Carsten Flohr

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.).

New insights into the epidemiology of childhood atopic dermatitis

There is a growing desire to explain the worldwide rise in the prevalence of atopic dermatitis (AD). Trend data on the burden of AD suggest that the picture in the developing world may soon resemble that of wealthier nations, where AD affects over 20% of children. This, combined with significant variations in prevalence within countries, emphasizes the importance of environmental factors. Many hypotheses have been explored, from the modulation of immune priming by hygiene, gut microbiota diversity, and exposure to endotoxins through farm animals to the effects of pollution, climate, and diet. The discovery of the filaggrin skin barrier gene and its importance in AD development and severity has brought the focus on gene–environment interactions and the identification of environmental factors that impact on skin barrier function. This article reviews our current understanding of the epidemiology of AD, with an emphasis on the findings reported in the international literature over the last 5 years.

Do helminth parasites protect against atopy and allergic disease

Allergic diseases are rare in areas with high helminth parasite exposure and common where helminth exposure is lacking or significantly reduced, such as urban areas of developing countries and industrialized nations. Studies suggest that helminths induce a systemic immuno‐modulatory network, including regulatory T cells and anti‐inflammatory IL‐10, which might play a key role in the protection against the allergic phenotype. Here, we review the current cross‐sectional, birth cohort, and intervention study evidence for a protective effect of helminth infection on allergy. There is increasing evidence for a causal relationship between helminth infection and reduced skin prick test responsiveness to allergens. Cross‐sectional studies have shown a consistent negative relationship, and these results have been confirmed in several, although not all, intervention studies. The immunological basis for this protective effect is less clear. Recent studies do not support the mast‐cell IgE saturation hypothesis, but suggest that protection is associated with IL‐10 production. As for allergic disease, cross‐sectional studies support a negative relationship between clinical asthma and infection with some helminth species, particularly hookworm, but more studies are required to draw conclusions for eczema and rhinitis. In addition, none of the few intervention studies to date have demonstrated an increase in clinical allergy after helminth treatment, and further studies are needed. Furthermore, we are only beginning to understand the host genetic factors that are potentially involved. A genetically predetermined T‐helper type 2 cell‐dominated cytokine milieu reduces parasite burden and may enhance host survival in an environment where helminth parasites are prevalent. Lack of parasite exposure in such hosts might lead to hypersensitivity to seemingly minor environmental allergen stimuli. Large birth cohort studies in helminth‐endemic areas that use epidemiological, genetic, and immunological tools are required to further examine how helminth parasites affect the development of atopy and allergic disease. Intervention studies with hookworm in parasite‐naïve allergic individuals are currently ongoing in the United Kingdom to test the above hypotheses further.

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.

Towards global consensus on outcome measures for atopic eczema research: results of the HOME II meeting

The use of nonstandardized and inadequately validated outcome measures in atopic eczema trials is a major obstacle to practising evidence‐based dermatology. The Harmonising Outcome Measures for Eczema (HOME) initiative is an international multiprofessional group dedicated to atopic eczema outcomes research. In June 2011, the HOME initiative conducted a consensus study involving 43 individuals from 10 countries, representing different stakeholders (patients, clinicians, methodologists, pharmaceutical industry) to determine core outcome domains for atopic eczema trials, to define quality criteria for atopic eczema outcome measures and to prioritize topics for atopic eczema outcomes research. Delegates were given evidence‐based information, followed by structured group discussion and anonymous consensus voting. Consensus was achieved to include clinical signs, symptoms, long‐term control of flares and quality of life into the core set of outcome domains for atopic eczema trials. The HOME initiative strongly recommends including and reporting these core outcome domains as primary or secondary endpoints in all future atopic eczema trials. Measures of these core outcome domains need to be valid, sensitive to change and feasible. Prioritized topics of the HOME initiative are the identification/development of the most appropriate instruments for the four core outcome domains. HOME is open to anyone with an interest in atopic eczema outcomes research.

Reduced helminth burden increases allergen skin sensitization but not clinical allergy: a randomized, double‐blind, placebo‐controlled trial in Vietnam

Background: Observational evidence suggests that infection with helminths protects against allergic disease and allergen skin sensitization. It is postulated that such effects are mediated by helminth‐induced cytokine responses, in particular IL‐10.

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.

How well do questionnaires perform compared with physical examination in detecting flexural eczema? Findings from the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two

Background  Questionnaires are widely used in epidemiological studies to measure eczema symptom prevalence, but there are concerns regarding their accuracy if used as a diagnostic tool.

Atopic Dermatitis and the Hygiene Hypothesis Revisited

BACKGROUND We published a systematic review on atopic dermatitis (AD) and the hygiene hypothesis in 2005. Since then, the body of literature has grown significantly. OBJECTIVES We therefore repeated our systematic review to examine the evidence from population-based studies for an association between AD risk and specific infections, childhood immunizations, the use of antibiotics and environmental exposures that lead to a change in microbial burden. METHODS Medline was searched from 1966 until June 2010 to identify relevant studies. RESULTS We found an additional 49 papers suitable for inclusion. There is evidence to support an inverse relationship between AD and endotoxin, early day care, farm animal and dog exposure in early life. Cat exposure in the presence of skin barrier impairment is positively associated with AD. Helminth infection at least partially protects against AD. This is not the case for viral and bacterial infections, but consumption of unpasteurized farm milk seems protective. Routine childhood vaccinations have no effect on AD risk. The positive association between viral infections and AD found in some studies appears confounded by antibiotic prescription, which has been consistently associated with an increase in AD risk. CONCLUSIONS There is convincing evidence for an inverse relationship between helminth infections and AD but no other pathogens. The protective effect seen with early day care, endotoxin, unpasteurized farm milk and animal exposure is likely to be due to a general increase in exposure to non-pathogenic microbes. This would also explain the risk increase associated with the use of broad-spectrum antibiotics. Future studies should assess skin barrier gene mutation carriage and phenotypic skin barrier impairment, as gene-environment interactions are likely to impact on AD risk.

Prevalence and associated factors of atopic dermatitis symptoms in rural and urban Ethiopia

Background Allergic diseases, including atopic dermatitis (AD), are increasingly becoming a clinical problem in developing countries.