3 - 24 - ALLERGIC CONTACT DERMATITIS Flashcards
(112 cards)
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.
