Preventing Respiratory Syncytial Virus Infection to Prevent Asthma: The Missing Link

To the Editor:

The association between early-life respiratory syncytial virus (RSV)-related lower respiratory tract infection and later asthma development is consistent across most studies with large effect sizes, a dose–response relationship, and observational evidence that preventing RSV in select populations decreases recurrent wheezing or asthma risk (1). A definitive clinical trial of prevention of RSV on childhood asthma, with an intervention such as palivizumab, has not been performed (2). The study by Mochizuki and colleagues [this issue, pp. 29–38] provides additional important observational data that support the finding that prevention of severe RSV during infancy decreases later wheezing in children, and provides us estimates of the effect size on both wheezing and asthma, which is essential information in designing a clinical trial with optimal power (3). Although this study is not a randomized clinical trial, and despite the small number of infants studied, infants who received palivizumab were significantly less likely to have recurrent wheezing throughout childhood. There was a nonsignificant effect on decreasing asthma at 6 years. We cannot infer much about the effect of palivizumab on asthma outcomes, as this study is too small and underpowered for the primary outcome of asthma. This study had 349 subjects receiving palivizumab and a comparison group of 95 infants who did not receive palivizumab. The effect size reported for asthma outcome with relative risk (0.82; 95% confidence interval, 0.39–1.70) lacks precision. Power calculations project a sample size of more than 5,000 subjects, using 18% relative reduction in asthma risk and the conservative scenario of only 21% children who did not receive palivizumab (4).

These types of observational studies are also very challenging to design and interpret, because the infants who receive palivizumab and those who do not receive palivizumab are significantly different (5). As a consequence, infants who received palivizumab differ fundamentally from infants who did not receive palivizumab, making confounding by indication a major concern in these studies. The best solution to this problem is to conduct a properly designed randomized controlled trial (2, 5). A randomized controlled trial will ultimately answer the question of whether prevention of infant RSV lower respiratory tract infection prevents later development of recurrent wheezing and asthma outcomes. In the absence of data from such a trial, we lack sufficient information to inform change in use of an expensive drug requiring intramuscular injections in infants. Thus, it is the right time for us in science and healthcare to review the evidence, to define its preventive and clinical implications, and to design and conduct a definitive trial.