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doi:10.1378/chest.06-1610
(Chest. 2007; 131:696-704)
© 2007 American College of Chest Physicians
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Impact of COPD Exacerbations on Patient-Centered Outcomes*

Claudia G. Cote, MD, FCCP; Luis J. Dordelly, BS and Bartolomé R. Celli, MD, FCCP

* From the Respiratory Disease Section (Dr. Cote), Bay Pines Veterans Affairs Health Care System, Bay Pines, FL; Research and Development (Mr. Dordelly), Bay Pines Foundation, Bay Pines, FL; and the COPD Center (Dr. Celli), Caritas-St. Elizabeth's Medical Center, Boston, MA.

Correspondence to: Claudia G. Cote, Bay Pines Veterans Affairs Health Care System, Respiratory Disease Section 111A, 10,000 Bay Pines Blvd, Bay Pines, FL 33744; e-mail: Claudia.cote{at}med.va.gov

Abstract

Background: Frequent exacerbations are associated with a faster decline in FEV1, impaired health status, and worse survival. Their impact and temporal relationship with other outcomes such as functional status, dyspnea, and the multidimensional body mass index, obstruction, dyspnea, exercise capacity (BODE) index remain unknown.

Hypothesis: We reasoned that exacerbations affect the BODE index and its components, and that changes in the BODE index could be used to monitor the effect of exacerbations on the host.

Study design: Prospective observational study in a Veterans Affairs medical center.

Methods: We studied 205 patients with COPD (mean [± SD] FEV1, 43 ± 15% predicted), and recorded the body mass index, FEV1 percent predicted, modified Medical Research Council dyspnea scale, 6-min walk distance, and the BODE index at baseline, during the exacerbation, and at 6, 12, and 24 months following the first episode, and documented all exacerbations for 2 years after the first acute exacerbation.

Results: From the cohort, 130 patients (63%) experienced 352 exacerbations or (0.85 exacerbations per patient per year); 48 patients (23%), experienced one episode, 82 patients (40%) experienced 2 or more exacerbations, and 50 patients required hospitalization. At study entry, exacerbators had a worse mean baseline BODE index score (4.2 ± 2.1 vs 3.57 ± 2.3, respectively; p < 0.03). The BODE index score worsened by 1.38 points during the exacerbation, and remained 0.8 and 1.1 points above baseline at 1 and 2 years, respectively. There was little change in BODE index score at 2 years in nonexacerbators.

Conclusion: COPD exacerbations negatively impact on the BODE index and its components. The BODE index is a sensitive tool used to assess the impact of exacerbations and to monitor COPD disease progression.

Key Words: body mass index • COPD • dyspnea • exacerbations • exercise capacity • modified Medical Research Council • obstruction • 6-minute walk distance

COPD will become the number one cause of respiratory-related disability in the world by the year 2020.1 Patients with advanced COPD experience frequent exacerbations that often require medical intervention (ie, acute exacerbation [AE]),23 and hospitalizations4 resulting in increased health-care expenditure5678 and poor outcomes.9 Frequent exacerbations are associated with worsening of the FEV1,410 decreased health-related quality of life (HRQOL),11 and survival.9121314 Risk factors for severe exacerbations include the following: a history of prior hospitalization; a lower FEV1; untreated hypoxemia; hypercarbia; poor health status; comorbidity; and severe respiratory symptoms.9121315 We have gained valuable information on risk factors for exacerbations but had lacked the availability of an integrated clinical tool that was capable of expressing the impact of the exacerbation in the short term and on the subsequent course of the disease.

Our group has validated the body mass index, obstruction, dyspnea, exercise capacity (BODE) index as a tool to measure disease severity and predict survival in COPD patients.16 The BODE index incorporates the following markers that are known to be independent predictors of survival: the body mass index (BMI)17; the degree of airflow obstruction (ie, FEV1)18; the measurement of functional dyspnea (modified Medical Research Council [MMRC] dyspnea scale)19; and exercise capacity assessed by the 6-min walk distance (6MWD) test.2021 The predictive value of the BODE index has been extended to COPD hospitalizations, as shown by Ong et al,22 with the highest scores associated with a higher risk for hospital admissions. Also, we have shown23 that the BODE index can be changed with pulmonary rehabilitation and that the changes observed predict outcomes at 2 years. Imfeld et al24 showed that changes in the BODE index after lung volume reduction surgery also predict survival and therefore lend support to the concept that the BODE index could be used as a surrogate marker of disease progression.

Because exacerbations can impact on the components of the BODE index, we hypothesized that the BODE index could be a useful tool to evaluate the effect of exacerbations on the host. Thus, we planned this study to evaluate the immediate and subsequent impact of moderate exacerbations on the BODE index and its components, and the value of the change in the BODE index to help predict subsequent outcomes.

Materials and Methods

Patients
Patients with a diagnosis of COPD, according to the criteria of the American Thoracic Society (ATS),25 were recruited between June 2001 and June 2004, and were followed up until May 2006 at one of the BODE Cohort Study Centers. The inclusion/exclusion criteria have been previously published.16 The study was prospective and observational, and included 205 consecutive patients. All patients signed a consent form, and the protocol was approved by the Internal Review Board.

Measurements
Pulmonary function tests26 and the 6-min walk test27 were performed following ATS guidelines. Dyspnea was assessed using the MMRC dyspnea scale.28 Comorbidity was measured with the validated Charlson score.29 The BODE index was computed as previously reported.16 The St. George Respiratory Questionnaire was used to assess HRQOL.30

Exacerbations
A moderate exacerbation was defined, using a modified version of the definition proposed by Rodriguez-Roisin,31 as an event characterized by a sustained worsening of respiratory symptoms for at least 2 days, requiring the following: a visit to a doctor or the emergency department; and treatment with antibiotics or systemic steroids or both, but not necessitating a hospitalization. This classification corresponds to a type I exacerbation according to the European Respiratory Society/ATS classification.25 Patients experiencing milder exacerbations not requiring intervention or severe exacerbations, type II (admission to the hospital) and type III (admission to the ICU), were not enrolled in the study.

Follow-up
A baseline BODE index score was determined while the patients were clinically stable. Patients attended the clinic at regular intervals, every 6 months or until death. Patients who experienced an exacerbation at any time after study enrollment were instructed to contact the clinic within 48 h of the onset of exacerbation symptoms. Those patients who were identified as having experienced a moderate exacerbation31 were included in the study and underwent a BODE index evaluation within 48 h of the onset of symptoms. The last BODE index evaluation obtained with the patient in the stable state prior to the exacerbation was used as a baseline. Exacerbation patients were then followed up at 6-month intervals after the index event. An interim history of exacerbations and/or hospitalizations for COPD was obtained at each visit, and the event was confirmed by reviewing the computerized patient record system. COPD Patients who remained exacerbation free for the 2 years of the study were used as control subjects. Figure 1 shows the protocol design and the number of patients completing each one of the evaluations.


Figure 1
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  		Figure 1. Protocol design.

 
Statistical Analysis
Continuous variables are reported as the mean ± SD. The groups were compared by Student t test. Corrections were used to account for multiple comparisons. The change in BODE index and its components over time was evaluated using analysis of variance.

Correlations were obtained between different variables and the change in the BODE index. A linear regression model using the change in BODE index at 2 years as the dependent variable was performed to assess the contribution of variables showing significant correlations to the change in BODE index over time.

Results

The cohort consisted primarily of men. A total of 1.5% of patients were in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I, 32% in GOLD stage II, 45% in GOLD stage III, and 21.5% in GOLD stage IV. One hundred thirty patients experienced exacerbations; 75 patients who did not experience exacerbations during the same period served as control subjects. The median exacerbation rate was 1 episode per patient; therefore we defined those patients experiencing two or more exacerbations per year as frequent exacerbators. The exacerbation rate increased with GOLD stage from GOLD stage I and II (0.41) to GOLD stage III (1.05), and remained the same for GOLD stage IV (1.08).

The baseline characteristics of these patients are shown in Table 1 . Exacerbators had a lower FEV1 percent predicted, and more were oxygen-dependent and steroid-dependent. Their mean St. George Respiratory Questionnaire scores at baseline were higher (57 ± 19 vs 50 ± 20, respectively; p = 0.01) and worsened with the exacerbation (61 ± 18 vs 49 ± 21, respectively; p = 0.009), as well as at 1 and 2 years (60 ± 15 vs 50 ± 20, respectively; and 64 ± 18 vs 51 ± 23, respectively; p < 0.002).


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  		Table 1. Baseline Patient Characteristics According to Exacerbation Status*

 
The groupings of patients and their outcomes are shown in Figure 2 . Among exacerbation patients, 63% were frequent exacerbators. They differed in that more were dependent on treatment with corticosteroids and oxygen, and had worse gas exchange. Their characteristics are compared in Table 2 . Significant correlations were obtained between exacerbations and a history of COPD hospitalization (r = 0.25; p < 0.0002), FEV1 percent predicted (r = 0.22; p < 0.001), BODE index (r = 0.17; p < 0.03); and GOLD stage (r = 0.15; p < 0.02).


Figure 2
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  		Figure 2. Outcomes of patients by exacerbation status and after 2 years of follow-up. Non-Exac = nonexacerbators; Hosp = hospital; Lung CA = lung cancer.

 

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  		Table 2. Patient Characteristics According to Exacerbation Frequency*

 
Change in BODE Index and Its Components With Exacerbation
Exacerbators showed a worsening in BODE index of 1.38 points during the episode, which remained above baseline at 1 year (0.8 points) and at 2 years (1.09 points). In contrast, the BODE index for nonexacerbators did not change over time. The components of the BODE index changed during the episode as follows: the FEV1 percent decreased by 16%; the MMRC dyspnea scale score increased by 0.47 U, and the 6MWD declined by 72 m. At 6 months and 1 year following the exacerbation, there was persistent worsening in lung function, dyspnea, and exercise capacity with the largest deterioration seen in the BODE index. The control group showed no change from baseline at 6 months, and a small decline in the FEV1 percent predicted measured at 1 and 2 years, without significant change in 6MWD or dyspnea. The BMI component of the BODE index did not change in either group. These changes are summarized in Table 3 and Figure 3 .


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  		Table 3. Change in BODE and Its Components During the Index Exacerbation and After the Initial Episode

 

Figure 3
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  		Figure 3. Baseline values and changes in BODE index and its components with an AE and over time.

 
Compared with single exacerbators, frequent exacerbators had a larger deterioration in BODE index (1.17 vs 0.77 point, respectively; p < 0.05) after 2 years of follow-up. Although FEV1 percent predicted and 6MWD declined similarly, the MMRC dyspnea scale score worsened 8% vs 16%, respectively.

At 2 years, the BODE index correlated significantly with exacerbation rate (0.34; p < 0.0001), hospitalizations (0.32; p < 0.004), and frequent Exacerbations (0.25; p < 0.004). A linear regression model with change in BODE index at 2 years as the dependent variable showed that the number of exacerbations experienced by the patients during the study period and the hospitalization status had the best association with the change in BODE index (r2= 17; p < 0.0001).

Hospitalizations and Mortality
Fifty exacerbation patients (25%) were hospitalized for COPD following the index event. The mean time from the first exacerbation episode to hospitalization was 5 ± 9 months. Among hospitalized patients, 39% of patients required one hospitalization, 35% required two hospitalizations, and 26% required three or more hospitalizations. There were 20 deaths, 6 among the nonexacerbators and 14 among exacerbators. One patient in the control group died from end-stage COPD at home, 3 patients died from nonrespiratory causes, and 2 patients died from lung cancer, whereas 12 exacerbators died from COPD and 2 died from lung cancer. Among the exacerbation patients who died, 64% had been hospitalized for COPD; the mean follow-up time from the index exacerbation to death was 27 ± 14 months, and from the last hospitalization to death it was 5.2 ± 5 months. Nonsurvivors had a higher baseline BODE index (6.14 vs 4.03, respectively; p < 0.004), and were more dependent on treatment with oxygen (60% vs 29%, respectively) and corticosteroids (20% vs 14%, respectively). Current smoking was also higher among nonsurvivors (30% vs 17%, respectively). Nonsurvivors had worse mean baseline FEV1 (31 ± 14% vs 40 ± 14% predicted, respectively), a higher exacerbation rate (4.6 ± 13% vs 2.63 ± 2%, respectively), and more hospitalizations (1.5 ± 1.3 vs 0.78 ± 1.5, respectively) than survivors.

Discussion

This study provides us with the following three important findings: first, the BODE index captures short-term changes during moderate exacerbations. Second, exacerbations are important determinants of the rate of change in BODE index over time. Third, patients who do not experience an exacerbation have little change in BODE index scores.

It is known that exacerbations contribute to a further loss of FEV1,410 a worsening of HRQOL,11 a high socioeconomic burden,68 and an increase in mortality.9121314 Severe exacerbations resulting in hospitalizations (type II and III) are associated with even worse outcomes.1232 Therefore, preventing exacerbations has become a major objective in the management of COPD patients. Currently, it is thought that an exacerbation occurs as a consequence of worsening inflammation in the airways.33343536373839 However, little is known about the impact of exacerbations and their recurrence on outcomes other than FEV1, including changes in BODE index. In the East-London Cohort, "frequent exacerbators," exhibited a larger decline in FEV1 than did "infrequent exacerbators." Our study shows changes in a similar direction (Table 4 ) and of a similar magnitude.440 In their initial report of 32 patients who had spirometry data, the rate of decline in FEV1 of frequent exacerbators was 4.22% vs 3.59% per year among nonfrequent exacerbators. The exacerbation rate among our patients was lower than the one reported by these investigators, and we found that our infrequent exacerbators did not lose FEV1, while our frequent exacerbators lost 4% per year. We have no clear explanation for this discrepancy, but perhaps the current treatment of COPD patients with long-acting bronchodilators could explain the difference in the results. However, it is clear that exacerbations are associated with a faster rate of decline in lung function in particular as they increase in frequency. We found that control subjects and infrequent exacerbators had better FEV1 levels than frequent exacerbators at baseline, and no decline over time. Our findings differ from the 30 mL reported as a normal decline in epidemiologic studies. However, in none of these studies have exacerbators and nonexacerbators been separated, and it is likely that there were patients whose conditions did not decline over time. We believe that the absence or infrequency of exacerbations contributed to the preservation of lung function among our control subjects and single-exacerbator patients. In our study, we observed a large decline in FEV1 in the short term (16%) and found that nonsurvivors had the highest percentage of lung function decline over time (change in FEV1, 31.2 ± 13% to 21.3 ± 8% predicted), for a relative loss of 32% in 2 years. Compared with survivors, nonsurvivors also had the highest rate of exacerbations and hospitalizations, and accordingly, in the patients reported on here, the mortality rate was highest among hospitalized exacerbators (18% vs 4%, respectively).


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  		Table 4. Subgroup Analysis of the Change in BODE Index and Its Components Acutely During the Exacerbation and Over Time in Single vs Frequent Exacerbators*

 
Ours is the first study to evaluate the short-term and long-term consequences of exacerbations on exercise capacity and functional dyspnea (Fig 3). In contrast to the short-term change in FEV1, which showed short-term recovery, the worsening of the 6MWD and dyspnea did not improve over time. The 6MWD not only had the largest change of any of the variables measured during the exacerbation (20% decrease), but it remained the most affected variable over time, with a loss of 75 m at 2 years, which is well above the value that has been thought to be clinically significant. We observed similar changes in dyspnea, with frequent exacerbators and hospitalized patients showing the largest increase. The reason for the dissociation between lung function and the other variables remains unexplained, but it is possible that exacerbations lead to a worsening of deconditioning among patients with already compromised peripheral muscles. Such deconditioning will then worsen preexisting dyspnea and exercise capacity. If so, it raises the question of whether more attention should be directed to rehabilitate patients recovering form exacerbations. A metaanalysis40 on the benefits of pulmonary rehabilitation after AEs of COPD indicated that patients who participate in such programs after an AE may have reduced risk for readmissions to the hospital and improved survival.

We believe it is important that our study was not limited to patients with mild exacerbations or to those with more severe exacerbations requiring hospitalizations. The information we report has applicability to the COPD population most frequently encountered in daily practice. We chose the definition proposed by Rodriguez-Roisin31 because it is easily recognized by clinicians and is well suited as an outcome in clinical trials. Additionally, the operational definition of exacerbation was "action-based," requiring a medical intervention and thereby guaranteeing a certain degree of urgency that makes unlikely other conditions leading to similar symptoms.

Our study has limitations. Since few women were included, we cannot generalize the results to both genders, and since patients were recruited from a specialty clinic, they may not represent the COPD population at large. However, these patients represent the ones more likely to experience exacerbations. Further, patients were not recruited into the study after an exacerbation, which introduces selection bias, but had actually been enrolled in an observational study and evaluated preexacerbation while in the stable state.

In summary, we found that the BODE index can be used to determine the magnitude of the effect of exacerbations on patients with COPD. We also showed that the frequency of exacerbations negatively impacted on the progression of disease severity as measured by the BODE index. We believe that the BODE index helps to stratify disease severity and that its changes relate to the progression of disease that may respond to medical interventions. Such interventions should be aimed at restoring patients to prior levels of functioning and to decrease their symptoms. In turn, this could potentially result in disease modification and better outcomes.

Footnotes

Abbreviations: AE = acute exacerbation; ATS = American Thoracic Society; BMI = body mass index; BODE = body mass index obstruction dyspnea exercise capacity; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HRQOL = health-related quality of life; MMRC = modified Medical Research Council; 6MWD = 6-min walk distance

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication June 28, 2006. Accepted for publication November 3, 2006.

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