Chronic obstructive pulmonary disease (COPD) is an increasing, worldwide health problem [1], characterized by acute periods of worsening symptoms called exacerbations. An exact definition of an acute exacerbation of COPD (AECOPD) remains controversial [2], but one group has suggested that it reflects "a sustained worsening of the patient's condition from the stable state and beyond normal day-to-day variations that is acute in onset and may warrant additional treatment in a patient with underlying COPD" [3].
Comprehensive reviews of this topic [2,3] emphasize the heterogeneity of the disease [4], which has led to varying definitions for AECOPD by various authors. A list of selected interventional and observational studies is presented in Table 1.
 | TABLE 1. Varying definitions for acute exacerbations of chronic bronchitis in selected interventional and observational studies |
It is evident, however, that two major approaches have been taken: symptom-based and event-based definitions. Symptom-based definitions are the most frequently used, as is the case with Anthonisen et al [5]. Although these definitions are most applicable to patient care, some investigators have documented that the symptoms may not be reported to health care personnel in a significant proportion of patients [6]. In an attempt to circumvent difficulties with quantifying symptom changes, event-based definitions have been increasingly utilized, particularly in the context of clinical trials. Given that as many as 50% of exacerbations are not reported to health care providers [6,26], this approach may capture a significantly smaller number of events. An analysis from a large trial of an inhaled corticosteroid/long-acting β-agonist used for COPD compared a symptom-based definition using a diary card (adapted from asthma studies, a limitation of the analysis) and an event-based definition(treatment with steroids, antibiotics, or hospitalization). The clinicians reported poor concordance between diary card definitions and event-based definitions. Intensive investigation continues to optimize definitions for clinical use and research studies [2].
NATURAL HISTORY OF EXACERBATIONS AND THEIR FREQUENCY
The frequency and severity of exacerbations are quite variable among COPD patients [3]. This in part reflects the nature of data collection (prospective vs retrospective), as well as confounders such as disease severity, medications administered, vaccinations, and smoking status [3]. Table 2 enumerates a series of studies that defined the number of exacerbations per year in COPD patients. Studies that define AECOPDs by use of diary cards tend to identify a greater number of episodes per year [6,26]. Similarly, studies that include patients with more severe underlying disease are associated with a greater number of yearly episodes, although the various classification schemes exhibit differing relationships with frequency of hospitalizations [36]. One group examined 132 patients during almost 3 years of follow-up by carefully documenting exacerbations through the use of diary cards [37]. They confirmed that patients with severe COPD (FEV1 [forced expiratory volume in 1 s] <30% predicted) experienced a higher exacerbation frequency (3.43 per year) than did those with moderate COPD (FEV1 ≥30% but <80% predicted; 2.68 per year). Interestingly, the annual exacerbation frequency remained constant throughout the period of study, although physiological and clinical recovery from exacerbations was significantly longer each year.
 | TABLE 2. Frequency of AECOPD episodes per year in selected studies |
IMPACT OF AN AECOPD ON HEALTH STATUS
Numerous investigative groups have demonstrated the negative implications of AECOPDs on health status (Table 3). As such, individual exacerbation episodes are associated with worsening of health status [26,39]. In addition, recurrent episodes exert significant negative effects on health status in COPD patients. Aaron and colleagues demonstrated the significant impact of exacerbation recurrence during the first 10 days after emergency room treatment of an exacerbation and the longitudinal change in the Chronic Respiratory Questionnaire (CRQ) [39]. Results derived from the GLOBE trial of gemifloxacin for treatment of exacerbations of COPD have shown a change in health status as recorded by the St.George Respiratory Questionnaire (SGRQ) after an exacerbation and the impact of recurrence during 26 weeks of follow-up. Patients with more frequent exacerbations experience a worse health status than do patients with less frequent exacerbations [6]. The most comprehensive study was reported by Miravitlles and colleagues [35]. In 336 patients with COPD, more frequent exacerbations had a deleterious effect on health status in patients with moderate disease (FEV1 35% to 50% predicted) [35]. Patients who experience an early recurrence of an AECOPD after treatment experience a sustained negative effect on health status [39,40].
 | TABLE 3. Impact of an acute exacerbation on health status in selected studies |
IMPACT OF AN AECOPD ON PULMONARY FUNCTION
A limited number of investigative groups have examined the impact of frequent exacerbations on longitudinal changes in pulmonary function (Table 4). The Lung Health Study investigative group noted that more frequent AECOPDs are associated with additional decline in lung function (7 mL per year in FEV1 per lower respiratory tract infection [LRTI] per year [14]). A separate group noted a ~8 mL per year decrement in patients with frequent exacerbations compared to those with infrequent exacerbations (Figure 1) [29].
 | TABLE 4. Effect of an exacerbation on pulmonary function |
 | Figure 1. Percentage change in forced expiratory volume in 1 s (FEV1) with standard errors over 4 years. Squares represent infrequent exacerbators; circles represent frequent exacerbators.
(Reproduced with permission from Donaldson G, Seemungal T, Bhowmik A, Wedzicha J. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57(10):847-852. Copyright © 2002 BMJ Publishing Group) |
IMPACT OF AN AECOPD ON HEALTH CARE UTILIZATION
Numerous groups have examined the economic impact of COPD [45] and exacerbations on measures of health care utilization (Table 5). It is evident that a wide range of medical resource utilization has been reported. Importantly, hospitalization costs are frequently the largest contributor to the economic impact of COPD (Figure 2). Exacerbations resulting in hospitalization are particularly problematic as they are associated with significant mortality, particularly in those requiring intensive care admission [46]. After hospital admission, one multicenter group reported 13.4% mortality in 180 days, 22% mortality in 1 year, and 35.6% mortality in 2 years [47].
 | TABLE 5. Cost of exacerbations in various health care systems trought the world |
 | Figure 2. Distribution of costs for acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease in 2414 patients managed in general practice setting in Spain.
(Reprinted with permission from Miravitlles M, Murio C, Guerrero T, Gisbert R; on behalf of the DAFNE Study Group. Pharmacoeconomic evaluation of acute exacerbations of chronic bronchitis and COPD. Chest 2002;121:1449-1455) |
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