Role of viral infections in the development and exacerbation of asthma in children
Authors: Tuomas Jartti, James E. Gern
Journal: Journal of Allergy and Clinical Immunology (2017)

Viral infections are closely linked to wheezing illnesses in children of all ages. Respiratory syncytial virus (RSV) is the main causative agent of bronchiolitis, whereas rhinovirus (RV) is most commonly detected in wheezing children thereafter. Severe respiratory illness induced by either of these viruses is associated with subsequent development of asthma, and the risk is greatest for young children who wheeze with RV infections. Whether viral illnesses actually cause asthma is the subject of intense debate. RSV-induced wheezing illnesses during infancy influence respiratory health for years. There is definitive evidence that RSV-induced bronchiolitis can damage the airways to promote airway obstruction and recurrent wheezing. RV likely causes less structural damage and yet is a significant contributor to wheezing illnesses in young children and in the context of asthma. For both viruses, interactions between viral virulence factors, personal risk factors (eg, genetics), and environmental exposures (eg, airway microbiome) promote more severe wheezing illnesses and the risk for progression to asthma. In addition, allergy and asthma are major risk factors for more frequent and severe RV-related illnesses. Treatments that inhibit inflammation have efficacy for RV-induced wheezing, whereas the anti-RSV mAb palivizumab decreases the risk of severe RSV-induced illness and subsequent recurrent wheeze. Developing a greater understanding of personal and environmental factors that promote more severe viral illnesses might lead to new strategies for the prevention of viral wheezing illnesses and perhaps reduce the subsequent risk for asthma. Viral infections are closely linked to wheezing illnesses in children of all ages. Respiratory syncytial virus (RSV) is the main causative agent of bronchiolitis, whereas rhinovirus (RV) is most commonly detected in wheezing children thereafter. Severe respiratory illness induced by either of these viruses is associated with subsequent development of asthma, and the risk is greatest for young children who wheeze with RV infections. Whether viral illnesses actually cause asthma is the subject of intense debate. RSV-induced wheezing illnesses during infancy influence respiratory health for years. There is definitive evidence that RSV-induced bronchiolitis can damage the airways to promote airway obstruction and recurrent wheezing. RV likely causes less structural damage and yet is a significant contributor to wheezing illnesses in young children and in the context of asthma. For both viruses, interactions between viral virulence factors, personal risk factors (eg, genetics), and environmental exposures (eg, airway microbiome) promote more severe wheezing illnesses and the risk for progression to asthma. In addition, allergy and asthma are major risk factors for more frequent and severe RV-related illnesses. Treatments that inhibit inflammation have efficacy for RV-induced wheezing, whereas the anti-RSV mAb palivizumab decreases the risk of severe RSV-induced illness and subsequent recurrent wheeze. Developing a greater understanding of personal and environmental factors that promote more severe viral illnesses might lead to new strategies for the prevention of viral wheezing illnesses and perhaps reduce the subsequent risk for asthma. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: October 2017. Credit may be obtained for these courses until September 30, 2018.Copyright Statement: Copyright © 2017-2018. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Tuomas Jartti, MD, and James E. Gern, MD (authors); Cezmi A. Akdis, MD (editor)Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: T. Jartti has received a grant from the Sigrid Juselius Foundation. J. E. Gern has received a grant from the National Institutes of Health/National Institutes of Allergy and Infectious Disease; has consultant arrangements with Janssen, Regeneron, and PReP Biosciences; and has received travel support from Boehringer Ingelheim. C. A. Akdis disclosed no relevant financial relationships.Activity Objectives:1.To become familiar with current evidence pertaining to the role of viral respiratory tract infections in the development and exacerbation of asthma.2.To provide an overview of interactions between aeroallergen sensitization and viral infection in the development of asthma.3.To highlight the gaps in existing knowledge regarding the role of viral infection in asthmatic patients.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Nicholas Klaiber, MD, and Wei Zhao, MD, PhD.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.Bronchiolitis, acute wheezing illnesses, and asthma are a huge clinical burden. The prevalence of bronchiolitis is approximately 20% to 30% in the first year and 10% to 20% in the second year of life.1Taussig L.M. Wright A.L. Holberg C.J. Halonen M. Morgan W.J. Martinez F.D. Tucson children's respiratory study: 1980 to present.J Allergy Clin Immunol. 2003; 111: 661-675Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, 2Meissner H.C. Viral bronchiolitis in children.N Engl J Med. 2016; 374: 1793-1794Crossref PubMed Scopus (77) Google Scholar Up to 30% to 50% of children have acute wheezing at least once before school age.1Taussig L.M. Wright A.L. Holberg C.J. Halonen M. Morgan W.J. Martinez F.D. Tucson children's respiratory study: 1980 to present.J Allergy Clin Immunol. 2003; 111: 661-675Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar Of these, 30% to 40% will have recurrent wheezing.1Taussig L.M. Wright A.L. Holberg C.J. Halonen M. Morgan W.J. Martinez F.D. Tucson children's respiratory study: 1980 to present.J Allergy Clin Immunol. 2003; 111: 661-675Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar Eventually, the prevalence of asthma is approximately 5% to 10% in children.3Lai C.K. Beasley R. Crane J. Foliaki S. Shah J. Weiland S. et al.Global variation in the prevalence and severity of asthma symptoms: phase three of the International Study of Asthma and Allergies in Childhood (ISAAC).Thorax. 2009; 64: 476-483Crossref PubMed Scopus (426) Google Scholar Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: October 2017. Credit may be obtained for these courses until September 30, 2018. Copyright Statement: Copyright © 2017-2018. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Tuomas Jartti, MD, and James E. Gern, MD (authors); Cezmi A. Akdis, MD (editor) Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: T. Jartti has received a grant from the Sigrid Juselius Foundation. J. E. Gern has received a grant from the National Institutes of Health/National Institutes of Allergy and Infectious Disease; has consultant arrangements with Janssen, Regeneron, and PReP Biosciences; and has received travel support from Boehringer Ingelheim. C. A. Akdis disclosed no relevant financial relationships. Activity Objectives:1.To become familiar with current evidence pertaining to the role of viral respiratory tract infections in the development and exacerbation of asthma.2.To provide an overview of interactions between aeroallergen sensitization and viral infection in the development of asthma.3.To highlight the gaps in existing knowledge regarding the role of viral infection in asthmatic patients. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Nicholas Klaiber, MD, and Wei Zhao, MD, PhD. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships. The diagnostics of viral respiratory tract infections has improved markedly during the last 2 decades because of the development of PCR techniques. Several new respiratory viruses and their subgroups have been discovered, and especially rhinovirus (RV) diagnostics have markedly improved.4Jartti T. Soderlund-Venermo M. Hedman K. Ruuskanen O. Makela M.J. New molecular virus detection methods and their clinical value in lower respiratory tract infections in children.Paediatr Respir Rev. 2013; 14: 38-45Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar We have learned that bronchiolitis and early wheezing episodes are almost always (90% to 100% of cases) associated with viral infections.5Turunen R. Koistinen A. Vuorinen T. Arku B. Söderlund-Venermo M. Ruuskanen O. et al.The first wheezing episode: respiratory virus etiology, atopic characteristics, and illness severity.Pediatr Allergy Immunol. 2014; 25: 796-803Crossref PubMed Scopus (32) Google Scholar, 6Jackson D.J. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. Pappas T.E. et al.Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.Am J Respir Crit Care Med. 2008; 178: 667-672Crossref PubMed Scopus (683) Google Scholar The overall virus detection rates slightly decrease by age, being 80% to 95% in older children.7Jartti T. Lehtinen P. Vuorinen T. Ruuskanen O. Bronchiolitis: age and previous wheezing episodes are linked to viral etiology and atopic characteristics.Pediatr Infect Dis J. 2009; 28: 311-317Crossref PubMed Scopus (77) Google Scholar Prediction of childhood asthma has been limited for many years to assessment of traditional risk factors, such as atopic characteristics (aeroallergen sensitization, increased blood eosinophil count, or atopic eczema), parental asthma, or factors related to parental atopy. Acute wheezing illnesses with RV and respiratory syncytial virus (RSV) are early markers for recurrent wheezing.6Jackson D.J. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. Pappas T.E. et al.Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.Am J Respir Crit Care Med. 2008; 178: 667-672Crossref PubMed Scopus (683) Google Scholar, 8Kotaniemi-Syrjänen A. Vainionpää R. Reijonen T.M. Waris M. Korhonen K. Korppi M. Rhinovirus-induced wheezing in infancy—the first sign of childhood asthma?.J Allergy Clin Immunol. 2003; 111: 66-71Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 9Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar, 10Sigurs N. Aljassim F. Kjellman B. Robinson P.D. Sigurbergsson F. Bjarnason R. 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 (301) Google Scholar, 11Ruotsalainen M. Hyvarinen M.K. Piippo-Savolainen E. Korppi M. Adolescent asthma after rhinovirus and respiratory syncytial virus bronchiolitis.Pediatr Pulmonol. 2013; 48: 633-639Crossref PubMed Scopus (0) Google Scholar, 12Midulla F. Pierangeli A. 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Once asthma is established, exposure to allergens and RV infections are important triggers of asthma exacerbations in children.15Khetsuriani N. Lu X. Teague W.G. Kazerouni N. Anderson L.J. Erdman D.D. Novel human rhinoviruses and exacerbation of asthma in children.Emerg Infect Dis. 2008; 14: 1793-1796Crossref PubMed Scopus (87) Google Scholar This review will focus on the role of viral infections on the development and exacerbation of asthma in children. Understanding the mechanisms of these events could suggest novel insights into the pathogenesis of asthma and would help to identify novel strategies for the prevention and treatment of asthma. Bronchiolitis is a virus-induced infection with inflammation of the small bronchioles and their surrounding tissue. Clinically, it is characterized as the first expiratory breathing difficulty in children less than 2 years of age. Other lower respiratory tract symptoms include dry cough, tachypnea, hyperinflation, chest retraction, and widespread crackles or wheezing. In many studies wheezing is not a mandatory diagnostic criterion, and the upper age limit varies from 6 months to 2 years.16Korppi M. Koponen P. Nuolivirta K. Upper age limit for bronchiolitis: 12 months or 6 months?.Eur Respir J. 2012; 39 (author reply 788-9): 787-788Crossref PubMed Scopus (0) Google Scholar Wheezing is defined as a whistling sound during expiration accompanied by dyspnea.17National Asthma Education and Prevention ProgramNational Heart, Lung, and Blood Institute, National Institutes of Health. Expert panel report 3: guidelines for the diagnosis and management of asthma. US Department of Health and Human Services, Bethesda2007Google Scholar Wheezing can be diagnosed if there is a reversible expiratory airway obstruction and the illness does not fulfill the diagnosis of bronchiolitis or asthma. Moreover, wheezing is divided into different phenotypes based on natural history, such as "transient early," "persistent," and "late-onset" wheezing. Typically, the 2 latter phenotypes are more closely associated with sensitization and asthma.1Taussig L.M. Wright A.L. Holberg C.J. Halonen M. Morgan W.J. Martinez F.D. Tucson children's respiratory study: 1980 to present.J Allergy Clin Immunol. 2003; 111: 661-675Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar Asthma is a chronic disorder characterized by airway inflammation, increased mucus secretion, and bronchial hyperresponsiveness, all of which cause reversible airflow obstruction.17National Asthma Education and Prevention ProgramNational Heart, Lung, and Blood Institute, National Institutes of Health. Expert panel report 3: guidelines for the diagnosis and management of asthma. US Department of Health and Human Services, Bethesda2007Google Scholar The chronic inflammation, disrupted epithelium, and airway remodeling increase the susceptibility to many environmental factors, such as viral infections and allergens. RVs are nonenveloped positive-strand RNA viruses in the family Picornaviridae and genus Enterovirus and are classified into 3 species (RV-A, RV-B and RV-C; Fig 1).18McIntyre C.L. Knowles N.J. Simmonds P. Proposals for the classification of human rhinovirus species A, B and C into genotypically assigned types.J Gen Virol. 2013; 94: 1791-1806Crossref PubMed Scopus (85) Google Scholar There are more than 160 distinct RV genotypes, including 80 RV-A and 32 RV-B serotypes and 65 newly identified RV-C serotypes. RV structural and genetic variability has inhibited efforts to develop antivirals. For example, small molecules ("capsid binding agents") that inhibit RV-A and RV-B binding and replication are not effective against RV-C because of differences in capsid structure.19Basta H.A. Ashraf S. Sgro J.Y. Bochkov Y.A. Gern J.E. Palmenberg A.C. Modeling of the human rhinovirus C capsid suggests possible causes for antiviral drug resistance.Virology. 2014; 448: 82-90Crossref PubMed Scopus (11) Google Scholar 3C protease inhibitors are effective in vitro, but results in clinical trials were disappointing.20Hao W. Bernard K. Patel N. Ulbrandt N. Feng H. Svabek C. et al.Infection and propagation of human rhinovirus C in human airway epithelial cells.J Virol. 2012; 86: 13524-13532Crossref PubMed Scopus (42) Google Scholar, 21Hayden F.G. Turner R.B. Gwaltney J.M. Chi-Burris K. Gersten M. 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Bronchiolitis: age and previous wheezing episodes are linked to viral etiology and atopic characteristics.Pediatr Infect Dis J. 2009; 28: 311-317Crossref PubMed Scopus (77) Google Scholar RV predominates as an etiologic agent in 50% to 80% of wheezing episodes and asthma exacerbations in children.6Jackson D.J. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. Pappas T.E. et al.Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.Am J Respir Crit Care Med. 2008; 178: 667-672Crossref PubMed Scopus (683) Google Scholar, 7Jartti T. Lehtinen P. Vuorinen T. Ruuskanen O. Bronchiolitis: age and previous wheezing episodes are linked to viral etiology and atopic characteristics.Pediatr Infect Dis J. 2009; 28: 311-317Crossref PubMed Scopus (77) Google Scholar, 8Kotaniemi-Syrjänen A. Vainionpää R. Reijonen T.M. Waris M. Korhonen K. Korppi M. 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Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar The Childhood Origins of Asthma (COAST) study demonstrated that the risk for asthma by age 6 years was increased if the children had wheezing with RV (odds ratio [OR], 9.8) versus RSV (OR, 2.6) during the first 3 years, and furthermore, 90% of the children with RV-induced wheezing in the third year of life had asthma by age 6 years (OR, 26).6Jackson D.J. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. Pappas T.E. et al.Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.Am J Respir Crit Care Med. 2008; 178: 667-672Crossref PubMed Scopus (683) Google Scholar, 40Lemanske Jr., R.F. Jackson D.J. Gangnon R.E. Evans M.D. Li Z. Shult P.A. et al.Rhinovirus illnesses during infancy predict subsequent childhood wheezing.J Allergy Clin Immunol. 2005; 116: 571-577Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar Although RV-induced wheezing was an independent asthma risk factor, aeroallergen sensitization markedly increases the RV-associated risk of asthma.6Jackson D.J. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. Pappas T.E. et al.Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.Am J Respir Crit Care Med. 2008; 178: 667-672Crossref PubMed Scopus (683) Google Scholar, 9Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar An Australian birth cohort study showed that the risk for wheezing at age 5 years was increased if the wheezing at less than 1 year of age was associated with RV either alone (OR, 3.2) or with concomitant RSV (OR, 4.1) but only in children with sensitization at an age of less than 2 years.9Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnst