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Introduction

Contact dermatitis (CD) is one of the leading reasons for patients to seek dermatology consultation, with an estimated 72 million people in the United States afflicted with this condition. There are two main types of CD, all of which result from contact of the skin or mucous membranes with an exogenous agent. The most common form of CD, accounting for ∼80 % of cases, is irritant contact dermatitis (ICD), followed by allergic contact dermatitis (ACD), which represents ∼20 % of cases and is the primary focus of this handbook [2–4]. Recent patch test studies in US-based populations, confirmed equal prevalence of contact allergy in pediatric and adult populations [5]. Furthermore, rates of contact allergy vary based on regional and social differences in allergen exposure, as well as differing referral patterns, selection criteria for patch testing, and allergens tested [6]. Finally, much less commonly observed are contact urticaria (CU) and protein contact dermatitis, which are beyond the scope of this handbook, but are mentioned briefly for completeness, and the reader is directed to key sources on these topics below.

Background on Diagnostic Patch Testing in the US

In the United States, Marion Baldur Sulzberger first introduced the epicutaneous patch test technique, developed by Josef Jadassohn, in the 1930’s at New York Skin and Cancer Unit.

Furthermore, in 1931 Helene Ollendorff-Curth, also trained by Jadassohn, came to the United States and introduced patch testing to industries in order to improve safety measures on commercially available products. Over the next three decades, patch testing clinics were developed worldwide, and in 1962, the Scandinavian Committee for Standar­dization of Routine Patch Testing began to formalize patch testing procedure and materials. By the early 1980s, the Food and Drug Administration (FDA) proposed a ban on the production and sale of allergens for the patch tests based on the lack of availability of scientific evidence for its procedure, safety, and efficacy. A mandate was set for companies to standardize their medicinal chemicals.

In response, the North American Contact Dermatitis Group (NACDG) developed a research arm and worked with Stiefel Laboratories to help the German subsidiary of Hermal receive approval for the European based Hermal/Trolab 20 standard allergen test. This test was available through the American Academy of Dermatology (AAD). Then, under the leadership of Howard Maibach and the Pharmacia-Upjohn Company, the 20 Allergen Test was transformed into what is now the commercially available Thin-layer Rapid Use Epicutaneous (T.R.U.E.) TestTM(Mekos Laboratories A/S, Hillerod, Denmark), whose first 23 allergens were approved by the FDA in 1997 [7]. By 2012, 12 new allergens/mixes had received FDA approval for commercial availability for a total of 35 chemicals/mixes.

Approximately 1,700 new synthetic chemicals on average are being brought to the U.S. market annually and, notably, the Environmental Protection Agency (EPA) tests only chemicals that demonstrate evidence of significant health risk potential. Thus, the situation is such that only about 25 % (of the 82,000 chemicals in use in the U.S.) have ever been subject to basic testing, which is why A. Fischer is astute in his observation that the physician should suspect anything and everything under the sun.

Fortunately, major culprit allergens have been identified through extensive tracking by the International Contact Dermatitis Research Group (ICDRG) and the North American Contact Dermatitis Group (NACDG) over the last 30 years. This has allowed for the compilation and generation of series of panels of allergens, which can serve as a base point to initiate screening. For example, available series include: the American Contact Dermatitis Society (ACDS) 80 Core Series [8], the fragrances series [9], the vehicle and cosmetic series [10], and then occupationally customized panels such as dentistry [11] and bakery panels [12] (see Tables1.1 1.2 1.3 1.4, and1.5). Further series be can found on Chemotechnique Diagnostics’ (Sweden) websitehttp://www.chemotechnique.se/Online-Catalogue.htm, or the allergEAZE™ (Calgary, AB) websitehttp://www.allergeaze.com/allergens.aspx?ID=Series.

Table 1.1 American contact dermatitis society (ACDS) 80 core series
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Table 1.2 Fragrance series (perfumes/flavors)
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Table 1.3 Cosmetic series
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Table 1.4 The dentistry series (dental materials)
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Table 1.5 The bakery series
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As many of these allergens are found in a variety of household and cosmetic products, as well as items with which patients come in contact with daily, tailoring the patch test to patients’ specific exposure history can be very effective when used in conjunction with an appropriately broad- based screening panel. Customizing patch testing chambers allows for a comprehensive approach to testing by placing specific allergens or product samples into individual chambers on separate panels then applying the panels to unaffected regions of the patient’s back.

Allergic Contact Dermatitis (the Disease State Once the Patient Has Developed Contact Allergy)

ACD is a complex immunologic reaction that ultimately results in a delayed (∼48–120 h) presentation, referred to as a Type IV hypersensitivity reaction. This immune response is characterized by two main stages, sensitization and ­elicitation. An individual may become sensitized to a particular substance when his or her skin barrier is impaired, allowing for the entry of exogenous allergens into the epidermis. These allergens or haptens are small, lipophilic chemicals with low molecular weight (<10,000 Da) that bind with self proteins to form complete antigens upon entry into the epidermis. Dendritic cells, which are the antigen presenting cells (APCs) of the skin, then uptake and express these complete antigens on cell surface major ­histocompatibility complexes (MHC). The antigen is then presented by dendritic cells to naïve antigen-specific T-cells in the regional lymph nodes. These naïve T-cells then differentiate into effector/memory T-cells, which are capable of acting on APC’s in the future [13–16].

Elicitation, the second phase of ACD, refers to the clinical dermatitic presentation, and occurs after repeated exposure to a particular allergen to which memory T-cells have been cloned. Exposure may occur transepidermally or systemically through ingestion, inhalation or intravenous entry [17]. In this stage, T-helper cells dominate as opposed to T-suppressor cells, which would create a state of relative or complete tolerance [16].

Because this process is delayed, patients may have difficulty discovering or temporally associating the initial source of their dermatitis, especially if it was years prior; therefore, patch test screening with an appropriate base panel is of utmost importance. Moreover, the distribution of the dermatitis may not follow the exposure pattern. ACD can present as a local, generalized, or ectopic dermatitis.

Adolescents [Age 13–17]

Childhood presentations of ACD are becoming more recognized as a significant problem, accounting for approximately 20 % of all cases of pediatric dermatitis [15 16]. Moreover, adolescents account for a large proportion of pediatric ACD, especially in females when compared to their male ­counterparts, according to international literature. This trend has been observed with particular allergens, such as nickel and ­fragrance, likely due to their presence in classically female sources, i.e. jewelry, cosmetics, and fragranced personal products [16 18]. Recent studies, however, have reported an even distribution of allergens across all pediatric groups without noting gender bias [19 20]. One relevant source of ACD in adolescents is sports equipment, i.e. wrist supports, shin and knee guards [21–23], athletic tape [24], and swimming goggles [25], often due to the allergen p-tert-butylphenol formaldehyde resin [26]. In addition, the warm, moist, occluded environment to which athlete’s skin is subjected, may also make them more susceptible to ACD. The moisture may also contribute to chemical breakdown and release of allergens [27].

Clinical Presentation

ACD often presents with pruritic, eczematous papules and plaques, and occasional vesicles and bulla (Figs.1.1 1.2 1.3, and1.4). Because these descriptive terms are not unique to ACD, distinguishing it from AD and ICD can prove to be a challenge [16]. More specifically, acute ACD and AD often have similar morphological appearances, and furthermore, the two may occur simultaneously. In fact, it has been suggested that AD may predispose individuals to developing ACD due to a damaged epidermal barrier to allergens [28 29]. Acute presentations of ACD and ICD may be distinguished based on their temporal relationship to the inciting event as well as clinical distribution (see Table1.6) [15 16 30]. ACD may present in an ectopic manner, meaning that the location of the dermatitis is not directly related to exposure site. This can occur in different ways, such as by transferring an allergen from one region of the body to another. For example, AD sites may flare after exposure to nail polish upon scratching [29] or eyelid dermatitis may ensue after a cashier rubs his or her eyes after handling monies. Even more challenging to diagnose are idiopathic (id) ACD reactions, which are non-specific, widespread eruptions that occur when the patient contacts a particular allergen [15 16].

Figure 1.1
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Sparing of axillary vault with allergic contact dermatitis

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Figure 1.2
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Erythroderma from advanced allergic contact dermatitis

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Figure 1.3
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Allergic contact hand dermatitis

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Figure 1.4
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Chronic, allergic contact dermatitis of the foot, with lichenification and scarring

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Table 1.6 Differences between acute ACD vs. acute ICD
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Irritant Contact Dermatitis

ICD is not considered an immunologic reaction, but rather is related to direct contact with an irritating substance that damages epidermal keratinocytes and induces inflammation, without activating an immune cascade. Therefore, previous chemical exposure and prior sensitization are not required for this reaction [31]. Classic examples of irritants include urine (diaper dermatitis), soap (hand dermatitis), and saliva (lip licker dermatitis) (Fig.1.5). Moreover, the severity of an ICD reaction is not solely dependent on the concentration of the instigating agent, but is directly proportional to the exposure time as well [15 32].

Figure 1.5
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Irritant contact dermatitis of the dorsal (a) and palmar (b) surfaces of the hand

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Contact Urticaria

Unlike the type IV delayed immunologic reaction of ACD, CU is mediated by an immediate IgE type I immunologic reaction. Clinically, CU appears as a wheal and flare reaction, appearing within 30 min of exposure to a eliciting substance and resolving within hours [33]. Testing is usually performed by an allergist, who uses the RAST (radioallergosorbent test) or prick testing. Desensitization can then be attempted, which is much more difficult with Type IV reactions [16].

Protein Contact Dermatitis

The term protein contact dermatitis (PCD) was introduced in 1976 by Hjorth and Roed-Peterson [34], and refers to the development of a Type-I, immediate, IgE-mediated reaction upon exposure to protein. Clinically, the most common presentation of PCD is chronic or recurrent eczema; however, urticaria may also be observed upon contact with particular proteins, such as certain foods and drinks (almonds, banana, carrot, celery, kiwi, melon, tomato, seafood, cow’s milk), airborne ragweed particles, and natural rubber latex [33 35].

Clinical Diagnosis

Investigative history and diagnostic clues are important elements to making a proper diagnosis of ACD. For instance, distinguishing between ACD and AD can be challenging, especially when occurring simultaneously. Luckily, certain clinical clues can increase the index of suspicion for ACD, such as new-onset, and/or a progressing or deteriorating dermatitis that is recalcitrant to standard therapies [36]. Epicutaneous patch testing, however, is the gold standard for the diagnosis of ACD [15 16 30] (see Table1.7) [15 28].

Table 1.7 Allergen determination for comprehensive patch testing
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Pre-patch Consult and Education

In the pre-patch education/instruction session, a provider must explain basic guidelines prior to testing (see Table1.8) [36] as well as the testing procedure. As these instructions can be extensive, patients may not be willing or able to follow these rules. Therefore, a basic explanation of ACD being a delayed reaction in the initial consultation often helps patients to understand the lengthy testing timeline. There may be some patients, however, that do not appear capable of understanding all of the instructions and explanations, and the provider must then assess whether they would be a proper candidate as well [28]. Not only may the test itself be inaccurate based on patient’s inability to follow instruction, but subsequent attempts at avoidance may not be possible.

Table 1.8 Patch testing guidelines
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Pediatric Patch Testing

Pediatric patch testing poses more of a challenge when compared to testing adult patients. Selectivity of proper candidates not only includes taking a patient’s age into account, but their family’s ability to understand the process and their willingness to complete the journey. In addition, patch testing itself can be limited by the relatively smaller surface area available for chamber application (especially in dermatitic patients). Therefore, there is an increased need for selectivity when choosing which allergens to include in the series. Logistically, it is also difficult to ask a young child to sit still for a long period of time during patch application, removal, and interpretation. Moreover, patients’ parents or legal guardians must be made aware that the procedure has not received Food and Drug Administration indication in pediatric patients [28]. Preliminary avoidance of allergens with a high likelihood of reactivity is especially helpful with pediatric patients, as testing may not be necessary if the patient has shown >50 % improvement in their condition in 4–6 weeks of avoidance. This also allows for a snapshot of the family’s ability to comply with an avoidance plan.

Procedure Outline (see Fig.1.6)

Figure 1.6
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Patch testing algorithm

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Patch testing can be achieved by using either commercially available pre-packaged allergen panels or by loading each allergen onto individual chambers on a tape strip. Some types of the patient’s own products may also be applied directly to patch testing chambers, and placed on patients in addition to individual component chemicals [37] (Fig.1.7). Panels of allergens and/or products should be placed on unaffected areas of patient’s backs or arms in linear configurations and marked according to a pre-determined number scheme (Figs.1.8and1.9). Securing these panels with hypoallergenic tape, such as hypafix tapeTM(Smith & Nephew, London, UK), is crucial, as these strips of allergens must remain in place under occlusion for 24–48 h. The 48 h point was selected to allow for optimized time of contact with the substance without increasing the number of irritant reactions [38]. Of note, the German Contact Dermatitis Research Group (DKG) suggests a 24 h contact time for children ages 6–12.

Figure 1.7
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Sample from an athletic shoe is removed using a punch biopsy instrument, dissected into parts, such as cloth and foam, and placed in patch testing chambers

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Figure 1.8
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Patch test application. Panels of allergens placed in linear configurations and marked according to a pre-determined number scheme

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Figure 1.9
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Avoidance of marked regions due to pre-existing dermatitis

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An initial reading of the patch testing sites is performed upon removal of the allergen panels at the 48 h point and outlining individual chambers with a fluorescent marker (Fig.1.10). Skin changes, such as erythema, induration, papules, vesicles, and blistering are noted at this time, and rated accordingly. Reactions may range in intensity from macular erythema to a 3+ positive patch test (PPT) (see Table1.9). However, the final interpretation must be done at a delayed reading in 72–120 h from initial placement, as initial cutaneous changes may be due to ICD, of which the majority resolve by the final interpretation (Figs.1.11 1.12 1.13, and1.14). In addition, 48 h may not be long enough for some of these type IV delayed reactions to appear or peak in intensity [15 16]. Notably, corticosteroids, neomycin sulfate, and sodium gold thiosulfate appear late (see Table1.10) [39 40]. The final interpretation can be aided by the use of a wood’s lamp, which will illuminate the highlighter in order to locate and directly feel the patch testing sites (Fig.1.15).

Figure 1.10
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Patch test removal. An initial reading of the patch testing sites is performed at the 48 h point, with chambers outlined in highlighter and each allergen re-numbered with surgical marker

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Table 1.9 Reaction rating scale
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Figure 1.11
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Final interpretation, macular erythematous reaction (arrow) to p-tert butylphenol formaldehyde resin (PTBFR)

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Figure 1.12
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Final interpretation, 2+ reaction to bacitracin (arrow)

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Figure 1.13
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Final interpretation, 2+ reaction cobalt chloride

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Figure 1.14
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Reactions. (a) macular erythema; (b) macular erythema; (c) 1+ reaction; (d) 1+ reaction; (e) 2+ reaction; (f) 2+ reaction; (g) 2+ reaction; (h) 2+ reaction; (i) 3+ reaction

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Table 1.10 Early vs. late reactions
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Figure 1.15
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Final interpretation with the use of a wood’s lamp to illuminate the highlighter in order to directly feel the patch testing sites

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Certain chemicals and products, however, are not designed to be used under occlusion or to remain in contact with a patient’s skin for long periods of time, and for that reason, a provider may decide to test particular products by employing provocative use testing. This form of testing, also called, repeat open application testing (R.O.A.T.) utilizes the inner or anterior arm of the patient, and involves placing a small amount of the product in question to a 2.5 cm drawn circle twice daily for 7 days (see Fig.1.16). Importantly, this technique does not involve occluding chemicals as in classic patch testing; therefore, the allergen potency is not as great, which decreases risk of intense reactions, but also may require longer time to elicit a response.

Figure 1.16
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Repeat open application testing (R.O.A.T.)

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Expected Adverse Reactions of Patch Testing

The most common adverse reactions associated with patch testing are expected cutaneous changes at the sites that were in contact with the testing substances, especially if the patient exhibited contact allergy (PPT). These reactions may include erythema, induration, papules, and vesicles, occasionally accompanied by pruritus, burning and inflammation at the site of application.

Less commonly seen are pustular and blistering reactions, post-inflammatory hypo/hyper-pigmentation, and persistent granulomatous reactions. The most rare of reactions would be anaphylactic type reactions, which have been reported as individual case reports in which the patients have had contact urticarial syndrome (Type I) or developed a Type I hypersensitivity reaction to the agent. Some patients may experience a worsening of their initial dermatitis, which can serve as a diagnostic clue in assigning clinical relevance, as this phenomenon can be observed when one is tested and reacts to the same allergen that contributed to the initial and current presentation.

Moreover, based on information extrapolated from adult studies, active sensitization to one of the allergens tested at the standardized concentrations are very rarely reported (0.0–0.69 %) [40–43]. Published concentrations of chemicals used in commercially available patch testing kits are associated with the fewest side effects and are generally accepted [44]. Ultimately, the potential risks and side-effects presented by patch testing are considerably outweighed by its usefulness, both as a diagnostic tool and as a guide to avoiding clinically relevant specific contact allergens.

Post-patch Education – Avoidance

While patch testing can provide a diagnosis of ACD and facilitate discovery of culprit allergens, it is patients that are responsible for the resolution of their dermatitis. This is because avoidance is crucial in the treatment of ACD, and can only be achieved with proper patient education. A post-patch testing session is necessary to inform the patient and their families of potential sources of exposure based on a thorough explanation of what their clinically relevant, positive allergens are and where they are often found. Patient-directed literature is available and should be provided to patients to aid in this endeavor. As there are endless products commercially available, teaching patients how to read the ingredient labels is also important, but there are online databases available for this purpose as well. Individualized lists of “safer” alternatives can then be generated, by entering relevant, positive allergens into the database [28]. Both programs also offer information about various allergens. There are two main programs that can provide this service, the Contact Allergen Management Program (C.A.M.P.) and the Contact Allergen Replacement Database (C.A.R.D.) [45 46]. Products on these listings should be used with caution, however, as patients are generally not patch tested for every chemical ingredient. For this reason, educating the patient and family on performing provocative use testing or R.O.A.T. should be performed.

Management and Therapy (see Fig.1.17)

Figure 1.17
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Management algorithm

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Avoidance of causative allergens is the most crucial component of ACD resolution and management [47]. As mentioned earlier, patch testing can provide a means of discovering ­relevant, positive allergens, allowing a provider to focus post-patch education on how to avoid specific chemicals [28 47]. Patients are also educated on allergen substitution, which is aided by certain resources, such as the Alternatives for the 2007 NACDG Standard Screening Tray [48] and a 4-part series providing data from the American Contact Alternatives Group [49–52]. This series focuses on facial cosmetics, hair products, lip and dental care products, as well as personal care products. With these interventions, it may be possible to achieve a sustained remission.

There are times, however, when complete avoidance is not possible or when avoidance is not sufficient to clear a dermatitis outbreak. Moreover, patch testing may fail to identify any or all inciting agents, especially if multiple chemicals are involved. Adjuvant measures, such as topical and/or systemic therapies may be necessary in these instances. In addition, physical barrier creams or emollients, such as petrolatum, can be utilized in many different situations as a form of exposure avoidance or prophylaxis. Topical agents are used as first line therapy, specifically corticosteroids, which may elicit side effects or induce sensitization to the vehicle ingredients or corticosteroids themselves with prolonged or widespread use [53–55]. Due to the issues surrounding long-term use of topical corticosteroids, topical immune modulators, such as calcineurin inhibitors [56 57], may prove beneficial, especially in regions of thin skin or those prone to atrophy, such as the face and intertriginous areas. The next step in management involves the use of systemic therapies, which may be necessary for severe or widespread dermatitis with or without mucous membranes manifestations, or for dermatitis that continues to progress despite the use of topical agents.

Oral corticosteroids, such as prednisone [58], can be effective for acute exacerbations of ACD and tapered after symptoms are controlled. For chronic cases, however, ‘steroid sparing’ agents should be considered, such as phototherapy, usually with shortwave ultra-violet light (UVB), and systemic immune modulators (azathioprine, methotrexate, mycophenolate mofetil, and cyclosporine) [47].