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 five sites in the Regional Prospective Observational Research on Tuberculosis (RePORT) India consortium (2015-2019). Using multivariable Poisson regression, we assessed independent 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 two months of TB treatment. Unfavorable outcome was defined as a composite of treatment failure, death, or relapse within 6 months of treatment completion. Findings 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 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 four and five-fold higher rate of death, respectively. Interpretations 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 for addressing this widely prevalent TB comorbidity. Nutritional assessment should be integrated into standard TB care.

Background Gene expression signatures have been used as biomarkers of tuberculosis (TB) risk and outcomes. Platforms are needed to simplify access to these signatures and determine their validity in the setting of comorbidities. We developed a computational profiling platform of TB signature gene sets and characterized the diagnostic ability of existing signature gene sets to differentiate active TB from LTBI in the setting of malnutrition. Methods We curated 45 existing TB-related signature gene sets and developed our TBSignatureProfiler software toolkit that estimates gene set activity using multiple enrichment methods and allows visualization of single- and multi-pathway results. The TBSignatureProfiler software is available through Bioconductor and on GitHub. For evaluation in malnutrition, we used whole blood gene expression profiling from 23 severely malnourished Indian individuals with TB and 15 severely malnourished household contacts with latent TB infection (LTBI). Severe malnutrition was defined as body mass index (BMI) < 16 kg/m2 in adults and based on weight-for-height Z scores in children < 18 years. Gene expression was measured using RNA-sequencing. Results The comparison and visualization functions from the TBSignatureProfiler showed that TB gene sets performed well in malnourished individuals; 40 gene sets had statistically significant discriminative power for differentiating TB from LTBI, with area under the curve ranging from 0.662–0.989. Three gene sets were not significantly predictive. Conclusion Our TBSignatureProfiler is a highly effective and user-friendly platform for applying and comparing published TB signature gene sets. Using this platform, we found that existing gene sets for TB function effectively in the setting of malnutrition, although differences in gene set applicability exist. RNA-sequencing gene sets should consider comorbidities and potential effects on diagnostic performance.

Setting: India’s National Tuberculosis Elimination Programme (NTEP) covers diagnostic and therapeutic costs of TB treatment. However, persons living with TB (PLWTB) continue to experience financial distress due to direct costs (payment for testing, treatment, travel, hospitalization, and nutritional supplements) and indirect costs (lost wages, loan interest, and cost of domestic helpers).Objective: To analyze the magnitude and pattern of TB-related costs from the perspective of Indian PLWTB.Design: We identified relevant articles using key search terms (‘tuberculosis,’ ‘India,’ ‘cost,’ ‘expenditures,’ ‘financing,’ ‘catastrophic’ and ‘out of pocket’) and calculated variance-weighted mean costs.Results: Indian patients incur substantial direct costs (mean: US$46.8). Mean indirect costs (US$666.6) constitute 93.4% of the net costs. Mean direct costs before diagnosis can be up to four-fold that of costs during treatment. Treatment in the private sector can result in costs up to six-fold higher than in government facilities. As many as one in three PLWTB in India experience catastrophic costs.Conclusion: PLWTB in India face high direct and indirect costs. Priority interventions to realize India’s goal of eliminating catastrophic costs from TB include decreasing diagnostic delays through active case finding, reducing the need for travel, improving awareness and perception of NTEP services, and ensuring sufficient reimbursement for inpatient TB care.

BackgroundMost individuals exposed to Mycobacterium tuberculosis (Mtb) develop latent tuberculosis infection (LTBI) and remain at risk for progressing to active tuberculosis disease (TB). Malnutrition is an important risk factor driving progression from LTBI to TB. However, the performance of blood-based TB risk signatures in malnourished individuals with LTBI remains unexplored. The aim of this study was to determine if malnourished and control individuals had differences in gene expression, immune pathways and TB risk signatures.MethodsWe utilized data from 50 tuberculin skin test positive household contacts of persons with TB - 18 malnourished participants (body mass index [BMI] &lt; 18.5 kg/m2) and 32 controls (individuals with BMI ≥ 18.5 kg/m2). Whole blood RNA-sequencing was conducted to identify differentially expressed genes (DEGs). Ingenuity Pathway Analysis was applied to the DEGs to identify top canonical pathways and gene regulators. Gene enrichment methods were then employed to score the performance of published gene signatures associated with progression from LTBI to TB.ResultsMalnourished individuals had increased activation of inflammatory pathways, including pathways involved in neutrophil activation, T-cell activation and proinflammatory IL-1 and IL-6 cytokine signaling. Consistent with known association of inflammatory pathway activation with progression to TB disease, we found significantly increased expression of the RISK4 (area under the curve [AUC] = 0.734) and PREDICT29 (AUC = 0.736) progression signatures in malnourished individuals.ConclusionMalnourished individuals display a peripheral immune response profile reflective of increased inflammation and a concomitant increased expression of risk signatures predicting progression to TB. With validation in prospective clinical cohorts, TB risk biomarkers have the potential to identify malnourished LTBI for targeted therapy.