Azithromycin therapy during respiratory syncytial virus bronchiolitis: Upper airway microbiome alterations and subsequent recurrent wheeze.
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ABSTRACT:
SUBMITTER: Zhou Y
PROVIDER: S-EPMC5056860 | biostudies-literature | 2016 Oct
REPOSITORIES: biostudies-literature
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Azithromycin therapy during respiratory syncytial virus bronchiolitis: Upper airway microbiome alterations and subsequent recurrent wheeze.
Zhou Yanjiao Y Bacharier Leonard B LB Isaacson-Schmid Megan M Baty Jack J Schechtman Kenneth B KB Sajol Geneline G Wylie Kristine K Storch Gregory A GA Castro Mario M Beigelman Avraham A
The Journal of allergy and clinical immunology 20160518 4
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Project description:BackgroundEarly-life severe respiratory syncytial virus (RSV) bronchiolitis is a risk factor for childhood asthma. Because azithromycin may attenuate airway inflammation during RSV bronchiolitis, we evaluated whether it would reduce the occurrence of post-RSV recurrent wheeze.MethodsWe prospectively enrolled 200 otherwise healthy 1- to 18-month-old children hospitalized with RSV bronchiolitis in this single-center, double-blind, placebo-controlled study and randomly assigned them to receive oral azithromycin (10 mg/kg daily for 7 days, followed by 5 mg/kg daily for 7 days) or placebo. Randomization was stratified by recent open-label antibiotic use. The primary outcome was the occurrence of recurrent wheeze, defined as a third episode of post-RSV wheeze over the following 2 to 4 years.ResultsAs an indication of the biologic activity of azithromycin, nasal wash interleukin-8 levels, at day 14 after randomization, were lower among azithromycin-treated participants (P<0.01). Despite evidence of biologic activity, azithromycin did not reduce the risk of post-RSV recurrent wheeze (47% in the azithromycin group vs. 36% in the placebo group; adjusted hazard ratio, 1.45; 95% confidence interval [CI], 0.92 to 2.29; P=0.11). Azithromycin also did not modify the risk of recurrent wheeze among participants already receiving other antibiotic treatment at the time of enrollment (hazard ratio, 0.94; 95% CI, 0.43 to 2.07). There was a potential signal among antibiotic-naïve participants who received azithromycin to have an increased risk of recurrent wheeze (hazard ratio, 1.79; 95% CI, 1.03 to 3.1).ConclusionsAzithromycin therapy for 14 days during acute severe RSV bronchiolitis did not reduce recurrent wheeze occurrence over the following 2 to 4 years. Our data suggest no benefit of azithromycin administration with the goal of preventing recurrent wheeze in later life. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02911935.).
| S-EPMC10448891 | biostudies-literature
Project description:BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Following RSV bronchiolitis, 50% of children develop post-bronchiolitis wheeze (PBW). Animal studies have suggested that interleukin (IL)-10 plays a critical role in the pathogenesis of RSV bronchiolitis and subsequent airway hyperresponsiveness. Previously, we showed that ex vivo monocyte IL-10 production is a predictor of PBW. Additionally, heterozygosity of the single-nucleotide polymorphism (SNP) rs1800872 in the IL10 promoter region was associated with protection against RSV bronchiolitis. METHODS: This study aimed to determine the in vivo role of IL-10 in RSV pathogenesis and recurrent wheeze in a new cohort of 235 infants hospitalized for RSV bronchiolitis. IL-10 levels in nasopharyngeal aspirates (NPAs) were measured at the time of hospitalization and the IL10 SNP rs1800872 genotype was determined. Follow-up data were available for 185 children (79%). RESULTS: Local IL-10 levels during RSV infection turned out to be higher in infants that later developed physician diagnosed PBW as compared to infants without PBW in the first year after RSV infection (958 vs 692 pg/ml, p = 0.02). The IL10 promoter SNP rs1800872 was not associated with IL-10 concentration in NPAs. CONCLUSION: The relationship between high local IL-10 levels during the initial RSV infection and physician diagnosed PBW provides further evidence of the importance of the IL-10 response during RSV bronchiolitis.
| S-EPMC3179726 | biostudies-literature
Project description:BackgroundInfants 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.MethodsWe 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+CD25hi Foxp3hi ) cells were measured by flow cytometry. Wheezing was assessed every 6 months. Recurrent wheezing was defined as three or more episodes following the initial RSV bronchiolitis.ResultsSixty-seven percent (n = 111) of children had wheezing after their initial RSV infection, with 30% having recurrent wheezing. The percentage of peripheral Treg (CD4+CD25hi Foxp3hi ) cells was not significantly different between the wheezing groups. Decreased TNF-α production from anti-CD3/CD28- and anti-CD3/CD46- activated CD4+ T cells was observed in the recurrent wheezers, compared with nonwheezers (p = .048 and .03, respectively). There were no significant differences in the GZB+ CD4+ T cells and production of other inflammatory cytokines between these groups.ConclusionsWe 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.
| S-EPMC7016853 | biostudies-literature
Project description:Introduction: Acute bronchiolitis is one of the most common respiratory infections in infancy. Although most infants with bronchiolitis do not get hospitalized, infants with hospitalized bronchiolitis are more likely to develop wheeze exacerbations during the first years of life. The objective of this prospective cohort study was to develop machine learning models to predict incidence and persistence of wheeze exacerbations following the first hospitalized episode of acute bronchiolitis. Methods: One hundred thirty-one otherwise healthy term infants hospitalized with the first episode of bronchiolitis at a tertiary pediatric hospital in Athens, Greece, and 73 age-matched controls were recruited. All patients/controls were followed up for 3 years with 6-monthly telephone reviews. Through principal component analysis (PCA), a cluster model was used to describe main outcomes. Associations between virus type and the clusters and between virus type and other clinical characteristics and demographic data were identified. Through random forest classification, a prediction model with smallest classification error was identified. Primary outcomes included the incidence and the number of caregiver-reported wheeze exacerbations. Results: PCA identified 2 clusters of the outcome measures (Cluster 1 and Cluster 2) that were significantly associated with the number of recurrent wheeze episodes over 3-years of follow-up (Chi-Squared, p < 0.001). Cluster 1 included infants who presented higher number of wheeze exacerbations over follow-up time. Rhinovirus (RV) detection was more common in Cluster 1 and was more strongly associated with clinical severity on admission (p < 0.01). A prediction model based on virus type and clinical severity could predict Cluster 1 with an overall error 0.1145 (sensitivity 75.56% and specificity 91.86%). Conclusion: A prediction model based on virus type and clinical severity of first hospitalized episode of bronchiolitis could predict sensitively the incidence and persistence of wheeze exacerbations during a 3-year follow-up. Virus type (RV) was the strongest predictor.
| S-EPMC8974688 | biostudies-literature
Project description:BackgroundRespiratory syncytial virus (RSV) bronchiolitis in infancy is a major risk factor for recurrent wheezing and asthma. Because azithromycin attenuated neutrophilic airway inflammation in a murine viral bronchiolitis model, demonstration of similar effects in human subjects might provide a strategy for the prevention of postbronchiolitis recurrent wheezing.ObjectivesWe sought to investigate whether azithromycin treatment during RSV bronchiolitis reduces serum and nasal lavage IL-8 levels and the occurrence of postbronchiolitis recurrent wheezing.MethodWe performed a randomized, double-masked, placebo-controlled proof-of-concept trial in 40 otherwise healthy infants hospitalized with RSV bronchiolitis who were treated with azithromycin or placebo for 14 days. IL-8 levels were measured in nasal lavage fluid and serum on randomization, day 8, and day 15 (nasal lavage only). The occurrence of wheezing episodes was assessed monthly over the ensuing 50 weeks.ResultsCompared with placebo, azithromycin treatment did not reduce serum IL-8 levels at day 8 (P = .6) but resulted in a greater decrease in nasal lavage fluid IL-8 levels by day 15 (P = .03). Twenty-two percent of azithromycin-treated participants experienced at least 3 wheezing episodes compared with 50% of participants in the placebo group (P = .07). Azithromycin treatment resulted in prolonged time to the third wheezing episode (P = .048) and in fewer days with respiratory symptoms over the subsequent year in comparison with placebo (36.7 vs 70.1 days, P = .01).ConclusionIn this proof-of-concept study azithromycin treatment during RSV bronchiolitis reduced upper airway IL-8 levels, prolonged the time to the third wheezing episode, and reduced overall respiratory morbidity over the subsequent year.
| S-EPMC4426225 | biostudies-literature
Project description:ImportanceRhinovirus infection in early life, particularly with allergic sensitization, is associated with higher risks of developing recurrent wheeze and asthma. While emerging evidence links different rhinovirus species (eg, rhinovirus C) to a higher severity of infection and asthma exacerbation, to our knowledge, little is known about longitudinal associations of rhinovirus C infection during infancy with subsequent morbidities.ObjectiveTo examine the association of different viruses (respiratory syncytial virus [RSV], rhinovirus species) in bronchiolitis with risks of developing recurrent wheeze.Design, setting, and participantsThis multicenter prospective cohort study of infants younger than 1 year who were hospitalized for bronchiolitis was conducted at 17 hospitals across 14 US states during 3 consecutive fall to winter seasons (2011-2014).ExposuresMajor causative viruses of bronchiolitis, including RSV (reference group) and 3 rhinovirus species (rhinovirus A, B, and C).Main outcomes and measuresDevelopment of recurrent wheeze (as defined in national asthma guidelines) by age 3 years.ResultsThis analytic cohort comprised 716 infants who were hospitalized for RSV-only or rhinovirus bronchiolitis. The median age was 2.9 months (interquartile range, 1.6-3.8 months), 541 (76%) had bronchiolitis with RSV only, 85 (12%) had rhinovirus A, 12 (2%) had rhinovirus B, and 78 (11%) had rhinovirus C infection. Overall, 231 (32%) developed recurrent wheeze by age 3 years. In the multivariable Cox model, compared with infants with RSV-only infection, the risk of recurrent wheeze was not significantly different in those with rhinovirus A or B (rhinovirus A: hazard ratio [HR], 1.27; 95% CI, 0.86-1.88; rhinovirus B: HR, 1.39; 95% CI, 0.51-3.77; both P > .10). By contrast, infants with rhinovirus C had a significantly higher risk (HR, 1.58; 95% CI, 1.08-2.32). There was a significant interaction between virus groups and IgE sensitization on the risk of recurrent wheeze (P for interaction < .01). Only infants with both rhinovirus C infection and IgE sensitization (to food or aeroallergens) during infancy had significantly higher risks of recurrent wheeze (HR, 3.03; 95% CI, 1.20-7.61). Furthermore, compared with RSV-only, rhinovirus C infection with IgE sensitization was associated with significantly higher risks of recurrent wheeze with subsequent development of asthma at age 4 years (HR, 4.06; 95% CI, 1.17-14.1).Conclusions and relevanceThis multicenter cohort study of infants hospitalized for bronchiolitis demonstrated between-virus differences in the risk of developing recurrent wheeze. Infants with rhinovirus C infection, along with IgE sensitization, had the highest risk. This finding was driven by the association with a subtype of recurrent wheeze: children with subsequent development of asthma.
| S-EPMC6547078 | biostudies-literature
Project description:Air pollution exposures have been suggested as risk factors for childhood respiratory diseases. We investigated proximity to major roads, an indicator of air pollution exposure, and its associations with childhood recurrent wheeze and asthma. We used data from a multicenter prospective cohort study of 921 infants hospitalized for bronchiolitis and recruited from 14 U.S. states. Primary exposure was residential proximity to the nearest major road at birth through age 3 years. Residential distance from nearest major road was divided into four categories: <100, 100-200, 201-300, and >300 m. Outcomes were parent-reported recurrent wheeze by age 3 years and asthma by age 5 years. Associations between residential proximity to major roads and respiratory outcomes were investigated using multivariable Cox proportional hazards modeling and logistic regression, adjusted for confounders. Out of 920 participants with home address data, pooled estimates identified 241 (26%) participants resided within 300 m of a major road, 296 (32%) developed recurrent wheeze by age 3, and 235 out of 858 participants (27%) developed asthma by 5 years. Participants who resided close to a major road had the highest risk of recurrent wheeze (adjusted hazards ratio for <100 m, 1.59, 95%CI: 1.08-2.33) and asthma (adjusted odds ratio for 201-300 m, 1.62, 95%CI: 1.16-2.25), compared to those residing >300 m from a major road. Proximity to major roads is associated with increased risks of recurrent wheeze and asthma in young children.
| S-EPMC8071463 | biostudies-literature
Project description:BackgroundAcute bronchiolitis caused by respiratory syncytial virus (RSV) has been associated with greater risk of recurrent wheezing and asthma. However, it is unclear whether this association is causal. RSV-specific monoclonal antibodies have been shown to reduce RSV-related hospitalisations in high-risk infants, but the longer-term follow-up has given conflicting evidence for prevention of recurrent wheeze or asthma.ObjectiveWe performed a systematic review and meta-analysis to determine whether monoclonal antibody prophylaxis against RSV bronchiolitis reduces the risk of subsequent recurrent wheeze or asthma. If so, this may support the hypothesis of causality.MethodsStudies were identified via an online database search using Embase, MEDLINE, PubMed, Web of Science and the Cochrane Library. Manufacturers of monoclonal antibodies were contacted directly for unpublished data. The intervention of interest was RSV monoclonal antibody prophylaxis, and the primary outcome measure was recurrent wheeze and/or asthma. Studies were screened according to inclusion/exclusion criteria. Included studies were evaluated for quality and assessed for bias independently by 3 reviewers using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) approach. Results were extracted into 2 × 2 outcome tables and a meta-analysis carried out producing forest plots based on relative risk. Heterogeneity was assessed using the I2 statistic.ResultsThe search identified 141 articles, which, after screening, resulted in eight studies (2 randomised controlled trials), thus including 11,195 infants in the meta-analysis. The overall result demonstrated a non-statistically significant reduction in relative risk of developing recurrent wheeze or asthma (RR 0.60; 95% CI 0.31 to 1.16). Study quality was generally low with evidence of publication bias and statistical heterogeneity. However, sub-group analysis excluding studies deemed to be 'very low' quality showed a relative risk of 0.42 (95% CI 0.22 to 0.80, p = 0.008). A further sub-group analysis for infants aged 32 to < 36 weeks showed a statistically significant relative risk of 0.35 (95% CI 0.14 to 0.86, p = 0.02).DiscussionWe did not identify an overall statistically significant benefit. However, our two sub-group analyses did find statistically significant benefits of monoclonal antibody therapy on the risk of recurrent wheeze and asthma. The main limitation of this study is the lack of high-quality randomised controlled trials, highlighting the need for more research in this field.
| S-EPMC7690183 | biostudies-literature
Project description:Infant respiratory syncytial virus (RSV) bronchiolitis in the first 6 months of life was associated with increased odds of pneumonia, otitis media, and antibiotic prescription fills in the second 6 months of life. These data suggest a potential value of future RSV vaccination programs on subsequent respiratory health.
| S-EPMC7312311 | biostudies-literature
Project description:BackgroundAlthough bronchiolitis contributes to substantial acute (eg, intensive care use) and chronic (eg, recurrent wheeze) morbidities in young children, the pathobiology remains uncertain. We examined the associations of serum soluble receptor for advanced glycation end products (sRAGE) with acute and chronic morbidities of bronchiolitis including recurrent wheeze.MethodsA multicenter, multiyear, cohort study of infants hospitalized for bronchiolitis was analyzed. We measured the serum sRAGE level at hospitalization and its association with intensive care use (use of mechanical ventilation and/or admission to the intensive care unit) and development of recurrent wheeze by age 3 years. We performed causal mediation analysis to estimate indirect (mediation) and direct effects of sRAGE on recurrent wheeze.ResultsIn 886 infants with bronchiolitis, the median age was 2.9 months. Overall, 15% underwent intensive care and 32% developed recurrent wheeze. In multivariable modeling adjusting for 11 confounders, a higher presenting sRAGE level was associated with lower risk of intensive care (odds ratio for each 1-log increment, 0.39; 95% confidence interval [CI], .16 -.91; P = .03) and significantly lower rate of recurrent wheeze (hazard ratio [HR], 0.58; 95% CI, .36 -.94; P = .03). In mediation analysis, the direct effect was significant (HR, 0.60; 95% CI, .37 -.97; P = .04), while the indirect effect was not (P = .30).ConclusionsSerum sRAGE levels were inversely associated with acute and chronic morbidities of bronchiolitis. The effect of sRAGE on development of recurrent wheeze is potentially driven through pathways other than acute severity of bronchiolitis.
| S-EPMC8563181 | biostudies-literature