Rationale: The effect of disease management for chronic obstructive pulmonary disease (COPD) is not well established.
Objectives: To determine whether a simplified disease management program reduces hospital admissions and emergency department (ED) visits due to COPD.
Methods: We performed a randomized, adjudicator-blinded, controlled, 1-year trial at five Veterans Affairs medical centers of 743 patients with severe COPD and one or more of the following during the previous year: hospital admission or ED visit for COPD, chronic home oxygen use, or course of systemic corticosteroids for COPD. Control group patients received usual care. Intervention group patients received a single 1- to 1.5-hour education session, an action plan for self-treatment of exacerbations, and monthly follow-up calls from a case manager.
Measurements and Main Results: We determined the combined number of COPD-related hospitalizations and ED visits per patient. Secondary outcomes included hospitalizations and ED visits for all causes, respiratory medication use, mortality, and change in Saint George's Respiratory Questionnaire. After 1 year, the mean cumulative frequency of COPD-related hospitalizations and ED visits was 0.82 per patient in usual care and 0.48 per patient in disease management (difference, 0.34; 95% confidence interval, 0.15–0.52; P < 0.001). Disease management reduced hospitalizations for cardiac or pulmonary conditions other than COPD by 49%, hospitalizations for all causes by 28%, and ED visits for all causes by 27% (P < 0.05 for all).
Conclusions: A relatively simple disease management program reduced hospitalizations and ED visits for COPD.
The effectiveness of chronic disease management programs for chronic obstructive pulmonary disease is not well established.
This multicenter, randomized trial showed that a simple disease management program across a variety of health care delivery settings reduced hospitalizations and emergency department visits for chronic obstructive pulmonary disease.
Disease management can be broadly defined as a comprehensive strategy for improving overall health status and reducing healthcare costs in chronic conditions. These programs may include education about disease, optimization of evidence-based medications, information and support from case managers, and institution of self-management principles (5). Disease management programs have been successfully implemented for chronic conditions such as heart failure and diabetes mellitus (6, 7). However, compelling evidence that disease management improves COPD care is lacking, and the authors of a recent metaanalysis concluded that larger, randomized controlled trials are needed (8–10). The few trials showing positive outcomes used resource-intensive home visits or multiple clinic appointments (11–15). We therefore sought to determine if a simpler disease management program, with a focus on early recognition and self-treatment of COPD exacerbations, would improve outcomes in patients with severe COPD.
Full methodologic details are provided in the online supplement (Appendix 1).
We conducted a randomized, controlled trial at five Veterans Affairs (VA) medical centers. Patients with COPD were randomly assigned to disease management or usual care. The primary outcome was the combined number of hospitalizations and ED visits for COPD over 12 months. The institutional review board of each medical center approved the study. All subjects provided written informed consent.
Inclusion criteria included spirometrically confirmed COPD at high risk for hospitalization as predicted by one or more of the following during the previous year: hospital admission or ED visit for COPD, chronic home oxygen use, or a course of systemic corticosteroids for COPD (16).
Patients assigned to usual care received a one-page handout containing a summary of the principles of COPD care and the telephone number for the 24-hour VA nursing helpline, which is a service available to all VA patients. Patients assigned to the disease management arm attended a single 1- to 1.5-hour group education session conducted by a respiratory therapist case manager. The patient education session included general information about COPD, direct observation of inhaler techniques, a review and adjustment of outpatient COPD medications, smoking cessation counseling, recommendations concerning influenza and pneumococcal vaccinations, encouragement of regular exercise, and instruction in hand hygiene (17). Each subject received an individualized written action plan that included refillable prescriptions for prednisone and an oral antibiotic, contact information for a case manager, and the telephone number of the 24-hour VA helpline (see Appendix 2 in the online supplement). Subjects were to be in possession of action plan medications at all times and were to refill prescriptions immediately upon initiating the action plan. The case manager made monthly phone calls to patients in disease management. We encouraged patients to call the case manager during regular working hours if they took action plan medications or if they had questions relating to their medical care. There were no subsequent scheduled clinic visits.
The primary outcome was the combined number of hospital admissions and ED visits for COPD during the 12-month follow-up period. Secondary outcomes included individual components of the primary outcome, hospitalizations and ED visits for other causes, hospital and intensive care unit (ICU) lengths of stay, respiratory medication use, change in respiratory quality of life as measured by the self-administered Saint George's Respiratory Questionnaire (18), and all-cause mortality. Blinded pulmonologists independently reviewed all discharge summaries and ED reports and assigned a primary cause for each.
For the primary outcome, we compared the estimated mean cumulative functions between disease management and usual care (19). We also used a generalized linear model with log link and negative binomial random component to compare the rate of hospital admissions and ED visits and a general or generalized linear regression function to compare all-cause and site-adjusted mortality rates, total days hospitalized, total days in the ICU, number of outpatient respiratory medication prescriptions, and changes in quality of life.
We used a two-sided P value < 0.05. Our sample size of 720 was based on a two-sided Type 1 error (α) = 0.05, with an 80% power to detect a 25% relative reduction in the primary outcome.
We mailed invitations to 1,739 patients with COPD considered to be at high risk for an exacerbation (details about study recruitment, enrollment, and follow-up are shown in Figure 1). Of the 761 subjects who attended the visit, 18 did not meet spirometric criteria. Of the remaining 743, 371 were randomized to usual care and 372 to disease management. All patients were followed for 12 months or until the time of death if it occurred before 12 months. The average duration of follow-up was 341 days for usual care patients and 349 days for disease-management patients.
The baseline characteristics of the two treatment groups were generally well matched, with small differences in age and lung function (Table 1). Most patients had severe COPD, as indicated by the overall mean FEV1 < 37% of predicted and by the 55% rate of home oxygen use. The overwhelming preponderance of men reflects the population receiving care in the Veterans Affairs.
Disease Management* (n = 372)
Usual Care* (n = 371)
|Mean age, yr (SD)||69.1 (9.4)||70.7 (9.7)|
|Male, n (%)||363 (97.6)||365 (98.4)|
|Mean FEV1, % predicted (SD)||36.1 (14.5)||38.1 (14.4)|
|Current smoker, n (%)||80 (21.6)||85 (23.0)|
|Hospitalized for COPD in the past year, n (%)||133 (35.8)||145 (39.1)|
|ED visit for COPD in the past year, n (%)||218 (58.6)||195 (52.6)|
|Systemic steroid for COPD in the past year, n (%)||210 (56.6)||197 (53.5)|
|Home oxygen, n (%)||200 (53.9)||209 (56.6)|
|Comorbidities, n (%)|
|Hypertension||220 (59.5)||239 (64.8)|
|Cardiac||180 (48.9)||183 (49.7)|
|Gastrointestinal||127 (34.4)||151 (41.1)|
|Musculoskeletal||119 (32.5)||118 (32.1)|
|Endocrine||137 (37.0)||125 (33.9)|
|Genitourinary||124 (33.5)||99 (26.9)|
|Neurologic||80 (21.8)||80 (21.7)|
|Respiratory medications, n (%)|
|Long-acting β-agonist||220 (59.1)||199 (53.6)|
|Inhaled corticosteroid||211 (56.7)||195 (52.7)|
|Chronic systemic corticosteroid||69 (18.6)||83 (22.5)|
| Theophylline||44 (11.9)||39 (10.5)|
The status of all 743 patients was determined after 1 year. Electronic medical records were available for all hospitalizations and ED visits that occurred within the VA medical system. The success rate for obtaining discharge summaries and ED records for self-reported events that occurred outside the VA was 99% in the usual care group and 98% in the disease management group. The concordance between the two adjudicators in assigning the primary cause of hospitalizations and ED visits was 96.5% (kappa 0.94; 95% confidence interval [CI], 0.89–0.99).
The effect of disease management on the mean cumulative frequency of the primary outcome was discernible soon after randomization, and the event rates and the relative differences remained roughly constant over the entire study period (0.82 vs. 0.48 at 1 yr; difference, 0.34; 95% CI, 0.15–0.52; P < 0.001) (Figure 2A). The percentage of patients who experienced at least one primary outcome was 39.1% in the usual care group and 27.4% in the disease management group (difference, 11.7%; 95% CI, 4.9–18.4; P < 0.001).
The primary outcome rate of hospitalizations and emergency visits for COPD among the disease management patients was 48.4 per 100 patient-years compared with 82.2 per 100 patient-years among the usual care patients, a statistically significant 41% reduction (rate ratio [RR], 0.59; 95% CI, 0.44–0.78; P < 0.001); the result was essentially unchanged after adjustment for baseline age and FEV1 (RR, 0.57; 95% CI, 0.43–0.75; P < 0.001) (Table 2). Separate analysis of the primary outcome components showed a nonsignificant reduction for COPD-related hospitalizations (39.8 vs. 27.6 per 100 patient-years; RR, 0.69; 95% CI, 0.47–1.01; P = 0.08) and significant reduction for COPD-related ED visits (42.4 vs. 20.8 per 100 patient-years; RR, 0.49; 95% CI, 0.33–0.72; P < 0.001), compared with usual care (Table 2).
Rate Ratio (95% CI)
|Hospitalization or ED visit||48.4||82.2||0.59 (0.44–0.78)||<0.001|
|ED visit||20.8||42.4||0.49 (0.33–0.72)||<0.001|
|Cardiac or non-COPD pulmonary|
|Hospitalization or ED visit||18.3||26.8||0.68 (0.44–1.05)||0.06|
|ED visit||9.6||9.8||0.98 (0.56–1.70)||0.93|
|Other than pulmonary or cardiac|
|Hospitalization or ED visit||56.6||60.9||0.93 (0.69–1.25)||0.58|
|ED visit||36.0||39.0||0.92 (0.65–1.31)||0.64|
|Hospitalization or ED visit||123.8||170.5||0.73 (0.58–0.90)||<0.003|
| ED visit||67.0||91.2||0.73 (0.56–0.96)||0.02|
The effect of disease management on the mean cumulative frequency of each component of the primary outcome is shown in Figures 2b and 2c. After 1 year of follow-up, the average number of COPD-related hospitalizations per patient was 30% lower in disease management than usual care, and the average number of COPD-related ED visits was 50% lower. The percentage of patients who experienced at least one COPD-related hospitalization was 23.2% in the usual care group and 16.7% in the disease management group (difference, 6.5; 95% CI, 0.8–12.2; P = 0.03); for COPD-related ED visits, the percentages were 22.9 and 13.7%, respectively (difference, 9.2; 95% CI, 3.7–14.7; P = 0.001).
The positive effect of disease management on the primary outcome was consistent across the subgroups defined by baseline clinical characteristics including age, smoking status, FEV1, medication use, previous hospitalizations or ED use, and home oxygen use (Figure 3). No statistically significant interaction was found between treatment and any of these characteristics. A benefit from disease management was observed at all study sites with no statistically significant interaction.
Compared with the usual care arm, disease management significantly reduced the rate of hospitalizations, but not ED visits, for cardiac disease and pulmonary conditions other than COPD (Table 2). For all conditions unrelated to cardiac or pulmonary disease, the rates of hospitalizations and ED visits, separately and combined, did not significantly differ between the two treatment arms. Disease management significantly reduced all-cause hospitalizations and ED visits, separately and combined (P < 0.05 for all comparisons).
Disease management patients spent on average 36% less time in the hospital for all causes (1.7 vs. 2.8 d; P = 0.03) and less time in the ICU (0.1 vs. 0.4 d; P = 0.08; both differences adjusted for length of patient follow-up) (Table 3). Considering only hospitalized patients, the average number of days spent in the hospital per admission was the same (4.8 d for each group), but the disease-management patients spent less time in an ICU (0.2 vs. 0.7 d; P = 0.07).
Disease Management (n = 372)
Usual Care (n = 371)
Difference (95% CI)
|Mortality per 100 patient-years (± SD)||10.1||13.8||3.7 (−1.4 to 8.8)||0.09|
|Mean total hospital days (± SD)||1.7||2.8||1.1 (0.2–2.0)||0.03|
|Mean total ICU days (± SD)||0.1||0.4||0.3 (0.0–0.7)||0.08|
|Mean SGRQ change (± SD)||1.3||6.4||5.1 (2.5–7.6)||<0.001|
|Mean (± SD) respiratory medications prescribed during follow-up|
|Prednisone, mg||1,631 (1,873)||852 (1,528)||775 (528–1,022)||<0.001|
|Antibiotic, courses||4.2 (4.0)||1.6 (2.6)||2.5 (2.0–3.0)||<0.001|
|SABA, MDIs||6.4 (8.3)||5.6 (8.0)||0.8 (−0.4 to 2.0)||0.18|
|Ipratropium, MDIs||5.6 (7.4)||5.9 (7.0)||0.3 (−0.7 to 1.3)||0.61|
|LABA, days supply||164 (153)||135 (150)||26 (5–48)||0.02|
|Tiotropium, days supply||51 (110)||31 (84)||19 (5–33)||0.008|
| ICS, MDIs||5.9 (7.1)||5.6 (6.7)||0.3 (−0.7 to 1.3)||0.54|
Fifty-five percent of patients in the usual care group and 60% of patients in the disease management group returned a completed the Saint George's Respiratory Questionnaire in response to a single mailing at the end of the study. Respiratory health status after 1 year worsened by an average of 6.4 points in the usual care group and by 1.3 points in the disease management arm (difference, 5.1; 95% CI, 2.5–7.6; P < 0.001) (Table 3). A four-point change with this instrument is considered to be clinically significant (20).
Compared with usual care patients, disease managed patients filled more outpatient prescriptions for prednisone, respiratory antibiotics, long-acting β-agonists, and tiotropium during the 1-year follow-up period (Table 3). The numbers of prescriptions filled for short-acting bronchodilators and inhaled corticosteroids did not differ significantly between the two groups.
There were 48 deaths (13.8 per 100 patient-years) in the usual care group and 36 deaths (10.1 per 100 patient-years) in the disease management group over the 1-year study period (difference, 3.7 per 100 patient-years; 95% CI, −1.4 to 8.8; P = 0.09) (Table 3).
We examined the relationship of completed telephone contacts to the primary outcome in patients in the disease management arm by comparing the number of COPD-related hospitalizations and ED visits in patients who had 0 to 3 (n = 39), 4 to 8 (n = 106), and 9 or more (n = 227) calls. The rate ratios of the primary outcome were 0.78 (95% CI, 0.35–1.74; P = 0.53) for the patients with 4 to 8 calls versus 0 to 3 calls and 0.46 (95% CI, 0.22–0.96; P = 0.04) for the patients with 9 or more calls versus 0 to 3 calls.
In this large, multicenter trial we found that a relatively simple disease management program for patients with severe COPD reduced the composite frequency of COPD hospitalizations and emergency visits by 41%. Furthermore, the intervention was associated with a significant decrease in all-cause hospitalizations and ED visits and with a significant improvement in self-reported respiratory health status. The effect became evident soon after randomization and remained consistent over time and across multiple patient subgroups and study sites. To our knowledge, this is the largest published randomized trial of disease management in patients with COPD.
Previous trials of disease management have been heterogeneous in terms of size, intervention, duration of follow-up, and outcomes. Systematic reviews have reached differing conclusions about the overall value of disease management for advanced COPD, but all reviews have recognized the potential value of this type of intervention and the need for larger and more detailed studies (8–10). Several previous smaller trials have shown sizeable reductions in selected aspects of health care use, including hospitalization in some (11–15). The interventions in all of those studies included various combinations of multiple home visits or clinic visits, using physicians or nurses or both. Our results are similar in magnitude to the positive results obtained in those studies, despite important differences in our intervention program. We required a single on-site educational session supplemented by monthly reinforcing telephone calls, all of which were performed by respiratory therapists. Whether our program is as effective as the more complex resource-intensive programs, can be demonstrated only by direct comparative trials.
We cannot identify with certainty the relative contribution of individual components of our interventions. Multicomponent interventions, usually including a patient-initiated action plan for disease exacerbation, seem to be associated with larger reductions in COPD hospitalizations than single component interventions (8). In a metaanalysis of three smaller studies, Turnock and colleagues found insufficient evidence that an action plan alone reduces health care use or improves respiratory health status (21). However, the potential importance of an action plan is supported by a number of observational studies. More than one half of COPD exacerbations are not reported to health care providers; unreported exacerbations tend to be less severe but still clinically significant (22). Prodromal symptoms of an exacerbation commonly occur up to a week before a discernible reduction in lung function (23), and about one-half of patients who seek ED treatment report having had characteristic symptoms for at least 4 days (24). Prompt treatment of an exacerbation may hasten recovery, and delay in treatment may increase the risk of hospitalization (25). The much higher rates of antibiotic and prednisone use in the disease management arm of our trial strongly suggest that patients were recognizing and self-treating respiratory events that otherwise might have resulted in emergency room visits or hospitalizations.
Optimizing the use of long-acting bronchodilators and inhaled corticosteroids according to evidence-based guidelines was one of the goals of our disease management intervention. Each class of drugs reduces COPD exacerbations requiring health care intervention by about 20% (26). Compared with usual care, we observed a significant increase in the use of both classes of long-acting bronchodilators in the disease management arm. However, these increases amounted to an average of only 46 days per patient-year for long-acting β-agonists and 19 days per patient-year for tiotropium, making it unlikely that these modest increases contributed substantially to the overall 41% reduction in the frequency of primary outcomes.
The benefits of disease management may extend beyond COPD-related emergency visits and hospitalizations, as indicated by reductions in hospitalizations for cardiac or non-COPD pulmonary conditions, most of which were due to heart failure and other cardiac conditions. It has been shown that pneumonia and other respiratory conditions are strong independent predictors of hospitalization for heart failure, and conversely, any cardiovascular condition is a strong independent predictor of COPD hospitalization (16, 27). These findings could represent misdiagnosis because the clinical presentations of a COPD exacerbation and acute heart failure are similar. Alternatively, it is plausible that the two conditions are mechanistically linked; passive lung congestion from heart failure could precipitate respiratory failure in a patient with severe COPD, whereas the stress and hypoxia from a severe COPD exacerbation could trigger a major cardiovascular event.
A disease management program might imperil patient safety by substituting self-care when an ED visit might be more appropriate. Failure to seek timely medical treatment might also result in more ICU stays or deaths, but mean ICU days per patient-year and all-cause mortality were lower in the disease management arm, although not to a statistically significant level. Patients in the disease management arm also had considerably more exposure to antibiotics and prednisone, both of which can be associated with serious adverse effects. Patients and medical providers should be fully informed of potential medication hazards, and medication use should be closely monitored.
Our study has limitations. Our patients were almost exclusively male, reflecting the current demographics of patients receiving care in the VA medical system. We restricted our study to relatively high-risk patients, and it is uncertain whether the same intervention would be effective in patients with milder disease. We cannot determine the benefits of the individual components of our intervention without performing trials that directly compare them. Whether pulmonary rehabilitation would add benefit to disease management is an important but unanswered question. Because our trial lasted for only 1 year, longer-term risks and benefits remain unknown. Our study was substantially larger than most other similar trials, but it lacked sufficient power to detect a mortality effect. Finally, our conclusion about the effect of disease management on self-reported respiratory health status was limited by the low response rate of 59%.
In summary, a relatively simple COPD disease management program implemented within a regional VA medical system reduced by 41% the composite endpoint of ED visits and hospitalizations in patients with advanced COPD. The intervention also reduced hospitalizations due to cardiac and non-COPD conditions, reduced all-cause ED visits and hospitalizations, and may have improved respiratory health status. Although a formal cost benefit analysis has not been done, this intervention shows potential for reducing health care costs in addition to improving quality. Confirmatory studies should be performed in other settings.
The authors thank the following study coordinators: Donald Anderson, Karen Donovan, Lucinda M. Jacobs, Marie Sanders; also Robert Petzel M.D., VISN 23 Director, VISN 23, and Janet Murphy, Primary Care Service Line CEO.
|1.||Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J 2006;28:523–532.|
|2.||Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance—United States, 1971–2000. MMWR Surveill Summ 2002;51:1–16.|
|3.||Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418–1422.|
|4.||Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med 2001;164:358–364.|
|5.||Hunter DJ, Fairfield G. Disease management. BMJ 1997;315:50–53.|
|6.||Glasgow RE, Funnell MM, Bonomi AE, Davis C, Beckham V, Wagner EH. Self-management aspects of the improving chronic illness care breakthrough series: implementation with diabetes and heart failure teams. Ann Behav Med 2002;24:80–87.|
|7.||Ofman JJ, Badamgarav E, Henning JM, Knight K, Gano AD Jr, Levan RK, Gur-Arie S, Richards MS, Hasselblad V, Weingarten SR. Does disease management improve clinical and economic outcomes in patients with chronic diseases? A systematic review. Am J Med 2004;117:182–192.|
|8.||Adams SG, Smith PK, Allan PF, Anzueto A, Pugh JA, Cornell JE. Systematic review of the chronic care model in chronic obstructive pulmonary disease prevention and management. Arch Intern Med 2007;167:551–561.|
|9.||Taylor SJC, Candy B, Bryar RM, Ramsay J, Vrijhoef HJM, Esmond G, Wedzicha JA, Griffiths CJ. Effectiveness of innovations in nurse led chronic disease management for patients with chronic obstructive pulmonary disease: systematic review of evidence. BMJ 2005;331:485.|
|10.||Effing TW, Monninkhof EM, van der Valk PDLPM, Zielhuis GA, van Herwaarden CLA, Partridge MR, Walters EH, van der Palen J. Self-management education for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007; DOI 10.1002/14651858.CD002990.pub2.|
|11.||Bourbeau J, Julien M, Maltais F, Rouleau M, Beaupre A, Begin R, Renzi P, Nault D, Borycki E, Schwartzman K, Singh R, Collet JP. Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease-specific self-management intervention. Arch Intern Med 2003;163:585–591.|
|12.||Casas A, Troosters T, Garcia-Aymerich J, Roca J, Hernandez C, Alonso A, del Pozo F, de Toledo P, Anto JM, Rodrıguez-Roisın R, et al. Integrated care prevents hospitalisations for exacerbations in COPD patients. Eur Respir J 2006;28:123–130.|
|13.||Rea H, McAuley S, Stewart A, Lamont C, Roseman P, Didsbury P. A chronic disease management programme can reduce days in hospital for patients with chronic obstructive pulmonary disease. Intern Med J 2004;34:608–614.|
|14.||Farrero E, Escarrabill J, Prats E, Maderal M, Manresa F. Impact of a hospital-based home-care program on the management of COPD patients receiving long-term oxygen therapy. Chest 2001;119:364–369.|
|15.||Sridhar M, Taylor R, Dawson S, Roberts NJ, Partridge MR. A nurse-led intermediate care package in patients who have been hospitalised with an acute exacerbation of chronic obstructive pulmonary disease. Thorax 2008;63:194–200.|
|16.||Niewoehner DE, Lokhnygina Y, Rice K, Kuschner WG, Sharafkhaneh A, Sarosi GA, Krumpe P, Pieper K, Kesten S. Risk indices for exacerbations and hospitalizations due to chronic obstructive pulmonary disease. Chest 2007;131:20–28.|
|17.||American College of Chest Physicians and the Chest Foundation. Living well with COPD: chronic bronchitis and emphysema (accessed November 4, 2008). Available from|
|18.||Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321–1327.|
|19.||Nelson WB. Recurrent events data analysis for product repairs, disease recurrences, and other applications. Alexandria, VA and Philadelphia, PA: ASA-SIAM Series on Statistics and Applied Probability; 2002.|
|20.||Schünemann HJ, Griffith L, Jaeschke R, Goldstein R, Stubbing D, Guyatt GH. Evaluation of the minimal important difference for the feeling thermometer and the St. George's respiratory questionnaire in patients with chronic airflow obstruction. J Clin Epidemiol 2003;56:1170–1176.|
|21.||Turnock AC, Walters EH, Walters JAE, Wood-Baker R. Action plans for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005; DOI 10.1002/14651858.CD005074.pub2.|
|22.||Langsetmo L, Platt RW, Ernst P, Bourbeau J. Underreporting exacerbation of chronic obstructive pulmonary disease in a longitudinal cohort. Am J Respir Crit Care Med 2008;177:396–401.|
|23.||Seemungal TAR, Donaldson GC, Bhomik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608–1613.|
|24.||Camargo CA Jr, Ginde AA, Clark S, Falsey A, Cartwright CP, Niewoehner DE. Viral pathogens in acute exacerbations of chronic obstructive pulmonary disease. Intern Emerg Med 2008;3:355–359.|
|25.||Wilkinson TMA, Donaldson GC, Hurst JR, Seemungal TAR, Wedzicha JA. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;169:1298–1303.|
|26.||Wilt TJ, Niewoehner D, MacDonald R, Kane RL. Management of stable chronic obstructive pulmonary disease: a systematic review for a clinical practice guideline. Ann Intern Med 2007;147:639–653.|
|27.||Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, O'Connor CM, Pieper K, Sun JL, Yancy CW, et al., OPTIMIZE-HF Investigators and Hospitals. Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF. Arch Intern Med 2008;168:847–854.|