Global Tuberculosis Research Articles

Recent Developments in Mycobacteria-Based Live Attenuated Vaccine Candidates for Tuberculosis.

Vaccination is an excellent approach to stimulating the host immune response and reducing human morbidity and mortality against microbial infections, such as tuberculosis (TB). Bacillus Calmette-Guerin (BCG) is the most widely administered vaccine in the world and the only vaccine approved by the World Health Organization (WHO) to protect against TB. Although BCG confers "protective" immunity in children against the progression of Mycobacterium tuberculosis (Mtb) infection into active TB, this vaccine is ineffective in protecting adults with active TB manifestations, such as multiple-, extensive-, and total-drug-resistant (MDR/XDR/TDR) cases and the co-existence of TB with immune-compromising health conditions, such as HIV infection or diabetes. Moreover, BCG can cause disease in individuals with HIV infection or other immune compromises. Due to these limitations of BCG, novel strategies are urgently needed to improve global TB control measures. Since live vaccines elicit a broader immune response and do not require an adjuvant, developing recombinant BCG (rBCG) vaccine candidates have received significant attention as a potential replacement for the currently approved BCG vaccine for TB prevention. In this report, we aim to present the latest findings and outstanding questions that we consider worth investigating regarding novel mycobacteria-based live attenuated TB vaccine candidates. We also specifically discuss the important features of two key animal models, mice and rabbits, that are relevant to TB vaccine testing. Our review emphasizes that the development of vaccines that block the reactivation of latent Mtb infection (LTBI) into active TB would have a significant impact in reducing the spread and transmission of Mtb. The results and ideas discussed here are only based on reports from the last five years to keep the focus on recent developments.

Tuberculosis recovery in Georgia: implementing more by 24

The 2022 Global Tuberculosis Report released by WHO again contained more bad news: diagnoses are not slowing enough to meet WHO's End TB strategy, and deaths from the disease continue to increase.1 Although the COVID-19 pandemic has adversely affected global efforts to eliminate tuberculosis, even before the pandemic the tuberculosis community was not on track to meet any indicators set at the 2018 United Nations High-Level Meeting on Tuberculosis.2

First insights into the phylogenetic diversity of Mycobacterium tuberculosis in Kuwait and evaluation of REBA MTB-MDR assay for rapid detection of MDR-TB

Early detection of Mycobacterium tuberculosis (Mtb) in clinical specimens, its susceptibility to anti-TB drugs and disruption of infection transmission to new hosts are essential components for global tuberculosis (TB) control efforts. This study investigated major Mtb genotypes circulating in Kuwait and evaluated the performance of REBA MTB-MDR (REBA) test in comparison to GenoType MTBDRplus (gMTBDR+) assay for rapid detection of resistance of Mtb to isoniazid and rifampicin (MDR-TB). M. tuberculosis isolates (n = 256) originating predominantly from expatriate patients during a 6-month period were tested by spoligotyping and a dendrogram was created by UPGMA using MIRU-VNTRplus software. Phenotypic drug susceptibility testing (DST) was performed by MGIT 960 system. Genotypic DST for isoniazid and rifampicin was done by REBA and gMTBDR+ assays. Spoligotyping assigned 188 (73.4%) isolates to specific spoligotype international type (SIT) while 68 isolates exhibited orphan patterns. All major M. tuberculosis lineages were detected and EAI, CAS and Beijing families were predominant. Phylogenetic tree showed 131 patterns with 105 isolates exhibiting a unique pattern while 151 isolates clustered in 26 patterns. Fifteen isolates were resistant to one/more drugs. REBA and gMTBDR+ detected isoniazid resistance in 11/12 and 10/12 and rifampicin resistance in 4/5 and 4/5 resistant isolates, respectively. The diversity of SIT patterns are highly suggestive of infection of most expatriate patients with unique Mtb strains, likely acquired in their native countries before their arrival in Kuwait. Both, REBA and gMTBDR+ assays performed similarly for detection of resistance of Mtb to isoniazid and rifampicin for rapid detection of MDR-TB.

Comparing the usability of the World Health Organization's conventional tuberculosis guidelines to the eTB recommendations map: A two-arm superiority randomised controlled trial.

Best practices for the dissemination of global health guidelines has not undergone rigorous research. We used a new approach to digitizing World Health Organization (WHO) global tuberculosis guideline recommendations (eTB RecMap) and compared its usability to the conventional method of accessing TB recommendations using the WHO website. We conducted a two-arm superiority randomised controlled trial using a survey among global stakeholders who were past or planned future users of TB guidelines, recommendations, or policy advice. We assigned participants randomly (1:1) to complete an activity using the WHO eTB RecMap or the conventional website. The primary outcome was the accessibility of information and secondary outcomes understanding, satisfaction, and preference for one of the two formats. Between February 26 and August 29, 2021, we received 478 responses from stakeholders, of whom 244 (122 per group) were eligible and provided analysable results. Participants rated the eTB RecMap as more accessible, on average, when compared to the conventional website (on a seven-point scale, the mean difference {MD} was 0.9; 95% confidence interval {CI}: 0.6, 1.2; p < 0.001) and were more likely to correctly answer understanding questions. This is the first trial comparing digitized dissemination formats of health guideline recommendations. Stakeholders rated the WHO eTB RecMap as more accessible than the conventional WHO website for the tested recommendations. They also understood presented information better. The findings support better usability of TB information through the eTB RecMap and contribute to the effort to end the TB epidemic. Trial registration: This trial was registered with ClinicalTrials.gov (NCT04745897) on February 9, 2021.

Stigma and Depression among Tuberculosis Patients in Kedah, Malaysia

INTRODUCTION: Tuberculosis (TB) related stigma is one of the significant barriers in the global TB control programme and it may lead to depression. This study aims to assess the level of stigma among TB patients and its associated factors, as well as to ascertain the correlation between stigma and depression in Kedah, Malaysia. MATERIALS AND METHODS: This was a cross-sectional study using the proportionate sampling method. TB patients were recruited from respiratory clinics in three government hospitals in Kedah. Case report form, Malay version of TB stigma scale (TSS) and Beck Depression Inventory (BDI-Malay) were used for data collection. Data were then analyzed using the linear regression and correlation analysis. RESULTS: A total of 200 respondents were enrolled and the mean score of TB stigma from patient’s perspective was 13.3 (6.87). Younger patient, currently married, higher education, unemployment, and HIV co-infection were significantly associated with the stigma experienced. 27.5% (n=55) of the TB patients were found to be depressed, with the majority categorized into mild severity (20%, n=40), followed by moderate (5.5%, n = 11) and severe depression (2%; n = 4). There was a moderate, positive correlation between stigma and depression which was statistically significant (r = 0.345, p&lt;0.001). CONCLUSION: Although the stigma score among TB patients was not as high as has been postulated, there was a moderate, positive correlation between stigma and depression. Thus, the intervention to reduce the stigma among TB patients may be helpful as it may reduce the depression level.

Celebrating choice in the care of people living with drug-resistant tuberculosis

The loss of sense of self is a common theme in the narratives of people who have survived drug-resistant tuberculosis.1 Instead of identifying options for diagnosis and treatment that could best serve the individual preferences and needs of people seeking care, the global tuberculosis community seems focused on providing a universal approach to drug-resistant tuberculosis treatment.2 As a result, not only does tuberculosis remain one of the leading infectious killers of adults worldwide,3 but the fields of tuberculosis diagnosis and therapeutic development have stagnated.

Integration of national tuberculosis elimination programme with child and adolescent health: India on track of end tuberculosis strategy

As per the global tuberculosis (TB) report 2020, 56% adult males, 32% adult females and 12% children worldwide, have TB. In India, an estimated 3.33 lakh children in the 0-14 years age group become ill with TB each year (28% of global childhood TB burden), with a slightly higher burden among males. In 2019, the national tuberculosis elimination programme (NTEP) reported 1.5 lakh TB cases of children aged 0-14 years, indicating a gap of 55% in TB notifications in this age group.1 In order to address the gaps in pediatric TB coverage, the NTEP collaborated with child health and adolescent health programmes of the ministry of health and family welfare (MoHFW). The two primary health programmes that serve children and adolescents across the country are Rashtriya Bal Swasthya Karyakram (RBSK) and Rashtriya Kishor Swasthya Karyakram (RKSK), respectively. This integration will bring the country forward towards the efforts of its goal to achieve the target of end TB strategy.

A Scoping Review on Accentuating the Pragmatism in the Implication of Mobile Health (mHealth) Technology for Tuberculosis Management in India.

Background: India continues to share a colossal count of the global tuberculosis load, with a perturbing 19% spring in the reported cases in 2021. With the National Tuberculosis Elimination Program (NTEP) consolidated to bring this epidemic to an end by 2025, the rapidly growing mobile health technologies can be utilized to offer promising results. Even though the implementation of this novel strategy is escalating around the globe, its triumph is still sub optimal in India. Objectives: This scoping review intends to explore the available mobile health (mHealth) technologies and analyse the effectiveness of the same for tuberculosis management in India. Methods: An elaborate search in electronic databases, such as PubMed and Google scholar, using the key terms and focussing from the year 2015, provided very broad results focussing on mHealth interventions and their utilisation in TB management in India. Further selection of the inclusive publications was carried out based upon the eligibility requirements as formulated for this review, pertaining to the objective of this study. Results: The collaborate search yielded a total of 858 scientific research papers. After the filtering of the obtained results, a total of 45 articles were selected to be analysed for this review. Published manuscripts, articles in peer review and abstracts from reliable databases were included to obtain vast range of information. Conclusion: The extensive literature search showed a preponderance of mHealth intervention studies focusing on TB treatment and drug monitoring. There exists a paucity of mHealth applications targeted to educate the public and intercept this infectious disease. The scientific articles reviewed and analysed in this scoping review strongly recommend the demployment of mHealth applications to achieve the target of eradicating TB by 2025 in India.

Whole-Genome Sequencing for Resistance Prediction and Transmission Analysis of Mycobacterium tuberculosis Complex Strains from Namibia.

ABSTRACTNamibia is among 30 countries with a high burden of tuberculosis (TB), with an estimated incidence of 460 per 100,000 population and around 800 new multidrug-resistant (MDR) TB cases per year. Still, data on the transmission and evolution of drug-resistant Mycobacterium tuberculosis complex (Mtbc) strains are not available. Whole-genome sequencing data of 136 rifampicin-resistant (RIFr) Mtbc strains obtained from 2016 to 2018 were used for phylogenetic classification, resistance prediction, and cluster analysis and linked with phenotypic drug susceptibility testing (pDST) data. Roughly 50% of the strains investigated were resistant to all first-line drugs. Furthermore, 13% of the MDR Mtbc strains were already pre-extensively drug resistant (pre-XDR). The cluster rates were high, at 74.6% among MDR and 85% among pre-XDR strains. A significant proportion of strains had borderline resistance-conferring mutations, e.g., inhA promoter mutations or rpoB L430P. Accordingly, 25% of the RIFr strains tested susceptible by pDST. Finally, we determined a potentially new bedaquiline resistance mutation (Rv0678 D88G) occurring in two independent clusters. High rates of resistance to first-line drugs in line with emerging pre-XDR and likely bedaquiline resistance linked with the ongoing recent transmission of MDR Mtbc clones underline the urgent need for the implementation of interventions that allow rapid diagnostics to break MDR TB transmission chains in the country. A borderline RIFr mutation in the dominant outbreak strain causing discrepancies between phenotypic and genotypic resistance testing results may require breakpoint adjustments but also may allow individualized regimens with high-dose treatment.IMPORTANCE The transmission of drug-resistant tuberculosis (TB) is a major problem for global TB control. Using genome sequencing, we showed that 13% of the multidrug-resistant (MDR) M. tuberculosis complex strains from Namibia are already pre-extensively drug resistant (pre-XDR), which is substantial in an African setting. Our data also indicate that the ongoing transmission of MDR and pre-XDR strains contributes significantly to the problem. In contrast to other settings with higher rates of drug resistance, we found a high proportion of strains having so-called borderline low-level resistance mutations, e.g., inhA promoter mutations or rpoB L430P. This led to the misclassification of 25% of the rifampicin-resistant strains as susceptible by phenotypic drug susceptibility testing. This observation potentially allows individualized regimens with high-dose treatment as a potential option for patients with few treatment options. We also found a potentially new bedaquiline resistance mutation in rv0678.

Bedaquiline-Based Short Course Regime for MDR-TB -“The Indian Scenario”

India ranks highest in number of Tuberculosis (TB) and Multi Drug Resistant (MDR) TB patients globally (World Health Organization. Global tuberculosis report (2018). Maximum number of deaths due to TB also occur in India. A short course regime for treating Fluroquinolone (FQ) Sensitive MDR TB has been recommended by the World Health Organization (WHO) in 2020 with a duration of 9-11 months. India has also adopted the BDQ Short course regime for MDR-TB patients with multiple exclusion criteria. The excluded patients would receive a longer BDQ based regime which may last 18-20 months. The purpose of this mini-review is to emphasize the possibilities of high failure rates in the BDQ based short course regime, especially in the Context of India due to high baseline FQ resistance and an acute shortage of Drug Sensitivity Tests (DST) tests especially for FQ. Moreover, the need of High dose Isoniazid (Hh ) in the regime may be only a toxic addition in about 80% of patients leading to adverse effects, some of which may be fatal. Failure of BDQ-based short course regime would lead to a catastrophic amplification of the resistance of critically essential drugs such as BDQ and Clofazimine (CFZ). Chances of cure in such patients with Extensively Drug Resistant (XDR) TB would be slim, if not altogether absent.

MAPPING OF CHILDREN'S TUBERCULOSIS INCIDENCE BY COVERAGE OF BCG IMMUNIZATION, MALNUTRITION, AND HOME ENVIRONMENT

Background: Based on the Global Tuberculosis (TB) Report, Indonesia is one of the countries with a triple burden of TB, and TB disease can attack all age groups, including children. East Java Province in 2019 was ranked third in the highest number of pediatric TB cases in Indonesia. Purpose: This study aims to describe the distribution trend of tuberculosis cases in children in East Java Province in 2017-2018 based on BCG immunization coverage, cases of malnutrition, amount of healthy houses, and households with PHBS. Methods: The research design was a descriptive study with a correlation study design. The populations were all districts/cities in East Java Province, with as many as 38 districts. The data analysis technique to describe the trend distribution of tuberculosis in children was the health mapper software on a computer developed by World Health Organization (WHO). Results: The distribution of the incidence of tuberculosis in children in East Java from 2017 to 2018 tends to increase. The city of Surabaya became the area with the highest incidence of tuberculosis in children from 2017 to 2018. Based on a spatial map, most districts or cities with BCG immunization coverage, cases of malnutrition, several healthy homes, and high PHBS households experience tuberculosis incidence in children is high. Conclusion: Based on the map, spatially, districts or cities with high cases of tuberculosis in children mainly occur in areas with cases of malnutrition, the number of healthy home environments, and high coverage of BCG immunization as well.

Pengaruh sanitasi lingkungan fisik rumah, sosial budaya dan kontak serumah terhadap kejadian Tuberkulosis Paru di Pulau Bengkalis Kabupaten Bengkalis

The degree of public health is influenced by four factors, namely environment, behavior, health services, and heredity. Data from 2019 WHO Global Tuberculosis Report, Indonesia ranks third with the highest tuberculosis cases in the world. The purpose of this study was to analyze the sanitary conditions of the house environment (temperature, humidity, type of floor, ventilation, lighting), socio-culture (trust), and household contact against the incidence of pulmonary tuberculosis on Bengkalis Island. This research is an analytical study with a case-control design. This research was conducted on Bengkalis Island, namely in two sub-districts (Bengkalis District and Bantan District) and in the working area of Puskesmas Bengkalis, Puskesmas Pematang Duku, Puskesmas Selatbaru and Puskesmas Teluk Pambang. The data used are quantitative data sourced from observations, interviews, and questionnaires. The research sample was 80 people consisting of 40 cases and 40 controls. Data analysis was performed by multiple logistic regression tests. The results of the study concluded that the most dominant variable affecting the incidence of pulmonary tuberculosis was temperature with a p-value of 0.008. Confounding variables for tuberculosis incidence were ventilation, floor type, lighting, and confidence. The multivariate model formed is fit/fit for use. Based on the results of the calculation of the equation, it can be concluded that if a person has temperature risk factors, humidity risk factors, ventilation risk factors, floor type risk factors, lighting risk factors, trust risk factors, and household contact risk factors, then he will have a chance of suffering from pulmonary tuberculosis by 94 percent (with a probability value of 0.94).

Prevalence and Onset of Hepatotoxicity Caused by Anti-Tuberculosis Drugs on Pulmonary TB Patients in Wangaya General Hospital Denpasar – Bali in 2016

Introduction: As tuberculosis (TB) endemic country, TB becomes a community health problem in Indonesia. Data from the Global TB Report in 2016 showed that Indonesia is the second most country with TB burden after India. WHO and the Ministry of Health issue a TB prevention program based on the End TB Strategy aimed to reduce morbidity, mortality, and disability due to TB. One of the challenges faced in the management of TB is the side effects of the anti-tuberculosis drug. Hepatotoxicity is the most common side effect. Aims: This study aims to determine the prevalence and onset of anti-TB drug-induced hepatotoxicity in TB patients after receiving the anti-TB drug in Wangaya Hospital Denpasar Bali. Method: This study used a cross-sectional method by obtaining secondary data of pulmonary TB patients visiting the pulmonary clinic in Wangaya General Hospital from January to December 2016. Result: Of 77 subjects, fifty-six percent of them were men. The highest prevalence was found in the 41-50 years age group (26.9%), while the lowest was found in the 81-90 years age group (1.2%). Anti-TB drug-induced hepatotoxicity occurred in 6.5% of subjects. The most frequent onset of hepatotoxicity occurred within the second week of medication. Anti-TB drug-induced hepatotoxicity occurred in 6.5% of subjects. The most frequent onset of hepatotoxicity occurred within the second week of medication. Conclusion: Based on this study, we suggest a liver function test before and after two weeks of an anti-TB drug.

Qualitative Identification of Intervention Preferences to Support Men's Engagement and Retention in TB Care in South Africa.

Globally and in South African specifically, men account for 56% and 62% of all tuberculosis (TB) cases, respectively. Men are at increased risk of not accessing TB testing or treatment, and having poor treatment outcomes. Unfortunately, no interventions exist to address these issues. Toward the development of targeted, patient-centered TB care and support interventions, we used semistructured interviews to explored men’s social network composition, TB testing behaviors, disclosure and treatment support, clinical experiences, and TB’s influence on daily living. Data were analyzed using a thematic approach guided by the Network Individual Resource Model to identify mental and tangible resources influential and preferred during engagement in TB treatment. Men emphasized the desire for peer-to-peer support to navigate TB-related stigma and unhealthy masculinity norms. Men advocated for awareness events to educate communities about their challenges with TB. Men strongly suggested that interventions be delivered in familiar locations where men congregate. Since 2022, no TB treatment support interventions have included the preferred components or delivery modes described by men in our study. To improve men’s TB-related health outcomes, the global TB community must identify and address men’s unique challenges when designing interventions.

Whole genome sequencing of Bulgarian rifampicin resistant Mycobacterium tuberculosis strains.

The transmission of drug-resistant tuberculosis is one of the greatest challenges facing the global tuberculosis control. The aim of the study was to investigate the resent transmission of rifampicin resistant tuberculosis in Bulgaria and to describe the mutations related to the antimicrobials' resistance using whole genome sequencing. As part of an ECDC funded pilot study for evaluation of the systematic use of whole genome sequencing (WGS) of Mycobacterium tuberculosis (MTB) surveillance (EUSeqMyTB), Bulgaria provided 65 rifampicin resistant isolates over a three years' timeframe (2017-2019) representing 87.5% of the notified rifampicin resistant cases. Drug resistance prediction and relatedness analysis of the resistant isolates was performed in collaboration with San Raffaele Scientific Institute, Milan, Italy. Almost all of the isolates were identified as Euro-American lineage (96.9%); 18.5% of the isolates were found to be resistant to fluoroquinolones, but no mutations conferring resistance to bedaquiline or linezolid could be identified. Less than half (43.3%) of the isolates were clustered (<5 SNPs distance) into a total of seven national SNP-based clusters, while a total of six isolates were found to be part of different cross-border clusters. All clustered cases originated from Bulgaria. WGS has proven to be a reliable tool for surveillance and tracing of recent transmission of tuberculosis and has the potential for resistance prediction for most of the antituberculosis drugs.

GeneXpert rollout in three high-burden tuberculosis countries in Africa: A review of pulmonary tuberculosis diagnosis and outcomes from 2001 to 2019.

BackgroundThe rollout of GeneXpert aimed at increasing early diagnosis of tuberculosis to improve treatment outcomes and global tuberculosis targets.ObjectiveThis study evaluated trends in tuberculosis diagnosis and outcomes pre- and post-introduction of GeneXpert in three African countries – the Democratic Republic of the Congo (DRC), Nigeria and South Africa.MethodsData from 2001 to 2019 were extracted from the World Health Organization’s data repository. Descriptive analysis, paired t-tests and interrupted time series models were used.ResultsEstimated tuberculosis incidence decreased from 327/100 000 to 324/100 000 in the DRC, and from 1220/100 000 to 988/100 000 in South Africa. Incidence remained at 219/100 000 in Nigeria. The tuberculosis case notification rate did not change significantly. Increases in the new case treatment success rates were statistically significant (DRC: p = 0.0201; Nigeria: p = 0.0001; South Africa: p = 0.0017); decreases in mortality were also statistically significant (DRC: p = 0.0264; Nigeria: p = 0.0001; South Africa: p < 0.0001). Time series models showed insignificant increases in new tuberculosis cases in DRC (n = 1856, p = 0.085) and Nigeria (n = 785, p = 0.555) from 2011 to 2019; and a statistically significant decrease in South Africa (n = 15 269, p = 0.006).ConclusionImprovements in tuberculosis treatment outcomes were achieved, but little progress has been made in new case notification due to varied implementation and scale-up of GeneXpert across the three countries. Implementation barriers need to be addressed to achieve the required tuberculosis targets.

The importance for tuberculosis of mitigating economic crises

The importance for tuberculosis of mitigating economic crises

Nonadherence Predictors to Tuberculosis Medications among TB Patients in Gambella Region of Ethiopia.

Background Global tuberculosis (TB) disease deaths rise comparable to the one seen in 2015 (by 200,000) or even in 2012 (by 400,000) as a result of the potential impact of the COVID-19 pandemic. Ethiopia's Gambella region is leading for years in terms of TB cases and its comorbidities. The TB control program effectiveness depends on in large on the patients completing the appropriate treatment regimen. Hence, the objective of this study was to determine the determinants of nonadherence to anti-TB drug treatment among patients in Gambella regional state of Ethiopia. Methods A case-control study was conducted on cohorts of TB patients sampled from four public health facilities in Gambella Region from January 2019 to 2020, followed by 18 months of follow-up. The total sample size was 296 patients (74 cases and 222 controls) with a response rate of 97.3% (288 : 72 nonadhered cases and 216 controls). Cases (nonadhered) were TB patients who missed 10% of the doses while controls were patients, who completed 90% or more doses. Results TB patients, who perceived stigma [AOR = 2.7 at 95% CI (1.1–6.6) with P value <0.05], failed to receive any counseling during the treatment course [AOR = 65.24 at 95% CI (11.69–363.95) with P value <0.01], patients who used to smoking during treatment [AOR = 15.4 at 95% CI (7.7–30) with P value <0.01], taking TB medications regularly has no benefits [AOR = 6.8 at 95% CI (1.8–24.9) with P value <0.05], and patients believing TB disease as not severe [AOR = 8.38 at 95% CI (2.0–34.6) with P value <0.05] were significantly or highly significantly associated with nonadherence to anti-TB drugs medications. Conclusion The determinants of nonadherence to anti-TB treatment among TB patients in the Gambella region during the study period were the absence of counselling services, and patients' behavior (smoking habits, undermining the severity of TB disease, lack of trust in the outcomes of regular medications, and perceived stigmatization). Accordingly, capacitating healthcare providers and workers at all TB clinics for effective counseling , preventing perceived stigma by protecting the patient's secrecy, and routine health education has paramount importance for effective TB control in Gambella.

Determinants of losses in the tuberculosis infection cascade of care among children and adolescent contacts of pulmonary tuberculosis cases: A Brazilian multi-centre longitudinal study

Approximately 10% of the global tuberculosis (TB) burden is in children. Identification, diagnosis, and early treatment of Mycobacterium tuberculosis infection (TBI) is critical to prevent progression to TB in children. The risk of TB, including severe disease, is highest in children <5 years old. We evaluated the cascade of TBI care among child and adolescent TB contacts to identify factors associated with losses in the cascade. Close contacts ≤ 18 years old of pulmonary TB patients enrolled between 2015 and 2019 in a multi-centre Brazilian cohort were followed for up to 24 months and classified according to age groups: <5 years, 5-9 years, 10-14 years and 15-18 years. Data on clinical investigation, radiographic examination, IGRA testing at baseline and 6 months, initiation and completion of TB preventive treatment (TPT) were collected. Multivariable regression analyses identified factors associated with TBI and losses in the cascade of care in children and adolescents. Among 1795 TB contacts initially identified, 530 (29·5%) were ≤18 years old. Losses for all steps in the cascade were especially high in children <5 years old (88%) because at this age all contacts are recommended to initiate TPT. As a proportion of all children, completion of TPT was low (between 10% and 13%) in all age-groups. Furthermore, multivariable regression revealed that younger age of contacts and TB index cases who were female, had pulmonary cavities, and persistent cough were independently associated with losses in the cascade of care among persons ≤18 years old. Losses in the TBI cascade were the highest among children <5 years, which was the group at highest risk for TB among the four age groups. The findings highlight the need to improve screening, initiation, and completion of TPT of young children who are close contacts of people with TB in Brazil. National Institutes of Allergy and Infectious Diseases.

High fluoroquinolone resistance proportions among multidrug-resistant tuberculosis driven by dominant L2 Mycobacterium tuberculosis clones in the Mumbai Metropolitan Region

BackgroundMultidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains are a serious health problem in India, also contributing to one-fourth of the global MDR tuberculosis (TB) burden. About 36% of the MDR MTBC strains are reported fluoroquinolone (FQ) resistant leading to high pre-extensively drug-resistant (pre-XDR) and XDR-TB (further resistance against bedaquiline and/or linezolid) rates. Still, factors driving the MDR/pre-XDR epidemic in India are not well defined.MethodsIn a retrospective study, we analyzed 1852 consecutive MTBC strains obtained from patients from a tertiary care hospital laboratory in Mumbai by whole genome sequencing (WGS). Univariate and multivariate statistics was used to investigate factors associated with pre-XDR. Core genome multi locus sequence typing, time scaled haplotypic density (THD) method and homoplasy analysis were used to analyze epidemiological success, and positive selection in different strain groups, respectively.ResultsIn total, 1016 MTBC strains were MDR, out of which 703 (69.2%) were pre-XDR and 45 (4.4%) were XDR. Cluster rates were high among MDR (57.8%) and pre-XDR/XDR (79%) strains with three dominant L2 (Beijing) strain clusters (Cl 1–3) representing half of the pre-XDR and 40% of the XDR-TB cases. L2 strains were associated with pre-XDR/XDR-TB (P < 0.001) and, particularly Cl 1–3 strains, had high first-line and FQ resistance rates (81.6–90.6%). Epidemic success analysis using THD showed that L2 strains outperformed L1, L3, and L4 strains in short- and long-term time scales. More importantly, L2 MDR and MDR + strains had higher THD success indices than their not-MDR counterparts. Overall, compensatory mutation rates were highest in L2 strains and positive selection was detected in genes of L2 strains associated with drug tolerance (prpB and ppsA) and virulence (Rv2828c). Compensatory mutations in L2 strains were associated with a threefold increase of THD indices, suggesting improved transmissibility.ConclusionsOur data indicate a drastic increase of FQ resistance, as well as emerging bedaquiline resistance which endangers the success of newly endorsed MDR-TB treatment regimens. Rapid changes in treatment and control strategies are required to contain transmission of highly successful pre-XDR L2 strains in the Mumbai Metropolitan region but presumably also India-wide.