An ecological study to evaluate the association of Bacillus Calmette-Guerin (BCG) vaccination on cases of SARS-CoV2 infection and mortality from COVID-19

As the SARS-CoV2 pandemic has progressed, there have been marked geographical differences in the pace and extent of its spread. We evaluated the association of BCG vaccination on morbidity and mortality of SARS-CoV2, adjusted for country-specific responses to the epidemic, demographics and health. SARS-CoV2 cases and deaths as reported by 31 May 2020 in the World Health Organization situation reports were used. Countries with at least 28 days following the first 100 cases, and available information on BCG were included. We used log-linear regression models to explore associations of cases and deaths with the BCG vaccination policy in each country, adjusted for population size, gross domestic product, proportion aged over 65 years, stringency level measures, testing levels, smoking proportion, and the time difference from date of reporting the 100th case to 31 May 2020. We further looked at the association that might have been found if the analyses were done at earlier time points. The study included 97 countries with 73 having a policy of current BCG vaccination, 13 having previously had BCG vaccination, and 11 having never had BCG vaccination. In a log-linear regression model there was no effect of country-level BCG status on SARS-CoV2 cases or deaths. Univariable log-linear regression models showed a trend towards a weakening of the association over time. We found no statistical evidence for an association between BCG vaccination policy and either SARS-CoV2 morbidity or mortality. We urge countries to rather consider alternative tools with evidence supporting their effectiveness for controlling SARS-CoV2 morbidity and mortality

Exploring the promise and reality of ward-based primary healthcare outreach teams conducting TB household contact tracing in three districts of South Africa.

BACKGROUND: Tuberculosis (TB) household contact tracing is a form of targeted active case-finding for which community health workers ('outreach teams') in South Africa are primarily responsible for its implementation. We conducted an exploratory qualitative study to understand the role of outreach teams in delivering TB household contact tracing. METHODS: The study took place in three districts of South Africa between May 2016 and February 2017. We conducted 78 in-depth interviews (IDI) (comprising 35 key stakeholders, 31 TB index patients and 12 HHCs) and five focus group discussions (FGD) (40 outreach team members in four FGDs and 12 community stakeholders in one FGD). RESULTS: Outreach teams contributed positively by working across health-related programmes, providing home-based care and assisting with tracing of persons lost to TB care. However, outreach teams had a limited focus on TB household contact tracing activities, likely due to the broad scope of their work and insufficient programmatic support. Outreach teams often confused TB household contact tracing activities with finding persons lost to TB care. The community also had some reservations on the role of outreach teams conducting TB household contact tracing activities. CONCLUSIONS: Creating awareness among outreach workers and clinic personnel about the importance of and activities related to TB household contact tracing would be required to strengthen the delivery of TB household contact tracing through the community-based primary health care teams. We need better monitoring and evaluation systems, stronger integration within a realistic scope of work, adequate training on TB household contact tracing and TB infection prevention control measures. Involving the community and educating them on the role of outreach teams could improve acceptance of future activities. These timely results and lessons learned should inform contact tracing approaches in the context of COVID-19

Scaling up evidence-based approaches to tuberculosis screening in prisons

People deprived of liberty have among the highest rates of tuberculosis globally. The incidence of tuberculosis is ten times greater than the incidence of tuberculosis in the general population. In 2021, WHO updated its guidance to strongly recommend systematic screening for tuberculosis in prisons and penitentiary systems. Which case-finding strategies should be adopted, and how to effectively implement these strategies in these settings, will be crucial questions facing ministries of health and justice. In this Viewpoint, we review the evidence base for tuberculosis screening and diagnostic strategies in prisons, highlighting promising approaches and knowledge gaps. Drawing upon past experiences of implementing active case-finding and care programmes in settings with a high tuberculosis burden, we discuss challenges and opportunities for improving the tuberculosis diagnosis and treatment cascade in these settings. We argue that improved transparency in reporting of tuberculosis notifications and outcomes in prisons and renewed focus and resourcing from WHO and other stakeholders will be crucial for building the commitment and investments needed from countries to address the continued crisis of tuberculosis in prisons

Performance of GeneXpert MTB/RIF for diagnosing tuberculosis among symptomatic household contacts of index patients in South Africa

Background We describe the performance of GeneXpert MTB/RIF (Xpert) for diagnosing tuberculosis (TB) among symptomatic household contacts (HHCs) of rifampicin-resistant and drug-sensitive index cases. Methods We conducted a cross-sectional study among HHCs of recently diagnosed (<2 weeks) smear-positive and Xpert-positive index cases in the Bojanala District, South Africa. The HHCs were screened for TB symptoms; persons with ≥1 TB symptom provided 1 sputum for smear microscopy, Xpert, and mycobacterial growth indicator tube (MGIT) culture. Diagnostic test performance of Xpert was determined using MGIT as the reference standard. Results From August 2013 to July 2015, 619 HHCs from 216 index cases were enrolled: 60.6% were female, median age was 22 years (interquartile range, 9–40), and 126 (20.4%) self-reported/tested human immunodeficiency virus positive. A total of 54.3% (336 of 619) of contacts had ≥1 TB symptom (cough, fever, night sweats, weight loss), 297 of 336 (88.4%) of which provided a sputum; 289 (97.3%) had complete testing and 271 were included in the analysis. In total, 42 (6.8%) of 619 HHCs had microbiologically confirmed TB. The MGIT identified 33 HHCs as positive for Mycobacterium tuberculosis; of these, 7 were positive on Xpert resulting in a sensitivity of 21.2% (95% confidence interval [CI], 9.0–38.9), specificity of 98.3% (95% CI, 95.6–99.5), positive predictive value of 63.6% (95% CI, 30.8–89.1), and negative predictive value of 90.0 (95% CI, 85.7–93.4). Conclusions Among symptomatic HHCs investigated for TB, Xpert performed suboptimally compared with MGIT culture. The poor performance of Xpert for diagnosing TB suggests that a more sensitive test, such a Xpert Ultra or culture, may be needed to improve yield of contact investigation, where feasible

Qualitative study exploring the feasibility of using medication monitors and a differentiated care approach to support adherence among people receiving TB treatment in South Africa

OBJECTIVES: The tuberculosis (TB) MATE study evaluated whether a differentiated care approach (DCA) based on tablet-taking data from Wisepill evriMED digital adherence technology could improve TB treatment adherence. The DCA entailed a stepwise increase in adherence support starting from short message service (SMS) to phone calls, followed by home visits and motivational counselling. We explored feasibility of this approach with providers in implementing clinics. DESIGN: Between June 2020 and February 2021, in-depth interviews were conducted in the provider's preferred language, audiorecorded, transcribed verbatim and translated. The interview guide included three categories: feasibility, system-level challenges and sustainability of the intervention. We assessed saturation and used thematic analysis. SETTING: Primary healthcare clinics in three provinces of South Africa. PARTICIPANTS: We conducted 25 interviews with 18 staff and 7 stakeholders. RESULTS: Three major themes emerged: First, providers were supportive of the intervention being integrated into the TB programme and were eager to be trained on the device as it helped to monitor treatment adherence. Second, there were challenges in the adoption system such as shortage of human resources which could serve as a barrier to information provision once the intervention is scaled up. Healthcare workers reported that some patients received incorrect SMS's due to delays in the system that contributed to distrust. Third, DCA was considered as a key aspect of the intervention by some staff and stakeholders since it allowed for support based on individual needs. CONCLUSIONS: It was feasible to monitor TB treatment adherence using the evriMED device and DCA. To ensure successful scale-up of the adherence support system, emphasis will need to be placed on ensuring that the device and the network operate optimally and continued support on adhering to treatment which will enable people with TB to take ownership of their treatment journey and help overcome TB-related stigma. TRIAL REGISTRATION NUMBER: Pan African Trial Registry PACTR201902681157721

A qualitative exploration into the presence of TB stigmatization across three districts in South Africa

BACKGROUND: Tuberculosis (TB) stigma is a barrier to active case finding and delivery of care in fighting the TB epidemic. As part of a project exploring different models for delivery of TB contact tracing, we conducted a qualitative analysis to explore the presence of TB stigma within communities across South Africa. METHODS: We conducted 43 in-depth interviews with 31 people with TB and 12 household contacts as well as five focus group discussions with 40 ward-based team members and 11 community stakeholders across three South African districts. RESULTS: TB stigma is driven and facilitated by fear of disease coupled with an understanding of TB/HIV duality and manifests as anticipated and internalized stigma. Individuals are marked with TB stigma verbally through gossip and visually through symptomatic identification or when accessing care in either TB-specific areas in health clinics or though ward-based outreach teams. Individuals' unique understanding of stigma influences how they seek care. CONCLUSION: TB stigma contributes to suboptimal case finding and care at the community level in South Africa. Interventions to combat stigma, such as community and individual education campaigns on TB treatment and transmission as well as the training of health care workers on stigma and stigmatization are needed to prevent discrimination and protect patient confidentiality

Comparing the performance of QuantiFERON-TB Gold Plus with QuantiFERON-TB Gold in-tube among highly TB exposed gold miners in South Africa

Background: QuantiFERON-TB-Gold-in-tube (QFT-GIT) is an interferon-gamma release assay (IGRA) used to diagnose latent tuberculosis infection. Limited data exists on performance of QuantiFERON-TB Gold-Plus (QFT-Plus), a next generation of IGRA that includes an additional antigen tube 2 (TB2) while excluding TB7.7 from antigen tube 1 (TB1), to measure TB specific CD4+ and CD8+ T lymphocytes responses. We compared the performance of QFT-Plus with QFT-GIT among highly TB exposed goldminers in South Africa. Methods: We enrolled HIV-negative goldminers in South Africa, aged ≥33 years with no prior history of TB disease or evidence of silicosis. Blood samples were collected for QFT-GIT and QFT-Plus. QFT-GIT was considered positive if TB1 tested positive; while QFT-Plus was positive if both or either TB1 or TB2 tested positive, as per manufacturer's recommendations. We compared the performance of QFT-Plus with QFT-GIT using Cohen’s Kappa. To assess the specific contribution of CD8+ T-cells, we used TB2−TB1 differential values as an indirect estimate. A cut-off value was set at 0.6. Logistic regression was used to identify factors associated with having TB2-TB1&gt;0.6 difference on QFT-Plus. Results: Of 349 enrolled participants, 304 had QFT-Plus and QFT-GIT results: 205 (68%) were positive on both assays; 83 (27%) were negative on both assays while 16 (5%) had discordant results. Overall, there was 94.7% (288/304) agreement between QFT-Plus and QFT-GIT (Kappa = 0.87). 214 had positive QFT-Plus result, of whom 202 [94.4%, median interquartile range (IQR): 3.06 (1.31, 7.00)] were positive on TB1 and 205 [95.8%, median (IQR): 3.25 (1.53, 8.02)] were positive on TB2. A TB2-TB1&gt;0.6 difference was observed in 16.4% (35/214), with some evidence of a difference by BMI; 14.9% (7/47), 9.8% (9/92) and 25.3% (19/75) for BMI of 18.5-24.9, 18.5-25 and &gt;30 kg/m2, respectively (P=0.03). Conclusion: In a population of HIV-negative goldminers, QFT-Plus showed high agreement with QFT-GIT, suggesting similar performance.</ns3:p

Comparing QuantiFERON-TB Gold Plus with QuantiFERON-TB Gold in-tube for diagnosis of latent tuberculosis infection among highly TB exposed gold miners in South Africa.

BACKGROUND: QuantiFERON-TB-Gold-in-tube (QFT-GIT) is an interferon-gamma release assay (IGRA) used to diagnose latent tuberculosis infection. Limited data exists on performance of QuantiFERON-TB Gold-Plus (QFT-Plus), a next generation of IGRA that includes an additional antigen tube 2 (TB2) while excluding TB7.7 from antigen tube 1 (TB1), to measure TB specific CD4+ and CD8+ T lymphocytes responses. We compared agreement between QFT-Plus and QFT-GIT among highly TB exposed goldminers in South Africa. METHODS: We enrolled HIV-negative goldminers in South Africa, aged ≥33 years with no prior history of TB disease or evidence of silicosis. Blood samples were collected for QFT-GIT and QFT-Plus. QFT-GIT was considered positive if TB1 tested positive; while QFT-Plus was positive if both or either TB1 or TB2 tested positive, as per manufacturer's recommendations. We compared the agreement between QFT-Plus and QFT-GIT using Cohen’s Kappa. To assess the specific contribution of CD8+ T-cells, we used TB2−TB1 differential values as an indirect estimate. A cut-off value was set at 0.6. Logistic regression was used to identify factors associated with having TB2-TB1>0.6 difference on QFT-Plus. RESULTS: Of 349 enrolled participants, 304 had QFT-Plus and QFT-GIT results: 205 (68%) were positive on both assays; 83 (27%) were negative on both assays while 16 (5%) had discordant results. Overall, there was 94.7% (288/304) agreement between QFT-Plus and QFT-GIT (Kappa = 0.87). 214 had positive QFT-Plus result, of whom 202 [94.4%, median interquartile range (IQR): 3.06 (1.31, 7.00)] were positive on TB1 and 205 [95.8%, median (IQR): 3.25 (1.53, 8.02)] were positive on TB2. A TB2-TB1>0.6 difference was observed in 16.4% (35/214), with some evidence of a difference by BMI; 14.9% (7/47), 9.8% (9/92) and 25.3% (19/75) for BMI of 18.5-24.9, 18.5-25 and >30 kg/m 2, respectively (P=0.03). CONCLUSION: In a population of HIV-negative goldminers, QFT-Plus showed high agreement with QFT-GIT, suggesting similar performance

Monocyte metabolic transcriptional programs associate with resistance to tuberculin skin test/interferon-γ release assay conversion.

After extensive exposure to Mycobacterium tuberculosis (Mtb), most individuals acquire latent Mtb infection (LTBI) defined by a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA). To identify mechanisms of resistance to Mtb infection, we compared transcriptional profiles from highly exposed contacts who resist TST/IGRA conversion (resisters, RSTRs) and controls with LTBI using RNAseq. Gene sets related to carbon metabolism and free fatty acid (FFA) transcriptional responses enriched across 2 independent cohorts suggesting RSTR and LTBI monocytes have distinct activation states. We compared intracellular Mtb replication in macrophages treated with FFAs and found that palmitic acid (PA), but not oleic acid (OA), enhanced Mtb intracellular growth. This PA activity correlated with its inhibition of proinflammatory cytokines in Mtb-infected cells. Mtb growth restriction in PA-treated macrophages was restored by activation of AMP kinase (AMPK), a central host metabolic regulator known to be inhibited by PA. Finally, we genotyped AMPK variants and found 7 SNPs in PRKAG2, which encodes the AMPK-γ subunit, that strongly associated with RSTR status. Taken together, RSTR and LTBI phenotypes are distinguished by FFA transcriptional programs and by genetic variation in a central metabolic regulator, which suggests immunometabolic pathways regulate TST/IGRA conversion