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IntroductionHost 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.MethodsA 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.ResultsBaseline 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.ConclusionsWe 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.

In this prospective cohort of 2006 individuals with drug-susceptible tuberculosis in India, 18% had unfavorable treatment outcomes (4.7% treatment failure, 2.5% recurrent infection, 4.1% death, 6.8% loss to follow-up) over a median 12-month follow-up period. Age, male sex, low education, nutritional status, and alcohol use were predictors of unfavorable outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Pulmonary medicine began on tuberculosis wards in the preantibiotic era. Its first practitioners were often themselves physician victims of tuberculosis, observing its effects on their own breathing and that of other patients. Not only were lungs damaged by smoldering tuberculosis itself but by the more radical treatments of the time, including pneumothorax and plombage procedures (methods for collapsing lungs to close cavities) and excisional surgery. Such procedures required pretreatment risk assessment of lung function, resulting in pulmonary function testing, and posttreatment management of often worsened lung function. However, with the introduction of effective chemotherapy in the midtwentieth century, tuberculosis elimination was predicted, and a public health approach focused on making widely available standardized diagnosis, treatment, and bacteriologic assessment of cure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) recently changed its guidance for tuberculosis (TB) preventive treatment (TPT) recommending TPT for all pulmonary TB (PTB) exposed household contacts (HHC) to prevent incident TB disease (iTBD), regardless of TB infection (TBI) status. However, this recommendation was conditional as the strength of evidence was not strong. We assessed risk factors for iTBD in recently-exposed adult and pediatric Indian HHC, to determine which HHC subgroups might benefit most from TPT. We prospectively enrolled consenting HHC of adult PTB patients in Pune and Chennai, India. They underwent clinical, microbiologic and radiologic screening for TB disease (TBD) and TBI, at enrollment, 4–6, 12 and 24 months. TBI testing was performed by tuberculin skin test (TST) and Quantiferon®- Gold-in-Tube (QGIT) assay. HHC without baseline TBD were followed for development of iTBI and iTBD. Using mixed-effect Poisson regression, we assessed baseline characteristics including TBI status, and incident TBI (iTBI) using several TST and/or QGIT cut-offs, as potential risk factors for iTBD. Of 1051 HHC enrolled, 42 (4%) with baseline TBD and 12 (1%) with no baseline TBI test available, were excluded. Of the remaining 997 HHC, 707 (71%) had baseline TBI (TST #x2265; 5 mm or QGIT #x2265; 0.35 IU/ml). Overall, 20 HHC (2%) developed iTBD (12 cases/1000 person-years, 95%CI: 8–19). HIV infection (aIRR = 29.08, 95% CI: 2.38–355.77, p = 0.01) and undernutrition (aIRR = 6.16, 95% CI: 1.89–20.03, p = 0.003) were independently associated with iTBD. iTBD was not associated with age, diabetes mellitus, smoking, alcohol, and baseline TBI, or iTBI, regardless of TST (#x2265; 5 mm, #x2265; 10 mm, #x2265; 6 mm increase) or QGIT (#x2265; 0.35 IU/ml, #x2265; 0.7 IU/ml) cut-offs. Given the high overall risk of iTBD among recently exposed HHCs, and the lack of association between TBI status and iTBD, our findings support the new WHO recommendation to offer TPT to all HHC of PTB patients residing in a high TB burden country such as India, and do not suggest any benefit of TBI testing at baseline or during follow-up to risk stratify recently-exposed HHC for TPT. [ABSTRACT FROM AUTHOR]

Background: Gene expression profiling is emerging as a tool for tuberculosis diagnosis and treatment response monitoring, but limited data specific to Indian children and incident tuberculosis infection (TBI) exist.Methods: Sixteen pediatric Indian tuberculosis cases were age- and sex-matched to 32 tuberculosis-exposed controls (13 developed incident TBI without subsequent active tuberculosis). Longitudinal samples were collected for ribonucleic acid sequencing. Differential expression analysis generated gene lists that identify tuberculosis diagnosis and tuberculosis treatment response. Data were compared with published gene lists. Population-specific risk score thresholds were calculated.Results: Seventy-one genes identified tuberculosis diagnosis and 25 treatment response. Within-group expression was partially explained by age, sex, and incident TBI. Transient changes in gene expression were identified after both infection and treatment. Application of 27 published gene lists to our data found variable performance for tuberculosis diagnosis (sensitivity 0.38-1.00, specificity 0.48-0.93) and treatment response (sensitivity 0.70-0.80, specificity 0.40-0.80). Our gene lists found similarly variable performance when applied to published datasets for diagnosis (sensitivity 0.56-0.85, specificity 0.50-0.85) and treatment response (sensitivity 0.49- 0.86, specificity 0.50-0.84).Conclusions: Gene expression profiles among Indian children with confirmed tuberculosis were distinct from adult-derived gene lists, highlighting the importance of including distinct populations in differential gene expression models. [ABSTRACT FROM AUTHOR]

Background More than 20% of tuberculosis (TB) disease worldwide may be attributable to smoking and alcohol abuse. India is the second largest consumer of tobacco products, a major consumer of alcohol particularly among males, and has the highest burden of TB globally. The impact of increasing tobacco dose, relevance of alcohol misuse and past versus current or never smoking status on TB treatment outcomes remain inadequately defined. Methods We conducted a multi-centric prospective cohort study of newly diagnosed adult pulmonary TB patients initiated on TB treatment and followed for a minimum of 6 months to assess the impact of smoking status with or without alcohol abuse on treatment outcomes. Smokers were defined as never smokers, past smokers or current smokers. Alcohol Use Disorder Identification Test (AUDIT) scores were used to assess alcohol misuse. The association between smoking status and treatment outcomes was assessed in univariate and multivariate random effects poisson regression models. Results Of 455 enrolled, 129 (28%) had a history of smoking with 94 (20%) current smokers and 35 (8%) past smokers. Unfavourable treatment outcomes were significantly higher among past and current smokers as compared to never smokers. Specifically, the risk of treatment failure was significantly higher among past smokers (aIRR = 2.66, 95% CI: 1.41–4.90, p = 0.002), recurrent TB among current smokers (aIRR = 2.94, 95% CI: 1.30–6.67, p = 0.010) and death among both past (2.63, 95% CI: 1.11–6.24, p = 0.028) and current (aIRR = 2.59, 95% CI: 1.29–5.18, p = 0.007) smokers. Furthermore, the combined effect of alcohol misuse and smoking on unfavorable treatment outcomes was significantly higher among past smokers (aIRR: 4.67, 95% CI: 2.17–10.02, p<0.001) and current smokers (aIRR: 3.58, 95% CI: 1.89–6.76, p<0.001). Conclusion Past and current smoking along with alcohol misuse have combined effects on increasing the risk of unfavourable TB treatment outcomes. Innovative interventions that can readily address both co-morbidities are urgently needed. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Potential conflicts of interest . D. J. C., N. P., and S. P. B. report grants or contracts to institution from the Warren Alpert Foundation. N. S. H. reports a Warren Alpert Foundation grant paid to institution and current employment with the Novartis Institute for Biomedical Research. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: Conflict of interest: A.N. Gupte has nothing to disclose. Conflict of interest: P. Kumar has nothing to disclose. Conflict of interest: M. Araújo-Pereira has nothing to disclose. Conflict of interest: V. Kulkarni has nothing to disclose. Conflict of interest: M. Paradkar has nothing to disclose. Conflict of interest: N. Pradhan has nothing to disclose. Conflict of interest: P. Menon has nothing to disclose. Conflict of interest: C. Padmapriyadarsini reports funding from the Dept of Biotechnology, Government of India, within the scope of the present manuscript. Conflict of interest: L-E. Hanna has nothing to disclose. Conflict of interest: S.V.B. Yogendra Shivakumar has nothing to disclose. Conflict of interest: N. Rockwood has nothing to disclose. Conflict of interest: E. Du Bruyn has nothing to disclose. Conflict of interest: R. Karyakarte has nothing to disclose. Conflict of interest: S. Gaikwad has nothing to disclose. Conflict of interest: R.C. Bollinger reports research support from the NIH and Ujala Foundation, within the scope of the present manuscript. Conflict of interest: J. Golub reports grants to their institution from the NIH, within the scope of the present manuscript. Conflict of interest: N. Gupte reports grants to their institution from the NIH, within the scope of the present manuscript. Conflict of interest: V. Viswanathan has nothing to disclose. Conflict of interest: R.J. Wilkinson has nothing to disclose. Conflict of interest: V. Mave has nothing to disclose. Conflict of interest: S. Babu has nothing to disclose. Conflict of interest: H. Kornfeld has nothing to disclose. Conflict of interest: B.B. Andrade has nothing to disclose. Conflict of interest: A. Gupta reports grants to their institution from the National Institutes of Health within the scope of the present manuscript; grants to their institution from CRDF outside the scope of the present manuscript; and membership of an NIH/NIAID Advisory Council and the Indo-US Science Technology Forum Board., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Higher levels of IL-6 and slow-to-resolve TGF-β 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., Competing Interests: Conflict of interest: A.N. Gupte has nothing to disclose. Conflict of interest: S. Selvaraju has nothing to disclose. Conflict of interest: S. Gaikwad has nothing to disclose. Conflict of interest: V. Mave has nothing to disclose. Conflict of interest: P. Kumar has nothing to disclose. Conflict of interest: S. Babu has nothing to disclose. Conflict of interest: B.B. Andrade has nothing to disclose. Conflict of interest: W. Checkley has nothing to disclose. Conflict of interest: R. Bollinger reports grants from US NIH during the conduct of the study; and nonfinancial support from Hologic Inc., Merck & Company, and Emocha Health, outside the submitted work. Conflict of interest: A. Gupta reports grants from NIH during the conduct of the study., (Copyright ©ERS 2021.)