Severe Respiratory Syncytial Virus Bronchiolitis In Infancy Research Articles

Lung function trajectories and bronchial hyperresponsiveness during childhood following severe RSV bronchiolitis in infancy.

Children with severe respiratory syncytial virus (RSV) bronchiolitis in infancy have increased risks of asthma and reduced lung function in later life. There are limited studies on the longitudinal changes of lung function and bronchial hyperreactivity from early to late childhood in infants hospitalized for RSV bronchiolitis. In a prospective cohort of 206 children with their first episode of RSV-confirmed bronchiolitis in the first year of life, 122 had spirometry performed at least twice between 5-16years of age. Methacholine bronchoprovocation was available in 127 and 79 children at 7 and 12years of age, respectively. Longitudinal changes in FEV1 , FVC, and FEV1 /FVC z-scores and methacholine PC20 were analyzed. 55% of the study cohort (N=122) were male, and 55% were Caucasian. During follow-up, longitudinal changes in z-scores for pre- and post-bronchodilator FEV1 (P<.0001) FVC (P<.0001) and FEV1 /FVC (P<.0001 for pre- and 0.007 for post-bronchodilator) from age 5 to 10-16years were observed. Declined lung function in late childhood was significantly associated with gender, physician diagnosis of asthma, and allergic sensitization. PC20 geometric mean increased from 0.28mg/mL at 7years to 0.53mg/mL at 12years of age, and the frequency of abnormal bronchial hyperreactivity decreased from 96% to 78% (P=.0003). Following severe RSV bronchiolitis, there appear to be significant longitudinal changes in pre- and post-bronchodilator lung function during childhood. The study has several limitations including significant dropouts and the lack of a control group and post-bronchodilator measurements. Bronchial hyperreactivity is common in children following severe RSV bronchiolitis; however, it appears to decrease as they enter late childhood.

Airway microbiome, host immune response and recurrent wheezing in infants with severe respiratory syncytial virus bronchiolitis

Early interactions between respiratory viruses and microbiota might modulate host immune responses and subsequently contribute to later development of recurrent wheezing and asthma in childhood. We aimed to study the possible association between respiratory microbiome, host immune response, and the development of recurrent wheezing in infants with severe respiratory syncytial virus (RSV) bronchiolitis. Seventy-four infants who were hospitalized at Beijing Children's Hospital during an initial episode of severe RSV bronchiolitis at 6months of age or less were included and followed up until the age of 3years. Sputum samples were collected, and their microbiota profiles, LPS, and cytokines were analyzed by 16S rRNA-based sequencing, ELISA, and multiplex immunoassay, respectively. Twenty-six (35.1%) infants developed recurrent wheezing by the age of 3years, and 48 (64.9%) did not. The relative abundance of Haemophilus, Moraxella, and Klebsiella was higher in infants who later developed recurrent wheezing than in those who did not (LDA score >3.5). Airway levels of LPS (P=.003), CXCL8 (P=.004), CCL5 (P=.029), IL-6 (P=.004), and IL-13 (P<.001) were significantly higher in infants who later developed recurrent wheezing than in those who did not. Moreover, high airway abundance of Haemophilus was associated with CXCL8 (r=0.246, P=.037) level, and that of Moraxella was associated with IL-6 level (r=0.236, P=.046) and IL-10 level (r=0.266, P=.024). Our study suggests that higher abundance of Haemophilus and Moraxella in airway microbiome might modulate airway inflammation during severe RSV bronchiolitis in infancy, potentially contributing to the development of subsequent recurrent wheezing in later childhood.

Reduced PRF1 enhancer methylation in children with a history of severe RSV bronchiolitis in infancy: an association study

BackgroundAcute lower respiratory tract infection is the commonest disease affecting children under five worldwide. Respiratory syncytial virus (RSV) is among the most common causative pathogens. Epidemiological data suggest an association between severe viral respiratory infections in infancy and increased incidence of childhood wheeze and asthma. DNA methylation is involved in immune cell differentiation and identity. It provides an avenue for environmental influences on the genome and therefore has potential as a marker for sustained effects of infectious insults. In this study we investigated the association between DNA methylation patterns in the perforin gene (PRF1) in childhood and a history of hospitalisation for severe RSV disease in the first two years of life.MethodsIn this retrospective study, we explored patterns of whole blood DNA methylation at a methylation sensitive region of the proximal PRF1 enhancer in a group of children with a record of hospitalisation for severe RSV disease during infancy (n = 43) compared to healthy controls matched for age and sex with no similar hospitalisation history, no allergy and no persistent wheeze (n = 43). Univariate and bivariate conditional logistic regression analyses were conducted to test the association between PRF1 enhancer methylation and record of hospitalisation for RSV disease.ResultsChildren with a record of hospitalisation for severe RSV bronchiolitis demonstrated markedly lower levels of DNA methylation at two cytosine-phosphate-guanine dinucleotide (CpG) loci of the PRF1 proximal enhancer, corresponding to a signal transducer and activator of transcription 5 (STAT5) responsive element, compared to controls, adjusted odds ratios of 0.82 (95% confidence interval [CI] 0.71, 0.94) and 0.73 (95% CI 0.58, 0.92) for each 1% increase in DNA methylation. Smoking in the household showed a significant influence on DNA methylation at the assayed positions.ConclusionsOur findings support an association between childhood DNA methylation patterns in PRF1 and a record of severe RSV infection in infancy. Longitudinal studies are required to establish the utility of PRF1 methylation as a marker of severe RSV disease.

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.

Causal Direction Between Respiratory Syncytial Virus Bronchiolitis and Asthma Studied in Monozygotic Twins

Respiratory syncytial virus (RSV) bronchiolitis has been associated with later development of asthma, wheezing, abnormal pulmonary function, and sensitization. Our aim was to determine the differential effect within monozygotic (MZ) twin pairs discordant for severe RSV bronchiolitis in infancy on the subsequent development of asthma, pulmonary function, and allergy. Thirty-seven MZ twin pairs discordant for RSV hospitalization in infancy (mean age 10.6 months) were compared at the mean age of 7.6 years for lung function, bronchial responsiveness, fractional exhaled nitric oxide (Feno), asthma diagnosis, use of asthma medication, and skin prick test to common inhalant allergens. There were no differences within MZ twin pairs discordant for RSV hospitalization in infancy with respect to pulmonary function, Feno, asthma prevalence, asthma medication use, or sensitization (P > .1 for all comparisons). We found no differential effect from severity of RSV infection on the development of asthma and allergy in MZ twin pairs discordant for RSV hospitalization in infancy. This argues against a specific effect of severe RSV infection in the development of asthma and allergy. Because of the small sample size, this study must be considered as a hypothesis-generating study.

Respiratory Syncytial Virus Bronchiolitis and Asthma – Insights from Recent Studies and Implications for Therapy

Infection with respiratory syncytial virus (RSV) is a leading cause of upper and lower respiratory tract infection in infants. It is accompanied by a considerably disease burden and a hospitalisation rate of up to 3% in infected infants. Besides, it is still a matter of intensive discussion whether severe RSV infection in early infancy causes the development of asthma later in live or whether RSV bronchiolitis just chronologically precedes asthma in children who are susceptible to asthma. The latter could be due to a common genetic background of both diseases predisposing to an exaggerated inflammatory response of the lungs to allergens and pathogens. Genetic studies might help to elucidate the mechanisms leading to both diseases and to highlight common as well as diverse pathways. The results of such investigations will influence the current understanding of the diseases and might even change our therapeutical approaches to both disorders. This review summarizes current findings in the genetics of bronchial asthma and severe RSV bronchiolitis. The question whether a relationship exists between severe RSV bronchiolitis in infancy and childhood asthma will also be discussed by taking recent epidemiological studies in account. A special focus is laid on the implications of these findings for a targeted drug therapy of both diseases.

Genetic association study for RSV bronchiolitis in infancy at the 5q31 cytokine cluster

Background:The pathophysiological basis of severe respiratory syncytial virus (RSV) bronchiolitis in infancy is poorly understood and has hindered vaccine development. Studies implicate the cell-mediated immune response in the pathogenesis of...

Enhanced IL-4 responses in children with a history of respiratory syncytial virus bronchiolitis in infancy.

Infants who recover from respiratory syncytial virus (RSV)-induced bronchiolitis are at high risk of developing asthma and recurrent wheezing. It is not known whether severe RSV infection itself causes persistent effects or is a marker of a "wheezy" predisposition. To determine the long-term immunological correlates of infantile bronchiolitis, interleukin (IL)-4 and interferon (IFN)-gamma responses to a panel of antigens were studied in a well-characterised cohort of 7-8-yr-old children with a history of severe RSV bronchiolitis in infancy. Peripheral blood lymphocytes from 37 children who were hospitalised with RSV bronchiolitis in infancy and from 69 age-, sex- and location-matched controls were stimulated in vitro with RSV, house-dust mite, birch and cat antigens. Cellular proliferation, and enzyme-linked immunoSPOT IFN-gamma and IL-4 production were measured. IL-4 producing T-cells responding to RSV and cat antigens were significantly more frequent in exbronchiolitics. Other responses (including the IFN-gamma response to RSV) were equally strong in exbronchiolitics and controls. Respiratory syncytial virus infection primes memory T-cells that make interferon-gamma, but virus and aeroallergen-specific and interleukin-4 producing T-cells are also frequently primed in bronchiolitics. Respiratory syncytial virus bronchiolitis in infancy may increase the risk of allergic sensitisation by providing a local interleukin-4-rich environment, in which airborne allergens are first encountered.