Tuberculosis (TB), a leading cause of global mortality, disproportionately affects low socioeconomic households and deepens poverty. In India, persons with TB (PWTB) and their families face disrupted education and reduced income, further limiting access to care. TB must be recognized not just as a clinical condition but as a social disease—intertwined with education, nutrition, and economic stability—if elimination goals are to be met. Household Income Over Course of Treatment by Education Discontinuation StatusFigure 1.Comparison of household income over course of TB treatment between households that have at least one individual who experienced educational disruption versus the control group.Multidimensional Poverty Index Score Comparison Based on Education StatusFigure 2.Comparison of Multidimensional Poverty Index score between households that have at least one individual who experienced interrupted schooling We used data from the RePORT India cohort, which follows PWTB in Puducherry, Tamil Nadu, Maharashtra, and Telangana. Participants were assessed at baseline; months 1 and 2 (intensive phase); month 6 (treatment completion); and at 6 and 12 months post-treatment. Clinical data included symptoms, treatment history, BMI, and Karnofsky scores. Structured interviews assessed TB’s socioeconomic effects using the Multidimensional Poverty Index (MPI), which includes education, living standards, and household composition. Among 663 households surveyed, 14% reported disrupted education, 85% of which involved household contacts of PWTB. Disruption often affected multiple members; 26 unique households reported educational interruption. Households without disruption showed steady income gains between months 2 and 6 post-treatment, while those with disruption exhibited fluctuating income, suggesting prolonged vulnerability. MPI scores averaged 38.4 in disrupted households vs. 30.8 in others (poverty threshold: 33). TB’s impact extends beyond the patient, disrupting education and eroding household resilience. Each missed year of schooling reduces lifetime earnings by ∼8%. Protecting education during TB illness is critical to achieving household stability and national TB elimination targets. Robert C. Bollinger, Jr., MD, MPH, [SCENE] Health: Advisor/Consultant|[SCENE] Health: Board Member|[SCENE] Health: Stocks/Bonds (Private Company)|Merck: Advisor/Consultant|miDiagnostics: Co-inventor of IP owned by Johns Hopkins University|miDiagnostics: Eligible for equity and royalty payments received by Johns Hopkins University

BACKGROUND:Undernutrition is the leading population-attributable risk factor for tuberculosis (TB), yet whether associated immune impairments are reversible with nutritional rehabilitation remains unclear. METHODS:In TB LION (Puducherry, India), 105 QuantiFERON-positive household contacts were stratified by BMI (<18.5 vs ≥18.5 kg/m2). Participants with low BMI (n=53) received 6 months of food rations plus daily multiple micronutrient supplement (MMS) without iron. Fourteen cytokines were measured by Luminex in supernatants from the unstimulated (Nil) and M. tuberculosis (Mtb)-antigen-stimulated (TB2) IGRA assay at baseline and 6 months; 11 with acceptable detection rates constituted the primary analytic set. Linear regression tested associations of weight and hemoglobin change with composite immune pathway scores. RESULTS:At baseline, participants with low BMI had attenuated Mtb-specific Th1 cytokine responses (interaction GMR 0.70 for IFN-γ, 0.55 for IL-2; both p=0.005), despite comparable or elevated innate and regulatory cytokines. After 6 months, Th1 responses increased (IFN-γ change GMR 1.41, 95% CI 1.10-1.80, p=0.005, q=0.06; IL-2 1.63, 1.01-2.63, p=0.046, q=0.25, suggestive). This increase reflected falling unstimulated background, not higher stimulated output. Weight gain was unrelated to composite scores but associated with elevated concentrations of 7 of 14 cytokines (all p<0.05). Hemoglobin gain was inversely associated with Th17 and pro-inflammatory scores but not Th1. CONCLUSIONS:Six months of combined food rations and daily MMS was followed by improved antigen-specific Th1 cytokine responses, suggesting this impairment may be partially reversible on a clinically feasible timescale. As a single-arm study without a concurrent comparator with undernutrition measured at follow-up, observed changes cannot be causally attributed to the intervention. Trial registration: NCT03598842.

OBJECTIVES:The Xpert MTB/RIF Ultra (Ultra) assay is widely used to diagnose pulmonary tuberculosis (TB), but "very low" or "trace" results may reflect either paucibacillary TB or TB-negative disease, complicating clinical decision-making. We evaluated host transcriptomic signatures to identify culture-confirmed paucibacillary TB among individuals with Ultra very low or trace results. METHODS:We performed whole blood targeted transcriptional profiling of 90 symptomatic adults from Uganda, Kenya, and South Africa with Ultra very low/trace sputum results. An 81-gene customized NanoString panel representing 13 published TB signatures was analyzed using machine learning to derive a novel four-gene host signature ("TRACE4") predicting MGIT and LJ culture positivity. Validation included individuals with other respiratory diseases (n = 18) and North American-TB-negative controls (n = 20). Data were randomly split 75/25 into training (n = 67) and test (n = 23) sets. Diagnostic performance was evaluated against WHO targets. RESULTS:TRACE4 outperformed all published signatures in both training (AUC 0.89) and test sets (AUC 0.88), achieving 82% specificity at 75% sensitivity. It also exceeded reclassification based on prior TB history (specificity 0.58 (95% CI: 0.45-0.69); sensitivity 0.35 (95% CI: 0.15-0.61)). TRACE4 showed 100% specificity in non-TB controls. CONCLUSION:TRACE4 shows promise for identifying paucibacillary culture-positive pulmonary TB in this diagnostically challenging group.

BACKGROUND:To understand how lung pathology relates to symptoms, microbiology, and progression risk in tuberculosis and to advance diagnostic development, we determined the frequency at screening of tuberculosis-consistent lesions in asymptomatic individuals within 5 years of tuberculosis diagnosis using highly sensitive imaging ([18F]-fluorodeoxyglucose PET-CT) and compared with chest x-ray computer-aided detection (CAD). METHODS:We enrolled a prospective longitudinal cohort in Khayelitsha, Cape Town, South Africa, of asymptomatic, HIV-uninfected contacts aged 18-65 years of patients with rifampicin-resistant tuberculosis, a tuberculosis high-risk group not eligible for chemoprophylaxis. Participants underwent baseline PET-CT, chest x-ray, phlebotomy, and intensive sputum collection, and were classified into four PET-CT lung categories: consistent with tuberculosis, inactive tuberculosis, other lesions, and normal. Chest x-ray was processed by three types of CAD software (CAD4TB [version 7.0], qXR [version 3.0.0], and Lunit [version 3.1.4.111]). Follow-up included symptom-agnostic tuberculosis screening (23-38 months) and provincial register review (≤74 months), and a subgroup had repeat PET-CT (5-15 months). Tuberculosis was defined as bacteriologically confirmed or clinically diagnosed. The primary outcome measures were hazard ratio (HR) for tuberculosis diagnosis and treatment by baseline PET-CT lung abnormality category with normal as the reference group, and diagnostic performance of chest x-ray CAD software using area under the receiver operator characteristic curve (AUC). FINDINGS:250 asymptomatic adults were enrolled between March 3, 2015, and Oct 11, 2017, irrespective of tuberculosis history or previous infection, and followed up for 1107 person-years (median 4·7 years [IQR 4·0-5·1]). 18 (7%) participants were treated for tuberculosis (16 [89%] of 18 bacteriologically confirmed). Six of 18 participants were diagnosed at baseline (four requiring induced sputum culture) and 12 of 18 after a median of 32 months (IQR 12-35). By baseline PET-CT category, tuberculosis was diagnosed and treated in 12 (41%) of 29 participants with scans consistent with tuberculosis, two (7%) of 30 with scans consistent with inactive tuberculosis, two (2%) of 83 with scans showing other lesions, and two (2%) of 108 with scans showing normal lungs. Participants with baseline PET-CT scans consistent with tuberculosis had the highest risk of 5-year tuberculosis diagnosis (HR 28·54 [95% CI 6·37-127·81] compared with those with scans showing normal lungs, p<0·0001), with no significant risk for scans consistent with inactive tuberculosis (3·55 [0·50-25·21], p=0·21) or other lung lesions (1·30 [0·18-9·23], p=0·79). 11 (69%) of the 16 participants with bacteriologically confirmed tuberculosis were asymptomatic at bacteriological confirmation, and ten (91%) of 11 had baseline PET-CT scans consistent with tuberculosis. Using baseline PET-CT classification as reference, the AUC for chest x-ray CAD software ranged from 0·86 (95% CI 0·72-0·99) to 0·89 (0·75-1·00) for bacteriologically confirmed tuberculosis. INTERPRETATION:Most adult asymptomatic contacts diagnosed with tuberculosis over 5 years had baseline radiographically evident disease, not radiographically negative incipient tuberculosis. Although PET-CT is not feasible for routine screening, it provides a highly sensitive reference benchmark for diagnostic development, with chest x-ray CAD performing comparatively well. FUNDING:South Africa Medical Research Council, US National Institutes of Health, Gates Foundation, Wellcome, UK Research and Innovation Medical Research Council, and Walter and Eliza Hall Institute of Medical Research.

IntroductionMemory CD4+ T cells are central to long-term immunity in tuberculosis (TB), yet their functional roles that define their protective capacity remain unclear. Understanding the immune mechanisms that prevent clinical progression from latent TB infection (LTBI) to active TB disease is critical for the development of next-generation vaccines and biomarkers.MethodsWe characterized the transcriptomic, metabolic, and functional programs of Mycobacterium tuberculosis (Mtb) antigen-stimulated peripheral CD4+ T stem cell (T-SCM), central (T-CM), transitional (T-TM), and effector (T-EM) memory subsets from individuals with remote LTBI. We utilized a multi-platform validation strategy that integrated RNA-sequencing data with protein-level metabolic profiling using “Met-Flow” cytometry and functional growth restriction assays to link memory CD4+ T cell differentiation states to immunometabolism and antimycobacterial function. Finally, we evaluated the immunometabolic profiles of memory CD4+ T cell subsets in an independent, longitudinal cohort of Mtb-exposed progressors and non-progressors from Brazil (GSE112104).ResultsWe identified a differentiation gradient associated with distinct immunometabolic states. T-SCM and T-CM subsets exhibited elevated mitochondrial activity and oxidative metabolism (fatty acid oxidation), supporting their proliferative capacity. In contrast, T-TM and T-EM subsets underwent glycolytic reprogramming and engaged the pentose phosphate pathway, which fueled enhanced cytokine production and Mtb growth restriction. Importantly, we observed that non-progressors exhibit fatty acid oxidation-driven, stem/central memory-like signatures, while progressors and active TB cases display elevated exhaustion markers, glycolytic reprogramming and pro-inflammatory profiles aligned with disease progression.ConclusionCollectively, findings from our proof-of-concept study suggest metabolic state as a key axis connecting Mtb antigen-induced memory T cell differentiation, restimulation-induced transcriptional programming, and durability of immune control. The findings provide the basis for future longitudinal studies to examine the dynamic metabolic and functional modulation in Mtb antigen-specific memory T cell subsets from contained infection to disease progression.

Abstract Soil-transmitted helminths (STH) are a plausible but under-characterized comorbidity in tuberculosis. In this prospective South Indian cohort, multiplex stool PCR detected STH in 43% of 137 adults with pulmonary tuberculosis and 34% of 230 household contacts. Food insecurity independently predicted co-infection. Current adult deworming gaps warrant evaluation.

Background:Diagnosis of pulmonary tuberculosis (TB) in people living with HIV remains difficult. Since the first pathogen-host interaction in TB occurs in the upper airway, we hypothesized that host transcriptomic analysis on nasal specimens may identify novel diagnostic biomarkers. We aimed to demonstrate differences in nasal gene expression between people with HIV and TB disease versus people with HIV without TB, evaluate the performance of nasal signatures in classifying TB and compare nasal gene profiles with blood gene profiles from the same cohort. Methods:We enrolled adults in Uganda with newly diagnosed HIV and symptoms of pulmonary TB disease We collected nasal cells and blood for RNA sequencing to identify differentially expressed genes and enriched pathways between people with HIV and TB disease and people with HIV without TB. Supervised machine-learning of gene expression data was used to predict TB status. Results:40 adults living with HIV were enrolled (median age: 34 years, median CD4 count: 182), including 20 with TB disease and 20 without. We identified 44 nasal differentially expressed genes and 238 blood differentially expressed genes, with three overlapping genes between sample types. Models trained using all 44 nasal differentially expressed genes had a cross-validated area under the curve between 0.87-0.90 for predicting TB disease amongst adults living with HIV. A simplified four-gene signature (SPIB, SHISA2, TESPA1 and CD1B) met the World Health Organization criteria for a TB triage test. Among adults with TB, pathways related to the inflammatory response and innate immune system were down regulated in nasal samples and upregulated in blood. Conclusion:This proof-of-concept study demonstrated that there were distinct nasal gene expression patterns associated with TB, not seen in blood. Differences in nasal gene expression in people with HIV who have TB disease, versus those without TB, highlight their potential as diagnostic biomarkers. Further validation studies of gene signatures using minimally invasive nasal samples are recommended in other difficult to diagnose groups.

This prospective cohort study evaluated rifampin pharmacokinetics in pregnant and nonpregnant women with tuberculosis in India. Pregnant women had significantly lower drug exposure, with <20% of the participants achieving target concentrations at any trimester. Findings highlight potential underdosing in pregnancy and underscore the need for dedicated pharmacokinetics studies in pregnancy, and revised rifampin dosing guidelines.

With the remarkable success of antiretroviral programmes for the prevention of vertical HIV transmission, there has been a notable reduction in the proportion of children born with HIV and, subsequently, a corresponding increase in the population of children who are HIV-exposed but uninfected (CHEU). There is growing appreciation for the increased risk of childhood morbidity and mortality among CHEU compared with children who are HIV-unexposed, particularly from infectious diseases. Given the high prevalence of tuberculosis in populations with high HIV prevalence, the effect of HIV exposure on tuberculosis is therefore of particular interest. In this Review, we contextualise and reflect on the existing literature for CHEU with regard to prevention, prevalence, and outcomes of tuberculosis infection and tuberculosis disease. In so doing, we identify gaps in reported knowledge on CHEU to guide future research.

More than half of the people with microbiologically cured tuberculosis (TB) present with post-TB lung disease (PTLD). PTLD compromises long-term respiratory health and adds to the global burden of chronic lung diseases. Despite its prevalence, the mechanisms driving tissue damage in TB are not well understood. In this review, we discuss the global burden of PTLD, evaluate host-directed therapies as promising interventions, and highlight the C3HeB/FeJ mouse model as a powerful tool for advancing pre-clinical PTLD research.

Background Tuberculosis (TB) remains a foremost public health concern in India, disproportionately affecting disadvantaged socioeconomic groups and amplifying poverty and inequality. This study explores longitudinal changes in socioeconomic status (SES) and sociodemographic characteristics among household contacts of patients with pulmonary TB over six years in Puducherry, India. Methods A secondary analysis was conducted using the data from the RePORT India cohort, involving patients with pulmonary TB and their household contacts in Puducherry. Baseline data (2019) included 197 households, with follow-up data (2024) available for 93 households. Changes in SES and sociodemographic indicators were analyzed using descriptive and inferential statistics in Stata 14. Results The proportion of elders (60+ years) rose from 5.3 % to 13.9 %, and larger households (≥6 members) were more likely to experience SES deterioration (p < 0.02). Households with one wage earner decreased, while those with three or more increased. A 14 % rise in lower-middle-class households was observed, alongside declines in upper-middle and middle-class groups. Conclusion This study findings reveal a significant SES shift in TB-affected households, emphasizing the long-term socioeconomic impact of TB. Interventions addressing income stability and housing conditions are essential for mitigating TB's economic burden and improving health equity in vulnerable populations.

Background Highly-sensitive molecular tests like GeneXpert MTB/RIF Ultra improve detection of paucibacillary pulmonary tuberculosis (TB) but occasionally detect Mycobacterium tuberculosis (Mtb) DNA in sputum from culture-negative individuals, with unclear significance. We hypothesized that Ultra may be detecting culture-negative TB, and manifest in a higher prevalence of TB biomarkers compared to Ultra-negative/culture-negative (‘sputum-negative’) individuals. Methods From 1200 symptomatic African adults undergoing evaluation for TB, we identified 66 with discordant results (Ultra-positive, culture-negative), and matched 52 sputum-negative (Ultra-negative, culture-negative) and 30 sputum-positive (Ultra-positive, culture-positive) participants. Over 12 months, participants were assessed for Mtb biomarkers (Mtb growth in augmented or follow-up sputum cultures, Mtb mRNA in baseline sputum, and symptomatic Ultra-positive after baseline) and TB-associated host transcriptional signatures. Results At baseline, TB-associated biomarker(s) were detected in 51.5 % of sputum-discordant versus 59.6 % of sputum-negative participants (p = 0.46), with at least one Mtb biomarker in 16.7 % versus 26.9 % respectively (p = 0.26). Longitudinally, 26.5 % of untreated sputum-discordant versus 41.7 % of untreated sputum-negative participants had Mtb biomarkers (p = 0.17) despite most reporting symptom improvement. Notably, 30 % of untreated sputum-negative participants converted to Ultra-positive at month 2. One sputum-discordant and one sputum-negative participant developed culture-confirmed TB at follow-up. Conclusion TB bacterial and host biomarkers were prevalent and no different between sputum-discordant and sputum-negative participants, raising concern for a considerable population of undiagnosed culture-negative TB. These findings parallel new evidence of Mtb aerosolization from sputum-negative individuals and highlight a need for more comprehensive diagnostics that detect sputum culture-negative TB with respect to infectiousness, pathology, and risk of progression.

Pediatric tuberculosis is a major global public health challenge, with reliable diagnosis being a main obstacle to identifying and treating affected children. New and improved diagnostics, ideally on non-sputum samples, are urgently required, especially in the most vulnerable group of children under five years of age. Studies to date have been limited by small sample sizes and few bacteriologically-confirmed cases. Here, we describe the study protocol of the NIH-funded NOD-pedFEND study, which will be one of the largest diagnostic studies to date of children at greatest risk of tuberculosis. In this prospective observational cohort study, we aim to evaluate existing and novel diagnostic assays, including pathogen- and host-based tests and combinations of tests. A consecutive cohort of children under five years of age with signs and symptoms of tuberculosis is enrolled in Uganda and Peru. All children undergo an extensive baseline workup with signs- and symptoms recording, microbiological reference tests, chest X-ray and tuberculin skin test for rigorous classification according to internationally recognized microbiological, composite reference and strict standards. An array of samples is collected for investigational tests. Follow-up visits are conducted at 2 weeks, 2 months and 6 months. A small cohort of healthy controls is enrolled to evaluate the specificity of selected diagnostics. The study has been approved by the relevant institutional review boards. With this large cohort study of children under five years of age, we aim to make an important contribution to the evaluation of new diagnostics for pediatric tuberculosis. By establishing a comprehensive biorepository, the study will also enable the assessment of novel tests as they become available during and after the study.

Background:Diagnosing tuberculosis in children remains challenging due to the paucibacillary nature of the disease, non-specific symptoms, and difficulty collecting samples. New tests are urgently needed. We evaluated the diagnostic accuracy of FujiLAM version 1 urine test in children under 5 years with presumptive tuberculosis in Uganda. Methods:This was a cross-sectional evaluation nested in the NOD-pedFEND diagnostic study. Children under 5 years with signs or symptoms of tuberculosis were recruited from three hospitals in Uganda. All participants underwent comprehensive baseline investigations, including culture and Xpert MTB/RIF Ultra on reference samples and chest X-ray. Culture and Xpert MTB/RIF Ultra results were used to define a microbiological reference standard. FujiLAM version 1 testing was performed on fresh urine at the baseline visit. Results:Seventy-nine children were included in the study. Fifteen participants (19%) were classified as having microbiologically confirmed TB, 44 (56%) as unconfirmed TB, thirteen (16%) as unlikely TB, and seven participants (9%) were unclassifiable. Only one participant (with unlikely TB) had a positive FujiLAM test. Culture and Xpert MTB/RIF Ultra on reference samples were negative in this child, indicating poor diagnostic accuracy with a sensitivity of 0% (95% CI: 0 - 21.8) of FujiLAM version 1 against the microbiological reference standard. Conclusion:The poor diagnostic accuracy of FujiLAM version 1 in children under five years of age makes it unsuitable as a diagnostic test in this age group. Further evaluation with the optimized version 2 of this test is needed.

Tuberculosis remains a major health threat, infecting nearly a third of the world's population. Of those infected, 5-10% progress from latent infection to active tuberculosis (TB) disease and biomarkers to identify which individuals will progress are needed to allow targeted prophylactic treatment. Several risk biomarkers have been developed to predict progression but have not been tested head-to-head on the same platform. Here, we used the NanoString platform and compared the performance of 15 published gene signatures in predicting progression at baseline in a household contact cohort. Expression of gene signatures was profiled in RNA extracted from whole blood and scored using GSVA and PLAGE. We found that specificity is enhanced by combining signatures and report that the performance of a combined signature that includes a newly derived parsimonious signature through machine learning and a published signature met WHO TPP levels for a triage test. The combined signature had a 90.9% sensitivity and 88% specificity with a PPV of 0.24 and NPV of 1. This combined signature has potential clinical utility in identifying high-risk individuals for targeted prophylaxis to prevent TB morbidity and mortality.

BACKGROUND:The population-level impact of risk factors for unfavorable TB treatment outcomes depends on their relative prevalence in the population. Unadjusted and adjusted attributable fractions (AFs) were calculated to estimate the proportion of unfavorable TB treatment outcomes that can be attributed to key risk factors in India. RESEARCH QUESTION:What proportion of unfavorable TB treatment outcomes can be attributed to key risk factors in India? STUDY DESIGN AND METHODS:Adults with drug-sensitive pulmonary TB were enrolled from 5 diverse clinical sites at treatment initiation and prospectively evaluated for 24 months. The primary outcome was a composite unfavorable treatment outcome of failure, recurrence, or death. Unadjusted and adjusted AFs were estimated for potentially modifiable risk factors of unfavorable treatment outcomes. RESULTS:A total of 2,930 adults contributed 32,912 person-months of follow-up. Median age was 43 years (interquartile range, 31-52 years), 2,136 (72.9%) participants were male, 1,609 (55.5%) were undernourished, 1,182 (40.4%) had ever smoked, 956 (32.8%) had diabetes, 437 (14.9%) reported alcohol misuse, and 65 (2.2%) were HIV positive. Overall, treatment failed in 129 participants, 80 had recurrence, and 101 died. In the unadjusted analysis, 32.2% (95% CI, 23.1-40.3) of all unfavorable outcomes were attributable to undernutrition, 19.4% (95% CI, 12.3-25.8) were attributable to ever-smoking, 8.5% (95% CI, 4.3-12.6) to alcohol misuse, and 1.6% (95% CI, 0.1-3.0) to HIV coinfection. After adjusting for simultaneous presence of multiple risk factors, 29.0% (95% CI, 17.6-38.8) of all unfavorable outcomes were found to be attributable to undernutrition. Alcohol misuse and ever-smoking accounted for 15.4% (95% CI, 7.9-22.3) and 17.9% (95% CI, 1.1-31.9) of treatment failures, respectively. INTERPRETATION:In this study, undernutrition, ever-smoking, and alcohol misuse accounted for more than one-third of all unfavorable treatment outcomes and may present high-yield intervention targets to improve TB treatment outcomes in India.

BACKGROUND:A study was conducted to examine variations in latent tuberculosis infection (LTBI) risk factors among household contacts (HHCs) of tuberculosis (TB) patients. OBJECTIVES:The objective of this study was to assess LTBI prevalence among first-degree relatives (FDRs) and spouses of TB patients and identify associated risk factors. MATERIALS AND METHODS:A cohort study at JIPMER under Regional Prospective Observational Research for TB India included HHCs of newly diagnosed pulmonary TB patients. Prevalence ratios with 95% confidence intervals (CIs) were calculated using generalized linear modeling. RESULTS:Among 1318 HHCs of 548 TB patients, the mean ages were 45.2 (13.7) and 29.5 (16.1) years, respectively. LTBI prevalence was 58.1%, with 0.5% progressing to active TB. Spouses had a higher LTBI prevalence (64.2%) than FDR (55.8%), with a significantly elevated risk (PRR: 1.42, 95% CI: 1.11-1.83). Older age (40-59 and ≥60 years), bed-sharing, female gender, prolonged exposure, undernutrition, overweight/obesity, and alcohol use were linked to higher LTBI prevalence. Female spouses spent more time caring for index cases than male spouses. CONCLUSION:Spouses had a higher LTBI prevalence than FDR. Screening programs should prioritize female spouses, undernourished individuals, overweight/obese individuals, and alcohol users to reduce TB transmission.

The COVID pandemic and tuberculosis (TB) endemicity is double trouble to much of the world. SARS-CoV-2 and Mycobacterium tuberculosis (Mtb), causative agents of COVID and TB, respectively, are both infectious respiratory pathogens involving close communities and individuals. Both pathogens can cause lung disease, involving unbalanced inflammatory cell immune responses that can lead to a syndemic impact. Moreover, dual infection is common in certain settings. In low- and middle- income countries, most individuals with SARS-CoV-2 infection or COVID-19, in fact, will have been exposed to or infected with Mtb and some will develop active TB. Here we review the literature examining the diverse interactions of M. tuberculosis infection and of BCG vaccination with SARS-CoV-2. We discuss areas in which contradictory results have been published and conclude that there are still several unresolved issues that warrant further study on the co-pathogenesis of SARS-CoV-2 and Mtb and BCG- mediated heterologous protection against COVID-19.