Allergic contact dermatitis (ACD) is one of the more frequent, vexing, and costly

dermatologic problems. When the

incidence of all occupationally related illness in the United States was last estimated,
ACD accounted for 7 percent, at an
annual cost of $250 million in lost productivity, medical care, and disability payments.
1 Given data suggesting that the
actual annual incidence rate of ACD may be 10 to 50 times greater than reported in
the US Bureau of Labor Statistics
data, the total annual cost of occupational ACD alone may reach $1.25 billion. 1 It
should be noted that these estimates
were based on the assumption that 80 percent of occupational contact dermatitis
(OCD) is irritant and 20 percent allergic.
However, recent data from the United Kingdom 2 and the United States 3 suggest that
the percentage of OCD due to
allergy may be much higher, ranging between 50 and 60 percent, thus raising the
economic impact of occupational ACD
to greater than $3 billion annually. The additional costs of nonoccupational contact
dermatitis are difficult to assess. In
one study, nonoccupational ACD was found three times more frequently than
occupational disease. 3 Furthermore, these
estimates do not include the economic impact of retraining workers and “quality of
life” issues.
HISTORICAL ASPECTS
Although ACD has probably plagued humans for millennia, the term allergy and its
clinical recognition by patch testing
are barely a century old. With the advent of experimental animal models for ACD in
the 1920s, studies concerning its
pathophysiology became possible. Despite all the clinical and scientific research
since, a thorough understanding of the
disease remains elusive.
EPIDEMIOLOGY
Incidence and Prevalence of Disease
The relatively few population-based studies assessing incidence and prevalence
rates of ACD have primarily centered
on specific allergens. Occupational data provide most of the available estimates.
However, as previously noted, these
data are subject to considerable underreporting. In one of the few population-based
studies available, 86 (15.2 percent)
of 567 randomly recruited adults had evidence of at least 1 allergic reaction to the 23
allergens tested. 4 Of note, more
women (18.8 percent) were found to have contact allergies than men (11.5 percent)
in this study. However, it must be
understood that these numbers refer to the prevalence of ACD in the population (i.e.,
the number of individuals who have
the capability to develop ACD when exposed to an allergen), and not to its incidence
(i.e., number of individuals who
develop ACD over a defined period of time).
Age-Related Effects
Clinically, aged individuals have various defects in the induction and/or elicitation of
ACD. 5 In studies on Rhus reactivity,
younger (18 to 25 years) individuals had a quicker onset and a quicker resolution of
the dermatitis than did older
persons. 6 When sensitization rates to standard allergens were evaluated as a
function of age, incidence rates dropped
significantly in individuals older than 70 years. 6 For potent allergens such as
dinitrochlorobenzene (DNCB), the effect of
age on the induction of sensitization is more controversial. 7, 8 The precise reason for
this age-related decline in contact
sensitivity is unknown. Experiments in which contact-sensitized aged mice were
reconstituted with naïve young T cells so
that they subsequently demonstrated normal responses upon antigenic challenge
suggest that a failure of T cell
amplification signals and/or the generation of sufficient T effector cells may be the
primary deficiencies in aged animals. 9
The competency of T cell–mediated immune reactions in children is controversial. 5 It
was believed that children rarely
developed ACD because of an immature immune system. However, as suggested
by Strauss 10 who was able to sensitize
35 of 48 infants (1 to 4 days old) to Toxicodendron oleoresin, the apparent
hyporesponsiveness of children may be due
to limited exposure and not to deficient immunity. Thus, documented allergic
reactions are seen mostly in older pediatric
patients and are secondary to topical medications, plants, nickel, fragrances, or
shoe-related allergens. 5
Patterns of Exposure
Allergen exposure, and, hence, the likelihood of sensitization, varies not only with
age, but also with social customs,
environmental factors, avocation, and occupation. Although most of the gender-
related and geographic variations in ACD
have been attributed to social and environmental factors, 5 avocation and occupation
have more pronounced effects.
Allergic reactions to thiurams (and other rubber constituents), topical medicaments
(benzocaine and neomycin), and
nickel are common among sports enthusiasts, who are frequently exposed to these
materials. 11Health care workers
have high rates of sensitization to thiurams in gloves, while dental personnel and
endoscopic technicians frequently react
to glutaraldehyde, which is a rare allergen in the general population. 12 Finally, one
must be constantly vigilant for the
arrival of potentially new allergens into the environment. For example, the North
American Contact Dermatitis Group
recently added a number of amide anesthetics, once considered rare sensitizers, to
its screening tray given the recent
widespread use of topical anesthetic creams containing these agents.
Concomitant Disease
Impairment of cell-mediated immunity has been reported in certain diseases. In
addition to the obvious disorders
associated with immunologic deficiency, such as AIDS or severe combined
immunodeficiency, diseases as diverse as
lymphoma, sarcoidosis, lepromatous leprosy, and atopic dermatitis have been
associated with diminished reactivity or
anergy. However, while atopic individuals may be less-readily sensitized, the
repeated application of topical preparations
to their damaged skin can result in a significant incidence of ACD in this population.
13
PATHOPHYSIOLOGY
The Allergens
Most environmental allergens are haptens, simple chemicals that must link to
proteins to form a complete antigen before
they can sensitize. These haptens are primarily small (= 500 kDa) electrophilic
molecules that bind to carrier proteins via
covalent bonds ( Table 120-1). Although there are more than 3700 known
environmental allergens, 15not all electrophilic,
protein-binding substances are haptens. The nature of the antigenic determinants,
the type of binding that the hapten
undergoes with the carrier, the final three-dimensional configuration of the conjugate,
and a variety of unknown factors
contribute to the antigenicity of a chemical. However, the importance of the carrier
for the hapten cannot be
underestimated because potent contact sensitizers, when complexed to
nonimmunogenic carriers, can induce tolerance
rather than sensitization. HLA-DR or class II antigens on the surface of the antigen-
presenting Langerhans cells (LCs)
act as the binding site (carrier) for contact allergens. The pathophysiologic basis of
ACD, a type IV, cell-mediated,
delayed hypersensitivity is reviewed in Chap. 23.
TABLE 120-1 The Twenty-five Most Frequent Allergens in the United States:
1996 to 1998*†
Induction and Elicitation
In order for ACD to develop, a genetically susceptible individual must have
biologically significant, and often repeated,
contact with the allergen. As delineated by Friedmann 16 in his review of the
dose/response induction of ACD to DNCB,
“An apparently ineffective sensitizing stimulus is…registered immunologically…[and
results in] enhanced subsequent
responses to the same antigen.” This progressive subclinical induction of disease is
consistent with the multitude of
clinical observations that induction of allergy often takes months to years of exposure
to low levels of the allergen. 17
Furthermore, a variety of endogenous and exogenous factors can influence both the
induction and elicitation of allergic
reactions ( Table 120-2).
TABLE 120-2 Endogenous and Exogenous Factors Affecting Thresholds for
Allergic Contact Dermatitis
The concentrations for inducing ACD are probably the same as those for eliciting the
disease in “real life,” as opposed to
the higher concentrations of allergen required to induce and elicit disease acutely in
the laboratory. The point is
reinforced by the data on incidence rates of occupational ACD, for example, to
chromium in cement workers chronically
exposed to low levels (10 to 50 ppm) of the sensitizing hexavalent form of this metal.
18Because cement is diluted with
water prior to use, chromium concentrations necessary for induction and elicitation of
clinical disease in cement workers
are significantly lower than the chromium concentrations typically used for inducing
or eliciting the allergy by patch
testing (2500 to 5000 ppm).
Primary Sensitization
The route of primary sensitization has a profound effect on the subsequent
immunologic response. Tolerance induction
has been reported after primary systemic injection or oral ingestion of allergens, and
after primary epicutaneous
application of allergens to areas deficient in HLA-DR–positive LCs. The exact
mechanism by which tolerance ensues is
controversial and partly depends on the route of exposure. In most instances, either
induction of hapten-specific
suppressor T cells or clonal deletion of the responding T cells seems responsible.
Antibodies directed against the
antigen recognition site of the T cell receptor (anti-idiotypic antibodies) may also play
a role in tolerance. After tolerance
is induced, it is long-lived and difficult to break. The mechanism(s) of tolerance
induction is reviewed elsewhere. 19
GENETIC FACTORS
Specific Allergens
Although animal studies show strain (presumably genetic) variation in cell-mediated
immunity, the evidence for a genetic
influence in humans is slight. Studies on the induction of ACD to DNCB and para-
nitrosodimethylaniline (PNDA) suggest
a genetic association. 20 However, attempts to correlate HLA haplotype with nickel
sensitivity or other contact allergies
have shown no association. Thus, definitive evidence of class II-related influences
on ACD in humans has been meager,
probably because of our diverse genetic pool and the limitations of technology.
Racial Differences
Whether African Americans develop significantly fewer reactions than do Caucasians
to potent allergens such as DNCB,
PNDA, or paraphenylenediamine (PPD) is controversial. 6 However, in the limited
studies performed to date, the rate of
sensitization to weaker allergens (e.g., nickel and neomycin) seem to be reduced in
African Americans when compared
to Caucasians. 6 This reduced rate of sensitization most likely relates to the greater
compaction and lipid content in the
stratum corneum of African American in contrast to white skin. This enhanced barrier
function of African American skin,
which is also thought to account for reduced rates of irritant contact dermatitis in this
population, likely results in the
observed differences in ACD, rather than any innate, genetically based, immunologic
factors. 6
Studies regarding ACD in other racial groups are very limited. In human
“maximization tests” of cosmetic ingredients,
Japanese individuals showed more severe allergic reactions than did Caucasians,
although incidence rates for reactivity
were the same. 21 Furthermore, Goh found no differences in the incidence of ACD
among the indigenous (Malay,
Chinese, and Indian) subpopulations in Singapore. 22Additional studies evaluating
racial influences on immunologic and
nonimmunologic (e.g., barrier function) factors affecting ACD are needed.
Gender
The genetic effects of gender on ACD remain controversial because few studies
have looked at induction of sensitization
under similar circumstances in men and women. When the “human repeat insult
patch testing” method was used to
assess induction rates to 10 common allergens, women were found to be more often
sensitized to 7 of the 10 allergens
studied. 23However, in “maximization studies” looking at allergens of different
potencies, women reacted more frequently
only to the weakest sensitizers. 24 Nonetheless, when challenged with the potent
allergen DNCB, women had significantly
more severe reactions at lower doses than did men. 25Thus, female gender seems to
correlate with higher rates of
sensitization and frequently more severe reactivity, at least for some allergens.
Notwithstanding this, most gender
differences in ACD seem to relate to cultural patterns and/or exposures in the
workplace. 5
PREVENTION
Avoidance of Allergens
In most cases, “prevention” of ACD has been through avoidance of allergen(s) once
the individual has become
sensitized. However, for some chemicals (such as the metals nickel and chromium),
avoidance once sensitization has
occurred does not necessarily result in symptomatic improvement. Burrows 18 found
that more than 70 percent of
chromium-sensitive workers in Northern Ireland had persistence of their skin disease
for greater than 10 years. The
persistence of ACD to metals, especially nickel and chrome, may partly be related to
their trace levels in foods.
Investigators have demonstrated that levels of nickel and/or chromium similar to
those in foods are capable of eliciting
allergic reactions in some sensitized individuals. 26
Overall, the prognosis for occupationally acquired allergy is poor. In an Australian
study of nearly 1000 workers with
occupational skin disease, 54.7 percent had persistent problems, including many of
the >40 percent who changed jobs.
27 Thus, allergen avoidance once sensitization occurs is inadequate prevention.
Furthermore, advising workers with ACD
to leave their current positions may not be the best advice, especially if a job change
will result in a significantly negative
economic impact.
Induction Thresholds
True prevention of ACD lies in the determination of thresholds for induction of
disease. Armed with this information,
products can be marketed and workplaces designed that contain allergens at levels
below these thresholds. Led by
Denmark, the European Economic Community (EEC) has restricted nickel content in
metals that can contact the skin to =
0.5 μg nickel per cm 2 of skin per week. A decreased rate of nickel dermatitis has
been noted. 28Recently, some authors
have argued for restrictions on chromium content in consumer products to =5 ppm to
reduce rates of nonoccupational
chromate dermatitis. 29Already, many European countries add ferrous sulfate to
cement to lessen the concentration of
hexavalent chromium below the 10 to 50 ppm range, and hence reduce the
sensitizing capacity of cements. As with
nickel restriction, these occupational measures have significantly reduced the
development of new cases of contact
dermatitis to chromium in those countries where they have been instituted. Recently,
European Economic Community
(EEC) investigators have begun to focus on threshold induction levels for certain
allergenic fragrances, such as
isoeugenol.
In the US and EEC, labeling laws give the consumer access to the specific
ingredients contained in cosmetics and
over-the-counter/ prescription medicaments, but do not guarantee that these have
been formulated to minimize
sensitization by potential allergens. Although the safety of individual cosmetic
ingredients is reviewed by the Cosmetic
Ingredient Review's (CIR's) Expert Panel (Washington, DC), and although the panel
has set limits on the use of specific
ingredients based upon their ability to sensitize [e.g., parabens should not be used in
products designed for use on
damaged skin and the concentration of
methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) should be = 7.5 ppm
in “leave on” products], the panel's findings are not binding upon manufacturers
unless the US Food and Drug
Administration (FDA) chooses to enforce its rulings. However, one might anticipate
that manufacturers would not take the
legal and/or financial risks of marketing a product that sensitizes a significant
proportion of consumers, especially if the
sensitizer has been restricted by CIR.
In workplaces in the US, individuals have less assurance regarding exposure to
potential allergens. Although material
safety data sheets (MSDS) should be available for materials handled occupationally,
many times the contents are labeled
proprietary. In addition, MSDS sheets do not need to list chemicals present in
amounts <1 percent, unless they are
carcinogenic. Unfortunately, many common sensitizers, such as biocides, are
present at =1 percent. Even latex, the
cause of life-threatening urticarial reactions in some individuals, is labeled on
medical, but not nonmedical, products.
Currently, prevention requires postsensitization counseling and allergen avoidance.
The success of such efforts after the
diagnosis of ACD largely depends upon how rapidly the correct diagnosis is made.
The longer the dermatitis persists
before adequate treatment, the poorer the prognosis for complete resolution.
Furthermore, patient education regarding
allergen avoidance is crucial to improving outcome. In a study of 230 workers, 30only
one-third accurately recalled their
diagnosis and treatment regimens and, among those workers who could not
remember, persistent dermatitis was three
times more likely.
CLINICAL MANIFESTATIONS
Physical Findings
The clinical appearance of ACD can vary depending on its location and duration. In
most instances, acute eruptions are
characterized by macular erythema and papules, vesicles, or bullae, depending on
the intensity of the allergic response (
Fig. 120-1). However, in acute ACD in certain areas of the body, such as the eyelids,
penis, and scrotum, erythema and
edema usually predominate rather than vesiculation. In contrast, chronic ACD of
nearly all cutaneous sites presents as a
lichenified, scaling, occasionally fissured dermatitis, with or without accompanying
papulovesiculation ( Fig. 120-2 and
Fig. 120-3).
FIGURE 120-1 Acute dermatitis due to poison ivy. Note the linear arrangement of
the lesions typical of phytodermatitis
acquired by inadvertent contact with the plant. The severe vesiculobullous reaction is
typical for urushiol, the
pentadecylcatechol of Toxicodendron spp.
FIGURE 120-2 Chronic dermatitis of ( A) the eyelids and ( B) the neck, but not the
hands, from an allergen in nail-care
products. The patient was allergic to tosylamide/formaldehyde resin in her nail
polish. Similar reactions caused by
tosylamide/epoxy resin in nail polish, or to cyanoacrylate-containing nail glue and
other acrylic products used about the
nails, can be observed. The absence of an associated dermatitis of the fingers or
hands is not unusual.
FIGURE 120-3 Chronic dermatitis of the hands. A. ACD involving the dorsal aspects
of the hands and the distal
forearms, but with minimal involvement of the palms, due to thiuram present in
rubber gloves prescribed for treatment of
an irritant hand dermatitis. B. ACD involving primarily the palms in a florist allergic to
Tuliposide A, the allergen in
Alstroemeria spp. Note the more prominent involvement of the dominant hand.
At its inception, ACD usually involves the cutaneous site of principal exposure.
However, as it evolves, it can spread to
other more distant sites either by inadvertent contact or, under certain
circumstances, by autosensitization (see Chap.
121). Of note, the scalp, palms, and soles are relatively resistant to ACD; these
areas may exhibit little pathology despite
contact with an allergen that produces significant dermatitis in adjacent areas.
A Geographic Approach
While the failure of an eczematous dermatitis to respond to standard treatments may
suggest the possibility of ACD, the
shape and location(s) of the eruption provide the most important clues, especially to
the causal allergen. ACD due to
plants (e.g., poison ivy, poison oak, Primula obconica, and English ivy) is often
characterized by linear lesions ( Fig.
120-1). Aeroallergens, such as the sesquiterpene lactones in Compositae, involve
the more exposed areas of skin with
relative sparing of clothed areas ( Fig. 120-4). In contrast, textile-related allergens
(azoaniline dyes or urea formaldehyde
resins) produce dermatitis of clothed areas with accentuation about the posterior
neck, upper back, lateral thorax,
waistband, flexor surfaces, and periaxillary areas with relative sparing of the axillary
vault and undergarment areas. This
pattern of textile-related ACD points out the importance of such nonimmunologic
factors as pressure, friction, heat, and
perspiration on the ultimate clinical response.
FIGURE 120-4 Airborne ACD to sesquiterpene lactones in ragweed (Ambrosia). This
outdoorsman had annually
developed increasingly more severe outbreaks of dermatitis about the face, neck,
upper chest, and forearms beginning in
late summer and lasting through the fall. The involvement of the submental
area/upper neck and posterior auricular areas
helps to differentiate airborne contact from photocontact. Although he reacted
strongly to the crushed leaf and stem of
native ragweed, he did not react to the commercially available sesquiterpene lactone
mix. The failure to react to the
commercial mix is not unusual and testing to the plant (as is) should be undertaken,
if possible. Although some authors
feel that ragweed dermatitis can be photo-accentuated, this was not the case for this
patient.
A careful clinical assessment of the patient is required before any diagnostic tests to
correctly identify causal allergens.
Krasteva et al. 31 have published on the most frequently encountered causes of ACD
in the major anatomic areas of the
body. Summarized below is an overview of regional contact dermatitis.
HEAD AND NECK ACD of the head and neck can present particular difficulties in
determining the causative allergen(s)
because many substances could potentially be responsible. One must consider not
only the components of facial
cosmetics (vehicles, preservatives, emulsifiers, fragrances), airborne allergens (plant
resins, fragrances), or photocontact
allergens (see Chap. 136), but also grooming aids such as eyelash curlers (nickel,
rubber) or make-up applicators
(rubber). In addition, allergy to chemicals applied to the scalp, which has a greater
resistance to ACD, may manifest itself
on the face, ears, and neck while sparing the scalp (e.g., ACD from para-
phenylenediamine in hair dyes). Finally, the
hands can be an unwitting source of transmission of allergens to the face, ear, and
neck, yet manifest no evidence of
dermatitis themselves. Indeed, in women, a frequent cause of patchy ACD over the
eyelids, face, and neck, but not the
hands, are allergens in nail-care products (see Fig. 120-2).
HANDS Dermatitis of the hands, especially when chronic, is the bane of patients and
practitioners alike. A history of
atopy is frequently seen in many of these patients. In occupationally induced skin
diseases, the hand is involved in
one-third or more of cases. Among certain “wet work” occupations (health care, food
handlers, cosmetologists, etc.), the
number of cases of hand dermatitis is even higher. 1 The etiology of hand dermatitis
is complex because multiple factors,
in addition to atopy, contribute to its development. In some patients, an acute allergic
or irritant contact dermatitis
unmasks an endogenous disease (dyshidrosis, psoriasis, etc.) that otherwise might
not have produced clinical symptoms.
Not unusually, a secondary ACD of the hands will develop in a patient with an
underlying, nonallergic hand dermatitis
who begins using rubber gloves and/or topical creams and who becomes sensitized
to a chemical in these products (see
Fig. 120-3A). Significantly greater involvement of the finger webs and dorsa of the
hands, rather than the palms,
suggests ACD if the allergen contacts all areas of the hand equally ( Fig. 120-3A).
However, the floral worker who snaps
the stems and leaves of Peruvian lilies ( Alstroemeria spp.) with the palmar aspects
of the dominant hand and fingers
may present with dermatitis restricted primarily to these areas ( Fig. 120-3B). When
seeking an allergic cause for hand
dermatitis, one must pay particular attention to those chemicals, listed in standard
texts, 32, 33 that are encountered in the
occupation(s) and hobbies of the patient. In addition, the many household and
cosmetic products used must be identified.
FEET ACD of the feet is usually recognizable because, like the palms of the hands,
the soles of the feet are relatively
resistant to the manifestations of ACD. Thus, the typical picture is a dermatitis over
the dorsal feet that is frequently
accentuated over the joints of the toes. When the plantar aspects of the feet are
involved, ACD typically spares the arch,
toe creases, and webs. Nonetheless, despite a clinical picture suggesting allergy, the
clinician must consider other
diseases (psoriasis, dyshidrosis, juvenile plantar dermatosis, etc.), even when
dermatitis is confined only to the feet.
When allergic, the principal allergens are rubber accelerators (present in rubber-
based liners and/or glues), isocyanates
(present in foam rubber), p-tert-butylphenol formaldehyde resin (glue), or potassium
dichromate (tanned leather) present
in shoes. 34Dyes (in either shoes or socks) are a rare cause of ACD of the feet.
Because the range of potential allergens
in shoes frequently goes beyond that in standard testing kits (e.g., dithiodimorphilone
and isocyanates), 34patch testing
with materials taken from the shoe can be helpful. When testing with pieces of the
shoe, the length of adhesion of the
patch to the skin often must be exaggerated beyond 48 hours, perhaps as long 1
week. Before testing, it is important to
rule out underlying fungal disease, because at least one investigator has transmitted
dermatophyte infection with such
patch testing (William P. Jordan, Jr., MD, personal communication). Finally, when
evaluating dermatitis of the feet, it is
important to note that many cases of secondary ACD develop in individuals applying
topical antibiotics
(neomycin/bacitracin) and/or topical steroids to an underlying nonallergic dermatitis.
34 As with hand dermatitis, the
clinical picture can be confusing.
IATROGENIC Iatrogenic ACD must always be suspected when the primary
dermatitis does not respond to usual
therapies. A secondary ACD of the hands can develop in a patient with nonallergic
hand dermatitis who uses rubber
gloves to protect the hands ( Fig. 120-3A). Iatrogenic contact dermatitis can also
develop from the various topical
preparations, including prescriptions, that patients apply. In a recent study, 9 of 70
(12.9 percent) individuals with
suspected ACD of the foot had iatrogenic disease secondary to topical steroids (1 of
9), topical antifungals (1 of 9), or
topical antibiotics (7 of 9). 34 It can be particularly difficult to identify the allergic
nature of iatrogenic ACD because the
eczematous quality can be muted by the underlying disease for which the topical
preparation was used.
MUCOSAL AND OTHER INTERNAL EXPOSURES ACD of the mucosa is rare. 20 ,
35 Patients allergic to flavorings such
as cinnamic aldehyde in toothpastes or mouthwashes frequently present not with
intraoral complaints but with a perioral
dermatitis extending onto, but not past, the vermilion border of the lips. The unusual
individual reacting to nickel,
mercury, palladium, or gold in dental amalgams may present with a localized
stomatitis and/or systemic contact dermatitis
(see below). Given the widespread exposure of the oral mucosa to allergens, the
scarcity of reports in the literature
makes it obvious that patients only rarely react to allergens intraorally. Thus, one
should be wary to ascribe cutaneous
symptoms beyond the perioral area to contact with known intraoral allergens (e.g., a
patient with scalp dermatitis, nickel
allergy and dental amalgams containing nickel most likely has seborrhea or psoriasis
and probably will not experience
relief of the scalp disease following removal of the amalgams). The paucity of
intraoral ACD has frequently been ascribed
to the dilutional effects of saliva. Similarly, tearing of the eyes has been thought to
explain why ACD to preservatives,
such as thimerosal, in eye drops presents as pronounced erythema and edema of
the eyelids with only mild injection of
the conjunctiva. Although the dilutional effects of mucosal secretions in modifying
ACD cannot be discounted, other
unknown factors peculiar to mucosal surfaces are likely to account for the diminished
responsiveness. The rectal
mucosa, where chemicals are unlikely to be diluted or necessarily promptly swept
away, is rarely involved in allergic
reactions. ACD from medications and other materials administered per rectum
presents as a perianal dermatitis and/or
systemic contact dermatitis with little or no rectal pathology ( Fig. 120-5).
FIGURE 120-5 Systemic contact dermatitis due to balsam of Peru. The patient had a
history of chronic constipation and
used a variety of suppositories. For 7 months she had been bothered by pruritus ani
but only recently developed this
generalized eruption unresponsive to glucocorticoids and light therapy. The multiple
areas of excoriation are indicative of
the intense pruritus. The rash was particularly severe about the anus and, for
unknown reasons, about the lower torso,
buttocks, and genital areas. Her dermatitis cleared when suppositories were
discontinued and she was placed on a
balsam-free diet. Colonoscopic examination revealed only minimal irritation of the
sigmoid colon and rectum compatible
with spastic colitis.
Although mucosal exposure to allergens infrequently causes symptoms, other
internal exposures are even rarer causes
of dermatitis. Given the frequency of nickel and cobalt sensitivity in the population,
and given the large number of
orthopedic implants performed worldwide, the very small number of reports linking
dermatitis to intraarticular metals
makes it unlikely, although not impossible, that the nickel or cobalt allergic individual
with a dermatitis and an artificial
joint is reacting to metals in the orthopedic appliance. The literature linking metals in
cardiac pacemakers and other
implantable devices to dermatitis is even scarcer than that for orthopedic appliances.
In a recent controversial article that
suggested an increased risk of cardiac stent stenosis in individuals with ACD to
nickel and/or molybdenum, none of the
10 patients with metal allergies exhibited evidence of active dermatitis, although one
had a history of metal intolerance. 36
Similarly, intramuscular administration of small amounts of an allergen is unlikely to
generate a cutaneous reaction. For
example, it has been shown that >90 percent of thimerosal-allergic individuals can
be safely vaccinated intramuscularly
with thimerosal-containing vaccines. The small percentage of reactors develop a
dermatitis about the vaccination site,
most likely secondary to accidental skin contamination. 37 Although not as well
studied, the same is likely true for
neomycin-sensitive individuals exposed to neomycin in vaccines.
Systemic Manifestations
Systemic contact dermatitis is an uncommon condition that highlights one of the
poorly understood aspects of ACD: the
potential for long-lasting immunologic memory in previously sensitized areas of skin.
The phenomenon occurs in an
individual who has been sensitized topically to an allergen and is subsequently
exposed systemically. Although the
clinical reaction is typically a dermatitis limited to the site of the original sensitization
(recall reaction), a more pronounced
eruption ranging from an extensive, bizarre-appearing dermatitis ( Fig. 120-5) to
erythroderma may rarely occur.
GENERALIZED DERMATITIS Generalized and/or bizarre patterns of dermatitis are
not only caused by systemic
exposures, but can also follow topical exposure to allergens that are ubiquitous in
the environment. Nickel is a frequent
offender as it is present not only in jewelry, but also in hair and eyelash curlers,
hooks and buttons, eyelets of shoes,
dental amalgams, some of our coinage, and a multitude of other products. 38 Indeed,
nickel is also found in food and
water and is believed by many Scandinavian dermatologists to cause recurrent,
vesicular hand dermatitis (pompholyx) in
some patients. Fortunately, most patients are aware of contact with metal-based
products. This is not true of other
common environmental allergens. Formaldehyde is not only ubiquitous but is
frequently present in materials in which it is
not suspected. Among these many products are insulating materials, rugs, paper
products (including sanitary napkins
and toilet tissue), and even smoke. 38Many preservatives used in cosmetics,
pharmaceuticals, and industry can release
formaldehyde, such as 2-bromo-2-nitropropane-1,3-diol (Bronopol), quaternium-15
(Dowicil), DMDM hydantoin (Glydant),
tris-(hydroxy-methyl)-nitro-methane (Tris Nitro), imidazolidinyl urea (Germal I), and
diazolidinyl urea (Germal II). The urea
formaldehyde resins used to impart color-fastness and wrinkle resistance to clothing
can also release free formaldehyde.
Thus, ACD to formaldehyde can present with a variety of clinical pictures, which can
be confusing to the practitioner.
Furthermore, although many wash-off products (e.g., shampoos and liquid soaps)
are preserved with formaldehyde or its
releasers, they are rarely problematic because the material is rapidly diluted and
quickly rinsed off. Nonetheless, in areas
where the product can be trapped (ear canals, under rings), or in the exquisitely
formaldehyde-sensitive patient, such
wash-off products can cause ACD. Balsam of Peru or its cross-reacting allergens
can, like formaldehyde, be present but
unsuspected in a variety of products. The allergen is itself a mixture of many
chemicals derived from wounding the bark
of Myroxolon pereirae, a tree native to El Salvador. Approximately two-thirds of the
native balsam consists of a volatile oil
containing cinnamic acid, cinnamyl cinnamate, benzyl benzoate, benzoic acid, and
benzyl alcohol, among other
ingredients. The remaining one-third, which is thought to harbor the principal
allergen, contains esterified polymers of
coniferyl alcohol with benzoic acid and cinnamic acid. 38 Peruvian balsam is used as
a “tacking” agent in cosmetics,
topical medications, suppositories, and dental liquids/cements. Furthermore, as
might be expected of a substance
containing numerous constituent chemicals, balsam of Peru can cross-react with
many other substances including
benzoic acid, benzoin, benzyl alcohol, benzyl benzoate, cinnamic acid, cinnamon,
clove, eugenol, and isoeugenol,
among others. The balsam itself or, more typically, modified fractions are frequently
used as fragrance and flavoring
additives. In a recent publication, 39 47 percent of balsam of Peru- and/or fragrance-
allergic patients required dietary
modification to control their dermatitis, while 18 percent of patients who failed to
modify their diet had persistent disease
and only 36 percent improved without some form of dietary modification. Thus, the
patient allergic to balsam of Peru can
present with a spectrum of clinical symptoms ranging from limited dermatitis at the
site of application of a cosmetic
product to a more generalized dermatitis bordering on erythroderma (see Fig. 120-
5). Both natural and synthetic rubber
are also ubiquitous. ACD to rubber products can therefore produce patchy dermatitis
in various areas of the body. Among
the sites most frequently involved are the face (make-up sponges), ear canals (ear
plugs), periocular area (goggles),
brassiere and/or waistline areas (elasticized undergarments), genital areas
(condoms, diaphragms, pessaries), hands
(gloves), feet (shoes), and/or joints (orthopedic braces). The allergens are typically
either the accelerants (thiurams,
carbamates, guanidines, and/or benzothiazoles) or the antioxidants (para-
phenylenediamine derivatives) that are found
in both natural and synthetic rubber. 38
Noneczematous Variants of ACD
ACD need not be eczematous in appearance. 20 Noneczematous variants ( Table
120-3) include lichenoid contact,
erythema multiforme (EM), the cellulitic-like appearing dermal contact
hypersensitivity, contact leukoderma, contact
purpura, and erythema dyschromicum perstans, among others. Of these, the
lichenoid and EM-like variants are seen
most frequently.
TABLE 120-3 Etiologic Factors in Noneczematous Allergic Contact Dermatitis
Metals are the most likely cause of lichenoid allergic contact reactions, and have
been linked to some cases of oral
lichen planus. Many drugs can also cause a systemic lichenoid hypersensitivity, 20
the most notorious being the quinine
derivatives, hydroxyurea, angiotensin-converting enzyme inhibitors, beta blockers,
and antiepileptic agents. EM-like ACD
is most frequently seen following contact with exotic woods, common plants, and
topical medications. The other
noneczematous variants of ACD are rare, most likely because they have many fewer
causal agents. Of note, most cases
of contact leukoderma are due to either postinflammatory hypopigmentation or direct
chemical toxicity (e.g.,
hydroquinones, catechols, phenols, mercaptoamines). 40
Allergic Contact Urticaria
As noted above, chemicals in rubber, especially those contained in black rubber mix,
can cause a variety of
noneczematous ACD, which includes not only those patterns delineated in Table
120-3, but also rarely plantar
pustulosis, pitted keratolysis, and pyoderma gangrenosum. However, in addition to
contact dermatitis, natural rubber
latex (but not synthetic rubber) is responsible for a currently ongoing epidemic of
allergic contact urticaria (ACU), an
IgE-mediated phenomenon pathophysiologically distinct from the T cell–mediated
ACD reactions discussed earlier in this
chapter. Since 1979, when Nutter first called attention to ACU induced by latex,
thousands of cases have been reported
worldwide.
There are few good studies designed to look at the prevalence of immediate
hypersensitivity to latex in the US. In 1996,
Ownby et al. 41evaluated 1000 volunteer blood donors in southeastern Michigan.
They specifically targeted donors at
mobile workplace sites and excluded all health facility sites. These authors found
that, overall, 6.4 percent of their
population was latex allergic. While this study revealed a remarkably high incidence
rate of latex allergy in the general
population, it may have underestimated the true rate because health care workers
were specifically excluded, as were
certain (but unknown) proportions of systemically medicated atopic patients. Both of
these excluded populations have
high incidence rates of latex urticaria. Among hospital workers most likely to be
exposed to natural rubber latex gloves,
the rate of latex ACU has been reported to range from a low of 5.5 percent 42to as
high as 38 percent. 43
Atopic dermatitis predisposes to the development of ACU, as does mucosal xposure
to latex. In one study, three of seven
patients developed ACU following mucosal exposure. 44 In two of these individuals,
anaphylactic reactions developed
within minutes of contact. Thus, in addition to hospital personnel, paraplegics
(especially patients with spina bifida),
sexually active individuals exposed to latex condoms, and others with repeated
mucosal exposure to latex must be
considered high-risk groups for development of ACU. The failure to detect ACU to
latex can have grave consequences in
the allergic patient.
The presentation of ACU from latex is varied. For many patients, the symptoms are
immediate burning, stinging, or
itching with or without localized urticaria upon contact with latex. In some, symptoms
include disseminated urticaria,
allergic rhinitis, asthma, and/or anaphylaxis. The respiratory symptoms are
frequently a result of the latex allergen
binding to, and being aerosolized by, glove powder. Patients with latex ACU may
also present with an
eczematous-appearing dermatitis. This clinical pattern is usually due to concomitant
ACD to a rubber additive, which, in
many cases, precedes the development of ACU. 44 However, some patients
presenting with an eczematous pattern may
have protein contact dermatitis, an IgE-mediated reaction to proteins (especially in
foods) that clinically has the
appearance of ACD.
In contrast to those with ACD from rubber gloves, many patients with ACU from latex
gloves present with the palmar
aspects of the hands as involved as, or more involved than, the dorsal surfaces. This
may relate to the lipid composition
of the palmar epidermis, which allows it to be more easily penetrated by the water-
soluble protein allergens of latex.
Urticarial reactions can occur to any combination of at least 10 different water-
soluble proteins within latex (termed Hev b
1 through Hev b 10) rather than to just one, or a few, proteins. This makes the
diagnosis very difficult. However, with
cloning of these allergens (except Hev b 4) as recombinant proteins, more precise
diagnostic tools may soon be
available. 45
Among the commercially available in vitro tests for IgE-mediated latex allergy, the
CAP system, a solid-phase
immunoassay (Kabi-Pharmacia, Uppsala, Sweden), seems to perform better than
Ala STAT, the liquid-phase
immunoassay (DPC, Los Angeles, California). For CAP, the sensitivity is 94 percent
and the specificity is 82 percent; for
Ala STAT, the sensitivity is 74 percent and the specificity is 92 percent. 46Recently,
an in-office serum dipstick method
(Allergodip, Allergopharma, Reinbek, Germany) has been tested against the CAP
assay and found to have nearly
equivalent sensitivity and specificity. 47 However, the Allergodip is not yet FDA-
approved. Furthermore, these in vitro tests
do miss some individuals with ACU to latex. Therefore, in vivo prick and/or use
testing are necessary if the in vitro tests
are negative and ACU to latex remains a consideration.
When performing in vivo tests, one would ideally want the purified allergens
extracted from natural latex; however,
although cloned, these are not yet commercially available. Instead, one can leach
out the responsible allergen(s) by
soaking the rubber material in water at room temperature for 30 min. 48 In most, but
not all, cases, use of such an eluate
for prick testing is sufficient for detecting ACU. Whenever in vivo testing for latex is
performed, the investigator must be
aware of the potential for life-threatening anaphylactic reactions, especially in
patients whose symptoms suggest prior
systemic reactions to latex products. Such reactions may even follow prick testing.
LABORATORY FINDINGS
In Vivo Tests for ACD: The Patch Test
The only useful and reliable method for the diagnosis of ACD remains the patch test.
Only 23 commercially prepared
allergens are currently available in the United States ( Table 120-4). A comparison of
Table 120-1 with Table 120-4
makes it apparent that some, but not all, of the common allergens in the environment
are contained on this tray.
Therefore, given the fact that there are more than 3700 potential environmental
allergens, practitioners interested in fully
evaluating patients with ACD must be prepared to perform tests with other materials.
For physicians compounding their
own allergens, texts detailing appropriate concentrations and vehicles are available.
15
TABLE 120-4 Allergens Currently Available in the United States*
Relevance
As with any in vivo assay, patch testing is subject to pitfalls. A primary concern is
that even when a chemical is found to
be allergenic for a given patient, it cannot de facto be assumed to be the cause of
ACD. As Table 120-1 shows, the
relevance of presumably true-positive reactions to episodes of ACD ranges from as
low as 16.8 percent for thimerosal to
as high as 93.4 percent for DMDM hydantoin. This lack of relevance does not mean
that patients are not allergic to the
chemical in question, but rather that the specific allergen is not responsible for the
current dermatitis. The temptation to
“force” relevance for an irrelevant allergen can frustrate and disappoint the patient.
This is particularly true for allergens
that historically have low relevance, such as thimerosal. Many patients with positive
patch tests to thimerosal have been
asymptomatically sensitized by vaccines. 49
To determine the relevance of a positive patch test requires correlation with the
materials encountered by the involved
areas of skin. Furthermore, even in some instances when patients are allergic to
chemicals in products they are using,
the allergen may be present in only minimal amounts and may not be responsible for
the dermatitis. In this regard,
“repeat open application testing” (ROAT), in which the patient applies the
commercial product to normal skin several
times daily for 1 to 2 weeks, can be helpful. With use of such provocative tests,
members of the North American Contact
Dermatitis Group (NACDG) found that 5 of 10 individuals who tested positive to
MCI/MI at 100 ppm in water did not react
to a generic skin care lotion preserved with 15 ppm MCI/MI. 50 This is of particular
note given the CIR's recommendation
that MCI/MI not be used in “leave on” cosmetics above 7.5 ppm.
False Positives and Negatives
Physicians performing patch tests must also be concerned with the possibility of
false-positive and false-negative
reactions. False-positive reactions due either to the use of allergens at irritant
concentrations or to the “excited skin
syndrome” have received much attention in the literature. 51 In addition, metal
allergens can produce irritant pustular
reactions and cobalt is notorious for producing a “cayenne pepper” appearance to
the skin, which represents deposition
of cobalt in the pores and is not an allergic reaction. 35The “false” nature of these
reactions can usually be resolved by
repeating the patch tests individually and/or in lower concentrations, or by ROAT. In
contrast, false-negative reactions
require high levels of suspicion and diligence to uncover.
One common and easily correctable cause of false-negative reactions is the failure
to perform a second reading of the
test sites after the initial 48-h inspection. This second reading, sometime between 3
and 7 days after application of the
patches, is particularly important for elderly patients, who take longer o mount an
allergic reaction. 8 A second reading is
also important in detecting positive reactions to allergens such as neomycin, more
than half of which are not evident until
96 h after application of the patch test. 52False-negative reactions can also occur
when the allergen is used in too low a
concentration for patch testing, as can happen when cosmetic products are used as
is. Therefore, if clinical suspicion
warrants, and despite a negative patch test, additional testing such as ROAT with
the suspect product can unmask the
cause of ACD. In doing so, one must be aware of the “paraben paradox” and “lanolin
paradox”: 53neither chemical seems
to be a potent allergen when applied to intact skin; however, when they are applied
to dermatitic skin (e.g., stasis
dermatitis), ACD may ensue.
With more than 3700 potential allergens, 15 negative reactions may simply indicate
that the responsible chemical has not
been tested. There is a particular problem in the US, where only 23 allergens have
been FDA-approved ( Table 120-4).
Contrasting this table with Table 120-1 reveals that 40 percent of the 25 most
common allergens in the US are not readily
available for testing!
Although it has been widely quoted that 70 to 80 percent of patients with ACD can be
diagnosed with use of screening
trays such as the TRUE Test (Kabi Pharmacia Service A/S, Hillerød, Denmark),
these numbers have recently been
questioned. In an analysis of the 1994–1996 NACDG data on 3120 patients, 54 it was
found that 62 percent had at least
one positive reaction to an allergen present on the TRUE Test, of which 45 percent
were relevant to the current
dermatitis. However, by expanding the panel from 23 to 50 allergens, additional
allergens of potential relevance were
identified in 31 percent. In their study of 732 patients over 5.5 years, Cohen et al.
55found that only 23 percent of patients
reacted exclusively to allergen(s) on a similar (but not identical) standard series, 37
percent reacted to allergens on both
the standard series and other supplementary tests, and 40 percent reacted only to
supplementary allergens. Thus, to
maximally benefit patients, practitioners must use allergens beyond those present on
“standard” trays. In the case of
fragrance allergens, Larsen et al. 56 found that the addition of a “natural mix” of 2%
jasmine absolute, 2% ylang-ylang oil,
2% narcissus absolute, 2% sandalwood oil, and 2% spearmint oil increased the
sensitivity of detecting fragrance allergy
to 95 percent from the 81 percent detected by using only the “standard” allergens,
fragrance mix and balsam of Peru.
In Vitro Tests for ACD
In vitro and animal tests for the diagnosis of ACD have received much attention in
the past decade. Laboratory studies
such as lymphocyte transformation or macrophage migration inhibition have been
evaluated as measurements of ACD in
both humans and animals. A major problem in developing in vitro systems is the lack
of knowledge about what
constitutes the antigenic moiety of a particular chemical. Nonetheless, these assays
are now being extensively studied
and reliably standardized. In a review of 209 chemicals, the accuracy of the local
mouse lymph node assay (LLNA, a
lymphocyte transformation test) versus all guinea pig tests (GPTs) was 86 percent
and versus human data was 72
percent, whereas that of all GPTs versus human tests was 73 percent. 57 In terms of
accuracy, sensitivity, specificity, and
positive/negative predictability, the performance of the LLNA was similar to that of
the GPT. Equally important, the
performance of the LLNA and the GPT were similar when each was compared with
human data.
In vitro predictive methodologies have been hampered by the lack of LC lines.
Recent advances in culturing LC-like
dendritic cells from CD34+ precursors under appropriate cytokine conditions and the
development of stable LC-like cell
lines should enhance the utility of in vitro methodologies. Based upon current data, a
chemical that enhances CD86
expression and interleukin (IL)-1ß production, downregulates E-cadherin, causes
endocytosis of surface major
histocompatibility complex (MHC) class II, and induces tyrosine phosphorylation in
LC cultures will likely be sensitizing. 57
However, given the variability in these assays among individuals, more work needs
to be done in this area. Finally,
studies are continuing in order to improve the predictive capabilities of LC/T cell
cocultures and skin
equivalent/reconstituted epidermal cultures. Thus, although in vivo patch testing, in
which the skin can process the
allergen for presentation, currently remains the “gold standard,” there are exciting
prospects for in vitro testing in the
future.
Computer Modeling
Quantitative structure–activity relationships (QSAR) represent a chemistry-based
predictive approach that uses computer
modeling. DEREK (“deductive estimation of risks from existing knowledge”) has
been tested extensively for its ability to
predict allergenicity. Based upon data from animal studies, DEREK uses a set of =50
rules describing chemical
substructures responsible for sensitization. Although the predictive capabilities of
DEREK are high (=80 percent), 58
further refinements in the scope of existing rules and the generation of new rules
based on a chemical's biological activity
are needed to enhance its validity. Data derived from the LLNA should enhance the
capabilities of QSAR.
PATHOLOGY AND DIFFERENTIAL DIAGNOSES
Eczematous Dermatitis
For most episodes of ACD, the end result of the exquisitely orchestrated interplay of
cytokines and adhesion molecules is
the entrance into the skin of T helper (T H)-1 cells secreting IL-2 and interferon (IFN)-
? ( Chap. 23). IFN-? acts in a
number of ways to amplify the immune response. 59 It activates cytotoxic T cells,
natural killer (NK) cells, and
macrophages. In addition, the induction of interferon-inducible protein 10 on
keratinocytes adds to the recruitment of
monocytes/macrophages, as does the IL-1- and tumor necrosis factor (TNF)-a–
enhanced production of monocyte
chemoattractant-1, monocyte chemotactic and activating factor, and macrophage
inflammatory protein-2 by
keratinocytes. This collection of monocytes/macrophages and proliferating T cells,
along with their chemical mediators, is
responsible for the epidermal spongiosis (intercellular edema) and superficial,
perivascular, lymphohistiocytic dermal
infiltrate that are the histologic hallmarks of ACD ( Fig. 120-6). The clinicopathologic
differential diagnoses include irritant
contact, atopic, nummular, dyshidrotic, and autosensitization dermatitis.
FIGURE 120-6 Histopathology of acute allergic contact dermatitis. The biopsy shows
epidermal intercellular edema and
microvesiculation ( v), which are characteristic of an allergic response, as well as
other eczematous dermatitides. The
superficial perivascular infiltrate ( solid arrow) consists of lymphocytes,
macrophages, and, occasionally, eosinophils. The
orthokeratotic stratum corneum ( open arrow) is indicative of the acute nature of this
eruption. In subacute to chronic
allergic reactions, the stratum corneum is parakeratotic.
Noneczematous Variants
The pathologic findings of the noneczematous variants of ACD are nearly identical to
the diseases they simulate.
Lichenoid ACD does have some features that help to distinguish it from idiopathic
lichen planus ( Chap. 49), including a
less-intense lichenoid infiltrate with more eosinophils and neutrophils, less epidermal
hyperplasia with fewer necrotic
keratinocytes, and some degree of epidermal spongiosis. 60 In contrast, EM-like ACD
has no epidermal spongiosis and
the findings are indistinguishable from other causes of EM ( Chap. 58). Dermal
contact hypersensitivity also lacks
spongiosis, but has the characteristic lymphohistiocytic, perivascular infiltrate that
often goes deeper in the dermis
(mid-dermal) than eczematous ACD. 61 The histopathology of acute allergic contact
leukoderma has not been studied. In
the best-documented cases, 62eczematous patch test reactions to PPD subsequently
depigmented, at which time the
biopsy was indistinguishable from chemically induced vitiligo ( Chap. 90). Allergic
contact purpura is pathologically
similar to the eczematous variant of ACD, but with a capillaritis that results in
extravasated red blood cells. 63 It is difficult
to separate from the other pigmented purpuric dermatoses ( Chap. 176).
In all of the noneczematous and eczematous variants of ACD, patch testing is the
only means for accurate diagnosis.
The history, physical examination, and/or pathology are not diagnostic. For example,
it has been reported that 46 percent
of patients with a clinically apparent nickel-induced dermatitis are, in fact, not allergic
to nickel. 64
TREATMENT
Allergic Contact Dermatitis
ALLERGEN AVOIDANCE The treatment of ACD lies in identifying its cause and
thoroughly instructing the patient to
avoid the responsible allergen(s). For certain allergens (e.g., vehicles, preservatives,
stabilizers, and emulsifiers) found
in topical preparations, it is important to impress upon patients the need to read
labels. In addition, a recurrently updated,
electronic database of ingredients in cosmetics and over-the-counter/prescription
topical preparations (CARD: Contact
Allergen Database) is available on the Internet ( http://www.contactderm.org/) and
allows practitioners to generate a
unique list of topical preparations appropriate for the individual with specified
allergies. Patients with allergies to
preservatives must be aware that these materials can be found in any water-based
formulation, such as latex paint.
Furthermore, the name given a chemical used in a cosmetic or pharmaceutical
product is frequently changed when it is
used in a commercial product. For instance, the cosmetic preservative quaternium-
15, when used in industry, is referred
to as Dowicil 100 or Dowicil 200. Practitioners guiding patients through the
synonymic jungle of these chemicals are
advised to consult standard texts on the subject. 33 , 38 Unfortunately for patients and
physicians, the allergenic
component of many materials will almost never be labeled. Rubber-, textile-, and
metal-related allergens are but a few
examples. In counseling patients with reactions to these materials, the physician
must provide information about what
kinds of products are likely to contain the allergen, as well as appropriate
replacements. Such information can be found
in standard texts. 33, 38, 65 Furthermore, some allergens are incompletely labeled.
Given the proprietary nature of a
fragrance's formulation, the individual fragrances that have been combined in the
product are never listed. Patients with
an allergic reaction to a fragrance should be advised to use fragrance-free materials,
which include not only topical
preparations but also a variety of other products such as toilet paper and sanitary
napkins. 38 , 65 It is important to realize
that products labeled “unscented” contain masking fragrances, although they are
usually present in very low
concentrations and do not cause problems. Because many allergens may share
common antigenic moieties, the patient
must be instructed not only about the known allergen, but also about possible cross-
reacting allergens. For example, the
individual allergic to benzocaine must be aware of the many potentially cross-
reacting substances, which include agents
as diverse as other anesthetics (e.g., procaine), certain medications (e.g.,
sulfonamides), hair dyes (e.g.,
para-phenylenediamine), textile dyes (e.g., aniline dyes), some sunscreens (e.g.,
para-aminobenzoic acid), and other
products. 38Because cross-reactions are not always evident to the nonchemist (e.g.,
benzoyl peroxide with cocaine),
physicians must consult standard texts 38 , 65 when instructing their patients.
SYMPTOMATIC THERAPY In addition to avoidance of further contact with the
allergen and its cross-reactants, treatment
of ACD should be directed to amelioration of symptoms. Acute vesicular, weeping
eruptions benefit from drying agents
such as topical aluminum sulfate/calcium acetate; chronic, lichenified eruptions are
best treated with emollients. Pruritus
can be controlled with topical antipruritics or oral antihistamines; topical
antihistamines or anesthetics are best avoided
because of the risk of inducing a secondary allergy in already dermatitic skin.
Treatment with physicochemical agents
that downregulate responsiveness may also be required. Glucocorticoids,
macrolactams, and ultraviolet radiation are
most widely used. A variety of other pharmacologic agents have been reported to
interfere with the induction and/or
elicitation of ACD in mouse models. 66 These include calcium channel blockers,
amiloride, pentoxifylline, pentamidine,
clonidine, spiperone, N-acetylcysteine, and flavonoids. Of these, only pentoxifylline
has been evaluated in humans,
where it was found to induce a slight reduction in responsiveness, perhaps by an
effect on TNF-a. Whether the other
pharmacologic agents exert any effect on the human response remains to be
determined. Of note, with the possible
exception of azelastine, 66H 1-antihistamines do not affect the induction or elicitation
of ACD. H 2-antihistamines
enhance induction, but have no effect on elicitation. 67 Topical glucocorticoids or
macrolactams (pimecrolimus or
tacrolimus) usually suffice for treating most patients with ACD. However, individuals
with involvement of greater than 25
percent of their body surface area and/or those exposed to certain allergens [such as
Toxicodendron (Rhus) oleoresin,
which may persist locally in the skin for weeks after exposure] may require treatment
with systemic glucocorticoids. In
those patients in whom systemic steroid therapy is inappropriate, phototherapy with
UVB or PUVA can be beneficial.
Individuals with occupational ACD who are economically unable to discontinue
working with the offending allergen and
who are also unable to work with gloves or effective barrier creams may also benefit
from chronic maintenance therapy
with UVB or PUVA. The advent of topical macrolactams, which do not cause
cutaneous atrophy, are another option for
these chronically exposed workers. In the future, inhibitors of cellular metabolic
activity, inhibitors of cell adhesion
molecules, targeted skin application of regulatory cytokines, and neutralization of
proinflammatory cytokines with
antisense oligonucleotides, anticytokine antibodies, or soluble cytokine receptors,
may also be added to the therapeutic
armamentarium.
PHYSICOCHEMICAL BARRIERS While prevention of ACD rests with avoidance of
the allergen, for various reasons,
principally economic, this is not always possible. Many chemicals, especially organic
molecules, can rapidly penetrate
vinyl and synthetic or natural latex rubber gloves, and exposed workers may be
unable to avoid daily contact with the
allergen. These individuals may benefit from a plastic glove made of a proprietary
laminate (4H, North Safety Products,
Cranston, Rhode Island). In clinical trials, the 4H glove, which is only 0.07 mm thick,
was impervious to more than 90
percent of all randomly selected organic chemicals for 4 h at 35°C (95°F). 68
However, this glove is not form-fitting and is
thought by many professionals to impede the fine dexterity needed in their work. In
the future, barrier creams may be
available to help such patients. Now, however, barrier creams are available for only
a limited number of allergens
(principally poison ivy and poison oak), are effective only if the protected area is
washed within several hours of contact
with the allergen, and are objectionable to many patients because of their thick tack
and greasy consistency.
HYPOSENSITIZATION Although the possibility of hyposensitization for ACD has
intrigued dermatologists for decades, it
remains a nonviable alternative. Despite early encouraging work, Kligman 69
concluded that “complete desensitization of
the highly sensitive subject by oral or intramuscular administration is impossible,” a
statement later echoed by others. In
these studies, months of treatment with Toxicodendron oleoresin resulted in a
temporary lessening of the intensity, but
not ablation, of the allergic response. Of the topical desensitization programs, only
that for mechlorethamine
hydrochloride (nitrogen mustard) has shown any success in a limited number of
patients. 70 However, this success has
been contested by others, as has the nature of the reaction (allergic or irritant) to
mechlorethamine hydrochloride. 71
TOLERANCE INDUCTION One theoretical possibility for prevention of occupational
ACD is the induction of tolerance to
known occupational allergen(s) before employment. When an antigen to which an
individual has not yet been sensitized
is administered either systemically or topically to areas deficient in functional LCs,
long-lived tolerance rather than
sensitization often ensues. However, because allergic reactions to otherwise
apparently innocuous materials, such as
nickel, persist in the human genotype, one must question on a Darwinian basis
whether there is selective advantage to
the trait. In the absence of information concerning the antigenic moieties of many
simple chemicals and how they might
relate to antigenically more complex viruses and malignancies, one cannot assume
that simple chemical allergens do not
cross-react with viral- or tumor-related antigens. At present, it is a matter of debate
whether it is ethical to induce
tolerance to even the most problematic environmental allergens given the theoretical
risk of enhancing susceptibility to
potentially more life-threatening diseases