The Impact of Respiratory Syncytial Virus Disease Prevention on Pediatric Asthma

To the Editor: Respiratory syncytial virus (RSV) is the leading viral cause of lower respiratory tract illness (LRTI) in infants worldwide, and is estimated to cause approximately 34 million episodes annually.1 Although the global mortality burden of RSV is uncertain, estimates range from 66,000 to 234,000, 99% of which occur in low-income countries.1,2 Although likely underdiagnosed in developing countries, asthma is estimated to affect 235 million people globally.3 As with RSV, most asthma-related deaths are believed to occur in low- and low-middle income nations. Prevalence varies widely by region, influenced by numerous specific environmental exposures and genetics.4 The link between early severe RSV disease and subsequent wheezing illness has been documented in many observational studies in high-income countries with consistent findings and large effect sizes.5,6 Infant birth before the winter virus peak increased the odds of developing asthma years later, suggesting that asthma inception is not determined exclusively by familial predisposition.6 Prospective studies in preterm babies demonstrated a protective role for palivizumab [a monoclonal antibody (mAb) licensed to prevent severe RSV infections] against development of recurrent wheezing during infancy.7 This effect may particularly benefit children with no family history of atopy or asthma.8 Studies evaluating the contribution of RSV infection to asthma inception in monozygotic twins suggest a primary role for genetic inheritance, with heritability estimated at 16%–22%, rather than the virus itself in acquisition of disease.9 It is likely that both genetic susceptibility as well as early life RSV infection are important in asthma development. In the developing world, the relationship between RSV LRTI and asthma is unclear and may differ from that in high-income countries probably as a result of environmental exposures, chronic infections and host genetics. Whether the prevention of RSV LRTI, either through administration of RSV vaccines or extended half-life RSV mAbs, influences the development of recurrent wheezing or asthma inception is unknown. However, the surge in RSV vaccine and mAb research in recent years (http://sites.path.org/vaccinedevelopment/respiratory-syncytial-virus-rsv/) has created potential opportunities to address this question directly. For these reasons, the Bill & Melinda Gates Foundation convened a panel of experts in the areas of RSV and pediatric asthma to discuss available information, identify knowledge gaps and explore how upcoming interventional studies might be leveraged to assess the impact of RSV LRTI prevention on long-term pulmonary outcomes. Studying asthma inception after RSV LRTI in developing countries may prove challenging. First, asthma itself is not a single disease, but an umbrella diagnosis comprising several phenotypes with distinct mechanisms. Among environmental factors possibly associated with these phenotypes, exposure to high levels of bacterial lipopolysaccharide in infancy (often linked in the developing world to poverty and socioeconomic vulnerability) may reduce the frequency of wheezing episodes and childhood asthma.5,10 Also, infestations with helminths, such as Ascaris lumbricoides that has a phase of larval migration through the lungs, may increase the risk of wheezing illness and asthma particularly among children with evidence of allergic sensitization to the parasite (ie, with IgE to A. lumbricoides), while infections with hookworm appear to have a tolerogenic effect and may reduce the risk of wheeze and asthma.11 Furthermore, A. lumbricoides sensitization may interact with RSV infection potentiating the risk of airways reactivity.12 Whether other tolerogenic or allergogenic parasitic infections interact with RSV LRTI, affecting acute severity and/or long-term outcomes is unknown. The association between severity of RSV LRTI in infants and subsequent development of recurrent wheezing and asthma has been described.5 Furthermore, RSV load in the respiratory tract may affect severity of disease, but whether RSV load with initial infection also influences development of recurrent wheezing and asthma is unknown. In addition, different RSV strains may have specific effects on acute RSV severity as well as asthma inception.5 A better understanding of the potential benefits of RSV prevention in decreasing recurrent wheezing and asthma may now be close at hand. However, even preliminary assessments of the magnitude of this effect will require large numbers of patients and prolonged follow up after completion of efficacy studies. Validated biomarkers that can predict asthma inception in small proof of principle trials are not available. In this context, the expert panel concluded that long-term follow-up of children participating in RSV vaccine efficacy studies might provide unique opportunities to assess the effect of prevention of RSV LRTI in infancy on reduction of recurrent wheezing and asthma across multiple gestational ages (Table 1). Long-term follow-up might be accomplished using a variety of simple, noninvasive assessments. These could include yearly active surveillance in early childhood for episodes of recurrent wheezing using the asthma component of the International Study of Asthma and Allergies in Childhood questionnaire, and evaluation of pulmonary function in participating children between ages 3 and 5 years using tests that do not require sedation. Spirometry has been the standard method to assess the presence and severity of airway obstruction, and particularly important in the diagnosis of asthma to assess reversibility to bronchodilators. Other techniques that require less cooperation, such as the forced oscillation technique and resistance by airflow interruption technique may also be useful in preschoolers (Table 1). As these evaluations would be conducted after completion of the efficacy trials, consent to be contacted for potential long-term follow-up would ideally be obtained during the initial course of the trials.Table 1: Available Tools for Evaluation of Recurrent Wheezing/Asthma in ChildrenThe field of acute pediatric respiratory infections may experience significant changes in the coming decade. Among them, prevention of severe RSV LRTI in infants may decrease the rates of recurrent wheezing and pediatric asthma, should the virus be causally linked to disease inception. Leveraging the unique opportunity to address these questions during efficacy trials may contribute to a better understanding of the breadth of benefits associated with prevention of acute RSV LRTI. ACKNOWLEDGMENTS Other members of the RSV & Pediatric Asthma Working Group are as follows: Larry J. Anderson, Emory University School of Medicine, Atlanta, GA, USA; Allison August, Novavax, Gaithersburg, MD, USA; Quique Bassat, ISGlobal, CRESIB, Universitat de Barcelona, Barcelona, Spain; Abdullah Brooks, Johns Hopkins University, Baltimore, MD, USA; Philip J. Cooper, St George’s University of London, London, UK; Adnan Custovic, University of Manchester, Manchester, UK; Filip Dubovsky, MedImmune, Gaithersburg, MD, USA; Tamer Farag, Bill & Melinda Gates Foundation, Seattle, WA, USA; Jorge Flores, PATH, Seattle, WA, USA; James E. Gern, University of Wisconsin School of Medicine, Madison, WI, USA; Gregory Glenn, Novavax, Gaithersburg, MD, USA; Frederick Hayden, University of Virginia SOM, Charlottesville, VA, USA; Deborah Higgins, PATH, Seattle, WA, USA; Prabhat Jha, University of Toronto, ON, Canada; Kendall L. Krause, Bill & Melinda Gates Foundation, Seattle, WA, USA; Romina Libster, Fundación Infant, Buenos Aires, Argentina; Conrado J. Llapur, Fundación Infant, Buenos Aires, Argentina; Shabir A. Madhi, University of the Witwatersrand, Johannesburg, South Africa; Ashish Satav, Mahatma Gandhi Tribal Hospital, Maharashtra, India; Vasee S. Moorthy, World Health Organization, Geneva, Switzerland; Tonya Villafana, MedImmune, Gaithersburg, MD, USA and Sherif Zaki, Centers for Disease Control, Atlanta, GA, USA. Mauricio T. Caballero, MD Fundación INFANT Buenos Aires, Argentina Marcus H. Jones, MD, PhD Centro Infant at Pontifícia Universidade Católica de Rio Grande do Sul Alegre, Brazil Ruth A. Karron, MD Johns Hopkins University Baltimore, Maryland Tina V. Hartert, MD, MPH Center for Asthma Research Vanderbilt University Nashville, Tennessee Eric A. F. Simões, MD University of Colorado Denver and Center for Global Health Colorado School of Public Health Aurora, Colorado Renato T. Stein, MD, PhD Centro Infant at Pontifícia Universidade Católica de Rio Grande do Sul Porto Alegre, Brazil Niteen Wairagkar, MD Bill & Melinda Gates Foundation Seattle, Washigton Fernando P. Polack, MD Fundación INFANT, Buenos Aires, Argentina Department of Pediatrics Vanderbilt University Nashville, Tennessee RSV & Pediatric Asthma Working Group

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