Atopic dermatitis and skin disease

Does atopic dermatitis cause food allergy?

A systematic review
Teresa Tsakok, MRCP, MA,a* Tom Marrs, MRCPCH, MSc,b,c* Mahrose Mohsin, MD,d Susannah Baron, MRCP,d
George du Toit, FRCPCH,b,c Stephen Till, FRCP, PhD,c and Carsten Flohr, FRCP, FRCPCH, PhDa London and Canterbury,
United Kingdom

Background: The association between atopic dermatitis (AD) indicated that AD of earlier onset or increased persistence is
and food allergy (FA) is not fully understood, although a causal particularly associated with FA. Finally, one study found that AD
relationship has been suggested. This has important preceded the development of FA.
implications for prevention and treatment. Conclusions: This systematic review confirms a strong and
Objective: We aimed to review the association between AD and dose-dependent association between AD, food sensitization, and
FA, the effect of FA on AD severity, chronicity, and age of onset, FA. AD of increased severity and chronicity is particularly
and the temporal relationship between the two. associated with FA. There is also evidence that AD precedes the
Methods: Medline and Embase were systematically searched development of food sensitization and allergy, in keeping with a
from inception to November 2014 for studies investigating both causal relationship. (J Allergy Clin Immunol 2016;137:1071-8.)
AD and FA.
Results: Sixty-six studies were identified. Eighteen were Key words: Atopic dermatitis, eczema, food allergy, food
population-based, 8 used high-risk cohorts, and the rest sensitization
comprised patients with either established AD or FA. In
population-based studies, the likelihood of food sensitization was Atopic dermatitis (AD; synonyms: atopic eczema and eczema)
up to 6 times higher in patients with AD versus healthy control is the most common chronic inflammatory disorder of the skin,
subjects at 3 months of age (odds ratio, 6.18; 95% CI, 2.94-12.98; affecting more than 20% of children in industrialized countries1-3
P <.001). Other population-based studies reported that up to 53% and up to 3% of adults.4 Although up to two thirds of patients with
of subjects with AD were food sensitized, and up to 15% AD do not show sensitization to environmental allergens or
demonstrated signs of FA on challenge. Meanwhile, studies foods,5 AD is often associated with other atopic diseases, such
including only patients with established AD have reported food as IgE-mediated food allergy (FA),6 and around one third of all
sensitization prevalences up to 66%, with challenge-proven FA children with early-onset AD progress through the so-called
prevalences reaching up to 81%. Sixteen studies suggested that atopic march.7 It has been suggested that food allergen recogni-
FA is associated with a more severe AD phenotype. Six studies tion via antigen-presenting cells in eczematous skin might act
as an important mediator of food sensitization and FA.8,9
From aSt John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust This systematic review critically appraises the current body of
and King’s College London; bthe Department of Children’s Allergies, Guy’s and evidence according to the Bradford Hill principles10 of inferring cau-
St Thomas’ NHS Foundation Trust, London; cthe Division of Asthma, Allergy sality from clinical studies, to further assess a potential causal
and Lung Biology, King’s College London; and dthe Department of Dermatology, pathway between AD and IgE-mediated FA. These principles take
East Kent Hospitals University NHS Foundation Trust, Canterbury.
*These authors contributed equally to this work.
into account (1) the strength of the association between AD and
Disclosure of potential conflict of interest: S. Baron has served as a consultant for Abbvie, FA in selected and unselected populations; (2) whether a dose-
receives payment for lectures regarding psychodermatology training and also received response effect is demonstrated, with more severe AD showing a
travel support from Abbvie. G. du Toit receives research funding from National greater association with FA, and equally whether FA can predict
Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health
age of onset or chronicity of AD; and (3) the temporal sequence of
(NIH), Food Allergy & Research Education (FARE), the MRC & Asthma UK Centre,
the UK Department of Health through the NIHR, the National Peanut Board (NPB), events—in other words, whether AD or FA arises first among infants.
and Osem and received grants from UK Food Standards Agency (FSA) during the
conduct of the study. S. Till serves as a consultant for ALK-Abello, receives payment
for lectures for Thermo Fisher, and receives unrestricted research funding from ALK-
METHODS
Abell o. C. Flohr serves as a consultant for Roche/Regeneron and has received This systematic review was registered on the International Prospective
payments for lecture from Nutricia. The rest of the authors declare that they have no Register of Systematic Reviews (PROSPERO),11 and Preferred Reporting
relevant conflicts of interest. Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance12
Received for publication January 21, 2015; revised September 28, 2015; accepted for was followed throughout. Medline and Embase were searched from inception
publication October 27, 2015. to the end of November 2014, with no language limits imposed. Search terms
Available online February 18, 2016. included the Cochrane Skin Group strategy for AD combined with terms
Corresponding author: Carsten Flohr, FRCP, FRCPCH, PhD, St John’s Institute of describing FA, food hypersensitivity, and food sensitization both overall and
Dermatology, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH,
to specific foods (including milk, egg, peanut, tree nuts, wheat, sesame, and
United Kingdom. E-mail: carsten.flohr@kcl.ac.uk.
seafood). The full search strategy is available in the Methods section in this
The CrossMark symbol notifies online readers when updates have been made to the
article such as errata or minor corrections article’s Online Repository at www.jacionline.org. This online search was
0091-6749/$36.00 supplemented by an extensive hand search of the literature and
Ó 2016 American Academy of Allergy, Asthma & Immunology communication with individual authors where necessary. The Medline search
http://dx.doi.org/10.1016/j.jaci.2015.10.049 identified 339 articles, the Embase search identified 1704 articles, and the

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control subjects, P < .05) during adolescence, no significant

Abbreviations used differences persisted for milk and egg sensitization.
AD: Atopic dermatitis Investigations among younger children reflected the higher
aOR: Adjusted odds ratio prevalence of milk and egg allergies within that age group (Fig 1).
DBPCFC: Double-blind placebo-controlled food challenge
Two high-quality population-based articles were based on the
FA: Food allergy
FLG: Filaggrin
Isle of Wight allergy birth cohort (n 5 1456), with Arshad et al16
OFC: Open food challenge reporting that at 4 years of age, the highest independent
OR: Odds ratio risk factor for AD was SPT sensitization to peanut (odds ratio
PPV: Positive predictive value [OR], 4.65; 95% CI, 1.02-21.34). There was also a positive
sIgE: Specific IgE association with egg sensitization that just missed statistical
SPT: Skin prick test significance (OR, 6.08; 95% CI, 0.88-42.01), likely because of
UK: United Kingdom a lack of power while a proportion of children were outgrowing
their egg allergy.
Meanwhile, the United Kingdom (UK) cross-sectional study
by Peroni et al17 of 1402 children aged 3 to 5 years found that egg
hand search identified a further 34 articles (see Fig E1 in this article’s Online
sensitization on SPTs was strongly associated with AD (OR, 9.53;
Repository at www.jacionline.org).
95% CI, 2.40-37.82), whereas milk sensitivity was not (OR, 1.26;
Two authors (T.T. and M.M.) independently screened all abstracts for
suitability, resulting in 164 articles that were read in full. Discrepancies in the 95% CI, 0.27-6.00).
assessment were resolved through discussion with a third author (CF). Article The Danish Allergy Research Cohort18 (DARC) monitored
selection for further analysis was based on the following inclusion criteria: (1) children from the age of 3 months to 6 years, undertaking food
the majority of subjects being less than 18 years old and (2) at least a challenges in children with food-specific SPT responses of
proportion of subjects having AD and an overlapping proportion of subjects 3 mm or greater/sIgE levels of class 1 or greater, and also in
having food sensitization and/or FA, as evidenced by at least one of skin prick children with parent-reported adverse reactions to food. The
testing (SPT; standard cutoff, 3-mm wheal), serum specific IgE (sIgE; investigators reported that 18 (15%) of 122 children with AD
standard cutoff, 0.35 kU/L), open food challenge (OFC), or double-blind demonstrated symptoms on food challenge, and that 52% of the
placebo-controlled food challenge (DBPCFC). Exclusion criteria were as
remainder were food sensitized. More recently, Flohr et al9
follows: (1) AD diagnostic criteria including SPT/sIgE sensitization to
analyzed those undergoing SPTs at 3 months within the Enquiring
common allergens, as well as typical skin findings; (2) FA evidenced only
by parent- or patient-reported symptoms; and (3) data referring to mixed food About Tolerance (EAT) study UK birth cohort (n 5 619),
and aeroallergen sensitization, with no separate values provided for food reporting that children with AD were significantly more likely
allergens. Furthermore, we excluded management guidance documents, than healthy control subjects to be sensitized to at least 1 of 6
reviews, intervention trials, and studies using animal models. foods (milk, egg, sesame, peanut, wheat, or cod), with an adjusted
Data were extracted from 66 selected articles using a predefined pro forma. odds ratio (aOR) of 8.53 (95% CI, 3.51-20.65; P < .001). This
Formal meta-analysis was considered neither feasible nor appropriate because association was independent of filaggrin (FLG) loss-of-function
of marked heterogeneity in study design, participants, and diagnostic criteria mutation inheritance. Equally, there was a positive association
for both FA and AD. Therefore we assigned a quality score to each article between AD and sensitization to individual foods, including
(maximum score, 3 points) based on AD diagnostic criteria (1 5 clear
egg (aOR, 9.48; 95% CI, 3.77-23.83; P < .001), milk (aOR,
validated criteria or physician’s diagnosis, 0 5 unclear diagnostic criteria or
9.11; 95% CI, 2.27-36.59; P 5 .002), and peanut (aOR, 4.09;
process), study size (1 5 > _500 subjects, 0 5 <500 subjects), and a modified
Newcastle-Ottawa score13 (1 5 > _4 of 5 points, 0 5 <4 points). Articles were 95% CI, 1.00-13.16.76; P 5 .05).
then ranked by quality score. Those with the same quality score were further In Figs 2 to 4, ORs for each of the major food allergens are
ranked by number of participants. presented in order of ascending age of participants at
cross-sectional analysis. Pooling of results between allergens
and beyond the first 6 years of childhood was not considered
RESULTS appropriate in view of the contrasting natural history of individual
Strength of association between AD and FA allergens, as well as the changes in association seen for each food
Population-based studies (see Table E1 in this allergen as a child becomes older.
article’s Online Repository at www.jacionline.org). High-risk cohort studies (see Table E2 in this article’s
Eleven population-based studies scored 3 points for quality, and Online Repository at www.jacionline.org). Eight articles
their results closely reflect the age groups of the children they were based on high-risk cohorts that recruited according to
investigated (Fig 1). parental atopy. The UK study (n 5 497) by Burr et al19 reported a
The largest study14 used a case-control design nested within significant association between AD arising before the patient’s
the consecutively recruited Barn (Children’s) Allergy Milieu first birthday and a positive SPT response to egg at 6 months
Stockholm Epidemiology (BAMSE) birth cohort (n 5 2256), (OR, 5.57; 95% CI, 2.70-11.5); this was even stronger at 1 year
reporting that 27% of patients with AD at 2 years had positive (OR, 7.57; 95% CI, 3.57-16.05).20
SPT responses to food (egg, 21%; peanut, 15%; milk, 8%; Three articles used the Melbourne Atopy Cohort Study
and cod, 2%). However, the investigators did not compare this (MACS) cohort (n 5 552), including the report by Lowe et al21
with sensitization amongst children without AD. The second- that food SPT-determined sensitization at 6 months was
largest study15 investigated SPT sensitization among 1501 older associated with an increased risk of AD (hazard ratio, 1.63;
children aged 12 to 16 years who were participating in the Danish 95% CI, 1.13–2.35) up to 7 years of age. This was in line with
Adolescent Odense Cohort (TOACS). Although a strongly other MACS data from Hill et al,22 who found that more patients
positive association was demonstrated between current AD and with AD had positive SPT responses to milk, egg, or peanut at 6
peanut sensitization (16.2% of patients with AD vs 0.5% of months (22% vs 5%, P < .001) and at 12 months (36% vs 11%,
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FIG 1. Egg/milk/peanut SPT sensitization among AD and control subgroups in population-based cohorts.

P <.001) than those without AD (see Fig E2 in this article’s Online Hill et al25 reported that 64% of those with AD commencing before
Repository at www.jacionline.org). Four years later, the same 3 months of age were sensitized to egg and/or milk and/or peanut,
group reported that 36% of infants with AD had a positive based on sIgE values greater than 95% of positive predictive value
food-related SPT response compared with 12% of infants without (PPV). The following year, de Benedictis et al26 compared the
AD (P < .001).23 allergic sensitization patterns associated with AD between the 12
Recently, Brough et al24 investigated whether AD and disease countries, reporting that positive sIgE levels to egg predominated
severity modified the strength of the association between in each country (53% in the UK), whereas milk sensitization was
environmental peanut protein exposure and the risk of peanut highest in Italy (48%) and peanut sensitization was highest in
sensitization and peanut allergy. Five hundred twelve American in- Australia (45%).
fants (<15 months old) with egg/milk SPT-determined Of note, 16 studies in patients with established AD reported
sensitization plus either parent-reported egg/milk allergy or both oral food challenge and sensitization data. However, many
parent-reported AD were recruited from the Consortium of Food failed to apply systematic criteria in determining who was eligible
Allergy Research (CoFAR) study (n 5 512). Environmental pea- for food challenges, limiting their insight. One of the largest
nut exposure was quantified from dust on the living room floor. studies27 in this category was performed in Finland and reported a
An association between environmental peanut exposure and the prevalence of 54% for milk allergy among 183 children with AD
likelihood of peanut sensitization or allergy was only seen in up to 3 years old.
participants with a history of AD. Indeed, a history of AD and Burks et al28 proposed a standard food SPT panel for patients
increased environmental peanut exposure in participants was with AD recruited from a pediatric allergy clinic in the United
found to increase the risk of both peanut sensitization (OR, 1.97; States. This group reported that of 165 participants aged between
95% CI, 1.26-3.09; P < .01) and peanut allergy (OR, 2.34; 95% 4 months and 22 years, 60% had at least 1 positive SPT response.
CI, 1.31-4.18) per log2 unit environmental peanut exposure in- The investigators then performed 266 DBPCFCs, and 39% of
crease. The effect for peanut sensitization was further augmented patients reacted to 7 foods (milk, egg, peanut, soy, wheat,
with a history of severe AD (OR, 2.41; 95% CI, 1.30-4.47; P <.01), cod/catfish, and cashew), accounting for 89% of the positive
although this was not observed for peanut allergy. challenge results.
Studies investigating FA and food sensitization Finally, Gray et al29 investigated 100 black or mixed-race
among children with established AD (see Table E3 in children who attended an urban Cape Town clinic with
this article’s Online Repository at www.jacionline. moderate-to-severe AD. The authors reported high rates of food
org). Thirty-four studies selected groups of patients with estab- sensitization (66%) and challenge-confirmed FA (44%), with
lished AD rather than taking a population-based approach, and egg and peanut being the most common allergens.
therefore are likely to have inflated prevalence estimates of atopy. Studies investigating AD among children with
Two investigations25,26 comprising more than 2000 subjects aged established FA (see Table E4 in this article’s Online
11.8 to 25.8 months from 12 countries were derived from the Early Repository at www.jacionline.org). Four investigations
Prevention of Asthma in the Atopic Child (EPAAC) study cohort. selected patients with established FA and then measured the
1074 TSAKOK ET AL J ALLERGY CLIN IMMUNOL
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FIG 2. ORs of egg sensitization in patients with AD, in ascending age order.

FIG 3. ORs of milk sensitization in patients with AD, in ascending age order.

prevalence of AD. Two of these focused on children with peanut association between the severity of a flexural rash (as determined
allergy and were particularly enlightening. by topical steroid use) in the first 6 months, and a history of peanut
Fox et al30 compared 133 patients with peanut allergy, 160 high- allergy and a positive peanut challenge result (P < .001 for both
risk control subjects with allergy to egg but not peanut, and 150 associations). When the same research group performed
low-risk control subjects with no known allergy. Cases and screening assessments in 834 infants to enroll those with egg
high-risk control subjects were recruited from an FA clinic, allergy and/or severe AD into the Learning Early About
whereas low-risk control subjects were recruited from children Peanut (LEAP) trial, a strong association between food
attending a general pediatric clinic with a nonallergic complaint. sensitization and AD severity was evident.32 When the infants
A parent-reported history of AD in the first year of life was highly were split into 3 SCORAD severity groups, increasing AD
prevalent among both peanut allergic patients (92%) and high-risk severity was associated with a higher likelihood of sensitization
control subjects (88%) but significantly less so among low-risk to peanut (Ptrend < .001), raw egg (Ptrend < .001), pasteurized
control subjects (42%, P < .001). egg (Ptrend < .001), milk (Ptrend 5 .001), and ‘‘any food’’
More recently, Brown et al8 investigated the role of FLG (Ptrend < .001).
mutations as a risk factor for peanut allergy. The study design In a group of Australian infants whose AD did not respond to
comprised 71 patients aged up to 18 years from the UK, Ireland, topical steroid therapy, the equivalent rates of SPT-determined
and The Netherlands with challenge-proven peanut allergy, and food sensitization were 83% at 6 months and 65% at 12 months.
1000 non–peanut-sensitized population control subjects. The relative risk estimates for SPT-determined food sensitization
Covariate analysis using both AD and FLG as predictors in the also rose with increasing AD severity as defined by topical steroid
logistic regression model demonstrated a strong association use in the first year of life.23
between AD and peanut allergy in patients with positive challenge In a later study by the same group, based on the Early
results (OR, 7.4; 95% CI, 4.1-13.7). The association between FLG Prevention of Asthma in the Atopic Child (EPAAC) cohort of
mutation inheritance and peanut allergy remained significant, 2084 infants with AD, the authors used regression analysis to
even after adjusting for a history of AD in early life (OR, 3.8; show that children with sIgE to milk, egg, or peanut (greater than
95% CI, 1.7-8.3; P < .001). 95% PPV cutoff) were more likely to have severe AD of early
onset up to 1 year of age (P < .001).25 Lastly, data from the South
African pediatric cohort (n 5 100)29 showed that 15 (30%) of 50
Is FA associated with AD of increased severity? children with moderate AD had FA, compared with 25 (50%) of
Twenty-two articles addressed the question of whether FA 50 of those with severe AD (P 5 .04).
affects AD severity. A UK population-based study9 among 619
exclusively breast-fed 3-month-old infants was the highest
quality article in this area, showing that the association between Is FA associated with AD of earlier onset and
AD and sensitization to milk, raw egg, cod, sesame, and peanut greater chronicity?
was significantly stronger in AD patients with SCORAD scores Six articles examined whether FA is associated with AD of
of greater than 20 (aOR, 25.60; 95% CI, 9.03-72.57; P < .001) early onset or increased chronicity, including the 2008 EPAAC
than in patients with SCORAD scores of less than 20 (aOR, article by Hill et al,25 as mentioned above. The best quality
3.91; 95% CI, 1.70-9.00; P 5 .001). study33 assessed the relationship between FLG status, AD, food
Four articles were awarded 2 quality points; for instance, the sensitization, and FA (inferred from symptom-based diagnosis)
case-control study by Lack et al31 found a trend toward an in patients up to 18 years of age on the Isle of Wight
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FIG 4. ORs of peanut sensitization in patients with AD, in ascending age order.

(n 5 1456). AD at 1 and 2 years of age was associated with both capture allergic sensitization at the earliest possible stage.
FA (OR, 6.04; 95% CI, 1.25-29.9; P <.001) and food sensitization Therefore all IgE levels exceeding 0.7 kUA/L were omitted in
(OR, 20.1; 95% CI, 4.40-54.50; P < .001) at 4 years and the risk analysis. AD at 2 years of age was associated with
sensitization at 18 years (OR, 18.2; 95% CI, 5.47-65.3; increased low-level sensitization to egg, milk, or both at 6 months
P < .001). In addition, AD at 4 years was linked to food (OR, 3.07; 95% CI, 1.44-6.55), 12 months (OR, 3.33; 95% CI,
sensitization at 10 years (OR, 6.9; 95% CI, 3.65-13.04; 1.60-6.96), and 24 months (OR, 1.74; 95% CI, 1.01-3.01).
P < .001) and at 18 years (OR, 3.82; 95% CI, 2.44-5.99; However, 35% of 6-month-old infants already had AD and
P < .001), supporting the hypothesis that early childhood AD were not excluded from the analysis, meaning that low-grade
raises the risk of food sensitization as a subsequent complication. sensitization might relate more to persistence of AD that is
Further support in this area comes from the retrospective already established, as opposed to newly arising AD. Further-
analysis by Ricci et al34 of 252 infants with AD, in which egg more, no follow-up data on clinical FA status were reported.
sensitization was associated with more persistent AD Four articles investigated cord blood sIgE, attempting to assess
(egg sensitized: 11.1 6 6.9 years mean duration vs non–egg- the possibility that food sensitization precedes the development of
sensitized: 8.3 6 6.9 years mean duration; P < .02). As described AD. The Avon Longitudinal Study of Parents and Children
above, the case-control study by Fox et al30 examining peanut (ALSPAC) cohort31 followed children until they had challenge-
allergy showed that parent-reported AD in the first year of life proven peanut allergy, but found no relationship with cord blood
was significantly less prevalent among low-risk control subjects peanut sIgE levels. Likewise, in the DARC cohort,37 food sIgE
recruited from general as opposed to FA clinics; furthermore, levels proved no better than total cord IgE levels in predicting
AD in low-risk control subjects was significantly later in onset AD within the first 18 months of life. Overall, the key message
and also less severe (P < .001). from these studies is that cord blood sIgE is rarely detectable
The Belgian Early Treatment of the Atopic Child and not a significant risk factor for FA, in line with the hypothesis
(ETAC) cohort (n 5 397)35 showed that egg and milk sIgE that AD precedes and is likely to drive food sensitization.
sensitization at enrollment was associated with persisting AD
(SCORAD score > 7) at 18 months’ follow-up (P 5 .006). Burks
et al28 showed that children with both positive SPT and DBPCFC DISCUSSION
responses had a significantly lower age of AD onset than patients This review investigates whether AD causes FA, according to
without positive responses (2 vs 7 months, P 5 .003). Finally, the the established Bradford Hill principles.10 We found a significant
South African study by Gray et al29 reported that onset of AD association between FA, food sensitization, and AD in both
before 6 months was a significant risk factor for FA (P 5 .002). selected and unselected populations. FA is associated with AD
of increased severity and chronicity. In addition, there is evidence
from a Danish population cohort showing that AD arises before
Is there a temporal relationship between the FA, as well as data from the Isle of Wight demonstrating
development of AD and FA? associations between early childhood AD and later food
Two articles18,33 described repeatedly examining for AD and sensitization and allergy.
food sensitization throughout childhood, and the DARC cohort18 Our systematic review protocol was registered online in
initiated this early enough to discriminate between the emergence advance, in keeping with PRISMA guidelines.12 Cognizant of
of AD and FA. Five hundred sixty-two participants were recruited the potential for bias in literature searching, we supplemented
at birth in the Danish general population and followed up at 3, 6, 9, the online search strategy with an extensive hand search to
12, 18, 36, and 72 months of age. All follow-ups except the maximize capture of relevant publications. However, this would
9-month visit included an interview, clinical examination, and not overcome inherent limitations, such as publication bias.
SPT/sIgE measurements. Where food-related symptoms were Sixty-six publications fulfilled our selection criteria, of which
declared, OFCs were undertaken. By 3 months of age, 2% of 12 scored 3 of 3 in our a priori independent quality grading.
the cohort was found to have signs of AD on examination, and The 66 selected articles represent 3% of the total number of
yet none of the participants demonstrated symptoms on OFCs articles identified through our online search and hand search.
(Fig 5).18 Among these, substantial methodological differences and study
Unfortunately, the Isle of Wight cohort33 only investigated heterogeneity (different age groups, sIgE/SPT cutoffs, and food
food sensitization among children whose families reported challenge protocols) precluded formal meta-analysis. Only 49
adverse food reactions before 4 years of age, preventing a (74%) of 66 studies stated the use of a doctor’s diagnosis,
population-based comparison. validated diagnostic criteria for AD, or both, and only 26 (39%)
Of note, the high-risk birth cohort study by Soderstrom et al36 of 66 studies used food challenges to determine FA status.
was unique in focusing solely on low sIgE levels in an attempt to Furthermore, the rationale for investigating certain subgroups of
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FIG 5. Temporal sequence of AD and FA onset in the Danish Allergy Research Cohort (DARC).18

participants was often unclear, with numerous studies using food application of ovalbumin to intact yet FLG-deficient mouse
challenges only in selected patients. Where food sensitization was skin was sufficient to induce cutaneous inflammation and increase
investigated, only 4 articles used values equating to the 95% PPV ovalbumin sIgE levels. Bartnikas et al39 contrasted the
cutoff as part of their methodology for diagnosing FA (see the physiologic effect of epicutaneous sensitization with that of oral
summary of study limitations in Table E5 in this article’s Online tolerance induction. BALB/c mice were epicutaneously
Repository at www.jacionline.org). sensitized with repeated applications of ovalbumin to tape-
It is a challenge for any study to capture the emergence of both stripped skin over 7 weeks, or orally immunized with ovalbumin
AD and FA, partly because AD characteristically waxes and and cholera toxin over 8 weeks. Both the epicutaneous and orally
wanes. In addition, clinical FA, in particular to egg and exposed groups of mice demonstrated sIgE antibody responses,
peanut, often arises without the child having ever directly and yet only those without oral immunization had signs in
ingested the food in question. Therefore the only way to keeping with anaphylaxis on oral challenge. Thus the
investigate the emergence of FA is to prospectively screen for determination of FA or tolerance depends not only on a period
food sensitization at regular intervals and perform OFCs of cutaneous sensitization, but also the timing and likely dose
throughout infancy. Given the strong association found between of gastrointestinal tract allergen exposure.
early onset and also moderate-to-severe AD and food The design of methodologically sound studies examining the
sensitization, as well as the lack of sIgE in cord blood, it is likely dynamic and interrelated nature of AD and FA will facilitate
that food sensitization occurs primarily across the inflamed skin the generation of future therapeutic and preventative
barrier in eczematous skin, potentially leading to the development interventions (see Table E5). Recent data in human subjects
of clinical FA. Brough et al24 have recently shown that food have shown that carrying an FLG mutation disrupts the infant
protein content in dust samples collected from the infant’s skin barrier by 3 months of age, even before AD emerges.40
environment (such as the living room floor) predisposes toward Two small intervention studies41,42 suggest that the regular
early food sensitization—especially in the presence of application of emollients from birth reduces the risk of AD
eczematous skin inflammation. Indeed, carrying a FLG mutation development and might thus affect FA, although a pilot study
also increases this risk, further supporting the evidence that a investigating egg sensitization did not find a significant
disrupted skin barrier predisposes to sensitization. However, reduction.41
detailed work from our own birth cohort demonstrated that it Finally, it is important to remember that FA can develop in
is the presence of AD and its severity, rather than FLG patients without a prior diagnosis of AD. The seminal article by
mutation carriage per se, that relates to food sensitization risk Lack et al31 showed that 5 (0.06%) of 824 children without a history
in early life.9 of a rash over joints or skin creases had peanut allergy on
When investigating the role of food allergen ingestion as a DBPCFCs. However, even in the absence of AD, skin barrier
prevention strategy, the interplay between environmental versus alterations of a different nature might play a role in the
oral food allergen exposure alongside AD status and management development of FA. For instance, the previously discussed study
becomes of crucial importance. Fallon et al38 used the by Flohr et al9 also found an independent positive association
FLG-deficient flaky tail mouse model to demonstrate that the between skin barrier impairment (increased transepidermal water
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loss) and food sensitization, in the absence of clinically visible 15. Mortz CG, Lauritsen JM, Andersen KE, Bindslev-Jensen C. Type I sensitization in
skin inflammation. Other environmental factors, such as water adolescents: prevalence and association with atopic dermatitis. Acta Derm
Venereol 2003;83:194-201.
hardness, the use of soaps and detergents, and the frequency of 16. Arshad SH, Tariq SM, Matthews S, Hakim E. Sensitization to common allergens
washing, could further contribute to skin barrier permeability and and its association with allergic disorders at age 4 years: a whole population birth
thus food sensitization.1 These are all areas that warrant further cohort study. Pediatrics 2001;108:E33.
research. 17. Peroni DG, Piacentini GL, Bodini A, Rigotti E, Pigozzi R, Boner AL. Prevalence
and risk factors for atopic dermatitis in preschool children. Br J Dermatol 2008;
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further support for skin barrier repair, early proactive AD 18. Eller E, Kjaer HF, Host A, Andersen KE, Bindslev-Jensen C. Food allergy and food
treatment, and reduction of environmental food allergen exposure sensitization in early childhood: results from the DARC cohort. Allergy 2009;64:
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criteria and gold standard food challenges are required to test this 20. Burr ML, Dunstan FD, Hand S, Ingram JR, Jones KP. The natural history
hypothesis further. of eczema from birth to adult life: a cohort study. Br J Dermatol 2013;168:
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21. Lowe AJ, Abramson MJ, Hosking CS, Carlin JB, Bennett CM, Dharmage SC, et al.
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cohort, Professor Magnus Wickman and Dr Natalia Ballardini for providing Exp Allergy 2007;37:536-42.
data from the BAMSE cohort, and Professor Katrina Allen and Dr Jennifer 22. Hill DJ, Sporik R, Thorburn J, Hosking CS. The association of atopic
Koplin for providing data from the HealthNuts cohort. dermatitis in infancy with immunoglobulin E food sensitization. J Pediatr
2000;137:475-9.
23. Hill DJ, Hosking CS. Food allergy and atopic dermatitis in infancy: an
Key messages epidemiologic study. Pediatr Allergy Immunol 2004;15:421-7.
24. Brough HA, Liu AH, Sicherer S, Makinson K, Douiri A, Brown SJ, et al.
d There is a strong association between AD, food sensitiza- Atopic dermatitis increases the effect of exposure to peanut antigen in dust on
tion, and FA. peanut sensitization and likely peanut allergy. J Allergy Clin Immunol 2015;135:
164-70.
d AD of increased severity and chronicity is particularly 25. Hill DJ, Hosking CS, de Benedictis FM, Oranje AP, Diepgen TL, Bauchau V, et al.
associated with FA. Confirmation of the association between high levels of immunoglobulin E food
d AD arises before the development of food sensitization in sensitization and eczema in infancy: an international study. Clin Exp Allergy
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The allergic sensitization in infants with atopic eczema from different countries.
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