Juan P. de Torres

Distance and Oxygen Desaturation During the 6-min Walk Test as Predictors of Long-term Mortality in Patients With COPD

RATIONALE The distance walked in the 6-min walk test (6MWT) predicts mortality in patients with severe COPD. Little is known about its prognostic value in patients with a wider range of COPD severity, living in different countries, and the potential additional impact of oxygen desaturation measured during the test. METHODS We enrolled 576 stable COPD outpatients in Spain and the United States and observed them for at least 3 years (median, 60 months). We measured FEV1, body mass index, Pao2, Charlson comorbidity score, 6-min walk distance (6MWD), and oxygen saturation by pulse oximetry (Spo2) during the 6MWT. Desaturation was defined as a fall in Spo2 > or = 4% or Spo2 < 90%. Regression analysis helped determine the association between these variables and all-cause and respiratory mortality. RESULTS The 6MWD was a good predictor of all-cause and respiratory mortality primarily in patients with FEV1 < 50% of predicted (p < 0.001) after adjusting for all covariates. Patients with desaturation during the 6MWT had a higher mortality rate than patients without desaturation (67% vs 38%, p < 0.001). Oxygen desaturation predicted mortality (relative risk, 2.63; 95% confidence interval, 1.53 to 4.51; p < 0.001) but with less power than Pao2 at rest. CONCLUSIONS The 6MWD helps predict mortality primarily in patients with severe COPD. Although the oxygen desaturation profile during the 6MWT improves the predictive ability of the 6MWD, it appears to be of less relevance than in other lung diseases and than the resting Pao2.

Lung cancer in patients with chronic obstructive pulmonary disease-- incidence and predicting factors.

RATIONALE Little is known about the clinical factors associated with the development of lung cancer in patients with chronic obstructive pulmonary disease (COPD), although airway obstruction and emphysema have been identified as possible risk factors. OBJECTIVES To explore incidence, histologic type, and factors associated with development of lung cancer diagnosis in a cohort of outpatients with COPD attending a pulmonary clinic. METHODS A cohort of 2,507 patients without initial clinical or radiologic evidence of lung cancer was followed a median of 60 months(30–90). At baseline, anthropometrics, smoking history, lung function,and body composition were recorded. Time to diagnosis and histologic type of lung cancer was then registered. Cox analysis was used to explore factors associated with lung cancer diagnosis. MEASUREMENTS AND MAIN RESULTS A total of 215 of the 2,507 patients with COPD developed lung cancer (incidence density of 16.7 cases per 1,000 person-years). The most frequent type was squamous cell carcinoma (44%). Lung cancer incidence was lower in patients with worse severity of airflow obstruction. Global Initiative for Chronic Obstructive Lung Disease Stages I and II, older age, lower body mass index,and lung diffusion capacity of carbon monoxide less than 80%were associated with lung cancer diagnosis. CONCLUSIONS Incidence density of lung cancer is high in outpatients with COPD and occurs more frequently in older patients with milder airflow obstruction (Global Initiative for Chronic Obstructive Lung Disease Stages I and II) and lower body mass index. A lung diffusion capacity of carbon monoxide less than 80% is associated with cancer diagnosis. Squamous cell carcinoma is the most frequent histologic type. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management.

C-Reactive Protein Levels and Survival in Patients With Moderate to Very Severe COPD

BACKGROUND Serum levels of C-reactive protein (CRP) are increased in patients with COPD and correlate modestly with variables predictive of outcomes. In epidemiologic studies, CRP level is associated with all-cause mortality in patients with mild-to-moderate disease. OBJECTIVE To determine if CRP levels are associated with survival in patients with moderate to very severe COPD in comparison with other well-known prognostic parameters of the disease. METHODS In 218 stable patients with COPD, we measured baseline serum CRP level, BODE (body mass index, obstruction, dyspnea, and exercise capacity) index and its components, arterial oxygenation (Pao(2)), inspiratory capacity (IC) to total lung capacity (TLC) ratio, and Charlson comorbidity score. We followed up the patients over time and evaluated the strength of the association between the variables and all-cause mortality. RESULTS During the follow-up time (median, 36 months; 25th to 75th percentiles, 24 to 50 months), 54 patients (25%) died. CRP levels were similar between survivors and the deceased (median, 3.8 mg/L; 95% confidence interval, 1.9 to 8.1; vs median, 4.5 mg/L; 95% confidence interval, 2.1 to 11.5; p = 0.22) and was not significantly associated with survival. CONCLUSIONS In this population of patients with clinically moderate to very severe COPD, the level of CRP level was not associated with survival compared with other prognostic clinical tools such as the BODE index, modified Medical Research Council scale, 6-min walk distance, percentage of predicted FEV(1), IC/TLC ratio < 0.25, and Pao(2). Other long-term studies of well-characterized patients with COPD could help determine the exact role of CRP levels as a biomarker in patients with clinical COPD.

The Progression of Chronic Obstructive Pulmonary Disease Is Heterogeneous

RATIONALE Chronic obstructive pulmonary disease (COPD) is thought to result in rapid and progressive loss of lung function usually expressed as mean values for whole cohorts. OBJECTIVES Longitudinal studies evaluating individual lung function loss and other domains of COPD progression are needed. METHODS We evaluated 1,198 stable, well-characterized patients with COPD (1,100 males) recruited in two centers (Florida and Tenerife, Spain) and annually monitored their multidomain progression from 1997 to 2009. Patients were followed for a median of 64 months and up to 10 years. Their individual FEV(1) (L) and BODE index slopes, expressed as annual change, were evaluated using regression models for repeated measures. A total of 751 patients with at least three measurements were used for the analyses. MEASUREMENTS AND MAIN RESULTS Eighteen percent of patients had a statistically significant FEV(1) slope decline (-86 ml/yr; 95% confidence interval [CI], -32 to -278 ml/yr). Higher baseline FEV(1) (relative risk, 1.857; 95% CI, 1.322-2.610; P < 0.001) and low body mass index (relative risk, 1.071; 95% CI, 1.035-1.106; P < 0.001) were independently associated with FEV(1) decline. The BODE index had a statistically significant increase (0.55, 0.20-1.37 point/yr) in only 14% of patients and these had more severe baseline obstruction. Concordance between FEV1 and BODE change was low (κ Cohen, 16%). Interestingly, 73% of patients had no significant slope change in FEV1 or BODE. Only the BODE change was associated with mortality in patients without FEV(1) progression. CONCLUSIONS The progression of COPD is very heterogeneous. Most patients show no statistically significant decline of FEV(1) or increase in BODE. The multidimensional evaluation of COPD should offer insight into response to COPD management.

MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus

Infection by RNA viruses is detected by the host through Toll-like receptors or RIG-I-like receptors. Toll-like receptors and RIG-I-like receptors signal through the adaptors MyD88 and MAVS, respectively, to induce type I IFNs (IFN-I) and other antiviral molecules, which are thought to be essential for activating the adaptive immune system. We investigated the role of these adaptors in innate and adaptive immune responses against respiratory syncytial virus (RSV), a common human pathogen. Deletion of Mavs abolished the induction of IFN-I and other proinflammatory cytokines by RSV. Genome-wide expression profiling in the lung showed that the vast majority of RSV-induced genes depended on MAVS. Although Myd88 deficiency did not affect most RSV-induced genes, mice lacking both adaptors harbored a higher and more prolonged viral load and exhibited more severe pulmonary disease than those lacking either adaptor alone. Surprisingly, Myd88−/−Mavs−/− mice were able to activate a subset of pulmonary dendritic cells that traffic to the draining lymph node in response to RSV. These mice subsequently mounted a normal cytotoxic T-lymphocyte response and demonstrated delayed but effective viral clearance. These results provide an example of a normal and effective adaptive immune response in the absence of innate immunity mediated by MAVS and MyD88.

Original ResearchInterventional PulmonologyDiagnostic Yield of Electromagnetic Navigation Bronchoscopy Is Highly Dependent on the Presence of a Bronchus Sign on CT Imaging: Results From a Prospective Study

BACKGROUND Electromagnetic navigation bronchoscopy (ENB) has been developed as a novel ancillary tool for the bronchoscopic diagnosis of pulmonary nodules. Despite successful navigation in 90% of patients, ENB diagnostic yield does not generally exceed 70%. We sought to determine whether the presence of a bronchus sign on CT imaging conditions diagnostic yield of ENB and might account for the discrepancy between successful navigation and diagnostic yield. METHODS We conducted a prospective, single-center study of ENB in 51 consecutive patients with pulmonary nodules. ENB was chosen as the least invasive diagnostic technique in patients with a high surgical risk, suspected metastatic disease, or advanced-stage disease, or in those who demanded a preoperative diagnosis prior to undergoing curative resection. We studied patient and technical variables that might condition diagnostic yield, including size, cause, location, distance to the pleural surface, and fluorodeoxyglucose uptake of a given nodule; the presence of a bronchus sign on CT imaging; registration point divergence; and the minimum distance from the tip of the locatable guide to the nodule measured during the procedure. RESULTS The diagnostic yield of ENB was 67% (34/51). The sensitivity and specificity of ENB for malignancy in this study were 71% and 100%, respectively. ENB was diagnostic in 79% (30/38) patients with a bronchus sign on CT imaging but only in 4/13 (31%) with no discernible bronchus sign. Univariate analysis identified the bronchus sign (P = .005) and nodule size (P = .04) as statistically significant variables conditioning yield, but on multivariate analysis, only the bronchus sign remained significant (OR, 7.6; 95% CI, 1.8-31.7). No procedure-related complications were observed. CONCLUSIONS ENB diagnostic yield is highly dependent on the presence of a bronchus sign on CT imaging.

Multicomponent indices to predict survival in COPD: the COCOMICS study

Guidelines recommend defining chronic obstructive pulmonary disease (COPD) by airflow obstruction and other factors, but no studies have evaluated the ability of existing multicomponent indices to predict mortality up to 10 years. We conducted a patient-based pooled analysis. Survival analysis and C statistics were used to determine the best COPD index/indices according to several construct variables and by varying time-points. Individual data of 3633 patients from 11 COPD cohorts were collected, totalling the experience of 15 878 person-years. Overall, there were 1245 death events within our cohorts, with a Kaplan–Meier survival of 0.963 at 6 months, which was reduced to 0.432 at 10 years. In all patients, ADO (age, dyspnoea and forced expiratory volume in 1 s), BODE (body mass index, airflow obstruction, dyspnoea and exercise capacity) and e-BODE (BODE plus exacerbations) were the best indices to predict 6-month mortality. The ADO index was the best to predict 12-month (C statistic 0.702), 5-year (C statistic 0.695) and 10-year mortality (C statistic 0.698), and was significantly better than BODE (all p<0.05). The best indices to predict death by C statistics when adjusting by age were e-BODE, BODEx (substitution of exacerbations for exercise capacity) and BODE. No index predicts short-term survival of COPD well. All BODE modifications scored better than ADO after age adjustment. The ADO and BODE indices are overall the most valid multicomponent indices to predict time to death in all COPD patients.

The Impact of Steroids Given with Macrolide Therapy on Experimental Mycoplasma pneumoniae Respiratory Infection

BACKGROUND Systemic steroids have been advocated in addition to antimicrobial therapy for severe Mycoplasma pneumoniae pneumonia. We evaluated the efficacy of clarithromycin, dexamethasone, and combination therapy for M. pneumoniae respiratory infection. METHODS Mice infected with M. pneumoniae were treated with clarithromycin, dexamethasone, combined clarithromycin/dexamethasone, or placebo daily; mice were evaluated at baseline and after 1, 3, and 6 days of therapy. Outcome variables included M. pneumoniae culture, lung histopathologic score (HPS), and bronchoalveolar lavage cytokine, chemokine, and growth factor concentrations. RESULTS Clarithromycin monotherapy resulted in the greatest reductions in M. pneumoniae concentrations. After 3 days of treatment, combination therapy significantly reduced lung HPS compared with placebo, clarithromycin, and dexamethasone alone, whereas, after 6 days of therapy, clarithromycin alone and combination therapy significantly reduced lung HPS compared with placebo. Concentrations of interleukin (IL)-12 p40, RANTES, macrophage chemotactic protein-1, and cytokine-induced neutrophil chemoattractant were significantly lower in mice treated with clarithromycin alone and/or combination therapy compared with dexamethasone alone and/or placebo; combination therapy resulted in a significantly greater reduction than clarithromycin alone for IL-12 p40 and RANTES. CONCLUSIONS Although monotherapy with clarithromycin had the greatest effect on reducing concentrations of M. pneumoniae, combination therapy had the greatest effect on decreasing levels of cytokines and chemokines as well as pulmonary histologic inflammation.

Gender and respiratory factors associated with dyspnea in chronic obstructive pulmonary disease

RationaleWe had shown that COPD women expressed more dyspnea than men for the same degree of airway obstruction.ObjectivesEvaluate gender differences in respiratory factors associated with dyspnea in COPD patients.MethodsIn a FEV1 % matched population of 100 men and women with COPD we measured: age, MMRC, FEV1, FVC, TLC, IC/TLC, PaO2, PaCO2, DLCO, Pimax, P0.1, Ti/Ttot, BMI, ffmi, 6MWD and VAS scale before and after the test, the Charlson score and the SGRQ. We estimated the association between these parameters and MMRC scores. Multivariate analysis determined the independent strength of those associations.ResultsMMRC correlated with: BMI (men:-0.29, p = 0.04; women:-0.28, p = 0.05), ffmi (men:-0.39, p = 0.01), FEV1 % (men:-0.64, p < 0.001; women:-0.29, p = 0.04), FVC % (men:-0.45, p = 0.001; women:-0.33, p = 0.02), IC/TLC (men:-0.52, p < 0.001; women: -0.27, p = 0.05), PaO2 (men:-0.59, p < 0.001), PaCO2 (men:0.27, p = 0.05), DLCO (men:-0.54, p < 0.001), P0.1/Pimax (men:0.46, p = 0.002; women:0.47, p = 0.005), dyspnea measured with the Visual Analog Scale before (men:0.37, p = 0.04; women:0.52, p = 0.004) and after 6MWD (men:0.52, p = 0.002; women:0.48, p = 0.004) and SGRQ total (men:0.50, p < 0.001; women:0.59, p < 0.001). Regression analysis showed that P0.1/Pimax in women (r2 = 0.30) and BMI, DLCO, PaO2 and P0.1/Pimax in men (r2 = 0.81) were the strongest predictors of MMRC scores.ConclusionIn mild to severe COPD patients attending a pulmonary clinic, P0.1/Pimax was the unique predictor of MMRC scores only in women. Respiratory factors explain most of the variations of MMRC scores in men but not in women. Factors other than the respiratory ones should be included in the evaluation of dyspnea in women with COPD.

Microalbuminuria and Hypoxemia in Patients with Chronic Obstructive Pulmonary Disease

RATIONALE Microalbuminuria (MAB), a marker of endovascular dysfunction, is a predictor of cardiovascular events and all-cause mortality in the general population. There is evidence of vascular dysfunction in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES To assess the prevalence and relationship of MAB with clinical and physiological parameters in stable patients with COPD. METHODS We measured urinary albumin rate (urinary albumin to creatinine ratio: UACR), smoking history, arterial blood pressure, gas exchange, body mass index, lung function, BODE index (body mass index, airflow obstruction, dyspnea, exercise performance), and comorbidity index in 129 patients with stable COPD and 51 smokers with normal spirometry without known cardiovascular disease. MAB levels were compared between groups. A multivariate analysis was performed to determine the best determinants of MAB levels. MEASUREMENTS AND MAIN RESULTS MAB was higher in patients with COPD than in control smokers (8 [5th-95th percentile (P₅₋₉₅), 2.9-113] vs. 4.2 [P₅₋₉₅, 1.8-22.7] mg/g, P < 0.001]). The difference remained significant even after using the standard pathologic threshold (MAB, 30-299 mg/g in women and 20-299 mg/g in men; 24% in patients with COPD vs. 6% in control smokers; P = 0.005). In patients with COPD, there was a negative correlation between Pa(O₂) and MAB (r = -0.40, P < 0.001). Using multivariate analysis, MAB was only associated with the Pa(O₂) (relative risk, 0.934; 95% confidence interval, 0.880-0.992; P < 0.001) and with the systolic arterial blood pressure (relative risk, 1.034; 95% confidence interval, 1.011-1.057; P = 0.003). CONCLUSIONS MAB is frequent in patients with COPD and is associated with hypoxemia independent of other cardiovascular risk factors. Further studies are necessary to investigate whether MAB could be an early simple biomarker of cardiovascular compromise in patients with COPD.