47 Role of Allergy Testing in Atopic Eczema
U. Darsow, J. Ring
47.1
Introduction
The chronic inflammatory skin disorder atopic eczema (AE, atopic dermatitis, neurodermatitis, atopic ecze- ma/dermatitis syndrome) is diagnosed by a combina- tion of clinical criteria without being sustained by a laboratory marker specific for the disease [1 – 4]. Atopy is an inherited tendency to develop certain diseases (extrinsic bronchial asthma, allergic rhinoconjunctivi- tis, and/or atopic eczema) based on a hypersensitivity of skin and mucous membranes against environmental substances. Atopy is associated with increased produc- tion of immunoglobulin E (IgE) and/or altered nonspe- cific reactivity [5, 6]. Thus this concept is not restricted to the increased production of IgE antibodies. How- ever, apart from chronically relapsing course, intense pruritus, and an age-specific typical distribution of skin lesions and morphology, IgE plays an important role in the definition of the disease. The significance of allergic (IgE)-mediated reactions for elicitation and maintenance of AE is controversial and the diagnosis of a causal relationship is often difficult to prove in a sin- gle case. A high number of IgE-mediated sensitizations with questionable clinical relevance due to the lack of specificity is often found in allergological routine work-up of AE. Aeroallergens and food allergens play an important role from a clinical point of view because allergen avoidance has improved the course of AE in many cases [7 – 10]. Before introducing difficult aller- gen avoidance methods in a patient’s environment, the clinical relevance of a sensitization has to be evaluated [11].
47.2
Food Allergy in Atopic Eczema
There is no indication for extensive elimination diets without previous allergy diagnosis. The suspicion of an adverse reaction to food often comes from clinical his- tory or obvious inefficiency of dermatological therapy in a patient. Exacerbation of AE after ingestion of cer- tain food is frequently seen in children [10, 12]. Most commonly (80 % – 90 %) hen’s egg, cow’s milk, and dairy products, wheat flour, soy products, nuts, fish, and especially in the United States peanuts are identi- fied as trigger factors [10, 12, 13]. Wheat flour is more often relevant in children. Pollen-associated cross allergens such as apple and celery are of higher impor- tance in adults [13]. Food allergy is regarded as an indi- cator for a more severe course of AE and associated respiratory atopy [14]. Apart from IgE-mediated reac- tions, nonimmunological, pseudo-allergic reactions to food additives or citrus fruits also play a role in some patients [10, 12].
An increased intestinal permeability was hypothe- sized in AE allowing high-molecular food proteins to pass the intestinal barrier, eventually causing a system- ic or cutaneous reaction in sensitized patients. Thus antigens might interact directly with specific IgE bound on mast cells, basophils, or Langerhans cells to Fc 5 -receptorI or may come in contact with other immunologically relevant cell populations. This hy- pothesis can explain the different morphology and time course of clinical reaction patterns after oral pro- vocation tests when food allergens reach the skin by circulation [13].
Three reaction patterns have been described that
can occur solely or in combination with others after
oral provocation testing [13, 15 – 17]:
1. Immediate-type reactions are often seen after 15 – 30 min and appear as pruritus, urticaria, angioedema, gastrointestinal symptoms, rhino- conjunctivitis, bronchial asthma, or cardiovascular reactions.
2. Intensive itching beginning within 30 – 60 min after provocation, eventually leading to massive excoria- tion and eczematous skin lesions.
3. Elicitation of exacerbation of AE after 6 – 48 h (delayed type). Often no relevant IgE-mediated sensitization is found with this reaction type, especially in children. Allergen-specific T lympho- cytes have been proposed as playing a role in this type of reaction [13].
47.3
Practical Approach to the Patient with Suspected Food Allergy and AE
The extensive and often repeated clinical history is the backbone of allergy diagnosis [6]. However, validity of the history with regard to food is lower in AE than in other food-associated diseases, which may partially be explained by the different reaction patterns [18]. In addition, the well-known problem of hidden sources of food allergens (especially milk, egg, and nuts) in indus- trially processed food has to be taken in account [19]. If clinical history gives no clear information, food diaries are recommended for a specified time of 4 – 6 weeks.
Skin prick test with an appropriate panel of food extracts accomplished by native testing of food (“prick-to-prick”) is the second step of diagnosis.
False-negative results are often seen with commercially available food extracts due to a lack of stability of the allergen in such preparations. On the other hand, posi- tive test results do not prove a relevant allergy. In addi- tion, all variables that may influence the results of a skin prick test must also be recognized for valid results [6, 18]. The predictive value of intracutaneous/intra- dermal testing is not higher than in skin prick test, but a higher risk of systemic reaction exists [18].
Especially in patients with severe AE, urticaria facti- tia, or those under anti-histamine medication, the determination of specific serum IgE plays an important role since in these patients skin tests are often not pos- sible. In addition, a high positive predictive value of elevated specific serum IgE to some foods for a subse- quently positive oral challenge test has been shown in
retrospective studies in children [18]. However, the predictive value of specific IgE is controversial in adults with AE because no strong correlation between specific IgE to food allergens and the results of provocation tests was seen [9]. Other in-vitro methods such as his- tamine release, lymphocyte proliferation tests, or other cellular tests are not yet used in routine diagnosis.
At the beginning of diagnostics, specific elimination diets are often recommended for patients with AE.
According to most authors, the oral provocation test is the gold standard for the diagnosis of food-associated exacerbations of AE [18]. Open oral challenge tests have a higher validity for patients with negative results than for patients with positive results. If possible, oral provocation tests are performed double-blind and pla- cebo-controlled, introducing the food after a corre- sponding elimination diet (at least 1 week) in a neutral base marked with colored and artificial flavors. At this stage of diagnosis, the patient must be treated by per- sonnel in a hospital experienced in coping with ana- phylactic reactions. Assessment of positive reactions also needs experience with regard to the differentiation of early and late reactions (see preceding section). The repeated quantification of eczema intensity using a scoring system such as SCORAD is recommended [19].
The choice of tested food depends on the clinical histo- ry, skin tests, and specific IgE. Table 47.1 gives an over- view of diagnostic diets for adults and children (modi- fied from [6, 10]). New food is introduced every 1 – 2 days, depending on the time between ingestion and symptoms. Details for standardization of oral provocation tests and security measures in highly sen- sitized patients have been published [17].
Most studies on the influence of food allergens on AE were conducted in children. Sampson et al. [18, 20]
Table 47.1. Diagnostic diet in patients with atopic eczema
Adults Food
Day 1+2 1 Carbohydrates, cereals, and vegetable Day 3+4 2 Cow’s milk and dairy products Day 5+6 3 Meat and spices
Day 7+8 4 Poultry and egg Day 9+10 5 Fish and seafood Day 11+12 6 Fruits (and tree nuts) Day 13+14 7 Additives and dyes Children
Day 1+2 1 Cereals and vegetable Day 3+4 2 Cow’s milk and dairy products
Day 5+6 3 Egg
442 47 Role of Allergy Testing in Atopic Eczema
reported on a prevalence of 40 % positive oral provoca- tion tests in children with AE, describing correlations of positive oral provocation tests, skin prick tests, and specific IgE as well as increased serum histamine. In a group of 320 patients with extensive AE, 63 % positive oral provocation tests were seen (skin symptoms in 75 %). Population-based data is missing for AE. In sus- pected adverse reactions to additives (idiosyncrasy or pseudo-allergy), skin tests and determination of spe- cific serum IgE give mostly negative results. In these cases, oral provocation tests with standardized proto- cols are also performed placebo-controlled; additives may be administered in capsules [6]. In addition, oral provocation tests may be done in patients with type IV contact allergy (nickel, fragrance, or artificial flavor).
In suspected cow’s milk allergy, lactose intolerance has to be ruled out.
The atopy patch test (APT, see below) with foods is still a nonstandardized experimental method. Native foods such as hen’s egg, wheat flour, cow’s milk, or soy products were applied in 12-mm aluminium test cham- bers for 24 or 48 h on the patient’s skin. Majamaa et al.
[15] investigated 142 children under 2 years with sus- pected cow’s milk allergy. In 50 %, the oral provocation test was positive (22 immediate-type reactions). Of these patients, 26 % had an increased corresponding specific IgE, 14 % a positive skin prick test, and 44 % a positive APT with cow’s milk. In this age group, most positive APT reactions were seen without correspond- ing positive skin prick test results. Further investiga- tions by Isolauri and Turjanmaa [16] showed an associ- ation between the clinical pattern of the reaction and the result of skin prick test and APT. They also suggest- ed doing the skin prick test and the APT simultaneous- ly to increase the precision of diagnosis. In the investi- gated group of children (2 – 36 months) with AE, the skin prick test with cow’s milk was positive in 67 % of cases with immediate-type reactions in the oral chal- lenge, mostly accompanied by negative APT. On the other hand, a positive APT was seen in 89 % of cases with delayed eczematous reaction, whereas in these cases the skin prick test was mostly negative.
An association of eczema flare-ups following oral provocation in patients with positive APT with native preparations of cow’s milk, hen’s egg, wheat flour, and soy was described by Niggemann et al. [21, 22]. For the APT with these native foods, Roehr et al. [23] calculat- ed a sensitivity of 47 % – 89 % and a specificity of 86 % – 96 % with regard to the result of the oral provo-
cation. The positive predictive value of the diagnostic method could be increased to 94 % – 100 % when posi- tive skin prick tests, elevated specific IgE, and a posi- tive APT were combined for these calculations [23]. A practical problem for such combinations, however, are discordant test results. Our own investigations in a multicenter study in six European countries using an APT with food preparations in petrolatum [24] showed concordance of APT result and clinical history of 77 % (hen’s egg), 78 % (wheat flour), and 79 % (celery). The specificity of this APT with regard to a predictive clini- cal history was 91 %, but the sensitivity was only 30 % – 33 % (n = 314). Varying results of different study groups are obvious, especially for the sensitivity of APT; further clinical studies for standardization and patient group selection for the method are necessary.
To date, the oral provocation tests under controlled conditions may not be replaced by skin tests. The indi- cation for oral challenge is not made with the proof of elevated specific IgE, but by exact allergological histo- ry. In addition, a positive APT may also be a reason for oral provocation testing in selected pediatric cases.
However, it is often forgotten that oral food challenges themselves may also have problems with their sensitiv- ity and specificity and may sometimes have false results or an uncertain outcome.
47.4
Aeroallergens and Atopic Eczema
Elevated levels of specific serum IgE against aeroaller-
gens are very frequent in patients with AE [25]. A cor-
relation with disease activity was described for the
total serum IgE concentration [26 – 28]. Environmen-
tal influence, including aeroallergens, has been pro-
posed to elicit eczematous flare-ups in patients with
AE for many years [29, 30]. Accordingly, aeroallergen
avoidance (i.e., house dust mites) often results in
improvement of the clinical course [7, 8, 31]. After an
extensive clinical history (eczema flare-ups after con-
tact with dust of furred animals, seasonal exacerba-
tions, etc.), the regionally relevant standards of sea-
sonal and perennial aeroallergens should be tested in
the skin prick test in every patient with AE. In addi-
tion, the measurement of specific serum IgE against
these aeroallergens is necessary in many cases, espe-
cially in patients with extensive eczematous lesions or
in children. Typically, these classic measures for evalu-
D. pter. 200 IR/g
ation of IgE-mediated sensitizations give a lot of posi- tive results with questionable clinical relevance, which is often only partially explained with clinical history [19].
47.5
Atopy Patch Test with Aeroallergens
Different groups reported that aeroallergens can elicit eczematous skin lesions by epicutaneous testing in patients with AE [32 – 41]. This procedure, an epicuta- neous patch test with allergens known to elicit IgE- mediated reactions and the evaluation of eczematous skin reactions after 48 and 72 h, is called atopy patch test (APT) (Fig. 47.1) [32 – 34]. More recently, the APT is used as a diagnostic tool in patients with AE, on an experimental basis also with food. Patch testing of aeroallergens was published in 1937 [29]. In 1982, Mit- chell et al. first published work on epicutaneous patch tests of aeroallergens particularly for patients with AE [40]. The reaction frequencies reported by different authors were not comparable due to different methods used with experimental APT, some with additional manipulations of the stratum corneum to improve allergen penetration.
No clear correlations of the results of the skin prick test or specific IgE with APT results were established in experimental APT systems. Systematic investigations of the clinical relevance (concordance with clinical his- tory) or provocation were only possible after introduc- tion of better standardized APT methods.
Fig. 47.1. APT reaction after 48 h. At this time point, the eczematous appearance of APT reactions often reaches its maximum in contrast to the classical type IV contact allergy showing a crescendo at 72 h
Pathophysiological background of the APT reaction in patients with AE (nonatopic controls and patients with only respiratory atopy show no positive reaction in most APT systems) is the penetration of high-molecu- lar immediate-type allergens through the patient’s dis- turbed epidermal barrier. IgE and IgE-binding struc- tures were recognized on the surface of epidermal Lan- gerhans cells colocalized with house dust mite aller- gens [42 – 45], leading to the hypothesis that these anti- gen-presenting cells may play an essential role in initi- ating and maintaining a cellular inflammatory reaction in the skin of patients with AE. From APT biopsies, allergen-specific T cell clones could be isolated, which initially showed a characteristic Th2 cytokine pattern (interleukin-4, 5, 13). After 48 h, a Th1 pattern with secretion of INF- * had developed; the same pattern is known from chronic lesions of AE [46, 47]. Several methodological studies defining the associations with clinical covariates were performed to standardize the APT for the European Task Force on Atopic Dermatitis (ETFAD). A petrolatum vehicle as carrier for the aller- gen lyophilisates gave significantly better results than an aqueous vehicle [33]. The most frequent aeroaller- gens (house dust mite, Dermatophagoides pteronyssi-
nus [D. pter.], cat dander, and grass pollen) have to betested in allergen concentrations exceeding those of many commercial skin prick test extracts [33].
Grading of APT reactions is possible following the
rules of conventional patch testing [33]. Today the
more differentiated consensus reading key of the
ETFAD is preferred [19]. The most frequent reactions
in patients with AE in the APT (34 % – 40 %) were seen
444 47 Role of Allergy Testing in Atopic EczemaTable 47.2. APT and specific IgE (from [49]). Allergen: D. pter., 48 h APT in adult patients with AE
slgE e 0.35 kU/l sIgE pos. Total
APT negative 49 29 78
APT positive 13 60 73
Total 62 89 151
(Fisher’s exact test p < 0.00001)
to D. pter., whereas vehicle control areas and nonatopic volunteers showed no positive APT reactions [33, 48, 49]. In a monocentric study, the allergen-specific con- cordance of APT with skin prick test was 0.39 – 0.59 depending on the allergen; the concordance with aller- gen-specific IgE in serum was 0.42 – 0.69 [33]. Thus high allergen-specific serum IgE is not a prerequisite for a positive APT, which also holds true for the corre- lation with the skin prick test. Table 47.2 gives an exam- ple for a cross-tabulation from a multicenter study [49]. As in most patients with a positive APT, specific IgE was elevated compared to patients with negative APT. A role of IgE in the pathophysiology of an APT reaction is proposed, but other (cellular) mechanisms may also be important.
In a prospective dose-response study [48] with four concentrations of different aeroallergens, patients with eczematous lesions predominantly in air-exposed areas such as hands, forearms, head, and neck showed a significantly higher frequency of positive APT reac- tions than a control group of patients with a nonspecif- ic AE pattern (69 % vs 39 %; p = 0.02). In addition, low- er allergen concentrations were necessary to elicit posi- tive APT reactions in the at-risk population. Several studies addressing reproducibility of APT (Table 47.3) indicate that the intraindividual APT reactivity is
Table 47.3. Reproducibility of APT. Reproducibility of positive APT reactions at different time points
Patch test N Time
(months) Repro- ducible
APT petrolatuma 20 6 – 12 18
D. pter., grass and birch pollen, no tape stripping
APT petrolatuma 16 12 – 24 15
D. pter., cat, grass and birch pollen, no tape stripping
APT aqueousb 5 6 5
D. pter., 10× tape stripping
aOur data bData from [50]
maintained for a long time [50]. Differently from the situation in the diagnosis of food allergies, no gold standard for provocation testing of aeroallergens in AE is known. We used allergen-specific clinical history to evaluate the clinical relevance of APT reactions. As sea- sonal variations of AE course can be easily identified by clinical history, the validity of the APT with grass pol- len was initially evaluated with regard to this clinical history. In a study in 79 patients with AE [51], we showed a significantly higher frequency of positive APT reactions (grass pollen mixture in petrolatum and 10 mg unprocessed native pollen of Dactylis glomerata) in patients with a corresponding clinical history of eczema flare-ups in the previous grass pollen season (75 % positive APT vs 16 % in patients without a sea- sonal history; p< 0.001). In this as well as in following studies, the results of skin prick tests and specific serum IgE were significantly correlated with APT results. Sensitivity and specificity of an APT method could be calculated in comparison to the classical test methods with regard to a prospectively obtained clini- cal history (Table 47.4). The specificity of the APT is higher than the specificity of skin prick test and aller- gen-specific serum IgE, whereas the sensitivity of the classical methods is higher due to a high frequency of positive reactions to aeroallergens in the investigated patient group. The clinical relevance of grass pollen for the course of atopic eczema in a group of patients is underscored by the observation that eczematous le-
Table 47.4. Sensitivity and specificity of different test systems in patients with AE. Studies used different allergen standardi- zation systems
Test Sensitivitya Specificitya
Different grass pollen preparations,n = 79
Skin prick 100 % 33 %
sIgE 92 % 33 %
APT 75 % 84 %
European multicenter studyn = 314, 4 allergens
Skin prick 68 % – 80 % 50 % – 71 %
sIgE 72 % – 84 % 52 % – 69 %
APT 14 % – 45 % 64 % – 91 %
German multicenter studyn = 253, 3 allergens
Skin prick 69 % – 82 % 44 % – 53 %
sIgE 65 % – 94 % 42 % – 64 %
APT 42 % – 56 % 69 % – 92 %
aDepending on allergen, with regard to a clinical history with eczema flare-ups in the pollen season or after direct contact with allergen
n=31 D. pter.
n=7 Cat dander n=8 Grass pollen n=16 Birch pollen n=11 Egg white n=16 Celery n=18 Wheat flour
sions in these patients were also elicited by native pol- len on skin that had not been pretreated.
For the most frequent aeroallergens in Germany, optimal allergen doses were determined between 5,000 and 7,000 protein nitrogen units (PNU)/g in a random- ized double-blind multicenter study including 253 adults and 30 children with AE [49]. Of these patients, 10 % – 52 % had reported a history of eczema flare-ups after contact with at least one of the tested allergens (D.
pter., cat dander, grass pollen, birch, and mugwort pol- len). The frequencies of positive reactions were (aller- gen-dependent) from 36 % to 65 % (skin prick test), 49 % to 75 % (elevated specific IgE), and 3 % to 34 % (APT, 48 h). The number of positive reactions per allergen was always lower with the APT compared to the classical tests. The results of this multicenter trial also showed significant correlations of APT result, clinical history, skin prick test, and corresponding specific serum IgE (p < 0.001) with a higher specificity of the APT.
Similar reaction frequencies with some regional dif- ferences for aeroallergens were also seen in a recent international multicenter trial we conducted simulta- neously in 12 study centers in six European countries (first results in [24]). Results of that study corroborated the characteristic differences in sensitivity and speci- ficity of APT, skin prick test, and specific IgE (Table 47.4) using an allergen standardization with biological units and defined major allergen content.
Patients with a predictive aeroallergen-specific clin- ical history and/or with a predictive eczema pattern showed significantly more positive APT reactions, sug- gesting that the APT may be an important diagnostic tool, especially for these patient groups. 100 % concor- dance between APT and the classical methods of diag- nosing an IgE-mediated sensitization does not exist,
Fig. 47.2. Positive APT reactions without corresponding posi- tive skin prick test and specific IgE were seen in 53 of 314 patients (17 %) for one allergen (17 %); 22 (7 %) patients had a positive APT reaction with no positive reaction in the whole panel of skin prick tests and specific serum IgE
nor is complete concordance of skin prick tests and ele- vated serum IgE expected (Fig. 47.2). The reason for this is that different compartments or dimensions of the allergic inflammation are investigated. The lower sensitivity accompanied by higher specificity of the APT in comparison suggests the use of a combination of different test methods as a practical approach. How- ever, the problem of discordant test results is already known from skin prick tests and specific IgE measure- ment.
47.6 Outlook
B. Wüthrich’s concept of distinguishing extrinsic from intrinsic forms of AE [52] is sustained by the results of many studies, whereas the new nomenclature of the EAACI may lead to problems in some cases [53]. Fur- ther control studies involving specific provocation and elimination procedures in patients with positive and negative APT are necessary to elucidate the clinical rel- evance of the APT with aeroallergens. Better standard- ized APT with food allergens may replace a part of the oral provocation procedures in the future [23], but not to date. In addition, further allergens were shown to be relevant for patients with AE in inducing APT reac- tions: Pityrosporum orbiculare [54] and Coprinus
comatus [55], a basidiomycete. Apart from the citedclinical studies, experimental evidence is accumulating for the allergen specificity of APT reactions [56, 57].
This leads to the question of whether patients identi- fied by a positive APT not only show benefit from aller- gen avoidance, but also from a specific immunotherapy (hyposensitization) with the identified aeroallergens (for a review, see [58]).
Independently of the APT, the classical epicutaneo- us patch test for the proof of a contact sensitization to lower molecular weight allergens is an integral part of the diagnostic management of AE. In contrast to earlier claims of a rather low frequency of classical contact allergies in patients with AE, more recent studies in larger groups of patients could only show a different sensitization pattern for patients with AE [59 – 61].
Thus an extensive clinical history may lead to further epicutaneous patch tests in selected cases. The search for trigger factors of AE remains a challenge for the future of allergological diagnosis.
446 47 Role of Allergy Testing in Atopic Eczema
References
1. Rajka G (1989) Essential aspects of atopic dermatitis.
Springer, Berlin Heidelberg New York
2. Ruzicka T, Ring J, Przybilla B (eds) (1991) Handbook of atopic eczema, 1st edn. Springer, Berlin Heidelberg New York
3. Hanifin JM, Rajka G (1980) Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 114:146 – 148 4. Hanifin JM (1983) Clinical and basic aspects of atopic der-
matitis. Semin Dermatol 2:5
5. Ring J (1991) Atopy: condition, disease, or syndrome? In:
Ruzicka T, Ring J, Przybilla B (eds) Handbook of atopic eczema. Springer, Berlin, Heidelberg New York, pp 3 – 8 6. Ring J (2004) Angewandte Allergologie. 3. Aufl. Urban &
Vogel Verlag, München
7. Fukuda H, Imayama S, Okada T (1991) Mite-free room (MFR) for the management of atopic dermatitis. Jpn J All- ergol 40:626 – 632
8. Sanda T, Yasue T, Oohashi M, Yasue A (1992) Effectiveness of house-dust mite allergen avoidance through clean room therapy in patients with atopic dermatitis. J Allergy Clin Immunol 89:653 – 657
9. Werfel T, Kapp A (1998) Environmental and other major provocation factors in atopic dermatitis. Allergy 53:731 – 739
10. Przybilla B, Ring J (1990) Food allergy and atopic eczema.
Semin Dermatol 9:220 – 225
11. Ring J, Brockow K, Abeck D (1996) The therapeutic con- cept of “patient management” in atopic eczema. Allergy 51:206 – 215
12. Van Bever HP, Docx M, Stevens WJ (1989) Food and food additives in severe atopic dermatitis. Allergy 44:588 – 594
13. Breuer K, Kapp A, Werfel T (2000) IgE-vermittelte Reak- tionen auf Nahrungsmittel bei Neurodermitis. Akt Der- matol 26:19 – 22
14. Guillet G, Guillet MH (1992) Natural history of sensitiza- tions in atopic dermatitis: a 3-year follow-up in 250 chil- dren. Arch Dermatol 128:187 – 192
15. Majamaa H, Moisio P, Holm K, Kautiainen H, Turjanmaa K (1999) Cow’s milk allergy: diagnostic accuracy of skin prick test and specific IgE. Allergy 54:346 – 351
16. Isolauri E, Turjanmaa K (1996) Combined skin prick and patch testing enhances identification of food allergy in infants with atopic dermatitis. J Allergy Clin Immunol 97:
9 – 15
17. Niggemann B, Kleine-Tebbe J, Saloga J, Sennekamp J, Vie- luf I, Vieths S, Werfel T, Jäger L (1998) Standardisierung von oralen Provokationstests bei IgE-vermittelten Nah- rungsmittelallergien. Allergo J 7:45 – 50
18. Sampson HA (1999) Food allergy. Part 2: diagnosis and management. J Allergy Clin Immunol 103:981 – 989 19. Darsow U, Ring J (2000) Airborne and dietary allergens in
atopic eczema: a comprehensive review of diagnostic tests.
Clin Exp Dermatol 25:544 – 551
20. Sampson HA, Albergo R (1984) Comparison of results of skin tests, RAST, and double-blind placebo-controlled food challenges in children with atopic dermatitis. J Aller- gy Clin Immunol 74:26 – 33
21. Niggemann B, Reibel S, Wahn U (2000) The atopy patch test (APT) – a useful tool for the diagnosis of food allergy in children with atopic dermatitis. Allergy 55:281 – 285 22. Niggemann B, Reibel S, Roehr CC, Felger D, Ziegert M,
Sommerfeld C, Wahn U (2001) Predictors of positive food challenge outcome in non-IgE-mediated reactions to food in children with atopic dermatitis. J Allergy Clin Immunol 108:1053 – 1058
23. Roehr CC, Reibel S, Zieger M, Sommerfeld C, Wahn U, Niggemann B (2001) Atopy patch tests, together with determination of specific IgE levels, reduce the need for oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol 107:548 – 552.
24. Darsow U, Laifaoui J, Didierlaurent A, Andr´e C, Seidenari S, Ring J (2004) Atopy patch test with biologically stan- dardized aeroallergens and food allergens in petrolatum.
Allergy Clin Immunol Int 16 [Suppl 1]:259 – 262
25. Leung DYM, Rhodes AR, Geha RS, Schneider LC, Ring J (1993) Atopic dermatitis (atopic eczema). In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF (eds) Der- matology in general medicine, 4th edn. McGraw Hill, New York, pp 1543 – 1563
26. Meneghini CL, Bonifazi E (1985) Correlation between clin- ical and immunological findings in atopic dermatitis. Acta Derm Venereol (Stockh) 114:140 – 142
27. Barnetson RSC, MacFarlane HAF, Benton EC (1987) House dust mite allergy and atopic eczema: a case report. Br J Dermatol 116:857 – 860
28. Jones HE, Inouye JC, McGerity JL, Lewis CW (1975) Atopic disease and serum immunoglobulin-E. Br J Dermatol 92:17 – 25
29. Rostenberg A, Sulzberger MD (1937) Some results of patch tests. Arch Dermatol 35:433 – 454
30. Rowe AH (1946) Dermatitis of the hand due to atopic aller- gy to pollen. Arch Dermatol Syph 53:437
31. Lau S, Ehnert B, Cremer B, Nasert S, Büttner P, Czarnetzki BM, Wahn U (1995) Häusliche Milbenallergenreduktion bei spezifisch sensibilisierten Patienten mit atopischem Ekzem. Allergo J 4:432 – 435
32. Ring J, Kunz B, Bieber T, Vieluf D, Przybilla B (1989) The
“atopy patch test” with aeroallergens in atopic eczema (abstract). J Allergy Clin Immunol 82:194 – 201
33. Darsow U, Vieluf D, Ring J (1995) Atopy patch test with dif- ferent vehicles and allergen concentrations – an approach to standardization. J Allergy Clin Immunol 95:677 – 684 34. Vieluf D, Kunz B, Bieber T, Przybilla B, Ring J (1993) “Atopy
patch test” with aeroallergens in patients with atopic ecze- ma. Allergo J 2:9 – 12
35. Platts-Mills T, Mitchell E, Rowntree S, Chapman M, Wil- kins S (1983) The role of dust mite allergens in atopic der- matitis. Clin Exp Dermatol 8:233 – 247
36. Cabon N, Ducombs G, Mortureux P, Perromat M, Taieb A (1996) Contact allergy to aeroallergens in children with atopic dermatitis: comparison with allergic contact der- matitis. Contact Dermatitis 35:27 – 32
37. Adinoff A, Tellez P, Clark R (1988) Atopic dermatitis and aeroallergen contact sensitivity. J Allergy Clin Immunol 81:736 – 742
38. Bruijzeel-Koomen C, van Wichen D, Spry C, Venge P, Bru- ijnzeel P (1988) Active participation of eosinophils in
patch test reactions to inhalant allergens in patients with atopic dermatitis. Br J Dermatol 118:229 – 238
39. Clark R, Adinoff A (1989) Aeroallergen contact can exacer- bate atopic dermatitis: patch test as a diagnostic tool. J Am Acad Dermatol 21:863 – 869
40. Mitchell E, Chapman M, Pope F, Crow J, Jouhal S, Platts- Mills T (1982) Basophils in allergen-induced patch test sites in atopic dermatitis. Lancet I:127 – 130
41. Tanaka Y, Anan S, Yoshida H (1990) Immunohistochemi- cal studies in mite antigen-induced patch test sites in atop- ic dermatitis. J Dermatol Sci 1:361 – 368
42. Bieber T, Rieger A, Neuchrist C, Prinz JC, Rieber EP, Boltz- Nitulescu G, Scheiner O, Kraft D, Ring J, Stingl G (1989) Induction of FCeR2/CD23 on human epidermal Langer- hans-cells by human recombinant IL4 and IFN. J Exp Med 170:309 – 314
43. Bieber T, de la Salle H, Wollenberg A, Hakimi J, Chizzonite R, Ring J, Hanau D, de la Salle C (1975) Human Langerhans cells express the high affinity receptor for IgE (FCeR1). J Exp Med 175:1285 – 1290
44. Bruijnzeel-Koomen C, van Wichen DF, Toonstra J, Berrens L, Bruijnzeel PLB (1986) The presence of IgE molecules on epidermal Langerhans-cells in patients with atopic derma- titis. Arch Dermatol Res 278:199 – 205
45. Maeda K, Yamamoto K, Tanaka Y, Anan S, Yoshida H (1992) House dust mite (HDM) antigen in naturally occur- ring lesions of atopic dermatitis (AD): the relationship between HDM antigen in the skin and HDM antigen- specific IgE antibody. J Dermatol Sci 3:73 – 77
46. Van Reijsen FC, Bruynzeel-Koomen CAFM, Kalthoff FS, Maggi E, Romagnani S, Westland JKT, Mudde GC (1992) Skin-derived aeroallergen-specific T-cell clones of TH2 phenotype in patients with atopic dermatitis. J Allergy Clin Immunol 90:184 – 192
47. Sager N, Feldmann A, Schilling G, Kreitsch P, Neumann C (1992) House dust mite-specific T cells in the skin of sub- jects with atopic dermatitis: frequency and lymphokine profile in the allergen patch test. J Allergy Clin Immunol 89:801 – 810
48. Darsow U, Vieluf D, Ring J (1996) The atopy patch test: an increased rate of reactivity in patients who have an air- exposed pattern of atopic eczema. Br J Dermatol 135:
182 – 186
49. Darsow U, Vieluf D, Ring J for the APT study group (1999) Evaluating the relevance of aeroallergen sensitization in atopic eczema with the atopy patch test: a randomized,
double-blind multicenter study. J Am Acad Dermatol 40:
187 – 193
50. Langeveld-Wildschut EG, van Marion AM, Thepen T, Mudde GC, Bruijnzeel PLB, Bruijnzeel-Koomen CAFM (1995) Evaluation of variables influencing the outcome of the atopy patch test. J Allergy Clin Immunol 96:66 – 73 51. Darsow U, Behrendt H, Ring J (1997) Gramineae pollen as
trigger factors of atopic eczema: evaluation of diagnostic measures using the atopy patch test. Br J Dermatol 137:
201 – 207
52. Wüthrich B (1983) Neurodermitis atopica sive constitutio- nalis. Ein pathogenetisches Modell aus der Sicht des Aller- gologen. Akt Dermatol 9:1 – 7
53. Kerschenlohr K, Decard S, Darsow U, Ollert M, Wollen- berg A (2003) Clinical and immunologic reactivity to aero- allergens in “intrinsic” atopic dermatitis patients. J Allergy Clin Immunol 111:195 – 197
54. Tengvall Linder M, Johansson C, Scheynius A, Wahlgren CF (2000) Positive atopy patch test reactions to Pityrospo- rum orbiculare in atopic dermatitis patients. Clin Exp Allergy 30:122 – 131
55. Fischer B, Yawalkar N, Brander KA et al (1999) Coprinus comatus (shaggy cap) is a potential source of aeroallergen that may provoke atopic dermatitis. J Allergy Clin Immu- nol 104:836 – 841
56. Clark RA, Adinoff AD (1989) The relationship between positive aeroallergen patch test reactions and aeroallergen exacerbations of atopic dermatitis. Clin Immunol Immu- nopathol 53: S132 – S140
57. Wistokat-Wülfing A, Schmidt P, Darsow U, Ring J, Kapp A, Werfel T (1998) Atopy patch test reactions are associated with T-lymphocyte mediated allergen-specific immune responses in atopic dermatitis. J Allergy Clin Immunol 101:196 – 197
58. Darsow U, Forer I, Ring J (2005) Spezifische Hyposensibili- sierung bei atopischem Ekzem. Allergologie 28:53 – 61 59. Enders F, Przybilla B, Ring J, Burg G, Braun-Falco O (1989)
Epikutantestung mit einer Standardreihe. Ergebnisse bei 12026 Patienten. Hautarzt 39:779 – 786
60. De Groot AC (1990) The frequency of contact allergy in atopic patients with dermatitis. Contact Dermatitis 22:
273 – 277
61. Giordano-Labadie F, Ranc´e F, Pellegrin F, Bazex J, Dutau G, Schwarze HP (1999) Frequency of contact allergy in chil- dren with atopic dermatitis: results of a prospective study of 137 cases. Contact Dermatitis 40:192 – 195
448 47 Role of Allergy Testing in Atopic Eczema
