The Atopy Patch Test

The presence of specific T cells directed to inhalant allergens along with the effects seen in AD patients upon epicutaneous or bronchial allergen administration highlight their possible impact on AD. Therefore, a major approach to the management of this part of the disease is to avoid these potential triggers. Identification of the offending allergens on the basis of history and diagnostic testing is needed to specify avoidance recommendations for the individual patient (Table 9.2).

Many patients are highly sensitized to inhalant allergens. In this regard, a number of well-established allergologic test procedures help to verify or exclude the presence of IgE mediated hypersensitivity. However, the absence of allergen specific IgE in the serum does not necessarily indicate a lack of sensitization. Therefore, an extension of allergy testing is represented by the SPT that evaluates IgE bound on mast cells. Nevertheless, neither test procedure considers those AD patients characterized by cell-mediated sensitizations. Since the finding of Mitchell et al89 that epicutaneous application of inhalant allergens on unaffected skin of AD patients elicits delayed type IV eczematous reactions, this so-called ATP, as termed by Ring in 1989,90 has additionally gained enormous interest during the past few years in completing the test procedure spectrum. Thus the parallel use of prick and patch tests increases the rate of positive reactions. It is notable that there is even a strong correlation between both test systems pointing towards the coexistence of immediate and delayed immune responses in AD.

This has led to the concept that the APT could serve as a 'provocation' test for a subgroup of AD patients similar to the bronchial or nasal provocation tests in asthma and rhinitis.84 It has emerged as a suitable in vivo model to study the induction of eczema by inhalant allergens after 24-72 hours. Darsow et al91 performed the first controlled, double-blind designed multicentre study to describe significant associations of APT results and the data obtained from SPT and in vitro IgE measurement. They calculated sensitivity and specificity in 253 AD patients and found that APT had higher specificity towards inhalants (69-92%) than SPT (44-53%) and serum IgE (42-64%). Thus the classical tests may have some value as screening tests yet, specificity may be added through the APT. Additionally, APT are usually negative in patients with respiratory allergy and in healthy volunteers,92 suggesting that this technique involves AD specific triggering mechanisms and that it may represent a specific diagnostic tool since positive reactivity is obviously not related to irritant factors present in the material.

As previously mentioned, the APT reflects the second pathophysiological aspect of AD: namely, the T-cell based and dendritic cell-mediated skin inflammation following exposure to and contact with an inhalant allergen. In this respect, it is conceivable that IDECs with the capacity of high affinity IgE receptor expression are recruited into the APT lesions of allergic AD patients although up-regulation of this receptor seems to be restricted to those with IgE sensitization.30 In contrast, the results of Langeveld-Wildschut et al93 demonstrated the requirement of epidermal IgE+CD1a+ cells for APT positivity. However, Wistokat-Wulfing et al94 described the association of this test with proliferation and activation of allergen specific circulating T cells, which, along with the findings of Kerschenlohr et al,95 definitely confirm the involvement of T-cell intervention via IDECs in the APT with a more or less prominent IgE contribution. A further criterion that strengthens the role of T cells in the APT reaction is the notion of positive results in allergic AD patients without IgE sensiti-zation as documented by the studies of Seidenari et al,96 Manzini et al97 and Ingordo et al98 The aspect of a non-IgE T-cell regulated mechanism is clearly supported by the recent finding of Manzini et al97 showing that among 313 AD patients the agreement between APT and SPT was 58%, thus implying that allergen specific IgE is not obligatory for a positive APT reaction. Instead, the presence of allergen specific IgG4 antibodies as described by Kerschenlohr et al might reveal an important precipitating factor in this subgroup of AD patients.95

Former studies on APTs utilized a variety of allergenic materials (different allergen fractions) and methodologies. Potentially irritating procedures like skin abrasion, tape stripping, and detergent application were used to enhance allergen penetration, and grading of positive responses varied from centre to centre. Thus lack of uniformity yielded broadly differing positive results99 and made the reported data difficult to interpret and to reproduce. Since even minor test modifications greatly influence the outcome of the test, much effort has been undertaken to standardize the APT procedures in terms of allergen concentration, vehicle, skin pre-treatment, and time intervals to develop a reliable diagnostic tool for routine clinical use in AD patients. Currently, the protocol of the European Task Force on Atopic Dermatitis (ETFAD) provides a standardized APT technique and therefore is the most widely used.100

Several studies have pointed out the importance of technical aspects in generating reliable APT results. De Groot et al101 reviewed APT studies carried out from 1982-88 and noticed a relation between the type of allergen used and the number of positive tests. Yet, only few studies described allergen doses in units permitting comparison with environmental allergen levels.102 One such study was from Mitchell et al89 showing responses to house dust mites at concentrations as low as 1000 protein nitrogen units (PNU)/g whereas other researchers observed a clear dose-response relationship between allergen concentration (1000 and 10 000PNU) and positive reactions.103 In contrast, according to the work of Seidenari et al,104 increase in mite allergen concentration did not improve the results in AD patients but instead was considered too irritating to the skin, thus enhancing reactivity in healthy volunteers. In addition, these proteins did not necessarily correspond to the allergenic ones and so made the concentration of the material undefinable. Therefore, to achieve a better reproducibility in multi-centre studies, the ETFAD has developed a standardized approach to APT proposing a concentration between 5000 and 7000 PNU/g or 200 index of reactivity (IR)/g to obtain a useful ratio between sensitivity and specificity. In children, approximately 50% of the adult dose is sufficient.105

In terms of the vehicle, petrolatum is not only suitable for all inhalant allergen lyophilisates, but is even more preferred to aqueous vehicles by providing stable conditions for the preparations and inducing consistently higher positive reactions.106 Moreover, large Finn chambers (12 mm diameter) are used instead of the smaller ones (6 mm diameter) throughout Europe which enable a better penetration and subsequent presentation of intact protein allergens. Application of these test substances occurs on clinically uninvolved skin to reflect most closely the 'real life' situation of the skin.89 Some researchers even disrupt the epidermal barrier of the test site prior to application of the APT to improve the test condition. Yet, at the same time this procedure favours irritant reactions, explaining why the ETFAD protocol does not include any pre-treatment.

Once applied on the patient's skin, the test chambers are removed after 48 hours and the first reading is performed. Of note, reactions to patch testing on normal skin may not be maximal until 72 hours as AD patients with significantly lower specific IgE levels may react to the relevant allergen much later. Subsequently, test evaluation follows the criteria as defined by the ETFAD based on the appearance of erythema and the number as well as distribution pattern of the papules while only the latter feature along with infiltration grades a positive reaction. However, before introducing APTs in the routine diagnostic work-up of AD patients the issue of reproducibility should be also considered. Indeed, APT fulfils this criterion very well because as demonstrated in the study of Langeveld-Wildschut et al99 repetition of the test under exactly the same conditions yielded identical clinical scores and reaction patterns in all of the investigated patients after 6 months. With reference again to the ETFAD protocol, AD patients showed a very high reproducibility of 94% of all positive APT reactions within a mean 16 months observation period.107

Although many studies on APT have preferentially evaluated the relevance of house dust mite, as being the most important inhalant allergen in AD, some authors have also drawn their attention to other allergens. In this respect, a German multicentre study has been patch testing AD patients with cat dander (n = 243), grass pollen (n = 243), birch pollen (n = 88) and mug-wort pollen (n = 88).91 As a conclusion, these inhalants did act as triggers for AD exacerbation upon epidermal application in certain patients. Most importantly, these findings could be underlined by the results of a very recently performed European multicentre study involving 314 AD patients distributed over 12 study centres and following the ETFAD criteria.108 Again cat dander, grass, and birch pollen extracts have been investigated, thereby revealing a higher specificity for the APT technique (64-91% depending on the allergen) than for SPT (50-85%) or serum IgE (52-85%).

Despite these impressive data the final scientific proof for the relevance of inhalant allergens - identified by positive APT reactions - for the clinical manifestation of AD is still missing. Thus up to now, the diagnostic value of this test appears to be controversial, as no simple correlation exists between the outcome and the clinical relevance of positive APT reactions.93,94 The question still remains whether the APT can be really used for selection of patients who may benefit from allergen avoidance. Related to this aspect Clark et al109 and Adinoff et al110 found that among AD patients with moderate to severe eczema and positive prick tests to numerous inhalant allergens only those allergens known to precipitate dermatitis historically or that were identified in the surroundings of the patients elicited positive patch reactions. In a similar context, Pajno et al111 showed that children with AD had a higher SCORAD index, and a higher rate of positive SPT and APT for mites as well as higher environmental exposure to this relevant allergen than 3 years ago at the time of first recruitment. Furthermore, reactivities have been noted to occur significantly more often in patients with a typical airexposed predilection for the skin lesions112 suggesting that the APT may provide an important diagnostic tool in patients with eczematous lesions of predominantly uncovered areas.103 Nevertheless, it is important to demonstrate the clinical relevance of a positive APT; but intervention studies are still lacking in patients having been positively tested with APT.

Although the clinical relevance of the APT still remains a matter of debate, mite allergens provide the most notable results in APTs. As shown by the very recent study of Giusti et al113 55% of AD patients reacted positively and with a high reproducibility rate to the corresponding allergen indicating that dust mites are frequently involved in the development of such APT skin lesions. Because of these data and the fact that numerous APTs have been performed with this special kind of perennial allergen as well as the fact that mites belong to the most potent allergen sources, this subgroup of inhalants deserves to be discussed in more detail.

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