ARTICLE
Auteur(s) : Audrey Nosbaum1,2, Anca
Hennino2, Frédéric Berard1,2, Jean-François
Nicolas1,2
1Department of Allergology and Clinical
Immunology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon,
69495 Pierre Bénite, France
2Unit INSERM 851, IFR 128 Biosciences Lyon-Gerland,
21 Avenue Tony Garnier, 69007 Lyon, France
Patch tests are used for diagnosing delayed hypersensitivity
allergic reactions, like allergic contact dermatitis (ACD). More
recently, atopy patch tests (APT) have been developed with
aeroallergens and food allergens to diagnose delayed allergic
outbreaks of atopic dermatitis (AD) [1, 2]. In fact, exposure of
patients suffering from AD to aeroallergens (house dust mites, cat
dander, grass pollens) or food allergens can provoke an
exacerbation or prolongation of the disease [2-4]. Prick tests and
specific IgE can be useful for detecting aggravating factors, but
their precise implication in the genesis of the skin lesions should
be controlled by carrying out APT, which are more adapted to the
pathophysiology of AD [5, 6].
Summary of the pathophysiology of atopic
dermatitis
Atopic dermatitis (AD) is a disease caused by specific T cells to
allergens, which occurs in the context of a genetic disorder
inducing a cutaneous xerosis and an alteration of the epidermal
barrier [7]. The AD develops on an atopic field, characterised by
an increase in total IgE and in specific IgE to certain
aeroallergens or foods [8].
Changes in the skin barrier of patients with AD favour their
sensitization to allergenic proteins: the allergen penetrates the
epidermis and fixes on the specific IgE present on the surface of
Langerhans cells (LC). This binding activates the LC, which migrate
to a lymph node and present the allergen to T cells, provoking a
cascade of events like those described in allergic contact
dermatitis [9]. The appearance of lesions of eczema is not due to
IgE but to the cytotoxic activity of T cells, leading to the
apoptosis of keratinocytes [10]. The distinctive features of AD
compared to ACD are the possibility for the allergen to penetrate
the skin, in particular for house dust mite antigens, and the
capacity of LC to fix the IgE, via their FcεRI receptor. This
explains why the great majority of AD patients have isolated
positive APT tests without positive IgE or positive prick
tests.
The influence of age
Sensitisation to allergens is an early phenomenon which coincides
with the beginning of AD in childhood. A study has recently
shown that atopic children aged from 3 to 12 months have
positive APT in 89% of cases, positive prick tests in 16% and
positive specific IgE in 30% of cases. These children, tested in
the same conditions 2 years later, present positive APT only
in 60% of cases, whereas prick tests and the specific IgE is
positive in 63% and 73.5% of cases [11].
The hypothesis is then that there is initially a sensitization
of T cells (manifesting as the eczema of AD), with only a
subsequent sensitization of the IgE responsible for the respiratory
symptoms (asthma and allergic rhinitis).
Principles and usage of atopy patch tests
APT are defined as the epicutaneous application of allergens in
order to evaluate their ability to reproduce an eczema in the
person being tested. With regard to the pathophysiology of AD, the
APT can be considered as provocation tests similar to those used
for the diagnosis of food or respiratory allergies [12]. Their aim
is thus to identify the aeroallergens and/or foods aggravating an
AD, and ultimately to propose avoidance measures when possible.
APT are indicated, in adults as well as in children, in the
following situations [13]:
- – persistent and/or severe AD (SCORAD>40), in the
absence of a known trigger of allergic contact dermatitis, after
the failure of topical treatments which have been correctly used
(including immunomodulators) and phototherapy (for adults);
- – suspicion that symptoms are aggravated by
aeroallergens and/or food, with negative specific IgE and/or
negative prick tests;
- – multiple IgE sensitizations without clinical
relevance.For Taieb et al., an allergological check-up is also
justified [2]:
- – in a child with moderate AD (SCORAD between 15-40)
requiring the use of dermal corticosteroids >
30 g/month.
Beyond the clinical indications, APT also enable the
pathophysiology of AD to be studied by reproducing, in an
experimental setting, an eczema at the site of application of
allergens.
Technical aspects of atopy patch tests
Materials: allergens, vehicle and controls
The European standardization of APT to aeroallergens has been
coordinated by the European Task Force on Atopic Dermatitis (ETFAD)
and APT are now carried out in a similar manner to conventional
patch tests, as used for the diagnosis of allergic contact
dermatitis [14]. The skin tests are prepared from lyophilized
aeroallergens diluted in petrolatum which gives a more stable
solution and reactions which are more frequent and more visible
than those of aqueous solutions [15]. The concentrations are higher
than those used for prick tests. In adults they consist of between
5,000 and 7,000 PNU/g (protein nitrogen units) or 200 IR/g
(biological units) but can be reduced by 50% in children [16].
Several commercial preparations are available: house dust mites
(Dermatophagoides pteronyssinus-Der p and Dermatophagoides
farinae-Der f), dog, cat, artemisia, birch, five grasses, dactylis,
pheole and plantain (Stallergènes, Antony, France; Allerbio,
Courbevoie, France; Chemotechnique, Malmö, Sweden). The
concentration of the commercial extract of house dust mites (a
mixture of Der p and Der f, Chemotechnique, Malmo, Sweden) diluted
to 20% in petrolatum is probably too high, since a dilution of 0.1%
of this mixture can be sufficient to identify allergy to house dust
mites in AD patients [17].
The APT to food, on the other hand, are not standardized and
until validated results are available, fresh foods should be
preferred to commercial extracts. In a study by Niggemann
et al., the food allergens tested were diluted at 1/10, in
order to eliminate false positives induced by irritation. The
authors found as many positive reactions with the APT diluted at
10% as for the non-diluted APT, but with stronger reactions for the
latter. The raw food item should therefore be placed undiluted on
blotting paper: a liquid like milk should be soaked into blotting
paper, or it can be in the form of a homogenised paste (wheat
flour, peanut…) [18]. More recently, an atopy patch test to
cow's milk has been developed in a ready-to-use form and is
available in pharmacies (Diallertest®). If its
specificity is comparable to that of a home-made test with a Finn
Chamber®, its sensitivity seems to be higher [19]. In
the future, the use of recombinant food allergens might be
interesting, as is already the case for Malassezia furfur allergens
[20]. Petrolatum is not an adequate vehicle for recombinant
allergens which should be diluted in an aqueous solution for good
dispersion.
The preparation of APT should also include a negative control
with the vehicle alone (petrolatum), associated with a control for
irritation (Sodium Lauryl Sulfate 0.5%). A second negative
control using just the chamber can also be applied.
Prior precautions
There is no age limit for carrying out APT and many studies have
been undertaken on babies from the age of 3 months [11]. The
tests should be made on healthy skin, without any pre-treatment
(scratch test, acetone). The prior precautions concerning
concomitant treatments are summarised in table 1 [5]. The influence of antihistamines
on APT results has not been clearly determined, but stopping their
use at least 72 hours before carrying out the tests is
recommended [13]. Finally, surprisingly, tacrolimus, the only
calcineurin inhibitor available in France, does not modify the APT
results, while pimecrolimus, which has a weaker anti-inflammatory
and immunomodulatory activity, reduces the severity of the APT
reactions [21, 22]. We recommend that an immunomodulatory treatment
should not be used on the APT site for at least 48 hours
before carrying out the tests.
Table 1 Conditions necessary before carrying out APT
[5, 13]
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No current outbreak of the disease, no pregnancy
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No application of corticosteroids on the APT site
for the previous 7 days
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No phototherapy treatment on the APT site
for the previous 4 weeks
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No oral corticosteroids
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No cyclosporine or oral tacrolimus
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No antihistamine treatments for at least 72 hours
(to be adapted to the molecule)
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Procedure and reading of atopy patch tests
The tests are applied on the back using 12mm Finn
Chambers®, (Epitest Ltd Oy, Tuusala, Finland), held in
place with hypoallergenic adhesive tape. They are left in place for
48 hours and reading of the tests is carried out at
48 and 72 hours. Contrary to standard patch tests,
positive reactions can diminish between 48 and 72 hours.
Only reactions which are palpable and infiltrated are classed as
positive, according to the international criteria for reading patch
tests, amended by the European Task Force on Atopic Dermatitis
(ETFAD) (table 2) [23]. It is
essential to clearly distinguish positive reactions from negative
or doubtful ones, since only papular or infiltrated reactions are
of clinical relevance. Reactions in babies and children are
generally more severe than those of adults, their thinner skin
encourages the penetration of allergens. New techniques are being
developed to ensure a more reproducible reading of patch tests
[24].
Table 2 International Criteria for reading APT,
revised by the ETFAD (European Task Force on Atopic
Dermatitis) [23]
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-
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Negative
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?
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Erythema alone, doubtful
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+
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Erythema and infiltration
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++
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Erythema and a few papules
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+++
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Erythema and numerous or diffuse papules
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++++
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Erythema and blisters
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Side effects
The occurrence of secondary effects during APT is infrequent (7.9%
of cases) [25]. The reactions observed are moderate and most often
localised to the site of application of the APT. It mainly concerns
a local recurrence of the AD, contact urticaria, irritative
contact dermatitis to the adhesive, pruritis or infiltrated
erythema lasting several weeks. A generalised relapse of the
AD (3 cases have been described) or exacerbation of underlying
asthma (2 cases described) have exceptionally been found [26, 27].
There are no cases of active sensitization induced by APT described
in the literature.
Interpretation of the results
Sensitivity, specificity and reproducibility of atopy
patch tests
The sensitivity and specificity of APT can only be determined by
looking at the clinical information (histories of exacerbation due
to promoting factors before the tests) and not the results of prick
tests or IgE, which do not evaluate the cellular composition of the
AD. However, as the clinical history often contributes little and
the re-introduction of the allergen is not feasible, the
sensitivity and specificity of APT are often weak, even in
standardized conditions. The sensitivity and specificity of APT,
prick tests and specific IgE in adults are summarized in table 3 [23]. In children, the APT
carried out by Niggeman et al. had a sensitivity of 76% and a
specificity of 95% for diagnosing exacerbations of AD induced by
food [18]. The APT had a higher specificity than the prick tests
and specific IgE tests regarding their clinical relevance, despite
a lower sensitivity.
Concerning allergological investigations of children with AD and
suspected food allergy, recent studies have shown that APT only
render oral provocation tests unnecessary in 0.5% to 14% of cases
and that APT to food have only a weak positive predictive value
[28, 29]. The value of APT in the diagnosis of food allergy,
associated or not to AD, seems therefore to be limited, the oral
provocation test remaining the gold standard for applying a
specific avoidance diet.
Finally, the APT carried out according to the protocol of Darsow
and Ring, using non-commercial solutions of aeroallergens, had a
reproducibility of 94% over an average observation of
16 months [30]. The results obtained from commercially
available solutions are less reproducible: 56% of tests are new
positives 4 to 12 weeks after a first test [31].
Table 3 Sensitivity and specificity of APT, prick
tests and specific IgE tests with reference
to the clinical history of 253 patients with
AD; The allergens studied were house dust (Der. P), cat hairs and
grass pollens [16]
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Test
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Sensitivity
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Specificity
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Prick tests
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69%-82%
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44%-52%
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Specific IgE
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65%-94%
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42%-64%
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APT
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42%-56%
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69%-92%
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Clinical relevance of atopy patch tests
During the history, the discovery of a previous exacerbation
induced by a specific allergen is a positive predictive factor for
the corresponding APT. Although a history of exacerbation by house
dust is often difficult to show, house dust mites (Der p, Der f)
are the main aeroallergens detected (36% of cases), followed by cat
hairs (22%), and grass pollens (16%) [14]. It should be noted that
APT to house dust mites can be positive in healthy individuals in
up to 23% of cases, but they are more frequently positive (49%)
with a higher positivity, in AD patients [32]. An exception seems
to be healthy individuals who have scabies, among whom 70% have
positive Der p APT, probably due to a cross-reaction with the
allergens of Sarcoptes scabei [33].
There are several differences in function of the clinical forms
of AD. The frequency of positivity of APT is in fact significantly
increased in the case of AD affecting “exposed” parts of the body
and when the AD worsens during spring and summer (frequency of APT
to grass pollens).
In the event of positive APT, what action should be taken? What
should be recommended to the patient? The results of avoidance
diets seem poor in practice and there is no specific immunotherapy
adapted to AD. For example, two randomised studies on the avoidance
of house dust mites, carried out double blind against placebo,
showed no significant clinical benefit for patients with AD. These
avoidance strategies only seem to be partial as the professional,
school and exterior environment are not concerned by the preventive
measures applied in the home [34, 35].
Conclusion
APT are able to identify aeroallergens and food allergens
implicated in the occurrence or aggravation of AD. The main
allergens identified by this method are house dust mites, cat hair
and grass pollens. APT enable more specific results to be obtained
than prick tests and specific IgE tests because their epicutaneous
application induces a reaction in which the pathophysiological
mechanism is similar to that of AD. If the standardization of APT
to aeroallergens has brought a certain reliability to this method,
the same cannot be said for APT to food allergens, where the
positive predictive value needs to be improved to avoid unjustified
dietary modifications. Improvements in APT and progress in
knowledge of the pathophysiology of eczemas will thus allow for new
immunobiological diagnostic methods and the possibility of specific
immunotherapies adapted to AD.
Acknowledgements
We are indebted to Jenny Messenger for translating this article
from French. (It first appeared in French in Ann Dermatol Venereol
2009; 136: 630-4).
Financial support: none. Conflict of interest: none.
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