The role of viruses in acute exacerbations of asthma
Authors: David J. Jackson, Sebastian L. Johnston
Journal: Journal of Allergy and Clinical Immunology (2010)

Viral respiratory infections are the most common cause of an acute asthma exacerbation in both children and adults and represent a significant global health burden. An increasing body of evidence supports the hypothesis that these infections cause a greater degree of morbidity in asthmatic subjects than in the healthy population, emphasizing a discrepancy in the antiviral response of asthmatics. In this review we discuss why such a discrepancy might exist, examining the role of the bronchial epithelium as well as the main inflammatory cells, mediators, and molecular pathways that are involved in the immune response. In addition, the potential impact of virus-induced asthma exacerbations on airway remodelling is reviewed and we explore which therapeutic options might be of benefit in preventing the deterioration of asthma control seen following viral infection. Viral respiratory infections are the most common cause of an acute asthma exacerbation in both children and adults and represent a significant global health burden. An increasing body of evidence supports the hypothesis that these infections cause a greater degree of morbidity in asthmatic subjects than in the healthy population, emphasizing a discrepancy in the antiviral response of asthmatics. In this review we discuss why such a discrepancy might exist, examining the role of the bronchial epithelium as well as the main inflammatory cells, mediators, and molecular pathways that are involved in the immune response. In addition, the potential impact of virus-induced asthma exacerbations on airway remodelling is reviewed and we explore which therapeutic options might be of benefit in preventing the deterioration of asthma control seen following viral infection. 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: June 2010. Credit may be obtained for these courses until May 31, 2012.Copyright Statement: Copyright © 2010-2012. 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 these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members:Authors: David J. Jackson, MD, and Sebastian L. Johnston, MDActivity Objectives1.To understand the importance of acute respiratory tract viral infections as triggers of asthma exacerbations.2.To understand the mechanisms of airway inflammatory response to respiratory tract viral infections in patients with asthma.3.To recognize potential therapeutic approaches for asthma exacerbations.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: D. Jackson has declared that he has no conflicts of interest. S. L. Johnston has consultant arrangements with AstraZeneca, Centocor, Sanofi-Pasteur, Synairgen, GlaxoSmithKline, anc Chiesi; has a share option with Synairgen; receives research support from Sanofi-Pasteur, the Medical Research Council, the University of Leicester, the British Medical Association, Asthma UK, Imperial College Healthcare NHS Trust, EU ERC MoRIAE, Centocor Inc, and the National Institute for Health Research.Viral respiratory tract infections are one of the most common illnesses in human subjects, with 500 million cases and an economic burden estimated at $40 billion annually in the United States alone.1Fendrick A.M. Monto A.S. Nightengale B. Sarnes M. The economic burden of non-influenza-related viral respiratory tract infection in the United States.Arch Intern Med. 2003; 163: 487-494Crossref PubMed Scopus (232) Google Scholar Since the early 1970s, viral respiratory tract infections have been reported as triggers for exacerbations of asthma in both adults and children.2Lambert H.P. Stern H. Infective factors in exacerbations of bronchitis and asthma.BMJ. 1972; 3: 323-327Crossref PubMed Google Scholar, 3Minor T.E. Dick E.C. DeMeo A.N. Ouellette J.J. Cohen M. Reed C.E. Viruses as precipitants of asthmatic attacks in children.JAMA. 1974; 227: 292-298Crossref PubMed Google Scholar The development of highly sensitive and specific molecular diagnostic and detection techniques in the 1990s led to greatly improved detection of respiratory tract viruses and allowed clear demonstration of the important link between viral infections and asthma exacerbations. When RT-PCR is used to supplement or instead of conventional culture techniques, viruses have been found in approximately 80% of wheezing episodes in school-aged children and in approximately one half to three quarters of the acute wheezing episodes in adults. Of the respiratory tract viruses identified in these circumstances, rhinoviruses are most commonly found and are detected approximately 65% of the time.4Johnston S.L. Pattemore P.K. Sanderson G. Smith S. Lampe F. Josephs L. et al.Community study of role of viral infections in exacerbations of asthma in 9-11 year old children.BMJ. 1995; 310: 1225-1229Crossref PubMed Google Scholar, 5Nicholson K.G. Kent J. Ireland D.C. Respiratory viruses and exacerbations of asthma in adults.BMJ. 1993; 307: 982-986Crossref PubMed Google Scholar, 6Wark P.A. Johnston S.L. Moric I. Simpson J.L. Hensley M.J. Gibson P.G. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma.Eur Respir J. 2002; 19: 68-75Crossref PubMed Scopus (196) Google Scholar, 7Grissell T.V. Powell H. Shafren D.R. Boyle M.J. Hensley M.J. Jones P.D. et al.Interleukin-10 gene expression in acute virus-induced asthma.Am J Respir Crit Care Med. 2005; 172: 433-439Crossref PubMed Scopus (110) 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: June 2010. Credit may be obtained for these courses until May 31, 2012. Copyright Statement: Copyright © 2010-2012. 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 these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members:Authors: David J. Jackson, MD, and Sebastian L. Johnston, MD Activity Objectives1.To understand the importance of acute respiratory tract viral infections as triggers of asthma exacerbations.2.To understand the mechanisms of airway inflammatory response to respiratory tract viral infections in patients with asthma.3.To recognize potential therapeutic approaches for asthma exacerbations. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: D. Jackson has declared that he has no conflicts of interest. S. L. Johnston has consultant arrangements with AstraZeneca, Centocor, Sanofi-Pasteur, Synairgen, GlaxoSmithKline, anc Chiesi; has a share option with Synairgen; receives research support from Sanofi-Pasteur, the Medical Research Council, the University of Leicester, the British Medical Association, Asthma UK, Imperial College Healthcare NHS Trust, EU ERC MoRIAE, Centocor Inc, and the National Institute for Health Research. In addition to rhinoviruses, other respiratory tract viruses, such as respiratory syncytial virus (RSV), influenza viruses, coronaviruses, human metapneumoviruses, parainfluenza viruses, adenoviruses, and bocaviruses, have all been detected in subjects with asthma exacerbations. However, in a recent epidemiologic study performed after the discovery of several newer viruses, such as bocavirus, the only virus type significantly associated with asthma exacerbations in children aged 2 to 17 years were rhinoviruses.8Khetsuriani N. Kazerouni N.N. Erdman D.D. Lu X. Redd S.C. Anderson L.J. et al.Prevalence of viral respiratory tract infections in children with asthma.J Allergy Clin Immunol. 2007; 119: 314-321Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Understanding the mechanisms provoking virus-induced airway inflammation in asthmatic subjects might offer significant opportunities for improved disease management. The reality at present is that current drugs for the treatment of virus-induced exacerbations of asthma are poorly effective, and alternative therapies to modulate viral pathogenesis are desperately needed. Experimental human9Message S.D. Laza-Stanca V. Mallia P. Parker H.L. Zhu J. Kebadze T. et al.Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production.Proc Natl Acad Sci U S A. 2008; 105: 13562-13567Crossref PubMed Scopus (175) Google Scholar and murine10Bartlett N.W. Walton R.P. Edwards M.R. Aniscenko J. Caramori G. Zhu J. et al.Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation.Nat Med. 2008; 14: 199-204Crossref PubMed Scopus (148) Google Scholar models of rhinovirus-induced asthma exacerbations have recently been developed, and these offer great potential in increasing our understanding, with the goal of arriving at novel therapies in the future. In a recent study of this kind, experimental infection of both asthmatic and healthy volunteers with rhinovirus led to increased lower respiratory tract symptoms typical of a mild exacerbation in asthmatic subjects with only minimal lower respiratory tract symptoms in healthy volunteers. Increases in airway hyperresponsiveness and decreases in both peak expiratory flow and FEV1 were demonstrated in asthmatic subjects without any change in these measures in healthy subjects.9Message S.D. Laza-Stanca V. Mallia P. Parker H.L. Zhu J. Kebadze T. et al.Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production.Proc Natl Acad Sci U S A. 2008; 105: 13562-13567Crossref PubMed Scopus (175) Google Scholar This study, along with several others, supports the idea that respiratory tract viral infections cause a greater degree of morbidity in asthmatic subjects than in the healthy population. In this review we discuss why such a discrepancy in antiviral immune response might exist. In addition, we explore which therapeutic options might be of benefit in preventing the deterioration of asthma control seen after viral infection. The bronchial epithelium provides a barrier between the microbe-rich outside world and the internal parenchyma. It is, however, far more than simply an inert barrier and is immunologically active, playing a pivotal role in both innate and adaptive immunity. All respiratory tract viruses enter and replicate within airway epithelial cells and can damage both ciliated and nonciliated respiratory epithelial cells, leading to necrosis of the airway epithelium, ciliostasis, loss of cilia, and impairment of mucociliary clearance.11van der Schans C.P. Bronchial mucus transport.Respir Care. 2007; 52: 1150-1156PubMed Google Scholar, 12Ahern W. Bird T. Court S. et al.Pathological changes in virus infections of the lower respiratory tract in children.J Clin Invest. 1970; 23: 7-18Google Scholar, 13Thornton D.J. Rousseau K. McGuckin M.A. Structure and function of the polymeric mucins in airways mucus.Annu Rev Physiol. 2008; 70: 459-486Crossref PubMed Scopus (202) Google Scholar However, it is likely that the clinical manifestations might be secondary to the release of proinflammatory mediators by damaged bronchial epithelial cells (BECs), as well as a direct cytotoxic effect of the virus. Rhinoviruses attach to epithelial cells through intercellular adhesion molecule 1 (ICAM-1) for major human rhinovirus (HRV) serotypes or low-density lipoprotein receptor for minor HRV serotypes. The receptor or receptors for the recently identified group C rhinoviruses are yet to be identified. Indeed, rhinovirus infection itself upregulates expression of ICAM-1 both in vivo and in vitro to further the availability of receptors to bind to and infect epithelial cells.14Grünberg K. Sharon R.F. Hiltermann T.J. Brahim J.J. Dick E.C. Sterk P.J. et al.Experimental rhinovirus 16 infection increases intercellular adhesion molecule-1 expression in bronchial epithelium of asthmatics regardless of inhaled steroid treatment.Clin Exp Allergy. 2000; 30: 1015-1023Crossref PubMed Scopus (48) Google Scholar, 15Papi A. Papadopoulos N.G. Degitz K. Holgate S.T. Johnston S.L. Corticosteroids inhibit rhinovirus-induced intercellular adhesion molecule-1 up-regulation and promoter activation on respiratory epithelial cells.J Allergy Clin Immunol. 2000; 105: 318-326Abstract Full Text Full Text PDF PubMed Google Scholar Infection of BECs with rhinovirus induces the secretion of a wide range of cytokines and chemokines, including IL-1, IL-6, CXCL8/IL-8, GM-CSF, CCL5/RANTES, and CXCL10/interferon-inducible protein 10 (IP-10), as well as many others.16Schroth M.K. Grimm E. Frindt P. Galagan D.M. Konno S.I. Love R. et al.Rhinovirus replication causes RANTES production in primary bronchial epithelial cells.Am J Respir Cell Mol Biol. 1999; 20: 1220-1228Crossref PubMed Google Scholar, 17Papadopoulos N.G. Papi A. Meyer J. Stanciu L.A. Salvi S. Holgate S.T. et al.Rhinovirus infection up-regulates eotaxin and eotaxin-2 expression in bronchial epithelial cells.Clin Exp Allergy. 2001; 31: 1060-1066Crossref PubMed Scopus (94) Google Scholar, 18Zhu Z. Tang W. 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Holgate S.J. et al.Frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic individuals: a longitudinal cohort study.Lancet. 2002; 359: 831-834Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar demonstrated more severe and prolonged virus-induced symptoms (including lower respiratory tract symptoms) in asthmatic compared with nonasthmatic subjects, suggesting for the first time that there might be some inherent differences in the way that asthmatic subjects respond to respiratory tract viral infections. Wark et al21Wark P.A. Johnston S.L. Bucchieri F. Powell R. Puddicombe S. Laza-Stanca V. et al.Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus.J Exp Med. 2005; 201: 937-947Crossref PubMed Scopus (534) Google Scholar subsequently provided a mechanistic insight into why this might be the case with studies involving cultured BECs from adult asthmatic and nonasthmatic subjects obtained by means of bronchoscopy, followed by infection with rhinovirus in vitro. Although rhinovirus induction of the proinflammatory cytokine IL-6 and CCL5 was not different between the 2 groups, asthmatic BECs produced lower levels of the type I IFN-β and also had higher levels of rhinovirus replication. Importantly, deficient IFN-β expression was observed in both steroid-treated and steroid-naive asthmatic subjects. The asthmatic BECs responded to exogenous treatment with IFN-β, exhibiting reduced rhinovirus release and demonstrating that the deficiency in asthmatic cells was associated with production of antiviral IFN-β rather than the actions of IFN-β. Contoli et al22Contoli M. Message S.D. Laza-Stanca V. Edwards M.R. Wark P.A. Bartlett N.W. et al.Role of deficient type III interferon-lambda production in asthma exacerbations.Nat Med. 2006; 12: 1023-1026Crossref PubMed Scopus (447) Google Scholar provided further evidence of the importance of antiviral interferons using a human experimental infection model of adults with mild-to-moderate asthma. Not only did bronchoalveolar lavage (BAL) cells from asthmatic subjects have lower levels of rhinovirus and LPS-induced type III IFN-λ, but deficient IFN-λ in asthmatic cells was related to the pathogenesis of asthma exacerbations in vivo, with abundance of IFN-λ being negatively correlated with airway symptom scores, changes in lung function, virus load, and markers of inflammation in vivo. In a more recent study, this time in subjects with moderate-to-severe asthma, Bullens et al23Bullens D.M. Decraene A. Dillssen E. Meyts I. De Boeck K. Dupont L.J. et al.Type III IFN-lambda mRNA expression in sputum of adult and school-aged asthmatics.Clin Exp Allergy. 2008; 38: 1459-1467Crossref PubMed Scopus (29) Google Scholar demonstrated that IFNL1, but not IFNL2/3, mRNA levels obtained from sputum cells negatively correlated with asthma symptoms, again highlighting a protective role for IFN-λ in asthma. At present, the precise mechanism or mechanisms behind deficient interferon production in asthmatic subjects remain unknown. Because asthmatic subjects have deficient IFN-β, IFN-λ, and perhaps some of the IFN-αs,24Gehlhar K. Bilitewski C. Reinitz-Rademacher K. Rohde G. Bufe A. Impaired virus-induced interferon-alpha2 release in adult asthmatic patients.Clin Exp Allergy. 2006; 36: 331-337Crossref PubMed Scopus (58) Google Scholar it is less likely a result of a polymorphism in one of these genes or their promoters. A polymorphism in a gene encoding a transcription factor or signaling molecule required for the expression of all these interferons is a more likely possibility, however.25Edwards M.R. Johnston S.L. Deficient IFN in virus-induced asthma exacerbations.Clin Exp Allergy. 2008; 38: 1416-1418Crossref PubMed Scopus (5) Google Scholar Interestingly, Thomas et al26Thomas B.J. Lindsay M. Dagher H. Freezer N.J. Li D. Ghildyal R. et al.Transforming growth factor-beta enhances rhinovirus infection by diminishing early innate responses.Am J Respir Cell Mol Biol. 2009; 41: 339-347Crossref PubMed Scopus (13) Google Scholar recently demonstrated that excess TGF-β present in asthmatic airways mediates enhanced rhinovirus replication, probably through its suppressive actions on host type I interferon responses. Specifically, the effect of TGF-β appeared to be mediated through actions on interferon regulatory factor (IRF) 3 pathways.26Thomas B.J. Lindsay M. Dagher H. Freezer N.J. Li D. Ghildyal R. et al.Transforming growth factor-beta enhances rhinovirus infection by diminishing early innate responses.Am J Respir Cell Mol Biol. 2009; 41: 339-347Crossref PubMed Scopus (13) Google Scholar Macrophages are the predominant leukocyte in the airway and are distributed from the upper airways down to the alveoli. They produce inflammatory cytokines to recruit cells of the adaptive immune system, express a number of innate pattern-recognition receptors (PRRs), and play a key role in phagocytosis of bacterial organisms. They also modulate the immune response by inhibiting antigen presentation by dendritic cells, T-cell activation, and B-cell antibody production.27Holt P.G. Down-regulation of immune responses in the lower respiratory tract: the role of alveolar macrophages.Clin Exp Immunol. 1986; 63: 261-270PubMed Google Scholar, 28Holt P.G. Oliver J. Bilyk N. McMenamin C. McMenamin P.G. Kraal G. et al.Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages.J Exp Med. 1993; 177: 397-407Crossref PubMed Google Scholar The interaction between rhinoviruses and macrophages stimulates secretion of proinflammatory cytokines, such as IL-1, IL-8, IFN-γ, and CCL3/macrophage inflammatory protein 1α. In addition, TNF-α, a highly inflammatory cytokine, is produced by macrophages in response to rhinovirus, and this has been shown to require viral replication.29Laza-Stanca V. Stanciu L.A. Message S.D. Edwards M.R. Gern J.E. Johnston S.L. Rhinovirus replication in human macrophages induces NF-kappaB-dependent tumor necrosis factor alpha production.J Virol. 2006; 80: 8248-8258Crossref PubMed Scopus (50) Google Scholar Rhinovirus infection also induces release of type I interferons from airway macrophages, a process that might limit viral spread by inducing an antiviral state in epithelial cells.29Laza-Stanca V. Stanciu L.A. Message S.D. Edwards M.R. Gern J.E. Johnston S.L. Rhinovirus replication in human macrophages induces NF-kappaB-dependent tumor necrosis factor alpha production.J Virol. 2006; 80: 8248-8258Crossref PubMed Scopus (50) Google Scholar More recently, Oliver et al30Oliver B.G. Lim S. Wark P. Laza-Stanca V. King N. 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Role of nasal interleukin-8 in neutrophil recruitment and activation in children with virus-induced asthma.Am J Respir Crit Care Med. 1997; 155: 1362-1366Crossref PubMed Google Scholar provided the first in vivo evidence of an important role for IL-8 in the neutrophil influx during viral-associated asthma exacerbations. Studies have since demonstrated that numbers of neutrophils correlate with levels of IL-8 after rhinovirus infection,33Gern J.E. Vrtis R. Grindle K.A. Swenson C. Busse W.W. Relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection.Am J Respir Crit Care Med. 2000; 162: 2226-2231Crossref PubMed Google Scholar, 35Pizzichini M.M. Pizzichini E. Efthimiadis A. Chauhan A.J. Johnston S.L. 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