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.