24 - ALLERGIC CONTACT DERMATITIS Flashcards
cell-mediated (type IV), delayed type, hypersensitivity reaction caused by skin contact with an environmental allergen.
Allergic contact dermatitis (ACD)
clinical manifestation of ACD
eczematous dermatitis. The acute phase is characterized by pruritus, erythema, edema, and vesicles, usually confined to the area of direct exposure. Recurrent contact to the causative allergen may lead to chronic disease, characterized by lichenified erythematous plaques with variable hyperkeratosis, fissuring, and pigmentary changes that may spread beyond the areas of direct exposure.
diagnostic test of choice to identify causal allergens and is indicated for patients with persistent or recurrent dermatitis in whom ACD is suspected
Patch testing
mainstay of ACD treatment
Allergen avoidance
Educating patients about avoiding the allergen and related substances, and providing suitable alternatives, are crucial to a good outcome.
EPIDEMIOLOGY OF ACD
Several 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 4 performed a retrospective study that reviewed the main findings from previously published epidemiologic studies on contact allergy in unselected populations of all age groups and from 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 1 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. The prevalence of contact allergy to specific allergens differs among various countries 5-7 and the prevalence to specific allergens is not necessarily static, as prevalence is influenced by regional changes and developments, exposure patterns, regulatory standards, and societal customs and values.
AGE PREDILECTION OF ACD
Multiple studies have recognized contact dermatitis as an important and common cause of childhood dermatitis. Although ACD is equally as likely to develop in childhood as in adulthood, 8,9 the most common allergens identified differ between the age groups. While fragrance was an important sensitizer in all ages, certain studies, such as the 2001 Augsburg study based on adults 28 to 75 years of age, showed a significant increase in fragrance allergy with increasing age.10 Similarly, a recent Danish study demonstrated the prevalence allergy to preservatives to be higher among those 41 to 60 years of age.
GENDER PREDILECTION OF ACD
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 patchtesting method was used to assess induction rates for 10 common allergens, women were more often sensitized to 7 of the 10 allergens studied. 12 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. Looking specifically at nickel sensitivity, the same study showed the prevalence to be much higher among women than men (17.1% in women vs 3% in men). This may be because pierced ears are a significant risk factor for development of nickel allergy,13-17 and there was a higher prevalence of pierced ears in women in comparison with men (81.5% vs 12%) in the population studied.
CUTANEOUS FINDINGS OF ACD
The classic presentation of ACD is a pruritic, eczematous dermatitis initially localized to the primary site of allergen exposure. Geometric, linear, or focal patterns of involvement are suggestive of an exogenous etiology. For example, ACD from plants such as poison ivy, poison oak, or poison sumac, typically presents as a linear or streaky array of erythematous papules and vesicles. Occasionally, the sensitizing substance in these plants, an oleoresin named urushiol may be aerosolized when the plants are burned, leading to a more generalized and severe eruption on exposed areas. 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 (eg, genital involvement in a patient with poison ivy). Because the mechanism of allergen exposure influences the clinical presentation, relevant historic data gathered from thoughtful questioning may prove as useful as the distribution of the lesions.
Importantly, ACD will vary morphologically depending on the stage of the disease and severity of reaction. During the acute phase, lesions are marked by edema, erythema, and vesicle formation. Stronger allergens often result in vesicle formation, whereas weaker allergens often lead to papular lesion morphology, with surrounding erythema and edema. In the subacute phase, vesicular rupture leads to oozing, and scaly juicy papules associated with weeping and crusting dominate the clinical picture. Finally, the chronic phase is characterized by scaling, fissuring, and lichenification. A key symptom for ACD is pruritus, which seems to occur more typically than a symptom of a burning sensation.
Moreover, there are some noneczematous clinical variants of ACD (Table 24-1) that are infrequently observed. 18,19 Erythema multiforme-like ACD has been linked primarily to exotic woods, topical medicaments, and numerous miscellaneous chemicals. In contrast to true erythema multiforme, which typically presents on acral sites, lesions of erythema multiforme-like ACD are typically at the periphery site of contact with the allergen, fever is usually absent, and mucosal involvement is rare. Purpuric ACD is mainly observed on the lower legs and/or feet and has been reported with a wide variety of allergens, including rubber and textile dyes. Lichenoid ACD is considered a rare variant that can mimic lichen planus; it is associated with color developers and metallic dyes in tattoos. Also, oral lichenoid ACD from dental amalgams can resemble typical oral lichen planus. Pigmented ACD has been mainly described in Asian-ethnicity populations. It is linked to textile dyes, cosmetics, and fragrances. Lymphomatoid ACD is based only on histopathologic criteria (presence of significant dermal infiltrate displaying features of pseudolymphoma). Nonspecific clinical signs include erythematous plaques, sometimes very infiltrated, at the site of application of the contact allergen. Allergens implicated in lymphomatoid ACD include metals (nickel and gold), para-phenylenediamine (hair dye), para-tert-butylphenol resin (glue), and dimethylfumarate (a mold inhibitor found in sachets within some furniture implicated in causing a previously severe epidemic of ACD).
ETIOLOGY AND PATHOGENESIS
ACD represents a classic cell-mediated (type IV), delayed hypersensitivity reaction. Type IV hypersensitivity reactions result from exposure and sensitization of a genetically susceptible host to an environmental allergen, followed by subsequent reexposure that triggers a complex inflammatory reaction. The resulting clinical picture is that of erythema, edema, and papulovesiculation, usually in the distribution of contact with the instigating allergen, and with pruritus as a major symptom. 20 To mount such a reaction, the individual must have sufficient contact with a sensitizing chemical, develop immunologic memory, and then have repeated contact with that substance later to elicit the immune response. This is an important distinction from irritant contact dermatitis in which sensitization is not required, and in which the intensity of the irritant inflammatory reaction is proportional to the dose (concentration and amount) of the irritant. By contrast, in ACD, even minute quantities of an allergen can elicit overt allergic reactions in a sensitized individual. There are two distinct phases in the development of ACD: the sensitization phase and the elicitation phase.
SENSITIZATION PHASE
Unprocessed allergens are more correctly called haptens, which are typically small, lipophilic molecules with a low molecular weight (<500 daltons). Once a hapten penetrates the skin, it binds with epidermal carrier proteins to form a hapten–protein complex, which produces a complete antigen. Simultaneously, innate immunity is activated by keratinocyte release of several cytokines including interleukins 1, 8, and 18, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor. 22 Next, the antigen-presenting cells of the skin (Langerhans cells [LCs] and/or dermal dendritic cells), take up the hapten–protein complex (“the antigen”) and express it on the cell surface on an human leukocyte antigen molecule. The antigen-presenting cell then migrates via lymphatics to regional lymph nodes where it presents the human leukocyte antigen complex to naïve antigen-specific T cells. These naïve T cells are then primed and differentiate into memory (effector) T cells, which expand clonally, acquire skin-specific homing antigens, and immigrate into circulation where they can act as effectors on target cells presenting the same antigen in the future. 23,24 The sensitization phase generally lasts 10 to 15 days and often is asymptomatic. 25 Subsequent exposure to the antigen (called rechallenge) leads to the elicitation phase and can occur via multiple routes, including transepidermal, subcutaneous, intravenous, intramuscular, inhalation, and oral ingestion.26
Of note, LCs have long been assumed to be the antigen-presenting cell responsible for inducing T cells in ACD, because of their abundance in the epidermis, easy accessibility to haptens, and strong antigenpresentation ability in vitro. However, recent studies reveal that depletion of LCs during the sensitization phase does not completely impair contact hypersensitivity responses. 27,28 Interestingly, it seems that CD1a+/ CD141+ dermal dendritic cells may be the primary cells responsible for contact sensitization, although LCs may still play a role in some sitations. 22,27,29 Furthermore, it is important to note that sensitization can stimulate both helper (Th) and cytotoxic (Tc) T cells. While the most important population of cells in allergic sensitization is the Th1/Tc1 subset (interferon-γ producing), induction of Th2 and Th17/Tc17 subsets has been described and may play a role in the sensitization phase of ACD.
ELICITATION PHASE
During this phase, subsequent exposure to an allergen to which the patient is already sensitized leads to clinical disease. First, hapten exposure leads to low-grade nonspecific inflammation through cellular stress as well as activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors, leading to neutrophil recruitment and, subsequently, effector T-cell recruitment. 28 Once antigen-specific effector T cells are recruited into skin containing their target antigen, they interact with antigen-presenting cells (LCs and dermal dendritic cells) in a cluster around postcapillary venules. This cluster of immune cells previously was considered the skin-associated lymphoid tissue but is now called inducible skin-associated lymphoid tissue because the clusters of immune cells only appear when they are induced by inflammation, rather than in the steady state. 28,30 In response, the antigen-specific T cells amplify the specific immune response, releasing cytokines, including interferon-γ and tumor necrosis factor-α, which, in turn, recruit other inflammatory cells while stimulating macrophages and keratinocytes to release more cytokines. 31,32 An inflammatory response occurs as monocytes migrate into the affected area, mature into macrophages, and attract more T cells. The inflammatory response elicited typically lasts several weeks, and if allowed to run its natural course, it is thought that regulatory T cells are involved in suppression of the response. Interestingly, LCs may be involved in promoting the development of regulatory T cells that subsequently suppress the immune response in ACD, although the exact mechanisms are not yet clear.
DIAGNOSIS OF ACD
Any patient who presents with an eczematous dermatitis should be regarded as possibly having ACD. Additionally, one must consider contact allergy in patients with other types of dermatitis (eg, atopic) that is persistent and recalcitrant despite appropriate standard therapies, as well as in patients with erythroderma, or scattered generalized dermatitis. 33 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 33 and include the following:
■ ACD is not always bilateral even when the antigen exposure is bilateral (eg, shoe or glove allergy).
■ Even when exposure to an allergen is uniform (eg, contact allergy to an ingredient of a cream that is applied on the entire face), eczematous manifestations are very often patchy.
■ ACD can and does affect the palms and the soles.
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(s) of onset and the topical agents used to treat the problem (including over-the-counter and prescription medications). A history of skin disease, atopy, and general health should be investigated routinely and followed by details 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 patient’s 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 chemical exposure should be prime suspects.
SUPPORTIVE STUDIES
Typically, ACD is diagnosed based on history, clinical examination, and patch test results. Occasionally, prior to determining that a dermatitis is of the allergic contact type, workup may include laboratory studies or skin biopsy. In these cases, a complete blood count may demonstrate eosinophilia or may be normal. Histologically, the presence of eosinophilic spongiosis and multinucleate dermal dendritic fibrohistiocytic cells is especially suggestive of ACD, when encountered in the presence of acanthosis, a lymphocytic infiltrate, dermal eosinophils, and hyperkeratosis.
DIAGNOSTIC ALGORITHM
Independent of patch testing (discussed in “PatchTesting Mechanics” below), the causative allergen(s) can rarely be identified by skillful analysis of the patient’s exposure history and distribution of dermatitis. Most of the time, an exact cause cannot be identified based on history and examination alone, so one must develop a clinical approach that will guide patch testing. In the opinion of the authors, the two most useful approaches are a topographic approach (based on the distribution of dermatitis on the patient’s skin) and an allergen-specific approach (based on knowledge of trends in dermatitis to specific allergens). Each of these approaches is reviewed in this section.
TOPOGRAPHIC APPROACH
Figure 24-1 identifies the allergens to consider based on skin lesion topography. Dermatitis distribution is often 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 periumbilical or 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. 24-2). 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—whereas eczematous dermatitis on the weight-bearing 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 cosmeticrelated contact allergy. However, for all these presentations, correct identification of the culprit chemical(s) will still require patch testing, as 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 to determine 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 2 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.
The face is a common site for ACD.
Among patients with facial dermatitis, women are more commonly affected than men, particularly by cosmetic-associated allergens such as fragrances, para-phenylenediamine (PPD), preservatives, and lanolin alcohols. 35 Allergens can be applied to the face directly, or inadvertently contacted 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, are also reported to produce facial dermatitis in rubber-sensitive patients. 36 A similar situation can be seen with nickel-plated objects such as eyelash curlers, tweezers, and bobby pins. Cellphones and accessories may also result in facial ACD. The prototypical presentation is that of a preauricular facial dermatitis in a nickel-allergic patient.
SCALP
Scalp-applied allergens paradoxically show a predilection for causing dermatitis on nonscalp sites. Downstream anatomical sites, such as the face, eyelids, ears, neck, and hands, may show ACD while the scalp remains relatively uninvolved. This is likely secondary to regional differences affording the scalp a greater degree of epidermal barrier protection to potential allergens. 38 Nevertheless, patients exquisitely sensitive to certain chemicals in hair products, such as PPD or glyceryl monothioglycolate (GMT), 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. 39-42 GMT is a chemical substance used in permanent wave solutions. Allergic sensitivity to GMT can manifest as intense scalp pruritus with scaling, edema, and crusting.
EYELIDS
The eyelids are one of the most sensitive skin areas and are highly susceptible to irritants and allergens. This is likely a consequence of the thinness of the eyelid skin, as compared with other skin, and perhaps because the offending chemical may accumulate in eyelid 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. 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, eyeliner and eye shadow, adhesive in fake eyelashes, and nickel and rubber in eyelash curlers. Furthermore, marked edema of the eyelids is often a feature of hairdye dermatitis. 44 As mentioned earlier, 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, 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 gold45 ) can also cause eyelid contact dermatitis. In fact, in the 2007 NACDG analysis of contact allergens associated with eyelid dermatitis, 46 gold was the most common allergen, accounting for isolated 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. 47 Aside from gold, fragrances and preservatives are the main cosmetic allergens to cause isolated eyelid dermatitis. 48 ACD caused by allergens found in ophthalmic medicaments should also be considered. The most frequent allergens in ophthalmic preparations are the preservative phenylmercuric acetate and antibiotics. 49 Benzalkonium chloride is another preservative that is frequently used in ophthalmic preparations, and a potential irritant and allergen.
LIPS
According to a NACDG study, approximately onethird of patients with isolated cheilitis—without other areas of dermatitis—are typically found to have an allergen as a contributing factor. 51,52 Allergic contact cheilitis 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; Fig. 24-3).53-55 Allergic contact cheilitis has a marked female predominance, with most studies reporting a range of 70.7% to 90% female patients. 56 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.57 Of note, some uncommonly reported allergens, namely, benzophenone-3 and gallates, may be relevant to a dermatitis localized to the lips. Benzophenone-3 (oxybenzone), a major constituent of many sunscreens, is also a common ingredient in many lip products and is increasingly reported as a culprit for allergic contact cheilitis. 58,59 Gallates are antioxidants used in waxy or oily products such as lip balms, lipsticks, and lip glosses. 60 Patch testing directly to the patient’s lip cosmetics can be of particular usefulness in the evaluation of isolated cheilitis. It is also important to consider wind instruments as a cause of perioral ACD in musicians.
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. 61 Furthermore, as a cultural practice, perfumes are typically 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. 62 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 differential diagnosis of an eczematous dermatitis affecting the torso can be broad. There is a multitude of potentially allergenic chemical exposures to consider if the diagnosis of ACD is entertained. The torso is typically exposed to fragrances, preservatives, surfactants, and other chemicals daily with the use of personal care products. Textile-associated chemicals may also provide a source of sensitization and elicitation of ACD. The primary potential textile allergens are disperse dyes and formaldehyde textile resins. In the past, formaldehyde textile resins contained large amounts of free formaldehyde, which led to many cases of ACD to clothing in the 1950s and 1960s.
Today, most textile finishes use modified dimethyloldihydroxyethylene urea. Blended fabrics labeled “wrinkle resistant” or “permanent press” are most likely to contain formaldehyde textile resins. Recent studies suggest that the amount of free formaldehyde in most garments today is likely below the threshold for the elicitation of dermatitis for all but the most sensitive patients.
AXILLAE
Textile-associated allergens are implicated in causing ACD of the axillae. Heat, humidity, and friction may contribute to the leaching of textile resins and dyes. The prototypical presentation is an eczematous dermatitis affecting the axillary folds with relative sparing of the axillary vault. 64 The axillary region is also uniquely exposed to deodorants and antiperspirants. These products may contain high concentrations of fragrances 65 in addition to preservatives (eg, formaldehyde releasers, parabens).
HANDS AND FEET
Hand dermatitis is common and accounts for up to 80% of occupational skin disease. Certain occupations are at an increased risk for hand dermatitis, including health care workers, food handlers, and hairdressers. Hand dermatitis is most often multifactorial (eg, irritant exposure, atopy, pompholyx or chronic vesicular hand eczema, psoriasis, dermatophyte infection) adding to the complexity of both diagnosing and treating these patients. Clinical clues to an underlying component of ACD include pruritus, vesicular dermatitis affecting the finger tips, and destabilization of chronic dermatitis. Destabilization of chronic dermatitis refers to a change in treatment response, symptoms, or extent of a preexisting chronic dermatitis, and is a clue to the development of ACD. Chronic hand dermatitis in and of itself is an indication for patch testing. Similarly, the evaluation of foot dermatitis should include patch testing. The most common class of allergens to cause ACD of the feet are rubber-related chemicals (such as mercaptobenzothiazole, carbamates, thiurams, black rubber mix, and mixed dialkyl thioureas). Other allergens that need to be considered are glues and adhesives such as p-tert-butylphenol formaldehyde resin and potassium dichromate found in tanned leather. Footwear, such as socks and shoes, may also serve to retain topical medicaments (antibiotics, corticosteroids, antifungals) used on the feet and provide continued skin exposure over time.
MUCOUS MEMBRANES
ACD of the oral mucosa may present with contact stomatitis from dental metals, and ACD of the perianal area may be caused by sensitizing chemicals in proctologic preparations such as benzocaine.
SCATTERED GENERALIZED DISTRIBUTION
Patients with dermatitis in a scattered generalized distribution (SGD) can present a difficult diagnostic and therapeutic challenge. SGD is defined as involvement of more than 3 body sites or involvement of 3 body sites if the sites are trunk, arms, and legs. Patch testing is often an important part of the workup in refractory cases of SGD dermatitis. In 2008, Zug and NACDG colleagues 66 examined the yield of patch testing as well as the relevant allergens in patients with SGD rashes referred for patch testing. Of 10,061 patients studied during a period of 4 years, 14.9% were categorized as SGD. Interestingly, a higher incidence of SGD was seen in males and patients with a history of atopic dermatitis. Of the patients presenting with SGD rashes, 49% had at least 1 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
Systemic exposure to an allergen in a sensitized patient with the subsequent development of a cutaneous delayed hypersensitivity reaction is termed systemic contact dermatitis (SCD). 67 Sensitization typically occurs with cutaneous exposure as with other forms of ACD. There are multiple routes of exposure for the elicitation of SCD—subcutaneous, intravenous, intramuscular, inhalation, and oral ingestion. By definition, there is no occurrence of topical skin contact to the allergen in SCD.
The clinical presentation of SCD can be complex with a high degree of variability. The simplest presentation seen is a localized recall reaction where the dermatitis occurs at the site of prior topical sensitization. The other end of the spectrum would be erythrodermic SCD. The term “baboon syndrome” was introduced in 1984 to describe a specific dermatologic response to a systemic contact allergen in which erythema of the buttocks and upper inner thighs was seen resembling the red rump of baboons. 68 Mercury, nickel, and ampicillin were the first described causative agents. 69 Over time use of the term baboon syndrome has broadened to include cases of drug-induced erythema of the buttocks and upper inner thighs in which previous cutaneous sensitization has not occurred. This is a deviation from the strict definition of SCD, and some have advocated for a change in nomenclature to drug-related baboon syndrome with or without previous cutaneous exposure to reflect the difference in pathogenic mechanisms. 69 Others have suggested the term symmetrical drug-related intertriginous and flexural exanthema as a more precise term which by definition denotes a specific cutaneous adverse drug reaction in which previous cutaneous sensitization is not a necessary condition. Table 24-2
shows the diagnostic criteria for symmetrical drugrelated intertriginous and flexural exanthema. 69 The term allergic contact dermatitis syndrome has been proposed to encompass all cutaneous reactions that share the commonality of sensitization occurring through cutaneous exposure. These reactions can be further delineated based on the extent of dermatitis and route of exposure driving the elicitation phase (Table 24-3).18 Table 24-4 lists some known oral or IV medications which may cause systemic reactivation of ACD in patients previously sensitized to related allergens by direct skin contact.70-73
A few specific examples of SCD are worth noting. Dietary nickel and balsam of Peru are associated with dyshidrosiform hand eczema. 74 The major constituents of balsam of Peru (cinnamic acid, cinnamyl cinnamate, benzyl benzoate, benzoic acid, benzyl alcohol, and esterified polymers of coniferyl alcohol) are naturally derived and have a significant number of natural cross-reactors. Tomatoes, citrus peel/zest, chocolate, ice cream, wine, beer, dark-colored sodas, and spices such as cinnamon, cloves, curry, and vanilla are potential cross-reactors with balsam of Peru. 75 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 the potential for dietary triggers to induce SCD in patients sensitive to balsam of Peru. In their study, almost half of the participants with a positive patch test to balsam of Peru noted clinical improvement in their dermatitis on a balsam of Peru elimination diet.
Allergic Contact Dermatitis Syndrome
Systemic Drugs That Can Cause Systemic Reactivation of Allergic Contact Dermatitis
Nickel
Nickel is an ubiquitous metal found in
a variety of objects that get in contact with the skin, including costume jewelry, suspenders, zippers, button snaps, belt buckles, eyeglasses frames, cell phones, nickel-containing coins, and keys. 77 High rates of sensitization to nickel have been ascribed in women to ear piercing at an early age and in both men and women to the rising trend in piercings of other body parts. 77 Classic nickel dermatitis presents as an eruption on the earlobes, the neckline, the wrist, or the periumbilical area, which are commonly exposed to nickel-containing jewelry and to button snaps, zippers, and belt buckles. Facial dermatitis caused by nickel has also been reported to musical instruments and to cell phones.37
Nickel and other metals in implantable medical devices are implicated as a source of sensitization and cause of complications from local and systemic inflammation resulting from such allergy in metalsensitive individuals. While fully confirmed cases of joint replacement failure associated with nickel or other metal sensitivity are rare, and arthroplasty prostheses uncommonly cause problems in nickelsensitive patients, the true relevance of metal allergy
in the failure of metal orthopedic implants and cardiovascular devices has yet to be fully elucidated. 78 Existing publications have largely been retrospective and can thus only suggest a possible association of metal allergy with implant failure rather than determine causation. 79 Moreover, eczematous reactions related temporally to joint replacements, stents, pacemakers, or other implants continue to be reported, albeit infrequently. With sustained use of metal implants as medical devices, we are likely to see a rise in cases referred for patch testing to help adjudicate the relevance of metal allergy. Preoperatively, patch testing may guide the choice of implants based on allergy to ingredients; postoperatively, it may help diagnose the cause of complications.80
To prevent development of nickel sensitivity, the European Union, in 1994, regulated the amount of nickel that may be released from objects with direct and prolonged skin contact to ≤0.5 µg nickel/cm2 /week; in 2014 this restriction was strengthened to ≤0.2 µg nickel/cm2 /week for items inserted as pierced body parts. Among Danish women, the prevalence of nickel allergy decreased from 28% in 1985 to 17% in 2007.81 The American Academy of Dermatology and the American Contact Dermatitis Society favor enacting similar legislation in the United States.
Spot tests containing dimethylgloxime are available commercially to detect the presence of nickel concentrations >1:10,000 (or >0.44 µg/cm2) producing a pink precipitate on a white cotton swab and the intensity of this color read-out increasing with nickel concentration.
Cobalt
Cobalt is often added to other metals to
increase the overall strength of an alloy. Cobalt is a common contaminant in nickel ores and thus frequently found in nickel compounds. 82 As with nickel, most sensitization exposures result from contact with jewelry, clothing snaps, buckles, coins, keys, and other metal objects. Like nickel, cobalt can be found in prosthetic joint replacements and dental alloys. Cobalt is also often used in ceramics, paints, and tattoos to impart a blue color. On jewelry, this blue color confers a darker appearance to alloys containing cobalt. 83 Cobalt is an ingredient of multivitamins containing vitamin B 12 or cyanocobalamine.84
Cobalt often produces a pseudopurpuric appearance on patch testing in the absence of erythema or edema. This is not a positive patch test reaction, but rather an irritant effect from deposition of cobalt within eccrine glands. 78 Concomitant patch test positivity to nickel and cobalt is a common occurrence, most likely from cosensitization to both allergens. Avoidance of nickelplated objects is a practical way of managing ACD to cobalt.
Similar to the dimethylgloxime test for nickel, a spot test using 2-nitroso-1-naphthol-4-sulfonic acid was created to detect cobalt. In contrast to the pink readout from the dimethylgloxime test for nickel, the spot test for cobalt yields a yellow-orange color in the presence of cobalt.83
other metals causing ACD
Chromium (potassium chromate in patch tests) has been long-considered the classic marker for allergy to leather goods and to wet cement. However, cobalt is also a relevant marker for allergy to both leather and cement. 83 Gold is a controversial aller-
gen as it can often give produce a positive patch test but fail to meet standards for relevance. Conversely, gold frequently manifests extremely delayed hypersensitivity that runs the risk of being interpreted as negative in patch tests that are only read less than 96 hours after application.
Formaldehyde and Formaldehyde Releasers
Formaldehyde is a colorless gas with preservative
and disinfectant properties. Even though formaldehyde and formaldehyde-like agents have a broad range of uses as glues, biocides, and photographic developing agents, these chemicals are now rarely used in personal care products because of their potent sensitization capacity. 85 Instead manufacturers have replaced formaldehyde with other preservatives to prolong the microbe-free shelf life of their products. These substitutes for formaldehyde can be sorted into agents that can release formaldehyde (formaldehyde releasers) and those that do not. Formaldehyde-releasing preservatives include 2-bromo-2-nitropropane-1,3-diol (bronopol), diazolidinyl urea (Germall II), DMDM hydantoin (Glydant), imidazolidinyl urea (Germall I), quaternium-15, and tris-nitromethane (Tris Nitro). 86 Of these preservatives, quaternium-15 is the most common cosmetic allergen.87-89
Note that formaldehyde-containing resins are linked to 2 other forms of ACD. The first form involves the glues, toluene sulfonamide formaldehyde resin or tosylamide (used in artificial nails) and p-tert butylphenol formaldehyde resin (used in shoes and other garments). The second form involves use of formaldehyde derivatives to make wrinkle-free or permanentpress fabrics and clothing.
Nonreleasers of Formaldehyde
The 2 major
preservatives in this category are methyldibromoglutaronitrile/phenoxyethanol (MDGN/PE) also known as Euxyl K400 and methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) also known as Kathon CG. Because of their high propensity for causing ACD, both of these preservatives have been banned from use in cosmetics in Europe. 90 However cosmetics produced outside the European Union and toiletries sold elsewhere may contain them. Most allergic reactions to these preservatives originate from personal care products such as creams, lotions, wet wipes, liquid soaps, and medicated tissue and toilet paper containing the allergens. Also note that, because of peculiarities related to concentrations of allergens, optimal testing may require assaying both the combined allergen pairs (Euxyl K400 and Kathon CG) as well as their individual components (MDGN or PE; MCI or MI), as patch tests to only the former can miss reactions to specific allergens.
FRAGRANCES
Fragrances are aromatic compounds that impart a scent. Fragrances can be natural (from botanical or animal products) or synthetic in origin. Up to 4% of the general population are allergic to fragrances, 91,92 making these chemicals among the top causes of ACD to personal care products, with typical sites of involvement including the face and hands, behind the ears, and the neck and axillae, yielding a scattered but generalized distribution of eczematous dermatitis. 93,94 Among the main substances used by most patch test groups for screening are M. pereirae, fragrance mix I (mixture of 8 fragrance allergens), and fragrance mix II (6 additional allergens). 95 It is estimated that M. pereirae can identify up to 50% of fragrance-allergic individuals.96 Fragrance allergens are found in many cosmetics, perfumes, pharmaceutical preparations, toothpastes, and mouthwashes, as well as in scents and flavorings for foods and drinks. Fragrance allergens can be included in skin-care products without being labeled as fragrances if they are not used primarily as fragrances but as neutralizers of unwanted scents within the merchandise.
Neomycin
Neomycin is a member of the amino-
glycoside family of antibiotics commonly used in topical formulations to prevent and treat skin, ear, and eye infections. At least 1% of the general population is allergic to neomycin, with sensitization rates as high as 10% in North America. 97 This latter high rate is most likely a result of the presence of neomycin in numerous over-the-counter preparations, especially in combination with polymyxin and bacitracin as a “triple antibiotic” cream or ointment. 98 Patients at higher risk include those with stasis dermatitis and leg ulcers, anogenital dermatitis, and otitis externa. Because antibiotic preparations are applied to already damaged skin, ACD to neomycin is not always easily recognized as it often presents as persistence or worsening of a preexisting dermatitis. 99 It may also mimic cellulitis, for which the clue for ACD is itching rather than pain. Occupational dermatitis involving the hands can occur in nurses, physicians, pharmacists, dentists, and veterinarians.
Bacitracin
Like neomycin, bacitracin is a topical antibiotic frequently used for postoperative and general wound care by both the medical profession and the general public as it is readily available in over-the-counter preparations. Not only can bacitracin cause ACD, but it has been reported in association with urticarial reactions and even, rarely, anaphylaxis.101 Despite its high prevalence as an allergen, bacitracin is not included in the currently available T.R.U.E. (thinlayer rapid-use epicutaneous) test series. Interestingly, many patients show simultaneous sensitivity to bacitracin and neomycin, although the 2 substances are not chemically related, thereby indicating cosensitization (rather than coreactivity) to both substances.
PARAPHENYLENEDIAMINE
PPD is an oxidizing agent used as a permanent hair dye. Both consumers and hairdressers are at risk for sensitization. Interestingly, ACD to PPD often spares the scalp, while presenting as dermatitis on thinner skin of the face, eyelids, and neck. 103 Once oxidized, PPD is no longer allergenic, so that dyed hair itself does not pose further risk of allergic stimulation. This is in contrast to permed or waved hair, in which the allergen, GMT, persists in its ability to cause ACD in a sensitized individual long after the allergen has been exposed to the air (eg, from contaminated sites in a hair salon). Table 24-5 lists other allergens commonly associated with hair care. PPD can cross-react with other para-amino–group chemicals such as paraaminobenzoic acid, sulfonylureas, hydrochlorothiazide, benzocaine, procainamide, and certain azo and aniline dyes. 104,105 Additionally, PPD has gained notoriety as an adulterant added to natural henna for temporary tattoos; it darkens the henna tattoo.
RUBBER
Rubber allergens can be classified into chemicals associated with processing of natural latex derived from the proteinaceous sap of the rubber tree (Hevea brasiliensis) and synthetic rubber that is unrelated to latex. Latex is a common cause of immediate-type hypersensitivity mediated by latex protein-specific immunoglobulin E. Rarely, latex itself can also cause ACD, but it is the accelerator and vulcanizing chemicals (carbamates, mercaptobenzothiazole, thiuram) and dyes (PPD) used to convert latex into commercial products (gloves, condoms, automobile tires) that are the principal causes of ACD to rubber. From a general perspective, individuals allergic to either the rubber accelerator/vulcanizer chemicals (or to latex itself) can safely use Vicryl gloves, which are safer than nitrile gloves (in lieu of latex gloves). From an epidemiologic perspective, ACD to synthetic rubber is a lesser but growing problem, with these new forms of rubber (dialkyl thioureas, neoprene, polyurethane) being incorporated into athletic clothing and equipment as well as daily wear.
Hair Product Allergens
TOPICAL STEROIDS
ACD to topical steroids is uncommon but important to consider, especially in patients whose dermatitis is unimproved or worsens despite treatment with topical steroids. On the other hand, allergy to a steroid-containing preparation is frequently due to components other than the steroid (eg, propylene glycol or preservatives). In the absence of real evidence from patch testing, desoximethasone ointment is the safest topical steroid from an allergic standpoint. The currently available T.R.U.E. Test series includes 3 markers for topical steroid allergy, namely tixocortol pivalate, budesonide, and hydrocortisone-17-butyrate. Table 24-6 lists the 5 classes of steroids based on chemical structure, the patch test allergen marker for each class, and cross reactions. The least-allergenic steroids belong to class C, as exemplified by desoximethasone.
ALLERGEN SELECTION AND PLACEMENT
Patch testing remains the gold standard for identification of the allergen or allergens causing ACD. The T.R.U.E. Test (SmartPractice, Hillerod Denmark) was introduced in 1995 and is an epicutaneous patch test system that is approved by the U.S. Food and Drug Administration for use in the diagnosis of ACD in persons 18 years of age and older. The T.R.U.E. test originally contained 23 allergens and 1 control; today, it consists of 3 panels with a total of 35 allergens plus 1 blank control. Expanded patch testing with other commercially available allergens, patch testing with patient items, and patch testing in pediatric patients remains off-label but is considered standard practice in the diagnosis of ACD. Among the 30 most frequently positive allergens found by the NACDG the T.R.U.E. test is missing the following 9 allergens: fragrance mix II, lanolin, iodopropynyl butylcarbamate, cinnamal, carmine, propylene glycol, oleamidopropyl betaine, 2-hydroxyethyl methacrylate, compositae, propolis. 76 It is challenging to quantify the sensitivity of the T.R.U.E. test system, but there is consensus that patch testing with a greater number of allergens increases the sensitivity. 108-112 A previous study noted that less than one-third of patch test patients would have all their allergens completely identified if only a
standard series of 28 allergens was used, 113 thus highlighting the need for expanded patch testing in many patients.
Patch testing with the T.R.U.E. test, commercially available standardized allergens, or a patient’s personal care products generally follows a standard closed-test protocol. With this protocol the allergens are placed on the back under occlusion, removed at 48 hours, and a final delayed read is performed at 72 or 96 hours. Many patch testers will perform a preliminary or early read at the 48-hour visit, but it is important to allow time after patch test removal for tape irritation to subside prior to performing a read. An interval of 20 minutes is usually sufficient. Certain situations call for an extended reading time up to 7 to 10 days out. Metals, antibiotics, and corticosteroids are notable allergens which may produce a delayed reaction. This protocol differs from the repeat open application test or use test in which a substance is applied to the cubital fossa twice a day for 1 to 3 weeks to simulate real life use. The repeat open application test can be useful for testing leave-on personal care products. A semiopen patch test protocol can be useful if testing to liquid products with irritant potential. Here the test substance or dilutions of the test substance are applied to the skin surface covering a 1 cm 2 area. The liquid is allowed to evaporate and dry. Excess material can be removed with a cotton swab. The completely dry skin is then covered with hypoallergenic tape and readings are performed at standard time intervals as noted above.
Steroid Allergens
GRADING AND INTERPRETING RESULTS OF PATCH TESTING
At each test reading, it is traditional to note the results as positive, negative, questionable, or irritant. Positive results are also given a grade based on the strength of the reaction. The International Contact Dermatitis Research Group recommends using the grading scale for positive patch test reactions outlined by Wilkinson and colleagues, 114 which is 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 (Fig. 24-4). Very weak or questionable reactions where there is only faint or macular (nonpalpable) erythema are recorded by a question mark (which is +/– in the Wilkinson system), and irritant reactions are recorded as “IR.” Irritant patch test reactions have varied findings that are related to the nature and the concentration of the irritant 115 and are classically described as (a) 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, glutaraldehyde, and thiuram mix are identified as the most common allergens to produce such marginal irritant reactions. (b) Purpuric reactions with petechial hemorrhage, which are seen in approximately 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. Pustular reactions indicate an irritant reaction and are most commonly encountered with metallic salts such as potassium dichromate, cobalt, nickel, gold, and copper. Individuals with an atopic diathesis may show pustular irritant reactions more frequently. Other allergens in which marginal reactions should be interpreted with caution given their mild irritant potential include the preservatives formaldehyde, benzalkonium chloride, and iodopropynyl butylcarbamate; 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 morphologic 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 resolving (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. The irritant pattern is often described as decrescendo, while the allergic pattern is crescendo.
Of note, 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; consequently, palpation of the patch test site can help detect allergic reactions in patients with darker skin types. Additionally, the darker the skin type, the more difficult it is to mark the patch test site after removal. For very dark skin, a florescent marking ink is probably best (such as a yellow highlighter), and the markings can subsequently be located by a Wood light in a darkened room at the time of patch test reading.
ASSIGNING CLINICAL RELEVANCE
A positive patch test indicates a state of cutaneous sensitization to a particular allergen but does not equate to the diagnosis of ACD. A good example of this point is thimerosal. This mercuric preservative is unique in the sense that it commonly causes positive patch test reactions but very seldom does thimerosal allergy account for the patient’s dermatitis. Most allergic patients presumably have been sensitized to the thimerosal present in vaccines, but have no clinical disease associated with this allergen. 117 Establishing the relevance of a positive patch test result is a critical and challenging part of patch testing. Often preliminary relevance is assigned at the time of the final patch test reading with final relevance given retrospectively at a later followup visit when the dermatitis has cleared after avoidance measures were implemented. Relevance is deemed to be definitive if a use test with a suspected item is positive or a patch test of a suspected object or product is positive. Current relevance is possible if the allergen is among the chemicals a patient is exposed to and can be upgraded to probable if the distribution of the dermatitis is consistent with exposure to that particular allergen. Past relevance is designated if there is a history of dermatitis in association with previous exposure to the particular allergen but to which the patient is no longer exposed. An example is a patient who is patch testpositive to neomycin who reports a rash with prior use of over-the-counter antibiotic ointments but has had no further difficulties following avoidance of products containing neomycin. Doubtful relevance is designated when there is no identifiable exposure source or if the clinical history and presentation do not fit with exposure to a particular allergen.
COMPLICATIONS OF PATCH TESTING
Patch testing is considered a safe diagnostic procedure and unwanted effects are seldom encountered. The most common side effects are expected, such as itching at the site of a positive test reaction, and irritation or pruritus from tape application. Less commonly described effects include postinflammatory pigmentary changes, infections, scarring, persistent patch test reactions, induction of flares of dermatitis, sensitization to the tested allergen, and, rarely, anaphylaxis. 118 Postinflammatory hypopigmentation or hyperpigmentation can occur, with hyperpigmentation being more likely in darkly pigmented persons; it typically fades with time and the use of topical corticosteroids. Exposure to sunlight or artificial ultraviolet light immediately following removal of patch tests, especially to fragrance materials, can lead to hyperpigmentation of the patch test site in relation to allergen-related photosensitivity. Infection is typically mild impetiginization of the patch test site with Staphylococcus aureus, although other infections can occur. Scarring is most likely when patients develop bullous reactions; patients who are prone to keloids can develop keloids at these sites. Patch test reactions that persist for more than 1 month (>30 days) are considered persistent patch test reactions; this occurs most commonly from gold salts in a gold-sensitive patient (Fig. 24-5). Induction of a dermatitis flareup 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, if possible. 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. 119 Although the risk of active sensitization during patch testing is low, it is most common to strong sensitizers, such as PPD. It typically presents as a “new reaction” noticed by the patient 10 to 21 days after patch testing, when initial patch test readings are negative at 48- and 96-hour readings. Sometimes this can be difficult to distinguish from a delayed reaction (such as with gold or topical steroids). Anaphylaxis is an exceedingly rare side effect of patch testing that may occur with allergens known to cause a type I (immediate) hypersensitivity reaction, such as bacitracin, neomycin, ammonium persulfate (most often reported), latex, formaldehyde, and penicillin.
Differential Diagnosis of Allergic Contact Dermatitis
Erythema multiforme-like allergic contact dermatitis (ACD)
Lichenoid ACD
Pigmented ACD
Lymphomatoid ACD
Diagnostic Criteria for (symmetrical drug-related intertriginous and flexural exanthema) SDRIFE
encompass all cutaneous reactions that share the commonality of sensitization occurring through cutaneous exposure
allergic contact dermatitis syndrome
Systemic Drugs That Can Cause Systemic Reactivation of Allergic Contact Dermatitis
Hair Product Allergens
