemias. Leukopenia portends
and do not require intense immunosuppression a 25% mortality risk from sepsis [158–160].
[152–154]. Rheumatoid vasculitis is uncommon (<5%),
and typically occurs in patients with long-stand-
ing, erosive RA with RF seropositivity and
11.8.1 Emergent Complications rheumatoid nodules. Cutaneous manifestations
are digital gangrene and leg ulcers along the
RA is associated with exudative pleural effusions lateral malleolus or pretibial region, and
with low fluid glucose levels that can be mistaken nonspecific erythema, hemorrhagic blisters,
for empyema. Patients with cutaneous rheuma- livedo reticularis, erythema elevatum diutinum, and
toid nodules can have associated pulmonary nod- atrophie blanche [163, 164]. Visceral involvement
ules, which are usually asymptomatic, but can of different organ systems (eye, heart, lung, GI)
rarely cavitate and cause bronchopleural fistulas and the peripheral nerves can occur [161].
or pneumothorax. Symptomatic ILD is reported Features include scleritis, pericarditis, myocar-
in up to 10% of RA population studies. Some dial infarction, neuropathy, and acute abdomen
forms of RA-associated ILD such as cryptogenic [161, 166, 167]. Decreased survival has been
obstructive pneumonia are very steroid respon- noted in patients with a younger age at diagno-
sive, whereas usual interstitial pneumonitis is sis, delayed diagnosis, abnormal urinary sedi-
progressive despite treatment [155]. ment, and hypergammaglobulinemia. Cardiac
Cervical spine involvement is frequent in involvement, gangrene, bowel infarctions, and
patients with severe RA. Patients complaining of mononeuritis multiplex also suggest poor prog-
neck pain or upper extremity paresthesias should nosis [168]. As the pathogenesis is immune
alert the clinician to possible cervical spinal cord complex mediated, it has been suggested that
compression from atlantoaxial subluxation. Other direct immunofluorescence of skin biopsy may
symptoms include sensation of the “head falling detect early or subclinical vasculitis in RA
off,” weakness, incontinence, and positive patients [156].
Babinski reflex. Atlantoaxial subluxation occurs
as a result of a lax C1 transverse ligament or from
erosion of the odontoid process. Diagnosis is 11.8.2 Laboratory Findings
confirmed with a lateral flexion–extension X-ray,
in which the space between the C1 anterior arch Rheumatoid factor is an autoantibody against
and C2 odontoid process is greater than 5 mm. IgG, seen in 80% of RA patients, but can also be
Basilar invagination can also occur, from upward seen in Sjögren’s syndrome, cryoglobulinemia,
migration of the odontoid process into the fora- and SLE among others diseases. Low titers may
men magnum. Both processes can lead to verte- also be seen in the elderly, and patients with
bral artery compression [157]. long-standing infection. Anti-citrullinated pep-
Active RA can be associated with episcleritis, tide antibodies (anti-CCP antibody or ACPA) can
scleritis, and peripheral ulcerative keratitis. be seen in up to 85% of RA patients later in the
Scleritis, when untreated, can progress from eye course of the disease, and has higher specificity
redness and pain to necrotizing scleritis, which is for RA than the RF does [170].
associated with underlying vasculitis, vision loss, The 2010 ACR/EULAR classification incor-
and high mortality [213]. porates joint involvement, serology, duration of
symptoms and acute phase reactants for diagnosis. drome can be a primary disorder, or can be seen in
The acute phase reactants, erythrocyte sedimen- association with other autoimmune diseases such
tation rate (ESR), and C reactive protein as SLE and RA [176]. The disease can manifest
(CRP) are also used in monitoring disease with a variety of cutaneous signs, the most common
activity [165]. being xerosis. Cutaneous vasculitis, including
cryogolubulinemia, may suggest more serious sys-
temic and extraglandular involvement [177].
11.8.3 Treatment Lymphocytic infiltration of various organs can
yield interstitial pneumonitis, pericarditis, and
Once rheumatoid arthritis is diagnosed, aggres- interstitial nephritis. These features usually
sive therapy with disease-modifying antirheu- appear early in the disease and follow a benign
matic drugs (DMARDs) should be initiated, in course. Arthritis and arthralgias are seen in over
order to prevent further joint damage and subse- half of patients. PBC and celiac sprue have also
quent permanent deformity. been noted to be associated with SS [178, 179].
Methotrexate is considered the anchor drug. If
disease control is not achieved, other DMARDs
such as leflunomide, or sulfasalazine with 11.9.1 Emergent Complications
hydroxychloroquine can be added, or biologic
agents can be employed. Adjunctive treatments There is a 10- to 40-fold increased risk of lym-
for helping with pain and function include gluco- phoma in SS patients. The overall risk of devel-
corticoids, NSAIDs, and physical and occupa- oping lymphoma is 5% in patients with SS.
tional therapy. Patients with SS also have a predilection for vas-
Treatment of rheumatoid vasculitis requires culitis, and in particular type II cryoglobulinemic
high-dose glucocorticoids with or without cyclo- vasculitis is associated with lymphoma (most
phosphamide. Methotrexate is not only a commonly non-Hodgkins type) both indepen-
DMARD, but is also used to improve Felty’s syn- dently and in those with SS. Other risk factors for
drome associated cytopenias. Splenectomy is lymphoma include C4 hypocomplementemia and
indicated for recurrent infections or noncorrect- hard enlargement of parotid or lacrimal glands
ing leukopenia, and may also improve leg ulcers [180]. Neurologic complications include senso-
[165, 171]. rimotor neuropathy, though cranial neuropathies,
Scleritis requires topical or local steroids with central demyelinating disease, and optic atrophy
or without systemic immunosuppressants. have also been described. Central nervous system
Hematologic findings such as anemia of chronic vasculitis is uncommon [181].
disease and thrombocytosis, tend to resolve as Three prognostic factors for adverse outcomes
the RA comes under control with immunosup- in primary SS are purpura, hypocomplement-
pression. Peripheral neuropathy from inflamed emia, and cryoglobulinemia, as identified in sev-
synovial entrapment will also improve with RA eral prospective studies of SS pts. Such outcomes
treatment. Atlantoaxial subluxation greater than include systemic vasculitis, B cell lymphoma,
8 mm from cervical involvement usually requires and death [182, 183, 184].
surgical intervention [163, 173–175].

11.9 Sjögren’s Syndrome
The presence of SSA/Ro and SSB/La antibodies
Sjögren’s syndrome (SS) is an autoimmune disor- are part of the diagnostic criteria, and occur in
der characterized by lymphocytic infiltration of high frequency, along with RF and ANA. Elevated
exocrine glands, primarily manifesting as ESR is seen in most patients, as is hypergamma-
xerophthalmia and xerostomia. Sjögren’s syn- globulinemia [177].
11.9.3 Treatment
Ocular and oral disease is treated symptomati-

cally with preservative-free artificial tears, lubri-
cating ointments, methylcellulose drops, good
dental hygiene, and antifungal medications if
needed. Muscarinic stimulants such as pilo-
carpine and cevimeline can aid with salivary
gland secretion though side effects such as dia-
phoresis, nausea, and diarrhea can be limiting.
For Sjögren’s associated arthritis, hydroxychlo-
roquine can be helpful. Corticosteroids and
immunosuppressives such as cyclophosphamide
Fig. 11.20 Oral aphthous ulcers of Behçet’s disease
and azathioprine can be used for severe
extraglandular disease, but are not helpful for
alleviating symptoms of xerosis [185–187].
11.10 Behçet’s Disease
Behçet’s disease is a systemic vasculitis, with an

increased prevalence along the old “silk route,”
specifically Turkey, Iran, and Japan. Though there
is no diagnostic test for Behçet’s disease, criteria
have been developed by the International Study
Group for Behçet’s disease, which include recur-
rent oral aphthous ulcers (Fig. 11.20) as the major
criterion, and any two of the following minor cri-
teria: recurrent genital ulcers (most commonly of Fig. 11.21 Scrotal ulcers found in Behçet’s disease
the scrotum in males (Fig. 11.21) and labia majora
of women), eye lesions (uveitis, retinal vasculitis),
cutaneous findings such as erythema nodosum, likely than females to have severe ocular involve-
papulopustules, pseudofolliculitis, acneiform ment. Ocular inflammation is the initial manifes-
lesions, or a positive pathergy test. The pathergy tation in about 20%. Anterior uveitis is seen more
reaction is characterized by papule or pustule for- commonly in females, while posterior uveitis is
mation 1–2 days after skin trauma, such as a nee- more common in males [190, 191].
dle prick. Behçet’s differs from other autoimmune An important cause of morbidity in patients
diseases in its lack of B-cell hyperreactivity or with Behçet’s disease is major vessel disease,
T-cell dysfunction, and lack of association with particularly arterial aneurysm and/or occlusions,
Raynaud’s phenomenon or secondary Sjögren’s hepatic vein occlusion (Budd-Chiari syndrome),
syndrome [188, 189]. and thrombophlebitis of superficial and deep
veins of the legs. Behcet’s syndrome is the only
vasculitis that causes pulmonary artery aneu-
11.10.1 Emergent Complications rysms, which is the primary cause of mortality.
Significant neurological involvement can be seen,
Ocular disease occurs in 70% of cases of Behçet’s including central nervous system disease, especially
disease; approximately 25% may lose their vision involving the brainstem, aseptic meningitis, and
despite therapeutic intervention. Males are more cerebral venous sinus thrombosis [192–195].
Laboratory findings are usually nonspecific, and

also found in other inflammatory diseases, such
as anemia of chronic disease, and elevated acute
phase reactants. Autoantibodies are typically
negative [189].
11.10.3 Treatment
Mild to moderate mucocutaneous disease can be

treated with topical or intralesional corticosteroids,
Fig. 11.22 Keratoderma blennorrhagicum of reactive
topical sucralfate, and local anesthetics. For more arthritis (ReA)
severe cases, colchicine, thalidomide, or azathio-
prine can be used. The nonerosive arthritis of
Behçet’s can be managed with colchicine. Ocular
disease is treated with prednisone and azathioprine
[196, 197]. As it is believed that vascular
inflammation is the cause of venous thromboses,
treatment strategy is aimed toward immunosup-
pression rather than anticoagulation. Vascular
involvement is treated with systemic corticoster-
oids alone, or in combination with other immuno-
suppressives such as azathioprine, chlorambucil,
cyclophosphamide, cyclosporine, and interferon-a.
Mycophenolate mofetil, IV immunoglobulin, and Fig. 11.23 Circinate balanitis of ReA
anti-TNF-a agents have also been used [198, 199].
after the start of arthritis, usually involving the
soles of the feet (Fig. 11.22), but can affect the legs,
hands, nails, and scalp. Circinate balanitis (25%) is
11.11 Reactive Arthritis most frequently seen in Chlamydia-associated
ReA, and presents as either hyperkerototic plaques
Reactive arthritis (ReA), formerly known as on circumcised males, or shallow ulcers on uncir-
Reiter’s syndrome, is a multisystem disease char- cumcised males, typically on the glans penis, or on
acterized by a sterile oligo- or monoarthritis and the shaft or scrotum (Fig. 11.23). Yersinia infection
either urethritis, cervicitis, or bilateral conjunctivi- can be associated with erythema nodosum. Oral
tis following a urogenital or enteric infection. ulcers can also be seen in ReA [200, 202].
Triggering organisms include Chlamydia tracho-
matis (or less frequently, Chlamydia pneumoniae),
Salmonella, Shigella, Campylobacter, and Yersinia. 11.11.1 Emergent Complications
The pathogenesis is not clearly understood, but it
is thought that bacterial components may trigger Conjunctivitis is the most common eye finding,
the disease in genetically susceptible individuals, but anterior uveitis (iritis), often unilateral, is also
perhaps via molecular mimicry [200, 201]. seen. Topical glucocorticoid eye drops and a
There are many classic skin findings. mydriatic agent may be needed to dilate the
Keratoderma blennorrhagicum (10%) is a scaly, involved eye and prevent synechiae formation
often pustular, eruption that manifests 1–2 months between the pupil and lens.
Acute reactive arthritis may be severe enough

to mimic septic arthritis and be associated with 11.12 Adult-Onset Still’s Disease
high fevers and extreme malaise. Septic arthritis
can occur in Campylobacter and Salmonella infec- Adult-onset Still’s disease (AOSD) is an uncom-
tions. Furthermore, gonococcal arthritis (a septic mon febrile autoimmune disease, typified by high
arthritis) must be distinguished from an aseptic spiking fevers, polyarthritis, and a transient rash.
arthritis arising in a patient developing ReA with The etiology of AOSD is unknown, and it typi-
a gonococcal infection. Synovial fluid gram stain cally affects adults in the second and fourth
and culture helps distinguish the two [202]. decades of life with equal incidence between
males and females. A similar syndrome occurs in
the systemic subset of juvenile idiopathic arthri-
11.11.2 Laboratory Findings tis. Other AOSD symptoms include pharyngitis
which can be a presenting symptom, lymphade-
Diagnosis relies on finding the triggering infec- nopathy, hepatosplenomegaly, leukocytosis,
tion. Chlamydia trachomatis can be found in thrombocytosis, elevated transaminases, and
morning urine or by genital swab. By the time serositis [207].
arthritis presents, enteric organisms may not be Fever of unknown origin is the most frequent
identifiable in the stool. There is a strong associa- cause for investigation, as high fever is the initial
tion between the genetic marker HLA-B27 and symptom in most patients. The classic fever pat-
reactive arthritis. Furthermore, HLA-B27 can be tern is one–two spikes exceeding 39 °C, most
predictive of future development of spondyloar- often late in the day, and resolving within hours,
thritis and uveitis [203]. also known as quotidian fever [207, 208]. AOSD
can be mistaken for sepsis, and other disorders
such as hepatitis and reactive hemophagocytic
11.11.3 Treatment syndrome must be excluded. The classic AOSD
rash is maculopapular and salmon-colored,
Patients infected with C. trachomatis and their mainly over the trunk and proximal extremities,
sexual partners should be treated with azithromy- most pronounced during febrile episodes.
cin or doxycycline. The arthritis itself can be Dermatographism is present in up to 60% of
treated with NSAIDs, and with local glucocorti- patients with the rash [207].
coid injections for mono- and oligoarthritis and
enthesitis. Systemic corticosteroids can be used if
there are systemic symptoms. The role of antibi-
otics in the treatment of reactive arthritis is ques- 11.12.1 Emergent Complications
tionable. Although it may be helpful in the
infective phase, once the arthritis has developed, Chronic AOSD can lead to joint destruction akin
antibiotics typically do not modify the disease to seropositive rheumatoid arthritis, with resul-
course. As half of affected patients recover from tant severe functional impairment [207]. Up to
reactive arthritis within the first 6 months, the use 5% of patients can develop amyloidosis within
of disease-modifying antirheumatic drugs are 10 years of the disease onset [209]. Macrophage
often not considered, though sulfasalazine may activation syndrome is reported in 5–10% of
be helpful in achieving faster remission if used in patients. This massive, potentially deadly immune
the first few months and for those with chronic response is associated with cytopenias, dissemi-
reactive arthritis. Cutaneous lesions can be treated nated intravascular coagulation, and liver dys-
with topical steroids [202, 204–206]. function [210].

References
AOSD is typically seronegative for ANA and RF. 1. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised
However, acute phase reactants such as ferritin, criteria for the classification of systemic lupus erythe-
ESR, and platelets are often elevated. Ferritin matosus. Arthritis Rheum. 1982;25:1271–7.
levels more than five times the upper limit of nor- 2. Hochberg MC. Updating: the American College of
Rheumatology revised criteria for the classification of
mal is specific for AOSD. Serum albumin is com- systemic lupus erythematosus. Arthritis Rheum.
monly low. A majority of patients have 1997;40:1725.
leukocytosis, mild anemia of chronic disease, and 3. Iaboni A, Ibanez D, Gladman DD, Urowitz MB,
thrombocytosis. Patients with hepatomegaly may Moldofsky H. Fatigue in systemic lupus erythemato-
sus: contributions of disordered sleep, sleepiness, and
have elevated LFTs [207]. depression. J Rheumatol. 2006;33(12):2453–7.
Histology of skin lesions is nonspecific with a 4. Omdal R, Mellgren SI, Koldingsnes W, Jacobsen EA,
mild perivascular infiltrate in the superficial der- Husby G. Fatigue in patients with systemic lupus ery-
mis consisting of lymphocytes and histiocytes. thematosus: Lack of associations to serum cytokines,
antiphospholipid antibodies, or other disease charac-
Myalgias and joint pains also worsen with the teristics. J Rheumatol. 2002;29(3):482–6.
rash and fever [207]. 5. Pipili C, Sfritzeri A, Cholongitas E. Review article:
deforming arthropathy in systemic lupus erythemato-
sus. Eur J Intern Med. 2008;19:482–7.
6. Gladman DD, Urowitz MB. Prognosis, mortality and
11.12.3 Treatment morbidity in systemic lupus erythematosus. In:
Wallace DJ, Hahn BH, editors. Dubois’ lupus erythe-
NSAIDs are first-line treatment for the symptoms matosus. 7th ed. Philadelphia, PA: Lippincott Williams
of adult-onset Still’s disease, but most affected & Wilkins; 2007. p. 1333–53.
7. Hepburn AL, Narat S, Mason JC. The management of
individuals need oral corticosteroids to treat the peripheral blood cytopenias in systemic lupus erythe-
acute systemic symptoms. About 20% of patients matosus. Rheumatology (Oxford).
have chronic relapsing disease, which may 2010;49(12):2243–54.
require steroid-sparing agents, namely metho- 8. Budman DR, Steinberg AD. Hematologic aspects of
systemic lupus erythematosus: current concepts. Ann
trexate for polyarthritis. Cyclosporine, IVIG, Intern Med. 1977;86:220–9.
biologics such as anti-TNF-a agents, rituximab, 9. Vila LM, Alarcón GS, McGwin G, et al.: for the
and the IL-1 receptor antagonist anakinra have LUMINA study group. Systemic lupus erythematosus
been used successfully as well [211]. in a multiethnic US cohort: XXXVII. Association of
lymphopenia with clinical manifestations, serologic
abnormalities, disease activity, and damage accrual.
Arthritis Care Res 2006; 55:799–806.
11.13 Conclusion 10. Musio F, Bohen EM, Yuan CM, Welch PG. Review of
thrombotic thrombocytopenic purpura in the setting
of systemic lupus erythematosus. Semin Arthritis
The connective tissue diseases span a broad clini- Rheum. 1998;28:1–19.
cal spectrum with varied presentations in multi- 11. Cervera R, Khamashta MA, Font J, et al. Systemic
ple organ systems. As such, the diagnosis of lupus erythematosus: clinical and immunologic pat-
connective tissue disease is difficult, and can be terns of disease expression in a cohort of 1,000
patients. Medicine. 1993;72:113–24.
delayed, leading to deleterious end organ effects. 12. Lemos J, Santos L, Martins I, Nunes L, Santos O,
The clinical picture is further muddled by the fact Henriques P. Systemic lupus erythematosus—a diag-
that patients with underlying collagen vascular nosis in cardiology. Rev Port Cardiol.
diseases may develop unrelated disease pro- 2008;27(6):841–9.
13. Kahl LE. The spectrum of pericardial tamponade in
cesses, which can mimic a disease “flare” or systemic lupus erythematosus. Report of ten patients.
exacerbation. Cutaneous findings often provide Arthritis Rheum. 1992;35(11):1343–9.
an invaluable clue to diagnosis and management, 14. Asherson RA, Cervera R, Piette JC, et al. Catastrophic
and are thus critical to preventing the multitude antiphospholipid syndrome: clinical and laboratory
features of 50 patients. Medicine. 1998;77:195–207.
of associated secondary complications.
15. Santos-Ocampo AS, Mandell BF, Fessler BJ. Alveolar regarding mucocutaneous involvement. Clin Exp
hemorrhage in systemic lupus erythematosus. Chest. Rheumatol. 1996;14 Suppl 16:s17–22.
2000;118:1083–90. 31. Obermoser G, Sontheimer RD, Zelger B. Overview of
16. Zamora MR, Warner ML, Tuder R, et al. Diffuse alve- common, rare and atypical manifestations of cutane-
olar hemorrhage and systemic lupus erythematosus: ous lupus erythematosus and histopathological corre-
clinical presentation, histology, survival, and out- lates. Lupus. 2010;19(9):1050–70.
come. Medicine (Baltimore). 1997;76:192–202. 32. Ting W, et al. Toxic epidermal necrolysis-like acute
17. Manzi S, Meilahn EN, Rairie JE, et al. Age-specific cutaneous lupus erythematosus and the spectrum of
incidence rates of myocardial infarction and angina in the acute syndrome of apoptotic pan-epidermolysis
women with systemic lupus erythematosus: compari- (ASAP): a case report, concept review and proposal
son with the Framingham study. Am J Epidemiol. for new classification of lupus erythematosus vesicu-
1997;145:408–15. lobullous skin lesions. Lupus. 2004;13:941.
18. de Leeuw K, Freire B, Smit AJ, et al. Traditional and 33. Sontheimer RD. Subacute cutaneous lupus erythema-
non-traditional risk factors contribute to the develop- tosus. Clin Dermatol. 1985;3(3):58–68.
ment of accelerated atherosclerosis in patients with sys- 34. Vera-Recabarren MA, et al. Comparative analysis of sub-
temic lupus erythematosus. Lupus. 2006;15:675–82. acute cutaneous lupus erythematosus and chronic cutane-
19. Petri M, Kasitanon N, Lee SS, et al.: for the Systemic ous lupus erythematosus: clinical and immunological
Lupus International Collaborating Clinics. Systemic study of 270 patients. Br J Dermatol. 2010;162:91–101.
Lupus International Collaborating Clinics renal activ- 35. Sontheimer RD, Maddison PJ, Reichlin M, et al.
ity/response exercise: development of a renal activity Serologic and HLA associations in subacute cutane-
score and renal response index. Arthritis Rheum ous lupus erythematosus, a clinical subset of lupus
2008;58:1784–8. erythematosus. Ann Intern Med. 1982;97(5):664–71.
20. Isenberg DA, Lesavre P. Lupus nephritis: assessing 36. Patel P, Werth V. Cutaneous lupus erythematosus: a
the evidence, considering the future. Lupus. review. Dermatol Clin. 2002;20(3):373–85.
2007;16:210–1. 37. Liu K, Mohan C. What do mouse models teach us
21. Weening JJ, D’Agati VD, Schwartz MM, et al. The about human SLE? Clin Immunol. 2006;119:123.
classification of glomerulonephritis in systemic 38. Massone C, et al. Lupus erythematosus panniculitis
lupus erythematosus revisited. Kidney Int. 2004;65: (lupus profundus): clinical, histopathological, and
521–30. molecular analysis of nine cases. J Cutan Pathol.
22. Baizabal-Carvallo JF, Cantu-Brito C, Garcia-Ramos 2005;32(6):396–404.
G. Acute neurolupus manifested by seizures is associ- 39. Arai S, Katsuoka K. Clinical entity of Lupus erythe-
ated with high frequency of abnormal cerebral blood matosus panniculitis/lupus erythematosus profundus.
flow velocities. Cerebrovasc Dis 2008;25(4):348–e354. Autoimmun Rev. 2009;8(6):449–52.
Academic Press: San Diego, 1999, pp. 687e–706. 40. Ruiz H, Sanchez JL. Tumid lupus erythematosus. Am
23. Ozgencil E, Gulucu C, Yalcyn S, Alanoglu Z, Unal N, J Dermatopathol. 1999;21(4):356–60.
Oral M, et al. Seizures and loss of vision in a patient 41. Hedrich CM, Fiebig B, et al. Chilblain lupus erythe-
with systemic lupus erythematosus. Neth J Med. matosus: a review of the literature. Clin Rheumatol.
2007;65(7):274. 2008;27(8):949–54.
24. McCune WJ, Golbus J. Neuropsychiatric Lupus. 42. Ramos-Casals M, et al. Vasculitis in systemic lupus ery-
Rheum Dis Clin North Am. 1988;14(1):149–67. thematosus: prevalence and clinical characteristics in 670
25. Rothfield N, Sontheimer RD, Bernstein M. Lupus patients. Medicine (Baltimore). 2006;85(2):95–104.
erythematosus: systemic and cutaneous manifesta- 43. Satirapoj B, et al. Predictors of renal involvement in
tions. Clin Dermatol. 2006;24(5):348–62. patients with systemic lupus erythematosus. Asian
26. Pinkus H. Lichenoid tissue reactions: a speculative Pac J Allergy Immunol. 2007;25(1):17–25.
review of the clinical spectrum of epidermal basal cell 44. Wilson CL, Burge SM, Dean D, et al. Scarring alope-
damage with special reference to erythema dyschro- cia in discoid lupus erythematosus. Br J Dermatol.
micum perstans. Arch Dermatol. 1973;107:840–6. 1992;126(4):307–14.
27. Tebbe B, Orfanos CE. Epidemiology and socioeco- 45. Ortize VG, Krishnan RS, Chen LL, Hsu S.
nomic impact of skin disease in lupus erythematosus. Papulonodular mucinosis in systemic lupus erythema-
Lupus. 1997;6:96. tosus. Dermatol Online J. 2004;10:16.
28. Watanabe T, Tsuchida T. Classification of lupus ery- 46. Rongioletti F, Parodi A, Rebora A. Papular and nodu-
thematosus based upon cutaneous manifestations. lar mucinosis as a sign of lupus erythematosus.
Dermatological, systemic and laboratory findings in Dermatologica. 1990;180:221–3.
191 patients. Dermatology. 1995;190:277. 47. Bean SF, Lynch FW. Senear-Usher syndrome (pem-
29. Walling HW, Sontheimer RD. Cutaneous lupus ery- phigus erythematosus). Immunofluorescent studies in
thematosus: issues in diagnosis and treatment. Am J a patient. Arch Dermatol. 1970;101(6):642–5.
Clin Dermatol. 2009;10(6):365–81. 48. Giannouli S, Voulgarelis M, Ziakas PD, Tzioufas AG.
30. Vitali C, et al. International survey on the manage- Anaemia in systemic lupus erythematosus: from
ment of patients with SLE: I. General data on the par- pathophysiology to clinical assessment. Ann Rheum
ticipating centers and the results of a questionnaire Dis. 2006;65(2):144–8.
49. Avihingsanon Y, Hirankarn N. Major lupus organ 63. Gladman G, Silverman ED, et al. Fetal echocardio-
involvement: severe lupus nephritis. Lupus. graphic screening of pregnancies of mothers with
2010;19(12):1391–8. anti-Ro and/or anti-La antibodies. Am J Perinatol.
50. Jessop S, Whitelaw D, Jordaan F. Drugs for discoid 2002;19(2):73–80.
lupus erythematosus. Cochrane Database Syst Rev 64. Mevorach D, Elchalal U, Rein AJ. Prevention of com-
2001;CD002954. plete heart block in children of mothers with anti-
51. Clowse ME, Magder L, Witter F, Petri M. SSA/Ro and anti-SSB/La autoantibodies: detection
Hydroxychloroquine in lupus pregnancy. Arthritis and treatment of first-degree atrioventricular block.
Rheum. 2006;54:3640–7. Curr Opin Rheumatol. 2009;21(5):478–82.
52. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, 65. Neiman AR, Lee LA, Weston WL, Buyon JP.
Khamashta MA. Clinical efficacy and side effects of Cutaneous manifestations of neonatal lupus without
antimalarials in systemic lupus erythematosus: a sys- heart block: characteristics of mothers and children
tematic review. Ann Rheum Dis. 2010;69:20–8. enrolled in a national registry. J Pediatr. 2000;137(5):
53. Avina-Zubieta J, Johnson E, Suaarez-Almazor M, 674–80.
Russell A. Incidence of myopathy in patients treated 66. Miyakis S, Lockshin MD, Atsumi T, et al. International
with antimalarials: a report of three cases and a review consensus statement on an update of the classification
of the literature. Br J Rheumatol. 1995;34:166–70. criteria for definite antiphospholipid syndrome (APS).
54. Marmor MF, Carr RE, Easterbrook M, et al. J Thromb Haemost. 2006;4:295–306.
Recommendations on screening for chloroquine and 67. Bowie EJ, Thompson Jr JH, Pascuzzi CA, Owen Jr
hydroxychloroquine retinopathy: a report by the CA. Thrombosis in systemic lupus erythematosus
American Academy of Ophthalmology. despite circulating anticoagulants. J Lab Clin Med.
Ophthalmology. 2002;109:1377–82. 1963;62:416–30.
55. Bertsias G, Ioannidis JP, Boletis J, et al. Task Force of 68. Rand JH. The antiphospholipid syndrome. Annu Rev
the EULAR Standing Committee for International Med. 2003;54:409–24.
Clinical Studies Including Therapeutics. EULAR rec- 69. Francès C, Niang S, Laffitte E, et al. Dermatologic
ommendations for the management of systemic lupus manifestations of the antiphospholipid syndrome: two
erythematosus. Report of a Task Force of the EULAR hundred consecutive cases. Arthritis Rheum. 2005;
Standing Committee for International Clinical Studies 52:1785–93.
Including Therapeutics. Ann Rheum Dis. 2008;67(2): 70. Brey RL. Differential diagnosis of central nervous
195–205. system manifestations of the antiphospholipid anti-
56. Callen JP, Spencer LV, Burruss JB, Holtman J. body syndrome. J Autoimmun. 2000;15:133–8.
Azathioprine. An effective, corticosteroid-sparing 71. Lockshin MD, Quamar T, Drusin ML, et al. Antibody
therapy for patients with recalcitrant cutaneous lupus to cardiolipin, lupus anticoagulant, and fetal death. J
erythematosus or with recalcitrant cutaneous leukocy- Rheumatol. 1987;14:259–62.
toclastic vasculitis. Arch Dermatol. 72. Branch DW, Khamashta MA. Antiphospholipid syn-
1991;127(4):515–22. drome: obstetric diagnosis, management, and contro-
57. Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, versies. Obstet Gynecol. 2003;101:1333–44.
Merrill JT, Petri MA, Ginzler EM, Chatham WW, 73. Cervera R, Piette JC, Font J, et al. Antiphospholipid
McCune WJ, Fernandez V, Chevrier MR, Zhong ZJ, syndrome: clinical and immunologic manifestations
Freimuth WW. A phase II, randomized, double-blind, and patterns of disease expression in a cohort of 1,000
placebo-controlled, dose-ranging study of belimumab patients. Arthritis Rheum. 2002;46:1019–27.
in patients with active systemic lupus erythematosus. 74. Brandt JT, Triplett DA, Alving B, et al. Criteria for the
Arthritis Rheum. 2009;61(9):1168–78. diagnosis of lupus anticoagulants: an update. On
58. Kazatchkine MD, Kaveri SV. Immunomodulation of behalf of the Subcommittee on Lupus Anticoagulant/
autoimmune and inflammatory diseases with intrave- Antiphospholipid Antibody of the Scientific and
nous immune globulin. N Engl J Med. 2001;345: Standardisation Committee of the ISTH. Thromb
747–55. Haemost. 1995;74:1185–90.
59. Herzinger T, Plewig G. Use of sunscreens to protect 75. Pengo V, Tripodi A, Reber G, et al. Update of the
against ultraviolet induced lupus erythematosus. guidelines for lupus anticoagulant detection. J Thromb
Arthritis Rheum. 2004;50:3045–6. Haemost. 2009;10:1737–40.
60. Sontheimer RD. Subacute cutaneous lupus erythema- 76. Wilson WA, Gharavi AE, Koike T, et al. International
tosus: 25-year evolution of a prototypic subset (subphe- consensus statement on preliminary classification cri-
notype) of lupus erythematosus defined by characteristic teria for definite antiphospholipid syndrome: report of
cutaneous, pathological, immunological, and genetic an international workshop. Arthritis Rheum. 1999;
findings. Autoimmun Rev. 2005;4:253–63. 42:1309–11.
61. Lee LA. Neonatal lupus: clinical features and man- 77. Cohen D, Berger SP, Steup-Beekman GM,
agement. Pediatr Drugs. 2004;6(2):71–8. Bloemenkamp KW, Bajema IM. Diagnosis and man-
62. Boh EE. Neonatal lupus erythematosus. Clin agement of the antiphospholipid syndrome. BMJ.
Dermatol. 2004;22(2):125–8. 2010;340:c2541.
78. Boren T, Reyes C, Montenegro R, Raimer K. A case study with screening recommendations. Arch
of Evan’s syndrome in pregnancy refractory to pri- Dermatol. 2010;146(7):729–38.
mary treatment options. J Matern Fetal Neonatal 94. Fathi M, Dastmalchi M, Rasmussen E, et al.
Med. 2007;20(11):843–5. Interstitial lung disease, a common manifestation of
79. Garcia DA, Khamashta MA, Crowther MA. How we newly diagnosed polymyositis and dermatomyositis.
diagnose and treat thrombotic manifestations of the Ann Rheum Dis. 2004;63:297–301. P-31.
antiphospholipid syndrome: a case-based review. 95. Alyan O, Ozdemir O, Geyik B, Demirkan D.
Blood. 2007;110:3122–7. Polymyositis complicated with complete atrioven-
80. Tektonidou MG, Laskari K, Panagiotakos DB, tricular block: a case report and review of the litera-
Moutsopoulos HM. Risk factors for thrombosis ture. Angiology. 2003;54:729–31.
and primary thrombosis prevention in patients with 96. Yazici Y, Kagen LJ. Cardiac involvement in myosi-
systemic lupus erythematosus with or without tis. Curr Opin Rheumatol. 2002;14:663–5.
antiphospholipid antibodies. Arthritis Rheum 97. Airio A, et al. Elevated cancer incidence in patients
(Arthritis Care Res). 2009;61:29–36. with dermatomyositis: a population based study. J
81. Bayry J, Negi VS, Kaveri SV. Intravenous immuno- Rheumatol. 1995;22:1300.
globulin therapy in rheumatic diseases. Nat Rev 98. Yazici Y, Kagen LJ. The association of malignancy
Rheumatol. 2011;7(6):349–59. with myositis. Curr Opin Rheumatol. 2000;12:498.
82. Tripodi A, de Groot PG, Pengo V. Antiphospholipid 99. Stockton D, et al. Risk of cancer in patients with der-
syndrome: laboratory detection, mechanisms of action matomyositis or polymyositis, and follow-up impli-
and treatment. J Intern Med. 2011;270(2):110–22. cations: a Scottish population-based cohort study. Br
83. Asherson RA, Cervera R, De Groot PG, et al. J Cancer. 2001;85:41.
Catastrophic antiphospholipid sydrome: interna- 100. Chen YJ, et al. Predicting factors of malignancy in
tional consensus statements on classification criteria dermatomyositis and polymyositis: a case–control
and treatment guidelines. Lupus. 2003;12:530–4. study. Br J Dermatol. 2001;144:825.
84. Petri M, Qazi U. Management of antiphospholipid 101. Hill CL, Zhang Y, Sigurgeirsson B, Pukkala E,
syndrome in pregnancy. Rheum Dis Clin North Am. Mellemkjaer L, Airio A, Evans SR, Felson DT.
2006;32:591–607. Frequency of specific cancer types in dermatomyosi-
85. Le Thi Huong D, Wechsler B, Vauthier-Brouzes D, tis and polymyositis: a population-based study.
et al. The second trimester Doppler ultrasound Lancet. 2001;357:96–100.
examination is the best predictor of late pregnancy 102. Sontheimer RD. Cutaneous features of classic der-
outcome in systemic lupus erythematosus and/or the matomyositis and amyopathic dermatomyositis.
antiphospholipid syndrome. Rheumatology Curr Opin Rheumatol. 1999;11:475–82.
(Oxford). 2006;45:332–8. 103. Pachman LM, Hayford JR, Chung A, Daugherty
86. Santmyire-Rosenberger B, Dugan E. Skin involve- CA, Pallansch MA, Fink CW, Gewanter HL, Jerath
ment in dermatomyositis. Curr Opin Rheumatol. R, Lang BA, Sinacore J, Szer IS, Dyer AR, Hochberg
2003;15:714–22. MC. Juvenile dermatomyositis at diagnosis: clinical
87. Bohan A, Peter JB. Polymyositis and dermatomyosi- characteristics of 79 children. J Rheumatol.
tis. N Engl J Med. 1975;292:344–7. 1998;25(6):1198–204.
88. Gerami P, Schope JM, McDonald L, et al. A system- 104. Robinson AB, Reed AM. Clinical features, patho-
atic review of adult onset clinically amyopathic der- genesis and treatment of juvenile and adult dermato-
matomyositis (dermatomyositis sine myositis): a myositis. Nat Rev Rheumatol. 2011;7(11):664–75.
missing link within the spectrum of the idiopathic 105. Targoff IN. Laboratory testing in the diagnosis and
inflammatory myopathies. J Am Acad Dermatol. management of idiopathic inflammatory myopathies.
2006;54:597–613. Rheum Dis Clin North Am. 2002;28(4):859–90.
89. Kang EH, Lee EB, Shin KC, et al. Interstitial lung 106. Oddis CV. Idiopathic inflammatory myopathy: man-
disease in patients with polymyositis, dermatomyo- agement and prognosis. Rheum Dis Clin North Am.
sitis and amyopathic dermatomyositis. Rheumatology. 2002;28:979–1001.
2005;44:1282–6. 107. Christopher-Stine L, Plotz PH. Adult inflammatory
90. Suda T, Fuijsawa T, Enomoto N, et al. Interstitial myopathies. Best Pract Res Clin Rheumatol.
lung diseases associated with amyopathic dermato- 2004;18:331–44.
myositis. Eur Respir J. 2006;28:1005–12. 108. Dalakas MC, Illa I, Dambrosia JM, et al. A con-
91. Tillie-Leblond I, Wislez M, Valeyre D, et al. Interstitial trolled trial of high-dose intravenous immune globu-
lung disease and anti-Jo-1 antibodies: difference between lin infusions as treatment for dermatomyositis. N
acute and gradual onset. Thorax. 2008;63:53–9. Engl J Med. 1993;329:1993–2000.
92. Quain RD, Werth VP. Management of cutaneous 109. Buchbinder R, Forbes A, Hall S, Dennett X, Giles G.
dermatomyositis: current therapeutic options. Am J Incidence of malignant disease in biopsy-proven
Clin Dermatol. 2006;7(6):341–51. inflammatory myopathy. A population-based cohort
93. Morganroth PA, Kreider ME, Okawa J, Taylor L, study. Ann Intern Med. 2001;134:1087–95.
Werth VP. Interstitial lung disease in classic and 110. Perera A, Fertig N, Lucas M, et al. Clinical subsets,
skin-predominant dermatomyositis: a retrospective skin thickness progression rate, and serum antibody
levels in systemic sclerosis patients with anti-topoi- HH, Coppock J, Herrick A, Merkel PA, Simms R,
somerase I antibody. Arthritis Rheum. Denton CP, Furst D, Nguyen N, Gaitonde M, Black
2007;56:2740–6. C. Digital ulcers in systemic sclerosis: prevention by
111. Steen V, Medsger T. Severe organ involvement in treatment with bosentan, an oral endothelin receptor
systemic sclerosis with diffuse scleroderma. Arthritis antagonist. Arthritis Rheum. 2004;50(12):3985–93.
Rheum. 2000;43(11):2437–44. 127. Admou B, Essaadouni L, Amal S, Arji N, Chabaa L,
112. Poormoghim H, Lucas M, Fertig N, Medsger Jr TA. El Aouad R. Autoantibodies in systemic sclerosis:
Systemic sclerosis sine scleroderma: demographic, clinical interest and diagnosis approach. Ann Biol
clinical, and serologic features and survival in forty- Clin (Paris). 2009;67(3):273–81.
eight patients. Arthritis Rheum. 2000;43(2):444–51. 128. Steen VD, Ziegler GL, Rodnan GP, Medsger Jr TA.
113. Steen V, Medsger Jr TA. Predictors of isolated Clinical and laboratory associations of anticentrom-
pulmonary hypertension in patients with systemic ere antibody in patients with progressive systemic
sclerosis and limited cutaneous involvement. sclerosis. Arthritis Rheum. 1984;27(2):125–31.
Arthritis Rheum. 2003;48(2):516–22. 129. Kuwana M, Kaburaki J, Okano Y, Tojo T, Homma
114. Shand L, Lunt M, Nihtyanova S, Hoseini M, Silman M. Clinical and laboratory associations of anticen-
A, Black CM, Denton CP. Relationship between tromere antibody in patients with progressive sys-
change in skin score and disease outcome in diffuse temic sclerosis. Arthritis Rheum.
cutaneous systemic sclerosis: application of a latent 1994;37(1):75–83.
linear trajectory model. Arthritis Rheum. 130. Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands
2007;56(7):2422–31. P, Goh NS, Roberts C, Desai S, Herrick AL, McHugh
115. Steen VD. Scleroderma renal crisis. Rheum Dis Clin NJ, Foley NM, Pearson SB, Emery P, Veale DJ,
North Am. 2003;29(2):315–33. Denton CP, Wells AU, Black CM, du Bois RM. A
116. Teixeira L, Mahr A, Berezne A, et al. Scleroderma multicenter, prospective, randomized, double-blind,
renal crisis, still a life threatening complication. Ann placebo-controlled trial of corticosteroids and intra-
N Y Acad Sci. 2007;1108:249–305. venous cyclophosphamide followed by oral azathio-
117. Tashkin DP, Elashoff R, Clements PJ, et al. prine for the treatment of pulmonary fibrosis in
Cyclophosphamide versus placebo in scleroderma scleroderma. Arthritis Rheum.
lung disease. N Engl J Med. 2006;354(25): 2006;54(12):3962–70.
2655–66. 131. Kowal-Bielecka O, Landewé R, Avouac J, Chwiesko
118. Steen VD, Conte C, Owens GR, Medsger Jr TA. S, Miniati I, Czirjak L, Clements P, Denton C, Farge
Severe restrictive lung disease in systemic sclerosis. D, Fligelstone K, Földvari I, Furst DE, Müller-
Arthritis Rheum. 1994;37(9):1283–9. Ladner U, Seibold J, Silver RM, Takehara K, Toth
119. Plastiras SC, Karadimitrakis SP, Ziakas PD, et al. BG, Tyndall A, Valentini G, van den Hoogen F,
Scleroderma lung: Initial forced vital capacity as Wigley F, Zulian F, Matucci-Cerinic M, EUSTAR
predictor of pulmonary function decline. Arthritis Co-Authors. EULAR recommendations for the treat-
Rheum. 2006;55(4):598–602. ment of systemic sclerosis: a report from the EULAR
120. Al-Dhaher FF, Pope JE, Ouimet JM. Semin Arthritis Scleroderma Trials and Research group (EUSTAR).
Rheum. 2010;39(4):269–77. Ann Rheum Dis. 2009;68(5):620–8. Epub 2009 Jan
121. Di Bello V, Ferri C, Giorgi D, Bianchi M, Bertini A, 15.
Martini A, Storino FA, Paterni M, Pasero G, Giusti 132. Badesch DB, Abman SH, Ahearn GS, Barst RJ,
C. Ultrasonic videodensitometric analysis in sclero- McCrory DC, Simonneau G, McLaughlin VV,
derma heart disease. Coron Artery Dis. American College of Chest Physicians. Medical
1999;10(2):103–10. therapy for pulmonary arterial hypertension: ACCP
122. Plazak W, Zabinska-Plazak E, Wojas-Pelc A, Podolec evidence-based clinical practice guidelines. Chest.
P, Olszowska M, Tracz W, Bogdaszewska- 2004;126(1 Suppl):35S–62.
Czabanowska J. Heart structure and function in sys- 133. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin
temic sclerosis. Eur J Dermatol. 2002;12(3):257–62. LJ, Badesch D, Fleming T, Parpia T, Burgess G,
123. Ebert EC. Esophageal disease in scleroderma. J Clin Branzi A, Grimminger F, Kurzyna M, Simonneau G,
Gastroenterol. 2006;40:769–75. Sildenafil Use in Pulmonary Arterial Hypertension
124. Ingraham KM, O’Brien MS, Shenin M, Derk CT, (SUPER) Study Group. Sildenafil citrate therapy for
Steen VD. Gastric antral vascular ectasia in systemic pulmonary arterial hypertension. N Engl J Med.
sclerosis: demographics and disease predictors. J 2005;353(20):2148–57.
Rheumatol. 2010;37(3):603–7. 134. Kent PD, Michet Jr CJ, Luthra HS. Relapsing poly-
125. Rigamonti C, Shand LM, Feudjo M, et al. Clinical chondritis. Curr Opin Rheumatol.
features and prognosis of primary biliary cirrhosis 2004;16(1):56–61.
associated with systemic sclerosis. Gut. 135. Francès C, ElRassi R, Laporte JL, Rybojad M,
2006;55(3):388–94. Papo T, Piette JC. Dermatologic manifestations of
126. Korn JH, Mayes M, Matucci Cerinic M, Rainisio M, relapsing polychondritis. A study of 200 cases at a
Pope J, Hachulla E, Rich E, Carpentier P, Molitor J, single center. Medicine (Baltimore). 2001;80(3):
Seibold JR, Hsu V, Guillevin L, Chatterjee S, Peter 173–9.
136. Eng J, Sabanathan S. Airway complications in 155. Amital A, Shitrit D, Adir Y. The lung in rheumatoid
relapsing polychondritis. Ann Thorac Surg. arthritis. Presse Med. 2011;40(1 Pt 2):e31–48.
1991;51(4):686–92. 156. Galor A, Thorne JE. Scleritis and peripheral ulcerative
137. Ernst A, Rafeq S, Boiselle P, Sung A, Reddy C, et al. keratitis. Rheum Dis Clin North Am. 2007;33(4):
Relapsing polychondritis and airway involvement. 835–54.
Chest. 2009;135:1024–30. 157. Rapoport RJ, Kozin F, Mackel SE, Jordon RE.
138. Staats BA, Utz JP, Michet CJ. Relapsing polychon- Cutaneous vascular immunofluorescence in rheumatoid
dritis. Sem Respir Crit Care Med. 2002;23: arthritis. Correlation with circulating immune com-
145–54. plexes and vasculitis. Am J Med. 1980;68:325–31.
139. Barretto S, Oliveira GH, Michet CJ, Nyman M, 158. Smith PH, Benn RT, Sharp J. Natural history of
Edwards WD, Kullo IJ. Multiple cardiovascular rheumatoid cervical luxations. Ann Rheum Dis.
complications in a patient with relapsing polychon- 1972;31(6):431–9.
dritis. Mayo Clin Proc. 2002;77:971–4. 159. Felty AR. Chronic arthritis in the adult associated
140. Dib C, Moustafa SE, Mookadam M, Zehr K, Michet with splenomegaly and leukopenia: a report of five
CJ, Mookadam F. Surgical treatment of the cardiac cases of an unusual clinical syndrome. Bull Johns
manifestations of relapsing polychondritis. Mayo Hopkins Hosp. 1924;35:16–20. 1991;23:3328–9.
Clin Proc. 2006;81:772–6. 160. Gridley G, Klippel JH, Hoover RN, Fraumeni Jr JF.
141. Dalal BI, Wallace AC, Slinger RP. IgA nephropathy Incidence of cancer among men with the Felty
in relapsing polychondritis. Pathology (Phila). syndrome. Ann Intern Med. 1994;120:35–9.
1988;20(1):85–9. 161. Campion G, Maddison PJ, Goulding N, James I,
142. Chang-Miller A, Okamura M, Torres VE, et al. Renal Ahern MJ, Watt I, et al. The Felty syndrome: a case-
involvement in relapsing polychondritis. Medicine matched study of clinical manifestations and out-
(Baltimore). 1987;66(3):202–17. come, serologic features, and immunogenetic
143. Isaak BL, Liesegang TJ, Michet CJ. Ocular and sys- associations. Medicine. 1990;69:69–80.
temic findings in relapsing polychondritis. 162. Wilkinson M, Torrance WN. Clinical background of
Ophthalmology. 1986;93(5):681–9. rheumatoid vascular disease. Ann Rheum Dis.
144. Piette JC, Papo T, Chavanon P, Huong DL, Frances 1967;26:475–80.
C, Godeau P. Myelodysplasia and relapsing poly- 163. Thurtle OA, Cawley MI. The frequency of leg ulcer-
chondritis. J Rheumatol. 1995;22(6):1208–9. ation in rheumatoid arthritis: a survey. J Rheumatol.
145. Saadoun D, Deslandre CJ, Allanore Y, et al. Sustained 1983;10:507–9.
response to infliximab in 2 patients with refractory 164. Scott DG, Bacon PA, Tribe CR. Systemic rheuma-
relapsing polychondritis. J Rheumatol. toid vasculitis: a clinical and laboratory study of 50
2003;30:1394–5. cases. Medicine. 1981;602:88–97.
146. Goldenberg G, Sangueza OP, Jorizzo JL. Successful 165. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson
treatment of relapsing polychondritis with mycophe- DT, Bingham III CO, Birnbaum NS, Burmester GR,
nolate mofetil. J Dermatol Treat. 2006;17:158–9. Bykerk VP, Cohen MD, Combe B, Costenbader KH,
147. Wendling D, Govindaraju S, Prati C, et al. Efficacy Dougados M, Emery P, Ferraccioli G, Hazes JM,
of anakinra in a patient with refractory relapsing Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien
polychondritis. Joint Bone Spine. 2008;75:622–4. TK, Laing T, Mease P, Ménard HA, Moreland LW,
148. Woodbury K, Smith LJ. Relapsing polychondritis: a Naden RL, Pincus T, Smolen JS, Stanislawska-
rare etiology of dysphonia and novel approach to Biernat E, Symmons D, Tak PP, Upchurch KS,
treatment. Laryngoscope. 2011;121(5):1006–8. Vencovský J, Wolfe F, Hawker G. Rheumatoid
149. Young A, Koduri G. Extra-articular manifestations arthritis classification criteria: an American College
and complications of rheumatoidarthritis. Best Pract of Rheumatology/European League Against
Res Clin Rheumatol. 2007;21(5):907–27. Rheumatism collaborative initiative. Arthritis
150. Sayah A, English III JC. Rheumatoid arthritis: a Rheum. 2010;62(9):2569–81.
review of the cutaneous manifestations. J Am Acad 166. Geirsson AJ, Sturfelt G, Truedsson L. Clinical and
Dermatol. 2005;53(2):191–209. quiz 210–2. serological features of severe vasculitis in rheuma-
151. Chu P, Connolly MK, LeBoit PE. The histopatho- toid arthritis: prognostic implications. Ann Rheum
logic spectrum of palisaded neutrophilic and granu- Dis. 1987;46:727–33.
lomatous dermatitis in patients with collagen 167. Chen KR, Toyohara A, Suzuki A, Miyakawa S.
vascular disease. Arch Dermatol. 1994;130:1278. Clinical and histopathological spectrum of cutane-
152. Hata T, Kavanaugh A. Rheumatoid arthritis in der- ous vasculitis in rheumatoid arthritis. Br J Dermatol.
matology. Clin Dermatol. 2006;24(5):430–7. 2002;147:905–13.
153. Bywaters EG. Peripheral vascular obstruction in 168. Vollertsen RS, Conn DL, Ballard DJ, Ilstrup DM,
rheumatoid arthritis and its relationship to other vas- Kazmar RE, Silverfield JC. Rheumatoid vasculitis:
cular lesions. Ann Rheum Dis. 1957;16(1):84–103. survival and associated risk factors. Medicine.
154. Watts RA, Carruthers DM, Scott DG. Isolated nail 1986;65:365–75.
fold vasculitis in rheumatoid arthritis. Ann Rheum 169. Aggarwal R, Liao K, Nair R, Ringold S, Costenbader
Dis. 1995;54(11):927–9. KH. Anti-citrullinated peptide antibody assays and
their role in the diagnosis of rheumatoid arthritis. 183. Papas AS, Sherrer YS, Charney M, Golden HE,
Arthritis Rheum. 2009;61(11):1472–83. Medsger Jr TA, Walsh BT, Trivedi M, Goldlust B,
170. Scott DG, Bacon PA. Intravenous cyclophosphamide Gallagher SC. Successful treatment of dry mouth
plus methylprednisolone in treatment of systemic and dry eye symptoms in Sjögren’s syndrome
rheumatoid vasculitis. Am J Med. patients with oral pilocarpine: a randomized, pla-
1984;76(3):377–84. cebo-controlled, dose-adjustment study. J Clin
171. Muramatsu K, Tanaka H, Taguchi T. Peripheral neu- Rheumatol. 2004;10(4):169–77.
ropathies of the forearm and hand in rheumatoid 184. Fox RI, Chan E, Benton L, Fong S, Friedlaender M,
arthritis: diagnosis and options for treatment. Howell FV. Treatment of primary Sjögren’s syn-
Rheumatol Int. 2008;28(10):951–7. drome with hydroxychloroquine. Am J Med.
172. Masson C. Rheumatoid anemia. Joint Bone Spine. 1988;85(4A):62–7.
2011;78(2):131–7. 185. Ng WF, Bowman SJ. Biological therapies in primary
173. Kim DH, Hilibrand AS. Rheumatoid arthritis in the Sjögren’s syndrome. Expert Opin Biol Ther.
cervical spine. J Am Acad Ortho Surg. 2011;11(7):921–36.
2005;13(7):463–74. 186. International Study Group for Behçet’s Disease.
174. Ramos-Casals M, Solans R, Rosas J, Camps MT, Gil Criteria for diagnosis of Behçet’s disease. Lancet.
A, Del Pino-Montes J, Calvo-Alen J, Jiménez- 1990;335(8697):1078–80.
Alonso J, Micó ML, Beltrán J, Belenguer R, Pallarés 187. Kapsimali VD, Kanakis MA, Vaiopoulos GA,
L, GEMESS Study Group. Primary Sjögren syn- Kaklamanis PG. Etiopathogenesis of Behçet’s dis-
drome in Spain: clinical and immunologic expres- ease with emphasis on the role of immunological
sion in 1010 patients. Medicine (Baltimore). aberrations. Clin Rheumatol. 2010;29(11):1211–6.
2008;87(4):210–9. 188. Yazici Y, Yurdakul S, Yazici H. Behçet’s syndrome.
175. Fox RI, Fox CM. Sjogren’s syndrome. In: Hertl M, Curr Rheumatol Rep. 2010;12(6):429–35.
editor. Autoimmune diseases of the skin: pathogen- 189. Mendes D, Correia M, Barbedo M, Vaio T, Mota M,
esis, diagnosis, and management. New York, NY: Gonçalves O, Valente J. Behçet’s disease—a contem-
Springer Wien NewYork; 2011. p. 283–324. porary review. J Autoimmun. 2009;32(3–4):178–88.
176. Invernizzi P, Battezzati PM, Crosignani A, Zermiani 190. Taylor SR, Singh J, Menezo V, Wakefield D,
P, Bignotto M, Del Papa N, Zuin M, Podda M. McCluskey P, Lightman S. Behçet Disease: visual
Antibody to carbonic anhydrase II is present in pri- prognosis and factors influencing the development
mary biliary cirrhosis (PBC) irrespective of antimi- of visual loss. Am J Ophthalmol. 2011;152(6):
tochondrial antibody status. Clin Exp Immunol. 1059–66. Epub 2011 Aug 26.
1998;114(3):448–54. 191. Saadoun D, Wechsler B, Desseaux K, Le Thi Huong
177. Sheikh SH, Shaw-Stiffel TA. The gastrointestinal D, Amoura Z, Resche-Rigon M, Cacoub P. Mortality
manifestations of Sjögren’s syndrome. Am J in Behçet’s disease. Arthritis Rheum.
Gastroenterol. 1995;90(1):9–14. 2010;62(9):2806–12.
178. Voulgarelis M, Dafni UG, Isenberg DA, 192. Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel
Moutsopoulos HM. Malignant lymphoma in primary SE, Kremers HM. Epidemiology and clinical charac-
Sjögren’s syndrome: a multicenter, retrospective, teristics of Behçet’s disease in the US: a population-
clinical study by the European Concerted Action on based study. Arthritis Rheum. 2009;61(5):600–4.
Sjögren’s Syndrome. Arthritis Rheum. 193. Calamia KT, Schirmer M, Melikoglu M. Major ves-
1999;42(8):1765–72. sel involvement in Behçet’s disease: an update. Curr
179. Font J, Ramos-Casals M, de la Red G, Pou A, Opin Rheumatol. 2011;23(1):24–31.
Casanova A, García-Carrasco M, Cervera R, Molina 194. Siva A, Saip S. The spectrum of nervous system
JA, Valls J, Bové A, Ingelmo M, Graus F. Pure sen- involvement in Behçet’s syndrome and its differen-
sory neuropathy in primary Sjögren’s syndrome. tial diagnosis. J Neurol. 2009;256(4):513–29.
Long-term prospective follow up and review of the 195. Yazici H, Pazarli H, Barnes CG, Tüzün Y, Ozyazgan
literature. J Rheumatol. 2003;30(7):1552–7. Y, Silman A, Serdaroğlu S, Oğuz V, Yurdakul S, Lovatt
180. Brito-Zerón P, Ramos-Casals M, Bove A, Sentis J, GE, et al. A controlled trial of azathioprine in Behçet’s
Font J. Predicting adverse outcomes in primary syndrome. N Engl J Med. 1990;322(5):281–5.
Sjogren’s syndrome: identification of prognostic fac- 196. Kaklamani VG, Kaklamanis PG. Treatment of
tors. Rheumatology (Oxford). 2007;46(8):1359–62. Behçet’s disease—an update. Semin Arthritis
181. Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long- Rheum. 2001;30(5):299–312.
term risk of mortality and lymphoproliferative dis- 197. Ahn JK, Lee YS, Jeon CH, Koh EM, Cha HS.
ease and predictive classification of primary Sjögren’s Treatment of venous thrombosis associated with
syndrome. Arthritis Rheum. 2002;46(3):741–7. Behçet’s disease: immunosuppressive therapy alone
182. Theander E, Manthorpe R, Jacobsson LT. Mortality versus immunosuppressive therapy plus anticoagu-
and causes of death in primary Sjögren’s syndrome: lation. Clin Rheumatol. 2008;27(2):201–5.
a prospective cohort study. Arthritis Rheum. 198. Willkens RF, Arnett FC, Bitter T, Calin A, Fisher L,
2004;50(4):1262–9. Ford DK, Good AE, Masi AT. Reiter’s syndrome.
Evaluation of preliminary criteria for definite dis- 206. Cagatay Y, Gul A, Cagatay A, Kamali S, Karadeniz
ease. Arthritis Rheum. 1981;24(6):844–9. A, Inanc M, Ocal L, Aral O, Konice M. Adult-onset
199. Carter JD. Bacterial agents in spondyloarthritis: a Still’s disease. Int J Clin Pract. 2009;63(7):
destiny from diversity? Best Pract Res Clin 1050–5.
Rheumatol. 2010;24(5):701–14. 207. Crispín JC, Martínez-Baños D, Alcocer-Varela J.
200. Carter JD, Hudson AP. The evolving story of Adult-onset still disease as the cause of fever of
Chlamydia-induced reactive arthritis. Curr Opin unknown origin. Medicine (Baltimore). 2005;84(6):
Rheumatol. 2010;22(4):424–30. 331–7.
201. Schneider JM, Matthews JH, Graham BS. Reiter’s 208. Ishii T, Sasaki T, Muryoi T, Murai C, Hatakeyama A,
syndrome. Cutis. 2003;71(3):198–200. Oosaki H, Yusa A, Kawanami T, Yoshinaga K.
202. Wu IB, Schwartz RA. Reiter’s syndrome: the classic Systemic amyloidosis in a patient with adult onset
triad and more. J Am Acad Dermatol. 2008;59(1): Still’s disease. Intern Med. 1993;32(1):50–2.
113–21. 209. Fukaya S, Yasuda S, Hashimoto T, Oku K, Kataoka
203. Kvien TK, Gaston JS, Bardin T, Butrimiene I, H, Horita T, Atsumi T, Koike T. Clinical features of
Dijkmans BA, Leirisalo-Repo M, Solakov P, haemophagocytic syndrome in patients with sys-
Altwegg M, Mowinckel P, Plan PA, Vischer T, temic autoimmune diseases: analysis of 30 cases.
EULAR. Three month treatment of reactive arthritis Rheumatology (Oxford). 2008;47(11):1686–91.
with azithromycin: a EULAR double blind, placebo 210. Schmidt E, Brocker EB, Goebeler M. Rituximab in
controlled study. Ann Rheum Dis. 2004;63(9): treatment-resistant autoimmune blistering skin disor-
1113–9. ders. Clin Rev Allergy Immunol. 2008;34(1):56–64.
204. Egsmose C, Hansen TM, Andersen LS, Beier JM, 211. Moreland LW, Curtis JR. Systemic nonarticular
Christensen L, Ejstrup L, Peters ND, van der Heijde manifestations of rheumatoid arthritis: focus on
DM. Limited effect of sulphasalazine treatment in inflammatory mechanisms. Semin Arthritis Rheum.
reactive arthritis. A randomised double blind pla- 2009;39(2):132–43.
cebo controlled trial. Ann Rheum Dis. 1997;56(1): 212. Irie F, Kobayashi M, Hirayama K, Nagase S, Iitsuka
32–6. T, Yamaguchi N, Koyama A. Rheumatoid arthritis
205. Bagnari V, Colina M, Ciancio G, Govoni M, Trotta associated with membranous nephropathy and IgA
F. Adult-onset Still’s disease. Rheumatol Int. nephritis with necrotizing lesions. Nephrol Dial
2010;30(7):855–62. Transplant. 1996;11(7):1338–41.
Burn and Other Exposure Injuries
12
Alexander M. Sailon and Peter J. Taub
loss resulting in multi-organ system failure and a

12.1 Introduction protracted ICU course. In more serious cases, it is
imperative that burn care extend far beyond the
Man’s primitive fascination with fire has led to initial insult. Burns can significantly alter quality
affliction with burn injuries since the dawn of our of life and are a common cause of disability.
history. Therapy has evolved from the application Debilitating contractures and cosmetically unac-
of mud and excrement in Egyptian times, to ceptable scars may have long-lasting physical
dressings impregnated with pig fat and resin in and psychological consequences, requiring con-
the Roman era, to the emergence of a relatively tinued physician involvement and support.
modern concept of first aid from the military
battlefield [1]. Still today, burn injuries and their
sequelae represent one of the most potentially 12.2 Evaluation
devastating and challenging conditions in medi-
cine. Over one million burns occur annually in Burns occur via numerous etiologic insults and may
the USA, with the majority being treated in an damage the skin and appendageal structures at vari-
outpatient setting. Children up to 4 years of age ous depths. Skin may be harmed by contact with
and working age adults comprise nearly 90% of heat, noxious chemicals, and/or electrical current.
patients with burn injuries. Injuries to children With the exception of minor injuries, all burn
largely involve scald injuries, whereas flame patients should be treated as trauma patients.
burns are predominant in the working age popu- Initial evaluation should assess life-threatening
lation [2]. Presentation may vary considerably, conditions and focus on the airway, vital signs,
from simple sunburns requiring no more than neurological status, etc. A careful history identi-
counseling and a topical agent to extensive tissue fying the cause, type, and exact time of injury is
paramount in determining initial fluid resuscita-
tion, expected clinical course, and disposition.
Exposure to smoke or heated gas may cause
A.M. Sailon, M.D.
Division of Plastic and Reconstructive Surgery, airway edema which can quickly progress to
Department of Surgery, Mount Sinai School of Medicine, obstruction. Facial burns, carbonaceous sputum,
New York, NY, USA elevated blood carboxyhemoglobin, and tachyp-
P.J. Taub, M.D., F.A.C.S., F.A.A.P. (*) nea should raise concern for airway injury.
Division of Plastic and Reconstructive Surgery, Progressive hoarseness often indicates impend-
Department of Surgery and Pediatrics, Mount Sinai
ing airway obstruction. Intubation by an experi-
School of Medicine, 5 East 98th Street, 15th Floor,
New York, NY 10029, USA enced anesthesiologist or emergency room
e-mail: peter.taub@mountsinai.org physician should be ideally performed prior to

236 A.M. Sailon and P.J. Taub
Table 12.1 American Burn Association criteria for referral to a burn center
Partial thickness burns greater than 10% total body surface area (TBSA)
Burns that involve the face, hands, feet, genitalia, perineum, or major joints
Third-degree burns in any age group
Electrical burns, including lightning injury
Chemical burns
Inhalation injury
Burn injury in patients with preexisting medical disorders that could complicate management, prolong recovery, or
affect mortality
Any patients with burns and concomitant trauma (such as fractures) in which the burn injury poses the greatest risk
of morbidity or mortality. In such cases, if the trauma poses the greater immediate risk, the patient may be initially
stabilized in a trauma center before transfer
Burned children in hospitals without qualified personnel or equipment for the care of children
Burn injury in patients who will require special social, emotional, or rehabilitative intervention
the development of a complete obstruction. appearance without blister formation. Capillary

A history of smoke exposure in an enclosed space refill is brisk, as is bleeding on pin-prick. The clas-
or for a prolonged time merits screening for car- sic example is a sunburn, although superficial burns
bon monoxide poisoning via measurement of are frequently caused by flash burns (i.e., brief,
blood levels. Although standard blood tests intense thermal exposure) as well.
suffice, noninvasive pulse carbon monoxide oxi- Partial-thickness or second-degree burns
metry should be used where available. The clini- involve the epidermis and part of the dermis. They
cian should be aware that standard pulse oximetry are further subdivided into superficial and deep
and arterial blood gases erroneously report nor- partial thickness burns depending on the depth of
mal oxygen levels in the setting of carbon mon- dermal involvement. Superficial partial-thickness
oxide poisoning. Specific and severe burn injuries burns are pink and painful with delayed capillary
require immediate transfer to a burn center once refill. They will generally heal in 2–3 weeks with-
the patient has been stabilized (Table 12.1) [3]. out significant scarring, although depigmentation
A thorough full-body assessment is critical in of the affected skin is possible. Scald burns typi-
major injuries to avoid missing any areas of soft cally result in superficial partial-thickness burns.
tissue damage. For electrical injuries, potentially Deep partial-thickness burns are characterized
hidden points of entry and exit should be sought. by injury extending into the reticular dermis.
These commonly occur on the palms and soles They appear “cherry red” or pale and dry with
since electrical cables are inadvertently grasped mottling (Fig. 12.1). The neural plexus in the
and the current travels to the ground. In these deep dermis is often injured resulting in variable
cases, damage along the path of the current is sensation and burns that are generally less painful
hidden but should be suspected. to touch. They will not blanch with gentle pres-
sure, and bleeding from pin-prick will be delayed.
The rate of healing is variable depending on the
12.2.1 Depth of Burn Injury number of intact adenxal structures left in the
skin. As a result, thin, hairless skin (e.g., eyelids)
Careful assessment of burn depth is the next critical will heal more slowly than thick or hairy skin
step in determining appropriate management and (e.g., back, scalp). Typically, these burns will
can help predict prognosis and long-term scarring. heal in 1–3 months, but with a significant amount
It is important to keep in mind that most burns rep- of scarring and possible contractures because
resent a mixture of different depths. Superficial or follicular structures needed for re-epithelializa-
first-degree burns involve only the epidermis. They tion may be destroyed. Often, they are best treated
are painful and have an erythematous, glistening by excision and grafting.
12 Burn and Other Exposure Injuries 237
Fig. 12.2 Full-thickness burn to the chest, neck, and

Fig. 12.1 Contact burn exhibiting a mixture of deep par- chin
tial thickness injury on the distal aspect of the leg and
superficial partial thickness injury proximally. Note the
rapid demarcation to normal skin secondary to protection
from the patient’s footwear
12.2.2 Determining Total Burn
Surface Area
Full-thickness or third-degree burns extend Calculating total burn surface area (TBSA) is the
through the entirety of the dermis (Fig. 12.2). They next critical step as it serves to guide initial fluid
appear dry, leathery and can be white, brown, or resuscitation, nutritional requirements, and appro-
black. These wounds are insensate, do not blanch, priate triage. Of note, partial thickness burns cov-
and do not bleed upon pin-prick. Thrombosed ves- ering more than 10% of TBSA and those in
sels may be visible and are pathognomonic for anatomically sensitive areas (i.e., genitalia, hands,
third-degree burns. Fourth-degree burns extend crossing joints) should be immediately referred to
completely through the skin and subcutaneous tis- a burn center (Table 12.1). It can be estimated by
sues, affecting underlying muscle and bone [4]. either of two methods. Regardless of the technique
Assessing burn depth requires experience and employed, it is important to note that only areas of
often takes several days of observation to deter- partial- and full-thickness injury (second- and
mine the appropriate management. Patients may third-degree burns) should be counted. Superficial
be admitted for observation and reexamined every burns involving only the epidermis (i.e., first-
day as the appearance of the wound becomes degree burns) need not be considered. The “rule of
clearer. Serial debridement of necrotic tissue may nines” is the most popular method and divides the
be required to accurately assess the degree of adult body into anterior torso (18%), posterior
injury. Generally, the wounds that appear likely to torso (18%), legs (18% each), arms (9% each),
heal within 3 weeks can be managed conserva- head/neck (9%), hands (1% each), and perineum
tively, whereas those that will take longer are best (1%) (Fig. 12.3). The percentage assigned to a
treated by excision and grafting. body area reflects its total area, therefore a burn
a b 18%
9%
36% 36%
9%
1% 1%
18% 13.5%
Fig. 12.3 Rule of nines to calculate total burn surface area in (a) adults and (b) children
involving one-third of the leg should be considered degree of tissue damage, and blood flow. The zone
a 6% TSBA burn. A modified rule of nines is used of coagulation is the portion of the wound that was
for children dividing the body into anterior torso most directly affected by the insult and is charac-
(18%), posterior torso (18%), head/neck (18%), terized by irreversible tissue damage. The zone of
legs (13.5% each), arms (9% each), hands (1% stasis is the surrounding ischemic area that is
each), and perineum (1%). Because the propor- potentially salvageable. Fluid resuscitation seeks
tions for infants and children differ significantly to increase perfusion in this area and prevent pro-
from each other and adults, Lund and Browder gression to skin necrosis. The zone of hyperemia
charts are available to provide a more precise esti- is the most peripheral area and is characterized by
mate of TBSA based on the patient’s age. For inflammation leading to increased blood flow and
small or scattered burns, a second technique for increased vascular permeability causing edema.
calculating burn area involves using the patient’s This area invariably recovers rapidly over the
hand (note: not the examiner’s). The patient’s hand course of a few days [2].
represents approximately 1% of the body surface
area and can be used to estimate TBSA by count-
ing how many “hands” are required to cover the 12.3 Management
area of a burn [5].
12.3.1 Fluid Resuscitation
12.2.3 Zones of Injury Historically, high early mortality rates seen fol-
lowing burn injury were in part related to unrec-
The initial effect caused by a burn can be generally ognized fluid loss and inadequate resuscitation.
divided into three distinct zones based on histology, Hypovolemia develops quickly due to evaporation
Table 12.2 Parkland Formula: used to determine fluid potential systemic sequelae such as bacteremia,
resuscitation in the first 24 h sepsis, and multi-organ dysfunction syndrome.
Parkland formula Minimizing exposure to pathogens and treating
Total fluid volume = 4 (cc/kg) × weight (kg) × TBSA (%) infections early are critical to successful burn
One-half of the total fluid volume should be administered management as infection remains responsible for
in the first 8 h, the second half in the subsequent 16 h. the majority of mortalities. Although wound
Total burn surface area (TBSA)
infections are common, many burn patients are
also at risk for pneumonia if they are intubated,
from a compromised skin barrier and extravas- immobile, or septic, or if they have suffered an
tion of fluid into unburned tissue. Today, burns of inhalation injury or chest wall injury that limits
significant size (greater than 10% total body sur- thoracic cage excursion.
face area) are managed with fluid replacement Although burn wounds are initially sterile,
according to one of several described protocols. gram-positive bacteria may survive within the
The more widely used Parkland Formula calcu- sweat glands and hair follicles and will quickly
lates the amount of total fluid requirement over colonize the wound within 24–48 h if no antimi-
the first 24-h period following the injury. Total crobial agent is used. At approximately 1 week
fluid volume is calculated as the patient’s weight post-injury, the wound may be colonized by an
in kilograms multiplied by four and then by the assortment of gram-positive bacteria, gram-nega-
total body surface area of second- and third- tive bacteria, and yeast or fungi. Microbes that
degree burns in percentage points. One-half the colonize the wound may arise from the host’s
calculated volume is given over the first 8 h from own gastrointestinal or respiratory flora, or they
the time of injury (not from the time of evalua- may originate from the hospital environment.
tion). The second half is given over the next 16 h Staphylococcus aureus is a common etiologic
(Table 12.2). Regardless of the formula used, the agent of burn wound infections, particularly ones
clinician should bear in mind that any mathemati- arising soon after injury. However, Pseudomonas
cal calculation of fluid requirements is merely an aeruginosa has become the predominant agent
estimate. Close monitoring of the response to overall in a number of burn centers. It is often
fluid administration and physiologic tolerance of characterized by a greenish-blue discharge and a
the patient is crucial. Fluid management in the characteristic grape-like odor. Gram-negative
pediatric population can be challenging, espe- bacteria have become a more frequent cause of
cially in infants where lack of renal maturation invasive infections as a result of their numerous
and reduced GFR makes resuscitation more deli- virulent factors and antimicrobial resistance
cate. Adequacy of resuscitation should be care- traits. Anaerobes are a less common source of
fully monitored in multiple ways via heart rate, infection and typically occur in the setting of
blood pressure, mental status, acid–base balance, electrical injury or when open wound dressings
etc. Among these methods, urine output is the are used [6].
most accurate. A urine output of 0.5–1.0 ml/kg/h Fungi and yeast tend to colonize wounds later,
indicates that hydration is appropriate. Higher and patients on broad-spectrum antibiotics may
urine outputs may be desired in patients with be at increased risk. Fungal wound infections are
crush or high-voltage electrical injuries where associated with a high mortality and their resis-
myoglobinuria can damage the renal tubules. tance to topical antimicrobials highlights the
importance of aggressive wound debridement.
12.3.2 Burn Wound Infections

12.3.3 Topical Burn Care
Diagnosing burn wound infections by regular
monitoring of vital signs and frequent wound Burn care is largely dependent on the depth, size,
inspection prevents delays in wound healing and and location of the burn sustained. It is imperative
that the treating clinician be mindful of the fact normal skin should be applied first only in patients
that each burn may vary in depth and, therefore, with a known sulfa allergy.
require different treatment. Initial treatment for
all but superficial burns remains the same. 12.3.3.2 Mafenide Sodium
Clothing, jewelry, and debris should be gently Mafenide sodium (Sulfamylon®) is available as a
removed. Mineral oil can be applied to painlessly water-soluble cream or solution. Like silver sul-
remove charred clothing adherent to a burn. fadiazine, it has broad-spectrum antimicrobial
Wounds should be cleansed with soap and water coverage but unlike other topical agents, mafenide
to remove smaller debris and loose tissue. Intact has excellent penetration, making it the “gold
bullae are best left alone, whereas burst, flaccid standard” for burns of the ear or in the presence
blisters, and frankly necrotic tissue should be of a burn eschar. In such cases, twice daily appli-
scraped off or debrided sharply to prevent infec- cation is necessary. Application tends to be pain-
tion and accurately assess burn depth. A mini- ful, potentially limiting its use. Mafenide is a
mally adherent dressing such as potent carbonic anhydrase inhibitor that can
Vaseline-impregnated gauze should be applied to cause metabolic acidosis, in addition to osmotic
minimize contamination and evaporative loss. diuresis and electrolyte abnormalities [5].
Topical agents play an important role in burn
care by their ability to augment wound healing and 12.3.3.3 Silver Nitrate
prevent infection. Given the variety of agents avail- Silver nitrate is available as a solution-soaked
able, one needs to understand their subtle nuances dressing, and as such, dressings need to be
in order to maximize their potential. Superficial, changed frequently (3–6 times per day) to keep
partial thickness burns that should heal without the wound moist. Application is painless although
surgical intervention should be dressed with an care must be taken as silver nitrate stains clothing
easy-to-apply, topical antimicrobial agent. It is and linens black. It too has broad-spectrum anti-
important to keep in mind that although burn microbial coverage. Silver nitrate is prepared as a
wounds can be initially considered sterile they are hypotonic solution, which can result in electro-
typically colonized quickly by both gram-positive lyte abnormalities, most commonly hyponatremia
and gram-negative bacteria, necessitating the need or hypochloremia, requiring frequent monitoring
for broad-spectrum topical antimicrobial cover- for those with large wounds. The silver ions in
age. Parenteral agents are not recommended in the both silver nitrate and silver sulfadiazine can
absence of multi-organ system involvement. rarely cause methemoglobinemia. Should this
Deeper, partial thickness burns should generally develop, any silver containing agents should be
be treated by tangential excision and grafting. In a immediately discontinued.
similar fashion, full-thickness burns should be
treated with an antimicrobial topical agent capable 12.3.3.4 Other Topical Antimicrobial
of eschar penetration until excision is appropriate. Agents
Over-the-counter ointments, such as bacitracin,
12.3.3.1 Silver Sulfadiazine neomycin, and polymyxin, are commonly used
Silver sulfadiazine (Silvadene®) remains one of for superficial partial-thickness burns, especially
the most popular agents. It is formulated as a on the face, as mentioned previously. These prod-
white, water-soluble cream with broad-spectrum ucts carry a low risk of allergic dermatitis. Of
antimicrobial coverage (including Pseudomonas). note, mupirocin (Bactroban®) is the only agent in
Its application is painless and often found to be this class to be bactericidal against methicillin-
soothing. However, silver sulfadiazine is not able resistant staphylococcus aureus (MRSA).
to penetrate a burn eschar, limiting its use in such
wounds. A transient, self-limiting leukopenia 12.3.3.5 Topical Debriding Agents
develops in 3–5% of patients and should not Ointments containing collagenase or papain-urea
require discontinuation. A small test dose on stand apart from the previously mentioned agents
due to their ability to enzymatically debride non- Table 12.3 Figure 5. Harris-Benedict equation: used to
viable tissue. They are an excellent choice in burn estimate basal energy expenditure (BEE)
wounds with mild necrotic or fibrinous material. Harris-Benedict equation
In these wounds, they can result in a clean dermis For males: BEE = 66 + (13.7 × weight in kg) +
earlier, leading to faster re-epithelialization [5]. (5 × height in cm) − (6.8 × age in years)
For females: BEE = 655 + (9.6 × weight in kg) +
(1.8 × height in cm) − (4.7 × age in years)
12.3.4 Systemic Derangements

tion, critically ill patients benefit from tight glu-
Significant burn injury results in a large-volume cose control and therefore require regular
fluid shifts and a systemic inflammatory response monitoring of blood glucose levels. Adequate
that affects nearly all organ systems. As a result, levels of vitamins and minerals are provided in
burn patients may present with or develop hypo- most commercially available enteral feeding for-
thermia during their hospital course. Forced-air mulas. However, administering supernormal lev-
warming blankets and gently heated intravenous els of certain nutrients (termed immunonutrition)
fluids should be used to achieve or maintain nor- may be beneficial. For example, omega-3-fatty
mothermia. Hypothermia has been associated acids can suppress proinflammtory cytokines,
with increased mortality rates and a higher inci- arginine can enhance lymphocyte function, and
dence of acute lung injury. glutamine can improve gut barrier function [4].
Severe burns results in a hypermetabolic state, Burn injury can cause renal failure from myo-
which may last several months. The increase in globinuria secondary to muscle breakdown or
energy expenditure is proportional to burn sur- hemolysis. Inadequate urine output despite ade-
face area and can lead to a doubling of the basal quate fluid resuscitation often heralds renal fail-
metabolic rate in severe burns. Enteral nutrition ure. Dialysis may be required and should not be
should be started early and is preferable as paren- delayed. In the presence of myoglobinuria, urine
teral nutrition is associated with immunosuppres- output must be kept high with intravenous fluids,
sion and higher mortality rates. Generally, and diuretic use should be considered.
patients with a total body burn surface area of Heart failure is a potential complication from
greater than 20% should undergo tube feeding to circulating myocardial depressants (namely
ensure caloric needs are met. Close attention lipopolysaccharide) after a major burn. Diastolic
must be paid to changes in nutritional status as dysfunction predominates and should be treated
the patient recovers. by administering an inotropic agent. Drugs should
Basal energy expenditure (BEE) determines be chosen that minimize vasoconstriction so as to
the required caloric intake and can be estimated avoid worsening already hypoxic wounds.
using the Harris-Benedict equation (Table 12.3)
[4]. BEE is then multiplied by a factor based
upon the severity of the stress (i.e., in large burns 12.3.5 Surgical Management
this factor is 1.8–2.1). Indirect calorimetry is a
more accurate way of measuring caloric expendi- Distal perfusion after an extremity burn may be
ture by determining measured oxygen consump- compromised by compartment syndrome, a con-
tion and carbon dioxide production in ventilated dition characterized by increased compartment
patients. pressures secondary to edema. Pain out of pro-
Caloric intake should be appropriately bal- portion to the injury and aggravated by passively
anced between lipids, carbohydrates, and proteins stretching muscles within the compartment is
with the assistance of nutritionist. Highly stressed often reported early and nearly universal.
patients have higher protein needs, and may Paresthesia and loss of pulses are much later
require up to 2 g/kg/day (assuming normal renal findings. Although generally clinical examina-
function) to prevent muscle breakdown. In addition is sufficient for diagnosis, intra-compartment
pressures of greater than 30 mmHg are meshed at a 3:1 ratio since the resultant skin
confirmatory. Fasciotomies of the affected bridges may rotate to the dermal side when the
extremity are indicated to prevent muscle necro- graft is placed on the recipient site. A meshed
sis and limb loss. graft also minimizes fluid accumulation beneath
Burn injury may also cause acute damage to the graft. Unmeshed grafts are preferred in cos-
regions distal to the injury as a result of circum- metically sensitive areas such as the face since
ferential compression to either the trunk and/or meshed grafts have a hatched or waffle pattern
an extremity due to necrotic skin and soft tissue. once they heal. To prevent accumulation of fluid
Full-thickness injury can produce a tough eschar beneath unmeshed grafts, multiple incisions may
that may compromise distal perfusion of an be made to allow egress of serum or blood.
extremity or ventilation by limiting thoracic cage The skin graft may be affixed to the periphery
excursion. In either situation, an escharotomy is of the debrided area using sutures, staples, or tape.
indicated. This should be done soon after the ini- Several sutures should also be placed centrally to
tial assessment as fluid resuscitation may worsen minimize shearing forces. For added support, a
the problem. Because the skin is insensate, this tie-over bolster, circumferential dressing or nega-
can often be done at the bedside with hand-held tive pressure sponge should be used. If the latter is
electrocautery through the eschar and into the chosen, pressure should be low enough to allow
subcutaneous adipose. The skin should subse- for ingrowth of blood vessels. A splint is also
quently spread restoring distal perfusion. Eventual helpful for burns on an extremity to limit move-
coverage may be completed with autologous split ment and, therefore, shearing forces on the graft.
and full thickness grafts, xenografts, cultured The dressing is changed in 3–5 days to confirm
cells, or alloplastic dressings. take of the graft. Longer times until the first dress-
Following an adequate period of time to allow ing change may be appropriate for meshed grafts
for fluid resuscitation and demarcation of areas with adequate postoperative compression since
of questionable depth, the patient may undergo fluid accumulation is rarer. The first dressing
tangential excision of those areas deemed too change should occur earlier for unmeshed grafts
deep to heal within a reasonable period of time. which may not have ideal compression. At 3 days,
Damage to the appendageal structures in these fluid may be aspirated from beneath a skin graft
deep partial thickness burns limits their ability to without affecting its viability. Graft survival is
reepithelialize. The skin is excised using a thin much less likely if aspiration is delayed. Care
blade with an overlying guard until viable tissue should be exercised such that the graft is not inad-
is encountered. A tourniquet may or may not be vertently removed with the dressing. Failure of
used on an extremity since punctate bleeding graft take is due to one or more complications,
determines adequate perfusion. including an inadequately vascularized wound
Skin is harvested from donor sites that are bed, infection, seroma or hematoma formation,
relatively flat and unnoticeable, such as the lat- and movement of the graft (i.e., shear forces).
eral thigh, lower back, or scalp. Split thickness For areas prone to complications due to sec-
skin is harvested at a depth of roughly 8 to ondary skin contraction with healing (e.g., the
12/1,000 of an inch using an electric dermatome lower eyelid), full thickness grafts should be
that moves a thin blade side to side between a used. These are generally harvested by hand
guarded handle (Fig. 12.4). Firm, consistent pres- using a scalpel just above the level of the subcu-
sure is used to harvest skin of suitable quality. taneous fat. Any remaining fat is then removed
Skin grafts may be placed through a mesher, with a sharp, fine scissor from the undersurface
which punches small holes in the graft at regu- of the graft prior to placement.
larly spaced intervals in order to increase the total In the absence of sufficient healthy skin for
surface area. A graft that is meshed either 1 ½ or grafting, a small amount of epithelial cells may
3 times is valuable when larger amounts of skin be harvested from an unburned area such as the
are needed. Care must be taken with grafts perineum or inner thigh and grown in a labora-
Fig. 12.4 A standard

dermatome in the
foreground with a control
for skin graft thickness. A
mesher in the background
increases the surface of the
skin graft. By changing the
cutting roller, skin grafts
can be meshed at a ratio
from 1.5:1 to 3:1
tory as cultured sheets. Use of cultured epithelial 12.3.6 Caring for Healed Wounds
cells is indicated for very large burns where donor
area is limited. Unfortunately, high cost and lower Caring for a burn does not end once the wound
strength are barriers to more widespread use. has been successfully grafted or re-epithelialized
Xenografts (tissues from other species) have (Fig. 12.5). Nutrition plays a large role in healing
held the promise of a natural replacement mate- and adequate caloric intake following injury must
rial in large supply. They have been used for years be monitored. Healing wounds are sensitive to
but still are complicated by immunologic rejec- ultraviolet (UV) rays, and protection from the
tion. Today, pig skin is used for large burns as a sun is critical. Patients must be reminded to use
temporary occlusive dressing or as a test graft for sunscreen or clothing that covers the wound when
wounds of questionable vascularity. If the xeno- outdoors. Sun exposure can lead to hyperpigmen-
graft fails to take, the wound bed is presumed to tation of the graft or wound.
be inadequate for more valuable autogenous skin. Pruritus is a common complaint since healed
However, if the xenograft successfully takes, it wounds lack adnexal structures needed to keep
may be completely removed in favor of an autog- skin moist. A mild alcohol- and fragrance-free
enous skin graft. Another option is to remove the moisturizer should be applied daily and after
antigenic epidermis from the inert dermis by washing. Despite liberal moisturizer use, many
dermabrasion replacing it with a thinner skin patients still complain of iprutitus. In these cases,
graft. This allows the epidermis to regenerate an oral antihistamine may be beneficial.
more rapidly and subsequently becoming quickly Epidermal inclusion cysts can develop when
available for repeat harvest. skin grafts are placed over a wound bed that con-
Synthetic skin may also be used but is not able tains intact dermal structures or small, micro-
to completely obviate the need for an autogenous scopic patches of epidermis that were not visible
graft. Integra™ (Life Sciences) is composed of to the surgeon at the time of graft placement.
collagen fibrils bound to a silicone sheet replicat- Inclusion cysts may be treated by incision and
ing the dermal and epidermal elements of natural drainage. Larger cysts may require excision [2].
skin. The collagen fibrils are incorporated into Burn scar contractures are one of the most dev-
the healing wound bed to recreate the dermis, astating sequelae of severe injuries. They result
while the silicone acts as a temporary barrier to from prolonged healing, delayed re-epithelializa-
fluid loss similar to a natural epidermis. In 2 or tion, or excessive immobility in a flexed position.
more weeks, the silicone sheet is removed and a Compression dressings, massage, silicone sheets,
thinner skin graft than normal may be applied. and active and passive range of motion activities
extensive muscle and nerve injury. Electrical

burns often do not fully declare themselves at
first and the extent of soft tissue injury often
extends beyond what is initially evident. Muscle
injury and edema can result in increased com-
partment pressures and, ultimately, compartment
syndrome. Consequently, patients at risk should
have serial neurologic exams. Myoglobinuria
from muscle necrosis results in tea-colored urine
and necessitates maintaining a high urine output
Fig. 12.5 Fully healed split thickness skin graft over the
extensor surface of the elbow. A meshed graft was used in
(approximately 100 cc/h) to prevent renal dam-
the case age. If the urine does not clear despite adequate
fluid resuscitation, mannitol can be administered.
In addition, some advocate the alkalinization of
can reduce long-term scar formation. Severe con- urine to prevent precipitation of myoglobulin in
tractures are both physically and psychologically kidney tubules.
debilitating. Such patients should be referred to a Given the propensity of cardiac arrythmias as
plastic surgeon experienced in burn reconstruc- a result of electrical injuries, all patients should,
tion for further management. at a minimum, have an electrocardiogram.
Although not evidence-based, cardiac monitor-
ing for 24 h is protocol at some institutions.
12.4 Electrical Burns Electrical injuries can result in significant
long-term sequelae. Most commonly, neurologi-
Electrical injuries represent an uncommon but cal deficits involving either the peripheral (i.e.,
potentially devastating event that can affect mul- peripheral neuropathy) or central nervous system
tiple organs outside of the area directly affected. (i.e., cognitive changes, poor motor skills) which
It should be noted that tissue damage results from can occur even months after the injury. In addi-
a combination of both thermal and nonthermal tion, cataracts occur in approximately 5% of
energy via protein denaturation and altering the electrical injury patients, with other ocular inju-
permeability of the cell plasma membrane (i.e., ries occurring less frequently.
electroporation). Electrical injuries are classi-
cally divided into low-voltage (less than 1,000 V)
and high-voltage (greater than 1,000 V). Electrical 12.5 Chemical Burns
injuries in the home are usually low-voltage,
while high-voltage injuries typically occur at fac- Chemical injuries constitute only 3% of cutane-
tory or construction sites. This distinction dic- ous burns; however, they account for 30% of burn
tates subsequent management. Low-voltage deaths [7]. They are broadly classified into acid
injuries may generally be treated on an outpatient or alkali (base) burns. Alkali burns have a more
basis, assuming there are no significant injuries insidious course and generally cause more injury
or arrhythmias. than acid burns as a result of liquefaction necro-
High-voltage injuries are typically arc-medi- sis, allowing the alkali to penetrate deeper into
ated, meaning the patient is unlikely to have had the tissues. Acid burns, on the other hand, cause
direct contact with the electrical source. Since immediate, more-limited tissue damage.
electrical energy travels along the path of least Coagulation necrosis results in eschar formation,
resistance, one should look carefully for entrance which prevents further penetration of the acid.
and exit sites on initial evaluation. Cutaneous The first step in treatment should be removal of
burns do not necessarily reflect deep tissue dam- the inciting agent. This includes discarding
age, and, as a result, these patients may have contaminated clothing. Healthcare workers must
take appropriate precautions as some chemicals course is more insidious, and treatment should
can erode through standard protective equipment. assume that burns will progress significantly in
The affected skin should be copiously irrigated depth during the 24 h after injury. Unlike acids,
for at least 30 min to an hour with room tempera- which result in coagulation necrosis, alkali
ture water. Irrigation should be avoided in the burns are characterized by liquefaction necrosis
presence of chemicals that ignite upon contact and fat saponification. Prolonged vigorous water
with water (e.g., elemental sodium, potassium, lavage for 60 min or more is necessary. Lye
and lithium). Neutralizing the chemical agent (found in drain cleaners and paint thinners) and
should not be attempted, as an exothermic reac- cement are the most common agents causing
tion often develops, potentially causing further alkali burns [7].
injury. Depending on the inciting agent, patients
should be monitored for systemic effects. For
example, phenol causes central nervous system 12.5.3 Tar and Grease
depression and cardiopulmonary collapse.
Although hundreds of chemicals can cause burns, Tar and grease burns are two of the more com-
a few deserve specific mention for their unique monly encountered chemical burns and should be
treatments. initially treated by applying cold water to the hot,
adherent material. In order to easily remove the
tar, bacitracin, mineral oil, or Neosporin should
12.5.1 Hydrofluoric Acid be applied and washed off 12 h later.
Hydrofluoric acid, commonly found in industrial

cleaning solutions and frequently used in the glass References
and silicon chip industries, penetrates skin and tis-
sue until its fluoride ion chelates with a calcium 1. Cuttle L, Kimble RM. First aid treatment of burn inju-
source, usually bone. Subsequent hypocalcemia ries. Wound Pract Res. 2010;18(1):6–13.
2. Hettiaratchy S, Papini R, Dziewulski P. ABC of burns.
may result in dysrhythmias. A topical calcium 1st ed. Malden, MA: Blackwell Publishing Ltd;
gluconate gel may prevent further damage and is 2005.
most effective when applied soon after exposure. 3. Committee on Trauma, American College of Surgeons.
Subcutaneous injection of calcium gluconate can Guidelines for the operation of burn centers. In:
Resources for optimal care of the injured patient 2006.
also be beneficial, although one must be cautious American College of Surgeons; 2006: 79–86.
in its administration as it may cause skin necrosis. 4. Weinzweig J. Plastic surgery secrets. 2nd ed.
As a last resort, calcium gluconate can be injected Philadelphia, PA: Mosby; 2010.
intra-arterially. A marked decrease in pain signifies 5. Klein M. Thermal, chemical, and electrical injuries. In:
Thorne CH, Beasley RW, Aston SJ, Bartlett SP, Gurtner
effective treatment [7]. GC, Spear SL, editors. Grabb and Smith’s plastic sur-
gery. 6th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2006. p. 132–49.
12.5.2 Alkali 6. Church D, Elsayed S, et al. Burn wound infections.
Clin Microbiol Rev. 2006;19(2):403–34.
7. Mathes SJ. Thermal and electrical injuries. In: Mathes
Alkali burns tend to penetrate deeper, causing SJ, editor. Plastics. 2nd ed. Philadelphia, PA: Saunders;
more severe burns than acids. However, their 2005.
Dermatological Emergencies: Skin
Manifestations of Abuse 13
Rachel Nazarian, Joy Checa, and Orit Markowitz
elderly, are unable to articulate their condition or

13.1 Overview alert authorities of any wrongdoing and rely
nearly exclusively on the awareness of astute pro-
Abuse takes many forms, including physical fessionals. Many cases of abuse are left unrecog-
abuse, sexual abuse, emotional abuse, and neglect. nized by professionals, the findings being
The definition of child abuse, by the Center for exceedingly subtle, often written off as innocu-
Prevention and Treatment of Child Abuse (USA), ous lesions. Early recognition is crucial, not only
is stated as the mental and physical injury, sexual to prevent subsequent injury which occurs in
abuse, neglect, or mistreatment of individuals 30–70% of children, but reports have indicated
under 18 years of age, perpetrated by a caregiver, that abuse tends to increase in severity with time
which indicates that the health of the child is [2], and early intervention may avert these avoid-
threatened [1]. Physicians must always be alert able events.
for signs indicating any manifestation of abuse, Advances in scientific analysis and medicine
looking for symptoms beyond skin lesions. The have allowed for objective evaluation and higher
authors consider any form of abuse a medical accuracy of garnering a correct diagnosis.
emergency, recognizing that most children, or This chapter primarily addresses the skin man-
ifestations of child abuse, including common con-
ditions that mimic lesions of abuse, and those
brought on cultural practices that are oftentimes
misdiagnosed as child abuse. It is equally impor-
R. Nazarian, M.D.
Department of Dermatology, Mt. Sinai Hospital, tant that a physician does not wrongly accuse any-
New York, NY, USA one of such a horrific crime as the repercussions
e-mail: nazarianrachel@yahoo.com of false accusations are grave; existing reports
J. Checa, B.A., M.S.III have included suicide of distraught parents mis-
American University of the Caribbean School of takenly accused of abusing their child [3].
Medicine, Coral Springs, FL, USA Reports of child abuse have been increasing
e-mail: joy.checa@gmail.com
significantly [4–6] and dermatologists are in a
O. Markowitz, M.D. (*) unique position to identify and prevent further
Department of Dermatology, Mt. Sinai Hospital,
New York, NY, USA abuse of children. The cutaneous signs of abuse,
including bruises and burns, are the most frequent
Faculty Practice Associates-Dermatology,
5 East 98th Street, 5th Floor, New York, NY 10021, USA injury caused by physical abuse; all physicians,
e-mail: omarkowitz@gmail.com dermatologists especially, must remain vigilant

248 R. Nazarian et al.
in recognizing these signs despite little to no form relationships with others. Studies have also
training or guidance. The challenge remains in shown that feeling of worthlessness continues
distinguishing intentional from accidental injury, into adulthood, causing some victims of abuse to
which occurs commonly in childhood, and recog- consider or attempt suicide [12].
nizing even uncommon skin diseases that may
mimic maltreatment [7].
Approximately 48 States, and the District of 13.3 Workup
Columbia, among other regions, designate pro-
fessionals who are mandated by law to report When initially facing a case of suspected abuse,
child abuse and maltreatment. Physicians and the physician should approach the history like that
other health-care workers are included, as they of any other patient. Clues in the history that sug-
typically have frequent contact with children, gest abuse include an inconsistent or changing
most especially dermatologists, pediatricians, history with vague or absent details [13, 14].
and emergency room physicians, and are the first A delay by the caretaker in seeking help, fre-
professionals to observe and hopefully recognize quently defined as waiting more than 2 h before
the signs of intentional injury. obtaining medical attention, without reasonable
cause, or a child or a patient who has repeated vis-
its for the treatment of injuries is suspicious for
13.2 Demographics abuse. Subtle signs by the child, such as overly
passive or withdrawn behavior, should also be
According to Child Protective Services, more noted by the physician and may be a strong indi-
than 700,000 children were abused or neglected rect indication of abuse. The most common
in 2009. In reality, these cases likely represent findings in the exam of a physically abused child
only a fraction of all cases of abuse [8]. It is include ecchymoses, burns (often cigarette burns),
thought that many cases of abuse remain unre- bites, lacerations, bites, and traumatic alopecia
ported, and abuse is rarely seen or acknowledged [15]; the common findings of maltreatment and
by individuals outside of the immediate family. how to recognize them are reviewed here.
Child maltreatment and abuse remains a con-
cealed and hidden problem and despite the num-
ber of reported cases, some studies estimate that 13.4 Ecchymoses
nearly 25% of the US children undergo some
form of child abuse [9]. Ecchymoses and contusions, recognized clini-
Although the short-term effects of physical cally as subcutaneous purpura, are the most fre-
abuse include lacerations, ecchymoses, burns, quently seen signs of abuse [16, 17] (Fig. 13.1),
and bone fractures, recent studies have found that seen in about 80% of physical abuse cases [18].
the effects of abuse are long-lasting and include Interpreting these findings can be difficult, as
physical and emotional health problems. Cardiac most children are exceedingly physically active
and pulmonary diseases in adulthood have been and will sustain multiple ecchmyoses from rou-
associated with childhood abuse [10, 11]; it is tine play. More than three ecchymoses, larger
thought that prolonged mistreatment of children than 1.0 cm or of varying stages of evolution,
may lead to disruption of brain development and signal possible signs of abuse [7]. Contusions
ultimately lead to dysfunctional immune and ner- and ecchymoses on bony prominences, usual
vous systems [11]. locations for accidental injury, such as the knees,
Skin manifestations of abuse are the most vis- forehead, anterior tibia, are common areas for
ible of all injuries; however other forms of abuse nonviolent trauma in ambulatory children. Areas
including neglect may also beget continuing of the body that are normally protected and not
damage. Emotional effects of maltreatment routinely affected during day-to-day physical
include anxiety, depression, and the inability to play include the posterior and medial thighs,
13 Dermatological Emergencies: Skin Manifestations of Abuse 249
discouraged by most experts in childcare, and

has been associated with poor cognitive devel-
opment in early childhood [19]. Although
spanking is legal, and common, in the United
States, many European countries have outlawed
the practice [19]. Spanking will produce typical
lesions on the skin, with parallel linear purpuric
lesions and a small triangle at the base, corre-
sponding to the interdigital space [7]. Objective
measures have been developed to aid in the
evaluation of ecchymoses. Using the fundamen-
tal pattern of color transformation undergone
with time, bruises can be aged allowing differ-
Fig. 13.1 Classic ecchymosis on flank (reprinted by per-
mission, Dr. Pieter J. Offringa, M.D., Ph.D., Pediatrician entiation between old and new lesions [20]. The
Sint Maarten, Dutch West Indies pjosxm@yahoo.com) timeline for color change, from red to blue/pur-
ple and then green/yellow, can be assessed by
spectrophotometry to quantitatively determine
hands, ears, buttocks, and genitals. The abdomi- age, and thus be used in the investigation of
nal region is also rarely injured by accidental child abuse [20]. The practice of using spectro-
trauma, due to the protective layer of fat, and photometry to analyze and age bruises based on
ecchymoses in this area require a large amount color change over time has not been introduced
of force and may be accompanied by internal into routine clinical practice, but may play a
injury; these children should be examined fully significant role in social cases of child abuse.
and appropriate imaging and workup should be
done to rule out internal organ damage [7]. When
signs of trauma are seen in usually protected 13.5 Burns
areas, the physician should consider them suspi-
cious for abuse and conduct a thorough history Burns are the third most frequent cause of injury
and physical. resulting in death in the pediatric population after
Ecchymoses seen on non-ambulatory or pre- car accidents and drowning [21]. They comprise
ambulatory children should be noted with great about 5–22% of all physical abuse cases, most
concern. Contusions are typically sustained dur- commonly in children younger than 3 years old
ing ambulatory movement by physically active [7]. The typical age of children most likely to
children; young children without mobility and experience burn abuse ranges from 22 to 40
with any soft tissue ecchymoses or signs of months [22]. When gathering the history of
trauma should be regarded as likely abused. This injury, the child’s age and motor skills should be
is in contrast to children who are beginning in noted, and any discrepancy with the child’s phys-
their attempts to walk and may suffer multiple ical limitations and the history should be consid-
ecchymoses, often on their legs and forehead, ered suspicious for abuse.
with their unstable movements [7]. A recent review of 258 injury cases was con-
Examination of each ecchymosis and its ducted to determine distinguishing characteris-
shape may also offer clues as to its etiology; tics between intentional and unintentional injuries
Ropes, belt straps, and buckles leave ecchy- based on best evidence. Maguire et al. determined
moses behind that reflect their form. These that the most common intentional scalds were
specific patterns and shapes are not typically immersion injuries and caused by hot tap water.
seen with accidental trauma and are suspicious, Areas most frequently affected were the extremi-
and often confirmatory, for abuse [7]. Spanking ties, and buttocks (Fig. 13.2) and perineum,
of children less than 2 years old is strongly involved in 40–100% of cases while only involved
Fig. 13.2 Hot water burn on buttock (reprinted by per- Fig. 13.3 Oval-shaped cigarette burn, accidental
mission, Dr. Pieter J. Offringa, M.D., Ph.D., Pediatrician
Sint Maarten, Dutch West Indies pjosxm@yahoo.com)
in less than 15% of accidental scalding cases

[22, 23]. Distinguishing features of these burns
were their symmetry and clear margins; cases
were frequently associated with current or previ-
ous fractures and other injuries [23]. Forced
immersion of a child in hot water will spare the
folds and the resting point of the gluteal region.
This type of abuse creates symmetric and accu-
rate borders with uniform depth, while forced
scalding of hands or feet will lead to “glove” or
“sock” distribution burns. “Zebra stripes” and
“doughnut hole” burns refer to two other presen-
tations of abusive submersion in hot water. Forced
submersion with flexed extremities will spare the
flexural creases and create the striped “zebra”
appearance [22]. Pressing a child’s buttocks down Fig. 13.4 Bullous arthropod bite
along the cooler surface of a container of hot
water spares the center giving the often-seen
“doughnut hole” burn [22]. Intentional burns are and contact dermatitis [25]. Cigarette burns,
usually found in multiplicity, and may be inflicted especially when multiple, in various stages of
by hair curling or straightening irons, stoves, healing, may be easily misdiagnosed as varicella
radiators, and commonly cigarettes. Cigarette or staphylococcal bullous impetigo. The authors
burns, when intentional, are usually seen as mul- have had experience with a case of suspected
tiple, often grouped, circular lesions of uniform child abuse presenting as bullous lesions on the
size, typically 0.5–0.8 cm, with well-defined bor- lower extremities of a young girl (Fig. 13.4). The
ders and a central crater; these lesions typically suspicion that the lesions represented cigarette
regress forming a scar [24]. Accidental cigarette burns led to involvement of child protective ser-
burns are more superficial, and oval in shape vices and the removal of the child from caretak-
(Fig. 13.3), as usually the child is able to quickly ers. This case emphasizes the utility of biopsy,
withdraw from the pain. Misdiagnosis of burns which revealed a perivascular eosinophilic
may occur with common mimickers, such as epi- infiltrate in the superficial and deep dermis, con-
dermolysis bullosa, impetigo, papular urticaria, sistent with bullous arthropod (blistering bug
bites) and undermining any suspicions of abuse. tions and bruising around the genitals, or
We recommend close communication with the scarring. Sexually transmitted disease in chil-
dermatopathologist reading these particularly dren outside the perinatal period is highly suspi-
sensitive cases allowing for more specific com- cious for sexual abuse. Children more than 3
menting on pertinent positives or negatives of tis- years old who are diagnosed with Chlamydia
sue section. If available, these biopsies should be trachomatis, Trichomonas vaginalis, syphilis,
sent for rush evaluation. Neisseria gonorrhoeae, HIV, HPV infections,
The features of intentional burn injury greatly and anogenital warts or HSV should have a thor-
contrast with those of unintentional injury, such ough investigation to rule out abuse as these
as hot liquid spills, which are more likely to affect findings are strongly diagnostic. It must be noted
the head, neck, and anterior trunk, and have irreg- that Chlamydia trachomatis infection when
ular margins and varied depth [23]. Any findings acquired perinatally may be seen until the sec-
indicating abuse should be documented, with ond or third year of life [29].
notation of location, size, and color, and a photo- Genital warts are most commonly diagnosed
graph taken as an objective record. It is also rec- by dermatologists, and children beyond the peri-
ommended that a skeletal survey be performed natal period with these findings should be evalu-
due to the frequent association with additional ated carefully. Genital warts have been reported
injuries in 20–33% of cases [2, 26, 27]. in children with a history of sexual abuse, but it
can also be seen in children without abuse, much
like bacterial vaginosis, and is not sufficient to
13.6 Sexual Abuse prove sexual abuse [30, 31]; vertical transmission
should be excluded. The verification of sexually
Sexual abuse is defined as any sexual activity transmitted genital warts is made more difficult
with a child below the age of legal consent. by the long latency period before clinical presen-
Sexual activity may be vaginal, oral, rectal, and tation. Specific serotypes of HPV, including
viewing or fondling of any sexual anatomy. The HPV-2 and HPV-3, are typically associated with
sheer volume of children being sexual abused, cutaneous warts, but have also been reported to
currently about 1% of all children yearly, makes cause anogenital HPV lesions in children as well
this diagnosis one that the physician should [32]. Both inappropriate contact via sexual abuse
always remain especially vigilant, as it has and innocuous transmission through casual con-
reached epidemic proportions. According to tact may present similarly as genital warts.
community surveys, prevalence of sexual abuse Currently, detection of HPV DNA is not standard
in children ranges from 6 to 62% and 3 to 16% in practice; HPV is diagnosed through clinical
girls and boys, respectively. It appears that cases identification or through biopsy of lesions.
of child abuse affect girls nearly 2.5 times more Physicians must be cautious with their accusa-
often than boys [28]. tions of abuse. Multiple normal congenital varia-
The most common offender of sexual abuse tions may mimic the findings of abuse. Before
includes nonrelatives who are known to the child declarations of abuse are made against caretak-
and family members [28]. The physician must try ers, variations and conditions including periure-
to illicit a thorough history from the child in thral bands, perineal grooves, lichen sclerosus et
question. The victim is frequently truthful, and atrophicus, lichen planus, Beçhet’s disease, peri-
the confirmatory history by the child is com- anal streptococcal dermatitis, and Kawasaki syn-
monly the gold standard in cases of abuse. drome, among others, should be ruled out.
Unfortunately, there are rarely dermatologic Additional situational findings such as foreign
findings in sexual abuse. body masturbation may also be mistaken for
The physical examination for a sexually abuse. A child who is confirmed to have one sex-
abuse child includes signs of penetrating ano- ually transmitted disease should undergo testing
genital trauma such as hymenal injury, lacera- to look for additional diseases.
insufficiency may lead to fractures, the most com-

13.7 Additional Signs of Abuse mon cause of multiple fractures in young children
is nonaccidental trauma [34]. A child with multi-
The oral cavity is an often overlooked aspect of ple fractures simultaneously, or one that is brought
the physical exam, but can identify many signs of to the emergency room repeatedly for separate
abuse. Forced oral sex may cause petechiae or events of bone trauma, highly suggests abuse.
hematomas on the palate, specifically on the area Bites illustrate another method of physical
of transition between the soft and hard palate. injury, but are unique in that they can be objec-
Signs of bruising, abrasions, or lip and lingual tively used to identify the abuser. Typical human
frenulum fissures can also be visualized in the bite marks are 2–5 cm oval, semicircular or oval
mouth following aggressive forced feedings or marks, occasionally with ecchymoses or with
forced oral sexual abuse. Clinical oral manifesta- punctures caused by the canines; an intercanine
tions of HPV infection may also indicate signs of distance less than 3.0 cm suggests a bite likely
sexual abuse, but are difficult to support objec- caused by a child, rather than an adult [35].
tively. Condyloma acuminatum may be seen in Unlike animal bites that usually tear flesh, human
the oral cavity, but HPV has also been correlated bites are more likely to compress flesh and may
with other oral conditions, such as lichen planus, be a source of disease transmission, mainly hepa-
verrucous carcinoma, and pemphigus vulgaris. titis [35]. Dental characteristics, or salivary DNA,
Oral HPV infection in healthy children has a prev- may ultimately expose the abuser and have been
alence varying from 12.3 to 48.1% [33]. Due to used in court cases to match perpetrators to bite
the varying routes of transmission of HPV, the marks on victims [36]. Forensic dentists may
role of subtyping has not yet been clarified. Sexual swab lesions for collection of DNA material, or
intercourse or direct contact with infected mucosa make molds of the dental arch, and the physician
and skin is the predominant route of infection; should take accurate photographs of any sus-
however perinatal transmission, breast milk, auto- pected bites for documentation [35].
inoculation, or heteroinoculation also remain Traumatic or violent hair pulling, ultimately
other possible routes [33]. Further signs of child presenting as alopecia, petechiae, or hematomas of
abuse include tooth loss or fractures in the mouth. the scalp, may be an additional sign of child abuse.
These signs may indicate not only physical abuse The child will show signs of tenderness on palpa-
but also abuse in the form of dental neglect. tion of affected areas of scalp. An extensive subgal-
Neglect, usually chronic in nature, is defined by eal hematoma was documented to occur following
the failure of the caretaker to provide a child’s severe sheer stress from forceful hair pulling of a
basic needs and provisions, including nutritional young child; this phenomenon is referred to as
needs, clothing, education, or healthcare. Chronic “scalping” due to the distinctive radiologic findings
neglect may manifest dermatologically as scabies, [37]. Much like trichotillomania or traction alope-
pediculosis, or vitamin deficiencies. cia, violent hair pulling of the scalp will show
Hypovitaminosis A is seen most often in children localized areas of hair loss with an irregular margin
aged 1–6 years; the role of vitamin A in maintain- or outline; loose anagen syndrome, tinea capitis,
ing epithelial integrity leads to many dermatologic and alopecia areata should be ruled out [7]. Tinea
signs of its deficiency. Children with hypovita- capitis, or kerion, when active or resolving, may
minosis A may present with generalized xerosis present as uneven and patchy hair loss (Fig. 13.5).
(dryness), often with scaling or fine wrinkling of
the skin. Follicular hyperkeratosis, or phryno-
derma, may be seen on thighs, arms, or bony 13.8 Mistaken for Abuse
prominences of the knees and elbows. Unlike
other vitamin insufficiencies, vitamin D deficiency Many clinical findings may mimic those of abuse,
was not shown to be associated with the diagnosis and these must be identified and distinguished
of child abuse [34]. Although vitamin D early by physicians to prevent erroneously
and males and may mimic sexual abuse. Typically

it presents as white papules, coalescing into
plaques, with epidermal atrophy. Comedo-like
plugs may be seen under dermoscopy which cor-
respond to obliterated appendigeal ostia or folli-
cular plugging, a feature also seen with discoid
lupus or chronic cutaneous lupus [38]. Vulvar
lichen sclerosus may cause symptoms of pruritus,
dysuria, and even bleeding; penile lesions may
present as new phimosis or urinary obstruction.
Characteristic of lichen sclerosus is the figure-8
pattern, or butterfly lesions, typically on the
perivaginal or perianal region, with sparing of the
perineum between. Lesions found in the genital
region may occasionally vesiculate secondary to
excessive levels of inflammation, making trauma
a consideration for the examining physician. The
lesions of lichen sclerosus evolve into smooth,
shiny white plaques, and although they can
resemble lesions of trauma or sexual abuse if
found on the anogenital, or vulvar, region, the
Fig. 13.5 Resolving kerion from tinea capitis physician must consider alternate conditions and
evaluate the patient closely. Lichen sclerosus may
accusing caretakers and exposing them to unnec- ultimately lead to obliteration and stenosis of the
essary turmoil and possible prosecution. Several introitus, and represents an additional dermato-
conditions ranging from congenital abnormali- logic emergency, requiring correct identification
ties to various cultural practices may present as to prevent grave, irreversible results. Skin biopsy,
clinical findings that are also similarly seen in specifically punch or snip section, remains an
cases of abuse. additional tool for diagnosing equivocal cases of
Dermatologists often encounter mimickers of lichen sclerosus. The longest-standing lesion
abuse, and can more readily identify these should be biopsied and evaluated by a
findings with accuracy. For physicians who only dermatopathologist.
occasionally manage these somewhat rare der- Congenital dermal melanocytosis, also
matologic findings, the similarities between these referred to as Mongolian spots, are blue-gray
conditions and those findings of abuse may lead patches or macules seen on the lumbosacral or
to incorrect conclusions. buttock area of infants, often observed at birth or
Anal fissures may result from forced sexual within the first few weeks of life. Occasionally
abuse and, when seen in a child with significant these lesions can be found in the perineal area
behavior changes of sexualized behaviors, may and, if multiple, may be mistaken for bruises or a
raise concerns for sexual abuse. More commonly, sign of sexual abuse [39, 40]. The authors have
however, the child will confirm a history of con- also seen these blue-gray pigmented lesions on
stipation, or large bowl movements or hard stool, the face, one mimicking bruising around the eye
a more likely source of anal fissuring. Findings of an infant (Fig. 13.6). Features that help differ-
more specific for abuse include anal bruising, entiate these benign lesions from those of abuse
abrasions, and a history elicited by the child indi- include the classical fixed homogeneous blue-
cating sexual abuse. gray color, unlike the variable spectrum of colors
Lichen sclerosus is a chronic inflammatory experienced by bruising and ecchymoses. These
dermatosis that can present on young females melanocytic lesions typically appear at birth, or
children that can be misdiagnosed and misinter-

preted as a sign of child abuse. It can be recog-
nized as a well-demarcated brightly erythematous
patch on perianal skin, and is caused by group
A-beta hemolytic streptococci (Fig. 13.5).
Children between the ages of 6 months and 10
years are commonly affected [42]. The affected
child often complains of pain, pruritus, and may
experience blood-streaked stool.
The literature contains multiple cases of sus-
pected child abuse ultimately diagnosed as peria-
nal streptococcal dermatitis, with a specific case
involving skin beyond the perianal area and
affecting penile skin [43, 44]. The condition may
also involve vulvar skin, and the physician should
be reminded of this disorder when examining
Fig. 13.6 Dermal melanocytosis (blue pigmentation)
children with pain and erythema in the genital
area which may be suspicious of sexual abuse
[45].
Diagnosis is easily and quickly confirmed
with a rapid streptococcal test, and a skin culture
can be sent for alternative affirmation. Amoxicillin
or penicillin remains first-line treatment.
The pediatric population is subject to many
cultural practices not well understood by western
physicians. Without knowledge of many of these
practices, the impulse to misdiagnose the cutane-
ous findings as those of abuse may be great, but
physicians should be culturally aware and sensi-
tive to these traditions.
The practice of “cupping” has been performed
by a variety of cultures, including Middle-
Eastern, Egyptian, Chinese, Greek, and European,
and these practices are slowly gaining popularity
in western culture [46]. Used for the treatment of
Fig. 13.7 Congenital nevus various medical conditions, including polymyal-
gia rheumatica [46], cups of various shapes and
within the first few weeks of life, and resolve by sizes are placed on the skin and suction is created
the fourth year of life, although occasionally will using low air pressure through heating of the cup
persist, more commonly in lesions found distal to or the air inside it. Lancing of the cup may allow
the lumbosacral region. Histologic analysis of the vacuum to draw blood into the cup, a practice
these lesions will show spindle-shaped melano- known as “wet cupping.” Clinically, circular ery-
cytes at the lower levels of the dermis [41]. Nevi, thema, ecchymoses, or hemorrhagic bullae may
or birthmarks, may come in all shapes and sizes be seen, commonly on the back, shoulders, or
(Fig. 13.7), but their even pigmentation and his- thorax. Frequently, these lesions are erroneously
tory of long-standing presence make the diagno- thought to be due signs of abuse leading to regret-
sis straightforward. Perianal streptococcal table social and legal consequences for the family
dermatitis represents another condition seen in involved [47–49].
Coin rubbing, also known as spooning or fric- emergency and taking necessary action. There is
tion stroking, is a cultural practice seen in Chinese a moral, ethical, and legal obligation to report any
and Vietnamese cultures, and other Southeast strong suspicion or confirmation of child abuse to
Asian countries such as Cambodia and Laos [50]. child protective services or to make a referral to a
A smooth-edged surface, such as the back of a child advocacy center. All healthcare workers
coin, is placed against lubricated or pre-oiled skin should be able to identify signs of abuse with the
and pressed deep while being dragged down the level of confidence required to potentially set into
muscles along acupuncture meridians [50]; a action the removal of a child from its family. Any
symmetric, linear, “Christmas-tree” pattern on tests, imaging, or biopsies that may help in iden-
the back made up of linear ecchymotic or pete- tifying lesions of abuse, or to rule out their pres-
chial streaks is commonly seen [50, 51]. ence, should be ordered and done quickly with
Children who are subjected to practices based results expedited.
on cultural beliefs may be reluctant to discuss The diagnosis of child abuse is a weighty one
these traditions with their healthcare providers. with severe and enduring consequences. With
Embarrassment over cultural differences or shame confirmation of abuse, and a systematic exclu-
in un-American practices may prevent full-disclo- sion of any potential mimickers or dermatologic
sure when these lesions are noticed by the practi- conditions, child protective services and the facil-
tioner. Physicians should remain sensitive to ethnic ity social worker should be alerted.
differences and consider these customs and cul- A missed diagnosis of child abuse may result in
tural rituals when confronted with unusual cutane- death of the child or continued violence and cruelty
ous lesions suspicious for abuse, and yet are not against the child. Scientific literature shows the sta-
considered harmful to the children affected. tistically increased probability of behavioral, cog-
When evaluating a patient for elder abuse, the nitive, and psychological disorders that emerge in
same signs and findings as those with child abuse adulthood of those abused in childhood, including
may be applied. Delay in seeking treatment, inju- depression, suicide, and addiction [52]; these and
ries in various stages of evolution, or injuries other consequences can be minimized or avoided
inconsistent with history are findings and obser- with a vigilant and conscientious physician, alert to
vations strongly suspicious for abuse. Often signs signs of abuse. However, the physician must always
of neglect, such as malnutrition, poor hygiene, or bear in mind that an erroneous charge of child
decubitus ulcers, are seen, and as most thorough abuse may cause undue anguish and distress and
exams require, the patient should be fully dis- possible loss of reputation to the individual charged
robed and evaluated in entirety. Although much with simultaneous legal ramifications, and ulti-
of elder abuse lies beyond the scope of this chap- mately may lead to unnecessary separation of a
ter, the ubiquitous finding of multipharmacy in child from its home and family.
the geriatric population makes overdosing or
underdosing of their medication another form of
References
abuse.
1. Lyden C. Caring of the victim of child abuse in the
pedriatric intensive care unit. Dimens Crit Care Nurs.
13.9 Conclusion 2009;28:61–6.
2. Purde GF, Hunt JL, Prescott PR. Child abuse by burn-
ing: an index of suspicion. J Trauma. 1988;28:221–4.
Dermatologic emergencies are few in number, 3. Nong The Anh. ‘Pseudo-battered child’ syndrome.
but represent significant clinical scenarios that JAMA 1976;236:2288.
require prompt attention and response by 4. Peddle N, Wang C, Diaz J, Reid R. Current trends in
dermatologists and all health professionals. The child abuse reporting and fatalities: The results of the
2000 annual fifty state survey. Chicago: National
high frequency and incidence of child abuse Committee to Prevent Child Abuse; 2002.
worldwide necessitate a level of suspicion by 5. Herman-Giddens ME, Brown G, Verbiest S, Carlson
physicians in identifying this true dermatologic PJ, Hooten EG, Howell E, Butts JD. Underascertainment
of child abuse mortality in the United States. JAMA. intentional scalds in children. Burns. 2008;34(8):1072–
1999;282(5):463–7. 81. Epub 2008 Jun 6.
6. Feldman W, Feldman E, Goodman JT, McGrath PJ, 24. Shavit I, Knaani-Levinz H. Images in emergency
Pless RP, Corsini L, Bennett S. Is childhood sexual medicine. Child abuse caused by cigarette burns. Ann
abuse really increasing in prevalence? An analysis of Emerg Med. 2008;51(5):579. 582.
the evidence. Pediatrics. 1991;88(1):29–33. 25. Hobbs CJ. ABC of child abuse. Burns and scalds.
7. Gondim RM, Muñoz DR, Petri V. Child abuse: skin BMJ. 1989;298(6683):1302–5.
markers and differential diagnosis. An Bras Dermatol. 26. Yeoh C, Nixon JW, Dickson W, Kemp A, Sibert JR.
2011;86(3):527–36. Patterns of scald injuries. Arch Dis Child. 1994;71:
8. Hanson RF, Resnick HS, Saunders BE, Kilpatrick DG, 186–8.
Best C. Factors related to the reporting of childhood 27. Renz BM, Sherman R. Abusive scald burns in infants
sexual assault. Child Abuse Negl. 1999;23:559–69. and children: a prospective study. Am Surg. 1993;59:
9. Hopper J. Child sexual abuse: statistics, research. 329–34.
Boston, MA: Boston University School of Medicine 28. Ermertcan AT, Ertan P. Skin manifestations of child
Resources; 1998. abuse. Indian J Dermatol Venereol Leprol. 2010;76(4):
10. Lanier P, Jonson-Reid M, Stahlschmidt MJ, Drake B, 317–26.
Constantino J. Child maltreatment and pediatric 29. Bell TA, Stamm WE, Wang SP, Holmes KK, Grayston
health outcomes: a longitudinal study of low-income JT. Chronic Chlamydia trachomatis infections in
children. J Pediatr Psychol. 2010;35(5):511–22. Epub infants. JAMA. 1992;267:400–2.
2009 Oct 1. 30. Hammerschlag MR, Cummings M, Doraiswamy B,
11. Goodwin RD, Stein MB. Association between child- Cox P, McCormack WM. Nonspecific vaginitis fol-
hood trauma and physical disorders among adults in lowing sexual abuse in children. Pediatrics. 1985;75:
the United States. Psychol Med. 2004;34(3):509–20. 1028–31.
12. Kearney CA, Wechsler A, Kaur H, Lemos-Miller A. 31. Marcoux D, Nadeau K, McCuaig C, Powell J,
Posttraumatic stress disorder in maltreated youth: a Oligny LL. Pediatric anogenital warts: a 7-year
review of contemporary research and thought. Clin review of children admitted to a tertiary-care hospi-
Child Fam Psychol Rev. 2010;13:46–76. tal in Montreal. Can Pediatr Dermatol. 2006;23:
13. Kos L, Shwayder T. Cutaneous manifestations of 199–207.
child abuse. Pediatr Dermatol. 2006;23:311–20. 32. Handley J, Hanks E, Armstrong K, Bingham A,
14. Hettler J, Greenes DS. Can the initial history predict Dinsmore W, Swann A, Evans MF, McGee JO,
whether a child with a head injury has been abused? O’Leary J. Common association of HPV 2 with ano-
Pediatrics. 2003;111:602–7. genital warts in prepubertal children. Pediatr Dermatol.
15. Swerdlin A, Berkowitz C, Craft N. Cutaneous signs of 1997;14:339–43.
child abuse. J Am Acad Dermatol. 2007;57:371–92. 33. Pinheiro Rdos S, de França TR, Ferreira Dde C, Ribeiro
16. Chadwick DL. The diagnosis of inflicted injury in infants CM, Leão JC, Castro GF. Human papillomavirus in the
and young children. Del Med J. 1997;69:345–54. oral cavity of children. J Oral Pathol Med. 2011;40(2):121–6.
17. van Rijn RR, Sieswerda-Hoogendoorn T. Educational doi:10.1111/j.1600-0714.2010.00954.x. Epub 2010
paper: imaging child abuse: the bare bones. Eur J Oct 24.
Pediatr. 2012;172(2):215–24 [Epub ahead of print]. 34. Schilling S, Wood JN, Levine MA, Langdon D,
18. Hobbs CJ, Hanks HGI, Wynne JM. Child abuse and Christian CW. Vitamin D status in abused and nona-
neglect: a clinician’s handbook. 2nd ed. London: bused children younger than 2 years old with frac-
Churchill Livingstone; 1999. tures. Pediatrics. 2011;127(5):835–41. Epub 2011
19. Zolotor AJ, Robinson TW, Runyan DK, Barr RG, Apr 11.
Murphy RA. The emergence of spanking among a 35. Kemp A, Maguire SA, Sibert J, Frost R, Adams C,
representative sample of children under 2 years of age Mann M. Can we identify abusive bites on children?
in North Carolina. Front Psychiatry. 2011;2:36. Epub Arch Dis Child. 2006;91(11):951.
2011 Jun 24. 36. Bernitz H, Owen JH, van Heerden WF, Solheim T. An
20. Mimasaka S, Ohtani M, Kuroda N, Tsunenari S. integrated technique for the analysis of skin bite
Spectrophotometric evaluation of the age of bruises in marks. J Forensic Sci. 2008;53(1):194–8.
children: measuring changes in bruise color as an 37. Seifert D, Püschel K. Subgaleal hematoma in child
indicator of child physical abuse. J Exp Med. abuse. Forensic Sci Int. 2006;157(2–3):131–3. Epub
2010;220(2):171–5. 2005 Sep 26.
21. Toon MH, Maybauer DM, Arceneaux LL, Fraser JF, 38. Isaac R, Lyn M, Triggs N. Lichen sclerosus in the dif-
Meyer W, Runge A, Maybauer MO. Children with ferential diagnosis of suspected child abuse cases.
burn injuries-assessment of trauma, neglect, violence Pediatr Emerg Care. 2007;23(7):482–5.
and abuse. J Inj Violence Res. 2011;3(2):98–110. 39. AlJasser M, Al-Khenaizan S. Cutaneous mimickers of
22. Stratman E, Melski J. Scald abuse. Arch Dermatol. child abuse: a primer for pediatricians. Eur J Pediatr.
2002;138(3):318–20. 2008;167(11):1221–30. Epub 2008 Jul 26.
23. Maguire S, Moynihan S, Mann M, Potokar T, Kemp 40. Oates RK. Overturning the diagnosis of child abuse.
AM. A systematic review of the features that indicate Arch Dis Child. 1984;59(7):665–6.
41. Leung AK, Robson WL. Superimposed Mongolian therapeutic purposes. Actas Dermosifiliogr. 2006;
spots. Pediatr Dermatol. 2008;25(2):233–5. 97(3):212–4.
42. Barzilai A, Choen HA. Isolation of group A strepto- 47. Asnes RS, Wisotsky DH. Cupping lesions simulating
cocci from children with perianal cellulitis and from child abuse. J Pediatr. 1981;99(2):267–8.
their siblings. Pediatr Infect Dis J. 1998;17:358–60. 48. Look KM, Look RM. Skin scraping, cupping, and
43. Duhra P, Ilchyshyn A. Perianal streptococcal cellulitis moxibustion that may mimic physical abuse. J
with penile involvement. Br J Dermatol. Forensic Sci. 1997;42(1):103–5. Review.
1990;123(6):793–6. 49. Wong HC, Wong JK, Wong NY. Signs of physical
44. Byard RW, Donald TG, Rutty GN. Non-traumatic abuse or evidence of moxibustion, cupping or coin-
causes of perianal hemorrhage and excoriation in the ing? CMAJ. 1999;160(6):785–6.
young. Forensic Sci Med Pathol. 2008;4(3):159–63. 50. Ravanfar P, Dinulos JG. Curr Opin Pediatr. Cultural
Epub 2008 Jan 9. practices affecting the skin of children. 2010;22(4):
45. Berth-Jones J, Graham-Brown RA, Burns DA. Lichen 423–31. Review.
sclerosus et atrophicus—a review of 15 cases in young 51. Morris R, Usatine R. An unusual pattern of bruising.
girls. Clin Exp Dermatol. 1991;16(1):14–7. West J Med. 2000;172(5):298.
46. Mataix J, Belinchón I, Bañuls J, Pastor N, Betlloch I. 52. Dumaret AC, Tursz A. Long-term consequences of
Skin lesions from the application of suction cups for child abuse and neglect. Rev Prat. 2011;61(5):663–6.
Dermatologic Surgery
Complications 14
Amylynne J. Frankel and Ellen S. Marmur
tions should be approached with well-rounded

14.1 Introduction knowledge and managed accordingly. This chap-
ter presents several of the most common surgical
Dermatologic surgery is often performed in an considerations for safe surgery and prevention
outpatient surgical suite with local anesthesia, and management of emergencies in dermatologic
and moderate to advanced dermatologic proce- surgery.
dures may be done without monitoring vital
signs. A sound knowledge of the common der-
matologic surgery complications is essential to a 14.2 The Golden Rule: Prevention
safe surgical practice. For example, identifying
at-risk patients is key to preventing avoidable The main approach in reducing complications is
complications. Complications are to be expected prevention. Prevention of complications requires
in high volume practices. However, complica- an excellent informed consent which consists of
1. A clear definition of the procedure
2. A discussion of the key alternative therapeutic
A.J. Frankel, M.D. options
Department of Dermatology, Mt. Sinai School of Medicine, 3. Education regarding the normal recovery time
New York, NY, USA
for different procedures
Mount Sinai Medical Center, 5 East 98th Street, 4. Education regarding the common and rare,
Box 1048, New York, NY 10029, USA
major and minor side effects
e-mail: AFrankelmd@gmail.com
Before any procedure in dermatologic surgery is
E.S. Marmur, M.D. (*)
performed, knowing how to treat the possible
Mount Sinai Medical Center, 5 East 98th Street,
Box 1048, New York, NY 10029, USA side effects is essential. An experienced dermato-
logic surgeon will take a moment to imagine the
Department of Dermatology, The Mount Sinai Medical
Center, New York, NY, USA procedure from start to finish, including manage-
ment of any and all potential side effects before
Department of Genetics and Genomic Research,
The Mount Sinai Medical Center, New York, NY, USA actually starting the procedure. In this way, many
side effects can be prevented. For example, if the
Cosmetic & Surgical Dermatology, The Mount Sinai
Medical Center, New York, NY, USA patient is known to be on anticoagulation therapy
and the possibility of a hematoma is anticipated,
Procedural Dermatology, The Mount Sinai Medical Center,
New York, NY, USA the intra-operative management of coagulation
will be more conservative.
Cosmetic Dermatology, The Mount Sinai Medical Center,
New York, NY, USA Finally, management of unforeseeable com-
e-mail: EMarmur@gmail.com; ellen.marmur@mssm.edu plications in dermatologic surgery also requires

260 A.J. Frankel and E.S. Marmur
sensitivity regarding patients’ expectations and beyond the area of a hematoma, as in dependent
emotions. For example, bruising, which is an areas or areas inferior to a surgical site, such as a
accepted side effect in many procedures, is stress- wound on a cheek with an ecchymosis that
ful for patients. Dermatologic surgeons should be extends around the jaw and submentally, or a
readily available for follow-up appointments if wound on the forehead with periorbital bruising.
only to offer reassurance while minor side effects Ecchymoses resolve after 5–14 days depending
and complications are resolving. When major on the location. In contrast, a hematoma resolves
side effects occur, the ability to discuss the poten- much more slowly and often confers an increased
tial cause and the management plan with the risk of infection. The most common factor lead-
patient, while accepting appropriate responsibil- ing to hematomas in patients presenting for der-
ity for that complication, is essential for success- matologic surgery is concurrent anticoagulation
ful management of dermatologic surgical therapy. Of the many types of anticoagulants, it is
complications. often aspirin, ibuprofen, or clopidogrel that con-
Four of the most common complications in tribute to increased risk of hemorrhage more than
dermatologic surgery include hemorrhage, infec- warfarin.
tion, dehiscence, and necrosis of the skin. Each Assessing potential bleeding risk includes a
of these will be discussed below. thorough history of significant bleeding during
prior low-risk surgical or dental procedures, com-
mon medical problems such as hypertension,
14.3 Hemorrhage alcoholism, and anxiety, and known medical con-
ditions that contribute to abnormal coagulation,
Even the most skilled surgeon will encounter such as liver disease, renal dysfunction, and
bleeding at some point in his or her practice. To malignancies [2]. Finally, it is imperative to
minimize the clinical sequelae of excessive bleed- obtain a medication history that includes medica-
ing, the astute surgeon anticipates the potential tions the patient takes both daily and as needed,
difficulties and recognizes and manages prob- as well as the last date the patient may have taken
lems as they arise. However, much of the battle is each of these medications. Several common over
to be won off of the operating table with a thor- the counter medications may have anticoagula-
ough preoperative assessment, familiarization tion effects, including Alka-Seltzer, which con-
with current guidelines for withholding blood tains aspirin, and Advil Cold and Sinus, which
thinners, knowledge of management of delayed contains ibuprofen. Gingko biloba, garlic, gin-
bleeding, and excellent pressure bandaging for seng, ginger, feverfew, vitamin E, and saw pal-
the postoperative period of time [1]. metto have all been implicated in increased
Beyond excessive bleeding intra-operatively, operative and postoperative bleeding. Many stud-
postoperative bleeding can be both distressing for ies suggest waiting 3 days after the last dose of
the patient and have the potential for hematoma aspirin to reduce the risk of bleeding. However,
formation. A hematoma is a localized collection the life span of a platelet is 12 days, the half life
of blood outside of the blood vessel, usually in is 6 days, and one baby aspirin (81 mg) effects all
liquid form in the tissue. It appears as a deep pur- of the platelets in circulation. Therefore, 1 week
ple, grape jelly-like nodule in or adjacent to the is the ideal time to request patients avoid non-
area of surgery. One common area for a hema- medically necessary supplements or anticoagu-
toma is the infraorbital space occurring after sur- lants. Excessive bleeding secondary to acquired
gery near or trauma to the infraorbital vessels. abnormalities in coagulation or platelet function
Another is the leg where superficial vessels may from medications or ingested substances is sur-
bleed or clot. A hematoma differs from an ecchy- prisingly common (Table 14.1). For example,
mosis, or a bruise, which is due to the spread of alcohol decreases vasoconstriction and impairs
blood under the skin—usually throughout the coagulation of platelets. Furthermore, various
fat—in a thin layer. An ecchymosis may extend dietary supplements and alternative medicines
14 Dermatologic Surgery Complications 261
Table 14.1 Common anticoagulants of complications and is not statistically increased

Warfarin Dabigatran Crataegues oxyacantha compared with patients in whom the same medi-
(Hawthorne) cations are discontinued [7–9].
Heparin Aspirin Ethanol Despite the current literature, the decision
Clopidogrel High salicylate Gingko biloba about whether to discontinue anticoagulation
containing foodsa
remains, and one must consider the real and
Ticlodopine Omega-3 fatty Garlic
acids
increased risk of bleeding and hemorrhage with
Enoxaparin Vitamin E Ginger the lower but potentially life-threatening risk of a
a thrombotic event should an anticoagulant be tem-
Ex prunes, cherries, cranberries, blueberries, grapes, and
strawberries porarily discontinued [10–13]. For instance, the
risk of a thrombotic event from discontinuing
anti-thrombotic medications may outweigh the
Table 14.2 Current recommendations regarding discon- risks of intra-operative bleeding [11]. Kirkorian
tinuing and resumption of oral medicines and supplements et al. surveyed current practice regarding periop-
to prevent complications due to bleedinga erative management of anticoagulant therapy
Medicine/herbal Preoperative Postop among dermatologic surgeons finding 87% dis-
Vitamin supplement/herbal 10–14 days 1 week continue prophylactic aspirin therapy, 37% dis-
medications continue medically necessary aspirin, 44%
NSAIDs 3 days 1 week discontinue warfarin, 77% discontinue NSAIDs,
Aspirin (primary preventative) 10–14 days 1 week and 77% discontinue vitamin E therapy perioper-
Warfarin/aspirin (medically Do not N/A
atively at least some of the time. Although clopi-
necessary) discontinue
Clopidogrelb Do not N/A
dogrel was not surveyed in this article, 78
discontinue physicians included comments about the manage-
a
Semin Cutan Med Surg 26:40–46 © 2007 ment of this agent [14]. Bordeaux et al. concluded
b
Further studies regarding this medication and complica- that warfarin or clopidogrel increased bleeding
tions are necessary risk, but these medications should be continued to
avoid adverse thrombotic events [2, 15].
have the potential to alter the coagulation cascade Should there be excessive bleeding during sur-
and should therefore also be taken in to account gery, the use of proper bandages after surgery
when obtaining a medication history [3]. will help prevent hematoma formation. In our
The decision to discontinue nonsteroidal anti- practice we use condensed cotton dental roles
inflammatory medicines (NSAIDs) is important under 4 × 4 gauze followed by Hypafix™ paper
(Table 14.2). Many take NSAIDs for nonmedical tape which has an elastic property to create a
but necessary reasons such as comfort. However, pressure dressing that remains on the site for 24 h
a significant proportion take NSAIDs or other following Mohs or excisional surgery. In addi-
anticoagulant/antiplatelet medications for medi- tion, we recommend that those on anticoagulant
cally necessary reasons such as prevention of car- medications or who present with excessive bleed-
diac and/or cerebrovascular events, making the ing during surgery employ ice packs for 20 min
decision to discontinue such medications moot. every hour for the first 6 h. Patients are given a
Studies comparing hemorrhagic complications detailed, written handout with instructions on
have generally not shown an increased risk of how to manage excessive bleeding including
severe hemorrhagic complications in patients on application of ice and pressure for 20 min con-
anticoagulants versus those who are not [2, 4–6]. tinuously without removing the pressure to exam-
This topic has been debated in the dermatologic ine the area. Patients are advised to call or return
surgery literature, specifically regarding warfa- to the office promptly if they have concerns such
rin, aspirin, and NSAID use, and there is a gen- as a warm, expanding and possibly painful mass,
eral consensus that continuation of these or especially if involving the periorbital or cervi-
anticoagulants is associated with a very low risk cal spine areas.
Fig. 14.1 Proper

placement of a patient for
surgery
Fig. 14.2 Proper

surgery
The primary method to treat an expanding Clinical Pearl: To prevent a hematoma

hematoma is (1) partial or complete opening of intra-operatively, take time to implement
the surgical wound, (2) identifying the culprit proper positioning of the patient, the surgeon,
vessels and stopping bleeding by suture ligation and the instrument tray. Something as simple
or electrosurgery, (3) and either a full-layer re- as proper positioning may yield a better field
closure of the wound or allowing the wound to for the dermatologic surgeon to visualize the
heal by secondary intention [2]. The latter is con- source of bleeding, and ensure effective peri-
sidered if there is a high risk of more bleeding or operative hemostasis (Figs. 14.1, 14.2, 14.3,
the wound is contaminated. and 14.4).
Fig. 14.3 Improper

surgery, forcing the
surgeon into a less than
optimal position given the
location of the surgery on
the patient
Fig. 14.4 Improper

surgery, forcing the
surgeon into a less than
optimal position given the
location of the surgery on
the patient
therapy and close follow-up care are adequate.

14.4 Infection However, if the wound is fluctuant, if there is
purulent exudate or inflammatory edema, or if
Surgical site infections (SSIs) after dermato- systemic symptoms are present, the wound
logic surgery cause pain, prolong healing, may must be opened, lavaged with sterile sodium
result in altered cosmesis, and lead to excessive chloride solution and packed with iodoform
use of antibiotics [16]. Signs and symptoms of gauze. Cultures and gram stains should be per-
wound infection usually present 4–6 days post- formed, and broad-spectrum antibiotics should
operatively with erythema, pain, warmth, and be instituted while awaiting results. Patients
swelling at the wound site. If cellulitis and fever should be closely monitored to evaluate clinical
are present, prompt institution of oral antibiotic response.
Table 14.3 AHA guidelines for preventative antibiotics gastrointestinal and genitourinary tracts. For legs
prior to certain dental procedures with granulating wounds, common causes of
Artificial heart valves postoperative infections are from E. coli from
History of infective endocarditis above. For this reason, this author instructs all
Cardiac transplant with known heart valve problem patients to use Hibiclens surgical scrub from the
Congenital heart conditions: groin down. Pseudomonas species are a common
• Unrepaired or incompletely repaired cyanotic
congenital heart disease, including those with
pathogen of the external ear. If the patient has
palliative shunts and conduits chondritis of the ears postoperatively, it may not
• A completely repaired congenital heart defect with be a true infection. However, patients are often
prosthetic material or device during the first 6 put on ciprofloxin 500 mg by mouth twice a day
months after the procedure
• Any repaired congenital heart defect with residual
for 7 days to cover for Pseudomonas. Additionally,
defect at the site or adjacent to the site of a any time a patient has a laser procedure, photody-
prosthetic patch or a prosthetic device namic therapy or surgical procedure around the
lips, it is important to get a full history of herpes
infections—ask about fever blisters—and insti-
Despite the potential for SSI, antimicrobial tute prophylaxis with acyclovir or a related medi-
prophylaxis is rarely appropriate for dermato- cation. This author uses Famvir 500 mg by mouth
logic surgery. Reported infection rates for Mohs twice daily for 3 days for anyone with a history of
micrographic surgery (MMS) range from less HSV, or for anyone receiving ablative procedures
than 0.7–3.5% and occur most frequently on such as CO2 laser resurfacing.
the legs [17, 18]. Dermatologic procedures sel- As mentioned in Table 14.2, dermatologic sur-
dom cause bacteremia, and they have been gery is not considered in the AHA guidelines for
implicated in only an extremely small fraction endocarditis prophylaxis [22]. In one review, the
of cases of endocarditis or infections of vascu- authors did not recommend routine prophylaxis
lar grafts or orthopedic prostheses. According for high-risk patients undergoing procedures of
to the newest guidelines, systemic prophylactic less than 20 min duration on intact skin
antibiotics are rarely indicated in patients (Table 14.3). Patients at high risk for endocarditis
undergoing dermatologic surgery, even those should receive prophylaxis in cases where there
who would otherwise require prophylaxis for is infected skin, breach of oral mucosa, or nonin-
dental procedures (Table 14.3). Because wound fected site at high risk for SSI [23]. This prophy-
infections following dermatologic surgery are laxis should be administered 30–60 min prior to
uncommon, usually mild, and generally easily performing the procedure to allow the antibiotic
treatable, systemic antimicrobial prophylaxis is to be present in the blood at the time of the initial
not indicated to prevent postoperative wound incision [24]. Appropriate specialists should be
infections either. Topical antibiotic ointments consulted—and documented for each procedure
for that purpose are also ineffective, yet often performed on patients with orthopedic prosthe-
used regardless [19]. ses, those with ventriculoatrial and peritoneal
Although the overall trend in the literature shunts, and in any case where the surgeon is not
supports decreased use of antimicrobials in der- comfortable making the decision alone. A 2008
matologic surgery as a whole, it is important to advisory statement on antibiotic prophylaxis is
know which situations still warrant antibiotics the most recent and widely used reference algo-
[20]. Patients at high risk for wound infection rithm for dermatologic surgeons [25].
should receive prophylactic antibiotics chosen to Clinical Pearl: Three main factors are essen-
cover the organism most likely to cause infection tial in the decision making process regarding
[21]. Staphylococcus aureus is the most common antibiotic prophylaxis.
agent of skin wound infections. However, • How contaminated is the wound (or will it be)?
Streptococcus viridans is commonly found in • Where is the lesion located and what kind of
oral flora, and Escherichia coli is present near the procedure is intended?
• Is the patient among the highest risk group for one pack per day. When necrosis does occur, the
endocarditis? area involved tends to be greater in smokers com-
Infection control measures including active pared to those who have never smoked. Stopping
surveillance of SSI, implementation of a protocol or decreasing smoking for at least 2 days prior to
for dealing with SSI, compliance observations surgery and for at least 1 week postoperatively
and instruction/training of healthcare workers, can potentially reverse some of the negative
clipping surrounding hair instead of shaving, effects of smoking on the microvasculature [28].
and following the often-times confusing periop- When necrosis occurs, treatment is conserva-
erative antibiotic prophylaxis guidelines are tive. Except in cases of hematoma formation and
essential measures in the prevention of SSI. infection, the full extent of the necrosis should be
Though preoperative MRSA screening and allowed to manifest. Debriding the wound prior to
implementation of a decontamination protocol this may injure viable tissue [27]. When the eschar
appears to decrease postoperative MRSA wound is freely separable from the wound bed, careful
infections after Mohs surgery, the clinical and sharp debridement may be performed, and the
efficacy and cost effectiveness of this screening wound may be allowed to granulate. Necrotic
has yet to be determined [26]. Finally, infection wounds are at higher risk for infection and the
control includes safety of the surgical team from surgeon should observe the affected area carefully
exposure to HIV or Hepatitis C virus. Vigilant and frequently, and consider systemic antibiotics.
infection control for both the patient and the
team is critical to surgical safety.
14.6 Dehiscence
14.5 Necrosis Wound dehiscence is a surgical complication in

which the layers of a wound unintentionally
Necrosis of tissue occurs secondary to ischemia. reopen. Wound dehiscence may be caused by any-
Any condition that results in a decrease of oxy- thing that causes excessive tension on the wound
genated blood flow to the wound has the potential edges. This includes inadequate undermining or
to cause necrosis. Too much tension on wound putting undo strain on the wound after surgery.
edges, excessive suturing and undermining, and When wounds are located in highly mobile or
superficial undermining all may result in tissue high tension areas such as the back, shoulders, or
compromise and decreased blood flow to the dis- legs, the risk of wound dehiscence is higher.
tal wound margins. Hematomas may create Underlying conditions such as Ehlers-Danlos
excessive tension on the wound, increasing the syndrome, allergic contact dermatitis to adhesive
risk of necrosis. Flaps and grafts with a length-to- or topical antibiotics, infection, spitting sutures,
base ratio of greater than 4:1 are at high risk of or obesity can also increase risk for wound dehis-
necrosis because of the tenuous circulation at the cence. Other risk factors include smoking, previ-
wound edges. Location of the wound is also an ous scarring or radiation, cancer, recent use of
important consideration; high-risk areas include Accutane, or chronic use of corticosteroids.
the lips, ears, nose, and skin grafts. Additionally, Dehiscence can be prevented by adequately
anesthesia type, amount, and addition of epineph- undermining the tissue and using as much tissue
rine all affect circulation around the wound and reservoir as necessary to close the wound without
can contribute to ischemia [27]. tension. The patient should be instructed to avoid
Cigarette smoking results in vasoconstriction, heavy lifting or extra activity, maintain adequate
increased blood viscosity, hypoxia, increased nutrition to speed wound healing, control underly-
platelet aggregation, and clots. Smoking more ing conditions that might alter wound healing
than one pack of cigarettes per day increases the (such as uncontrolled diabetes), and avoid predni-
risk of necrosis by threefold compared to never sone use during the healing period. Because hema-
smokers, ex-smokers, and smokers of less than tomas may also contribute to wound dehiscence,
appropriate postoperative bandaging is important, vascular lesions, tattoos, lentigines, birthmarks,

as is perioperative bleeding management. cutaneous aging and laxity, and psoriasis [30]. In
If wound dehiscence occurs, the surgeon has many cases, laser complications result from col-
several options, including allowing the wound to lateral damage created when energy intended for
granulate on its own or recutting and re-suturing the target chromophore is nonselectively diffused
the wound edges [29]. For wound dehiscence on and absorbed by surrounding tissues. The theory
the face, there are several options based on the of selective photothermolysis aims to reduce
nature, time, and condition of the wound after laser complications by selectively heating a tar-
dehiscence. For instance, if dehiscence is caused get chromophore while sparing the nonintended
by trauma (e.g., a patient trips and falls and hits a but nearby targets. For example, melanin selec-
graft site on the nose) or premature suture removal tively absorbs photons in the 532 nm wavelength
(e.g., the wound needs more than the standard creating heat, resulting in pigment destruction,
7-day period to heal), refreshing the wound edges while sparing the surrounding cells. Mild, short-
and re-suturing is acceptable if there is no evi- term complications of laser treatment include
dence of infection or the edges look intact. If erythema, edema, urticaria, crusting or erosion,
signs of infection are present, appropriate antibi- ecchymoses, blistering, and infection, such as
otic therapy is recommended. Areas such as the reactivation of herpes simplex virus (HSV). More
temple are known to heal poorly due to poor cir- moderate, longer-lasting complications include
culation. Allowing small dehiscent areas to gran- pigmentary changes, visible lines of demarca-
ulate for 2–6 weeks is often the best course of tion, burns, textural abnormalities, or delayed
action. The skin will heal, there will be less serous reepithelialization. Severe, long-term complica-
fluid, and the wound edges will be more amena- tions include permanent dyspigmentation, scar-
ble to refreshing and re-suturing. Too much inter- ring, and ocular damage [31]. The complications
vention, or premature intervention, may worsen noted above are devastating, but are not emergent
the cosmetic outcome. However, deeper dehis- [32]. Fortunately, there are few, emergencies
cence involving muscle, such as wedge recon- from laser treatment other than ocular damage.
structions of the lip may require immediate All potential side effects of a particular device
intervention. One tip: if Vicryl™ sutures were should be discussed and provided in writing
rejected prematurely resulting in dehiscence, ahead of time to a patient, along with instructions
switch to Monocryl™ when reconstructing the for appropriate cutaneous care following laser
wound. Because Monocryl is monofilament and treatment. Additionally, if the patient has a his-
less inflammatory, it has a longer duration and tory of HSV, prophylaxis should be instituted
lower probability of spitting suture. In summary, prior to the procedure. Close follow-up is essen-
for most cases of wound dehiscence, appropri- tial in the management of these potentially upset-
ately manage infection, excess moisture, and ting but non-emergent problems.
allow granulation to occur unless the dehiscence
involves deeper layers where cosmesis will be
difficult to achieve with a delayed intervention. 14.7.2 Filler Emergencies
Inappropriate placement of filler such as

14.7 Other Dermatologic Procedural superficial placement is one of the most frequent
Emergencies reasons for patient dissatisfaction. Some fillers,
including hyaluronic acid, are reversible with
14.7.1 Laser Emergencies hyaluronidase, and these complications can be
easily corrected. Hypersensitivity to current FDA
Today in dermatology, hundreds of different laser approved products is rare and can most often be
and light devices exist for various indications, managed with anti-inflammatory agents. Infection
including excessive hair, superficial and deep is also uncommon and is managed with antibiotics
or antivirals, depending on the etiology. The most Given that hyperbaric oxygen has proven
concerning complication is necrosis [33]. successful in healing of nasal tip grafting in cases
The risk of skin necrosis following injection of cancer or trauma reconstruction, this author
of filler is increased in certain potential danger suggests administration of oxygen via nasal can-
zones, including the glabella, nasal skin, temple, nula, face-mask or in the form of hyperbaric oxy-
alar groove, and even the lip [34, 35]. The most gen for ischemia secondary to cosmetic filler
common of area for filler-related necrosis is the injection [43, 44]. For cases with severe, unremit-
glabella. Major facial vessels of concern during ting swelling, oral antihistamines may also be
soft tissue augmentation are the superior and employed. Finally, treatment with low molecular
inferior labial arteries, both branching off the weight heparin (5,000 IE daily) has been reported
facial artery at the angle of the mouth; the angu- to treat impending necrosis after hyaluronic acid
lar artery, the terminal branch of the facial injection in the treatment of frown lines of the
artery; the lateral nasal artery, branch of the glabella due to occlusion or compression of the
angular artery; the dorsal nasal artery, which supratrochlear vessels [45].
forms an anastomosis with the angular artery;
the supratrochlear artery, one of the terminal
branches of the ophthalmic artery; and the 14.7.3 Botox Emergencies
superficial temporal artery, arising from the
external carotid artery [36]. There are many neurotoxins approved by the
Several treatment algorithms for impending FDA in use today. Botox acts via prevention of
facial necrosis due to filler injection have been the release of acetylcholine at the presynaptic
proposed in the literature [37–41]. If tissue nerve terminal, thereby stopping the electrical
blanching is observed, injection should be impulse and blocking muscular movement.
stopped immediately. Warm gauze (to facilitate Complications of botox include
vasodilation) and tapping (to potentially break up • Overcorrection
product) are then recommended. If the filler was • Undercorrection
an HA, immediate injection of hyaluronidase • Asymmetric result
should be used. The authors recommend injec- • Upper eyelid ptosis
tion of a 1:1 volume of hyaluronidase to HA in • Dysphagia
the zone of ischemia or necroses. Typically, a • Neck weakness
range of 8–16 mL vitrase 0.5 mL of HA will dis- • Perioral droop
solve the cosmetically imperfect swelling. For • Bruising
emergency situations when occlusion or ischemia • Headache
is suspected, use more. No absolute maximum • Intravascular injection
dose has been published but this author has used • Globe perforation
50 mL hyaluronidase in the area of the alar crease • Diplopia
to correct a 0.2 mL compression induced isch- Particularly distressing can be true eyelid pto-
emia of the ipsilateral ala. Per the literature, it is sis, which occurs when botox is injected or dif-
exceedingly rare to dissolve native HA with fuses into the levator palpebrae superiorus
hyaluronidase. Immediate use of nitroglycerin muscle. Though temporary, this effect can be dis-
paste to facilitate vascular dilatation and blood tressing for the patient and can impact their qual-
flow to the area should be applied [42]. ity of life. To avoid this complication, all
Additionally, anticoagulants such as aspirin and injections should be at least 1 cm above the bony
nonsteroidal anti-inflammatory agents, as well as orbital rim. If this complication occurs, iopidine
vitamins that inhibit platelet aggregation, should (apraclonidine) 0.5% drops may be used to stim-
be encouraged in any protocol to treat cutaneous ulate Muller’s muscle, providing some lid open-
tissue ischemia. ing to partially alleviate the ptosis [46].
Similar to those complications encountered tions, cardiac monitoring during the procedure
with laser treatment, the adverse effects of Botox and in the immediate recovery period, as well as
can be distressing to the patient, but few, if any, pausing treatment for 15 min between each cos-
represent a true emergency. metic unit is recommended. Regarding laryngeal
edema, heavy smokers seem to be most at risk for
this rare but serious complication.
14.7.4 Chemical Peel Emergencies One very real emergency of any chemical peel
is a burn of the eye from an accidental splash.
Common chemical peel side effects include sting- Cover the eyes with proper protection such as
ing, redness, and desquamation of the skin. These tape or stickers. Arrange the procedure tray to
side effects should be expected by any patient avoid accidental spillage; always label of the peel
who undergoes a chemical peel, as the mecha- container to ensure the proper product, and place
nism of the peel is controlled skin injury in an the original bottle on the counter as opposed to
attempt to remodel the epidermis [30, 47]. the Mayo stand, where it can more easily spill.
Chemical peels can target the superficial, medium Additionally, a clearly marked eye wash station is
or deep layers of the epidermis, depending on the essential should a splash occur. Furthermore,
type of chemical used and the desired outcome. immediate evaluation by an ophthalmologist or
Other complications of peels include contact der- transfer to the emergency department is war-
matitis, milia formation, infection, acne or rosa- ranted should an accident occur.
cea flare, and pigmentary changes [30]. It is Clinical Pearl: To avoid complications of
important to discuss the common side effects chemical peels:
prior to performing the procedure on any patient. • Take a good medication history, including use
Additionally, certain medications may potentiate of cosmeceuticals, retinoids, and glycolics, as
the effects of the peel and are thus necessary to be well as a history of previous chemical peels or
aware of prior to performing the procedure. contact dermatitis.
The most superficial chemical peels include • Consider performing a small patch test prior
alpha-hydroxy acids (AHA), such as glycolic to the procedure.
acid, and these peels are associated with minimal
side effects. The two major side effects of AHA
peels are irritation and sun sensitivity, which are 14.8 Conclusion
transient. Medium depth peels include trichloroa-
cetic acids (TCA). Side effects are similar to Dermatologic surgery is an art that involves
AHA peels but last longer. The deepest peels complex procedures involving excisions, repairs,
include phenols, and can be painful requiring injections, and devices. Thorough understand-
local anesthetic or sedation. Healing time is lon- ing of the anatomy and pathophysiology of the
ger—usually 2–3 weeks—and the most consis- skin, proper patient evaluation, appropriate
tent side effect is pigmentary alteration (hypo- or selection of procedures based on each patient,
hyperpigmentation). Other serious side effects of and divulging potential complications of each
phenol include scarring, infection, as well as rare procedure are essential to achieving optimal
cardiac arrhythmias and temporary laryngeal results and minimizing complications in cutane-
edema [30]. Patients who have impaired liver or ous procedures [30].
kidney function are most at risk of phenol toxic-
ity, as phenol is absorbed through the skin and
subsequently metabolized by the liver and
excreted by the kidneys. In addition, the size of
References
the treatment areas, rather than the concentration 1. Hurst EA, Yu SS, Grekin RC, Neuhaus IM. Bleeding
of the phenol, determines the extent of cutaneous complications in dermatologic surgery. MD Semin
absorption. To minimize these serious complica- Cutan Med Surg. 2007;26:40–6.
2. Bunick CG, Aasi SZ. Hemorrhagic complications in 18. Hurst EA, Grekin RC, Yu SS, Neuhaus IM. Infectious
dermatologic surgery. Dermatol Ther. 2011;24:537–50. complications and antibiotic use in dermatologic sur-
3. Dinehart SM, Henry L. Dietary supplements: altered gery. Semin Cutan Med Surg. 2007;26(1):47–53.
coagulation and effects on bruising. Dermatol Surg. 19. Hirschmann JV. Antimicrobial prophylaxis in derma-
2005;31:819–26. tologic surgery. Cutis. 2007;79(6 Suppl):43–51.
4. Billingsley EM, Maloney ME. Intraoperative and 20. Shurman DL, Benedetto AV. Antimicrobials in der-
postoperative bleeding problems in patients taking matologic surgery: facts and controversies. Clin
warfarin, aspirin, and nonsteroidal anti-inflammatory Dermatol. 2010;28(5):505–10.
agents. Dermatol Surg. 1997;23:381–5. 21. http://emedicine.medscape.com/article/1128404-
5. Alcalay J, Alkalay R. Controversies in perioperative overview Accessed 11 Mar 2012.
management of blood thinners in dermatologic sur- 22. [Guideline] Wilson W, Taubert KA, Gewitz M, et al.
gery: continue or discontinue? Dermatol Surg. Prevention of infective endocarditis: guidelines from
2004;30:1091–4. the American Heart Association: a guideline from the
6. Alcalay J. Cutaneous surgery in patients receiving American Heart Association Rheumatic Fever,
warfarin therapy. Dermatol Surg. 2001;27:756–8. Endocarditis, and Kawasaki Disease Committee,
7. Otley CC, Fewkes JL, Frank W, et al. Complications Council on Cardiovascular Disease in the Young, and
of cutaneous surgery in patients who are taking warfa- the Council on Clinical Cardiology, Council on
rin, aspirin, or nonsteroidal anti-inflammatory drugs. Cardiovascular Surgery and Anesthesia, and the
Arch Dermatol. 1996;132:161–6. Quality of Care and Outcomes Research
8. Lam J, Lim J, Clark J, et al. Warfarin and cutaneous Interdisciplinary Working Group. Circulation
surgery: a preliminary prospective study. Br J Plast 2007;116(15):1736–54.
Surg. 2001;52:372–3. 23. Saleh K, Sonesson A, Persson B, Riesbeck K,
9. Bartlett GR. Does aspirin affect the outcome of minor Schmidtchen A. A descriptive study of bacterial load
cutaneous surgery? Br J Plast Surg. 1999;52:214–6. of full-thickness surgical wounds in dermatologic sur-
10. Kovich O, Oltey CC. Thrombotic complications gery. Dermatol Surg. 2011;37(7):1014–22.
related to discontinuation of warfarin and aspirin ther- 24. Wood L, Warner N, Billingsley E. Infectious compli-
apy perioperatively for cutaneous operation. J Am cations of dermatologic procedures. Dermatol Ther.
Acad Dermatol. 2003;48:233–7. 2011;24:558–70.
11. Alam M, Goldberg LH. Serious adverse vascular 25. Wright TI, Baddour LM, Berbari EF, et al. Antibiotic
events associated with perioperative interruption of prophylaxis in dermatologic surgery: advisory state-
antiplatelet and anticoagulant therapy. Dermatol Surg. ment 2008. J Am Acad Dermatol. 2008;59(3):
2002;28:992–8. 464–73.
12. Schanbacher CF, Bennett RG. Postoperative stroke 26. Cordova KB, Grenier N, Chang KH, Dufresne Jr R.
after stopping warfarin for cutaneous surgery. Preoperative methicillin-resistant Staphylococcus
Dermatol Surg. 2000;26:785–9. aureus screening in Mohs surgery appears to decrease
13. Kovich O, Otley CC. Perioperative management of postoperative infections. Dermatol Surg.
anticoagulants and platelet inhibitors for cutaneous 2010;36(10):1537–40.
surgery: a survey of current practice. Dermatol Surg. 27. Delaney A, Diamantis S, Marks V. Complications of
2002;28:513–7. tissue ischemia in dermatologic surgery. Dermatol
14. Kirkorian AY, Moore BL, Siskind J, Marmur ES. Ther. 2011;24:551–7.
Perioperative management of anticoagulant therapy 28. Lawrence WT, Murphy RC, Robson MC, Heggers JP.
during cutaneous surgery: 2005 survey of Mohs sur- The detrimental effect of cigarette smoking on flap
geons. Dermatol Surg. 2007;33(10):1189–97. survival: an experimental study in the rat. Br J Plast
15. Bordeaux JS, Martires KJ, Goldberg D, Pattee SF, Fu Surg. 1984;37(2):216–9.
P, Maloney ME. Prospective evaluation of dermato- 29. Khachemoune A, Kreici-Papa N, Finn DT, Rogers
logic surgery complications including patients on GS. Dehisced clean wound: resuture it or steri-strip it?
multiple antiplatelet and anticoagulant medications. J Dermatol Surg. 2004;30(3):431–2.
Am Acad Dermatol. 2011;65(3):576–83. Epub 2011 30. Zhang AY, Obagi S. Diagnosis and management of
Jul 22. skin resurfacing—related complications. Oral
16. Saleh K, Sonesson A, Persson B, Riesbeck K, Maxillofacial Surg Clin N Am. 2009;21:1–12.
Schmidtchen A. A descriptive study of bacterial 31. Alam M, Warycha M. Complications of lasers and
load of full-thickness surgical wounds in dermato- light treatments. Dermatol Ther. 2011;24:571–80.
logic surgery. Dermatol Surg. 2011;37(7):1014–22. 32. Batra RS, Jacob CI, Hobbs L, Arndt KA, Dover JS. A
doi:10.1111/j.1524-4725.2011.02040.x. Epub 2011 prospective survey of patient experiences after laser
May 25. skin resurfacting: results from 2 ½ years of follow-up.
17. Martin JE, Speyer LA, Schmults CD. Heightened Arch Dermatol. 2003;139:1295–9.
infection-control practices are associated with 33. Cohen JL. Understanding, avoiding, and managing
significantly lower infection rates in office-based dermal filler complications. Dermatol Surg. 2008;34
Mohs surgery. Dermatol Surg. 2010;36(10):1529–36. Suppl 1:S9209.
34. Grunebaum LD, Allemann IB, Dayan S, et al. The (CaHA) mixed with lidocaine and CaHA alone for
risk of alar necrosis associated with dermal filler correction of nasolabial fold wrinkles. Dermatol Surg.
injection. Dermatol Surg. 2009;35:1635–40. 2008;36:760–5.
35. Winslow C. The management of dermal filler compli- 42. Sclafani A, Fagien S. Treatment of injectable soft
cations. Facial Plast Surg. 2009;25(2):124–8. tissue filler complications. Dermatol Surg. 2009;35:
36. Bolognia J, Jorizzo J, Rapini R (eds) Dermatology, 1672–80.
2nd ed. Mosby, 2007. 43. Nichter LS, Morwood DT, Williams GS, Spence RJ.
37. Bailey SH, Cohen JL, Kenkel JM. Etiology, preven- Expanding the limits of composite grafting: a case report
tion and treatment of dermal filler complications. of successful nose replantation assisted by hyperbaric
Aesthetic Surg J. 2011;31:110–21. oxygen. Plast Reconstr Surg. 1991;87:337–40.
38. Cohen JL. Understanding, avoiding and managing 44. Rapley JH, Lawrence WT, Witt PD. Composite graft-
dermal filler complications. Dermatol Surg. 2008;34: ing and hyperbaric oxygen therapy in pediatric nasal
s92–9. tip reconstruction after avulsive dog bite injury. Am
39. Cohen JL, Brown MR. Anatomic considerations for Plast Surg. 2001;46:434–8.
soft tissue augmentation of the face. J Drugs Dermatol. 45. Sanchz S, Schippert W, Ulmer A, et al. Arterial embo-
2009;8:13–6. lization caused by injection of hyaluronic acid
40. Glaich D, Cohen J, Goldberg L. Injection necrosis of (Restylane). Br J Dermatol. 2002;146:928–9.
the glabella: protocol for prevention and treatment after 46. Niamtu J. Complications in fillers and botox. Oral
use of dermal fillers. Dermatol Surg. 2006;32:276–81. Maxillofacial Surg Clin N Am. 2009;21:13–21.
41. Grunebaum LD, Elsaie ML, Kaufman JY. Six-month, 47. Khunger N, IADVL Task Force. Standard guidelines
double-blind, randomized, split-face study to compare of care for chemical peels. Indian J Dermatol Venereol
the efficacy and safety of calcium hydroxylapatite Leprol. 2008;74(Suppl):S5–12.
Bites and Stings
15
Annemarie Uliasz
(wasps, hornets, yellow jackets, paper wasps),

15.1 Introduction and formicidae (imported fire ants).
As travel increases and humans continue to

expand their presence throughout the world, der- 15.2.2 Apidae and Vespidae
matologists must be familiar with a number of
creatures capable of inflicting medically The stinging apparatus of apidae and vespidae is
significant injury. This chapter describes those connected to a venom-filled sac. In honey and
creatures which, when encountered by the unsus- bumble bees, the barbed stinger and venom sac
pecting human, may result in notable morbidity detach following contact, resulting in death of
and mortality. the insect. The barbed stingers of bees should be
removed immediately to prevent further release
of venom and potential foreign body reaction
15.2 Insects [1]. Hornets and wasps, on the other hand, are
able to sting multiple times as their stinger does
15.2.1 Hymenoptera not detach.
The resultant injury sustained by apidae and
Hymenoptera are the most common cause of vespidae stings ranges from mild local reactions
insect stings (Fig. 15.1). Most hymenoptera are to systemic reactions including anaphylaxis. The
social creatures that build nests or hives. venom of bees, hornets, and wasps contains
Hymenoptera stings usually occur in self-defense, phospholipase A which is thought to be respon-
when the insect is swatted or stepped on. If the sible for IgE sensitization. Local reactions to
hive or colony is disturbed, hundreds to thou- bee, hornet, or wasp stings commonly manifest
sands of stings may follow. Medically significant as painful, papular urticaria which develops
hymenoptera are discussed below and include within minutes and typically resolves within
apidae (honey and bumble bees), vespidae hours to days.
In large local reactions, the pruritus, erythema,
edema may spread to encompass a more exten-
sive area (over 10 cm), peaking at 24–48 h before
A. Uliasz, M.D. (*)
resolving [2]. Those who experience large local
Spring Street Dermatology, 73 Spring Street, Suite 601,
New York, NY 10012, USA reactions may develop similar reactions upon
subsequent exposure to the same insect.
Department of Dermatology, Mount Sinai School
of Medicine, New York, NY, USA Additionally, in these patients, there is an approx-
e-mail: druliasz@springstderm.com imate 5–15% risk of anaphylaxis with subsequent

272 A. Uliasz
Fig. 15.1 Vespid

(Courtesy of Dirk
M. Elston, M.D.).
Photograph in the public
domain
stings. Reactions limited to the skin may be the diagnosis of anaphylaxis. Immediate intra-
symptomatically treated with cold compresses, muscular epinephrine is the initial acute treat-
antihistamines, nonsteroidal anti-inflammatory ment and patients should be discharged with a
drugs, and high potency topical corticosteroids. prescription for an epinephrine auto-injector and
Oral corticosteroids may be required for large clear instructions for use as well as an allergy
local reactions and immunotherapy may be con- identification bracelet. Additionally, all patients
sidered to reduce the risk of future stings. with systemic reactions should be referred to an
Toxic systemic reactions to vespids may result allergist for skin prick or serum immunoassays to
when a large number of stings is sustained. confirm venom-specific IgE [4] as well as venom
Although clinically similar to an allergic reac- immunotherapy which is available for both hon-
tion, toxic systemic reactions due to multiple eybee and vespid allergies. Venom immunother-
stings are caused by the vasoactive constituents apy is highly effective and has been demonstrated
of the venom rather than an allergic mechanism, to lower the risk of a subsequent systemic allergic
and radioallergosorbent testing, which detects reaction from 30 to 60% to less than 5% [5–11].
allergen-specific IgE antibodies in the serum sug-
gesting an allergic reaction, is recommended to
distinguish the etiology. 15.2.3 Formicidae
Anaphylaxis, a type I IgE-mediated hypersen-
sitivity reaction, is estimated to occur in 1.5–34% Imported fire ants (Solenopsis invicta and
of patients sustaining an insect sting [3]. Those at Solenopsis richteri) are believed to have been
increased risk for severe systemic reactions imported from South America via ship to Mobile,
include those with increased age, prior venom Alabama in the 1950s with subsequent spread
sensitization, underlying cardiovascular disease, throughout the southern USA. They are also
and patients with mastocytosis. Symptoms of found in regions of Mexico, the Caribbean,
anaphylaxis may occur as early as 10 min or as New Zealand, Australia, Taiwan, and China [12].
late as 72 h after the sting. Early signs and symp- In endemic areas, they are the leading cause of
toms include generalized urticaria, angioedema, hymenoptera hypersensitivity reactions [13].
and flushing, and may progress to bronchocon- Fire ants are notoriously difficult to avoid. In fact,
striction, laryngeal edema manifesting as wheez- one study revealed that more than 50% of people
ing, hypotension, cardiovascular collapse, and, fall victim to the sting of this aggressive crea-
potentially, death. Elevated concentrations of ture within 3 weeks of moving to an endemic
serum histamine, tryptase, and mast cells support area [14].
15 Bites and Stings 273
Fig. 15.2 Imported fire

ant mound (Courtesy of
Dirk M Elston, M.D.).
domain
Fire ants typically live in mounds proportional

to the size of the colony (Fig. 15.2). When dis-
turbed, the ants stream out of the mound in a
swarm, stinging anything they encounter includ-
ing both humans and animals. During times of
flooding, these resourceful insects have been
observed to self-assemble into waterproof rafts to
avoid drowning. These “ant rafts” may float into
houses where they may subsequently inflict stings
on the inhabitants [15].
Equipped with a stinging apparatus located on
the distal tip of the abdomen, fire ants are capable
of inflicting multiple stings within a brief period of
time. After grasping the skin with their mandibles,
they sting while pivoting their body in a circular
pattern (Fig. 15.3). They should be removed
promptly to prevent further injury. In those who are Fig. 15.3 Imported fire ant stinging (Courtesy of Dirk M
immobile such as nursing home patients or infants, Elston, M.D.). Photograph in the public domain
dramatic reports exist of massive attacks in which
ants were found completely covering the victims life-threatening anyphylaxis. Local reactions are
resulting in death in some cases due to cardiovas- characterized by a wheal and flare reaction with
cular or respiratory collapse or anaphylaxis [16]. intense burning sensation. In the majority of cases,
The venom of fire ants is composed of pre- characteristic sterile pustules develop within 24 h
dominantly of water-insoluble piperidine alka- (Fig. 15.4). Large local reactions are notable for
loids, responsible for the formation of sterile expanding erythema and edema contiguous with
pustules. The remainder of the venom consists of the sting site which may persist for 2–3 days. The
allergenic proteins, Sol i I-IV, which may cross- sequelae of a massive attack is due to a toxic reac-
react to the venoms of honeybees, yellow jackets, tion to the hemolytic, cytotoxic, neurotoxic prop-
and the centipede Centuroides vittacus [17]. erties of the venom [18]. Anaphylaxis may occur
The sting of the fire ant results in varying clini- in up to 1% of those who are stung and may result
cal presentations ranging from local reactions to from a single fire ant sting [19, 20].
274 A. Uliasz
Fig. 15.5 Black widow spider (Courtesy of CDC/Paula

Smith, photo credit: James Gathany). Photograph in the
public domain
Fig. 15.4 Characteristic pustules resulting from imported

fire ant sting (Courtesy of CDC/Dr. Harold G. Scott).
Photograph in the public domain
Local reactions may be treated with topical

corticosteroids and oral antihistamines. Allergic
patients should be provided with an allergy
identification bracelet and an epinephrine auto-
injector and proper instructions for use.
Furthermore, referral to an allergist for appropri-
ate diagnostic studies and immunotherapy is vital
to prevent another potentially life-threatening Fig. 15.6 Brown recluse spider (Courtesy of CDC).
anaphylactic event. Confirmation of an allergy to Photograph in the public domain
fire ant venom may be accomplished by skin-
prick testing or serum testing for the presence to
venom-specific immunoglobulin E antibodies. pose a medical risk to humans include the black
Fire ant whole body extract is used for immuno- widow (Fig. 15.5), the brown recluse (Fig. 15.6),
therapy with conventional protocols that may last the Australian funnel web spider, and the South
3–6 months or more and comprise 25–28 injec- American armed spider.
tions to reach the maintenance dose. Recent stud- The black widow spider (Latrodectus species)
ies have demonstrated the efficacy of rushed is found throughout tropical and temperate lati-
1-day protocols in which ten injections are given tudes worldwide [22]. In the USA, it is predomi-
during the course of 1 day with maintenance dos- nantly found in the southern and western states
ing commencing on day 8 [21]. under stones, within woodpiles, or in outhouses.
The black widow spider is characterized by a
glossy, black body with a red hourglass on its
15.3 Arachnids abdomen. Although males may bite, it is only the
female black widow that is capable of significant
15.3.1 Spiders envenomation. A bite by a black widow spider
may result in local erythema and pain. Black
Armed with venom that is nontoxic to mammals widow venom, alpha-latrotoxin, is a neurotoxin
and mouth parts too small or weak to pierce that causes the presynaptic release of autonomic
human skin, the vast majority of arachnids are neurotransmitters resulting in the rapid onset of
harmless to humans. The spiders most likely to systemic symptoms including nausea, vomiting,
diaphoresis, agitation, hypertension, and muscle the following weeks, a thick eschar gradually
cramping [23, 24]. Abdominal rigidity may forms and then falls off to reveal a necrotic ulcer.
mimic an acute abdomen. In rare cases, myositis A small minority of patients may experience
[25, 26], priaprism [27], respiratory arrest, and systemic reactions including hemolysis, renal
death may occur. failure, and disseminated intravascular coagula-
Treatment includes local wound care, ice, ele- tion [35–37].
vation, and immobilization. Tetanus prophylaxis Treatment includes cleaning the wound,
should be given following all envenoming spider compression, ice, elevation, analgesics, and
bites as Clostridium tetani spores and bacteria are tetanus prophylaxis. The use of dapsone has
commonly found throughout the environment been demonstrated to be ineffective [38].
and may gain entrance to the body via abrasions Furthermore, it carries the risk of methemoglo-
and wounds [28]. Muscle relaxants and analge- binemia, and in those who are glucose-6-phos-
sics are often used for black widow bites. Equine- phate dehydrogenase (G6PD) deficient severe
derived antivenom may be employed for severe hemolysis may occur due to oxidative denatur-
systemic cases; however, symptoms may subside ation of hemoglobin which G6PD normally
spontaneously within hours to days. Furthermore, prevents. Early excision and intralesional corti-
antivenin has been associated with immediate costeroids are contraindicated as these mea-
hypersensitivity reactions anaphylaxis, and may sures may result in more tissue damage than
produce serum sickness 1–2 weeks following conservative treatment. Healing may take sev-
administration in up to 75% of patients [29, 30]. eral weeks to occur and excision and grafting
Its use is recommended in those cases involving may be considered for chronic ulcers 6–8 weeks
patients with marked systemic symptoms unre- after the initial injury [28, 39].
sponsive to other measures. It should be used Internationally, the Australian funnel web
only in locations where anaphylaxis may be ade- spider (Atrax and Hadronyche spp.) is consid-
quately treated [31, 32]. ered the most lethal spider in the world. It resides
The brown recluse spider (Loxosceles spp.) is in southeastern and coastal Australia. Although
found in North and South America. In the USA, cases of envenomation are rare, the Australian
the brown recluse predominantly inhabits the funnel spider bite remains a relevant medical
south central USA. It is identified by its brown entity given its life-threatening nature and the
color, and in females, a characteristic darker availability of an effective antivenom. The spi-
brown violin-shaped marking on the dorsal ders are large (4 cm long) and aggressive. The
cephalothorax. The bite of the brown recluse bite of the Australian funnel spider is remarkable
may result in necrotic skin lesions due to venom for visible puncture wounds created by long,
containing sphingomyelinase D and hyaluroni- sturdy fangs up to 5 mm in length capable of
dase [33, 34]. The platelet aggregation, derma- piercing fingernails. Cases of mild envenoma-
tonecrosis, and hemolysis caused by tion with its venom, the neurotoxin d-atraco-
sphingomyelinase D is felt to result in cutaneous toxin, may yield local paresthesias, numbness,
ulceration and systemic effects. Hyaluronidase and spasms while severe envenomation results in
may increase the spread of the lesion. The bite autonomic and neuromuscular excitability with
itself may go unnoticed and commonly occurs initial hypertension, tachycardia, diaphoresis,
when the spider is trapped between bedsheets or and nausea progressing to bradycardia, hypoten-
clothing and the skin of the victim. The majority sion, respiratory edema, and in some cases,
of cases are self-limited with mild erythema and coma. Deaths have been reported to occur within
edema and heal spontaneously without support- 15 min in children [39]. Treatment consists of
ive care. In cases of dermatonecrotic loxos- application of a pressure immobilization dress-
celism, initially, a dark macule with surrounding ing until the administration of antivenom, a
erythema may appear, progressing within hours purified IgG derived from rabbits hyperimmu-
to cyanosis with a central vesicle or bulla. During nized with Atrax venom.
276 A. Uliasz
The South American armed spider (Phoneutria

spp.), as its name suggests, is found in South
America as well as Central America. A large spi-
der with a body reaching up to 5 cm in length, it
often resides in banana clusters. When threat-
ened, it raises its front legs, displays its fangs,
and bristles its arm hairs. Armed spider venom,
containing the neurotoxin, PhTx-3, targets both
the peripheral and central nervous systems. In
the majority of cases, the bite of the spider may
result in local effects such as extreme pain, pilo-
erection, and diaphoresis at the bite site. Systemic Fig. 15.7 Scorpion (Courtesy of Dirk M. Elston, M.D.).
effects are less common and may include hyper- Photograph in the public domain
tension, tachycardia, nausea, vomiting, pri-
aprism, increased salivation, vertigo, and in rare found in North America, only the genus
cases, death. The treatment of armed spider bites Centuroides (Fig. 15.7), which resides in the
should include tetanus prophylaxis, elevation southwest USA and Mexico, is considered to be
and immobilization of the involved extremity, medically important [43]. However, as interna-
and analgesics. Following antivenom skin test- tional travel has increased, cases of envenoma-
ing, the equine-derived antivenom may be tion by non-endemic scorpions inadvertently
administered [40]. transported to the USA have been reported [44].
It is important to keep in mind that the major- Stings occur when the victim encounters a
ity of presumed spider bites are in fact caused by scorpion hidden in shoes, under sleeping bags, in
another etiology. A definitive diagnosis of a spi- closets, cellars, or woodpiles. Neurotoxic pep-
der bite may be made only if the spider was tides are the main active component of venom
observed inflicting the bite and then subsequently from dangerous scorpions occurring at varying
captured and positively identified by an expert levels depending on the species.
entomologist [41]. The differential diagnosis The severity of a scorpion sting hinges on
includes infections (MRSA, herpes, erythema the species involved and may range from a mild
migrans), vasculitis, other arthropod bites, urti- local reaction comparable to a bee sting to a life-
caria, and contact dermatitis. Multiple bites or threatening systemic reaction due to activation
bites simultaneously sustained by multiple mem- of both the sympathetic and parasympathetic
bers of the same household should cast in doubt nervous systems. Children and the elderly are at
the diagnosis of a spider bite. a higher risk of developing respiratory, cardio-
vascular, and neurologic complications. In severe
envenomations, the evolution of symptoms is
15.3.2 Scorpions rapid. Following the initial sting, pain may be
accompanied first by a cholinergic stage (brady-
Scorpions are characterized by their large claws, cardia, hypotension, nausea, emesis, diaphoresis,
four pairs of legs, and segmented tail which increased salivation, nystagmus, and priapism),
ends in a venom-containing stinger (Fig. 15.7). then followed by an adrenergic stage (hyperten-
Globally, scorpions are a significant cause of sion, tachycardia, tachypnea, dyspnea, agita-
morbidity and mortality. Of the roughly 1,500 tion). It has been noted that the presence of
species of scorpions found worldwide, approxi- gastrointestinal symptoms may be a harbinger of
mately 30 pose a health threat to humans [42]. a more severe course and vigilance is recom-
The South American Buthidae is considered the mended. Potentially lethal envenomation may
most dangerous family of scorpions worldwide. lead to cardiovascular collapse and pulmonary
Of the approximately 70 species of scorpion edema [42].
Management consists of local wound care

and pain management as well as tetanus pro-
phylaxis when indicated. Cases of systemic
involvement may necessitate supportive therapy
and immediate administration of antivenom
where available. Anaphylaxis and serum sick-
ness are potential complications of antivenom
treatment. Studies have also demonstrated
benefit of prazosin via blockade of alpha-1 Fig. 15.8 Centipede (Courtesy of Dirk M. Elston, M.D.).
Photograph in the public domain
receptors in reversing the cardiovascular mani-
festations [45, 46].
15.3.3 Centipedes
Chiropods, or centipedes, are fast-moving, aggres-

sive arthropods. These nocturnal creatures are
characterized by a long, segmented body with
pairs of legs attached to all but the final segment
(Fig. 15.8). Modified appendages which are
attached to the first segment act as claws and are
capable of releasing venom through specialized
ducts. The most dangerous centipede is of the
Scolopendra genus which may reach a length
of 30 cm. They are found world-wide in temp-
erate and tropical zones; in the USA, they are Fig. 15.9 Millipede (Courtesy of Dirk M. Elston, M.D.).
found predominantly in the southern states and Photograph in the public domain
Hawaii.
Centipede venom has been found to contain 15.3.4 Millipedes
several enzymes including metalloproteinases
and hyaluronidases, as well as nonenzymatic tox- Diplopods, or millipedes, differ from centipedes
ins (neurotoxins, cardiotoxins, and myotoxins) in that they have two pairs of legs attached to
[47]. A bite may result in excruciating pain, pru- each segment of their bodies (Fig. 15.9). They are
ritus, erythema, edema, and bleeding, but is gen- vegetarians and are not known to bite humans.
erally self-resolving with no serious morbidity or When disturbed, they release noxious substances
mortality. However, there are case reports of cen- such as benzoquinone, hydroquinone, and hydro-
tipede stings causing necrosis [48], myocardial gen cyanide secreted by repugnatorial glands
infarction [49], proteinuria [50], rhabdomyolysis along the length of their body [56]. However,
with renal failure [51], Well’s syndrome [52], and some species are capable of squirting the sub-
toxicity following ingestion [53]. stance up to 25 cm [57].
Treatment includes local wound care and Cutaneous exposure results in a prickling or
pain management. Pain control may be achieved burning sensation with or without paresthesias
with ice packs, hot water immersion, local that may progress to vesiculation. A characteris-
anesthetics, and oral analgesics [54, 55]. Anti- tic mahogany discoloration develops simulating
histamines and topical and/or systemic corti- cyanosis, necrosis, or gangrene. This discolor-
costeroids may be employed, and antibiotics ation occurs due to oxidation of quinones and
may be administered as needed for secondary may persist for months [58, 59]. Treatment
bacterial infection. Tetanus prophylaxis is includes profuse irrigation to remove the toxins,
recommended. analgesics, and topical corticosteroids [60].
278 A. Uliasz
15.4 Snakes
Worldwide, it is estimated that almost 200,000

people die each year of snake bites [61]. However
this may be an underestimate due to lack of report-
ing in much of the developing world. According
to the 2010 American Association of Poison
Control Centers, there were over 3,000 reports of
venomous snake bites treated in medical facilities
in the USA [62]. Snakes use their venom to immo-
bilize their prey and as self-defense when threat-
ened or provoked. Of the 3,000 species of snakes
found globally, approximately 15% are venom-
ous, all of which are found in four families: Fig. 15.10 Western diamondback rattlesnake, Crotalus
Atractaspididae, Colubridae, Elapidae, and atrox (Courtesy of CDC/Edward J. Wozniak D.V.M.,
Viperidae. The venomous snakes indigenous to Ph.D., Photo credit: Michael Smith). Photograph in the
public domain
North America are confined to the Elapidae and
Viperidae families which are discussed below.
results in immediate pain and the appearance of
one or two fang puncture marks. Within the
15.4.1 Viperidae hours, erythema, edema, bullae, eccchymosis,
lymphangitis, and lymphadenopathy may
Rattlesnakes, copperheads, and water moccasins, develop. Associated nonspecific systemic symp-
members of the subclass Crotalinae of the family toms may include nausea, emesis, lethargy, weak-
Viperidae, are responsible for the majority of ness, and diaphoresis.
venomous snake bites in the USA. This group of Patients should be closely monitored for the
snakes is commonly referred to as pit vipers development of more severe systemic manifesta-
owing to the infrared heat-sensing pits located tions including hypotension, tachycardia, com-
posterior to the nostrils. Other characteristic fea- partment syndrome, rhabdomyolysis with renal
tures include prominent fangs, elliptical pupils, toxicity, and disseminated intravascular coagula-
and triangular-shaped heads (Fig. 15.10). With tion. Neurotoxicity is rare in crotalid envenoma-
the exception of Maine, Alaska, and Hawaii, rat- tion except in bites caused by the Mohave
tlesnakes inhabit all states of the continental rattlesnake.
USA. Copperheads are found predominantly in Treatment begins in the field and includes
the eastern USA, and water moccasins are native removing the victim from the vicinity of the
to the southeastern USA. snake and immediately transporting the victim to
The spectrum of clinical presentations due to the nearest health care facility. An attempt to cap-
crotalid envenomation may range from local ture the snake for identification purposes is dis-
reactions to fatal systemic reactions. Severity is couraged owing to the risk of creating another
dependent on the age and underlying health of victim. Instead, a photo may be taken from a safe
the victim, the location of the bite, and the amount distance if possible. Due to the risk of increased
of venom injected. Interestingly, approximately morbidity, several dangerous practices should be
25% of crotalid bites are “dry,” meaning that no avoided including incising and suctioning venom
venom was injected. Furthermore, the compo- from the wound, cryotherapy, electrotherapy, and
nents of the venom may vary according to sea- applying a tourniquet [64, 65].
son, as well as the age and nutritional status of Wound management includes thoroughly
the snake [63]. Crotalid envenomation commonly cleaning the area, repeated circumferential mea-
Fig. 15.11 Venomous

“Texas coral” snake,
Micrurus tener tener
(Courtesy of CDC/Edward
J. Wozniak D.V.M., Ph.D.).
domain
surement along the affected limb, gentle immobi-

lization, elevation of the limb, and administration
of analgesics and tetanus prophylaxis as needed.
Serial neurologic exams should be performed
hourly until the edema resolves. Laboratory stud-
ies should be performed to evaluate for the devel-
opment of coagulopathy and rhabdomyolysis.
Fasciotomy should be reserved for compartment
syndrome that does not resolve after the adminis-
tration of antivenom.
Candidates for antivenom therapy include
those with progressive worsening of local injury,
coagulopathy, or systemic manifestations. An Fig. 15.12 Harmless “milk” snake, Lampropeltis trian-
gulum annulata (Courtesy of CDC/Edward J. Wozniak
ovine-derived antivenom, Crotalidae Polyvalent D.V.M., Ph.D.). Photograph in the public domain
Immune Fab is currently available in the USA
and is infused four times over a period of 18 h. It
is associated with acute hypersensitivity reac- which display alternating red and black banding
tions in 16% and serum sickness in 14.1% [66]. (Fig. 15.12) recalled by the colloquialism: “Red
and yellow, kill a fellow. Red and black, venom
lack.” Unlike crotalids, coral snakes lack long
15.4.2 Elapidae fangs. Instead, they have small rows of teeth, and
upon biting a victim, must gnaw the skin in order
Elapidae, or coral snakes, are found primarily in to pierce it and deliver venom.
Florida and Texas. Although coral snake enveno- Unlike crotalid envenomation, significant
mation is much less common that crotalid enven- local tissue injury and coagulopathy are not char-
omation, deaths have been reported and acteristic of coral snake envenomations. Instead,
neurotoxicity is characteristic [67]. Venomous the site of the bite may be erythematous with
coral snakes are notable for their distinctive red, mild edema and pain. In further contrast, the vic-
yellow, and black stripes (Fig. 15.11). They can tim may demonstrate neurological manifestations
be distinguished from non-venomous species ranging from mental status changes, tremors, and
280 A. Uliasz
hypersalivation to obtundation and respiratory

paralysis necessitating ventilatory support. It is
important to note that the onset of neurologic
effects may be delayed for up to 24 h.
Field treatment is similar to that of crotalids
with emphasis placed on transporting the victim
immediately to the closest medical facility.
Tetanus prophylaxis should be administered as
appropriate. Serial neurologic and cardiorespira-
tory evaluation should be conducted with intuba-
tion and mechanical ventilation if needed. In
confirmed coral snake envenomations, North
American elapidae antivenom, if available,
should be administered immediately. Derived
from horse serum, North American antivenom
may cause an acute hypersensitivity reaction and
serum sickness. If antivenom is not available,
respiratory support should result in complete
recovery in the majority of patients. However, the
duration of mechanical ventilation may be as
long as 1 week.
15.5 Marine Creatures

Fig. 15.13 The Portuguese man-of-war, Physalia physa-
15.5.1 Jellyfish lis (Courtesy of Dirk M. Elston, M.D.). Photograph in the
public domain
Jellyfish are members of the phylum Cnidaria. Of

the approximately 9,000 species of Cnidaria, at war, Fig. 15.13) and the Gonionemus found in the
least 100 pose a threat to humans. There are three Sea of Japan.
classes of Cnidaria which are hazardous to Jellyfish are armed with stinging cells, or nem-
humans. The first, the Scyphozoans, or “true” atocysts, which contain venom and are triggered
jellyfish, are characterized by tentacles which are upon chemical or physical stimuli. Nematocysts
arranged radially at regular intervals around and are capable of stinging even after the jellyfish is
within the bell. dead or when the tentacles are separated from the
The second, and most deadly class, the jellyfish. Venom is delivered to small dermal cap-
Cubozoans, or “box” jellyfish, are distinguished illaries and dermal tissue, where it is thought to be
by tentacles arising only from the corners of their absorbed systemically via the lymphatic system.
box or cube-shaped bells. The Cubozoans com- The venom contains both toxic and antigenic
prise two subgroups containing the Carybdeids properties that are dermatonecrotic, cardiopathic,
and the Chiropods. The Carybdeids include the hemolytic, or neurotoxic.
Hawaiian box jelly fish and Carukia barnesi, the The majority of reactions to jellyfish are
small jellyfish responsible for “Irukandji localized. However, systemic and fatal reactions
Syndrome.” The Chiropods include Chironex may occur. The severity of the reaction is depen-
fleckeri, the Australian sea wasp, considered the dent on the size, age, and underlying health of
most dangerous animals in the world [68]. the victim, the body surface area involved, the
The third class, the Hydrozoa (“other” jellyfish), number of nematocysts discharged, and the tox-
includes the Physalia species (Portuguese man-o’- icity of the venom.
Death due to jellyfish envenomation may

occur from anaphylaxis or as a result of expo-
sure to toxins. Potentially life-threatening
envenomation may result from contact with
Chironex fleckeri (the Australian box jellyfish or
sea wasp) a large bell-shaped creature whose
bell may span up to 30 cm and whose long ten-
tacles may span up to several meters. Its potent
venom contains dermatonecrotic factors and
cardiotoxins. It is believed that approximately
Fig. 15.14 Cutaneous reaction to jellyfish sting (Courtesy 10 cm of tentacles are sufficient to deliver a fatal
of Dirk M. Elston, M.D.). Photograph in the public dose. Contact with the Australian box jelly may
domain results in whip or ladder-like cutaneous lesions,
and in some cases, death from cardiovascular
Localized cutaneous lesions appear as linear, collapse within minutes.
urticarial erythema (Fig. 15.14) which may prog- Management of all jellyfish stings should
ress within minutes to hours to vesiculation and include removing the victim from water to pre-
sometimes necrosis in the area of contact with vent drowning with assessment of the victim and
tentacles. Pain, burning sensation, paresthesias, initiation of basic life support as needed. Steps
and hyperhidrosis may accompany the skin should be taken to prevent further stinging by
lesions. Cases of recurrent eruptions occurring at non-discharged nematocysts. The sting should
variable intervals after the initial injury have been not be rubbed or rinsed with fresh water due to
reported [69–73]. the danger of massive nematocyst discharge.
Systemic symptoms may accompany the cuta- Different species respond differently to various
neous manifestations of a jellyfish sting and treatments [82], and it is important to note that
include local cramping and muscle spasms, par- vinegar (3–6% acetic acid) effectively inhibits
esthesias, nausea and vomiting, weakness, dizzi- nematocyst discharge in some jellyfish, but may
ness, and malaise. The Irukandji syndrome, named trigger discharge in other species [83]. The
after the aboriginal Australian tribe who inhabit Australian Resuscitation Council recommends
Northeast Queensland, was first described in 1952. vinegar use for the Australian box jellyfish and
Jack Barnes positively identified the culpable for cases of Irukandji syndrome [84]. If vinegar is
jellyfish, which came to be known as Carukia not available, seawater may be used to rinse the
barnesi, by envenomating himself, his 9-year-old sting. There is no evidence supporting the use of
son, and a local lifeguard in 1961 [74]. Carukia urine in the treatment of jellyfish stings. Once
barnesi is a small jellyfish characterized by four nematocysts are deactivated, all remaining tenta-
tentacles and a bell of approximately 2 cm. cles should be removed from the victim.
Approximately 20–30 min after a relatively innoc- Although inactivation of further nematocyst
uous sting, victims experience severe, cramping firing is critical, it does not provide pain relief for
pain, nausea, vomiting, diaphoresis, shortness of venom that has already been injected. Following
breath, and a sense of impending doom. Massive removal of remaining tentacles, hot water may be
catecholamine release is thought to be responsi- applied to the area for pain relief and denaturing
ble. The majority of envenomations resolve spon- of venom [85, 86].
taneously [75]. However, cases of heart failure, Localized reactions may then be symptomati-
pulmonary edema, and hypertensive stroke neces- cally treated with antihistamines, topical corti-
sitating supportive therapy have been reported costeroids, and local anesthetics. Tetanus
[76] as well as death [77, 78]. Various reports of prophylaxis should be administered, if indicated.
Irukandji-like syndromes have been described in Systemic reactions secondary to Irukandji
Thailand, Hawaii, and Florida [79–81]. syndrome may require analgesics, oxygen, anti-
282 A. Uliasz
emetics, and supportive treatment as necessary.

The toxic effects of envenomation by Chironex
fleckeri may be neutralized by antivenom which
is composed of immunoglobulins from hyperim-
munized sheep serum. It should be administered
in cases of severe pain, dyspnea, dysphagia, dys-
phonia, unconsciousness, cardiorespiratory
arrest, hypotension, or dysrhythmia. Basic or
advanced life support and intensive care mea-
sures should be taken as appropriate.
Fig. 15.15 Sea urchin (Courtesy of Dr. James P. McVey,
NOAA Sea Grant Program). Photograph in the public
domain
15.5.2 Sea Urchins
radiographs, ultrasound, or MRI may be per-
Found in all oceans, sea urchins belong to the formed to confirm the complete removal of
phylum Echinodermata which also includes sea retained spines. Antibiotics are indicated for sec-
cucumbers and starfish. Sea urchins are slow- ondary infections.
moving, coastal dwellers with numerous spines
(Fig. 15.15). Depending on the species of sea
urchin, the spines may be sharp or blunt, solid or 15.5.3 Stingrays
hollow, and may or may not be venomous. Most
venomous species are found in tropical and sub- Stingrays, members of the class Chondrichthyes,
tropical regions. The flower sea urchin are flat bottom-dwellers that reside in shallow
(Toxopneustes pileolus), found off the coast of waters, hidden beneath a layer of sand with only
Japan, is the most venomous sea urchin known. their eyes visible (Fig. 15.16). Stingrays may be
Most injuries from sea urchins occur when the found in both saltwater (in temperate and tropical
brittle calcium carbonate spines break off and coastal regions throughout the world) and in fresh
become embedded in the skin when accidentally or brackish waters (in South America, Southeast
stepped on or handled. Penetration injury results Asia, and Africa) [94]. Injuries most frequently
in localized sharp pain, bleeding, erythema, and occur on the lower extremities when a swimmer
edema. Arthritis, synovitis, or tenosynovitis may or wader inadvertently startles the creature. Injury
occur if the injury is periarticular. The pigment of may be avoided by shuffling one’s feet when
the implanted spines may leave behind a purple walking in shallow water, alerting the stingray of
or black tattoo. human presence, and giving it ample time to
The affected area should be soaked in hot swim away. When provoked, the stingray’s whip-
water (as hot as the patient can tolerate) to deac- like tail swings forward impaling the victim with
tivate toxins and alleviate pain. Tetanus prophy- serrated spines which range in size from less than
laxis should be administered [87]. Although spine 2.5 cm to over 30 cm in length and release a heat-
fragments may be absorbed by the body within labile, vasoconstrictive venom [94]. The immedi-
1–3 weeks, an attempt to remove all embedded ate effects are local, severe pain out of proportion
fragments should be made as infections, granu- to the injury and vasoconstriction progressing to
loma formation, and arthritis may arise from necrosis of the involved area. Systemic effects
retained spine fragments and the ensuing foreign may include myocardial infarction, cardiovascu-
body reaction [88–91]. Removal is often compli- lar arrhythmias, and bradycardia [95]. Rarely,
cated by breakage of the delicate spines, and death may occur from penetration injuries to the
many techniques have been described using nee- thorax or abdomen [96, 97].
dles, forceps, punch biopsy [92], and erbium- Treatment consists of irrigating the area with
YAG laser [93]. Imaging studies including plain hot water to inactivate the venom and administering
Fig. 15.16 The freshwater

Polka Dot Stingray,
Potamotrygon leopoldi
(Courtesy of Dirk M.
Elston, M.D.). Photograph
in the public domain
local anesthetic or a nerve block without epi-

References
nephrine as well as parenteral analgesics. Tetanus 1. Visscher PK, Vetter RS, Camazine S. Removing bee
prophylaxis should be given. The wound should stings. Lancet. 1996;348(9023):301–2.
be debrided and explored for retained spines [98]. 2. Severino M, Bonadonna P, Passalacqua G. Large local
If superficially located, the spine should be reactions from stinging insects: from epidemiology to
management. Curr Opin Allergy Clin Immunol.
removed. However, if the spine is found to be 2009;9(4):334–7.
penetrating the neck, thorax, or abdomen, or 3. Bilo BM, Bonifazi F. Epidemiology of insect-venom
completely though an extremity, it is best left in anaphylaxis. Curr Opin Allergy Clin Immunol.
place until the patient is taken to a medical facil- 2008;8(4):330–7.
4. Bilo BM, et al. Diagnosis of Hymenoptera venom
ity where this can be performed safely [94]. allergy. Allergy. 2005;60(11):1339–49.
Radiographic studies may be employed to 5. Ross RN, Nelson HS, Finegold I. Effectiveness of
ensure complete removal. Secondary infections specific immunotherapy in the treatment of
by gram-negative (Vibrio) and gram-positive hymenoptera venom hypersensitivity: a meta-analy-
sis. Clin Ther. 2000;22(3):351–8.
(Staphylococcus and Streptococcus) bacteria are 6. Reisman RE. Natural history of insect sting allergy:
common and prophylactic antibiotics are recom- relationship of severity of symptoms of initial sting
mended, most commonly a 5-day course of a qui- anaphylaxis to re-sting reactions. J Allergy Clin
nolone or amoxicillin with clavulanic acid [99]. Immunol. 1992;90(3 Pt 1):335–9.
7. van der Linden PW, et al. Insect-sting challenge in 324
subjects with a previous anaphylactic reaction: current
criteria for insect-venom hypersensitivity do not pre-
15.6 Further Resources dict the occurrence and the severity of anaphylaxis. J
Allergy Clin Immunol. 1994;94(2 Pt 1):151–9.
8. Reisman RE, et al. Stinging insect allergy: natural his-
American Association of Poison Control Centers tory and modification with venom immunotherapy. J
and Poison Help Hotline: http://www.aapcc.org/ Allergy Clin Immunol. 1985;75(6):735–40.
dnn/default.aspx. 9. Graft DF, et al. Assessment of prolonged venom
World Health Organization World Directory immunotherapy in children. J Allergy Clin Immunol.
1987;80(2):162–9.
of Poison Centers: http://www.who.int/gho/phe/ 10. Golden DB, et al. Regimens of Hymenoptera venom
chemical_safety/poisons_centres/en/. immunotherapy. Ann Intern Med. 1980;92(5):620–4.
284 A. Uliasz
11. Carballada F, et al. Follow-up of venom immunother- 31. Moss HS, Binder LS. A retrospective review of black
apy (VIT) based on conventional techniques and mon- widow spider envenomation. Ann Emerg Med.
itoring of immunoglobulin E to individual venom 1987;16:188–91.
allergens. J Investig Allergol Clin Immunol. 2010; 32. Clark R, Wethern-Kestner S, Vance MV, et al. Clinical
20(6):506–13. presentation and treatment of black widow spider
12. Ascunce MS, et al. Global invasion history of the fire envenomation: a review of 163 cases. Ann Emerg
ant Solenopsis invicta. Science. Med. 1992;21:782–7.
2011;331(6020):1066–8. 33. Campbell BJ, Forrester LJ, Barrett TJ. Direct lysis of
13. Caplan EL, et al. Fire ants represent an important risk red blood cells by the venom of Loxosceles reclusa.
for anaphylaxis among residents of an endemic region. Fed Proc. 1977;36:669.
J Allergy Clin Immunol. 2003;111(6):1274–7. 34. Forrester LJ, Barrett JT, Campbell BJ. Red blood cell
14. Tracy JM, et al. The natural history of exposure to the lysis induced by venom of the Brown Recluse spider;
imported fire ant (Solenopsis invicta). J Allergy Clin the role of sphingomyelinase-D. Arch Biochem
Immunol. 1995;95(4):824–8. Biophys. 1978;187:335.
15. Mlot NJ, Tovey CA, Hu DL. Fire ants self-assemble 35. Vorse H, Seccareccio P, Woodruff K, Humphrey GB.
into waterproof rafts to survive floods. Proc Natl Acad Disseminated intravascular coagulopathy following
Sci U S A. 2011;108(19):7669–73. fatal brown recluse spider bite (necrotic arachnidism).
16. deShazo RD, et al. Fire ant attacks on patients in nurs- J Pediatr. 1972;80:1035–7.
ing homes: an increasing problem. Am J Med. 36. Elbahlawan LM, Stidham GL, Bugnitz MC, Storgion
2004;116(12):843–6. SA, Quasney MW. Severe systemic reaction to
17. Hoffman DR. Ant venoms. Curr Opin Allergy Clin Loxosceles reclusa spider bites in a pediatric popula-
Immunol. 2010;10(4):342–6. tion. Pediatr Emerg Care. 2005;21(3):177–80.
18. deShazo RD, Butcher BT, Banks WA. Reactions to 37. Elston DM. Systemic manifestations and treatment of
the stings of the imported fire ant. N Engl J Med. brown recluse spider bites. Cutis. 2004;74(6):336.
1990;323(7):462–6. 338, 340.
19. Triplett RF. The imported fire ant: health hazard or 38. Elston DM, Miller S, Young III RJ, Eggers J,
nuisance? South Med J. 1976;69(3):258–9. McGlasson D, et al. Comparison of colchicine, dap-
20. Stablein JJ, Lockey RF. Adverse reactions to ant sone, triamcinolone, and diphenhydramine therapy
stings. Clin Rev Allergy. 1987;5(2):161–75. for the treatment of brown recluse spider envenoma-
21. Dietrich JJ, et al. Imported fire ant hypersensitivity: a tions: a double-blind, controlled study in a rabbit
1-day rush immunotherapy schedule without premed- model. Arch Dermatol. 2005;141:595–97.
ication. Ann Allergy Asthma Immunol. 2009;103(6): 39. Saucier J. Arachnid envenomation. Emerg Med Clin
535–6. North Am. 2004;22(2):405–22.
22. Diaz J. The global epidemiology, syndromic 40. Bucaretchi F, Deus Reinaldo C, Hyslop S, Madureira
classification, management, and prevention of spider PR, De-Capitani EM, Vieira RJ. A clinico-epidemio-
bites. Am J Trop Med. 2004;71(2):239–50. logical study of bites by spiders of the genus Phoneutria.
23. Sudhof T. The global epidemiology, syndromic Rev Inst Med Trop Sao Paulo. 2000;42:17–21.
classification, management, and prevention of spider 41. Vetter RS, Isbister GK. Medical aspects of spider
bites. Annu Rev Neurosci. 2001;24:933–62. bites. Annu Rev Entomol. 2008;53:409–29.
24. Henkel AW, Sankaranarayanan S. Mechanisms of 42. Chippaux JP, Goyffon M. Epidemiology of scorpi-
alpha-latrotoxin action. Cell Tissue Res. onism: a global appraisal. Acta Trop. 2008;107(2):
1999;2(296):229–33. 71–9.
25. Kose A, Bozkurt S, Lok U, Zenginol M, Yildirim C, 43. Holve S. Venomous spiders, snakes, and scorpions in
Gunay N, Kose B. Presumptive Latrodectus bite with the United States. Pediatr Ann. 2009;38(4):210–7.
ileus and myocardial involvement. Wilderness Environ 44. West PL, Hendrickson RG. Scorpions on a plane? A
Med. 2010;21(3):271–2. case series of non-endemic scorpion envenomations. J
26. Sari I, Zengin S, Davutoglu V, Yildirim C, Gunay N. Emerg Med. 2011;41(1):89.
Myocarditis after black widow spider envenomation. 45. Bawaskar HS, Bawaskar PH. Utility of scorpion anti-
Am J Emerg Med. 2008;26(5):630. venin vs prazosin in the management of severe
27. Quan D, Ruha A. Priapism associated with Latrodectus Mesobuthus tamulus (Indian red scorpion) envenom-
mactans envenomation. Am J Emerg Med. 2009; ing at rural setting. J Assoc Physicians India. 2007;
27(6):759. 55:14–21.
28. Sams HH, Dunnick C, Smith ML, King Jr LE. 46. Bawaskar HS, Bawaskar PH. Efficacy and safety of
Necrotic arachnidism. J Am Acad Dermatol. 2001; scorpion antivenom plus prazosin compared with pra-
44:561–73. zosin alone for venomous scorpion (Mesobuthus tam-
29. Rf C. The safety and efficacy of antivenin Latrodectus ulus) sting: randomised open label clinical trial. BMJ.
mactans. J Toxicol Clin Toxicol. 2001;39:119–23. 2011;342:c7136.
30. O’Malley GF, Dart R, Kuffner EF. Successful treat- 47. Undheim EA, King GF. On the venom system of cen-
ment of lactrodectism with antivenin after 90 hours. N tipedes (Chilopoda), a neglected group of venomous
Eng J Med. 1999;340:657. animals. Toxicon. 2011;57(4):512–24.
48. Fung HT, Lam SK, Wong OF. Centipede bite victims: 67. Norris RL, Pfalzgraf RR, Laing G. Death following
a review of patients presenting to two emergency coral snake bite in the United States–first documented
departments in Hong Kong. Hong Kong Med J. case (with ELISA confirmation of envenomation) in
2011;17(5):381–5. over 40 years. Toxicon. 2009;53(6):693–7.
49. Yildiz A, et al. Acute myocardial infarction in a young 68. Tibballs J. Australian venomous jellyfish, envenoma-
man caused by centipede sting. Emerg Med J. tion syndromes, toxins and therapy. Toxicon.
2006;23(4):e30. 2006;48:830–56.
50. Hasan S, Hassan K. Proteinuria associated with centi- 69. Menahem S, Shvartzman P. Recurrent dermatitis from
pede bite. Pediatr Nephrol. 2005;20(4):550–1. jellyfish envenomation. Can Fam Physician. 1994;40:
51. Logan JL, Ogden DA. Rhabdomyolysis and acute 2116–8.
renal failure following the bite of the giant desert cen- 70. Tamanaha RH, Izumi AK. Persistent cutaneous hyper-
tipede Scolopendra heros. West J Med. 1985;142(4): sensitivity reaction after a Hawaiian box jellyfish sting
549–50. (Carybdea alata). J Am Acad Dermatol. 1996;35(6):
52. Friedman IS, et al. Wells’ syndrome triggered by cen- 991–3.
tipede bite. Int J Dermatol. 1998;37(8):602–5. 71. Uri S, Marina G, Liubov G. Severe delayed cutaneous
53. Barnett PL. Centipede ingestion by a six-month-old reaction due to Mediterranean jellyfish (Rhopilema
infant: toxic side effects. Pediatr Emerg Care. nomadica) envenomation. Contact Dermatitis.
1991;7(4):229–30. 2005;52(5):282–3.
54. Chaou CH, et al. Comparisons of ice packs, hot water 72. Rallis E, Limas C. Recurrent dermatitis after solitary
immersion, and analgesia injection for the treatment envenomation by jellyfish partially responded to tac-
of centipede envenomations in Taiwan. Clin Toxicol rolimus ointment 0.1%. J Eur Acad Dermatol
(Phila). 2009;47(7):659–62. Venereol. 2007;21(9):1287–8.
55. Balit CR, et al. Prospective study of centipede bites 73. Di Costanzo L, et al. Successful management of a
in Australia. J Toxicol Clin Toxicol. 2004;42(1): delayed and persistent cutaneous reaction to jellyfish
41–8. with pimecrolimus. J Dermatolog Treat. 2009;20(3):
56. Makarov SE, et al. Defensive secretions in three spe- 179–80.
cies of polydesmids (Diplopoda, Polydesmida, 74. Barnes JH. Cause and effect in Irukandji stingings.
Polydesmidae). J Chem Ecol. 2010;36(9):978–82. Med J Aust. 1964;1:897–904.
57. Radford AJ. Millipede burns in man. Trop Geogr 75. Nickson CP, et al. Irukandji syndrome case series
Med. 1975;27(3):279–87. from Australia’s Tropical Northern Territory. Ann
58. Shpall S, Frieden I. Mahogany discoloration of the Emerg Med. 2009;54(3):395–403.
skin due to the defensive secretion of a millipede. 76. Little M, Mulcahy RF, Wenck DJ. Life-threatening
Pediatr Dermatol. 1991;8(1):25–7. cardiac failure in a healthy young female with
59. Lima CA, et al. Exogenous pigmentation in toes Irukandji syndrome. Anaesth Intensive Care. 2001;
feigning ischemia of the extremities: a diagnostic 29(2):178–80.
challenge brought by arthropods of the Diplopoda 77. Fenner PJ, Hadok JC. Fatal envenomation by jellyfish
Class (“millipedes”). An Bras Dermatol. 2010;85(3): causing Irukandji syndrome. Med J Aust. 2002;
391–2. 177(7):362–3.
60. De Capitani EM, et al. Human accidents involving 78. Pereira P, et al. Intracerebral hemorrhage and death
Rhinocricus spp., a common millipede genus observed after envenoming by the jellyfish Carukia barnesi.
in urban areas of Brazil. Clin Toxicol (Phila). Clin Toxicol (Phila). 2010;48(4):390–2.
2011;49(3):187–90. 79. Fenner PJ, Lippmann J, Gershwin LA. Fatal and non-
61. Gutierrez JM, et al. Snakebite envenoming from a fatal severe jellyfish stings in Thai waters. J Travel
global perspective: towards an integrated approach. Med. 2010;17(2):133–8.
Toxicon. 2010;56(7):1223–35. 80. Yoshimoto CM, Yanagihara AA. Cnidarian (coelen-
62. Bronstein AC, et al. 2010 Annual Report of the terate) envenomations in Hawai’i improve following
American Association of Poison Control Centers’ heat application. Trans R Soc Trop Med Hyg. 2002;
National Poison Data System (NPDS): 28th Annual 96(3):300–3.
Report. Clin Toxicol (Phila). 2011;49(10):910–41. 81. Grady JD, Burnett JW. Irukandji-like syndrome in
63. Singletary EM, et al. Envenomations. Med Clin North South Florida divers. Ann Emerg Med. 2003;42(6):
Am. 2005;89(6):1195–224. 763–6.
64. Bush SP. Snakebite suction devices don’t remove 82. Yoshimoto CM. Jellyfish species distinction has
venom: they just suck. Ann Emerg Med. treatment implications. Am Fam Physician. 2006;
2004;43(2):187–8. 73(3):391.
65. Anz AW, et al. Management of venomous snakebite 83. Fenner PJ, et al. First aid treatment of jellyfish stings
injury to the extremities. J Am Acad Orthop Surg. in Australia. Response to a newly differentiated spe-
2010;18(12):749–59. cies. Med J Aust. 1993;158(7):498–501.
66. Dart RC, McNally J. Efficacy, safety, and use of snake 84. Council AR. Guideline 9.4.5 envenomation: jellyfish
antivenoms in the United States. Ann Emerg Med. stings. 2010 March 2011. Available from: http://www.
2001;37(2):181–8. resus.org.au/.
286 A. Uliasz
85. Nomura JT, et al. A randomized paired comparison 93. Boer A, et al. Effective removal of sea-urchin spines
trial of cutaneous treatments for acute jellyfish by erbium: YAG laser ablation. Br J Dermatol.
(Carybdea alata) stings. Am J Emerg Med. 2002; 2001;145(1):169–70.
20(7):624–6. 94. Diaz JH. The evaluation, management, and preven-
86. Atkinson PR, et al. Is hot water immersion an effec- tion of stingray injuries in travelers. J Travel Med.
tive treatment for marine envenomation? Emerg Med 2008;15(2):102–9.
J. 2006;23(7):503–8. 95. Ikeda T. Supraventricular bigeminy following a sting-
87. Rossetto AL, de Macedo Mora J, Haddad Jr V. Sea ray envenomation: a case report. Hawaii Med J.
urchin granuloma. Rev Inst Med Trop Sao Paulo. 1989;48(5):162. 164.
2006;48(5):303–6. 96. Parra MW, et al. Surviving a transfixing cardiac injury
88. Haddad Jr V, et al. Tropical dermatology: marine and caused by a stingray barb. J Thorac Cardiovasc Surg.
aquatic dermatology. J Am Acad Dermatol. 2009; 2010;139(5):e115–6.
61(5):733–50. quiz 751-2. 97. Fenner PJ, Williamson JA, Skinner RA. Fatal and
89. Ahmad R, et al. Sea urchin spine injuries of the hand. non-fatal stingray envenomation. Med J Aust.
J Hand Surg Eur Vol. 2008;33(5):670–1. 1989;151(11–12):621–5.
90. Wada T, et al. Sea urchin spine arthritis of the hand. 98. Trickett R, Whitaker IS, Boyce DE. Sting-ray injuries
J Hand Surg Am. 2008;33(3):398–401. to the hand: case report, literature review and a sug-
91. De La Torre C, Toribio J. Sea-urchin granuloma: gested algorithm for management. J Plast Reconstr
histologic profile. A pathologic study of 50 biopsies. Aesthet Surg. 2009;62(8):e270–3.
J Cutan Pathol. 2001;28(5):223–8. 99. Clark RF, et al. Stingray envenomation: a retro-
92. Sjoberg T, de Weerd L. The usefulness of a skin spective review of clinical presentation and treat-
biopsy punch to remove sea urchin spines. ANZ J ment in 119 cases. J Emerg Med. 2007;33(1):
Surg. 2010;80(5):383. 33–7.
Index
A differential diagnosis, 69
Abrahams, I., 134 epidemiology, 61–62
Abuse etiologies, 64
bites, 252 blood products, 66–67
burns, 249–251 food, 65–66
clinical oral manifestations, 252 hymenoptera stings, 68
contusions, 248–249 idiopathic reactions, 68
cutaneous signs, 247–248 latex, 67–68
definition of, 247 medications, 66–67
demographics, 248 physical stimuli, 68–69
ecchymoses, 248–249 viral infections, 69
follicular hyperkeratosis, 252 pathophysiology, 62–63
hypovitaminosis A, 252 risk factors, 64
mistaken for abuse, 252–255 treatment, 74–76
phrynoderma, 252 Angioedema
sexual abuse, 251 clinical features, 63–64
violent hair pulling, 252 definitions, 61
workup, 248 diagnosis, 69–72
Acanthosis nigricans, 196, 203–204 differential diagnosis, 69
Acute cutaneous lupus erythematosus (ACLE), epidemiology, 61–62
209–210 etiologies, 64
Acute generalized exanthematous pustulosis blood products, 66–67
(AGEP) food, 65–66
antibiotics, 50 hymenoptera stings, 68
clinical presentation, 50 idiopathic reactions, 68
HIV-positive patient, 95 latex, 67–68
Adult-onset Still disease (AOSD) medications, 66–67
emergent complications, 226 physical stimuli, 68–69
etiology, 226 viral infections, 69
laboratory findings, 226–227 pathophysiology, 62–63
treatment, 227 risk factors, 64
Ahmed, A.R., 151 treatment, 72–74
AIDS. See HIV-positive patient Anthrax, 24–25
Akhyani, M., 134 Antiphospholipid syndrome (APS)
Alkali burns, 245 definition, 214–215
American trypanosomiasis, 36–37 emergent complications, 215
Amyloidosis, 202–203 incidence, 215
Anal fissures, 253 laboratory findings,
Anaphylaxis 215–216
clinical features, 63–64 treatment, 216
definitions, 61 Apidae bites, 271–272
diagnosis, 72 Arachnids bite, 274–277

DOI 10.1007/978-1-4614-5031-3, © Springer Science+Business Media, LLC 2013
288 Index
Atopic dermatitis Burn injury

bacterial superinfection, 14 and abuse, 249–251
eczema herpeticum, 13–14 alkali burns, 245
erythroderma, 14 antimicrobial agents, 240
Australian funnel web spider bite, 275 chemical injuries, 244–245
Autologous serum skin tests (ASSTs), 72 depth of, 236–237
diagnosing infections, 239
electrical injuries, 244
B evaluation, 235–236
Bacillary angiomatosis (BA), 91 fluid resuscitation, 238–239
Bacterial infections healed wounds care, 243–244
anthrax, 24–25 hydrofluoric acid, 245
cellulitis, 21 silver nitrate, 240
ecthyma gangrenosum, 28–29 silver sulfadiazine, 240
HIV-positive patient surgical management, 241–243
bacillary angiomatosis, 91 systemic derangements, 241
Cancrum oris, 91 tar and grease, 245
Staphylococcus aureus, 90–91 topical burn care, 239–241
syphilis, 91 topical debriding agents, 240–241
lyme disease, 23–24 total burn surface area (TBSA) calculation,
malignant otitis externa, 21 237–238
meningococcemia, 22 zones of injury, 238
necrotizing fasciitis, 19–21
purpura fulminans, 28
rocky mountain spotted fever (RMSF), 22–23 C
staphyloccocal scalded skin syndrome, 26–27 Cahn, J.Y., 114
toxic shock syndrome (TSS), 27–28 Cancrum oris, 91
tularemia, 25–26 Candidiasis, 34, 88–89
Bacterial superinfection, 14 Centipedes bite, 277
Bart syndrome, 2 Chagas disease, 36–37
Behcet disease Chemical burn injury, 244–245
criteria for, 224 Chemical peel emergencies, 268
emergent complications, 224 Chen, Y.C., 48
laboratory findings, 224–225 Child abuse. See Abuse
treatment, 225 Chronic cutaneous LE (CCLE), 210–212
Behroozan, D., 203, 204 Churg–Strauss syndrome, 178, 182–183
Billingham, R.E., 105 Cirrhosis, 201–202
Bites Coin rubbing, 255
abuse, 252 Collagen vascular disease
arachnids, 274–277 adult-onset Still’s disease (AOSD),
insects, 271–274 226–227
marine creatures, 280–283 antiphospholipid syndrome (APS), 214–216
snakes, 277–280 Behcet disease, 224–225
Black widow spiders bite, 274–275 dermatomyositis (DM), 216–218
Bolognia, J.L., 59 lupus erythematosus, 207–214
Bordeaux, J.S., 261 neonatal lupus (NLE), 214
Botella–Estrada, R., 134 reactive arthritis (ReA), 225–226
Botox emergencies, surgical complications, relapsing polychrondritis (RP), 220–221
267–268 rheumatoid arthritis (RA), 221–223
Brown recluse spiders bite, 275 Sjogren syndrome (SS), 223–224
Bruce, A.J., 62 systemic sclerosis (SSc), 218–220
Budd–Chiari syndrome, 224 Collodion baby, 4–5
Bullae diabeticorum, 195–196 Colon cancer, 203
Bullous pemphigoid (BP) Congenital dermal melanocytosis, 253–254
age of onset, 160 Conradi–Hunermann syndrome, 4–5
clinical presentation, 161 Contusions, 248–249
incidence, 160–161 Cryoglobulinemic vasculitis, 180–181
relative risk, 161 Cryptococcus, 89–90
systemic corticosteroids, 161–162 Cushing syndrome, 198–199
target antigens, 161 Cytomegalovirus (CMV), 32–33, 92–93
Index 289
D E
D’Angelis, C., 168 Ecchymoses, 248–249
Dehiscence, 265–266 Ecthyma gangrenosum, 28–29
Dermatitis herpetiformis, 201 Eczema herpeticum, 13–14
Dermatologic surgical complications Ehlers–Danlos syndrome, 265
botox emergencies, 267–268 Elapidae bite, 279–280
chemical peel emergencies, 268 Electrical burn injury, 244
dehiscence, 265–266 Engraftment syndrome (ES), 110
filler emergencies, 266–267 Eosinophilia, 11
golden rule, prevention, 259–260 Eosinophilic folliculitis (EF), 87
hemorrhage, 260–263 Epidermolysis bullosa
infection, 263–265 causative factor, 2
laser emergencies, 266 differential diagnosis, 2
necrosis, 265 dystrophic epidermolysis bullosa, 3–4
procedural emergencies, 266–268 epidemiology, 2
Dermatomyositis (DM) epidermolysis bullosa simplex, 2
characteristics, 216–217 junctional epidermolysis bullosa, 3
diagnosis, 217 Epidermolysis bullosa acquisita (EBA), 166–167
emergent complications, 217–218 Epidermolysis bullosa simplex (EBS), 2, 159–160
laboratory findings, 218 Epinephrine, 74–75
treatment, 218 Erythema multiforme, 10
Dermatoses, 133–134 Erythroderma, 14
Diabetes, 195–196 clinical manifestations, 138–139
Donor lymphocyte infusion (DLI), 112 complications, 142
Dowling–Meara (DM) EBS, 2 cutaneous T-cell lymphoma, 136–137
Drug allergy, 66–67 dermatoses, 133–134
Drug eruptions drug hypersensitivity reactions, 135
acute generalized exanthematous epidemiology, 133
pustulosis, 50 etiology, 133–137
clinical features, 52 GVHD, 137
drug rash with eosinophilia and systemic symptoms, histopathology, 139–141
47–50 internal malignancy, 137
eosinophilia, 11 malignancy, 135–136
erythema multiforme, 10 pathogenesis, 137–138
exanthematous reaction, 9 pityriasis rubra pilaris, 135
fixed drug eruption, 9–10 prognosis, 142
rashes, 11 psoriasis, 134–135
serum sickness, 51–52 sezary syndrome, 139
serum sickness-like reaction, 9 treatment, 141–142
Stevens–Johnson syndrome, 10–11, Evans syndrome, 216
43–47
toxic epidermal necrolysis, 10–11, 43–47
urticaria, 8–9 F
Drug hypersensitivity reactions, 135. Felty syndrome, 222
See also Histamine-mediated Filler emergencies, 266–267
cutaneous lesions Fire ants, 272–274
Drug hypersensitivity syndrome (DHS), Fisher, M., 37, 168
93–94 Fluid resuscitation, burn injury, 238–239
Drug rash with eosinophilia and systemic symptoms Fogo selvagem (FS), 157–158
(DRESS), 11 Follicular hyperkeratosis, 252
anticonvulsants, 49 Food allergy, 65–66
clinical presentation of, 48 Formicidae bites, 272–274
diagnostic marker, 48 Fungal infections
Gell and Coombs classification, 48 histoplasmosis, 35–36
hypersensitivity syndrome, 48–49 HIV-positive patient
incidence, 47–48 candidiasis, 88–89
and liver, 49 cryptococcus, 89–90
steroid therapy, 49–50 mucormycosis, 35
systemic features, 49 neonatal, 8
Dystrophic epidermolysis bullosa (DEB), 3–4, pediatric, 16
167–168 systemic candidiasis, 34
290 Index
G Graves disease, 196–197

Garcia–Doval, I., 46 Grease burn injury, 245
Gastric antral vascular ectasia (GAVE), 219
Gastrointestinal disease, 200–202
German measles, 33 H
Giant cell arteritis, 186 Half-and-half nails, 194–195
Glucksberg, H., 113 Hemangiomas, 6–7
Goodpasture syndrome, 181 Hematopoietic stem cell transplantation (HSCT)
Gottron papules, 216 bone marrow extraction, 104–105
Graft-versus host disease (GVHD) graft-versus-leukemia (GVL) effect, 105–106
acute form (aGVHD) indications, 104
abnormal liver functions, 108–109 myeloablative conditioning, 103
anti-tumor effects, 111 treatment-related morbidity and mortality, 105
autoGVHD, 110–111 Hemorrhage, 260–263
classification, 106 Henoch–Schonlein purpura (HSP), 12, 178–179
clinical manifestation, 108–110 Hepatobiliary, 201–202
clinical signs, 110 Herlitz JEB, 3
clinical trials criteria, 106 Herpes simplex virus (HSV), 15–16
diagnosis, 108 clinical presentations, 5
donor lymphocyte infusion, 112 diagnosis, 5–6
engraftment syndrome, 110 epidemiology, 5
exanthematous drug reactions, 108 herpetic superinfection, 29–30
Glucksberg clinical stage and grade, 113 HIV-positive patient, 92–93
histopathology, 108 incidence, 29
IBMTR severity index, 113 transmission, 29
lymphocytic infiltration, 108–110 treatment, 6, 30
NK cells role, 107 Herpes zoster
organs involved, 107 immunosuppressed patients, 31–32
pathogenesis, 106–107 ophthalmicus, 32
prophylaxis and treatment, 114 Ramsay–Hunt syndrome, 32
signs and timing, 110 treatment, 32
solid organ transplantation, 111–112 Herpes zoster ophthalmicus, 32
staging and grading, 112–114 Histamine-mediated cutaneous lesions
transfusion, 112 discovery, 57–58
chronic form (cGVHD) hypersensitivity reactions, 59–61
B cell homeostasis, 120–121 mastocytosis, 76–80
chronic inflammation, 121 receptors of, 58
clinical manifestations, 115 systemic effects, 58–59
cytopenias, 120 urticaria, angioedema, and anaphylaxis, 61–76
definition, 114–115 Histoplasmosis, 35–36
diagnosis, 119–120 HIV-positive patient
fasciitis and myositis, 121–122 acute generalized exanthematous pustulosis, 95
fibrosis, 121 bacterial infections, 90–91
genital lesions, 119 diagnosis, 85
histopathologic features, 119 drug hypersensitivity syndrome, 93–94
incidence, 115 drug reactions, 93
interleukin-2 (IL-2) role, 123–124 eosinophilic folliculitis, 87
lichenoid, 115–116 fungal infections, 88–90
mesenchymal stem cells, 124 immune reconstitution inflammatory syndrome, 96–97
nail and hair abnormality, 119 infection process, 83–84
ocular manifestations, 119 infectious complications, 87–88
pathophysiology, 120 Kaposi sarcoma, 95–96
phototherapy, 122 primary HIV infection, 84
physiotherapy, 121–122 psoriasis, 86–87
pigment abnormalities, 119 retroviruses, 83
prophylactic treatment, 122 Stevens–Johnson syndrome, 94–95
pulmonary signs and symptoms, 120 toxic epidermal necrolysis, 94–95
sclerotic variants, 115 treatment, 85
signs and symptoms, 116–118 viral infections, 92–93
systemic therapy, 122–123 Hood, A.F., 110
Index 291
Hsieh, K.S., 186 Libman–Sacks endocarditis, 215

Hydrofluoric acid burn injury, 245 Lichen sclerosus, 253
Hymenoptera bites, 271 Linear IgA bullous dermatosis (LABD), 165–166
Hyperlipidemia, 193–194 Livedo reticularis, 215
Hypocomplemetemic utricarial vasculitis syndrome Lofgren syndrome, 198
(HUVS), 180 Lumbar syndrome, 7
Hypothyroidism, 197 Lupus erythematosus (LE)
Hypovitaminosis A, 252 acute cutaneous lupus erythematosus (ACLE),
209–210
chronic cutaneous LE (CCLE), 210–212
I classification criteria for, 208
Ichthyosis, 4–5 constitutional symptoms, 207
Immune reconstitution inflammatory syndrome (IRIS), emergent complications, 208–209
96–97 hematologic manifestations, 207
Infantile hemangiomas (IHs), 6–7 laboratory examination, 213
Insect bites nonspecific skin disease, 212–213
apidae, 271–272 subacute cutaneous lupus erythematosus (SCLE), 210
formicidae, 272–274 treatment, 213–214
hymenoptera, 271 Lyme disease, 23–24
vespidae, 271–272
International bone marrow transplant registry (IBMTR)
severity index, GVHD, 113–114 M
Interstitial lung disease (ILD), 217 Maintz, L., 59
Intraepidermal blistering diseases, 147–148 Malignant otitis externa, 21
Irukandji syndrome, 280 Marine creatures bite
jellyfish, 280–282
sea urchins, 282
J stingrays, 282–283
Jellyfish sting Martino, R., 113
death, 281 Mastocytosis
hazardous classes, 280 clinical features, 77–78
localized cutaneous lesions, 281 definition, 76
localized reactions, 281 diagnosis, 78–79
management, 281 epidemiology, 76
systemic reactions, 281–282 pathophysiology, 76–77
systemic symptoms, 281 treatment, 79–80
venom, 280 WHO classification, 76
Jorizzo, J.L., 59 Mayo, W., 203
Junctional epidermolysis bullosa (JEB), 3, 167–168 Measles, 33
Juvenile dermatomyositis (JD), 11–12 Meningococcemia, 22
Methicillin-resistant Staphylococcus aureus (MRSA),
90–91
K Meulener, M., 168
Kaposi sarcoma (KS), 95–96 Microscopic polyangitis, 181
Kawasaki disease (KD) Millipedes bite, 277
clinical manifestation, 13 Mohr, M., 168
treatment, 13 Molluscum contagiosum, 93
vasculitis, 185–186 Monoclonal antibody (mAb), 74
Kidney disease Mucocutaneous leishmaniasis, 37
half-and-half nails, 194–195 Mucormycosis, 35
uremic pruritus, 195 Mucous membrane pemphigoid (MMP)
Kindler syndrome, 2 diagnosis, 163–164
King, L.E., 134 incidence, 163
Krishnamurthy, K., 168 treatment modality, 164–165
Mycobacterial infections, 88
L
Laser emergencies, 266 N
Latex allergy, 67–68 Necrobiosis lipoidica, 195, 196
Leishmaniasis, 37 Necrosis, 265
292 Index
Necrotizing fasciitis, 15 systemic glucocorticoids, 151

antimicrobial regimens, 20 tetracycline, 152
characteristics, 19 topical therapy, 150–151
clinical features, 19–20 Phototherapy, 122
mortality rates, 21 Phrynoderma, 252
treatment, 20–21 Physiotherapy, 121–122
types, 19 Pityriasis rubra pilaris (PRP), 135
Neonatal dermatologic conditions Polyarteritis nodosa, 184–185
atopic dermatitis, 13–14 Port-wine stains (PWS), 7–8
drug eruptions, 8–11 Preseptal cellulitis, 21
epidermolysis bullosa, 2–4 Primary biliary cirrhosis (PBC), 219
herpes simplex virus, 5–6 Psoriasis, 86–87, 134–135
ichthyosis, 4–5 Pulmonary artery hypertension (PAH), 219
primary infections, 14–16 Pulmonary disease, 199–200
signs and symptoms, 1–2 Purpura fulminans, 28
systemic diseases, 11–13 Pyoderma gangrenosum, 200–201
vascular birthmarks, 6–8
Neonatal Gaucher disease, 4
Neonatal lupus (NLE), 214 R
Newcomer, V.D., 199, 200 Radioallergosorbent (RAST) test, 69
Nicolis, G.D., 134 Ramsay–Hunt syndrome, 32
Noma, 91 Rapini, R.P., 59
Nonbullous congenital ichthyosiform erythroderma Reactive arthritis (ReA)
(NCIE), 4–5 emergent complications, 225–226
laboratory findings, 226
skin findings, 225
O treatment, 226
Offringa, P.J., 249, 250 Red Man Syndrome, 67
Oplatek, A., 46 Reiter’s syndrome
Orbital cellulitis, 21 emergent complications, 225–226
Orthotopic liver transplant (OLT), 111–112 laboratory findings, 226
skin findings, 225
treatment, 226
P Relapsing polychrondritis (RP)
Pal, S., 134 characteristics, 220
Pancreatic panniculitis, 201 emergent complications, 220–221
Paraneoplastic pemphigus (PNP), 158–159 laboratory findings, 221
Parasitic infections treatment, 221
American trypanosomiasis, 36–37 Rheumatoid arthritis (RA), 221–223
mucocutaneous leishmaniasis, 37 bywater lesions, 221–222
Parvovirus B19, 33–34 emergent complications, 222
Peanut allergy, 66 laboratory findings, 222
PELVIS syndrome, 7 nodules, 221
Pemphigoid gestationis, 162–163 treatment, 223
Pemphigus foliaceus (PF), 154–157 Ritter’s disease. See Staphyloccocal scalded skin
Pemphigus vegetans, 154 syndrome (SSSS)
Pemphigus vulgaris (PV) Rocky mountain spotted fever (RMSF), 22–23
baseline laboratory data, 151–152 Rosen, D.I., 63, 77
blister formation, 148 Rowell syndrome, 213
dapsone, 152 Rowlings, P.A., 113
differential diagnosis, 149 Rubeola, 33
etiology, 148 Rym, B.M., 134
histology, 149
immunomodulatory procedures, 153–154
immunosuppressive agents, 152–153 S
mortality rate, 149–150 Sarcoidosis, 197–198
mucosal membrane erosions, 149 Schick, B., 51
plasmapheresis, 154 Schnitzler syndrome, 180
prevalence, 148 Scleroderma renal crisis (SRC), 219
systemic corticosteroids, 151 Scorpion stings, 276–277
Index 293
Sea urchins injury, 282 HIV-positive patient, 94–95

Sehgal, V.N., 134 incidence, 44
Senear–Usher syndrome, 212 lymphocyte transformation test, 47
Serum sickness neutropenia, 47
antibiotic causes, 51 Nikolsky sign, 45
clinical syndrome, 51 pathogenesis, 45
cutaneous manifestations, 51–52 SCORETEN assessment, 46
diagnosis, 52 systemic corticosteroids, 46–47
immune complexmediated hypersensitivity reaction, topical antibiotics, 46
51 Stingrays injury, 282–283
treatment, 52 Stings. See Bites
Serum sickness-like reactions (SSLRs). See Serum Sturge–Weber syndrome (SWS), 7–8
sickness Subacute cutaneous lupus erythematosus (SCLE), 210
Sexual abuse, 251 Subepidermal blistering diseases, 160
Sezary syndrome, 139 Surgical site infections (SSIs), 263–265
Shellfish allergy, 65 Sweet syndrome, 204
Sigurdsson, V., 134 Syphilis, 91
Sinusoidal obstruction syndrome (SOS), 109 Systemic sclerosis (SSc)
Sister Mary Joseph nodule, 203–204 definition, 218
Sjogren–Larsson syndrome, 4–5 disease presentation, 218–219
Sjogren syndrome (SS) emergent complications, 219
characteristics, 223 laboratory findings, 219–220
emergent complications, 223 treatment, 220
laboratory findings, 223
treatment, 223–224
Skin manifestations, internal disease T
amyloidosis, 202–203 Takayasu arteritis, 186
cushing syndrome, 198–199 Tar burn injury, 245
diabetes, 195–196 Terry nails, 202
gastrointestinal disease, 200–202 Thyroid disease, 196–197
hyperlipidemia, 193–194 Toxic epidermal necrolysis (TEN), 94–95
kidney disease, 194–195 Toxic shock syndrome (TSS), 27–28
malignancy, 203–204 Transfusion associated aGVHD (TA-GVHD), 112
pulmonary disease, 199–200 Trichothiodystrophy, 4
sarcoidosis, 197–198 Tuberculosis, 88
thyroid disease, 196–197 Tularemia, 25–26
Smoking effects, 265
Snakes bite
elapidae, 279–280 U
viperidae, 278–279 Uremic pruritus, 195
South American armed spider bite, 276 Urticaria, 8–9
Spider angiomas, 201–202 clinical features, 63–64
Spiders bite definitions, 61
Australian funnel web spider, 275 diagnosis, 69–72
black widow, 274–275 differential diagnosis, 69
brown recluse, 275 epidemiology, 61–62
south American armed spider, 276 etiologies, 64
treatment, 275 blood products, 66–67
Staphylococcal scalded skin syndrome (SSSS), food, 65–66
14–15 hymenoptera stings, 68
causative organism, 26 idiopathic reactions, 68
initial signs, 26–27 latex, 67–68
prognosis, 27 medications, 66–67
Stevens–Johnson syndrome, 10–11 physical stimuli, 68–69
causative agents, 45 viral infections, 69
clinical features, 44 pathophysiology, 62–63
diagnosis, 46 physical form, 70–71
erythema multiforme, 44–45 risk factors, 64
etiology, 43 treatment, 72–74
histopathologic analysis, 46 Urticarial vasculitis, 179–180
294 Index
V dystrophic epidermolysis bullosa (DEB),

Varicella zoster virus (VZV) 167–168
characteristics, 30 epidermolysis bullosa acquisita (EBA),
congenital form, 30–31 166–167
HIV-positive patient, 92 epidermolysis bullosa simplex, 159–160
neonatal form, 31 fogo selvagem (FS), 157–158
vaccine, 31 hereditary and non hereditary forms, 147
Vascular birthmarks intraepidermal blistering diseases, 147–148
hemangiomas, 6–7 junctional epidermolysis bullosa (JEB), 167–168
port-wine stains, 7–8 linear IgA bullous dermatosis (LABD), 165–166
Vasculitis mucous membrane pemphigoid, 163–165
Churg–Strauss syndrome, 182–183 paraneoplastic pemphigus (PNP), 158–159
classification, 175–177 pemphigoid gestationis, 162–163
connective tissue disorder-associated, 184 pemphigus foliaceus, 154–157
cryoglobulinemic, 180–181 pemphigus vegetans, 154
cutaneous small vessel vasculitis, 178 pemphigus vulgaris (PV), 148–154
definition, 178 subepidermal blistering diseases, 160
drug-associated, 184 therapies used, 155–156
emergent nature, 176 Vespidae bites, 271–272
giant cell arteritis, 186 Violent hair pulling, 252
Henoch–Schonlein purpura (HSP), 178–179 Viperidae bite, 278–279
histology, 188 Viral infections
history, 186–187 cytomegalo virus, 32–33
infection-associated, 183–184 German measles, 33
Kawasaki disease, 185–186 herpes Simplex Virus (HSV), 29–30
laboratory and radiologic evaluation, 187–188 herpes zoster, 31–32
malignancy-associated, 183 HIV-positive patient
microscopic polyangitis, 181 HSV, 92–93
pathogenesis, 176 molluscum contagiosum, 93
pathologic evaluation, 187 measles, 33
physical exam, 187 parvovirus B19, 33–34
polyarteritis nodosa, 184–185 varicella zoster virus, 30–31
Takayasu arteritis, 186 von Pirquet, C., 51
treatment
cyclophosphamide, 189
novel biologic therapy, 189–190 W
symptomatic, 188–189 Weber–Cockayne (WC) EBS, 2
systemic immunosuppression, 189 Wegener granulomatosis, 182
urticarial, 179–180 Well syndrome, 277
Wegener granulomatosis, 182 Wiley, J., 113
Venom
apidae and vespidae, 271–272
centipede, 277 X
fire ants, 273 Xanthelasmas, 194
jellyfish, 280 Xanthomas, 193–194
jellyfish sting, 280
scorpions, 276–277
sea urchins, 282 Y
snakes, 278–280 Yuan, X., 134
spiders, 274–276
stingrays, 282
Venom immunotherapy (VIT), 68 Z
Vesiculobullous dermatoses Zhou, H., 124
bullous pemphigoid (BP), 160–162 Zones of injury, 238
clinical characteristics, 147 Zygomycosis, 35

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Buka’s Emergencies in Dermatology

Bobby Buka Annemarie Uliasz

ISBN 978-1-4614-5030-6 ISBN 978-1-4614-5031-3 (eBook)

Library of Congress Control Number: 2012952281

© Springer Science+Business Media, LLC 2013

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

“A thick skin is a gift from God.”

As dermatology residents, long before we are asked to discern papu-

New York, NY, USA Robert L. Buka

To Mom, whose support turned every challenge into an opportunity for

To Uncles Steve and Dave and their spirit of mischief.

To Bari who showed me how to be a doctor first and a physician second.

To Bogi who taught me the periscope has two ends.

To Matt, my older and dearest friend.

1 Neonatal and Pediatric Dermatologic Emergencies ................ 1

14 Dermatologic Surgery Complications ....................................... 259

Index ..................................................................................................... 287

Maryam Afshar, MD Division of Dermatology, Department of Medicine,

Lawrence F. Eichenfield, MD Pediatric & Adolescent Dermatology, Rady

Rachel Nazarian, MD Department of Dermatology, Mt. Sinai Hospital,

potentially resulting in death. It is therefore

B. Buka et al. (eds.), Buka’s Emergencies in Dermatology, 1

level exhibiting the plane of separation. Speciﬁc

Epidermolysis bullosa (EB) is a group of con-

1.3.2 Junctional Epidermolysis

JEB (Fig. 1.1), characterized by mechanically

Fig. 1.2 PHACES. Infant with large segmental heman-

1.9 Drug Eruptions and Drug

To conﬁrm the diagnosis, a skin biopsy or

1.9.5 Erythema Multiforme

1.10.3 Kawasaki Disease bility or lethargy, urethritis and sterile pyuria,

1.11.1 Eczema Herpeticum

Eczema Herpeticum (EH, Kaposi’s varicelliform

Fig. 1.6 Eczema Herpeticum. Clustered “punched-out”

current bacterial infection with staphylococcus or

Gingivostomatitis is the most common clinical

adolescents, digital/genital contact is more com-

1.12.4 Fungal Infections

Cutaneous fungal infections, which include der-

2.1 Introduction 2.2 Bacterial Infections

While most infections with dermatological mani- 2.2.1 Necrotizing Fasciitis

B. Buka et al. (eds.), Buka’s Emergencies in Dermatology, 19

Table 2.1 Antimicrobial regimens for necrotizing fasciitis [3]

Meningococcemia is a serious medical emer-

Fig. 2.2 Ritter’s disease

Table 2.2 Antimicrobial regimens for TSS [3, 57]

2.2.11 Purpura Fulminans

Purpura fulminans is seen in three clinical set-

malignancy or immunosuppressive therapy. the neonate during the intrauterine (5%),

Fig. 2.4 Herpes simplex virus

Fig. 2.6 Varicella virus

an erythematous base resembling “dew drops on

of bones and muscles and malformed digits), central

2.6.2 Mucormycosis with cerebral, cutaneous, or pulmonary mucormy-

2.7.2 Mucocutaneous Leishmaniasis

Leishmaniasis, caused by protozoa in the genus