Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Rationale: The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development.Objectives: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV 1 decline.Methods: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV 1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM emph ) and functional small airways disease (PRM fSAD ), a measure of nonemphysematous air trapping.Measurements and Main Results: Mean (SD) rate of FEV 1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P , 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM fSAD but not PRM emph was associated with FEV 1 decline (P , 0.001). In GOLD 1-4 participants, both PRM fSAD and PRM emph were associated with FEV 1 decline (P , 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV 1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM fSAD and PRM emph in GOLD 1/2 and 3/4, respectively.Conclusions: CT-assessed functional small airway disease and emphysema are associated with FEV 1 decline, but the association with functional small airway disease has greatest importance in mildto-moderate stage chronic obstructive pulmonary disease where the rate of FEV 1 decline is the greatest.Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Rationale: Obesity may alter glucocorticoid response in asthma. Objectives: To evaluate the relationship between body mass index (BMI, kg/m 2 ) and glucocorticoid response in subjects with and without asthma. Methods: Nonsmoking adult subjects underwent characterization of lung function, BMI, and spirometric response to prednisone. Dexamethasone (DEX, 10 26 M)-induced mitogen-activated protein kinase phosphatase-1 (MKP-1) and baseline tumor necrosis factor (TNF)-a expression were evaluated by polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage cells. The relationship between BMI and expression of MKP-1 and TNF-a was analyzed. Measurements and Main Results: A total of 45 nonsmoking adults, 33 with asthma (mean [SD] FEV 1 % of 70.7 [9.8]%) and 12 without asthma were enrolled. DEX-induced PBMC MKP-1 expression was reduced in overweight/obese versus lean patients with asthma, with mean (6 SEM) fold-induction of 3.11 (60.46) versus 5.27 (60.66), respectively (P 5 0.01). In patients with asthma, regression analysis revealed a 20.16 (60.08)-fold decrease in DEX-induced MKP-1 per unit BMI increase (P 5 0.04). PBMC TNF-a expression increased as BMI increased in subjects with asthma, with a 0.27 unit increase in log (TNF-a [ng/ml]) per unit BMI increase (P 5 0.01). The ratio of PBMC log (TNF-a):DEX-induced MKP-1 also increased as BMI increased in patients with asthma (10.09 6 0.02; P 5 0.004). In bronchoalveolar lavage cells, DEX-induced MKP-1 expression was also reduced in overweight/obese versus lean patients with asthma (1.36 6 0.09-fold vs. 1.76 6 0.15-fold induction; P 5 0.05). Similar findings were not observed in control subjects without asthma. Conclusions: Elevated BMI is associated with blunted in vitro response to dexamethasone in overweight and obese patients with asthma.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown.Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up.Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV 1 decline based on reported exacerbations or acute respiratory events. Measurements and Main Results:In subjects with COPD, exacerbations were associated with excess FEV 1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV 1 decline.Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease.Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Multidrug-resistant tuberculosis, a disease caused by Mycobacterium tuberculosis strains that are resistant at least to rifampin and isoniazid, entails extended treatment, expensive and toxic regimens, and higher rates of treatment failure and death. We retrospectively analyzed the outcomes in 205 patients treated at our center for multidrug-resistant tuberculosis, with strains resistant to a median of six drugs, and compared the results with those of our previous series. Logistic regression and survival analysis were used to evaluate short- and long-term outcomes, respectively. Initial favorable response, defined as at least three consecutive negative sputum cultures over a period of at least 3 months, was 85% compared with 65% in the prior cohort. The current cohort had greater long-term success rates, 75% versus 56%, and lower tuberculosis death rates, 12% versus 22%, than the earlier one. Surgical resection and fluoroquinolone therapy were associated with improved microbiological and clinical outcomes in the 205 patients studied after adjusting for other variables. The improvement was statistically significant for surgery and among older patients for fluoroquinolone therapy.