Immunoglobulin E-Mediated Allergy Plays a Role in Atopic Eczema as Shown in the Atopy Patch Test
© World Allergy Organization; licensee BioMed Central Ltd. 2008
Received: 20 December 2007
Accepted: 20 December 2007
Published: 15 March 2008
Although the pathophysiology of immunoglobulin E (IgE)-mediated allergic rhinoconjunctivitis and bronchial asthma is rather well established, the role of allergy in atopic eczema (AE) is still controversial. By a technique called atopy patch test, aeroallergens like house dust mite, animal dander, or pollen were proven as relevant trigger factors in a subgroup of patients with AE. The atopy patch test is an epicutaneous patch test with such allergens known to elicit IgE-mediated reactions, and used for the evaluation of eczematous skin reactions. In a series of single-center and multicenter studies, a method was developed, standardized, and compared with other diagnostic techniques (radioallergosorbent test, skin prick test) in AE patients. With regard to clinical history, the most specific results were obtained with the atopy patch test (allergen-dependent, 69%-92%), whereas sensitivity was higher for skin prick test (range, 69%-82%) and specific IgE (range, 65%-94%). The characterization of a patient subgroup with relevant IgE-mediated allergy may lead to more efficient avoidance and eventually even specific immunotherapy strategies in the management of AE.
KeywordsIgE diagnostic techniques atopy patch test atopic eczema
Atopic eczema (AE, atopic dermatitis, AE/dermatitis syndrome) is a clinically well-defined inflammatory, chronically relapsing, highly pruritic skin disease with a typically age-related distribution and morphology[1–3] and a prevalence of 2% to 10% in the population [1, 4, 5]. Elevated immunoglobulin E (IgE) production, especially against aeroallergens and food allergens, and/or altered unspecific reactivity are frequent findings in patients with AE and concomitant respiratory atopic diseases [6, 7]. As a multifactorial disease with a genetic background, AE has a large number of individually different trigger factors [8–11].
The deterioration of AE skin lesions in some patients after contact with certain IgE-inducing allergens like house dust mite, pollen, or animal dander is an old clinical observation. Consequently, allergen avoidance strategies have been used to improve the course of AE in some studies [12–17].
The inflammatory infiltrate of AE lesions consists to a large proportion of CD4+ T helper (TH) cells. High IgE production in patients with AE is explained by an impaired balance of the T-cell populations TH1 and TH2, with a predominance of interleukin-4- and interleukin-13-producing TH2 cells [18–23]. Aeroallergens are able to penetrate the disturbed skin barrier in patients with AE and were found in direct contact with antigen-presenting Langerhans cells . The discovery of IgE and IgE-binding structures on the surface of epidermal Langerhans cells[26–29] resulted in a new concept that allergy contributes to the pathophysiology of AE because all of the major components of an IgE-mediated reaction are present in the epidermis. Subsequently, the function of IgE in antigen presentation was shown by Maurer et al. However, the question whether allergy plays a role in practice still remained: measurement of specific serum IgE and skin prick tests or intracutaneous injections of allergen solutions are clinical routine to diagnose IgE-mediated sensitizations,[6, 31] but in AE, they reveal often multiple sensitizations without clinical relevance. Furthermore, the morphology of skin test reactions (wheal and flare) does not resemble the clinical manifestation of AE, nor do they represent the appropriate dimensions of the skin immune system. An additional diagnostic tool for aeroallergen-triggered AE was needed, and the proof of concept study was done with a procedure our group called atopy patch test (APT) .
Rostenberg and Sulzberger described in 1937 a series of 12,000 patch tests with a wide variety of allergens, including aeroallergens in different patient groups. In 1982, Mitchell et al published the first experimental patch test with aeroallergens for patients with AE. By others, eczematous reactions could be elicited with different methods, but the methodology and definition of positive reactions in these trials were not comparable [35–45]. No clear correlation with history was obtained in larger groups of patients. Potentially irritating procedures like stratum corneum abrasion,[34, 46, 47] tape stripping,[48–50] or addition of sodium laurylsulfate were necessary to enhance allergen penetration. In 1989, the term atopy patch test was proposed with the following definition: an epicutaneous patch test with allergens known to elicit IgE-mediated reactions, and the evaluation of eczematous skin reactions after 48 and 72 hours [32, 52]. The first effort was to standardize APT and possibly develop a method for clinical routine giving positive results only in patients with AE and showing significant concordance to clinical relevance parameters of aeroallergen allergy.
Role of the vehicle
In a pilot study involving 36 patients with AE, the reactions of 17 patients (47%) were graded as clear-cut positive. Control sites (petrolatum, hydrogel) remained negative, non-atopic volunteers and patients with respiratory atopy (allergic rhinoconjunctivitis) only were also negative in APT. Allergens in petrolatum vehicle elicited twice as many positive APT reactions as the same dose in a hydrogel. Thirty-six percent of patients reacted to house dust mite D. pteronyssinus, 22% to cat dander, and 16% to grass pollen. A D. pteronyssinus-positive APT was accompanied in 77% by a corresponding elevated specific IgE (skin prick test, 62%).
Dose-response effects and role of localization of eczema
Allergen concentrations of 500, 3000, 5000, and 10,000 protein nitrogen units (PNU)/g in petrolatum were compared in another study in 57 patients. The frequency of clear-cut positive APT reactions was significantly higher in patients with eczematous skin lesions in air-exposed areas (69%) as compared with patients without this predictive pattern (39%; P = 0.02). In the first group, the maximum APT reactivity was reached at a lower allergen dose of around 5000 PNU/g.
Clinical Covariates of the APT in 2 Multicenter Studies With Different Allergen Standardization
In 30 children and adolescents 14 years old or younger with AE enrolled in a double-blind dose-response multicenter study, a lower frequency of positive APT reactions compared with adults was seen for D. pteronyssinus (34% vs 41% in adults) and cat dander (12% vs 17%). For D. pteronyssinus and grass pollen, lower allergen doses for APT seem possible in children because maximal response rates were obtained for these allergens with 3000 PNU/g, half of the adult allergen concentration.
Comparing different allergen standardization systems in 50 patients with parallel testing, the allergen doses of 7000 PNU/g and 200 IR/g (biological unit) were found to have similar concordance with the patients' clinical history: 71% to 73% of APTwere corroborated by a corresponding positive or negative history of AE flares after contact with the specific allergen. Expressed as major allergen content, 200 IR/g correspond to 59 μg/mL Der p1, 9 μg/mL Fel d1, or 2 μg/mL Phl p1.
In summary, these studies showed that:
a safe standardized APT method with positive reactions only in patients with AE was developed;
allergen lyophilisate in petrolatum is the preferred galenic preparation;
APT is possible on nonabraded skin without manipulation of the skin barrier function;
allergen concentrations higher than in most prick test solutions are necessary for APT, but lower doses can be used in children;
D. pteronyssinus is the most frequent allergen eliciting positive APT reactions, with reactions to pollen allergens also being very frequent; and
high allergen-specific IgE in serum is not a prerequisite for a positive APT.
APT and specific IgE
The percentages of positive reactions in different test systems for IgE-mediated hypersensitivity obtained from our multicenter studies are given in Table 1. These and previous APT studies showed that positive APT occurred less frequently than positive skin prick tests or radioallergosorbent tests (RASTs) to the same allergen. Logistic regression analysis revealed patient's history, skin prick test, and specific corresponding IgE for D. pteronyssinus, cat dander, and grass pollen as most important significant predictors of a positive APT (P < 0.001). However, the cross-tabulation also confirmed that high allergen-specific IgE in serum is not mandatory for a positive APT (example in Table 2), the same holds true for the correlation with skin prick tests. A European multicenter study on standardized APT in 6 countries (n = 314) showed a subgroup of 7% APT-positive AE patients without any positive skin prick test or elevated specific IgE in the investigated allergen panel (Figure 2). Nevertheless, these reactions can be of clinical relevance and immunological specificity . In conclusion,
the APT may give further diagnostic information in addition to patient's history and classical tests of IgE-mediated hypersensitivity;
the role for IgE in the reaction mechanism of APT is corroborated because in most APT-positive patients, elevated specific IgE was found compared with those with negative APT; and
a cellular mechanism without direct involvement of IgE may be hypothesized to explain the clear-cut positive APT reactions in a subgroup of AE patients.
Cross-Tabulation of APT and Specific IgE to House Dust Mite D. pteronyssinus, Results of a Multicenter Study
APT 48-h Results in Adult Patients for House Dust Mite D. pteronyssinus
IgE-mediated sensitization and APT: diagnostic precision
Sensitivity and Specificity of Different Diagnostic Methods in 2 Studies With Patients With AE
Single-center study, n = 79 (allergen, grass pollen)
APT multicenter study, n = 253 (3 allergens)
In a larger patient group in the German multicenter study, APT results of D. pteronyssinus, cat dander, and grass pollen were also statistically significantly associated with clinical history (P < 0.001, χ2 and logistic regression; birch pollen, P = 0.1). Thus, sensitivity and specificity of different diagnostic tests could be compared. Allergen-dependent, the APT showed a higher specificity with regard to clinical relevance of an allergen than skin prick test and specific IgE, but also in most allergens, a lower sensitivity (Table 3). In a subgroup of these patients, specific activation and proliferation of T cells in peripheral blood was compared with the patient's APT result . Positive APT reactions were significantly more frequent in patients with elevated CD54+ or CD30+ T cells after in vitro stimulation with the corresponding allergen. In addition, positive APT results were associated with an allergen-specific lymphocyte proliferation (P < 0.001). Positive APT reactions were not associated with disease severity in the SCORAD (scoring atopic dermatitis) system [62, 63].
From APT biopsies, allergen-specific T cells have been cloned. In serial biopsies, T cells showed a characteristic TH2 secretion pattern (interleukin-4, -13) at 24 hours, whereas after 48 hours, a TH1 pattern (interferon-γ) like in chronic AE lesions was predominant [64–66]. Taken together, these findings:
argue against the interpretation of APT results as irritative or nonspecific;
suggest that pollen are involved in AE flares in some patients previously diagnosed as having UV-triggered eczema;
demonstrate the clinical relevance of positive APT reactions and the different compartments of allergic inflammation that can be investigated with skin prick test, specific serum IgE determination, and APT;
show that allergen-specific T cells and IgE play a role in the pathophysiology of APT reactions; and
sustain the concept that AE is not only a disease of dry skin or barrier dysfunction, but also an allergic disease.
The future of the APT
The described APT methodology was evaluated in several hundreds of patients with AE. In a large subgroup of them, IgE-dependent allergic reactions that are elicited by the transdermal route play a pathophysiological role. For patients with aeroallergen-triggered disease, the APT may provide an important diagnostic tool, a provocation test of the skin in analogy to the specific provocation methods in respiratory atopy. As in respiratory atopy, the results of our studies sustain B. Wüthrich's concept of extrinsic/allergic versus intrinsic/idiopathic AE .
Positive APT results were obtained in some AE patients with negative skin prick tests and RAST, but predictive history. According to the previously mentioned concept, these cases may also be classified as "extrinsic," and with the back-ground of the recently proposed novel nomenclature for allergy, we suggested to diagnose these cases as "non-IgE-associated AE (dermatitis syndrome)."
This work was only possible with the significant contributions of the collaborators and coauthors of the cited studies.
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