Impaired tumor necrosis factor-α secretion by CD4 T cells during respiratory syncytial virus bronchiolitis associated with recurrent wheeze

BACKGROUND: Infants with severe respiratory syncytial virus (RSV) bronchiolitis have an increased risk of recurrent wheezing and asthma. We aimed to evaluate the relationships between regulatory T cell (Treg) percentage and cytokine production of in vitro-stimulated CD4+ T cells during acute bronchiolitis and the development of recurrent wheezing in the first 3 years of life. METHODS: We obtained peripheral blood from 166 infants hospitalized with their first episode of RSV-confirmed bronchiolitis. Granzyme B (GZB) expression, and interleukin-10, interferon-γ, tumor necrosis factor-α (TNF-α), IL-4, and IL-5 production by in vitro anti-CD3/CD28- and anti-CD3/CD46-activated CD4+ T cells, and percentage of peripheral Treg (CD4+CD25 RESULTS: Sixty-seven percent (n = 111) of children had wheezing after their initial RSV infection, with 30% having recurrent wheezing. The percentage of peripheral Treg (CD4+CD25 CONCLUSIONS: We demonstrated lower TNF-α production by in vitro stimulated CD4+ T cells during severe RSV bronchiolitis in children that subsequently developed recurrent wheezing, compared with children with no subsequent wheeze. These findings support the role of CD4+ T cell immunity in the development of subsequent wheezing in these children

Azithromycin therapy during respiratory syncytial virus bronchiolitis: Upper airway microbiome alterations and subsequent recurrent wheeze.

J Allergy Clin Immunol 2016 Oct; 138(4):1215-19

Pooled Sequencing of Candidate Genes Implicates Rare Variants in the Development of Asthma Following Severe RSV Bronchiolitis in Infancy.

Severe infection with respiratory syncytial virus (RSV) during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7th birthday (asthma) using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP) as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC20) at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6x10-4, 1.9x10-13 and 5.0x10-5, respectively), and NOS1 in African Americans (p = 2.3x10-11). One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888), which was also nominally associated with asthma (p = 0.027) and active asthma (p = 0.013) among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis

Results of replication in the BRASS study of four variants associated with asthma following severe RSV bronchiolitis in infancy (number of asthma cases = 81, number of asthma controls = 126).

<p>Results of replication in the BRASS study of four variants associated with asthma following severe RSV bronchiolitis in infancy (number of asthma cases = 81, number of asthma controls = 126).</p

QQplot showing the results of association testing at nonsynonymous variants for physician-diagnosed asthma following severe RSV bronchiolitis in infancy.

<p>Genotypes from the exome sequencing project (ESP) were used as controls. The shaded area represents the 95% confidence interval.</p

Counts of rare and private rare variants in asthma cases vs. controls in anonymous pooled sequencing of coding exons of 131 candidate genes.

<p>Private variants are those private to either cases or controls within an ethnicity. NS = nonsynonymous, Syn = synonymous, NC = non-coding.</p

Results of further association testing of candidate variants within individuals with severe RSV bronchiolitis in infancy, without including genotypes from the ESP.

<p>Phenotypes include physician diagnosed asthma, active asthma, persistent wheeze, and methacholine PC₂₀ at age 6 years. P-values < 0.05 are in bold italics, Freq = allele frequency, OR = odds ratio, SE = standard error.</p

Summary of clinical characteristics of participants in the RBEL study.

<p>Abbreviations used: SaO₂ = lowest oxygen saturation recorded during index hospitalization; IgE = immunoglobulin E; FEV₁ = forced expiratory volume in one second; BD = bronchodilator; PC₂₀ = provocative concentration of methacholine that causes a 20% decline in FEV_1.</p><p>Summary of clinical characteristics of participants in the RBEL study.</p