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The Proceedings of the American Thoracic Society 4:554-564 (2007)
© 2007 The American Thoracic Society
doi: 10.1513/pats.200701-003FM
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Exacerbations of Chronic Obstructive Pulmonary Disease

Antonio Anzueto1, Sanjay Sethi2 and Fernando J. Martinez3

1 South Texas Veterans Health Care System, Audie L. Murphy Division, and the University of Texas Health Science Center at San Antonio, San Antonio, Texas; 2 State University of New York and Western New York Veterans Health Care System, Buffalo, New York; and 3 Division of Pulmonary and Critical Care Medicine at the University of Michigan, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Antonio Anzueto, M.D., Pulmonary/Critical Care (111E), University of Texas Health Science Center, 7400 Merton Minter Boulevard, San Antonio, TX 78229. E-mail: anzueto{at}uthscsa.edu

ABSTRACT

The diagnosis and treatment of acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) is controversial. In this section, we review (1) the epidemiology of this condition; (2) the etiology—many patients with AECOPD are thought to have a combination of viral and bacterial infections, which contribute to their exacerbation. Bacterial organisms are isolated more commonly after viral infections in patients with COPD. The role that bacterial infections play in AECOPD remains a very controversial topic; (3) the use of diagnostic procedures; (4) efficacy of antibiotics; (5) clinical parameters to stratify patients' severity; (6) different groups of antibiotics that can be used; and (7) other therapies, including bronchodilators. We summarize the current literature, with special emphasis on the assessment of the long-term impact of this condition.

Key Words: acute exacerbations • antibiotics • chronic obstructive pulmonary disease • Haemophilus influenzae • Streptococcus pneumoniae

Chronic obstructive pulmonary disease (COPD) affects large numbers of patients and is associated with significant morbidity, disability, and mortality (1, 2). COPD is complicated by frequent and recurrent acute exacerbations (AEs), which are associated with enormous health care expenditures and high morbidity. An exacerbation of COPD is defined as "an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough, and/or sputum and beyond normal day-to-day variations, that is acute in onset and may warrant a change in regular medication in a patient with underlying COPD" (3, 4). Exacerbations are categorized in terms of either clinical presentation (number of symptoms) or heath care resources utilization (3, 4).

Exacerbations of COPD are estimated to result in approximately 110,000 deaths and more than 500,000 hospitalizations per year, with over $18 billion spent in direct costs annually (1, 2). 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 (QOL) are important features of this condition (5, 6).

Although respiratory infections are assumed to be the main risk factors for exacerbation of COPD, other conditions, including industrial pollutants, allergens, sedatives, congestive heart failure, and pulmonary embolism, have been identified (3, 4, 7, 8). The cause of an exacerbation of COPD may be multifactorial, so that viral infection or levels of air pollution may exacerbate the existing inflammation in the airways, which, in turn, may predispose to secondary bacterial infections.

To understand the impact of exacerbations in the natural history of COPD, we need to identify the frequency of these events and which factors are more likely associated with increased frequency. Several investigators have suggested that exacerbation frequency increases with disease severity (9, 10). Using a symptom-based definition, Donaldson and colleagues (11) reported that patients with severe COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] category III) had an annual exacerbation frequency of 3.43 per year compared with 2.68 per year for those with moderate COPD (GOLD category II; p = 0.029). Other investigators have used a symptom-based definition of exacerbation (12, 13). Patients with an FEV1 of more than 60% had a mean (± SD) of 1.6 (± 1.5) exacerbations per year compared with 1.9 (± 1.8) with an FEV1 of 59–40%, and 2.3 (± 1.9) with an FEV1 of less than 40% (10, 11). The results of follow-up studies show that patients who suffer a high number of exacerbations during a given period of time will continue to suffer frequent exacerbations in the future (14). Therefore, frequency of exacerbations will depend on patients' underlying severity of lung disease and number of prior exacerbations (15).

Significant comorbid conditions, particularly coexistent cardiopulmonary disease, have been shown to be a risk factor for hospital admission (16, 17), and mortality in patients with COPD exacerbation (18, 19). The presences of ischemic heart disease and/or congestive heart failure were also reported to increase the frequency of treatment failure in these patients (16, 17). However, in a hospital-based population of patients with severe COPD (29% with an FEV1 < 35%, and 27% with oxygen therapy) no association between cardiac comorbidity and outcome was found (19). The 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. In addition, older patients appear to be at risk for severe, life-threatening exacerbations, which may result in hospital admission and even be a cause of death. (15, 19, 20).

IMPACT OF EXACERBATIONS ON LUNG FUNCTION

The impact of repeated exacerbations on pulmonary function has been a matter of intense debate. Donaldson and colleagues (11) studied patients with moderate to very severe COPD. The mean FEV1 was 38% predicted. The mean exacerbation rate was 2.92 exacerbations per year; patients with more than 2.92 exacerbations per year were considered frequent exacerbators; those with less than 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). The mean rate of decline in FEV1 in the total cohort was 36 ml/year, but was greater in the frequent compared with infrequent exacerbators (40.1 vs. 32.1 ml/year, respectively; p < 0.05). Frequent exacerbations (> 2/yr) have been associated with increased dyspnea and reduced exercise capacity (11, 21), greater decline in health status (22, 23), and greater likelihood of becoming housebound (11, 24) (Table 1). 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. First, exacerbations are associated with transient decreases in pulmonary function, which, in some cases, take weeks to return to baseline (25, 26). Second, patients suffering from recurrent exacerbations have been shown to have increased concentrations of inflammatory markers in sputum, even in stable phase, which suggests persistent inflammation and potential lung damage (27). Third, neutrophils are attracted into the airway lumen during exacerbations (28). In fact, increased levels of neutrophils in sputum correlated with rapid decline in FEV1 in a 15-year follow-up study (29).There are recent reports that have identified a significant increase in eosinophils in patients with an AE of COPD (AECOPD) (30, 31). The significance of these findings are not fully understood. Fourth, in cross-sectional studies, higher bacterial load in respiratory secretions has been associated with increased inflammation and decreased lung function (32). Fifth, the urinary excretion of desmosine and isodesmosine, products of degradation of lung elastine, are significantly increased during exacerbations of COPD compared with stable phase (33) coinciding with an increase in free elastase during exacerbations (27, 34); furthermore, higher urinary concentrations of desmosine have been associated with faster decline in FEV1 in COPD (35). Finally, a correlation has been found between the number of previous exacerbations and the extent of emphysematous changes seen by computed tomography scan (36).


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  		TABLE 1. RISK FACTORS FOR FREQUENT EXACERBATIONS (> 2/YR) IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 
IMPACT OF EXACERBATIONS ON HEALTH CARE–RELATED QOL

Exacerbations have being shown to dramatically impair the feeling of well-being in patients with COPD. Differences in scores in health care–related QOL (HRQL) questionnaires between the stable phase and the exacerbation are very important in magnitude. A group of patients with COPD exacerbation showed a moderate-to-large improvement in all four domains of the Chronic Respiratory Disease Questionnaire after 10 days of treatment (37). This improvement was not observed in patients who relapsed after treatment of exacerbation.

Connors and colleagues (25) reported the QOL outcomes in patients hospitalized with AECOPD. At 6 months, 54% of patients required assistance with at least 1 activity of daily living, and 49% considered their health status to be fair or poor. No analysis was conducted on the relationship between readmissions and perceived QOL. The recovery of HRQL parameters after an AECOPD may be determined by several factors. In a study by Spencer and colleagues (23), exacerbated patients who did not relapse during follow-up experienced an improvement in the Chronic Respiratory Disease Questionnaire of 11.8 units at 1 month, and 17 units 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 after an exacerbation is 6 days for lung function and is 7 days for symptoms (26). However, this recovery may be influenced by the severity of the exacerbation. The more severe the exacerbation, the longer it takes to recover. Seemungal and colleagues showed that only 75% of patients return to their baseline peak flow values 35 days after the episode (26). The St. George's Respiratory Questionnaire (SGRQ) and Medical Research Council questionnaire were completed by patients at the end of the study. Exacerbations were more frequent in patients with frequent previous exacerbations (odds ratio [OR], 5.5; p = 0.001). Using the median number of exacerbations, patients were classified as infrequent exacerbators (0–2) or frequent exacerbators (3–8). SGRQ total score was significantly worse in frequent exacerbators (mean difference, 14.8; p < 0.001) (Figure 1).


Figure 1
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  		Figure 1. Relationship between exacerbations frequency and quality of life parameters. *p < 0.05. SGRQ = St. George's Respiratory Questionnaire. Reprinted by permission from Reference 26.

 
In multiple regression analyses, exacerbation frequency was strongly correlated with SGRQ total score and component scores. Miravitlles and colleagues (6) confirmed the impact of exacerbations on health status. Thus, these studies showed that patients who suffered more exacerbations had significantly worse SGRQ scores compared with infrequent exacerbators, and HRQL-related questionnaires offer complementary information to lung function and respiratory symptoms to monitor the course of recovery of an exacerbation. The slow recovery of HRQL after an exacerbation suggests that these patients will not return to their baseline condition and will experience further deterioration of their QOL over time.

Furthermore, the patient's therapy during the exacerbation may influence outcome. Anderson and colleagues (38) showed that patients who received long-term oxygen therapy had an improvement of the SGRQ scores by a mean of 14 units after 3 months; in contrast, the ones who did not receive oxygen showed a change of 9 units.

ECONOMIC IMPACT OF EXACERBATIONS

A further consequence of an AECOPD is the great economic burden associated with the medical care to these patients. Exacerbations are the largest direct cost for the treatment of COPD (5, 6, 39, 40). The major component was hospitalizations, which represented 58% of the total cost, followed by the total drug acquisition cost of 32.2% (5).

IMPACT OF EXACERBATIONS ON MORTALITY

Clinical studies have reported a high mortality rate in patients admitted to the hospital with an AECOPD (25, 41–44). Several studies have identified the risk factors associated with increased mortality. SUPPORT (the Study to Understand Prognosis and Preferences for Outcomes and Rates of Treatment) (25), in which patients were enrolled who had severe AECOPD, 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 2). The predictors of mortality include APACHE (Acute Physiology and Chronic Health Evaluation) III score, body mass index, age, functional status 2 weeks before admission, lower ratio of PO2 to FIO2, congestive heart failure, serum albumin level, cor pulmonale, lower activities of daily living scores, and lower 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 QOL 6 months after discharge (25).


Figure 2
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  		Figure 2. Mortality after chronic obstructive pulmonary disease exacerbation (reprinted by permission from Reference 25).

 
Several studies reported in-hospital mortality rates of 11–24% (27) and 22–35.6% after 1 and 2 years, respectively (41, 42). None of these studies have specifically examined the prognostic influence of an AECOPD by itself. Soler-Cataluna and colleagues (44) 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. Patients with frequent exacerbations had the highest mortality rate (p < 0.001), with a risk of death 4.3 times greater (95% confidence interval [CI], 2.62–7.02) than that for patients requiring no hospital management. Thus, exacerbation itself may be a significant factor associated with increased mortality in COPD, but the severity of the underlying disease may influence patient outcome.

ETIOLOGY: PATHOGENESIS OF EXACERBATIONS

A considerable body of empirical evidence now supports the concept that exacerbations are acute inflammatory events superimposed on the chronic inflammation characteristic of COPD. Several inflammatory cells and molecules measured in exhaled breath, induced or expectorated sputum, bronchoalveolar lavage, or bronchial biopsy have been found to be elevated during an AE (30–32, 45). Furthermore, increased levels of plasma fibrinogen, IL-6, C-reactive protein, and procalcitonin, demonstrating increased systemic inflammation, have been described during exacerbations (46–50).

A normal tracheobronchial tree has excellent innate defense mechanisms to maintain sterility that are compromised in the inflamed airway of COPD, allowing establishment and proliferation of microbial pathogens in the lower airway. Inflammatory and adaptive immune responses are recruited to deal with these proliferating microbial pathogens. Increased levels of inflammatory cells and cytokines induce airway secretions, bronchospasm, and mucosal edema, which, in turn, lead to worsening ventilation–perfusion mismatch and hyperinflation. The clinical consequences of these pathophysiologic changes are new onset, or worsening, of dyspnea, cough, sputum production, and sputum purulence (the cardinal symptoms of an exacerbation) (51). Systemic effects of this inflammatory process in the airways could result in clinical manifestations of fever and fatigue. Noninfectious stimuli, including environmental pollutants, both particulates and nonparticulate gases, can induce an acute increase in airway inflammation in COPD and undoubtedly contribute to exacerbations. However, infectious agents, including bacteria, viruses, and atypical pathogens, are currently implicated in up to 80% of AEs (51).

BACTERIAL EXACERBATIONS OF COPD

Results of recent studies with newer molecular and immunologic techniques form the basis of a new model of bacterial exacerbation pathogenesis (Figure 3) (52). Acquisition of new strains from the environment via aerosols or fomites of nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae appears to be the predominant initiating event for an exacerbation (Figure 4; Table 2) (53).


Figure 3
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  		Figure 3. Proposed model of bacterial infection in chronic obstructive pulmonary disease (reprinted by permission from Reference 52).

 

Figure 4
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  		Figure 4. Timelines and molecular typing for patients with chronic obstructive pulmonary disease. The horizontal line is a timeline, with each number indicating a clinic visit. The arrows indicate exacerbations (ex). Isolates of Haemophilus influenzae and Moraxella catarrhalis were assigned types based on sodium dodecyl sulfate–polyacrylamide gel and pulsed-field gel electrophoresis, respectively. The types are indicated by letters A to E. Molecular mass standards are noted on the left of the gels (reprinted by permission from Reference 53).

 

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  		TABLE 2. ISOLATION OF A NEW STRAIN OF A BACTERIAL PATHOGEN INCREASES THE RISK OF EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 
In healthy individuals, the natural niche for these pathogens is colonization of the upper respiratory tract. However, when acquired by patients with an abnormal tracheobronchial tree, these bacteria infect both the upper and lower respiratory tracts and cause mucosal and, occasionally, systemic infections. The time frame of increased risk appears to be up to 4–8 weeks after acquisition of a new strain. New strain acquisition is not related to exacerbation for Pseudomonas aeruginosa and its role in exacerbations Haemophilus parainfluenzae, S. aureus, and Enterobacteriaceae has not been elucidated.

A complex host–pathogen interaction in the airways likely determines the outcome of each new bacterial strain acquisition in COPD. The balance between host defense and pathogen virulence determines the level of proliferation of the pathogen (the bacterial load), which, in turn, determines the increase in airway inflammation. Large increases in airway inflammation result in greater pathophysiologic changes, which lead to symptoms intense enough that the patient seeks health care, and is often then diagnosed to be experiencing an exacerbation. On the other hand, if there is a limited increase in airway inflammation, symptoms may not increase to the extent that an exacerbation is diagnosed. Furthermore, over time, development of adaptive immune response may limit the proliferation of the pathogen, or regulatory mechanisms could dampen the inflammation, although the bacterial strain may still persist. In these situations, the bacterial infection would be addressed as colonization. To add to the complexity, patient perception, access to care, and physician interpretation of symptoms are additional determinants of the diagnosis of exacerbation.

Putative pathogen virulence factors for respiratory bacterial pathogens include adhesion to and invasion of airway epithelial cells, inactivation of host defense mechanisms, and elicitation of inflammatory mediators from airway cells. Chin and colleagues compared the virulence of well characterized H. influenzae strains isolated during exacerbations with colonizing strains and found that the former induced greater airway neutrophil recruitment in a mouse pulmonary clearance model than the latter (54). Furthermore, exacerbation strains adhered in significantly higher numbers to and elicited more IL-8 from primary human airway epithelial cells in culture when compared with colonizing strains (54).

Fernaays and colleagues used a genomics approach to determine if genetic differences underlie the pathogenic potential of H. influenzae strains isolated from sputum of patients with COPD. A specific combination of genes was found to be related to exacerbation, one of which is a novel IgA protease (55). Inactivation of host defenses appears to be an important determinant of disease expression among bacterial strains. These observations support pathogen virulence as an important determinant of clinical manifestations of new bacterial strain acquisition in COPD; however, additional observations are needed.

The host immune response also determines the clinical expression of bacterial strain acquisition in COPD. A mucosal IgA response to the infecting M. catarrhalis strain was more common and vigorous with colonization, whereas a systemic IgG immune response was more common and vigorous with exacerbations (56). Therefore, a vigorous mucosal immune response could "exclude" the bacteria from interaction with the epithelial mucosa, resulting in less airway inflammation and therefore favoring colonization.

Another relationship between host defense and exacerbation occurrence in COPD was found in peripheral blood mononuclear cell proliferation on exposure to an H. influenzae antigen, outer membrane protein P6. A history of exacerbation with H. influenzae in the preceding 12 months was associated with a diminished response to P6 when compared with control subjects (57). This suggests that a vigorous cellular response to H. influenzae antigens suppresses newly acquired strains and prevents exacerbations.

Exacerbations are inflammatory events; however, this inflammatory process is not uniform, and is related to the etiology of the exacerbation. Exacerbations associated with bacterial pathogens exhibit significantly more neutrophilic inflammation than nonbacterial episodes (32). Airway bacterial concentrations and intensity of neutrophilic inflammation are also related, suggesting a stimulus–response relationship (32, 58). A significant correlation between the clinical severity of an exacerbation and the level of sputum neutrophil elastase has been shown (32). Furthermore, resolution of symptoms of exacerbations associated with purulent sputum is associated with a consistent decrease in neutrophilic airway inflammation (32). Interestingly, when such clinical resolution is accompanied by eradication of the offending pathogen from sputum, there is a more marked reduction in airway inflammation compared with when bacterial pathogens persist in the airway in spite of clinical resolution (59).

Development of an adaptive immune response is strong evidence of an infective process. To establish the role of bacterial infection in exacerbations, several older studies examined the humoral immune response to bacterial pathogens in COPD after exacerbations, and came up with results that were contradictory and confusing because of methodologic limitations. Recent studies with strains homologous (infecting) to the antigen, and using immunoassays specific for antibodies that bind to surface antigens of the bacterial pathogen (60), have clearly demonstrated the development of antibodies that bind to the bacterial cell surface after exacerbations associated with H. influenzae, M. catarrhalis, and S. pneumoniae, as well as after colonization with M. catarrhalis (56). Furthermore, for H. influenzae, these bactericidal antibodies display a high degree of strain specificity (61, 62). The strain specificity of these immune responses accounts for recurrent exacerbations in COPD, as these antibodies are not protective against antigenically diverse strains of the same species.

P. aeruginosa has been isolated from sputum and bronchoscopic samples in COPD exacerbations, usually with underlying severe airflow obstruction. However, for P. aeruginosa, an association between exacerbations and new strain isolation was not identified in COPD. This suggests that alternative mechanisms underlie exacerbations due to this pathogen. Biofilms are complex communities enclosed in a matrix of extracellular polymeric substances. P. aeruginosa forms biofilms in the airways in cystic fibrosis, and a change from the biofilm state to a free-floating planktonic state has been associated with exacerbations of cystic fibrosis (63, 64). A similar mechanism may exist in COPD. Other alternative mechanisms include increased bacterial load or reinfection because of a markedly impaired immune response in these more severely ill patients.

Other gram-negative Enterobacteriaecae and S. aureus are often isolated from sputum during exacerbations and from bronchoscopy samples obtained during exacerbations of severe COPD. Little is known regarding strain changes, immune responses, and inflammatory responses to these pathogens. Therefore, their etiologic role in exacerbations and the mechanisms of such exacerbations is unclear.

VIRUSES AS A CAUSE OF AE

Proinflammatory actions of viral pathogens in vitro include airway epithelial damage, muscarinic receptor stimulation, and stimulation of RANTES (regulated upon activation, normal T-cell expressed and secreted), which induces eosinophilic influx. These actions could account for the pathophysiologic manifestations characteristic of AEs. Previous investigations of the viral causation of exacerbations of COPD relied on serologic studies and on viral cultures of upper airway samples. Currently, investigators are using polymerase chain reaction (PCR)–based detection of viral nucleic acids in sputum samples (65), and are able to detect viral nucleic acids in 48–56% of exacerbations and 6–19% of control samples (30, 59). Papi and colleagues (30) found that sputum eosinophilia was characteristic of exacerbations of viral etiology. With widespread use of the influenza vaccine, rhinovirus has become the predominant virus implicated in exacerbations (66). The respiratory syncytial virus is also now recognized as capable of causing significant illness in elderly adults with chronic lung and heart illness (67). Other viruses associated with exacerbations include influenza, parainfluenza, adenovirus, coronavirus, and human metapneumovirus.

ATYPICAL BACTERIA AS A CAUSE OF AE

Considerable confusion reigns in the literature regarding the importance of Mycoplasma pneumoniae and Chlamydia pneumoniae infections in exacerbations. The confusion is related to the diagnostic methods used in studies to define infection with these pathogens. These diagnostic methods include culture of respiratory secretions, PCR detection of microbial DNA, and serology. Culture for these pathogens is technically difficult and of extremely low yield. The interpretation of PCR is complicated by a substantial incidence of chronic infection by C. pneumoniae in COPD (68). Serology can be reliable if the serologic test used is highly specific, and a minimum fourfold increase in titer between acute and convalescent sera is required to diagnose an infection. Unfortunately, several studies have chosen an unreliable diagnostic criterion of a single titer above a certain threshold (69–71). Such high titers are common in stable COPD, and lead to overdiagnosis of acute infection in these patients. If one focuses on studies with rigorous methodology, M. pneumoniae is a rare cause of exacerbation, and the incidence of C. pneumoniae is 4–5% (72–74).

COINFECTION IN EXACERBATIONS OF COPD

An antecedent viral infection is not essential for the development of bacterial exacerbations of COPD. In fact, in the few studies that have addressed this issue, exacerbations could be attributed to virus alone, to both viral and bacterial infection, and to bacterial infection alone (30, 75, 76). In the study by Papi and colleagues, approximately 25% of exacerbations belonged to each of these three groups (30). Coinfection by virus and bacteria does seem to increase the severity of exacerbations. In hospitalized patients, a greater decrement of lung function and longer hospitalization was observed with coinfection (30). Among outpatients, coinfection was associated with more symptoms, a larger fall in FEV1, higher bacterial loads, and more systemic inflammation (75). Coinfection with C. pneumoniae and bacterial infection has also been described, however, without an impact on the clinical manifestations of exacerbation. Undoubtedly, coinfection in COPD exacerbations is an important phenomenon with clinical relevance, and presents a new frontier for exploration (77).

THERAPY

Optimal therapy for an AECOPD is multidisciplinary and depends, in part, on the site of therapy. The decision to treat in the outpatient or hospital setting remains controversial with varying guidelines (3, 4, 78). In general, the presence of respiratory failure, worsening of underlying comorbidity, failure to respond to outpatient management, or an uncertain diagnosis have been incorporated in recommendations to consider hospitalization.

Bronchodilators
Inhaled ß-agonists and anticholinergic agents have been documented to decrease obstruction during an AECOPD. Importantly, systematic reviews have suggested that both short-acting ß-agonists and anticholinergic inhaled bronchodilators have comparable effects on spirometry and a greater effect than parenterally administered bronchodilators (79). Although the combination of an anticholinergic and a ß-agonist has the potential for increased therapeutic benefit, studies combining agents from these classes have yielded varying results; on average, these results do not support the routine use of multiple agents for AECOPDs (79). It is reasonable to consider the addition of a second agent from a different class to a patient's regimen if there is suboptimal response to a single regimen (78). The evidence base for the addition of a methylxanthine to inhaled bronchodilators is similarly contradictory. It is clear, however, that the high incidence of adverse reactions makes it difficult to recommend its routine use for AECOPDs (78, 80).

Corticosteroids
The use of systemic corticosteroids for AECOPD has been studied by numerous investigators (81). A systematic review suggested that systemic steroids result in physiologic improvement over the first 72 hours and reduced the odds of a treatment failure over the subsequent 30 days (OR, 0.48; 95% CI, 0.34–0.68), although the risk of adverse drug reaction was increased (OR, 2.29; 95% CI, 1.55–3.38) (82). The largest study evaluated 271 patients from 25 Veterans Affairs medical centers (83). Patients were randomized to placebo or one of two steroid treatment arms (125 mg/d solumedrol for 3 d followed by either a 15-d or 8-wk taper). Both corticosteroid groups were associated with a faster improvement in FEV1, a lower number of treatment failures, and a shorter length of hospital stay. Patients in the corticosteroid groups were also more likely to experience complications from treatment; hyperglycemia was the most common.

Subsequently, other investigative groups have provided further guidance regarding dose, duration, and the use of steroids in an outpatient setting. One group randomized patients hospitalized with an AECOPD to methylprednisolone, 0.5 mg/kg every 6 hours for 3 days, followed by either no further steroids or a taper completed on Day 10 (84). Patients treated with a longer course of corticosteroids experienced a greater improvement in FEV1. A separate group randomized 56 patients admitted with an AECOPD to a smaller dose of prednisone (30 mg daily for 14 d) versus placebo (85). Patients treated with prednisone had a faster and greater improvement in FEV1 (26–32% predicted for placebo vs. 28–42% predicted for prednisone; p < 0.0001). The median length of stay was also shorter in the steroid-treated group (7 vs. 9 d; p = 0.027). No difference was noted in FEV1% predicted at the 6-week follow-up between the 2 groups. In a study of 27 outpatients with an AECOPD presenting to either a clinic or emergency department setting, Thompson and colleagues randomized patients to treatment for 9 days with prednisone (60 mg for 3 d, 40 mg for 3 d, and 20 mg for 3 d) or placebo (86). Patients treated with prednisone exhibited a faster and greater improvement in oxygenation and FEV1, while experiencing fewer treatment failures (0 vs. 57%; p = 0.002). An emergency room–based study randomized 147 of 202 eligible patients to prednisone (40 mg daily for 10 d) versus placebo; all patients received an oral antimicrobial agent and inhaled bronchodilators (87). Patients treated with prednisone experienced a reduced rate of relapse at 30 days (27 vs. 43%; p = 0.05), the primary endpoint of the study, as well as a prolonged time to relapse, improved dyspnea, and improved pulmonary function. There were no differences in health status, hospitalization rates, or mortality between the treatment groups. Prednisone-treated patients experienced more side effects (increased appetite, weight gain, and insomnia). Noncontrolled studies have suggested that prednisone therapy hastened AEs of chronic bronchitis recovery (by 2.63 d), while prolonging time to the next event (88). Lastly, an uncontrolled cohort study has suggested a longer disease-free interval in patients treated with steroids versus those not treated with oral steroids (87).

Recent comprehensive reviews of the topic suggested that systemic steroids be used in all patients with an AECOPD requiring hospitalization and in those outpatients with "appreciably worse" dyspnea (81, 89). Interestingly, one recent, prospective, emergency room–based study of elderly patients who required admission for an AECOPD reported that 60% of patients received systemic steroids (90). A separate, retrospective cohort study in 360 hospitals in the United States identified 69,820 patients treated for an AECOPD; 85% of patients were treated with systemic corticosteroids (91). Additional prospective data are required to better define which AECOPD patients in the outpatient setting are most likely to benefit from systemic steroid therapy.

Antibiotics
Given compelling data that bacterial infection is likely causative in a significant proportion of AECOPDs, it is not surprising that antimicrobial therapy has been intensively studied. Numerous placebo-controlled trials of antibiotics in AECOPDs have been published, with systematic reviews of these trials suggesting a beneficial treatment effect (92, 93); the most recent of these suggested a mortality benefit (93) (Figure 5).


Figure 5
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  		Figure 5. Comparison of effect of antibiotics versus placebo on short-term mortality during study intervention. Shaded symbols represent the confidence intervals (reprinted by permission from Reference 93).

 
There has been significant heterogeneity in the results of the individual studies; however, none was designed in an optimal fashion (94). Most international guidelines have interpreted these data to suggest that antimicrobial agents provide additional benefit in selected patients (95). Identifying which patients are most likely to benefit from antimicrobial therapy remains a topic of intense investigation. The classic study of Anthonisen and colleagues continues to be one of the sentinel studies in the field (51). This investigative group randomized patients during an AECOPD to an antibiotic, while stratifying the analyses based on the number of symptoms at presentation; patients with at least two cardinal symptoms (increased dyspnea, increased sputum production, and/or change in sputum color) experienced a greater benefit with antibiotics. The importance of sputum purulence has been increasingly appreciated. Stockley and colleagues noted that AECOPD associated with purulent sputum, as defined by a semiquantitative scoring system, were more likely to have positive sputum cultures (58). Importantly, episodes with mucoid sputum resolved without antibiotics in 32 of 34 patients, whereas 77 of 87 patients with purulent sputum resolved symptoms with antibiotic therapy. A large, multicenter, Italian investigative group used a similar semiquantitative colorimetric scale to confirm that increasing sputum purulence was associated with bacterial growth (96).

A bronchoscopic study employed quantitative cultures of protected specimen brush samples to confirm that patient self-reported sputum purulence was associated with bacterial infection (95). Given these data, it is not surprising that many international specialty societies have recommended antimicrobial therapy in AECOPDs that are associated with a change in sputum characteristics (95).

An evolving role for procalcitonin level to define patients with an AECOPD with a higher likelihood of bacterial infection has been recently suggested (97, 98). This protein is a small (116–amino acid, 13-kD) protein that is normally undetectable in plasma (99), but increases markedly in bacterial infections. Data from single-center, cluster-randomized, single-blinded studies suggest that procalcitonin-guided therapy can be used safely to reduce antibiotic use in patients with lower respiratory infection at a low likelihood of bacterial infection (50, 100). A recent, single-center study by Stolz and colleagues randomized 208 consecutive patients admitted to the hospital with an AECOPD to usual care (management based on standard criteria without access to procalcitonin levels) or to a procalcitonin-guided group in which antibiotic use was based on procalcitonin level at time of admission (100). In the procalcitonin-guided therapy group, a level less than 0.1 ug/L was considered to be nonbacterial, and antimicrobial use was discouraged. In those with a procalcitonin level greater than 0.25 ug/L, bacterial infection was believed to be present, and antimicrobial therapy was encouraged. For patients with levels between 0.1 and 0.25 ug/L, the use of antimicrobial agents was based on the clinical situation at admission and during early follow-up. Total antimicrobial use was decreased during the hospitalization (72% in usual care group compared with 40% in procalcitonin-guided therapy) at short-term follow-up and through 6 months. No difference was noted in clinical success rate during the index hospitalization, antimicrobial use during the subsequent 6 months, or in the time to the next exacerbation. Additional investigation is required to assess whether patients with low procalcitonin levels require antimicrobial therapy or if similar results can be achieved in a properly designed, multicenter trial (101).

The choice of antimicrobial agent remains controversial. Increasingly, guidelines have taken the approach of stratifying patients according to the risk of treatment failure (94). One such schema (Table 3), in which patient-level stratification relies on host and pathogen features, suggests a high likelihood of treatment failures. This may relate to infection with organisms that are not covered with standard antibiotic regimens (e.g., P. aeruginosa, drug-resistant bacteria) or host factors that predict treatment failure. The latter have generally included more impaired lung function, a higher frequency of exacerbations, and comorbidity (particularly ischemic heart disease) (94). The clinical implication of increasing antimicrobial resistance among common respiratory pathogens in patients with an AECOPD remains unclear (102), although patients with COPD are at higher risk for infection with such organisms (103–105). The impact of using different antimicrobial regimens based on different patient strata remains unproven. One investigative group segregated patients with an AECOPD at the time of evaluation into complicated and uncomplicated groups based on a stratification system similar to that shown in Table 3 (106). Patients with complicated exacerbations experienced inferior clinical response rate compared with those with uncomplicated AECOPD (106). Nevertheless, the lack of a well designed, prospective trial limits the ability to suggest that stratified antimicrobial therapy should be considered the standard of care.


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  		TABLE 3. POTENTIAL ANTIMICROBIAL OPTIONS FOR AN ACUTE EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE BASED ON HOST AND PATHOGEN FACTORS

 
Other Therapies
Additional therapeutic options have been evaluated in AECOPD. An analysis of five randomized, controlled trials concluded that pharmacologic mucus clearance strategies did not shorten the course of treatment, although they may have led to improved symptoms (107). The agents evaluated in these trials included domiodol, bromhexine, ambroxol, S-carboxymethylcysteine, and potassium chloride. Oxygen is considered a cornerstone of hospital treatment for an AECOPD (78). Among the multiple potential benefits are reduction of pulmonary vasoconstriction, decrease in right heart strain and possible ischemia, and improvement of cardiac output and oxygen delivery to the central nervous system and other vital organs (107). A systematic review found that the administration of supplemental oxygen therapy was associated with an increase in PaCO2 in most patients, although most patients did not require subsequent mechanical ventilation (107). Not surprisingly, patients with combined baseline hypercarbia and more severe hypoxemia experienced the highest risk of requiring mechanical ventilation after the administration of supplemental oxygen (107). In general, oxygen should be administered for patients with an AECOPD under tightly controlled circumstances, with a goal of oxygen saturations of 90–92% (PaO2, 60–65 mm Hg) (108).

Noninvasive Positive-Pressure Ventilation
Noninvasive positive-pressure ventilation (NPPV) has been used to rest fatigued respiratory muscles and to prevent the need for endotracheal intubation and mechanical ventilation (78). A Cochrane review of 14 randomized trials suggested that NPPV decreased mortality (relative risk [RR], 0.52; 95% CI, 0.35–0.76), the need for mechanical ventilation (RR, 0.41; 95% CI, 0.33–0.52), and treatment failure (RR, 0.48; 95% CI, 0.37–0.63), while improving pH (weighted mean difference [WMD], 0.03; 95% CI, 0.02–0.04), PaCO2 (WMD, –0.40; 95% CI, –0.78 to –0.03), and respiratory rate (WMD, –3.08; 95% CI, –4.26 to –1.89) within the first hour (109). Furthermore, complications associated with treatment and length of hospital stay were decreased with NPPV (109). Administration in an intensive care unit or other similar closely monitored setting appears to be associated with optimal results (110). A detailed clinical practice guideline for the use of NPPV in this setting has been published (111).

Prevention/Reduction of Exacerbations
The two most important prevention measures of COPD exacerbation are active immunizations, including influenza and pneumococcal vaccinations, and chronic maintenance pharmacotherapy (3, 4). Currently, both annual influenza vaccination and polyvalent pneumococcal vaccine are recommended in patients with COPD (3, 4).

Recent clinical studies have demonstrated that chronic maintenance therapy in patients with COPD can significantly decreased the frequency of exacerbations. These studies show that long-active bronchodilators, including long-acting ß-agonists (salmeterol, formoterol) (112), and long-acting anticholinergics (tiotropium) reduce the mean rate of COPD exacerbation (113, 114). These effects have also being reported with combination therapy of inhaled corticosteroids and long-acting ß-agonists (115, 116). Furthermore, these studies have demonstrated that the reduction in exacerbations result in a significant decrease in hospitalizations and health care utilization (113–116).

PRIORITIES FOR FUTURE STUDIES

CONCLUSIONS

All these studies demonstrate that exacerbations represent an important event in the natural history of patients with COPD, and are associated with significant morbidity and mortality. Although substantial progress has been made in the understanding of the etiology of exacerbations in COPD, much still needs to be learned. One impediment in this field of research has been the lack of animal models of smoking-induced airway disease that could be infected with the respiratory pathogens that cause exacerbations. The complexity of the host–pathogen interaction that determines the onset and course of exacerbations needs further exploration, including examination of host cellular and molecular mechanisms, the determinants of pathogen virulence, and their interaction with airway epithelial cells and macrophages. Interaction of the various causes of exacerbations needs to be better understood in order to develop prevention strategies based on these interactions. Novel methods of treatment and prevention would undoubtedly emerge from insight in to the mechanisms and pathophysiology of exacerbations.

Exacerbations are associated with increased morbidity and mortality, and have a significant socioeconomic impact. Patients with frequent exacerbations often experience impaired QOL and faster decline in lung function over time. In addition, exacerbations, including those requiring hospitalization, are the largest item associated with the direct cost in the treatment of COPD.

FOOTNOTES

Conflict of Interest Statement: A.A. has participated as a speaker in scientific meetings or courses organized and financed by various pharmaceutical companies, including Boehringer Ingelheim, Bayer Pharma, Pfizer, GlaxoSmithKline (GSK), Sanofi-Aventis, Sepracor, and Altana. He has been a consultant for Boehringer Ingelheim, Bayer, Pfizer, GSK, Sanofi-Aventis, and Sepracor. He has been the principal investigator for research grants through the University of Texas Health Science Center at San Antonio, was paid for participating in multicenter clinical trials sponsored by Boehringer Ingelheim, Bayer Pharma, BART, Lilly, GSK, and the National Institutes of Health. S.S. has received honoraria for consultancy, and less than $10,000 each from Bayer, Pfizer, GSK, Schering, Ortho McNeil, Sanofi-Aventis, and Oscient for lectures. He has received research funding from Bayer ($52,000) and GSK ($5,000). F.J.M. is a consultant for Altana Pharma and has received compensation greater than $10,000. He has been a member of several advisory boards, continuing medical education committees, and the speaker's bureau for Boehringer Ingelheim, Pfizer, and GSK. His total compensation per company is greater than $10,000. In addition, he is on the advisory board for Novartis and the speaker's bureau for Sepracor and Astra, receiving less than $10,000 per company. He has been an investigator for industry-sponsored studies for GSK, Boehringer Ingelheim, and Actelion.

(Received in original form January 2, 2007; accepted in final form March 27, 2007)

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