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The role of food allergy in atopic dermatitis

Matthew Greenhawt, M.D., M.B.A.


ABSTRACT
Atopic dermatitis (AD) affects 10% of children. Food allergy is a known provoking cause of AD in a subset of affected
children. A literature search of PubMed and Medline was conducted to review the epidemiology and pathophysiology of AD,
with special focus on the role of food allergy in the development of AD, its management, and its long-term preventive strategies.
A literature search of PubMed and Medline was conducted. Food allergens readily provoke AD in 35% of patients, as proven
through double-blind placebo-controlled food challenge studies. Milk, egg, wheat, soy, and peanut account for 75% of the cases
of food-induced AD. However, the positive predictive values of the parental history, skin-prick tests, or serum tests for detecting
food-specific IgE are low, making these unsuitable for use as single diagnostic modalities. Therefore, the use of a food challenge
test is very helpful in objectively confirming the history or positive tests. Elimination diets are often helpful in challenge-proven
cases, but care must be taken to evaluate the nutritional status of the child. There are few effective long-term strategies to
prevent the development of food allergeninduced AD. Early onset of AD has been shown to be a risk factor for the development
of other allergic diseases, including other food allergy/sensitization, as part of the atopic march. Treatment of other causes of
AD, such as barrier dysfunction and cutaneous infection, are of equal importance to food allergen avoidance. Food allergy is
an important provoking cause of AD, but it is only relevant in 35% of affected individuals.
(Allergy Asthma Proc 31:392397, 2010; doi: 10.2500/aap.2010.31.3393)

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topic dermatitis (AD) is a chronic relapsing inflammatory skin disease commonly associated
with atopy. It affects up to 10% of children.1,2 The
characteristic rash in AD has a typical distribution,
found in the antecubital and popliteal fossas, wrist
creases, scalp, eyelids, and flexor surfaces. AD is frequently the initial manifestation of atopy and often
affects very young children early within the 1st year of
life. Many children who develop AD go on to develop
other allergic diseases such as food allergy, asthma, or
allergic rhinitis (the atopic march).3 The clinical features of AD are well described and include, pruritus, a
relapsing eczematous rash typically found over flexor
surfaces, and a personal history of atopy. Minor features include elevated serum IgE, cutaneous skin infection (Staphylococcus, Streptococcus, or fungus); Dennie-Morgan lines, keratoconus, allergic shiners, white
dermatographism, ichthyosis, nonspecific hand/food

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From the University of Michigan Food Allergy Center, Division of Allergy and
Clinical Immunology, The University of Michigan Medical School, The University of
Michigan Health Systems, Ann Arbor, Michigan
Presented at the Eastern Allergy Conference, Palm Beach Florida, May 7, 2010
Received nonfinancial research support from the Food Allergy & Anaphylaxis Network
Disclosures/Conflicts: The author had nothing pertinent to this review
M. Greenhawt received speaking honorarium from Phadia, is a member of the medical
advisory team for Kids With Food Allergies, and is a member of speakers bureau for
Nutricia and Sepracor
Address correspondence and reprint requests to Matthew Greenhawt, M.D., M.B.A.,
The University of Michigan Food Allergy Center, Division of Allergy and Clinical
Immunology, The University of Michigan Medical School, The University of Michigan Health Systems, 24 Frank Lloyd Wright Drive, Lobby H-2100, Box 442, Ann
Arbor, MI 48106
E-mail address: mgreenha@med.umich.edu
Copyright 2010, OceanSide Publications, Inc., U.S.A.

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dermatitis, and cheilitis.2 The purpose of this article is


to review the epidemiology, pathophysiology, and immunobiology of AD and to discuss the specific role of
food allergy in the development AD, its management,
and long-term preventive strategies.

PREVALENCE
Most studies suggest that the prevalence of AD is
high and the incidence is increasing, which may mirror
the overall increase in atopy among the population. A
large Danish twin concordance study found that the
rates increased from 3% between 1960 and 1964 to 7%
between 1975 and 1979.4 A 1992 European cross-sectional study confirmed a prevalence rate of 15.6%.5 A
similar study of U.S. children aged 59 years found a
rate of 17%.6 Two studies from Japan found an 11.2%
point prevalence of AD in 1st graders and 6th graders
and a rate of 24% among children aged 5 6 years.7,8
Theories to explain the rise in AD include a decrease in
the amount of children who are exclusively breast-fed,
an overall increased awareness of AD, increased exposure to air pollution, and increased exposure to allergens.9,10
THE ROLE OF IgE AND CYTOKINE
IMMUNOBIOLOGY IN AD
Two distinct subtypes of AD have been identified.
The extrinsic subtype is associated with elevated serum IgE levels in up to 80% of affected patients,
whereas the intrinsic subtype lacks this and also is not
associated with allergen sensitization.9,11 Both subtypes are associated with peripheral eosinophilia.12

IgE-mediated responses in AD provoke pruritus, erythema, and mediator release from mast cells.9 Cyclic
adenosine monophosphatephosphodiesterase expression in leukocytes taken from patients afflicted with
AD is overactive, which contributes to increased IgE
production and increased IL-4 secretion.13 Similarly,
increased CD86 expression on B cells of patients with
AD compared with controls also promotes increased
IgE production.14 There is increased expression of
high-affinity IgE receptor (FcR-1) on Langerhans cells
and inflammatory dendritic epidermal cells, resulting
from increased FcR-1 -chain synthesis.15 Both cell
types are highly effective at antigen presentation and
are highly efficient at activating TH2 cells and inducing
further T-cell proliferation specific to particular antigen.16 Inflammatory dendritic epidermal cell stimulation through FcR-1 promotes more TH1 cytokine release, as opposed to FcR-1 stimulation on Langerhans
cells.17
Although food allergy is usually a type I hypersensitivity, involving IgE, AD is a mixed IgE and cellularmediated event, with a mechanism mediated through
T cells. However, the cytokine profile expressed by
these T cells in acute AD is characterized by IL-4,
IL-5, and IL-13, a TH2 milieu similar to that seen in
IgE-mediated reactions.1,18 T-cell cytokine expression more characteristic of delayed-type hypersensitivity involves interferon and IL-2.19,20 Several studies have shown a link between food ingestion,
symptom development, and release of specific cellular
markers that are elevated in patients with AD. Sampson noted that children with AD and food-specific IgE
undergoing challenge to that food had a detectable
elevation of plasma histamine levels compared with
control patients.21 He later showed that chronic ingestion of allergenic foods was associated with higher
spontaneous basophil histamine release in cell cultures
of patients with AD compared with controls.22 Suomalainen and Magnarin showed increased eosinophil
granule release in AD patients undergoing food challenge and food-induced symptoms correlated to
plasma eosinophil activation in these patients.23,24 A
recent Korean study suggested that elevated peripheral eosinophil counts may aid as a predictive tool in
the evaluation of patients with AD triggered by food
allergy, and showed a significant decrease in the eosinophilia after following a milk elimination diet in
patients with milk-triggered AD.25 Several groups
have described food-specific T cells reactive to casein,
ovalbumin, and peanut in serum of patient with
food-induced AD.26 29 Food-specific T cells have
been cloned from both affected and normal skin of
patients with AD. In addition, cutaneous lymphocyte antigen bearing T cells have been found in high
percentages in milk-allergic patients with AD but
not in milk-allergic patients without milk-induced

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AD.26,30 The role of cutaneous lymphocyte antigen is


to interact with E-selectin to direct the homing of T
cells to skin, which highlights a part of the mechanism of how these food-specific T cells are directed
to the skin, as well as how unknown or unrecognized
exposure may result in a specific T-cell sensitization.10,29,31,32 Barrier dysfunction, through loss-offunction mutations in the gene filaggrin (FLG), an
epidermal structural protein that is part of the natural moisturization factor, is an emerging risk factor
associated with early onset of severe AD and increased allergen sensitization, although no specific
role pertaining to food allergen sensitization has
been identified.33,34 FLG-deficient patients carry an
odds ratio of 1.91 for the development of allergic
sensitization.35

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DEFINING FOOD ALLERGY IN AD


Food allergy involves a combination of sensitization,
the presence of allergen-specific IgE (sIgE; positive skin
test or serum test), and symptomatic reactivity attributable to that particular food within 2 4 hours of ingestion.36 Sensitization without a history of reactivity
attributable to that particular food may be clinically
irrelevant, and thus the diagnosis of food allergy can
not be made by just a positive skin or blood test alone.
In patients with AD, nearly 80% will have positive food
(or pollen) sIgE, often against multiple foods, although
very few are clinically relevant.3739 Therefore, caution
must be taken before considering a positive test in the
setting of AD. Although negative skin tests confer upward of a 95% negative predictive value (NPV) for an
allergy, positive tests have a positive predictive value
(PPV) of only 60%.32,40,41 Serum tests (e.g., ImmunoCAP [Phadia US, Portage, MI], TurboRAST [Agilent
Technologies, Santa Clara, CA], and Immulite [Siemens Medical Solutions Diagnostics, Fort Madison,
IA]) have similar NPVs and slightly less PPVs.32,40,41 A
recent, large meta-analysis commissioned by the National Institutes of Health highlighted the heterogenicity of how food allergy diagnoses are made and recommended a combination approach involving sIgE
and a history of clinical reactivity, confirmed through
food challenge.42 Challenge may not be necessary in
cases with a strong supporting history of reaction,
where the ImmunoCAP or skin test wheal exceeds a
certain size (called the 95% cutoff diagnostic decision
point).36,41,43 45
THE ROLE OF FOOD ALLERGY IN AD
The first documented report of food allergy as a
provoking factor in AD was by Schloss in 1915, describing eczematous eruption in response to food, with
improvement on elimination.46 Since then numerous
case reports and double-blind, placebo-controlled food

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Table 1 Prevalence of food allergy confirmed by double-blind placebo-controlled food challenge in patients
with known atopic dermatitis
Authors
Sampson73
Burks51
Eigenmann39
Burks52
Niggemann49
Eigenmann58
Breuer47

Year

Allergy (%)

Selected for Presence of


Potential Food Allergy

Country

1985
1988
1998
1998
1999
2000
2004

113
46
63
165
107
74
64

56
33
37
39
51
34
46

Yes
Yes
No
Yes
Yes
No
Yes

United States
United States
United States
United States
Germany
Switzerland
Germany

Source: Adapted and modified from Ref. 50.

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challenge (DBPCFC) studies have shown that AD is


sometimes closely associated with the development of
food allergy.10,32 However, making an accurate diagnosis can be difficult because one must exclude other
potential confounding factors influencing the subjective interpretation. The delayed onset of symptoms in
AD (6 hours to as long as 48 hours after challenge) makes
observation difficult, although up to 25% will present
within 12 hours of ingestion.47,48 Moreover, results from
a single challenge may be different compared to what
may happen with chronic exposure.41 Studies show that
the parental history of a particular food causing AD has
a low PPV.47,49 Similarly, there is a low correlation of
positive skin and/or serum tests and challenge results.38,47,50 Chronically eczematous skin is prone to nonspecific irritation and false positive skin test results. Serum testing can be falsely positive in the setting of a
baseline elevation of IgE, resulting in a nonspecific binding.40 Therefore, caution must be taken in interpreting
such diagnostic modalities in isolation in the patient with
AD.32,41 As confirmed through several studies, cows
milk, hens eggs, wheat, soy, and peanut are responsible
for 75% of food-associated AD.51,52
Early challenge-based studies establishing the role of
food allergens were plagued by poor design and questionable effect of the food(s) involved.5355 There are a
number of later studies that provide good evidence
that a subset of children with AD are affected by food
allergy. Sampson and Scanlon, in a prospective 4-year
follow-up study of 34 children that used DBPCFCguided food elimination, found that 17/34 improved
on such a diet.56 Lever et al., using a dermatologybased referral population, showed that a randomized
controlled trial of egg elimination in egg-sensitized
children with AD led to improvement in the amount of
overall affected skin and symptom scores versus control patients without AD.57 Burks et al., in two studies
of patients with moderate-to-severe AD referred to an
allergy clinic, found that 33 and 38.7% of children
undergoing DBPCFC reacted to foods.51,52 Eigenmann

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et al., in two very similar studies of university-based


dermatology patients, found that in patients prescreened with ImmunoCAP and skin tests, 37 and
33.8% (respectively) had a relevant food allergy determined by challenge.39,58
More recently, Breuer found that in 64 children with
AD selected from a university dermatology clinic, 46%
reacted to selective foods on challenge, but, more importantly, the PPV for the presence of food-specific IgE
or atopy patch test in determining a positive food
challenge was only 64%.47 In contrast, however,
Thompson showed that in 23 children with AD presenting to a university dermatology clinic with foodspecific complaints, aggressive skin treatment despite
positive sensitizations significantly decreased parental
concern for food allergy as measured by a pre- and
posttreatment questionnaire.59 Table 1 summarizes the
results of several challenge-based studies determining
a rate of AD affected by food allergy. The overall rate
is best estimated that 35 40% of food-sensitized AD
will have a relevant food allergy on challenge.

EVALUATION OF THE AD PATIENT WITH


SUSPECTED FOOD ALLERGY
One should start by taking a thorough history, which
includes specific delineation of which suspected food
exposures actually are attributed to directly causing a
flare within hours after ingestion, the extent that particular food is consumed in the present diet, and the
extent that elimination of that food has helped, as well
as the extent of skin treatment that has been used to
help treat the AD. The history, despite a low PPV, is
still a helpful guide to understand the familys concerns, treatments already tried, and to rule in likely
food allergens. It is recommended to skin/serum test
only to relevant exposures supported by the history,
because of high false positive rates and low PPVs of
these tests. The use of screening panels that include
items unlikely to be contributing factors should be
discouraged.

velop recurring wheezing by age the of 5 years.3,10,32


Unfortunately, a subset of children will develop noneczematous food allergy. However, 33% will outgrow selected foods over 13 years with strict elimination (milk and egg, as opposed to peanut).56,65 68 It
has been observed that very often skin tests will
remain positive even in children who tolerate ingestion of that food, but the ImmunoCAP value generally does decrease in proportion to tolerance.32,69 To
date, no good preventative strategy exists despite
numerous suggested approaches.70 These include
the use of probiotic supplements, use of extensively
hydrolyzed casein formula in high-risk infants,
breast-feeding with selected maternal allergen
avoidance, and delayed introduction of solids.62,70 72
Much attention at present is being focused on the
role of reduced epidermal barrier (loss of function
fillagrin mutation) and how this may affect early
food allergy sensitization.35

In managing positive test results, consider a trial of


short-term elimination of relevant triggers if this has
not been tried already, with a plan for a time-limited
interval assessment of the effect. Nutritional referral
is strongly recommended to support caloric needs
during allergen avoidance, and it should be clearly
understood that dietary removal is not without
strong consequences to both the nutrition of the
child and the quality of life of the family.60 Despite
reports of successful resolution of AD with food
elimination, a challenge is still recommended to rule
out a placebo effect or influence of another confounding variable. Evidence-based decision points
indicating 95% diagnostic cutoff values are available
for selected foods and can serve as a guide in deciding if challenge is appropriate.36 Caution should be
taken, however, in universally applying such cutoff
values to ones own patient population without fully
understanding the study population and its characteristics that helped determine these decision
points.61 Most importantly, practitioners should simultaneously be maximizing other treatment options besides dietary intervention, because AD is
multifocal in influence.62
APPROACH TO THE ORAL FOOD CHALLENGE
IN AD
It is generally recommended that the patient undergo a prolonged period of strict avoidance of the
suspected food (2 weeks), while at the same time
aggressive and intense skin therapy should be initiated to clear the skin as best possible in preparation
for the challenge. It is acceptable to continue a lowpotency topical corticosteroid during the challenge
but only if necessary. However, antihistamine and
UV light therapy must be discontinued. Published
challenge protocols are available.50,63 One must be
able to observe the skin closely over the ensuing 48
hours, and, very often, patients are admitted to the
hospital so such observation is possible. It is highly
recommended to use a standardized skin scoring
system (e.g., SCORAD).64 Although any type of challenge can be used, the DBPCFC protocol is recommended to most objectively confirm the outcome.50,63

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CONCLUSION
A subset of children with AD have food allergy, but
a larger percentage have clinically irrelevant food sensitization. Care and caution must be undertaken when
evaluating the patient with AD suspected of having
food allergy, given poor PPV of both food sensitization, and parental histories. Food challenge is highly
recommended to confirm sensitization and to ensure
that a particular dietary avoidance is necessary. Attention must be paid to other confounding factors, such as
the role of cutaneous infection or genetically conferred
barrier dysfunction, and treatment options beyond dietary intervention should be maximized. In cases of
children allergic to eggs, wheat, and milk, the natural
history is to outgrow these sensitivities (as opposed to
peanut), although many children who develop AD at a
young age may develop other food sensitivities or
develop worsening food allergy with more classic
symptoms. Preventive strategies have not been well
established.

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RISKS FROM EARLY ONSET AD AND FOOD


ALLERGY PROGNOSIS
The atopic march is well described and is discussed in detail elsewhere.3 It is worth noting that in
patients with AD, up to 50% may develop other
atopic diseases by the age of 1 year (80% eventually);
35% with milk sIgE develop other food sensitization
by age the of 3 years; and 70% with egg white sIgE in
the setting of a positive family history of atopy de-

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ACKNOWLEDGMENTS
The author thanks James Baldwin, M.D., and Georgiana Sanders,
M.D., M.S., of the Division of Allergy and Clinical Immunology, The
University of Michigan Health Systems, for their assistance in reviewing this article.

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