PROGNOSTIC VALUE OF BRONCHIECTASIS IN PATIENTS WITH MODERATE-TO-SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE

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1 PROGNOSTIC VALUE OF BRONCHIECTASIS IN PATIENTS WITH MODERATE-TO-SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE Journal: American Journal of Respiratory and Critical Care Medicine Manuscript ID: Blue OC.R2 Manuscript Type: OC - Original Contribution Date Submitted by the Author: 19-Jan-2013 Complete List of Authors: Martinez-Garcia, Miguel-Angel; Polytechnic and University La Fe Hospital, Pneumology de la Rosa, David; Platon Hospital, Pneumology Unit Soler-Cataluña, Juan-Jose; Requena General Hospital, Pneumology Unit Donat-Sanz, Yolanda; Requena General Hospital, Pneumology Unit Catalan-Serra, Pablo; Requena General Hospital, Pneumology Unit Agramunt-Lerma, Marco; Requena General Hospital, Radiology Service Ballestín, Javier; Requena General Hospital, Radiology Service Valero-Sánchez, Irene; Polytechnic and University La Fe Hospital, Pneumology Selma-Ferrer, Maria Jose; Polytechnic and University La Fe Hospital, Pneumology Keywords: Bronchiectasis, COPD, Chronic obstructive pulmonary disease, Mortality, Bronchial colonization

2 Page 1 of 48 PROGNOSTIC VALUE OF BRONCHIECTASIS IN PATIENTS WITH MODERATE-TO-SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE Martínez-García MA, MD* +, De La Rosa D, MD, Soler-Cataluña JJ, MD**, Donat-Sanz Y, MD**, Catalán Serra P, MD**, Agramunt Lerma, M, MD ++, Ballestín J, MD ++, Valero Sánchez I, MD*, Selma Ferrer MJ, MD* *Pneumology Service. Polytechnic and University La Fe Hospital. Hospital Valencia. Spain. Pneumology Unit. Platón Hospital. Barcelona. Spain. **Internal Medicine Service. Hospital General de Requena. Valencia. Spain. ++ Radiology Service. Hospital General de Requena. Valencia. Spain. + CIBERes. CIBER de enfermedades Respiratorias Corresponding author: Miguel Ángel Martínez-García Pneumology Service. University and Polytechnic La Fe Hospital. Valencia. Spain. Bulevar Sur s/n Valencia (Spain) Telephone: mianmartinezgarcia@gmail.com 1

3 Page 2 of 48 Author contributions: -Dr. M.A. Martínez-García and Dr. D. de la Rosa designed the study, contributed to data acquisition and interpretation, supervised the study and wrote the manuscript. -Dr. J.J. Soler-Cataluña designed the study, contributed to data acquisition and interpretation and approved the final version to be published. -Dr. Y. Donat-Sanz and Dr. P. Catalán-Serra contributed to data acquisition and interpretation, critically revised the manuscript and approved the final version to be published. -Dr. M. Agramunt-Lerma and Dr. J. Ballestín independently interpreted chest high-resolution CT scans and approved the final version of the manuscript to be published -Dr. I. Valero Sánchez and Dr MJ Selma Ferrer performed statistical analyses and contributed to data interpretation, critically revised the manuscript and approved the final version to be published. Running head: Prognostic value of bronchiectasis in COPD patients Descriptor number: 9.12 COPD: Outcomes < LUNG DISEASES Word count: 4713 CONFLICT OF INTEREST: None of the authors has any conflict of interest FUNDING: This study was supported by a grant from Praxis Pharmaceutical 2

4 Page 3 of 48 AT A GLANCE COMMENTARY Scientific knowledge on the subject The prevalence of bronchiectasis is high in moderate-to-severe chronic obstructive pulmonary disease (COPD) patients 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 available about the relationship between bronchiectasis and mortality in COPD patients. What this study adds to the field The results of this study confirm a high prevalence of bronchiectasis in moderate-to-severe COPD patients and suggest that bronchiectasis is independently associated with an increased risk of all-cause mortality in these patients. 3

5 Page 4 of 48 ABSTRACT Rationale: The prevalence of bronchiectasis is high in patients with moderateto-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 COPD patients but no information about the relationship between bronchiectasis and mortality in COPD patients is currently available. Objective: To assess the prognostic value of bronchiectasis in moderate-tosevere COPD patients. Methods and Measurements: Multicenter prospective observational study in consecutive moderate-to-severe COPD patients. Bronchiectasis was diagnosed by high-resolution CT scan. A complete standardized protocol was used in all patients, covering general, anthrophometric, functional, clinical, and microbiological 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. Main results: Ninety-nine patients in GOLD II, 85 in GOLD III and 17 in GOLD IV stages were included. Bronchiectasis was present in 115 (57.2%) of patients. During the follow-up (median 48 months [IQR, 35-53]) there were 51 deaths (43 deaths in the bronchiectasic group). Bronchiectasis was associated with an increased risk of fully adjusted mortality (HR 2.54, 95%CI, ; p=0.02). Conclusions: Bronchiectasis was associated with an independent increased risk of all-cause mortality in moderate-to-severe COPD patients. Word count (abstract): 202 4

6 Page 5 of 48 Keywords: Chronic obstructive pulmonary disease. Bronchiectasis. Chronic colonization. Mortality. Prognostic factor. 5

7 Page 6 of 48 INTRODUCTION After vascular diseases and cancer, chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the developed world but, 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 probably the BODE index (3), which integrates the evaluation of dyspnea, exercise capacity, pulmonary function and the body mass index (BMI). 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 pathophysiological factors such as hypoxemia (9) and hypercapnia (10), air trapping (11), pulmonary hypertension (12), and some biological 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-tosevere 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 6

8 Page 7 of 48 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 COPD patient with bronchiectasis, according to the definition recently published by Han et al (20). It would also have a major clinical impact, as bronchiectasis can be reliably diagnosed by means of high-resolution algorithms of computed tomography 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 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 high-resolution computed tomography scan (HRCT) and patients with uninterpretable HRCT scan images were excluded. Those patients diagnosed with bronchiectasis prior to being diagnosed with COPD were also excluded. Previous bronchiectasis was diagnosed via HRCT images showing bronchiectasis from the patient s clinical history prior to the start of the study, or via the presence within the clinical history of a radiological report of an HRCT that would certify the presence of bronchiectasis. All the tests were performed in 7

9 Page 8 of 48 a stable phase, after no signs of any exacerbation for at least six weeks. All the patients signed an informed-consent 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 forced expiratory volume in 1 second (FEV 1 ) to forced vital capacity (FVC) of less than 70% in a patient with a smoking habit of more than 10 packs/year. COPD was defined as moderate if the post-bronchodilator FEV 1 was between 80% and 50% (GOLD II), severe if was between 49.9% and 30% (GOLD III) and very severe if 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 prior to 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 scanner (MDCT) (Bright Speed 16, General Electric CO, Fairfield, Connecticut, USA) 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-sec 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 -450 HU and a window width of 1500 HU. 8

10 Page 9 of 48 Emphysema extension was quantified in the HRCT in a semi-quantitative fashion. The radiological absence of emphysema was scored as 0 points; the presence of centriacinar emphysema in 2 or less pulmonary lobes as 1 point; the presence of centriacinar emphysema in 3-4 pulmonary lobes as 2 points, and the presence of centriacinar emphysema in more than 4 pulmonary lobes, or of bullous or panacinar emphysema as 3 points. Small cylindrical bronchiectasis visible in only a single pulmonary segment was not considered, as 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, blind to the patients basal characteristics. Any differences in the readings were resolved by consensus. The HRCT scan was interpreted for the presence, severity, radiological 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 et al (21): (a) lack of tapering of bronchi, (b) dilation of bronchi when the internal diameter was larger than that of the adjacent pulmonary artery, or (c) 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), as well as the presence of cystic bronchiectasis or central bronchiectasis. The severity of bronchiectasis was evaluated using the Bhalla score in its original version (Appendix 1, online supplement). This index presents an upward range 9

11 Page 10 of 48 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 1 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, broncho-arterial ratio, thickness-todiameter ratio and the percentage of wall area, in bronchiectasic patients; 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 [Kg/m 2 ]); 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 (po 2 [mmhg] and pco 2 [mmhg]) and forced spirometry, in both absolute and percentage values over theoretical values 15 minutes after bronchodilator treatment with 200 µg of inhaled salbutamol, following the guidelines established by the Spanish Society of Pneumology (SEPAR) (29). Furthermore, peripheral levels of α 1 -antitrypsin (ng/dl), ultra-sensitive C-reactive protein (UI/ml; US-CRP), and albumin (mg/dl) 10

12 Page 11 of 48 were obtained as markers of systemic inflammation and nutritional status, respectively. All the necessary complementary tests were performed to clarify the etiology of bronchiectasis in accordance with the Spanish Guidelines (22). Exacerbation variables All the 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, as well as recording 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 prior to the study HRCT. Since this is a study primarily involving COPD patients, 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 steroids 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 microbiological analysis of spontaneous morning sputum was requested from each patient in the six months subsequent to inclusion in the 11

13 Page 12 of 48 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 three hours after collection. Sputum samples were accepted if they contained less then 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 colony-forming units (CFU) per milliliter. For the purposes of this study, a cut-off point of 10 3 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 blind 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 12

14 Page 13 of 48 monitor their adherence to the treatment, review their general status, and maintain a protocolized record. The follow-up finished on July 31, A patient was considered lost to follow-up only if his/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 and, when necessary, telephone contact with the patient or his/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/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 s 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-squared test. Kappa value was calculated for assessment of inter-observer agreement for qualitative radiological variables (presence of bronchiectasis) and the intraclass correlation coefficient for quantitative variables (Bhalla Index and 13

15 Page 14 of 48 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. Both 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 s proportional hazard regression survival model. In the case of elevated collinearity between two variables (Spearman or Pearson correlation test >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 FEV 1 % value; MRC dyspnea, p0 2, BMI, presence of bronchiectasis, presence of PPM in sputum, presence of daily sputum production, number of severe exacerbations, Charlson Index and peripheral albumin and US-CRP concentration. The forward stepwise technique (Wald test) was used and variables with a p >0.1 were remove from the final model. This left only age, Charlson Index, post-bronchodilator FEV 1 % 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 mantaining the same set of adjustment variables in a new Cox s survival analysis. In this case, the model left only age, MRC dyspnea, and Bhalla score in the fully adjusted model. Hazard ratios (HR) and confidence intervals (95%CI) for the independent variables were also calculated. Survival curves for the groups with and without 14

16 Page 15 of 48 bronchiectasis were constructed according to the Kaplan-Meier method and then compared with the log-rank test. RESULTS Two-hundred and twenty-seven patients with moderate-to-severe COPD (GOLD II-IV) were analyzed. Sixteen were excluded from the study due to 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] years; 90.5% male). Ninety-nine patients (49.2%) were in GOLD II stage; 85 (42.3%) were GOLD III and 17 (8.5%) GOLD IV. Radiological signs of emphysema were observed in 77.4% of the patients. One hundred and fifteen patients (57.2%) presented bronchiectasis. The mean broncho-arterial index was 1.7 (0.59), with a mean Bhalla score of 8.2 (4.1); range: 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 alpha-1 antitrypsin, allergic bronchopulmonary aspergillosis, significant immunodeficiencies, systemic diseases, infection by non-tuberculous 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 six months of the study (range: 0-6 samples). In the group as a whole, the PPM most frequently isolated was Haemophilus influenzae (single isolation in 37 patients, with chronic colonization in 17 of them). Streptococcus 15

17 Page 16 of 48 pneumoniae was isolated in 16 patients, in six cases as chronic colonization, and Moraxella catarrhalis was isolated in 14 patients, in three cases as chronic colonization. Finally, Pseudomonas aeruginosa was isolated in nineteen patients (fifteen 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) On the other hand, Tables 1 and 2 show that patients with bronchiectasis presented a more severe form of COPD in clinical and functional terms, as well as 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=0.001). This measurement of the bronchial wall thickness was also associated with the presence of chronic expectoration (r=0.28; p=0.002) and more isolations of PPM (r=0.28; p=0.001). No significant differences were observed, however, between the extension of emphysema and the presence of bronchiectasis (Table 1), the degree of chronic expectoration (r=0.02, p=0.71), or the presence of PPM in the bronchial mucosa (r=0.10; p=0.14). 16

18 Page 17 of 48 Univariate analysis The median follow-up (IQR) 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, eleven 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=150) and of those who died (n=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 PPM, greater chronic PPM colonization, and lower peripheral albumin concentration. Multivariate survival analysis Figure 1 shows the Kaplan-Meier survival curves for moderate-severe COPD patients with (n=115; 43 deaths) and without (n=86; 8 deaths) bronchiectasis. There was a statistical difference between the curves (log-rank test: 15.7; p=0.001). Table 5 shows the unadjusted and fully adjusted Cox regression analysis. The risk of death in COPD patients with bronchiectasis (n=115) was higher than in those without bronchiectasis (n=86) (unadjusted HR: 4.07 [ ; p=0.0001). After adjustment for confounding variables (see Statistical analysis; fully adjusted model), the risk did not significantly change (adjusted HR: 2.54 [ ]; p=0.02). Age, Charlson Index, and post-bronchodilator FEV 1 (%) also showed an independent adverse prognostic value in both the 17

19 Page 18 of 48 unadjusted and fully 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 [ ]; p=0.002), along with age and the degree of dyspnea (Table 6). Using a sensitivity analysis, the inclusión 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 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), as well as 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 moderatesevere COPD, independently of other known factors such as pulmonary function or other comorbidities. Some studies have reported a high prevalence of bronchiectasis (between 29-52%) 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 COPD patients, especially in the severe stages (35). This situation, and the subsequent 18

20 Page 19 of 48 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 which 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). Since 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 COPD patients. 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 pre-existing COPD 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 moderate-to-severe COPD patients for many years, and so 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 follow-up and those who survived. Furthermore, 19

21 Page 20 of 48 patients with bronchiectasis presented a more severe form of COPD, in clinical and functional terms, as well as 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 anti-cholinergic treatment). Moreover, we have observed in the present study that both the number and severity of exacerbations and the presence of PPM in the sputum correlated significantly with the presence of bronchiectasis (r = 0.30, p = 0.03 and r = 0.33, p = 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 20

22 Page 21 of 48 cannot rule out the cause of death in patients with COPD and bronchiectasis largely being an exacerbation of infectious origin, compared to 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 due to 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 COPD patients 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 COPD patients 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 21

23 Page 22 of 48 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, as these are the COPD patients 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 COPD patients with chronic bronchitis phenotype (thicker bronchial wall, greater chronic expectoration, and a higher number of exacerbations) than those with the emphysematous phenotype, as 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 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 non-bronchiectasic 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 physiopathological terms by Cole et al (36), along with a chronic bronchitic phenotype and repeated exacerbations, who presented greater inflammation of 22

24 Page 23 of 48 the airways as a result of a greater degree of bronchial colonization by PPM. This physiopathological hypothesis needs to be confirmed by further studies, however, as 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 semi-quantitative 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 demostrated 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 10 3 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 months) than less severe ones (every 6 months); 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 allcause mortality in moderate-severe COPD patients. 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, as well as the role played by exacerbations in this relationship. 23

25 Page 24 of 48 Conflicts of interest. None of the authors have any financial or other potential conflict of interest. -Dr. M.A. Martínez-García has no financial or other potential conflict of interest. -Dr. D. De la Rosa has no financial or other potential conflict of interest. -Dr J.J. Soler-Cataluña has no financial or other potential conflict of interest. -Dr. Y. Donat Sanz has no financial or other potential conflict of interest. -Dr P. Catalán Serra has no financial or other potential conflict of interest. -Dr I Valero has no financial or other potential conflict of interest. -Dr M.J. Selma has no financial or other potential conflict of interest. The corresponding author (Dr. Martínez-García) confirms that he had full access to all the data in the study and had final responsibility for the decision to submit for publication. All the authors have approved this final draft. 24

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32 Page 31 of 48 Table 1. Baseline and clinical characteristics of subjects with COPD, with and without bronchiectasis Parameter Whole COPD with COPD without p group bronchiectasis bronchiectasis Subjects, n Gender n, (M/F) 182/19 107/8 75/11 ns Age, yr 70.3 (8.9) 71.4 (8.5) 68.8 (9.3) 0.04 Packs/year smoked 60.7 (30) 62.1 (31.9) 58.8 (25.9) ns BMI, Kg/m (4.9) 26.4 (4.8) 28.4 (4.9) Onset of symptoms, yrs 16 (15.2) 13.2 (12.5) 8.9 (11.6) Daily sputum production, n (%) 128 (63.4%) 84 (73%) 44 (51.1%) Charlson Index 2.3 (1.46) 2.32 (1.5) 2.27 (1.43) ns Depression, n (%) 36 (17.9%) 23 (20%) 13 (15.1%) ns Anxiety, n (%) 46 (22.8%) 30 (26.1%) 16 (18.6%) ns Daily treatments, n (%) Anti-cholinergic LABA Combined treatment Triple therapy Home oxygen therapy Inhaled antibiotics Macrolides 161 (80%) 109 (54.2%) 144 (71.6%) 118 (58.7%) 50 (24.9%) 4 (2%) 4 (2%) 90 (78.2%) 71 (61.7%) 84 (73%) 70 (60.9%) 40 (34.8%) 3 (2.6%) 3 (2.6%) 71 (82.6%) 38 (44.1%) 60 (69.8%) 48 (55.8%) 10 (11.6%) 1 (1.2%) 1 (1.2%) ns 0.01 ns ns ns ns Dyspnea MRC 1.6 (0.98) 1.76 (1) 1.41 (0.9) Previous tuberculosis, n (%) 21 (10.4%) 15 (13%) 6 (7%) ns Previous pneumonia, n (%) 55 (27.4%) 36 (31.3%) 19 (22.1%) ns p0 2 /pco 2, mmhg 63.2/ / / / ns FEV 1 /FVC, % predicted 52.6 (12.7) 50.5 (12.9) 55.2 (11.8) Post bd FEV 1, ml % predicted 1348 (479) 49 (12.9) 1249 (463) 45.4 (12.8) 1480 (470) 53.8 (11.5) Post bd FVC, ml % predicted 2596 (760) 71.1 (18.3) 2478 (698) 68.6 (17.8) 2751 (814) 74.3 (18.5) Exacerbations* Total ER visits ER ambulatory visits ER hospital visits Hospital admissions Severe exacerbations 1.56 (2.1) 0.79 (1.2) 0.75 (1.6) 0.4 (0.8) 0.86 (1.5) 1.88 (2.13) 0.94 (1.43) 0.97 (1.32) 0.51 (0.9) 1.12 (1.7) 1 (1.48) 0.60 (0.93) 0.44 (0.82) 0.26 (0.49) 0.51 (0.99) All-cause mortality, n (%) 51 (25.4%) 43 (37.4%) 8 (9.3%) Mortality, causes, n %** Exacerbation Cardiovascular Cancer Others 32 (62.7%) 11 (21.6%) 5 (9.8%) 3 (5.9%) 28 (65.1%) 9 (20.9%) 4 (9.3%) 2 (4.7%) 4 (50%) 2 (25%) 1 (12.5%) 1 (12.5%) ns Acute antibiotic treatments 1.5 (1.6) 1.9 (1.8) 0.97 (1.1) Acute oral steroid treatments 0.8 (1.3) 1.05 (1.5) 0.4 (0.87) Tree in bud pattern, n (%) 49 (24.4%) 32 (27.8%) 17 (19.8%) 0.04 Bronchial diameter (1.3) 6.5 (1.26) 6.7 (1.44) ns Wall Thickness (0.68) 2.1 (0.78) 1.5 (0.32) Emphysema, n (%) None Centriacinar in 2 or less pulmonary lobes Centriacinar in 3 or 4 pulmonary lobes Centriacinar in more than 4 pulmonary lobes, or bullous or panacinar 45 (22.6%) 51 (25.4%) 53 (26.2%) 52 (25.8%) 21 (18.3%) 26 (22.6%) 36 (31.3%) 32 (27.8%) 24 (27.9%) 25 (29.1%) 17 (19.7%) 20 (23.3%) ns 31

33 Page 32 of 48 Definition of abbreviations: LABA = long-acting beta-adrenergic; ER = Emergency Room All data are quoted as means (SD), except when noted otherwise. *Data referring to the year after the patient s inclusion in the study. ** Percentage with respect to the total number of deaths in each group + Bronchus of the posterior segment of the lower right lobe 32