Fucoxanthin levels in maternal serum at birth and eczema risk in offspring in early childhood: A birth cohort study.

BACKGROUND: Fucoxanthin, a marine xanthophyll carotenoid, has been shown to exert beneficial health effects. Cell-based and animal-based experimental studies have shown that fucoxanthin has the potential to mitigate eczema symptoms. Hence, we sought to assess whether fucoxanthinol 3-arachidate, a fucoxanthin metabolite, measured in maternal serum at birth is associated with eczema development during early childhood. METHODS: Data from the 1989/1990 Isle of Wight birth cohort were analyzed. We focused on data obtained from the 1, 2, and 4 years follow-ups. Fucoxanthinol 3-arachidate was measured in maternal serum at the child's birth as abundance relative to the reference lipids. Eczema was ascertained according to parent-reported clinical history and characteristic morphology and distribution. Log-binomial regression models were used to estimate adjusted risk ratios (aRR) and their 95% confidence intervals (CI). RESULTS: A total of 592 subjects (49.2% males and 50.8% females) were included in the current analysis. Associations between fucoxanthinol 3-arachidate levels and eczema risk during the first 4 years of life (longitudinal analysis) were evaluated using four modeling approaches, which showed higher fucoxanthinol 3-arachidate levels were associated with reduced eczema risk: (i) aRRper 10 unit increase = 0.88, 95% CI: 0.76-1.03; (ii) aRR>0 vs. =0 = 0.67, 0.45-0.99; (iii) aRR≥2.3 vs. <2.3 = 0.66, 0.44-0.98; and (iv) aRRtertile 3 vs. tertile 1 = 0.65, 0.42-0.99. CONCLUSION: Our findings suggest that increased fucoxanthinol 3-arachidate levels measured in maternal serum at the child's birth is associated with reduced eczema risk during the first 4 years of the offspring life.

The efficacy of the Dyson air purifier on asthma control: A single-center, investigator-led, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Air pollution is associated with poor asthma outcomes. High-efficiency particulate air air purifiers may reduce air pollution and thus improve asthma outcomes. However, the efficacy of such devices for this purpose remains inconclusive. OBJECTIVE: To investigate the effects of reducing the levels of pollutants on asthma outcomes in adults, using a novel Dyson high-efficiency particulate air air purifier. METHODS: In a single-center, double-blinded, randomized controlled trial, participants (N = 50) were randomized at a 1:1 ratio to active filters (intervention) or to dummy filters (placebo) for a total of 78 weeks. The primary outcomes were the changes in Asthma Control Questionnaire 6 (ACQ6) and Asthma-specific Quality of Life Questionnaire (AQLQ) scores from baseline. The secondary outcomes were changes in indoor air pollution and lung function measurements. The coronavirus disease 2019 pandemic limited spirometry measurements to 2 time points and assessment of fractional exhaled nitric oxide and bronchial hyperresponsiveness to baseline only. RESULTS: Air pollutant levels were significantly lower in the intervention group compared with the placebo group (P = .0003). Both groups had a significant improvement in their ACQ6 and AQLQ. However, there were no significant between-group differences in ACQ6, AQLQ, or spirometry, compared with baseline in multivariable repeated measures models. CONCLUSION: The Dyson air purifier significantly improved air quality. However, there were no significant improvements in asthma control, quality of life, or measures of lung function in the intervention group compared with the control group despite improvements in indoor air quality. Larger, extended studies are required to confirm or refute these findings, especially given that the coronavirus disease 2019 pandemic prevented the procurement of detailed objective data. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04729530; ttps://clinicaltrials.gov/ct2/show/NCT04729530.

Modeling Wheezing Spells Identifies Phenotypes with Different Outcomes and Genetic Associates.

Rationale: Longitudinal modeling of current wheezing identified similar phenotypes, but their characteristics often differ between studies. Objectives: We propose that a more comprehensive description of wheeze may better describe trajectories than binary information on the presence/absence of wheezing. Methods: We derived six multidimensional variables of wheezing spells from birth to adolescence (including duration, temporal sequencing, and the extent of persistence/recurrence). We applied partition-around-medoids clustering on these variables to derive phenotypes in five birth cohorts. We investigated within- and between-phenotype differences compared with binary latent class analysis models and ascertained associations of these phenotypes with asthma and lung function and with polymorphisms in asthma loci 17q12-21 and CDHR3 (cadherin-related family member 3). Measurements and Main Results: Analysis among 7,719 participants with complete data identified five spell-based wheeze phenotypes with a high degree of certainty: never (54.1%), early-transient (ETW) (23.7%), late-onset (LOW) (6.9%), persistent (PEW) (8.3%), and a novel phenotype, intermittent wheeze (INT) (6.9%). FEV1/FVC was lower in PEW and INT compared with ETW and LOW and declined from age 8 years to adulthood in INT. 17q12-21 and CDHR3 polymorphisms were associated with higher odds of PEW and INT, but not ETW or LOW. Latent class analysis- and spell-based phenotypes appeared similar, but within-phenotype individual trajectories and phenotype allocation differed substantially. The spell-based approach was much more robust in dealing with missing data, and the derived clusters were more stable and internally homogeneous. Conclusions: Modeling of spell variables identified a novel intermittent wheeze phenotype associated with lung function decline to early adulthood. Using multidimensional spell variables may better capture wheeze development and provide a more robust input for phenotype derivation.

Evolution of Eczema, Wheeze, and Rhinitis from Infancy to Early Adulthood: Four Birth Cohort Studies.

Rationale: The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. Objectives: To investigate within-individual patterns of morbidity of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood. Methods: We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin [FLG] mutations and 17q21 variants), increase the risk of multimorbidity. Measurements and Main Results: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema+wheeze+rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity. Conclusions: Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.

Early-life respiratory tract infections and the risk of school-age lower lung function and asthma: a meta-analysis of 150 000 European children.

BACKGROUND: Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. METHODS: We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. RESULTS: Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. CONCLUSIONS: Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.

Sex-specific developmental trajectories of eczema from infancy to age 26 years: A birth cohort study.

BACKGROUND: Eczema is a common inflammatory skin disease with varying developmental trajectories/patterns that are influenced by different risk factors. The aim of this study was to investigate eczema development from infancy to early adulthood by identifying distinct developmental trajectories that describe disease patterns over time and evaluate the role of prenatal and early-life risk factors. METHODS: The Isle of Wight Birth Cohort (n = 1456) was prospectively assessed at birth, 1, 2, 4, 10, 18 and 26 years. In all assessments, eczema was defined as chronic or chronically relapsing itchy dermatitis lasting >6 weeks with characteristic morphology and distribution in the past 12 months. Developmental trajectories of eczema between 1 or 2 and 26 years were identified separately for males and females by applying semiparametric mixture models. Associations were assessed by applying a modified Poisson regression to estimate adjusted risk ratios (aRR) and 95% confidence intervals (CI). RESULTS: In both males and females, the following eczema developmental trajectories were identified: unaffected/transient (males: 77.7% vs. females: 73.0%), mid-onset late-resolving (males: 7.8% vs. females: 4.4%), late-onset (males: 5.2% vs. females: 9.5%) and early-onset persistent (males: 9.3% vs. females: 5.4%). In females, an additional trajectory was identified as follows: early-onset early-resolving (7.7%). Among males, filaggrin gene (FLG) variants (aRR = 2.45, 95% CI: 1.34-4.46) and paternal eczema (2.66, 1.39-5.08) were associated with the early-onset persistent trajectory. Among females, maternal eczema (2.84, 1.42-5.70) and high birthweight (2.25, 1.08-4.69) were associated with the early-onset persistent trajectory. CONCLUSIONS: Four and five trajectories represented eczema development among males and females, respectively, with different predisposing risk factors. Our results indicate that males and females may experience a different course of eczema.

Newborn DNA methylation and asthma acquisition across adolescence and early adulthood.

BACKGROUND: Little is known about the association of newborn DNA methylation (DNAm) with asthma acquisition across adolescence and early adult life. OBJECTIVE: We aim to identify epigenetic biomarkers in newborns for asthma acquisition during adolescence or young adulthood. METHODS: The Isle of Wight Birth Cohort (IOWBC) (n = 1456) data at ages 10, 18 and 26 years were assessed. To screen cytosine-phosphate-guanine site (CpGs) potentially associated with asthma acquisition, at the genome scale, we examined differentially methylated regions (DMR) using dmrff R package and individual CpG sites using linear regression on such associations. For CpGs that passed screening, we examined their enrichment in biological pathways using their mapping genes and tested their associations with asthma acquisitions using logistic regressions. Findings in IOWBC were tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. RESULTS: In total, 2636 unique CpGs passed screening, based on which we identified one biological pathway linked to asthma acquisition during adolescence in females (FDR adjusted p-value = .003 in IOWBC). Via logistic regressions, for females, four CpGs were shown to be associated with asthma acquisition during adolescence, and another four CpGs with asthma acquisition in young adulthood (FDR adjusted p-value < .05 in IOWBC) and these eight CpGs were replicated in ALSPAC (all p-values < .05). DNAm at all the identified CpGs was shown to be temporally consistent, and at six of the CpGs was associated with expressions of adjacent or mapping genes in females (all p-values < .05). For males, 622 CpGs were identified in IOWBC (FDR = 0.01), but these were not tested in ALSPAC due to small sample sizes. CONCLUSION AND CLINICAL RELEVANCE: Eight CpGs on LHX5, IL22RA2, SOX11, CBX4, ACPT, CFAP46, MUC4, and ATP1B2 genes have the potential to serve as candidate epigenetic biomarkers in newborns for asthma acquisition in females during adolescence or young adulthood.

The role of epigenetics in multi-generational transmission of asthma: An NIAID workshop report-based narrative review.

There is mounting evidence that environmental exposures can result in effects on health that can be transmitted across generations, without the need for a direct exposure to the original factor, for example, the effect of grandparental smoking on grandchildren. Hence, an individual's health should be investigated with the knowledge of cross-generational influences. Epigenetic factors are molecular factors or processes that regulate genome activity and may impact cross-generational effects. Epigenetic transgenerational inheritance has been demonstrated in plants and animals, but the presence and extent of this process in humans are currently being investigated. Experimental data in animals support transmission of asthma risk across generations from a single exposure to the deleterious factor and suggest that the nature of this transmission is in part due to changes in DNA methylation, the most studied epigenetic process. The association of father's prepuberty exposure with offspring risk of asthma and lung function deficit may also be mediated by epigenetic processes. Multi-generational birth cohorts are ideal to investigate the presence and impact of transfer of disease susceptibility across generations and underlying mechanisms. However, multi-generational studies require recruitment and assessment of participants over several decades. Investigation of adult multi-generation cohorts is less resource intensive but run the risk of recall bias. Statistical analysis is challenging given varying degrees of longitudinal and hierarchical data but path analyses, structural equation modelling and multilevel modelling can be employed, and directed networks addressing longitudinal effects deserve exploration as an effort to study causal pathways.

Does allergen immunotherapy for allergic rhinitis prevent asthma?

Asthma and allergic rhinitis (AR) have overlapping clinical and pathologic features, sustained by an underlying T helper 2 bias, resulting in airway inflammation that extends from the nose to the lung. Children who are monosensitized often develop polysensitization over time, and they are at high risk of developing asthma. The effect of allergen immunotherapy (AIT) is allergen specific, resulting in symptom improvement and reduction in medication requirement. It is the only known treatment that alters the natural history of allergic disease and induces long-term remission. A bystander or allergen-nonspecific effect of AIT has also been proposed-that AIT to 1 allergen might reduce the risk of development of sensitization to other allergens. Furthermore, several observational studies and clinical trials, in seasonal (pollen) and perennial (house dust mite) AR, have investigated a protective effect of AIT to prevent asthma. The overall evidence favors an asthma preventive effect of AIT in AR to grass and birch tree pollen. Fewer studies have investigated the use of AIT in children with perennial AR due to house dust mite allergy to prevent asthma, and the results are less convincing. The use of AIT to reduce the risk of progression to asthma, in children with AR, potentially has high impact, and it will make AIT more attractive and cost-effective. However, most studies have been of small sample size or of poor design, using different allergens and AIT methodology, making it challenging to draw firm conclusions. There is a need to do adequately powered studies with optimal design and assess cost-effectiveness of this strategy.

DNA methylation at birth is associated with lung function development until age 26†years.

Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (forced expiratory volume in 1 s, forced vital capacity, their ratio, and forced expiratory flow at 25-75% of forced vital capacity) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys and 390 girls of IOWBC-F1. Replication in ALSPAC focussed on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of eight CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1, STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, aged 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBC-F2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.

Real-world Omalizumab and Mepolizumab treated difficult asthma phenotypes and their clinical outcomes.

BACKGROUND: Omalizumab and Mepolizumab are biologic drugs with proven efficacy in clinical trials. However, a better understanding of their real-world effectiveness in severe asthma management is needed. OBJECTIVES: To better understand the real-world effectiveness of Omalizumab and Mepolizumab, elucidate the clinical phenotypes of patients treated with these drugs, identify baseline characteristics associated with biologic response and assess the spectrum of responses to these medications. METHODS: Using real-world clinical data, we retrospectively phenotyped biologic naïve patients from the Wessex AsThma CoHort of difficult asthma (N = 478) commenced on Omalizumab (N = 105) or Mepolizumab (N = 62) compared to severe asthma patients not receiving biologics (SNB, N = 178). We also assessed multiple clinical endpoints and identified features associated with response. RESULTS: Compared to SNB, Omalizumab patients were younger, diagnosed with asthma earlier, and more likely to have rhinitis. Conversely, compared to SNB, Mepolizumab patients were predominantly older males, diagnosed with asthma later, and more likely to have nasal polyposis but less dysfunctional breathing. Both treatments reduced exacerbations, Acute Healthcare Encounters [AHE] (emergency department or hospital admissions), maintenance oral corticosteroid dose, and improved Asthma Control Questionnaire 6 (ACQ6) scores. Omalizumab response was independently associated with more baseline exacerbations (p = .024) but fewer AHE (p = .050) and absence of anxiety (p = .008). Lower baseline ACQ6 was independently associated with Mepolizumab response (p = .007). A composite group of non-responders demonstrated significantly more psychopathologies and worse baseline subjective disease compared to responder groups. CONCLUSIONS AND CLINICAL RELEVANCE: In a difficult asthma cohort, Omalizumab and Mepolizumab were used in distinct clinical phenotypes but were both multidimensionally efficacious. Certain baseline clinical characteristics were associated with poorer biologic responses, such as psychological co-morbidity, which may assist clinicians in biologic selection. These characteristics also emphasize the need for comprehensive approaches to support these patients.

Sex-specific associations of asthma acquisition with changes in DNA methylation during adolescence.

BACKGROUND: Underlying biological mechanisms involved in sex differences in asthma status changes from pre- to post-adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma. OBJECTIVE: We hypothesized that asthma acquisition from pre- to post-adolescence was associated with changes in DNAm during this period at asthma-associated cytosine-phosphate-guanine (CpG) sites and such an association was sex-specific. METHODS: Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n = 124 females, 151 males) were studied. Using a training-testing approach, epigenome-wide CpGs associated with asthma were identified. Logistic regression was used to examine sex-specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma-associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed. RESULTS: We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (P-values <1.0 × 10-3 ). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex-specific effects on asthma transition (P-values <.01 in both cohorts). CONCLUSION AND CLINICAL RELEVANCE: Gender reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre- to post-adolescence at asthma-associated CpGs. These CpGs are potential biomarkers of sex-specific asthma acquisition in adolescence.

Childhood food allergy and food allergen sensitisation are associated with adult airways disease: A birth cohort study.

BACKGROUND: Childhood food allergy (FA) and food allergen sensitization (FAS) are associated with allergic airway disease(s) [AAD] (asthma and rhinitis) in childhood. However, the associations between childhood FA/FAS and AAD in adulthood are not well described. METHODS: We investigated the longitudinal relationship between childhood FA/FAS to common food allergens and AAD at 18 and 26 years, in the Isle of Wight birth cohort. Study subjects (N = 1456) were followed up at fixed time points from ages 1-26 years for FA/FAS status. AAD were evaluated from 4 years onwards. The associations between FA/FAS and AAD were assessed with univariate analyses and then multivariable logistic regression, adjusting for clinically relevant co-variates. RESULTS: Food allergy at 4 years was significantly associated with asthma at 18 years [adjusted odds ratio (aOR): 2.75, 95% CI: 1.53-4.92, p = .001] and 26 years (aOR: 2.62, 95% CI: 1.32-5.20, p = .006). Conversely, childhood FA was not associated with adulthood rhinitis whatsoever. While FAS at ages 4 and 10 were associated with both AAD, the associations between FAS and rhinitis were less robust relative to asthma. CONCLUSION: Childhood FA increased the odds of asthma during adulthood by nearly threefold. Additionally, childhood FAS was also associated with increased odds of asthma in adulthood. Conversely, FAS but not FA in childhood was associated with rhinitis in adulthood. We suggest that children with FA/FAS should be followed up to facilitate early detection and intervention of subsequent AAD, particularly asthma.

Prediction models for childhood asthma: A systematic review.

BACKGROUND: The inability to objectively diagnose childhood asthma before age five often results in both under-treatment and over-treatment of asthma in preschool children. Prediction tools for estimating a child's risk of developing asthma by school-age could assist physicians in early asthma care for preschool children. This review aimed to systematically identify and critically appraise studies which either developed novel or updated existing prediction models for predicting school-age asthma. METHODS: Three databases (MEDLINE, Embase and Web of Science Core Collection) were searched up to July 2019 to identify studies utilizing information from children ≤5 years of age to predict asthma in school-age children (6-13 years). Validation studies were evaluated as a secondary objective. RESULTS: Twenty-four studies describing the development of 26 predictive models published between 2000 and 2019 were identified. Models were either regression-based (n = 21) or utilized machine learning approaches (n = 5). Nine studies conducted validations of six regression-based models. Fifteen (out of 21) models required additional clinical tests. Overall model performance, assessed by area under the receiver operating curve (AUC), ranged between 0.66 and 0.87. Models demonstrated moderate ability to either rule in or rule out asthma development, but not both. Where external validation was performed, models demonstrated modest generalizability (AUC range: 0.62-0.83). CONCLUSION: Existing prediction models demonstrated moderate predictive performance, often with modest generalizability when independently validated. Limitations of traditional methods have shown to impair predictive accuracy and resolution. Exploration of novel methods such as machine learning approaches may address these limitations for future school-age asthma prediction.

Breastfeeding duration modifies the effect of smoking during pregnancy on eczema from early childhood to adolescence.

BACKGROUND: Cigarette smoke contains compounds similar to coal tar, an ancient remedy of eczema. Some studies have reported protective effects of maternal gestational smoking on offspring eczema; however, others have shown no or increased risks. Similarly, studies linking breastfeeding duration and eczema have demonstrated contradictory findings. No study has yet investigated combined effects of these two factors on eczema. OBJECTIVE: Since tobacco compounds can pass to offspring via breast milk, we investigated their combined effects on eczema development from childhood to adolescence. METHODS: We obtained information regarding gestational smoking, exclusive breastfeeding duration, and eczema at ages 1-or-2, 4, 10, and 18 years from the Isle of Wight (IOW) birth cohort, UK. Using generalized estimating equations, we assessed the interaction of gestational smoking and residual exclusive breastfeeding duration (Resid-BF-duration, obtained by regressing the latter on maternal smoking) on eczema over time adjusting for confounders. For the three transition periods of 1-or-2 to 4 years, 4-10, and 10-18 years, we estimated risks of persistent, incident, and remitting eczema associated with the interaction using repeated measurements. RESULTS: If the mother smoked during gestation, longer Resid-BF-duration was associated with a lower risk of eczema, compared to if she did not smoke. The risk ratios (95% CI) if the mother smoked during gestation and exclusively breastfed for at least 3, 9, 15, 21 weeks are 0.7 (0.6, 1.7), 0.6 (0. 4, 0.9), 0.5 (0.3, 0.8), and 0.4 (0.2, 0. 8), respectively. Additionally, in all three transition periods, the risk of persistent eczema was lower with longer Resid-BF-duration if the mother smoked during gestation. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest a protective effect of gestational smoking combined with longer duration of exclusive breastfeeding on early-onset persistent eczema. Future studies should examine underlying biological mechanisms. Prolonged breastfeeding should be encouraged even if the mother smoked during gestation.

Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization.

BACKGROUND: Filaggrin loss-of-function (FLG-LOF) mutations are an established genetic cause of eczema. These mutations have subsequently been reported to increase the risk of aeroallergen sensitization and allergic airway disease. However, it is unclear whether FLG variants require both eczema and aeroallergen sensitization to influence airway disease development long-term outcomes. OBJECTIVE: To examine the effects of FLG-LOF mutations on allergic airway disease outcomes, with eczema and aeroallergen sensitization as intermediate variables, using the Isle of Wight birth cohort. METHODS: Study participants were evaluated at ages 1, 2, 4, 10 and 18 years to ascertain the development of allergic diseases (eczema, asthma and allergic rhinitis) and aeroallergen sensitization (determined by skin prick tests). FLG-LOF mutations were genotyped in 1150 subjects. To understand the complex associations between FLG mutations, intermediate variables (eczema and aeroallergen sensitization) and airway disease, path analysis was performed. RESULTS: There were significant total effects of FLG-LOF mutations on both asthma and allergic rhinitis at all ages as well as on aeroallergen sensitization up till 10 years old. In the filaggrin-asthma analysis, a direct effect of FLG-LOF mutations was observed on early childhood eczema (age 1 and 2 years) (relative risk (RR) 2.01, 95% CI: 1.74-2.31, P < .001), and all significant indirect pathways on asthma outcomes passed through eczema at these ages. In contrast, for the filaggrin-rhinitis model, FLG-LOF mutations exerted significant direct effects on early eczema as well as rhinitis at 10 years (RR 1.99; 95% CI: 1.72-2.29, P = .002). CONCLUSION: FLG-LOF mutations are a significant risk factor for later childhood asthma and rhinitis. However, the pathway to asthma is only through early childhood eczema while a direct effect was observed for childhood rhinitis.

NIAID, NIEHS, NHLBI, and MCAN Workshop Report: The indoor environment and childhood asthma-implications for home environmental intervention in asthma prevention and management.

Environmental exposures have been recognized as critical in the initiation and exacerbation of asthma, one of the most common chronic childhood diseases. The National Institute of Allergy and Infectious Diseases; National Institute of Environmental Health Sciences; National Heart, Lung, and Blood Institute; and Merck Childhood Asthma Network sponsored a joint workshop to discuss the current state of science with respect to the indoor environment and its effects on the development and morbidity of childhood asthma. The workshop included US and international experts with backgrounds in allergy/allergens, immunology, asthma, environmental health, environmental exposures and pollutants, epidemiology, public health, and bioinformatics. Workshop participants provided new insights into the biologic properties of indoor exposures, indoor exposure assessment, and exposure reduction techniques. This informed a primary focus of the workshop: to critically review trials and research relevant to the prevention or control of asthma through environmental intervention. The participants identified important limitations and gaps in scientific methodologies and knowledge and proposed and prioritized areas for future research. The group reviewed socioeconomic and structural challenges to changing environmental exposure and offered recommendations for creative study design to overcome these challenges in trials to improve asthma management. The recommendations of this workshop can serve as guidance for future research in the study of the indoor environment and on environmental interventions as they pertain to the prevention and management of asthma and airway allergies.