Immunological Evidence of LTBI among Noncontacts and Contacts with Index TB Patients [TBN 103]

The Final Note, Not the Final Story (check also: https://www.yosephsamodra.com/publications/)

A study assessed the detection of latent tuberculosis infection (LTBI) among individuals with and without tuberculosis (TB) contact using two interferon-gamma release assay (IGRA)-based methods, QuantiFERON-TB Gold In-Tube (QFT-GIT) and the ichroma™ IGRA-TB assay. It also evaluated the acceptability of the ichroma™ IGRA-TB assay, a fluorescence lateral flow assay designed as a potential point-of-care test for LTBI detection. This cross-sectional pilot study was conducted at the National Institute of TB and Respiratory Diseases, New Delhi, India, between March 2023 and January 2024.

See also: Lin TB Lab (Taiwan): https://lintblab.weebly.com/publications.html

The study enrolled 175 adults aged 18 years or older, divided into three groups: participants without recent TB contact (n = 92), participants with recent close contact with an index TB case (n = 45), and participants with casual contact, primarily healthcare workers, with an index TB case (n = 38). Participants younger than 18 years, those unwilling to participate or provide informed consent, individuals with active TB, severe illness, or immunocompromising conditions were excluded. LTBI was assessed using two IGRA-based methods. The QFT-GIT assay measured interferon-gamma (IFN-γ) released from whole blood stimulated with TB-specific antigens (ESAT-6, CFP-10, and TB7.7) using enzyme-linked immunosorbent assay. The ichroma™ IGRA-TB assay measured IFN-γ using an automated fluorescence lateral flow immunoassay with sandwich immunodetection technology. Test performance, positivity rates, indeterminate results, subgroup differences, and agreement between the two assays were evaluated.

Among the 175 participants, the mean age was 34.7 years (SD 12.4), 70.3% were male, and 53.7% were aged 18 to 33 years. Overall, LTBI was detected in 57 participants (32.6%) using the study assays. QFT-GIT identified LTBI in 47 participants (26.9%), while the ichroma™ IGRA-TB assay identified LTBI in 43 participants (24.6%). LTBI detection did not differ significantly between noncontacts, close contacts, and casual contacts with either assay. QFT-GIT positivity was 29.4% among noncontacts, 28.9% among close contacts, and 18.4% among casual contacts. Corresponding positivity rates with the ichroma™ assay were 28.3%, 24.5%, and 15.8%, respectively. The frequency of indeterminate results was lower with the ichroma™ assay than with QFT-GIT (4.0% vs. 9.1%). Among male participants, QFT-GIT positivity was higher than among females (30.8% vs. 17.3%), although this difference was not statistically significant (P = 0.175). In contrast, the ichroma™ assay demonstrated a statistically significant sex difference (P = 0.004). Age-stratified analyses showed no significant differences across exposure groups for most age categories. Among participants older than 50 years, the ichroma™ assay detected LTBI only in the noncontact group (53.3%), resulting in a statistically significant difference (P = 0.01), although the authors noted that interpretation was limited by the small sample size. Agreement between the two assays was 76.6%, with moderate agreement (κ = 0.504, P < 0.0001). Overall, 34 participants (19.4%) tested positive with both assays, 12 (6.9%) were positive only by QFT-GIT, 7 (4.0%) only by ichroma™, and 98 (56.0%) were negative by both assays.

The study concluded that QFT-GIT and ichroma™ IGRA-TB demonstrated comparable performance for LTBI detection, with no significant differences in positivity between TB contact and noncontact groups. The ichroma™ assay showed good agreement with QFT-GIT while producing fewer indeterminate results, suggesting that it may serve as a practical point-of-care alternative for LTBI screening in resource-limited settings. As a cross-sectional pilot study, the level of evidence is moderate for diagnostic comparison but cannot establish causal relationships or evaluate predictive performance over time. Important limitations include the small sample size, particularly in participants older than 50 years, and the single-center study design, which may limit generalizability. Funding sources and conflicts of interest were not specified.

Source: Verma AK, Yadav RN, Kumar L, Khan NH, Ranjan A, Kumar R, Kumar G, Panchal S, Dewan RK. Immunological Evidence of Latent Tuberculosis Infection among Noncontacts and Contacts with Index Tuberculosis Patients. Journal of Global Infectious Diseases. 2026 Apr 1;18(2):75-80.

Prevalence of TB Infection and Risk Factors Associated with LTBI among Household Contacts in Roi Et Province, Thailand [TBN 102]

A study assessed the prevalence of latent tuberculosis infection (LTBI) detected by Interferon-Gamma Release Assay (IGRA) and identified factors associated with LTBI among household contacts of pulmonary tuberculosis patients in Roi Et Province, Thailand. This cross-sectional analytic study was conducted between October 1, 2024, and September 30, 2025. The findings were intended to provide local evidence to support targeted contact investigation, improve LTBI screening strategies, and strengthen community-based tuberculosis prevention and control.

The study included 359 household contacts from 334 index pulmonary tuberculosis patients identified in Roi Et Province. Household contacts served as the unit of analysis, while pulmonary tuberculosis patients were recruited as index cases for contact investigation. LTBI was determined using IGRA. Clinical characteristics of index cases, including GeneXpert results and pulmonary cavitation, as well as household exposure characteristics, were compared between IGRA-positive and IGRA-negative contacts. Multivariable logistic regression was performed to identify factors independently associated with LTBI.

Among the 359 household contacts, 99 (27.6%) had positive IGRA results, indicating LTBI. Most index pulmonary tuberculosis patients were male, approximately half had positive GeneXpert results, and 24.5% had pulmonary cavitation. Household contacts with longer daily exposure to the index patient had a significantly higher prevalence of LTBI (p < 0.001). Pulmonary cavitation in the index patient was also significantly associated with LTBI among household contacts (p < 0.001). After adjustment, household contacts exposed to the index patient for more than 8 hours per day had 2.44 times higher odds of LTBI (adjusted OR 2.44, 95% CI 1.47 to 4.07, p = 0.001). Pulmonary cavitation in the index patient was independently associated with a more than fivefold increase in the odds of LTBI among household contacts (adjusted OR 5.11, 95% CI 2.95 to 8.86, p < 0.001).

The study concluded that more than one-quarter of household contacts of pulmonary tuberculosis patients in Roi Et Province had LTBI, and that prolonged daily exposure and pulmonary cavitation in the index patient were the strongest independent risk factors. As a cross-sectional study, the evidence level is moderate for identifying associations but cannot establish causality. The summary provided does not specify inclusion or exclusion criteria, recruitment procedures beyond contact investigation, funding sources, conflicts of interest, or study limitations. The findings support prioritizing household contacts with prolonged exposure and those exposed to patients with cavitary pulmonary tuberculosis for LTBI screening and tuberculosis prevention programs.

Source: Lawong S. Prevalence of Tuberculosis Infection by Interferon-Gamma Release Assay and Risk Factors Associated with Latent Tuberculosis Infection among Household Contacts of Pulmonary Tuberculosis Patients in Roi Et Province, Thailand. Journal of Health Research. 2026;40(1):285-292.

Impact of intermediate hyperglycemia and DM on immune dysfunction in TB [TBN 101]

A multicenter observational transcriptomic study investigated how diabetes mellitus (DM) and intermediate hyperglycemia (IH) influence the blood immune response in adults with newly diagnosed, bacteriologically confirmed pulmonary tuberculosis (TB). Participants were recruited between December 2013 and February 2016 from four sites in South Africa, Indonesia, Peru, and Romania. The study aimed to determine whether hyperglycemia alters the host blood transcriptome in TB and whether these changes affect established TB diagnostic transcriptomic signatures.

A total of 151 TB patients were classified as TB only, IH-TB, or DM-TB according to laboratory HbA1c criteria. Additional healthy controls (HCs) and individuals with DM without TB were recruited in South Africa and Romania. Patients were excluded if they had already started TB treatment, had multidrug-resistant TB, HIV infection, pregnancy, corticosteroid use, or other serious comorbidities. DM was defined as HbA1c ≥6.5% confirmed by repeat HbA1c ≥6.5% or fasting blood glucose ≥7 mmol/L, while IH was defined as HbA1c 5.7% to <6.5%. Venous blood was collected before TB treatment, and RNA sequencing was performed on 249 blood samples using polyA library preparation and single-read sequencing. Bioinformatic analyses included transcript quantification, differential gene expression, principal component analysis (PCA), modular enrichment analysis, and machine learning with random forest algorithms to evaluate published TB transcriptomic biomarkers.

Compared with healthy controls, TB alone was associated with upregulation of 345 genes, including known TB-associated genes such as C1QA, BATF2, SOCS3, and GBP5. DM alone produced relatively modest transcriptomic changes. In contrast, DM-TB showed marked transcriptomic perturbation, with 1,695 significantly upregulated genes and 1,623 significantly downregulated genes relative to healthy controls. Upregulated genes included inflammatory cytokines such as IL-1β, IL-15, IL-18, and IL-10, whereas downregulated genes included IL-8, IL-16, and IL-24. IH-TB demonstrated even greater transcriptomic disruption, with 2,576 upregulated and 2,140 downregulated genes. Similar findings were independently validated in the Romanian cohort. Comparative analyses showed that the TB transcriptional profile remained dominant, but hyperglycemia amplified its magnitude. PCA demonstrated that IH-TB and DM-TB clustered together, whereas healthy controls and DM without TB formed a separate cluster. Modular analysis showed stronger activation of inflammatory, myeloid cell, complement, and type I interferon pathways in IH-TB and DM-TB than in TB alone, together with greater suppression of natural killer cell and adaptive immune response modules, including T-cell and B-cell pathways. Combined analysis across all four countries confirmed these findings, identifying 292 upregulated and 130 downregulated genes in DM-TB versus TB only, and 432 upregulated and 126 downregulated genes in IH-TB versus TB only. The magnitude of differential expression generally increased with worsening hyperglycemia. Finally, established TB transcriptomic diagnostic signatures performed less well in patients with DM. The Kaforou signature achieved an AUC of 0.96 in TB-only patients but declined to 0.87 in DM-TB patients (ROC comparison P = .018), while the Sweeney signature also showed reduced performance (AUC 0.84).

The study concluded that both diabetes and intermediate hyperglycemia substantially amplify the blood transcriptomic response to active TB, with detectable effects already present before overt diabetes develops, and that these changes reduce the diagnostic performance of existing TB transcriptomic biomarkers. As an observational transcriptomic study, the findings demonstrate association rather than causation. Although the multicenter design across four countries supports generalizability, participants with HIV, multidrug-resistant TB, and several other comorbidities were excluded, which may limit applicability to those populations. 

Source: Eckold C, Kumar V, Weiner J, Alisjahbana B, Riza AL, Ronacher K, Coronel J, Kerry-Barnard S, Malherbe ST, Kleynhans L, Stanley K. Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis. Clinical infectious diseases. 2021 Jan 1;72(1):69-78.

Association between Tuberculosis, Statin Use, and Diabetes [TBN 100]

A nationwide retrospective cohort study examined whether statin use was associated with a lower risk of tuberculosis (TB), including whether the association differed according to diabetes status. The investigators conducted a propensity score-matched analysis using South Korea’s National Health Insurance Service databases from 2003 through 2013. These databases represent people of all ages and regions across South Korea and contain sociodemographic information, diagnoses, deaths, prescriptions, and insured medical service use.

Among 1,025,340 people in the National Health Insurance cohort, the researchers identified 125,841 new statin users with a first-ever statin prescription between 2003 and 2013. After excluding 189 people younger than 18 years and 2,184 who died or emigrated within 7 days of cohort entry, 123,468 statin users remained. Potential controls were drawn from 569,999 participants in the medical-checkup cohort. After excluding previous statin users, people younger than 18 years, and those who died or emigrated within 7 days, 439,546 never-users were eligible. Propensity scores were estimated at statin initiation for users and at the first medical checkup in the corresponding year for nonusers. Matching produced 28,018 statin users and 28,018 nonusers, with standardized differences below 10% for all adjusted variables. Analyses considered 22 covariates, including age, sex, socioeconomic characteristics, diabetes, hypertension, dyslipidemia, renal and pulmonary disease, rheumatoid disease, malignancy, and cardiovascular disease. The definition used to identify incident TB was not specified in the supplied text.

In the unmatched population, crude TB incidence was similar between groups: 168 cases during 158,491 person-years among statin users, or 1.06 per 1,000 person-years (95% CI, 0.90 to 1.22), compared with 2,845 cases during 3,026,596 person-years among nonusers, or 0.94 per 1,000 person-years (95% CI, 0.91 to 0.98). The unadjusted hazard ratio (HR) was 1.05 (95% CI, 0.89 to 1.23). After adjustment for 22 covariates, statin use was associated with a lower TB risk (HR, 0.60; 95% CI, 0.49 to 0.74). In the propensity score-matched analysis, 30 TB cases occurred among statin users during 30,303 person-years, compared with 235 cases among nonusers during 167,857 person-years. Incidence was 0.99 versus 1.40 per 1,000 person-years, corresponding to an HR of 0.67 (95% CI, 0.46 to 0.98). The association weakened after statin discontinuation. In the matched analysis, the HR was 0.73 within 1 month after discontinuation (95% CI, 0.51 to 1.05) and 1.00 within 6 months (95% CI, 0.72 to 1.38). Diabetes modified the association in the matched analysis. Among participants without diabetes, statin use was associated with substantially lower TB risk, with 7 versus 147 cases and an HR of 0.28 (95% CI, 0.13 to 0.60). Among those with diabetes, there was no evidence of reduced risk, with 23 versus 88 cases and an HR of 1.05 (95% CI, 0.66 to 1.67). The interaction was statistically significant (P for interaction = 0.003). Statin use was also associated with lower TB risk among patients with cardiovascular disease (HR, 0.51; 95% CI, 0.28 to 0.92), but not clearly among those without cardiovascular disease (HR, 0.74; 95% CI, 0.44 to 1.23), although the interaction was not significant.

In conclusion, statin use was associated with a modestly lower incidence of TB after extensive adjustment and propensity score matching, but this association was concentrated among people without diabetes and appeared to diminish after statin discontinuation. Because this was an observational claims-based study, it cannot establish that statins prevent TB. Residual confounding, differences between the insurance and medical-checkup cohorts, exposure misclassification, and the small number of TB events in several matched subgroups may limit precision and causal interpretation. 

Source: Kim MC, Yun SC, Lee SO, Choi SH, Kim YS, Woo JH, Kim SH. Association between Tuberculosis, Statin Use, and Diabetes: A Propensity Score-Matched Analysis. The American Journal of Tropical Medicine and Hygiene. 2019 Aug 1;101(2):350-356.

Statin Use Is Associated With a Lower Risk of TB [TBN 099]

A nationwide, population-based retrospective cohort study evaluated whether statin use was associated with a lower risk of incident tuberculosis (TB) disease. The study used Taiwan’s National Health Insurance Research Database from January 1, 2000, through December 31, 2013, which covers more than 99% of the Taiwanese population.

Adults aged 20 years or older with cumulative statin prescriptions for at least 30 days were included as statin users. Statins assessed included simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, and pitavastatin. Patients with TB before cohort entry, missing data, or no eligible matched control were excluded. Each new statin user was matched by age and sex to a nonuser using incidence-density sampling and the same index date. Statin exposure was quantified using cumulative defined daily doses (cDDDs), categorized as less than 180, 180 to 365, or more than 365 cDDDs. Incident TB required an ICD-9-CM code of 010 to 018 plus prescriptions for at least two anti-TB drugs for at least 4 weeks within 180 days of diagnosis. Participants were followed until TB diagnosis, death, withdrawal from insurance, or December 31, 2013. Analyses adjusted for age, sex, comorbidities, urbanization, and annual outpatient visits. This observational cohort provides moderate-level evidence for association, but not proof of causality.

The final analysis included 102,424 statin users and 202,718 nonusers, contributing 571,568 and 1,027,385 person-years of observation, respectively. Statin users had substantially more cardiometabolic and chronic diseases than nonusers, including diabetes (35.0% versus 7.1%) and coronary heart disease (18.3% versus 4.6%). After adjustment, statin use was associated with a 47% lower hazard of incident TB (adjusted hazard ratio [HR], 0.53; 95% CI, 0.47 to 0.61). The association showed a dose-response pattern: fewer than 180 cDDDs were not associated with reduced risk (HR, 1.06; 95% CI, 0.91 to 1.24), whereas 180 to 365 cDDDs were associated with lower risk (HR, 0.57; 95% CI, 0.45 to 0.72), and more than 365 cDDDs with the lowest risk (HR, 0.27; 95% CI, 0.22 to 0.33). A second exposure categorization reported in the supplied text produced similar estimates, including HRs of 0.65 for the intermediate category and 0.29 for the highest category. Independent predictors of higher TB risk included age 65 years or older (HR, 1.60; 95% CI, 1.42 to 1.80), male sex (HR, 3.68; 95% CI, 3.24 to 4.18), diabetes (HR, 1.22; 95% CI, 1.06 to 1.40), heart failure (HR, 1.51; 95% CI, 1.08 to 2.11), COPD (HR, 1.72; 95% CI, 1.42 to 2.10), asthma (HR, 1.51; 95% CI, 1.17 to 1.94), and systemic glucocorticoid use (HR, 1.47; 95% CI, 1.26 to 1.72).

In conclusion, statin use was associated with a substantially lower incidence of TB in Taiwan, particularly at higher cumulative exposure. Because the study was observational and based on administrative claims, residual confounding, exposure misclassification, healthy-user bias, and differences in underlying health status may remain. Generalizability outside Taiwan or to populations with different TB epidemiology is uncertain. Randomized or prospective studies would be needed before statins could be considered for TB prevention. 

Source: Su VY, Su WJ, Yen YF, Pan SW, Chuang PH, Feng JY, Chou KT, Yang KY, Lee YC, Chen TJ. Statin Use Is Associated With a Lower Risk of TB. Chest. 2017 Sep;152(3):598-606.

Statin treatment is associated with a decreased risk of active TB [TBN 098]

A study investigated whether statin use, which inhibits cholesterol biosynthesis, is associated with a lower risk of developing active tuberculosis (TB). This was a population-based cohort study using Taiwan's National Health Insurance Research Database (NHIRD). The cohort included all adults aged 18 years or older who were followed longitudinally from January 1999 through December 2011. Drug exposure was assessed during 1999, and participants were followed from January 1, 2000 until the first occurrence of active TB diagnosis, termination of insurance coverage, death, or the end of the study.

The study included all eligible adults in the NHIRD, with 8,098 patients who developed active TB and 809,800 controls. The mean follow-up period was 9.8 years. Statin users were defined as individuals with at least 7 days of statin prescriptions. Statins included simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, and pitavastatin. Exposure was categorized as current use (prescription within 30 days before the index date), recent use (31 to 90 days), past use (91 days to 1 year), and chronic use (more than 90 cumulative prescription days within the year of TB diagnosis). The analysis adjusted for multiple confounders, including disease risk score (DRS) adjustment, and also evaluated subgroup effects and duration-response relationships.

All categories of statin use, including current, recent, past, and chronic use, were associated with a reduced risk of active TB compared with non-users. Chronic statin use showed the strongest association, with an unadjusted relative risk (RR) of 0.74 (95% CI, 0.63 to 0.87), an adjusted RR of 0.66 (95% CI, 0.56 to 0.78), and a DRS-adjusted RR of 0.62 (95% CI, 0.53 to 0.72). Current statin use demonstrated a similar protective association. Subgroup analyses consistently showed reduced TB risk across all predefined groups, although none of the interaction tests reached statistical significance. A duration-response analysis found progressively lower TB incidence with longer statin use. When cumulative statin exposure was analyzed as a continuous variable, each additional day of statin therapy was associated with a 0.002% reduction in the risk of active TB (p < 0.010). Baseline comparisons showed that patients with TB generally had greater comorbidity, more TB risk factors, more outpatient visits, and higher cardiovascular medication use than controls.

In this large nationwide cohort from Taiwan, statin use, particularly chronic use, was associated with a significantly lower risk of developing active TB, with evidence of a duration-response relationship. As an observational cohort study, the findings support an association rather than causation. The excerpt does not specify the study's funding source, conflicts of interest, inclusion and exclusion criteria beyond age eligibility, or detailed limitations, so these cannot be assessed from the available text. The level of evidence is moderate for an observational population-based cohort study.

Source: Lai CC, Lee MT, Lee SH, Hsu WT, Chang SS, Chen SC, Lee CC. Statin treatment is associated with a decreased risk of active tuberculosis: an analysis of a nationally representative cohort. Thorax. 2016 Jul 1;71(7):646-51.

TB and increased incidence of cardiovascular disease [TBN 097]

A study investigated whether tuberculosis (TB) increases the risk of incident cardiovascular disease (CVD), while accounting for differences in CVD risk that existed before TB diagnosis. This was a retrospective matched cohort study conducted using large electronic health record databases from the United States and the United Kingdom. The study examined CVD incidence during the two years before and two years after TB diagnosis, allowing replication of findings across two independent healthcare systems.

The analysis included 17,941 people with TB (2,121 in the United States and 15,820 in the United Kingdom) and 130,494 matched individuals without TB. Most participants with TB had at least four matched controls. The median age at TB diagnosis was 59 years in the United States and 44 years in the United Kingdom. Covariates measured two years before TB diagnosis included smoking status, body mass index (BMI), comorbidities, and prescriptions for statins or antihypertensive medications. Incident CVD events were identified from primary care and hospital records using ICD-9 and ICD-10 diagnostic codes in the United States and primary care diagnostic codes together with ICD-10 codes in the United Kingdom. Incidence rates and incidence rate ratios (IRRs) were estimated, with adjustment for demographic and clinical covariates, followed by additional adjustment for baseline differences in CVD incidence before TB diagnosis.

Over the four-year observation period, 462 CVD events occurred among participants with TB in the United States and 622 in the United Kingdom, corresponding to incidence rates of 65 and 11 per 1,000 person-years, respectively. Among matched individuals without TB, CVD incidence rates were lower at 31 and 6 per 1,000 person-years. People with TB already had higher CVD incidence during the two years before diagnosis, but the greatest increase occurred during the acute period surrounding TB diagnosis. During this acute period, CVD incidence reached 127 versus 30 per 1,000 person-years in the United States and 16 versus 6 per 1,000 person-years in the United Kingdom for participants with and without TB, respectively. After adjustment for demographic and clinical factors, TB was associated with a significantly increased risk of CVD during the acute period, with adjusted IRRs of 3.5 (95% CI, 2.7 to 4.4) in the United States and 2.7 (95% CI, 2.2 to 3.3) in the United Kingdom. After further accounting for preexisting differences in CVD incidence before TB diagnosis, the association remained significant but was attenuated, with adjusted relative risks of 3.2 (95% CI, 2.2 to 4.4) in the United States and 1.6 (95% CI, 1.2 to 2.1) in the United Kingdom. Stratified analyses showed similar relative risks between men and women in the United Kingdom, with no consistent differences according to age or race/ethnicity.

Active TB was associated with a substantially increased risk of incident cardiovascular disease, particularly during the period surrounding TB diagnosis, even after accounting for preexisting cardiovascular risk. These findings were consistent across independent cohorts from the United States and the United Kingdom, supporting the robustness of the association. As a retrospective observational study, causal inference is limited, and residual confounding remains possible despite extensive adjustment. The findings suggest that cardiovascular risk assessment and monitoring may be important during and shortly after TB diagnosis.

Source: Critchley JA, Limb ES, Khakharia A, Carey IM, Auld SC, De Wilde S, Harris T, Phillips LS, Cook DG, Rhee MK, Chaudhry UA. Tuberculosis and increased incidence of cardiovascular disease: cohort study using United States and United Kingdom health records. Clinical Infectious Diseases. 2025 Feb 15;80(2):271-9.

BMI trajectories and association with TB risk in Southern Africa [TBN 096]

A study investigated the nutritional status of tuberculosis (TB)-affected households and evaluated the association between baseline body mass index (BMI), changes in BMI over time, and TB risk, while describing longitudinal BMI trajectories. This was a prospective, noninterventional observational household contact cohort study (ERASE-TB) conducted in Zimbabwe, Mozambique, and Tanzania. Recruitment began between March and September 2021, enrolling household contacts aged 10 years or older of individuals with microbiologically confirmed pulmonary TB. Participants were followed every six months for up to 24 months.

The study included 2,107 household contacts from 822 households (699 in Zimbabwe, 710 in Mozambique, and 698 in Tanzania), with a median follow-up of 23.8 months (IQR, 21.8 to 26.3). At enrollment and follow-up visits, investigators collected sociodemographic data, medical and TB history, and anthropometric measurements including height, weight, and mid-upper arm circumference (MUAC). Participants also underwent blood pressure, hemoglobin, and optional HIV testing. TB screening consisted of the World Health Organization symptom questionnaire and chest radiography, followed by Xpert MTB/RIF Ultra and mycobacterial culture when indicated. An independent endpoint review committee classified TB cases, with confirmed or likely TB used as study outcomes. Prevalent TB was defined as diagnosis at baseline, while incident TB was diagnosed more than 30 days after enrollment. Associations between BMI and TB were assessed using adjusted logistic regression, Cox proportional hazards models, restricted cubic spline analyses, Poisson regression with time-varying BMI changes, and growth mixture modeling to identify latent BMI trajectories.

Among participants, 62.2% were female, the median age was 27 years (IQR, 16 to 42), and 29.5% were adolescents. Underweight was common among adolescents (61.8%) but uncommon among adults (9.2%), whereas 36.6% of adults were overweight or obese. A household-level dual burden of malnutrition, with both underweight and overweight individuals, was observed in 14% to 19% of households across the three countries. Twenty-one participants (1.0%) had prevalent TB and 41 (1.9%) developed incident TB, corresponding to an incidence rate of 13.2 per 1,000 person-years (95% CI, 9.5 to 17.9). Baseline underweight alone was not associated with prevalent TB (adjusted odds ratio [aOR], 0.94; 95% CI, 0.28 to 2.73), but underweight combined with anemia was associated with a substantially higher odds of prevalent TB (aOR, 4.83; 95% CI, 1.03 to 16.8). Similarly, baseline underweight alone was not significantly associated with incident TB (adjusted hazard ratio [aHR], 1.06; 95% CI, 0.49 to 2.26), whereas overweight or obesity showed a nonsignificant trend toward lower risk (aHR, 0.42; 95% CI, 0.15 to 1.16). Underweight combined with anemia was associated with a markedly higher hazard of incident TB (aHR, 3.77; 95% CI, 1.50 to 9.51). Restricted cubic spline analysis demonstrated a nonlinear inverse relationship between BMI and TB risk, with sharply increasing risk below a BMI Z-score of 0. The population attributable fraction for underweight was estimated at 17.3% of incident TB. Among participants who developed incident TB and had repeated anthropometric measurements, 64.7% lost weight during follow-up, and 31.8% of these lost more than 10% of baseline BMI. Adults who developed TB generally started with higher BMI and lost weight before diagnosis, whereas adolescents were often underweight from baseline. Time-varying BMI loss of at least 10% was not significantly associated with incident TB (adjusted incidence rate ratio, 2.27; 95% CI, 0.22 to 22.9), likely reflecting limited statistical power. Growth mixture modeling identified four BMI trajectory groups: decreasing, low stable, high stable, and increasing BMI. Participants in the decreasing BMI trajectory had the highest TB incidence (5.8%) compared with the low stable (1.3%), high stable (0.8%), and increasing (0.0%) groups (P = .005). The decreasing BMI group also had the highest baseline median BMI (30.6 kg/m²).

In this East and Southern African household contact cohort, baseline underweight alone was not independently associated with prevalent or incident TB, but underweight combined with anemia identified individuals at substantially higher risk. Declining BMI over time, particularly among adults who were initially overweight or obese, was associated with subsequent TB development, highlighting the value of longitudinal nutritional monitoring. The observational design limits causal inference, and the relatively small number of TB events reduced statistical precision for some analyses. The findings support integrating repeated nutritional assessment, particularly BMI and anemia evaluation, into TB household contact follow-up programs.

Source: Larsson L, Calderwood CJ, Marambire ET, Held K, Banze D, Mfinanga A, Madziva K, Walsh P, Jacob J, Fernandez FT, Lungu P. Body mass index trajectories and association with tuberculosis risk in a cohort of household contacts in Southern Africa. Clinical Infectious Diseases. 2025 Dec 15;81(6):e600-11.

Prognostic value of CRP in adults with TB meningitis [TBN 095]

A prospective cohort study investigated whether baseline serum C-reactive protein (CRP), an inexpensive marker of systemic inflammation, predicts poor clinical outcomes in adults with tuberculous meningitis (TBM), particularly among people living with HIV. Participants were enrolled between March 2021 and November 2023 at Mulago and Kiruddu National Referral Hospitals in Kampala, Uganda. The study aimed to evaluate the prognostic value of CRP for disability or death after TBM treatment.

Adults aged 18 years or older with definite, probable, or possible TBM according to the uniform case definition were included. Microbiological confirmation was based on positive cerebrospinal fluid (CSF) Xpert MTB/RIF Ultra or mycobacterial culture. Participants presenting within 3 months of antiretroviral therapy initiation were classified as having unmasking immune reconstitution inflammatory syndrome (IRIS). All participants were enrolled through the HARVEST phase 3 randomized clinical trial, which compared high-dose rifampicin (35 mg/kg/day) with standard-dose rifampicin (10 mg/kg/day) for 8 weeks. All patients received dexamethasone starting at 0.4 mg/kg/day with tapering over 6 weeks. Baseline serum CRP was measured, typically within 24 hours of diagnostic lumbar puncture, using a Cobas c311 clinical chemistry analyzer. The primary outcome was poor neurological outcome, defined as a modified Rankin Scale (mRS) score of 4 or greater at 8 weeks.

Among 178 enrolled adults with TBM, 135 (75.8%) had both baseline CRP measurements and 8-week outcome data available for analysis. The median age was 36 years (IQR, 30 to 42), 46% were female, and 83% were living with HIV, with a median CD4 count of 79 cells/μL (IQR, 38 to 177). Altered mental status at presentation was common, occurring in 76% of participants. As a continuous predictor, baseline CRP demonstrated moderate discrimination for poor outcome, with an area under the receiver operating characteristic curve (AUC) of 0.70 (95% CI, 0.61 to 0.79), improving to 0.76 (95% CI, 0.68 to 0.84) after adjustment for rifampicin dose, TBM diagnostic certainty, Medical Research Council (MRC) severity grade, and HIV status. A CRP threshold of 40 mg/L provided the best balance between sensitivity (66%) and specificity (64%) for predicting mRS ≥4 at 8 weeks. Severe TBM (MRC grade 3) was more common among participants with CRP ≥40 mg/L than among those with lower CRP levels (33% vs 9%). Among participants with poor outcomes (mRS ≥4), 61.2% had baseline CRP ≥40 mg/L compared with 30.9% among those with better outcomes (mRS ≤3). Baseline CRP ≥40 mg/L was associated with a more than threefold increase in the odds of disability or death at 8 weeks (unadjusted OR, 3.53; 95% CI, 1.73 to 7.19; P < .001). This association remained significant after adjustment for potential confounders (adjusted OR, 2.78; 95% CI, 1.28 to 6.04; P = .010). The association did not differ significantly according to TBM diagnostic certainty or suspected unmasking TBM-IRIS status.

Elevated baseline serum CRP was independently associated with a substantially increased risk of disability or death at 8 weeks among adults with TBM, supporting its potential role as a low-cost prognostic biomarker. As an observational cohort analysis nested within a randomized clinical trial, the study provides moderate-level evidence for prognostic utility but does not establish causality. Important limitations include the relatively small sample size, missing CRP or outcome data in a subset of enrolled participants, and restriction to Ugandan referral hospitals, which may limit generalizability to other settings.

Source: Tugume L, Cresswell FV, Engen NW, Tukundane A, Kimuda S, Mugabi T, Namombwe S, Kagimu E, Kabahubya M, Ellis J, Bahr NC. Prognostic value of C-reactive protein in adults with tuberculous meningitis: a prospective cohort study. Clinical Infectious Diseases. 2025 Nov 15;81(5):e410-3.

Stool processing methods for Xpert ultra testing in childhood TB [TBN 094]

A prospective multicountry diagnostic accuracy study evaluated and compared three stool processing methods for Xpert MTB/RIF Ultra (Xpert Ultra) testing in children with presumed pulmonary tuberculosis (TB): the Simple Processing Kit (SPK), the Stool Optimization and Standardization (SOS) method, and the Optimized Sucrose Flotation (OSF) method. Children younger than 15 years were consecutively enrolled between June 2019 and March 2021 from tertiary hospitals and referral networks in India, South Africa, and Uganda. The study also assessed laboratory staff perceptions of the acceptability and usability of these stool processing approaches.

A total of 607 children were included. Eligible participants had microbiologically confirmed TB or at least one symptom suggestive of pulmonary TB, including prolonged cough, fever, failure to thrive, weight loss, or a chest radiograph consistent with TB. Children who had received anti-TB treatment for more than 72 hours were excluded. All participants underwent standardized TB evaluation including clinical assessment, chest radiography, and respiratory specimen collection. Respiratory samples were tested with Xpert Ultra and mycobacterial culture. Stool specimens were collected, processed within 72 hours, and tested using one or more of the three stool processing methods. Confirmed TB was defined by positive sputum Xpert Ultra or culture. Stool Xpert Ultra results were excluded from case classification. Laboratory personnel processing stool samples completed anonymous surveys evaluating usability and acceptability.

Among the 607 children, 61.1% were enrolled in Uganda, 60.5% were younger than 5 years, 50.7% were underweight, and 15.5% were living with HIV. Confirmed TB was diagnosed in 147 children (24.2%), and 92.5% of these cases were sputum Xpert Ultra positive. The proportion of valid stool test results was similar across methods, ranging from 87.4% for OSF to 90.3% for SPK. Positive stool Xpert Ultra results ranged from 9.3% (OSF) to 11.2% (SOS). Against the microbiological reference standard (MRS), all methods showed high specificity (97.1% to 98.2%) but modest sensitivity: 36.9% for SPK, 38.6% for SOS, and 31.3% for OSF. Sensitivities were substantially higher among children with higher sputum bacillary burden, reaching 95.8% to 100% when sputum Xpert Ultra semiquantitative results were low or higher, compared with only 16.7% to 22.6% among children with trace or very low sputum results (P < .001). 

Among the 179 children tested with all three methods, diagnostic performance was similar, with overlapping 95% confidence intervals. Compared with sputum culture, sputum Xpert Ultra sensitivity was 82.4% (95% CI, 56.6% to 96.2%), higher than stool Xpert Ultra, although the difference was not statistically significant. Combining stool and sputum testing increased sensitivity by 17.6% to 23.5% compared with stool testing alone, while adding stool testing to sputum Xpert Ultra increased sensitivity by up to 11.8% at the expense of a small reduction in specificity (2.1% to 2.9%). Survey responses from 17 laboratory staff indicated that all methods were acceptable and perceived as beneficial. SOS was viewed as the least time-consuming method, and 75% of respondents believed it could be performed by nonlaboratory staff in peripheral facilities.

The three stool processing methods demonstrated similar diagnostic accuracy, characterized by high specificity but limited sensitivity for childhood pulmonary TB. The SOS method appeared most favorable operationally because of its ease of use and lower time requirements. Key limitations include incomplete testing of all children with all three methods, variation in method implementation over time, and reliance on a microbiological reference standard that may miss pediatric TB cases. As a prospective multicountry diagnostic accuracy study, the evidence supports stool Xpert Ultra as a useful noninvasive adjunct to respiratory testing, particularly in settings where sputum collection is challenging.

Source: Jaganath D, Nabeta P, Nicol MP, Castro R, Wambi P, Zar HJ, Workman L, Lodha R, Singh UB, Bavdekar A, Sanghavi S. Stool processing methods for Xpert ultra testing in childhood tuberculosis: a prospective, multicountry accuracy study. Clinical Infectious Diseases. 2026 Mar 15;82(3):526-34.

Long-term mortality trends among individuals with TB in Brazil [TBN 093]

A study examined excess mortality among people diagnosed with tuberculosis (TB) in Brazil and assessed how mortality during the TB episode and the post-TB period contributed to long-term mortality. Using a retrospective population-based cohort design, investigators linked TB notifications from Brazil’s National Notifiable Disease Information System (SINAN) with mortality records from the Mortality Information System (SIM) for 2007–2016. The objective was to compare mortality among individuals with TB against the general population and evaluate how causes of death evolved over time after TB diagnosis.

The analysis included 834,594 individuals with TB after excluding records with postmortem diagnoses, revised non-TB diagnoses, missing demographic information, and individuals aged 90 years or older. Participants contributed 4,089,883 person-years of follow-up, with a mean follow-up of 4.9 years. Deaths were identified through linked mortality records and categorized into 11 cause-of-death groups based on ICD-10 codes. The primary outcome was mortality rate ratios (MRRs) comparing the TB cohort with the general population by year since diagnosis. The TB episode was defined as the first 12 months after diagnosis, while follow-up beyond 12 months was considered the post-TB period. Analyses were stratified by age, sex, and region, and adjusted MRRs (aMRRs) were estimated for risk factors associated with mortality.

Among 834,594 individuals, 120,330 deaths occurred during follow-up (14.4%). Mortality was markedly elevated during the first year after TB diagnosis (MRR 11.28, 95% CI 11.18–11.37) and declined over time but remained above that of the general population even 10 years later (MRR 1.46, 95% CI 1.34–1.59). During the TB episode, mortality was highest among individuals aged 30–44 years (MRR 24.97, 95% CI 24.59–25.33) and lowest among those aged 75–89 years (MRR 4.04, 95% CI 3.94–4.15). HIV infection was the strongest predictor of mortality during the TB episode (aMRR 5.16, 95% CI 5.05–5.27). Other factors associated with higher mortality included female sex (aMRR 1.67, 95% CI 1.64–1.70), combined pulmonary and extrapulmonary TB (aMRR 1.57, 95% CI 1.52–1.62), and abnormal chest X-ray findings (aMRR 1.77, 95% CI 1.65–1.89). During the post-TB period, elevated mortality remained associated with HIV infection (aMRR 2.80, 95% CI 2.73–2.87), treatment reinitiation after abandonment (aMRR 1.78, 95% CI 1.74–1.84), alcohol use disorder (aMRR 1.52, 95% CI 1.49–1.55), female sex (aMRR 1.41, 95% CI 1.38–1.43), treatment loss to follow-up, and drug-resistant TB requiring regimen changes (aMRR 1.65, 95% CI 1.53–1.77). Excess mortality accumulated substantially over time. At 1 year, cumulative mortality was 6.82% in the TB cohort versus 0.70% in the general population, yielding 6.12% excess mortality. By year 10, cumulative mortality reached 17.88% versus 7.97%, corresponding to 9.90% excess mortality, of which 5.22% occurred during the post-TB period. Causes of death shifted over time. In the first year, TB (31.3%) and HIV (23.9%) were the leading causes of death. By year 10, respiratory disease (16.3%), cardiovascular disease (16.1%), and cancer (13.3%) became the predominant causes.

The findings indicate that TB is associated with substantial excess mortality that persists for at least a decade after diagnosis, with more than half of total excess mortality occurring after completion of the initial TB episode. This large national cohort provides strong observational evidence, although causal inference is limited by its retrospective design and reliance on routinely collected administrative data. The results suggest that long-term follow-up and management of chronic comorbidities may be important components of care for TB survivors.

Source: Kim S, Pelissari DM, Harada LO, Sanchez M, Oliveira PB, Johansen FD, Maciel EL, Cohen T, Castro MC, Menzies NA. Long-term mortality trends among individuals with tuberculosis: a retrospective cohort study of individuals diagnosed with tuberculosis in Brazil. Clinical Infectious Diseases. 2026 Jan 15;82(1):e1-8.

A point-of-care prediction tool for recurrent tuberculosis [TBN 092]

A study aimed to develop and validate a simple prediction model for recurrent tuberculosis (TB) that could be used at treatment completion by outreach workers to identify TB survivors at highest risk for recurrence in resource-limited, high-burden settings. The analysis used data from the TB Aftermath noninferiority trial conducted in Maharashtra, India. Participants were enrolled between January 2021 and October 2023, and follow-up data through October 2024 were analyzed.

The TB Aftermath trial enrolled 1,076 adults (≥18 years) who had completed or been cured of TB according to India's National TB Elimination Programme (NTEP) definitions. Individuals with pulmonary and/or extrapulmonary TB were eligible regardless of treatment regimen. Participants entered the study within 60 days of treatment completion and were randomized to phone-based or home-based symptom screening at 6 and 12 months after treatment. All participants also received an 18-month home visit. For this analysis, investigators included participants with at least 12 months of follow-up or those who experienced an outcome. Individuals lost to follow-up within 12 months and those who died without documented TB recurrence were excluded. The primary outcome was recurrent TB diagnosed within 18 months of treatment completion, including both microbiologically confirmed and clinically confirmed recurrences. Candidate predictors were evaluated using exploratory analyses and LASSO regression, followed by model development and validation using separate training (60%) and validation (40%) datasets.

Among 1,033 eligible TB survivors, 85 (8.2%) experienced recurrent TB within 18 months. Of these recurrences, 52 (61%) were microbiologically confirmed and 64 (75%) involved pulmonary disease. The median participant age was 35 years (IQR 27-48), 52% were male, and the median BMI was 19.9 kg/m² (IQR 17.6-23.2). Nine predictors were shortlisted: sex, household income, biomass fuel exposure, BMI, unhealthy alcohol use (AUDIT), smoking history, peak expiratory flow (PEF), disease site, and history of more than one TB episode. The highest-performing and most practical models contained five variables. Several five-item models demonstrated moderate discrimination, all including BMI and PEF. The selected model consisted of sex, household income, BMI, PEF, and history of more than one TB episode, achieving a cross-validated c-statistic of 0.69 (95% CI 0.56-0.83). Model calibration in the validation set was acceptable (Hosmer-Lemeshow P=.053; calibration intercept 0.03, 95% CI -0.03 to 0.09; slope 0.66, 95% CI 0.08-1.24). Performance did not differ significantly between early and late recurrence. Sensitivity analyses, including complete-case analyses and analyses restricted to microbiologically confirmed recurrence, identified the same five predictors and supported the robustness of the model.

The study concluded that a parsimonious five-item model using routinely obtainable characteristics can moderately predict TB recurrence after treatment completion among TB survivors in India. As a prediction-model development and validation study, the level of evidence is moderate. Limitations include modest discriminatory performance, relatively low recurrence event numbers, missing and poor-quality PEF measurements, and potential limitations in generalizability beyond similar high-burden public-sector settings. 

Source: Cox SR, Moe AH, Gupte AN, Kadam A, Valawalkar S, Gupte N, Lele G, Kendall EA, Baillie C, Barthwal MS, Kakrani A. A point-of-care prediction tool for recurrent tuberculosis. Clinical Infectious Diseases. 2025 Dec 15;81(6):e612-22.

BMI and incident tuberculosis in close TB contacts [TBN 091]

A longitudinal observational study developed and internally validated a prediction model for progression to active tuberculosis (TB) among close contacts of culture-confirmed pulmonary TB patients in the RePORT-Brazil cohort. The study enrolled participants between June 2015 and June 2019 across four cities in three Brazilian states (Rio de Janeiro, Bahia, and Amazonas) and followed contacts for 24 months. The objective was to identify predictors of progression from exposure or latent infection to active TB disease.

The study included 1,846 close contacts of 619 pulmonary TB index patients, with 86% completing at least 1.5 years of follow-up. Close contacts were defined as individuals exposed to a culture-positive pulmonary TB patient for at least 4 hours per week during the 6 months preceding diagnosis. At baseline, contacts underwent clinical evaluation, chest radiography, interferon-gamma release assay (IGRA) testing, HIV testing, and collection of sociodemographic and clinical data. Contacts were eligible only if they were asymptomatic for TB at enrollment. Follow-up assessments occurred at 6 months in person and every 6 months thereafter by telephone, with clinical evaluation if symptoms developed. Progression to TB was defined by microbiological confirmation or clinical diagnosis. Thirty baseline variables were initially considered. Predictor selection involved empirical review followed by least absolute shrinkage and selection operator (LASSO) regression with 5-fold cross-validation. Cox proportional hazards models were used after variable selection.

Among the 1,846 contacts, 25 (1.4%) developed TB within 24 months. Of these, 13 cases were microbiologically confirmed, 2 had histopathological evidence suggestive of TB, and 10 were clinically diagnosed; 75% had pulmonary TB. Baseline IGRA positivity was more common among progressors than non-progressors (75% vs 36.3%). The final prediction model identified three predictors of progression: tuberculosis preventive therapy (TPT), smoking status, and baseline IGRA positivity. 

Internal validation demonstrated good discrimination with an optimism-corrected AUC of 0.81 (95% CI 0.74-0.88). Contacts who never initiated TPT had substantially higher risk of developing TB than those who completed TPT (adjusted hazard ratio [aHR] 16.55, 95% CI 2.20-124.43). Among IGRA-positive contacts, TPT remained the only retained predictor, with an optimism-corrected AUC of 0.73 (95% CI 0.64-0.79); failure to start TPT was associated with increased TB risk (aHR 14.75, 95% CI 1.95-111.68). In the subgroup of IGRA-positive contacts who did not receive TPT or received it for less than 30 days, lower body mass index (BMI) emerged as an additional predictor. Each 1 kg/m² increase in BMI was associated with a 13% reduction in TB risk (aHR 0.89, 95% CI 0.80-0.99). A BMI threshold of approximately 25 kg/m² was identified, with BMI <25 kg/m² associated with higher risk of progression (aHR 4.14, 95% CI 1.17-14.67). In this high-risk subgroup, TB incidence was 8.4% among those with BMI <25 kg/m² compared with 2.1% among those with BMI ≥25 kg/m².

The study concluded that lack of TPT, baseline IGRA positivity, smoking status, and lower BMI are important predictors of progression to active TB among close contacts of pulmonary TB patients. Completion of TPT appeared to be the strongest protective factor. Major limitations include the small number of TB progressors (25 events), which may have reduced statistical precision and increased uncertainty around effect estimates. Internal validation showed good model performance, but external validation in other populations is needed before broader implementation. 

Source: Arriaga MB, Amorim G, Figueiredo MC, Staats C, Kritski AL, Cordeiro-Santo M, Rolla VC, Rebeiro PF, Andrade BB, Sterling TR. Body mass index and incident tuberculosis in close tuberculosis contacts. Clinical Infectious Diseases. 2026 Jan 15;82(1):e100-9.

Asymptomatic TB in children with household exposure to Mtb [TBN 090]

A study aimed to evaluate both asymptomatic and symptomatic tuberculosis (TB) among young children with household exposure to drug-susceptible TB, using standardized investigations regardless of symptom status. It was a prospective observational cohort study conducted in Worcester, South Africa, between September 2019 and March 2024. Children aged 2 to 60 months with documented household exposure to an adult with TB within the previous 12 months were enrolled. Children with HIV infection or other medical conditions that could alter TB risk were excluded. Participants without prevalent TB at baseline were followed for up to 36 months.

All enrolled children underwent comprehensive baseline TB evaluation irrespective of symptoms. Investigations included symptom screening, interferon-γ release assay (QuantiFERON-TB Gold Plus), induced sputum testing with liquid mycobacterial culture (MGIT) and Xpert MTB/RIF Ultra, chest radiography (CXR), and multiplex respiratory pathogen PCR testing. TB was classified using a modified childhood TB consensus case definition that allowed inclusion of asymptomatic children. Confirmed TB required microbiological confirmation by culture or Xpert Ultra (excluding trace-positive results). Unconfirmed TB required at least two features among TB-compatible symptoms, TB-compatible CXR findings, household TB exposure, or trace-positive Xpert Ultra results. Prevalent TB was defined as meeting TB criteria within 60 days of enrollment.

Among 506 screened child household contacts, 430 (85.0%) were enrolled. Prevalent TB was identified in 154/430 children (35.8%), including 21/430 (4.9%) with Confirmed TB and 133/430 (30.9%) with Unconfirmed TB. Notably, 17/21 (81.0%) children with Confirmed TB were asymptomatic. Overall, 55/154 (35.7%) children with prevalent TB were asymptomatic and 99/154 (64.3%) were symptomatic. Compared with symptomatic TB cases, asymptomatic TB cases were more likely to have microbiologically confirmed disease (30.9% vs 4.0%, P < .001) and a TB-compatible CXR (54.4% vs 15.2%, P < .001). 

TB treatment was initiated in 78/154 (50.6%) children meeting the TB case definition, including all Confirmed TB cases. Treatment was started more frequently in asymptomatic than symptomatic TB cases (80.0% vs 34.3%, P = .01). Among treated children, positive IGRA was associated with asymptomatic TB compared with children without TB (adjusted odds ratio [aOR] 3.23, 95% CI 1.66–6.30), as was male sex (aOR 1.98, 95% CI 1.01–3.87). Compared with symptomatic TB, microbiological confirmation was associated with asymptomatic TB (aOR 3.73, 95% CI 1.08–12.88).

The findings suggest that a substantial proportion of TB among young household-exposed children is asymptomatic, including most microbiologically confirmed cases. Reliance on symptom-based screening alone would likely miss many children with TB. Key limitations include incomplete CXR availability during the COVID-19 pandemic, potential diagnostic uncertainty among Unconfirmed TB cases, and conduct at a single South African site, which may limit generalizability. 

Source: Mulenga H, Shenje J, Mendelsohn SC, Luabeya AK, Tameris M, Tredoux EN, Nemes E, Bilek N, Beyers E, Ivacik-Goncalves D, Andrews JR. Asymptomatic tuberculosis in children with household exposure to Mycobacterium tuberculosis. Clinical Infectious Diseases. 2026 May 15;82(5):e1005-13.

Keterbatasan Penggunaan Gejala sebagai Dasar Klasifikasi Tuberkulosis [TBN 089]

Cara mengategorikan tuberkulosis (TB) telah berkembang seiring waktu, mengikuti perubahan metode utama yang digunakan untuk mendeteksinya. Pada pertengahan abad ke-20, banyak negara, terutama negara maju, menggunakan skrining massal dengan foto rontgen dada yang memungkinkan identifikasi spektrum penyakit TB yang luas, termasuk pada individu tanpa gejala yang jelas. Ketika angka TB menurun di negara-negara berpendapatan tinggi pada paruh kedua abad ke-20, upaya pencegahan dan pelayanan TB global beralih ke negara berpendapatan rendah dan menengah. Dalam konteks ini, keterbatasan sumber daya mendorong fokus pada diagnosis dan pengobatan TB menular yang bergejala, yang pada saat itu dianggap sama dengan TB BTA positif, sehingga memperkuat pandangan bahwa gejala merupakan penentu utama adanya penyakit.

Sebagai respons terhadap meningkatnya perhatian terhadap TB tanpa gejala yang jelas, Organisasi Kesehatan Dunia (WHO) menerbitkan laporan mengenai TB asimtomatik pada tahun 2025. Laporan tersebut memperkenalkan pembedaan antara TB simptomatik (symptomatic TB, sTB) dan TB asimtomatik (asymptomatic TB, aTB), yang semata-mata didasarkan pada ada atau tidaknya gejala TB yang dilaporkan saat skrining.

Gejala TB yang dilaporkan memang berkorelasi dengan tingkat keparahan penyakit. Sebagai contoh, tinjauan terhadap survei prevalensi TB nasional menunjukkan adanya hubungan berkekuatan sedang antara keluhan batuk dan hasil sputum BTA positif. Gejala yang lebih berat dan/atau menetap kemungkinan mencerminkan tingkat keparahan TB yang lebih tinggi dibandingkan gejala ringan, seperti batuk sesekali. Beberapa bukti juga menunjukkan bahwa gejala yang cukup berat hingga mendorong seseorang mencari pelayanan kesehatan dan terdiagnosis secara pasif (petugas kesehatan didatangi pasien) mungkin merupakan indikator keparahan penyakit yang lebih bermakna dibandingkan gejala yang hanya dilaporkan saat skrining aktif (petugas kesehatan mendatani pasien). Namun demikian, adanya hubungan statistik tidak cukup untuk menjadi satu-satunya dasar penggunaan gejala yang dilaporkan oleh pasien sebagai alat klasifikasi penyakit.

Meskipun berkaitan dengan tingkat keparahan penyakit, gejala yang dilaporkan pasien tidak menjadi indikator yang kuat, andal, maupun dapat digeneralisasikan untuk menentukan status penyakit. Status gejala memang menarik sebagai cara mengklasifikasikan tingkat keparahan TB karena biayanya rendah, sederhana, dan mudah diterapkan dalam skala besar. Namun, alternatif yang lebih mumpuni dan objektif untuk mengklasifikasikan status penyakit sebetulnya sering kali sudah tersedia, misalnya kuantifikasi beban kuman Mtb dalam sputum menggunakan diagnostik molekuler atau penilaian luas serta morfologi kerusakan paru pada foto rontgen dada, baik berdasarkan interpretasi radiolog maupun hasil perangkat computer-aided detection (CAD) berbasis akal imitasi.

Laporan WHO juga menimbulkan pertanyaan mengenai optimalisasi pengobatan untuk TB asimtomatik. Pengembangan rejimen yang lebih singkat, lebih mudah ditoleransi, serta pendekatan pengobatan TB yang lebih beragam sesuai kondisi pasien tentu patut disambut baik. Namun, mengingat keterbatasan gejala yang dilaporkan sebagai indikator keparahan penyakit, gejala, terutama gejala ringan, sebaiknya tidak dijadikan kriteria utama dalam menentukan siapa yang layak menerima rejimen yang kurang intensif. Sebaliknya, metode yang lebih objektif kemungkinan dapat memberikan gambaran yang lebih akurat mengenai penentuan manakah individu yang cukup diberi rejimen obat yang lebih ringan. Pendekatan ini juga akan memerlukan pedoman pengobatan yang spesifik untuk berbagai setting dan kelompok risiko, mengingat pelaporan gejala dapat sangat bervariasi antar populasi.

Pengumpulan data mengenai gejala yang dilaporkan saat skrining akan memerlukan perubahan besar pada sistem pengumpulan data di sebagian besar negara, karena saat ini data yang lebih detail umumnya baru dikumpulkan setelah diagnosis ditegakkan. Jika negara memiliki kapasitas untuk mengumpulkan data notifikasi tambahan, penambahan penilaian yang lebih objektif terkait keparahan penyakit akan lebih bermanfaat, seperti kategori semikuantitatif Xpert atau informasi mengenai apakah kasus ditemukan melalui penemuan kasus pasif atau aktif. Perbedaan tersebut kemungkinan lebih mencerminkan tingkat keparahan penyakit dibandingkan hanya berdasar pada gejala yang dilaporkan saat skrining. Pada negara yang memiliki kapasitas memadai, kombinasi indikator mikrobiologis, radiologis, dan klinis akan memberikan gambaran paling komprehensif mengenai tingkat keparahan penyakit.

Saat ini, estimasi insidens TB WHO belum membedakan antara TB asimtomatik dan TB simptomatik. Meskipun survei prevalensi menunjukkan bahwa sekitar setengah dari individu dengan TB prevalen tidak melaporkan adanya gejala, mengukur peran gejala dalam estimasi insidens jauh lebih sulit. Kesulitan ini disebabkan oleh keterbatasan data yang tersedia untuk menghasilkan estimasi yang kuat serta berbagai kelemahan penggunaan data gejala yang dilaporkan sebagai indikator status penyakit. 

===

Translation © 2026 Yoseph Samodra. This text is a translated adaptation of portions of: McCreesh N, MacPherson P, Bampi JV, Engel N, Kranzer K, Khan PY. Reported tuberculosis symptoms: an inadequate classifier of disease state. Clinical Infectious Diseases. 2026 Mar 15;82(3):e589-94. Available at: https://doi.org/10.1093/cid/ciaf611.

The original article is licensed under CC BY 4.0: https://creativecommons.org/licenses/by/4.0/. Copyright in the original work remains with the original authors. This translation was prepared by Yoseph Samodra. Translation-related contributions are © Yoseph Samodra. Any translation errors are the translator’s responsibility.

Impact of Diabetes Mellitus in TB Patients on TB Transmission [TBN 088]

A longitudinal analysis evaluated whether diabetes mellitus (DM) in patients with microbiologically confirmed tuberculosis (TB) affects TB transmissibility to household contacts (HHCs) and the risk of TB disease development among exposed contacts. The study was embedded within a prospective cohort conducted between September 2009 and August 2012 across 20 districts in Lima, Peru. The investigators hypothesized that if DM increased infectiousness, household contacts of TB patients with DM would have higher rates of TB infection and might develop disease earlier than contacts of TB patients without DM.

The study systematically enrolled all newly diagnosed TB patients aged 16 years or older presenting to participating health clinics, avoiding convenience sampling. TB diagnoses were confirmed by sputum smear microscopy and mycobacterial culture. Household contacts were visited within 2 weeks of index patient diagnosis and were evaluated for TB symptoms. Baseline TB infection was assessed using the tuberculin skin test (TST), except among contacts with co-prevalent TB, prior TB disease, or a previous positive TST. Follow-up assessments occurred at 6 and 12 months. Index patients were classified as having DM based on self-reported prior diagnosis or use of hypoglycemic medication. Serum fructosamine levels were additionally measured in 1,523 randomly selected smear-positive index patients to assess recent glycemic control. The analysis included 12,767 HHCs of 3,109 microbiologically confirmed TB patients; DM status was available for 3,083 index patients, of whom 173 (5.6%) had DM.

Index TB patients with DM were more likely to be sputum smear-positive than those without DM (80.2% vs 72.5%, P = .03), suggesting potentially greater bacillary burden. However, among 4,259 child HHCs with known baseline infection status, exposure to a DM index patient was not associated with a higher prevalence of TB infection at baseline (adjusted prevalence risk ratio [aPRR] 1.05, 95% CI 0.78-1.42). Results remained similar across multiple sensitivity analyses, including alternative DM definitions based on fructosamine levels, adjustment for Mycobacterium tuberculosis lineage, restriction to older index patients, and stratification by metformin use. Among 4,812 initially uninfected HHCs, exposure to a DM index patient was not associated with increased incident TB infection during follow-up (adjusted cumulative rate ratio [aCRR] 0.85, 95% CI 0.66-1.09), and all sensitivity analyses yielded similar null findings. 

In contrast, among 12,442 HHCs free of TB disease at enrollment, 368 (3.0%) developed incident TB disease over 12 months. Contacts exposed to TB patients with DM had a substantially lower risk of developing incident TB disease than contacts exposed to TB patients without DM (aCRR 0.33, 95% CI 0.13-0.85), representing approximately a two-thirds reduction in risk. This association remained generally consistent across sensitivity analyses, including alternative DM classifications, adjustment for M. tuberculosis lineage and isoniazid preventive therapy use, and restriction to index patients aged 40 years or older. Among the subgroup of contacts exposed to DM index patients, contacts who themselves had DM showed numerically higher rates of incident TB infection (6.7% vs 2.2%) and incident TB disease (3.3% vs 0.8%) than contacts without DM, although neither comparison reached statistical significance.

TB patients with DM were more likely to be smear-positive but did not appear to transmit TB infection more frequently to household contacts. Unexpectedly, household contacts exposed to TB patients with DM had a lower risk of developing incident TB disease during follow-up. As an observational cohort study, the findings are susceptible to residual confounding and cannot establish causality. The apparent protective association for incident TB disease warrants further investigation to determine whether it reflects biological mechanisms, differences in contact patterns, treatment-related factors, or unmeasured confounding.

Source: Huang CC, Tan Q, Becerra MC, Calderon R, Contreras C, Howard NC, Lecca L, Jimenez J, Madden AE, Yataco R, Galea JT. Impact of Diabetes Mellitus in Tuberculosis (TB) Patients on TB Transmission. Clinical Infectious Diseases. 2026 May 15;82(5):829-40.

Diagnostic accuracy of CXR CAD software for detection of TB in household contacts [TBN 087]

A prospective cohort study evaluated digital chest X-ray computer-aided detection (CAD) among adult household contacts of patients with rifampicin-resistant tuberculosis (RR-TB) in Khayelitsha, South Africa. Recruitment occurred from November 2014 to September 2017, with follow-up until May 2021. The objectives were to assess the diagnostic accuracy of three CAD packages for prevalent and incident pulmonary TB, evaluate recommended CAD thresholds, and compare or combine CAD scores with blood-based biomarkers.

Eligible participants were household contacts aged 18 years or older. Pregnant participants, those already on TB treatment, and those without CAD readings were excluded. At baseline, all participants underwent symptom screening, HIV testing, physical examination, digital posterior-anterior CXR, and microbiological testing regardless of symptoms, using spontaneous and induced sputum samples processed by smear microscopy, Xpert MTB/RIF, and MGIT culture. Three CAD tools were evaluated: CAD4TBv7, qXRv3, and Lunitv3, using thresholds of 50, 0.5, and 0.15, respectively. No participants received preventive therapy, consistent with guidelines at the time. A nested subgroup of HIV-uninfected, asymptomatic participants also underwent CRP, ESR, QuantiFERON-Gold, and 3-gene RNA MTB-HR testing.

Among 483 analyzed participants, median age was 33 years, 61% were female, 23% had previous TB, and 28% were people with HIV. Median follow-up was 4.6 years. Prevalent bacteriologically confirmed TB was found in 23 participants (4.7%), and 38 of 460 participants without prevalent TB later developed incident TB (8.3%). CAD tools performed well for prevalent TB, with AUCs of 0.87 to 0.91 for all prevalent cases, but were less accurate for predicting incident TB from baseline CXR, with AUCs of 0.60 to 0.65. At recommended thresholds, sensitivity and specificity for all prevalent TB were 0.70/0.93 for CAD4TBv7, 0.57/0.94 for qXRv3, and 0.87/0.86 for Lunitv3, compared with 0.61/0.87 for human CXR reading. CAD accuracy was better in participants without previous TB. In the biomarker subgroup, CAD outperformed blood biomarkers for asymptomatic prevalent TB, and adding blood biomarkers did not significantly improve detection of prevalent or incident TB.

Overall, CAD-based CXR screening was useful for detecting prevalent TB among adult RR-TB household contacts, including asymptomatic cases, but had limited ability to predict future incident TB. Key limitations include a single high-burden setting, exclusion of children and pregnant participants, incomplete follow-up sputum rescreening, and reduced generalizability to populations receiving preventive therapy.

Source: Macpherson L, Kik SV, Quartagno M, Lakay F, Jaftha M, Yende N, Galant S, Aziz S, Daroowala R, Court R, Taliep A. Diagnostic accuracy of chest X-ray computer-aided detection software for detection of prevalent and incident tuberculosis in household contacts. Clinical Infectious Diseases. 2025 Mar 15;80(3):626-36.

Reducing Household Tuberculosis Transmission [TBN 086]

A pilot cluster-randomized controlled trial used a hybrid type 1 effectiveness-implementation design to evaluate whether a targeted respiratory bundle could reduce acquisition of Mycobacterium tuberculosis (Mtb) infection among household contacts (HHCs) of patients with pulmonary tuberculosis. The study was conducted in Santiago, Chile, between October 2021 and April 2024 across three healthcare districts comprising 44 primary healthcare clinics. Healthcare districts were randomized at the cluster level to either the intervention arm (2 districts, 25 clinics) or control arm (1 district, 19 clinics) to minimize contamination and facilitate real-world implementation.

Eligible index patients had newly diagnosed pulmonary tuberculosis confirmed by culture, acid-fast bacillus smear, or Xpert MTB/RIF Ultra PCR and had received no more than three daily doses of anti-tuberculosis therapy. Household contacts aged >5 years were invited to participate. The intervention consisted of a two-week respiratory bundle: KN95/FFP2 mask use by both patients and household contacts when sharing indoor spaces, sleeping separately for the index patient, improved ventilation through open windows, and educational materials. Controls received routine tuberculosis care. Household contacts underwent symptom screening, chest radiography, and QuantiFERON-TB Gold Plus (QFT) testing at baseline and, if initially QFT-negative, again after 12 weeks. The primary outcome was incident tuberculosis infection, defined by QFT conversion.

A total of 157 index patients and 384 household contacts were included in the analysis. Among household contacts, 32.3% had positive baseline QFT results and 67.7% were QFT-negative. Of the 216 QFT-negative contacts assigned to intervention or control groups, 179 (82.9%) completed 12-week follow-up. QFT conversion occurred in 10.8% (10/93) of controls and 12.8% (11/86) of intervention participants, yielding a risk ratio (RR) of 1.10 (95% CI, 0.71-1.71; P = .68), indicating no significant reduction in new tuberculosis infection with the intervention. In the per-protocol analysis, participants with good adherence to the respiratory bundle at both day 7 and day 14 had a QFT conversion rate of 6.7%, compared with 10.8% in controls (RR 0.69, 95% CI 0.25-1.91; P = .47), although this difference was not statistically significant. Factors independently associated with increased risk of QFT conversion included high sputum bacillary burden in index patients (adjusted RR [adjRR] 12.10, 95% CI 2.52-55.81), drug use by the index patient (adjRR 10.02, 95% CI 2.70-36.33), suboptimal treatment adherence (adjRR 3.56, 95% CI 1.17-10.74), and household contact age below 45 years (adjRR 7.56, 95% CI 1.57-35.37). The intraclass correlation coefficient for QFT conversion within households was 0.085 (95% CI 0.005-0.360).

In this pilot cluster-randomized trial, the respiratory bundle did not significantly reduce incident Mtb infection among household contacts in the intention-to-treat analysis. However, lower infection rates among participants with good adherence suggest that adherence may influence effectiveness and warrants further investigation in larger trials. Important implementation barriers included household overcrowding, limited ability to isolate index patients, family social dynamics around meals, and stigma related to tuberculosis disclosure. As a pilot study, statistical power was limited, and confidence intervals were wide. The study provides moderate-level evidence from a randomized design regarding feasibility and implementation challenges in real-world household tuberculosis prevention.

Source: Ruiz-Tagle C, Seguel R, Villarroel L, Bernales M, Vargas-García S, Pizarro A, Peña C, Neira V, García P, Allel K, Nathavitharana RR. Reducing Household Tuberculosis Transmission: A Pilot Cluster-Randomized Controlled Trial. Clinical Infectious Diseases. 2026 Feb 15;82(2):291-8.

Gendered Patterns of Suboptimal Care Engagement Among TB Patients Who “Successfully” Completed Treatment [TBN 085]

A prospective cohort study examined patterns of care engagement among adults with drug-susceptible pulmonary TB who were programmatically classified as having treatment success. The study used latent class trajectory modeling of medication refill data and was conducted from February 2021 to August 2022 in 21 government healthcare facilities in Buffalo City Metro Health District, Eastern Cape Province, South Africa.

The analysis included 548 of 657 enrolled adults (83.4%) who were classified as cured or treatment completed. Eligible participants were aged 18 years or older, spoke English or isiXhosa, lived in a participating clinic catchment area, and gave informed consent; people with extrapulmonary TB without lung involvement or drug-resistant TB were excluded. Participants completed staff-administered questionnaires on sociodemographic factors, health status, PHQ-9 depression symptoms, AUDIT alcohol use, GAD-7 anxiety symptoms, TB knowledge, attitudes, and beliefs. Refill dates, scheduled visits, treatment start dates, and outcomes were abstracted from medical records. The main outcome was cumulative missed TB medication refill days during treatment, analyzed using latent class trajectory modeling. Level of evidence: prospective observational cohort.

Among those with treatment success, median age was 38 years (IQR, 30 to 47), 67% were men, 78.3% were unemployed, 46.2% were living with HIV, 28.1% had previous TB, and 38.9% screened positive for moderate to severe depression. Three overall engagement trajectories were identified: consistent engagement (84.1%), suboptimal engagement after 2 months (7.7%), and suboptimal engagement from onset (8.2%). By treatment completion, predicted cumulative missed refill days were 9.68 (95% CI, 7.41 to 11.83), 68.42 (95% CI, 60.35 to 76.92), and 55.47 (95% CI, 48.05 to 62.66), respectively. Men had three classes, while women had two; overall suboptimal engagement was higher among men than women (16.9% vs 10.5%). Recent TB within the past 2 years was strongly associated with suboptimal engagement overall (aOR, 4.38; 95% CI, 2.29 to 8.36), among men, and among women. Among men, HIV-negative status was also associated with suboptimal from-initiation engagement (aOR, 2.72; 95% CI, 1.13 to 6.54).

In conclusion, many patients labeled as having TB treatment success still had meaningful refill delays, especially men and those with recent prior TB. Key limitations include use of refill timing as a proxy for adherence, restriction to patients classified as treatment success, and generalizability mainly to similar public-sector TB settings in South Africa.

Source: Medina-Marino A, Arua E, de Vos L, Fiphaza K, Bezuidenhout D, Ngcelwane N, Charalambous S, Daniels J. Hidden in Success: Gendered Patterns of Suboptimal Care Engagement Among Tuberculosis Patients Who “Successfully” Completed Treatment in South Africa. Clinical Infectious Diseases. 2025 Dec 19:ciaf714.

Characterizing Treatment Adherence Trajectories in the endTB Multisite Cohort of DR-TB Patients [TBN 084]

A study analyzed adherence patterns and their relationship with treatment outcomes among patients with multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB) enrolled in the endTB Observational Study, a prospective multicountry cohort conducted between April 2015 and December 2019. The study included patients treated with regimens containing at least bedaquiline and/or delamanid across 12 countries. The objective was to identify distinct adherence trajectories during treatment and assess how these trajectories were associated with unsuccessful treatment outcomes, defined as treatment failure, death, or loss to follow-up.

A total of 1,787 patients were included from an original cohort of 2,803 consenting participants. Eligible patients had started an endTB regimen after enrollment, had at least one month of adherence data, a recorded final treatment outcome, and complete covariate information. Monthly adherence was calculated as the proportion of prescribed treatment days on which all medications were taken as prescribed. Adherence data were collected through directly observed therapy (DOT), self-report, or pill counts, depending on treatment delivery. The investigators applied a joint latent class mixed model consisting of a multinomial logistic model for class membership, a class-specific linear mixed model for adherence trajectories, and a class-specific survival model for time to unsuccessful treatment outcome. The survival model adjusted for age, sex, previous TB treatment, HIV/antiretroviral therapy status, hepatitis C virus (HCV) infection, diabetes, extensive disease, low BMI, fluoroquinolone resistance, baseline regimen drugs, and study site.

The median age was 35 years (IQR 26-45), 36.9% were female, 65.0% had fluoroquinolone resistance, and 65.7% had extensive disease. Median treatment duration was 20 months, and median monthly adherence was 95.9% (IQR 88.8%-100%). Overall, 19.0% of patients experienced an unsuccessful outcome, including 7.6% deaths, 3.3% treatment failures, and 8.1% loss to follow-up. Four adherence trajectory classes were identified: "consistently high" (72.5%), "high to low" (14.3%), "low to high" (7.3%), and "consistently low" (5.9%). Median adherence ranged from 98.0% in the consistently high group to 42.1% in the consistently low group. Unsuccessful outcomes occurred in 74.3% of the consistently low group, 1.5% of the low-to-high group, and 6.8% of the consistently high group. Compared with the consistently high group, the adjusted hazard ratio (aHR) for unsuccessful outcomes was 23.2 (95% CI 15.7-24.3) in the high-to-low group and 43.2 (95% CI 26.2-71.5) in the consistently low group. The low-to-high group did not have a significantly different risk (aHR 0.7, 95% CI 0.1-3.8). Adherence trajectory classification predicted unsuccessful outcomes substantially better than conventional adherence measures, with an AUROC of 0.84 (95% CI 0.82-0.86) versus approximately 0.65 for classifications based on overall adherence rates.

Distinct longitudinal adherence trajectories were strongly associated with MDR/RR-TB treatment outcomes, and trajectory-based classification predicted unsuccessful outcomes more accurately than conventional summary adherence measures. These findings suggest that patterns of adherence over time may be more clinically informative than overall adherence percentages alone. Limitations include exclusion of several study sites because of adherence data quality concerns, reliance on adherence measures that partly used self-report or pill counts, and inclusion only of patients with complete data. As an observational cohort study, residual confounding cannot be excluded. 

Source: Law S, Fulcher I, Ashraf S, Bastard M, Docteur W, Franke MF, Guerra D, Hewison C, Huerga H, Khan M, Khan P. Characterizing Treatment Adherence Trajectories in the endTB Multisite Cohort of Drug-Resistant Tuberculosis Patients: An Application of Group-Based Trajectory Modeling. Clinical Infectious Diseases. 2026 Mar 15;82(3):e571-9.