The aim of the study was to assess the microbial composition of bronchial secretions in chronic obstructive pulmonary disease (COPD), focusing on the impact of the exacerbation patterns on the common components of the respiratory flora and their relationship with inflammatory proteins. A total of 72 clinically stable COPD patients provided sputum and blood samples for 16S rRNA gene amplification and peripheral biomarkers. Beta-diversity analyses of the bronchial microbiome showed significant differences between infrequent and frequent (≥2) exacerbators (p = 0.001). Haemophilus was underrepresented in frequent exacerbators (relative abundance [RA] 0.07 [0.003-0.31] vs. 0.24 [0.06-2.36], p = 0.02) while the presence of Pseudomonas was increased (7.70 [0.66-11.68] vs. 1.11 [0.37-2.88], p = 0.01). Eight common taxa, Prevotella, Moryella, Atopobium, Megasphaera, Parvimonas, Veillonella, Bulleidia and Selenomonas, showed significant decreases in their RAs when exacerbations required hospitalization. RAs of Haemophilus and eight common taxa were positively correlated (p < 0.01). Among them, Porphyromonas, Leptotrichia and Selenomonas showed a negative correlation with blood interleukin-8 (IL-8) (p < 0.01) and an equivalent correlation was found for Haemophilus parainfluenzae. Frequent exacerbations cause a decrease in the RA of Haemophilus and have a more extensive impact when hospitalization is required. The RAs of common bronchial bacteria were closely related and some of them were inversely associated with blood IL-8 levels.

Background:Non-invasive ventilation (NIV) improves outcomes in acute life-threatening hypercapnic respiratory failure due to exacerbations of COPD (ECOPD), but the benefits of long-term home NIV (LTH-NIV) for managing hypercapnic chronic respiratory failure (CRF) in COPD remain unclear. Purpose:1) To assess the long-term survival of severe COPD patients with hypercapnic CRF started on LTH-NIV and mortality related factors; 2) To evaluate the impact of LTH-NIV on ECOPD and hospital admissions at follow-up. Patients and Methods:COPD patients who started LTH-NIV between January 2009 and December 2018 were included. Medical records and clinical outcomes were retrospectively reviewed. Results:Forty-four COPD patients (mean [SD] age 66.5 [10.4] years, 81.8% men) with severe airflow obstruction (mean [SD] FEV1 36 [16] % of predicted), hypercapnic CRF (mean [SD] PaCO2 60.8 [9.2] mmHg) and exacerbator phenotype (mean [IQR] moderate-severe ECOPD 3 [3] in previous year) were included. Median survival from LTH-NIV was 100.3 months. Survival at one, three and five years was 86.4%, 72.7% and 68.2%, respectively. In a multivariate Cox regression model, patients with a significantly increased risk of death were those with older age, lower absolute FVC, more hospitalisations and especially those adapted to LTH-NIV in the acute phase (HR 3.67 (IC 1.04-13), p<0.05). LTH-NIV allowed an estimated mean reduction in ECOPD of 39.7% (65.2% in hospitalisations) at 12 months and 57.4% (81% in hospitalisations) at 24 months. Conclusion:The survival rate of COPD patients with hypercapnic CRF on LTH-NIV is currently high (>50% at 5 years). Adaptation to LTH-NIV in the stable phase is the most important prognostic determinant and should be considered especially in patients with more hospitalisations and lower FVC values. Initiation of LTH-NIV reduces moderate to severe ECOPD at follow-up.

Aims:Analysis of patient-ventilator interactions in patients on chronic home mechanical ventilation can be time consuming, and the consequences of individual interaction on pulmonary gas exchange are not well understood. The objective was to analyse the relationship between interactions and nocturnal oximetry and arterial blood gases. Methods:A cross-sectional study was carried out in restrictive and neuromuscular patients who underwent respiratory polygraphy with a system that allowed interactions to be correlated with mean saturation in 5-min periods. Unintentional leaks, periodic decreases in flow and primary patient-ventilator asynchronies were analysed. Each interaction was correlated with mean oxygen saturation measured by pulse oximetry (S pO2 ) and baseline arterial blood gases obtained at the recruitment visit, and the 5-min S pO2 analysis was individualised for each patient based on their mean±sd S pO2 during polygraphy. Results:40 patients were included. There was a correlation between interactions and mean S pO2 in periods with mean accidental leak >20 L·min-1 (ANOVA test). After exclusion of periods with leakage above this threshold, a relationship was documented between periodic decreases in flow and asynchronies with mean S pO2 in 5-min periods. However, there was no relationship between patient-ventilator interactions and baseline arterial blood gases at recruitment. Conclusion:The presence of interactions was associated with a decrease in mean S pO2 when 5-min recordings are analysed. Therefore, it seems advisable to systematically detect and correct patient-ventilator interactions in home mechanical ventilated patients.

The respiratory microbiome may influence the development and progression of COPD by modulating local immune and inflammatory events. We aimed to investigate whether relative changes in respiratory bacterial abundance are also associated with systemic inflammation, and explore their relationship with the main clinical COPD phenotypes. Multiplex analysis of inflammatory markers and transcript eosinophil-related markers were analyzed on peripheral blood in a cohort of stable COPD patients (n = 72). Respiratory microbiome composition was analyzed by 16S rRNA microbial sequencing on spontaneous sputum. Spearman correlations were applied to test the relationship between the microbiome composition and systemic inflammation. The concentration of the plasma IL-8 showed an inverted correlation with the relative abundance of 17 bacterial genera in the whole COPD cohort. COPD patients categorized as eosinophilic showed positive relationships with blood eosinophil markers and inversely correlated with the degree of airway obstruction and the number of exacerbations during the previous year. COPD patients categorized as frequent exacerbators were enriched with the bacterial genera Pseudomonas which, in turn, was positively associated with the severity of airflow limitation and the prior year’s exacerbation history. The associative relationships of the sputum microbiome with the severity of the disease emphasize the relevance of the interaction between the respiratory microbiota and systemic inflammation.

BackgroundContinuous treatment with azithromycin may lead to fewer acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but little is known of its impact on systemic and functional outcomes in real-life settings. MethodsThis was a multicenter prospective observational study of patients with severe COPD who started treatment with azithromycin. Tests were compared at baseline and after 3 and 12 months of treatment. These included lung function tests, a 6-min walking test (6MWT), and enzyme-linked immunosorbent assays of serum and sputum markers, such as interleukins (IL-6, IL-8, IL-13, IL-5), tumor necrosis factor receptor 2 (TNFR2), and inflammatory markers. Incidence rate ratios (IRR) and their 95% confidence intervals (95% CI) are reported. ResultsOf the 478 eligible patients, the 42 who started azithromycin experienced reductions in AECOPDs (IRR, 0.34; 95% CI, 0.26-0.45) and hospitalizations (IRR, 0.39; 95% CI, 0.28-0.49). Treatment was also associated with significant improvement in the partial arterial pressure of oxygen (9.2 mmHg, 95% CI 1.4-16.9) at 12 months. While TNFR2 was reduced significantly in both serum and sputum samples, IL-13 and IL-6 were only significantly reduced in serum samples. Moreover, an elevated serum and sputum IL-8 level significantly predicted good clinical response to treatment. ConclusionContinuous azithromycin treatment in a cohort of patients with severe COPD and frequent exacerbations can significantly reduce the number and severity of exacerbations and improve gas exchange. Treatment changes the pattern of microorganism isolates and decreases the inflammatory response. Of note, IL-8 may have utility as a predictor of clinical response to azithromycin treatment.

Background: Long-term azithromycin therapy significantly reduces the frequency of COPD exacerbations (ECOPD). However, previous studies have used different dosing regimens, and the efficacy of these regimens has not been compared. Objective: Compare the efficacy of low-dose with high-dose continuous cyclic azithromycin (CC-A) in severe COPD. Methods: Patients with severe COPD and repeated exacerbations (ECOPD ≥4 or ≥3 with at least 1 hospital admission in the previous year) were prospectively recruited (January 2017 to December 2019) as a multicenter cohort (from 3 university hospitals in the Barcelona area) and treated with low-dose CC-A: 250 mg 3 times per week (250-CC-A group). This cohort was compared with a historical (January 2007 to December 2013) single-center cohort of severe COPD with frequent ECOPD treated with high-dose CC-A: 500 mg 3 times per week (500-CC-A group). To assess differences in ECOPD prevention according to the administration of low-dose or high-dose CC-A, moderate-to-severe ECOPD was evaluated during the 12-month period before and after starting CC-A therapy. Results: Fifty-eight patients with severe COPD were evaluated: 37 in the low-dose group and 21 in the high-dose group. The 250-CC-A therapy group achieved a mean reduction in moderate-to-severe ECOPD of 65.6% at 12 months after starting CC-A therapy (with a 61.5% reduction in hospitalizations), while the 500-CC-A group achieved a reduction of 60.5% (with a 44.8% reduction in hospitalizations). No significant differences between 250-CC-A and 500-CC-A dosages were observed in the mean annual reduction of moderate-to-severe ECOPD (p = 0.55) or hospitalizations (p = 0.07) with respect to the year prior to starting CC-A. Conclusions: Low-dose 250-CC-A therapy over a 1-year period is similar to high-dose 500-CC-A in reducing exacerbation frequency in severe COPD patients with frequent ECOPD despite maximal medical therapy.

We compared the bacterial microbiomes lodged in the bronchial tree, oropharynx and nose of patients with early stage cystic fibrosis (CF) not using chronic antibiotics, determining their relationships with lung function and exacerbation frequency. CF patients were enrolled in a cohort study during stability and were checked regularly over the following 9 months. Upper respiratory samples (sputum [S], oropharyngeal swab [OP] and nasal washing [N]) were collected at the first visit and every 3 months. 16S rRNA gene amplification and sequencing was performed and analyzed with QIIME. Seventeen CF patients were enrolled (16.6 SD 9.6 years). Alpha-diversity of bacterial communities between samples was significantly higher in S than in OP (Shannon index median 4.6 [IQR: 4.1–4.9] vs. 3.7 [IQR: 3-1-4.1], p = 0.003/Chao 1 richness estimator median 97.75 [IQR: 85.1–110.9] vs. 43.9 [IQR: 31.7–59.9], p = 0.003) and beta-diversity analysis also showed significant differences in the microbial composition of both respiratory compartments (Adonis test of Bray Curtis dissimilarity matrix, p = 0.001). Dominant taxa were found at baseline in five patients (29.4%), who showed lower forced expiratory volume in the first second (FEV1%, mean 74.8 [SD 19] vs. 97.2 [SD 17.8], p = 0.035, Student t test). The Staphylococcus genus had low RAs in most samples (median 0.26% [IQR 0.01–0.69%]), but patients with RA > 0.26% of Staphylococcus in bronchial secretions suffered more exacerbations during follow-up (median 2 [IQR 1–2.25] vs. 0 [0–1], p = 0.026. Mann–Whitney U test), due to S. aureus in more than a half of the cases, microorganism that often persists as bronchial colonized in these patients (9/10 [90%] vs. 2/7 [28.6%], p = 0.034, Fisher’s exact test). In conclusion, the bronchial microbiome had significantly higher diversity than the microbial flora lodged in the oropharynx in early stage CF. Although the RA of the Staphylococcus genus was low in bronchial secretions and did not reach a dominance pattern, slight overrepresentations of this genus was associated with higher exacerbation frequencies in these patients.

Trabajo presentado en el 29th European Congress of Clinical Microbiology and Infectious Diseases (ESCMID), celebrado en Amsterdam (Paises Bajos), del 13 al 16 de abril de 2019

The respiratory microbiome is altered in COPD patients but its relationship with core components of the disease, such as the severity of airflow limitation, the frequency of exacerbations or the circulating levels of eosinophils, is unclear. Cross-sectional study comprising 72 clinically stable COPD patients (mean age 68 [SD 7.9] years; FEV1 48.7 [SD 20.1]% of reference) who provided spontaneous sputum samples for 16S rRNA gene amplification and sequencing. The microbiome composition was analysed with QIIME. We observed that: (1) more severe airflow limitation was associated with reduced relative abundance (RA) of Treponema and an increase in Pseudomonas; (2) patients with ≥2 exacerbations the previous year showed a significantly different bacterial community with respect to non-exacerbators (p = 0.014), with changes in 13 genera, including an increase of Pseudomonas, and finally, (3) peripheral eosinophils levels ≥2% were associated with more diverse microbiome [Chao1 224.51 (74.88) vs 277.39 (78.92) p = 0.006; Shannon 3.94 (1.05) vs 4.54 (1.06) p = 0.020], and a significant increase in the RAs of 20 genera. The respiratory microbiome in clinically stable COPD patients varies significantly according to the severity of airflow limitation, previous history of exacerbations and circulating eosinophils levels.

Introduction:Long-term use of nebulized or oral antibiotics is common in the treatment of cystic fibrosis and non-cystic fibrosis bronchiectasis. To date, however, few studies have focused on the use of nebulized antibiotics in COPD patients. The aims of this study are: to establish whether a combination of nebulized colistin plus continuous cyclic azithromycin in severe COPD patients with chronic bronchial infection due to Pseudomonas aeruginosa reduces the frequency of exacerbations, and to assess the effect of this treatment on microbiological sputum isolates.Material and methods:A retrospective cohort was created for the analysis of patients with severe COPD and chronic bronchial infection due to P. aeruginosa treated with nebulized colistin at the Respiratory Day Care Unit between 2005 and 2015. The number and characteristics of COPD exacerbations (ECOPD) before and up to two years after the introduction of nebulized colistin treatment were recorded.Results:We analyzed 32 severe COPD patients who received nebulized colistin for at least three months (median 17 months [IQR 7-24]). All patients but one received combination therapy with continuous cyclic azithromycin (median 24 months [IQR 11-30]). A significant reduction in the number of ECOPD from baseline of 38.3% at two years of follow-up was observed, with a clear decrease in P. aeruginosa ECOPD (from 59.5% to 24.6%) and a P. aeruginosa eradication rate of 28% over the two-year follow-up.Conclusion:In patients with severe COPD and chronic bronchial infection due to P. aeruginosa, combination therapy with nebulized colistin and continuous cyclic azithromycin significantly reduced the number of ECOPD, with a marked decrease in P. aeruginosa sputum isolates.

Concepción Montón Elena Prina Xavier Pomares 1,3 Jose R Cugat 4 Antonio Casabella Joan Carles Oliva Miguel Gallego 1,3 Eduard Monsó 1Department of Respiratory Medicine, Hospital De Sabadell, Institut Universitari Parc Taulí-UAB, Sabadell, Spain; 2Health Services Research on Chronic Diseases Network-REDISSEC, Galdakao, Spain; 3CIBER de Enfermedades Respiratorias, CIBERES, Madrid, Spain; 4Department of Respiratory Medicine, Fundació Althaia, Manresa, Spain; 5Laboratory of Microbiology-UDIAT, Institut Universitari Parc Taulí-UAB, Sabadell, Spain; 6Epidemiology and Assessment Unit, Fundació Parc Taulí, Universitat Autònoma de Barcelona, Sabadell, Spain Introduction: Long-term use of nebulized or oral antibiotics is common in the treatment of cystic fibrosis and non-cystic fibrosis bronchiectasis. To date, however, few studies have focused on the use of nebulized antibiotics in COPD patients. The aims of this study are: to establish whether a combination of nebulized colistin plus continuous cyclic azithromycin in severe COPD patients with chronic bronchial infection due to Pseudomonas aeruginosa reduces the frequency of exacerbations, and to assess the effect of this treatment on microbiological sputum isolates. Material and methods: A retrospective cohort was created for the analysis of patients with severe COPD and chronic bronchial infection due to P. aeruginosa treated with nebulized colistin at the Respiratory Day Care Unit between 2005 and 2015. The number and characteristics of COPD exacerbations (ECOPD) before and up to two years after the introduction of nebulized colistin treatment were recorded. Results: We analyzed 32 severe COPD patients who received nebulized colistin for at least three months (median 17 months [IQR 7–24]). All patients but one received combination therapy with continuous cyclic azithromycin (median 24 months [IQR 11–30]). A significant reduction in the number of ECOPD from baseline of 38.3% at two years of follow-up was observed, with a clear decrease in P. aeruginosa ECOPD (from 59.5% to 24.6%) and a P. aeruginosa eradication rate of 28% over the two-year follow-up. Conclusion: In patients with severe COPD and chronic bronchial infection due to P. aeruginosa, combination therapy with nebulized colistin and continuous cyclic azithromycin significantly reduced the number of ECOPD, with a marked decrease in P. aeruginosa sputum isolates.

Aim: To characterize the respiratory virome in moderate/severe chronic obstructive pulmonary disease (COPD) patients using metagenomics, with healthy subjects as the reference. Patients & Methods: Sputum COPD samples were collected during stability and exacerbations with negative usual-care microbiologic analysis. Results: Eukaryotic viruses from the Anelloviridae, Herpesviridae and Retroviridae families and phages from the Shiphoviridae family were commonly found in COPD, and the respiratory virome in stability and noninfectious exacerbations showed a substantial similarity. DNA viruses with the highest relative abundance in COPD are Anelloviridae. Conclusion: These results support a colonizing role for eukaryotic viruses in COPD and highlight the importance of analyzing both DNA and RNA viruses when focusing on the respiratory virome.

Chronic obstructive pulmonary disease (COPD) is an entity with a heterogeneous presentation. For this reason, attempts have been made to characterize different phenotypes and endotypes to enable a more individualized approach. The aim of the Biomarkers in COPD (BIOMEPOC) project is to identify useful biomarkers in blood to improve the characterization of patients. Clinical data and blood samples from a group of patients and healthy controls will be analyzed. The project will consist of an exploration phase and a validation phase. Analytical parameters in blood will be determined using standard techniques and certain ‘omics’ (transcriptomics, proteomics, and metabolomics). The former will be hypothesis-driven, whereas the latter will be exploratory. Finally, a multilevel analysis will be conducted. Currently, 269 patients and 83 controls have been recruited, and sample processing is beginning. Our hope is to use the results to identify new biomarkers that, alone or combined, will allow a better characterization of patients.

Chronic obstructive pulmonary disease (COPD) is an entity with a heterogeneous presentation. For this reason, attempts have been made to characterize different phenotypes and endotypes to enable a more individualized approach. The aim of the Biomarkers in COPD (BIOMEPOC) project is to identify useful biomarkers in blood to improve the characterization of patients. Clinical data and blood samples from a group of patients and healthy controls will be analyzed. The project will consist of an exploration phase and a validation phase. Analytical parameters in blood will be determined using standard techniques and certain 'omics' (transcriptomics, proteomics, and metabolomics). The former will be hypothesis-driven, whereas the latter will be exploratory. Finally, a multilevel analysis will be conducted. Currently, 269 patients and 83 controls have been recruited, and sample processing is beginning. Our hope is to use the results to identify new biomarkers that, alone or combined, will allow a better characterization of patients. (C) 2018 SEPAR. Published by Elsevier Espana, S.L.U. All rights reserved.

BACKGROUND: Exacerbations of COPD (ECOPD) are a major cause of mortality and morbidity. Continuous cyclic azithromycin (CC-A) reduces the exacerbation rate, but it is unknown whether it remains effective and safe beyond the first year. METHODS: This study was a retrospective analysis of patients with severe COPD (Global Initiative for Chronic Obstructive Lung Disease grade D) with >= 4 moderate to severe ECOPD who received CC-A (500 mg three times per week) as add-on therapy. Patients treated over 24 months were considered long-term continuous cyclic azithromycin (LT-CC-A) users, and ECOPD, hospitalizations, and length of hospital stays during the first, second, and third years were compared with the previous 12 months. Microbiologic monitoring, assessment of macrolide resistance, and analysis of side effects were maintained throughout the study period. RESULTS: A total of 109 patients with severe COPD treated with CC-A (39 for >= 24 months) comprised the LT-CC-A group (35.8%). This group presented average reductions in ECOPD from baseline of 56.2% at 12 months, 70% at 24 months, and 41% at 36 months, paralleled by respective reductions in hospitalizations of 62.6%, 75.8%, and 39.8%. ECOPD due to common microorganisms fell by 12.5% and 17.3% at 12 and 24 months of LT-CC-A, respectively, with a 50% increase in macrolide resistance. Pseudomonas aeruginosa ECOPD rose by 7.2% and 13.1% at these two time points. CC-A therapy was well tolerated with few side effects: digestive disorders in the short term (7.1%) and hearing loss in the long term (5.1%). CONCLUSIONS: LT-CC-A therapy over a 24- to 36-month period in patients with COPD (Global Initiative for Chronic Obstructive Lung Disease grade D) achieved sustained reductions in ECOPD and hospitalizations of > 50% with few adverse events, although macrolide resistance increased.

Objective: To evaluate the relationships between respiratory microbiome and main COPD phenotyes Methods: Sputum samples from COPD patients were obtained during stability and 16S rRNA gene was analyzed. Taxonomic and diversity information were correlated with frequent exacerbator (FE) and eosinophilic COPD (EC) phenotypes Results: 78 subjects were analyzed, mean age 67 (SD 9) years. Patients with ≥2 exacerbations the previous year were considered FE (n=23). Their bacterial community was significantly different (p=0.014) from patients with no exacerbations (n=31), with changes in RA of 3 phyla and 13 genera, which included an increase in Pseudomonas. Patients with 1 exacerbation (n=18) showed borderline differences in their bacterial community (p=0.081) compared to no exacerbations patients, with a loss of RA of 2 phyla and 13 genera. Patients with 1 or ≥2 exacerbations showed similar borderline differences (p=0.087) with changes in RA of 4 genera. EC patients, identified by a systemic eosinophil level ≥2%, showed a significantly more diverse respiratory microbiome [Chao1 224.5 (74.9) vs 280.5 (79.6) p=0.003; Shannon 3.9 (1.1) vs 4.6 (1.1) p= 0.010] and a different community structure (p=0.037), mediated by a significant increment of 4 phyla and 26 genera Conclusion: A specific bacterial composition was shown in stability samples of FE and EC phenotypes. The presence of 1 exacerbation the previous year produces significant changes in the RA of specific OTUs and in patients with ≥2 exacerbations these changes lead to significant differences in their bacterial community. The respiratory microbiome was more diverse in EC patients and with a specific bacterial community Funded by FIS 15/00167, SEPAR and BRN-Pla Armengol