ARTICLE
Auteur(s) : Alain Taïeb
National Reference Center for Rare Skin Diseases INSERM E 217
Service de Dermatologie et Dermatologie Pédiatrique, Hôpital St
André, 1 rue Jean Burguet, 33076 Bordeaux Cedex France
accepté le 2 Mars 2007
An allergy workup is carried out in many children with atopic
dermatitis but both its appropriateness and practical benefit for
disease management need to be questioned. This editorial emphasizes
the need for a global assessment of the young patient, including
compliance with previous treatments and evaluation of true disease
severity. In this perspective, allergy testing should be considered
as a second line option, integrated to global management, and
including a survey of food, contact and environment allergens
(atopens). Food allergy is found in one third of children with
moderate/severe disease. Symptoms are not only limited to the skin,
but avoidance diets in such patients may help reducing topical
corticosteroid consumption, when skin symptoms are enhanced by food
allergens. In adults with long lasting and severe disease, patients
with multiple sensitisation to atopens have usually developed
auto-immunization and their disease is not amenable to significant
improvement with allergen avoidance, standard skin care and even
phototherapies. Systemic therapy should address the
auto-inflammatory element in priority, using immunosuppressants to
stop the vicious circle of the disease. In milder and limited forms
such as head and neck or hand dermatitis, local therapy and careful
patch testing should be carried out to rule out common aggravating
contact allergies. Apart from a better delineation of the
indication of the tests, there is a need to make allergy workups
more simple, and a better standardization of tests is needed.Most
of the workup in atopic dermatitis (AD) is today focused on
allergy. However the appropriateness of this type of diagnostic
intervention is rarely questioned. Our objective is to show that
rather than being set apart, allergy tests should be integrated
into the general management of atopic dermatitis.
The child with AD: a thorough clinical examination and history
taking is needed before discussing allergy testing
The vast majority of infants and children seen at dermatology
clinics are basically healthy, but it remains of paramount
importance to take a careful history and to make a complete
clinical examination. Delayed growth is mostly caused by
sleeplessness due to excessive scratching, rather than to an
associated illness. Any unusual manifestation such as
gastrointestinal symptoms or repeated infections should however
prompt specific investigations.
Apart from some common skin conditions associated with pruritus
(scabies) and involving flexures – asymmetric periflexural exanthem
of children or APEC [1] –, which are frequently treated first as AD
because of the argument of frequency of the latter, psoriasis and
rarer disorders such as Langerhans cell histiocytosis can be
misdiagnosed as AD.
Genetic conditions which present with atopic dermatitis-like
symptoms must be considered in cases with unusual presentation.
Those involving the epidermis and adnexae include ichthyosis
vulgaris, a common phenotype whose limits are blurred with those of
AD, as recently demonstrated by molecular genetics [2]. More
rarely, several genetic types of hypohidrotic ectodermal dysplasia,
where genes are important during development for TNFα signaling
[3], carry symptoms like atopic eczema. Those involving the immune
system include the common IgA primary deficiency, but also rare
phenotypes such as the Wiskott-Aldrich syndrome, SCID and hyper IgE
syndrome (Job-Buckley). Especially, hyper IgE syndrome is
frequently confused clinically with atopic dermatitis. In infants,
recurrent scalp staphylococcal abscesses are a good marker of the
disease and later the coarse facial appearance is also diagnostic
when associated with recurrent, deep, mostly staphylococcal
infections [4].
Comel-Netherton syndrome is an inherited disorder associated
with atopic dermatitis-like symptoms which involves both the immune
system and skin, due to the lack of a serine protease inhibitor
LEKTI, physiologically expressed in the stratum granulosum of the
epidermis and in thymus epithelium. Comel-Netherton syndrome often
presents in childhood with a failure to thrive and erythroderma,
but can also have features of flexural atopic dermatitis with
associated peripheral desquamation. Hair defects (bamboo hairs) are
diagnostic, but immunohistochemistry staining of a skin biopsy has
recently been undertaken to detect the absence of LEKTI, the
protein encoded by the defective SPINK 5 gene [5].
After ruling out these unusual conditions which may present with
eczema, assessment of previous therapies, both successful and
unsuccessful, is essential and this will influence the severity
grading of the disease. Experience suggests that treatment failure
in atopic dermatitis is often associated with inadequate compliance
and that bad communication of therapeutic objectives adversely
affects the correct use of established treatments. A suitable
method to assess the severity of atopic dermatitis is the SCORAD
index, developed by the European Task Force on Dermatitis [6]. The
system has been validated in both adults and in children. In our
practice, it is the basis of a management schedule which includes
criteria for allergy testing as summarised in table 1 and a similar scheme is also part of the
classification adopted by the European task force on AD [7]. In the
case of moderate to severe disease, a validated stepwise allergy
diagnostic procedure using skin tests (to food, contact allergens
and atopens), and challenges if needed, preceded by intensive skin
care. If allergy testing is indicated but cutaneous tests are not
possible, specific IgE testing can be required first. Some
thresholds for specific IgE to food allergens have a good
predictive value of true allergy [8]. In any case, a careful
assessment of the relevance of test results is essential.
Table 1 Use of SCORAD index to allocate treatment and
decide allergy workup in children with AD
|
SCORAD
|
Severity
|
Treatments
|
|
< 15
|
Minor/mild
|
- Emollients, counselling
- (including diet).
|
|
15-40
|
Moderate
|
- Topical steroids, plus/minus macrolactam derivatives (> 2
years); anti H1 agents and antibiotics for flares.
- Allergy work-up if more than 30 g/month of topical
steroids
|
|
> 40
|
Severe
|
- Compliance assessment; Allergy workup and strict allergen
avoidance if relevant
- Consider hospitalisation if dermatological treatment
ineffective.
- Phototherapy and systemic immunosuppressive treatments
exceptionally needed
|
Recommendations for allergy testing in children with AD
Without testing, it makes sense to implement avoidance on a
probabilistic basis for example in the case of house dust mite,
which is the most prevalent allergen in western households.
However, testing remains mandatory to analyse the role of food or
contact allergens.
Allergy testing has both benefits and drawbacks. Benefits
include making a clear distinction between allergy and
sensitisation at challenge tests. It will allow for a better
avoidance when such a demonstration of true allergy has been
carried out. Limits concern the variable or in some cases
near-absent IgE dependency of the disease, e.g. the benefit of
allergy testing in atopic dermatitis may not be as apparent as in
allergic rhinitis when efficient hyposensitization follows.
Furthermore, test procedures are time-consuming and costly, and
interpretation is not always straightforward. Allergy testing
during a flare-up often gives uninterpretable results (angry back
or anergy). It may not always be possible to stop the current
therapy, which if continued could give false negative tests. Not to
mention that reading requires experience, good lighting and
interpretable controls.
The main issue in infants and young children concerns food
allergy and its relevance to eczema. Around one-third of children
with atopic dermatitis referred to a secondary care clinic have at
least one positive immediate reaction to a food [9]. Egg is the
most frequently encountered allergen, followed by either peanuts or
cow’s milk. Tolerance is most likely to develop with milk, then egg
and least with peanuts. Delayed reactions as may occur with milk
are difficult to detect, even using patch tests with food allergens
in addition to skin prick tests. The Finnish experience with patch
testing with foods shows clearly that patch testing with milk can
increase the number of cases detected [10].
How relevant for eczematous lesions are food allergens? The
careful study by Niggemann and colleagues [11] tried to address
this, based on immediate and late reaction results to food
challenges. Of 77 children with positive food challenges, 39 had
early type I reactions, whereas 12 had late reactions and 17
combined early and late reactions. Early type I reactions were
associated with skin (urticaria), respiratory and gastrointestinal
symptoms. Late reactions were skin restricted (exacerbation of AD).
Combined reactions were either skin restricted (early urticaria
followed by exacerbated AD) or associated early GI symptoms and
later exacerbation of AD.
The effect of avoiding documented food allergens on the severity
of atopic dermatitis is not fully known. Food allergy is clearly an
aggravating factor in a subset of patients. In hospital pediatric
practice it is rarely a causative factor, because elimination diets
in isolation do not cure patients. Some eczema patients outgrow
their food allergy yet still have eczema. The reverse is also seen,
e.g. urticarial rashes following egg consumption without remaining
eczema. Thus, diet management should not be considered as the only
endpoint in disease management and allergy testing is only included
as part of second-line management in young children in our current
approach.
Is it possible to simplify testing procedures, especially for
food allergens?
If guidelines for testing procedures in AD children are needed,
their simplification would be welcome. The ‘gold standard’ for food
allergens still remains the double-blind placebo-controlled food
challenge introduced by Sampson [12], but single-blind challenges
are also helpful. Tests can be done at a day hospital, the patient
having stopped anti-histamines five days beforehand. It is
essential to clear the eczema with prior intensive treatment to
assess food challenges properly.
Labial food challenge [13] (LFC) might be an alternative to
classic food challenge, particularly when testing egg and peanut
allergy. A drop of commercial food extracts or crushed food
re-suspended in saline is applied to the lower lip. The result can
be read after 15 minutes. Grading of the LFC is as follows: [1]
swelling of the lip [2] erythema of the buccal area of the lip [3]
contiguous urticaria [4] edema of the cheek, rhinitis and watery
eyes and [5] systemic reaction. The test is simple and fast, but
has a low sensitivity. It may be a useful screening test in busy
clinics. However an international standardisation of the test and
its validation is needed. For patch tests, a ready-to-use patch
test to cow’s milk has been developed recently [14] and exhibits a
promising good sensitivity and specificity.
My personal approach with adults
The persistence into adulthood of AD can lead to a wide spectrum of
disease severity. It is also becoming more and more common to
diagnose AD in adults and even in elderly patients without a known
personal history of eczema. In all these patients, it is important
to determine if skin inflammation is primarily driven by allergy to
atopens or contact allergens, or by other factors. In many patients
with long lasting disease and poor response to topical treatments,
including the newly introduced topical macrolactam
immunosuppressants, auto-inflammation is probably the major force
driving eczema. The groups of A Scheynius and P Schmid-Grendelmeier
have already shown a mechanism of cross reactivity between
superoxide dismutase in yeasts and human cells which can perpetuate
auto-immunity [15]. How much of auto-inflammation is in a patient’s
skin would be the key question to making a good therapeutic choice.
It is indeed clear that avoidance of proven allergies may not be
sufficient in severe patients, who, moreover, are not amenable to
skin testing due to the severity of their disease. If occupational
allergy is not in cause, an option which is not always easy to
clear, my personal preference, if well managed topical treatments
and phototherapies fail, including supervision of treatment under
inpatient care, or if disease recurrence or worsening occurs after
several attempts, is to start an immunosuppressive treatment,
cyclosporine 300 mg/day usually in young adults or azathioprine
(100 mg/d) or methotrexate (15 mg/week) after 40 years of age [16,
17], under strict clinical and biological monitoring for 6 to 24
months, in order to switch again to local treatments and retest the
patients. This approach may work if other variables, including
indoor allergen avoidance and psychological interventions, are also
managed during the period of systemic treatment, which allows the
patient a kind of break in his suffering.
Can allergy testing offer clues to the aetiology of atopic
dermatitis and other atopic disorders?
Based on the interpretation of the role of allergens in infantile
eczema, several propositions have been made concerning its
pathogenesis. Most pediatricians consider that food allergy is the
most important factor, skin symptoms being only considered as the
target of the effector arm of allergy. AD in infants may also
involve the cutaneous expression on skin of a more mysterious
atopic diathesis, also fitting this inside-outside hypothesis.
However, if sensitisation to external agents is causative, the
primary permissive defect may involve the skin. The hypothesis that
infantile atopic dermatitis is merely the expression of increased
skin penetration of allergens, corresponding to the penetration
phase of the disease, has been proposed [18]. A strong argument is
that the majority of infants with AD below the age of one year,
without any other sensitization criteria (no detectable specific
IgE, no positivity to skin prick tests), have a delayed eczematous
reaction to aeroallergens such as house dust mites or pollens at
skin patch tests. The elicitation of positive patch tests decreases
with age, reflecting the delayed maturation of the epidermal
barrier in atopic infants. This “penetration syndrome” step is
probably underestimated given the importance of aeroallergens in
the “atopic march” leading from AD to asthma and rhinitis.
Mouse models also show that it is possible to produce
sensitisation through the skin leading to asthma [19]. Food
allergens are probably of less importance than aeroallergens,
because acquired tolerance is seen in most cases after infancy and
childhood.
References
1 Coustou D, Leaute-Labreze C, Bioulac-Sage P,
Labbe L, Taieb A. Asymmetric periflexural exanthem of
childhood: a clinical, pathologic, and epidemiologic prospective
study. Arch Dermatol 1999; 135: 799-803.
2 Palmer CN, Irvine AD, Terron-Kwiatkowski A,
et al. Common loss-of-function variants of the epidermal
barrier protein filaggrin are a major predisposing factor for
atopic dermatitis. Nat Genet 2006; 38: 441-6.
3 Smahi A, Courtois G, Rabia SH,
Doffinger R, Bodemer C, Munnich A, Casanova JL,
Israel A. The NF-kappaB signalling pathway in human diseases:
from incontinentia pigmenti to ectodermal dysplasias and
immune-deficiency syndromes. Hum Mol Genet 2002; 11: 2371-5.
4 Buckley RH. The hyper-IgE syndrome. Clin Rev Allergy
Immunol 2001; 20: 139-54.
5 Bitoun E, Micheloni A, Lamant L, et al.
LEKTI proteolytic processing in human primary keratinocytes, tissue
distribution and defective expression in Netherton syndrome. Hum
Mol Genet 2003; 12: 2417-30.
6 Kunz B, Oranje AP, Labreze L, Stalder JF,
Ring J, Taieb A. Clinical validation and guidelines for
the SCORAD index: consensus report of the European Task Force on
Atopic Dermatitis. Dermatology 1997; 195: 10-9.
7 Darsow U, Lubbe J, Taieb A, Seidenari S,
Wollenberg A, Calza AM, Giusti F, Ring J,
European Task Force on Atopic Dermatitis. Position paper on
diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol
Venereol 2005; 19: 286-95.
8 Celik-Bilgili S, Mehl A, Verstege A,
Staden U, Nocon M, Beyer K, Niggemann B. The
predictive value of specific immunoglobulin E levels in serum for
the outcome of oral food challenges. Clin Exp Allergy 2005; 35:
268-73.
9 Eigenmann PA, Calza AM. Diagnosis of IgE-mediated
food allergy among Swiss children with atopic dermatitis. Pediatr
Allergy Immunol 2000; 11: 95-100.
10 Isolauri E, Turjanmaa K. Combined skin prick and
patch testing enhances identification of food allergy in infants
with atopic dermatitis. J Allergy Clin Immunol 1996; 97(1 Pt 1):
9-15.
11 Niggemann B, Reibel S, Wahn U. The atopy patch
test (APT)- a useful tool for the diagnosis of food allergy in
children with atopic dermatitis. Allergy 2000; 55: 281-5.
12 Sampson HA, McCaskill CC. Food hypersensitivity and
atopic dermatitis: evaluation of 113 patients. J Pediatr 1985; 107:
669-75.
13 Rance F, Dutau G. Labial food challenge in children
with food allergy. Pediatr Allergy Immunol 1997; 8: 41-4.
14 Kalach N, Soulaines P, de Boissieu D,
Dupont C. A pilot study of the usefulness and safety of a
ready-to-use atopy patch test (Diallertest) versus a comparator
(Finn Chamber) during cow’s milk allergy in children. J Allergy
Clin Immunol 2005; 116: 1321-6.
15 Schmid-Grendelmeier P, Fluckiger S, Disch R,
Trautmann A, Wuthrich B, Blaser K, Scheynius A,
Crameri R. IgE-mediated and T cell-mediated autoimmunity
against manganese superoxide dismutase in atopic dermatitis. J
Allergy Clin Immunol 2005; 115: 1068-75.
16 Samochocki Z, Owczarek W, Zabielski S. Can
atopy patch tests with aeroallergens be an additional diagnostic
criterion for atopic dermatitis? Eur J Dermatol 2006; 16(2):
151-4.
17 Goujon C, Berard F, Dahel K, Guillot I,
Hennino A, Nosbaum A, Saad N, Nicolas JF.
Methotrexate for the treatment of adult atopic dermatitis. Eur J
Dermatol 2006; 16(2): 155-8.
18 Taieb A. Hypothesis: from epidermal barrier dysfunction
to atopic disorders. Contact Dermatitis 1999; 41: 177-80.
19 Spergel JM, Mizoguchi E, Brewer JP,
Martin TR, Bhan AK, Geha RS. Epicutaneous
sensitization with protein antigen induces localized allergic
dermatitis and hyperresponsiveness to methacholine after single
exposure to aerosolized antigen in mice. J Clin Invest 1998; 101:
1614-22.
|
Version imprimable
Version PDF