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Pre- and post-bronchodilator lung function as predictors of mortality in the Lung Health Study

Chronic obstructive pulmonary disease (COPD) is supposed to be classified on the basis of post-bronchodilator lung function. Most longitudinal studies of COPD, though, do not have post-bronchodilator lung function available. We used pre-and post bronchodilator lung function data from the Lung Health Study to determine whether these measures differ in their ability to predict mortality.

Methods: We limited our analysis to subjects who were of black or white race, on whom we had complete data, and who participated at either the 1 year or the 5 year follow-up visit. We classified subjects based on their baseline lung function, according to COPD Classification criteria using both pre- and post-bronchodilator lung function. We conducted a survival analysis and logistic regression predicting death and controlling for age, sex, race, treatment group, smoking status, and measures of lung function (either pre- or post-bronchodilator. We calculated hazard ratios (HR) with 95% confidence intervals (CI) and also calculated area under the curve for the logistic regression models.

Results: By year 15 of the study, 721 of the original 5,887 study subjects had died. In the year 1 sample survival models, a higher FEV1 % predicted lower mortality in both the pre-bronchodilator (HR 0.87, 95% CI 0.81, 0.94 per 10% increase) and post-bronchodilator (HR 0.84, 95% CI 0.77, 0.90) models. The area under the curve for the respective models was 69.2% and 69.4%. Similarly, using categories, when compared to people with "normal" lung function, subjects with Stage 3 or 4 disease had similar mortality in both the pre- (HR 1.51, 95% CI 0.75, 3.03) and post-bronchodilator (HR 1.45, 95% CI 0.41, 5.15) models. In the year 5 sample, when a larger proportion of subjects had Stage 3 or 4 disease (6.4% in the pre-bronchodilator group), mortality was significantly increased in both the pre- (HR 2.68, 95% CI 1.51, 4.75) and post-bronchodilator (HR 2.46, 95% CI 1.63, 3.73) models.

Conclusions: Both pre- and post-bronchodilator lung function predicted mortality in this analysis with a similar degree of accuracy. Post-bronchodilator lung function may not be needed in population studies that predict long-term outcomes.

Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment

A phase III trial in Japan showed that pirfenidone is effective for idiopathic pulmonary fibrosis (IPF). To find out which patients specifically benefit from pirfenidone, we analyzed in an exploratory manner the data from the phase III trial.

Methods: The patients in the phase III trial were stratified by baseline percentage predicted vital capacity (%VC), arterial oxygen partial pressure (PaO2), and the lowest oxygen saturation by pulse oximetry (SpO2) during the 6-minute steady-state exercise test (6MET). In the subpopulations, changes in VC and subjective symptoms (cough and dyspnea on the Fletcher, Hugh-Jones (F, H-J) Classification scale) were evaluated in patients treated with high-dose (1800 mg/day) pirfenidone, low-dose (1200 mg/day) pirfenidone, and placebo at week 52.

Results: Significant efficacy of pirfenidone in reducing the decline in VC could be seen in a subpopulation having %VC of more than 70% and SpO2 of less than 90% at baseline. This favorable effect was accompanied by categorical change in VC and progression-free survival time. In the subpopulation, pirfenidone significantly suppressed cough and dyspnea.

Conclusions: IPF patients having %VC of more than 70% and SpO2 of less than 90% at baseline will most likely benefit from pirfenidone when evaluated using changes in VC (and %VC), and cough and dyspnea symptoms. This subpopulation could expect to benefit most from pirfenidone treatment.

Trial RegistrationThis clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (Registration Number: JAPICCTI050121).

Relationship between the anti-inflammatory properties of Salmeterol/Fluticasone and the expression of CD4+CD25+Foxp3+ Regulatory T Cells in COPD

Salmeterol and fluticasone combination (SFC) has anti-inflammatory effects and improves clinical symptoms in patients with chronic obstructive pulmonary disease (COPD). However, the anti-inflammatory mechanism of SFC remains unclear.

In this study, we investigated the inflammatory responses of COPD, as well as the relationship of the inflammatory factors with the levels of CD4+CD25+Foxp3+ regulatory T cells (Foxp3+Tregs) after SFC therapy.

Methods: Twenty-one patients with moderate or severe COPD received treatment with 50/500 mug of SFC twice a day for 12 weeks. Before and after treatment, the patients were evaluated using the Modified Medical Research Council (MMRC) dyspnea scale and by conducting a 6-min walking test. The number of neutrophils, monocytes and lymphocytes in induced sputum were counted. Levels of cytokines, including pre-inflammatory IL-8, TNF-alpha, IL-17A and cytokine IL-10, in the sputum supernatant and peripheral blood were measured by ELISA. The proportion of Foxp3+Tregs in the total CD4+ T cell of the peripheral blood was determined by flow cytometry. The relationship between IL-17A levels and the percentage of Foxp3+Tregs was analyzed by statistical analysis.

Results: After treatment with SFC, the forced expiratory volume in 1 s as a percentage of predicted values (FEV1%) and the 6-min walk distance in the COPD patients significantly increased, while dyspnea scores decreased. The total number of cells, neutrophil, and the percentage of neutrophils in induced sputum reduced notably, while the proportion of monocytes was significantly increased. Levels of the inflammatory cytokines IL-8, TNF-alpha, and IL-17A in the sputum supernatant and in the blood were markedly lowered, while IL-10 levels were unchanged. The proportion of Foxp3+Tregs in the total CD4+T cell population in the peripheral blood was drastically higher than that before treatment. The level of IL-17A was negatively correlated with the proportion of Foxp3+Tregs in CD4+T cells.

Conclusion: SFC can reduce the levels of inflammatory factors and improve symptoms of COPD. The levels of inflammatory factors are associated with the variation of Foxp3+Tregs in COPD.Trial registrationThis study was registered with chictr.org (Chinese Clinical Trial Register) as follows:ChiCTR-TNC-10001270

Pseudomonas aeruginosa and Mortality after Hospital Admission for Chronic Obstructive Pulmonary Disease

Background:Pseudomonas aeruginosa (PA) is isolated in advanced stages of chronic obstructive pulmonary disease (COPD).

Objectives: The aim of our study was to determine whether PA isolation during hospitalization for COPD exacerbation was associated with a poorer prognosis after discharge. Methods: We prospectively studied all patients with COPD exacerbation admitted between June 2003 and September 2004. A sputum culture was obtained at admission. Comorbidity, functional dependence, hospitalizations during the previous year, dyspnea, quality of life and other variables previously associated with mortality in COPD were studied. Spirometry and a 6-min walking test were performed 1 month after discharge. Mortality was evaluated 3 years after discharge.

Results: A total of 181 patients were included in the study. Of these, 29 (16%) had PA in the sputum. The mean age was 72 years, and mean basal postbronchodilator forced expiratory volume in 1 s was 45.2% predicted (SD 14.4). The mean point value on the BODE index was 5.1 (SD 2.5). At 3 years, 17 of 29 patients (58.6%) in the PA group had died, compared to 53 of the 152 non-PA patients [34.9%; p < 0.004; hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.29–3.86]. In the multivariate analysis, PA remained statistically related to posthospital mortality (p = 0.02; HR 2.2, 95% CI 1.2–4.2) after adjustment for age (p < 0.02; HR 1.04, 95% CI 1.007–1.07), BODE index (p < 0.02; HR 1.15, 95% CI 1.02–1.3) and comorbidity (p < 0.02; HR 1.24, 95% CI 1.03–1.5).

Conclusions: PA isolation in sputum in patients hospitalized for acute exacerbation of COPD is a prognostic marker of 3-year mortality. Poor prognosis is independent of other significant predictors of mortality such as BODE index, age and comorbidity, as measured by the Charlson index.

Early Prediction of In-Hospital Mortality of Patients with Hemoptysis: An Approach to Defining Severe Hemoptysis

Background: The severity of hemoptysis is usually assessed on the amount of blood expectorated, although no threshold has been agreed upon. Respiratory or hemodynamic failures are additional severity criteria but occur in few cases.

Objectives: Early identification of the in-hospital mortality determinants might be helpful to best characterize severe hemoptysis.

Methods:This is a retrospective cohort study of consecutive patients with hemoptysis admitted to the ICU of a teaching hospital during a 14-year period. The model for early prediction of in-hospital mortality was developed on a derivation sample (67% of patients) using multiple logistic regression. Calibration and discrimination of the model were tested using the remaining validation sample. A scoring system was developed for clinical use.

Results: The in-hospital mortality of the 1,087 patients (age 54 years, 71% male) was 6.5% (95% CI 5–8). Chronic alcoholism, cancer or aspergillosis, pulmonary artery involvement, infiltrates involving two quadrants or more on the admission radiograph, and mechanical ventilation at referral predicted independently mortality. The model showed good concordance between predicted and observed probabilities of death and good discrimination (receiver operating characteristic curve area 0.87; 95% CI 0.82–0.92). The model-based score (chronic alcoholism, pulmonary artery involvement, and radiographic patterns, 1 point each; cancer, aspergillosis, and mechanical ventilation, 2 points each) predicted the probability of death as follows: score 0, 1%; score 1, 2%; score 2, 6%; score 3, 16%; score 4, 34%; score 5, 58%; score 6, 79%, and score 7, 91%.

Conclusions: Our results provide useful information about the short-term prognosis of patients with hemoptysis, which could help design therapeutic approaches and management plans according to the risk of in-hospital mortality.

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