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Abstract Background A pleural fluid adenosine deaminase (ADA) has been used globally to assist in the diagnosis of a tuberculous pleural effusion (TPE) with a notable negative predictive value. Case presentation We report a case of a patient with a negative pleural fluid ADA who was found to have culture-positive and biopsy-proven Mycobacterium tuberculosis. Conclusions This case shows the importance of pursuing gold standard diagnostic studies when clinical suspicion remains high despite negative preliminary testing. We further describe gaps in research to improve pleural fluid biomarkers for TPE.

Objectives We developed and tested a mobile health-based programme to enhance integration of HIV and tuberculosis (TB) care and to promote a patient-centred approach in a region of high coinfection burden. Phases of programme development included planning, stakeholder interviews and platform re-build, testing and iteration.Setting In Irkutsk, Siberia, HIV/TB coinfection prevalence is high relative to the rest of the Russian Federation.Participants Pilot testing occurred for a cohort of 60 people with HIV and TB.Results Key steps emerged to ensure the mobile health-based programme could be operational and adequately adapted for the context, including platform language adaptation, optimisation of server management, iteration of platform features, and organisational practice integration. Pilot testing of the platform rebuild yielded favourable patient perceptions of usability and acceptability at 6 months (n=47 surveyed), with 18 of 20 items showing scores above 4 (on a scale from 1 to 5) on average. Development of this mobile health-based programme for integrated care of infections highlighted the importance of several considerations for tailoring these interventions contextually, including language adaptation and technological capacity, but also, importantly, contextualised patient preferences related to privacy and communication with peers and/or providers, existing regional capacity for care coordination of different comorbidities, and infection severity and treatment requirements.Conclusions Our experience demonstrated that integration of care for TB and HIV can be well served by using multimodal mobile health-based programmes, which can enhance communication and streamline workflow between providers across multiple collaborating institutions and improve continuity between inpatient and outpatient care settings. Further study of programme impact on contextual disease-related stigma and social isolation as well as evaluation of implementation on a broader scale for HIV care is currently under way.Trial registration number NCT03819374.

Background: In 2018, an estimated 10.0 million people contracted tuberculosis (TB), and 1.5 million died from it, including 1.25 million HIV-negative persons and 251,000 HIV-associated TB fatalities. Drug-resistant tuberculosis (DR-TB) is an important contributor to global TB mortality. Multi-drug-resistant TB (MDR-TB) is defined as TB resistant to at least isoniazid (INH) and rifampin (RMP), which are recommended by the WHO as essential drugs for treatment. Objective: To investigate the effectiveness of bedaquiline addition to the treatment of drug-resistant TB infections on the African continent. Methodology: The search engine databases Medline, PubMed, Google Scholar, and Embase were used to obtain published data pertaining to DR-TB between 2012 and 2021 in Africa. Included studies had to document clinical characteristics at treatment initiation and outcomes at the end of treatment (i.e., success, failure, recurrence, loss to follow-up, and death). The included studies were used to conduct a meta-analysis. All data analysis and visualization were performed using the R programming environment. The log risk ratios and sample variances were calculated for DR-TB patients treated with BBQ monotherapy vs. BDQ and other drug therapy. To quantify heterogeneity among the included studies, random effect sizes were calculated. Results: A total of 16 studies in Africa from Mozambique (N = 1 study), Eswatini (N = 1 study), Democratic Republic of the Congo (N = 1 study), South Africa (N = 12 studies), and a multicenter study undertaken across Africa (N = 1 study) were included. In total, 22,368 individuals participated in the research studies. Among the patients, (55.2%; 12,350/22,368) were male while 9723/22,368 (44%) were female. Overall, (9%; 2033/22,368) of patients received BDQ monotherapy, while (88%; 19,630/22,368) patients received bedaquiline combined with other antibiotics. In total, (42%; 9465/22,368) of the patients were successfully treated. About (39%; 8653/22,368) of participants finished their therapy, meanwhile (5%; 1166/22,368) did not finish their therapy, while people (0.4%; 99/22,368) were lost to follow up. A total of (42%; 9265/22,368) patients died. Conclusion: Very few studies on bedaquiline usage in DR-TB in Africa have been published to date. Bedaquiline has been shown to enhance DR-TB results in clinical studies and programmatic settings. Hence, the World Health Organization (WHO) has recommended that it be included in DR-TB regimens. However, in the current study limited improvement to DR-TB treatment results were observed using BDQ on the continent. Better in-country monitoring and reporting, as well as multi-country collaborative cohort studies of DR-TB, can expand the knowledge of bedaquiline usage and clinical impact, as well as the risks and benefits throughout the continent.

BackgroundIn recent non-pandemic periods, tuberculosis (TB) has been the leading killer worldwide from a single infectious disease. Patients with DM are three times more likely to develop active TB and poor treatment outcomes. Single glycemic measurements at TB diagnosis may inaccurately diagnose or mischaracterize DM severity. Data are limited regarding glycemic dynamics from TB diagnosis through treatment.MethodsProspective study of glycemia dynamics in response to TB treatment measured glycosylated haemoglobin (HbA1c) in patients presenting to TB screening centres in Bangladesh to determine the prevalence and risk factors of hyperglycemia before and at TB treatment completion.Results429 adults with active TB disease were enrolled and divided into groups based on history of DM and initial HbA1c range: normoglycemia, prediabetes, and DM. DM was diagnosed in 37%. At treatment completion,14(6%) patients from the normoglycemia and prediabetes groups had HbA1c>6.5%, thus increasing the prevalence of DM to 39%. The number needed to screen to diagnose one new case of DM at TB diagnosis was 5.7 and 16 at treatment completion in the groups without DM. Weight gain>5% at treatment completion significantly increased the risk of hyperglycemia in the groups without DM at TB diagnosis (95% CI 1.23-26.04, pConclusionHbA1c testing prior to and at TB treatment completion found a high prevalence of prediabetes and DM, including a proportion found at treatment completion and commonly in people with a higher percentage of weight gain. Further longitudinal research is needed to understand the effects of TB disease and treatment on insulin resistance and DM complications.

Therapeutic drug monitoring may improve multidrug-resistant tuberculosis (MDR-TB) treatment outcomes. Levofloxacin demonstrates significant individual pharmacokinetic variability. Thus, we sought to develop and validate a high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection for levofloxacin in patients on MDR-TB treatment. The HPLC-UV method is based on a solid phase extraction (SPE) and a direct injection into the HPLC system. The limit of quantification was 0.25 μg/mL, and the assay was linear over the concentration range of 0.25-15 μg/mL (y = 0.5668x-0.0603, R2 = 0.9992) for the determination of levofloxacin in plasma. The HPLC-UV methodology achieved excellent accuracy and reproducibility along a clinically meaningful range. The intra-assay RSD% of low, medium, and high quality control samples (QC) were 1.93, 2.44, and 1.90, respectively, while the inter-assay RSD% were 3.74, 5.65, and 3.30, respectively. The mean recovery was 96.84%. This method was then utilized to measure levofloxacin concentrations from patients' plasma samples from a retrospective cohort of consecutive enrolled subjects treated for MDR-TB at the national TB hospital in Tanzania during 5/3/2013-8/31/2015. Plasma was collected at 2 hours after levofloxacin administration, the time of estimated peak concentration (eCmax) treatment. Forty-one MDR-TB patients had plasma available and 39 had traceable programmatic outcomes. Only 13 (32%) patients had any plasma concentration that reached the lower range of the expected literature derived Cmax with the median eCmax being 5.86 (3.33-9.08 μg/ml). Using Classification and Regression Tree analysis, an eCmax ≥7.55 μg/mL was identified as the threshold which best predicted cure. Analyzing this CART derived threshold on treatment outcome, the time to sputum culture conversion was 38.3 ± 22.7 days vs. 47.8 ± 26.5 days (p = 0.27) and a greater proportion were cured, in 10 out of 15 (66.7%) vs. 6 out of 18 (33.3%) (p = 0.06) respectively. Furthermore, one patient with an eCmax/minimum inhibitory concentration (MIC) of only 1.13 acquired extensively drug resistant (XDR)-TB while undergoing treatment. The individual variability of levofloxacin concentrations in MDR-TB patients from Tanzania supports further study of the application of onsite therapeutic drug monitoring and MIC testing.

BACKGROUND:We aimed to evaluate the antibody in lymphocyte supernatant (ALS) assay as a biomarker to diagnose tuberculosis among adults from Tanzania with and without HIV. METHODS:Adults admitted with suspicion for tuberculosis had sputa obtained for GeneXpert MTB/RIF, acid-fast bacilli smear and mycobacterial culture; blood was obtained prior to treatment initiation and after 4 weeks. Adults hospitalized with non-infectious conditions served as controls. Peripheral blood mononuclear cells were cultured unstimulated for 72 hours. Anti-mycobacterial antibodies were measured from culture supernatants by ELISA, using BCG vaccine as the coating antigen. Median ALS responses were compared between cases and controls at baseline and between cases over time. RESULTS:Of 97 TB cases, 85 were microbiologically confirmed and 12 were clinically diagnosed. Median ALS responses from TB cases (0.366 OD from confirmed cases and 0.285 from clinical cases) were higher compared to controls (0.085, p

ABSTRACT Genotypic methods for drug susceptibility testing of Mycobacterium tuberculosis are desirable to speed the diagnosis and proper therapy of tuberculosis (TB). However, the numbers of genes and polymorphisms implicated in resistance have proliferated, challenging diagnostic design. We developed a microfluidic TaqMan array card (TAC) that utilizes both sequence-specific probes and high-resolution melt analysis (HRM), providing two layers of detection of mutations. Twenty-seven primer pairs and 40 probes were designed to interrogate 3,200 base pairs of critical regions of the inhA, katG, rpoB, embB, rpsL, rrs, eis, gyrA, gyrB, and pncA genes. The method was evaluated on 230 clinical M. tuberculosis isolates from around the world, and it yielded 96.1% accuracy (2,431/2,530) in comparison to that of Sanger sequencing and 87% accuracy in comparison to that of the slow culture-based susceptibility testing. This TAC-HRM method integrates assays for 10 genes to yield fast, comprehensive, and accurate drug susceptibility results for the 9 major antibiotics used to treat TB and could be deployed to improve treatment outcomes. IMPORTANCE Multidrug-resistant tuberculosis threatens global tuberculosis control efforts. Optimal therapy utilizes susceptibility test results to guide individualized treatment regimens; however, the susceptibility testing methods in use are technically difficult and slow. We developed an integrated TaqMan array card method with high-resolution melt analysis that interrogates 10 genes to yield a fast, comprehensive, and accurate drug susceptibility result for the 9 major antituberculosis antibiotics.