The Journal of Allergy and Clinical Immunology
Volume 122, Issue 4 , Pages 662-668, October 2008

Epidemiology of asthma exacerbations

  • Malcolm R. Sears, MB, FRACP, FRCPC, FAAAAI

      Affiliations

    • Corresponding Author InformationReprint requests: Malcolm R. Sears, MB, FRACP, FRCPC, FAAAAI, Professor of Medicine, McMaster University, Research Director, Firestone Institute for Respiratory Health, St Joseph's Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Received 10 July 2008; received in revised form 31 July 2008; accepted 1 August 2008.

Article Outline

Exacerbations of asthma sufficient to require urgent medical intervention are often, but not always, associated with viral infection, especially rhinovirus, with significant interaction with allergen sensitization and exposure. Seasonal patterns of exacerbations are seen especially in children, and may be aggravated by lack of adequate maintenance anti-inflammatory drug treatment during the high-risk viral season most well described in the Northern Hemisphere after school return in September. Age and sex differences in the epidemiology of exacerbations remain less than fully explained, but hormonal influences are demonstrable. Frequent exacerbations may be an indication of greater severity of disease, significant comorbidities, or poor compliance with therapy. Recognizing risk factors for exacerbations and implementing appropriate long-term management strategies coupled with improved compliance should reduce morbidity and mortality associated with asthma exacerbations.

Key words: Asthma, exacerbations, seasonality, etiology, viral infection, prevention

Abbreviations used: ED, Emergency department, GOAL, Gaining Optimal Asthma controL, LABA, Long-acting β2-agonist, OR, Odds ratio, PEF, Peak expiratory flow

 

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Information for Category 1 CME Credit 

Credit can nowbe 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 JACIWeb site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.

Date of Original Release: October 2008. Credit may be obtained for these courses until September 30, 2010.

Copyright Statement: Copyright © 2008-2010. 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: Author: Malcolm R. Sears, MB, FRACP, FRCPC, FAAAAI

Activity Objectives

1. To identify trends in the epidemiology of asthma exacerbations.

2. To recognize the risk factors associated with increased frequency and severity of asthma exacerbations.

3. To identify common infectious and environmental triggers of asthma and biomarkers under investigation for guiding asthma management.

4. To identify the pharmacologic and educational interventions that have been shown to be effective in reducing asthma exacerbations.

Recognition of Commercial Support: This CME activity has not received external commercial support.

Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: Malcolm R. Sears has served as a consultant for AstraZeneca, GlaxoSmithKline, and Merck Sharp Dohme and has received research support from Merck Frost Canada. His position is endowed by AstraZeneca.

Several definitions have been used for documenting exacerbations of asthma in clinical practice and in research studies. Exacerbations have also been graded in severity as mild, moderate, severe, and life-threatening. A practical working definition of an exacerbation that is useful clinically and has also been applied in several recent trials of pharmacologic therapies has been a worsening of asthma of sufficient severity to require intervention from a medical professional or self-administration of oral corticosteroids. Exacerbations requiring medical intervention result in significant cost for healthcare resources and affect the quality of life for the patient and family. Objective definitions of exacerbations using variability of peak expiratory flow (PEF) and identifying exacerbations as a ≥20% or ≥30% fall in PEF have proven less useful. In the Formoterol and Corticosteroid Establishing Therapy study, a 30% decrease in PEF often went unnoticed by both the patient and the treating physician, and was detected only retrospectively during data analysis rather than being associated with symptoms sufficient to require medical help.1

Debate continues over the boundary between mild asthma exacerbations and poorly controlled asthma.2 Intermittent worsening of asthma that is self-treated by varying doses of bronchodilators or anti-inflammatory therapy is generally not regarded as sufficiently severe to warrant the label exacerbation. Definitions of exacerbations, and the interactions and differences between asthma control and severity, have been recently evaluated by a joint Task Force of the American Thoracic Society and the European Respiratory Society, and that report is anticipated shortly.3

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Prevalence of exacerbations 

Although there has been a gradual decrease in the number of hospital admissions for asthma over the last 2 decades, this may not really reflect a reduction of exacerbations. For economic reasons, there is an increasing reluctance to hospitalize patients and an emphasis on treatment in the emergency department (ED) and discharge home. However, more effective early intervention may be preventing exacerbations from becoming sufficiently severe to warrant hospitalization.4

The prevalence rate of exacerbations in clinical trials is likely substantially lower than in the real world. Patients in trials are usually selected as having stable asthma, and a recent exacerbation is often an exclusion criterion. Study patients are more compliant with therapy in trial situations and are usually monitored at regular intervals to assess asthma control.

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Effects of sex and age 

Administrative data from many countries as well as data from carefully conducted epidemiologic studies demonstrate a greater incidence and prevalence of asthma among boys compared with girls before puberty, with more exacerbations requiring hospitalization and ED visits (Table I). At puberty, the sex difference reverses, and until at least midadult life, and likely also thereafter, females have a greater incidence and prevalence of asthma with more exacerbations and hospitalizations.5, 6 Durations of hospitalization tend to be longer in females, and readmission is also more common.7 Hormonal influences have been postulated, and certainly use of hormone replacement therapy postmenopause has been associated with more asthma8 and more exacerbations.9 Reduction of hormonal fluctuations through use of oral contraceptives in women of child-bearing age has been shown to reduce airway hyperresponsiveness.10

Table I. Ten key messages
1. Before puberty, exacerbations of asthma are more common in boys than in girls, with reversal of this trend at puberty.
2. During adulthood, women have exacerbations more frequently, with greater severity, more admissions, and longer duration of admission than men.
3. There are predictable seasonal epidemics of exacerbations of asthma, occurring in early fall in children, and in winter in adults.
4. The dominant trigger for exacerbations in both children and adults is viral infection.
5. There is a synergistic relationship between viral infection and allergen sensitization and exposure in provoking exacerbations.
6. Frequent exacerbations usually indicate underlying comorbidity, especially psychosocial factors.
7. The combination of inhaled corticosteroid and LABA is effective in reducing exacerbations.
8. Use of LABA without inhaled corticosteroid is inappropriate in asthma and may increase exacerbations.
9. Tailoring therapy according to markers of inflammation (airway hyperresponsiveness, exhaled nitric oxide, sputum eosinophilia) can reduce exacerbations.
10. Adding a leukotrine receptor antagonist to usual therapy during the predictable seasonal epidemic of asthma exacerbations in children in the fall reduced morbidity. The efficacy of inhaled corticosteroid in this situation needs further evaluation.

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Cycles of asthma exacerbations 

Anecdotal reports and epidemiologic and clinical studies have long suggested that children frequently experience a worsening of asthma after return to school after the long summer vacation, whereas older adults more frequently have exacerbations associated with the winter season. More precise documentation of these age-related trends has recently been possible using large computer-searchable administrative databases. Johnston and Sears11 examined data obtained through the Canadian Institute for Health Information for hospitalizations and ED visits on a daily basis and found significant and striking differences in the seasonality of asthma according to age. Among school-age children 5 to 15 years, hospitalizations or ED visits were relatively stable, with a minor increase through the first 6 months of each calendar year, then declined significantly in the summer months, followed by a rapid and substantial increase in hospitalizations and ED visits for asthma beginning in mid-August and reaching the peak some 2 weeks after school return (the “September epidemic”).12 The peak rate of admissions in September in most years reached 3 to 4 times that of the average admission rate throughout the remainder of the year. In younger children (2-4 years old), the same pattern was evident but with a slightly less striking peak. Among older adolescents and young adults (16-35 years), a similar but somewhat blunted increase in exacerbations was noted in September, with a peak a week later than that of the school age children. In older adults with asthma, the September peak became less evident, and above the age of 50 years, it was barely noticeable. In contrast, in these older age groups, the greatest increase in asthma admissions and ED visits was in December to January, which is not a high-risk period for exacerbations in children and adolescents (Fig 1).13 This pattern has been confirmed in many countries in the Northern Hemisphere.14, 15, 16 A similar pattern is evident in some Southern Hemisphere countries at corresponding seasons.17, 18

  • View full-size image.
  • Fig 1. 

    The annual cycle of asthma exacerbations in children 2 to 15 years, adults 16 to 49 years, and adults 50 years and older. Data represent all ED visits for asthma in Ontario, Canada, from April 2001 to March 2005 condensed to a single year, by week of the year and expressed as multiples of the weekly mean number. Reprinted with permission from Johnston N. The similarities and differences of epidemic cycles of chronic obstructive pulmonary disease and asthma exacerbations. Proc Am Thorac Soc 2007;4:591-6.13

An example of a shorter-phase cyclical increase in risk of asthma worsening is seen in a proportion of women with perimenstrual asthma.19 However, although as many as 40% of women experience such changes related to the menstrual cycle, few have sufficiently severe episodes to qualify as exacerbations.

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Etiology of asthma exacerbations 

Although much childhood and adult asthma is associated with atopy, the classic notion that the majority of exacerbations in atopic patients with asthma are related to allergen exposure with resultant inflammation has been challenged by a number of studies.20 The availability of monitoring of airway inflammation through measuring cell counts in induced sputum has indicated significant heterogeneity and changing patterns of inflammation during exacerbations, as well as during periods of unstable or poorly controlled asthma.21, 22 Eosinophilic inflammation, which is generally highly responsive to corticosteroid therapy, is considered to be a hallmark feature of exacerbations associated with allergen exposure, whereas neutrophilic inflammation is more generally associated with infective exacerbations, whether viral or bacterial. In children age 9 to 11 years, 80% to 85% of asthma exacerbations resulting in reduced PEF and wheezing were associated with upper respiratory viral infections.23 Among adults, the proportion was somewhat lower but still substantial, with approximately 50% to 60% of adult exacerbations associated with upper respiratory tract infections.24 Rhinovirus has been the most commonly detected infectious agent in these studies.25, 26 Among children 2 to 17 years old with exacerbations, compared with controls, rhinovirus was the most prevalent (60% among cases, 18% among controls) and the only virus significantly associated with exacerbations (odds ratio [OR], 6.8; 95% CI, 3.2-14.5).26

To determine the underlying cause of the marked increase in exacerbations in children in September, Johnston et al27 undertook a case control study in EDs in southern Ontario, examining children (cases) who presented during the September epidemic and comparing findings contemporaneously with children from the same community (controls) with equally severe asthma not requiring an ED visit. Although most indicators of chronic severity of asthma were similar between cases and controls, cases were about 50% less likely to have been prescribed regular anti-inflammatory therapy, and were much more likely to have had multiple ED visits in the past. The prevalence of viral infection, dominantly rhinovirus, was 61% in cases and 40% in the community controls. Although this difference appears significant, the cases were seen during a time of acute illness, whereas the controls, although studied during the same 3 weeks of September, did not necessarily have symptoms of an infection, so this difference may reflect a bias intrinsic to the study design rather than indicating that cases were more susceptible to viral infections. The substantially lower use of anti-inflammatory therapy, whether inhaled corticosteroids or leukotriene receptor antagonists, was considered a key factor in allowing the viral-associated worsening of asthma to develop substantially to the degree that it required an ED visit and therapeutic intervention.

Similar findings were reported by Murray et al,28 who studied 84 children age 3 to 7 years admitted to hospital over a 1-year period with an acute asthma exacerbation. Children were matched for age and sex with a control group of stable patients with asthma and another control group of children admitted to the hospital with nonrespiratory conditions. The regular use of inhaled corticosteroids was significantly less common in those admitted with acute exacerbations than in the stable controls with asthma. A significantly higher proportion had evidence of viral infection and also sensitization and exposure to a known sensitizing allergen compared with the stable asthma group. Although neither sensitization and exposure nor virus detection independently were associated with hospital admission, the combination of virus detection and sensitization with a high allergen exposure increased the risk of admission to a hospital (OR, 19.4; 95% CI, 3.7-101.5; P < .001).

Kling et al29 studied children age 4 to 12 years admitted to an ED with acute severe asthma, examining skin test responses and the presence of rhinovirus RNA and respiratory syncytial virus RNA in nasal aspirates by using validated PCR assays, with follow-up at 6 weeks and 6 months. More than 80% of children had detectable rhinovirus RNA, with persistence of rhinovirus RNA in the nasal secretions in 44% of those restudied at 6 weeks, and 25% of those restudied at 6 months. Those with detectible rhinovirus after 6 weeks had more severe persistent asthma with lower PEF, and a slower recovery than those in whom it was absent at 6 weeks, suggesting that the severity of acute asthma may be linked with prolonged and more severe rhinovirus infections.

More recently, the human metapneumovirus has been identified as associated with asthma exacerbations, with detection in 7% of subjects at the time of hospitalization versus only 1% at follow-up.30 These findings suggest that the human metapneumovirus has a direct etiologic role in acute exacerbations.

There is very likely a synergistic interaction between allergic sensitization and the effect of respiratory viruses in precipitating acute episodes of asthma.31, 32 Experimentally induced rhinovirus infections in both allergic and nonallergic individuals, studied by using bronchoalveolar lavage and segmental allergen challenge, have provided evidence of this interaction. Green et al33 showed a substantial increased risk for asthma admission with allergen sensitization and exposure. The OR of 2.3 increased to 8.4 in the presence of virus in addition to sensitization and exposure. On the contrary, patients who were sensitized without exposure, or exposed without sensitization, with or without viral infection, did not have an increased risk of asthma exacerbation.

Air pollutants have been frequently considered as a cause of exacerbations, although the impact is generally recognized to be much less than that of viruses and allergen sensitization. There is a lag of 1 to several days between peaks of air pollution and peaks of hospitalization, which has made interpretation of causation more difficult.34 Furthermore, peaks of air pollution may be associated with the conditions that also increase allergen exposure. Thunderstorms and extreme weather conditions have been associated with epidemics of asthma exacerbations.35 Exposure to increased levels of fungal spores is a well recognized cause of exacerbations.36

Psychological stress may also trigger exacerbation. Sandberg et al37 studied 60 children with chronic asthma over a period of 18 months with daily symptom diaries and peak flow measurements, with repeated interview assessments of life events. They reported an immediate effect on asthma exacerbations within 2 days after a severely negative life event with OR 4.69, but this was not seen in the period 3 to 10 days after the severe event. However, there was an almost 2-fold increased risk 5 to 7 weeks after the severe event, indicating that there is both an immediate risk and a more delayed increase in risk.

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Frequent exacerbations 

A number of studies have looked at patients with multiple exacerbations. Among Japanese patients with multiple exacerbations despite regular maintenance treatment, there was evidence of substantially increased severity as reflected in use of inhaled and oral corticosteroid therapy, concomitant disease including chronic sinusitis, and intolerance to nonsteroidal anti-inflammatory drugs in comparison with controls.38 Those with multiple exacerbations had persistent air flow limitation and reduced reversibility.

Griswold et al39 reviewed over 3000 patients with asthma with 0, 1 to 2, 3 to 5, or 6 or more ED visits. The number of ED visits was associated with older age, nonwhite race, lower socioeconomic status, and several markers of asthma severity, but not to sex or to having a primary care provider. In multivariate analysis, independent predictors of high ED use (6 or more visits a year) were nonwhite race, Medicaid insurance, no insurance, and markers of chronic asthma severity. Patients with 6 or more ED visits accounted for 2/3 of all previous ED visits in the past year.

Similarly, ten Brinke et al40 studied clinical and environmental factors potentially associated with recurrent exacerbations in 136 patients with difficult-to-treat asthma. Factors associated with frequent exacerbations included psychological dysfunctioning (OR, 10.8), recurrent respiratory infections (OR, 6.9), gastroesophageal reflux (OR, 4.9), severe nasal sinus disease (OR, 3.7), and obstructive sleep apnea (OR, 3.4). Severe chronic sinus disease and psychological dysfunctioning were the only independently associated factors (OR, 5.5 and 11.7, respectively). All patients with frequent exacerbations exhibited at least 1 of these 5 factors, whereas more than half showed 3 or more factors. Hence recurrent exacerbations are strongly associated with comorbidity, some of which is treatable. Attention to these cofactors could potentially reduce morbidity significantly.

Although recent asthma exacerbations are a predictor of future exacerbations,41 not all exacerbations are associated with severe disease. Dusser et al42 reported that mild asthma can lead to severe exacerbations with a frequency of 0.12 to 0. 77 per patient-year, and that severe exacerbations in mild asthma represent 30% to 40% of exacerbations requiring emergency consultation.

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Severe exacerbations 

A small proportion of patients have exacerbations of sufficient severity to be judged life-threatening, and require urgent resuscitative measures including intubation and ventilation until the airway obstruction can be relieved. Factors predicting such severe episodes, generally but not uniformly, include chronic severity with impaired lung function even when maximally treated suggesting chronic airway remodeling from persistent inflammation, and poorly controlled chronic asthma with comorbidities, psychosocial factors, and noncompliance with treatment compounding the problem of severe asthma. Certain pathological features of asthma may also predict greater severity and more frequent and more severe exacerbations. Lemiere et al43 studied 32 subjects with severe asthma and 35 subjects with moderate asthma, obtaining bronchial biopsies, induced sputum cell counts, and exhaled nitric oxide measurements. Although both eosinophilic and noneosinophilic phenotypes were identified among subjects with severe asthma by using bronchial biopsies and sputum cell counts, the majority of subjects with high sputum eosinophil counts did not have high mucosal eosinophil counts. Exhaled nitric oxide was increased among those with bronchial biopsy evidence of eosinophilia. Those with high sputum eosinophil counts had more asthma exacerbations than those with low counts. The authors suggested that the use of sputum cell counts allowed the identification of patients with more severe asthma who were at risk of more frequent exacerbations. Patients with severe exacerbations, in common with patients with more severe asthma, may well have a degree of refractoriness to both inhaled and systemically administered corticosteroid. In the Gaining Optimal Asthma controL (GOAL) study, only a small percentage of subjects refractory to high levels of inhaled corticosteroid achieved increased control of asthma with a 2-week course of prednisone.44 There may be multiple mechanisms underlying corticosteroid resistance, perhaps reflecting different diseases with a common phenotype.45

Although exacerbations in children and adults follow a seasonal pattern, the proportion of hospitalizations for asthma requiring admission to an intensive care unit or intubation is constant month to month in relation to the total admissions in that month.46 Alvarez et al,47 in a systematic review of risk factors associated with near fatal and fatal asthma, found that increased use of medication such as β2-agonist by metered-dose inhaler or nebulizer, and oral corticosteroids, were predictors of near-fatal asthma whereas a previous ED visit did not confer a greater risk. Dhuper et al48 identified a previous history of intubation and steroid dependence as risk factors for future intubations with severe exacerbations. A history of serious asthma exacerbations adds to the ability of other clinical tools including pulmonary function and airway hyperresponsiveness to predict current disease activity and future clinical course.49

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Prevention of asthma exacerbations 

One of the major problems in long-term management of asthma is the lack of awareness of many patients of the chronic nature of the disease and resultant noncompliance with therapy.50 Rather, many believe they have intermittent asthma that is only troublesome when they have overt symptoms, and so they do not continue regular therapy, which has been shown in numerous studies to reduce exacerbations substantially in mild to moderate asthma.51, 52, 53 Many patients believe that asthma comes in attacks and accept that periodic exacerbations even to the point of needing ED treatment are to be expected. Given that acute asthma, especially hospitalizations, accounts for a substantial proportion of healthcare costs as well as of risk for the patient, maintenance of long-term control of asthma has become a priority, but continues to be suboptimal.54 Many studies have focused attention on the frequency of exacerbations as the primary or a major secondary outcome, especially studies of combination therapy with inhaled corticosteroids and long-acting β2-agonist (LABA) therapy. The GOAL study clearly showed that exacerbations could be reduced, and well controlled asthma achieved in the majority, by escalating therapy using increasing daily doses of inhaled corticosteroid with LABA until the patient was virtually symptom-free.55 However, in a proportion of patients, even well controlled asthma as defined in that study could not be achieved on doses of corticosteroid reaching 1000 μg fluticasone propionate daily together with maintenance salmeterol. A series of studies using the combination of formoterol with budesonide either as maintenance therapy, or more recently as both maintenance and reliever therapy, has shown the potential for this strategy to reduce exacerbations.56, 57, 58 This “maintenance and reliever” strategy, which allows a lower maintenance dose when the patient is well and provides both bronchodilator and additional corticosteroid when symptoms are increasing, reduced exacerbations more than comparator treatments in double-blind studies and in the majority of open real-world studies.

A number of studies have looked at reducing exacerbations by careful monitoring of asthma, with techniques ranging from monitoring symptoms or PEF to more recent use of markers of inflammation. Exhaled nitric oxide,59 responsiveness to methacholine challenge,60 and sputum eosinophil counts61, 62 have been used to guide asthma treatment. In each case, this additional monitoring has resulted in more optimal management with fewer exacerbations, especially when using sputum monitoring in patients with dominantly eosinophilic asthma.62

Implementation of asthma education programs, action plans, self-monitoring, and self-initiation of oral corticosteroid treatment have been shown to reduce exacerbations in the compliant patient who can follow such instructions.63 However, many patients have difficulty with compliance, especially with inhaled therapy taken twice daily. Doubling the dose of inhaled corticosteroid, previously advised as a means of preventing asthma worsenings escalating into full exacerbations requiring oral corticosteroid, has been proven relatively ineffective,64, 65 but a greater increase in corticosteroid dose may reduce the likelihood of the exacerbation.66 Use of an inhaled corticosteroid/LABA combination, and particularly use of budesonide/formoterol as maintenance and reliever therapy, which provides additional inhaled corticosteroid with every dose of bronchodilator, is also effective in reducing exacerbations.56, 57, 58

Studies in children have shown that the addition of a leukotriene receptor antagonist reduces exacerbations, both given on a regular daily basis67 and given in short courses when the child had symptoms of a cold or of asthma.68 More recently, Johnston et al69 undertook a randomized double-blind study of montelukast versus placebo as add-on therapy during the 6-week period of high risk of exacerbations associated with the back-to-school September epidemic. Once-daily montelukast added to usual therapy reduced days of worsening asthma by more than 50% and events requiring a visit to a physician or ED or use of oral corticosteroid therapy by 78%. In this real-world study, many of the children were poorly compliant with their prescribed inhaled corticosteroid or combination therapy, and the addition of an oral therapy for 6 weeks during this predictable high-risk period was clearly beneficial in providing protection against an exacerbation.

The Childhood Asthma Management Program demonstrated a 40% to 45% reduction in severe exacerbations with the use of inhaled budesonide,53 whereas the Steroid Treatment as Regular Therapy study reported a 44% reduction in severe exacerbations among patients with newly diagnosed asthma treated with budesonide.70 Although it is not clear whether exacerbations in these studies were predominantly viral, the epidemiology of exacerbations would suggest that most were. These recent studies give more credence to the value of inhaled corticosteroid in reducing exacerbations than previous studies that found relatively small effects of corticosteroid in preventing virus-induced exacerbations, although a recent study of fluticasone in viral-associated asthma showed limited efficacy.71

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Outcome of exacerbations 

Although ED visits and hospitalizations for exacerbations remain relatively common in children and adults, mortality is fortunately rare and is declining.72 Nevertheless, mortality is the most serious outcome of an exacerbation. The disparity in mortality rates in different races and social economic groups likely reflects the greater frequency and severity of exacerbations, which in turn reflects less well controlled asthma and less satisfactory long-term care.73, 74 Once the patient is hospitalized, mortality does not differ between races, so the increased deaths particularly among black patients in the United States cannot be attributed to in-hospital factors but are likely related to factors preceding hospitalization.75 Mortality was increased in patients given salmeterol compared with placebo in addition to usual therapy in a large US trial; post hoc analysis of that study strongly suggested the increased risk was seen dominantly or only in those not concomitantly prescribed inhaled corticosteroid.76 The use of inhaled corticosteroid is now mandated whenever LABA therapy is used in management of asthma.

Finally, Bai et al,77 using data from a historic cohort of patients with asthma in the Netherlands, showed that the rate of decline of lung function over time was significantly greater among those with more than the median number of exacerbations per annum. Hence, improved control of exacerbations may not only reduce acute morbidity and mortality but also lead to improved long-term outcomes with preservation of lung function.78

In summary, exacerbations of asthma sufficient to require urgent medical intervention are often, but not always, associated with viral infection, follow seasonal patterns especially in children, and are aggravated by lack of adequate maintenance anti-inflammatory drug treatment. Age and sex differences in the epidemiology of exacerbations remain less than fully explained. Frequent exacerbations may be an indication of greater severity of disease, significant comorbidities, or poor compliance with therapy. Recognizing risk factors for exacerbations and implementing appropriate long-term management strategies should reduce morbidity and mortality associated with asthma exacerbations.79

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 Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

PII: S0091-6749(08)01484-X

doi:10.1016/j.jaci.2008.08.003

The Journal of Allergy and Clinical Immunology
Volume 122, Issue 4 , Pages 662-668, October 2008