Prevalence of non-communicable diseases among household contacts of people with tuberculosis: A systematic review and individual participant data meta-analysis.

OBJECTIVE: To investigate the prevalence of non-communicable diseases among household contacts of people with tuberculosis. METHODS: We conducted a systematic review and individual participant data meta-analysis. We searched Medline, Embase and the Global Index Medicus from inception to 16 May 2023. We included studies that assessed for at least one non-communicable disease among household contacts of people with clinical tuberculosis. We estimated the non-communicable disease prevalence through mixed effects logistic regression for studies providing individual participant data, and compared it with estimates from aggregated data meta-analyses. Furthermore, we compared age and sex-standardised non-communicable disease prevalence with national-level estimates standardised for age and sex. RESULTS: We identified 39 eligible studies, of which 14 provided individual participant data (29,194 contacts). Of the remaining 25 studies, 18 studies reported aggregated data suitable for aggregated data meta-analysis. In individual participant data analysis, the pooled prevalence of diabetes in studies that undertook biochemical testing was 8.8% (95% confidence interval [CI], 5.1%-14.9%, four studies). Age-and sex-standardised prevalence was higher in two studies (10.4% vs. 6.9% and 11.5% vs. 8.4%) than the corresponding national estimates and similar in two studies. Prevalence of diabetes mellitus based on self-report or medical records was 3.4% (95% CI 2.6%-4.6%, 14 studies). Prevalence did not significantly differ compared to estimates from aggregated data meta-analysis. There were limited data for other non-communicable diseases. CONCLUSION: The prevalence of diabetes mellitus among household contacts was high while that of known diabetes was substantially lower, suggesting the underdiagnosis. tuberculosis household contact investigation offers opportunities to deliver multifaceted interventions to identify tuberculosis infection and disease, screen for non-communicable diseases and address shared risk factors.

Global tuberculosis disease and infection in systemic lupus erythematosus patients: A systematic review and meta-analysis.

BACKGROUND: Tuberculosis (TB) is one of the most common infections among systemic lupus erythematosus (SLE) patients. We aimed to evaluate the global prevalence of TB infection and disease, its type, and medication risk factors in SLE patients. METHODS: We searched PubMed, Science Direct, EBSCO, and Web of Science databases from inception to April 30, 2023, and included studies assessing TB among SLE patients. We estimated the prevalence of TB disease (including type of TB disease), TB infection, and SLE medication as TB risk factors. Meta-analysis was performed using Stata 14.2 and Review Manager 5.3. RESULTS: Twenty-seven studies met the eligibility criteria. The global prevalence of TB disease was 4% (95% confidence interval (CI): 3-4%, n = 25) and TB infection was 18% (95% CI: 10-26%, n = 3). The pooled prevalence of pulmonary TB, extrapulmonary TB, and disseminated TB were 2% (95% CI: 2-3%, n = 20), 1% (95% CI: 1-2%, n = 17), and 1% (95% CI: 0-1%, n = 6), respectively. The 1-year cumulative glucocorticoid (GC) dose in SLE patients contracting TB was higher than in those without TB, having a mean difference of 2.56 (95% CI: 0.22-4.91, p < .00001, n = 3). The odd ratio of TB was 2.11 (95% CI: 1.01-4.41, p = .05, n = 3) in SLE patients receiving methylprednisolone (MP) pulse therapy as compared to those without MP pulse therapy. Other immunosuppressive agents were not significantly associated with TB. CONCLUSION: TB prevalence in SLE was relatively high and associated with GC. Awareness of TB and lowering GC dose are warranted to alleviate the TB burden in SLE.

Assessing the Diagnostic Performance of New Commercial Interferon-γ Release Assays for Mycobacterium tuberculosis Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: We compared 6 new interferon-γ release assays (IGRAs; hereafter index tests: QFT-Plus, QFT-Plus CLIA, QIAreach, Wantai TB-IGRA, Standard E TB-Feron, and T-SPOT.TB/T-Cell Select) with World Health Organization (WHO)-endorsed tests for tuberculosis infection (hereafter reference tests). METHODS: Data sources (1 January 2007-18 August 2021) were Medline, Embase, Web of Science, Cochrane Database of Systematic Reviews, and manufacturers' data. Cross-sectional and cohort studies comparing the diagnostic performance of index and reference tests were selected. The primary outcomes of interest were the pooled differences in sensitivity and specificity between index and reference tests. The certainty of evidence (CoE) was summarized using the GRADE approach. RESULTS: Eighty-seven studies were included (44 evaluated the QFT-Plus, 4 QFT-Plus CLIA, 3 QIAreach, 26 TB-IGRA, 10 TB-Feron [1 assessing the QFT-Plus], and 1 T-SPOT.TB/T-Cell Select). Compared to the QFT-GIT, QFT Plus's sensitivity was 0.1 percentage points lower (95% confidence interval [CI], -2.8 to 2.6; CoE: moderate), and its specificity 0.9 percentage points lower (95% CI, -1.0 to -.9; CoE: moderate). Compared to QFT-GIT, TB-IGRA's sensitivity was 3.0 percentage points higher (95% CI, -.2 to 6.2; CoE: very low), and its specificity 2.6 percentage points lower (95% CI, -4.2 to -1.0; CoE: low). Agreement between the QFT-Plus CLIA and QIAreach with QFT-Plus was excellent (pooled κ statistics of 0.86 [95% CI, .78 to .94; CoE: low]; and 0.96 [95% CI, .92 to 1.00; CoE: low], respectively). The pooled κ statistic comparing the TB-Feron and the QFT-Plus or QFT-GIT was 0.85 (95% CI, .79 to .92; CoE: low). CONCLUSIONS: The QFT-Plus and the TB-IGRA have very similar sensitivity and specificity as WHO-approved IGRAs.

Safety and Side Effects of Rifampin versus Isoniazid in Children.

BACKGROUND: The treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment - 9 months of isoniazid - has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid. METHODS: In this multicenter, open-label trial, we randomly assigned 844 children (<18 years of age) with latent M. tuberculosis infection to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events of grade 1 to 5 that resulted in the permanent discontinuation of a trial drug. Secondary outcomes were treatment adherence, side-effect profile, and efficacy. Independent review panels whose members were unaware of trial-group assignments adjudicated all adverse events and progression to active tuberculosis. RESULTS: Of the children who underwent randomization, 829 were eligible for inclusion in the modified intention-to-treat analysis. A total of 360 of 422 children (85.3%) in the rifampin group completed per-protocol therapy, as compared with 311 of 407 (76.4%) in the isoniazid group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% confidence interval [CI], 7.5 to 19.3). There were no significant between-group differences in the rates of adverse events, with fewer than 5% of the children in the combined groups with grade 1 or 2 adverse events that were deemed to be possibly related to a trial drug. Active tuberculosis, including 1 case with resistance to isoniazid, was diagnosed in 2 children in the isoniazid group during 542 person-years of follow-up, as compared with no cases in the rifampin group during 562 person-years (rate difference, -0.37 cases per 100 person-years; 95% CI, -0.88 to 0.14). CONCLUSIONS: Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).

Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

BACKGROUND: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects. METHODS: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels. RESULTS: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events. CONCLUSIONS: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Health System Costs of Treating Latent Tuberculosis Infection With Four Months of Rifampin Versus Nine Months of Isoniazid in Different Settings.

BACKGROUND: Four months of rifampin treatment for latent tuberculosis infection is safer, has superior treatment completion rates, and is as effective as 9 months of isoniazid. However, daily medication costs are higher for a 4-month rifampin regimen than a 9-month isoniazid regimen. OBJECTIVE: To compare health care use and associated costs of 4 months of rifampin and 9 months of isoniazid. DESIGN: Health system cost comparison using all health care activities recorded during 2 randomized clinical trials. (ClinicalTrials.gov: NCT00931736 and NCT00170209). SETTING: High-income countries (Australia, Canada, Saudi Arabia, and South Korea), middle-income countries (Brazil and Indonesia), and African countries (Benin, Ghana, and Guinea). PARTICIPANTS: Adults and children with clinical or epidemiologic factors associated with increased risk for developing tuberculosis that warranted treatment for latent tuberculosis infection. MEASUREMENTS: Health system costs per participant. RESULTS: A total of 6012 adults and 829 children were included. In both adults and children, greater health system use and higher costs were observed with 9 months of isoniazid than with 4 months of rifampin. In adults, the ratios of costs of 4 months of rifampin versus 9 months of isoniazid were 0.76 (95% CI, 0.70 to 0.82) in high-income countries, 0.90 (CI, 0.85 to 0.96) in middle-income countries, and 0.80 (CI, 0.78 to 0.81) in African countries. Similar findings were observed in the pediatric population. LIMITATION: Costs may have been overestimated because the trial protocol required a minimum number of follow-up visits, although fewer than recommended by many authoritative guidelines. CONCLUSION: A 4-month rifampin regimen was safer and less expensive than 9 months of isoniazid in all settings. This regimen could be adopted by tuberculosis programs in many countries as first-line therapy for latent tuberculosis infection. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Early Clearance of Mycobacterium tuberculosis: The INFECT Case Contact Cohort Study in Indonesia.

BACKGROUND: Early clearance of Mycobacterium tuberculosis is the eradication of infection before an adaptive immune response develops. We aimed to identify host factors associated with early clearance. METHODS: Indonesian household contacts patients with smear-positive tuberculosis (TB) had an interferon-γ release assay (IGRA) at baseline and 14 weeks later. Early clearance was defined as a persistently negative IGRA. Contact characteristics, exposure, and disease phenotype were assessed for association with a positive IGRA at each time point. RESULTS: Of 1347 contacts of 462 TB cases, 780 (57.9%) were IGRA positive and 490 (36.3%) were IGRA negative. After 14 weeks, 116 of 445 (26.1%) initially negative contacts were IGRA converters; 317 (71.2%) remained persistently negative. BCG vaccination reduced the risk of a positive baseline IGRA (relative risk [RR], 0.89 [95% confidence interval {CI} .83-.97]; P = .01), and strongly reduced the risk of IGRA conversion (RR, 0.56 [95% CI, .40-.77]; P < .001). BCG protection decreased with increasing exposure (P = .05) and increasing age (P = .004). Risk of IGRA conversion was positively associated with hemoglobin concentration (P = .04). CONCLUSIONS: A quarter of household TB case contacts were early clearers. Protection against M. tuberculosis infection was strongly associated with BCG vaccination. Lower protection from BCG with increasing M. tuberculosis exposure and age can inform vaccine development.

Early Clearance of Mycobacterium tuberculosis Is Associated With Increased Innate Immune Responses.

BACKGROUND: A proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed "early clearance." METHODS: Indonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post recruitment. Blood cell populations and ex vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive. RESULTS: Among 1347 case contacts, 317 were early clearers and 116 were converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA-negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA-negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae. CONCLUSIONS: Early clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity.

Latent tuberculosis infection in healthcare workers in low- and middle-income countries: an updated systematic review.

Healthcare workers (HCWs) are at increased risk of latent tuberculosis (TB) infection (LTBI) and TB disease.We conducted an updated systematic review of the prevalence and incidence of LTBI in HCWs in low- and middle-income countries (LMICs), associated factors, and infection control practices. We searched MEDLINE, Embase and Web of Science (January 1, 2005-June 20, 2017) for studies published in any language. We obtained pooled estimates using random effects methods and investigated heterogeneity using meta-regression.85 studies (32 630 subjects) were included from 26 LMICs. Prevalence of a positive tuberculin skin test (TST) was 14-98% (mean 49%); prevalence of a positive interferon-γ release assay (IGRA) was 9-86% (mean 39%). Countries with TB incidence ≥300 per 100 000 had the highest prevalence (TST: pooled estimate 55%, 95% CI 41-69%; IGRA: pooled estimate 56%, 95% CI 39-73%). Annual incidence estimated from the TST was 1-38% (mean 17%); annual incidence estimated from the IGRA was 10-30% (mean 18%). The prevalence and incidence of a positive test was associated with years of work, work location, TB contact and job category. Only 15 studies reported on infection control measures in healthcare facilities, with limited implementation.HCWs in LMICs in high TB incidence settings remain at increased risk of acquiring LTBI. There is an urgent need for robust implementation of infection control measures.

Evaluation of matricellular proteins in systemic and local immune response to Mycobacterium tuberculosis infection.

Matricellular proteins such as osteopontin (OPN), galectin-9 (Gal-9), and tenascin-C (TN-C) are expressed not only under normal physiological conditions, but also during infection, inflammation and tumorigenesis. Plasma concentrations of matricellular proteins were studied to determine their diagnostic value as potential markers of tuberculosis (TB) activity. It was found that concentrations of OPN and TN-C were higher in patients with active TB than in healthy controls and individuals with latent infection. Moreover, LTBI patients had higher concentrations of OPN than did healthy controls. Gal-9 concentrations did not differ significantly between groups. Concentrations of matricellular proteins were higher in pleural fluid than in the plasma of patients with TB. Expression of matricellular proteins was also investigated in TB granulomas and other granulomatous diseases. Positive OPN and Gal-9 staining was observed in TB and sarcoidosis granulomas, but not in Crohn disease granulomas. The fibrotic ring around granulomas stained positive for TN-C in TB and sarcoidosis, but not in Crohn disease. Of the three matricellular proteins studied, OPN and TN-C may serve as reliable plasma markers for monitoring TB activity, whereas Gal-9 seems to be expressed more at the site of infection than in the systemic circulation.

Pharmacokinetics of standard versus high-dose rifampin for tuberculosis preventive treatment: A sub-study of the 2R2 randomized controlled trial.

BACKGROUND: Pharmacokinetic data of rifampin, when used for tuberculosis preventive treatment (TPT) are not available. We aimed to describe the pharmacokinetics of rifampin used for TPT, at standard and higher doses, and to assess predictors of rifampin exposure. METHODS: A pharmacokinetic sub-study was performed in Bandung, Indonesia among participants in the 2R2 randomized trial, which compared TPT regimens of 2 months of high-dose rifampin at 20 mg/kg/day (2R20) and 30 mg/kg/day (2R30), with 4 months of standard-dose rifampin at 10 mg/kg/day (4R10) in adolescents and adults. Intensive pharmacokinetic sampling was performed after 2-8 weeks of treatment. Pharmacokinetic parameters were assessed non-compartmentally. Total exposure (AUC0-24) and peak concentration (Cmax) between arms were compared using one-way ANOVA and Tukey's post-hoc tests. Multivariable linear regression analyses were used to assess predictors of AUC0-24 and Cmax. RESULTS: We enrolled 51 participants in this study. In the 4R10, 2R20, and 2R30 arms, the geometric mean AUC0-24 was 68.0, 186.8, and 289.9 h⋅mg/L, and Cmax was 18.4, 36.7, and 54.4 mg/L, respectively; high interindividual variabilities were observed. Compared with the 4R10 arm, AUC0-24 and Cmax were significantly higher in the 2R20 and 2R30 arms (P < 0.001). Drug doses, body weight, and female sex were predictors of higher rifampin AUC0-24 and Cmax (P < 0.05). AUC0-24 and Cmax values were much higher than those previously reported in persons with TB disease. CONCLUSIONS: Doubling and tripling the rifampin dose led to three- and four-fold higher exposure compared to standard dose. Pharmacokinetic/pharmacodynamic modelling and simulations are warranted to support trials of shortening the duration of TPT regimens with high-dose rifampin.

Tuberculin skin test and Interferon-gamma release assay agreement, and associated factors with latent tuberculosis infection, in medical and nursing students in Bandung, Indonesia.

BACKGROUND: No gold standard diagnostic test exists for latent tuberculosis infection (LTBI). The intra-dermal tuberculin skin test (TST) has known limitations and Interferon-gamma release assays (IGRA) have been developed as an alternative. We aimed to assess agreement between IGRA and TST, and risk factors for test positivity, in Indonesian healthcare students. METHODS: Medical and nursing students starting their clinical training were screened using IGRA and TST. Agreement between the two tests was measured using Cohen's Kappa coefficient. Logistic regression was used to identify factors associated with test positivity. RESULTS: Of 266 students, 43 (16.2%) were IGRA positive and 85 (31.9%) TST positive. Agreement between the two tests was 74.7% (kappa 0.33, 95% CI 0.21-0.45, P<0.0001). Students who had direct contact with family or friends with TB were less likely to be test positive using IGRA (AOR 0.18, 95% CI 0.05-0.64) and using TST (AOR 0.51, 95% CI 0.26-0.99). CONCLUSION: Test positivity for LTBI was lower when measured by IGRA than by TST, with poor agreement between the two tests. Known close TB contact was unexpectedly negatively associated with positivity by either test. Longitudinal studies may be required to help determine the best test for LTBI in healthcare students in Indonesia.

High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial.

BACKGROUND: Tuberculosis preventive treatment (TPT) is a key component of tuberculosis elimination. To improve completion and reduce the burden for people and health systems, short, safe, and effective TPT regimens are needed. We aimed to compare safety and treatment completion of various doses and durations of rifampicin in people who were recommended to receive TPT. METHODS: This partially blinded, parallel-arm, non-inferiority, randomised, controlled, phase 2b trial was done at seven university-affiliated clinics in Canada, Indonesia, and Viet Nam. Participants aged 10 years or older were included if they had an indication for TPT according to WHO guidelines for Indonesia and Viet Nam, or Canadian guidelines for Canadian sites, and a positive tuberculin skin test or interferon-γ release assay. Participants were randomly assigned (1:1:1) to receive oral rifampicin at 10 mg/kg once daily for 4 months (standard-dose group), 20 mg/kg daily for 2 months (20 mg/kg group), or 30 mg/kg daily for 2 months (30 mg/kg group). The randomisation sequence was computer generated with blocks of variable size (three, six, and nine) and stratified by country for Indonesia and Viet Nam, and by city within Canada. Participants and investigators were masked to dose in high-dose groups, but unmasked to duration in all groups. The two co-primary outcomes were safety (in the safety population, in which participants received at least one dose of the study drug) and treatment completion (in the modified intention-to-treat [mITT] population, excluding those ineligible after randomisation). Protocol-defined adverse events were defined as grade 3 or worse, or rash or allergy of any grade, judged by an independent and masked panel as possibly or probably related to the study. A margin of 4% was used to assess non-inferiority. This study is registered with ClinicalTrials.gov, NCT03988933 (active). FINDINGS: Between Sept 1, 2019, and Sept 30, 2022, 1692 people were assessed for eligibility, 1376 were randomly assigned, and eight were excluded after randomisation. 1368 participants were included in the mITT population (454 in the standard group, 461 in the 20 mg/kg group, and 453 in the 30 mg/kg group). 589 (43%) participants were male and 779 (57%) were female. 372 (82%) in the standard-dose group, 329 (71%) in the 20 mg/kg group, and 293 (65%) in the 30 mg/kg group completed treatment. No participants in the standard-dose group, one (<1%) of 441 participants in the 20 mg/kg group, and four (1%) of 423 in the 30 mg/kg group developed grade 3 hepatotoxicity. Risk of protocol-defined adverse events was higher in the 30 mg/kg group than in the standard-dose group (adjusted risk difference 4·6% [95% CI 1·8 to 7·4]) or the 20 mg/kg group (5·1% [2·3 to 7·8]). There was no difference in the risk of adverse events between the 20 mg/kg and standard-dose groups (-0·5% [95% CI -2·4 to 1·5]; non-inferiority met). Completion was lower in the 20 mg/kg group (-7·8% [95% CI -13·6 to -2·0]) and the 30 mg/kg group (-15·4% [-21·4 to -9·4]) than in the standard-dose group. INTERPRETATION: In this trial, 2 months of 30 mg/kg daily rifampicin had significantly worse safety and completion than 4 months of 10 mg/kg daily and 2 months of 20 mg/kg daily (the latter, a fully blinded comparison); we do not consider 30 mg/kg to be a good option for TPT. Rifampicin at 20 mg/kg daily for 2 months was as safe as standard treatment, but with lower completion. This difference remains unexplained. FUNDING: Canadian Institutes of Health Research.

Spatial and Temporal Analysis of COVID-19 Cases in West Java, Indonesia and Its Influencing Factors.

Coronavirus Disease 2019 (COVID-19) spread quickly and reached epidemic levels worldwide. West Java is Indonesia's most populous province and has a high susceptibility to the transmission of the disease, resulting in a significant number of COVID-19 cases. Therefore, this research aimed to determine the influencing factors as well as the spatial and temporal distribution of COVID-19 in West Java. Data on COVID-19 cases in West Java obtained from PIKOBAR were used. Spatial distribution was described using a choropleth, while the influencing factors were evaluated with regression analysis. To determine whether COVID-19s policies and events affected its temporal distribution, the cases detected were graphed daily or biweekly with information on those two variables. Furthermore, the cumulative incidence was described in the linear regression analysis model as being significantly influenced by vaccinations and greatly elevated by population density. The biweekly chart had a random pattern with sharp decreases or spikes in cumulative incidence changes. Spatial and temporal analysis helps greatly in understanding distribution patterns and their influencing factors, specifically at the beginning of the pandemic. Plans and strategies for control and assessment programs may be supported by this study material.

High dose rifampin for 2 months vs standard dose rifampin for 4 months, to treat TB infection: Protocol of a 3-arm randomized trial (2R2).

INTRODUCTION: Tuberculosis preventive treatment (TPT) is an essential component for TB elimination. In order to be successfully implemented on a large scale, TPT needs to be safe, affordable and widely available in all settings. Short TPT regimens, that are less burdensome than longer regimens, to patients and health systems, are needed. Doses of rifampin higher than the standard 10mg/kg/day were tolerated in studies to reduce duration of treatment for tuberculosis disease (TBD). The objective of this trial is to test the safety of high dose rifampin monotherapy to shorten the duration of the currently recommended TPT of 4 months rifampin. METHODS AND ANALYSIS: This is a phase 2b, randomised, controlled, parallel group, superiority, partially-blind trial. Primary outcomes are completion of treatment (as a proxy measure of tolerability) and safety. The two experimental arms comprise 60 days of (i) 20mg/kg/day or (ii) 30mg/kg/day rifampin; the control arm comprises 120 days of 10mg/kg/day rifampin as TPT. Participants are adults and children 10 years or older, eligible for TPT. Completion is the primary outcome, measured by pill count and is defined as taking minimum of 80% of treatment in 120% of allowed time; it will be tested for superiority by logistic regression. Safety outcome comprises proportion of grade 3-5 adverse events and grade 1-2 rash, adjudicated related to study drug, and resulting in permanent drug discontinuation; compared for non-inferiority between each of the two high dose arms and the standard arm, using Poisson regression. A sample size of 1,359 participants will give 80% power to detect a 10% difference in completion rates and a 1% difference in the safety outcome. The study is conducted in Canada, Indonesia and Vietnam. Enrolment is ongoing at all sites. ETHICS AND DISSEMINATION: Approvals from a local research ethics board (REB) have been obtained at all participating sites and by the trial coordinating centre. Approval has been given by drug regulatory agencies in Canada and Indonesia and by Ministry of Health in Vietnam; participants give written informed consent before participation. All data collected are non-nominal. Primary results will be submitted for publication in a peer-reviewed journal when all participants have completed treatment; results of secondary outcomes will be submitted for publication at the end of study; all sites will receive the final data of participants from their sites. TRIAL REGISTRATION: Trial registered in ClinicalTrials.gov (Identifier: NCT03988933). Coordinating center is the study team working at McGill University Health Center-Research Institute (MUHC-RI); sponsor is the MUHC-RI; funding has been granted by Canadian Institute of Health Research (FDN-143350).

Neutrophils and lymphocytes in relation to MMP-8 and MMP-9 levels in pulmonary tuberculosis and HIV co-infection.

Background: Matrix metalloproteinase (MMP) activity has an important role in lung cavitary formation occurred in pulmonary tuberculosis (TB). Low number and viability of CD4 + T-lymphocytes in patients with TB/HIV co-infection leads to impaired neutrophils production, causing further impaired MMPs production. Objective: To explore association of neutrophils and lymphocytes count to MMP-8 and MMP-9 among pulmonary TB patients with cavitary lesion and HIV co-infection. Methods: We conducted a cross-sectional study using a purposive sampling technique among patients with non-cavitary TB (n = 50), cavitary TB (n = 50) and TB/HIV (n = 27). Complete blood count was examined, including neutrophils and lymphocytes count. MMP-8 and MMP-9 were measured from plasma samples using ELISA method. Statistical analysis was conducted to determine the relation between neutrophils, lymphocytes and MMPs. Result: MMP-8 and MMP-9 were positively correlated with neutrophils, but not to lymphocytes in all groups. Neutrophils, lymphocytes, and MMP-9 were significantly lower in TB/HIV co-infection, whereas MMP-8 was higher compared to new pulmonary TB. Interestingly, in cavitary TB, low lymphocytes were significantly correlated with higher level of MMP-8 and larger extent of lung affected. Conclusion: MMP-8 and MMP-9 are associated with neutrophil count, suggesting that neutrophils contribute significantly to their secretion. MMP-8 is significantly higher in TB/HIV co-infection and extent of lung damage in cavitary TB with lower lymphocyte count. This study suggests that lower lymphocyte level is related to higher neutrophil orchestrated inflammation, leading to tissue destruction.

Tuberculosis infection control measures and knowledge in primary health centres in Bandung, Indonesia.

Background: Health care workers (HCWs) in low- and middle-income countries (LMICs) continue to have an unacceptably high prevalence and incidence of Mycobacterium tuberculosis infection due to high exposure to tuberculosis (TB) cases at health care facilities and often inadequate infection control measures. This can contribute to an increased risk of transmission not only to HCWs themselves but also to patients and the general population. Aim: We assessed implementation of TB infection control measures in primary health centres (PHCs) in Bandung, Indonesia, and TB knowledge among HCWs. Methods: A cross-sectional study was conducted between May and November 2017 amongst a stratified sample of the PHCs, and their HCWs, that manage TB patients in Bandung. Questionnaires were used to assess TB infection control measures plus HCW knowledge. Summary statistics, linear regression and the Kruskal-Wallis test were used for analysis. Results: The median number of TB infection control measures implemented in 24 PHCs was 21 of 41 assessed. Only one of five management controls was implemented, 15 of 24 administrative controls, three of nine environmental controls and one of three personal respiratory protection controls. PHCs with TB laboratory facilities and high TB case numbers were more likely to implement TB infection control measures than other PHCs (p=0.003). In 398 HCWs, the median number of correct responses for knowledge was 10 (IQR 9-11) out of 11. Discussion: HCWs had good TB knowledge. TB infection control measures were generally not implemented and need to be strengthened in PHCs to reduce M. tuberculosis transmission to HCWs, patients and visitors.

Mycobacterium tuberculosis infection and disease in healthcare workers in a tertiary referral hospital in Bandung, Indonesia.

Background: Healthcare workers (HCWs), especially in high tuberculosis (TB) incidence countries, are at risk of Mycobacterium tuberculosis infection and TB disease, likely due to greater exposure to TB cases and variable implementation of infection control measures. Aim: We aimed to estimate the prevalence of tuberculin skin test (TST) positivity, history of TB and to identify associated risk factors in HCWs employed at a tertiary referral hospital in Bandung, Indonesia. Methods: A cross-sectional study was conducted from April to August 2018. A stratified sample of the HCWs were recruited, screened by TST, assessed for TB symptoms, history of TB disease and possible risk factors. Prevalence of positive TST included diagnosis with TB after starting work. HCWs with TB disease diagnosed earlier were excluded. Survey weights were used for all analyses. Possible risk factors were examined using logistic regression; adjusted odds ratios and 95% confidence intervals (CI) are presented. Results: Of 455 HCWs recruited, 42 reported a history of TB disease (25 after starting work) and 395 had a TST result. The prevalence of positive TST was 76.9% (95% CI 72.6-80.8%). The odds increased by 7% per year at work (95% CI 3-11%) on average, with a rapid rise in TST positivity up to 10 years of work and then a plateau with around 80% positive. Discussion: A high proportion of HCWs had a history of TB or were TST positive, increasing with longer duration of work. A package of TB infection control measures is needed to protect HCWs from Mycobacterium tuberculosis infection.

High risk of Mycobacterium tuberculosis infection among medical and nursing students in Indonesia: a 1-year prospective study.

BACKGROUND: Medical and nursing students entering their clinical programmes are at increased risk for tuberculosis (TB) in TB-endemic settings. Relatively little is known about Mycobacterium tuberculosis infection among such students in high-endemic countries. METHODS: We examined M. tuberculosis infection among medical and nursing students starting clinical training in Bandung, Indonesia using interferon-γ release assay (IGRA) QuantiFERON-TB Gold Plus. IGRA-negative students had a repeat test after 1 y and logistic regression was used to identify factors associated with IGRA positivity or conversion. RESULTS: There were 379 students included in this study: 248 (65.4%) were medical students and 131 (34.6%) were nursing students. Of 379 students, 70 (18.5%) were IGRA positive at baseline. Of 293 IGRA-negative students with 1-y results, 26 (8.9%) underwent IGRA conversion. Being a medical student (adjusted relative risk [ARR] 5.15 [95% confidence interval {CI} 1.82 to 14.59], p=0.002) and participation in sputum collection or bronchoscopy were associated with IGRA conversion (ARR 2.74 [95% CI 1.29 to 5.79], p=0.008). CONCLUSIONS: Medical and nursing students entering clinical training are at high risk of M. tuberculosis infection and need improved infection prevention and control strategies.