Assessing the strength of evidence for a causal effect of respiratory syncytial virus lower respiratory tract infections on subsequent wheezing illness: a systematic review and meta-analysis

Abstract

Summary Background Although a positive association has been established, it is unclear whether lower respiratory tract infections (LRTIs) with respiratory syncytial virus (RSV) cause chronic wheezing illnesses. If RSV-LRTI were causal, we would expect RSV-LRTI prevention to reduce the incidence of chronic wheezing illnesses in addition to reducing acute disease. We aimed to evaluate the strength of evidence for a causal effect of RSV-LRTI on subsequent chronic wheezing illness to inform public health expectations for RSV vaccines. Methods We did a systematic review and meta-analysis of observational studies evaluating the association between RSV-LRTI and subsequent wheezing illness (exposure studies) and studies evaluating the association between RSV immunoprophylaxis and subsequent wheezing illness (immunoprophylaxis studies). Exposure studies were included if the exposure group members had an LRTI with laboratory-confirmed RSV and if the exposure ascertainment period began before 2 years of age and ended before 5 years of age. We required a wash-out period of more than 30 days between the index RSV-LRTI and the outcome measurement to allow for resolution of the acute illness. Comparisons between RSV-LRTI and non-RSV-LRTI were not included. Immunoprophylaxis studies were included if they measured the association with subsequent wheezing illness relative to a control group, either in a randomised controlled trial (RCT) or an observational design. For the immunoprophylaxis drugs in question, we required evidence of efficacy in targeting RSV-LRTI from at least one RCT to ensure biological plausibility. All variations of wheezing illness were combined into a single outcome that refers broadly to asthma or any other respiratory illness with wheezing symptoms. Ovid MEDLINE and Embase databases were searched from inception up to Aug 28, 2018. We evaluated whether data from exposure studies could provide evidence against the most viable non-causal theory that RSV-LRTI is a marker of respiratory illness susceptibility rather than a causal factor. Additionally, we tested whether RSV immunoprophylaxis reduces the odds of subsequent wheezing illnesses. We used a random-effects modelling framework and, to accommodate studies providing multiple correlated estimates, robust variance estimation meta-regressions. Meta-regression coefficients ( b ) quantify differences between exposure and comparator groups on the log e odds ratio (log e OR) scale. Findings From 14 235 records we identified 57 eligible articles that described 42 studies and provided 153 effect estimates. 35 studies estimated the direct effect of RSV-LRTI on wheezing illnesses (exposure studies) and eight evaluated the effect of RSV immunoprophylaxis (immunoprophylaxis studies). Exposure studies that adjusted for genetic influences yielded a smaller mean adjusted OR estimate (aOR + ...

Cord-blood respiratory syncytial virus antibodies and respiratory health in first 5-years of life.

“…While passive immunoprophylaxis can reduce RSV-associated hospitalization, the preventative effect on subsequent wheeze is still unclear. A recent systematic review and meta-analysis of observational studies and RCTs evaluated the association of RSV-ALRI on subsequent wheezing illness 38 . Eight immunoprophylaxis studies contributed to the analysis, and although the odds point estimate of subsequent wheezing illnesses was higher in those who had not received RSV monoclonal antibodies (palivizumab or motavizumab), the effect was weak (odds ratio 1.21; 95%CI: 0.73-1.99).…”

Factors and mechanisms contributing to the development of preschool wheezing disorders

“…Gene association studies have shown several polymorphisms in innate immune response genes are associated with both severity of RSV infection and risk of persistent wheezing, including in IL-4 R, IL-13, TNF, IL1R1, IL-10 and TLR-4 genes [61]. A recent meta-analysis of 35 studies estimated the effect of RSV infections on subsequent wheezing illnesses as OR 4.17 (95% CI 2.36-7.37), but after adjustment for some genetic and environmental influences the effect size was significantly lower (aOR 2.45, 95% CI 1.23-4.88), suggesting a significant amount of the association was non-causal [142]. If RSV infections played a causal role in wheeze development, we would expect effective RSV immunoprophylaxis to reduce subsequent risk of wheezing.…”

Risk of asthma in children diagnosed with bronchiolitis during infancy: protocol of a longitudinal cohort study linking emergency department-based clinical data to provincial health administrative databases

“… 1 However, a more recent systematic review has reported that this association may not be causal. 13 This association appears most pronounced during the first 5 years of life but may extend up to 10 years of age. 1 14–16 The mechanism through which RSV contributes to asthma is not fully understood but appears to relate to the viral injury, disease severity, pre-existing abnormal lung function, genetic susceptibility, altered immunology and environmental factors.…”