Nestor Soler

Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease

The effect of bacterial colonization of the bronchi on the progress of airflow limitation is not well known. Therefore, the pattern of airway inflammation in smokers and patients with stable chronic obstructive pulmonary disease (COPD) and its relation to bronchial microbial colonization was assessed. Eight nonsmoking and 18 smoking controls as well as 52 patients with COPD (28 mild, 11 moderate and 13 severe) were studied. All subjects were investigated by means of flexible bronchoscopy including protected specimen brush and bronchoalveolar lavage (BAL) sampling. Differential cell counts, cytokine (interleukin (IL)-1beta, IL-6, IL-8, IL-10 and tumour necrosis factor-alpha(TNF-alpha) concentrations and microbial patterns were determined in BAL fluid. Forced expiratory volume in one second (FEV1) % of the predicted value was inversely correlated with pack-yrs of cigarette smoking (r=-0.47, p<0.0001), the percentage of neutrophil (p=-0.56, p<0.0001) and IL-6 (p=-0.37, p=0.01) and IL-8 concentration (p=-0.43, p=0.004) in BAL fluid. Accordingly, pk-yrs of cigarette smoking (p=0.39, p=0.01) and IL-8 (p=0.69, p<0.0001) and TNFalpha (p=0.4, p<0.005) were positively correlated with the percentage of neutrophils in BAL fluid. Smoking controls and COPD patients were mainly colonized in the bronchial tree (33%) by community endogenous potentially pathogenic micro-organisms (PPMs). Colonization rates and patterns of PPMs were not affected by severity of airflow obstruction. The presence of PPMs was significantly associated with higher percentages of neutrophils (33.2+/-10.4% versus 10.1+/-3.5%, p=0.02) and TNF-alpha concentration (29.9+/-10.8 versus 6.3+/-2.1 pg x mL(-1), p=0.01) in BAL fluid. In conclusion, bronchial neutrophilia is a key inflammatory pattern in chronic obstructive pulmonary disease patients. Bronchial colonization with potentially pathogenic micro-organisms may represent an independent stimulus for additional airway inflammation.

Oxidative stress and airway inflammation in severe exacerbations of COPD

Background: A study was undertaken to assess both oxidative stress and inflammation in the lungs of patients with chronic obstructive pulmonary disease (COPD) during severe and very severe exacerbations compared with those with stable COPD, healthy smokers, and non-smokers. Two sites within the lungs were compared: the large airways (in sputum) and the peripheral airways (by bronchoalveolar lavage (BAL)). Methods: BAL fluid cell numbers and levels of tumour necrosis factor (TNFα) and interleukin (IL)-8 were measured as markers of airway inflammation and glutathione (GSH) levels as a marker of antioxidant status. Nuclear translocation of the pro-inflammatory transcription factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) were also measured by electromobility shift assay in BAL fluid leucocytes and lung biopsy samples. Results: Influx of inflammatory cells into the peripheral airways during exacerbations of COPD was confirmed. Increased IL-8 levels were detected in BAL fluid from patients with stable COPD compared with non-smokers and healthy smokers, with no further increase during exacerbations. In contrast, IL-8 levels in the large airways increased during exacerbations. GSH levels were increased in the BAL fluid of smokers (444%) and patients with stable COPD (235%) compared with non-smokers and were reduced during exacerbations (severe 89.2%; very severe 52.3% compared with stable COPD). NF-κB DNA binding in BAL leucocytes was decreased in healthy smokers compared with non-smokers (41.3%, n = 9, p<0.001) but did not differ in COPD patients, whereas AP-1 DNA binding was significantly decreased during exacerbations of COPD. Conclusion: There is evidence of increased oxidative stress in the airways of patients with COPD that is increased further in severe and very severe exacerbations of the disease. This is associated with increased neutrophil influx and IL-8 levels during exacerbations.

Bacterial colonization of distal airways in healthy subjects and chronic lung disease: a bronchoscopic study

In contrast to the healthy population, distal airway bacterial colonization may occur in patients with chronic lung diseases, who often have altered pulmonary defences. However, the information dealing with this issue is insufficient and is based mainly on nonspecific samples, such as sputum cultures. Using quantitative cultures of bronchoscopic protected specimen brush (PSB) and bronchoalveolar lavage (BAL) samples, we studied the bacterial colonization of distal airways in 16 healthy subjects, 33 patients with bronchogenic carcinoma, 18 with chronic obstructive pulmonary disease (COPD), 17 with bronchiectasis, and 32 with a long-term tracheostomy due to laryngeal carcinoma. All patients were without exacerbation, and free from antibiotic treatment at least 1 month before the study protocol. Thresholds for quantitative cultures to define colonization were > or = 10(2) colony-forming units (cfu) x mL(-1) for PSB and > or = 10(3) cfu x mL(-1) for BAL. Only one healthy subject was colonized by a potential pathogenic microorganism (PPM) (Staphylococcus aureus 4x10(2) cfu x mL(-1) in a PSB culture). Colonization was observed in 14 (42%) bronchogenic carcinoma patients (19 non-PPMs, and 10 PPMs); in 15 (83%) COPD patients (22 non-PPMs and 7 PPMs); in 15 (88%) bronchiectasis patients (20 non-PPMs and 13 PPMs); and in 15 (47%) long-term tracheostomy patients (5 non-PPMs and 13 PPMs). The two most frequent non-PPMs isolated in all groups studied were Streptococcus viridans and Neisseria spp. Haemophilus spp., Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis were the most frequent PPMs isolated in bronchogenic carcinoma, COPD, bronchiectasis and long-term tracheostomized patients, respectively. Pseudomonas aeruginosa colonization was infrequent in all the groups. Our results show that distal airway bacterial colonization is a frequent feature in stable patients with chronic lung diseases and also in patients with long-term tracheostomy. However, the pattern of colonization differs among groups studied. The knowledge of different colonization patterns may be important for future antibiotic prophylactic strategies and for the empirical antibiotic regimens when exacerbations occur in these patients.

Bronchoscopic validation of the significance of sputum purulence in severe exacerbations of chronic obstructive pulmonary disease

Background: Antibiotics are commonly prescribed in exacerbations of chronic obstructive pulmonary disease (COPD). However, the role of bacteria in these exacerbations is controversial. Objective: To identify clinical predictors of bacterial infection as a cause of exacerbation, considering the protected specimen brush (PSB) as the gold standard. Methods: Clinical data, sputum and PSB samples were collected from 40 patients with COPD requiring hospitalisation due to severe exacerbations who had not received previous antibiotic treatment. Results: Quantitative cultures of PSB samples (n = 40) yielded 23 potential pathogenic microorganisms (PPMs) at concentrations of ⩾102 colony-forming units/ml in 18 (45%) patients. Sputum samples were obtained from all 40 patients. Culture of good-quality sputum samples (n = 18) yielded 16 PPMs corresponding to 14 (35%) patients. The concordance between the PSB and sputum rate was high (κ = 0.85, p<0.002). The self-reporting patient observation of sputum purulence (odds ratio (OR) 27.20 (95% confidence interval (CI) 4.60 to 60.69), p = 0.001), the percentage predicted forced expiratory volume in 1 s (FEV1%) <50 (OR 2.27 (95% CI 1.55 to 3.21), p = 0.014), >4 exacerbations in the past year (OR 6.9 (95% CI 0.08 to 1.08), p = 0.028) and previous hospitalisations due to COPD (OR 4.13 (95% CI 1.02 to 16.07), p = 0.041) were associated with the presence of PPMs in the distal airways. The operative characteristics for predicting distal airway infection when patients presented with purulent exacerbation were as follows: sensitivity 89.5%, specificity 76.2%, positive predicted value 77.3% and negative predicted value 88.9%. Conclusions: The self-reporting presence of purulence in the sputum, as well as common previous exacerbations and hospitalisations due to COPD in patients with severe airflow obstruction (FEV1% <50) predict the presence of bacterial infection in the distal airways. The use of these clinical variables may help in selecting candidates to receive antibiotic treatment.

Stomach as a source of colonization of the respiratory tract during mechanical ventilation: association with ventilator-associated pneumonia

The aetiopathogenesis of ventilator-associated pneumonia (VAP) requires abnormal oropharyngeal and gastric colonization and the further aspiration of their contents to the lower airways. VAP develops easily if aspiration or inoculation of microorganisms occur in patients with artificial airways, in whom mechanical, cellular and/or humoral defences are altered. Well-known risk factors for gastric colonization include: alterations in gastric juice secretion; alkalinization of gastric contents; administration of enteral nutrition; and the presence of bilirubin. However, the role of the colonized gastric reservoir in the development of VAP remains debatable. Evidence in favour of the role of the stomach in the development of VAP comes mainly from randomized, controlled trials of selective gut decontamination and stress ulcer prophylaxis in the intensive care unit (ICU), in which reducing the bacterial burden of the stomach decreases the incidence of nosocomial respiratory infections. However, at least three studies of flora have found an absence of stomach origin of pneumonia occurring during mechanical ventilation. Prophylactic measures suggested to prevent VAP in relation to the gastric reservoir include: treatment for stress ulcers with sucralfate; prevention of duodenal reflux with metoclopramide; reduction of gastric burden and bacterial translocation by selective digestive decontamination; acidification of enteral feeding; and jejunal feeding. Gastro-oesophageal reflux can be prevented by using small bore nasogastric tubes and jejunal feeding. The aspiration of gastric contents can be reduced by positioning patients in a semirecumbent position, checking the patency of the tube cuff, and aspiration of subglottic secretions. The role of the stomach as a reservoir for microorganisms causing ventilator-associated pneumonia is still controversial but despite the debate, there is major evidence in the literature in favour of the gastric origin of part of these pulmonary infections.

Sputum purulence-guided antibiotic use in hospitalised patients with exacerbations of COPD

In patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) needing hospitalisation, sputum purulence is associated with bacteria in the lower respiratory tract. We performed a prospective non-randomised interventional pilot study applying a sputum purulence-guided strategy of antibiotic treatment and investigating the relationship between sputum purulence and biomarkers. In hospitalised patients with acute exacerbation of COPD antibiotics were restricted to those with purulent sputum. The primary end-point was rate of therapeutic failure during hospitalisation. Secondary end-points were parameters reflecting short- and long-term outcomes. We included 73 patients, 34 with non-purulent sputum. No differences were observed on therapeutic failure criteria (9% non-purulent versus 10% purulent (p=0.51)). Serum C-reactive protein (CRP) was significantly increased in the purulent group at admission (11.6 versus 5.3, p=0.006) and at day 3 (2.7 versus 1.2, p=0.01). Serum procalcitonin (PCT) was similar between the groups. No differences were found in short-term outcomes. The exacerbation rate at 180 days was higher in the purulent group. These results support the hypothesis of performing a randomised trial using a sputum purulence-guided antibiotic treatment strategy in patients with acute exacerbations of COPD. CRP, but not PCT, may be a useful parameter to increase confidence of the absence of bacterial bronchial infection.

Pneumonic and Nonpneumonic Exacerbations of COPD: Inflammatory Response and Clinical Characteristics

BACKGROUND Community-acquired pneumonia (CAP) is a frequent event in patients with COPD, although it is not currently considered an acute exacerbation of COPD (AECOPD). To our knowledge, no studies have compared the inflammatory response of patients with COPD who develop CAP or AECOPD. The aim of our study was to compare clinical and evolutive manifestations and biologic signaling of AECOPD and CAP + COPD. METHODS Prospective data were collected from 249 consecutively hospitalized patients with COPD. Comparative analyses were performed in patients with AECOPD (n = 133) and patients with CAP + COPD (n = 116). Measures of clinical characteristics, blood biomarkers, and evolution were recorded on admission, after 3 and 30 days, and in a follow-up period of 30 days, 90 days, and 1 year. RESULTS Patients with CAP + COPD had higher FEV1 compared with patients with COPD without pneumonia. In-hospital and long-term outcomes (1 year) were similar for both populations. However, patients with AECOPD had more readmissions, and patients with CAP had more prior episodes of pneumonia. At day 1 and day 3, patients with CAP + COPD had significantly (P < .001) higher serum levels of C-reactive protein (CRP), procalcitonin, tumor necrosis factor-α, and IL-6. Repetition of the analyses after stratifying patients based on severity of disease, current inhaled pharmacotherapy, and noninfectious AECOPD cause confirmed higher levels of the same biomarkers in patients with CAP + COPD. Chills, pleuritic pain, sputum purulence, and CRP levels at day 1 were independent clinical predictors of CAP + COPD. CONCLUSIONS Our study confirms that two different clinical and inflammatory profiles exist in hospitalized patients with COPD in response to CAP (stronger response) and AECOPD, although with similar short-term and long-term outcomes.

Predictors of Adverse Outcome in Patients Hospitalised for Exacerbation of Chronic Obstructive Pulmonary Disease

Background: It is crucial to identify risk factors for poor evolution of patients admitted to hospital with chronic obstructive pulmonary disease (COPD) in order to provide adequate intensive therapy and closer follow-up. Objectives: To identify predictors of adverse outcomes in patients hospitalised for exacerbation of COPD. Methods: A prospective, observational study was conducted in patients admitted for exacerbation of COPD. Demographic and clinical parameters were evaluated, including different multidimensional prognostic scores. Adverse outcomes included the following: death during hospitalisation or 1-month follow-up, intensive care unit admission, invasive or non-invasive mechanical ventilation, prolonged hospitalisation (>11 days) and COPD-related emergency visit or readmission within 1 month after discharge. Univariate and multivariate analysis were performed. Results: Of 155 patients included, an adverse outcome occurred in 69 (45%). Patients with an adverse outcome had lower forced expiratory volume in 1 s (p = 0.004) and more frequent exacerbations (p = 0.011), more frequently used oxygen at home (p = 0.042) and presented with lower pH (p < 0.001), lower ratio of arterial oxygen pressure to the fraction of inspired oxygen (p = 0.006), higher arterial carbon dioxide pressure (p < 0.001) and a worse score on several prognostic indices at admission. Independent predictors of adverse outcome were exacerbation of COPD in the previous year [odds ratio 3.9, 95% confidence interval (CI) 1.6–9.9; p = 0.004], hypercapnia (odds ratio 9.4, 95% CI 3.7–23.6; p < 0.001) and hypoxaemia (odds ratio 4.3, 95% CI 1.5–12.6; p = 0.008). In the presence of all three characteristics, the probability of an adverse outcome was 95%, while hypercapnia was the strongest prognostic factor with a risk of 54%. Conclusions: Patients with previous exacerbation of COPD, hypercapnia and hypoxaemia had the highest risk of an unfavourable evolution. The calculation of prognostic indices did not provide additional discriminative power.

Original ResearchCOPDPneumonic and Nonpneumonic Exacerbations of COPD: Inflammatory Response and Clinical Characteristics

BACKGROUND Community-acquired pneumonia (CAP) is a frequent event in patients with COPD, although it is not currently considered an acute exacerbation of COPD (AECOPD). To our knowledge, no studies have compared the inflammatory response of patients with COPD who develop CAP or AECOPD. The aim of our study was to compare clinical and evolutive manifestations and biologic signaling of AECOPD and CAP + COPD. METHODS Prospective data were collected from 249 consecutively hospitalized patients with COPD. Comparative analyses were performed in patients with AECOPD (n = 133) and patients with CAP + COPD (n = 116). Measures of clinical characteristics, blood biomarkers, and evolution were recorded on admission, after 3 and 30 days, and in a follow-up period of 30 days, 90 days, and 1 year. RESULTS Patients with CAP + COPD had higher FEV1 compared with patients with COPD without pneumonia. In-hospital and long-term outcomes (1 year) were similar for both populations. However, patients with AECOPD had more readmissions, and patients with CAP had more prior episodes of pneumonia. At day 1 and day 3, patients with CAP + COPD had significantly (P < .001) higher serum levels of C-reactive protein (CRP), procalcitonin, tumor necrosis factor-α, and IL-6. Repetition of the analyses after stratifying patients based on severity of disease, current inhaled pharmacotherapy, and noninfectious AECOPD cause confirmed higher levels of the same biomarkers in patients with CAP + COPD. Chills, pleuritic pain, sputum purulence, and CRP levels at day 1 were independent clinical predictors of CAP + COPD. CONCLUSIONS Our study confirms that two different clinical and inflammatory profiles exist in hospitalized patients with COPD in response to CAP (stronger response) and AECOPD, although with similar short-term and long-term outcomes.

Evaluation of antimicrobial treatment in mechanically ventilated patients with severe chronic obstructive pulmonary disease exacerbations.

Objective: To study microbial and susceptibility patterns and antimicrobial treatment responses in patients with severe, acute exacerbations of chronic obstructive pulmonary disease requiring mechanical ventilation. Design: Microbial investigation using tracheobronchial aspirates, bronchoscopy with a protected specimen brush, and bronchoalveolar lavage, as well as paired serologies. Evaluation of antimicrobial treatment by results of the initial investigation, susceptibility testing, and a repeated microbial investigation (tracheobronchial aspirates, bronchoscopy with a protected specimen brush, and bronchoalveolar lavage) after 72 hrs. Setting: A respiratory intensive care unit of a 1,000‐bed teaching hospital. Patients: Fifty severely exacerbated and mechanically ventilated patients with chronic obstructive pulmonary disease. Interventions: Initial empirical antimicrobial treatment according to clinical judgment. Measurements and Main Results: Overall, 36 of 50 patients (72%) had evidence of a microbial origin. Community‐acquired endogenous pathogens were present in 70% of patients, and Gram‐negative enteric bacilli and Pseudomonas/Stenotrophomonas species were present in 30%. All five isolates of Streptococcus pneumoniae were resistant to penicillin (three intermediately and two highly), and three were resistant to multiple antibiotics. Pseudomonas species revealed multiresistance in four of nine isolates (44%), and Stenotrophomonas maltophilia revealed multiresistance in one of two isolates. Antimicrobial treatment was modified according to diagnostic results in 11 of 31 patients (36%) with potentially pathogenic microorganisms. In patients who underwent a repeat investigation after 72 hrs, 24% of the initially present and potentially pathogenic microorganisms persisted. Inappropriate initial antimicrobial therapy was associated significantly with bacterial persistence (p < .002). Conclusions: Considering the diversity of microbial pathogens and the resistance rates especially to S. pneumoniae in this patient population, antimicrobial treatment should be based on the constant study of local microbial and susceptibility patterns along with routine microbial investigation of the individual patient.