• FREQUENCY OF EXACERBATIONS
• IMPACT OF FAILURE
• IMPACT OF EXACERBATIONS ON LUNG FUNCTION
• IMPACT OF EXACERBATIONS ON HEALTH-CARE-RELATED QUALITY OF LIFE
• ECONOMIC IMPACT OF EXACERBATIONS
• IMPACT OF EXACERBATIONS ON MORTALITY
• SUMMARY
• REFERENCES

Chronic obstructive pulmonary disease (COPD) affects a large percentage of patients and is associated with significant morbidity, disability, and mortality [1,2]. The overwhelming cause of COPD is exposure to tobacco smoke (in over 90% of cases), which leads to an accelerated decline in forced expiratory volume in 1 s (FEV₁; annual loss of 80 to 100 mL per year compared with 20 to 30 mL per year in a nonsmoker) [3]. In response to the devastating morbidity and mortality from this disease, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [4,5] and scientific societies [6,7] have launched combined efforts with the National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO). The goals of these initiatives are to increase awareness of COPD and decrease morbidity and mortality by improving the prevention and management of this disease.
COPD is complicated by frequent and recurrent acute exacerbations, which are known to be associated with enormous health care expenditures and high morbidity. [1,2,6,8]. In addition to the financial burden required to care for these patients, other costs such as days missed from work and severe limitations in quality of life are important features of this condition [9]. This chapter will address the factors associated with frequent exacerbations; the impact of failure of therapy; and how exacerbations affect lung function, quality of life, and mortality.

FREQUENCY OF EXACERBATIONS

In order to understand the impact of exacerbations in the natural history of COPD, the frequency of these events and the factors that are more likely associated with increased frequency need to be identified. Several investigators suggested that exacerbation frequency increases with disease severity [10,11]. Patients with moderate COPD (mean FEV₁ = 50 to 55% predicted) have been shown to suffer from a mean number of approximately 2 exacerbations per year [10,11]. Using a symptom-based definition, Donaldson et al [12] reported that patients with severe COPD (GOLD category III, n = 38) had an annual exacerbation frequency of 3.43 per year compared with 2.68 per year in those with moderate COPD (GOLD category II, n = 94; p = .029). Greenberg et al [13] found that exacerbations defined as acute respiratory illnesses with increased cough, shortness of breath, or sputum production and/or a change in sputum color were more frequent in patients with moderate COPD (3 per year) than they were in those with mild COPD (1.8 per year).
In an observational study, patients with mean FEV₁ = 47% also presented a mean of 2 episodes per year, with this number dependent on the degree of functional impairment at baseline [14].These investigators used a symptom-based definition of exacerbation-patients with FEV₁ >60% had mean 1.6 ± 1.5 exacerbations per year (mean ± SD), compared with 1.9 ± 1.8 with FEV₁ = 59 to 40% and 2.3 ± 1.9 with FEV₁ < 40%. Figure 1 summarizes some of these clinical results and the association between incidence of exacerbations per year in relation to lung function (FEV₁).

Figure 1. Mean incidence of exacerbations per year in relation to forced expiratory volume in 1 s (FEV1) in the placebo arm of 3-year studies. First 3 bars are from the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE), the fourth bar represents data from the Copenhagen City Lung Study, and the final bar data from the European Society Study on COPD. (Modified from Burge S, Wedzicha JA. COPD exacerbations:definitions and classification. Eur Respir J 2003;21:46-53)

The results of follow-up studies show that patients who suffer a high number of exacerbations during a given period will continue to suffer frequent exacerbations in the future [15]. Therefore, frequency of exacerbations will depend on patients underlying severity of lung disease and number of prior exacerbations [16]. The following is a summary of the factors associated with increased frequency of exacerbation (more than 2 per year) [21-23,30,37,38]:

• Increased age
• Severity of FEV₁ impairment
• Chronic bronchial mucus hypersecretion
• Frequent past exacerbations
• Daily cough and wheeze
• Persistent symptoms of chronic bronchitis

Clinical studies demonstrated that chronic maintenance therapy in patients with COPD can significantly decrease the frequency of exacerbations. These studies show that long-acting bronchodilators, including long-acting β-agonists (LABA; salmeterol, formoterol) [17] and long-acting anticholinergics (tiotropium), reduce the mean rate of COPD exacerbation [18,19]. These effects have also been reported with combination therapy of inhaled corticosteroids and LABA [20]. In addition, the reduction in exacerbations results in a significant decrease in hospitalizations and health care utilization [18-20].

IMPACT OF FAILURE

Relapses (treatment failures requiring return visit or hospitalization within 14 to 28 days of index visit) occur in up to 25% of patients and are associated with high morbidity [16,21-26]. Patients who fail their initial outpatient therapy use the largest percentage of total resources spent for COPD, especially when they subsequently require hospitalization [8,27-29]. However, many of these patients do not seek medical care despite persistent symptoms. Results of clinical trials show a lower incidence of relapse, usually lower than 10%. These results cannot be extrapolated to everyday practice because patients included in clinical trials consist of those with chronic bronchitis and ages ranging from 18 to 90 years, a significant proportion of nonsmokers, and individuals without ventilatory impairment (not COPD). In comparison, more recent studies address treatment failure in observational "real-life" studies and show a failure rate ranging from 12 to 26% [9-12,30,31]. Several investigators suggest that this failure rate can be reduced by a patient's therapy, and several retrospective trials emphasize the importance of choosing the correct antibiotic for treatment of exacerbations.
A retrospective study of outpatients with documented COPD, conducted at this author's institution, evaluated the risk factors for therapy failure at 14 days after an acute exacerbation [22]. Participating patients had a total of 362 exacerbations over an 18-month period. One group received antibiotics (270 visits), and the second group (92 visits) did not. Both groups had similar demographics and severity of underlying COPD. The patients' mean age was 67 ± 10 years (±SD), 100% of patients had >50 pack-per-year smoking history, and 45% were active smokers. Based on the American Thoracic Society's COPD classification, 39% had mild disease, 47% moderate, and 14% severe disease. Most of the patients (95%) with severe symptoms at presentation (type 1; 95%) received antibiotics, versus only 40% with mild symptoms. The overall relapse rate (defined as a return visit with persistent or worsening symptoms within 14 days) was 22%. After an extensive multivariate analysis, the major risk factor for relapse was lack of antibiotic therapy (32 versus 19%, p <.001 compared to the antibiotic-treated group). The type of antibiotic used was also an important variable associated with the 14-day treatment failure. Patients treated with amoxicillin had a 54% relapse rate compared with only 13% for the other antibiotics (p <.01). Furthermore, treatment with amoxicillin resulted in a high incidence of failure, even when compared with those who did not receive antibiotics (p = .006; Figure 2). Other variables, such as COPD severity, types of exacerbation, prior or concomitant use of corticosteroids, and current use of chronic oxygen therapy were not significantly associated with the 14-day relapse. Other investigators have shown that the type of antibiotic the patient's received during an exacerbation may impact outcome. Miravitlles et al [32] showed that the factor associated with decreased failure and late recovery was the type of antibiotic used. Patients who received moxifloxacin had a significant decrease in failure as compared with those taking macrolides (odds ratio [OR] = 0.41; 95% confidence interval [CI] = 0.31 to 0.55) and amoxicillin/clavulanic acid OR = 0.35 (95% CI = 0.26 to 0. 45). It is important to point out that Wilson et al [33] found that differences observed in outcomes of antibiotic treatment could be confounded by factors related to medical history, severity of disease, and use of concomitant medications such as bronchodilators. However, all these studies showed that the use of antibiotics was associated with a significantly low rate of therapy failure.

	Figure 2. Acute exacerbations of chronic obstructive pulmonary disease: 14-day relapse rates after treatment with or without antibiotics. (Reprinted with permission from Adams SG, Melo J, Luther M, Anzueto A. Antibiotics are associated with lower relapse rates in outpatients with acute exacerbations of COPD. Chest 2000; 117:1345-1352)

Since relapse after initial treatment for acute exacerbation may lead to prolonged disability, a new course of antibiotics, an emergency visit, or even hospital admission, it is crucial to identify patients most at risk for relapse. Identification of risk factors for failure may permit the implementation of more aggressive broad spectrum treatment and close follow-up. In a further step, risk factors associated with relapse should be incorporated into management guidelines to aid in identifying at-risk patients.
Among the risk factors for relapse, severity of the underlying disease is probably the most important. Although impairment of respiratory function does not in itself make patients susceptible to infection, it does influence the outcome of a lower respiratory tract infection. Severe airflow obstruction, hypoxemia, and the presence of hypercapnia are all risk factors leading to poor outcome. Kessler et al [34] observed that carbon dioxide retention (PaCO₂ higher than 44 mmHg) and pulmonary hypertension (mean pulmonary artery pressure at rest higher than 20 mmHg) were the best predictors of hospitalization.
In ambulatory patients, those with more severe dyspnea at baseline are more at risk for returning to the physician with persistence or increase in symptoms [31]. In a retrospective study of 1001 COPD patients recruited in primary care, severity of FEV₁ impairment was independently associated with increasing risk of suffering two or more acute exacerbations of COPD per year; furthermore, FEV₁ impairment was associated with increasing risk of hospital admission during the same period [16]. Grossman et al [35] found that patients with severe airflow obstruction were more than four times more likely to be admitted to the hospital than were patients with mild to moderate disease, and the risk was similar for patients with disease for more than 10 years.
An increased number of previous exacerbations are associated with the risk of relapse. Seemungal et al [36] found that frequent past exacerbations constituted one of the factors most strongly associated with recurrent exacerbations. In two other studies, the number of previous exacerbations was a risk factor for relapse after ambulatory treatment for an exacerbation [16,21]. A large study in the community found that the risk of failure increased by 7.6% for every extra visit to the primary care physician during the year previous to the study [32]. In a case-control study, García-Aymerich et al [37] observed that a low FEV₁, underprescription of long-term oxygen therapy in hypoxemic patients, and having been admitted more than 3 times the previous year were all significantly and independently associated with a high probability of admission in the future.
Significant comorbidity, particularly coexistent cardiopulmonary disease, has been shown to be a risk factor for referral to the hospital after treatment for an acute exacerbation [9,11,22,31], and cardiac comorbidity was found to be among the best predictors of mortality of COPD patients discharged after an acute exacerbation [30,38]. The presence of ischemic heart disease or cardiac insufficiency correlated strongly with an increased risk of hospital admission for decompensate COPD with an odds ratio of 1.97 (CI 95% = 1.24 to 3.14) [16]. However, in a hospital-based population of severe COPD patients (29% with an FEV₁ <35% and 27% with oxygen therapy), no association between comorbidity and outcome was found [22]. These results suggest that cardiac comorbidity is a risk factor of poor outcome, particularly in patients with mild to moderate COPD; however, when the lung disease is severe, impairment in pulmonary function prevails over cardiac disease. Additionally, comorbidity appears to be a risk factor for severe life-threatening exacerbations that may result in hospital admission and may even be a cause of death, particularly in older patients [39]. Other risk factors for poor outcome include increasing age [16,38] and the presence of chronic mucus hypersecretion (CMH), both of which are facilitating factors for exacerbations. In a previous population-based study, CMH was found to be a significant predictor of COPD-related death with implicated pulmonary infection [40].The following is a summary of risk factors for relapse after ambulatory treatment of acute exacerbation of COPD [21-23,30,37,38]:

• Coexisting cardiopulmonary disease
• Increasing number of previous visits to the general practitioner for respiratory problems
• Increasing number of previous exacerbations
• Increasing baseline dyspnea
• Severity of FEV₁ impairment
• Use of home oxygen

IMPACT OF EXACERBATIONS ON LUNG FUNCTION

The impact of repeated exacerbations on pulmonary function has been a matter of intense debate. Patients with frequent exacerbations (more than 2 per year) have been associated with having more dyspnea and reduced exercise capacity [41], greater decline in health status [42,43], and greater likelihood of becoming housebound than have patients with fewer acute exacerbations [12,44].
It would seem logical that repeated episodes may potentially impair lung tissues and lead to an accelerated rate of decline in pulmonary function. This is supported by a number of experimental observations:

1. Exacerbations are associated with transient decreases in pulmonary function, which in some cases take weeks to return to baseline [45,46].
2. Patients suffering from recurrent exacerbations have been shown to have increased concentrations of inflammatory markers in sputum even in the stable phase, which suggest persistent inflammation and potential lung damage [47].
3. Neutrophils are attracted into the airway lumen during exacerbations [48] and release proteinase enzymes during phagocytosis that are incompletely neutralized [47,49]. In fact, increased levels of neutrophils in sputum correlated with rapid decline in FEV₁ in a 15-year follow-up study [50].
4. In cross-sectional studies, high bacterial load in respiratory secretions has been associated with increased inflammation and decreased lung function [24].
5. The urinary excretion of desmosine and isodesmosine, products of degradation of lung elastine, are significantly increased during exacerbations of COPD than when compared during the stable phase [51], coinciding with an increase in free elastase during exacerbations [47,49]. Furthermore, high urinary concentrations of desmosine have been associated with faster decline in FEV₁ in COPD [52].
6. A correlation has been found between the number of previous exacerbations and the extent of emphysematous changes seen by a computed tomography scan [53].

The negative impact of exacerbations on lung function has also been demonstrated in a longitudinal two-year followup study in patients with emphysema due to α₁-antitrypsin deficiency. Dowson and associates [54] observed a significant correlation between exacerbation frequency and rate of decline in forced vital capacity. The correlation between the rate of FEV₁ decline was not statistically significant. Results from the Lung Health Study, a 5-year prospective, randomized, multicenter study of smoking cessation, involved 5887 smokers followed for 5 years. Spirometric parameters and the number of LRTI resulting in a physician visit were recorded annually.The analysis showed no relationship between LRTI and FEV₁ decline in patients who stopped smoking completely. In patients who smoke intermittently, FEV₁ declined by 7.3 mL per year (p <.005) and for those who smoke continuously FEV₁ declined 7.1 mL per year (p <.001) for each additional LRTI per year. These investigators demonstrated that the number of respiratory infections influenced the decline in FEV₁ in patients who continued to smoke [55]. Donaldson et al [12] examined 109 patients with a median age of 68.1 years with moderate to very severe COPD. The mean FEV₁ was 38% predicted. Patients were followed for 4 years with daily FEV₁ measurements and daily recordings of respiratory symptoms. Exacerbations were identified from patient diaries; patients were encouraged to report symptoms consistent with a COPD exacerbation to the clinical team so that they could be seen and evaluated. The mean exacerbation rate was 2.92 exacerbations per year; patients with ≥2.92 exacerbations per year were considered frequent exacerbators and those with <2.92 exacerbations per year were considered infrequent exacerbators. A higher percentage of frequent exacerbators were hospitalized for exacerbations compared with infrequent exacerbators (43 vs 11% patients hospitalized, respectively). FEV₁ data were evaluated over 4 years in 16 frequent exacerbators compared with 16 infrequent exacerbators. In this subgroup, frequent exacerbators were young (median age 61.6 vs 71.5 years, p = .03) and a higher number of frequent exacerbators were current smokers (9/16 vs 1/16, respectively). The mean rate of decline in FEV₁ in the total cohort was 36 mL per year.The mean rate of decline in FEV₁ per year was greater in the frequent exacerbator group than it was in the infrequent exacerbator group (40.1 mL per year vs 32.1 mL per year, respectively, p <.05; Figure 3).

Figure 3. Frequency of COPD exacerbations and rate of decline in lung function (FEV1). Percentage change in lung function over 4-year period, squares represent infrequent exacerbations (3.59% per year); circles, frequent exacerbations (4.22% per year). FEV1 decline 46.1 mL per year in frequent exacerbators and 25.3 mL per year in infrequent exacerbators. (Reprinted with permission from Donaldson GC, Seemungal TAR, Bhomik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847-852)

Why is it so difficult to demonstrate the influence of respiratory infections on the rate of decline in FEV₁ despite all existing evidence? Several reasons account for this difficulty: First, longitudinal studies are difficult to perform. Furthermore, owing to the slow progression of COPD, large populations must be followed for prolonged periods for small effects to become evident. Second, exacerbations are limited in number; an average patient may suffer one or two episodes per year, which signifies between 7 and 20 days per year with symptoms and increased inflammation. Even if an effect really exists, many years would be required to accumulate enough days with increased inflammation for this effect to become clinically evident.Third, no clear definition of exacerbation exists and many exacerbations are not reported to the attending physician, making it difficult to investigate the influence of such episodes on evolution of the disease [9,36,46]. Finally, FEV₁ may not be sufficiently sensitive to detect small effects on the evolution of COPD. In fact, the influence of infections on the evolution of COPD has become evident in patients with added risk factors for rapid progression of the disease, such as active smokers [55] or patients with α₁-antitrypsin deficiency [54]. These observations suggest that respiratory infections really have an effect on the evolution of the disease, but the magnitude is so small that in individuals with no other risk factors, large groups of patients with extended follow-up periods would be required to detect such a small effect. Otherwise, patients with more severe illness and frequent exacerbations must be studied with frequent measurements of lung function and accurate diagnosis of exacerbations by means of diary cards.
With current knowledge, it can be hypothesized that the decline in lung function in COPD may be described, at least in part, based on the episodes of exacerbation (Figure 4).

	Figure 4. Impact of exacerbations in the natural history of lung function impairment in patients with COPD.

IMPACT OF EXACERBATIONS ON HEALTH-CARE-RELATED QUALITY OF LIFE

Health-care-related quality of life (HRQL) is an important outcome in medical care. A patient's health status may determine the impact that a disease process has on an individual's ability to carry out daily activities and derive personal fulfillment in life. HRQL is now considered a key component in the management of patients with COPD [4-7].
The impact of exacerbations on patients'well-being can be quantified using disease-specific quality-of-life questionnaires. Frequent instruments that are used to assess these patients are the Chronic Respiratory Disease Questionnaire (CRDQ) and the St.George's Respiratory Questionnaire (SGRQ).The main advantage is that these instruments detect small physiological changes more easily than does a generic questionnaire and provide more detail on which clinical variables are most affected by treatment and/or another condition such as exacerbations. These questionnaires were designed to quantify the impact of chronic airflow limitation on health and well-being. The SGRQ addresses the impact of respiratory conditions on an individual's social life, household activities, and employment and is sufficiently sensitive to respond to changes in disease activity. A change in score of 4 points or more is considered to be clinically significant [56].
Exacerbations dramatically impair the feeling of wellbeing in COPD patients. Differences in scores in HRQL questionnaires between the stable phase and the exacerbation are very important in magnitude. There have been relatively few studies looking at the relationship between COPD exacerbations and quality of life in patients with COPD. A group of patients with COPD exacerbation showed a moderate-to-large improvement in all four domains of the CRDQ, ranging from 1.4 to 1.9 in each domain (p <.001), after 10 days of treatment [57]. A change in score in any domain of the CRDQ of 0.5 or more represents the minimal clinically important difference that is noticeable to patients, and changes of the CRDQ of 1.0 or more and 1.5 or more represent moderate or large improvements, respectively [58].This improvement was not observed in patients who relapsed after treatment of exacerbation; similarly, patients in the stable phase who were administered the CRDQ 10 days apart did not show any significant difference in their scores [57].
Connors et al [45] reported the quality-of-life outcomes in patients hospitalized with acute exacerbations of COPD. Patients were interviewed at 2 and 6 months after their index hospitalization. At 2 months, the Sickness Impact Profile (SIP) was used to evaluate perceived health and functional status (high scores indicate worse health). At 6 months, 514 patients were interviewed about their activities of daily living. Approximately 54% required assistance with at least one activity of daily living and 49% considered their health status to be fair or poor. Trade-off scores showed that 64% of patients were willing to trade a year of their current health status for less than a year of excellent health. No analysis was conducted on the relationship between readmissions and perceived quality of life.
The recovery of HRQL parameters after an acute COPD exacerbation may be determined by several factors. In a study by Spencer et al [43], exacerbated patients who did not relapse during follow-up experienced an improvement in the CRDQ of 11.8 points at 1 month, and 17 points after 5 months of the onset of the exacerbation. These results indicate that recovery of health status after an exacerbation may take longer than previously expected. In contrast, median recovery time for lung function after an exacerbation is 6 days and for symptoms is 7 days [46]. However, this recovery may be influenced by the severity of the exacerbation. The more severe the exacerbation, the longer it takes to recover. Seemungal et al showed that only 75% of patients return to their baseline peak flow values 35 days following the episode [46]. These investigators also reported data on daily peak flow and respiratory symptoms for 1 year in 73 patients with COPD attending outpatient clinics (71% male; mean age 67 ± 8.3 years, mean FEV₁ 40% predicted) [36]. Exacerbations were identified from the diary cards and from acute visits for treatment of exacerbations. The SGRQ and Medical Research Council (MRC) questionnaire were completed by patients at the end of the study. During the 1-year observation period, there were 190 exacerbations (mean 2.7 per patient; median, 3; range 1 to 10). Exacerbations were more frequent in patients with repeated previous exacerbations (OR = 5.5, p = .001). Using the median number of exacerbations, patients were classified as infrequent exacerbators (0 to 2) or frequent exacerbators (3 to 8). SGRQ total score was significantly worse in frequent exacerbators (mean difference 14.8, p <.001; Figure 5). In multiple regression analyses, exacerbation frequency was strongly correlated with SGRQ total score and component scores. Miravitlles et al [9] studied a group of 336 patients with moderate-to-severe COPD who were followed over 2 years. This study showed that patients with moderate COPD, who suffered more than 3 exacerbations during the study, presented a change in SGRQ score that was 2 points per year worse than that of patients with less than 3 exacerbations (p = .04). This study confirms the impact of exacerbations on health status, but it is also important to point out that this deterioration in health status was not accompanied by a significant deterioration in lung function parameters [9]. Thus, these studies showed that patients who suffered more exacerbations had significantly worse SGRQ scores than did infrequent exacerbators. They also show that HRQL questionnaires offer complementary information to lung function and respiratory symptoms, which helps monitor the course of recovery of an exacerbation.The slow progress of patients'HRQL after an exacerbation suggests that these patients will not return to their baseline condition and will experience further deterioration of their HRQL over time.
Furthermore, therapy during the exacerbation may influence outcome. Andersson and associates [59] showed that patients who received long-term oxygen therapy improved their SGRQ scores by a mean of 14 points after 3 months; in contrast those who did not receive oxygen showed a 9-point change.

	Figure 5. Relationship between exacerbation frequency and quality-of-life parameters. (Reprinted with permission from Seemungal TAR, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418-1422)

ECONOMIC IMPACT OF EXACERBATIONS

A further consequence of acute exacerbations of COPD is the great economic burden associated with medical care. Exacerbations, including those requiring hospitalization, are the largest direct cost for the treatment of COPD [8,9,27,60,61]. A study in the primary care setting showed that the mean total cost of an acute COPD exacerbation was estimated to be €140 ($179.34) [8]. The major component was hospitalizations, which represented 58% of the total cost followed by the total drug acquisition cost of 32.2% (Figure 6) [8].These costs may not be applicable to other countries because of the differences in reference prices, management practices, and health care systems; however, if the high prevalence of COPD and the frequency of exacerbations are considered, the magnitude of the health care burden derived from this disease can be appreciated. As an example, in a similar study using the reference prices for different Latin American countries, costs of exacerbation varied greatly, but taken all together, clinical failure was responsible for 52% of the global costs of the exacerbation [27].
From all these studies it is clear that exacerbations represent the most important event in the natural history of patients with COPD and are associated with significant morbidity and mortality. However, frequent exacerbations significantly impair HRQL and lung function and represent a high burden both to the patient and society.

	Figure 6. Distribution of cost for the treatment of patients with acute exacerbation of chronic bronchitis. (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)

IMPACT OF EXACERBATIONS ON MORTALITY

Different studies have reported a high mortality rate in patients admitted to the hospital with an acute exacerbation of COPD [45,62-65]. Several studies have tried to identify the risk factors associated with mortality in patients with acute exacerbation of COPD. The Study to Understand Prognosis and Preferences for Outcomes and Rates of Treatment (SUPPORT) [45] enrolled 1016 patients who had severe acute exacerbation of COPD at hospital admissions due to respiratory infections, including pneumonia (48%), congestive heart failure (26%), worsening respiratory failure due to lung cancer (3.3%), pulmonary emboli (1.4%), and pneumothorax (1%). This study reported an in-hospital mortality rate of 11% in patients with acute hypercapnic respiratory failure. The 180-day mortality rate was 33%, and the 2-year mortality rate was 49% (Figure 7). Significant predictors of mortality include acute physiology and chronic health evaluation (APACHE III) score, body mass index, age, functional status 2 weeks prior to admission, low ratio of PO₂ to FiO₂,congestive heart failure, serum albumen level, cor pulmonale, low activities of daily living scores, and low scores on the Duke Activity Status Index. This study also reported that only 25% of patients were both alive and able to report a good, very good, or excellent quality of life 6 months after discharge [45].

	Figure 7. Mortality after COPD exacerbation. (Reprinted with permission from Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators [Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments]. Am J Respir Crit Care Med 1996;154:959-967)

In another large prospective cohort study of patients who were admitted to intensive care units with COPD-related respiratory failure [66], the in-hospital mortality rate, 23.8%, was predicted by the number of hospital days before transfer to the intensive care unit and the nonrespiratory component of the APACHE III score. A separate analysis to identify true predictors of 180-day mortality included acute physiological score, age, and hospital days before transfer to the intensive care unit. Activities of daily living were also significant predictors of univariate analysis [67]. Almagro et al [62], in a study of 135 patients, reported respiratory mortality of 22 and 35.6% after 1 and 2 years, respectively. Groenewegen and coworkers [63] in a study of 171 patients reported 23% mortality rate after 1 year. Based on these studies, admission to hospital for acute exacerbation of COPD allows the identification of a subgroup of patients with poor prognosis. None of these studies have specifically examined the prognostic influence of acute exacerbation by itself. Soler-Cataluna et al [65] were the first to report that severe exacerbations of COPD have an independent negative prognostic impact, with mortality increasing with the frequency of severe exacerbations and those requiring hospitalization. Multivariate techniques were used to analyze the prognostic influence of acute exacerbation of COPD that required hospitalization and included patient age, smoking status, body mass index, comorbidity, long-term oxygen therapy, spirometry parameters, and arterial blood gases. The study was performed in a prospective cohort of 304 men with COPD followed for up to 5 years. Only older age (hazard ratio 5.28, 95% CI, 1.75 to 15.93), arterial carbon dioxide tension (HR 1.07, 95% CI, 1.02 to 1.12), and acute exacerbations of COPD were found to be independent indicators of poor prognosis. A total of 116 deaths (38.2%) were recorded; 78 (25.7%) were due to respiratory causes and 38 (12.5%) died of cardiovascular disease; 7 (2.3%) died from cerebrovascular-related conditions; 11 (3.6%) from cancer. Patients with frequent exacerbations had the highest mortality rate (p < .001) with a risk of death 4.3 times greater (95% CI, 2.62 to 7.02) than did patients requiring no hospital management. Eighty-nine patients (29.3%) were admitted to the hospital at least once during the study period. Mortality in this group after 12, 24, 36, 48, and 60 months was 11.6% (p = .2), 25.9% (p = .4), 40.2% (p = .6), 46.6% (p = .8), and 55% (p = 1.0), respectively (Figure 8). Therefore, exacerbations are a significant factor associated with increased mortality in COPD.

	Figure 8. Survival curves according to the frequency of acute exacerbations of COPD. (Reprinted with permission from Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, et al Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60:925-931)

SUMMARY

Exacerbations of COPD are associated with increased morbidity and mortality and have a significant socioeconomic impact. Patients with frequent exacerbations often experience impaired HRQL and a faster decline in lung function over time. Severe exacerbations that lead to hospitalization constitute a risk for mortality both during the hospitalization and during the subsequent year. In addition, exacerbations, including those requiring hospitalization, are the largest direct cost for the treatment of COPD.

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