Is there a causal relationship between respiratory syncytial virus lower respiratory tract infection and chronic wheezing?
Authors: Reinout A Bem
Journal: The Lancet Respiratory Medicine (2020)

Respiratory syncytial virus (RSV) is a common respiratory pathogen that causes a heavy burden on the health of young children (aged <2 years) worldwide.1Shi T McAllister DA O'Brien KL et al.Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.Lancet. 2017; 390: 946-958Summary Full Text Full Text PDF PubMed Scopus (797) Google Scholar RSV can cause acute lower respiratory tract infections (LRTI), most commonly referred to as bronchiolitis, which involves small airway inflammation and injury, mucus plugging, and bronchial hyper-reactivity. Because the development of RSV-LRTI is specifically linked to young children, it can be considered as one of the earliest possible injurious hits to the respiratory system after the perinatal period and as such, could function as an important driver in lung function trajectories reaching into adulthood.2Agusti A Faner R Lung function trajectories in health and disease.Lancet Respir Med. 2019; 7: 358-364Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar From this perspective, the well established association between RSV-LRTI and development of wheezing illnesses, including asthma, in later life are of high interest for current policy and science campaigns on child health (eg, WHO, UNICEF, and The Lancet's 2020 campaign), as strategies to prevent the acute phase of RSV-LRTI (eg, vaccines) might have the additional effect of decreasing an important subset of chronic respiratory disease. However, a long term beneficial effect on chronic respiratory disease by preventing RSV-LRTI in early life would imply causality, a matter that has been of debate since the early case-control studies in the late 70s.3Sims DG Downham MA Gardner PS Webb JK Weightman D Study of 8-year-old children with a history of respiratory syncytial virus bronchiolitis in infancy.BMJ. 1978; 1: 11-14Crossref PubMed Scopus (202) Google Scholar In fact, the rather limited progress in reaching a conclusion on the nature of the association between RSV-LRTI and wheezing illnesses over a period of more than 40 years is somewhat unnerving. Therefore, Steven Brunwasser and colleagues4Brunwasser SM Snyder BM Driscoll AJ et al.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.Lancet Respir Med. 2020; 8: 795-806Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar deserve much credit for their recent, meticulously designed systematic review, published in The Lancet Respiratory Medicine, in which they use meta-regression strategies for causal inference. In their two-way approach, the authors consider both exposure (observational) studies and immunoprophylaxis studies, which assess prevention by anti-RSV monoclonal antibodies to evaluate the association between RSV-LRTI and subsequent wheezing illness. As is the case for many meta-analyses, the combining of data from a heterogeneous group of studies—particularly in respect to the definition of (transient) recurrent wheezing or asthma and time of follow-up after RSV-LRTI—will always be imperfect and based on certain assumptions. However, from a policy maker's perspective, looking at broader effects on health care, this type of larger evaluation can be of great value. For the exposure studies, Brunwasser and colleagues reason that studies that adjusted for susceptibility for respiratory dysfunction (eg, genetic predisposition or pre-existing external events such as environmental or perinatal hits) might decrease the effect estimate of the association between RSV-LRTI and subsequent wheezing illness, if there is a non-causal association between the two (eg, both RSV-LRTI and chronic wheezing are markers of susceptibility for respiratory disease).4Brunwasser SM Snyder BM Driscoll AJ et al.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.Lancet Respir Med. 2020; 8: 795-806Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar The finding that adjustment for genetic predisposition, albeit determined in a suboptimal way, indeed resulted in a smaller association effect, reduces the confidence in a causal relationship. Notably, adjustment for perinatal health status did not yield a smaller effect estimate. This result would hint that genetic factors play a more important part than external events in a possible non-causal model of RSV-LRTI and chronic wheezing (although this study was not designed to compare the relative contribution of genetic versus external factors). In this light, it would have been informative to include adjustments specifically for maternal or household smoking as an important early life external risk factor for respiratory dysfunction. From the immunoprophylaxis studies, the finding was that this preventive strategy for RSV-LRTI is not significantly associated with a reduction in wheezing illnesses in later life.4Brunwasser SM Snyder BM Driscoll AJ et al.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.Lancet Respir Med. 2020; 8: 795-806Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar However, it is important to note that the current use of anti-RSV monoclonal antibodies is limited to patient groups at high risk (eg, pre-term infants) to prevent (severe) LRTI after exposure to RSV, whereas the majority of children presenting with RSV-LRTI are considered previously healthy.5Hall CB Weinberg GA Iwane MK et al.The burden of respiratory syncytial virus infection in young children.N Engl J Med. 2009; 360: 588-598Crossref PubMed Scopus (1277) Google Scholar As such, this evaluation only addresses a possible direct causal link between (severity of) RSV-LRTI and subsequent wheezing illnesses in a specific subgroup of patients. True biological gradient for a causal connection might be much better determined by preventive strategies with much broader implementation, such as currently planned maternal vaccination programmes, which might affect the population viral load and thus result in an overall lower exposure of infants to RSV. Overall, the conclusion of the study by Brunwasser and colleagues reduces confidence in a causal effect of RSV-LRTI on the origin of chronic wheezing illnesses. However, it would be an unfortunate misunderstanding if this would also reduce enthusiasm of both policy makers and clinical researchers to develop and plan preventive and therapeutic interventions for RSV-LRTI. Besides the need to diminish the tremendous effect of the acute phase of RSV-LRTI on young children in both low-income and high-income countries, the nature of the association between RSV-LRTI and long-term respiratory dysfunction has still not been defined definitively. Several gaps in knowledge still exist, including possible explanations in which RSV-LRTI acts as a marker of respiratory disease susceptibility in addition to either a sufficient or contributory cause. Adding to the complexity, there might be a synergistic interaction between RSV-LRTI at a young age and genetic susceptibility or environmental exposure (eg, smoking), which increases the risk to develop a wheezing phenotype.6Khor CC Hibberd ML Revealing the molecular signatures of host-pathogen interactions.Genome Biol. 2011; 12: 229Crossref PubMed Scopus (6) Google Scholar, 7Voraphani N Stern DA Wright AL Guerra S Morgan WJ Martinez FD Risk of current asthma among adult smokers with respiratory syncytial virus illnesses in early life.Am J Respir Crit Care Med. 2014; 190: 392-398Crossref PubMed Scopus (37) Google Scholar In the analytical strategy by Brunwasser and colleagues, such scenarios would be more difficult to grasp. Finally, part of the controversy on causal inference for wheezing illnesses might lie in the difficulty to discriminate whether we should focus on RSV per se or RSV-LRTI in conjunction with other viral and bacterial pathogens or (iatrogenic) treatments during hospital admission. As such, it is ever more meaningful to integrate research programmes and clinical long-term follow-up after exposure to respiratory disease in early life. Hopefully, in the future, by this type of platform in combination with sophisticated data analysis as done by Brunwasser and colleagues,4Brunwasser SM Snyder BM Driscoll AJ et al.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.Lancet Respir Med. 2020; 8: 795-806Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar we can help children to gain better protection against chronic diseases such as wheezing illnesses. I have not received personal fees or other benefits. Amsterdam UMC previously received minor funding for invited lectures from AbbVie. 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-analysisOur findings, limited to exposure and immunoprophylaxis studies, do not support basing policy decisions on an assumption that prevention of RSV-LRTI will reduce recurrent chronic wheezing illnesses. Full-Text PDF Open Access