Association between the age of solid food introduction and eczema: A systematic review and a meta-analysis.

INTRODUCTION: Eczema is a common childhood ailment responsible for a considerable disease burden. Both timing of introduction to solid food and allergenic food are believed to be related to childhood eczema. Despite the growing body of evidence, the relationship between timing of any solid food introduction (allergenic and/or non-allergenic) and development of eczema has not previously been systematically reviewed. METHODS: PubMed and EMBASE databases were searched using food and eczema terms. Two authors selected papers according to the inclusion criteria and extracted information on study characteristics and measures of association. Meta-analyses were performed after grouping studies according to the age and type of exposure. RESULTS: A total of 17 papers met the inclusion criteria, reporting results from 16 study populations. Of these, 11 were cohort studies, 2 case-controls, 1 cross-sectional study and 2 randomized controlled trials. Limited meta-analyses were performed due to heterogeneity between studies. Timing of solid food introduction was not associated with eczema. One randomized controlled trial provided weak evidence of an association between early allergenic (around 4 months) food introduction and reduced risk of eczema. CONCLUSIONS: The available evidence is currently insufficient to determine whether the timing of introduction of any solid food influences the risk of eczema.

The practice and perception of precautionary allergen labelling by the Australasian food manufacturing industry.

BACKGROUND: The precautionary allergen labelling (PAL) and Voluntary Incidental Trace Allergen Labelling (VITAL® ) tools were designed by industry to assist consumers with selecting safe foods for consumption. However, a sizeable proportion of food products bear no label, and it is unclear whether these products are free from allergens and therefore safe to consume or have simply not undergone a risk assessment and therefore remain unlabelled for that reason. OBJECTIVE: To assess the prevalence of unlabelled products that have undergone a risk assessment process and to examine the factors influencing industry's uptake of the VITAL® process. METHODS: A web-based questionnaire was distributed to Australasian food and grocery manufacturers. RESULTS: One hundred and thirty-seven Australasian manufacturers were contacted, and 59 questionnaires were returned (response rate: 43%). The respondents represented 454 different manufacturing sites. Manufacturers reported that 23% (95% CI 19-28) of products (n=102/434) that had been through the VITAL® risk assessment process had no PAL statement on the label. 34% (95% CI 30-38), (n=204/600) of products that had undergone another (non-VITAL® ) risk assessment process had no PAL statement. In examining the factors that influenced industry's uptake of the VITAL® process, 25 manufacturers reported on factors that influenced the uptake of the VITAL® process, 76% (CI 95% 55-91) reported that VITAL® was an effective tool because it was based on science; 52% (CI 95% 31-72) reported that it was too time-consuming and 36% (CI 95% 18-57) identified a concern with it not being endorsed by the government. CONCLUSION AND CLINICAL RELEVANCE: Currently, we estimate that at least 30% of products may have been through a risk assessment process and yet bear no PAL statement on the label. Permissive labelling could be incorporated onto these products if they have been assessed to be safe for consumption.

Overview of systematic reviews in allergy epidemiology.

BACKGROUND: 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. METHODS: We searched PubMed and EMBASE up to 12/2014 for systematic reviews on epidemiological research on allergic diseases. We indexed diseases and topics covered and extracted data on the search characteristics of each systematic review. RESULTS: The search resulted in 3991 entries after removing duplicates, plus 20 other items found via references and conference abstracts; 421 systematic reviews were relevant and included in this overview. The majority contained some evidence on asthma (72.9%). Allergic rhinitis, atopic eczema and food hypersensitivity were covered in 15.7%, 24.5% and 9.0%, respectively. Commonly studied risk factors for atopic eczema included dietary and microbial factors, while for asthma, pollution and genetic factors were often investigated in systematic reviews. There was some indication of differing search characteristics across topics. CONCLUSION: We present a comprehensive overview with an indexed database of published systematic reviews in allergy epidemiology. We believe that this clarifies where most research interest has focussed and which areas could benefit from further research. We propose that this effort is updated every few years to include the most recently published evidence and to extend the search to an even broader list of hypersensitivity/allergic disorders.

Vitamin D insufficiency in the first 6 months of infancy and challenge-proven IgE-mediated food allergy at 1 year of age: a case-cohort study.

BACKGROUND: Ecological evidence suggests vitamin D insufficiency (VDI) due to lower ambient ultraviolet radiation (UVR) exposure may be a risk factor for IgE-mediated food allergy. However, there are no studies relating directly measured VDI during early infancy to subsequent challenge-proven food allergy. OBJECTIVE: To prospectively investigate the association between VDI during infancy and challenge-proven food allergy at 1 year. METHODS: In a birth cohort (n = 1074), we used a case-cohort design to compare 25-hydroxyvitamin D3 (25(OH)D3 ) levels among infants with food allergy vs a random subcohort (n = 274). The primary exposures were VDI (25(OH)D3 <50 nM) at birth and 6 months of age. Ambient UVR and time in the sun were combined to estimate UVR exposure dose. IgE-mediated food allergy status at 1 year was determined by formal challenge. Binomial regression was used to examine associations between VDI, UVR exposure dose and food allergy and investigate potential confounding. RESULTS: Within the random subcohort, VDI was present in 45% (105/233) of newborns and 24% (55/227) of infants at 6 months. Food allergy prevalence at 1 year was 7.7% (61/786), and 6.5% (53/808) were egg-allergic. There was no evidence of an association between VDI at either birth (aRR 1.25, 95% CI 0.70-2.22) or 6 months (aRR 0.93, 95% CI 0.41-2.14) and food allergy at 1 year. CONCLUSIONS: There was no evidence that VDI during the first 6 months of infancy is a risk factor for food allergy at 1 year of age. These findings primarily relate to egg allergy, and larger studies are required.

Does LEAP change the screening paradigm for food allergy in infants with eczema?

The LEAP randomized controlled trial provides the first direct evidence that delayed introduction of peanut in an infant's diet significantly increases the risk of peanut allergy. However, as often is the case in ground-breaking research, the LEAP study raises almost as many questions as it resolves. Although the quality of design and excellence in study execution is unquestioned, the particular difficulty this study raises is how to generalize results from a trial of high-risk infants, which screened infants for the presence of peanut allergy prior to peanut introduction, to the general population. Although many existing infant feeding guidelines already allow for the introduction of allergenic foods from 4 to 6 months of age irrespective of co-existent risk factors for peanut allergy, these will now need to be revised to more strongly state that avoidance may be harmful. Interim guidelines have already been published which incorporate these recommendations. However, the question as to how to achieve timely introduction of peanut into an infant's diet in a safe and cost-effective way, particularly in high-risk infants, remains unresolved.

Nut allergy prevalence and differences between Asian-born children and Australian-born children of Asian descent: a state-wide survey of children at primary school entry in Victoria, Australia.

BACKGROUND: Asian infants born in Australia are three times more likely to develop nut allergy than non-Asian infants, and rates of challenge-proven food allergy in infants have been found to be unexpectedly high in metropolitan Melbourne. To further investigate the risk factors for nut allergy, we assessed the whole-of-state prevalence distribution of parent-reported nut allergy in 5-year-old children entering school. METHODS: Using the 2010 School Entrant Health Questionnaire administered to all 5-year-old children in Victoria, Australia, we assessed the prevalence of parent-reported nut allergy (tree nut and peanut) and whether this was altered by region of residence, socio-economic status, country of birth or history of migration. Prevalence was calculated as observed proportion with 95% confidence intervals (CI). Risk factors were evaluated using multivariable logistic regression and adjusted for appropriate confounders. RESULTS: Parent-reported nut allergy prevalence was 3.1% (95% CI 2.9-3.2) amongst a cohort of nearly 60 000 children. It was more common amongst children of mothers with higher education and socio-economic index and less prevalent amongst children in regional Victoria than in Melbourne. While children born in Australia to Asian-born mothers (aOR 2.67, 95% CI 2.28-3.27) were more likely to have nut allergy than non-Asian children, children born in Asia who subsequently migrated to Australia were at decreased risk of nut allergy (aOR 0.1, 95% CI 0.03-0.31). CONCLUSION: Migration from Asia after the early infant period appears protective for the development of nut allergy. Additionally, rural regions have lower rates of nut allergy than urban areas.

Timing of routine infant vaccinations and risk of food allergy and eczema at one year of age.

BACKGROUND: Epidemiological evidence suggests that routine vaccinations can have nontargeted effects on susceptibility to infections and allergic disease. Such effects may depend on age at vaccination, and a delay in pertussis vaccination has been linked to reduced risk of allergic disease. We aimed to test the hypothesis that delay in vaccines containing diphtheria-tetanus-acellular pertussis (DTaP) is associated with reduced risk of food allergy and other allergic diseases. METHODS: HealthNuts is a population-based cohort in Melbourne, Australia. Twelve-month-old infants were skin prick-tested to common food allergens, and sensitized infants were offered oral food challenges to determine food allergy status. In this data linkage study, vaccination data for children in the HealthNuts cohort were obtained from the Australian Childhood Immunisation Register. Associations were examined between age at the first dose of DTaP and allergic disease. RESULTS: Of 4433 children, 109 (2.5%) received the first dose of DTaP one month late (delayed DTaP). Overall, delayed DTaP was not associated with primary outcomes of food allergy (adjusted odds ratio (aOR) 0.77; 95% CI: 0.36-1.62, P = 0.49) or atopic sensitization (aOR: 0.66; 95% CI: 0.35-1.24, P = 0.19). Amongst secondary outcomes, delayed DTaP was associated with reduced eczema (aOR: 0.57; 95% CI: 0.34-0.97, P = 0.04) and reduced use of eczema medication (aOR: 0.45; 95% CI: 0.24-0.83, P = 0.01). CONCLUSIONS: There was no overall association between delayed DTaP and food allergy; however, children with delayed DTaP had less eczema and less use of eczema medication. Timing of routine infant immunizations may affect susceptibility to allergic disease.

Which infants with eczema are at risk of food allergy? Results from a population-based cohort.

BACKGROUND: The relationship between early onset eczema and food allergy among infants has never been examined in a population-based sample using the gold standard for diagnosis, oral food challenge. OBJECTIVE: We characterised the risk of challenge-proven food allergy among infants with eczema in the general population. METHODS: One-year-old infants (n = 4453 meeting criteria for this analysis) were assessed for history of eczema, received a nurse-administered eczema examination and underwent skin prick testing to peanut, egg and sesame. Those with a detectable wheal to one of the test foods underwent an oral food challenge irrespective of wheal size. The risk of food allergy, stratified by eczema severity and age of onset, was estimated using multivariate logistic regression with population sampling weights. RESULTS: One in five infants with eczema were allergic to peanut, egg white or sesame, compared to one in twenty-five infants without eczema (OR 6.2, 95% CI 4.9, 7.9, P < 0.001). The prevalence of peanut allergy was low in the absence of eczema (0.7% 95% CI 0.4, 1.1). Infants with eczema were 11.0 times more likely to develop peanut allergy (95% CI 6.6, 18.6) and 5.8 times more likely to develop egg allergy (95% CI 4.6, 7.4) by 12 months than infants without eczema. 50.8% of infants (95% CI 42.8, 58.9) with early eczema onset (<3 months) who required doctor-prescribed topical corticosteroid treatment developed challenge-proven food allergy. CONCLUSION AND CLINICAL RELEVANCE: Eczema, across the clinical severity spectrum in infancy, is a strong risk factor for IgE-mediated food allergy. Infants with eczema were six times more likely to have egg allergy and 11 times more likely to have peanut allergy by 12 months than infants without eczema. Our data suggest that a heightened awareness of food allergy risk among healthcare practitioners treating infants with eczema, especially if early onset and severe, is warranted.

Differential factors associated with challenge-proven food allergy phenotypes in a population cohort of infants: a latent class analysis.

BACKGROUND: Food allergy, eczema and wheeze are early manifestations of allergic disease and commonly co-occur in infancy although their interrelationship is not well understood. Data from population studies are essential to determine whether there are differential drivers of multi-allergy phenotypes. We aimed to define phenotypes and risk factors of allergic disease using latent class analysis (LCA). METHODS: The HealthNuts study is a prospective, population-based cohort of 5276 12-month-old infants in Melbourne, Australia. LCA was performed using the following baseline data collected at age 12 months: food sensitization (skin prick test ≥ 2 mm) and allergy (oral food challenge) to egg, peanut and sesame; early (< 4 months) and late-onset eczema; and wheeze in the first year of life. Risk factors were modelled using multinomial logistic regression. RESULTS: Five distinct phenotypes were identified: no allergic disease (70%), non-food-sensitized eczema (16%), single egg allergy (9%), multiple food allergies (predominantly peanut) (3%) and multiple food allergies (predominantly egg) (2%). Compared to the baseline group of no allergic disease, shared risk factors for all allergic phenotypes were parents born overseas (particularly Asia), delayed introduction of egg, male gender (except for single egg allergy) and family history of allergic disease, whilst exposure to pet dogs was protective for all phenotypes. Other factors including filaggrin mutations, vitamin D and the presence of older siblings differed by phenotype. CONCLUSIONS AND CLINICAL RELEVANCE: Multiple outcomes in infancy can be used to determine five distinct allergy phenotypes at the population level, which have both shared and separate risk factors suggesting differential mechanisms of disease.

The role of circulating 25 hydroxyvitamin D in asthma: a systematic review.

Asthma is a major public health issue. The co-occurrence of the high prevalence of asthma and vitamin D deficiency documented globally in recent decades has prompted several investigations into a possible association between the two conditions. The objective of this paper was to synthesize the evidence from studies that have measured the association between serum vitamin D and asthma incidence, prevalence, severity and exacerbations. A systematic search of the literature was performed in PubMed, and the available evidence was summarized both qualitatively and by meta-analysis. Only English language, observational studies measuring serum levels of 25(OH)D as the exposure were included, as this is the most robust measure of vitamin D levels. The search identified 23 manuscripts: two case-control, 12 cohort and nine cross-sectional studies. Collectively, the evidence suggests that higher serum levels of 25(OH)D are associated with a reduced risk of asthma exacerbations, but there was little evidence to suggest an association with asthma incidence, prevalence or severity. A significant amount of heterogeneity between study methodology and results restricted the scope for meta-analysis. These results suggest that vitamin D supplementation may be effective for the prevention of asthma exacerbations, but the findings need to be confirmed by clinical trials.

Increased risk of peanut allergy in infants of Asian-born parents compared to those of Australian-born parents.

BACKGROUND: Asian infants appear to be over-represented among patients with clinical food allergy in Australia, but this has not been formally examined at the population level. Any difference in prevalence according to parental country of birth may be secondary to modifiable lifestyle factors. We aimed to quantify (i) differences in the prevalence of peanut allergy by parental country of birth and (ii) contribution of measured environmental exposures to these differences. METHODS: The population-based HealthNuts study in Melbourne, Australia, screened 5276 infants (74% participation) with skin prick tests and sensitized infants underwent food challenge. Of these, 535 had a parent born in East Asia and 574 in UK/Europe. Associations between parents' country of birth and offspring peanut allergy were examined using multiple logistic regression. RESULTS: Compared to infants with two Australian-born parents, peanut allergy was more common among infants with parent/s born in East Asia (OR 3.4, 95% CI 2.2-5.1) but not those with parent/s born in the UK/Europe (OR 0.8, 95% CI 0.4-1.5). Paradoxically rates of allergic disease were lower among Asian parents. A higher prevalence of eczema among infants of Asian parents explained around 30% of the increase in peanut allergy, while differences in dog ownership explained around 18%. CONCLUSIONS: The high peanut allergy prevalence among infants of Asian-born parents appears to have occurred in a single generation and was not present among infants with parents migrating from other countries, suggesting gene-environment interactions are important. The role of eczema and microbial exposure in food allergy prevention warrants exploration.

Optimal timing for solids introduction - why are the guidelines always changing?

There have been dramatic changes in timing of first exposure to solid foods for children over the last 40 years, ranging from exposure prior to 4 months of age for most infants in the 1960s, to guidelines recommending delaying solids until after 6 months of age introduced in the 1990s. Infant diet, specifically age of weaning and age at introduction of allergenic foods, has long been thought to play a role food allergy. However, controversy surrounding the relationship between timing of introduction of foods and development of food allergy has lead to a plethora of inconsistent infant feeding guidelines both between and within countries. The aims of this article were to discuss the history of changing guidelines for optimal timing of introduction of solids in general and allergenic solids in particular and the evidence (or lack thereof) underpinning recommendations at each of these time-points. We present the current clinical equipoise with regards to recently revised guidelines published almost simultaneously in the UK, US and Australia and argue that guideline modification about timing of introduction (both for high risk infants but also for the general population) will require careful review of emerging literature to provide a true evidence base to inform public health practice such as infant feeding guidelines.

The prevalence and socio-demographic risk factors of clinical eczema in infancy: a population-based observational study.

BACKGROUND: Socio-demographic predictors for the development of clinically observed, infantile eczema have not been formally examined in a large population-based study. Few studies of eczema risk factors have included current, objective eczema outcomes as well as parent-reported history. OBJECTIVES: We aimed to measure the population prevalence of infantile eczema using novel sampling methodology, and identify socio-demographic risk factors for eczema in the first year of life. METHODS: A population-based cross-sectional study of infantile allergy (the HealthNuts study, n = 4972, response rate 74.1%) was conducted from 2008-2011 in Melbourne, Australia. Infants were examined for current eczema at age 12 months (mean 12.7, SD 0.7). Parents provided information about the infants' history of eczema and demographic factors. Factors associated with eczema were modelled using multinomial logistic regression. RESULTS: The population prevalence of observed eczema at 12 months was 20.3% (95% CI 19.0, 21.5), while cumulative prevalence for parent-reported eczema was 28.0% (95% CI 26.7, 29.4). The strongest predictors of eczema were maternal eczema and asthma (multinomial (M)-OR 1.7, P < 0.001, and M-OR 1.4, P = 0.007), male sex (M-OR 1.4, P < 0.001), and East Asian ethnicity (M-OR 1.6, P < 0.001) with over 80% of infants with all risk factors exhibiting eczema. East Asian parents, particularly recent migrants, reported fewer allergies than other parents. CONCLUSIONS AND CLINICAL RELEVANCE: Approximately, one in three infants developed eczema by 12 months of age. East Asian infants are at increased risk of eczema despite their parents having lower rates of allergy than non-Asian parents. Gene-environment interactions may explain the differential effect seen in this minority group.

Characterization of plasma cytokines in an infant population cohort of challenge-proven food allergy.

BACKGROUND: Sensitization to food allergens indicates the production of food-specific IgE; however, sensitization is not a definite indicator of allergic reaction upon ingestion (N Engl J Med, 344, 2001, 30: J Allergy Clin Immunol, 120, 2007, 491). Currently, food challenge is the best approach to identify the presence or absence of allergy. While 95% positive predictive values (PPVs) thresholds for sIgE can assist with identifying increased likelihood of allergy among those who are sensitized, there are no specific biological markers that differentiate between allergic and sensitized individuals. OBJECTIVES: To determine whether plasma serum cytokine profiles predict (i) sensitization to peanut and egg and (ii) food allergy among sensitized infants. METHODS: Peanut-sensitized (PT) and egg-sensitized 14-month-old infants and nonsensitized controls enrolled in HealthNuts, a population-based study of food allergy, underwent an oral food challenge (OFC). Blood was collected within 1 h after OFC. Serum levels of Th1, Th2 and regulatory cytokines were determined in allergic (n = 79), sensitized (n = 40) and nonsensitized, nonallergic (n = 37) infants by multiplex assay. RESULTS: Food-sensitized infants had significantly higher plasma IL-4, IL-13, IL-12p70 and lower IL-10 levels compared to nonsensitized infants. IL-10 and IL-6 levels were significantly higher in sensitized compared with allergic infants. Egg-allergic infants had significantly higher IL-13 and IL-12p70 levels compared to peanut-allergic (PA) infants. CONCLUSION: Levels of Th2-related cytokines in plasma are higher in food-sensitized infants, irrespective of clinical food allergy status. In contrast, IL-10 levels appear to predict food allergy among sensitized infants. Differences in IL-13 and IL-12p70 between egg- and peanut-allergic infants could help explain the different resolution rates of the allergies.

Environmental and demographic risk factors for egg allergy in a population-based study of infants.

BACKGROUND: Although egg allergy is the most common food allergy in infants and young children, risk factors for egg allergy remain largely unknown. This study examined the relationship between environmental and demographic factors and egg allergy in a population-based infant cohort. METHODS: In a study of 5276 infants (HealthNuts), infants underwent skin prick testing (SPT) to egg white at 12 months of age. Questionnaire data on relevant exposures were obtained. 699/873 (80%) infants eligible for oral food challenge (detectable wheal on SPT) attended for formal assessment of egg allergy status; 453 had confirmed egg allergy (positive challenge and SPT ≥ 2 mm). Associations between environmental and demographic factors and egg allergy were investigated using multivariable logistic regression. RESULTS: Children with older siblings and those with a pet dog at home were less likely to develop egg allergy by 1 year of age (adjusted OR [aOR], 0.72; 95% CI, 0.62, 0.83 per sibling; and aOR, 0.72; 95% CI, 0.52, 0.99, respectively). Caesarean section delivery, antibiotic use in infancy, childcare attendance and maternal age were not associated with egg allergy. History of allergic disease in an immediate family member and having parents born in East Asia were strong risk factors for infantile egg allergy (aOR, 1.82; 95% CI, 1.40, 2.36; and aOR, 3.30; 95% CI, 2.45, 4.45, respectively). CONCLUSIONS: Exposure in the first year of life to siblings and dogs may decrease the risk of subsequent egg allergy. Infants with a family history of allergy and those with parents born in East Asia are at increased risk of egg allergy.

The HealthNuts population-based study of paediatric food allergy: validity, safety and acceptability.

BACKGROUND: The incidence of hospital admissions for food allergy-related anaphylaxis in Australia has increased, in line with world-wide trends. However, a valid measure of food allergy prevalence and risk factor data from a population-based study is still lacking. OBJECTIVE: To describe the study design and methods used to recruit infants from a population for skin prick testing and oral food challenges, and the use of preliminary data to investigate the extent to which the study sample is representative of the target population. METHODS: The study sampling frame design comprises 12-month-old infants presenting for routine scheduled vaccination at immunization clinics in Melbourne, Australia. We compared demographic features of participating families to population summary statistics from the Victorian Perinatal census database, and administered a survey to those non-responders who chose not to participate in the study. RESULTS: Study design proved acceptable to the community with good uptake (response rate 73.4%), with 2171 participants recruited. Demographic information on the study population mirrored the Victorian population with most the population parameters measured falling within our confidence intervals (CI). Use of a non-responder questionnaire revealed that a higher proportion of infants who declined to participate (non-responders) were already eating and tolerating peanuts, than those agreeing to participate (54.4%; 95% CI 50.8, 58.0 vs. 27.4%; 95% CI 25.5, 29.3 among participants). CONCLUSION: A high proportion of individuals approached in a community setting participated in a food allergy study. The study population differed from the eligible sample in relation to family history of allergy and prior consumption and peanut tolerance, providing some insights into the internal validity of the sample. The study exhibited external validity on general demographics to all births in Victoria.