RSV prevention in infancy and asthma in later life

Abstract

The MAKI trial1Scheltema NM Nibbelke EE Pouw J et al.Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial.Lancet Respir Med. 2018; 6: 257-264Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 2Blanken MO Rovers MM Molenaar JM et al.Respiratory syncytial virus and recurrent wheeze in healthy preterm infants.N Engl J Med. 2013; 368: 1791-1799Crossref PubMed Scopus (456) Google Scholar examined the causal association between respiratory syncytial virus (RSV) infection during infancy and wheeze or asthma up to age 6 years in infants born at 32–35 weeks of gestation. Although MAKI does provide further insight into this association, the main conclusion drawn by the authors—that RSV infection during infancy does not have a major effect on asthma—does not appear to be a fair reflection of the results presented and strays from the stated aim by concentrating on the effectiveness of palivizumab. This conclusion was predicated on a post-hoc endpoint (physician-diagnosed asthma), whereas the primary outcome (parent-reported asthma) was significantly different between the palivizumab and placebo groups.1Scheltema NM Nibbelke EE Pouw J et al.Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial.Lancet Respir Med. 2018; 6: 257-264Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar Although physician-diagnosed asthma might be considered a more objective endpoint than parent-reported asthma, the conflicting results obviate such a strong conclusion being drawn. It is also questionable whether the MAKI trial, which was powered on the basis of a between-group mean difference of 5 wheeze days (SD 15) during the first year of life,2Blanken MO Rovers MM Molenaar JM et al.Respiratory syncytial virus and recurrent wheeze in healthy preterm infants.N Engl J Med. 2013; 368: 1791-1799Crossref PubMed Scopus (456) Google Scholar was of sufficient size to ascertain any difference in asthma prevalence between the groups at 6 years. The difficulties associated with confirming a diagnosis of asthma by age 6 years is another salient issue. The strength of MAKI lies in the results related to wheeze, and perhaps these results should have been the focus of the 6-year analysis. Several studies,1Scheltema NM Nibbelke EE Pouw J et al.Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial.Lancet Respir Med. 2018; 6: 257-264Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 2Blanken MO Rovers MM Molenaar JM et al.Respiratory syncytial virus and recurrent wheeze in healthy preterm infants.N Engl J Med. 2013; 368: 1791-1799Crossref PubMed Scopus (456) Google Scholar, 3Carbonell-Estrany X Pérez-Yarza EG García LS et al.Long-term burden and respiratory effects of respiratory syncytial virus hospitalization in preterm infants—the SPRING study.PLoS One. 2015; 10: e0125422Crossref PubMed Scopus (47) Google Scholar, 4Sigurs N Aljassim F Kjellman B et al.Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life.Thorax. 2010; 65: 1045-1052Crossref PubMed Scopus (488) Google Scholar, 5Stein RT Sherrill D Morgan WJ et al.Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years.Lancet. 1999; 354: 541-545Summary Full Text Full Text PDF PubMed Scopus (1324) Google Scholar including MAKI, have reported an increased prevalence of wheeze after RSV infection. The pertinent question is how long does wheeze persist after RSV infection, with estimates ranging from a few years to more than a decade.3Carbonell-Estrany X Pérez-Yarza EG García LS et al.Long-term burden and respiratory effects of respiratory syncytial virus hospitalization in preterm infants—the SPRING study.PLoS One. 2015; 10: e0125422Crossref PubMed Scopus (47) Google Scholar, 4Sigurs N Aljassim F Kjellman B et al.Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life.Thorax. 2010; 65: 1045-1052Crossref PubMed Scopus (488) Google Scholar, 5Stein RT Sherrill D Morgan WJ et al.Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years.Lancet. 1999; 354: 541-545Summary Full Text Full Text PDF PubMed Scopus (1324) Google Scholar MAKI, and the other major study to have investigated respiratory morbidity in children born at 32–35 weeks of gestation, SPRING,3Carbonell-Estrany X Pérez-Yarza EG García LS et al.Long-term burden and respiratory effects of respiratory syncytial virus hospitalization in preterm infants—the SPRING study.PLoS One. 2015; 10: e0125422Crossref PubMed Scopus (47) Google Scholar both showed a clear association between RSV infection in infancy and recurrent wheeze (defined as three or more episodes within 12 months in both studies), which persisted to at least age 3 years, but appeared to normalise by age 6 years (table). Severity of infection might have an important role, with SPRING showing that RSV-related hospital admission is the most important independent risk factor for wheeze.3Carbonell-Estrany X Pérez-Yarza EG García LS et al.Long-term burden and respiratory effects of respiratory syncytial virus hospitalization in preterm infants—the SPRING study.PLoS One. 2015; 10: e0125422Crossref PubMed Scopus (47) Google Scholar This finding is supported by MAKI, which showed that the highest prevalence of asthma was in children with RSV-related hospital admission during the first year of life, albeit the numbers were small.1Scheltema NM Nibbelke EE Pouw J et al.Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial.Lancet Respir Med. 2018; 6: 257-264Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar Both studies1Scheltema NM Nibbelke EE Pouw J et al.Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial.Lancet Respir Med. 2018; 6: 257-264Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 3Carbonell-Estrany X Pérez-Yarza EG García LS et al.Long-term burden and respiratory effects of respiratory syncytial virus hospitalization in preterm infants—the SPRING study.PLoS One. 2015; 10: e0125422Crossref PubMed Scopus (47) Google Scholar reported that lung function was similar between groups at 6 years, and atopic status did not appear to affect outcomes.TableWheeze through the first 6 years of life in children born at 32–35 weeks of gestation in MAKI1Scheltema NM Nibbelke EE Pouw J et al.Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial.Lancet Respir Med. 2018; 6: 257-264Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 2Blanken MO Rovers MM Molenaar JM et al.Respiratory syncytial virus and recurrent wheeze in healthy preterm infants.N Engl J Med. 2013; 368: 1791-1799Crossref PubMed Scopus (456) Google Scholar and SPRING3Carbonell-Estrany X Pérez-Yarza EG García LS et al.Long-term burden and respiratory effects of respiratory syncytial virus hospitalization in preterm infants—the SPRING study.PLoS One. 2015; 10: e0125422Crossref PubMed Scopus (47) Google ScholarMAKI (n=429)SPRING (n=487)Year 1RSVH or placebo21%..No RSVH or palivizumab11%..p value0·005..Year 2RSVH or placebo..41%No RSVH or palivizumab..12%p value..<0·001Year 3RSVH or placebo..29%No RSVH or palivizumab..15%p value..0·001Years 1–3RSVH or placebo29%..No RSVH or palivizumab20%..p value<0·05..Year 4RSVH or placebo..19%No RSVH or palivizumab..13%p value..NSYear 5RSVH or placebo..15%No RSVH or palivizumab..9%p value..NSYear 6RSVH or placebo7%12%No RSVH or palivizumab6%10%p valueNRNSYears 2–6RSVH or placebo..47%No RSVH or palivizumab..27%p value..0·001For MAKI, years 1–3 data were the proportion of children with wheeze since their first birthday, and frequent wheeze at year 6 was defined as more than three episodes within 12 months (results calculated from data provided in MAKI paper). For SPRING, year 1 data were not available because the study was a follow-up of the FLIP-2 study;6Figueras-Aloy J Carbonell-Estrany X Quero-Jiménez J et al.Risk factors linked to respiratory syncytial virus infection requiring hospitalization in premature infants born in Spain at a gestational age of 32 to 35 weeks.Pediatr Infect Dis J. 2008; 27: 788-793Crossref PubMed Scopus (106) Google Scholar years 2–6 data were the proportion of children with recurrent wheeze. RSVH=respiratory syncytial virus hospitalisation. NS=not significant. NR=not reported. Open table in a new tab For MAKI, years 1–3 data were the proportion of children with wheeze since their first birthday, and frequent wheeze at year 6 was defined as more than three episodes within 12 months (results calculated from data provided in MAKI paper). For SPRING, year 1 data were not available because the study was a follow-up of the FLIP-2 study;6Figueras-Aloy J Carbonell-Estrany X Quero-Jiménez J et al.Risk factors linked to respiratory syncytial virus infection requiring hospitalization in premature infants born in Spain at a gestational age of 32 to 35 weeks.Pediatr Infect Dis J. 2008; 27: 788-793Crossref PubMed Scopus (106) Google Scholar years 2–6 data were the proportion of children with recurrent wheeze. RSVH=respiratory syncytial virus hospitalisation. NS=not significant. NR=not reported. Considering all of these findings, perhaps a more appropriate conclusion from MAKI would have been that RSV infection is an important mechanism for wheeze, at least in the first few years of life. I have received honoraria for acting as an expert adviser and speaker for AbbVie. RSV prevention in infancy and asthma in later lifeThe association between respiratory syncytial virus (RSV) and asthma has been contentious for a long time.1 Prevention of lower respiratory tract infection caused by RSV with a monoclonal antibody such as palivizumab is the best way to test this association. It was hoped that Scheltema and colleagues' randomised, placebo-controlled MAKI trial2 in preterm (32–35 weeks gestational age) infants would provide clarity as to the long-term (6 year) effects of preventing RSV infection in the first year of life. Full-Text PDF RSV prevention in infancy and asthma in later life – Authors' replyWe thank Eric A F Simões, Andrew H Liu, Xavier Carbonell-Estrany, and William Dupont and colleagues for their valuable comments on our trial1 published in The Lancet Respiratory Medicine describing the effect of respiratory syncytial virus (RSV) prevention in infancy, by use of the monoclonal antibody palivizumab, on asthma and lung function at age 6 years. Simões and Liu inquired whether RSV prophylaxis might prevent asthma development in a subgroup of infants at high risk of recurrent wheeze. We agree that a subgroup analysis might reveal benefit for RSV prevention in specific populations. Full-Text PDF Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trialIn otherwise healthy preterm infants, this single-blind, randomised, placebo-controlled trial showed that RSV prevention did not have a major effect on current asthma or lung function at age 6 years. Future research will inform on the effect of RSV prevention on asthma at school age in the general population. Full-Text PDF RSV prevention in infancy and asthma in later lifeIn The Lancet Respiratory Medicine, Scheltema and colleagues1 report the results of a single-blind extension of the randomised, placebo-controlled MAKI trial (ISRCTN73641710), which investigated the effect of respiratory syncytial virus (RSV) immunoprophylaxis in late preterm infants on parent-reported current asthma at age 6 years. Investigation of this outcome is important because wheeze and asthma cause substantial respiratory morbidity in children, and primary prevention strategies are needed. Full-Text PDF