Incidence Of Tuberculosis Disease Research Articles

Tuberculosis and increased incidence of cardiovascular disease: Cohort study using US and UK health records.

Limited evidence suggests elevated risks of cardiovascular disease (CVD) among people diagnosed with tuberculosis (TB) disease, though studies have not adjusted for pre-existing CVD risk. We carried out a cohort study using two separate datasets, estimating CVD incidence in people with TB versus those without. Using data from the United States (Veterans Health Administration) and the United Kingdom (Clinical Practice Research Datalink) for 2000-2020 we matched adults with incident TB disease and no CVD history 2-years before TB diagnosis (US n=2,121; UK n=15,820) with up to 10 people without TB on the basis of age, sex, race/ethnicity and healthcare practice. Participants were followed beginning 2-years before TB diagnosis and for 2-years subsequently. The acute period was defined as 3-months before/after TB diagnosis. TB, CVD and covariates were identified from electronic routinely collected data (primary and secondary care; mortality). Poisson models estimated incident rate ratios (IRR) for CVD events in people with TB compared to those without. CVD incidence was consistently higher in people with TB, including during the baseline period (pre-TB) and particularly in the acute period: IRRs were US 3.5 (95% Confidence Interval 2.7-4.4), UK 2.7 (2.2-3.3). Rate Ratios remained high after adjusting for differences in pre-existing CVD risk: US 3.2 (2.2-4.4), UK 1.6 (1.2-2.1). Increased CVD incidence was observed in people with TB versus those without, especially within months of TB diagnosis, persistent after adjustment for differences in pre-existing risk. Enhancing CVD screening and risk management may improve long-term outcomes in people with TB.

Sex differences in tuberculosis infection and disease among people with HIV.

Worldwide, adult men experience an excess burden of tuberculosis (TB) disease compared to women, but few studies have examined sex differences in TB among people with HIV. In this study, we aimed to investigate sex differences in TB infection and disease among people with HIV in Rio de Janeiro, Brazil. Analysis of data from a randomized controlled trial and retrospective cohort study. We analyzed data from two studies conducted between 2005 and 2017. The THRio Study (2005-2012) evaluated increasing tuberculin skin testing (TST) and TB preventive therapy (TPT) and UnivART (2010-2017) was a virtual cohort study of people with HIV and TB with data from four national electronic registries. Among 4,606 people with HIV in THRio, 2,992 (65.0%) had a TST placed and read, of whom 312/1,865 (17%) males and 203/1,127 (18%) females (p = 0.37) had prevalent TB infection. TB disease incidence was higher among males compared to females overall (IRR 1.33, 95% CI 1.04-1.69), among males compared to females who did not receive TPT (IRR 1.30, 95% CI 1.01-1.67), and among males compared to females on ART (IRR 1.64, 95% CI 1.17-2.29). Among 54,957 people with HIV in UnivART, TB disease incidence rates were higher among males than females overall (IRR 1.28, 95% CI 1.18-1.39), among males compared to females on ART (IRR 1.58, 95% CI 1.40-1.77), and among males compared to females not on ART (IRR 1.11, 95% CI 0.99-1.25). In this medium TB and HIV burden setting, TB disease incidence was higher among males than females with HIV, despite similar prevalence of TB infection.

Progress Toward Tuberculosis Elimination and Tuberculosis Program Performance - National Tuberculosis Indicators Project, 2016-2022.

Elimination of tuberculosis (TB) is defined as reducing TB disease incidence in the United States to less than 1 case per million persons per year. In 2022, TB incidence in the United States was 2.5 TB cases per 100,000 persons. CDC's TB program developed a set of national TB indicators to evaluate progress toward TB elimination through monitoring performance of state and city TB program activities. Examining TB indicator data enables state- and city-level TB programs to identify areas for program evaluation and improvement activities. These data also help CDC identify states and cities that might benefit from technical assistance. The 5-year period for which the most recent data were available for each of five indicators: 1) overall TB incidence (2018-2022), 2) TB incidence among non-U.S.-born persons (2018-2022), 3) percentage of persons with drug susceptibility results reported (2018-2022), 4) percentage of contacts to sputum acid-fast bacillus (AFB) smear-positive TB patients with newly diagnosed latent TB infection (LTBI) who completed treatment (2017-2021), and 5) percentage of patients with completion of TB therapy within 12 months (2016-2020). The National TB Indicators Project (NTIP) is a web-based performance monitoring tool that uses national TB surveillance data reported through the National TB Surveillance System and the Aggregate Reports for TB Program Evaluation. NTIP was developed to facilitate the use of existing data to help TB program staff members prioritize activities, monitor progress, and focus program improvement efforts. The following five indicators were selected for this report because of their importance in Federal TB funding allocation and in accelerating the decline in TB cases: 1) overall TB incidence in the United States, 2) TB incidence among non-U.S.-born persons, 3) percentage of persons with drug susceptibility results reported, 4) percentage of contacts to sputum AFB smear-positive TB cases who completed treatment for LTBI, and 5) percentage of patients with completion of TB therapy within 12 months. For this report, 52 TB programs (50 states, the District of Columbia, and New York City) were categorized into terciles based on the 5-year average number of TB cases reported to National TB Surveillance System. This grouping allows comparison of TB programs that have similar numbers of TB cases and allocates a similar number of TB programs to each category. The following formula was used to calculate the relative change by TB program for each indicator: [(% from year 5 - % from year 1 ÷ % from year 1) × 100]. During the 5-year period for which the most recent data were available, most TB programs had improvements in reducing overall TB incidence (71.2%) and increasing the percentage of contacts receiving a diagnosis of LTBI who completed LTBI treatment (55.8%); the majority of programs (51.0%) also had improvements in reducing incidence among non-U.S.-born persons. The average percentage of persons with drug susceptibility results reported in most jurisdictions (28 of 52, [53.9%]) met or exceeded the 5-year national average of 97% (2018-2022). The percentage of contacts to sputum acid-fast bacillus (AFB) smear-positive TB patients with newly diagnosed latent TB infection (LTBI) who completed treatment increased in 29 of 52 (55.8%) jurisdictions from 2017 to 2021, signifying that, for most jurisdictions, steps have been taken to enhance performance in this area. The average percentage of patients with completion of TB therapy within 12 months was at or above the national average of 89.7% in approximately two-thirds (32 of 52 [61.5%]) of jurisdictions. This report is the first to describe a 5-year relative change for TB program performance. These results suggest that TB programs are making improvements in activities that help identify persons with TB and LTBI and ensure patients complete treatment in a timely manner. Use of NTIP data from individual TB programs enables a more detailed examination of trends in program performance and identification of areas for program improvement. Assessing indicator trends by TB program provides an opportunity to gain a better understanding of program performance in comparison to other programs. It can also facilitate communication between programs regarding successes and challenges in program improvement. This information is valuable for TB programs to allocate resources effectively and provide additional context on TB control for public health policymakers.

Comparison of Tuberculin Skin Testing and Interferon-γ Release Assays in Predicting Tuberculosis Disease

Elimination of tuberculosis (TB) disease in the US hinges on the ability of tests to detect individual risk of developing disease to inform prevention. The relative performance of 3 available TB tests-the tuberculin skin test (TST) and 2 interferon-γ release assays (IGRAs; QuantiFERON-TB Gold In-Tube [QFT-GIT] and SPOT.TB [TSPOT])-in predicting TB disease development in the US remains unknown. To compare the performance of the TST with the QFT-GIT and TSPOT IGRAs in predicting TB disease in high-risk populations. This prospective diagnostic study included participants at high risk of TB infection (TBI) or progression to TB disease at 10 US sites between 2012 and 2020. Participants of any age who had close contact with a case patient with infectious TB, were born in a country with medium or high TB incidence, had traveled recently to a high-incidence country, were living with HIV infection, or were from a population with a high local prevalence were enrolled from July 12, 2012, through May 5, 2017. Participants were assessed for 2 years after enrollment and through registry matches until the study end date (November 15, 2020). Data analysis was performed in June 2023. At enrollment, participants were concurrently tested with 2 IGRAs (QFT-GIT from Qiagen and TSPOT from Oxford Immunotec) and the TST. Participants were classified as case patients with incident TB disease when diagnosed more than 30 days from enrollment. Estimated positive predictive value (PPV) ratios from generalized estimating equation models were used to compare test performance in predicting incident TB. Incremental changes in PPV were estimated to determine whether predictive performance significantly improved with the addition of a second test. Case patients with prevalent TB were examined in sensitivity analysis. A total of 22 020 eligible participants were included in this study. Their median age was 32 (range, 0-102) years, more than half (51.2%) were male, and the median follow-up was 6.4 (range, 0.2-8.3) years. Most participants (82.0%) were born outside the US, and 9.6% were close contacts. Tuberculosis disease was identified in 129 case patients (0.6%): 42 (0.2%) had incident TB and 87 (0.4%) had prevalent TB. The TSPOT and QFT-GIT assays performed significantly better than the TST (PPV ratio, 1.65 [95% CI, 1.35-2.02] and 1.47 [95% CI, 1.22-1.77], respectively). The incremental gain in PPV, given a positive TST result, was statistically significant for positive QFT-GIT and TSPOT results (1.64 [95% CI, 1.40-1.93] and 1.94 [95% CI, 1.65-2.27], respectively). In this diagnostic study assessing predictive value, IGRAs demonstrated superior performance for predicting incident TB compared with the TST. Interferon-γ release assays provided a statistically significant incremental improvement in PPV when a positive TST result was known. These findings suggest that IGRA performance may enhance decisions to treat TBI and prevent TB.

Burden of tuberculosis in underserved populations in South Africa: A systematic review and meta-analysis.

Identifying case-finding strategies to reduce tuberculosis (TB) incidence in high-burden countries requires better knowledge of the disease burden in key contributing populations and settings. To inform South Africa's National Tuberculosis Strategic Plan 2023-2028, we conducted a systematic review of active TB disease and latent TB infection (LTBI) prevalence and incidence in underserved populations, defined as those living in informal settlements, townships, or impoverished communities. We identified articles published from January 2010 to December 2023, assessed study quality, and conducted a meta-analysis to estimate pooled TB and LTBI prevalence stratified by HIV status. We calculated prevalence ratios for underserved populations compared to the overall South African population. The search yielded 726 unique citations. We identified 22 studies reporting TB prevalence (n = 12), TB incidence (n = 5), LTBI prevalence (n = 5), and/or LTBI incidence (n = 2) eligible for the review, including six high-quality studies. Meta-analysis demonstrated a high prevalence of TB disease among persons living without HIV (2.7% 95% CI 0.1 to 8.5%) and persons living with HIV (PLWH) (22.7%, 95% CI 15.8 to 30.4%), but heterogeneity was high (I2 = 95.5% and 92.3%, p-value<0.00). LTBI prevalence was high among persons living without HIV (44.8%, 95% 42.5 to 47%) with moderate heterogeneity (I2 = 14.6%, p-value = 0.31), and lower among PLWH (33%, 95% CI 22.6 to 44.4%) based on one study. Compared to the national average, underserved populations of persons living without HIV had a 4-fold higher TB prevalence and a 3.3-fold higher LTBI prevalence. Underserved PLWH had a 31-fold higher TB prevalence than the national average, but similar LTBI prevalence as measured in one study. Our findings illustrate that underserved populations in South Africa have a substantially higher TB and LTBI prevalence than the general population, making targeted TB interventions potentially beneficial. More research is needed to explore the heterogeneous TB epidemiology in South Africa.

Phase 1 Open-Label Dose Escalation Trial for the Development of a Human Bacillus Calmette-Guérin Challenge Model for Assessment of Tuberculosis Immunity In Vivo.

A controlled human infection model for assessing tuberculosis (TB) immunity can accelerate new vaccine development. In this phase 1 dose escalation trial, 92 healthy adults received a single intradermal injection of 2 × 106 to 16 × 106 colony-forming units of Bacillus Calmette-Guérin (BCG). The primary endpoints were safety and BCG shedding as measured by quantitative polymerase chain reaction, colony-forming unit plating, and MGIT BACTEC culture. Doses up to 8 × 106 were safe, and there was evidence for increased BCG shedding with dose escalation. The MGIT time-to-positivity assay was the most consistent and precise measure of shedding. Power analyses indicated that 10% differences in MGIT time to positivity (area under the curve) could be detected in small cohorts (n = 30). Potential biomarkers of mycobacterial immunity were identified that correlated with shedding. Transcriptomic analysis uncovered dose- and time-dependent effects of BCG challenge and identified a putative transcriptional TB protective signature. Furthermore, we identified immunologic and transcriptomal differences that could represent an immune component underlying the observed higher rate of TB disease incidence in males. The safety, reactogenicity, and immunogenicity profiles indicate that this BCG human challenge model is feasible for assessing in vivo TB immunity and could facilitate the vaccine development process. NCT01868464 (ClinicalTrials.gov).

Prevalence and predictors of tuberculosis among HIV patients who completed isoniazid preventive therapy (IPT) at Reach out Mbuya community health initiative

Tuberculosis (TB) continues to be the leading cause of morbidity and mortality among human immunodeficiency virus (HIV) infected individuals in Sub Saharan Africa, including Uganda. Isoniazid prophylaxis therapy (IPT) is a major public health intervention to limit tuberculosis disease among people living with HIV. However, there is limited information about the influence of IPT on TB disease incidence and its associated risk factors among HIV positive patients in Uganda especially at Reach out-Mbuya community health initiative hence the study. A cross sectional study was conducted among HIV positive adult patients who completed a 6-months long daily treatment of Isoniazid preventive therapy. Sputum samples and urine samples were collected and analysed using Gene Xpert and lateral flow urine Lipoarabinomannan (LF-LAM) tests respectively for presence of Tuberculosis disease. Data analysis was performed using STATA (version 14). Bivariate and multivariate logistic regression were performed to assess the risk factors associated with tuberculosis among the study population and significance estimated at 95% confidence level. A total of 103 HIV positive adults was studied. The mean age of the participants was 42.1 (10.5) and median age was 43 (IQR = 16). The prevalence of tuberculosis disease among HIV positive adult patients who completed Isoniazid preventive therapy was 5.8% (6/103). Counselling, the only significant factor, reduced the likelihood of occurrence of TB disease among HIV patients on IPT treatment (aOR:0.028, P-value < 0.001). A low prevalence of TB disease was observed among HIV patients on IPT treatment. Counselling is a protective factor of TB disease among HIV patients on IPT treatment.

Baseline Cytomegalovirus Viremia at Cryptococcal Meningitis Diagnosis Is Associated With Long-term Increased Incident TB Disease and Mortality in a Prospective Cohort of Ugandan Adults With HIV.

Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes. We conducted a cohort study of 2-week survivors of cryptococcal meningitis during 2010-2021 to determine TB incidence and all-cause mortality over time stratified by baseline CMV status. We followed 497 Ugandans with HIV-associated cryptococcal meningitis for a median (interquartile range) of 4.6 (2.6-53.9) months. Overall, 42% (210/497) developed incident TB disease or died. One-fifth (98/497, 19.7%) developed incident TB disease, and 29% (142/497) of participants died during follow-up. Of 259 participants with CMV viral load measured at baseline, 37% (96/259) had concurrent CMV viremia (defined as anyone with detectable CMV DNA in plasma/serum by qualitative polymerase chain reaction [PCR] detection). Of 59 with measured CMV immunoglobulin G (IgG), 100% had positive CMV IgG antibody serology (≥10 enzyme-linked immunosorbent assay units/mL). CMV viremia was positively associated with higher HIV viral load (196 667 vs 73 295 copies/mL; P = .002) and higher cerebrospinal fluid fungal burden (68 500 vs 14 000 cfu/mL; P = .002) compared with those without. Participants with high-level CMV viremia (defined as CMV viral load ≥1000 IU/mL) had twice the risk of incident TB (subdistribution adjusted hazard ratio [aHR], 2.18; 95% CI, 1.11-4.27) and death (aHR, 1.99; 95% CI, 1.14-3.49) compared with participants with no or low-level CMV viremia. There was no association between the CMV IgG index and the incidence of TB/death (P = .75). CMV viremia >1000 IU/mL at meningitis diagnosis was associated with increased incident TB disease and mortality during long-term follow-up. Future studies to determine the causal relationship and potential for therapeutic intervention are warranted.

Impact of micro- and macronutrient status on the incidence of tuberculosis: An examination of an African cohort initiating antiretroviral therapy.

Macronutrient and micronutrient deficiencies are associated with tuberculosis (TB) incidence. However, evidence is limited on the impact of micronutrient (vitamins and minerals) supplementation among underweight individuals. We conducted a secondary data analysis of a randomised controlled trial of lipid nutritional supplements with and without high-dose vitamin and mineral supplementation (LNS-VM vs LNS) for underweight (Body Mass Index [BMI] <18.5 kg/m2) adults with human immunodeficiency virus (HIV) initiating antiretroviral therapy (ART) in Tanzania and Zambia (2011-2013). Incident TB disease diagnoses were extracted from trial records. We used multivariable Cox regression to estimate hazard ratios (HR) for the impact of receiving LNS-VM on TB incidence, and the dose-response relationship between baseline BMI and TB incidence. Overall, 263 (17%) of 1506 participants developed TB disease. After adjusting for age, sex, CD4 count, haemoglobin, and C-reactive protein, receiving LNS-VM was not associated with TB incidence (aHR [95%CI] = 0.93 [0.72-1.20]; p = 0.57) compared to LNS alone. There was strong evidence for an association between lower BMI and incident TB (aHR [95%CI]: 16-16.9kg/m2 = 1.15 [0.82-1.62] and <16kg/m2 = 1.70 [1.26-2.30] compared to 17-18.5kg/m2; linear trend p<0.01). There was strong evidence that the rate of developing TB was lower after initiating ART (p<0.01). In conclusion, the addition of micronutrient supplementation to LNS was not associated with lower TB incidence in this underweight ART-naive population.

Tuberculosis Infection and Disease Among Pregnant People Living in Sweden With Origin in Tuberculosis-Endemic Countries.

Pregnancy has been associated with elevated incidence of tuberculosis (TB) disease. Since 2014, people living in Sweden with origin in TB-endemic countries have been offered screening for TB infection in antenatal care (ANC) using Quantiferon-TB assays. We assessed factors associated with TB infection in this population and determined the incidence of TB disease during pregnancy and postpartum periods with regard to ANC Quantiferon-TB results. Quantiferon-TB results obtained during ANC in Sweden, 2014-2018, were linked to data from national registers (Pregnancy Register, Patient Register and Tuberculosis Register). Factors associated with TB infection (defined as Quantiferon-TB ≥0.35 IU/mL) were identified using logistic regression analysis. Incidence of TB disease was determined with regard to pregnancy, postpartum and subsequent periods, and ANC Quantiferon-TB results. Among 7638 screened individuals, 1424 (18.6%) had TB infection. Tuberculosis infection was independently associated with higher age at immigration (adjusted odds ratio, 1.04 [95% confidence interval, 1.03-1.05]; P < .001), and was more common among people originating from Africa compared to other world regions (845/3088 [27.4%] vs 579/4550 [12.7%]; P < .001). In total, 16 participants were diagnosed with TB disease (10 during pregnancy, 4 at <6 months after delivery, 2 at >6 months after delivery); among these, all diagnosed during pregnancy/postpartum had positive ANC Quantiferon-TB results (constituting 14/1424 [1%] of people with TB infection). Among pregnant people screened in Swedish ANC, TB infection was associated with higher age and African origin. All cases of TB disease reported in persons with TB infection at ANC screening occurred during pregnancy or postpartum.

Gene expression in cord blood and tuberculosis in early childhood: A nested case-control study in a South African birth cohort.

Transcriptomic profiling of adult tuberculosis patients has become increasingly common, predominantly for diagnostic and risk prediction purposes. However few studies have evaluated signatures in children, particularly in identifying those at risk for developing TB disease. We investigated the relationship between gene expression obtained from umbilical cord blood and both tuberculin skin test conversion as well as incident tuberculosis disease through the first 5 years of life. We conducted a nested case-control study in the Drakenstein Child Health Study, a longitudinal, population-based birth cohort in South Africa. We applied transcriptome-wide screens to umbilical cord blood samples from neonates born to a subset of selected mothers (n=131). Signatures identifying tuberculin conversion and risk of subsequent tuberculosis disease were identified from genome wide analysis of RNA expression. Gene expression signatures revealed clear differences predictive of tuberculin conversion (n=26) and tuberculosis disease (n=10); 114 genes were associated with tuberculin conversion and 30 genes were associated with the progression to tuberculosis disease among children with early infection. Co-expression network analysis revealed six modules associated with risk of tuberculosis infection or disease, including a module associated with neutrophil activation in immune response (p<0.0001) and defense response to bacterium (p<0.0001). These findings suggest multiple detectable differences in gene expression at birth which were associated with risk of tuberculosis infection or disease throughout early childhood. Such measures may provide novel insights into tuberculosis pathogenesis and susceptibility.

Completion, safety, and efficacy of tuberculosis preventive treatment regimens containing rifampicin or rifapentine: an individual patient data network meta-analysis

3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R. We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs. We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found. In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment. None. For the French and Spanish translations of the abstract see Supplementary Materials section.

Solid organ transplant recipients with tuberculosis disease in California, 2010 to 2020

Using California Tuberculosis (TB) Registry data from 2010-2020, we compared the presentation and outcomes of patients with TB aged >15 years with and without solid organ transplantation (SOT). We matched to the United Network for Organ Sharing registry for 1987-2020 and the estimated time from transplantation to the diagnosis of TB, the incidence of posttransplant TB, and the probability of death and graft failure in SOT recipients with TB, compared to those without TB. From 2010-2020, there were 148 posttransplant TB cases. Patients with posttransplant TB were more likely to have extrapulmonary disease and more than twice as likely to die as TB patients without SOT (relative risk [RR], 2.2; 95% confidence interval [CI], 1.6-2.9). The median time from transplantation to TB diagnosis was 1.2 years, with the shortest time among lung transplant recipients. The incidence of TB disease among Californians with SOT was 56.0 per 100 000 person-years. The risk of death was higher among SOT recipients with posttransplant TB than those without (adjusted hazard ratio, 2.8; 95% CI, 2.0-4.1); the risk of graft failure was higher among kidney transplant recipients with posttransplant TB than those without (adjusted hazard ratio, 3.4; 95% CI, 1.7-6.9). An increased risk of death and graft failure in SOT recipients with posttransplant TB highlights the need for enhanced pretransplant TB prevention.

Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysis

Evidence on the comparative performance of purified protein derivative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) for predicting incident active tuberculosis (TB) remains conflicting. We conducted an individual participant data meta-analysis to directly compare the predictive performance for incident TB disease between TST and IGRA to inform policy. We searched Medline and Embase from 1 January 2002 to 4 September 2020, and studies that were included in previous systematic reviews. We included prospective longitudinal studies in which participants received both TST and IGRA and estimated performance as hazard ratios (HR) for the development of all diagnoses of TB in participants with dichotomised positive test results compared to negative results, using different thresholds of positivity for TST. Secondary analyses included an evaluation of the impact of background TB incidence. We also estimated the sensitivity and specificity for predicting TB. We explored heterogeneity through pre-defined sub-group analyses (e.g. country-level TB incidence). Publication bias was assessed using funnel plots and Egger's test. This review is registered with PROSPERO, CRD42020205667. We obtained data from 13 studies out of 40 that were considered eligible (N=32,034 participants: 36% from countries with TB incidence rate ≥100 per 100,000 population). All reported data on TST and QuantiFERON Gold in-Tube (QFT-GIT). The point estimate for the TST was highest with higher cut-offs for positivity and particularly when stratified by bacillus Calmette-Guérin vaccine (BCG) status (15mm if BCG vaccinated and 5mm if not [TST5/15 mm]) at 2.88 (95% CI 1.69-4.90). The pooled HR for QFT-GIT was higher than for TST at 4.15 (95% CI 1.97-8.75). The difference was large in countries with TB incidence rate <100 per 100,000 population (HR 10.38, 95% CI 4.17-25.87 for QFT-GIT VS. HR 5.36, 95% CI 3.82-7.51 for TST5/15 mm) but much of this difference was driven by a single study (HR 5.13, 95% CI 3.58-7.35 for TST5/15 mm VS. 7.18, 95% CI 4.48-11.51 for QFT-GIT, when excluding the study, in which all 19TB cases had positive QFT-GIT results). The comparative performance was similar in the higher burden countries (HR 1.61, 95% CI 1.23-2.10 for QFT-GIT VS. HR 1.72, 95% CI 0.98-3.01 for TST5/15 mm). The predictive performance of both tests was higher in countries with TB incidence rate <100 per 100,000 population. In the lower TB incidence countries, the specificity of TST (76% for TST5/15 mm) and QFT-GIT (74%) for predicting active TB approached the minimum World Health Organization target (≥75%), but the sensitivity was below the target of ≥75% (63% for TST5/15 mm and 65% for QFT-GIT). The absolute differences in positive and negative predictive values between TST15 mm and QFT-GIT were small (positive predictive values 2.74% VS. 2.46%; negative predictive values 99.42% VS. 99.52% in low-incidence countries). Egger's test did not show evidence of publication bias (0.74 for TST15 mm and p=0.68 for QFT-GIT). IGRA appears to have higher predictive performance than the TST in low TB incidence countries, but the difference was driven by a single study. Any advantage in clinical performance may be small, given the numerically similar positive and negative predictive values. Both IGRA and TST had lower performance in countries with high TB incidence. Test choice should be contextual and made considering operational and likely clinical impact of test results. YH, IA, and MXR were supported by the National Institute for Health and Care Research (NIHR), United Kingdom (RP-PG-0217-20009). MQ was supported by the Medical Research Council [MC_UU_00004/07].

Understanding the biology, morbidity and social contexts of adolescent tuberculosis: a prospective observational cohort study protocol (Teen TB)

IntroductionA considerable burden of the tuberculosis (TB) epidemic is found in adolescents. The reasons for increased susceptibility to TB infection and higher incidence of TB disease in adolescence, compared with...

Effects of long-term ambient air pollution exposure on township-level pulmonary tuberculosis notification rates during 2005–2017 in Ningxia, China

Studies examining long-term effects of ambient air pollution exposure, measured as annual averages, on pulmonary tuberculosis (TB) incidence are scarce, particularly in endemic, rural settings. We performed a small-area study in Ningxia Hui Autonomous Region (NHAR), a high TB-burden area in rural China, using township-level (n = 358 non-overlapping townships) annual TB notification data (2005–2017). We aimed to determine if annual average concentrations of ambient air pollution (particulate matter <2·5 μm [PM2·5], nitrogen dioxide [NO2] ozone [O3]) were associated with TB notification rates (as a proxy for incidence). Air pollution effects on TB notification rates at township-level were estimated as incidence rate ratios (IRR), fitted using a generalised estimating equation (GEE) adjusted for covariates (age, sex, occupation, education, ethnicity, remoteness [urban or rural], household crowding and solid fuel use). A total of 38,942 TB notifications were reported in NHAR between 2005 and 2017. The mean annual TB notification rate was 67 (standard deviation [SD]; 7) per 100,000 people. Median concentrations of PM2·5, NO2, and O3 were 42 μg/m3 (interquartile range [IQR]; 38–48 μg/m3), 15 ppb (IQR; 12–16 ppb), and 56 ppb (IQR; 56–57 ppb), respectively. In single pollutant models, adjusted for covariates, an interquartile range (IQR) increase (10 μg/m3) in PM2·5 was significantly associated with higher TB notification rates (IRR: 1∙35; 95% CI: 1·25–1·48). Comparable effects on notifications of TB were observed for increases in NO2 exposure (IRR: 1·20 per IQR (4 ppb) increase; 95% CI: 1·08–1·31). Ground-level ozone was not associated with TB notification rate in any models. The observed effects were consistent over time, in multi-pollutant models, and appeared robust to additional adjustment for indicators of household crowding, solid fuel use and remoteness. More rigorous study designs are needed to understand if improving air quality has population-level benefits on TB disease incidence in endemic settings.

A retrospective longitudinal study on tuberculosis disease among people with HIV

The use of Isoniazid Prevention Therapy (IPT) helps normalize the health issues of patients with TB. The majority of patients suffering from these diseases are from a low-income group with poor education. They do not have adequate knowledge related to prevention and approaches that reduce the occurrence of TB disease soon after ART initiation where risk is higher. The study aims to determine the incidence of tuberculosis disease among patients with HIV while taking IPT and after its completion. This is a retrospective, observational, longitudinal study that used existing records of patients from Department of Pulmonary Medicine, D Y Patil Medical College, Nerul, Navimumbai, Maharashtra, India. The period of the study was from January 2020 to June 2021. STATA statistical software Version 12 was used to analyse the data. The sample size was estimated based on simple proportion formula taking incident TB disease after starting IPT 1.5% based on the study in a similar setting. In this study, 960 patients were involved with mean age of 30 years, ranged between 25-37 years. TB was developed in 9.2% patients, out of which, 2.2% of patients were diagnosed while receiving IPT and 6.97% after IPT. Moreover, 55.2% of patients were on this treatment at the last observation. The unfavourable count of patients was 152 (15.8%). Most of the patients with unfavourable follow-up outcomes were lost to follow-up. 0.6% of patients have stopped treatment during the follow-up and 28.9% was transferred out. Finally, 4.7% of patients died and remaining were recovered. Breakthrough TB was uncommon and shown a significant proportion of it occurrence in the first month of treatment. This could be due to difficulty in diagnosing TB disease with HIV. The proper screening of patients is essential for offering treatment and providing effective care services.

Contribution of Reinfection to Annual Rate of Tuberculosis Infection (ARI) and Incidence of Tuberculosis Disease.

Modeling studies have concluded that 60-80% of tuberculosis (TB) infections result from reinfection of previously infected persons. The annual rate of infection (ARI), a standard measure of the risk of TB infection in a community, may not accurately reflect the true risk of infection among previously infected persons. We constructed a model of infection and reinfection with Mycobacterium tuberculosis to explore the predictive accuracy of ARI and its effect on disease incidence. We created a deterministic simulation of the progression from TB infection to disease and simulated the prevalence of TB infection at the beginning and end of a theoretical year of infection. We considered 10 disease prevalence scenarios ranging from 100/100 000 to 1000/100 000 in simulations where TB exposure probability was homogeneous across the whole simulated population or heterogeneously stratified into high-risk and low-risk groups. ARI values, rates of progression from infection to disease, and the effect of multiple reinfections were obtained from published studies. With homogeneous exposure risk, observed ARI values produced expected numbers of infections. However, when heterogeneous risk was introduced, observed ARI was seen to underestimate true ARI by 25-58%. Of the cases of TB disease that occurred, 36% were among previously infected persons when prevalence was 100/100 000, increasing to 79% of cases when prevalence was 1000/100 000. Measured ARI underestimates true ARI as a result of heterogeneous population mixing. The true force of infection in a community may be greater than previously appreciated. Hyperendemic communities likely contribute disproportionally to the global TB disease burden.

The Contribution of Chest Radiography to the Clinical Management of Children Exposed to Tuberculosis.

Rationale: Although World Health Organization guidelines emphasize contact investigation for tuberculosis (TB)-exposed children, data that support chest radiography as a useful tool are lacking. Objectives: We evaluated the diagnostic and prognostic information of chest radiography in children exposed to TB and measured the efficacy of isoniazid preventive therapy (IPT) in those with relevant radiographic abnormalities. Methods: Between September 2009 and August 2012, we enrolled 4,468 TB-exposed children who were screened by tuberculin skin testing, symptom assessment, and chest radiography. Those negative for TB disease were followed for 1 year for the occurrence of new TB diagnoses. We assessed the protective efficacy of IPT in children with and without abnormal chest radiographs. Measurements and Main Results: Compared with asymptomatic children with normal chest films, asymptomatic children with abnormal radiographs were 25.1-fold more likely to have coprevalent TB (95% confidence interval [CI], 1.02-613.76) and 26.7-fold more likely to be diagnosed with incident TB disease during follow-up (95% CI, 10.44-68.30). Among the 29 symptom-negative and CXR-abnormal child contacts, 20% (3/15) of the isoniazid recipients developed incident TB, compared with 57% (8/14) of those who did not receive IPT (82% IPT efficacy). Conclusions: Our results strongly support the use of chest radiography as a routine screening tool for the evaluation of child TB contacts, which is readily available. Radiographic abnormalities not usually considered suggestive of TB may indicate incipient or subclinical disease, although TB preventive treatment is adequate in most cases.

Incidence of active tuberculosis among people living with HIV receiving long-term antiretroviral therapy in high TB/HIV burden settings in Thailand: implication for tuberculosis preventive therapy.

IntroductionAmong high tuberculosis (TB) and HIV burden countries in Asia, tuberculosis preventive therapy (TPT) in people living with HIV (PLWH) has been underutilized despite its proven benefits independent of antiretroviral therapy (ART). Therefore, we determined the incidence of active TB and mortality among 9179 adult PLWH who attended and received ART from 15 tertiary care hospitals across Thailand.MethodsA retrospective study was conducted in 2018 using follow‐up data from 1999 to 2018. The primary endpoint was incident TB disease after ART initiation. Factors associated with TB incidence were analysed using competing risk regression. The Kaplan–Meier method was used to estimate mortality after ART initiation.ResultsDuring a median of 5.1 years of ART (IQR 2.2–9.5 years), 442 (4.8%) PLWH developed TB (TB/HIV), giving an overall incidence of 750 (95% CI 683–823) per 100,000 persons‐year of follow up (PYFU). In multivariate analysis, lower CD4 at ART initiation (≤100 cells/mm3, adjusted sub‐distribution hazard ratio [aSHR]: 2.08, 95% CI, 1.47–2.92; 101–200 cells/mm3, aSHR: 2.21, 95% CI, 1.54–3.16; 201–350 cells/mm3, aSHR: 1.59, 95% CI, 1.11–2.28 vs. >350 cells/mm3), male sex (aSHR: 1.40, 95% CI, 1.11–1.78), lower body weight (<50 kg, aSHR: 1.52, 95% CI, 1.17–1.95) and prior TB event (aSHR: 3.50, 95% CI, 2.72–4.52) were associated with TB incidence. PLWH with HIV RNA ≥50 copies/ml had 5–9 times higher risk of active TB disease higher than those with HIV RNA <50 copies/ml at the same CD4 level. The risk for developing TB was remarkably high during the initial period of ART (175,511 per 100,000 PYFU at<3 months) and was comparable to the general population after 10 years of ART (151 per 100,000 PYFU). TB/HIV had higher mortality (10% vs. 5%) and poorer HIV treatment outcomes: HIV RNA <50 copies/ml (63.8% vs. 82.8%), CD4 cells count (317 vs. 508 cells/mm3) at the most recent visit.ConclusionsIn this high TB burden country, TB incidence was remarkably high during the first few years after ART initiation and thereafter decreased significantly. Rapid ART initiation and appropriate TPT can be potential key interventions to tackle the TB epidemic and reduce mortality among PLWH in TB/HIV high burden settings.