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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., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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.)

India has made substantial advancements in reducing the burden of tuberculosis (TB), but persons living with active TB (PLWATB) still face myriad challenges in seeking and receiving care, including TB-related stigma. To meet the END TB targets, it is critical that PLWATB engage in care and are able to adhere to treatment. This qualitative study aimed to understand TB-related stigma (perceived, enacted, and internalised) and possible interventions to reduce stigma in Puducherry and Tamil Nadu, India. We conducted 47 in-depth interviews with PLWATB and household members and eight focus group discussions: two each with PLWATB, their household members, healthcare workers, and key informants. We found varying TB-related knowledge: the vast majority of interview participants reported incorrect modes of transmission, although most were also aware that TB is curable. Participants reported high levels of perceived stigma, with nearly two-thirds of PLWATB choosing to hide their disease to avoid being stigmatised in their community. Participants supported interventions including celebrity advocacy and school-based programming to increase community knowledge and reduce enacted stigma as well as support groups and counselling to reduce internalised stigma in PLWATB. This study has the potential to inform future interventions to reduce TB-related stigma in India.

Background: Comorbidities such as undernutrition and parasitic infections are widespread in India and other tuberculosis (TB)-endemic countries. This study examines how these conditions as well as food supplementation and parasite treatment might alter immune responses to Mycobacterium tuberculosis (Mtb) infection and risk of progression to TB disease., Methods: This is a 5-year prospective clinical trial at Jawaharlal Institute of Post Graduate Medical Education and Research in Puducherry, Tamil Nadu, India. We aim to enroll 760 household contacts (HHC) of adults with active TB in order to identify 120 who are followed prospectively for 2 years: Thirty QuantiFERON-TB Gold Plus (QFT-Plus) positive HHCs ≥ 18 years of age in four proposed groups: (1) undernourished (body mass index [BMI] < 18.5 kg/m 2 ); (2) participants with a BMI ≥ 18.5 kg/m 2 who have a parasitic infection (3) undernourished participants with a parasitic infection and (4) controls-participants with BMI ≥ 18.5 kg/m 2 and without parasitic infection. We assess immune response at baseline and after food supplementation (for participants with BMI < 18.5 kg/m 2 ) and parasite treatment (for participants with parasites). Detailed nutritional assessments, anthropometry, and parasite testing through polymerase chain reaction (PCR) and microscopy are performed. In addition, at serial time points, these samples will be further analyzed using flow cytometry and whole blood transcriptomics to elucidate the immune mechanisms involved in disease progression., Conclusions: This study will help determine whether undernutrition and parasite infection are associated with gene signatures that predict risk of TB and whether providing nutritional supplementation and/or treating parasitic infections improves immune response towards this infection. This study transcends individual level care and presents the opportunity to benefit the population at large by analyzing factors that affect disease progression potentially reducing the overall burden of people who progress to TB disease. Trial registration ClinicalTrials.gov; NCT03598842; Registered on July 26, 2018; https://clinicaltrials.gov/ct2/show/NCT03598842., (© 2021. The Author(s).)

Background: Undernutrition impairs immunity to Mycobacterium tuberculosis and is a risk factor for tuberculosis disease (TB). We aim to investigate if severe undernutrition affects the tuberculin skin test (TST) response among household contacts (HHCs) of pulmonary TB cases., Methods: We analyzed data from HHCs (> five years) of pulmonary TB cases in Southern India. Undernutrition was defined as per World Health Organization based on body mass index (BMI) for adults (undernutrition 16-18.4 and severe undernutrition <16 kg/m2) and BMI relative to the mean for children (undernutrition 2SD-3SD and severe undernutrition < 3SDs below mean). Univariate and multivariate models of TST positivity (> five mm) were calculated using logistic regression with generalized estimating equations., Results: Among 1189 HHCs, 342 were children (age 5-17 years) and 847 were adults. Prevalence of TST positivity in well-nourished, undernourished and severely undernourished children was 135/251 (53.8%), 32/68 (47.1%), and 7/23 (30.4%) respectively; among adults, prevalence of TST positivity was 304/708 (42.9%), 43/112 (38.4%) and 12/26 (46.2%), respectively. Severe undernutrition in children was associated with decreased odds of TST positivity (adjusted odds ratio 0.3; 95%CI 0.1-0.9)., Conclusion: Severe undernutrition in children was associated with decreased odds of TST positivity. False-negative TSTs may result from undernutrition; caution is warranted when interpreting negative results in undernourished populations., Competing Interests: The authors have declared that no competing interests exist.

Setting: Alcohol use increases the risk of tuberculosis (TB) disease and is associated with worse outcomes., Objective: To determine whether alcohol use affects TB severity at diagnosis in a high-burden setting., Design: Participants were smear-positive people living with TB (PLWTB) in India. Disease severity was assessed as 1) high versus low smear grade, 2) time to positivity (TTP) on liquid culture, 3) chest radiograph cavitation, and 4) percent lung affected. Alcohol use and being at-risk for alcohol use disorders (AUD) were assessed using the AUDIT-C. Univariable and multivariable analyses were conducted., Results: Of 1166 PLWTB, 691 (59.3%) were drinkers; of those, 518/691 (75.0%) were at-risk for AUD. Drinkers had more lung affected than non-drinkers (adjusted mean difference 10.8%, p<0.0001); this was not significant for those at-risk for AUD (adjusted mean difference 3.7%, p = 0.11). High smear grade (aOR 1.0, 95%CI: 0.7-1.4), cavitation (aOR 0.8, 95%CI 0.4-1.8), and TTP (mean difference 5.2 hours, p = 0.51) did not differ between drinkers and non-drinkers, nor between those at-risk and not at-risk for AUD., Conclusions: A large proportion of PLWTB were drinkers and were at-risk for AUD. Alcohol drinkers had more lung affected than non-drinkers. Studies are needed to explore mechanisms of this association., Competing Interests: The authors have declared that no competing interests exist.

Identifying predictors of loss to follow-up (LTFU; treatment lapse ≥ 2 months) among people with tuberculosis (TB) may assist programmatic efforts in controlling the spread of TB. Newly diagnosed smear-positive TB patients were enrolled in the Regional Prospective Observational Research for TB study in Puducherry and Tamil Nadu, India. Treatment records were used to identify LTFU of those who were enrolled from May 2014 through December 2017. This nested case-control study evaluated male TB patients. Predictors were assessed using multivariable logistic regression. Of 425 men with TB, 82 (19%) were LTFU. In the adjusted analyses of males, divorced/separated marital status (adjusted odds ratio [aOR] 3.80; 95% CI: 1.39-10.38) and at-risk alcohol use (aOR 1.92; 95% CI: 1.12-3.27) were significant predictors for increased risk of LTFU, and diabetes was a significant predictor for decreased risk of LTFU (aOR 0.52; 95% CI: 0.29-0.92). Of 53 men with recorded date of last treatment visit, 23 (43%) and 43 (81%) had LTFU within the first 2 and first 4 months of treatment, respectively. Addressing at-risk alcohol use and providing more intensive follow-up could lead to improved treatment completion.

Background: Malnutrition and diabetes are risk factors for active tuberculosis (TB), possible risk factors for latent TB infection (LTBI), and may interact to alter their effect on these outcomes. Studies to date have not investigated this interaction., Methods: We enrolled 919 newly diagnosed active TB patients and 1113 household contacts at Primary Health Centres in Puducherry and Tamil Nadu, India from 2014 to 2018. In cross-sectional analyses, we used generalized estimating equations to measure additive and multiplicative interaction of body mass index (BMI) and diabetes on two outcomes, active TB and LTBI., Results: Among overweight or obese adults, active TB prevalence was 12-times higher in diabetic compared to non-diabetic participants, 2.5-times higher among normal weight adults, and no different among underweight adults (P for interaction < 0.0001). Diabetes was associated with 50 additional active TB cases per 100 overweight or obese participants, 56 per 100 normal weight participants, and 17 per 100 underweight participants (P for interaction < 0.0001). Across BMI categories, screening 2.3-3.8 active TB patients yielded one hyperglycemic patient. LTBI prevalence did not differ by diabetes and BMI*diabetes interaction was not significant., Conclusions: BMI and diabetes are associated with newly diagnosed active TB, but not LTBI. Diabetes conferred the greatest risk of active TB in overweight and obese adults whereas the burden of active TB associated with diabetes was similar for normal and overweight or obese adults. Hyperglycemia was common among all active TB patients. These findings highlight the importance of bi-directional diabetes-active TB screening in India.

Background: The relationship between malnutrition and tuberculosis (TB) severity is understudied. We investigated the effect of malnutrition on radiographic findings and mycobacterial burden., Methods: Subjects included newly diagnosed, smear-positive, culture-confirmed, pulmonary TB cases enrolled in the Regional Prospective Observational Research for TB (RePORT) cohort. Multivariate regression models were used to evaluate the relationship at start of treatment between body mass index (BMI) and chest radiograph (CXR) findings of cavitation and percentage of lung affected and mycobacterial growth indicator tube (MGIT) time to positive (TTP). Severe malnutrition was defined as BMI<16 kg/m2, moderate malnutrition as 16-18.4kg/m2, and "normal"/overweight as ≥18.5 kg/m2., Results: Of 173 TB cases with chest x-ray data, 131 (76%) were male. The median age was 45 years (range 16-82); 42 (24%) had severe malnutrition and 58 (34%) moderate malnutrition. Median percentage of lung affected was 32% (range 0-95), and 132 (76%) had cavitation. Individuals with severe malnutrition had, on average, 11.1% [95% CI: 4.0-13.3] more lung affected, compared to those with normal BMI, controlling for diabetes and cavitation. In multivariable analyses, cases with severe malnutrition had a 4.6-fold [95% CI, 1.5-14.1] increased odds of cavitation compared to those with normal BMI, controlling for smoking. Median MGIT TTP was 194.5 hours. Neither severe (aRR 0.99; 95% CI, 0.9-1.2) nor moderate (aRR 0.97; 95% CI, 0.8-1.1) malnutrition was associated with MGIT TTP., Conclusion: We found that malnutrition was associated with increased extent of disease and cavitation on CXR. These findings may reflect the immunomodulatory effect of malnutrition on pulmonary pathology., Competing Interests: The authors have declared that no competing interests exist.

Background: Isoniazid preventive therapy (IPT) reduces mortality among people living with HIV (PLHIV) and is recommended for those without active tuberculosis (TB) symptoms. Heavy alcohol use, however, is contraindicated for liver toxicity concerns. We evaluated the risks and benefits of IPT at antiretroviral therapy (ART) initiation to ART alone for PLHIV who are heavy drinkers in 3 high TB-/HIV-burden countries., Methods: We developed a Markov simulation model to compare ART alone to ART with either 6 or 36 months of IPT for heavy drinking PLHIV enrolling in care in Brazil, India, and Uganda. Outcomes included nonfatal toxicity, fatal toxicity, life expectancy, TB cases, and TB death., Results: In this simulation, 6 months of IPT + ART (IPT6) extended life expectancy over both ART alone and 36 months of IPT + ART (IPT36) in India and Uganda, but ART alone dominated in Brazil in 51.5% of simulations. Toxicity occurred in 160/1000 persons on IPT6 and 415/1000 persons on IPT36, with fatal toxicity in 8/1000 on IPT6 and 21/1000 on IPT36. Sensitivity analyses favored IPT6 in India and Uganda with high toxicity thresholds., Conclusions: The benefits of IPT for heavy drinkers outweighed its risks in India and Uganda when given for a 6-month course. The toxicity/efficacy trade-off was less in Brazil where TB incidence is lower. IPT6 resulted in fatal toxicity in 8/1000 people, whereas even higher toxicities of IPT36 negated its benefits in all countries. Data to better characterize IPT toxicity among HIV-infected drinkers are needed to improve guidance.

Several studies have identified blood transcriptomic signatures that can distinguish active from latent Tuberculosis (TB). The purpose of this study was to assess how well these existing gene profiles classify TB disease in a South Indian population. RNA sequencing was performed on whole blood PAXgene samples collected from 28 TB patients and 16 latently TB infected (LTBI) subjects enrolled as part of an ongoing household contact study. Differential gene expression and clustering analyses were performed and compared with explicit predictive testing of TB and LTBI individuals based on established gene signatures. We observed strong predictive performance of TB disease states based on expression of known gene sets (ROC AUC 0.9007-0.9879). Together, our findings indicate that previously reported classifiers generated from different ethnic populations can accurately discriminate active TB from LTBI in South Indian patients. Future work should focus on converting existing gene signatures into a universal TB gene signature for diagnosis, monitoring TB treatment, and evaluating new drug regimens., (Copyright © 2018 Elsevier Ltd. All rights reserved.)