The Students' Health and Welfare Centres Organisation (SHAWCO) is a student-run non-profit community development organisation based at the University of Cape Town (UCT). In 2012 SHAWCO celebrates its 69th anniversary, making it the oldest active student-run free clinic in South Africa. Over the past 7 decades, SHAWCO has become an integral part of UCT's Faculty of Health Sciences. This article reviews its history, current activities, and plans for the future.
Introduction Multisystem inflammatory syndrome in children (MIS-C) is a severe acute inflammatory reaction to SARS-CoV-2 infection in children. There is a lack of data describing differential expression of immune genes in MIS-C compared to healthy children or those with other inflammatory conditions and how expression changes over time. In this study, we investigated expression of immune-related genes in South African MIS-C patients and controls. Methods The cohort included 30 pre-treatment MIS-C cases and 54 healthy non-inflammatory paediatric controls. Other controls included 34 patients with juvenile systemic lupus erythematosus, Kawasaki disease or other inflammatory conditions. Longitudinal post-treatment MIS-C specimens were available at various timepoints. Expression of 80 immune-related genes was determined by real-time quantitative PCR. Results A total of 29 differentially expressed genes were identified in pre-treatment MIS-C compared to healthy controls. Up-regulated genes were found to be overrepresented in innate immune pathways including interleukin-1 processing and pyroptosis. Post-treatment follow-up data were available for up to 1,200 hours after first treatment. All down-regulated genes and 17/18 up-regulated genes resolved to normal levels in the timeframe, and all patients clinically recovered. When comparing MIS-C to other febrile conditions, only IL27 expression could differentiate these two groups with high sensitivity and specificity. Conclusions These data indicate a unique 29-gene signature of MIS-C in South African children. The up-regulation of interleukin-1 and pyroptosis pathway genes highlights the role of the innate immune system in MIS-C. IL-27 is a potent anti-inflammatory and antiviral cytokine that may distinguish MIS-C from other conditions in our setting.
Identification of individuals with tuberculosis for antibiotic treatment is a major component of the of WHO's End TB Strategy.1WHOThe End TB Strategy: global strategy and targets for tuberculosis prevention, care and control after 2015. World Health Organization, 2015https://www.who.int/tb/strategy/End_TB_Strategy.pdf?ua=1Date accessed: September 6, 2019Google Scholar Diagnostic tests for tuberculosis rely on detection of Mycobacterium tuberculosis in sputum expectorated by a person with productive cough. The search for new sputum-independent diagnostic tests is gaining momentum, as exemplified by advances in urine-based point-of-care lipoarabinomannan lateral flow assays for use in hospitalised patients with HIV.2Broger T Sossen B du Toit E et al.Novel lipoarabinomannan point-of-care tuberculosis test for people with HIV: a diagnostic accuracy study.Lancet Infect Dis. 2019; 19: 852-861Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar Active case-finding strategies are crucial for reducing transmission and achieving population-level tuberculosis control.3Dowdy DW Basu S Andrews JR Is passive diagnosis enough? The impact of subclinical disease on diagnostic strategies for tuberculosis.Am J Respir Crit Care Med. 2013; 187: 543-551Crossref PubMed Scopus (79) Google Scholar A non-sputum-based triage test that can identify individuals with undiagnosed disease for further clinical investigation could shorten the time to diagnosis and treatment. The response to this need has included extensive development of blood transcriptomic signatures as diagnostic or screening tests for tuberculosis.4Warsinske H Vashisht R Khatri P Host-response-based gene signatures for tuberculosis diagnosis: a systematic comparison of 16 signatures.PLoS Med. 2019; 16e1002786Crossref PubMed Scopus (81) Google Scholar Identification of asymptomatic individuals with subclinical and so-called incipient tuberculosis, who are at high risk of progression to active disease, has also gained momentum. However, available tests for M tuberculosis infection, the tuberculin skin test and interferon-γ release assay (IGRA), perform poorly as predictors of disease progression, with pooled positive predictive values of less than 3%.5Diel R Loddenkemper R Nienhaus A Predictive value of interferon-gamma release assays and tuberculin skin testing for progression from latent TB infection to disease state: a meta-analysis.Chest. 2012; 142: 63-75Summary Full Text Full Text PDF PubMed Scopus (212) Google Scholar Blood transcriptomic incipient tuberculosis signatures could have better accuracy6Zak DE Penn-Nicholson A Scriba TJ et al.A blood RNA signature for tuberculosis disease risk: a prospective cohort study.Lancet. 2016; 387: 2312-2322Summary Full Text Full Text PDF PubMed Scopus (481) Google Scholar and might allow targeted therapy to prevent disease before symptoms emerge and potentially stop transmission of M tuberculosis. Mathematical modelling suggests that a targeted preventive therapy strategy using IGRA at 30% screening coverage in South African adults without HIV infection could reduce tuberculosis incidence in 2035 by 39% (95% CI 31–48).7Sumner T Scriba TJ Penn-Nicholson A Hatherill M White RG Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy.Sci Rep. 2019; 911126Crossref PubMed Scopus (12) Google Scholar By comparison, a transcriptomic biomarker for incipient tuberculosis would reduce incidence by 20% (15–27).7Sumner T Scriba TJ Penn-Nicholson A Hatherill M White RG Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy.Sci Rep. 2019; 911126Crossref PubMed Scopus (12) Google Scholar However, more individuals would have to be treated per tuberculosis case averted with the IGRA (84 [59–123]) than with an incipient tuberculosis biomarker (49 [29–77]).7Sumner T Scriba TJ Penn-Nicholson A Hatherill M White RG Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy.Sci Rep. 2019; 911126Crossref PubMed Scopus (12) Google Scholar To maximise their effect, such strategies could be employed for mass screening in tuberculosis-endemic communities and targeted screening in high-risk groups, such as contacts of tuberculosis patients, previous tuberculosis cases, migrants, the homeless, HIV-infected, diabetic, and immunosuppressed individuals, prison inmates, and individuals residing in high density peri-urban slums. In The Lancet Respiratory Medicine, Rishi Gupta and colleagues8Gupta RK Turner CT Venturini C et al.Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis.Lancet Respir Med. 2020; (published online Jan 17)https://doi.org/10.1016/S2213-2600(19)30282-6Summary Full Text Full Text PDF Scopus (76) Google Scholar applied 17 published tuberculosis diagnostic and predictive mRNA signatures to pooled transcriptomic datasets from four published, longitudinal studies. Eight concise signatures differentiated samples with incipient tuberculosis from controls with very similar accuracy over a 2-year period. None of the signatures met the minimum performance criteria for an incipient tuberculosis test defined in a WHO target product profile,9WHOConsensus Meeting Report: Development of a Target Product Profile (TPP) and a framework for evaluation for a test for predicting progression from tuberculosis infection to active disease. World Health Organization, 2017http://apps.who.int/iris/handle/10665/259176Date accessed: September 6, 2019Google Scholar except when measured within 3 months of diagnosis. Waning transcriptomic signature accuracy when tested more than 3 months before diagnosis, but detection of signature positivity in some individuals up to 24 months before disease diagnosis, is consistent with the heterogenous duration of disease progression and the dynamic course of incipient and subclinical tuberculosis disease states between individuals. Disease progression and regression are also likely to occur in infected individuals,10Drain PK Bajema KL Dowdy D et al.Incipient and subclinical tuberculosis: a clinical review of early stages and progression of infection.Clin Microbiol Rev. 2018; 31: e00021-e00118Crossref PubMed Scopus (220) Google Scholar reducing the sensitivity and specificity of any test for disease progression. Given the spectrum of incipient and subclinical tuberculosis disease suggested by these scenarios, we question the achievability of a predictive test with sensitivity and specificity of more than 90% over a 24-month time horizon that are outlined as the optimal criteria in the target product profile. The study by Gupta and colleagues8Gupta RK Turner CT Venturini C et al.Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis.Lancet Respir Med. 2020; (published online Jan 17)https://doi.org/10.1016/S2213-2600(19)30282-6Summary Full Text Full Text PDF Scopus (76) Google Scholar informs rational selection of transcriptomic signatures for further development towards a point-of-care test. It also highlights the paucity of longitudinal cohort studies with incident tuberculosis cases on which analyses of incipient and subclinical tuberculosis biomarkers depend. The next step is assessment of the best performing biomarkers in prospective field studies that enrol participants without the stringent inclusion and exclusion criteria typically used in case-control studies, which might lead to selection biases and exaggerated test performance. Transcriptomic signature evaluation should also include individuals with previous tuberculosis disease, HIV infection, diabetes mellitus, and malnutrition and children and individuals from wider geographical distributions, to assess how these variables affect biomarker performance. Although RNA sequencing and microarrays are necessary for discovery, application of these signatures at the point-of-care will require cheaper and more tractable technologies. The Correlate of Risk Targeted Intervention Study (NCT02735590) addresses these points. Results from this randomised controlled trial of isoniazid and rifapentine therapy to prevent pulmonary tuberculosis in high-risk individuals identified by a PCR-based, transcriptomic signature are anticipated in early 2020. Feasibility and cost are major implementation hurdles for any biomarker and realisation of a mass screen-and-treat preventive strategy for tuberculosis will require new technologies that are able to process samples rapidly and at high throughput at the point of care. Targeted preventive therapy could have a substantial impact on tuberculosis incidence. Time will tell if host-response biomarkers of incipient tuberculosis could be incorporated into the WHO End TB Strategy. TJS is co-inventor of patents pending on the Zak16 and Suliman4 signatures that were assessed in the paper by Gupta and colleagues. SCM declares no competing interests. Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysisBlood transcriptional biomarkers reflect short-term risk of tuberculosis and only exceed WHO benchmarks if applied to 3–6-month intervals. Serial testing among carefully selected target groups might be required for optimal implementation of these biomarkers. Full-Text PDF Open Access
Rationale: South African adolescents carry a high tuberculosis disease burden. It is not known if schools are high-risk settings for Mycobacterium tuberculosis (MTB) transmission. Objectives: To detect airborne MTB genomic DNA in classrooms. Methods: We studied 72 classrooms occupied by 2,262 students in two South African schools. High-volume air filtration was performed for median 40 (interquartile range [IQR], 35-54) minutes and assayed by droplet digital PCR (ddPCR)-targeting MTB region of difference 9 (RD9), with concurrent CO2 concentration measurement. Classroom data were benchmarked against public health clinics. Students who consented to individual tuberculosis screening completed a questionnaire and sputum collection (Xpert MTB/RIF Ultra) if symptom positive. Poisson statistics were used for MTB RD9 copy quantification. Measurements and Main Results: ddPCR assays were positive in 13/72 (18.1%) classrooms and 4/39 (10.3%) clinic measurements (P = 0.276). Median ambient CO2 concentration was 886 (IQR, 747-1223) ppm in classrooms versus 490 (IQR, 405-587) ppm in clinics (P < 0.001). Average airborne concentration of MTB RD9 was 3.61 copies per 180,000 liters in classrooms versus 1.74 copies per 180,000 liters in clinics (P = 0.280). Across all classrooms, the average risk of an occupant inhaling one MTB RD9 copy was estimated as 0.71% during one standard lesson of 35 minutes. Among 1,836/2,262 (81.2%) students who consented to screening, 21/90 (23.3%) symptomatic students produced a sputum sample, of which one was Xpert MTB/RIF Ultra positive. Conclusions: Airborne MTB genomic DNA was detected frequently in high school classrooms. Instantaneous risk of classroom exposure was similar to the risk in public health clinics.
Background: Multiple host blood transcriptional signatures have been developed that show potential for further development as non-sputum triage tests for tuberculosis (TB). We aimed to compare the diagnostic accuracy of 20 candidate blood transcriptomic TB signatures and identify which ones most accurately differentiate between symptomatic patients with TB and those with other respiratory diseases (ORD).Methods: Study participants presenting for care with symptoms associated with TB were recruited from primary health care clinics in Ethiopia, Malawi, Namibia, Uganda, South Africa, and The Gambia. TB was diagnosed based on clinical, microbiological, and radiological findings. Transcriptomic signatures were measured in whole blood samples using microfluidic RT-qPCR; signature scores were computed from cycle threshold values. Diagnostic performance was benchmarked against the WHO Target Product Profile (TPP) for a non-sputum TB triage test.Results: Among 541 participants, 158 had definite, microbiologically-confirmed and 32 probable TB, while 389 participants had ORD. Nine signatures achieved equivalent performance (Satproedprai7: area under the curve, AUC 0.83 [95% CI 0.79-0.87], Jacobsen3: 0.83 [0.79-0.86]; Suliman2: 0.82 [0.78-0.86]; Roe1: 0.82 [0.78-0.86]; Kaforou22: 0.82 [0.78-0.86]; Sambarey10: 0.81 [0.77-0.85]; Duffy9: 0.81 [0.76-0.86]; Gliddon3: 0.8 [0.75-0.85]; and Suliman4 0.79 [0.75-0.84] for differentiating patients with ORD from all TB cases. With sensitivity benchmarked against the WHO TPP (90%), these nine signatures achieved specificities between 44% (95% CI 38-49) and 54% (49-59), which fall short of the TPP criteria. Factors associated with signature scores included HIV and country. Country-specific analyses showed that several signatures, such as Satproedprai7 and Penn-Nicholson6, met the minimal TPP criteria for a triage test in Ethiopia, Malawi, and South Africa.Conclusion: None of the signatures met the TPP criteria in a pooled analysis of all countries, but several signatures met the minimum criteria for a non-sputum TB triage test in some countries.Funding: Both AE-TBC and ScreenTB were funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) under the 1st and 2nd European & Developing Countries Clinical Trials Partnership Programmes respectively (Grant Agreement Numbers IP_2009_32040 and DRIA2014-311). This project was supported by the Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council (SAMRC) with funds received from the South African Department of Science and Technology.Declaration of Interest: GW and TJS report grants from the Bill & Melinda Gates Foundation during the conduct of the study. TJS and NNC report grants from the South African Medical Research Council during the conduct of the study. GW reports grants from the South African National Research Foundation and EDCTP. TJS has patents of the RISK11 (Darboe11), RISK6 (Penn-Nicholson6) and RISK4 (Suliman4) signatures issued. GW and NC have patents “TB diagnostic markers” (PCT/IB2013/ 054377), “Serum host biomarkers for tuberculosis disease” [PCT/IB2017/052142], “Method for diagnosing TB” (PCT/IB2017/052142) granted but receive no royalties on these patents. All other authors had nothing to disclose.Ethical Approval: Study protocols for the ScreenTB and AE-TBC studies were approved by the Health Research Ethics Committee of Stellenbosch University, and at all participating sites. All participants provided written, informed consent in accordance with the Declaration of Helsinki. The transcriptomic signatures sub-study protocol was reviewed and approved by the University of Cape Town HREC (589/2019).
Background: An effective adult vaccine is needed to control tuberculosis. We evaluated safety and immunogenicity of a live-attenuated Mycobacterium tuberculosis (Mtb) vaccine (MTBVAC).Methods: This randomized, double-blind, BCG-controlled, dose-escalation trial (NCT02933281) conducted between January 15, 2019, and September 07, 2020, enrolled previously BCG-vaccinated, HIV-negative, South African adults, aged 18-50 years, with/without Mtb sensitisation assessed by QuantiFERON-TB Gold-Plus assay (QFT). Participants were randomised (1:2) to BCG revaccination (5×10⁵ CFU dose; 24 QFT-negative, 24 QFT-positive) or MTBVAC (5×103, 5×104, 5×105, or 5x106 CFU doses; 12 QFT-negative, 12 QFT-positive). Safety outcomes included local and systemic adverse events (AE) within 7, 28, and 84 days and serious adverse events (SAE) within 365 days. Immunogenicity outcomes included frequencies of Th1 cytokine-expressing MTBVAC-specific CD4 T cells measured by intracellular cytokine staining and IFN- levels measured by QFT.Results: Among 485 volunteers screened,144 were enrolled (38.5% female). Injection site pain, discharge, erythema, and swelling increased with MTBVAC dose level. MTBVAC 5×105 CFU recipients reported a similar rate of related AE (23/24; 95.8%) as BCG recipients (45/47; 95.7%). QFT-positive MTBVAC recipients reported more injection site reactions [46/48; 95.5% (95%CI 85.7-99.5%)] than QFT-negative MTBVAC recipients [32/48; 66.6% (95%CI 51.6-79.6%)]. No vaccine-related SAE were reported. All doses of MTBVAC were immunogenic; vaccine-induced antigen-specific CD4 T cell responses peaked 28 days post-vaccination. MTBVAC 5×105 and 5×106 CFU doses induced Th1 cytokine-expressing CD4 T cell responses that exceeded BCG-induced responses in QFT-negative and QFT-positive participants. QFT conversion was observed at day 28 in >50% of baseline QFT-negative MTBVAC recipients vaccinated with the 3 highest doses of MTBVAC, but most reverted to QFT-negative by 365 days.Conclusion: MTBVAC showed safety and reactogenicity comparable to BCG at the 5×105 CFU dose. At an equivalent dose, MTBVAC was more immunogenic than BCG in adults with/without prior Mtb sensitisation.Trial Registration: Registered under the ClinicalTrials.gov Identifier NCT02933281.Funding: CDMRP and NIH of the US government.Declaration of Interest: noneEthical Approval: The University of Cape Town Human Research Ethics Committee and South African Health Products Regulatory Authority (SAHPRA) approved the study. Participants provided written, informed consent and were screened for eligibility within 28 days before randomization and vaccine administration.
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