High TB Burden Settings Research Articles

Management implications of latent TB among under-five children at risk: Insights from a community study in Mumbai, India.

Latent tuberculosis infection (LTBI) management is crucial to WHO's End TB Strategy. Indian guidelines recommend treating under-five children with household TB contacts after ruling out active TB, regardless of TBI testing. However, the precise LTBI burden among children in high TB burden settings like India is unknown. A community-based study in Mumbai's urban slums screened and managed under-five children at LTBI risk to understand its epidemiology and inform TB control interventions. Total 369 eligible under-five children were enrolled for the study. LTBI screening was done using Tuberculin skin test and Interferon gamma release assay. Active TB was ruled out before initiation of TB preventive therapy among LTBI positives. Statistical tests like chi-square, logistic regression analysis and Hosmer-Lemeshow test were used. Overall, LTBI prevalence among under-five children was 12.4% by IGRA and 21.4% by TST. Undernourished children had significantly lower LTBI positivity by IGRA (p = 0.027), while those with household contacts, longer contact duration and drug-resistant tuberculosis (DR-TB) exhibited proportionally greater IGRA positivity (p = <0.001). The study found a lower LTBI prevalence among under-five children compared to adults, with key risk factors being HHC, DR-TB contact, and prolonged exposure. These findings suggest the need to revise or revisit the TPT framework for this age group in India, particularly by implementing a test-and-treat approach.

Navigating complex care pathways-healthcare workers' perspectives on health system barriers for children with tuberculous meningitis in Cape Town, South Africa.

Tuberculous meningitis (TBM) occurs when tuberculosis (TB) bacilli disseminate and seed into the meninges, triggering a severe inflammatory response that often leads to brain infarction. It is the most severe and debilitating form of childhood TB with high mortality, and children who survive TBM often suffer lifelong physical and neuro-disability resulting in emotional, social, and economic burdens for families. In the early stages the symptoms may be non-specific and so the diagnosis is often made late when the patient already has significant brain injury. To facilitate earlier diagnosis, it is important to understand how patients are evaluated. This study aimed to chart health systems for paediatric TBM care at both primary healthcare (PHC) and hospital level in Cape Town, South Africa. We conducted fourteen in-depth interviews and eight days of semi-structured observations of patient flow across eight healthcare facilities. We found that children with TBM navigate multiple levels of care categorised into pre-admission and primary care, hospital admission and inpatient care, and post-discharge follow-up care. Healthcare workers identified the following health system barriers along the TBM care pathway for children: limited post-training and mentorship opportunities to manage TBM, overburdened facilities, time constraints, lack of recognition of TBM symptoms, delays in referral between PHC and hospital, lack of standardized diagnostic algorithms, limited diagnostic tests and a lack of child-friendly, easy-to-administer treatment. Regular and compulsory training on TB and TBM in children, including continuous mentoring and support to healthcare workers working in child health and TB services in high TB-burden settings, can facilitate early recognition of symptoms and rapid referral for diagnosis. Algorithms outlining referral criteria for patients with possible TBM at both PHC facilities and district level hospitals can guide healthcare providers and facilitate timely referral between different levels of healthcare services. An integrated data system and alert functions could flag multiple healthcare visits and improve communication between different healthcare facilities during diagnosis and treatment. Children and families affected by TBM are an especially vulnerable sub-population requiring high priority attention and support.

Strategies for isoniazid preventive therapy in HIV-positive patients who consume alcohol.

<sec><title>BACKGROUND</title>WHO guidance to defer isoniazid preventive therapy (IPT) among those with regular alcohol use because of hepatotoxicity concerns may exclude many people living with HIV (PLWH) at high TB risk in these settings.</sec><sec><title>OBJECTIVE</title>To evaluate hepatotoxicity during TB preventive therapy (TPT) in PLWH who report alcohol use in Uganda over 10 years.</sec><sec><title>METHODS</title>We developed a Markov model of latent TB infection, isoniazid preventive therapy (IPT - a type of TPT), and TB disease using data from the Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPTT) study. We modeled several treatment scenarios, including no IPT, IPT with liver enzyme monitoring (AST/ALT) during treatment, and IPT with pre-screening using the tuberculin skin test (TST).</sec><sec><title>RESULTS</title>The no IPT scenario had 230 TB deaths/100,000 population over 10 years, which is more than that seen in any IPT scenario. IPT, even with no monitoring, was preferred over no IPT when population TB disease incidence was >50 in 100,000.</sec><sec><title>CONCLUSIONS</title>For PLWH who report alcohol use in high TB burden settings, IPT should be offered, ideally with regular AST/ALT monitoring. However, even if regular monitoring is not possible, IPT is still preferable to no IPT in almost every modeled scenario.</sec>.

Comparing patterns of recent and remote Mycobacterium tuberculosis infection determined using the QuantiFERON-TB Gold Plus assay in a high TB burden setting.

One quarter of the world's population is estimated to be infected with Mycobacterium tuberculosis. Identifying recent TB infection (TBI) offers an avenue to targeted TB preventative therapy provision, and prevention to disease progression. However, detecting recent TBI remains challenging. The QuantiFERON-TB Gold Plus assay (QFT-Plus) claims to have improved sensitivity in detecting recent TBI, by the addition of the TB2 antigen tube to the TB1 tube used in previous tests. TB2 detects CD8-mediated interferon gamma response, a potential marker of recent infection. We compared QFT-Plus TB1 and TB2 responses in individuals with recent and remote infection in high-burden settings. The Tuberculosis Reduction through Expanded Antiretroviral Treatment and TB Screening (TREATS) Project followed a cohort of adolescents and young people (AYP) aged 15-24 years in Zambia and South Africa to determine TBI incidence measured by QFT-Plus over 24 months. We categorised individuals with QTF-Plus positive result into recent and remote infection. We compared their TB1 and TB2 responses and the antigen tube differential [TB2-TB1], an indicator of CD8-activity, using logistic regression. At baseline, 3876 AYP, 1852/3876 (47.8%) were QFT-Plus positive whilst 2024/3876 (52.2%) QFT-Plus negative. Of the QFT-Plus baseline positives, 1069/1852 (57.7%) tested positive at both 12 and 24 months-remote infection. Of the QFT-Plus baseline negatives, 274/2024(13.3%) converted within a 12-month period- recent infection. TB1 and TB2 responses were higher in remote than recent infection. In recent infection, TB2 responses were greater than TB1 responses. The mean differential was 0.01 IU/ml in recent and -0.22 IU/ml in remote infection, (p = 0.145). The quantitative QFT-Plus results did not appear to reflect a marked distinction between recent and remote infection. Further analysis of the responses of infected individuals who developed disease is required to determine whether any signal in QFT-Plus results may predict progression to disease.

An early and trustable indicator suggestive of non-tuberculosis mycobacteria isolation in a high tuberculosis burden setting

Distinguishing between nontuberculous mycobacterial (NTM) lung infections and pulmonary tuberculosis becomes challenging due to their similar clinical manifestations and radiological images. Consequently, instances of delayed diagnosis or misdiagnosis are highly frequent. A feasible and reliable indicator of the existence of NTM in the early stages of the disease would help to solve this dilemma. In this study, we evaluated the potential of smear-positive and Xpert assay (Cepheid, USA) negative outcomes as an early indicator of possible NTM infection in a high TB-burden setting retrospectively and prospectively. During the study period, 12·77% (138/1081) of the smear-positive cases yielded negative outcomes with the simultaneous Xpert assay. From the 110 patients who yielded smear-positive/Xpert-negative outcomes and cultivated strain as well, 105 (95·45%) were proved to have NTM isolated. By incorporating an additional criterion of a negative result from the Interferon-gamma release assay, the accuracy of the screening method reached 100%. Regarding the NTM presence prediction value, smear-positive/Xpert-negative has a sensitivity of 24·86% (45/181) in all NTM isolated cases but 93·75-96·55% accuracy in retrospective study or 93·75% accuracy in prospective study in smear-positive NTM isolated cases. In addition, the specificity was ∼99·47% (943/948) in smear-positive tuberculosis cases. The clue of the presence of NTM could be obtained on the first day of the hospital visit due to the point of care (POC) feature of smear testing and Xpert assay. About one-fourth of the NTM-isolated patients would benefit from this rapid, convenient, and reliable screening strategy in the given circumstance. Smear-positive/Xpert-negative outcome is an early, trustable indicator that is indicative of NTM isolation.

Knowledge, attitudes, and practice toward tuberculosis in high school students in Qingdao, China.

The purpose of this study is to assess the levels of knowledge, attitude, and practice (KAP) related to TB, and to analyze the differences among various demographic groups. A total of 621 students enrolled in Qingdao High School, coming from high TB burden settings. The cross-sectional study was conducted from May to July of 2022. Participants completed an online questionnaire. Differences in knowledge and practice based on participant characteristics were analyzed using the Wilcoxon rank test and Kruskal-Wallis rank test. Group differences were assessed using a rank-based analysis of variance. The mean percentage of correct answers for TB knowledge and practice was 82.09% and 83.25%, respectively. Grade Three students showed higher knowledge and practice scores than Grade One or Grade Two students (t = -3.9935, p = 0.0002, t = 3.4537, p = 0.0018. 8.58 vs 7.94, 8.58 vs 8.23. t = 3.4562, p = 0.0018, t = -2.8688, p = 0.0128. 1.78 vs 1.61, 1.78 vs 1.64). A significant majority (78.42%) of students expressed fear of being affected by TB. 49.28% of the students would support and help TB patients. 88.08% of participants had heard of TB, with 72.94% learning about it at school, mainly through visual aids like posters. Information was predominantly obtained from online sources (websites, microblogs, WeChat, etc.). It is recommended to develop a TB curriculum for lower-grade students to enhance awareness of TB prevention through various means, including the internet and social media.

Inferring Mycobacterium Tuberculosis Drug Resistance and Transmission using Whole-genome Sequencing in a High TB-burden Setting in China

ObjectiveChina is among the 30 countries with a high burden of tuberculosis (TB) worldwide, and TB remains a public health concern. Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China. However, molecular epidemiological studies of Kashgar are lacking. MethodsA population-based retrospective study was conducted using whole-genome sequencing (WGS) to determine the characteristics of drug resistance and the transmission patterns. ResultsA total of 1,668 isolates collected in 2020 were classified into lineages 2 (46.0%), 3 (27.5%), and 4 (26.5%). The drug resistance rates revealed by WGS showed that the top three drugs in terms of the resistance rate were isoniazid (7.4%, 124/1,668), streptomycin (6.0%, 100/1,668), and rifampicin (3.3%, 55/1,668). The rate of rifampicin resistance was 1.8% (23/1,290) in the new cases and 9.4% (32/340) in the previously treated cases. Known resistance mutations were detected more frequently in lineage 2 strains than in lineage 3 or 4 strains, respectively: 18.6% vs. 8.7 or 9%, P < 0.001. The estimated proportion of recent transmissions was 25.9% (432/1,668). Multivariate logistic analyses indicated that sex, age, occupation, lineage, and drug resistance were the risk factors for recent transmission. Despite the low rate of drug resistance, drug-resistant strains had a higher risk of recent transmission than the susceptible strains (adjusted odds ratio, 1.414; 95% CI, 1.023–1.954; P = 0.036). Among all patients with drug-resistant tuberculosis (DR-TB), 78.4% (171/218) were attributed to the transmission of DR-TB strains. ConclusionOur results suggest that drug-resistant strains are more transmissible than susceptible strains and that transmission is the major driving force of the current DR-TB epidemic in Kashgar.

Bacterial pathogens in Xpert MTB/RIF Ultra-negative sputum samples of patients with presumptive tuberculosis in a high TB burden setting: a 16S rRNA analysis.

In patients with presumptive tuberculosis (TB) in whom the diagnosis of TB was excluded, understanding the bacterial etiology of lower respiratory tract infections (LRTIs) is important for optimal patient management. A secondary analysis was performed on a cohort of 250 hospitalized patients with symptoms of TB. Bacterial DNA was extracted from sputum samples for Illumina 16S rRNA sequencing to identify bacterial species based on amplicon sequence variant level. The bacterial pathogen most likely to be responsible for the patients' LRTI could only be identified in a minority (6.0%, 13/215) of cases based on 16S rRNA amplicon sequencing: Mycoplasma pneumoniae (n = 7), Bordetella pertussis (n = 2), Acinetobacter baumanii (n = 2), and Pseudomonas aeruginosa (n = 2). Other putative pathogens were present in similar proportions of Xpert Ultra-positive and Xpert Ultra-negative sputum samples. The presence of Streptococcus (pseudo)pneumoniae appeared to increase the odds of radiological abnormalities (aOR 2.5, 95% CI 1.12-6.16) and the presence of S. (pseudo)pneumoniae (aOR 5.31, 95% CI 1.29-26.6) and Moraxella catarrhalis/nonliquefaciens (aOR 12.1, 95% CI 2.67-72.8) increased the odds of 6-month mortality, suggesting that these pathogens might have clinical relevance. M. pneumoniae, B. pertussis, and A. baumanii appeared to be the possible causes of TB-like symptoms. S. (pseudo)pneumoniae and M. catarrhalis/nonliquefaciens also appeared of clinical relevance based on 16S rRNA amplicon sequencing. Further research using tools with higher discriminatory power than 16S rRNA sequencing is required to develop optimal diagnostic and treatment strategies for this population.IMPORTANCEThe objective of this study was to identify possible bacterial lower respiratory tract infection (LRTI) pathogens in hospitalized patients who were initially suspected to have TB but later tested negative using the Xpert Ultra test. Although 16S rRNA was able to identify some less common or difficult-to-culture pathogens such as Mycoplasma pneumoniae and Bordetella pertussis, one of the main findings of the study is that, in contrast to what we had hypothesized, 16S rRNA is not a method that can be used to assist in the management of patients with presumptive TB having a negative Xpert Ultra test. Even though this could be considered a negative finding, we believe it is an important finding to report as it highlights the need for further research using different approaches.

Evaluation of radiological capacity and usage in paediatric TB diagnosis: A mixed-method protocol of a comparative study in Mozambique, South Africa and Spain.

Tuberculosis remains one of the top ten causes of mortality globally. Children accounted for 12% of all TB cases and 18% of all TB deaths in 2022. Paediatric TB is difficult to diagnose with conventional laboratory tests, and chest radiographs remain crucial. However, in low-and middle-income countries with high TB burden, the capacity for radiological diagnosis of paediatric TB is rarely documented and data on the associated radiation exposure limited. A multicentre, mixed-methods study is proposed in three countries, Mozambique, South Africa and Spain. At the national level, official registry databases will be utilised to retrospectively compile an inventory of licensed imaging resources (mainly X-ray and Computed Tomography (CT) scan equipment) for the year 2021. At the selected health facility level, three descriptive cross-sectional standardised surveys will be conducted to assess radiology capacity, radiological imaging diagnostic use for paediatric TB diagnosis, and radiation protection optimization: a site survey, a clinician-targeted survey, and a radiology staff-targeted survey, respectively. At the patient level, potential dose optimisation will be assessed for children under 16 years of age who were diagnosed and treated for TB in selected sites in each country. For this component, a retrospective analysis of dosimetry will be performed on TB and radiology data routinely collected at the respective sites. National inventory data will be presented as the number of units per million people by modality, region and country. Descriptive analyses will be conducted on survey data, including the demographic, clinical and programmatic characteristics of children treated for TB who had imaging examinations (chest X-ray (CXR) and/or CT scan). Dose exposure analysis will be performed by children's age, gender and disease spectrum. As far as we know, this is the first multicentre and multi-national study to compare radiological capacity, radiation protection optimization and practices between high and low TB burden settings in the context of childhood TB management. The planned comparative analyses will inform policy-makers of existing radiological capacity and deficiencies, allowing better resource prioritisation. It will inform clinicians and radiologists on best practices and means to optimise the use of radiological technology in paediatric TB management.

1898. Optimizing selection of latent TB management strategies among immigrants from high TB burden settings to the United States

Abstract Background Treatment for latent tuberculosis infection (LTBI) with rifampin and isoniazid is very effective but carries significant hepatotoxicity risks, increasing with age. Further, since the risk of progression to tuberculosis (TB) disease declines with increasing time from exposure, the risk is highest among recent immigrants. Current guidelines may therefore promote overtreatment of LTBI, particular in older immunocompetent individuals who immigrated many years previously. Methods Using observed data from the Boston Medical Center/Boston Public Health Commission TB clinic and best literature estimates, we designed a microsimulation model to simulate TB progression among immunocompetent adult immigrants from high TB burden countries without abnormal radiography, alcohol or tobacco use, or recent TB contacts over a 30-year horizon (Table 1). We assumed that the simulated individuals were exposed to TB immediately prior to immigration. TB progression rates are based on years since exposure (Table 1). We evaluated three strategies: 1. No treatment 2. Rifampin and 3. Isoniazid for new 35 years-old and 65 years-old immigrants and for 35 and 65 years-old immigrants who had immigrated 25 years previously. We simulated hepatotoxicity using published estimates (Table 2). The model calculates costs and outcomes (TB cases and disability-adjusted life years) associated with each strategy. We used deterministic and probabilistic sensitivity analyses to test robustness of our results. Results Among new immigrants both 35 and 65 years-old, rifampin provides better outcomes at lower cost than both the isoniazid and no treatment strategies (Table 3). Among those who immigrated 25 years ago, Rifampin remains the preferred strategy in 75% of simulations for 35 years-old individuals and no treatment was preferred in 100% of iterations for 65 years-old patients. For those unable to receive rifampin due to drug interactions, no treatment became the preferred strategy for a broader range of individuals (Figures 1a and 1b). Conclusion Age and time since immigration must be considered to determine whether LTBI therapy is indicated in immunocompetent immigrants from high TB burden countries. Our results could help clinicians optimize strategies for LTBI treatment and minimize harm. Disclosures All Authors: No reported disclosures

Effect of integrating traditional care with modern healthcare to improve tuberculosis control programs in Ethiopia: a protocol for a cluster-randomized controlled trial

BackgroundTuberculosis (TB) remains a major cause of morbidity and mortality in the world, despite being a preventable and curable disease. The World Health Organization (WHO) End-TB Strategy, aligned with the Sustainable Development Goals (SDGs), sets a target of reducing the TB mortality rate by 95%, TB incidence rate by 90%, and catastrophic costs due to TB by 2035, compared with a 2015 level. To achieve these ambitious targets, several interventions have been implemented in the last few years, resulting in major progress toward reducing the burden of TB. However, over one-third of the global TB cases remained undetected and never received treatment. Most of those undetected cases were found in low- and middle-income countries such as Ethiopia. Though several interventions were implemented to increase TB case detection and mitigate catastrophic costs associated with TB, sustaining these interventions in resource-constrained settings remains challenging. Consequently, an alternative method is needed to increase TB case detection while decreasing diagnosis delays and catastrophic costs. Therefore, this study aimed to integrate traditional TB care into modern TB care to improve TB control programs, including early TB case detection, and reduce catastrophic costs in high TB burden settings such as Ethiopia.MethodsA cluster randomized controlled trial will be conducted in northwest Ethiopia to determine the effectiveness of integrating traditional care with modern TB care. The intervention will be conducted in randomly selected districts in the South Gondar Zone. The control group will be an equal number of districts with usual care. The intervention comprised three key components, which include referral linkage from traditional to modern health care; training of health professionals and traditional care providers in three different rounds to increase their knowledge, attitude, and skills toward the referral systems; and TB screening at traditional health care sites. The primary outcomes of interest will be an increase in case detection rate, and the secondary outcomes of interest will be decreased diagnosis delays and catastrophic costs for TB patients. Data will be collected in both the intervention and control groups on the main outcome of interest and a wide range of independent variables. Generalized linear mixed models will be used to compare the outcome of interest between the trial arms, with adjustment for baseline differences.DiscussionThis cluster-randomized controlled trial study will assess the effectiveness of a strategy that integrates traditional healthcare into the modern healthcare system for the control and prevention of TB in northwest Ethiopia, where nearly 90% of the population seeks care from traditional care systems. This trial will provide information on the effectiveness of traditional and modern healthcare integration to improve TB case detection, early diagnosis, and treatment, as well as reduce the catastrophic costs of TB.Trial registrationClinicalTrials.gov NCT05236452. Registered on July 22, 2022.

Strategies to increase childhood tuberculosis case detection at the primary health care level: Lessons from an active case finding study in Zambia.

In high TB burden settings, it is estimated that 10-20% of total notifications should be children, however, currently only 6-8% of the total TB notifications in Zambia are children. We assessed whether the implementation of a multicomponent strategy, at primary healthcare facilities, that systematically targets barriers at each step of the childhood TB diagnostic cascade can increase childhood TB case detection. We conducted a controlled, interrupted time series analysis to compare childhood TB case notifications before (January 2018-December 2019), and during implementation (January 2020-September 2021) in two intervention and two control Level 1 hospitals in Lusaka, Zambia. At each of the intervention facilities, we implemented a multicomponent strategy constituting: (1) capacity development on childhood TB and interpretation of chest x-ray, (2) TB awareness-raising and demand creation activities, (3) setting up fast track TB services, (4) strengthening of household contact tracing, and (5) improving access to digital chest X-ray for TB screening and Xpert MTB/Rif Ultra for TB diagnosis, through strengthening sample collection in children. Among 5,150 children < 15 years screened at the two intervention facilities during the study period, 503 (9.8% yield) were diagnosed with TB. Of these, 433 (86.1%) were identified through facility-based activities (10.5% yield) and 70 (13.9%) were identified through household contact tracing (6.9% yield). Overall, 446 children (88.7%) children with TB were clinically diagnosed. Following implementation of the multicomponent strategy, the proportion children contributed to total TB notifications immediately changed by +1.5% (95%CI: -3.5, 6.6) and -4.4% (95%CI: -7.5, 1.4) at the intervention and control sites, respectively (difference 6.0% [95%CI: -0.7, 12.7]), p = 0.08); the proportion of childhood notifications increased 0.9% (95%CI: -0.7, 2.5%) each quarter at the intervention sites relative to pre-implementation trends, while declining 1.2% (-95%CI: -1.8, -0.6) at the control sites (difference 2.1% [95%CI: 0.1, 4.2] per quarter between, p = 0.046); this translated into 352 additional and 85 fewer childhood TB notifications at the intervention and control sites, respectively, compared to the pre-implementation period. A standardized package of strategies to improve childhood TB detection at primary healthcare facilities was feasible to implement and was associated with a sustained improvement in childhood TB notifications.

Factors affecting implementation of tuberculosis contact investigation and tuberculosis preventive therapy among children in Sabah, East Malaysia: A qualitative study.

Contact investigation and TB preventive treatment of children under five years of age who are close contacts of a TB case is a key component of TB prevention. However, the uptake of TB preventive treatment is low in many high-TB burden settings. This study explores factors affecting the implementation of TB contact investigation and preventive treatment among children in Malaysia's city of Kota Kinabalu, Sabah State. This study was conducted in three primary health clinics between 2019 and 2020. We purposively sampled 34 parents and guardians of child contacts eligible for TB preventive treatment, and 25 healthcare providers involved in the management of child contacts. We conducted thematic analysis of semi-structured interviews and focus group discussions to illicit factors affecting implementation and uptake of TB contact investigation and TB preventive therapy. Six main themes emerged from the analyses-four of these relating to contact investigation and two relating to TB preventive therapy. Factors affecting TB contact investigation were addressed under system related factors (external factors, stakeholder collaboration, healthcare workers' and clients' concerns), clinic related factors (perceived performance, clinic schedule, and space), healthcare worker related factors (cooperation, commitment, knowledge, misconception, counselling and communication) and patient and contact related factors (cooperation and commitment). Factors affecting TB preventive treatment delivery were addressed under guardian related factors (cooperation, commitment, knowledge and misconception) and treatment related factors (child-friendly form and adverse effects). To address gaps and barriers identified in our study, we recommend developing system capacity to maintain routine contact investigation and preventive treatment in the context of external program risks, providing training to healthcare workers to address misconceptions, safeguarding vulnerable clients against the risk of detention and deportation while accessing care, ensuring public and private services are provided regardless of migration status, and improving processes and resources for contact investigation and preventive treatment.

Determinants of QuantiFERON Plus-diagnosed tuberculosis infection in adult Ugandan TB contacts: A cross-sectional study.

The tuberculin skin test is commonly used to diagnose latent tuberculosis infection (LTBI) in resource-limited settings, but its specificity is limited by factors including cross-reactivity with BCG vaccine and environmental mycobacteria. Interferon-gamma release assays (IGRA) overcome this problem by detecting M. tuberculosis complex-specific responses, but studies to determine risk factors for IGRA-positivity in high TB burden settings are lacking. We conducted a cross-sectional study to determine factors associated with a positive IGRA by employing the QuantiFERON-TB® Gold-plus (QFT Plus) assay in a cohort of asymptomatic adult TB contacts in Kampala, Uganda. Multivariate logistic regression analysis with forward stepwise logit function was employed to identify independent correlates of QFT Plus-positivity. Of the 202 participants enrolled, 129/202 (64%) were female, 173/202 (86%) had a BCG scar, and 67/202 (33%) were HIV-infected. Overall, 105/192 (54%, 95% CI 0.48-0.62) participants had a positive QFT Plus result. Increased risk of QFT-Plus positivity was independently associated with casual employment/unemployment vs. non-casual employment (adjusted odds ratio (aOR) 2.18, 95% CI 1.01-4.72), a family vs. non-family relation to the index patient (aOR 2.87, 95% CI 1.33-6.18), living in the same vs. a different house as the index (aOR 3.05, 95% CI 1.28-7.29), a higher body mass index (BMI) (aOR per additional kg/m2 1.09, 95% CI 1.00-1.18) and tobacco smoking vs. not (aOR 2.94, 95% CI 1.00-8.60). HIV infection was not associated with QFT-Plus positivity (aOR 0.91, 95% CI 0.42-1.96). Interferon Gamma Release Assay positivity in this study population was lower than previously estimated. Tobacco smoking and BMI were determinants of IGRA positivity that were previously unappreciated.

Pre-sensitization with tuberculosis and non-tuberculosis mycobacteria and its impact on TB incidence in different age groups: Chengalpattu BCG trial revisited

Individuals pre-sensitized with Mycobacterium tuberculosis (MTB), non-tuberculosis mycobacteria, and its impact on TB incidence are relatively unexplored in a high TB burden setting. We conducted secondary data analysis of a double-blind, randomized Chengalpattu BCG trial, India. Induration to Purified Protein Derivative (PPD)-S and PPD-B were proxies for exposures to MTB and M. intracellulare respectively. Optimum cut-off for PPD-S and B were determined using Receiver-Operating Characteristic curves and induration ≥12 mm for PPD-S and ≥10 mm for PPD-B were considered strong reaction. Incidence rates of culture positive pulmonary TB per 100,000 person-years (PY) were calculated. Of 270,043 individuals with skin test results, children <14 years (n = 109,383, 64% showed strong-reaction to PPD-B and 17% to PPD-S) and adults between 25 and 34 years (n = 40,292, 98% were strong reactors to PPD-B and 73% to PPD-S). Overall incidence rate was lower in individuals with PPD-S < PPD-B (136, 95% CI: 130–141/100,000 PY) compared to individuals with PPD-S > PPD-B (447, 95% CI: 427–468/100,000 PY). Incidence rates of culture positive pulmonary TB was affected by early age of exposure to cross-reactive mycobacterial antigens represented by PPD-B and exposure to MTB represented by PPD-S during adolescence and early adulthood.

High sensitivity of ultrasound for the diagnosis of tuberculosis in adults in South Africa: A proof-of-concept study

There are limited data on the performance characteristics of ultrasound for the diagnosis of pulmonary tuberculosis in both HIV-positive and HIV-negative persons. The objective of this proof-of-concept study was to determine the sensitivity and specificity of ultrasound for the diagnosis of tuberculosis in adults. Comprehensive thoracic and focused abdominal ultrasound examinations were performed by trained radiologists and pulmonologists on adults recruited from a community multimorbidity survey and a primary healthcare clinic in KwaZulu-Natal Province, South Africa. Sputum samples were systematically collected from all participants. Sensitivity and specificity of ultrasound to detect tuberculosis were calculated compared to a reference standard of i) bacteriologically-confirmed tuberculosis, and ii) either bacteriologically-confirmed or radiologic tuberculosis. Among 92 patients (53 [58%] male, mean age 41.9 [standard deviation 13.7] years, 49 [53%] HIV positive), 34 (37%) had bacteriologically-confirmed tuberculosis, 8 (9%) had radiologic tuberculosis with negative bacteriologic studies, and 50 (54%) had no evidence of active tuberculosis. Ultrasound abnormalities on either thoracic or abdominal exams were detected in 31 (91%) participants with bacteriologic tuberculosis and 27 (54%) of those without tuberculosis. Sensitivity and specificity of any ultrasound abnormality for bacteriologically-confirmed tuberculosis were 91% (95% confidence interval [CI] 76%-98%) and 46% (95% CI 32%-61%). Sensitivity and specificity of any ultrasound abnormality for either bacteriologically-confirmed or radiologic tuberculosis were 86% (95% CI 71%-95%) and 46% (95% CI 32%-61%). Overall performance did not appear to differ markedly between participants with and without HIV. A comprehensive ultrasound scanning protocol in adults in a high TB burden setting had high sensitivity but low specificity to identify bacteriologically-confirmed tuberculosis.

TB screening, prevention and treatment cascade in a Malawi prison.

BACKGROUND Incarcerated individuals, especially in high HIV and TB burden settings, are at increased risk of latent TB infection and/or TB disease. We implemented a comprehensive HIV-TB intervention in a Malawi prison and studied its feasibility.METHODS Between February and December 2019, consenting individuals underwent screening for HIV, TB infection and TB disease. HIV-positive individuals without TB disease were treated with a fixed-dose combination of isoniazid, cotrimoxazole and vitamin B6 (INH-CTX-B6). HIV-negative persons with TB infection received 12 weeks of isoniazid and rifapentine (3HP).RESULTS Of 1,546 consenting individuals, 1,498 (96.9%) were screened and 1,427 (92.3%) included in the analysis: 96.4% were male, the median age was 31 years (IQR 25-38). Twenty-nine (2.1%) participants were diagnosed with TB disease, of whom 89.7% started and 61.5% completed TB treatment. Of the 1,427 included, 341 (23.9%) were HIV-positive, of whom 98.5% on antiretroviral therapy and 95% were started on INH-CTX-B6. Among 1,086 HIV-negative participants, 1,015 (93.5%) underwent the tuberculin skin test (TST), 670 (65.9%) were TST-positive, 666 (99.4%) started 3HP and 570 (85.5%) completed 3HP treatment.CONCLUSION A comprehensive TB screening and treatment package among incarcerated individuals was acceptable and feasible, and showed high prevalence of HIV, TB disease and TB infection. Treatment uptake was excellent, but treatment completion needs to be improved. Greater investment in comprehensive HIV-TB services, including access to shorter TB regimens and follow-up upon release, is needed for incarcerated individuals.

Stakeholder perspectives around post-TB wellbeing and care in Kenya and Malawi.

There is growing awareness of the burden of post-TB morbidity, and its impact on the lives and livelihoods of TB affected households. However little work has been done to determine how post-TB care might be delivered in a feasible and sustainable way, within existing National TB Programmes (NTPs) and health systems, in low-resource, high TB-burden settings. In this programme of stakeholder engagement around post-TB care, we identified actors with influence and interest in TB care in Kenya and Malawi, including TB-survivors, healthcare providers, policy-makers, researchers and funders, and explored their perspectives on post-TB morbidity and care. Stakeholder mapping was completed to identify actors with interest and influence in TB care services in each country, informed by the study team's local, regional and international networks. Key international TB organisations were included to provide a global perspective. In person or online one-to-one interviews were completed with purposively selected stakeholders. Snowballing was used to expand the network. Data were recorded, transcribed and translated, and a coding frame was derived. Data were coded using NVivo 12 software and were analysed using thematic content analysis. Online workshops were held with stakeholders from Kenya and Malawi to explore areas of uncertainty and validate findings. The importance of holistic care for TB patients, which addresses both TB comorbidities and sequelae, was widely recognised by stakeholders. Key challenges to implementation include uncertainty around the burden of post-TB morbidity, leadership of post-TB services, funding constraints, staff and equipment limitations, and the need for improved integration between national TB and non-communicable disease (NCD) programmes for care provision and oversight. There is a need for local data on the burden and distribution of morbidity, evidence-informed clinical guidelines, and pilot data on models of care. Opportunities to learn from existing HIV-NCD services were emphasised. This work addresses important questions about the practical implementation of post-TB services in two African countries, exploring if, how, where, and for whom these services should be provided, according to a broad range of stakeholders. We have identified strong interest in the provision of holistic care for TB patients in Kenya and Malawi, and key evidence gaps which must be addressed to inform decision making by policy makers, TB programmes, and funders around investment in post-TB services. There is a need for pilot studies of models of integrated TB care, and for cross-learning between countries and from HIV-NCD services.

Paediatric multidrug-resistant tuberculosis in a resource-limited high TB burden setting: a case report

MDR-TB is a matter of growing concern especially in children. The case presented here is a four years MDR-TB girl belonging to the Saharia tribe, a high TB burden ethnic group in central India. She was noticed by the project staff during contact tracing visit to the family as her father had MDR TB. The sputum smear and Cartridge- Based Nucleic Acid Amplification Test (CBNAAT) tests confirmed the diagnosis of M. tuberculosis with Rifampicin resistance. She was promptly initiated on shorter MDR regimen under National TB Elimination Programme (NTEP) and was monitored regularly with successful outcome at the end of the treatment. Though household contact investigations are integral part of NTEP, it is rarely done routinely in resource-limited settings, thereby missing a large number of children with TB disease. The carefully performed household contact investigation in this case, led to prompt detection and timely treatment of this MDR-TB girl in the remote setting who was otherwise missed by the routine programme surveillance. This also led to a favorable outcome. The findings emphasize the need for strengthening household contact tracing mechanism in the national TB elimination programme particularly in hard to reach and marginalised ethnic populations in the country.

Cerebrospinal fluid AFB smear in adults with tuberculous meningitis: A systematic review and diagnostic test accuracy meta-analysis

BackgroundCerebrospinal fluid (CSF) Ziehl–Neelsen acid-fast bacilli (AFB) smear is a rapid, cheap, widely available test for tuberculous meningitis (TBM). Yet, reported test sensitivity is highly variable. We performed a systematic review and meta-analysis for CSF AFB smear vs. other mycobacterial tests to diagnose TBM. MethodsWe searched MEDLINE and Embase for studies reporting sensitivity and specificity of AFB smear against mycobacterial tests (reference standard) in adults (≥15 years) with suspected TBM. We used the QUADAS-2 tool to assess risk of bias. We estimated pooled sensitivity and specificity of AFB smear versus the reference standard using random-effects bivariate modeling. We used the I2 statistic to assess heterogeneity between studies. ResultsOf 981 articles identified, 11 were eligible for inclusion with a total of 1713 participants. Seven studies were from high-TB burden settings and 4 from low-TB burden settings. The pooled sensitivity and specificity of CSF AFB smear were 8% (95%CI 3–21) and 100% (95%CI 90–100), with substantial heterogeneity in diagnostic performance (I2 >95% for both) and reference standards. ConclusionCSF AFB smear has poor sensitivity in most settings. If other more sensitive tests are available, those should be used preferentially rather than CSF AFB smear.