As the largest organ in the human body, the skin is a complex and dynamic organ that serves

among many other purposes, the function of maintaining a physical and immunologic barrier to
the environment. Therefore, the skin is the first line of defense after exposure to a variety of
chemicals. Allergic contact dermatitis (ACD) accounts for at least 20% or more of the new incident
cases in the subgroup of contact dermatitides (irritant contact dermatitis accounts for the remaining
80%). ACD, as the name implies, is an adverse cutaneous inflammatory reaction caused by contact
with a specific exogenous allergen to which a person has developed allergic sensitization. More
than 3,700 chemicals have been implicated as causal agents of ACD in humans. Following contact
with an allergen, the skin reacts immunologically, giving the clinical expression of eczematous
inflammation. In ACD the severity of the eczematous dermatitis can range from a mild, short-lived
condition to a severe, persistent, chronic disease. Appropriate allergen identification through
proper epicutaneous patch testing has been demonstrated to improve quality of life as measured
by standard tools, as it allows for appropriate avoidance of the inciting allergen and possibly
sustained remission of this potentially debilitating condition. Recognition of the presenting signs
and symptoms, and appropriate patch testing are crucial in the evaluation of a patient with
suspected ACD.

Epidemiology

A small but substantial number of studies have investigated the prevalence of contact allergy in
the general population and in unselected subgroups of the general population. In 2007, Thyssen
and colleagues performed a retrospective study that reviewed the main findings from previously
published epidemiological studies on contact allergy in unselected populations including all age
groups and most publishing countries (mainly North America and Western Europe). Based on
these heterogeneous published data collected between 1966 and 2007, the median prevalence of
contact allergy to at least one allergen in the general population was 21.2%. Additionally, the study
found that the most prevalent contact allergens in the general population were nickel, thimerosal,
and fragrance mix. Importantly, the prevalence of contact allergy to specific allergens differs
between various countries and the prevalence to a specific allergen is not necessarily static, as it is
influenced by changes and developments in the regional environment, exposure patterns,
regulatory standards, and societal customs and values. On a final note about epidemiology, contact
allergy caused by ingredients found in personal care products (cosmetics, toiletries) is a well-
known problem, with approximately 6% of the general population estimated to have a cosmetic-
related contact allergy. Contact allergy to ingredients in personal care products will be further
discussed in this chapter.

Age

Over the past decade, multiple studies have recognized contact dermatitis as an important cause of
childhood dermatitis, and a common diagnosis among children; being equally as likely in
childhood as in adulthood, although the most common allergens identified differ between the age
groups. On the other hand, although fragrance mix allergy is an important sensitizer in all ages,
certain studies, such as the 2001 Augsburg study, which was based on adults aged 28–75 years,
have shown a significant increase in fragrance mix allergy with increasing age. Similarly,
Magnusson et al demonstrated a high prevalence rate (4.7%) of Myroxylon pereirae (balsam of
Peru—a marker for fragrance allergy) sensitization among 65-year-old Swedish patients.
Similarly, a recent Danish study demonstrated the prevalence allergy to preservatives being higher
among those aged 41–60 years.

Gender and Race

Because very few studies have looked at the induction of allergic contact sensitization in men and
women under controlled circumstances, gender differences in the development of ACD are largely
unknown. When the human repeat-insult patch testing method was used to assess induction rates
for ten common allergens, women were more often sensitized to seven of the ten allergens studied.
With regard to frequency, Thyssen and colleagues found that the median prevalence of contact
allergy among the general population was 21.8% in women versus 12% in men. When looking
specifically at nickel sensitivity, the same study showed that the prevalence was much higher
among women than men (17.1% in woman vs. 3% in men). This might be due to the fact that
numerous studies have demonstrated that pierced ears are a significant risk factor for development
of nickel allergy.Thus, the higher prevalence of nickel allergy in women may be explained by the
higher median prevalence of pierced ears in women in comparison with men (81.5% in women vs.
12% in men) of the population studied. The role of race, if any, in the development of ACD to
some potent allergens such as para-phenylenediamine (PPD), remains controversial. Limited
studies have suggested lower sensitizations rates to nickel and neomycin in African Americans
compared to Caucasians. With regard to the patch-test protocol, the evaluation of positive reactions
may be slightly more difficult in darker skin types (Fitzpatrick types V and VI), as erythema may
not be as obvious, posing the risk of overlooking a mild positive allergic reaction. However, the
edema and papules/vesicles are usually obvious and palpable; therefore palpation of the patch-test
site can help to detect allergic reactions in patients with darker skin types. Finally, the darker the
skin, the more difficult it is to mark the patch-test site after removal. For very dark skin, a florescent
marking ink is probably best, the markings being located by a Wood’s light in a darkened room.

Etiology and Patohogenesis

Allergic contact dermatitis represents a classic cellmediated, delayed (type IV) hypersensitivity
reaction. Such immunological reaction, results from exposure and subsequent sensitization of a
genetically susceptible host, to an environmental allergen, which on reexposure triggers a complex
inflammatory reaction. The resulting clinical picture is that of erythema, edema, and papulo-
vesiculation, usually in the distribution of contact with the instigating allergen, and with pruritus
as a major symptom Fig. 13-1. To mount such reaction, the individual must have sufficient contact
with a sensitizing chemical, and then have repeated contact with that substance later. This is an
important distinction to irritant contact dermatitis (ICD) in which no sensitization reaction takes
place, and the intensity of the irritant inflammatory reaction is proportional to the dose—
concentration and amount of the irritant. In ACD, only minute quantities of an allergen are
necessary to elicit overt allergic reactions. There are two distinct phases in the development of
ACD: the sensitization phase and the elicitation phase.

Sensitization Phase

Most environmental allergens are small, lipophilic molecules with a low molecular weight (<500
Daltons). The unprocessed allergen is more correctly referred to as a hapten. Once the hapten
penetrates the skin, it binds with epidermal carrier proteins to form a hapten–protein complex,
which produces a complete antigen. Next, the antigen presenting cells (APC) of the skin
(Langerhans cells and/or dermal dendritic cells), take up the hapten–protein complex and express
it on its surface as an HLA-DR molecule. The antigen-presenting cell then migrates via the
lymphatics to regional lymph nodes where it presents the HLA-DR–antigen complex to naive
antigen-specific T cells that express both a CD4 molecule that recognizes the HLA-DR and more
specifically a T-cell receptor CD3 complex that recognizes the processed antigen. The antigen can
also be presented in the context of the MHC class I molecules, in which case it would be recognized
by CD8 cells. Subsequently, the naive T cells are primed and differentiate into memory (also
referred to as effector T cells) which undergo clonal expansion, acquire skin-specific homing
antigens, and emigrate out of the lymph node into the circulation. These clones of CD4+ Th1 and
CD8+ type 1 cytotoxic T cells are then able to act as effectors on target cells presenting the antigen
in the future. The sensitization phase generally lasts 10–15 days and is often asymptomatic.
Subsequent exposure to the antigen, or rechallenge, leads to an elicitation phase. Such rechallenge
can occur via multiple routes, including transepidermal, subcutaneous, intravenous, intramuscular,
inhalation, and oral ingestion.

Elicitation Phase

During this phase, both the APCs and the keratinocytes can present antigen and lead to subsequent
recruitment of hapten-specific T cells. In response, the T cells release cytokines, including IFN-γ
and TNF-α, which, in turn, recruit other inflammatory cells while stimulating macrophages and
keratinocytes to release more cytokines. An inflammatory response occurs as monocytes migrate
into the affected area, mature into macrophages, and thereby attract more T cells. This localized
proinflammatory state results in the classical clinical picture of spongiotic inflammation (redness,
edema, papules and vesicles, and warmth). Recent advances in the knowledge of the
pathophysiology of ACD have demonstrated the important role of the skin innate immunity in the
sensitization process; have revisited the dogma that Langerhans cells are mandatory for ACD; and
have addressed the nature, mode, and site of action of the regulatory T cells that control the skin
inflammation (Box 13-1) (see also Chapter 10). This new understanding may facilitate the
development of strategies for tolerance induction, as well as the identification of novel targets for
pharmacological agents for the treatment of ACD.
Clinical Approach

An algorithmic approach to the patient is described in the following sections.

CONSIDERAT ION OF THE DIAGNOSIS

The character and distribution of the dermatitis should raise the index of suspicion for ACD.
Therefore, any patient who presents with an eczematous dermatitis should be regarded as possibly
having ACD (Fig. 13-2). Additionally, one must also consider contact allergy in patients with other
types of dermatitis (e.g., atopic) that is persistent and recalcitrant despite appropriate standard
therapies, as well as in patients with erythroderma, or scattered generalized dermatitis.46
Furthermore, it is important to note that patients with stasis dermatitis are at increased risk of
developing ACD from topical medications and lotions which are often applied under occlusion
over chronically inflamed and broken skin (Fig. 13-3). For that reason, ACD should always be in
the differential of eczematous lesions surrounding leg ulcers. Finally, it is important to avoid some
commonly held misconceptions about ACD that can alter a physician’s ability to recognize contact
dermatitis. These were described by Marks and DeLeo and include the following: ACD is not
always bilateral even when the antigen exposure is bilateral (i.e., shoe or glove allergy). Even
when exposure to an allergen is uniform (e.g., contact allergy to an ingredient of a cream that is
applied on all of the face), eczematous manifestations are very often patchy. ACD can and does
affect the palms and the soles.

HISTORY TAKING

The first step in the diagnosis of ACD is a careful medical and environmental exposure history.
History taking should begin with a discussion of the present illness focusing on the site of onset of
the problem and the topical agents used to treat the problem (including over the counter and
prescription medications). A past history of skin disease, atopy, and general health should be
routinely investigated. This is followed by a detailed history of the usage of personal care products
(soap, shampoo, conditioner, deodorant, lotions, creams, medications, hair styling products, etc.),
and investigation of the patient’s avocations or hobbies. The occupation should be ascertained as
well, and if it appears contributory, or there are potential allergenic exposures, then a thorough
occupational history should be taken. Occupations. Requiring frequent hand washing, glove use,
or frequent chemical exposure should be prime suspects, among others.

CLINICAL MANIFESTATIONS

CUTANEOUS FINDINGS

The classic presentation of ACD is a pruritic, eczematous dermatitis initially localized to the
primary site of allergen exposure. Geometric or linear patterns or involvement of focal skin areas,
may also be suggestive of an exogenous etiology (Fig. 12-4B). A linear or streaky array on the
extremities, for example, often represents ACD from poison ivy, poison oak, or poison sumac.
Occasionally, the actual sensitizing substance in these plants, an oleoresin named urushiol may be
aerolized when the plants are burned, leading to a more generalized and severe eruption on exposed
areas such as the face and arms. Transfer of the resin from sources other than directly from the
plant (such as clothes, pets, or hands) may result in rashes on unexpected sites (i.e., genital
involvement in a patient with poison ivy). Thus, relevant historic data gathered from thoughtful
questioning may prove as useful as the distribution of the lesions. It is important to note that lesions
of ACD will vary morphologically depending on the stage of the disease. For example, during the
acute phase, lesions are marked by edema, erythema, and vesicle formation. As the vesicles
rupture, oozing ensues and papules and plaques appear. Stronger allergens often result in vesicle
formation, whereas weaker allergens often lead to papular lesion morphology, with surrounding
erythema and edema. Subacute ACD on the other hand, will present with erythema, scaly juicy
papules and weeping; whereas chronic ACD can present with scaling, fissuring, and
lichenification. A key symptom for allergy is pruritus, which seems to occur more typically with
allergy, than a complaint of burning. Moreover, there are some noneczematous clinical variants of
ACD that are infrequently observed. These include among others:

 Purpuric ACD is mainly observed on the lower legs and/or feet and has been reported with
a wide variety of allergens including textile dyes.
 Lichenoid ACD is considered a rare variant. Clinical features mimic lichen planus and has
been associated with metallic dyes in tattoos. Oral lichenoid ACD from dental amalgams
can resemble typical oral lichen planus.
 Pigmented ACD has been mainly described in populations from Asian ethnicity.
 Lymphomatoid ACD is based only on histopathological criteria (presence of significant
dermal infiltrate displaying features of pseudolymphoma). Clinical signs which are
nonspecific include erythematous plaques, sometimes very infiltrated, at the site of
application of the contact allergen. Some examples include allergy to metal, allergy to hair
dye, and to dimethylfumarate, a mold inhibitor found in sachets within some furniture
implicated in causing a severe epidemic of ACD

TOPOGRAPHIC APPROACH

Dermatitis distribution is usually the single most important clue to the diagnosis of ACD.
Typically, the area of greatest eczematous dermatitis is the area of greatest contact with the
offending allergen(s). Location, in fact, can be one of the most valuable clues as to which
chemical might be the culprit of a patient’s ACD. For instance, an eczematous dermatitis in
the peri/infraumbilical area suggests contact allergy to metal snaps in jeans and belt buckles,
whereas eczema distributed around the hairline and behind the ears suggests contact allergy to
an ingredient(s) in hair products (hair dyes, shampoo, conditioners, styling products) (Fig. 13-
4). Using the same rationale, eczema on the dorsum of the feet suggests contact allergy to
products used to make shoe uppers like leather, rubber, or dyes, while eczematous dermatitis
on the weightbearing surfaces of the feet suggests contact allergy to products used to make
insoles/soles like rubber and adhesive materials. Notably, facial, eyelid, lip, and neck patterns
of dermatitis should always raise suspicion of a cosmetic-related contact allergy. However, for
all of these presentations, correct identification of the culprit chemical(s) will still require patch
testing, since even the most astute and experienced clinician is, for the most part, unable to
properly surmise the positive allergen(s) prior to testing. The pattern of dermatitis should be
mainly used in determining whether or not to patch test, and which allergens and screening
series to test. Occasionally, the topographic approach does not hold, and the distribution can
actually be misleading. This mainly refers to cases of ectopic ACD or airborne ACD. Ectopic
ACD can follow two circumstances: Auto transfer, in which the allergen is inconspicuously
transferred to other body sites by the fingers—the classical example being nail lacquer
dermatitis located on the eyelids or lateral aspects of the neck; and heterotransfer, in which the
offending allergen is transferred to the patient by someone else (spouse, parent, etc.); this is
described in the literature as connubial or consort ACD. A discussion of allergens in the context
of common patterns of presentation is briefly detailed below.

FACE

The face is a common site for ACD. Among patients with facial dermatitis, women are more
commonly affected than men, particularly by cosmeticassociated allergens such as fragrances,
PPD, preservatives, and lanolin alcohols (eFig. 13-4.1 in online edition). Allergens can be
applied to the face directly but can also be indirectly transferred from airborne or hand-to-face
exposure. In addition to allergens found as ingredients in cosmetics, products used to apply
them—such as cosmetic sponges, have also been reported to produce facial dermatitis in
rubbersensitive patients. A similar situation is seen with nickel-plated objects used on the hair,
such as bobby pins and curlers that may produce scalp and facial dermatitis in nickel-sensitive
patients

SCALP

Allergens applied to the scalp most often produce patterns of dermatitis on the forehead and
lateral aspect of the face, eyelids, ears, neck, and hands; whereas the scalp remains uninvolved,
suggesting that the scalp is particularly “resistant” to contact dermatitis. Nevertheless, patients
exquisitely sensitive to certain ingredients in hair products such as PPD or glyceryl
monothioglycolate may show a marked scalp reaction with edema and crusting. PPD is one of
the most potent sensitizers known and is widely used as an ingredient in hair dyes. In general,
PPD sensitization manifests on the face and scalp of female adult patients who had contact
with a hair dye. Glyceryl thioglycolate (GMT), on the other hand, is a chemical substance used
in permanent wave solutions. Allergic sensitivity to GMT can manifest as intense scalp
reactions with scaling, edema, and crusting.
EYELIDS

The eyelids are one of the most sensitive skin areas, and are highly susceptible to irritants and
allergens perhaps due to the thinness of the eyelid skin, as compared with the rest of the skin,
and perhaps because they can accumulate the offending chemical in the skin folds. Transfer of
small amounts. of allergens used on the scalp, face, or hands can be enough to cause an
eczematous reaction of the eyelids, while the primary sites of contact remain unaltered (eFig.
13-4.2 in online edition). Similarly, volatile agents may affect the eyelids first and exclusively,
causing airborne eyelid contact dermatitis. Sources of contact dermatitis of the eyelids include
cosmetics such as mascara, eyeliners and eye shadows, adhesive in fake eyelashes, and nickel
and rubber in eyelash curlers. Furthermore, marked edema of the eyelids is often a feature of
hair-dye dermatitis. As mentioned earlier in this chapter, eyelids are also known for being a
typical site for “ectopic contact dermatitis” caused by ingredients found in nail lacquer, such
as tosylamide formaldehyde resin (TSFR), the chemical added to nail varnish to facilitate
adhesion of the varnish to the nail and epoxy resin, also added to some nail polishes. Topical
antibiotics (like bacitracin and neomycin) and certain metals such as gold can also cause eyelid
contact dermatitis. In fact, in the 2007 NACDG analysis of contact allergens associated with
eyelid dermatitis, gold was the most common allergen accounting for pure eyelid dermatitis.
Notably, it has been observed that upon contact with hard particles such as titanium dioxide
(used to opacify facial cosmetics, and in sunscreens as a physical blocker of ultraviolet light),
gold found in jewelry may abrade, resulting in the release of gold particles that can then make
contact with facial and eyelid skin, causing dermatitis. Aside from gold, fragrances and
preservatives have been found to be the main cosmetic allergens to cause dermatitis limited to
the eyelids.

LIPS.

According to an NACDG study, approximately one-third of patients with cheilitis—without

other areas of dermatitis—are typically found to have an allergen as a contributing factor.
Allergic contact cheilitis (ACC) has been reported to result from the use of a wide array of
products including cosmetics such as lip balms, lipsticks, lip glosses, moisturizers, sunscreens,
nail products, and oral hygiene products (mouthwashes, toothpastes, dental floss). ACC has a
marked female predominance, with most studies reporting a range of 70.7%–90% female
patients. This is likely explained by the assumption that women wear more cosmetics and lip
products than men. Most studies have reported fragrance allergens [such as fragrance mix and
Myroxylon pereirae (Balsam of Peru)] as the most common cause of contact allergy in patch-
tested patients with cheilitis. Of note, some uncommonly reported allergens, namely,
benzophenone-3 and gallates, may be relevant to a dermatitis localized to the lips.
Benzophenone-3, a major constituent of many sunscreens, is also a common ingredient in
many lip products and is increasingly reported as a culprit for ACC. Gallates are antioxidants
used in waxy or oily products such as lip balms, lipsticks, and lip glosses

NECK.

The neck is also a highly reactive site for ACD. Cosmetics applied to the face, scalp, or hair
often initially affect the neck. Nail-polish ingredients (tosylamide formaldehyde resin and
epoxy resin) are common culprits in this region. Furthermore, as a cultural practice, perfumes
are sprayed on the neck. In a fragrance-sensitized individual, the practice of repeated
application of fragrances to the anterior neck may result in the appearance of a dermatitic
plaque on the neck, which has been coined the “atomizer sign.” Also, in this topographic area,
metal allergy can manifest as chronic eczematous dermatitis from exposure to necklaces and
jewelry clasps that contain nickel and/ or cobalt.

TORSO

The torso can encounter fragrances, preservatives, surfactants, and other chemicals from the
use of personal care products; yet it is also susceptible to allergens found in textiles. Textile-
associated allergens include disperse dyes (azoanilines) and formaldehyde-releasers used as
durable press chemical finishes (DPCF). In the past, finishes used to contain large amounts of
free formaldehyde, which led to many cases of allergic contact dermatitis to clothing in the
1950s and 1960s. However, currently most finishes are based on modified dimethylol
dihydroxyethyleneurea, which releases less formaldehyde. Importantly, recent studies have
shown that the amount of free formaldehyde in most garments will likely be below the
threshold for the elicitation of dermatitis for all but the most sensitive patients, and that the
amount of free cyclized urea in clothes is unlikely to be high enough to cause sensitization.

AXILLAE

Heat, humidity, and friction of the axillary fold may contribute to the leaching of textile resins
and dyes and dermatitis accentuation in these areas. The axillary region is also uniquely
exposed to deodorants and antiperspirants. These products contain most notably the contact
allergens fragrances and preservatives (formaldehyde releasers, parabens, etc.). A commonly
observed effect with the use of these products is the sparing of the axillary vault, mainly
secondary to perspiration diluting the allergens. Aerosolized exposure of the allergens through
antiperspirant/deodorants in spray, may lead to scattering of the allergen and the resulting
picture may be that of scattered satellite papules.

HANDS AND FEET

Hand dermatitis has a particularly high incidence secondary to the fact that the hands are the
main means of interaction with the environment, with increased possibility for numerous
allergen exposures. Hand dermatitis accounts for as much as 80% of the occupationally related
skin diseases, especially in certain “wet work” occupations such as health care workers, food
handlers, etc. Thus, careful consideration should be given to occupation-specific exposures in
the evaluation of patients with hand dermatitis. As an example, a hairdresser may be sensitized
to ingredients in hair-care products such as PPD, glyceryl monothioglycolate, or
cocamidopropyl betaine (a surfactant-detergent, commonly found in shampoos), whereas a
construction worker may become allergic to chromium through exposure to wet cement.
Clinical clues that should raise a higher index of suspicion of ACD include the involvement of
the finger web spaces and the dorsal hands, as well as the predominance of pruritus as a
symptom. Still the multifactorial etiology of hand dermatitis (irritant exposure, atopy,
pompholyx or chronic vesicular hand eczema, psoriasis, dermatophyte infection, among
 others) adds to the complexity of both diagnosing and treating these patients. Chronic hand
dermatitis is an indication for patch testing, as causal or contributing allergy can result in
improvement or resolution of the problem. Similarly, the evaluation of foot dermatitis should
include patch testing with the allergens most commonly associated with this condition. These
include, rubber-related chemicals (such as mercaptobenzothiazole, carba mix, thiuram mix,
mercapto mix, black rubber mix, and mixed dialkyl thioureas) potentially present as
components of shoes and insoles; glues and adhesives used in shoe manufacturing like 4-tert-
butylphenol formaldehyde resin; and potassium dichromate found in tanned leathermade
shoes. Testing materials should also include topical antibiotics, corticosteroids, or antifungal
medications (both over-the-counter and prescription) that may have been used by the patient
to treat the affected area. Other topographic areas affected by ACD include the oral mucosa,
which may present with contact stomatitis from dental metals and the perianal area, which may
react to sensitizing chemicals in proctologic preparations such as benzocaine.

Scattered Generalized Dermatitis

Patients with scattered generalized dermatitis (SGD) usually present a difficult diagnostic and
therapeutic challenge. Patch testing can be a strategy for evaluating ACD as a potential relevant
factor. In 2008, Zug and NACDG colleagues examined the yield of patch testing as well as the
relevant allergens in patients with SGD referred for patch testing. Of 10,061 patients studied during
a period of 4 years, 14.9% had SGD. Men and patients with a history of atopic eczema were more
likely to have dermatitis in this distribution. Of the total of patients presenting with SGD, 49% had
at least one relevant positive patch-test reaction. Preservatives, fragrances, propylene glycol,
cocamidopropyl betaine, ethyleneurea melamine formaldehyde, and corticosteroids were among
the more frequently relevant positive allergens.

SYSTEMIC CONTACT DERMATITIS

In 2001, members of the International Contact Dermatitis Research Group (ICDRG) developed
the concept of the allergic contact dermatitis syndrome (ACDS). This concept considers the
various facets of contact allergy, including morphological aspects and staging by symptomatology.
ACDS has three stages that can be defined (Table 13-1) and with many causes (Table 13-2).
Systemic contact dermatitis describes a systemic reactivation of allergic contact dermatitis; in
other words, a cutaneous eruption in response to systemic (nontopical) exposure to an allergen.78
In considering the chains of events resulting in the development of systemic reactivation of ACD,
the ICDRG has suggested that the occurrence of some successive steps is necessary. Initially,
direct skin contact with an allergen results in sensitization. Second, in some relatively uncommon
cases, weeks or even years after that first episode of ACD, the patient is systemically exposed to
exactly the same allergen, or to a related substance that is chemically closely related to it (cross-
sensitization), elicitating a systemic reactivation of ACD. There are multiple routes of exposure
for the elicitation of systemic contact dermatitis—subcutaneous, intravenous, intramuscular,
inhalation, and oral ingestion. It is important then to note, that by definition,

Table Stages of the Allergic Contact Dermatitis Syndrome

Stage 1 The skin symptoms are limited to the site (s) of

application of contact allergen(s).
Stage 2 There is a regional dissemination of symptoms (via
lymphatic vessels), extending from the site of
application of allergen(s).
Stage 3 Can be further subdivided in Stage 3A:
Corresponds to hematogenous dissemination of
ACD at a distance. Stage 3B: Corresponds to
systemic reactivation of ACD (nontopical trigger)

Table Systemic Drugs that Can Cause Systemic Reactivation of ACD

Contact Allergen * Related Drug with Potential to Cause Systemic

Reactivation of ACD
Ethylenediamine dihydrochloride (stabilizer Aminophylline Piperazine antihistamines:
infrequently found in skin care products) hydroxyzine, cetirizine, levocetirizine and
meclizine
 Thiuram (rubber antioxidant) Tetraethyl thiuram disulfide (generic name:
disulfiram)
Thimerosal (mercuryderived preservative) Piroxicam
* To which a patient had previously become sensitized by direct, topical application of the contact allergen
to the skin.

in systemic contact dermatitis, there is no occurrence of topical skin contact to the allergen.
Clinically, systemic contact dermatitis has a wide spectrum of presentation, from a recall reaction
(dermatitis at the site of prior topical sensitization), to widespread dermatitis and erythroderma.
Other patterns that have been associated with systemic contact dermatitis include axillary vaults,
upper inner thighs, and buttocks—sometimes described as “baboon syndrome,” which has been
associated with some internally ingested allergens, i.e., cashew nut shell oil causing a cross-
reaction to the allergen urushiol. Dyshidrotic hand eczema/pompholyx are conditions in which oral
challenges with nickel, and Myroxylon pereirae have demonstrated flaring of this type of hand
eczema in some studies (eFig. 13-5.1 in online edition). Of particular notoriety is the allergen
Myroxylon pereirae also known as balsam of Peru, a substance derived from Myroxolon
balsamum, a tree that is native to the country of El Salvador. Because the main components of
Myroxylon pereirae (cinnamic acid, cinnamyl cinnamate, benzyl benzoate, benzoic acid, benzyl
alcohol, and esterified polymers of coniferyl alcohol) are naturally derived, they have a significant
number of natural cross-reactors. Certain foods, such as tomatoes and tomato-containing products,
citrus fruit peel/zest, chocolate, ice cream, wine, beer, vermouth, dark colored sodas, and spices
such as cinnamon, cloves, curry, and vanilla, have chemical ingredients related to balsam of Peru.
Consumption of these foods may result in a systemic reactivation of ACD in some patients allergic
to balsam of Peru. Salam and Fowler drew attention to this ability of orally ingested balsam-related
substances to induce systemic contact dermatitis, and reported that, in their study, remarkably
almost half of the subjects with a positive patch test to Myroxylon pereirae who followed a balsam
of Peru-reduction diet, had a significant to complete improvement of their dermatitis. Finally, some
oral or IV medications may cause systemic reactivation of ACD in patients previously sensitized
to related allergens by direct skin contact (Table 13-2).
FREQUENCY APPROACH

Because “frequent is frequent,” the approach to a patient with suspected ACD can also be done
taking into account the most likely culprits based on frequency data of a given region, and the
patient’s occupation or other individual exposures. This approach should not replace by any means
actual patch testing; nevertheless, a working knowledge of the most common allergens can prove
to be useful when evaluating a patient with suspected ACD. Next is a brief description of the most
frequently patch-test positive allergens in North America. NICKEL. Nickel is a ubiquitous metal
used in a wide range of products including those that have a prolonged contact with the skin
(costume jewelry, suspenders, zippers, button snaps, belt buckles, eyeglasses frames, cell phones,
nickel-containing coins, keys, among many others). There is a well-documented rising incidence
of nickel allergy in the United States and elsewhere, with high nickel sensitization rates
documented in children. Ear piercing at an early age, in addition to the trend of a greater number
of other body piercings, are consistently linked to the rise in nickel sensitization in the recent
decade. Currently, nickel allergy is the most common cause of contact dermatitis in the industrial
world, particularly affecting females. Several studies have examined the striking discrepancy of
sensitization incidence to nickel in females versus males and have associated this with ear
piercing.90,91 Classically, nickel contact dermatitis presents as an eruption on the earlobes, the
neckline, the wristband, or the periumbilical area since those are common areas for exposure to
nickel-containing jewelry or button snaps, zippers, and belt buckles. Facial dermatitis caused by
nickel has also been reported to musical instruments and more recently to cell phones.
Furthermore, the presence of nickel in implantable medical devices and potential complications
derived from nickel allergy is a rising subject of discussion. The relevance of nickel allergy in the
failure of metal orthopedic implants and cardiac devices is not clear. Documented cases of joint
replacement failure associated with nickel or other metal sensitivity are clearly rare, and
arthroplasty prostheses rarely cause a problem in the nickel sensitive individual. Existing
publications are largely retrospective and thus can only suggest a possible association of nickel
allergy with implant failure rather than determine causation. Similarly, eczematous reactions
temporally related to joint replacement or implantation of other orthopedic devices (i.e., metallic
plates and screws) although reported, are infrequent (eFig. 13-5.2 in online edition). More studies
are needed in this area. In an attempt to prevent the development of nickel sensitivity, Denmark in
1990, and the rest of the European Union in 1994, have regulated the amount on nickel that may
be released from objects with direct and prolonged skin contact (≤0.5 μg nickel/cm2 /week;
revision for 2004: ≤0.2 μg nickel/cm2 /week for items inserted into pierced parts of the body).
Recent evidence indicates that the prevalence of nickel allergy is decreasing among young Danish
females from 27.6% in 1985 to 16.8% in 2007. The American Academy of Dermatology and the
American Contact Dermatitis Society favor enacting similar legislation in the United States.

FRAGRANCES

Fragrances are aromatic compounds that impart a smell or odor. They can be natural (from
botanical or animal products) or synthetic in origin. It has been estimated that between 1% and 4%
of the general population is allergic to fragrances. Fragrance allergy is one of the two top causes
of contact allergy to personal care products; the typical sites of involvement include the face and
hands, as well as behind the ears, neck, and axillae, in addition to a scattered generalized
distribution of eczematous dermatitis. Two of the main substances used by most patch-test groups
for screening are among the top ten allergens in North America. The first is fragrance mix I, which
is a mixture of eight fragrance allergens, and the second is Myroxylon pereirae (MP) also known
as balsam of Peru (BOP), whose main components are fragrance ingredients. MP is considered to
be a good marker for fragrance allergy, able to identify approximately 50% of fragrance allergic
individuals. MPrelated substances can be found in products such as cosmetics, perfumes,
pharmaceutical preparations, toothpastes and mouthwashes, as well as in scents and flavorings for
foods and drinks. Similarly, certain foods, such as the ones mentioned earlier in the chapter,
contain chemical ingredients related to MP. Surgical adhesives used postprocedure to secure
dressings also may cross-react and produce dermatitis in individuals sensitive to MP.

NEOMYCIN

Neomycin belongs to the aminoglycoside family of antibiotics commonly used in topical

formulations for the prevention and treatment of superficial skin, ear, and eye infections. The
frequency of neomycin sensitization in the general population is 1.1%,while reported sensitization
rates in selected patient populations referred for patch testing vary from as low as 1.1 to as high as
10%, the latter reported by the NACDG. This high rate of sensitization in North America may be
due to the availability of this antibiotic in numerous over-the-counter preparations, especially
“triple antibiotic” creams and ointments. Subgroups at higher risk include patients with stasis
dermatitis and leg ulcers, anogenital dermatitis, and otitis externa. Because antibiotic preparations
are applied to already damaged skin, ACD from neomycin is not always easily recognized. It often
presents as persistence or worsening of a preexisting dermatitis. Additionally, it may mimic
cellulitis; the clue for contact allergy is itching rather than pain. An intensification of itch and the
progression of lesions beyond the initial site of involvement may offer clues to the correct
diagnosis. Occupational dermatitis involving the hands can occur in nurses, physicians,
pharmacists, dentists, and veterinarians.

FORMALDEHYDE AND FORMALDEHYDERELEASING PRESERVATIVES.

Formaldehyde is a colorless gas with preservative and disinfectant properties. Although there is a
wide range of uses for formaldehyde-like cleansing products, glues, biocides, and photographic
developers, currently it is rarely used as-is in personal care because it has demonstrated to be a
frequent sensitizer. Therefore, many manufacturers have replaced the use of formaldehyde with
formaldehyde-releasing preservatives (FRPs) to preserve personal care products. FRPs include
quaternium-15, imidazolidinyl urea (Germall), diazolidinyl urea (Germall II), DMDM hydantoin
(Glydant), 2-bromo-2-nitropropane-1, 3-diol (Bronopol), and tris nitromethane (Tris Nitro).109 Of
these, Quaternium-15 is the most common cosmetic preservative allergen

COBALT.

Cobalt is a metal which is often added to other metals to increase overall strength. Cobalt is
commonly a contaminant present in nickel ores and is frequently a minor element in nickel
compounds. As with nickel, a majority of sensitization exposures result from contact with jewelry,
clothing snaps, buckles, coins, keys, and other metal objects. Furthermore, it can also be found in
prosthetic joint replacements, dental alloys, ceramics, paints, tattoo dyes, cement (mostly in
Europe), and multivitamins containing vitamin B12 (cobalt is a main component of vitamin B12,
Cyanocobalamine). Concomitant allergy to nickel and cobalt is often observed among patients
with dermatitis, probably as a result of cosensitization. In general, the best way of avoiding contact
with metallic cobalt is by avoiding contact with nickel-plated objects that come in direct contact
with the skin.

BACITRACIN

Bacitracin is a topical antibiotic frequently used for postoperative and general wound care by both
the medical profession and the general public since it is readily available in over-the-counter
preparations. Bacitracin is known to be a common sensitizer and can cause not only allergic contact
dermatitis but also urticarial reactions and even, rarely, anaphylaxis. It is important to note that
despite its high prevalence, bacitracin is not included as a screening allergen in the currently
available

T.R.U.E. Test series, which will be further discussed briefly in this chapter. Interestingly, patients
often show simultaneous sensitivity to bacitracin and neomycin, although the two substances are
not chemically related, meaning there is coreactivity but not crossreactivity between both
substances. Independent sensitization probably occurs to both antibiotics, which are often used
simultaneously in over-the-counter combinations.

METHYLDIBROMOGLUTARONITRILE/ PHENOXYETHANOL

Methyldibromoglutaronitrile/Phenoxyethanol (MDGN/PE) is a preservative combination also

known as Euxyl K400. It has become an increasingly important sensitizing agent, resulting in a
ban on use in Europe, first from stay-on cosmetics in 2005, and later from rinseoff cosmetics in
2007, in an attempt to decrease the rates of contact allergy. The use of MDGN/PE is not banned
in cosmetics produced outside the European Union, and therefore toiletries sold elsewhere may
contain MDGN/PE, albeit at a lesser concentration than had been allowed European formulations.
Most allergic reactions to MDGN/PE are due to the use of personal care products containing the
allergen, especially creams, lotions, wet wipes, and liquid soaps.
para-PHENYLENEDIAMINE

PPD is an oxidizing agent used as a permanent hair dye. Both consumers and hairdressers alike
are at risk for sensitization. As mentioned earlier in this chapter, contact allergy to PPD often
presents as facial dermatitis near the hairline, but it may also involve the eyelids and the neck,
while the scalp may or may not be spared. Once oxidized, PPD is no longer allergenic, thus, dyed
hair itself does not pose further risk of allergic stimulation. This is in contrast to permed hair, in
which the allergen, glyceryl monothioglycolate, retains ability to further stimulate dermatitis in
the allergic individual (i.e., an allergic hairdresser cutting the hair of a client who has had GMT
permanent waving applied to the hair weeks ago). PPD has the potential to cross-react with other
para-amino group chemicals such as paraaminobenzoic acid (PABA), sulfonylureas,
hydrochlorothiazide, benzocaine, procainamide, and certain azo and aniline dyes. Additionally,
PPD has gained notoriety for its use in adulterating natural henna to make “black henna,” a
substance increasingly used to make temporary tattoos.

PATCH TESTING

ALLERGEN SELECTION

T.R.U.E. TEST. The commercially available patch-test screening tool with US Food and Drug
Administration (FDA) approval is the Thin-layer Rapid Use Epicutaneous (T.R.U.E.) Test (Mekos
Laboratories AS, Hillerod, Denmark). As of March 2010, there were 28 (plus 1 negative control)
T.R.U.E. Test allergens organized into three panels (panels 1.1, 2.1, and 3.1). Of the top 30 most
frequently positive NACDG screening allergens for the 2005–2006 period, Zug and NACDG
colleagues found that 10 important allergens were not currently available for testing and
identification with the T.R.U.E. Test panels: bacitracin, methyldibromoglutaronitrile, bronopol,
cinnamic aldehyde, propylene glycol, DMDM hydantoin, iodopropynyl butylcarbamate,
ethyleneurea/melamine formaldehyde, disperse blue, and amidoamine. Of these, bacitracin is
likely the most important. Named Allergen of the Year in 2003 by the American Contact
Dermatitis Society, bacitracin is now the seventh most frequently positive allergen according to
prevalence data from this study group
RESULT INTERPRETATION

Reading reactions elicited by the patch test is a crucial step in the patch-test procedure. Patches
should be applied to healthy skin on the patient’s back and left under occlusion for 48 hours (eFig.
13-8.2 in online edition). Traditionally, patch-test reading is carried out in most patch-test clinics
twice: the day of patch-test removal 48 hours after application (day 2 = D2), and 96 hours after
epicutaneous exposure (day 4 = D4), or day 7. It is important to note that certain allergens are
acknowledged for being “late-reactors.” For example, if neomycin or PPD allergies are suspected,
additional readings at 5–7 days may be needed. Likewise, some researchers have also found that
readings for metals and corticosteroids should sometimes be delayed to 7 days. The reason for this
is that all these allergens are characterized as being “late-bloomers.” On the other hand, a study by
Geier and colleagues showed that by delaying readings to 7 days, some reactions to certain
fragrances and preservative allergens may dissipate. Therefore, the optimal protocol is probably
to read the test at day 2 and day 4, the conventional way, and then on day 7 if allergies to metals,
topical antibiotics (neomycin), and PPD are strongly suspected, or if the patient notes a newly
developed reaction after day 4. Patients are instructed to report back to their physician should any
additional positive reactions appear at day 5 or beyond to detect any late reactors or active
sensitization that may have occurred. At each test reading, it is traditional to note the results as
negative or positive, and grade the positive results on a quantitative scale. The ICDRG has
recommended to score patch-test reactions according to the scoring system recommended by
Wilkinson and colleagues which is on a + to +++ scoring system; where + represents a weak
nonvesicular reaction but with palpable erythema; ++ represents a strong (edematous or vesicular)
reaction; and +++ represents an extreme (bullous or ulcerative) reaction (Figs. 12-6C and 13-7).
Very weak or questionable reactions where there is only faint or macular (nonpalpable) erythema
are recorded by a question mark (?+), and irritant reactions are recorded as “IR.” Irritant patch-test
reactions have varied clinical signs which are related to the nature and the concentration of the
irritant and are classically described as (1) erythematous reactions limited to the site of application
of the chemical, with sharp, well-delineated margins; discretely scaly (may look “chapped”) and
usually not edematous. Among the patch-test allergens, fragrance mix, cocamidopropyl betaine,
iodopropynyl butylcarbamate, glutaraldhehyde, and thiuram mix are identified as the most
common allergens to produce such marginal irritant reactions. (2) Purpuric reactions with petechial
hemorrhage, which are seen in about 5% of patients tested to cobalt chloride. This is sometimes
referred as punctate purpura of cobalt and should always be interpreted as an irritant reaction.
Another top allergen that has been observed to cause purpuric reactions during patch testing is
PPD. (3) Pustular reactions: there can be a unique large pustule at the site of application (more
characteristic of caustic, strong irritant reactions), or more commonly, small follicular pustules
over an erythematous background. This type of reaction mainly occurs with metallic salts such as
potassium dichromate, cobalt, nickel, gold, and copper, and mainly in atopic patients. Other patch-
test reactions that should be interpreted with caution given their mild irritant potential include the
preservatives formaldehyde, benzalkonium chloride, and iodopropynyl butylcarbamate (IPBC);
the rubber allergen carba mix, fragrance chemicals such as fragrance mix I and propolis (bee glue);
the foaming agent cocamidopropyl betaine; and the emulsifiers: oleamidopropyl dimethylamine
and triethanolamine. It is important to mention that even paying close attention to the
aforementioned morphological features, irritant reactions are still difficult to interpret, and the
morphology of the patch-test response can still be a confusing guide to whether the response is
allergic or irritant. When morphology is not enough, it is advisable to keep in mind that in general
when the patch-test reaction is sufficiently strong, an irritant reaction will be early appearing
(during the first reading), and promptly healing (often times the reaction is not as strong or
sometimes not even present during the second reading). In contrast, a strong allergic reaction
usually spreads, is more slowly disappearing, and is more clearly eczematous.

ASSIGNING CLINICAL RELEVANCE

The diagnosis of contact allergy is mainly determined by the outcome of patch testing. However,
a positive test reaction is not necessarily an indicator of clinical disease, i.e., ACD, as the patch
test only measures whether the individual is sensitized or not. Sensitization does not necessarily
equate with clinical allergic disease. A good example of this point is the case of thimerosal. This
mercuric preservative is unique in the sense that it commonly causes positive patch-test reactions
but very seldom nowadays does thimerosal allergy account for the patient’s dermatitis. Most
allergic patients have presumably been sensitized to this preservative through vaccination but have
no clinical disease associated with this sensitization. Establishing the relevance of a positive patch-
test result is critical. However, it should be noted that lack of relevance does not mean a patient is
not allergic to the chemical in question, but more specifically that this chemical is not the causal
agent for the dermatitis currently being evaluated. Therefore determination of current clinical
relevance is essential in declaring ACD.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of ACD includes a wide range of inflammatory skin disorders

Diagnosis Diagnostic Clues

Irritant contact dermatitis (ICD) Physical findings can be indistinguishable
clinically; in general there is an absence of
vesiculation (only very strong irritants produce
vesicles) and burning exceeds itching. Does
not spread beyond the area of contact with
continued exposure.
Atopic dermatitis Distribution of skin findings can be helpful;
atopic patients can and do develop contact
allergies. Worsening disease can indicate new
contact allergy development.
Nummular dermatitis (ND) Widespread ACD can assume this pattern in
certain patients; nonetheless, the classical
morphology of coin-shaped, well-demarcated
plaques on the legs, dorsal hands, and extensor
surfaces favors ND.
Seborrheic dermatitis Greasy and scaly papulosquamous plaques
usually located in the hairbearing regions,
glabella, and nasolabial folds.
Asteatotic eczema Parchment-like patches with no edema or
vesiculation on the lower legs.
 Stasis dermatitis Papulosquamous plaques with dyschromia
located on the shins and medial surfaces of the
lower legs, with presence of concomitant
varicosities.
Pompholyx and/or dyshidrotic eczema Deep-seated vesicles on palms, soles, sides of
the fingers, and volar edges.
Psoriasis When it presents in its classic form, diagnosis
can be straightforward, however, when the
lesions are few and limited to the hands and/or
feet differentiation can be more difficult.
Classical location and predominance in areas
of trauma (Koebnerization) can be helpful as
well as the presence (if any) of concomitant
arthritis
Mycosis fungoides (patch/plaque stage The well demarcated, atrophic,
cutaneous T-cell lymphoma) poikilodermatous, scaly patches and plaques of
MF are usually found in nonsun-exposed areas
of the skin, such as the trunk, breasts, hips, and
buttocks (bathing suit distribution).

Histologically, the presence of eosinophilic spongiosis and multinucleate dermal dendritic

fibrohystiocytic cells is especially suggestive of ACD, when encountered in the presence of a
lymphocytic infiltrate, dermal eosinophils, and hyperkeratosis that approximately 16% of all
chronic eczema patients would benefit from patch testing. Clinical experience suggests this
number is much larger. Based on those figures, it could be estimated that approximately 2.2 million
patients each year in the United States would benefit from patch testing

COMPLICATIONS

COMPLICATIONS OF PATCH TESTING

Patch testing is considered a safe diagnostic procedure and unwanted effects are seldom
encountered. The most common side effect is itching at the site of a positive test reaction, and
irritation and pruritus from tape application. Less commonly, postinflammatory hypoor
hyperpigmentation can occur. Hyperpigmentation is more likely in darkly pigmented persons; it
fades progressively with time and the use of topical corticosteroids. It is important to note that
exposure to sunlight or artificial UV immediately following removal of patch tests especially to
fragrance materials, can lead to hyperpigmentation of the patch-test site in relation with
photosensitivity. Persistence of a positive reaction is another adverse reaction that may occur. A
patchtest reaction that may persist for more than 1 month is that due to gold in a gold sensitive
patient. Induction of a dermatitis flare-up at the original site of an existing or preexisting dermatitis
(that was caused by the positive patch-test allergen) can also occur. This can be minimized by
testing patients free of any current active dermatitis. Also, a positive patch-test reaction in a patient
who has active psoriasis or lichen planus may reproduce these dermatoses at the patch-test sites
(as a Koebner phenomenon), during the weeks following patch testing. These lesions can be
cleared with the use of topical corticosteroids. Finally, the possibility of becoming sensitized
(active sensitization) to one of the tested allergens exists; however, it has proven to be low. Serious
adverse effects during patch testing such as anaphylactoid reactions from allergens known to cause
a type I (immediate) hypersensitivity reaction such as bacitracin and neomycin are exceptionally
rare.

COMPLICATIONS DERIVED FROM FAILURE TO PATCH TEST

The greatest hazard is omission to patch-test appropriate patients with dermatitis. Such omission
potentially dooms the patient to repeated episodes of avoidable contact dermatitis. In 2004, the
American Academy of Dermatology and the Society of Investigative Dermatology studied the
burden of skin disease and estimated that 72 million people in the United States suffer from
ACD.140 It is the third most common reason for patients to seek consultation with a dermatologist,
accounting for 9.2 million visits in 2004 alone. Likewise, in that same year, primary care
physicians received 5 million visits for unexplained dermatitis or eczema. Whereas many of these
patients will respond readily to standard treatments, there will be others that demonstrate
recalcitrant eczema. It has been estimated that approximately 16% of all chronic eczema patients
would benefit from patch testing. Clinical experience suggests this number is much larger. Based
on those figures, it could be estimated that approximately 2.2 million patients each year in the
United States would benefit from patch testing.

PROGNOSIS

It is difficult to assess the actual prognosis of ACD because there is no standardized instrument for
such evaluation. The disruption of work, ability to return to work, and improvement of dermatitis
with time are among outcome measures that have been studied in patients with ACD. Recent study
designs have aimed to capture the increasingly important outcome measure of health-related
quality of life (QoL). When different QoL assessment tools have been applied to populations of
patients with ACD it has been demonstrated that ACD negatively impacts QoL significantly.
Holness and colleagues found that pain, itching, embarrassment, work interference, and sleep
difficulties were the most significant effects in QoL of their patch-test population. Kadyk et al
found the greatest impact on emotions, followed by symptoms, functioning, and occupational
impact. Similarly, Woo and colleagues reported that patients with the final diagnosis of ACD had
a mean baseline QoL equal to that of patients experiencing hair loss and psoriasis. Zug et al found
that patients referred for patch testing were severely affected by frustration, reported feeling
annoyed, and had a great concern about the persistence of their skin problem. Notably a factor that
is strongly predictive of a negative impact on QoL is hand involvement of ACD. Similarly, the
extent of the disease and the duration of symptoms before diagnosis are both correlated with a poor
prognosis and recalcitrant disease. On the other hand, increased patient knowledge has been
associated with improved prognosis in some studies. Much of this information is extrapolated from
data regarding occupational contact dermatitis.

TREATMENT

Because allergen identification can be achieved through proper patch testing, there is a good
potential for a sustained remission. Therefore, identification and removal of the inciting agent(s),
and they are often multiple, should always be the goal in the diagnosis and treatment of ACD