Semin Immunopathol (2016) 38:75–86

DOI 10.1007/s00281-015-0540-2

REVIEW

Adverse cutaneous drug eruptions: current understanding

W. Hoetzenecker 1 & M. Nägeli 1 & E. T. Mehra 2 & A. N. Jensen 3 & I. Saulite 1 &
P. Schmid-Grendelmeier 1 & E. Guenova 1 & A. Cozzio 1 & L. E. French 1

Received: 19 August 2015 / Accepted: 30 October 2015 / Published online: 9 November 2015
# Springer-Verlag Berlin Heidelberg 2015

Abstract Adverse cutaneous drug reactions are recognized as Keywords Adverse cutaneous drug eruptions .
being major health problems worldwide causing considerable Maculopapular rash . Stevens-Johnson syndrome .
costs for health care systems. Most adverse cutaneous drug Toxic epidermal necrolysis . AGEP . DRESS
reactions follow a benign course; however, up to 2 % of all
adverse cutaneous drug eruptions are severe and life-threaten-
ing. These include acute generalized exanthematous Introduction
pustulosis (AGEP), drug reaction with eosinophilia and sys-
temic symptoms (DRESS), Stevens-Johnson syndrome (SJS), As a result of improved treatment outcomes, longer patient
and toxic epidermal necrolysis (TEN). Physicians should be survival, extended treatment courses, and polymedication
aware of specific red flags to rapidly identify these severe of an ageing population, exposure to drugs has increased in
cutaneous drug eruptions and initiate appropriate treatment. frequency and duration. As a consequence, the likelihood
Besides significant progress in clinical classification and treat- of drug sensitization is rising with subsequent increases of
ment, recent studies have greatly enhanced our understanding adverse drug reactions (ADR). Of all organs affected by
in the pathophysiology of adverse cutaneous drug reactions. ADR, the skin is most frequently involved [1]. Cutaneous
Genetic susceptibilities to certain drugs have been identified adverse reactions to drugs are observed in 0.1–1 % of patients
in SJS/TEN patients, viral reactivation in DRESS has been during pre-marketing clinical trials, and post-marketing anal-
elucidated, and the discovery of tissue resident memory T cells yses suggest that their incidence can be as high as 1–8 % for
helps to better understand the recurrent site-specific inflam- certain types of drugs (NSAIDS, antibiotics, antiepileptics)
mation in patients with fixed drug eruption. [1]. The incidence of these reactions amongst hospitalized
patients ranges from 1 to 3 %. The majority of adverse cuta-
neous drug eruptions are benign in nature, mostly occurring as
This article is a contribution to the Special Issue on Immunodermatology maculopapular eruptions or urticaria [2]. Nonetheless, studies
- Guest Editors: Lars French and Alexander Navarini suggest that roughly a third of drug eruptions require hospital
management and are classified as severe, although fortunately
* W. Hoetzenecker only 2 % of cutaneous drug eruptions are really life-
wolfram.hoetzenecker@usz.ch threatening [1]. These include acute generalized exanthema-
* L. E. French tous pustulosis (AGEP), drug reaction with eosinophilia and
lars.french@usz.ch systemic symptoms (DRESS), Stevens-Johnson syndrome
(SJS), and toxic epidermal necrolysis (TEN). Although the
1
Department of Dermatology, University Hospital Zurich, pathomechanism of the benign and severe forms of cutaneous
Gloriastrasse 31, 8091 Zurich, Switzerland drug eruptions remains incompletely understood, great prog-
2
Medical Directorate, University Hospital of Zurich, Rämistrasse 100, ress in this field of medicine has been made in the past few
8091 Zurich, Switzerland years. Improvements range from the clinical classification
3
Department of Dermatology, Medical University of Vienna, that is essential for a better understanding of cutaneous
Währinger Gürtel 18-20, 1090 Vienna, Austria ADR to the identification of genetic susceptibilities to
76 Semin Immunopathol (2016) 38:75–86

certain drugs and consequently the implementation of the

first preventive genetic screening measures for selected
patient groups and drug classes [1]. Allergologic workup
to identify the culprit agent includes skin tests (prick, in-
tradermal, and epicutaneous testing [3]), in vitro assays
(basophil activation tests [4], lymphocyte activation tests
[5], measurements of drug-induced cytokine production
(e.g., Enzyme-Linked ImmunoSpot (ELISpot)) [6–8]),
and/or in some cases, serum measurement of drug-
specific IgEs [9]. The aim of this review is to give a current
overview of the field of cutaneous drug eruptions with a
special focus on the pathogenesis and immunopathology.

Benign drug-induced maculopapular rash

Drug-induced exanthematous reactions of the skin are the

most common hypersensitivity reactions. They have been
reported to occur in approximately 2 % of hospitalized
patients [10–12]. Cutaneous exanthematous drug reactions
most frequently present themselves clinically as a
maculopapular rash (MPR), but they can also present in
eczematoid-, psoriasiform-, or lichenoid-like pattern. The
MPR is characterized as erythematous maculae and/or pap-
ules, which are symmetrically distributed on the trunk and
extremities (Fig. 1). In contrast to severe adverse drug re-
actions like SJS and TEN, MPR is not associated with skin Fig. 1 Clinical pattern of a maculopapular rash after the intake of
detachment. However, some cutaneous lesions might de- amoxicillin in an EBV-positive patient
velop into bullous lesions. Furthermore, in MPR, the mu-
cosae are not involved. The exanthematous lesions show a
quite characteristic symmetric distribution, most often urticarial lesions might be a first sign of a more severe ana-
appearing on the ventral and dorsal trunk before expanding phylactic reaction and caution should be taken before the next
to the proximal extremities (Fig. 1). In some exanthemas dose. The drug classes of pharmacological agents responsible
with a more papular phenotype, a distribution starting on for the majority of cutaneous adverse reactions include antibi-
the extremities has been observed. Another pattern is char- otics, anti-infectious, and tuberculostatic drugs as well as an-
acterized by a distribution of the rash to the large body ticonvulsant and antihypertensive agents. In contrast, there are
folds (e.g., intertriginous, perigenital, and perianal area) some drugs that are very rarely associated with an adverse
sparing the central parts of the trunk. This particular pat- cutaneous reaction, such as antihistamines, digoxin, local an-
tern is observed in the so-called symmetrical drug-related esthetics, steroid hormones, acetylsalicylic acid, acetamino-
intertriginous and flexural exanthema (SDRIFE or so- phen, and coumarins [10].
called Baboon syndrome [13], which will be discussed in
detail further below). The chronology of the appearance of Pathophysiology
lesions in drug-induced MPR is quite characteristic and of
importance in the clinical diagnosis [2]. When exposed to Drug-induced exanthemas are often considered as immu-
the drug for the first time, the skin eruption will be delayed nologically mediated hypersensitivity reactions, although
until after a sensitization phase of at least 5 to 7 days. such a mechanism can only be proven in a minority of
Typically, full-blown skin lesions form around the eight cases. The underlying pathophysiological mechanisms are
to the tenth day after the first contact with the sensitizing manifold. In many cases, an immunological type IV hyper-
agent. In the following week, drug-reactive cells expand. sensitivity reaction according to Coombs and Gell is the
In previously exposed and sensitized patients, renewed ex- underlying pathomechanism [14]. Recently, a further sub-
posure to the same drug results in the appearance of the classification of type IV hypersensitivity reactions into
first skin lesions within 6 to 12 h. If typical wheals and types IVa to IVd has been proposed (Table 1) [15]. Type
flares appear within a few hours after drug intake, such IVa corresponds to a Th1-type immune reaction with
Semin Immunopathol (2016) 38:75–86 77

Table 1 Classification of delayed drug hypersensitivity reactions as HIV. Patients with certain autoimmune disorders such as
(adapted from Bircher et al. [92])
systemic lupus erythematosus also have a higher incidence
Type IVa Type IVb Type IVc Type IVd of ADR [17, 18].

Immune TH1 cells TH2 cells Perforin/ CXCL8, IL-17, Management

reactant granzyme GM-CSF
B (CTL) (T cells)
Antigen Antigen presented by Cell-associated Soluble antigen Identification and rapid discontinuation of the culprit drug
cells or direct antigen or presented by are the most important therapeutic measures. Depending
T cell stimulation direct T cell cells or direct on the nature and intensity of signs and symptoms, topical
stimulation T cell
stimulation corticosteroids and systemic antihistamines for symptom
Effector Macrophage Eosinophils T cells Neutrophils relief, especially itch control, can be helpful. In severe
Example Allergic DRESS Contact AGEP cases, treatment with systemic corticosteroids over a short
contact dermatitis, period of time is indicated.
dermatitis SJS, TEN
Red flags None Facial edema Mucous lesions Pustules
Eosinophilia Conjunctival
Hepatitis lesions Localized forms of drug-induced exanthemas
Nephritis Painful skin
Swollen LN Greyish skin
color Symmetrical drug-related intertriginous and flexural
Epidermal exanthema
detachment
Skin erosions
Diagnostic Patch test Patch test IC (late reading) IC (late reading)
SDRIFE, or Baboon Syndrome, is a drug-related exanthema
workup LTT, Patch test Patch test symmetrically located on the flexural areas (e.g., axillae, bot-
ELISpot LTT, ELISpot LTT, ELISpot toms) [13]. SDRIFE means symmetrical drug-related
intertriginous and flexural exanthema. In opposition to other
DRESS drug reaction with eosinophilia and systemic symptoms, SJS
Stevens-Johnson syndrome, TEN toxic epidermal necrolysis, AGEP acute drug-induced exanthematous reactions, men are more often
generalized exanthematous pustulosis, IC intracutan, LTT lymphocyte affected than women. Perigenital and perianal involvement
transformation test, LN lymph nodes, ELISpot Enzyme-Linked is associated with the involvement of the large body folds,
ImmunoSpot—a measurement of drug-induced cytokine production in such as the axilla, the elbows, and the knees. Papules, pus-
T cells
tules, or vesicles are rarely found, although erythematous
patches and plaques are typical. Systemic symptoms such as
macrophages as major effector cells secreting interferon-γ high fever, malaise, and visceral organ involvement are rare.
and stimulating a pro-inflammatory response via TNF-α The exanthema can subsequently result in rather heavy des-
and IL-12 (e.g., allergic contact dermatitis) (Fig. 2). Type quamation. Aminopenicillins are the most frequent causative
IVb corresponds to a Th2-type immune response involving in agent, but other drugs have also been associated [13]. The
particular cytokines IL-4, IL-13, and IL-5, which promote B chronology of SDRIFE development is still subject to con-
cell expansion and subsequent plasma cell activation with troversy, with long reaction times of up to 7 days between
production of IgE and IgG4. This type IVb pathomechanism initial exposure and onset of lesions having been reported,
can explain the eosinophil-rich inflammation that may be seen which could indicate a new sensitization. A T cell-mediated
in many drug-induced exanthemas and is especially relevant allergic reaction seems to be the most frequent pathomech-
in the pathogenesis of DRESS (Fig. 2). In type IVc reactions, anism. Rapid withdrawal of the causative pharmaceutical
the T cells themselves are the effector cells. Direct cytotoxicity agent and administration of topical or systemic corticoste-
is mediated by granzyme B, granulysin, and, in cells express- roids are recommended.
ing Fas (CD95), by FAS ligand (CD95L) (Fig. 2). This
pathomechanism is observed in maculopapular exanthemas, Fixed drug eruption
but more often in severe cutaneous drug reactions like SJS/
TEN. Type IVd reactions are mediated by CXCL8 (interleu- Solitary or few well-circumscribed, round and/or oval ery-
kin 8) and granulocyte-macrophage colony-stimulating factor thematous macules and plaques with dusky centers on the skin
(GM-CSF)-producing T cells, which recruit neutrophilic and/or mucous membrane are the most common lesions found
granulocytes and prevent their apoptosis. This pathomecha- in fixed drug eruption (FDE) (Fig. 3). Rarely, the lesions may
nism appears to play a major role in AGEP (Fig. 2). Cofactors evolve to become bullous. One pathognomonic characteristic
in the elicitation of exanthemas include concomitant viral of FDE is the site-specific reoccurrence of lesions with each
infections, particularly infections involving viruses of the new exposition to the causative agent. Usually, lesions appear
herpes family such as EBV, CMV, and HHV-6 [16], as well within 30 min to 8 h after exposition [19]. The appearance of
78 Semin Immunopathol (2016) 38:75–86

MPR DRESS AGEP SJS/TEN

Erythematous macules and papules Erythematous macules and papules Subcorneal pustules Blisters, detachment of epidermis

Necroc
CD4+ keranocytes

CD4+ Apoptoc
Fixed drug erupon CD8+
CD4+ keranocytes

CD8+
Fas-L Fas
CD4+ CD8+
CD4+ CD4+ CD95
Granulysin
TRM Perforin
Granzyme B
Neu Annexin A1
CD4+
CD8+ CD8+
Eo CD8+
TEM Drug IL-5 CD8+
Naive Eo Neu
T Cell IFN- IL-4
CD8+
TNF IL-13
Monocyte
IL-12 Eo IL-8 GM-CSF
NK cell
Drug
Skin-draining APC CD4+ CD4+
lymph node

Fig. 2 Pathophysiological mechanisms underlying adverse cutaneous toxic epidermal necrolysis (TEN). APC antigen-presenting cell, TRM
drug reactions. Maculopapular rash (MPR), drug reaction with resident memory T cell, TEM effector memory T cell, GM-CSF
eosinophilia and systemic symptoms (DRESS), acute generalized granulocyte-macrophage colony-stimulating factor, Eo eosinophilic
exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS)/ granulocyte, NK cell natural killer cell, Neu neutrophilic granulocyte

FDE lesions is often preceded and/or accompanied by a sen- after orally administered rather than parenterally adminis-
sation of itching or burning. FDE typically resolves after dis- tered drugs: the most common agents are pseudoephedrine,
continuation of the causative drug, leaving a circumscribed trimethoprim, tetracycline, barbiturates, sulfonamide,
hyperpigmented area at the site of resolved lesions. Although mefenamic acid, acetylsalicylic acid, phenolphthalein, ibu-
systemic manifestations are usually absent in cases with profen, and oxyphenbutazone. Recent data suggests that
solitary FDE lesions, multiple lesions are often associated the characteristic recurrent site-specific inflammation can
with systemic symptoms including malaise, high fever, be at least partially explained by the role played by tissue
nausea, and arthralgia [20–23]. Most FDE lesions occur sessile immune cells, so-called resident memory T cells
(Fig. 2). Tissue resident memory T cells (TRM) provide
long-lasting specific immunity to infection (e.g., herpes
virus) and remain resident in the skin for a long period of
time after antigen/drug exposure. They are also associated
with recurring site-specific inflammatory diseases (e.g.,
cutaneous T cell lymphoma, psoriasis, FDE) [24–27]. The
skin-infiltrating T cell phenotypes in FDE lesion are strik-
ingly similar to TRM, as various murine in vivo studies
have shown [28–30]. One hypothesis is that TRM (both
self- and drug-antigen-reactive) home to the inflammatory
lesions in FDE as an immunological response and remain
resident after inflammation subsides. Recurrent exposition
would then reflect the subsequent reactivation of these
TRM in response to local or systemic inflammatory signals.
Similarly, the involvement of new skin areas previously
unaffected could reflect the silent distribution of sensitized
effector memory T cells from the initially involved site or
draining lymph nodes to previously unaffected areas. This
hypothesis is further supported by the fact that patch test-
ing only yields diagnostic evaluable results when per-
Fig. 3 Fixed drug eruption after the intake of thiazide formed at the skin site involved during previous FDE, but
Semin Immunopathol (2016) 38:75–86 79

not in uninvolved skin. Therapeutic recommendations in- two ends of a spectrum of severe epidermolytic adverse cuta-
clude identification and cessation of the causative drug. Top- neous drug reactions differing only by the extent of skin de-
ical application of corticosteroids over a short period of time is tachment and should not be classified as two separate clinical
usually sufficient to clear the cutaneous inflammation. entities [1]. SJS and TEN are rare with an incidence of roughly
1.9 cases per million inhabitants per year [32, 33]. There are
several factors that seem to impact on the incidence of SJS and
Stevens-Johnson syndrome and toxic epidermal TEN: regional differences in drug prescription, the genetic
necrolysis—a disease spectrum of severe cutaneous background of patients (HLA, metabolizing enzymes), the
drug reactions coexistence of cancer, concomitant radiotherapy, and certain
infectious diseases (e.g., HIV) [34, 35].
Toxic epidermal necrolysis (TEN) and Stevens-Johnson Syn- Non-specific symptoms such as fever, stinging eyes, and
drome (SJS) are rare but severe medical emergencies. The discomfort upon swallowing precede the cutaneous onset of
average reported mortality rate for SJS is between 1 and TEN and SJS by hours to days. Cutaneous lesions in TEN and
5 %, and it increases up to 25–35 % in patients with TEN. SJS usually first appear in not only the presternal region and
SJS was first described by two US physicians, Stevens and the face but also the palms and soles. The involvement of the
Johnson. In 1922, they observed an acute mucocutaneous buccal, genital, and/or ocular mucosa, characterized by ery-
syndrome in two young boys, which was characterized by thema and erosions, occurs in more than 90 % of patients, and
purulent conjunctivitis, severe stomatitis with extensive in some cases the respiratory and gastrointestinal tract is also
mucosal necrosis, and purpuric macules. This condition affected [36, 37]. Ocular involvement is frequent [38, 39].
became known as SJS and was recognized as a severe Early skin lesions often present as erythematous and livid mac-
mucocutaneous disease with a prolonged course and po- ules, which may or may not show slight infiltration and have a
tentially lethal outcome. In most cases, it is drug-induced tendency to coalesce rapidly and evolve into tense bullae
and it should be distinguished from erythema multiforme (Fig. 4). As the disease progresses, lesions form large, conflu-
(EM) majus. A previously undescribed eruption resem- ent areas of epidermal detachment. The extent of skin involve-
bling scalding of the skin was named toxic epidermal ment is a major prognostic factor. However, only necrotic,
necrolysis in 1956 by the Scottish dermatologist Alan Lyell already detached skin (e.g., blisters, erosions) or detachable
[31]. The association of TEN with exposure to certain medi- skin (Nikolsky positive) should be included in the estimation
cations only became clear as more patients with TEN were of the extent of skin involvement. Bastuji-Garin et al. proposed
reported in the years following Lyell’s original publication. classifying patients into three groups according to the degree
Increasing evidence strongly suggests that SJS and TEN are of skin detachment: 1–10 % defined as SJS, 11–30 % defined

Fig. 4 Toxic epidermal

necrolysis after the intake of
A C
allopurinol due to gout.
a, b Maculopapular rash and skin
detachment with erosions at the
trunk. Please note the
involvement of the lips and
conjunctivae. c, d Full-blown
TEN with massive, detached and
detachable apoptotic skin (greyish
color), erosions, and hemorrhagic
crusts on the trunk, arm, and face

B D
80 Semin Immunopathol (2016) 38:75–86

as SJS/TEN overlap, and greater than 30 % defined as TEN carbamazepine-induced SJS [54]. Several lines of evidence
[40]. Sequelae are common in SJS and TEN and include cuta- suggest that immune activation by the drug-tissue complex
neous hyper- and hypopigmentation (62.5 % of cases), nail leads to a strong expression of the cytolytic molecule FasL
dystrophia (37.5 % of cases), and ocular complications on keratinocytes as well as granulysin and annexin A1 secre-
(50 % of cases) [41, 42]. tion from CTLs, NK cells, NKT cells, and monocytes [55–60]
Most TEN cases are strongly associated with drug in- (Fig. 2). FasL- and granulysin-mediated apoptosis and/or
take: i) preceding exposure to medications is reported in annexin-dependent necroptosis of keratinocytes with sub-
over 95 % of patients with TEN and ii) a strong association sequent epidermal necrosis and detachment follow. The
between drug ingestion and development of the cutaneous role of CD8+ cytotoxic T cells has been discussed in fixed
eruption is observed in 80 % of cases [1]. Other rare causes drug eruptions besides CD4+ helper T cells, which are a source
include infections and immunizations. The link between of IL-10 [61]. This indicates that in skin inflammation, a bal-
drugs and SJS is less strong, as only 50 % of reported ance between pro-inflammatory and immunomodulatory
SJS cases are claimed to be drug-related [1]. This is most mechanisms may critically determine the clinical outcome.
probably an underestimation, most likely due, in part, to Interestingly, in the blister fluid of SJS/TEN patients, but not
the confusion as to the clinical distinction between SJS and in EEM patients, Th17 cells were found alongside CD8+ T
erythema multiforme. Up to date, approx. 100 compounds cells, the former being a source of IL-17, a cytokine-
have been identified as the most likely triggers of individ- recruiting neutrophil [62]. The proportion of Th17 cells
ual SJS/TEN cases. The most frequently incriminated are has been reported to decrease in the periphery upon
allopurinol, antibiotics, non-steroidal anti-inflammatory treatment-related improvement of disease, suggesting a
drugs, and anticonvulsants [1, 43]. role for possible skin homing Th17 cells. In the light of
the recent finding that Th17 cells may functionally trans-
Pathophysiology differentiate to T regulatory cells [63], the decrease of
Th17 cells in improving SJS/TEN might be associated with
To date, the precise molecular and cellular pathomechanisms a simultaneous rise of Tregs and should be monitored in
leading to the development of SJS/TEN are only partially future studies. In accordance, neutropenia is generally as-
understood. The pathophysiology is considered to be initiated sociated with a bad prognosis in SJS/TEN patients [64].
by an immune response to an antigenic drug-host tissue com-
plex [37, 44–47]. Today, three different concepts relating to Management
the formation of the antigenic complex exist: i) covalent
binding of the drug to a cellular peptide (hapten/pro-hapten Diagnostic workup should include rapid histological exami-
concept); ii) non-covalent, direct interaction of the drug with nation including direct immunofluorescence analysis of the
a specific MHC I allotype (p-i concept); and iii) presentation skin biopsy. This approach helps rule out differential diagno-
of an altered-self repertoire by direct drug-MHC I interaction ses such as autoimmune blistering diseases, bullous fixed drug
(altered peptide concept). Whereas the well-known hapten eruption, acute generalized exanthematic pustulosis, and
model is less likely to be HLA-restricted, the other two staphylococcal scalded skin syndrome, which can clinically
concepts favor specific HLA phenotypes. According to mimic SJS/TEN. To date, prospective, controlled clinical trials
these concepts, the allergenic, pharmacological agent showing efficacy of specific therapies in TEN are lacking.
would directly bind to specific HLA molecules and/or T Cyclosporine, cyclophosphamide, plasmapheresis, N-
cell receptors without being processed beforehand in the acetylcysteine, TNF-α antagonists (e.g., etanercept,
antigen-presenting cell. In the case of the p-i concept, the infliximab), systemic corticosteroids, thalidomide, and IVIg
mere pharmacological interaction of certain drugs with im- have been reported to have shown patient benefit in case re-
mune receptors is sufficient to elicit a drug hypersensitivity ports and case series (reviewed in [1]). Regarding IVIg, early
reaction [48]. However, recent publications have shown administration of high doses (≤2 g/kg) is recommended in
modifications of the HLA peptide repertoire through abacavir TEN, even though the mechanism of action is still unclear
and carbamazepine, resulting in enhanced presentation of self- [65–68]. Alternatively, a recent study has shown excellent
peptides and autoimmune reactivity (altered peptide model) efficacy of cyclosporine in the treatment of TEN [69, 70].
[49, 50]. In line with the concepts of HLA-restricted drug
presentation are reports on the genetic susceptibility, as shown
by the identification of specific drug-related HLA alleles Acute generalized exanthematous pustulosis
which strongly increase the susceptibility for the development
of SJS or TEN [51–53]. This is of clinical importance as HLA- The term pustulose exanthématique aiguë généralisée (PEAG)
B*1502 screening in patients with Asian origin prior to drug was first introduced by Beylot et al. in 1980 [71]. The disease
intake could probably identify persons at risk from developing is now called acute generalized exanthematous pustulosis
Semin Immunopathol (2016) 38:75–86 81

(AGEP). The incidence of AGEP is estimated between 1 and 5 adverse drug reactions like SJS, TEN, and DRESS. The vast
cases per million inhabitants per year. Genetic predisposition majority of AGEP cases are drug-induced, although some viral
appears here also to play a role as HLA B51, DR11, and DQ3 infections have also been associated with the disease. Exposure
were found to be more frequently associated with AGEP than to beta-lactam antibiotics and non-steroidal anti-inflammatory
observed in the average population [72]. The hallmark of medications are the most frequent causes of AGEP.
AGEP is an edematous diffuse erythema with the rapid ap-
pearance of multiple, sterile non-follicular pustules [73] Pathophysiology
(Fig. 5). The pustules subsequently often merge together to
form large areas of pustulosis. The large body flexures are So far, the pathophysiology has remained largely unclear. The
classical sites of predilection. The acute phase of the disease neutrophilic process may be orchestrated by T cells that re-
is characterized by fever (>38 °C) and leukocytosis (neutrophil lease CXCL8 (IL-8) or IL-17 [76] (Fig. 2). Recent findings
counts above 7×109/l) [74]. Lymphadenopathy, a slightly suggest an involvement of IL-36. Indeed, a defect in IL36Ra
reduced creatinine clearance, or a mild elevation of liver has been related to pustular forms of psoriasis [77]. Further-
enzymes may be present, but visceral organ involvement is more, Navarini et al. showed that out of a cohort of 96 patients
rare [75]. AGEP usually resolves rapidly within 1–3 days having developed AGEP, 4 had mutations in the gene coding
after withdrawal of the causative agent leaving a characteristic IL-36 [78]. Mutations in IL36RN may lead to uncontrolled IL-
collaret-shaped desquamation pattern. Differential diagnoses 36 signaling and enhanced production of IL-6, IL-8, and IL-1,
for AGEP include other cutaneous pustuloses, such as gener- driving neutrophilic infiltration of the skin characteristic of the
alized acute pustular psoriasis; pustular vasculitis; subcorneal pustular eruptions of AGEP. In rare cases, a localized form of
pustular dermatosis (Sneddon-Wilkinson); or other cutaneous AGEP can occur [79].

Management

Rapid withdrawal of the culprit drug is the most important

therapeutic action to be taken. Short-term application of topi-
cal or systemic corticosteroids may help to clear inflammation
more quickly.

Drug reaction with eosinophilia and systemic

symptoms

Drug reaction with eosinophilia with systemic symptoms

(DRESS), also referred to as drug-induced hypersensitivity
syndrome (DIHS), is a life-threatening systemic reaction af-
fecting multiple organs and can be caused by a limited number
of drugs [80]. DRESS is a rare adverse drug reaction with
population-based studies in Japan reporting an incidence of
10 per million person-years. Upon drug intake, DRESS can
manifest itself as late as 2–3 months after the initial contact
with the causative agent, with symptoms including fever, rash,
lymphadenopathy, hepatitis, and leukocytosis with eosinophil-
ia. The cutaneous lesions are typically erythematous papules
and patchy erythematous macules, which may be pruritic and
confluent, sometimes resembling benign MPR and sometimes
targetoid. The individual lesions are often hemorrhagic and are
symmetrically distributed on the face, trunk, and extremities
(Fig. 6a). Fever usually precedes the rash by 1–2 days. The
most characteristic cutaneous lesions during the earliest phase
of the disease are periorbital and facial edema and erythema
with pinhead-sized pustules. Mucosal surfaces can show a few
lesions, particularly lips and oral mucous membranes although
Fig. 5 AGEP after the intake of terbinafine mucous involvement is much less severe than in SJS/TEN.
82 Semin Immunopathol (2016) 38:75–86

A included in the diagnostic criteria for DRESS syndrome

developed by Japanese experts. In Japan, DRESS syndrome
is known as drug-induced hypersensitivity syndrome or DIHS
[87]. Furthermore, studies have shown that reactivation of other
herpes viruses, namely, EBV, CMV, and HHV-7, is associated
with systemic manifestations and flares of DRESS [16, 88, 89].
Two pathophysiological explanations have been put forward to
explain viral involvement: i) an immune response against the
drug with secondary viral reactivation related to a cytokine
storm and ii) early viral reactivation responsible for most of
the manifestations of DRESS syndrome. While there is evi-
dence that certain drugs able to trigger DRESS can directly
Culprit drug > 3 weeks B induce viral replication in T cells in vitro, the latency between
Ig drug intake and first appearance of DRESS symptoms remains
B cells
NK cells HHV6 to be explained [90]. It has been suggested that expansion of
Exanthema
regulatory T cells might be of significance [83]; however,
most experts favor the hypothesis that virus reactivation is
a simple by-stander effect. While the detection of HHV
reactivation might be useful in the diagnosis of DRESS,
the significance of virus activation in the pathogenesis of
DRESS remains unclear.
Fever
Lymphadenopathy
Hepatitis
Eosinophilia Management

Fig. 6 a DRESS after the intake of trimethoprim/sulfamethoxazole. In most cases, patients with DRESS are treated with sys-
b Schematic diagram of the course of disease in DRESS patients
temic corticosteroids until complete disease control is
achieved [91]. Care should be taken not to withdraw cor-
Cervical, axillary, and inguinal lymphadenopathy can be
ticosteroids too early as this might result in reoccurrence
found in over 70 % of patients during the early course of the
of DRESS. In some situations, topical steroid therapy is
illness. Blood samples usually show a marked leukocytosis
sufficient without systemic therapy.
with atypical lymphocytosis and/or eosinophilia of various
degrees which may lead to an erroneous leukemia diagnosis.
Visceral involvement is common, with degree and patterns
determining disease severity and prognosis (Fig. 6b). The liver Conclusion
(70 %), kidneys (11 %), and lungs [81] are the organs most
frequently involved. Drugs causing DRESS are limited and Luckily, most ADR follow a benign course. However, as
often associated with the intake of carbamazepine, dapsone, approx. 2 % of all ADR are severe and potentially life-threat-
phenytoin, salazosulfapyridine, phenobarbital, allopurinol, ening, particular attention should be given to certain clinical
and zonisamide [79, 82]. symptoms which are to be considered red flags. These include
facial edema, marked eosinophilia, mucous or conjunctival
lesions, painful eyes or skin, greyish skin lesions, and epider-
Pathophysiology mal detachment/erosions and indicate the increased possibility
of a severe drug eruption (Table 1). Rapid identification and
So far, the pathogenesis of DRESS has not been completely withdrawal of the causative drug are critical, although it is
clarified. It has long been known that activated T cells play an often difficult to determine the culprit drug in patients with
important role [83] (Fig. 2). The second pathophysiological polymedication. Therefore, the correct diagnosis of the type of
mechanism involves viral reactivation. Studies done in the skin reaction is important, as it helps to better define the likely
past few years have shown that systemic manifestations of latency and subsequently the culprit drug. Therapeutic options
DRESS are related to human herpes virus (HHV) reactivation include topical corticosteroids as well as oral antihistamines
and to host immune response against the virus [84–86]. As the for symptom relief, as well as systemic corticosteroids in more
HHV can be detected in the blood of approximately 60– severe cases. In the absence of evidence supporting efficacy of
80 % of patients with DRESS at one time point during the other therapeutic options, high-dose IVIg treatment should be
course of the disease, HHV-6 reactivation has been considered for cases of TEN.
Semin Immunopathol (2016) 38:75–86 83

Funding The authors have no other relevant affiliations or financial Surveillance Program on 15,438 consecutive inpatients, 1975 to
involvement with any organization or entity with a financial interest in 1982. Jama 256(24):3358–3363
or financial conflict with the subject matter or materials discussed in the 11. Bigby M (2001) Rates of cutaneous reactions to drugs. Arch
manuscript apart from those disclosed. Dermatol 137(6):765–770
12. Nigen S, Knowles SR, Shear NH (2003) Drug eruptions: ap-
Compliance with ethical standards proaching the diagnosis of drug-induced skin diseases. J Drugs
Dermatol: JDD 2(3):278–299
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Conflict of interest The authors declare that they have no competing 14. Gell PGH, Coombs RRA (1963) Clinical aspects of immunology.
interests. Blackwell, Oxford
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