Prognostic Value of Bronchiectasis in Patients with ... - ATS Journals

Prognostic Value of Bronchiectasis in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease ˜ a4, Miguel-Angel Martıńez-Garcıá1,2, David de la Rosa Carrillo3, Juan-Jose Soler-Catalun 4 4 5 Yolanda Donat-Sanz , Pablo Catalań Serra , Marco Agramunt Lerma , Javier Ballestıń5, Irene Valero Sańchez1, Maria Jose Selma Ferrer1, Anna Roma Dalfo6, and Montserrat Bertomeu Valdecillos6 1

Pneumology Service, Polytechnic and University La Fe Hospital, Valencia, Spain; 2CIBERes, CIBER de Enfermedades Respiratorias, Bunyola, Spain; Pneumology Unit, Platoń Hospital, Barcelona, Spain; 4Internal Medicine Service and 5Radiology Service, Hospital General de Requena, Valencia, Spain; and 6Radiology Department, Platoń Hospital, Barcelona, Spain 3

Rationale: The prevalence of bronchiectasis is high in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and it has been associated with exacerbations and bacterial colonization. These have demonstrated some degree of prognostic value in patients with COPD but no information about the relationship between bronchiectasis and mortality in patients with COPD is currently available. Objectives: To assess the prognostic value of bronchiectasis in patients with moderate-to-severe COPD. Methods: Multicenter prospective observational study in consecutive patients with moderate-to-severe COPD. Bronchiectasis was diagnosed by high-resolution computed tomography scan. A complete standardized protocol was used in all patients covering general, anthrophometric, functional, clinical, and microbiologic data. After follow-up, the vital status was recorded in all patients. Multivariate Cox analysis was used to determine the independent adjusted prognostic value of bronchiectasis. Measurements and Main Results: Ninety-nine patients in Global Initiative for Chronic Obstructive Lung Disease (GOLD) II, 85 in GOLD III, and 17 in GOLD IV stages were included. Bronchiectasis was present in 115 (57.2%) patients. During the follow-up (median, 48 mo [interquartile range, 35–53]) there were 51 deaths (43 deaths in the bronchiectasic group). Bronchiectasis was associated with an increased risk of fully adjusted mortality (hazard ratio, 2.54; 95% confidence interval, 1.16–5.56; P ¼ 0.02). Conclusions: Bronchiectasis was associated with an independent increased risk of all-cause mortality in patients with moderate-tosevere COPD. Keywords: chronic obstructive pulmonary disease; bronchiectasis; chronic colonization; mortality; prognostic factor

(Received in original form August 22, 2012; accepted in final form January 24, 2013) Supported by a grant from Praxis Pharmaceutical. Author Contributions: M.-A.M.-G. and D.d.l.R.C. designed the study, contributed to data acquisition and interpretation, supervised the study, and wrote the manuscript. J.-J.S.-C. designed the study, contributed to data acquisition and interpretation, and approved the final version to be published. Y.D.-S. and P.C.S. contributed to data acquisition and interpretation, critically revised the manuscript, and approved the final version to be published. M.A.L., J.B., A.R.D., and M.B.V. independently interpreted chest high-resolution computed tomography scans and approved the final version of the manuscript to be published. I.V.S. and M.J.S.F. performed statistical analyses and contributed to data interpretation, critically revised the manuscript, and approved the final version to be published. Correspondence and requests for reprints should be addressed to Miguel-Angel Martıńez-Garcıá, M.D., Pneumology Service, University and Polytechnic La Fe Hospital, Bulevar Sur s/n, 46340 Valencia, Spain. E-mail: [email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 187, Iss. 8, pp 823–831, Apr 15, 2013 Copyright ª 2013 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201208-1518OC on February 7, 2013 Internet address: www.atsjournals.org

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject

The prevalence of bronchiectasis is high in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and has been associated with exacerbations and bacterial colonization. These factors have shown a certain prognostic value in these patients, although there is no information about the relationship between bronchiectasis and mortality in patients with COPD. What This Study Adds to the Field

The results of this study confirm a high prevalence of bronchiectasis in patients with moderate-to-severe COPD and suggest that bronchiectasis is independently associated with an increased risk of all-cause mortality in these patients.

After vascular diseases and cancer, chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the developed world. In contrast with the two leading diseases, the mortality of COPD continues to rise and will presumably continue to do so in the coming decades (1). Several new prognostic markers of COPD have been discovered beyond the decline in lung function (2). One of the most important of these new markers is the BODE index (3), which integrates the evaluation of dyspnea, exercise capacity, pulmonary function, and body mass index. Other factors that have also demonstrated prognostic value in patients with COPD include smoking habit (4); nutritional status (5); quality of life (6); the presence of comorbidities (7); the number and severity of exacerbations (8); other pathophysiologic factors, such as hypoxemia (9) and hypercapnia (10); air trapping (11); pulmonary hypertension (12); and some biologic parameters, such as the concentration of C-reactive protein (CRP) (13) and oxidative stress (14). Bronchiectasis is defined as a permanent and progressive dilation of the airways as a result of a vicious circle involving the inflammation, infection, and repair of the bronchial mucosa, which leads to lesions in the mucociliary system and subsequent destruction of the bronchial wall (15, 16). Some authors have observed a high prevalence of bronchiectasis in patients with moderate-to-severe COPD (17–19), associated with increased bronchial inflammation, longer and more intense exacerbations, more frequent colonization of the bronchial mucosa by potentially pathogenic microorganisms (PPM), and a higher degree of functional impairment (17). Taken overall, it is reasonable to hypothesize that the presence of bronchiectasis could be a new prognostic factor in patients with COPD. Confirmation of this hypothesis would permit the formulation of a new phenotype of

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patient with COPD with bronchiectasis, according to the definition recently published by Han and coworkers (20). It would also have a major clinical impact, because bronchiectasis can be reliably diagnosed by means of high-resolution (HR) algorithms of computed tomography (CT) scan (21) and effective therapy is available, primarily based on the treatment of the chronic bronchial inflammation and infection found in these patients (22, 23). Therefore, the objective of this study is to ascertain whether the presence of bronchiectasis is a prognostic marker in patients with moderate-to-severe COPD.

METHODS Study Subjects This was a multicenter prospective observational study of a consecutive cohort of patients diagnosed with moderate-to-severe COPD between January 2004 and February 2007 in two specialist COPD outpatient clinics in Spain. Patients whose deteriorated medical condition prevented them from undergoing a chest HRCT scan and patients with uninterpretable HRCT scan images were excluded. Those patients diagnosed with bronchiectasis before being diagnosed with COPD were also excluded. Previous bronchiectasis was diagnosed by HRCT images showing bronchiectasis from the patient’s clinical history before the start of the study, or by the presence within the clinical history of a radiologic report of an HRCT that would certify the presence of bronchiectasis. All the tests were performed in a stable phase, after no signs of any exacerbation for at least 6 weeks. All the patients signed an informedconsent agreement to participate in the study, which was approved by the Ethics Committee of both hospitals.

Diagnosis of COPD and Bronchiectasis COPD was defined, following the criteria published by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (24), as a postbronchodilator ratio of FEV1 to FVC of less than 70% in a patient with a smoking habit of more than 10 pack-years. COPD was defined as moderate if the post-bronchodilator FEV1 was between 80% and 50% (GOLD II); severe if it was between 49.9% and 30% (GOLD III); and very severe if it was less than 30% (GOLD IV). Special care was taken to identify and exclude from the study any patients with a possible diagnosis of bronchiectasis before COPD and those with any other diseases of the airways, especially asthma and other respiratory conditions. All the patients were diagnosed as having bronchiectasis after a chest HRCT scan. HRCT scans were obtained in both centers with a 16-slice multidetector CT scanner (Bright Speed 16, General Electric, Fairfield, CT) during fully suspended inspiration in the supine position from the lung apex to the diaphragm, using a thin-section technique (1-mm collimation at 10-mm intervals) with the following parameters: 150 kVp tube voltage, 250 mA, and 1-second scanning time. A high spatial frequency algorithm was used for image reconstruction. The images were obtained without any injection of contrast material and viewed at a window level of 2450 HU and a window width of 1,500 HU. Emphysema extension was quantified in the HRCT in a semiquantitative fashion. The radiologic absence of emphysema was scored as 0 points; the presence of centriacinar emphysema in two or less pulmonary lobes as 1 point; the presence of centriacinar emphysema in three to four pulmonary lobes as 2 points, and the presence of centriacinar emphysema in more than four pulmonary lobes or of bullous or panacinar emphysema as 3 points. Small cylindrical bronchiectasis visible in only a single pulmonary segment was not considered, because this can appear in a significant percentage of the healthy population, as previously reported (25). Radiologists in each participating center, all of them with at least 10 years of experience in diagnosing bronchiectasis, independently interpreted the HRCT scans, masked to the patients’ basal characteristics. Any differences in the readings were resolved by consensus. The HRCT scan was interpreted for the presence, severity, radiologic pattern, and distribution of bronchiectasis; associated disease processes, such as emphysema and small airway disease; and other factors. The presence of bronchiectasis was based on the criteria published by Naidich and coworkers (21): (1) lack of tapering of bronchi, (2) dilation

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of bronchi when the internal diameter was larger than that of the adjacent pulmonary artery, or (3) visualization of the peripheral bronchi within 1 cm of the costal pleural surface or adjacent mediastinal pleural surface. The extent and type of bronchiectasis was evaluated according to the number and location of the pulmonary lobes and segments affected (with the lingula considered as an independent lobe), and the presence of cystic bronchiectasis or central bronchiectasis. The severity of bronchiectasis was evaluated using the Bhalla score in its original version (see Appendix 1 in the online supplement). This index presents an upward range of 0–25 points of increased severity, taking into account the overall extension, morphology, size, and findings in the HRCT associated with the presence of bronchiectasis (26). Appendix 2 and Figure E1 of the online supplement include details of the quantitative HRCT measurements and their interpretation. The HRCT measurements were the diameter of the pulmonary artery, the bronchial lumen and the bronchial wall thickness, bronchoarterial ratio, thickness-to-diameter ratio, and the percentage of wall area in patients with bronchiectasis; and the diameter of the bronchus and the bronchial lumen of the posterior segment of the lower right lobe in all the patients (with or without bronchiectasis).

Interview Questionnaire, Lung Function, and Blood Samples A standardized protocol was used in all patients at a medical visit on admission into the study. It included information about general and anthopometric data (age, sex, and body mass index); smoking habit (pack-years); systemic and respiratory clinical history; clinical profile (onset of symptoms, presence and frequency of chronic expectoration, and Medical Research Council [MRC] scale for dyspnea) (27); and basal treatments (including chronic antibiotic and macrolide treatments). Comorbidity was quantified according to the Charlson Index (28) and a previous diagnosis of anxiety or depressive syndrome. Data were collected from arterial blood samples (PO2 and PCO2) and forced spirometry, in absolute and percentage values over theoretical values 15 minutes after bronchodilator treatment with 200 mg of inhaled salbutamol, following the guidelines established by the Spanish Society of Pneumology (29). Furthermore, peripheral levels of a1-antitrypsin, ultrasensitive CRP, and albumin were obtained as markers of systemic inflammation and nutritional status, respectively. All the necessary complementary tests were performed to clarify the cause of bronchiectasis in accordance with the Spanish Guidelines (22).

Exacerbation Variables All patients were instructed to visit their primary care physician, ambulatory urgent care, or hospital emergency room (depending on the severity of their condition) when symptoms of acute exacerbations appeared, and to record detailed information on their condition and prescribed medication (courses of oral steroids and antibiotics). This information was provided by the patients themselves in follow-up outpatient visits and later confirmed with the hospital’s clinical records and computerized medical records shared with primary care in the year before the study HRCT. Because this is a study primarily involving patients with COPD, COPD exacerbation was defined as an increase in at least two out of three clinical symptoms (increase in dyspnea, sputum quantity, and sputum purulence); or the need to seek urgent care or be hospitalized; or the prescription of antibiotic or steroid courses as a consequence of an increase in respiratory symptoms associated with COPD. Severe exacerbation was defined as the need for hospital management (hospital emergency room visits or hospitalizations). All the data concerning exacerbation rates refer to the year after the patient’s inclusion in the study.

Sputum Samples A monthly microbiologic analysis of spontaneous morning sputum was requested from each patient in the 6 months subsequent to inclusion in the study (six sputum samples per patient), following the procedure published by our group elsewhere (30). Briefly, patients were taught the correct procedure for collecting monthly sputum samples at home, using the most sterile technique possible, and they were asked to deposit these samples in the hospital laboratory, always within a maximum of 3 hours

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TABLE 1. BASELINE AND CLINICAL CHARACTERISTICS OF SUBJECTS WITH COPD, WITH AND WITHOUT BRONCHIECTASIS Parameter

Whole Group

COPD with Bronchiectasis

COPD without Bronchiectasis

P

Subjects, n Sex, n, M/F Age, yr Pack-years smoked Body mass index, kg/m2 Time since onset of symptoms, yr Daily sputum production, n (%) Charlson Index Depression, n (%) Anxiety, n (%) Daily treatments, n (%) Anticholinergic Long-acting b-adrenergic Combined treatment Triple therapy Home oxygen therapy Inhaled antibiotics Macrolides Dyspnea MRC Previous tuberculosis, n (%) Previous pneumonia, n (%) PO2/PCO2, mm Hg FEV1/FVC, % predicted Post-bronchodilator FEV1, ml % Predicted Post-bronchodilator FVC, ml % Predicted Exacerbations* Total ER visits ER ambulatory visits ER hospital visits Hospital admissions Severe exacerbations All-cause mortality, n (%) Mortality, causes, n (%)† Exacerbation Cardiovascular Cancer Others Acute antibiotic treatments Acute oral steroid treatments Tree-in-bud pattern, n (%) Bronchial diameter‡ Wall thickness‡ Emphysema, n (%) None Centriacinar in two or less pulmonary lobes Centriacinar in three or four pulmonary lobes Centriacinar in more than four pulmonary lobes, or bullous or panacinar

201 182/19 70.3 (8.9) 60.7 (30) 27.3 (4.9) 16 (15.2) 128 (63.4%) 2.3 (1.46) 36 (17.9%) 46 (22.8%)

115 107/8 71.4 (8.5) 62.1 (31.9) 26.4 (4.8) 13.2 (12.5) 84 (73%) 2.32 (1.5) 23 (20%) 30 (26.1%)

86 75/11 68.8 (9.3) 58.8 (25.9) 28.4 (4.9) 8.9 (11.6) 44 (51.1%) 2.27 (1.43) 13 (15.1%) 16 (18.6%)

— ns 0.04 ns 0.005 0.016 0.003 ns ns ns

161 (80%) 109 (54.2%) 144 (71.6%) 118 (58.7%) 50 (24.9%) 4 (2%) 4 (2%) 1.6 (0.98) 21 (10.4%) 55 (27.4%) 63.2/43.1 52.6 (12.7) 1,348 (479) 49 (12.9) 2,596 (760) 71.1 (18.3)

90 (78.2%) 71 (61.7%) 84 (73%) 70 (60.9%) 40 (34.8%) 3 (2.6%) 3 (2.6%) 1.76 (1) 15 (13%) 36 (31.3%) 63.2/43.7 50.5 (12.9) 1,249 (463) 45.4 (12.8) 2,478 (698) 68.6 (17.8)

71 (82.6%) 38 (44.1%) 60 (69.8%) 48 (55.8%) 10 (11.6%) 1 (1.2%) 1 (1.2%) 1.41 (0.9) 6 (7%) 19 (22.1%) 66.8/42.8 55.2 (11.8) 1,480 (470) 53.8 (11.5) 2,751 (814) 74.3 (18.5)

ns 0.01 ns ns 0.001 ns ns 0.013 ns ns 0.04/ns 0.008 0.001 0.001 0.03 0.01

1.56 0.79 0.75 0.4 0.86 51

(2.1) (1.2) (1.6) (0.8) (1.5) (25.4%)

1.88 0.94 0.97 0.51 1.12 43

(2.13) (1.43) (1.32) (0.9) (1.7) (37.4%)

1 0.60 0.44 0.26 0.51 8

(1.48) (0.93) (0.82) (0.49) (0.99) (9.3%)

0.002 0.05 0.001 0.01 0.002 0.001

32 11 5 3 1.5 0.8 49 6.6 1.8

(62.7%) (21.6%) (9.8%) (5.9%) (1.6) (1.3) (24.4%) (1.3) (0.68)

28 9 4 2 1.9 1.05 32 6.5 2.1

(65.1%) (20.9%) (9.3%) (4.7%) (1.8) (1.5) (27.8%) (1.26) (0.78)

4 2 1 1 0.97 0.4 17 6.7 1.5

(50%) (25%) (12.5%) (12.5%) (1.1) (0.87) (19.8%) (1.44) (0.32)

ns 0.001 0.001 0.04 ns 0.001

45 51 53 52

(22.6%) (25.4%) (26.2%) (25.8%)

21 26 36 32

(18.3%) (22.6%) (31.3%) (27.8%)

24 25 17 20

(27.9%) (29.1%) (19.7%) (23.3%)

ns

Definition of abbreviations: COPD ¼ chronic obstructive pulmonary disease; ER ¼ emergency room; MRC ¼ Medical Research Council. All data are quoted as means (SD), except when noted otherwise. * Data referring to the year after the patient’s inclusion in the study. y Percentage with respect to the total number of deaths in each group. z Bronchus of the posterior segment of the lower right lobe.

after collection. Sputum samples were accepted if they contained less than 25 squamous epithelial cells per low-powered field, and more than 25 leukocytes per high-powered field. The samples were separated from saliva, Gram stained, and homogenized. Diluted secretions were plated on blood, chocolate, McConkey, and Saboreaud agar. Sputum cultures were expressed as CFU per milliliter. For the purposes of this study, a cut-off point of 103 or more was defined as significant for the identification of abnormal positive culture results for PPM, following published methods (31–33). Isolated bacterial agents were classified into PPM strains, such as Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus parainfluenzae, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and other gram-negative rods. The presence of a single PPM in at least three different monthly sputum samples, without any concurrent antibiotic treatment, was considered chronic colonization (34). The bacterial colonization tests were

performed by technical staff masked to the clinical characteristics of the subjects in the study.

Follow-up Assessment After the initial assessment, including HRCT, all the patients were followed up every 3–6 months, depending on the severity of their clinical condition, to monitor their adherence to the treatment, review their general status, and maintain a protocolized record. The follow-up finished on July 31, 2010. A patient was considered lost to follow-up only if his or her vital status could not be established at the end of the study period. In all cases, the follow-up was censored at the date of the last visit or death. The endpoint of this study was all-cause mortality. Vital status at the end of the follow-up was thoroughly investigated on many fronts, including a review of hospital and out-patient medical records, computerized databases,

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TABLE 2. ANALYTICAL AND MICROBIOLOGIC CHARACTERISTICS OF SUBJECTS WITH COPD, WITH AND WITHOUT BRONCHIECTASIS Parameter

Whole Group COPD with Bronchiectasis COPD without Bronchiectasis

Subjects, n 201 Albumin, mg/dl 4.14 (0.5) US-CRP, IU/ml 7.1 (6.9) 160 (30) a1-Antitrypsin, ng/dl Patients with PPM isolates, n, % (at 85 (42.3%) least one isolate)* Patients with chronic colonization by 42 (20.9%) PPM, n (%) Pseudomonas aeruginosa isolates, n (%) 19 (9.5%) Haemophilus influenzae isolates, n (%) 37 (18.4%)

115 4.1 (0.58) 8.36 (8.3) 165 (30.4) 68 (59.1%)

4.24 5.33 155 17

86 (0.34) (4.04) (29.6) (20%)

P — 0.04 0.018 ns 0.001

37 (32.2%)

5 (5.8%)

0.001

15 (13%) 26 (22.6%)

4 (4.7%) 11 (12.8%)

0.01 0.04

Definition of abbreviations: COPD ¼ chronic obstructive pulmonary disease; PPM ¼ potentially pathologic microorganisms; US-CRP ¼ ultrasensitive C-reactive protein. All data are quoted as means (SD), except when noted otherwise. * Not including patients with chronic colonization.

and when necessary telephone contact with the patient or his or her relatives or primary care physician. When a patient died, information about the cause and date of death was obtained from hospital medical records if he or she died in the hospital, or from official death certificates in the remaining cases.

Statistical Analysis The statistical package SPSS version 19.0 (SPSS, Chicago, IL) was used for the statistical analysis. All the data were tabulated as mean and standard deviation in the case of quantitative variables and as absolute numbers and percentages in the case of qualitative variables. The Kolmogorov-Smirnov test was used to analyze the distribution of variables. In the bivariate analysis, variables were analyzed using the Student t test for independent variables, in cases of normal distribution, or the Mann-Whitney U test in other cases. Qualitative variables were compared with the chi-square test. Kappa value was calculated for assessment of interobserver agreement for qualitative radiologic variables (presence of bronchiectasis) and the intraclass correlation coefficient for quantitative variables (Bhalla Index and measurements of the bronchial lumen, bronchial wall, and arterial diameter). Spearman or Pearson coefficients were used for calculating the correlation between variables, according to their distribution. Those variables that presented statistically significant differences (P , 0.05) in the bivariate analysis and those considered by the researchers to be of clinical interest were included as independent variables in a Cox proportional hazard regression survival model. In the case of elevated collinearity between two variables (Spearman or Pearson correlation coefficient . 0.6), the variable with greater clinical significance was chosen, based on the judgment of the authors. The dependent variable in the model was all-cause mortality. Subsequently, the following initial variables were selected: age, post-bronchodilator FEV1% value, MRC dyspnea, PO2, body mass index, presence of bronchiectasis, presence of PPM in sputum, presence of daily sputum production, number of severe exacerbations, Charlson Index, and peripheral albumin and ultrasensitive CRP concentration. The forward stepwise technique (Wald test) was used and variables with a P greater than 0.1 were removed from the final model. This left only age, Charlson Index, post-bronchodilator FEV1% value, and presence of bronchiectasis in the fully adjusted model. Similarly, the dichotomic variable “presence of bronchiectasis” was substituted by the quantitative variable “Bhalla score,” which provides more complete information about the presence, extension, and severity of bronchiectasis maintaining the same set of adjustment variables in a new Cox survival analysis. In this case, the model left only age, MRC dyspnea, and Bhalla score in the fully adjusted model. Hazard ratios (HR) and 95% confidence intervals (95% CI) for the independent variables were also calculated. Survival curves for the groups with and without bronchiectasis were constructed according to the Kaplan-Meier method and then compared with the log-rank test.

RESULTS A total of 227 patients with moderate-to-severe COPD (GOLD II–IV) were analyzed. Sixteen were excluded from the study

because of previous diagnoses of bronchiectasis, eight were unable to undergo HRCT, and two had uninterpretable HRCT results. Of the 201 patients remaining in the study (mean age, 70.3 [8.9] yrs; 90.5% male) 99 patients (49.2%) were in GOLD II stage; 85 (42.3%) were in GOLD III stage; and 17 (8.5%) were in GOLD IV stage. Radiologic signs of emphysema were observed in 77.4% of the patients. A total of 115 patients (57.2%) presented bronchiectasis. The mean bronchoarterial index was 1.7 (0.59), with a mean Bhalla score of 8.2 (4.1; range, 2–17). Twenty-one patients presented a history of tuberculosis (10.4%) and 55 patients presented a history of at least one pneumonia (27.4%); of the latter, 36 presented bronchiectasis. Pneumonia occurred subsequent to the diagnosis of bronchiectasis in 45 of these 55 patients. No other disease capable of generating bronchiectasis was found in our patients (e.g., deficit of a1-antitrypsin, allergic bronchopulmonary aspergillosis, significant immunodeficiencies, systemic diseases, infection by nontuberculous micobacteria, or high-risk professions [51% were retired farm workers]). An average of three valid sputum samples was collected from each patient during the first 6 months of the study (range, 0–6 samples). In the group as a whole, the PPM most frequently isolated was H. influenzae (single isolation in 37 patients, with chronic colonization in 17 of them). S. pneumoniae was isolated in 16 patients, in six cases as chronic colonization. M. catarrhalis was isolated in 14 patients, in three cases as chronic colonization. Finally, P. aeruginosa was isolated in 19 patients (15 with bronchiectasis), in 11 cases as chronic colonization. No patient was found to have chronic colonization by fungi or atypical mycobacteria. Appendix 3 of the online supplement shows the baseline characteristics of the bronchiectasis found in the patients included in the study. Agreement between the two radiologists was excellent for the both detection of bronchiectasis by HRCT scan (kappa index, 0.87) and the Bhalla score (intraclass correlation coefficient, 0.83). Tables 1 and 2 show that patients with bronchiectasis presented a more severe form of COPD in clinical and functional terms, and a greater number and greater severity of exacerbations, higher parameters of systemic inflammation, and a greater number of isolations and chronic colonization by PPM in the bronchial mucosa. Similarly, patients with bronchiectasis presented a thicker bronchial wall, measured in the (nonbronchiectasic) bronchus of the posterior segment of the lower right lobe (2.1 [0.78] vs. 1.5 [0.32]; P ¼ 0.001). This measurement of the bronchial wall thickness was also associated with the presence of chronic expectoration (r ¼ 0.28; P ¼ 0.002) and more isolations of PPM (r ¼ 0.28; P ¼ 0.001). No significant differences were observed, however, between the extension of emphysema and the presence of bronchiectasis (Table 1); the degree of chronic

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TABLE 3. BASELINE AND CLINICAL CHARACTERISTICS OF SUBJECTS WITH COPD ACCORDING TO THEIR VITAL STATUS AT THE END OF THE STUDY Parameter

Whole Group

Death COPD

Survive COPD

P

Subjects, n Sex, n, M/F Age, yr Pack-years smoked Body mass index Time since onset of symptoms, yr Daily sputum production, n (%) Charlson Index Depression, n (%) Anxiety, n (%) Bronchiectasis n (%) Pulmonary segments affected Daily treatments n (%) Anticholinergic Long-acting b-adrenergic Combined treatment Triple therapy Home oxygen therapy Inhaled antibiotics Macrolides Dyspnea MRC Previous tuberculosis, n (%) Previous pneumonia, n (%) PO2/PCO2, mm Hg FEV1/FVC, % predicted Post-bronchodilator FEV1, mL % Predicted Post-bronchodilator FVC, mL % Predicted Exacerbations* Total ER visits ER ambulatory visits ER hospital visits Hospital admissions Severe exacerbations Acute antibiotic treatments Acute oral steroid treatments Tree-in-bud pattern, n (%) Emphysema, n (%) None Centriacinar in two or less pulmonary lobes Centriacinar in three or four pulmonary lobes Centriacinar in more than four pulmonary lobes, or bullous or panacinar

201 182/19 70.3 (8.9) 60.7 (30) 27.3 (4.9) 16 (15.2) 128 (63.4%) 2.3 (1.46) 36 (17.9%) 46 (22.9%) 105 (52.2%) 3.5 (3.9)

51 50/6 75.9 (6.4) 66.1 (39.7) 26.9 (5.1) 18.3 (17.1) 44 (86.2%) 2.8 (1.7) 12 (23.5%) 14 (27.5%) 43 (84.3%) 5.9 (4.6)

150 132/12 68.4 (8.9) 58.9 (24.9) 27.4 (4.9) 15.3 (13.8) 84 (56%) 2.1 (1.31) 24 (16%) 32 (21.3%) 72 (48%) 2.6 (1.31)

— ns 0.0001 ns ns ns 0.0001 0.002 ns ns 0.002 0.001

161 (80%) 109 (54.2%) 144 (71.6%) 118 (58.7%) 50 (24.9%) 4 (2%) 4 (2%) 1.6 (0.98) 21 (10.4%) 55 (27.4%) 63.2/43.1 52.6 (12.7) 1,348 (479) 49 (12.9) 2,596 (760) 71.1 (18.3)

37 (72.5%) 27 (52.9%) 37 (72.5%) 27 (52.9%) 22 (43.1%) 3 (5.9%) 3 (5.9%) 2.3 (1.1) 8 (15.7%) 19 (37.3%) 60.8/44.5 46.9 (13.6) 1,135 (485) 44.2 (13.4) 2,495 (660) 71.5 (16.6)

124 (82.6%) 82 (54.7%) 107 (71.3%) 91 (60.7%) 28 (18.7%) 1 (0.7%) 1 (0.7%) 1.4 (0.8) 13 (8.7%) 36 (24%) 66.4/42.8 54.4 (11.8) 1,422 (456) 50.7 (12.3) 2,630 (791) 70.6 (18.8)

ns ns ns ns 0.001 ns ns 0.0001 ns ns 0.003/ns 0.001 0.0001 0.0001 ns ns

1.56 0.79 0.75 0.4 0.86 1.5 0.8 49

(2.1) (1.2) (1.6) (0.8) (1.5) (1.6) (1.3) (24.4%)

2.1 1.04 1.1 0.51 1.27 2.3 1.6 14

(2.2) (1.7) (1.4) (0.8) (1.6) (2.1) (1.6) (27.4%)

1.27 0.7 0.6 0.37 0.72 1.2 0.5 35

45 51 53 52

(22.6%) (25.4%) (26.2%) (25.8%)

7 11 16 17

(13.7%) (21.6%) (31.4%) (33.3%)

36 42 36 36

(1.8) (1.1) (1.1) (0.8) (1.4) (1.3) (0.9) (23.3%) (24%) (28%) (24%) (24%)

0.01 0.10 0.01 ns 0.02 0.0001 0.0001 ns

ns

Definition of abbreviations: COPD ¼ chronic obstructive pulmonary disease; ER ¼ emergency room; MRC ¼ Medical Research Council. All data are quoted as means (SD), except when noted otherwise. * Data referring to the year after the patients inclusion in the study.

expectoration (r ¼ 0.02; P ¼ 0.71); or the presence of PPM in the bronchial mucosa (r ¼ 0.10; P ¼ 0.14).

PPM, greater chronic PPM colonization, and lower peripheral albumin concentration.

Univariate Analysis

Multivariate Survival Analysis

The median follow-up (interquartile range) was 48 months (35– 53) including patients with censored data. Fifty-one patients died (25.4%) during the follow-up. Thirty-two deaths (62.7%) had respiratory causes; 11 patients (21.6%) died from cardiovascular disease; five (9.8%) from malignant disease; and three (5.9%) from other causes. No patient was lost during the follow-up. Tables 3 and 4 show the differential characteristics of the group of patients who survived the follow-up (n ¼ 150) and of those who died (n ¼ 51). The patients with COPD who died were older and presented more symptoms, particularly more chronic expectoration and dyspnea, more comorbidities, higher exacerbation indices, higher prevalence of bronchiectasis, more severe airflow obstruction and hypoxemia, more positive cultures of

Figure 1 shows the Kaplan-Meier survival curves for patients with moderate-severe COPD with (n ¼ 115; 43 deaths) and without (n ¼ 86; 8 deaths) bronchiectasis. There was a statistical difference between the curves (log-rank test, 15.7; P ¼ 0.001). Table 5 shows the unadjusted and fully adjusted Cox regression analysis. The risk of death in patients with COPD with bronchiectasis (n ¼ 115) was higher than in those without bronchiectasis (n ¼ 86) (unadjusted HR, 4.07 [1.9–8.7]; P ¼ 0.0001). After adjustment for confounding variables (see STATISTICAL ANALYSIS; fully adjusted model), the risk did not significantly change (adjusted HR, 2.54 [1.16–5.56]; P ¼ 0.02). Age, Charlson Index, and post-bronchodilator FEV1 (%) also showed an independent adverse prognostic value in the unadjusted and fully

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TABLE 4. ANALYTICAL AND MICROBIOLOGIC CHARACTERISTICS OF SUBJECTS WITH COPD ACCORDING TO THEIR VITAL STATUS AT THE END OF THE STUDY Parameter

Whole Group

Death COPD

Survive COPD

P

Subjects, n Albumin, mg/dl US-CRP, IU/ml a1-Antitrypsin, ng/dl Patients with PPM isolates, n,% (at least one isolate)* Patients with chronic colonization by PPM, n (%) Pseudomonas aeruginosa isolates, n (%) Haemophilus influenzae isolates, n (%)

201 4.14 (0.5) 7.1 (6.9) 160 (30) 85 (42.3%) 42 (20.9%) 19 (9.5%) 37 (18.4%)

51 (0.6) (9.7) (26) (70.6%) (33.3%) (21.6%) (27.6%)

150 4.2 (0.4) 5.5 (5.1) 154 (20) 49 (32.7%) 25 (16.6%) 8 (5.3%) 23 (15.3%)

— 0.001 0.001 0.001 0.001 0.001 0.01 ns

3.9 10.6 175 36 17 11 14

Definition of abbreviations: COPD ¼ chronic obstructive pulmonary disease; PPM ¼ potentially pathologic microorganisms; US-CRP ¼ ultrasensitive C-reactive protein. All data are quoted as means (SD), except when noted otherwise. * Not including patients with chronic colonization.

adjusted models. Using the Bhalla score as a quantitative variable instead of the presence of bronchiectasis as a dichotomic variable shows that this index is also independently associated with higher mortality from COPD (adjusted HR, 1.15 [1.05–1.26]; P ¼ 0.002), along with age and the degree of dyspnea (Table 6). Using a sensitivity analysis, the inclusion of other covariables did not improve the prognostic capacity of the fully adjusted model in either the model using “presence of bronchiectasis” as a dichotomic variable or the model using the quantitative variable “Bhalla score.” Appendix 4 in the online supplement shows additional information about the prognostic value of the BODE index (which could be measured in 131 patients) and the BODEx index (measured in all patients), and the correlations between these indices and other interesting variables, such as severe exacerbations.

DISCUSSION Our results suggest that the presence of bronchiectasis and its severity are associated with an increase in all-cause mortality in patients with moderate-severe COPD, independently of other known factors, such as pulmonary function or other comorbidities.

Some studies have reported a high prevalence of bronchiectasis (between 29 and 52%) in patients with moderate-to-severe COPD, which varies according to the population analyzed (17– 19). Although no longitudinal study has yet demonstrated a causal link between the two diseases, it is biologically plausible to suggest that COPD may be a risk factor for bronchiectasis in patients with airway colonization by PPM, a condition found in up to 40% of patients with COPD, especially in the severe stages (35). This situation, and the subsequent increase in bronchial inflammation, provides the basis for the development of bronchiectasis in accordance with Cole’s pathogenic vicious circle (36). This finding is supported by studies that have found that patients with both COPD and bronchiectasis have increased bronchial inflammation; longer, more severe, and more frequent exacerbations; more PPM in the bronchial mucosa; and worse lung function (17, 30). Because some of these variables have been associated with increased mortality in patients with COPD (37), the presence of bronchiectasis could also have a prognostic value in patients with COPD. These patients would be subject to different diagnostic and therapeutic approaches and would therefore define a new phenotype of patients with COPD and bronchiectasis (20) or belong to a preexisting COPD

Figure 1. Kaplan-Meier survival curves for the groups, with and without bronchiectasis. COPD ¼ chronic obstructive pulmonary disease.

˜ a, et al.: Prognostic Value of Bronchiectasis in Patients with COPD Martıńez-Garcıá, de la Rosa Carrillo, Soler-Catalun TABLE 5. VARIABLES ASSOCIATED WITH DEATH IN MODERATETO-SEVERE COPD, USING THE PRESENCE OF BRONCHIECTASIS AS A DICHOTOMIC VARIABLE Unadjusted Variables Age FEV1 ppb % Charlson Index Bronchiectasis

HR (95% CI) 1.13 0.97 1.31 4.07

(1.08–1.18) (0.95–0.99) (1.11–1.56) (1.91–8.67)

Fully Adjusted P 0.0001 0.002 0.002 0.0001

HR (95% CI) 1.10 0.97 1.22 2.54

(1.05–1.15) (0.95–0.99) (1.02–1.46) (1.16–5.56)

P 0.0001 0.023 0.033 0.02

Definition of abbreviations: CI ¼ confidence interval; COPD ¼ chronic obstructive pulmonary disease; HR ¼ hazard ratio. Unadjusted and fully adjusted Cox multivariate regression analysis. Adjusted by dyspnea (Medical Research Council), PO2, body mass index, presence of potentially pathogenic microorganisms in sputum, presence of daily sputum production, number of severe exacerbations, and peripheral albumin and ultrasensitive C-reactive protein concentrations.

phenotype, although this hypothesis needs to be corroborated by specifically designed studies. Our results confirm that the prevalence of bronchiectasis in patients with COPD is high, particularly in its cylindrical, basal, and bilateral forms. To our knowledge, this is the first study in the literature to establish an independent association between the presence and severity of bronchiectasis and an increased risk of death in patients with COPD. Our research group has been working with patients with moderate-to-severe COPD for many years, and we have achieved a well-characterized, long-term cohort of these patients. These variables include the systematic performance of an HRCT scan, which allows us to study the presence of bronchiectasis and its characteristics in our patients. As can be seen from the univariate analysis, several variables previously considered as having prognostic value in patients with COPD (3–14) appear in our results as differentiators between those patients who died in the followup and those who survived. Furthermore, patients with bronchiectasis presented a more severe form of COPD, in clinical and functional terms, and a greater concentration of parameters of systemic inflammation and a greater presence of PPM in the airways. Although exacerbations, especially severe ones, have proved to be an independent prognostic factor in patients with COPD (8), they did not maintain any significant predictive value for mortality in our multivariate adjusted survival analysis. This phenomenon could have several explanations. It is possible that the number of patients included in the study is insufficient for the statistical power required to capture the predictive power of exacerbations. Another explanation, more plausible in our view, could be the intensive preventive therapy applied to our cohort for exacerbations in the last few years. This has resulted in a very high percentage of patients with double and triple inhaled therapy, probably leading to a steady decline in the number of hospitalizations. In the current series, 80% of patients had been treated with tiotropium bromide; 71% with combination therapy; and 58.7% with triple therapy (combined treatment plus anticholinergic treatment). Moreover, we have observed in the present study that the number and severity of exacerbations and the presence of PPM in the sputum correlated significantly with the presence of bronchiectasis (r ¼ 0.30, P ¼ 0.03 and r ¼ 0.33, P ¼ 0.01, respectively), but the presence of bronchiectasis was retained in the final model because of its greater predictive power. The substitution of the variable defining severe exacerbations or the presence of PPM by other exacerbation indices or the presence of chronic colonization by PPM did not change the results. In any case, although the presence of previous severe exacerbations was not independently associated with higher mortality in the patients in our study, we cannot rule out the

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cause of death in patients with COPD and bronchiectasis largely being an exacerbation of infectious origin, compared with patients with COPD without bronchiectasis. In fact, according to the results of the present study, the cause of death in patients with COPD with bronchiectasis was an exacerbation on 65% of occasions, as against 50% in COPD without bronchiectasis, although no statistically significant differences were observed, probably because of a lack of statistical power. Larger studies are therefore needed to clarify the real role of exacerbations in the relationship between COPD and bronchiectasis. Patients with bronchiectasis in our series were 2.5 times more likely to die than those without bronchiectasis, independently of other variables. These results were confirmed by using the Bhalla score as a joint marker of the extension and severity of bronchiectasis. The prognostic value of the presence and severity of bronchiectasis could suggest the existence of a new phenotype of patients with COPD with bronchiectasis, probably related to the exacerbation and chronic bronchitis phenotypes. The pathogenic vicious circle of infection-inflammation leading to the formation of bronchiectasis (30) can probably be broken by the early identification of this subgroup of patients with COPD and bronchiectasis and the establishment of early treatment, probably focusing on bronchial colonization by PPM. In this respect, the Pulse study (38) showed a decrease in exacerbations and chronic colonization in patients with COPD with bronchial hypersecretion treated with courses of oral moxifloxacin. Moreover, some studies have shown the effectiveness of inhaled antibiotic treatment in patients with bronchiectasis of any origin with chronic colonization by PPM (39–42), which opens up an interesting field of research on the role of inhaled antibiotics in the treatment of chronic colonization of patients with COPD. Both the conclusions of a study recently published by our research group (30) and the results of the present study endorse the use of a chest HRCT in patients with severe COPD, multiple or severe exacerbations, and chronic colonization by PPM, because these are the patients with COPD at greatest risk from bronchiectasis. One interesting notion that can be extracted from our results is that the presence of bronchiectasis in patients with COPD has a greater correlation with the parameters marking the patients with COPD with chronic bronchitis phenotype (thicker bronchial wall, greater chronic expectoration, and a higher number of exacerbations) than those with the emphysematous phenotype, because the relationship between the extension of emphysema and the presence of PPM, the presence of chronic expectoration, or the presence of bronchiectasis did not prove significant. Some authors have already observed that a thicker bronchial wall in patients with COPD is associated with increased chronic expectoration, whereas the degree of emphysema is more closely associated with deterioration in TABLE 6. VARIABLES ASSOCIATED WITH DEATH IN MODERATE-TO-SEVERE COPD USING THE BHALLA SCORE AS A CONTINUOUS VARIABLE Unadjusted Variables Age Dyspnea (MRC) Bhalla Score

Fully Adjusted

HR (95% CI)

P

HR (95% CI)

P

1.13 (1.08–1.18) 2.21 (1.72–2.84) 1.08 (1.01–1.16)

0.0001 0.0001 0.027

1.09 (1.03–1.16) 1.47 (1.06–2.03) 1.15 (1.05–1.26)

0.003 0.021 0.002

Definition of abbreviations: CI ¼ confidence interval; COPD ¼ chronic obstructive pulmonary disease; HR ¼ hazard ratio; MRC ¼ Medical Research Council. Unadjusted and fully adjusted Cox multivariate regression analysis. Adjusted by FEV1 (% post-bronchodilator), Charlson index, PO2, body mass index, presence of potentially pathogenic microorganisms in sputum, presence of daily sputum production, number of severe exacerbations, and peripheral albumin and ultrasensitive C-reactive protein concentrations.

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the pulmonary function (43). The present study, however, is the first in the literature to conclude that the degree of bronchial wall thickness, as measured in a segment of the nonbronchiectasic bronchus of a patient with COPD, is associated with the presence of bronchiectasis in distal bronchial generations. We also observed that those patients with COPD and bronchiectasis presented a greater presence of PPM in the airways, both as single isolates and as chronic colonization. All these results suggest that bronchiectasis could form in those patients with COPD, as defined in physiopathologic terms by Cole and coworkers (36), along with a chronic bronchitic phenotype and repeated exacerbations, who presented greater inflammation of the airways as a result of a greater degree of bronchial colonization by PPM. This physiopathologic hypothesis needs to be confirmed by further studies, however, because it has not yet been possible to demonstrate any causal relationship between COPD and bronchiectasis. One limitation of our study is that some variables that have been shown to predict mortality in patients with COPD, such as the presence of inactivity, BODE index, exercise test, pulmonary hypertension, and hyperinflation, were not included in the study. Nor did we have access to the software required to undertake a more precise quantification of the degree of emphysema, so we were only able to establish a semiquantitative measurement in this respect. Another limitation of the study is that we did not use any volumetric CT techniques with contiguous images of the entire thorax; these would have demonstrated a greater capacity for the diagnosis of bronchiectasis and emphysema. Furthermore, we were unable to make an exact measurement of the size of the bacterial load in the patient’s sputum sample and could only establish a cut-off point (at 103 UFC/ml) to identify an anomalous growth of PPM in the sputum. Finally, we cannot rule out a bias derived from the fact that the most severe patients were attended more regularly (every 3 mo) than less severe patients (every 6 mo); this could influence our final results. In summary, our results suggest that the presence and severity of bronchiectasis are associated with an independent increase in the risk of all-cause mortality in patients with moderate-severe COPD. Further studies are needed to confirm our results with respect to the prevalence and prognostic value of bronchiectasis in patients with moderate and severe COPD, and the role played by exacerbations in this relationship. Author disclosures are available with the text of this article at www.atsjournals.org.

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