First Indonesian report of WGS-based MTBC L3 discovery.

OBJECTIVE: Recent spoligotyping results in the island nation of Indonesia had revealed the existence of Mycobacterium tuberculosis complex lineage 3 (MTBC L3) or Central Asian (CAS) strains. In this work, whole-genome sequencing (WGS) - based methods were used to search for the presence of MTBC L3. RESULTS: Two unrelated Indonesian L3 strains discovered by WGS-based SNP phylogenomics are presented here for the first time. Assemblies of their genomes yielded 96.95% (MTBC strain Mtb_S6970) and 98.35% (Mtb_S19106) of the known reference strain H37Rv. Their respective constructed genome coverages are 45.38 ± 12.95x and 63.13 ± 21.10x. The two L3 genomes have 4062 and 4121 genes, respectively, which are well within the number of genes predicted in MTBC strains. Instead of having three rRNA genes usually, Mtb_S6970 possesses four. These L3 isolates exhibit cross-class antibiotic susceptibility. FadD26, fadE24, fbpA, lprO, and panC, which are thought to be important in the pathophysiology of MTBC, were discovered to have 3-7 times more loci in L3 than L2 or L4. The penetration of L3 in the nation, despite its antibiotic sensitivity, is a concerning indicator of borderless global spread that may eventually be overcome by the phenotypes of acquired drug resistance.

Tobacco smoking clusters in households affected by tuberculosis in an individual participant data meta-analysis of national tuberculosis prevalence surveys: Time for household-wide interventions?

Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95% CI: 1.11-1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions.

Correction: Service availability and readiness of malaria surveillance information systems implementation at primary health centers in Indonesia.

[This corrects the article DOI: 10.1371/journal.pone.0284162.].

Association of diabetes, smoking, and alcohol use with subclinical-to-symptomatic spectrum of tuberculosis in 16 countries: an individual participant data meta-analysis of national tuberculosis prevalence surveys.

Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50% being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities. Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679). Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1%-56.7% of TB were subclinical (median: 38.1%). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95% CI 1.27-2.40) and symptomatic TB (OR 1.49, 95% CI 1.34-1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95% CI 1.17-2.40) but not with subclinical TB (OR 0.92, 95% CI 0.55-1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95% CI 0.70-3.62) for subclinical TB and OR 1.43, 95% CI 0.59-3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I2 was high (76.5% (95% CI 62.0-85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs. Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB. Funding: None.

Nonadherence to anti-tuberculosis treatment, reasons and associated factors among pulmonary tuberculosis patients in the communities in Indonesia.

BACKGROUND: Tuberculosis (TB) is the world's major public health problem. We assessed the proportion, reasons, and associated factors for anti-TB treatment nonadherence in the communities in Indonesia. METHODS: This national coverage cross-sectional survey was conducted from 2013 to 2014 with stratified multi-stage cluster sampling. Based on the region and rural-urban location. The 156 clusters were distributed in 136 districts/cities throughout 33 provinces, divided into three areas. An eligible population of age ≥15 was interviewed to find TB symptoms and screened with a thorax x-ray. Those whose filtered result detected positive followed an assessment of Sputum microscopy, LJ culture, and Xpert MTB/RIF. Census officers asked all participants about their history of TB and their treatment-defined Nonadherence as discontinuation of anti-tuberculosis treatment for <6 months. Data were analyzed using STATA 14.0 (College Station, TX, USA). RESULTS: Nonadherence to anti-TB treatment proportion was 27.24%. Multivariate analysis identified behavioral factors significantly associated with anti-TB treatment nonadherence, such as smoking (OR = 1.78, 95% CI (1.47-2.16)); place of first treatment received: government hospital (OR = 1.45, 95% CI:1.06-1.99); private hospital (OR = 1.93, 95% CI: 1.38-2.72); private practitioner (OR = 2.24, 95% CI: 1.56-3.23); socio-demographic and TB status included region: Sumatera (OR = 1.44, 95% CI: 1.05-1.98); other areas (OR = 1.84, 95% CI: 1.30-2.61); low level of education (OR = 1.60, 95% CI: 1.27-2.03); and current TB positive status (OR = 2.17, 95% CI: 1.26-3.73). CONCLUSIONS: Nonadherence to anti-TB drugs was highly related to the personal perception of the respondents, despite smoking, current TB status, a place for the first treatment, education, and region. The position of the first TB treatment at the private practitioner was significantly associated with the risk of Nonadherence to treatment.

Service availability and readiness of malaria surveillance information systems implementation at primary health centers in Indonesia.

One of the most important indicators in malaria eradication is the malaria surveillance information system (SISMAL) for recording and reporting medical cases. This paper aims to describe the availability and readiness of SISMALs at primary health centers (PHCs) in Indonesia. A cross-sectional survey was implemented in seven provinces for this study. The data was analyzed using bivariate, multivariate, and linear regression. The availability of the information system was measured by assessing the presence of the electronic malaria surveillance information system (E-SISMAL) at the studied PHCs. The readiness was measured by averaging each component of the assessment. From 400 PHC samples, only 58.5% had available SISMALs, and their level of readiness was only 50.2%. Three components had very low levels of readiness: (1) the availability of personnel (40.9%), (2) SISMAL integration and storage (50.2%), and (3) the availability of data sources and indicators (56.8%). Remote and border (DTPK) areas had a 4% better readiness score than non-DTPK areas. Endemic areas were 1.4% better than elimination areas, while regions with low financial capacity were 3.78% better than regions with high financial capacity, with moderate capacity (2.91%). The availability rate of the SISMAL at PHCs is only 58.5%. Many PHCs still do not have SISMALs. The readiness of the SISMAL at these PHCs is significantly related to DTPK/remote area, high endemicity status, and low financial capacity. This study found that the implementation of SISMAL is more accessible to malaria surveillance for the remote area and regions with low financial capacity. Therefore, this effort will well-fit to address barrier to malaria surveillance in developing countries.

Comparison of chest X-ray lesion characteristics of multidrug-resistant tuberculosis and non-tuberculous mycobacterial infection.

PURPOSE: This research aimed to compared chest radiographic characteristics of multidrug-resistant tuberculosis (MDR-TB) and non-tuberculous mycobacteria (NTM) infection, which can be used in early diagnostic screening. MATERIAL AND METHODS: The method of this study was cross-sectional to obtain the relationship between radiographic findings. RESULTS: Among 538 subjects who were positive for TB during screening, 11 (2.04%) had MDR-TB, 147 (27.32%) had drug-sensitive TB, and 380 (70.63%) had NTM infection. The radiographic findings that correlated with MDR-TB were infiltrates (p = 0.010), cavities (p = 0.021), nodules (p = 0.001), and fibrosis (p = 0.010), with the best predictor of MDR-TB lesions being the presence of a nodule. The lesion locations related to MDR-TB were the upper right and left lung (p = 0.00). There were no specific lesions present in NTM infection (p < 0.05) because almost all had a meaningful correlation (p < 0.05), except the presence of a mass. The lesion location related to NTM infection was the medial aspect of the left lung (p = 0.01), and the lesion extent was also correlated (p < 0.05). CONCLUSIONS: Chest X-ray lesion characteristics of MDR-TB show significant correlation among cavities, nodules, and fibrosis. There were no specific lesions that could differentiate NTM infection from MDR-TB; however, the most common lesion location in NTM infection was the medial aspect of the left lung.

Thoracic Radiography Characteristics of Drug Sensitive Tuberculosis and Multi Drug Resistant Tuberculosis: A Study of Indonesian National Tuberculosis Prevalence Survey.

BACKGROUND: Tuberculosis (TB) remains a burden globally, including Indonesia. The primary objective of this study is to reveal the chest radiography characteristic of drug-sensitive TB (DS-TB) and multi-drug resistant TB (MDR-TB) in the Indonesian national tuberculosis prevalence survey 2013-2014. The secondary objective is to explore the correlation and incidence rate of chest radiography lesion of DS-TB and MDR-TB cases. METHODS: This is a cross-sectional retrospective analytical studies with national and regional coverage. Samples were selected by stratified multi-stage clustering sampling technique in a population aged ≥15 years old. The diagnosis of TB was based on culture and GeneXpert tests. RESULTS: There were 147 DS-TB and 11 MDR-TB patients that were analyzed in this study. The nodule is the only type of lesions that distinguish MDR-TB and DS-TB. In multivariate analysis of DS-TB, there were 3 significant chest radiography lesions, i.e infiltrate, cavity and consolidation with odd-ratio (OR) of 14, 13, and 3, respectively. In MDR-TB, the only significant lesion is a nodule, with OR of 19. CONCLUSION: Nodule is the only type of lesions that distinguish MDR-TB and DS-TB. Infiltrate, cavity and consolidation were the types of chest radiography lesions on DS-TB, meanwhile, a nodule was the only significant lesion for MDR-TB.

L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB). METHODS: In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339. RESULTS: 200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference -3%, 95% CI -19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI -9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes. CONCLUSION: Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes. REGISTRY: ClinicalTrials.gov. Registry number: NCT00677339.

The burden and treatment of HIV in tuberculosis patients in Papua Province, Indonesia: a prospective observational study.

BACKGROUND: New diagnoses of tuberculosis (TB) present important opportunities to detect and treat HIV. Rates of HIV and TB in Indonesia's easternmost Papua Province exceed national figures, but data on co-infection rates and outcomes are lacking. We aimed to measure TB-HIV co-infection rates, examine longitudinal trends, compare management with World Health Organisation (WHO) recommendations, and document progress and outcome. METHODS: Adults with newly-diagnosed smear-positive pulmonary TB managed at the Timika TB clinic, Papua Province, were offered voluntary counselling and testing for HIV in accordance with Indonesian National Guidelines, using a point-of-care antibody test. Positive tests were confirmed with 2 further rapid tests. Study participants were assessed using clinical, bacteriological, functional and radiological measures and followed up for 6 months. RESULTS: Of 162 participants, HIV status was determined in 138 (85.2%), of whom 18 (13.0%) were HIV+. Indigenous Papuans were significantly more likely to be HIV+ than Non-Papuans (Odds Ratio [OR] 4.42, 95% confidence interval [CI] 1.38-14.23). HIV prevalence among people with TB was significantly higher than during a 2003-4 survey at the same TB clinic, and substantially higher than the Indonesian national estimate of 3%. Compared with HIV- study participants, those with TB-HIV co-infection had significantly lower exercise tolerance (median difference in 6-minute walk test: 25 m, p = 0.04), haemoglobin (mean difference: 1.3 g/dL, p = 0.002), and likelihood of cavitary disease (OR 0.35, 95% CI 0.12-1.01), and increased occurrence of pleural effusion (OR 3.60, 95% CI 1.70-7.58), higher rates of hospitalisation or death (OR 11.80, 95% CI 1.82-76.43), but no difference in the likelihood of successful 6-month treatment outcome. Adherence to WHO guidelines was limited by the absence of integration of TB and HIV services, specifically, with no on-site ART prescriber available. Only six people had CD4+ T-cell counts recorded, 11 were prescribed co-trimoxazole and 4 received ART before, during or after TB treatment, despite ART being indicated in 14 according to 2006 WHO guidelines. CONCLUSIONS: TB-HIV co-infection in southern Papua, Indonesia, is a serious emerging problem especially among the Indigenous population, and has risen rapidly in the last 5 years. Major efforts are required to incorporate new WHO recommendations on TB-HIV management into national guidelines, and support their implementation in community settings.