key: cord-0938689-b3vbaedz authors: Jackson, David J.; Sykes, Annemarie; Mallia, Patrick; Johnston, Sebastian L. title: Asthma exacerbations: Origin, effect, and prevention date: 2011-12-31 journal: Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2011.10.024 sha: 445c2febbd9f9586a0ade6b12860ade814ee9fa7 doc_id: 938689 cord_uid: b3vbaedz 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. in the moderate group, and 54% in the severe group, suggesting that frequent exacerbations are related to disease severity. 6 Factors associated with frequent exacerbations include female sex, 7 obesity, 5 psychopathology, chronic sinusitis, gastroesophageal reflux, respiratory tract infections, and obstructive sleep apnea. 8 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. 9 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. 10 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 States 11 and 1400 estimated deaths in 2002 in the United Kingdom. 12 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. [13] [14] [15] [16] [17] [18] 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) asthmarelated hospitalizations. 11 Hospitalization constitutes about one third of the total $14.7 billion in US annual asthma-related health care expenditures. 19 The European Lung Foundation has estimated that the cost of asthma in the European Union is V17.7 billion, of which V9.8 billion is related to lost productivity. 20 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. 21, 22 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. [23] [24] [25] [26] 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 rhinoviruses 27, 28 ; 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. [29] [30] [31] 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, 32 whereas a detection frequency of 27% was seen in a similar British study. 33 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 al 34 demonstrated that 7.2% of hospitalizations for asthma in those older than 65 years were associated with RSV infection. 34 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. 35 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, 36 whereas a proportion of 20% was seen in another study during the flu season. 37 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. 36, 38 This phenomenon has been termed the September epidemic (Fig 1) . 39 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. 36 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 al 40 reported in an adult study that allergen sensitization, exposure to sensitizing allergens, and respiratory tract viral infection acted in a synergistic manner to significantly increase the risk of hospitalization with acute asthma. Four years later, Murray et al 41 observed even greater synergistic interaction in children. These factors alone, parental smoking, pet ownership, or housing characteristics, did not increase the risk for hospital admission in asthmatic children. 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. 42 Following on from this concept that atopic status is on a spectrum of severity rather than simply a yes or no diagnosis, Simpson et al 43 observed that most children classified as atopic by using conventional definitions were clustered into 4 distinct classes. Only one of these classes, termed multiple early sensitization, which comprised approximately a quarter of the atopic children, was significantly associated with risk of hospitalization with asthma (Fig 2) . 43 As we begin to better define asthma and allergy phenotypes, appreciating the heterogeneity in these disorders, we will better understand the degree of interaction that exists between them. More than 40 years ago, Berkovitch et al 44 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 Martin 45 reviewed 12 such studies and found that 9 of 12 demonstrated an association between infection with either M pneumoniae or C pneumoniae and exacerbations. These included a study by Allegra et al 46 reporting evidence of atypical bacterial infection with C pneumoniae in 10% of subjects, as well as a prospective study by Lieberman et al 47 demonstrating M pneumoniae infection in 18% of hospitalized asthmatic patients compared with 3% in a matched control group. More recently, Cosentini et al 48 reported acute infection with C pneumoniae, M pneumoniae, or both in 38% of 58 patients presenting to the hospital with an asthma exacerbation, and in the TELICAST study 60% were serologically positive. 49 Freymuth et al 50 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. 51 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. 33, 40, 52 Wark et al 53 found that more than one third of adults presenting with acute severe asthma showed an increase in C pneumoniaespecific antibodies, which is consistent with acute infection, reinfection, or reactivation of latent infection with C pneumoniae. These subjects exhibited a more intense inflammatory response during the acute exacerbations. Because 76% of these exacerbations were associated with viral infection, these data suggest that C pneumoniae might act as a cofactor increasing the severity of virus-induced exacerbations. Although a large body of data supports an interaction between viruses and allergy, additional interest now exists in whether viruses and bacteria interact to provoke exacerbations. The observation that respiratory tract viral infections commonly precede bacterial infections in both healthy subjects and those with chronic lung conditions is well described. Oliver et al 54 identified virus-induced impairment of antibacterial host defense in human alveolar macrophages, suggesting viral infection might alter this function to facilitate additional bacterial infection. After experimental infection with rhinovirus of subjects with and without chronic obstructive pulmonary disease, Mallia et al 55 recently demonstrated bacterial infection in 65% of volunteers with chronic obstructive pulmonary disease versus around 15% in smoking and nonsmoking control subjects. No bacterial infections were detected at baseline before inoculation. Whether similar findings are seen in asthmatic patients requires further study. Of note is that Huang et al 56 and Hilty et al 57 have both highlighted increased and more diverse lower airway bacterial flora in asthmatic patients. Moreover, bacteria have been detected as often as viruses in a recent study of acute episodes of wheeze in children less than 3 years of age. 58 Similar studies are now required in older children and adults to determine whether bacteria play an important role in these age groups. The effect of air pollutants is generally believed to be less than that of viruses or aeroallergens; however, there is convincing evidence that acute exposure to specific pollutants contributes to symptoms and increases the severity of asthma exacerbations. 59 A number of pollutants appear to contribute to exacerbations of asthma, with pollutants from the combustion of natural gas and motor fuel, such as nitrogen dioxide (NO 2 ) and particulate matter, along with ozone, being 3 of the major culprits. Children in particular spend more time outdoors and exercise more, and therefore they breathe a greater amount of pollution per kilogram of body weight than adults. However, even in the indoor environment there are many sources of NO 2 , including fireplaces, heaters, and gas stoves. In children with asthma, NO 2 exposure is associated with increased respiratory symptoms, [60] [61] [62] and increased personal levels of NO 2 are associated with increased severity of virus-induced exacerbations. 63 This highlights a potential synergistic effect of these 2 inflammatory stimuli. In addition, controlled exposure studies in asthmatic patients have demonstrated that NO 2 can enhance the allergic response to inhaled allergens. 64, 65 Although it is difficult to dissect out all the factors that might play a role in the September epidemic, it is possible that seasonal changes in domiciliary air pollution during this period increase the risk of virus-induced exacerbations. Smoking among asthmatic patients is unfortunately common and induces a noneosinophilic pattern of inflammation with relative corticosteroid resistance. 66 In adults hospital admissions and emergency department visits occur more frequently among cigarette smokers with asthma, 66 and there is evidence that current smoking is a risk factor for near-fatal and fatal asthma. 67 The relationship between secondhand smoke and asthma morbidity in children is also well recognized. After the implementation of a public smoking ban in Scotland, Mackay et al 68 demonstrated a reduction of 18.2% per year in the rate of asthma-related hospitalizations in children. Before the legislation was implemented, admissions for asthma were increasing at a mean rate of 5.2% per year. Studies in Europe and the United States have shown that 40% of children live with a smoker, and in the United States more than 200,000 episodes of childhood asthma per year have been attributed to parental smoking. 69 Exacerbations occur in approximately 20% of pregnant women with asthma, yet the mechanisms responsible for this are poorly understood. 70 Exacerbations can occur throughout pregnancy; however, there appears to be a clustering around the late second trimester. Unsurprisingly, severe asthma appears to be the most important risk factor, and viral infections are likely the most common trigger, although no studies have thus far identified the viruses responsible. 70, 71 Discontinuation of medication (because of the belief it might harm the fetus) might also be an important factor, and current guidelines recommend a stepwise approach to treatment with the aim of maintaining control of maternal asthma throughout the pregnancy. A relationship between psychological factors, such as stress and asthma outcomes, has been described for centuries, leading to the term asthma nervosa. Severe life events either in isolation or in conjunction with high levels of chronic stress have been shown to significantly increase the risk of exacerbation in children with asthma, and similar findings have been identified in adults. 72, 73 Sandberg et al 72 assessed 60 children with asthma over an 18month period and demonstrated both an immediate risk of exacerbation (within 2 days of the severely negative life event) and a more delayed increase in risk (5-7 weeks after the severe event). Psychological factors can influence adherence to treatment and clinical follow-up; however, Miller and Chen 74 demonstrated diminished expression of both glucocorticoid and b 2 -adrenergic receptor genes in asthmatic children experiencing acute and chronic stress. Relative to asthmatic children without comparable stressor exposure, there was a 5-fold reduction in glucocorticoid receptor mRNA and a 10-fold reduction in b 2 -receptor mRNA. Preventing an exacerbation, as opposed to treating the exacerbation once established, could reduce the social and financial burden of asthma exacerbations. Several commonly used asthma therapeutics have been demonstrated to reduce the frequency of asthma exacerbations, and some novel biologics have also shown potential. Respiratory tract viral infection remains the predominant cause of asthma exacerbations, 23 and prevention of infection by vaccination is potentially an effective strategy for preventing exacerbations. No effective vaccine exists for rhinovirus infection, the most common cause of asthma exacerbations, 23,36 because of its antigenic diversity and multiple serotypes, 75 and therefore vaccination programs have concentrated mainly on influenza viruses. Influenza infection has been associated with asthma exacerbations in many studies, and influenza vaccination in asthmatic patients is strongly recommended. Vaccination against pandemic H1N1 influenza is specifically recommended in asthmatic patients. It is safe, is effective at inducing seroprotection, 76 and can be combined with seasonal influenza vaccination. Asthma was the most commonly identified comorbidity associated with increased disease severity in the recent H1N1 pandemic, emphasizing the importance of the role of vaccination. However, it should be noted that although several studies do indeed demonstrate a reduction in the number of exacerbations after vaccination, other studies have not shown a clear benefit. [77] [78] [79] [80] Pharmacologic strategies ICS treatment reduces the risk of asthma exacerbations. Inhaled budesonide therapy decreased exacerbations by 25% in patients with newly diagnosed, mild persistent asthma, who required fewer courses of systemic corticosteroids compared with patients receiving placebo. 81 High-dose budesonide treatment also reduced asthma exacerbations by nearly 50% in adult asthmatic patients whose symptoms were poorly controlled despite moderate ICS treatment, and the benefits showed dose responsiveness. 82 A significant reduction in annual severe exacerbations, from 0.77 to 0.29, has also been observed in adult patients with milder asthma not previously prescribed ICS treatment, 83 and a reduced exacerbation risk with ICS treatment has also been demonstrated in children. 84, 85 The modes of action of inhaled steroids in preventing virus-induced exacerbations are poorly understood; however, Skevaki et al 86 demonstrated that the corticosteroid budesonide effectively suppressed rhinovirusmediated induction of proinflammatory (CCL5, CXCL8, IL-6, and CXCL10) and remodeling-associated (fibroblast growth factor and vascular endothelial growth factor) mediators in bronchial epithelial cells (BECs) in a concentration-dependent manner. Exacerbations have also been prevented by combined treatment with ICSs and LABAs. Combinations of budesonide and formoterol were more effective than budesonide alone, with annual exacerbations reduced from 0.46 with high-dose budesonide to 0.34 when the same dose was combined with formoterol. 82 This effect has also been reproduced with other ICS/LABA combinations. 87, 88 Edwards et al 89 have demonstrated that combination treatment synergistically suppressed induction of rhinovirus-induced chemokines in BECs. Combination therapy with budesonide and formoterol used as both preventer and reliever has also been demonstrated to reduce asthma exacerbations 90, 91 in both adults 90 Leukotriene receptor antagonists might also prevent asthma exacerbations in patients with mild asthma. 93, 94 In children aged 2 to 5 years, Bisgaard et al 95 demonstrated a reduction in the rate of asthma exacerbations by 31.9% with montelukast compared with placebo over a 12-month period, and a recent trial demonstrated some benefit in acute exacerbations as an add-on therapy. 96 However, although an earlier trial of montelukast treatment was shown to reduce the risk of exacerbations during the peak that follows summer vacations in children, 94 a more recent trial did not show any significant benefit in reducing the percentage of days with worsening asthma when initiated at the start of the school year. 97 mAbs The development of mAbs to molecular targets identified as important in patients with allergic asthma has shown some early potential in preventing asthma exacerbations. Anti-IgE. IgE has a key role in the development of allergy by influencing allergen uptake by dendritic cells and activation of mast cells. 98 The humanized anti-IgE mAb omalizumab is licensed for use in patients with asthma symptoms despite maximal therapy, and treatment results in a reduction in high-affinity IgE receptor density and reduced mast cell degranulation and has been associated with a significant reduction in asthma exacerbations in adult allergic asthmatic patients. [99] [100] [101] Omalizumab is effective in reducing asthma exacerbations when given in addition to ICS treatment (odds ratio, 0.52) or during periods of steroid weaning (odds ratio, 0.47) 101 and is associated with a reduction in both the number and duration of exacerbations. 102 Omalizumab treatment has also been shown to be effective in children. 103 In a randomized trial of 6-to 12-year-olds with multiple exacerbations despite ICS treatment, a 43% reduction in clinically significant exacerbations was observed in the treated group over a 1-year period. 104 Adolescents with moderate-to-severe allergic asthma despite ICS treatment have also been reported to require fewer asthma-related systemic corticosteroid courses after omalizumab treatment. 105 Anti-IL-5. IL-5 is a T H 2 cytokine that is essential for the maturation and differentiation of eosinophils. Mepolizumab, an anti-IL-5 mAb, was initially reported to reduce blood eosinophil numbers in patients with mild asthma with no effect on clinical asthma parameters. 106 Subsequent trials in patients with severe asthma demonstrated that, in addition to reduced blood and sputum eosinophil numbers, mepolizumab treatment was associated with reduced asthma exacerbations and improved asthma-related quality of life. 107 In addition, a further study of 20 patients with severe asthma demonstrated a 90% reduction in exacerbation frequency and a 50% reduction in prednisolone requirement after 6 months of mepolizumab treatment. 108 Although encouraging, these studies demonstrate that mepolizumab treatment might be effective in patients with severe steroid-refractory asthma with sputum eosinophilia, but it is unlikely to be helpful in asthmatic patients without evidence of eosinophilia. Other mAbs. In addition to anti-IgE and anti-IL-5, mAbs have been developed to other cytokines implicated in allergic responses. IL-4 and IL-13 were early targets because of their role in IgE production, suppression of T H 1-mediated immunity, mucin secretion, and adhesion molecule expression. Moreover, after experimental infection with rhinovirus, Message et al 109 observed that augmented IL-4, IL-5, and IL-13 levels were implicated in the increased severity of asthma exacerbations. Although initial trials of soluble IL-4 receptor blockers were disappointing, 110 more recent results have been more encouraging. 111 A recent trial of lebrikizumab (anti-IL-13) did not demonstrate any significant reductions in the rates of exacerbations; however, in a ''high-T H 2'' subgroup, the rate of exacerbations was 60% lower in the lebrikizumab group than in the placebo group. 112 TNF-a, a proinflammatory cytokine involved in upregulation of adhesion molecules, mucin secretion, and airway remodeling has also been targeted. Initial investigations in patients with severe asthma with high TNF-a levels treated with the recombinant human TNF-a receptor blocker etanercept demonstrated improvements in FEV 1 and quality of life. 113 Despite an encouraging start, a further study of 309 patients with severe asthma treated with the anti-TNF-a antibody golimumab did not show any change in pulmonary function and exacerbation rates, and the study was discontinued early because of serious side effects. 114 Bronchial thermoplasty reduces airway smooth muscle mass by ablating the central airways with radiofrequency energy during bronchoscopy. Early studies demonstrated a reduction in mild exacerbations when performed in patients with severe asthma. 115, 116 In the year after bronchial thermoplasty, mild asthma exacerbations were significantly reduced at 3 and 12 months (0.18 vs 0.35 in the untreated group), which the authors extrapolated to 10 fewer mild exacerbations per year, but no difference was observed in severe exacerbations. 117 A significant reduction in severe exacerbations was demonstrated in 288 adults with severe asthma randomized to thermoplasty or a sham procedure; however, this was at the expense of 6% more postprocedure hospitalizations in the treatment group. Reduced emergency department visits and work/school absence was also observed in the thermoplasty group up to 1 year after the procedure, and reduction in severe exacerbations has recently been demonstrated to persist until 3 years. 118 Despite these positive results, thermoplasty is unlikely to be widely used because it is very time consuming to administer. In recent years, it has become increasingly clear that immunemodulatory effects of macrolide antibiotics exist that are distinct from their antimicrobial actions. Jang et al 118 demonstrated reduced expression of intercellular adhesion molecule 1, IL-6, and IL-8 after treatment with erythromycin of rhinovirusinfected epithelial cells. Gielen et al 119 showed that pretreatment of BECs with azithromycin significantly increased RV-1B-and RV-16-induced type I and III interferons and interferonstimulated gene mRNA and protein expression. In addition, azithromycin reduced rhinovirus replication and release. 120 However, Strunk et al 121 did not demonstrate any superiority of azithromycin over placebo in a study of children in which the primary outcome was time from randomization to inadequate asthma control. In the case of RSV, treatment of infants with bronchiolitis with clarithromycin led to reduced systemic inflammation acutely and fewer wheezing episodes in the following 6 months. 122 Although this was a small study, a much larger study of asthmatic adults randomized to receive either telithromycin, a ketolide antibiotic, or placebo resulted in a greater reduction in asthma symptom scores and lung function in the ketolide-treated group. 48 Safety concerns have limited the widespread use of telithromycin, and further studies are needed to clarify the position of macrolides in the management of asthma exacerbations. 122 Patient education and self-management One nonpharmacologic approach rightly emphasized in recent years is the role of patient education combined with selfmanagement. It has been convincingly demonstrated that asthma morbidity can be reduced by a self-management program including self-monitoring, a written action plan, regular medical review, and asthma education. 123 In adults the risk of being admitted to the hospital decreased by more than 40%, and presentations to the emergency department with asthma decreased by more than 20% 123 ; a similar pattern is also seen for children. 124 Effective written action plans can be based on symptoms or peak expiratory flow (PEF) and use 2, 3, or 4 action points. PEF-based plans should use personal-best PEF rather than percent predicted PEF because the former consistently improved health outcomes, whereas the latter appears not to do so. In addition, the instructions regarding treatment of exacerbations should include both ICSs and oral corticosteroids. 125 The ability to predict an exacerbation could have a significant effect on asthma management. Meltzer et al 126 recently found a significant correlation between the measurements of the Asthma Control Questionnaire (ACQ), a validated composite measure of asthma control, and the risk of future asthma exacerbations. Although it is unrealistic to expect adherence to a full daily diary record, as was required in this study, shorter versions of the ACQ, such as the ACQ-5 or ACQ-6, could be potentially assessed by the patient outside the clinic setting to assess the risk for an asthma exacerbation. In addition to the mAbs described above, there are a number of other novel targets currently in development with the potential to prevent or reduce the frequency, severity, or both of asthma exacerbations. One such target is inhaled IFN-b. Interest in this target first arose after work by Corne et al, 127 who demonstrated more severe and more prolonged virus-induced asthma symptoms in asthmatic compared with nonasthmatic subjects. Wark et al 128 subsequently provided evidence that BECs from asthmatic patients produced lower levels of the type I IFN-b and also showed higher levels of rhinovirus replication. The BECs from asthmatic patients responded to exogenous treatment with IFN-b, exhibiting reduced rhinovirus release and demonstrating that the deficiency in asthmatic cells was associated with production of antiviral IFN-b rather than the actions of IFN-b. 128 These results suggest that delivery of IFN-b to the lower airways when a cold develops might result in the restoration of antiviral defenses in the lungs of asthmatic patients, limiting the resulting inflammation and thus either preventing or reducing the severity of exacerbations. Importantly, by boosting host defense rather than targeting specific respiratory tract viruses, IFN-b is anticipated to have a broad antiviral activity. The results of a phase 2 proofof-concept trial of IFN-b therapy are awaited with interest. Similar deficiencies of the antiviral type III IFN-ls have been observed in asthmatic patients, 129 and these interferons have also recently been reported to profoundly suppress allergic airway inflammation. 130 Thus this family of interferons is also a potential treatment of great interest. 131 Other BEC-derived cytokines, such as IL-25, IL-33, and thymic stromal lymphopoietin, are looking like increasingly interesting targets in asthmatic patients, and the next 10 years will likely see a surge in studies of these important mediators. Currently, an mAb directed against thymic stromal lymphopoietin (AMG 157) is in phase 1 development 132 and antibodies blocking IL-25 and IL-33 activity have been tested with some success in animal models of asthma 133 and influenza-induced airway hyperreactivity. 134 Other interesting targets currently being investigated are Tolllike receptor (TLR) agonists. TLR7 is a receptor for viral singlestranded RNA and signals through the adaptor molecule MyD88, activating transcription factors that induce production of a range of antiviral and inflammatory cytokines, such as interferons and TNF-a. 135 Kaufman et al 136 recently tested the effects of the synthetic TLR7 agonist imiquimod in guinea pigs in vivo, demonstrating the inhibition of bronchoconstriction within minutes of administration. This novel mechanism to limit bronchoconstriction during respiratory tract infections, in addition to their antiviral properties established some years ago, 137 makes compounds such as these attractive candidates in asthma treatment. In addition to these exciting targets, there are many other approaches currently in development, such as kinase inhibitors and phosphodiesterase inhibitors 138 ; however, a full review of these is beyond the scope of this article. One of the primary goals in the management of asthma is to minimize the risk of future exacerbations. Respiratory viruses are now well accepted as the main trigger for these exacerbations, and despite the emergence of newly discovered viruses, rhinoviruses remain the most common pathogens detected. Understanding the mechanisms provoking virus-induced airway inflammation in asthmatic patients will likely offer significant opportunities for improved disease management. However, the reality at present is that current drugs for the treatment of virusinduced exacerbations are poorly effective, and alternative therapies to modulate viral pathogenesis are desperately needed. To this end, experimental human and murine models of rhinovirus-induced asthma exacerbations have now been developed, 109, 139 offering great potential to increase our mechanistic understanding, as well as providing us with models in which to test potential new therapies. Further study is clearly required to better understand the complicated relationships that exist among viruses, bacteria, and allergic inflammation. Despite the development of newer asthma medications, a recent survey of 2500 asthmatic patients highlighted that in the years between 1998 and 2009, the percentage seeking acute care for their asthma in the preceding 12 months had not changed significantly, 140, 141 This is a sobering truth indicative of how much we still need to do. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial Asthma exacerbations in North American adults: who are the ''frequent fliers'' in the emergency department? Recent asthma exacerbations: a key predictor of future exacerbations Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group Risk factors of frequent exacerbations in difficult-to-treat asthma Real-world Evaluation of Asthma Control and Treatment (REACT): findings from a national Web-based survey Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study Asthma prevalence, health care use, and mortality: United States The challenge of inner-city asthma Case-control study of severe life threatening asthma (SLTA) in adults: psychological factors Risk factors for recurrent asthma hospital visits and death among a population of indigent older adults with asthma The diagnosis of potentially fatal asthma in hospitalized adults. Patient characteristics and increased severity of asthma 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 Mortality and markers of risk of asthma death among 1,075 outpatients with asthma Trends in asthma morbidity and mortality Infective factors in exacerbations of bronchitis and asthma Viruses as precipitants of asthmatic attacks in children Community study of role of viral infections in exacerbations of asthma in 9-11 year old children Respiratory viruses and exacerbations of asthma in adults Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma Interleukin-10 gene expression in acute virus-induced asthma Human rhinovirus C associated with wheezing in hospitalised children in the Middle East Clinical and molecular epidemiology of human rhinovirus C in children and adults in Hong Kong reveals a possible distinct human rhinovirus C subgroup Risk factors and outcomes among children admitted to hospital with pandemic H1N1 influenza Clinical features, risk factors, and complications among pediatric patients with pandemic influenza A (H1N1) Pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in Argentina Role of respiratory viruses in acute upper and lower respiratory tract illness in the first year of life: a birth cohort study Frequency of detection of picornaviruses and seven other respiratory pathogens in infants Respiratory syncytial virus infection in elderly and high-risk adults Prevalence of viral respiratory tract infections in children with asthma The September epidemic of asthma exacerbations in children: a search for etiology Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing The September epidemic of asthma hospitalization: school children as disease vectors Understanding the September asthma epidemic Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children Probability of hospital admission with acute asthma exacerbation increases with increasing specific IgE antibody levels Beyond atopy: multiple patterns of sensitisation in relation to asthma in a birth cohort study The association of viral and Mycoplasma infections with recurrence wheezing in the asthmatic child Chlamydophila pneumoniae and Mycoplasma pneumoniae: a role in asthma pathogenesis? Acute exacerbations of asthma in adults: role of Chlamydia pneumoniae infection Atypical pathogen infection in adults with acute exacerbation of bronchial asthma Severe asthma exacerbation: role of acute Chlamydophila pneumoniae and Mycoplasma pneumoniae infection The effect of telithromycin in acute exacerbations of asthma Detection of viral, Chlamydia pneumoniae and Mycoplasma pneumoniae infections in exacerbations of asthma in children Role of viruses and atypical bacteria in exacerbations of asthma in hospitalised children Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma Chlamydia pneumoniae immunoglobulin A reactivation and airway inflammation in acute asthma Rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages Bacterial infections following experimental rhinovirus infection in COPD Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma Disordered microbial communities in asthmatic airways Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study The role of air pollution in asthma and other pediatric morbidities A longitudinal study of indoor nitrogen dioxide levels and respiratory symptoms in inner-city children with asthma Health effects of indoor nitrogen dioxide and passive smoking on urban asthmatic children Short-term effects of air pollution on wheeze in asthmatic children in Personal exposure to nitrogen dioxide and the severity of virus induced asthma in children Effect of domestic concentrations of nitrogen dioxide on airway responses to inhaled allergen in asthmatic patients Repeated exposure to an ambient level of NO2 enhances asthmatic response to a nonsymptomatic allergen dose Asthma and cigarette smoking Near-fatal asthma: a population-based study of risk factors Smoke-free legislation and hospitalizations for childhood asthma Office of Environmental Health Hazard Assessment. Health effects of exposure to environmental tobacco smoke: final report Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes Pregnancy and asthma: recent developments The role of acute and chronic stress in asthma attacks in children A prospective study of the relationship of mood and stress to pulmonary function among patients with asthma Life stress and diminished expression of genes encoding glucocorticoid receptor and b2-adrenoceptor in children with asthma Rhinovirus vaccination: the case against Vaccination of patients with mild and severe asthma with a 2009 pandemic H1N1 influenza virus vaccine Vaccines for preventing influenza in people with asthma Does influenza vaccination prevent asthma exacerbations in children? Effectiveness of influenza vaccine for the prevention of asthma exacerbations Is influenza vaccination in asthma helpful? START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial Effect of inhaled formoterol and budesonide on exacerbations of asthma Low dose inhaled budesonide and formoterol in mild persistent asthma. The OPTIMA randomized trial Montelukast reduces asthma exacerbations in 2-to 5-year-old children with intermittent asthma Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children Budesonide and formoterol inhibit inflammatory mediator production by bronchial epithelial cells infected with rhinovirus Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma An observational study of fixed dose combination fluticasone propionate/salmeterol or fluticasone propionate alone on asthma-related outcomes* Combination therapy: synergistic suppression of virus-induced chemokines in airway epithelial cells Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study Budesonide/formoterol maintenance plus reliever therapy* Effect of leukotriene receptor antagonist therapy on the risk of asthma exacerbations in patients with mild to moderate asthma: an integrated analysis of zafirlukast trials Attenuation of the September epidemic of asthma exacerbations in children: a randomized, controlled trial of montelukast added to usual therapy Montelukast reduces asthma exacerbations in 2-to 5-year-old children with intermittent asthma Oral montelukast in acute asthma exacerbations: a randomised, double-blind, placebo-controlled trial The Back to School asthma study: the effect of montelukast on asthma burden when initiated prophylactically at the start of the school year IgE in allergy and asthma today Efficacy and safety of omalizumab in an Asian population with moderate to severe persistent asthma Omalizumab in severe allergic asthma inadequately controlled with standard therapy Anti-IgE for chronic asthma Review: omalizumab reduces exacerbation and steroid use in chronic asthma Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma Adding omalizumab to the therapy of adolescents with persistent uncontrolled moderate and severe allergic asthma Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response Mepolizumab and exacerbations of refractory eosinophilic asthma Mepolizumab for prednisonedependent asthma with sputum eosinophilia Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production Efficacy of soluble IL-4 receptor for the treatment of adults with asthma Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies Lebrikizumab treatment in adults with asthma Evidence of a role of tumor necrosis factor in refractory asthma A randomized, double-blind, placebocontrolled study of tumor necrosis factora blockade in severe persistent asthma Asthma control during the year after bronchial thermoplasty Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial Effect of clarithromycin on rhinovirus-16 infection in A549 cells Azithromycin induces anti-viral responses in bronchial epithelial cells Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study Macrolide antibiotics and asthma treatment Self-management education and regular practitioner review for adults with asthma Effects of educational interventions for self management of asthma in children and adolescents: systematic review and meta-analysis Written action plans for asthma: an evidence-based review of the key components Use of the Asthma Control Questionnaire to predict future risk of asthma exacerbation Frequency, severity, and duration of rhinovirus infections in asthmatic and nonasthmatic individuals: a longitudinal cohort study Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus Role of deficient type III interferon-lambda production in asthma exacerbations IL-28A (IFN-l2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease Interferon-lambda as a new approach for treatment of allergic asthma? Thymic stromal lymphopoietin Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma Innate lymphoid cells mediate influenzainduced airway hyper-reactivity independently of adaptive immunity Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs Attenuation of virus-induced airway dysfunction in rats treated with imiquimod New therapies for asthma: is there any progress? Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation The burden of asthma in the United States: level and distribution are dependent on interpretation of the national asthma education and prevention program guidelines