Michael R. Perkin

Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants

BACKGROUND The age at which allergenic foods should be introduced into the diet of breast-fed infants is uncertain. We evaluated whether the early introduction of allergenic foods in the diet of breast-fed infants would protect against the development of food allergy. METHODS We recruited, from the general population, 1303 exclusively breast-fed infants who were 3 months of age and randomly assigned them to the early introduction of six allergenic foods (peanut, cooked egg, cows milk, sesame, whitefish, and wheat; early-introduction group) or to the current practice recommended in the United Kingdom of exclusive breast-feeding to approximately 6 months of age (standard-introduction group). The primary outcome was food allergy to one or more of the six foods between 1 year and 3 years of age. RESULTS In the intention-to-treat analysis, food allergy to one or more of the six intervention foods developed in 7.1% of the participants in the standard-introduction group (42 of 595 participants) and in 5.6% of those in the early-introduction group (32 of 567) (P=0.32). In the per-protocol analysis, the prevalence of any food allergy was significantly lower in the early-introduction group than in the standard-introduction group (2.4% vs. 7.3%, P=0.01), as was the prevalence of peanut allergy (0% vs. 2.5%, P=0.003) and egg allergy (1.4% vs. 5.5%, P=0.009); there were no significant effects with respect to milk, sesame, fish, or wheat. The consumption of 2 g per week of peanut or egg-white protein was associated with a significantly lower prevalence of these respective allergies than was less consumption. The early introduction of all six foods was not easily achieved but was safe. CONCLUSIONS The trial did not show the efficacy of early introduction of allergenic foods in an intention-to-treat analysis. Further analysis raised the question of whether the prevention of food allergy by means of early introduction of multiple allergenic foods was dose-dependent. (Funded by the Food Standards Agency and others; EAT Current Controlled Trials number, ISRCTN14254740.).

Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age

Background  Filaggrin loss‐of‐function (FLG) mutations are associated with eczema and skin barrier impairment, but it is unclear whether skin barrier impairment precedes phenotypic eczema in FLG mutation carriers.

Atopic Dermatitis and Disease Severity Are the Main Risk Factors for Food Sensitization in Exclusively Breastfed Infants

Filaggrin (FLG) loss-of-function skin barrier gene mutations are associated with atopic dermatitis (AD) and transepidermal water loss (TEWL). We investigated whether FLG mutation inheritance, skin barrier impairment, and AD also predispose to allergic sensitization to foods. Six hundred and nineteen exclusively breastfed infants were recruited at 3 months of age and examined for AD and disease severity (SCORing Atopic Dermatitis (SCORAD)), and screened for the common FLG mutations. TEWL was measured on unaffected forearm skin. In addition, skin prick testing was performed to six study foods (cows milk, egg, cod, wheat, sesame, and peanut). Children with AD were significantly more likely to be sensitized (adjusted odds ratio (OR)=6.18, 95% confidence interval (CI): 2.94-12.98, P<0.001), but this effect was independent of FLG mutation carriage, TEWL, and AD phenotype (flexural vs. non-flexural). There was also a strong association between food sensitization and AD severity (adjusted ORSCORAD<20=3.91, 95% CI: 1.70-9.00, P=0.001 vs. adjusted ORSCORAD20=25.60, 95% CI: 9.03-72.57, P<0.001). Equally, there was a positive association between AD and sensitization with individual foods (adjusted ORegg=9.48, 95% CI: 3.77-23.83, P<0.001; adjusted ORcows milk=9.11, 95% CI: 2.27-36.59, P=0.002; adjusted ORpeanut=4.09, 95% CI: 1.00-16.76, P=0.05). AD is the main skin-related risk factor for food sensitization in young infants. In exclusively breastfed children, this suggests that allergic sensitization to foods can be mediated by cutaneous antigen-presenting cells.

Is there an association between microbial exposure and food allergy? A systematic review

The environmental factors driving the recent increase in the prevalence of food allergy (FA) are unclear. Since associations have been demonstrated between microbial exposure and the likelihood of eczema and respiratory allergies, we reviewed the evidence for FA. Medline was systematically searched from inception to the end of July 2012 for studies investigating links between FA and environmental exposures, likely to influence microbial exposure, such as Caesarean delivery, family size, day‐care attendance, childhood infections, immunizations and antibiotic use. We selected studies reporting food challenge data, reported doctor‐diagnosed (RDD) FA and food sensitization. Methodological differences and study heterogeneity precluded meta‐analysis. A total of 46 studies were identified, of which 28 (60.9%) were prospective and 13 (28.3%) used food challenges to diagnose FA. Caesarean delivery was investigated in 13 studies, of which three infant cohorts demonstrated an increase in challenge‐proven FA (one cohort) and food sensitization (two cohorts), and one cross‐sectional study reported increased RDDFA. Four studies investigated the effect of having siblings, with one infant cohort demonstrating less challenge‐proven FA and a cross‐sectional study showing a decrease in RDDFA. Attending childcare before 6 months was associated with less challenge‐proven FA in one cohort. A cross‐sectional survey identified an inverse relationship between hepatitis A serology and peanut sensitization. One of eleven trials investigating probiotics demonstrated a quicker acquisition of milk tolerance amongst allergic infants. Factors influencing microbial exposure may be partly responsible for rising FA burden, but further prospective studies using double‐blind placebo controlled food challenges as an outcome are required.

Enquiring About Tolerance (EAT) study: Feasibility of an early allergenic food introduction regimen

Background The influence of early exposure to allergenic foods on the subsequent development of food allergy remains uncertain. Objective We sought to determine the feasibility of the early introduction of multiple allergenic foods to exclusively breast-fed infants from 3 months of age and the effect on breastfeeding performance. Methods We performed a randomized controlled trial. The early introduction group (EIG) continued breastfeeding with sequential introduction of 6 allergenic foods: cows milk, peanut, hard-boiled hens egg, sesame, whitefish (cod), and wheat; the standard introduction group followed the UK infant feeding recommendations of exclusive breastfeeding for around 6 months with no introduction of allergenic foods before 6 months of age. Results One thousand three hundred three infants were enrolled. By 5 months of age, the median frequency of consumption of all 6 foods was 2 to 3 times per week for every food in the EIG and no consumption for every food in the standard introduction group (P < .001 for every comparison). By 6 months of age, nonintroduction of the allergenic foods in the EIG was less than 5% for each of the 6 foods. Achievement of the stringent per-protocol consumption target for the EIG proved more difficult (42% of evaluable EIG participants). Breastfeeding rates in both groups significantly exceeded UK government data for equivalent mothers (P < .001 at 6 and at 9 months of age). Conclusion Early introduction, before 6 months of age, of at least some amount of multiple allergenic foods appears achievable and did not affect breastfeeding. This has important implications for the evaluation of food allergy prevention strategies.

The predictive value of early life total immunoglobulin E measurement in identifying atopic children in a population-based birth cohort study

Atopy is common and the prevalence amongst children is rising. Measurements in early childhood that can predict subsequent development of atopy could be clinically useful for targeting preventive measures. We used the Children in Focus (CiF) subgroup of a large population‐based birth cohort study (the Avon Longitudinal Study of Parents and Children) to investigate whether total immunoglobulin E (IgE) measured at 12 and 18 months could predict subsequent development of atopy at 5 yr of age. Atopy was determined by positive skin prick test (≥3 mm wheal) to one or more of 14 inhalant and food allergens. Prevalence of skin prick positivity to any allergen was 14.5% (104 of 715; 95% CI: 12.0–17.1%). Total IgE levels were significantly higher at 12 months of age (p < 0.0005) but not 18 months of age in those children subsequently atopic. The highest positive predictive value was 41% with an IgE measurement of >51 kU/l, with a sensitivity of 13.5% and a specificity of 95.8%. Although significant differences in early life IgE measurements were seen, the extent of overlap was great, such that the overall performance of IgE at 12 months as a screening test for atopy was poor.

Unpasteurized milk: health or hazard?

Humans have been consuming animal milk for thousands of years, with evidence of consumption in the British Isles during the Neolithic period [1]. Before the industrial revolution, the majority of the population in the United Kingdom worked in agriculture and cow’s milk formed an integral part of the normal diet. Cow’s milk has therefore been an allergen to which humans have been exposed for millennia. The literature identifying that farming children have a reduced prevalence of allergic disorders compared with other rural children is now substantial. It is clear that a diversity of putative protective factors are involved: exposure to barns and stables, early contact with farm animals and working on a farm during pregnancy. The paper by Waser et al. [2] adds to the small but growing body of evidence that consumption of unpasteurized milk is another factor mediating a protective effect on allergic disorders. Unpasteurized milk consumption shares with the broader farming literature a heterogeneity in the effects that have been observed. Riedler found an independent protective effect of early unpasteurized milk consumption on asthma, current wheeze, hayfever, current rhinitis symptoms and atopic sensitization [3]. The latter was noteworthy as the definition of a positive response was the same as Waser (X3.5 kU/L) and the panel of inhalant allergens included house dust and storage mites, cat dander, grass and birch pollen and cow epithelium. An additive effect was seen from the combination of early milk consumption and early stable exposure. The paper by Radon, cited by Waser, was particularly interested in the issue of H. pylori and T. gondii infection and was based on adults rather than children [4]. This paper did not find an independent protective effect of unpasteurized milk consumption on atopy; it was only the combination of unpasteurized milk consumption and regular visits to animal houses before the age of 7 years that was protective [odds ratio (OR)adj 0.35%, 95% confidence interval (CI) 0.17–0.74] and the combination of unpasteurized milk consumption and IgG against H. pylori (ORadj 0.38%, 95% CI 0.15–0.98). Barnes’ study in Crete shared a similarity with the current paper in that both rural and urban children were included [5]. The results of Barnes’ study are difficult to interpret in that farm animal contact and unpasteurized milk consumption had protective effects on atopy for urban but not rural children. However, in the regression analysis, unpasteurized milk consumption, farm animal contact and being a rural child all had independent protective effects on atopy. The New Zealand study quoted by Waser was small (293 children) but found a very significant reduction in eczema (ORadj 0.2%, 95% CI 0.1–0.8) and a similar effect, but not statistically significant, for current allergic rhinitis (ORadj 0.3%, 95% CI 0.1–1.1) [6]. No significant effect was found for atopy (ORadj 0.6%, 95% CI 0.2–1.9). Our study found protective effects of unpasteurized consumption on current eczema and seasonal allergic rhinitis symptoms, but most significantly for atopy (ORadj 0.24%, 95% CI 0.10–0.53) [7]. Consistent with Waser, the protective effect was observed across farming groups and therefore cannot be explained by it being a proxy for another farm-based exposure. With regard to specific allergens, the results of Waser are confusing. One would have hypothesized that the effect of unpasteurized milk consumption would be broadly similar for sensitization to a range of different aeroallergens. In contrast, Waser found no effect for Phadiatop, storage mites and cat dander, a reduction in sensitization for pollen and horse dander and a borderline increase in sensitization for house dust mite (HDM). Our results were remarkably consistent for any aeroallergen, HDM and grass pollen. There are two issues to resolve: what is it about unpasteurized milk consumption that confers a protective effect and why is the effect heterogeneous depending on Correspondence: Dr M. R. Perkin, Division of Community Health Sciences at St George’s, University of London, Room 6.18, 6th floor Hunter Wing, Cranmer Terrace, Tooting, London SW17 0RE, UK. E-mail: m.perkin@sgul.ac.uk Clinical and Experimental Allergy, 37, 627–630

The investigation of chronic urticaria in childhood: which investigations are being performed and which are recommended?

Chronic urticaria (CU) is diagnosed on the basis of experiencing frequent weals, with or without angioedema, for 46 weeks. The most commonly identified avoidable precipitants are physical triggers such as exposure to pressure or cold. The prevalence of CU in the UK remains uncertain [1‐3]. CU has been shown to significantly impair the quality of life of suffers [4]. The precise pathophysiology of CU remains unknown; however, functional circulating antibodies (of the IgG1 and IgG3 subclass) directed against the FCeRIa or IgE have been demonstrated in a significant portion of both adults and children with CU [5, 6]. The British Society for Allergy and Clinical Immunology (BSACI) has recently joined the European Academy of Allergy and Clinical Immunology (EAACI/GA 2 LEN/EDF) in publishing recommendations for the investigation of CU [7, 8]. The BSACI makes specific recommendations for the investigation of CU in children. The BSACI recommendations state ‘if the clinical history and examination are typical of chronic idiopathic urticaria, then further laboratory investigations are rarely useful’. The recommended investigations are in two tiers; firstly, ‘if the clinical history suggests a candidate allergen, then allergy tests (skin testing or specific IgE tests) are warranted.’ A second tier of ‘additional investigations’ are also suggested‐if clinically indicated; these include, urine analysis, full blood count (FBC), erythrocyte sedimentation rate (ESR), liver function tests (and viral hepatitis screen if elevated) (LFTs), coeliac disease screen, thyroid function and anti-thyroid antibodies (TFTs), cold, dermographism and pressure provocation tests, elimination re-challenge diets, antinuclear antibodies (ANA), skin biopsy, complement/C1 inhibitor assays (C3/C4/C1 esterase), serum cryoproteins and an infectious disease screen (past/current viral, bacterial or parasitic).

Overview of systematic reviews in allergy epidemiology

There is a substantial body of evidence on the epidemiology of allergic conditions, which has advanced the understanding of these conditions. We aimed to systematically identify systematic reviews and meta‐analyses on the epidemiology of allergic diseases to assess what has been studied comprehensively and what areas might benefit from further research.

The RCPCH care pathway for food allergy in children: an evidence and consensus based national approach

Aims The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies; food allergy is the second pathway. The pathways focus on defining the competences required to improve the equity of care received by children with allergic conditions. Method The food allergy pathway was developed by a multidisciplinary working group and was based on a comprehensive review of the evidence. The pathway was reviewed by a broad group of stakeholders including the public and approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. The National Institute of Health and Clinical Excellence simultaneously established a short guideline review of community practice for children with food allergy; close communication was established between the two groups. Results The results are presented in two sections: a pathway algorithm and the competences. The entry points are defined and the ideal pathway of care is described from initial recognition and confirmed diagnosis through to follow-up. Conclusions The range of manifestations of food allergy/intolerance is much more diverse than hitherto recognised and diagnosis can be problematic as many patients do not have classical IgE mediated disease. The pathway provides a guide for training and development of services to facilitate improvements in delivery as close to the patients home as possible. The authors recommend that this pathway is implemented locally by a multidisciplinary team with a focus on creating networks.