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In a previously published controlled trial, maternal administration of vitamin D during pregnancy was found to protect against wheeze in the offspring at the age of 3 years. In this follow-up study involving the same children at the age of 6 years, that supplementation no longer had a protective effect.

The airway microbiome has an important role in asthma pathophysiology. However, little is known on the relationships between the airway microbiome of asthmatic children, loss of asthma control, and severe exacerbations. Here we report that the microbiota’s dynamic patterns and compositions are related to asthma exacerbations. We collected nasal blow samples (n = 319) longitudinally during a clinical trial at 2 time-points within one year: randomization when asthma is under control, and at time of early loss of asthma control (yellow zone (YZ)). We report that participants whose microbiota was dominated by the commensal Corynebacterium   +   Dolosigranulum cluster at RD experience the lowest rates of YZs (p = 0.005) and have longer time to develop at least 2 episodes of YZ (p = 0.03). The airway microbiota have changed from randomization to YZ. A switch from the Corynebacterium   +   Dolosigranulum cluster at randomization to the Moraxella- cluster at YZ poses the highest risk of severe asthma exacerbation (p = 0.04). Corynebacterium’s relative abundance at YZ is inversely associated with severe exacerbation (p = 0.002). How the airway microbiome influences asthma pathophysiology remains unclear. Here, the authors analyse nasal samples of cohort of school-age children with persistent asthma and find that the microbiota’s patterns and composition at time of early loss of asthma control associate with severe asthma exacerbations.

The Global Initiative for Asthma (GINA) was established in 1993 by the World Health Organization and the US National Heart Lung and Blood Institute to improve asthma awareness, prevention and management worldwide. GINA develops and publishes evidence-based, annually updated resources for clinicians. GINA guidance is adopted by national asthma guidelines in many countries, adapted to fit local healthcare systems, practices, and resource availability. GINA is independent of industry, funded by the sale and licensing of its materials. This review summarizes key practical guidance for primary care from the 2022 GINA strategy report. It provides guidance on confirming the diagnosis of asthma using spirometry or peak expiratory flow. GINA recommends that all adults, adolescents and most children with asthma should receive inhaled corticosteroid (ICS)-containing therapy to reduce the risk of severe exacerbations, either taken regularly, or (for adults and adolescents with “mild” asthma) as combination ICS–formoterol taken as needed for symptom relief. For patients with moderate–severe asthma, the preferred regimen is maintenance-and-reliever therapy (MART) with ICS–formoterol. Asthma treatment is not “one size fits all”; GINA recommends individualized assessment, adjustment, and review of treatment. As many patients with difficult-to-treat or severe asthma are not referred early for specialist review, we provide updated guidance for primary care on diagnosis, further investigation, optimization and treatment of severe asthma across secondary and tertiary care. While the GINA strategy has global relevance, we recognize that there are special considerations for its adoption in low- and middle-income countries, particularly the current poor access to inhaled medications.

Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia. We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10-18 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (32-38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia. Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61-1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD ≥30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.10-0.96). Differential expression of 348 vitamin D-associated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial [VDAART]; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity. Vitamin D supplementation initiated in weeks 10-18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia. ClinicalTrials.gov NCT00920621. Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.

Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment. In this 44-week, randomised, double-blind, placebo-controlled trial we enrolled children and adolescents with mild persistent asthma aged 5–18 years from five clinical centres in the USA. A computer-generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 μg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 μg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. This study is registered with clinicaltrials.gov, number NCT00394329. 843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)—555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37–61), the frequency of exacerbations was lower in the daily (28%, 18–40, p=0·03), combined (31%, 21–43, p=0·07), and rescue (35%, 24–47, p=0·07) groups. Frequency of treatment failure was 23% (95% CI 14–43) in the placebo group, compared with 5·6% (1·6–14) in the combined (p=0·012), 2·8% (0–10) in the daily (p=0·009), and 8·5% (2–15) in the rescue (p=0·024) groups. Compared with the placebo group, linear growth was 1·1 cm (SD 0·3) less in the combined and daily arms (p<0·0001), but not the rescue group (p=0·26). Only two individuals had severe adverse events; one in the daily beclomethasone group had viral meningitis and one in the combined group had bronchitis. Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided. National Heart, Lung and Blood Institute.

Phenotypic distinctions between severe asthma (SA) and nonsevere asthma (NONSA) may be confounded by differential adherence or incorrect use of corticosteroids. To determine if there are persistent phenotypic distinctions between SA (as defined by 2014 American Thoracic Society/European Respiratory Society guidelines) and NONSA after intramuscular triamcinolone acetonide (TA), and to identify predictors of a corticosteroid response in these populations. A total of 526 adults age 18 years and older (315 SA) and 188 children age 6 to less than 18 years (107 SA) in the NHLBI Severe Asthma Research Program III were characterized before and 3 weeks after TA. The primary outcome for corticosteroid response was defined as greater than or equal to 10-point improvement in percent predicted FEV . Adult asthma groups exhibited a small but significant mean FEV % predicted improvement after TA (SA group mean difference, 3.4%; 95% confidence interval, 2.2-4.7%; P = 0.001), whereas children did not. Adult SA continued to manifest lower FEV and worse asthma control as compared with NONSA after TA. In children, after TA only prebronchodilator FEV distinguished SA from NONSA. A total of 21% of adults with SA and 20% of children with SA achieved greater than or equal to 10% improvement after TA. Baseline bronchodilator response and fractional exhaled nitric oxide had good sensitivity and specificity for predicting response in all groups except children with NONSA. One in five patients with SA exhibit greater than or equal to 10% improvement in FEV with parenteral corticosteroid. Those likely to respond had greater bronchodilator responsiveness and fractional exhaled nitric oxide levels. In adults, differences in airflow obstruction and symptoms between SA and NONSA persist after parenteral corticosteroids, suggesting a component of corticosteroid nonresponsive pathobiology in adults with SA that may differ in children. Clinical trial registered with www.clinicaltrials.gov (NCT 01606826).

Mepolizumab (anti-IL5 therapy) reduces asthma exacerbations in urban children with exacerbation-prone eosinophilic asthma. We previously utilized nasal transcriptomics to identify inflammatory pathways (gene co-expression modules) associated with asthma exacerbations despite this therapy. In this study, we applied differential gene correlation analysis on these targeted gene co-expression modules to gain better insight into the treatment effects on correlation structure within gene networks. Mepolizumab treatment resulted in loss of correlation amongst eosinophil-specific genes but conservation and even strengthening of correlation amongst mast cell-specific genes, T2 cytokines, and airway epithelial inflammatory genes. Notably, mepolizumab induced significant gain in correlation of genes associated with multiple aspects of airway epithelial inflammation including those related to extracellular matrix production and nitric oxide synthesis, and this change was associated with a poor clinical response to mepolizumab. These findings highlight that using differential gene correlation analysis offers insight into the molecular regulatory effects of treatment on gene interactions and may lead to better understanding of disease mechanisms and therapeutic responses. ClinicalTrials.gov ID: NCT03292588. Mepolizumab (anti-IL-5 therapy) has been shown to reduce type 2 inflammation in asthma. Here the authors use bulk transcriptomics from nasal samples before and after mepolizumab treatment to assess the changes and associations with treatment outcomes.

IgE sensitization to cockroach allergens is associated with development of allergic diseases, such as asthma. To understand the relevance of different cockroach allergens for diagnosis and immunotherapy, a comprehensive analysis of IgE antibody levels and T cell reactivity to an expanded set of cockroach allergens and their relationship to disease was performed in a cohort of USA cockroach sensitized patients. IgE antibody levels to recombinant chitinase and hemocyanin were measured for 23 subjects by custom-made ImmunoCAPs and compared with IgE levels to eight cockroach allergens we previously reported for the same cohort. Ex vivo T cell activation (Ox40/PDL-1 expression) of PBMCs stimulated with peptide pools derived from 11 German cockroach proteins, including nine official cockroach allergens, plus chitinase and vitellogenin, was determined by flow cytometry. IgE prevalences to chitinase (17%) and hemocyanin (44%) were comparable to values for the other eight allergens that we previously reported (21–57%). Hemocyanin (Bla g 3), was a major allergen (one to which more than 50% of patients with an allergy to its source react) for a sub-group of 15 highly cockroach-sensitized subjects (IgE > 3.5 kU A /L: 53%). Chitinase was officially named as new allergen Bla g 12. Cockroach-specific IgE levels in plasma showed excellent correlation with the sum of 10 allergen-specific IgE (r = 0.94, p < 0.001). T cell reactivity to 11 proteins was highly variable among subjects, the highest being for vitellogenin, followed by Bla g 3. The main finding was that cockroach allergen-specific IgE and T cell reactivity patterns were unique per subject, and lacked immunodominant allergens and correlation with clinical phenotype/disease severity in the studied cohort. Knowing the subject-specific B/T cell reactivity profiles to a comprehensive panel of cockroach allergens will contribute to diagnosis of cockroach allergy and will be important for planning and assessing allergen immunotherapy outcomes, according to the allergen content in therapeutic cockroach extracts.

Background Single birth cohort studies have been the basis for many discoveries about early life risk factors for childhood asthma but are limited in scope by sample size and characteristics of the local environment and population. The Children’s Respiratory and Environmental Workgroup (CREW) was established to integrate multiple established asthma birth cohorts and to investigate asthma phenotypes and associated causal pathways (endotypes), focusing on how they are influenced by interactions between genetics, lifestyle, and environmental exposures during the prenatal period and early childhood. Methods and results CREW is funded by the NIH Environmental influences on Child Health Outcomes (ECHO) program, and consists of 12 individual cohorts and three additional scientific centers. The CREW study population is diverse in terms of race, ethnicity, geographical distribution, and year of recruitment. We hypothesize that there are phenotypes in childhood asthma that differ based on clinical characteristics and underlying molecular mechanisms. Furthermore, we propose that asthma endotypes and their defining biomarkers can be identified based on personal and early life environmental risk factors. CREW has three phases: 1) to pool and harmonize existing data from each cohort, 2) to collect new data using standardized procedures, and 3) to enroll new families during the prenatal period to supplement and enrich extant data and enable unified systems approaches for identifying asthma phenotypes and endotypes. Conclusions The overall goal of CREW program is to develop a better understanding of how early life environmental exposures and host factors interact to promote the development of specific asthma endotypes.

German cockroach extract is used clinically to evaluate allergen-specific sensitization and for subcutaneous allergen-specific immunotherapy, though there are no guidelines for standardization in its manufacture. We performed an immunological evaluation of 12 different cockroach extracts prepared from different sources and their potency to induce allergen-specific T cell reactivity. PBMC from 13 cockroach allergic donors were expanded with 12 different German cockroach extracts. After culture expansion, cells were re-stimulated with the different extracts and T cell responses were assessed by FluoroSpot (IL-5, IFNγ and IL-10 production). In parallel to the extracts, single allergen peptide pools for allergens from groups 1, 2, 4, 5, and 11 were tested to determine allergen immunodominance. Furthermore, to assess allergy specificity, PBMC from 13 non-allergic donors were also tested with the most potent extract and T cell responses were compared to the allergic cohort. Dramatic variations in T cell reactivity were observed to the different cockroach extract batches. Response magnitudes varied over 3 logs within a single donor. IL-5 production in the allergic cohort was significantly higher compared to the non-allergic cohort (p=0.004). Allergen content determination by ELISA detected much lower concentrations of Bla g 5 compared to Bla g 1 and 2. Mass spectrometric analysis revealed that Bla g 5 was present in similar amounts to Bla g 1 and 2 in extracts made from whole body, whereas it was not detected in extracts made from fecal matter, suggesting that Bla g 5 is not excreted into feces. Different donors exhibit different response patterns to different extracts, potentially dependent on the donor-specific T cell allergen immunodominance pattern and the allergen content of the extract tested. These findings have dramatic implications for the selection of potent extracts used for diagnostic purposes or allergen-specific immunotherapy.