- Email: [email protected]
Hospitalized Exacerbations of COPD
[
Original Research COPD
]
Hospitalized Exacerbations of COPD Risk Factors and Outcomes in the ECLIPSE Cohort Hana Müllerova, PhD; Diego J. Maselli, MD; Nicholas Locantore, PhD; Jørgen Vestbo, MD; John R. Hurst, MD, PhD; Jadwiga A. Wedzicha, MD; Per Bakke, MD, PhD; Alvar Agusti, MD, PhD; and Antonio Anzueto, MD; for the ECLIPSE Investigators
OBJECTIVE: Exacerbations of COPD requiring hospital admission have important clinical and societal implications. We sought to investigate the incidence, recurrence, risk factors, and mortality of patients with COPD exacerbations requiring hospital admission compared with those without hospital admission during 3-year follow-up. Patients with COPD (N 5 2,138) were identified from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) observational cohort.
An analysis of time to first event of hospital admission was performed using KaplanMeier curves and Cox proportional hazard regression adjusting for possible confounders.
METHODS:
RESULTS: Of the 2,138 patients, 670 (31%) reported a total of 1,452 COPD exacerbations requiring hospital admission during the study period; 313 patients (15%) reported multiple events. A prior history of exacerbation of COPD requiring hospital admission was the factor associated with the highest risk of a new hospitalization for exacerbation (hazard ratio, 2.71; 95% CI, 2.24-3.29; P , .001). Other risk factors included more severe airflow limitation, poorer health status, older age, radiologic evidence of emphysema, and higher WBC count. Having been hospitalized for exacerbation significantly increased the risk of mortality (P , .001).
Exacerbations of COPD requiring hospital admission occur across all stages of airflow limitation and are a significant prognostic factor of reduced survival across all COPD stages. Patients with COPD at a high risk for hospitalization can be identified by their past history for similar events, and other factors, including the severity of airflow limitation, poor health status, age, presence of emphysema, and leukocytosis.
CONCLUSIONS:
TRIAL REGISTRY:
ClinicalTrials.gov; No.: NCT00292552; URL: www.clinicaltrials.gov CHEST 2015; 147(4):999-1007
Manuscript received April 17, 2014; revision accepted September 17, 2014; originally published Online First October 30, 2014. ABBREVIATIONS: BODE 5 BMI, degree of airflow obstruction and dyspnea, and exercise capacity; ECLIPSE 5 Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; GOLD 5 Global Initiative for Chronic Lung Disease; HR 5 hazard ratio; PPPY 5 per person per year AFFILIATIONS: From Respiratory Epidemiology (Dr Müllerova), GlaxoSmithKline R&D, Uxbridge, England; Audie L. Murphy Hospital (Drs Maselli and Anzueto), South Texas Veterans Health Care System, San Antonio, TX; Division of Pulmonary Diseases/Critical Care Medicine (Drs Maselli and Anzueto), University of Texas Health Science Center at San Antonio, San Antonio, TX; Respiratory Medicines Development Center (Dr Locantore), GlaxoSmithKline, Research Triangle Park, NC; Gentofte (Dr Vestbo), Hellerup, Denmark; Respiratory Research Group (Dr Vestbo), Manchester Academic Health Science Centre, University of Manchester, Manchester, England; Centre of Inflammation and Tissue Repair (Dr Hurst), University College London, London, England; Centre for Respiratory Medicine (Dr Wedzicha), University College London,
London, England; Department of Clinical Science (Dr Bakke), University of Bergen, Bergen, Norway; Department of Thoracic Medicine (Dr Bakke), Haukeland University Hospital, Bergen, Norway; Thorax Institute (Dr Agusti), Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain; and FISIB, CIBER Enfermedades Respiratorias (Dr Agusti), Mallorca, Spain. Dr Wedzicha is currently at the National Heart and Lung Institute, Imperial College London (London, England). FUNDING/SUPPORT: The ECLIPSE study was funded by GlaxoSmithKline. CORRESPONDENCE TO: Antonio Anzueto, MD, Division of Pulmonary/ Critical Care Medicine, University of Texas Health Science Center at San Antonio, 7400 Merton Minter, MC111E, San Antonio, TX 78229; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0655
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COPD is a prevalent disease associated with significant morbidity, resulting in high health-care cost1 and mortality, currently being the third leading cause of death.2-4 Patients with COPD often suffer episodes of exacerbation during the course of their disease, some of which require hospitalization. Exacerbations of COPD accelerate disease progression5-7 and are the main contributor to the substantial economic cost of COPD, particularly if they require hospitalization.8 Identifying risk factors associated with the occurrence and recurrence of these episodes has, therefore, important clinical and societal implications. Previous results from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, a multicenter, prospective study,9
Materials and Methods Study Design and Ethics The design of the ECLIPSE study (SCO104960, NCT00292552) has been published elsewhere.9 In brief, patients between 40 and 75 years old were included if they had a history of ⱖ 10 pack-years of smoking, as well as an FEV1 , 80% of predicted value and a ratio of FEV1 to FVC ⱕ 0.7; both were measured after bronchodilator use. COPD severity for each subject was graded according to GOLD (Global Initiative for Chronic Obstructive Lung Disease).3 The study was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines, and was approved by the relevant ethics and review boards at the participating centers. All subjects provided written informed consent. Baseline Measurements The methodology used in the ECLIPSE study has been described in detail elsewhere.9 Briefly, standardized questionnaires were used to measure dyspnea (modified Medical Research Council dyspnea scale),13 health status (St. George’s Respiratory Questionnaire for patients with COPD),14 fatigue (Functional Assessment of Chronic Illness TherapyFatigue Questionnaire)15 and depression (Center for Epidemiologic Studies of Depression Scale).16 Likewise, information on symptoms of cough, sputum production, wheezing, and chronic bronchitis17; selfreported comorbidities, including cardiovascular disease, diabetes mellitus, and gastroesophageal reflux disease; and use of medications and home oxygen was collected. Exacerbation history during the 12 months that preceded the study baseline visit based on subject’s recall of exacerbations treated with antibiotics, corticosteroids or both requiring hospital admission was also ascertained. Standardized spirometry (before and after bronchodilator administration) and the 6-minute walk distance test using a standardized protocol18 were also measured. The BMI, degree of airflow obstruction and dyspnea, and exercise capacity (BODE) index was calculated according to the original publication.19 A low-dose volumetric CT scan at full inspiration was obtained in all patients. Emphysema was visually scored by two experienced chest radiologists, who independently scored all CT scans as follows: 0 5 no emphysema, 1 5 , 5% (trivial), 2 5 5% to 25% (mild), 3 5 26% to 50% (moderate), 4 5 51% to 75% (severe), and 5 5 ⱖ75% involvement of both lungs (very severe). Further, the extent of emphysema was estimated using the threshold technique quantifying the percent of voxels with an apparent x-ray attenuation value (%lower attenuation area) below 2950 Hounsfeld units. Finally, peripheral venous blood was collected, processed, and concentrations of inflammatory biomarkers (WBC counts, C-reactive protein, fibrinogen, and chemokine ligand 18) were
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identified several risk factors for moderate to severe exacerbations.10 However, the incidence and factors specifically associated with exacerbations requiring hospital admission have not been extensively described in large, prospective, longitudinal cohorts of patients with COPD with a wide range of disease clinical severity.11,12 Therefore, we sought to investigate the incidence, recurrence, risk factors, and mortality of patients with COPD with exacerbations requiring hospital admission, as compared with those without hospital admission, in the ECLIPSE cohort. This information may help clinicians identify patients with COPD in need of targeted strategies to reduce their risk of hospitalized exacerbations, such as self-management plans or improved access to health-care settings other than a hospital.
measured.20,21 Samples were collected using ethylenediaminetetraacetic acid tubes and, hence, for fibrinogen, 407 mg/dL was equivalent to 350 mg/dL, as measured with collection in sodium citrate bloodcollection tubes. Follow-up and Exacerbation Ascertainment Subjects were followed-up at 3 months, 6 months, and every 6 months thereafter for a maximum of 3 years. All patients had their vital status confirmed 3 years after recruitment. Information on COPD exacerbations was collected at scheduled visits by investigators using the case report forms and based on either subjects’ recall of exacerbation events or available medical records for exacerbation events, supplemented by monthly phone calls. For the purpose of the current analysis, we focused on those exacerbation episodes that required hospital admission (hospitalized exacerbation). Statistical Analysis To investigate the prespecified goals of the study, we used the following analyses: (1) baseline differences between patients with and without hospitalized exacerbation during follow-up were tested using analysis of variance or Wilcoxon rank-sum test for continuous variables, and x2 test for categorical variables; (2) the incidence (first hospitalized exacerbation during the prospective follow-up) and recurrence (second hospitalized exacerbation during the prospective follow-up) of hospitalized exacerbations was summarized as a rate per person per year (PPPY), using a sum of individual patient’s person-time in the study and standardized per year, accompanied by 95% CIs; (3) factors associated with first hospitalized (and recurrent) exacerbations during the 3-year follow-up, were explored using Cox proportional hazards models, adjusted for a wide range of demographics, and clinical and biologic markers. To investigate what factors were associated with the occurrence of hospitalized exacerbations for the first time during follow-up, we repeated the analysis after excluding the subjects reporting any hospitalized exacerbation in the 12 months prior to study baseline; and finally, (4) differences in survival and time to first hospitalized exacerbation in relation to hospitalized exacerbation occurrence prior to study entry were tested using log-rank test with results displayed as KaplanMeier curves. This analysis was repeated again considering the subject’s exacerbation status during the first year of the prospective follow-up. We did not test any prespecified hypothesis and, hence, did not conduct a sample-size estimation. As the analyses were of exploratory nature only, P values were evaluated at a nominal significance level of .05 without adjustment for multiplicity.
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Results Figure 1 presents the flow diagram of the study. In total, 2,138 patients with COPD with complete exacerbation data during follow-up were included in the analysis. Overall, the patient population baseline characteristics were similar to those of the entire ECLIPSE COPD population (N 5 2,164).22 Incidence/Recurrence of Hospitalized Exacerbations
In this cohort of 2,138 patients, during 3 years of follow-up, there were 555 patients (26%) who did not have an exacerbation, 913 (43%) who had at least one moderate but not hospitalized exacerbation, and 670 (31%) who had at least one hospitalized COPD exacerbation. Of 1,538 patients who had at least one moderate to severe exacerbation, 42% had a hospitalized exacerbation (Fig 2). In total, 1,452 hospitalized exacerbation events were observed. Table 1 shows the baseline characteristics of patients who had at least one hospitalized exacerbation during follow-up vs those who were not hospitalized. Patients with at least one hospitalized exacerbation were more
symptomatic (cough, phlegm, dyspnea, wheeze), had poorer health status, and also reported having had more frequently both moderate and severe COPD exacerbations in the 12 months prior to study entry. Airflow limitation, exercise capacity, dyspnea, and the BODE index were significantly worse, and levels of circulating inflammatory biomarkers were higher in these patients. The hospitalized exacerbation rate PPPY during follow-up was 0.26 (95% CI, 0.23-0.28). The COPD hospitalization rate increased with older age and with worsening severity of airflow limitation (from moderate airflow limitation [grade 2]: 0.12 PPPY [95% CI, 0.10-0.15], to very severe airflow limitation [grade 4]: 0.54 PPPY [95% CI, 0.44-0.63]) (e-Table 1). Of the 670 patients who suffered at least one hospitalized exacerbation during follow-up, 313 patients (47%) had more than one episode. Having been hospitalized for COPD exacerbation during the first 12 months of follow-up (n 5 289) resulted in a significantly increased risk (P , .001) of repeated hospital admissions during the remaining 2-year follow-up (Fig 3A). This trend was observed for all grades of airflow limitation.
Figure 1 – Study flow diagram. ECLIPSE 5 Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints.
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Figure 2 – Frequency distribution of hospitalized exacerbations during the follow-up, split by severity of airflow limitation assessed by GOLD grade.3 GOLD 5 Global Initiative for Chronic Obstructive Lung Disease.
Risk Factors for Hospitalized Exacerbations
The strongest risk factor for future hospitalized exacerbation during prospective follow-up was a history of hospitalized exacerbations in the 12 months prior to study entry (hazard ratio [HR]: 2.71; 95% CI, 2.24-3.29; P , .001). Other significant risk factors included poorer health status, severe airflow limitation, older age, a higher degree of emphysema, and an increased WBC count (Table 2). To investigate what factors were associated with the occurrence of hospitalized exacerbations for the first time during follow-up, we repeated the analysis after excluding the 325 patients with COPD who reported any hospitalized exacerbation in the 12 months prior to study entry. We identified a self-reported history of asthma, use of home oxygen, and elevated fibrinogen levels as additional significant risk factors (Table 3). Finally, the analysis of factors associated with recurrent hospitalized exacerbations any time during the prospective follow-up identified the severity of airflow limitation (HR: 1.11; 95% CI, 1.06-1.16) and poorer health status (HR: 1.05; 95% CI, 1.02-1.09) as the only significant risk factors. Mortality Associated With Hospitalized Exacerbations
During the total follow-up, 202 patients (9.4%) died. As shown in Figure 3B, we observed that mortality during follow-up was significantly higher in patients with 1002 Original Research
COPD who reported one or more hospitalized exacerbation during the first 12 months of follow-up (15%), as compared with those without such an event (5%) (logrank test P , .001). This effect was also observed when considering the full follow-up of 3 years, and was independent of the severity of airflow limitation (e-Figs 1, 2). Significant decrease in survival was observed in GOLD grades 2 or 3 of airflow limitation (P , .004 and P , .001, respectively), but not in grade 4 (P 5 .186).
Discussion The main findings of this study are (1) COPD exacerbations requiring hospital admission are relatively frequent events occurring in about 30% of patients during the 3-year follow-up; (2) past history of hospitalized exacerbations is most predictive of future events, and other risk factors include the severity of airflow limitation, poor health status, radiologic evidence of emphysema, older age, and presence of systemic inflammation; and (3) a history of hospitalized exacerbations heralds poor survival. Previous Studies
Our study complements and extends previous reports because of its larger size, prospective nature, and comprehensiveness of investigations, allowing the study of a breadth of relevant risk factors in one population.11,23-26 Importantly, the ECLIPSE population was recruited during clinical stability and, therefore, the prospective follow-up allows addressing questions of incidence and
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TABLE 1
] Baseline Characteristics of All Patients With COPD Included in the Analysis, Further Split by Occurrence or Absence of at Least One Hospitalized Exacerbation During the 3-Y Follow-up
Baseline Characteristics
Total COPD Cohorta (N 5 2,138)
Hospitalized Exacerbations During Prospective Follow-up 0 (n 5 1,468)
ⱖ 1 (n 5 670)
P Value (0 vs ⱖ 1)
Anthropometric data Age, y
63 (7)
Female patient, % BMI, kg/m
2
35 27 (6)
63 (7)
64 (7)
35 27 (6)
35 26 (6)
.001 .857 .006
Clinical data Current smoker, %
36
37
34
.199
Chronic cough, %
49
47
54
.002
Chronic phlegm, %
51
49
54
.032
Chronic wheeze, %
39
36
46
, .001
69
, .001
mMRC dyspnea score ⱖ 2, %
53
46
Depression, CES-D score
11 (9)
11 (9)
13 (9)
, .001
Fatigue, FACIT-F score
35 (11)
36 (10)
33 (11)
, .001
SGRQ total score
48 (18)
45 (18)
55 (16)
, .001
Hx of reflux or heartburn, %
26
24
29
.017
Hx of cardiovascular disease (excluding HT), %
33
32
37
.028
Any exacerbation, 12 mo prior to baseline visit, %
47
40
64
, .001
Hospitalized exacerbation, 12 mo prior to baseline, %
15
9
30
, .001
Physiology Post-BD FEV1, L
1.35 (0.52)
1.44 (0.53)
1.14 (0.44)
, .001
48 (16)
51 (15)
42 (14)
, .001
6-min walk distance, m
370 (121)
383 (122)
341 (116)
, .001
BODE index
3.2 (2.1)
2.7 (2.0)
4.1 (2.1)
, .001
18 (12)
16 (12)
21 (13)
, .001
75
70
85
, .001
Post-BD FEV1 % predicted
Imaging Emphysema, % LAA, –950 HU Has emphysema, % . 5% by radiology Systemic inflammation WBC count, 109/L
7.9 (2.3)
7.7 (2.2)
8.3 (2.6)
, .001
Neutrophils, 109/L
5.2 (2.0)
5.0 (1.8)
5.6 (2.3)
, .001
CRP, median [IQR], mg/L
3.2 [1.6-7.1]
3.0 [1.4-6.4]
3.9 [1.8-8.9]
, .001
Fibrinogen, median [IQR], mg/dL
445 [387-512]
437 [381-504]
467 [402-532]
, .001
CCL-18, median [IQR], ng/mL
105 [82-136]
103 [80-131]
112 [86-144]
, .001
Data given as mean [SD] unless otherwise indicated. BD 5 bronchodilator; BODE 5 BMI, degree of airflow obstruction and dyspnea, and exercise capacity; CCL-18 5 chemokine ligand 18; CES-D 5 Center for Epidemiologic Studies of Depression scale (higher score means higher load of depressive symptoms); CRP 5 C-reactive protein; FACIT-F 5 Functional Assessment of Chronic Illness Therapy - Fatigue questionnaire (higher score means less fatigue); HT 5 heart transplant; HU 5 Hounsfield units; Hx 5 history; IQR 5 interquartile range; LAA 5 lower attenuation area; mMRC 5 modified Medical Research Council; SGRQ 5 St. George’s Respiratory Questionnaire. aData on the total cohort have been published elsewhere.10
natural disease history in a broad clinical population, as opposed to a selective series of patients who had already been admitted to a hospital, a predominant design in the published literature.11,25,27,28
Interpretation of Findings
We found that a previous hospitalized exacerbation in the past year was the strongest predictor of future exacerbations requiring hospitalization. This is similar to
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TABLE 3
] Baseline Risk Factors of Hospitalized
Exacerbation in Patients With COPD Without a History of Hospitalized Exacerbation 12 Mo Prior to the Study HR
HR (95% CI)
P Value
SGRQ total score, per 4-point increase
1.08
(1.05, 1.11)
, .001
FEV1 % predicted, per 5% drop
1.11
(1.07, 1.15)
, .001
Has emphysema, . 5% by radiology
1.71
(1.28, 2.26)
, .001
Oxygen use at baseline
1.75
(1.30, 2.35)
, .001
Parametera
History of asthma
1.45
(1.17, 1.79)
, .001
Age, per 10-y increment
1.24
(1.07, 1.44)
.005
Fibrinogen, per 1 log SD
1.15
(1.04, 1.28)
.008
See Table 1 and 2 legends for expansion of abbreviations. aModel was also adjusted for sex and smoking status at baseline (both nonsignificant). Ordered by strength of association.
Figure 3 – A, Kaplan-Meier plot showing risk of recurrent hospital admissions for COPD in patients with and without hospitalized exacerbations during the first 12 mo of follow-up. B, Kaplan-Meier plot showing risk of mortality in patients with COPD with and without hospitalized exacerbations during the first 12 mo of follow-up. Hosp 5 hospitalization.
previously reported findings in all moderate to severe exacerbations in the ECLIPSE cohort.10 Several potential mechanisms may explain this observation specifically for hospitalized exacerbation, including, among others, that lung function and health status can take several weeks to recover to baseline, or may not recover at all TABLE 2
] Baseline Risk Factors of Hospitalized Exacerbation During Follow-up HR
HR (95% CI)
P Value
COPD hospitalization, prior 12 mo
2.71
(2.24, 3.29)
, .001
SGRQ total score, per 4-point increase
1.08
(1.06, 1.10)
, .001
FEV1 % predicted, per 5% drop
1.12
(1.09, 1.16)
, .001
Age, per 10-y increment
1.29
(1.13, 1.46)
, .001
Has emphysema, . 5% by radiology
1.56
(1.23, 1.97)
, .001
WBC count, per 1 3 109/L
1.15
(1.07, 1.24)
, .001
Parametera
HR 5 hazard ratio. See Table 1 legend for expansion of other abbreviations. aModel was also adjusted for sex and smoking status at baseline (both nonsignificant). Ordered by strength of association.
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following an exacerbation29-32; inactivity associated with hospitalization may cause muscle mass loss and dysfunction33; comorbidities may develop or worsen due to treatment side effects (eg, systemic steroids inducing hyperglycemia and/or muscle weakness)34; patients may be exposed to nosocomial infections35; and hospitalization may cause and/or aggravate depression.36 The degree of airflow limitation has been shown to correlate with the frequency of both moderate and severe exacerbations10 and hospitalized exacerbations.37-39 In our cohort, we also observed that the rate of hospitalized exacerbations increased with increasing severity of airflow limitation (Fig 2). It is important to note, however, that even 19% of patients with moderate airflow limitation were hospitalized at least once during the follow-up. Given that these moderate patients are mostly seen in primary care,40 our results indicate that hospitalized exacerbations pose a huge health-care and economic burden across all spectrum of disease severity. Similar to the analysis by Gudmundsson et al,41 we also found that worse health status is associated with an increased risk of future hospitalized exacerbations.42 All in all, these and our observations support the importance of considering symptoms (ie, health status) in the assessment of patients with COPD, as recommended by the GOLD 2011 strategy document43 and supported by the comparative analysis of several published cohorts.44 Our data showed an association between an increased risk of hospitalized exacerbations and the extent of emphysema present on chest CT scans, either quantitatively (percentage ratio of low attenuation areas) or qualitatively
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(as determined by the radiologist). These findings add to recent observations of 1,002 patients, where the presence of emphysema was associated with an increased risk of moderate to severe exacerbations,45 and suggest that the evaluation of the degree of emphysematous changes in the clinic may identify a subgroup of patients at increased risk of hospitalized exacerbations. In a subgroup of patients without recent hospitalized exacerbation at baseline, fibrinogen was identified as an additional risk factor of future risk of hospital admissions for COPD exacerbations. Inflammatory pathways play a prominent role in exacerbations of COPD. Fibrinogen has been recognized to independently contribute to clinically important outcomes in COPD, including hospitalization for COPD.46,47 Our results indicate fibrinogen levels are predictive of the future hospitalized exacerbations in the absence of information on past history of these events. Plasma fibrinogen is under regulatory qualification as a risk factor for mortality and hospitalization in COPD.48 Some prior studies identified a higher exacerbation frequency in those patients with COPD with features of asthma (the overlap syndrome) as compared with those with COPD only.49-51 To our knowledge, ours is the first that identifies a self-reported history of asthma as an independent risk factor for hospitalized exacerbations in patients with spirometrically well-defined COPD. Finally, our results show in a population of patients recruited from the community, that a past history of hospitalized exacerbations is associated with significantly reduced survival, independent of the severity of airflow limitation (Figs 3A, 3B). This emphasizes the importance of recognizing patients at risk for hospitalized exacerbations. Strengths and Limitations
Our study has several strengths and limitations. The large sample size inclusive of patients independent of
their prior history of hospitalizations, its prospective nature, long 3-year follow-up with complete ascertainment of mortality, the availability of information on the year before study entry, and a comprehensive clinical, functional, imaging and biologic characterization of participants, are all clear strengths. On the other hand, we acknowledge that our results may not be immediately generalizable to the entire primary care population of patients with COPD because in our study, patients were recruited mainly from pulmonary clinics. As we did not collect events of pneumonia, we cannot make statement or ascertain a possible impact of mixed cases of unrecognized pneumonic exacerbations on the estimates of exacerbations occurrence and outcomes.52 Finally, the ECLIPSE study was conducted in multiple countries, which may have different policies for hospitalizations and may follow (slightly) different treatment strategies. To explore this possibility, we analyzed the subset of data collected from three countries contributing the majority of patients (United States, United Kingdom, and Norway) and did not find significant differences among these countries in incidence of hospitalized exacerbations (e-Table 2), suggesting that if anything, this effect is likely small. In conclusion, this 3-year prospective observational study of a large clinical population of patients with COPD shows that COPD exacerbations requiring hospital admission are common, often recurring, and that they contribute to a substantially reduced survival. Patients with COPD who are at high risk for hospitalized exacerbations are those with a prior history of hospitalized exacerbations, worse airflow limitation, and poor health status. Other risk factors to consider include, older age, extent of emphysema, prior history of asthma, and presence of systemic inflammation. These findings may have important implications for the management, monitoring, and prognosis of patients with COPD.
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Acknowledgments Author contributions: H. M. had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects, and served as principal author. H. M., D. J. M., and N. L. contributed to drafting the manuscript; H. M., D. J. M., N. L., J. V., J. R. H., J. A. W., A. Agusti, and A. Anzueto contributed to study conception and design; H. M. and N. L. contributed to data analysis; and H. M., D. J. M., N. L., J. V., J. R. H., J. A. W., P. B., A. Agusti, and A. Anzueto contributed to data interpretation, critical revision of the manuscript, and approved the final version. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs Müllerova and Locantore are employed by and hold stock in GlaxoSmithKline plc, the study sponsor. Dr Vestbo has received consultation fees from AstraZeneca plc, Bioxydyn Ltd, BoehringerIngelheim GmbH, Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, Novartis AG, Pfizer Inc, and Takeda Pharmaceutical Co Ltd. He has also received lecture fees (including service on speakers bureaus) from AstraZeneca plc, Boehringer-Ingelheim GmbH, Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, Novartis AG, and Takeda Pharmaceutical Co Ltd; and research support from GlaxoSmithKline plc. His institution has received research from GlaxoSmithKline plc. He has also received an unconditional grant in 1985 from a charity foundation fully funded by Scandinavian Tobacco Company. Dr Vestbo’s spouse has worked in the pharmaceutical industry, including GlaxoSmithKline plc. Dr Hurst has had support from GlaxoSmithKline plc to attend ECLIPSE meetings and has received payments for lectures and reports personal fees from AstraZeneca plc, Bayer AG, BoehringerIngelheim GmbH, Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, and Pfizer Inc. Dr Wedzicha has received honoraria for lectures and/or for serving on advisory boards from Almirall SA, Bayer AG, BoehringerIngelheim GmbH, Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, Novartis AG, Takeda Pharmaceutical Co Ltd, Pfizer Inc, and Vectura Group plc, and has obtained research grant funding for her department from Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, Novartis AG, Takeda Pharmaceutical Co Ltd, and Johnson and Johnson. Dr Bakke has received lecture fees from AstraZeneca plc, GlaxoSmithKline plc, and Nycomed International Management GmbH, and has participated in clinical research studies sponsored by Boehringer-Ingelheim GmbH, GlaxoSmithKline plc, and Pfizer Inc. Dr Agusti has received consulting fees, fees for participating in review activities, and support for travel from GlaxoSmithKline plc for this work, is a board member for Almirall SA, AstraZeneca plc, Boheringer-Ingelheim GmbH, Esteve, GlaxoSmithKline plc, Novartis AG, Nycomed International Management GmbH, and Roche (F. Hoffmann-La Roche AG), and has received payments for lectures and/or
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speaking from Almirall SA, AstraZeneca plc, Boheringer-Ingelheim GmbH, Esteve, GlaxoSmithKline plc, and Nycomed International Management GmbH; and his institution has received grants from Almirall SA, GlaxoSmithKline plc, and Nycomed International Management GmbH. Dr Anzueto is a consultant and speaker for AstraZeneca plc, Bayer AG, Boehringer-Ingleheim GmbH, Forest Laboratories Inc, and GlaxoSmithKline plc. Dr Maselli has reported that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Role of sponsors: The study sponsor did not place any restrictions with regard to statements made in the final paper. The color figure and supplemental material processing charges were paid for by GlaxoSmithKline plc. Collaborators: Principal investigators and centers participating in ECLIPSE (NCT00292552, SC0104960): Yavor Ivanov, MD; Kosta Kostov, MD; Jean Bourbeau, MD; Mark Fitzgerald, MD; Paul Hernández, MD; Kieran Killian, MD; Robert Levy, MD; Francois Maltais, MD; Denis O´Donnell, MD; Jan Krepelka, MD; Jørgen Vestbo, MD; Emiel F. M. Wouters, MD; Dean Quinn, MD; Per Bakke, MD, PhD; Mitja Kosnik, MD, PhD; Alvar Agusti, MD, PhD; Yuri Feschenko, MD; Volodymyr Gavrisyuk, MD; Lyudmila Yashina, MD; William MacNee, MBChB, MD; S. David Singh, MD; Jadwiga Wedzicha, MD; Antonio Anzueto, MD; Sidney Braman, MD; Richard Casaburi, PhD, MD; Bart Celli, MD; Glenn Giessel, MD; Mark Gotfried, MD; Gary Greenwald, MD; Nicola Hanania, MD; Don Mahler, MD; Barry Make, MD; Stephen Rennard, MD; Carolyn Rochester, MD; Paul Scanlon, MD; Dan Schuller, MD; Frank Sciurba, MD; Amir Sharafkhaneh, MD; Thomas Siler, MD; Edwin Silverman, MD, PhD; Adam Wanner, MD; Robert Wise, MD; Richard Zu Wallack, MD. Steering Committee: Per Bakke, MD, PhD; Harvey Coxson, PhD; Lisa Edwards, PhD; David Lomas, MD, PhD; William MacNee, MBChB, MD; Edwin Silverman, MD, PhD; Ruth Tal-Singer, PhD (co-chair); Jørgen Vestbo, MD (co-chair); Julie Yates, PhD. Scientific Committee: Alvar Agusti, MD, PhD; Peter Calverley, MD; Bartolome Celli, MD; Courtney Crim, MD; Bruce Miller, PhD; William MacNee, MBChB, MD (chair); Stephen Rennard, MD; Ruth Tal-Singer, PhD; Emiel Wouters, MD. Other contributions: The authors thank participants for their willingness to contribute to medical research.
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Additional information: The e-Figures and e-Tables can be found in the Supplemental Materials section of the online article.
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27. Almagro P, Cabrera FJ, Diez J, et al; Working Group on COPD, Spanish Society of Internal Medicine. Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study. Chest. 2012;142(5): 1126-1133. 28. Lash TL, Johansen MB, Christensen S, et al. Hospitalization rates and survival associated with COPD: a nationwide Danish cohort study. Lung. 2011;189(1): 27-35. 29. Seemungal TA, Donaldson GC, Bhowmik 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(5):1608-1613. 30. Spencer S, Jones PW; GLOBE Study Group. Time course of recovery of health status following an infective exacerbation of chronic bronchitis. Thorax. 2003; 58(7):589-593. 31. Wedzicha JA, Donaldson GC. Exacerbations of chronic obstructive pulmonary disease. Respir Care. 2003;48(12):1204-1213. 32. Makris D, Moschandreas J, Damianaki A, et al. Exacerbations and lung function decline in COPD: new insights in current and ex-smokers. Respir Med. 2007;101(6): 1305-1312. 33. Vermeeren MA, Wouters EF, GeraertsKeeris AJ, Schols AM. Nutritional support in patients with chronic obstructive pulmonary disease during hospitalization for an acute exacerbation; a randomized controlled feasibility trial. Clin Nutr. 2004;23(5):1184-1192. 34. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative study group. N Engl J Med. 1999;340(25):1941-1947. 35. Girou E, Brun-Buisson C, Taillé S, Lemaire F, Brochard L. Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA. 2003;290(22):2985-2991. 36. Papaioannou AI, Bartziokas K, Tsikrika S, et al. The impact of depressive symptoms on recovery and outcome of hospitalised COPD exacerbations. Eur Respir J. 2013;41(4):815-823. 37. Tsoumakidou M, Tzanakis N, Voulgaraki O, et al. Is there any correlation between the ATS, BTS, ERS and GOLD COPD’s severity scales and the frequency of hospital admissions? Respir Med. 2004;98(2):178-183. 38. Lusuardi M, Lucioni C, De Benedetto F, Mazzi S, Sanguinetti CM, Donner CF. GOLD severity stratification and risk of hospitalisation for COPD exacerbations. Monaldi Arch Chest Dis. 2008;69(4): 164-169. 39. Garcia-Aymerich J, Serra Pons I, Mannino DM, Maas AK, Miller DP,
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Hospitalized Exacerbations of COPD Risk Factors and Outcomes in the ECLIPSE Cohort Hana Müllerova, PhD; Diego J. Maselli, MD; Nicholas Locantore, PhD; Jørgen Vestbo, MD; John R. Hurst, MD, PhD; Jadwiga A. Wedzicha, MD; Per Bakke, MD, PhD; Alvar Agusti, MD, PhD; and Antonio Anzueto, MD; for the ECLIPSE Investigators
OBJECTIVE: Exacerbations of COPD requiring hospital admission have important clinical and societal implications. We sought to investigate the incidence, recurrence, risk factors, and mortality of patients with COPD exacerbations requiring hospital admission compared with those without hospital admission during 3-year follow-up. Patients with COPD (N 5 2,138) were identified from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) observational cohort.
An analysis of time to first event of hospital admission was performed using KaplanMeier curves and Cox proportional hazard regression adjusting for possible confounders.
METHODS:
RESULTS: Of the 2,138 patients, 670 (31%) reported a total of 1,452 COPD exacerbations requiring hospital admission during the study period; 313 patients (15%) reported multiple events. A prior history of exacerbation of COPD requiring hospital admission was the factor associated with the highest risk of a new hospitalization for exacerbation (hazard ratio, 2.71; 95% CI, 2.24-3.29; P , .001). Other risk factors included more severe airflow limitation, poorer health status, older age, radiologic evidence of emphysema, and higher WBC count. Having been hospitalized for exacerbation significantly increased the risk of mortality (P , .001).
Exacerbations of COPD requiring hospital admission occur across all stages of airflow limitation and are a significant prognostic factor of reduced survival across all COPD stages. Patients with COPD at a high risk for hospitalization can be identified by their past history for similar events, and other factors, including the severity of airflow limitation, poor health status, age, presence of emphysema, and leukocytosis.
CONCLUSIONS:
TRIAL REGISTRY:
ClinicalTrials.gov; No.: NCT00292552; URL: www.clinicaltrials.gov CHEST 2015; 147(4):999-1007
Manuscript received April 17, 2014; revision accepted September 17, 2014; originally published Online First October 30, 2014. ABBREVIATIONS: BODE 5 BMI, degree of airflow obstruction and dyspnea, and exercise capacity; ECLIPSE 5 Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; GOLD 5 Global Initiative for Chronic Lung Disease; HR 5 hazard ratio; PPPY 5 per person per year AFFILIATIONS: From Respiratory Epidemiology (Dr Müllerova), GlaxoSmithKline R&D, Uxbridge, England; Audie L. Murphy Hospital (Drs Maselli and Anzueto), South Texas Veterans Health Care System, San Antonio, TX; Division of Pulmonary Diseases/Critical Care Medicine (Drs Maselli and Anzueto), University of Texas Health Science Center at San Antonio, San Antonio, TX; Respiratory Medicines Development Center (Dr Locantore), GlaxoSmithKline, Research Triangle Park, NC; Gentofte (Dr Vestbo), Hellerup, Denmark; Respiratory Research Group (Dr Vestbo), Manchester Academic Health Science Centre, University of Manchester, Manchester, England; Centre of Inflammation and Tissue Repair (Dr Hurst), University College London, London, England; Centre for Respiratory Medicine (Dr Wedzicha), University College London,
London, England; Department of Clinical Science (Dr Bakke), University of Bergen, Bergen, Norway; Department of Thoracic Medicine (Dr Bakke), Haukeland University Hospital, Bergen, Norway; Thorax Institute (Dr Agusti), Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain; and FISIB, CIBER Enfermedades Respiratorias (Dr Agusti), Mallorca, Spain. Dr Wedzicha is currently at the National Heart and Lung Institute, Imperial College London (London, England). FUNDING/SUPPORT: The ECLIPSE study was funded by GlaxoSmithKline. CORRESPONDENCE TO: Antonio Anzueto, MD, Division of Pulmonary/ Critical Care Medicine, University of Texas Health Science Center at San Antonio, 7400 Merton Minter, MC111E, San Antonio, TX 78229; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0655
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COPD is a prevalent disease associated with significant morbidity, resulting in high health-care cost1 and mortality, currently being the third leading cause of death.2-4 Patients with COPD often suffer episodes of exacerbation during the course of their disease, some of which require hospitalization. Exacerbations of COPD accelerate disease progression5-7 and are the main contributor to the substantial economic cost of COPD, particularly if they require hospitalization.8 Identifying risk factors associated with the occurrence and recurrence of these episodes has, therefore, important clinical and societal implications. Previous results from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, a multicenter, prospective study,9
Materials and Methods Study Design and Ethics The design of the ECLIPSE study (SCO104960, NCT00292552) has been published elsewhere.9 In brief, patients between 40 and 75 years old were included if they had a history of ⱖ 10 pack-years of smoking, as well as an FEV1 , 80% of predicted value and a ratio of FEV1 to FVC ⱕ 0.7; both were measured after bronchodilator use. COPD severity for each subject was graded according to GOLD (Global Initiative for Chronic Obstructive Lung Disease).3 The study was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines, and was approved by the relevant ethics and review boards at the participating centers. All subjects provided written informed consent. Baseline Measurements The methodology used in the ECLIPSE study has been described in detail elsewhere.9 Briefly, standardized questionnaires were used to measure dyspnea (modified Medical Research Council dyspnea scale),13 health status (St. George’s Respiratory Questionnaire for patients with COPD),14 fatigue (Functional Assessment of Chronic Illness TherapyFatigue Questionnaire)15 and depression (Center for Epidemiologic Studies of Depression Scale).16 Likewise, information on symptoms of cough, sputum production, wheezing, and chronic bronchitis17; selfreported comorbidities, including cardiovascular disease, diabetes mellitus, and gastroesophageal reflux disease; and use of medications and home oxygen was collected. Exacerbation history during the 12 months that preceded the study baseline visit based on subject’s recall of exacerbations treated with antibiotics, corticosteroids or both requiring hospital admission was also ascertained. Standardized spirometry (before and after bronchodilator administration) and the 6-minute walk distance test using a standardized protocol18 were also measured. The BMI, degree of airflow obstruction and dyspnea, and exercise capacity (BODE) index was calculated according to the original publication.19 A low-dose volumetric CT scan at full inspiration was obtained in all patients. Emphysema was visually scored by two experienced chest radiologists, who independently scored all CT scans as follows: 0 5 no emphysema, 1 5 , 5% (trivial), 2 5 5% to 25% (mild), 3 5 26% to 50% (moderate), 4 5 51% to 75% (severe), and 5 5 ⱖ75% involvement of both lungs (very severe). Further, the extent of emphysema was estimated using the threshold technique quantifying the percent of voxels with an apparent x-ray attenuation value (%lower attenuation area) below 2950 Hounsfeld units. Finally, peripheral venous blood was collected, processed, and concentrations of inflammatory biomarkers (WBC counts, C-reactive protein, fibrinogen, and chemokine ligand 18) were
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identified several risk factors for moderate to severe exacerbations.10 However, the incidence and factors specifically associated with exacerbations requiring hospital admission have not been extensively described in large, prospective, longitudinal cohorts of patients with COPD with a wide range of disease clinical severity.11,12 Therefore, we sought to investigate the incidence, recurrence, risk factors, and mortality of patients with COPD with exacerbations requiring hospital admission, as compared with those without hospital admission, in the ECLIPSE cohort. This information may help clinicians identify patients with COPD in need of targeted strategies to reduce their risk of hospitalized exacerbations, such as self-management plans or improved access to health-care settings other than a hospital.
measured.20,21 Samples were collected using ethylenediaminetetraacetic acid tubes and, hence, for fibrinogen, 407 mg/dL was equivalent to 350 mg/dL, as measured with collection in sodium citrate bloodcollection tubes. Follow-up and Exacerbation Ascertainment Subjects were followed-up at 3 months, 6 months, and every 6 months thereafter for a maximum of 3 years. All patients had their vital status confirmed 3 years after recruitment. Information on COPD exacerbations was collected at scheduled visits by investigators using the case report forms and based on either subjects’ recall of exacerbation events or available medical records for exacerbation events, supplemented by monthly phone calls. For the purpose of the current analysis, we focused on those exacerbation episodes that required hospital admission (hospitalized exacerbation). Statistical Analysis To investigate the prespecified goals of the study, we used the following analyses: (1) baseline differences between patients with and without hospitalized exacerbation during follow-up were tested using analysis of variance or Wilcoxon rank-sum test for continuous variables, and x2 test for categorical variables; (2) the incidence (first hospitalized exacerbation during the prospective follow-up) and recurrence (second hospitalized exacerbation during the prospective follow-up) of hospitalized exacerbations was summarized as a rate per person per year (PPPY), using a sum of individual patient’s person-time in the study and standardized per year, accompanied by 95% CIs; (3) factors associated with first hospitalized (and recurrent) exacerbations during the 3-year follow-up, were explored using Cox proportional hazards models, adjusted for a wide range of demographics, and clinical and biologic markers. To investigate what factors were associated with the occurrence of hospitalized exacerbations for the first time during follow-up, we repeated the analysis after excluding the subjects reporting any hospitalized exacerbation in the 12 months prior to study baseline; and finally, (4) differences in survival and time to first hospitalized exacerbation in relation to hospitalized exacerbation occurrence prior to study entry were tested using log-rank test with results displayed as KaplanMeier curves. This analysis was repeated again considering the subject’s exacerbation status during the first year of the prospective follow-up. We did not test any prespecified hypothesis and, hence, did not conduct a sample-size estimation. As the analyses were of exploratory nature only, P values were evaluated at a nominal significance level of .05 without adjustment for multiplicity.
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Results Figure 1 presents the flow diagram of the study. In total, 2,138 patients with COPD with complete exacerbation data during follow-up were included in the analysis. Overall, the patient population baseline characteristics were similar to those of the entire ECLIPSE COPD population (N 5 2,164).22 Incidence/Recurrence of Hospitalized Exacerbations
In this cohort of 2,138 patients, during 3 years of follow-up, there were 555 patients (26%) who did not have an exacerbation, 913 (43%) who had at least one moderate but not hospitalized exacerbation, and 670 (31%) who had at least one hospitalized COPD exacerbation. Of 1,538 patients who had at least one moderate to severe exacerbation, 42% had a hospitalized exacerbation (Fig 2). In total, 1,452 hospitalized exacerbation events were observed. Table 1 shows the baseline characteristics of patients who had at least one hospitalized exacerbation during follow-up vs those who were not hospitalized. Patients with at least one hospitalized exacerbation were more
symptomatic (cough, phlegm, dyspnea, wheeze), had poorer health status, and also reported having had more frequently both moderate and severe COPD exacerbations in the 12 months prior to study entry. Airflow limitation, exercise capacity, dyspnea, and the BODE index were significantly worse, and levels of circulating inflammatory biomarkers were higher in these patients. The hospitalized exacerbation rate PPPY during follow-up was 0.26 (95% CI, 0.23-0.28). The COPD hospitalization rate increased with older age and with worsening severity of airflow limitation (from moderate airflow limitation [grade 2]: 0.12 PPPY [95% CI, 0.10-0.15], to very severe airflow limitation [grade 4]: 0.54 PPPY [95% CI, 0.44-0.63]) (e-Table 1). Of the 670 patients who suffered at least one hospitalized exacerbation during follow-up, 313 patients (47%) had more than one episode. Having been hospitalized for COPD exacerbation during the first 12 months of follow-up (n 5 289) resulted in a significantly increased risk (P , .001) of repeated hospital admissions during the remaining 2-year follow-up (Fig 3A). This trend was observed for all grades of airflow limitation.
Figure 1 – Study flow diagram. ECLIPSE 5 Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints.
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Figure 2 – Frequency distribution of hospitalized exacerbations during the follow-up, split by severity of airflow limitation assessed by GOLD grade.3 GOLD 5 Global Initiative for Chronic Obstructive Lung Disease.
Risk Factors for Hospitalized Exacerbations
The strongest risk factor for future hospitalized exacerbation during prospective follow-up was a history of hospitalized exacerbations in the 12 months prior to study entry (hazard ratio [HR]: 2.71; 95% CI, 2.24-3.29; P , .001). Other significant risk factors included poorer health status, severe airflow limitation, older age, a higher degree of emphysema, and an increased WBC count (Table 2). To investigate what factors were associated with the occurrence of hospitalized exacerbations for the first time during follow-up, we repeated the analysis after excluding the 325 patients with COPD who reported any hospitalized exacerbation in the 12 months prior to study entry. We identified a self-reported history of asthma, use of home oxygen, and elevated fibrinogen levels as additional significant risk factors (Table 3). Finally, the analysis of factors associated with recurrent hospitalized exacerbations any time during the prospective follow-up identified the severity of airflow limitation (HR: 1.11; 95% CI, 1.06-1.16) and poorer health status (HR: 1.05; 95% CI, 1.02-1.09) as the only significant risk factors. Mortality Associated With Hospitalized Exacerbations
During the total follow-up, 202 patients (9.4%) died. As shown in Figure 3B, we observed that mortality during follow-up was significantly higher in patients with 1002 Original Research
COPD who reported one or more hospitalized exacerbation during the first 12 months of follow-up (15%), as compared with those without such an event (5%) (logrank test P , .001). This effect was also observed when considering the full follow-up of 3 years, and was independent of the severity of airflow limitation (e-Figs 1, 2). Significant decrease in survival was observed in GOLD grades 2 or 3 of airflow limitation (P , .004 and P , .001, respectively), but not in grade 4 (P 5 .186).
Discussion The main findings of this study are (1) COPD exacerbations requiring hospital admission are relatively frequent events occurring in about 30% of patients during the 3-year follow-up; (2) past history of hospitalized exacerbations is most predictive of future events, and other risk factors include the severity of airflow limitation, poor health status, radiologic evidence of emphysema, older age, and presence of systemic inflammation; and (3) a history of hospitalized exacerbations heralds poor survival. Previous Studies
Our study complements and extends previous reports because of its larger size, prospective nature, and comprehensiveness of investigations, allowing the study of a breadth of relevant risk factors in one population.11,23-26 Importantly, the ECLIPSE population was recruited during clinical stability and, therefore, the prospective follow-up allows addressing questions of incidence and
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TABLE 1
] Baseline Characteristics of All Patients With COPD Included in the Analysis, Further Split by Occurrence or Absence of at Least One Hospitalized Exacerbation During the 3-Y Follow-up
Baseline Characteristics
Total COPD Cohorta (N 5 2,138)
Hospitalized Exacerbations During Prospective Follow-up 0 (n 5 1,468)
ⱖ 1 (n 5 670)
P Value (0 vs ⱖ 1)
Anthropometric data Age, y
63 (7)
Female patient, % BMI, kg/m
2
35 27 (6)
63 (7)
64 (7)
35 27 (6)
35 26 (6)
.001 .857 .006
Clinical data Current smoker, %
36
37
34
.199
Chronic cough, %
49
47
54
.002
Chronic phlegm, %
51
49
54
.032
Chronic wheeze, %
39
36
46
, .001
69
, .001
mMRC dyspnea score ⱖ 2, %
53
46
Depression, CES-D score
11 (9)
11 (9)
13 (9)
, .001
Fatigue, FACIT-F score
35 (11)
36 (10)
33 (11)
, .001
SGRQ total score
48 (18)
45 (18)
55 (16)
, .001
Hx of reflux or heartburn, %
26
24
29
.017
Hx of cardiovascular disease (excluding HT), %
33
32
37
.028
Any exacerbation, 12 mo prior to baseline visit, %
47
40
64
, .001
Hospitalized exacerbation, 12 mo prior to baseline, %
15
9
30
, .001
Physiology Post-BD FEV1, L
1.35 (0.52)
1.44 (0.53)
1.14 (0.44)
, .001
48 (16)
51 (15)
42 (14)
, .001
6-min walk distance, m
370 (121)
383 (122)
341 (116)
, .001
BODE index
3.2 (2.1)
2.7 (2.0)
4.1 (2.1)
, .001
18 (12)
16 (12)
21 (13)
, .001
75
70
85
, .001
Post-BD FEV1 % predicted
Imaging Emphysema, % LAA, –950 HU Has emphysema, % . 5% by radiology Systemic inflammation WBC count, 109/L
7.9 (2.3)
7.7 (2.2)
8.3 (2.6)
, .001
Neutrophils, 109/L
5.2 (2.0)
5.0 (1.8)
5.6 (2.3)
, .001
CRP, median [IQR], mg/L
3.2 [1.6-7.1]
3.0 [1.4-6.4]
3.9 [1.8-8.9]
, .001
Fibrinogen, median [IQR], mg/dL
445 [387-512]
437 [381-504]
467 [402-532]
, .001
CCL-18, median [IQR], ng/mL
105 [82-136]
103 [80-131]
112 [86-144]
, .001
Data given as mean [SD] unless otherwise indicated. BD 5 bronchodilator; BODE 5 BMI, degree of airflow obstruction and dyspnea, and exercise capacity; CCL-18 5 chemokine ligand 18; CES-D 5 Center for Epidemiologic Studies of Depression scale (higher score means higher load of depressive symptoms); CRP 5 C-reactive protein; FACIT-F 5 Functional Assessment of Chronic Illness Therapy - Fatigue questionnaire (higher score means less fatigue); HT 5 heart transplant; HU 5 Hounsfield units; Hx 5 history; IQR 5 interquartile range; LAA 5 lower attenuation area; mMRC 5 modified Medical Research Council; SGRQ 5 St. George’s Respiratory Questionnaire. aData on the total cohort have been published elsewhere.10
natural disease history in a broad clinical population, as opposed to a selective series of patients who had already been admitted to a hospital, a predominant design in the published literature.11,25,27,28
Interpretation of Findings
We found that a previous hospitalized exacerbation in the past year was the strongest predictor of future exacerbations requiring hospitalization. This is similar to
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TABLE 3
] Baseline Risk Factors of Hospitalized
Exacerbation in Patients With COPD Without a History of Hospitalized Exacerbation 12 Mo Prior to the Study HR
HR (95% CI)
P Value
SGRQ total score, per 4-point increase
1.08
(1.05, 1.11)
, .001
FEV1 % predicted, per 5% drop
1.11
(1.07, 1.15)
, .001
Has emphysema, . 5% by radiology
1.71
(1.28, 2.26)
, .001
Oxygen use at baseline
1.75
(1.30, 2.35)
, .001
Parametera
History of asthma
1.45
(1.17, 1.79)
, .001
Age, per 10-y increment
1.24
(1.07, 1.44)
.005
Fibrinogen, per 1 log SD
1.15
(1.04, 1.28)
.008
See Table 1 and 2 legends for expansion of abbreviations. aModel was also adjusted for sex and smoking status at baseline (both nonsignificant). Ordered by strength of association.
Figure 3 – A, Kaplan-Meier plot showing risk of recurrent hospital admissions for COPD in patients with and without hospitalized exacerbations during the first 12 mo of follow-up. B, Kaplan-Meier plot showing risk of mortality in patients with COPD with and without hospitalized exacerbations during the first 12 mo of follow-up. Hosp 5 hospitalization.
previously reported findings in all moderate to severe exacerbations in the ECLIPSE cohort.10 Several potential mechanisms may explain this observation specifically for hospitalized exacerbation, including, among others, that lung function and health status can take several weeks to recover to baseline, or may not recover at all TABLE 2
] Baseline Risk Factors of Hospitalized Exacerbation During Follow-up HR
HR (95% CI)
P Value
COPD hospitalization, prior 12 mo
2.71
(2.24, 3.29)
, .001
SGRQ total score, per 4-point increase
1.08
(1.06, 1.10)
, .001
FEV1 % predicted, per 5% drop
1.12
(1.09, 1.16)
, .001
Age, per 10-y increment
1.29
(1.13, 1.46)
, .001
Has emphysema, . 5% by radiology
1.56
(1.23, 1.97)
, .001
WBC count, per 1 3 109/L
1.15
(1.07, 1.24)
, .001
Parametera
HR 5 hazard ratio. See Table 1 legend for expansion of other abbreviations. aModel was also adjusted for sex and smoking status at baseline (both nonsignificant). Ordered by strength of association.
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following an exacerbation29-32; inactivity associated with hospitalization may cause muscle mass loss and dysfunction33; comorbidities may develop or worsen due to treatment side effects (eg, systemic steroids inducing hyperglycemia and/or muscle weakness)34; patients may be exposed to nosocomial infections35; and hospitalization may cause and/or aggravate depression.36 The degree of airflow limitation has been shown to correlate with the frequency of both moderate and severe exacerbations10 and hospitalized exacerbations.37-39 In our cohort, we also observed that the rate of hospitalized exacerbations increased with increasing severity of airflow limitation (Fig 2). It is important to note, however, that even 19% of patients with moderate airflow limitation were hospitalized at least once during the follow-up. Given that these moderate patients are mostly seen in primary care,40 our results indicate that hospitalized exacerbations pose a huge health-care and economic burden across all spectrum of disease severity. Similar to the analysis by Gudmundsson et al,41 we also found that worse health status is associated with an increased risk of future hospitalized exacerbations.42 All in all, these and our observations support the importance of considering symptoms (ie, health status) in the assessment of patients with COPD, as recommended by the GOLD 2011 strategy document43 and supported by the comparative analysis of several published cohorts.44 Our data showed an association between an increased risk of hospitalized exacerbations and the extent of emphysema present on chest CT scans, either quantitatively (percentage ratio of low attenuation areas) or qualitatively
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(as determined by the radiologist). These findings add to recent observations of 1,002 patients, where the presence of emphysema was associated with an increased risk of moderate to severe exacerbations,45 and suggest that the evaluation of the degree of emphysematous changes in the clinic may identify a subgroup of patients at increased risk of hospitalized exacerbations. In a subgroup of patients without recent hospitalized exacerbation at baseline, fibrinogen was identified as an additional risk factor of future risk of hospital admissions for COPD exacerbations. Inflammatory pathways play a prominent role in exacerbations of COPD. Fibrinogen has been recognized to independently contribute to clinically important outcomes in COPD, including hospitalization for COPD.46,47 Our results indicate fibrinogen levels are predictive of the future hospitalized exacerbations in the absence of information on past history of these events. Plasma fibrinogen is under regulatory qualification as a risk factor for mortality and hospitalization in COPD.48 Some prior studies identified a higher exacerbation frequency in those patients with COPD with features of asthma (the overlap syndrome) as compared with those with COPD only.49-51 To our knowledge, ours is the first that identifies a self-reported history of asthma as an independent risk factor for hospitalized exacerbations in patients with spirometrically well-defined COPD. Finally, our results show in a population of patients recruited from the community, that a past history of hospitalized exacerbations is associated with significantly reduced survival, independent of the severity of airflow limitation (Figs 3A, 3B). This emphasizes the importance of recognizing patients at risk for hospitalized exacerbations. Strengths and Limitations
Our study has several strengths and limitations. The large sample size inclusive of patients independent of
their prior history of hospitalizations, its prospective nature, long 3-year follow-up with complete ascertainment of mortality, the availability of information on the year before study entry, and a comprehensive clinical, functional, imaging and biologic characterization of participants, are all clear strengths. On the other hand, we acknowledge that our results may not be immediately generalizable to the entire primary care population of patients with COPD because in our study, patients were recruited mainly from pulmonary clinics. As we did not collect events of pneumonia, we cannot make statement or ascertain a possible impact of mixed cases of unrecognized pneumonic exacerbations on the estimates of exacerbations occurrence and outcomes.52 Finally, the ECLIPSE study was conducted in multiple countries, which may have different policies for hospitalizations and may follow (slightly) different treatment strategies. To explore this possibility, we analyzed the subset of data collected from three countries contributing the majority of patients (United States, United Kingdom, and Norway) and did not find significant differences among these countries in incidence of hospitalized exacerbations (e-Table 2), suggesting that if anything, this effect is likely small. In conclusion, this 3-year prospective observational study of a large clinical population of patients with COPD shows that COPD exacerbations requiring hospital admission are common, often recurring, and that they contribute to a substantially reduced survival. Patients with COPD who are at high risk for hospitalized exacerbations are those with a prior history of hospitalized exacerbations, worse airflow limitation, and poor health status. Other risk factors to consider include, older age, extent of emphysema, prior history of asthma, and presence of systemic inflammation. These findings may have important implications for the management, monitoring, and prognosis of patients with COPD.
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Acknowledgments Author contributions: H. M. had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects, and served as principal author. H. M., D. J. M., and N. L. contributed to drafting the manuscript; H. M., D. J. M., N. L., J. V., J. R. H., J. A. W., A. Agusti, and A. Anzueto contributed to study conception and design; H. M. and N. L. contributed to data analysis; and H. M., D. J. M., N. L., J. V., J. R. H., J. A. W., P. B., A. Agusti, and A. Anzueto contributed to data interpretation, critical revision of the manuscript, and approved the final version. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs Müllerova and Locantore are employed by and hold stock in GlaxoSmithKline plc, the study sponsor. Dr Vestbo has received consultation fees from AstraZeneca plc, Bioxydyn Ltd, BoehringerIngelheim GmbH, Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, Novartis AG, Pfizer Inc, and Takeda Pharmaceutical Co Ltd. He has also received lecture fees (including service on speakers bureaus) from AstraZeneca plc, Boehringer-Ingelheim GmbH, Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, Novartis AG, and Takeda Pharmaceutical Co Ltd; and research support from GlaxoSmithKline plc. His institution has received research from GlaxoSmithKline plc. He has also received an unconditional grant in 1985 from a charity foundation fully funded by Scandinavian Tobacco Company. Dr Vestbo’s spouse has worked in the pharmaceutical industry, including GlaxoSmithKline plc. Dr Hurst has had support from GlaxoSmithKline plc to attend ECLIPSE meetings and has received payments for lectures and reports personal fees from AstraZeneca plc, Bayer AG, BoehringerIngelheim GmbH, Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, and Pfizer Inc. Dr Wedzicha has received honoraria for lectures and/or for serving on advisory boards from Almirall SA, Bayer AG, BoehringerIngelheim GmbH, Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, Novartis AG, Takeda Pharmaceutical Co Ltd, Pfizer Inc, and Vectura Group plc, and has obtained research grant funding for her department from Chiesi Pharmaceuticals Inc, GlaxoSmithKline plc, Novartis AG, Takeda Pharmaceutical Co Ltd, and Johnson and Johnson. Dr Bakke has received lecture fees from AstraZeneca plc, GlaxoSmithKline plc, and Nycomed International Management GmbH, and has participated in clinical research studies sponsored by Boehringer-Ingelheim GmbH, GlaxoSmithKline plc, and Pfizer Inc. Dr Agusti has received consulting fees, fees for participating in review activities, and support for travel from GlaxoSmithKline plc for this work, is a board member for Almirall SA, AstraZeneca plc, Boheringer-Ingelheim GmbH, Esteve, GlaxoSmithKline plc, Novartis AG, Nycomed International Management GmbH, and Roche (F. Hoffmann-La Roche AG), and has received payments for lectures and/or
1006 Original Research
speaking from Almirall SA, AstraZeneca plc, Boheringer-Ingelheim GmbH, Esteve, GlaxoSmithKline plc, and Nycomed International Management GmbH; and his institution has received grants from Almirall SA, GlaxoSmithKline plc, and Nycomed International Management GmbH. Dr Anzueto is a consultant and speaker for AstraZeneca plc, Bayer AG, Boehringer-Ingleheim GmbH, Forest Laboratories Inc, and GlaxoSmithKline plc. Dr Maselli has reported that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Role of sponsors: The study sponsor did not place any restrictions with regard to statements made in the final paper. The color figure and supplemental material processing charges were paid for by GlaxoSmithKline plc. Collaborators: Principal investigators and centers participating in ECLIPSE (NCT00292552, SC0104960): Yavor Ivanov, MD; Kosta Kostov, MD; Jean Bourbeau, MD; Mark Fitzgerald, MD; Paul Hernández, MD; Kieran Killian, MD; Robert Levy, MD; Francois Maltais, MD; Denis O´Donnell, MD; Jan Krepelka, MD; Jørgen Vestbo, MD; Emiel F. M. Wouters, MD; Dean Quinn, MD; Per Bakke, MD, PhD; Mitja Kosnik, MD, PhD; Alvar Agusti, MD, PhD; Yuri Feschenko, MD; Volodymyr Gavrisyuk, MD; Lyudmila Yashina, MD; William MacNee, MBChB, MD; S. David Singh, MD; Jadwiga Wedzicha, MD; Antonio Anzueto, MD; Sidney Braman, MD; Richard Casaburi, PhD, MD; Bart Celli, MD; Glenn Giessel, MD; Mark Gotfried, MD; Gary Greenwald, MD; Nicola Hanania, MD; Don Mahler, MD; Barry Make, MD; Stephen Rennard, MD; Carolyn Rochester, MD; Paul Scanlon, MD; Dan Schuller, MD; Frank Sciurba, MD; Amir Sharafkhaneh, MD; Thomas Siler, MD; Edwin Silverman, MD, PhD; Adam Wanner, MD; Robert Wise, MD; Richard Zu Wallack, MD. Steering Committee: Per Bakke, MD, PhD; Harvey Coxson, PhD; Lisa Edwards, PhD; David Lomas, MD, PhD; William MacNee, MBChB, MD; Edwin Silverman, MD, PhD; Ruth Tal-Singer, PhD (co-chair); Jørgen Vestbo, MD (co-chair); Julie Yates, PhD. Scientific Committee: Alvar Agusti, MD, PhD; Peter Calverley, MD; Bartolome Celli, MD; Courtney Crim, MD; Bruce Miller, PhD; William MacNee, MBChB, MD (chair); Stephen Rennard, MD; Ruth Tal-Singer, PhD; Emiel Wouters, MD. Other contributions: The authors thank participants for their willingness to contribute to medical research.
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Additional information: The e-Figures and e-Tables can be found in the Supplemental Materials section of the online article.
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