Xavier Pomares

Severity-Related Changes of Bronchial Microbiome in Chronic Obstructive Pulmonary Disease

ABSTRACT Bronchial colonization by potentially pathogenic microorganisms (PPMs) is often demonstrated in chronic obstructive pulmonary disease (COPD), but culture-based techniques identify only a portion of the bacteria in mucosal surfaces. The aim of the study was to determine changes in the bronchial microbiome of COPD associated with the severity of the disease. The bronchial microbiome of COPD patients was analyzed by 16S rRNA gene amplification and pyrosequencing in sputum samples obtained during stable disease. Seventeen COPD patients were studied (forced expiratory volume in the first second expressed as a percentage of the forced vital capacity [FEV1%] median, 35.0%; interquartile range [IQR], 31.5 to 52.0), providing a mean of 4,493 (standard deviation [SD], 2,598) sequences corresponding to 47 operational taxonomic units (OTUs) (SD, 17) at a 97% identity level. Patients were dichotomized according to their lung function as moderate to severe when their FEV1% values were over the median and as advanced when FEV1% values were lower. The most prevalent phyla in sputum were Proteobacteria (44%) and Firmicutes (16%), followed by Actinobacteria (13%). A greater microbial diversity was found in patients with moderate-to-severe disease, and alpha diversity showed a statistically significant decrease in patients with advanced disease when assessed by Shannon (ρ = 0.528; P = 0.029, Spearman correlation coefficient) and Chao1 (ρ = 0.53; P = 0.028, Spearman correlation coefficient) alpha-diversity indexes. The higher severity that characterizes advanced COPD is paralleled by a decrease in the diversity of the bronchial microbiome, with a loss of part of the resident flora that is replaced by a more restricted microbiota that includes PPMs.

Long-term azithromycin therapy in patients with severe COPD and repeated exacerbations

Background The aim of this study was to determine whether long-term intermittent azithromycin therapy reduces the frequency of exacerbation in severe chronic obstructive pulmonary disease (COPD). Methods We retrospectively investigated the clinical benefits of long-term azithromycin (500 mg orally three times per week) over 12 months in patients with severe COPD and a minimum of four acute exacerbations (AECOPD) per year or chronic bronchial colonization by Pseudomonas aeruginosa, comparing the number of AECOPD, hospitalizations due to respiratory disease, days of hospital stay, and bacterial infections during azithromycin treatment and in the year prior to this therapy. Results Twenty patients who completed the 12-month treatment period were analyzed. No clinically significant adverse events were observed during azithromycin treatment. Compared with baseline data, azithromycin therapy significantly reduced the number of AECOPD (2.8 ± 2.5 versus 6.8 ± 2.8, P < 0.001), hospitalizations (1.4 ± 1.5 versus 3.6 ± 1.4, P < 0.001), and cumulative annual days of hospital stay (25 ± 32.2 versus 43.7 ± 21.4, P = 0.01). The improvement was particularly significant in patients with exacerbations caused by common potentially pathogenic microorganisms, who had 70% fewer AECOPD and hospitalizations. Patients colonized by P. aeruginosa had reductions of 43% in AECOPD and 47% in hospitalizations. Conclusion Long-term azithromycin is well tolerated and associated with significant reductions in AECOPD, hospitalizations, and length of hospital stay in patients with severe COPD.

Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary disease: characterization and risk factors

BackgroundPatients with severe chronic obstructive pulmonary disease (COPD) are at increased risk of infection by P. aeruginosa. The specific role of bronchiectasis in both infection and chronic colonization by this microorganism in COPD, however, remains ill defined.To evaluate the prevalence and risk factors for P. aeruginosa recovery from sputum in outpatients with severe COPD, characterizing P. aeruginosa isolates by pulsed-field gel electrophoresis (PFGE) and focusing on the influence of bronchiectasis on chronic colonization in these patients.MethodsA case-cohort study of 118 patients with severe COPD attended at a Respiratory Day Unit for an acute infectious exacerbation and followed up over one year. High-resolution CT scans were performed during stability for bronchiectasis assessment and sputum cultures were obtained during exacerbation and stability in all patients. P. aeruginosa isolates were genotyped by PFGE. Determinants of the recovery of P. aeruginosa in sputum and chronic colonization by this microorganism were assessed by multivariate analysis.ResultsP. aeruginosa was isolated from 41 of the 118 patients studied (34.7%). Five of these 41 patients (12.2%) with P. aeruginosa recovery fulfilled criteria for chronic colonization. In the multivariate analysis, the extent of bronchiectasis (OR 9.8, 95% CI: 1.7 to 54.8) and the number of antibiotic courses (OR 1.7, 95% CI: 1.1 to 2.5) were independently associated with an increased risk of P. aeruginosa isolation. Chronic colonization was unrelated to the presence of bronchiectasis (p=0.75). In patients with chronic colonization the isolates of P. aeruginosa retrieved corresponded to the same clones during the follow-up, and most of the multidrug resistant isolates (19/21) were harbored by these patients.ConclusionsThe main risk factors for P. aeruginosa isolation in severe COPD were the extent of bronchiectasis and exposure to antibiotics. Over 10% of these patients fulfilled criteria for chronic colonization by P. aeruginosa and showed clonal persistence, independently of the presence of bronchiectasis.

Omalizumab in the management of oral corticosteroid-dependent IGE-mediated asthma patients

Abstract Background: Several studies have demonstrated the beneficial effects of omalizumab in asthma patients. Here we describe the drug’s tolerance and oral corticosteroid sparing capacity in a long-term observational study. Methods: Thirty-two patients aged ≥18 years with obstructive airway disease and FEV1 reversibility ≥12% and 200 mL, with an oral steroid requirement ≥7.5 mg per day of prednisolone during a period of ≥1 year, a positive prick test or in vitro reactivity (RAST) to at least one perennial aeroallergen and a baseline immunoglobulin E level ranking between 30–700 IU/mL were prospectively followed for 17.2 ± 8.5 months. Patients were visited once or twice a month, depending on their schedule for omalizumab administration. Intervention: blood analysis every six months; spirometry and nitric oxide measurement at every visit. Results: One patient who dropped out early was excluded. Follow-up period: the treatment benefited 83.9% (26/31) of the cohort; oral corticosteroids were reduced from 7.19 ± 11.1 to 3.29 ± 11.03 mg (p < 0.002) and withdrawn in 74.2% of patients. FEV1 (percent predicted) was 64.4 ± 22.7 at the beginning and 62.9 ± 24.3 at the end. IgE at entry was 322.2 ± 334.2 IU/mL and increased 2.34-fold. Respiratory function and NO did not present statistically significant changes. We identified three groups of patients: the first (n = 17) receiving oral steroid at entry in whom the accumulated dose of oral steroids progressively decreased; another (n = 10) including patients who had quit oral steroids before starting omalizumab although they had not been instructed to do so and whose oral steroid dose at the end of follow-up was zero; and a third group (n = 4) that did not benefit from omalizumab treatment. The only relevant side effect was a flu-like syndrome which required discontinuation of treatment in one patient. Conclusion: In our series, a substantial, safe decrease in oral corticosteroid requirements was observed due, at least to some extent, to omalizumab therapy. Oral corticosteroids were withdrawn in three-quarters of the patients. We were unable to identify a factor able to predict which patients would benefit most from omalizumab treatment.

Effect of Leak and Breathing Pattern on the Accuracy of Tidal Volume Estimation by Commercial Home Ventilators: A Bench Study

BACKGROUND: New home ventilators are able to provide clinicians data of interest through built-in software. Monitoring of tidal volume (VT) is a key point in the assessment of the efficacy of home mechanical ventilation. OBJECTIVE: To assess the reliability of the VT provided by 5 ventilators in a bench test. METHODS: Five commercial ventilators from 4 different manufacturers were tested in pressure support mode with the help of a breathing simulator under different conditions of mechanical respiratory pattern, inflation pressure, and intentional leakage. Values provided by the built-in software of each ventilator were compared breath to breath with the VT monitored through an external pneumotachograph. Ten breaths for each condition were compared for every tested situation. RESULTS: All tested ventilators underestimated VT (ranges of −21.7 mL to −83.5 mL, which corresponded to −3.6% to −14.7% of the externally measured VT). A direct relationship between leak and underestimation was found in 4 ventilators, with higher underestimations of the VT when the leakage increased, ranging between −2.27% and −5.42% for each 10 L/min increase in the leakage. A ventilator that included an algorithm that computes the pressure loss through the tube as a function of the flow exiting the ventilator had the minimal effect of leaks on the estimation of VT (0.3%). In 3 ventilators the underestimation was also influenced by mechanical pattern (lower underestimation with restrictive, and higher with obstructive). CONCLUSIONS: The inclusion of algorithms that calculate the pressure loss as a function of the flow exiting the ventilator in commercial models may increase the reliability of VT estimation.

Treatment of patients with COPD and recurrent exacerbations: the role of infection and inflammation.

Exacerbations of COPD represent an important medical and health care problem. Certain susceptible patients suffer recurrent exacerbations and as a consequence have a poorer prognosis. The effects of bronchial infection, either acute or chronic, and of the inflammation characteristic of the disease itself raise the question of the possible role of antibiotics and anti-inflammatory agents in modulating the course of the disease. However, clinical guidelines base their recommendations on clinical trials that usually exclude more severe patients and patients with more comorbidities, and thus often fail to reflect the reality of clinicians attending more severe patients. In order to discuss aspects of clinical practice of relevance to pulmonologists in the treatment and prevention of recurrent exacerbations in patients with severe COPD, a panel discussion was organized involving expert pulmonologists who devote most of their professional activity to day hospital care. This article summarizes the scientific evidence currently available and the debate generated in relation to the following aspects: bacterial and viral infections, chronic bronchial infection and its treatment with cyclic oral or inhaled antibiotics, inflammatory mechanisms and their treatment, and the role of computerized tomography as a diagnostic tool in patients with severe COPD and frequent exacerbations.

Causas de muerte en pacientes con EPOC grave. Factores pronósticos

OBJECTIVE The objective of this study was to assess the causes of death and risk factors for mortality in a cohort of patients with severe chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS We studied 203 patients with severe COPD (forced expiratory volume in 1 second [FEV(1)] <50%), who were attended in our respiratory department day hospital (2001-2006). Clinical variables were recorded on inclusion, and clinical course and causes of death were retrospectively reviewed. RESULTS The mean (SD) age of patients was 69 (8) years and the mean FEV(1) was 30.8% (8.2%). One-hundred and nine patients died (53.7%); death was attributed to respiratory causes in 72 (80.9%), with COPD exacerbation being the most frequent specific cause within this category (48.3%). During follow-up, 18.7% required admission to the intensive care unit (ICU). Survival at 1, 3, and 5 years was 80%, 53%, and 26%, respectively. The multivariate analysis showed that mortality was associated with age, stage IV classification according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), cor pulmonale, and hospital admission during the year prior to inclusion. Need for admission to the ICU during follow-up was a factor independently associated with higher mortality. CONCLUSIONS Mortality in patients with severe COPD was high and exacerbation of the disease was one of the most frequent causes of death. Age, GOLD stage, cor pulmonale, prior admission to hospital, and need for admission to the ICU during follow-up were independent predictors of mortality.

Functional Metagenomics of the Bronchial Microbiome in COPD

The course of chronic obstructive pulmonary disease (COPD) is frequently aggravated by exacerbations, and changes in the composition and activity of the microbiome may be implicated in their appearance. The aim of this study was to analyse the composition and the gene content of the microbial community in bronchial secretions of COPD patients in both stability and exacerbation. Taxonomic data were obtained by 16S rRNA gene amplification and pyrosequencing, and metabolic information through shotgun metagenomics, using the Metagenomics RAST server (MG-RAST), and the PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) programme, which predict metagenomes from 16S data. Eight severe COPD patients provided good quality sputum samples, and no significant differences in the relative abundance of any phyla and genera were found between stability and exacerbation. Bacterial biodiversity (Chao1 and Shannon indexes) did not show statistical differences and beta-diversity analysis (Bray-Curtis dissimilarity index) showed a similar microbial composition in the two clinical situations. Four functional categories showed statistically significant differences with MG-RAST at KEGG level 2: in exacerbation, Cell growth and Death and Transport and Catabolism decreased in abundance [1.6 (0.2–2.3) vs 3.6 (3.3–6.9), p = 0.012; and 1.8 (0–3.3) vs 3.6 (1.8–5.1), p = 0.025 respectively], while Cancer and Carbohydrate Metabolism increased [0.8 (0–1.5) vs 0 (0–0.5), p = 0.043; and 7 (6.4–9) vs 5.9 (6.3–6.1), p = 0.012 respectively]. In conclusion, the bronchial microbiome as a whole is not significantly modified when exacerbation symptoms appear in severe COPD patients, but its functional metabolic capabilities show significant changes in several pathways.

Can Omalizumab Be Effective in Chronic Eosinophilic Pneumonia

We have recently read with interest the article by Kaya et al 1 in CHEST (August 2012) reporting on a patient suffering from chronic eosinophilic pneumonia (CEP) who responded successfully to omalizumab. Five years ago, we attended a 43-year-old nonsmoking man who complained of cough, fever, dyspnea, and wheezing. On the basis of his clinical presentation, peripheral blood and BAL eosinophilia, and the presence of bilateral peripheral infi ltrates on the chest radiograph, the diagnosis of CEP was made. As in the Kaya et al 1 case, oral corticosteroids (OCs) were started with an initial successful response. After 3 months of therapy, the dose of OCs was progressively tapered. When the dose reached 10 mg prednisolone, a relapse occurred that forced us to increase the dose of OCs. The patient improved, and bronchospasm and chest infi ltrates disappeared. During the process of OC tapering, a new relapse occurred, bronchospasm being the most relevant clinical symptom that forced us to increase again the dose of OCs. A skin prick test was performed that was positive for mite dust. Total blood IgE level was 253 IU/mL. Omalizumab treatment was started at the dose calculated according to the patient’s weight and IgE concentration. The patient progressively improved, and after 18 months of treatment (6 months to check clinical response followed by 12 months of stabilization), according to our decreasing-dose protocol of omalizumab, 2 the dose of omalizumab was progressively tapered by 50% every 6 months. The patient’s tolerance was excellent, and omalizumab treatment could be safely quit 12 months later. The patient has remained free of symptoms of CEP for . 2 years, requiring only two short courses of OCs for his asthma. The IgE-dependent infl ammatory phenomena have been studied in depth and are clearly recognized in atopic subjects, and the anti-IgE blocking effect of omalizumab has been clearly shown. Additional benefi ts can be provided by the fi ndings of Kalesnikoff et al, 3 who observed that by binding to its high-affi nity receptor, Fc ́ RI, IgE was able to induce intracellular signaling pathways, resulting in the production of cytokines and the enhancement of mast-cell survival on its own, without cross-linking by allergens. In addition, IgE can directly bind and activate receptors present on eosinophils, neutrophils, and monocytes. As a result, the rationale for the use of omalizumab in diseases other than allergy is based on its blocking effect on IgE, which inhibits part of the T helper cell type 2 immune response, thus, reducing recruitment and activation of effector cells of the infl ammatory process, including eosinophils. Because IgE effector cells (ie, mast cells and basophils) are a source of proinfl ammatory molecules, anti-IgE therapy may have antiinfl ammatory properties that reduce circulating and tissue eosinophils 4 ; indeed, this role has been suggested in other diseases, such as eosinophil-associated GI disorders. 5 More recently, Noga et al 4 demonstrated an increase in eosino phil apoptosis and a decrease in granulocyte-macrophage colony-stimulating factor. All this information can help to explain the benefi ts of omalizumab in CEP. In their report, Kaya et al 1 communicate that their patient remains free of symptoms 15 months after omalizumab treatment began, but they do not state future treatment options. We believe some of these patients can benefi t from a decreasing dose protocol. 2

Ventilación mecánica no invasiva. Reflexiones sobre la monitorización a domicilio

Home-based noninvasive ventilation (NIV) was initiated in the early nineties in our environment as a treatment for patients with chronic respiratory failure, secondary to restrictive ventilatory disorders or neuromuscular disease. Subsequently, NIV also proved effective in patients with obesity-related hypoventilation syndromes, and to a lesser extent in some patients with chronic obstructive pulmonary disease in stable phase. There was a simultaneous growth in interest in whether the selected parameters suited the patients’ needs when using NIV in the home setting. Thus, the use of continuous overnight pulse oximetry monitoring as the gold standard for home monitoring in centers prescribing ventilation became widespread. The main issue with pulse oximetry has undoubtedly been its lack of specificity for correlation with certain patterns of patient–ventilator interaction. In other words, the effects of adverse events (desaturation) were detected, but there was a limited understanding of the underlying causes, and therefore of the potential solutions. In order to improve the performance of pulse oximetry, a series of simplified polygraphic systems have appeared in recent years, mostly in association with the ventilator manufacturers. These systems provide a set of data on the patient’s respiratory mechanics that can be downloaded from the ventilator’s internal memory. The main purpose is to provide the clinician with additional information on the potential reasons for inadequate ventilation periods and the pathophysiological causes (unintentional interface leaks, uncorrected upper airway episodes, asynchrony, etc.). Over the years, almost all manufacturers of ventilation systems have developed their own download system and data display.1 However, in our view, the performance and reliability of these devices, which are widely used today, should be analyzed in depth. The first premise to be considered by the clinician is that a number of values provided by these software systems are not measured directly. In single-tube systems, the most widely used in home