Tom Marrs

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.).

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.

Does atopic dermatitis cause food allergy? A systematic review

BACKGROUND The association between atopic dermatitis (AD) and food allergy (FA) is not fully understood, although a causal relationship has been suggested. This has important implications for prevention and treatment. OBJECTIVE We aimed to review the association between AD and FA, the effect of FA on AD severity, chronicity, and age of onset, and the temporal relationship between the two. METHODS Medline and Embase were systematically searched from inception to November 2014 for studies investigating both AD and FA. RESULTS Sixty-six studies were identified. Eighteen were population-based, 8 used high-risk cohorts, and the rest comprised patients with either established AD or FA. In population-based studies, the likelihood of food sensitization was up to 6 times higher in patients with AD versus healthy control subjects at 3 months of age (odds ratio, 6.18; 95% CI, 2.94-12.98; P < .001). Other population-based studies reported that up to 53% of subjects with AD were food sensitized, and up to 15% demonstrated signs of FA on challenge. Meanwhile, studies including only patients with established AD have reported food sensitization prevalences up to 66%, with challenge-proven FA prevalences reaching up to 81%. Sixteen studies suggested that FA is associated with a more severe AD phenotype. Six studies indicated that AD of earlier onset or increased persistence is particularly associated with FA. Finally, one study found that AD preceded the development of FA. CONCLUSIONS This systematic review confirms a strong and dose-dependent association between AD, food sensitization, and FA. AD of increased severity and chronicity is particularly associated with FA. There is also evidence that AD precedes the development of food sensitization and allergy, in keeping with a causal relationship.

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.

Patients' ability to treat anaphylaxis using adrenaline autoinjectors: a randomized controlled trial

Previous work has shown patients commonly misuse adrenaline autoinjectors (AAI). It is unclear whether this is due to inadequate training, or poor device design. We undertook a prospective randomized controlled trial to evaluate ability to administer adrenaline using different AAI devices.

The diagnosis and management of antibiotic allergy in children: Systematic review to inform a contemporary approach

Background Adverse drug reactions (ADRs) to antibiotics are commonly reported among children, with some representing genuine drug allergies. Accurate diagnostic tests are required. Drug provocation testing (DPT) is accepted as the gold standard investigation among children with suspected antibiotic allergy. We conducted this review to ascertain the strength of current evidence for using DPT as the first-line investigation for suspected antibiotic allergy among children. Methods Medline was searched in June 2014 for publications investigating antibiotic allergy among children. Results 865 publications were retrieved and 76 studies selected. ADRs are most common among children of 0–4 years, however only some reveal drug allergies. The best evidence demonstrates that around 0.21% of general paediatric outpatients demonstrate positive antibiotic intradermal (ID) testing or DPTs, while 6.8% of children attending emergency departments for suspected β-lactam allergy may fulfil DPT reactions. Four studies used DPT-based protocols to investigate suspected antibiotic allergy, with two of these conducting ID testing and DPTs across all participants. β-lactam and clarithromycin ID testing had sensitivities of 66.7% and 75%, with positive predictive values of 36% and 33%, respectively, when compared with DPT data. Conclusions Our literature review found four (6%) publications that performed DPTs to subjects’ index antibiotic across all participants. No rigorous evidence supports using skin prick, ID or in vitro diagnostic testing; indeed, the testing regimens, extracts and positivity criteria used are inconsistent. We recommend that suspected non-serious antibiotic allergy should be primarily investigated using DPT-based clinical protocols. Data examining their safety, acceptability and diagnostic performance are required.

The role of skin and gut microbiota in the development of atopic eczema.

Conventional culture‐based studies have suggested that a reduction in microbial exposure in early life predisposes to atopic eczema and allergies. However, molecular microbiological methods have shown that conventional culture fails to grow around 80% of the bacterial flora. More recent work reviewed in this paper has employed next generation sequencing to study the influence of the gut and skin microbiota, both with regard to the risk of developing atopic eczema but also the role of pathogenic and commensal bacteria in established disease. Birth cohorts investigating the gastrointestinal tract reported reduced faecal microbiota diversity among those who later developed atopic eczema, using gel electrophoresis, real‐time PCR or 16S ribosomal RNA gene pyrosequencing. However, the inverse association with reduced faecal bacterial diversity was not confirmed in cross‐sectional studies among patients with established atopic eczema. Only two studies investigated the cutaneous microbiota in a longitudinal study design and both were unable to provide evidence that Staphylococcus aureus colonisation precedes the development of atopic eczema. Next generation sequencing has confirmed the cross‐sectional association between atopic eczema and S. aureus colonisation. The two studies that used this approach have also shown that disease flares are associated with a significant fall in skin microbiota diversity and an increase in the relative abundance of both S. aureus and epidermidis. Interestingly, S. aureus elimination does not appear to be the main reason why atopic eczema improves after a flare and antimicrobial and anti‐inflammatory therapy enhances bacterial diversity. Further, well‐phenotyped birth cohorts that take key confounders, such as antibiotic exposure, into account are required.

Immune mechanisms of food allergy and its prevention by early intervention

The environmental factors driving the increase in food allergies are unclear and possibly involve dual exposure to allergens, microbiome-driven effects or other mechanisms. Until they can be better understood, early intervention aiming at establishing oral tolerance provides an effective way to decrease the window-of-risk when children may develop allergic sensitisation to foods due to the absence of a protective immune response. Thus, the recent LEAP (Learning Early About Peanut allergy) and LEAP-On studies achieved a high level of peanut allergy prevention by early introduction of peanuts in the infants diet and conveyed more information regarding the evolution of IgE and IgG4 antibody responses to food antigens over time.

Double-blind food challenges can be conducted effectively by using interspersed active and placebo doses among children

To the Editor: We welcome the PRACTALL consensus report outlining how double-blind, placebo-controlled food challenges (DBPCFCs) can best be standardized.DBPCFCs are regarded as the gold standard investigation for diagnosing food allergy and are thus of particular importance for the conduct of rigorous research. However, there is unfortunately little evidence examining how challenge protocols can optimize the diagnosis of food allergy. It is important that DBPCFC protocols are practicable among young children, who demonstrate the highest prevalence of food allergy. We note that the authors’ consensus guidelines recommend that all DBPCFCs should take place over 2 days or with at least a 3-hour interval between administering the active and placebo doses. Study participation is voluntary, with many of our participant families travelling considerable distances to attend their research visits. Following this guidance would require many families to stay overnight to complete DBPCFCs over 2 days. If symptoms are provoked during the first day, completing a further challenge procedure the following day has logistic difficulties if antihistamines have been used previously or families no longer wish to attend. Administering active and placebo doses on separate days would substantially increase the number of incomplete challenges and considerably complicate the conduct of clinical research into food allergy. We determine the prevalence of food allergy among children using single-day DBPCFC schedules by administering doses not less than 15 minutes apart and interspersing active and placebo doses. If an allergic response is elicited after a placebo dose, 2-day DBPCFCs are administered. Studies using both 2-day doubleblind protocols and interspersed single-day schedules report that the large majority of participants experiencing IgE-mediated allergic reactions report symptoms within 10 minutes of finishing active dose consumption. Our departmental clinical experience is that the vast majority of subjects with IgE-mediated food allergy manifest symptoms promptly and usually before the next dose is due, as also described in other specialist centers. Where mild symptoms are reported that do not fulfill challenge cessation criteria, repeat doses can be administered, as outlined by the consensus report authors. However, we recognize that investigating participants’ allergen elicitation thresholds necessarily involves the consumption of a greater number of doses during a challenge procedure and might be best conducted by administering active and placebo doses on separate days. We believe that single-day DBPCFC protocols, interspersing active and placebo doses, are effective in diagnosing food allergy among children. Tom Marrs, MSc George du Toit, FRCPCH Adam T. Fox, MD Michael R. Perkin, FRCPCH, PhD Gideon Lack, FRCPCH