Undernourished Household Contacts Are at Increased Risk of Tuberculosis (TB) Disease, but not TB Infection- a Multicenter Prospective Cohort Analysis.

Undernutrition is the leading risk factor for tuberculosis (TB) globally and in India. This multicenter prospective cohort analysis from India suggests that undernutrition is associated with increased risk of TB disease but not TB infection among household contacts of persons with TB.

The sound of silent RNA in tuberculosis and the lncRNA role on infection.

Tuberculosis (TB) is one of the leading causes of death worldwide, and Diabetes Mellitus is one of the major comorbidities (TB/DM) associated with the disease. A total of 103 differentially expressed ncRNAs have been identified in the TB and TB/DM comparisons. A machine learning algorithm was employed to identify the most informative lncRNAs: ADM-DT, LINC02009, LINC02471, SOX2-OT, and GK-AS1. These lncRNAs presented substantial accuracy in classifying TB from HC (AUCs >0.85) and TB/DM from HC (AUCs >0.90) in the other three countries. Genes with significant correlations with the five lncRNAs enriched common pathways in Brazil and India for both TB and TB/DM. This suggests that lncRNAs play an important role in the regulation of genes related to the TB immune response.

Glycated Hemoglobin Trajectories and Their Association With Treatment Outcomes Among Patients With Pulmonary TB in India: A Prospective Cohort Study.

BACKGROUND: Transient hyperglycemia is seen commonly during TB treatment, yet its association with unfavorable treatment outcomes is unclear. RESEARCH QUESTION: Does an association exist between glycated hemoglobin (HbA1c) trajectories and TB treatment outcomes? STUDY DESIGN AND METHODS: Adults with pulmonary TB were evaluated prospectively for 18 months after the second HbA1c measurement. HbA1c trajectories during the initial 3 months of treatment were defined as follows: persistent euglycemia, HbA1c < 6.5% at baseline and 3-month follow-up; persistent hyperglycemia, HbA1c ≥ 6.5% at baseline and 3-month follow-up; transient hyperglycemia, HbA1c ≥ 6.5% at baseline and < 6.5% at 3-month follow-up; incident hyperglycemia, HbA1c < 6.5% at baseline and ≥ 6.5% at 3-month follow-up. Multivariable Poisson regression was used to measure the association between HbA1c trajectories and unfavorable treatment outcomes of failure, recurrence, and all-cause mortality. RESULTS: Of the 587 participants, 443 participants (76%) had persistent euglycemia, 118 participants (20%) had persistent hyperglycemia, and 26 participants (4%) had transient hyperglycemia. One participant had incident hyperglycemia and was excluded. Compared with participants with persistent euglycemia, those with transient hyperglycemia showed a twofold higher risk of experiencing an unfavorable treatment outcome (adjusted incidence rate ratio [aIRR], 2.07; 95% CI, 1.04-4.15) after adjusting for confounders including diabetes treatment, and BMI; we did not find a significant association with persistent hyperglycemia (aIRR, 1.64; 95% CI, 0.71-3.79). Diabetes treatment was associated with a significantly lower risk of unfavorable treatment outcomes (aIRR, 0.38; 95% CI, 0.15-0.95). INTERPRETATION: Transient hyperglycemia and lack of diabetes treatment was associated with a higher risk of unfavorable treatment outcomes in adults with pulmonary TB.

Early Microbiologic Markers of Pulmonary Tuberculosis Treatment Outcomes.

Rationale: Earlier biomarkers of pulmonary tuberculosis (PTB) treatment outcomes are critical to monitor shortened anti-TB treatment (ATT). Objectives: To identify early microbiologic markers of unfavorable TB treatment outcomes. Methods: We performed a subanalysis of 2 prospective TB cohort studies conducted from 2013 to 2019 in India. We included participants aged ⩾18 years who initiated 6-month ATT for clinically or microbiologically diagnosed drug-sensitive PTB and completed at least one follow-up visit. Sputum specimens were subjected to a baseline Xpert Mycobacterium tuberculosis/rifampin (MTB/RIF) assay, acid-fast bacilli (AFB) microscopy and liquid and solid cultures, and serial AFB microscopy and liquid and solid cultures at weeks 2, 4, and 8. Poisson regression was used to assess the impact of available microbiologic markers (test positivity, smear grade, time to detection, and time to conversion) on a composite outcome of failure, recurrence, or death by 18 months after the end of treatment. Models were adjusted for age, sex, nutritional status, diabetes, smoking, alcohol consumption, and regimen type. Results: Among 1,098 eligible cases, there were 251 (22%) adverse TB treatment outcomes: 127 (51%) treatment failures, 73 (29%) recurrences, and 51 (20%) deaths. The primary outcome was independently associated with the Xpert MTB/RIF assay (medium-positive adjusted incidence rate ratio [aIRR], 1.91; 95% confidence interval [CI], 1.07-3.40; high-positive aIRR, 2.51; 95% CI, 1.41-4.46), positive AFB smear (aIRR, 1.48; 95% CI, 1.06-2.06), and positive liquid culture (aIRR, 1.98; 95% CI, 1.21-3.23) at baseline; Week 2 positive liquid culture (aIRR, 1.47; 95% CI, 1.04-2.09); and Week 8 positive AFB smear (aIRR, 1.63; 95% CI, 1.06-2.50) and positive liquid culture (aIRR, 1.54; 95% CI, 1.07-2.22). There was no evidence of Mycobacterium tuberculosis growth in the Mycobacterium Growth Indicator Tube at Week 4 conferring a higher risk of adverse outcomes (aIRR, 1.25; 95% CI, 0.89-1.75). Conclusions: Our analysis identifies Week 2 respiratory mycobacterial culture as the earliest microbiologic marker of unfavorable PTB treatment outcomes.

A multi-center, prospective cohort study of whole blood gene expression in the tuberculosis-diabetes interaction.

Diabetes mellitus (DM) increases tuberculosis (TB) severity. We compared blood gene expression in adults with pulmonary TB, with or without diabetes mellitus (DM) from sites in Brazil and India. RNA sequencing (RNAseq) performed at baseline and during TB treatment. Publicly available baseline RNAseq data from South Africa and Romania reported by the TANDEM Consortium were also analyzed. Across the sites, differentially expressed genes varied for each condition (DM, TB, and TBDM) and no pattern classified any one group across all sites. A concise signature of TB disease was identified but this was expressed equally in TB and TBDM. Pathway enrichment analysis failed to distinguish TB from TBDM, although there was a trend for greater neutrophil and innate immune pathway activation in TBDM participants. Pathways associated with insulin resistance, metabolic dysfunction, diabetic complications, and chromosomal instability were positively correlated with glycohemoglobin. The immune response to pulmonary TB as reflected by whole blood gene expression is substantially similar with or without comorbid DM. Gene expression pathways associated with the microvascular and macrovascular complications of DM are upregulated during TB, supporting a syndemic interaction between these coprevalent diseases.

Impact of Undernutrition on Tuberculosis Treatment Outcomes in India: A Multicenter, Prospective, Cohort Analysis.

BACKGROUND: Undernutrition is the leading risk factor for tuberculosis (TB) globally. Its impact on treatment outcomes is poorly defined. METHODS: We conducted a prospective cohort analysis of adults with drug-sensitive pulmonary TB at 5 sites from 2015-2019. Using multivariable Poisson regression, we assessed associations between unfavorable outcomes and nutritional status based on body mass index (BMI) nutritional status at treatment initiation, BMI prior to TB disease, stunting, and stagnant or declining BMI after 2 months of TB treatment. Unfavorable outcome was defined as a composite of treatment failure, death, or relapse within 6 months of treatment completion. RESULTS: Severe undernutrition (BMI <16 kg/m2) at treatment initiation and severe undernutrition before the onset of TB disease were both associated with unfavorable outcomes (adjusted incidence rate ratio [aIRR], 2.05; 95% confidence interval [CI], 1.42-2.91 and aIRR, 2.20; 95% CI, 1.16-3.94, respectively). Additionally, lack of BMI increase after treatment initiation was associated with increased unfavorable outcomes (aIRR, 1.81; 95% CI, 1.27-2.61). Severe stunting (height-for-age z score <-3) was associated with unfavorable outcomes (aIRR, 1.52; 95% CI, 1.00-2.24). Severe undernutrition at treatment initiation and lack of BMI increase during treatment were associated with a 4- and 5-fold higher rate of death, respectively. CONCLUSIONS: Premorbid undernutrition, undernutrition at treatment initiation, lack of BMI increase after intensive therapy, and severe stunting are associated with unfavorable TB treatment outcomes. These data highlight the need to address this widely prevalent TB comorbidity. Nutritional assessment should be integrated into standard TB care.

Sex Differences in TB Clinical Presentation, Drug Exposure, and Treatment Outcomes in India.

BACKGROUND: The role of sex differences in clinical presentation, TB drug pharmacokinetic variables, and treatment outcomes is unclear. RESEARCH QUESTION: What is the effect of sex on TB disease severity, drug exposure, and treatment outcome? STUDY DESIGN AND METHODS: This study was a prospective cohort study conducted in India. It assessed TB disease severity; risk of unfavorable treatment outcomes (failure, recurrence, and death) according to sex; and risk factors for unfavorable outcomes stratified according to sex. Effects of sex on the pharmacokinetic variables (maximum concentration and area under the curve) of rifampicin, isoniazid, and pyrazinamide were estimated by using noncompartmental analyses. RESULTS: Of 1,541 people with microbiologically confirmed TB, 567 (37%) were women. Women had a lower risk of high mycobacterial burden (smear grade ≥ 2 and/or time to detection < 7 days) with an adjusted OR of 0.70 (95% CI, 0.56-0.87). Among the 744 participants who were followed up prospectively, 261 (35%) were women. Women had a lower risk of unfavorable treatment outcomes (adjusted incidence risk ratio, 0.60; 95% CI, 0.43-0.85), mostly because recurrence was lower (adjusted incidence risk ratio, 0.45; 95% CI, 0.23-0.86). Isoniazid (but not rifampicin and pyrazinamide) maximum concentration and area under the curve were significantly higher among women (P < .01) than men. Among women, unfavorable outcomes were more likely among those with cavitary disease, but among men, increased risk of unfavorable outcomes was associated with alcohol use, higher BMI, and lower glycated hemoglobin level. INTERPRETATION: Women present with lower mycobacterial burden, achieve higher TB drug exposure, and are less likely to have unfavorable treatment outcomes than men. Strategies to improve TB treatment success should take into account sex differences in risk factors for unfavorable outcomes.

Tuberculosis (TB) Aftermath: study protocol for a hybrid type I effectiveness-implementation non-inferiority randomized trial in India comparing two active case finding (ACF) strategies among individuals treated for TB and their household contacts.

BACKGROUND: Approximately 7% of all reported tuberculosis (TB) cases each year are recurrent, occurring among people who have had TB in the recent or distant past. TB recurrence is particularly common in India, which has the largest TB burden worldwide. Although patients recently treated for TB are at high risk of developing TB again, evidence around effective active case finding (ACF) strategies in this population is scarce. We will conduct a hybrid type I effectiveness-implementation non-inferiority randomized trial to compare the effectiveness, cost-effectiveness, and feasibility of two ACF strategies among individuals who have completed TB treatment and their household contacts (HHCs). METHODS: We will enroll 1076 adults (≥ 18 years) who have completed TB treatment at a public TB unit (TU) in Pune, India, along with their HHCs (averaging two per patient, n = 2152). Participants will undergo symptom-based ACF by existing healthcare workers (HCWs) at 6-month intervals and will be randomized to either home-based ACF (HACF) or telephonic ACF (TACF). Symptomatic participants will undergo microbiologic testing through the program. Asymptomatic HHCs will be referred for TB preventive treatment (TPT) per national guidelines. The primary outcome is rate per 100 person-years of people diagnosed with new or recurrent TB by study arm, within 12 months following treatment completion. The secondary outcome is proportion of HHCs < 6 years, by study arm, initiated on TPT after ruling out TB disease. Study staff will collect socio-demographic and clinical data to identify risk factors for TB recurrence and will measure post-TB lung impairment. In both arms, an 18-month "mop-up" visit will be conducted to ascertain outcomes. We will use the RE-AIM framework to characterize implementation processes and explore acceptability through in-depth interviews with index patients, HHCs and HCWs (n = 100). Cost-effectiveness will be assessed by calculating the incremental cost per TB case detected within 12 months and projected for disability-adjusted life years averted based on modeled estimates of morbidity, mortality, and time with infectious TB. DISCUSSION: This novel trial will guide India's scale-up of post-treatment ACF and provide an evidence base for designing strategies to detect recurrent and new TB in other high burden settings. TRIAL REGISTRATION: NCT04333485 , registered April 3, 2020. CTRI/2020/05/025059 [Clinical Trials Registry of India], registered May 6 2020.

Clinical and Immunological Markers of Pulmonary Impairment Among People With HIV in India.

Background: Despite antiretroviral therapy, chronic lung diseases remain an important source of morbidity and mortality in people with HIV (PWH). We sought to identify clinical and immunological markers of pulmonary impairment among PWH in India. Methods: Two hundred ten adult PWH receiving antiretroviral therapy (ART) were prospectively evaluated for 3 years. Plasma concentrations of interleukin (IL)-6, IL-10, tumor necrosis factor alpha, D-dimer, C-reactive protein, soluble (s)CD14, and sCD163 were measured at enrollment. We used multivariable linear and logistic regression to measure the association of baseline and time-varying clinical and immunological variables with spirometry-defined chronic obstructive pulmonary disease (COPD), restrictive spirometry pattern (RSP), preserved ratio impaired spirometry (PRISm), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC) during the third year of follow-up. Results: After adjusting confounders, females were 7 times more likely to have RSP (95% CI, 2.81 to 17.62; P < .001) and 22 times more likely to have PRISm (95% CI, 7.42 to 69.92; P < .001) compared with men. Higher IL-6 concentrations were associated with lower FEV1 z-scores (ß, -0.14 per log-higher; 95% CI, -0.29 to 0.008; P = .06) and higher odds of COPD (adjusted odds ratio [aOR], 2.66 per log-higher; 95% CI, 1.16 to 6.09; P = .02). Higher D-dimer concentrations were associated with lower FVC z-scores (ß, -0.40 per log-higher; 95% CI, -0.78 to -0.01; P = .04). Conversely, higher IL-10 concentrations were associated with lower odds of PRISm (aOR, 0.76 per log-higher; 95% CI, 0.59 to 0.99; P = .04). Conclusions: Female sex, higher concentrations of IL-6 and D-dimer, and lower concentrations of IL-10 were associated with pulmonary impairment in adult PWH receiving ART in India.

Increased Moxifloxacin Dosing Among Patients With Multidrug-Resistant Tuberculosis With Low-Level Resistance to Moxifloxacin Did Not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India.

BACKGROUND: Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available. METHODS: We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes. RESULTS: Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6-2.4]) or adjusted (HR, 0.8 [95% CI, .5-1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2-8.8]). CONCLUSIONS: In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test-based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.

Previous tuberculosis disease as a risk factor for chronic obstructive pulmonary disease: a cross-sectional analysis of multicountry, population-based studies.

BACKGROUND: Risk factors for COPD in high-income settings are well understood; however, less attention has been paid to contributors of COPD in low-income and middle-income countries (LMICs) such as pulmonary tuberculosis. We sought to study the association between previous tuberculosis disease and COPD by using pooled population-based cross-sectional data in 13 geographically diverse, low-resource settings. METHODS: We pooled six cohorts in 13 different LMIC settings, 6 countries and 3 continents to study the relationship between self-reported previous tuberculosis disease and lung function outcomes including COPD (defined as a postbronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) below the lower limit of normal). Multivariable regressions with random effects were used to examine the association between previous tuberculosis disease and lung function outcomes. RESULTS: We analysed data for 12 396 participants (median age 54.0 years, 51.5% male); 332 (2.7%) of the participants had previous tuberculosis disease. Overall prevalence of COPD was 8.8% (range 1.7%-15.5% across sites). COPD was four times more common among those with previous tuberculosis disease (25.7% vs 8.3% without previous tuberculosis disease, p<0.001). The adjusted odds of having COPD was 3.78 times higher (95% CI 2.87 to 4.98) for participants with previous tuberculosis disease than those without a history of tuberculosis disease. The attributable fraction of COPD due to previous tuberculosis disease in the study sample was 6.9% (95% CI 4.8% to 9.6%). Participants with previous tuberculosis disease also had lower prebronchodilator Z-scores for FEV1 (-0.70, 95% CI -0.84 to -0.55), FVC (-0.44, 95% CI -0.59 to -0.29) and the FEV1:FVC ratio (-0.63, 95% CI -0.76 to -0.51) when compared with those without previous tuberculosis disease. CONCLUSIONS: Previous tuberculosis disease is a significant and under-recognised risk factor for COPD and poor lung function in LMICs. Better tuberculosis control will also likely reduce the global burden of COPD.

Host lipidome and tuberculosis treatment failure.

INTRODUCTION: Host lipids play important roles in tuberculosis (TB) pathogenesis. Whether host lipids at TB treatment initiation (baseline) affect subsequent treatment outcomes has not been well characterised. We used unbiased lipidomics to study the prospective association of host lipids with TB treatment failure. METHODS: A case-control study (n=192), nested within a prospective cohort study, was used to investigate the association of baseline plasma lipids with TB treatment failure among adults with pulmonary TB. Cases (n=46) were defined as TB treatment failure, while controls (n=146) were those without failure. Complex lipids and inflammatory lipid mediators were measured using liquid chromatography mass spectrometry techniques. Adjusted least-square regression was used to assess differences in groups. In addition, machine learning identified lipids with highest area under the curve (AUC) to classify cases and controls. RESULTS: Baseline levels of 32 lipids differed between controls and those with treatment failure after false discovery rate adjustment. Treatment failure was associated with lower baseline levels of cholesteryl esters and oxylipin, and higher baseline levels of ceramides and triglycerides compared to controls. Two cholesteryl ester lipids combined in a unique classifier model provided an AUC of 0.79 (95% CI 0.65-0.93) in the test dataset for prediction of TB treatment failure. CONCLUSIONS: We identified lipids, some with known roles in TB pathogenesis, associated with TB treatment failure. In addition, a lipid signature with prognostic accuracy for TB treatment failure was identified. These lipids could be potential targets for risk-stratification, adjunct therapy and treatment monitoring.

Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study.

BACKGROUND: Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment outcomes is unclear. METHODS: We identified and internally validated the association between 20 a priori selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively. RESULTS: Pre-treatment interferon-γ, interleukin (IL)-13 and IL-6 were associated with treatment failure in the discovery analysis. Internal validation confirmed higher pre-treatment IL-6 concentrations among failure cases compared with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95% CI 1.08-4.33; p=0.02), recurrence (aOR 5.36, 95% CI 2.48-11.57; p<0.001) and death (aOR 4.62, 95% CI 1.95-10.95; p<0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15% (C-statistic 0.66 versus 0.76; p=0.02). CONCLUSIONS: Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction.

Higher Serum Cholesterol Levels Are Associated With Reduced Systemic Inflammation and Mortality During Tuberculosis Treatment Independent of Body Mass Index.

Background: Lipids play a central role in the pathogenesis of tuberculosis (TB). The effect of serum lipid levels on TB treatment (ATT) outcomes and their association with serum inflammatory markers have not yet been characterized. Methods: Our retrospective cohort study on drug-susceptible TB patients, at the National Taiwan University Hospital, assessed the association of baseline serum lipid levels such as low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC) and triglycerides (TG) with all-cause and infection-related mortality during first 9 months of ATT and baseline inflammatory markers namely C-reactive protein (CRP), total leukocyte count (WBC), and neutrophil-lymphocyte ratio (NL ratio). Results: Among 514 patients, 129 (26.6%) died due to any-cause and 72 (14.0%) died of infection. Multivariable Cox-regression showed a lower adjusted hazard ratio (aHR) of all-cause mortality in the 3rd tertiles of HDL (aHR 0.17, 95% CI 0.07-0.44) and TC (aHR 0.30, 95% CI 0.14-0.65), and lower infection-related mortality in the 3rd tertile of HDL (aHR 0.30, 95% CI 0.14-0.65) and TC (aHR 0.30, 95% CI 0.14-0.65) compared to the 1st tertile. The 3rd tertiles of LDL and TG showed no association in multivariable analysis. Similarly, 3rd tertiles of HDL and TC had lower levels of baseline inflammatory markers such as CRP, WBC, and NL ratio using linear regression analysis. Body mass index (BMI) did not show evidence of confounding or effect modification. Conclusions: Higher baseline serum cholesterol levels were associated with lower hazards of all-cause and infection-related mortality and lower levels of inflammatory markers in TB patients. BMI did not modify or confound this association.

The association of atherosclerotic cardiovascular disease and statin use with inflammation and treatment outcomes in tuberculosis.

Tuberculosis (TB) and atherosclerotic cardiovascular disease (ASCVD) have a close epidemiological and pathogenetic overlap. Thus, it becomes essential to understand the relationship between ASCVD and TB outcomes. From our retrospective cohort on drug-susceptible TB patients at the National Taiwan University Hospital, we assessed the association of pre-existing ASCVD (coronary artery disease (CAD) and atherothrombotic stroke (ATS)) with 9-month all-cause and infection-related mortality and the extent of mediation by systemic inflammatory markers. We determined the effect of pre-existing ASCVD on 2-month sputum microbiological status. Among ASCVD patients, we assessed the association of statin use on mortality. Nine-month all-cause mortality was higher in CAD patients with prior acute myocardial infarction (CAD+AMI+) (adjusted HR 2.01, 95%CI 1.38-3.00) and ATS patients (aHR 2.79, 95%CI 1.92-4.07) and similarly, for infection-related mortality was higher in CAD+AMI+ (aHR 1.95, 95%CI 1.17-3.24) and ATS (aHR 2.04, 95%CI 1.19-3.46) after adjusting for confounding factors. Pre-existing CAD (AMI- or AMI+) or ATS did not change sputum culture conversion or sputum smear AFB positivity at 2 months. The CAD+AMI+ group had significantly higher levels of CRP at TB diagnosis in the multivariable linear regression analysis (Adjusted B(SE) 1.24(0.62)). CRP mediated 66% (P = 0.048) and 25% (P = 0.033) of the association all-cause mortality with CAD+AMI- and CAD+AMI+, respectively. In summary, patients with ASCVD have higher hazards of 9-month all-cause and infection-related mortality, with elevated serum inflammation mediating one to three-quarters of this association when adjusted for confounders. Statin use was associated with lower all-cause mortality among patients with ASCVD.

Male Sex Is Associated With Worse Microbiological and Clinical Outcomes Following Tuberculosis Treatment: A Retrospective Cohort Study, a Systematic Review of the Literature, and Meta-analysis.

BACKGROUND: Although the incidence of tuberculosis is higher in men than in women, the relationship of sex with tuberculosis treatment outcomes has not been adequately studied. METHODS: We performed a retrospective cohort study and a systematic review and meta-analysis of observational studies during the last 10 years to assess sex differences in clinical and microbiological outcomes in tuberculosis. RESULTS: In our cohort of 2894 Taiwanese patients with drug-susceptible pulmonary tuberculosis (1975 male and 919 female), male patients had higher adjusted hazards of 9-month mortality due to all causes (hazard ratio, 1.43 [95% confidence interval (CI), 1.03-1.98]) and infections (1.70 [1.09-2.64]) and higher adjusted odds of 2-month sputum culture positivity (odds ratio [OR], 1.56 [95% CI, 1.05-2.33]) compared with female patients. Smear positivity at 2 months did not differ significantly (OR, 1.27 [95% CI, .71-2.27]) between the sexes. Among 7896 articles retrieved, 398 were included in our systematic review describing a total of 3 957 216 patients. The odds of all-cause mortality were higher in men than in women in the pooled unadjusted (OR, 1.26 [95% CI, 1.19-1.34]) and adjusted (1.31 [1.18-1.45]) analyses. Men had higher pooled odds of sputum culture (OR, 1.44 [95% CI, 1.14-1.81]) and sputum smear (1.58 [1.41-1.77]) positivity, both at the end of the intensive phase and on completion of treatment. CONCLUSIONS: Our retrospective cohort showed that male patients with tuberculosis have higher 9-month all-cause and infection-related mortality, with higher 2-month sputum culture positivity after adjustment for confounding factors. In our meta-analysis, male patients showed higher all-cause and tuberculosis-related mortality and higher sputum culture and smear positivity rates during and after tuberculosis treatment.

Diabetes Mellitus and Tuberculosis Treatment Outcomes in Pune, India.

BACKGROUND: Diabetes mellitus (DM) increases the risk of tuberculosis (TB) disease. Knowledge of the impact of DM on TB treatment outcomes is primarily based on retrospective studies. METHODS: We conducted a prospective cohort study of new pulmonary TB patients with and without DM (TB-DM and TB only) in India. The association of DM with a composite unfavorable TB treatment outcome (failure, recurrence, mortality) over 18 months was determined, and the effect of DM on all-cause mortality and early mortality (death during TB treatment) was assessed. RESULTS: Of 799 participants, 574 (72%) had TB only and 225 (28%) had TB-DM. The proportion of patients with DM who experienced the composite outcome was 20%, as compared with 21% for TB-only participants (adjusted hazard ratio [aHR], 1.13; 95% CI, 0.75-1.70). Mortality was higher in participants with DM (10% vs 7%), and early mortality was substantially higher among patients with DM (aHR, 4.36; 95% CI, 1.62-11.76). CONCLUSIONS: DM was associated with early mortality in this prospective cohort study, but overall unfavorable outcomes were similar to participants without DM. Interventions to reduce mortality during TB treatment among people with TB-DM are needed.

Higher interleukin-6 levels and changes in transforming growth factor-ß are associated with lung impairment in pulmonary tuberculosis.

Higher levels of IL-6 and slow-to-resolve TGF-ß are associated with lung impairment in treated tuberculosis. These results have important implications for clinical trials of immunomodulatory therapies to prevent tuberculosis-associated lung disease. https://bit.ly/2FQEtsz.