Abstract
Allergic contact dermatitis, an inflammatory skin disease characterized by erythema, edema, vesiculation, and scaling, is a delayed type hypersensitivity reaction following cutaneous exposure to allergenic chemicals.
Case 1
A 40-year-old housewife presented with recurrent, intermittently itchy and stinging rashes on the face. She first noticed the lesions approximately 1 year ago. She had since visited several doctors and received various treatments, but the skin condition had recurred. For each recurrence, her skin was red and scaling, with extreme itching and stinging that was barely tolerable. Each episode tended to last for a week and did not resolve by itself, mandating either topical or systemic corticosteroids. She denied any change in her skin care routine, which included skin cleansing with water followed by “hypoallergenic” skin care products. Because of the skin lesions she had refrained from using any kinds of makeup cosmetics or fragrances for months
The patient’s medical history was unremarkable. She denied any occupational and environmental exposures to chemicals. She was not taking any medications and had no known drug allergies. Her family history was significant for hypertension and diabetes mellitus, but there was no family history of atopic dermatitis. She did not smoke or drink alcohol. The review of her systems was otherwise unremarkable
The physical examination revealed ill-defined, erythematous patches on the forehead and cheeks with mild scaling. There were no vesicles, discharge, or crusting. Similar patches were also noted on the neck. The eyelids were spared. Her vital signs were within normal limits, and her other physical findings were unremarkable
With the Presented Data What Is your Working Diagnosis?
The recurrent nature of her condition, the poor response to various topical treatments (most likely corticosteroids), and the involvement of forehead and neck might suggest contact dermatitis.
Differential Diagnosis
Seborrheic dermatitis, irritant contact dermatitis (ICD), allergic contact dermatitis (ACD).
Work-Up
-
1.
Detailed history is important in gathering more information once contact dermatitis is suspected. In this patient, detailed history suggests possibly temporal relationship to hair coloring performed monthly to every 6 weeks.
-
2.
Patch testing is the next step to clarify the nature of her condition as suggested by the history. On patch testing, she has positive patch test reactions to paraphenylenediamine (PPD) and paratoluenediamine (PTD).
What Is Your Diagnosis and Why?
The diagnosis is ACD to hair dye. The recurrent and recalcitrant nature of her skin condition is suggestive of contact dermatitis. The location of the skin rash and the history of a temporal relationship between skin eruption and hair coloring strongly suggest ACD to hair dye. Patch testing is the golden standard for the diagnosis of ACD. Her patch test results confirmed the chemicals to which she is allergic to, that is, PPD and PTD, which are chemicals commonly found in hair dye.
Management and Follow-Up
The patient was instructed on ways to dye her hair carefully (avoid direct skin contact with hair dye). On follow-up, her skin lesion cleared completely after 1 year.
Case 2
A 34-year-old female business executive presents with recurrent facial dermatitis of duration of many months. She has visited several doctors and has been told to have seborrheic dermatitis. She has been treated with topical corticosteroids but the skin lesions have never been completely resolved. The patient denies any changes in her diet, cosmetics, medications, or soaps that could account for the dermatitis. Her skin care routine included cleansing with a mild cleanser, followed by hypoallergenic facial cream and then makeup.
The patient’s medical history was unremarkable except for a history of allergic rhinitis. She denied any occupational and environmental exposures to chemicals. She denied any food or drug allergies. Her family history was unremarkable. She did not smoke or drink alcohol. The review of her systems was otherwise unremarkable.
On physical examination, there were patchy, low-grade erythema and scaling on the face, involving eyelid, forehead, cheeks, and chin. There were no vesicles, discharge, or crusting. Her vital signs were within normal limits, and her other physical findings were unremarkable.
With the Presented Data What Is Your Working Diagnosis?
The working diagnosis was endogenous and/or exogenous dermatitis. Given the covert nature of her eczema, the lack of history on exposures to chemicals, and the lack of temporal relationship with any event, the diagnosis may be challenging.
Differential Diagnosis
Seborrheic dermatitis, atopic dermatitis, ICD, ACD
Work-Up
-
1.
As described earlier, detailed history is important for further information. In this patient, however, an exhaustive history has failed to document any temporal sequence between the use of cosmetics and onset of rash.
-
2.
Patch testing is the next step to help clarifying the nature of her condition since ACD cannot be excluded. She was patch tested with routine series (to be discussed later) and her own products, and the patch testing revealed positive patch test reactions to formaldehyde and quaternium-15 (formaldehyde releasers) commonly used as preservatives in cosmetics and toiletries including fingernail polishers and hardeners, antiperspirants, makeup, bubble bath, bath oils, shampoos, creams, mouthwashes, and deodorants.
What Is Your Diagnosis and Why?
The diagnosis is ACD to preservatives. Despite the lack of temporal relationship as described in case 1, the prolonged and overt nature of, and the distribution of, her skin rash is still suggestive of contact dermatitis. Patch testing is the best tool to clarify the presence of ACD. Her positive patch test results were clinically relevant as scrutinization of the labels of her skin care products revealed the presence of formaldehyde and quarternium-15.
Management and Follow-Up
Clinical interventions included teaching patients how to read cosmetic labels and the avoidance of preservatives. On follow-up, her skin condition cleared up in a year.
Discussion
Definition
Contact dermatitis, defined as inflammation of the skin invoked as a result of exposure to an exogenous agent, is generally divided into ICD and ACD. ACD is the clinical definition of an eczematous skin reaction that results from (specifically) delayed type IV hypersensitivity (DTH), which occurs at the site of skin contact with a typical small-molecule allergen (1).
Brief History
ACD was described by Joseph Jadassohn in 1895. He developed patch testing to identify the chemicals to which the patient was allergic. Sulzberger popularized patch testing in the USA in the 1930s. The TRUE Test (thin-layer rapid use epicutaneous test) is currently the only allergen patch test that has received marketing approval from the US Food and Drug Administration (FDA). The Finn chamber, available since 1970s, has become the standard method for patch testing individuals to chemicals not found in the TRUE test. Commercially prepared allergens in either petrolatum or water are widely utilized.
Prevalence of ACD
ACD is a skin disease that affects around 1–4% of the global population at a considerable cost to society and industry. Studies on contact allergy in the general population have shown that the median prevalence of contact allergy to at least one allergen was 21.2% (range 12.5–40.6%), and the weighted average prevalence was 19.5%, based on data collected on all age groups and from all countries between 1966 and 2007. The most prevalent contact allergens were nickel (8.6%), thimerosal, and fragrance mix (1). The North American Contact Dermatitis Group (NACDG) reported the results of patch testing from January 1, 2001, to December 31, 2002 with an extended screening series of 65 allergens and found that the top ten allergens were nickel sulfate (16.7%), neomycin (11.6%), Myroxylon pereirae (balsam of Peru) (11.6%), fragrance mix (10.4%), thimerosal (10.2%), sodium gold thiosulfate (10.2%), quaternium-15 (9.3%), formaldehyde (8.4%), bacitracin (7.9%), and cobalt chloride (7.4%) (2).
New allergens may emerge due to the introduction of numerous new chemicals into the marketplace each year, some of which may eventually turn out to be allergenic under use condition. On the other hand, older allergenic chemicals employed in occupational settings will continue to be a constant source of ACD (3, 4).
Pathophysiology
Almost any chemical (including water) in sufficient concentration and under the right conditions can induce irritation, but typically only certain chemicals are allergens and only a small proportion of people become susceptible to them.
There are more than 3,700 suspected cutaneous allergens (5). The chemicals capable of inducing ACD are typically small (<500 dalton), uncharged, and fairly hydrophobic (5). ACD begins with a sensitization phase, in which molecules pass through the stratum corneum and are processed by Langerhans cells in the epidermis (6). Antigen-coupled Langerhans cells then leave the epidermis and migrate to the regional lymph nodes via the afferent lymphatics, where they present the antigen to naive CD4+ T cells. Only allergenic compounds are capable of inducing CD1a+ CD83+ Langerhans cell migration with partial maturation at subtoxic concentration. The responding T cells are then stimulated via a complex immunologic process to proliferate into memory and effector T cells, which are capable of inducing ACD after repeat exposure to the allergen. The initial sensitization typically takes 10–14 days from initial exposure to a strong contact allergen such as poison ivy, oak, and sumac. However, some individuals may develop specific sensitivity to allergens (e.g., chromate) following years of chronic low-grade exposure.
The elicitation of ACD typically occurs within 24–96 h after rechallenge of sensitized individuals and is typically presented as varying degree of erythema, edema, and vesiculation. CD4+ CCR10+ memory T cells persist in the dermis after ACD clinically resolves.
Clinical Manifestations
Onset
Individuals with presensitized ACD typically develop dermatitis (within a few days of exposure) in areas that were exposed directly to the allergen. Certain allergens (e.g., neomycin) penetrate intact skin poorly, and the onset of dermatitis may be delayed up to a week following exposure. Typically, a minimum of 10 days is required for individuals to develop specific sensitivity to a new contactant. Only potent allergens such as dinitrochlorobenzene (DNCB) sensitize and elicit with a single exposure.
Predisposing Factors
Mirshahpanah and Maibach (7) noted that eczematic skin is more prone to reactivity relative to healthy skin. However, there are numerous endogenous and exogenous factors that influence the development of ACD. Among these, age, gender, ethnicity, atopic constitution, environmental factors, and specific occupational risks have received the most attention in the literature.
Symptoms and Signs
The probability and severity of a reaction depend on the type of exposure and its duration. ACD may bear some similarities to irritant dermatitis but edema, erythema, and vesiculation are often prominent features. Acute ACD is characterized by pruritic papules and vesicles on an erythematous base, while chronic ACD may be manifested as lichenified pruritic plaques. Occasionally, ACD may affect the entire integument (i.e., erythroderma, exfoliative dermatitis). ACD can also complicate other dermatoses as a result of the application of numerous topical agents that then act as sensitizers (e.g., ACD to neomycin in stasis dermatitis), imposing diagnostic challenges to clinicians.
The initial site of dermatitis often provides the best clue regarding the potential cause of ACD. For example, the hands are noted to be the primary body part affected in many of the allergic occupational cases. Other common locations include facial, ear, and neck dermatitis in patients with ACD to chemicals used in hairdressing; and eyelid dermatitis suggestive of ACD to airborne allergens.
Diagnostic Procedures
History-Taking
A detailed history, both before and after patch testing, is crucial in evaluating individuals with ACD. Potential causes of ACD and the materials to which individuals are exposed should be patch tested. However, contact sensitivity cannot be reliably predicted from pretest historical information. Also, the sensitivity and specificity of patch testing are approximately 70%, with a 50% relevance for positive tests (8). Therefore, history is equally important after patch testing to determine whether the materials to which a patient is allergic are partly or wholly responsible for the current dermatitis.
Differential Diagnosis
The differential diagnosis of ACD includes common conditions such as ICD, superficial fungal infection, seborrheic dermatitis, and psoriasis (Table 5.1)
.
Acute ICD is sometimes easily diagnosed because of the significant erythema, vesicles, and/or bullae that develop in a sharply delineated area within minutes to hours after exposure. In contrast, chronic cumulative ICD may be clinically indistinguishable from ACD. There are no universally reliable clinical features to determine whether an eczema is ICD or ACD. The diagnosis of ICD is one of exclusion due to an absence of diagnostic test, whereas the diagnosis of ACD depends on proper diagnostic patch testing. Prior to patch testing, potassium hydroxide preparation and/or fungal culture to exclude tinea are often indicated for dermatitis of the hands and feet. Skin biopsy may be helpful in excluding other disorders, particularly tinea, psoriasis, cutaneous lymphoma, etc.
Patch Testing
Patch testing remains the “golden standard” for the diagnosis of ACD.
Patch testing is also highly recommended in patients suffering from various eczematous conditions considered (partly and entirely) endogenous (Atopica dermatitis, nummular dermatitis, seborrheic dermatitis, asteatotic eczema, stasis dermatitis, leg ulcers, dyshidrotic eczema, psoriasis) due to the fact that in many cases ACD may worsen underlying dermatitis, and the patch test results permit further avoidance of contact allergens in the management of eczematous conditions
In patch testing, a preparation is applied to a patient’s skin under an occlusive patch for 48 h and the skin is evaluated for evidence of erythema, edema, or more severe skin changes occurring 24, 48, or 72 h after removal of the patch. Allergenic materials are thereby identified by producing skin disease on a small scale. Patch testing must be performed by health care providers trained in the proper technique. Most dermatologists can perform patch testing using standard allergens, which can identify relevant allergies in as many as one-half of affected patients.
Individuals with suspected ACD without positive reactions with standard allergens or with chronic dermatitis or relapsing dermatitis, despite avoiding chemicals to which they are allergic (identified on routine patch testing), need additional patch testing with more extensive panels of chemicals. Testing to more allergens increases the accuracy of the diagnosis of ACD. Such extensive patch testing typically is available only in a limited number of dermatology offices and clinics.
Selection of allergens for patch testing requires consideration of the patient’s history and access to appropriate environmental contactants. In such cases, aim testing, as opposed to more generalized testing, can be performed (Tables 5.2–5.4)
Positive patch test result mandates wide clinical interpretation. Recently, investigations have become more specific in discussing patch test frequency data. The term allergic patch test reaction frequency typically refers to patch test positivity numbers – without attempt to correct for clinical relevance – that is, the clinical disease of ACD, present or past. The number may include the result of false positives and nonreproducible positives from the Excited Skin Syndrome (a hyperirritable skin condition that occurs when multiple concomitant inflammatory skin conditions prevail and is often associated with multiple positive patch test reactions due to the strong positive responses that induce unspecific reactions in contiguous test sites). The fact that contact allergy implies true delayed hypersensitivity (a true allergic patch test response) but does not imply clinical relevance has been established. False positive reactions can be defined as positive patch test reactions occurring in the absence of contact allergy (9) and can be caused by technical errors, a misinterpretation of the test results, etc. False negative reactions can be defined as negative patch test reactions occurring in the presence of contact allergy, causes of which include insufficient penetration of allergen, too early reading or testing in an “anergy” phase, systemic treatment with corticosteroids, etc. (9).
The most important aspect in the interpretation of diagnostic test results is an assessment of the clinical relevance of positive patch test findings to the diagnosis. The investigator must establish that positive patch test results are consistent with a history of exposure to a particular chemical in a product and must exclude other possible environmental exposure conditions. Next, the location of the present dermatitis must correspond to the site of contact with the putative offending chemical. Finally, the patch test concentration must be nonirritating, as demonstrated by a dose-response effect when dilution of the putative allergen is employed. In essence, clinicians may follow defined algorithms to establish the relation (causality) between a positive patch test and the likelihood of clinical ACD (Table 5.5) (10)
.
The evidence-based diagnosis of relevance can also be improved by requestioning the patient in the light of the test results, performing a worksite/home visit, seeking cross-reacting substances, considering concomitant/simultaneous sensitization and indirect/accidental/seasonal contact, obtaining information about environmental allergens from lists, textbooks, and the product’s manufacturer, performing chemical analysis of products, and sequential testing with the allergens and the suspected products (testing with extract, ROAT, PUT, etc.) (10).
Management/Treatment
Clinical management of ACD includes symptomatic treatment (e.g., cold compresses for vesicular dermatitis, oral sedating antihistamines for pruritus) and/or topical or systemic corticosteroids. Topical corticosteroids are the mainstay of treatment, with the strength and potency of the topical corticosteroid appropriate to the body site. Systemic corticosteroids or other immunosuppressive medications (e.g., azathioprine) may be occasionally needed for widespread and severe chronic dermatitis, such as ACD, due to airborne allergens such as feverfew (Parthenium hysterophores). Topical immunomodulators may be prescribed for corticosteroid-resistant ACD or cases of ACD when they offer safety advantages over topical corticosteroids (e.g., for chronic ACD on eyelid to avoid steroid-induced glaucoma or cataracts).
In any case, the cause of ACD must be identified or else the patient is at increased risk for chronic or recurrent dermatitis. ACD to chemicals that are ubiquitous in the environment often carries a chronic and relapsing course.
Not all ACDs clear completely when the responsible contactant is apparently eliminated. There are patients who never recover for unclear reasons. Among the potential contributing factors are the possibilities that the repair capacity of skin can be overwhelmed, or that contact dermatitis (allergic or irritant) may enter a self-perpetuating and recurrent cycle by virtue of the fact that the ACD triggered an underlying propensity to endogenous eczema, or that individuals may develop new allergies. Efforts must be taken to clarify and verify the source of ACD and the presence of any endogenous factors. It is sometimes necessary to repeat patch testing in such cases.
To prevent recurrence of ACD, instruct patients thoroughly concerning allergen(s) and the types of products likely to contain allergen(s). The Contact Allergan Replacement Database (CARD) of the American Contact Dermatitis Society allows the physician to create a list of products free of allergens to which the patient is allergic (www.contactderm.org).
Conclusion
ACD is a frequent and vexing dermatologic problem. While the disease has probably plagued humans for millennia, its clinical recognition by patch testing is barely a century old. The management of ACD lies in identifying its cause correctly and thoroughly instructing the patient to avoid the responsible allergen(s). Legislation can be an effective tool in the prevention of contact dermatitis by mandating the labeling of cosmetics and household products. Occupational safety has a long tradition of setting different types of rules and limitations to prevent hazardous exposure, and some focus on hazardous skin exposure. The advent of experimental animal models and noninvasive bioengineering methods on human testing will provide useful information on the pathophysiology of ACD, which will help to refine our current practices in the management and prevention of ACD. General references for ACD are listed (4, 6, 9).
Questions
-
1.
The proper management of ACD includes which of the following?
-
(a)
Use systemic corticosteroids as the first-line therapy for all types of ACD.
-
(b)
Topical corticosteroids are often not necessary because the clinical response is poor.
-
(c)
Instruct patients thoroughly concerning allergen(s) and the types of products likely to contain allergen(s).
-
(d)
Repeat patch testing for patients who do not recover despite the avoidance of allergen(s)
-
(a)
.
Answers: (c), (d)
-
2.
Choose one correct answer:
-
(a)
It is always easy to distinguish ICD from ACD based on clinical presentation.
-
(b)
Patch testing is the golden standard for the diagnosis of ACD.
-
(c)
Provocative use test (PUT)/repeat open application test (ROAT) is the golden standard for the diagnosis of ICD.
-
(d)
Skin biopsy is often necessary for the definite diagnosis of ACD.
-
(a)
Answer: (b)
-
3.
Choose one correct answer:
-
(a)
Almost any chemical in sufficient concentration and under the right conditions can induce ACD.
-
(b)
Repeat patch test is not necessary if excited skin syndrome is operative.
-
(c)
Serial dilution patch testing is not necessary to distinguish allergen from marginal irritant.
-
(d)
PUT or ROAT have limited value in verifying the clinical relevance of positive patch test results
-
(a)
.
Answer: (a)
-
4.
The assessment to reach the diagnosis of clinically relevant ACD includes the following:
-
(a)
History of exposure
-
(b)
Appropriate morphology
-
(c)
Positive patch test to a nonirritating concentration of the putative allergen
-
(d)
Resolution of dermatitis
-
(e)
All of the above
-
(a)
Answer: (e)
-
5.
Significant erythema, vesicles, and/or bullae that develop in a sharply delineated area within minutes to hours after exposure to a contactant are more likely to be
-
(a)
ACD
-
(b)
ICD
-
(c)
Seborrheic dermatitis
-
(d)
Atopic dermatitis
-
(a)
Answer: (b)
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© 2009 Humana Press, a part of Springer Science+Business Media, LLC
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Thong, HY., Maibach, H.I. (2009). Allergic Contact Dermatitis. In: Mahmoudi, M. (eds) Challenging Cases in Allergy and Immunology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-443-2_5
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