Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Summary and Appraisal of Published Evidence

The primary aims of this paper are 1) to summarize and evaluate published data that address care of patients with acute exacerbations of chronic obstructive pulmonary disease [COPD] and 2) to improve the care that these patients receive by identifying efficacious and inefficacious treatment strategies. This paper provides the background evidence for the clinical practice guideline in this issue (see pages 595-599). A joint panel from the American College of PhysiciansAmerican Society of Internal Medicine (ACPASIM) and the American College of Chest Physicians (ACCP) assisted in the design, conduct, and development of this paper. The paper is based largely on the evidence report produced by the Evidence-Based Practice Center at Duke University, Durham, North Carolina, under contract with the Agency for Healthcare Research and Quality (AHRQ) (1). We review the health impact of COPD, define the entity acute exacerbation, and describe the methods we used to identify and grade the available data on care of this condition. In addition, we assess studies that evaluate diagnostic techniques, prognostic and risk stratification models, and an array of therapies and interventions. In the concluding sections, we review important elements of postexacerbation management, with special attention to follow-up care, and gradual titration of such therapeutic agents as oxygen and corticosteroids. Last, we comment on areas of management for patients with acute exacerbations that would most benefit from further research. In the United States, more than 16 million adults have COPD, a slow-progressing condition that usually becomes symptomatic in the fifth and sixth decades of life. As the U.S. population ages, the prevalence of this disease is expected to increase (2). Chronic obstructive pulmonary disease currently accounts for approximately 110 000 deaths per year, making it, after heart disease, cancer, and stroke, the fourth leading cause of death. Nonasthma COPD in the United States annually accounts for 16 367 000 office visits, 500 000 hospitalizations, and $18 billion in direct health care costs (3, 4). The term COPD is used to describe a range of pathophysiologic entities characterized by airflow obstruction, including chronic bronchitis, emphysema, asthma, and bronchiectasis. In this paper and the accompanying guideline, we focus on the care of patients with the first two diagnoses. This approach is consistent with the National Heart, Lung, and Blood Institute's definition of COPD as an umbrella term used to encompass several more specific respiratory conditions, including chronic (obstructive) bronchitis and emphysema (5). In fact, separating these entities is difficult both when evaluating clinical studies and when practicing clinical medicine. Causes of COPD include smoking (85% to 90% of all cases), genetic factors (including 1 antitrypsin deficiency), passive smoking, occupational exposures, air pollution, and possibly hyperresponsive airways. Although precise distinctions between chronic bronchitis and emphysema are a subject of debate, tradition holds that chronic bronchitis is responsible for 85% of COPD. Patients with chronic bronchitis experience intermittent airway inflammation that leads to frequent, prolonged episodes of productive cough. In contrast, 15% of patients with COPD primarily have emphysema, a disease in which the infrastructure of alveoli and distal airspaces, and therefore the portion of the lung that provides elastic recoil, is destroyed. Both conditions predispose patients to a common constellation of symptoms and signs and a collection of impairments in respiratory function. Spirometric testing is used to confirm the diagnosis of COPD. Typical abnormalities include a decrease in FEV1 and a decrease in the ratio of FEV1 to FVC. Other abnormalities include an increased residual volume and total lung capacity and a limited and incomplete response of FEV1 to bronchodilators (incomplete reversibility). Diffusing capacity for carbon monoxide is often diminished in emphysema, and response to bronchodilators can be seen in patients with concomitant asthma. Several staging systems are available for patients with stable COPD. The staging systems of both the European Respiratory Society and the American Thoracic Society use FEV1 as the sole staging characteristic because it is most closely correlated with mortality and frequency of acute exacerbation. The British Thoracic Society staging system also includes clinical features of a patient's cough, sputum, dyspnea, and lung sounds (Table 1). Table 1. Available Staging Systems for Chronic Obstructive Pulmonary Disease In evaluating the published literature and in developing practice guidelines, we have attempted to adhere to a generally accepted and useful concept of an acute exacerbation or flare of COPD. However, many definitions exist, many authors use substantively different criteria, and many studies describe their inclusion criteria poorly. In general, most published definitions involve some combination of three clinical findings: worsening of dyspnea, increase in sputum purulence, and increase in sputum volume. Unlike the staging systems for stable COPD, there are no standardized, validated grading systems for severity of an acute exacerbation. Probably the most commonly used system is that developed by Anthonisen and colleagues (6). In this system, patients with type 1 (severe) exacerbations have all three of the main clinical findings and those with type 2 (moderate) exacerbations have two of the three. Patients with type 3 (mild) exacerbations have at least one of these clinical findings and at least one of the following clinical criteria: an upper respiratory infection in the past 5 days, fever without other apparent cause, increased wheezing, increased cough, or increase in respiratory rate or heart rate by 20% above baseline (Table 1). Clinicians should be aware that other conditions, such as heart failure and pulmonary embolism, can mimic an acute exacerbation. Tracheobronchial infections are believed to be a common inciting cause of acute exacerbations of COPD. However, controversy surrounds the nature of the infectious agent as well as its exact role. Sputum obtained from patients with mild to moderately severe chronic bronchitis routinely culture a variety of bacteria, including Haemophilus influenzae (22%), Pseudomonas aeruginosa (15%), Streptococcus pneumoniae (10%), and Moraxella catarrhalis (9%) (10). Nonpathogenic bacteria, such as H. parainfluenzae, account for up to one third of all isolates. Also, certain groups of patients, such as those living in nursing homes, those recently treated with antibiotics, and those admitted to intensive care units, are more likely to be colonized with resistant organisms, such as Pseudomonas species. The role of these colonizers in the pathogenesis of acute exacerbation remains unclear, and their presence makes interpretation of any sputum culture difficult. Some investigators have also proposed that Mycoplasma pneumoniae or Chlamydia pneumoniae may precipitate between 1% to 10% of exacerbations (11-13). Others have pointed out that the presence of eosinophilic inflammation in bronchial biopsy specimens from patients with exacerbations may indicate that viruses (notably rhinovirus) play an important role (14, 15). Acute exacerbations are clearly associated with environmental exposures as well. Significant correlations between levels of respirable particles (diameter < 10 m) and ozone have been linked to hospital admission rates (16). Finally, severe exacerbations may be precipitated by other serious clinical conditions, such as heart failure, nonpulmonary infections, pulmonary embolism, and pneumothorax (17). The outcomes of COPD exacerbations are similarly heterogeneous. Although nearly 50% of exacerbations are not reported to physicians (18, 19), exacerbations requiring hospitalization are associated with an inpatient mortality rate of 3% to 4% (20). Mortality rates are substantially higher among patients who require treatment in an intensive care unit (11% to 24% in-hospital and 43% to 46% by 1 year) (17, 21-24). After an acute exacerbation, most patients are expected to experience at least a temporary decrease in functional status and quality of life (19, 25, 26), and 50% of those hospitalized for the condition are expected to be readmitted at least once in the ensuing 6 months (17, 27). 1.0 Methods Identification of Topics for Literature Search Topics to be covered in this paper and in the practice guideline were determined through a consensus process that involved both the ACPASIM/ACCP expert panel and the technical advisory panel of the Evidence-Based Practice Center at Duke University. The topic list was generated to address three questions: 1) What information is available to aid clinicians in predicting the clinical course of a patient with an acute exacerbation? 2) What information is available about the utility of diagnostic tests used to evaluate patients with symptoms of acute exacerbation? 3) What information is available to help guide clinicians in using available therapies and interventions? We did not consider care of patients with chronic, stable COPD; experimental therapies that are not widely available; or invasive mechanical ventilation. Search Strategy We gathered information through systematic searches and ongoing surveillance of MEDLINE (1966 to 2000, week 5), EMBASE (1974 to 2000, week 18), HealthStar (1975 to June 2000), and the Cochrane Controlled Trials Register (2000, Issue 1). Search strategies included the index terms and textwords chronic obstructive pulmonary disease and acute exacerbation and specific terms relating to interventions and outcomes. Variations on several search strategies were tested in order to locate the greatest number of relevant articles. The abstracts of relevant articles were reviewed against predetermined criteria and appropriate articles were r