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.

Association of breast milk fatty acids with allergic disease outcomes-A systematic review.

INTRODUCTION: Dietary polyunsaturated fatty acids (PUFAs) have immunoregulatory properties. Breast milk is rich in PUFA, and it has been hypothesized that these PUFAs may be important in the aetiology of allergic diseases. Despite a growing body of evidence, the associations between breast milk PUFA and allergic disease have not previously been systematically reviewed. METHODS: The search was performed in PubMed and EMBASE databases using breastfeeding, fatty acid and allergic disease terms. Two authors were involved in selecting papers for review according to the inclusion criteria and extracting information on study characteristics and measures of association. Only studies that reported numeric associations between concentration of breast milk fatty acids and allergic disease outcomes were included. RESULTS: A total of 18 papers met the inclusion criteria, reporting results from 15 study populations. The majority were cohort studies (n=11), with data from only two case-control and two cross-sectional studies. Sample size varied between 30 and 352 participants, and follow-up time of the cohorts varied between 3 months and 14 years. Nine studies reported on eczema, seven reported on sensitization, and only five reported on asthma/wheeze. There was heterogeneity among studies in terms of presenting the association between PUFA and allergy; therefore, estimates could not be pooled. Only a few studies observed associations between n-3 and n-6 PUFAs and allergic disease, and the magnitude of this effect varied greatly. CONCLUSIONS: There is insufficient evidence to suggest that colostrum or breast milk polyunsaturated fatty acids influence the risk of childhood allergic diseases.

Grandmaternal smoking increases asthma risk in grandchildren: A nationwide Swedish cohort.

BACKGROUND: There is growing interest in exposures prior to conception as possible risk factors for offspring asthma. Although partially supported by evidence from limited human studies, current evidence is inconsistent and based on recall of exposure status. OBJECTIVE: We aimed to investigate grandmaternal smoking during pregnancy and the risk of asthma in grandchildren using prospectively collected population-based data. METHODS: Information on grandmaternal and maternal smoking during pregnancy and grandchild use of asthma medications was collected from national Swedish registries. Associations between grandmaternal smoking during pregnancy (10-12 weeks) and asthma medication use in grandchildren were investigated using generalized estimating equations. Ages at which asthma medications were prescribed classified childhood asthma into never, early transient (0-3 years), late onset (3-6 years) and early persistent (0-3 and 3-6 years) phenotypes. RESULTS: From 1982 to 1986, 44 583 grandmothers gave birth to 46 197 mothers, who gave birth to 66 271 grandchildren (born 1996-2010). Children aged 1-6 years had an increased asthma risk if their grandmothers had smoked during pregnancy, with a higher risk for more exposure (10+ cigs/d; adjusted OR 1.23; 1.17, 1.30). Maternal smoking did not modify this relationship. CONCLUSIONS & CLINICAL RELEVANCE: Children had an increased risk of asthma in the first 6 years of life if their grandmothers smoked during early pregnancy, independent of maternal smoking. Importantly, this exhibited a dose-response relationship and was associated with a persistent childhood asthma phenotype. These findings support possible epigenetic transmission of risk from environmental exposures in previous generations.

The effects of growing up on a farm on adult lung function and allergic phenotypes: an international population-based study.

RATIONALE: Evidence has suggested that exposure to environmental or microbial biodiversity in early life may impact subsequent lung function and allergic disease risk. OBJECTIVES: To investigate the influence of childhood living environment and biodiversity indicators on atopy, asthma and lung function in adulthood. METHODS AND MEASUREMENTS: The European Community Respiratory Health Survey II investigated ∼10 201 participants aged 26-54 years from 14 countries, including participants' place of upbringing (farm, rural environment or inner city) before age 5 years. A 'biodiversity score' was created based on childhood exposure to cats, dogs, day care, bedroom sharing and older siblings. Associations with lung function, bronchial hyper-responsiveness (BHR), allergic sensitisation, asthma and rhinitis were analysed. MAIN RESULTS: As compared with a city upbringing, those with early-life farm exposure had less atopic sensitisation (adjusted OR 0.46, 95% CI 0.37 to 0.58), atopic BHR (0.54 (0.35 to 0.83)), atopic asthma (0.47 (0.28 to 0.81)) and atopic rhinitis (0.43 (0.32 to 0.57)), but not non-atopic outcomes. Less pronounced protective effects were observed for rural environment exposures. Women with a farm upbringing had higher FEV1 (adjusted difference 110 mL (64 to 157)), independent of sensitisation and asthma. In an inner city environment, a higher biodiversity score was related to less allergic sensitisation. CONCLUSIONS: This is the first study to report beneficial effects of growing up on a farm on adult FEV1. Our study confirmed the beneficial effects of early farm life on sensitisation, asthma and rhinitis, and found a similar association for BHR. In persons with an urban upbringing, a higher biodiversity score predicted less allergic sensitisation, but to a lesser magnitude than a childhood farm environment.

Breast milk polyunsaturated fatty acids: associations with adolescent allergic disease and lung function.

BACKGROUND: It has been hypothesized that n-3 PUFA in breast milk may assist immune and lung development. There are very limited data on possible long-term effects on allergic disease and lung function. The aim was to investigate associations of n-3 and n-6 PUFA levels in colostrum and breast milk with allergic disease and lung function at ages 12 and 18 years. METHODS: Polyunsaturated fatty acids were measured in 194 colostrum samples and in 118 three-month expressed breast milk samples from mothers of children enrolled in the Melbourne Atopy Cohort (MACS) Study, a high-risk birth cohort study. Associations with allergic diseases, skin prick tests and lung function assessed at 12 and 18 years were estimated using multivariable regression. RESULTS: Higher levels of n-3 but not n-6 PUFAs in colostrum were associated with a trend towards increased odds of allergic diseases, with strong associations observed for allergic rhinitis at 12 (OR = 5.69[95% CI: 1.83,17.60] per weight%) and 18 years (4.43[1.46,13.39]) and eczema at 18 years (9.89[1.44, 68.49]). Higher levels of colostrum n-3 PUFAs were associated with reduced sensitization (3.37[1.18, 9.6]), mean FEV1 (-166 ml [-332, -1]) and FEV1 /FVC ratio (-4.6%, [-8.1, -1.1]) at 12 years. CONCLUSION: Higher levels of colostrum n-3 PUFAs were associated with increased risks of allergic rhinitis and eczema up to 18 years, and sensitization and reduced lung function at 12 years. As residual confounding may have caused these associations, they should be replicated, but these results could indicate that strategies that increase maternal n-3 PUFA intake may not aid in allergic disease prevention.

The march from early life food sensitization to allergic disease: a systematic review and meta-analyses of birth cohort studies.

BACKGROUND: There is growing evidence for an increase in food allergies. The question of whether early life food sensitization, a primary step in food allergies, leads to other allergic disease is a controversial but important issue. Birth cohorts are an ideal design to answer this question. OBJECTIVES: We aimed to systematically investigate and meta-analyse the evidence for associations between early food sensitization and allergic disease in birth cohorts. METHODS: MEDLINE and SCOPUS databases were searched for birth cohorts that have investigated the association between food sensitization in the first 2 years and subsequent wheeze/asthma, eczema and/or allergic rhinitis. We performed meta-analyses using random-effects models to obtain pooled estimates, stratified by age group. RESULTS: The search yielded fifteen original articles representing thirteen cohorts. Early life food sensitization was associated with an increased risk of infantile eczema, childhood wheeze/asthma, eczema and allergic rhinitis and young adult asthma. Meta-analyses demonstrated that early life food sensitization is related to an increased risk of wheeze/asthma (pooled OR 2.9; 95% CI 2.0-4.0), eczema (pooled OR 2.7; 95% CI 1.7-4.4) and allergic rhinitis (pooled OR 3.1; 95% CI 1.9-4.9) from 4 to 8 years. CONCLUSION: Food sensitization in the first 2 years of life can identify children at high risk of subsequent allergic disease who may benefit from early life preventive strategies. However, due to potential residual confounding in the majority of studies combined with lack of follow-up into adolescence and adulthood, further research is needed.

Breastfeeding and childhood acute otitis media: a systematic review and meta-analysis.

AIM: To synthesise the evidence on the association between duration and exclusivity of breastfeeding and the risk of acute otitis media (AOM). METHODS: Systematic review and meta-analysis following searching of PubMed, CINAHL and EMBASE electronic databases. RESULTS: Twenty-four studies, all from the USA or Europe, met the inclusion criteria. In the pooled analyses, any form of breastfeeding was found to be protective for AOM in the first 2 years of life. Exclusive breastfeeding for the first 6 months was associated with the greatest protection (OR 0.57 95% CI 0.44, 0.75), followed by 'more vs less' breastfeeding (OR 0.67; 0.59, 0.76) and 'ever vs never' breastfeeding (OR 0.67; 0.56, 0.80). CONCLUSION: This systematic review and meta-analysis provides evidence that breastfeeding protects against AOM until 2 years of age, but protection is greater for exclusive breastfeeding and breastfeeding of longer duration. Exclusive breastfeeding during the first 6 months was associated with around a 43% reduction in ever having AOM in the first 2 years of life. After 2 years of age, there is no evidence that breastfeeding protects against AOM; however, there were few studies and the evidence quality was low.

Breastfeeding and asthma and allergies: a systematic review and meta-analysis.

AIM: To systematically review the association between breastfeeding and childhood allergic disease. METHODS: Predetermined inclusion/exclusion criteria identified 89 articles from PubMed, CINAHL and EMBASE databases. Meta-analyses performed for categories of breastfeeding and allergic outcomes. Meta-regression explored heterogeneity. RESULTS: More vs. less breastfeeding (duration) was associated with reduced risk of asthma for children (5-18 years), particularly in medium-/low-income countries and with reduced risk of allergic rhinitis ≤5 years, but this estimate had high heterogeneity and low quality. Exclusive breastfeeding for 3-4 months was associated with reduced risk of eczema ≤2 years (estimate principally from cross-sectional studies of low methodological quality). No association found between breastfeeding and food allergy (estimate had high heterogeneity and low quality). Meta-regression found differences between study outcomes may be attributable to length of breastfeeding recall, study design, country income and date of study inception. Some of the protective effect of breastfeeding for asthma may be related to recall bias in studies of lesser methodological quality. CONCLUSION: There is some evidence that breastfeeding is protective for asthma (5-18 years). There is weaker evidence for a protective effect for eczema ≤2 years and allergic rhinitis ≤5 years of age, with greater protection for asthma and eczema in low-income countries.

Breastfeeding and the risk of dental caries: a systematic review and meta-analysis.

AIM: To synthesise the current evidence for the associations between breastfeeding and dental caries, with respect to specific windows of early childhood caries risk. METHODS: Systematic review, meta-analyses and narrative synthesis following searches of PubMed, CINAHL and EMBASE databases. RESULTS: Sixty-three papers included. Children exposed to longer versus shorter duration of breastfeeding up to age 12 months (more versus less breastfeeding), had a reduced risk of caries (OR 0.50; 95%CI 0.25, 0.99, I(2) 86.8%). Children breastfed >12 months had an increased risk of caries when compared with children breastfed <12 months (seven studies (OR 1.99; 1.35, 2.95, I(2) 69.3%). Amongst children breastfed >12 months, those fed nocturnally or more frequently had a further increased caries risk (five studies, OR 7.14; 3.14, 16.23, I(2) 77.1%). There was a lack of studies on children aged >12 months simultaneously assessing caries risk in breastfed, bottle-fed and children not bottle or breastfed, alongside specific breastfeeding practices, consuming sweet drinks and foods, and oral hygiene practices limiting our ability to tease out the risks attributable to each. CONCLUSION: Breastfeeding in infancy may protect against dental caries. Further research needed to understand the increased risk of caries in children breastfed after 12 months.

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.

Exposure to 'farming' and objective markers of atopy: a systematic review and meta-analysis.

There is growing interest in the 'farm effect' on the spectrum of allergy. Evidence concerning the farm effect on asthma, eczema, and allergic rhinitis has been systematically synthesized, but without a specific focus on objective markers of sensitization. This focus is important, as farm exposures may be related to allergy but not to non-allergic phenotypes of disease. We aimed to systematically review and meta-analyse literature that has investigated associations between farm exposure at any age and objective measures of atopy, that is serum IgE or skin prick tests results. Using predefined inclusion and exclusion criteria, we identified 29 articles for review. IgE levels were measured in either childhood or adulthood by eighteen studies, while skin prick testing was performed in sixteen studies. Newcastle-Ottawa Scale quality assessments indicated that the majority of these studies demonstrated a representative sample of selected participants. Due to significant heterogeneity in study measures and methodology between studies, only few were meta-analysed. This meta-analysis showed a significant protective effect of farm exposure before 1 year of life on allergic sensitization (OR = 0.60 [0.52-0.70]). Farm exposure during childhood was also associated with a reduced risk of sensitization to cat or timothy (OR = 0.60 [0.51-0.70]; OR=0.46 [0.41-0.51]). Studies investigating the effect of farm exposure in adult life could not be meta-analysed, and their results were inconsistent. Insufficient studies investigated food sensitization as an outcome to allow synthesis. The majority of studies included in this review investigated childhood farm exposure, finding evidence to support a protective childhood 'farm effect' against subsequent atopy. There is inconsistent evidence on the association between farm exposure in adulthood and allergic sensitization. Further studies are needed to tease out the exact exposures and timing associated with farming environments that protect against allergic disease.

Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: While paracetamol exposure in pregnancy and early infancy has been associated with asthma, it remains unclear whether this is confounded by respiratory tract infections, which have been suggested as an alternative explanation. We undertook a systematic review and meta-analysis of longitudinal studies that reported the association between paracetamol exposure during pregnancy or infancy and the subsequent development of childhood asthma (≥5 years). METHODS: Two independent researchers searched the databases EMBASE and PUBMED on 12 August 2013 for relevant articles using predefined inclusion and exclusion criteria. Study quality was assessed and results were pooled using fixed effect models or random effect models when moderate between-study heterogeneity was observed. We explicitly assessed whether the observed associations are due to confounding by respiratory tract infections. RESULTS: Eleven observational cohort studies met the inclusion criteria. Any paracetamol use during the first trimester was related to increased risk of childhood asthma (5 studies, pooled OR=1.39, 95% CI 1.01 to 1.91) but there was marked between-study heterogeneity (I(2)=63%) and only one of these studies adjusted for maternal respiratory tract infections. Increasing frequency of use of paracetamol during infancy was associated with increased odds of childhood asthma (3 studies, pooled OR=1.15, 95% CI 1.00 to 1.31 per doubling of days exposure), but in these same three studies adjusting for respiratory tract infections reduced this association (OR=1.06, 95% CI 0.92 to 1.22). DISCUSSION: The association during early pregnancy exposure was highly variable between studies and exposure during infancy appears to be moderately confounded by respiratory tract infections. There is insufficient evidence to warrant changing guidelines on early life paracetamol exposure at this time.

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.

CD14 polymorphisms, microbial exposure and allergic diseases: a systematic review of gene-environment interactions.

Asthma and allergy may develop as a result of interactions between environmental factors and the genetic characteristics of an individual. This review aims to summarize the available evidence for, and potential effects of, an interaction between polymorphisms of the CD14 gene and exposure to microbes on the risk of asthma and allergic diseases. We searched PubMed, MEDLINE and Global Health databases, finding 12 articles which met inclusion criteria. Most studies reported a significant interaction between CD14 polymorphisms and microbial exposure. When stratified by age at microbial exposure (early life vs adult life), there was evidence of a protective effect of gene-environment interaction against atopy in children, but not adults. We also found different effects of interaction depending on the type of microbial exposures. There was no strong evidence for asthma and eczema. Future studies should consider a three-way interaction between CD14 gene polymorphisms, microbial exposures and the age of exposure.

Exhaled breath condensate in pediatric asthma: promising new advance or pouring cold water on a lot of hot air? a systematic review.

BACKGROUND: Exhaled breath condensate (EBC) analysis is a simple non-invasive technique that allows repeated collection of breath samples with a minimum of inconvenience for the subject. These breath samples can potentially indicate lung disease activity and given the ease of collection, EBC is becoming a useful research tool in the study of respiratory diseases. It has the potential to be used in both population-based studies and in the context of pediatric asthma it may prove useful in diagnosis and monitoring. METHODS: A systematic review was conducted to identify studies of EBC markers in childhood asthma. RESULTS: Most of the studies were cross-sectional in design, and the results suggest that simple chemical entities such as hydrogen ions (as pH), hydrogen peroxide, and oxides of nitrogen are associated with pediatric allergic asthma and exacerbations. In addition, more complex molecules including leukotrienes, prostaglandins, and cytokines such as the interleukins IL-4 and IL-5 are also elevated in the breath of those with asthma. CONCLUSION: EBC has the potential to aid diagnosis, and to evaluate the inflammatory status of asthmatic children. Future studies may be able to refine further how best to collect EBC samples, to interpret them, and the technique has the potential to allow repeated sampling which will allow studies of natural history, pathogenesis and response to treatment to be undertaken.

Persistent pollen exposure during infancy is associated with increased risk of subsequent childhood asthma and hayfever.

BACKGROUND: Few studies have focused on pollen exposure and asthma in children. None have examined associations between persistent exposure to pollen in infancy and aeroallergen sensitisation and asthma in childhood. OBJECTIVES: To examine the association between higher ambient levels of pollen in the first 3-6 months of life and risk of eczema, sensitization to food and aeroallergens at 2 years and asthma or hayfever at age 6-7 years combined. METHODS: Using a birth cohort of 620 infants with a family history of allergic disease born between 1990 and 1994, we examined risk of eczema or allergic sensitization (SPT > 3 mm to at least one of cow's milk, egg white, peanut, house dust-mite, rye grass, and cat dander) by age 2 and asthma or hayfever at age 6-7. Daily ambient levels of pollen were measured during this period. RESULTS: Cumulative exposure to pollen concentrations up to 6 months was associated with aeroallergen sensitization with the highest risk occurring at 3 months (aOR = 1.34, 95% CI 1.06-1.72). Cumulative exposure to pollen up to 3 months was also associated with hayfever (aOR = 1.14, 95% CI 1.009-1.29) and between 4 and 6 months exposure with asthma only (aOR=1.35, 95% CI 1.07-1.72). CONCLUSION: Persistent pollen exposure in infancy appears to increase the risk of asthma and hayfever in children. These results support the hypothesis that there is a critical window of opportunity in early development which may be important for modification of allergic outcomes.