Guillermo Suarez-Cuartin

Neutrophil Elastase Activity is Associated with Exacerbations and Lung Function Decline in Bronchiectasis

Rationale: Sputum neutrophil elastase and serum desmosine, which is a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis. Methods: This was a single‐center prospective cohort study using the TAYBRIDGE (Tayside Bronchiectasis Registry Integrating Datasets, Genomics, and Enrolment into Clinical Trials) registry in Dundee, UK. A total of 433 patients with high‐resolution computed tomography‐confirmed bronchiectasis provided blood samples for desmosine measurement, and 381 provided sputum for baseline elastase activity measurements using an activity‐based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross‐sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3 years. Measurement and Main Results: Elastase activity in sputum was associated with the bronchiectasis severity index (r = 0.49; P < 0.0001) and was also correlated with the Medical Research Council dyspnea score (r = 0.34; P < 0.0001), FEV1% predicted (r = −0.33; P < 0.0001), and the radiological extent of bronchiectasis (r = 0.29; P < 0.0001). During a 3‐year follow‐up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (P < 0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV1 decline (&bgr; coefficient, −0.139; P = 0.001). Elastase showed good discrimination for severe exacerbations with an area under the curve of 0.75 (95% confidence interval [CI], 0.72‐0.79) and all‐cause mortality (area under the curve, 0.70; 95% CI, 0.67‐0.73). Sputum elastase activity increased at exacerbations (P = 0.001) and was responsive to treatment with antibiotics. Desmosine was correlated with sputum elastase (r = 0.42; P < 0.0001) and was associated with risk of severe exacerbations (hazard ratio 2.7; 95% CI, 1.42‐5.29; P = 0.003) but not lung function decline. Conclusions: Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.

Identification of airway bacterial colonization by an electronic nose in Chronic Obstructive Pulmonary Disease

BACKGROUND Airway bacterial colonization by potentially pathogenic microorganisms occurs in a proportion of patients with Chronic Obstructive Pulmonary Disease (COPD). It increases airway inflammation and influences outcomes negatively. Yet, its diagnosis in clinical practice is not straightforward. The electronic nose is a new non-invasive technology capable of distinguishing volatile organic compound (VOC) breath-prints in exhaled breath. We aim to explore if an electronic nose can reliably discriminate COPD patients with and without airway bacterial colonization. METHODS We studied 37 clinically stable COPD patients (67.8 ± 5.2 yrs, FEV1 41 ± 10% ref.) and 13 healthy controls (62.8 ± 5.2 yrs, FEV1 99 ± 10% ref.). The presence of potentially pathogenic microorganisms in the airways of COPD patients (n = 10, 27%) was determined using quantitative bacterial cultures of protected specimen brush. VOCs breath-prints were analyzed by discriminant analysis on principal component reduction, resulting in cross-validated accuracy values. Area Under Receiver Operating Characteristics (AUROC) was calculated using multiple logistic regression. RESULTS Demographic, functional and clinical characteristics were similar in colonized and non-colonized COPD patients but their VOC breath-prints were different (accuracy 89%, AUROC 0.92, p > 0.0001). Likewise, VOCs breath-prints from colonized (accuracy 88%, AUROC 0.98, p < 0.0001) and non-colonized COPD patients (accuracy 83%, AUROC 0.93, p < 0.0001) were also different from controls. CONCLUSIONS An electronic nose can identify the presence of airway bacterial colonization in clinically stable patients with COPD.

Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease

&NA; Figure. No caption available. Background: Neutrophil extracellular traps (NETs) have been observed in the airway in patients with chronic obstructive pulmonary disease (COPD), but their clinical and pathophysiologic implications have not been defined. Objective: We sought to determine whether NETs are associated with disease severity in patients with COPD and how they are associated with microbiota composition and airway neutrophil function. Methods: NET protein complexes (DNA‐elastase and histone‐elastase complexes), cell‐free DNA, and neutrophil biomarkers were quantified in soluble sputum and serum from patients with COPD during periods of disease stability and during exacerbations and compared with clinical measures of disease severity and the sputum microbiome. Peripheral blood and airway neutrophil function were evaluated by means of flow cytometry ex vivo and experimentally after stimulation of NET formation. Results: Sputum NET complexes were associated with the severity of COPD evaluated by using the composite Global Initiative for Obstructive Lung Disease scale (P < .0001). This relationship was due to modest correlations between NET complexes and FEV1, symptoms evaluated by using the COPD assessment test, and higher levels of NET complexes in patients with frequent exacerbations (P = .002). Microbiota composition was heterogeneous, but there was a correlation between NET complexes and both microbiota diversity (P = .009) and dominance of Haemophilus species operational taxonomic units (P = .01). Ex vivo airway neutrophil phagocytosis of bacteria was reduced in patients with increased sputum NET complexes. Consistent results were observed regardless of the method of quantifying sputum NETs. Failure of phagocytosis could be induced experimentally by incubating healthy control neutrophils with soluble sputum from patients with COPD. Conclusion: NET formation is increased in patients with severe COPD and associated with more frequent exacerbations and a loss of microbiota diversity.

Secreted mucins and airway bacterial colonization in non-CF bronchiectasis

Secreted mucins play a key role in antibacterial defence in the airway, but have not previously been characterized in non‐cystic fibrosis (CF) bronchiectasis patients. We aim to investigate the relationship between secreted mucins levels and the presence of bacterial colonization due to potentially pathogenic microorganisms (PPM) in the airways of stable bronchiectasis patients.

Pseudomonas aeruginosa resistance patterns and clinical outcomes in hospitalized exacerbations of COPD

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) due to Pseudomonas aeruginosa (PA) are associated with worse outcomes. PA antibiotic resistance is important to determine treatment and may influence clinical outcomes. The aim was to study clinical characteristics and outcomes in patients with AECOPD associated with PA based on their antibiotic resistance.

Diagnostic challenges of bronchiectasis

Bronchiectasis is a condition of increasing incidence and prevalence around the world. Many different diseases have been associated with bronchiectasis, and their treatment can differ widely. Recent guidelines have helped to approach aetiological diagnosis but it is still a complex process. Identifying the cause of the bronchiectasis may determine a change in the treatment of a large group of subjects. That is one of the main reasons why the aetiological diagnosis is crucial in the proper management of bronchiectasis patients. Postinfectious bronchiectasis is the most frequent entity among different studies, but a high percentage of cases still remain without a clear aetiology. Bronchiectasis related to allergic bronchopulmonary aspergillosis (ABPA), immunodeficiencies with antibody production deficiency, primary ciliary dyskinesia, cystic fibrosis and alpha-1-antitrypsin deficiency, among others, require a specific management that may improve quality of life and prognosis in a large group of individuals. Therefore, the aim of this article is to review the main bronchiectasis related diseases and to simplify the aetiological diagnosis, in order to improve the management of bronchiectasis patients, especially in those where a specific treatment is available.

Airway Mucin 2 Is Decreased in Patients with Severe Chronic Obstructive Pulmonary Disease with Bacterial Colonization

RATIONALE Mucins are essential for airway defense against bacteria. We hypothesized that abnormal secreted airway mucin levels would be associated with bacterial colonization in patients with severe chronic obstructive pulmonary disease (COPD) Objectives: To investigate the relationship between mucin levels and the presence of potentially pathogenic micro-organisms in the airways of stable patients with severe COPD Methods: Clinically stable patients with severe COPD were examined prospectively. All patients underwent a computerized tomography scan, lung function tests, induced sputum collection, and bronchoscopy with bronchoalveolar lavage (BAL) and protected specimen brush. Patients with bronchiectasis were excluded. Secreted mucins (MUC2, MUC5AC, and MUC5B) and inflammatory markers were assessed in BAL and sputum by ELISA. MEASUREMENTS AND MAIN RESULTS We enrolled 45 patients, with mean age (±SD) of 67 (±8) years and mean FEV1 of 41 (±10) % predicted. A total of 31% (n = 14) of patients had potentially pathogenic micro-organisms in quantitative bacterial cultures of samples obtained by protected specimen brush. Patients with COPD with positive cultures had lower levels of MUC2 both in BAL (P = 0.02) and in sputum (P = 0.01). No differences in MUC5B or MUC5AC levels were observed among the groups. Lower MUC2 levels were correlated with lower FEV1 (r = 0.32, P = 0.04) and higher sputum IL-6 (r = -0.40, P = 0.01). CONCLUSIONS Airway MUC2 levels are decreased in patients with severe COPD colonized by potentially pathogenic micro-organisms. These findings may indicate one of the mechanisms underlying airway colonization in patients with severe COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01976117).

Variabilidad del fenotipo inflamatorio del asma en el esputo inducido. Frecuencia y causas

INTRODUCTION Recent studies have found variability in asthma inflammatory phenotypes determined by the inflammatory cells in induced sputum (IS). The aim of this study was to determine the frequency and factors affecting inflammatory phenotype variability in IS. METHODS Retrospective observational study that included 61 asthmatic patients who underwent at least two IS tests over a period of 5 years. They were classified according to their baseline inflammatory phenotype and subsequently grouped according to phenotype variability (persistent eosinophilic, persistent non-eosinophilic and intermittent eosinophilic). Demographic, clinical and functional data and factors potentially influencing IS variability were collected in all cases. RESULTS Of the 61 patients, 31 (50.8%) had a change with respect to baseline inflammatory phenotype. Of these, 16 (51.6%) were eosinophilic, 5 (16.1%) neutrophilic, 1 (3.2%) mixed and 9 (29.1%) paucigranulocytic. According to phenotype variability, 18 patients (29.5%) were classified as persistent eosinophilic, 17 (27.9%) non-persistent eosinophilic, and 26 (42.6%) intermittent eosinophilic. Smoking and recent asthma exacerbation were significantly associated with increased risk of variability of the IS inflammatory phenotype (OR=6.44; p=.013; 95% CI=1.49-27.80 and OR=5.84; p=.022; 95% CI=1.29-26.37, respectively). CONCLUSION Half of asthma patients, predominantly those with eosinophilic phenotype, present a change in IS inflammatory phenotype. This variability is associated with smoking and recent asthma exacerbation. Data suggest these factors can modify the classification of IS inflammatory phenotype in clinical practice.

Identification of Pseudomonas aeruginosa and airway bacterial colonization by an electronic nose in bronchiectasis

RATIONALE Airway colonization by Potentially Pathogenic Microorganisms (PPM) in bronchiectasis is associated with worse clinical outcomes. The electronic nose is a non-invasive technology capable of distinguishing volatile organic compounds (VOC) in exhaled breath. We aim to explore if an electronic nose can reliably discriminate airway bacterial colonization in patients with bronchiectasis. METHODS Seventy-three clinically stable bronchiectasis patients were included. PPM presence was determined using sputum culture. Exhaled breath was collected in Tedlar bags and VOC breath-prints were detected by the electronic nose Cyranose 320®. Raw data was reduced to three factors with principal component analysis. Univariate ANOVA followed by post-hoc least significant difference test was performed with these factors. Patients were then classified using linear canonical discriminant analysis. Cross-validation accuracy values were defined by the percentage of correctly classified patients. RESULTS Forty-one (56%) patients were colonized with PPM. Pseudomonas aeruginosa (n = 27, 66%) and Haemophilus influenzae (n = 7, 17%) were the most common PPM. VOC breath-prints from colonized and non-colonized patients were significantly different (accuracy of 72%, AUROC 0.75, p < 0.001). VOC breath-prints from Pseudomonas aeruginosa colonized patients were significantly different from those of patients colonized with other PPM (accuracy of 89%, AUROC 0.97, p < 0.001) and non-colonized patients (accuracy 73%, AUROC 0.83, p = 0.007). CONCLUSIONS An electronic nose can accurately identify VOC breath-prints of clinically stable bronchiectasis patients with airway bacterial colonization, especially in those with Pseudomonas aeruginosa.

Pseudomonas aeruginosa in Chronic Obstructive Pulmonary Disease Patients with Frequent Hospitalized Exacerbations: A Prospective Multicentre Study

Background: Pseudomonas aeruginosa (PA) is a common microorganism related to severe exacerbations in Chronic Obstructive Pulmonary Disease (COPD). However, their role in COPD patients with frequent hospitalized exacerbations (FHE) is not well described. Objectives: We aimed to determine prevalence, risk factors, susceptibility patterns and impact on outcomes of PA in COPD patients with FHE. Methods: Prospective observational multicentre study that included COPD patients with FHE. The cohort was stratified in 2 groups according to the presence or absence of PA isolation in sputum. Patients were followed up for 12 months. Results: We enrolled 207 COPD patients with FHE. In 119 patients (57%), a valid sputum culture was collected. Of them, PA was isolated in 21 patients (18%). The risk factors associated with PA were prior use of systemic corticosteroids (OR 3.3, 95% CI 1.2–9.7, p = 0.01) and prior isolation of PA (OR 4.36, 95% CI 1.4–13.4, p < 0.01). Patients with PA had an increased risk of having ≥3 readmissions (OR 4.1, 95% CI 1.3–12.8, p = 0.01) and higher PA isolation rate (OR 7.7, 95% CI 2.4–24.6, p < 0.001) during the follow-up period. In 14 patients (67%), PA was resistant to at least one antibiotic tested. PA persisted in the sputum in 70% of patients. Conclusions: The presence of PA was related to 3 or more readmissions during the 1-year follow-up and PA persisted in the sputum despite an appropriate antibiotic treatment. This finding suggested an important role of PA in the course of the disease of COPD patients with FHE.