Asthma exacerbations: Origin, effect, and prevention
Authors: David J. Jackson, Annemarie Sykes, Patrick Mallia, Sebastian L. Johnston
Journal: Journal of Allergy and Clinical Immunology (2011)

Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children in the Western world. Despite advances in asthma management, acute exacerbations continue to occur and impose considerable morbidity on patients and constitute a major burden on health care resources. Respiratory tract viruses have emerged as the most frequent triggers for exacerbations in both children and adults; however, the mechanisms underlying these remain poorly understood. More recently, it has become increasingly clear that interactions might exist between viruses and other triggers, increasing the likelihood of an exacerbation. In this article we begin with an overview of the health, economic, and social burden that exacerbations of asthma carry with them. This is followed by a review of the pathogenesis of asthma exacerbations, highlighting the various triggers responsible and multiple interactions that exist between them. The final section first addresses what preventative measures are currently available for asthma exacerbations and subsequently examines which of the new treatments in development might lessen the burden of exacerbations in the future. Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children in the Western world. Despite advances in asthma management, acute exacerbations continue to occur and impose considerable morbidity on patients and constitute a major burden on health care resources. Respiratory tract viruses have emerged as the most frequent triggers for exacerbations in both children and adults; however, the mechanisms underlying these remain poorly understood. More recently, it has become increasingly clear that interactions might exist between viruses and other triggers, increasing the likelihood of an exacerbation. In this article we begin with an overview of the health, economic, and social burden that exacerbations of asthma carry with them. This is followed by a review of the pathogenesis of asthma exacerbations, highlighting the various triggers responsible and multiple interactions that exist between them. The final section first addresses what preventative measures are currently available for asthma exacerbations and subsequently examines which of the new treatments in development might lessen the burden of exacerbations in the future. Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children in the Western world. Despite advances in asthma management, acute exacerbations continue to occur and impose considerable morbidity on patients and constitute a major burden on health care resources. The frequency with which acute exacerbations occur in asthmatic patients varies depending on the definition used for the exacerbation, the severity and degree of control of the underlying disease, and the source of the data. The most comprehensive data on exacerbation incidence comes from therapeutic clinical trials in asthmatic patients. In the OPTIMA trial in patients with mild asthma, exacerbation rates were 0.92 per patient per year in those receiving low-dose inhaled corticosteroids (ICSs) compared with 0.36 in patients receiving high-dose ICSs and a long-acting β-agonist (LABA).1O'Byrne P.M. Barnes P.J. Rodriguez-Roisin R. et al.Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial.Am J Respir Crit Care Med. 2001; 164: 1392-1397Crossref PubMed Google Scholar In the Formoterol and Corticosteroids Establishing Therapy study in patients with moderate asthma, rates of severe exacerbations were 0.91 per patient per year in those treated with low-dose ICSs and 0.34 in patients receiving high-dose ICSs and LABAs.2Pauwels R.A. Lofdahl C.G. Postma D.S. et al.Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group [published erratum appears in N Engl J Med 1998;338:139].N Engl J Med. 1997; 337: 1405-1411Crossref PubMed Scopus (1222) Google Scholar In patients with more severe asthma, in a trial of anti-IgE therapy, exacerbation rates over a 48-week period were 0.88 in the placebo group and 0.66 in the treatment group.3Hanania N.A. Alpan O. Hamilos D.L. et al.Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial.Ann Intern Med. 2011; 154: 573-582Crossref PubMed Google Scholar Therefore these data suggest that asthmatic patients receiving optimum treatment should only experience 1 exacerbation every 3 years on average. However, these studies are unlikely to reflect real exacerbation rates because unstable patients and those with frequent exacerbations were excluded, and it is recognized that participation in a clinical trial improves asthma control, even in patients who receive placebo. Also, these figures do not reflect the heterogeneity of exacerbations within the asthmatic population. Some patients will rarely or never experience an exacerbation, whereas others experience frequent exacerbations. A survey of 3151 patients presenting to US emergency departments with acute asthma found that 73% reported at least 1 visit for asthma in the prior year, with 21% reporting 6 or more visits.4Griswold S.K. Nordstrom C.R. Clark S. Gaeta T.J. Price M.L. Camargo Jr., C.A. Asthma exacerbations in North American adults: who are the "frequent fliers" in the emergency department?.Chest. 2005; 127: 1579-1586Crossref PubMed Scopus (66) Google Scholar Asthmatic patients requiring an emergency department visit or hospitalization are at significantly increased risk of future exacerbations independent of demographic and clinical factors, asthma severity, and asthma control.5Miller M.K. Lee J.H. Miller D.P. Wenzel S.E. Recent asthma exacerbations: a key predictor of future exacerbations.Respir Med. 2007; 101: 481-489Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar However, in a study from the National Heart, Lung, and Blood Institute's Severe Asthma Research Program, the percentage of asthmatic patients with 3 or more exacerbations per year was 5% in the mild group, 13% in the moderate group, and 54% in the severe group, suggesting that frequent exacerbations are related to disease severity.6Moore W.C. Bleecker E.R. Curran-Everett D. et al.Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program.J Allergy Clin Immunol. 2007; 119: 405-413Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar Factors associated with frequent exacerbations include female sex,7Tattersfield A.E. Postma D.S. Barnes P.J. et al.Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group.Am J Respir Crit Care Med. 1999; 160: 594-599Crossref PubMed Google Scholar obesity,5Miller M.K. Lee J.H. Miller D.P. Wenzel S.E. Recent asthma exacerbations: a key predictor of future exacerbations.Respir Med. 2007; 101: 481-489Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar psychopathology, chronic sinusitis, gastroesophageal reflux, respiratory tract infections, and obstructive sleep apnea.8ten Brinke A. Sterk P.J. Masclee A.A. et al.Risk factors of frequent exacerbations in difficult-to-treat asthma.Eur Respir J. 2005; 26: 812-818Crossref PubMed Scopus (166) Google Scholar Therefore some asthmatic patients will experience frequent exacerbations, but it is unclear whether this is independent of traditional measures of asthma control. Surveys of real-life asthmatic patients indicate that the incidence of exacerbations is much higher than seen in patients recruited for clinical trials. In a survey of 1003 patients in the United States with uncontrolled asthma, 70% had an unscheduled physician's office visit, 36% had an emergency department visit, and 14% had a hospitalization in the last year. Even in patients with controlled asthma, 43% had an unscheduled physician's office visit, 10% had an emergency department visit, and 3% had a hospitalization in the last year.9Peters S.P. Jones C.A. Haselkorn T. Mink D.R. Valacer D.J. Weiss S.T. Real-world Evaluation of Asthma Control and Treatment (REACT): findings from a national Web-based survey.J Allergy Clin Immunol. 2007; 119: 1454-1461Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar In the Severe Asthma Research Program cohort 85% of patients with severe asthma had ever attended the emergency department, but even in the mild and moderate groups, the rates of attendance were 58% and 66%, respectively. A survey of 2050 adults and 753 children with asthma in 7 European countries reported that 36% of children and 28% of adults required an unscheduled urgent care visit in the past 12 months. Eighteen percent of children and 11% of adults required 1 or more emergency department visits because of asthma in the past year, and 7% of all patients required overnight hospitalization.10Rabe K.F. Vermeire P.A. Soriano J.B. Maier W.C. Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study.Eur Respir J. 2000; 16: 802-807Crossref PubMed Scopus (760) Google Scholar These studies suggest that asthma exacerbations are common and frequently result in unscheduled medical care. Although deaths from asthma are relatively rare, they are frequently associated with poor asthma care and therefore are a leading cause of preventable deaths, often in young people. There were 3447 deaths caused by asthma (3262 adults and 185 children aged 0-17 years) in 2007 in the United States11Akinbami L.J. Moorman J.E. Liu X. Asthma prevalence, health care use, and mortality: United States, 2005-2009.Natl Health Stat Rep. 2011; : 1-14PubMed Google Scholar and 1400 estimated deaths in 2002 in the United Kingdom.12Asthma UK. Available at: http://www.asthma.org.uk/document.rm?id=18. Accessed July 12, 2011.Google Scholar A number of factors have been associated with the fatal or near-fatal exacerbations, including lower socioeconomic status, psychiatric comorbidity, female sex, older age, obesity, smoking, noncompliance with medications, and a previous near-fatal attack.13Grant E.N. Alp H. Weiss K.B. The challenge of inner-city asthma.Curr Opin Pulm Med. 1999; 5: 27-34Crossref PubMed Google Scholar, 14Kolbe J. Fergusson W. Vamos M. Garrett J. Case-control study of severe life threatening asthma (SLTA) in adults: psychological factors.Thorax. 2002; 57: 317-322Crossref PubMed Scopus (60) Google Scholar, 15Hartert T.V. Speroff T. Togias A. et al.Risk factors for recurrent asthma hospital visits and death among a population of indigent older adults with asthma.Ann Allergy Asthma Immunol. 2002; 89: 467-473Abstract Full Text PDF PubMed Google Scholar, 16Miller T.P. Greenberger P.A. Patterson R. The diagnosis of potentially fatal asthma in hospitalized adults. Patient characteristics and increased severity of asthma.Chest. 1992; 102: 515-518Crossref PubMed Google Scholar, 17Prescott E. Lange P. Vestbo J. Effect of gender on hospital admissions for asthma and prevalence of self-reported asthma: a prospective study based on a sample of the general population. Copenhagen City Heart Study Group.Thorax. 1997; 52: 287-289Crossref PubMed Google Scholar, 18Ulrik C.S. Frederiksen J. Mortality and markers of risk of asthma death among 1,075 outpatients with asthma.Chest. 1995; 108: 10-15Crossref PubMed Google Scholar Therefore these factors can be used to identify patients at high risk of asthma mortality and to target appropriate preventative measures. The social and economic burden of asthma exacerbations relates to the direct costs of health care use and the indirect costs associated with lost productivity. In the United States in 2007, there were 1.75 million (1.11 million for adults and 0.64 million for children) asthma-related emergency department visits and 456,000 (299,000 for adults and 157,000 for children) asthma-related hospitalizations.11Akinbami L.J. Moorman J.E. Liu X. Asthma prevalence, health care use, and mortality: United States, 2005-2009.Natl Health Stat Rep. 2011; : 1-14PubMed Google Scholar Hospitalization constitutes about one third of the total $14.7 billion in US annual asthma-related health care expenditures.19American Lung Association. Trends in asthma morbidity and mortality. Available at: http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=33347. Accessed July 12, 2011.Google Scholar The European Lung Foundation has estimated that the cost of asthma in the European Union is €17.7 billion, of which €9.8 billion is related to lost productivity.20Available at: http://www.european-lung-foundation.org/16385-lung-health-in-europe.htm. Accessed July 12, 2011.Google Scholar In the Real-world Evaluation of Asthma Control and Treatment survey 24% of adults and 53% of children had missed at least 1 day of work or school, respectively. Therefore the social and economic burden of asthma exacerbations remains considerable. Since the early 1970s, viral respiratory tract infections have been reported as triggers for exacerbations of asthma in both adults and children.21Lambert H.P. Stern H. Infective factors in exacerbations of bronchitis and asthma.BMJ. 1972; 3: 323-327Crossref PubMed Google Scholar, 22Minor 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 using PCR technology in the 1990s led to greatly improved detection of respiratory tract viruses and allowed a clear demonstration of the important link between viral infections and asthma exacerbations. When PCR is used to supplement or instead of conventional techniques, viruses have been found in approximately 80% of wheezing episodes in school-aged children and in approximately one half to three quarters of acute wheezing episodes in adults.23Johnston S.L. Pattemore P.K. Sanderson G. 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, 24Nicholson K.G. Kent J. Ireland D.C. Respiratory viruses and exacerbations of asthma in adults.BMJ. 1993; 307: 982-986Crossref PubMed Google Scholar, 25Wark 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, 26Grissell T.V. Powell H. Shafren D.R. 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 With the exception of respiratory syncytial virus (RSV) in infants hospitalized with bronchiolitis, rhinoviruses are by far the most frequently detected virus type. Rhinoviruses are members of the Picornaviridae family, with more than 100 serotypes and no predictable pattern of infection based on serotype. They are the most common cause for the common cold in both children and adults and are distributed worldwide. Methods of virus typing classified rhinoviruses into RV-A and RV-B groups based on genetic sequence similarity and susceptibility to antiviral agents. More recently, a newly identified group, termed RV-C, has been identified based purely on sequencing data. Interestingly, a number of studies suggest that members of the RV-C group might be intrinsically more virulent, have a greater propensity to cause asthma exacerbations, or both than other rhinoviruses27Miller E.K. Khuri-Bulos N. Williams J.V. et al.Human rhinovirus C associated with wheezing in hospitalised children in the Middle East.J Clin Virol. 2009; 46: 85-89Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 28Lau S.K. Yip C.C. Lin A.W. et al.Clinical and molecular epidemiology of human rhinovirus C in children and adults in Hong Kong reveals a possible distinct human rhinovirus C subgroup.J Infect Dis. 2009; 200: 1096-1103Crossref PubMed Scopus (52) Google Scholar; however, further work is needed to better define whether a unique clinical picture is associated with RV-C infections. Influenza is a common infection during the winter months, frequently reaching local or national epidemic proportions. After the 2009 H1N1 influenza A pandemic, a number of studies highlighted asthma as an important comorbid condition in those infected with this virus. Markers of illness severity, such as hospitalization, admission to the intensive care unit, and mortality in 2009 patients with H1N1 influenza have been shown to be associated with a diagnosis of asthma.29O'Riordan S. Barton M. Yau Y. Read S.E. Allen U. Tran D. Risk factors and outcomes among children admitted to hospital with pandemic H1N1 influenza.CMAJ. 2010; 182: 39-44Crossref PubMed Scopus (163) Google Scholar, 30Plessa E. Diakakis P. Gardelis J. Thirios A. Koletsi P. Falagas M.E. Clinical features, risk factors, and complications among pediatric patients with pandemic influenza A (H1N1).Clin Pediatr (Phila). 2010; 49: 777-781Crossref PubMed Scopus (24) Google Scholar, 31Libster R. Bugna J. Coviello S. et al.Pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in Argentina.N Engl J Med. 2010; 362: 45-55Crossref PubMed Scopus (288) Google Scholar RSV is the main pathogen causing severe bronchiolitis in infants, with most infections occurring between December and February each year. Differentiating among acute wheeze, bronchiolitis, postbronchiolitis wheeze, and acute exacerbations of asthma is frequently difficult in infants and young children. Subsequently, the interpretation of pediatric studies is complex, and the prevalence of RSV can vary widely from study to study. In an Australian birth cohort study RSV accounted for 16.8% (second behind rhinovirus) of cases of wheezy respiratory tract infections in the first year of life,32Kusel M.M. de Klerk N.H. Holt P.G. et al.Role of respiratory viruses in acute upper and lower respiratory tract illness in the first year of life: a birth cohort study.Pediatr Infect Dis J. 2006; 25: 680-686Crossref PubMed Scopus (194) Google Scholar whereas a detection frequency of 27% was seen in a similar British study.33Legg J.P. Warner J.A. Johnston S.L. Warner J.O. Frequency of detection of picornaviruses and seven other respiratory pathogens in infants.Pediatr Infect Dis J. 2005; 24: 611-616Crossref PubMed Scopus (64) Google Scholar RSV in older children and adults is much less frequent; however, it is seen in older adults, in whom it is frequently an underrecognized trigger in acute asthma. A study by Falsey et al34Falsey A.R. Hennessey P.A. Formica M.A. Cox C. Walsh E.E. Respiratory syncytial virus infection in elderly and high-risk adults.N Engl J Med. 2005; 352: 1749-1759Crossref PubMed Scopus (555) Google Scholar demonstrated that 7.2% of hospitalizations for asthma in those older than 65 years were associated with RSV infection.34Falsey A.R. Hennessey P.A. Formica M.A. Cox C. Walsh E.E. Respiratory syncytial virus infection in elderly and high-risk adults.N Engl J Med. 2005; 352: 1749-1759Crossref PubMed Scopus (555) Google Scholar In addition to rhinoviruses, influenza, and RSV, other respiratory tract viruses, such as 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 new respiratory tract viruses, such as bocavirus, the only virus type significantly associated with asthma exacerbations in children aged 2 to 17 years were rhinoviruses.35Khetsuriani N. Kazerouni N.N. Erdman D.D. 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 Exacerbations of asthma are seasonal, and it is important to always take into account the season during which studies on asthma exacerbations are performed. For example, a study in infants carried out in September found no cases of influenza at all,36Johnston N.W. Johnston S.L. Duncan J.M. et al.The September epidemic of asthma exacerbations in children: a search for etiology.J Allergy Clin Immunol. 2005; 115: 132-138Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar whereas a proportion of 20% was seen in another study during the flu season.37Heymann P.W. Carper H.T. Murphy D.D. et al.Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing.J Allergy Clin Immunol. 2004; 114: 239-247Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar RSV, metapneumoviruses, and influenza viruses (with the exception of the 2009 H1N1 influenza virus) are usually limited to the winter and early spring. Rhinovirus infections can occur throughout the year but are most common in the spring and autumn. In children seasonal peaks in asthma exacerbations occur frequently in autumn, corresponding to the weeks after the start of the school term.36Johnston N.W. Johnston S.L. Duncan J.M. et al.The September epidemic of asthma exacerbations in children: a search for etiology.J Allergy Clin Immunol. 2005; 115: 132-138Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 38Johnston N.W. Johnston S.L. Norman G.R. Dai J. Sears M.R. The September epidemic of asthma hospitalization: school children as disease vectors.J Allergy Clin Immunol. 2006; 117: 557-562Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar This phenomenon has been termed the September epidemic (Fig 1).39Sears M.R. Johnston N.W. Understanding the September asthma epidemic.J Allergy Clin Immunol. 2007; 120: 526-529Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Among older adolescents and young adults, a similar, albeit more blunted, picture is seen, with a peak occurring a week after the school-aged children. In older adults a peak is seen in December to January. The September epidemic was investigated in a case-control study by a Canadian group by limiting recruitment of children with asthma exacerbations to September. Viruses were detected in 62% of cases, with picornaviruses detected in 52% of cases and 29% of control subjects.36Johnston N.W. Johnston S.L. Duncan J.M. et al.The September epidemic of asthma exacerbations in children: a search for etiology.J Allergy Clin Immunol. 2005; 115: 132-138Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar In view of the fact that other environmental exposures, including allergens and pollutants, also vary by season, it seems probable that a combination of factors results in the seasonal peaks seen in exacerbations. A growing body of evidence supports the view that viral infection and allergy interact to increase the risk of an exacerbation. In 2002, Green et al40Green R.M. Custovic A. 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Murray has since shown that levels of IgE antibodies to inhalant antibodies in children are associated with an increased risk of asthma hospitalization, with quantification of specific IgE to inhalant allergens being more predictive of exacerbation than using an arbitrary cutoff of serum IgE concentrations to define atopy. Furthermore, a highly significant interaction was observed between IgE concentration and respiratory tract viral infection in increasing the risk of exacerbation.42Custovic A. Probability of hospital admission with acute asthma exacerbation increases with increasing specific IgE antibody levels.Allergy Clin Immunol Int J World Allergy Org. 2007; : 270-273Google Scholar Following on from this concept that atopic status is on a spectrum of severity rather than simply a yes or no diagnosis, Simpson et al43Simpson A. Tan V.Y. 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Millian S.J. Snyder R.D. The association of viral and Mycoplasma infections with recurrence wheezing in the asthmatic child.Ann Allergy. 1970; 28: 43-49PubMed Google Scholar found evidence of infection with Mycoplasma pneumoniae in 18% of children with asthma exacerbations. Since then, numerous studies have investigated a possible association between bacteria (in particular the atypical organisms M pneumoniae and Chlamydophila pneumoniae) and asthma exacerbations. However, because many of the methods for detecting these organisms are not standardized, are insensitive, or are nonspecific, the results across these studies have been inconsistent. Johnston and Martin45Johnston S.L. Martin R.J. 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Brouard J. et al.Detection of viral, Chlamydia pneumoniae and Mycoplasma pneumoniae infections in exacerbations of asthma in children.J Clin Virol. 1999; 13: 131-139Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar reported more modest infection rates of 4.5% and 2.2% for C pneumoniae and M pneumoniae, respectively, in a study using PCR on a collection of 132 nasal aspirates from 75 children hospitalized with acute asthma. Another study of 82 children with acute asthma showed similar rates of 5% for both C pneumoniae and M pneumoniae.51Thumerelle C. Deschildre A. Bouquillon C. et al.Role of viruses and atypical bacteria in exacerbations of asthma in hospitalised children.Pediatr Pulmonol. 2003; 35: 75-82Crossref PubMed Scopus (79) Google Scholar No significant differences between asthmatic patients and control subjects have been reported in several other studies with rates of infection of less than 5%, highlighting the inconsistent nature of the association between atypical bacteria and asthma exacerbations.33Legg J.P. Warner J.A. Johnston S.L. Warner J.O. Frequency of detection of picornaviruses and seven other respiratory pathogens in infants.Pediatr Infect Dis J. 2005; 24: 611-616Crossref PubMed Scopus (64) Google Scholar, 40Green R.M. Custovic A. Sanderson G. et al.Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study.BMJ. 2002; 324: 763Crossref PubMed Google Scholar, 52Kusel M.M. de Klerk N.H. Kebadze T. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abst