BackgroundDrug-resistant tuberculosis (DR-TB) is undermining TB control in South Africa. However, there are hardly any data about the cost of treating DR-TB in high burden settings despite such information being quintessential for the rational planning and allocation of resources by policy-makers, and to inform future cost-effectiveness analyses.MethodologyWe analysed the comparative 2011 United States dollar ($) cost of diagnosis and treatment of drug sensitive TB (DS-TB), MDR-TB and XDR-TB, based on National South African TB guidelines, from the perspective of the National TB Program using published clinical outcome data.Principal FindingsAssuming adherence to national DR-TB management guidelines, the per patient cost of XDR-TB was $26,392, four times greater than MDR-TB ($6772), and 103 times greater than drug-sensitive TB ($257). Despite DR-TB comprising only 2.2% of the case burden, it consumed ∼32% of the total estimated 2011 national TB budget of US $218 million. 45% and 25% of the DR-TB costs were attributed to anti-TB drugs and hospitalization, respectively. XDR-TB consumed 28% of the total DR-TB diagnosis and treatment costs. Laboratory testing and anti-TB drugs comprised the majority (71%) of MDR-TB costs while hospitalization and anti-TB drug costs comprised the majority (92%) of XDR-TB costs. A decentralized XDR-TB treatment programme could potentially reduce costs by $6930 (26%) per case and reduce the total amount spent on DR-TB by ∼7%.Conclusion/SignificanceAlthough DR-TB forms a very small proportion of the total case burden it consumes a disproportionate and substantial amount of South Africa’s total annual TB budget. These data inform rational resource allocation and selection of management strategies for DR-TB in high burden settings.

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In patients with TB the alveolar compartment is enriched for CD4(+) T-Regs. Peripheral blood-derived T-Regs decrease the ability of alveolar and monocyte-derived macrophages to restrict the growth of Mycobacterium tuberculosis in the presence of effector cells. Collectively, these data suggest that CD4(+)CD25(+)FoxP3(+) T-Regs subvert antimycobacterial immunity in human TB.

Abstractobjectives Successful point-of-care (POC) testing (completion of test-and-treat cycle in one patient encounter) has immense potential to reduce diagnostic and treatment delays, and improve patient and public health outcomes. We explored what tests are done and how in public/private, rural/urban hospitals and clinics in South Africa and whether they can ensure successful POC testing.methods This qualitative research study examined POC testing across major diseases in Cape Town, Durban and Eastern Cape. We conducted 101 semi-structured interviews and seven focus group discussions with doctors, nurses, community health workers, patients, laboratory technicians, policymakers, hospital managers and diagnostic manufacturers.results In South Africa, diagnostics are characterised by a centralised system. Most tests conducted on the spot can be made to work successfully as POC tests. The majority of public/private clinics and smaller hospitals send samples via couriers to centralised laboratories and retrieve results the same way, via internet, fax or phone. The main challenge to POC testing lies in transporting samples and results, while delays risk patient loss from diagnostic/treatment pathways. Strategies to deal with associated delays create new problems, such as artificially prolonged turnaround times, strains on human resources and quality of testing, compounding additional diagnostic and treatment delays.conclusions For POC testing to succeed, particular characteristics of diagnostic ecosystems and adaptations of professional practices to overcome associated challenges must be taken into account.

Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis. Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity. Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection ( n = 14) and healthy lung tissue from control subjects without tuberculosis ( n = 10). RNA sequencing, immunohistochemistry, and bacterial load determination were performed at each cavity position. Differentially expressed genes were normalized to control subjects without tuberculosis, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways. Measurements and Main Results: The median (range) lung cavity volume on positron emission tomography/computed tomography scans was 50 cm 3 (15–389 cm 3 ). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple proinflammatory pathways were upregulated in the cavity wall, whereas a downregulation “sink” in the central caseum–fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and nitrogen species production, retinoic acid–mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden ( r > 0.6), whereas T-helper effector systems did not. Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis –related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.

BackgroundPoint of care testing promises to reduce delays in diagnosing and initiating treatment for infectious diseases such as Human Immuno-deficiency Virus (HIV). In South Africa, decentralized HIV testing with rapid tests offers important lessons for point of care testing programs. Yet, little is known about the strategies of providers and clients to make HIV testing successful in settings short of equipment, human resources and space. We aimed at examining these strategies.MethodsThis paper is based on a larger qualitative study of diagnostic practices across major diseases and actors in homes, clinics, communities, hospitals and laboratories in South Africa. We conducted 101 semi-structured interviews and 7 focus group discussions with doctors, nurses, community health workers, patients, laboratory technicians, policymakers, hospital managers and manufacturers between September 2012 and June 2013 in Durban, Cape Town and Eastern Cape. The topics explored included diagnostic processes and challenges, understanding of diagnosis, and visions of ideal tests. For this paper, the data on HIV testing processes in clinics, communities and hospitals was used.ResultsStrategies to make HIV testing work at point of care involve overcoming constraints in equipment, spaces, human resources and workload and actively managing diagnostic processes. We grouped these strategies into subthemes: maintaining relationships, adapting testing guidelines and practices to stock-outs, to physical space, and to different clients, turning the test into a tool to reach another aim and turning the testing process into a tool to enhance adherence. These adaptive strategies are locally negotiated solutions, often ad-hoc, depending on personal commitment, relationships, human resources, physical space and referral systems. In the process, testing is redefined and repurposed. Not all of these repurposing acts are successful in ensuring a timely diagnosis. Some lead to disruptions, unnecessary testing or delays with at times unclear implications for quality of diagnosis.ConclusionTests shape relationships, professional roles and practices of users at point of care. At the same time, testing processes are dynamic and test results and processes take on new meanings for clients and providers. These insights are crucial for understanding the contexts within which diagnostic devices and policies need to function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-017-2353-6) contains supplementary material, which is available to authorized users.

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BackgroundThere are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear.MethodsWe reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis.ResultsOf 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR-TB patients were empirically treated with capreomycin. Capreomycin resistance decreased the odds of sputum culture conversion. In capreomycin sensitive and resistant persons combined weight at diagnosis was the only independent predictor for survival (p=<0.001). By contrast, HIV status and use of co-amoxicillin/clavulanic acid were independent predictors of mortality (p=<0.05). Capreomycin usage was not associated with survival or culture conversion when the analysis was restricted to those whose isolates were resistant to capreomycin.ConclusionIn South Africa the frequency of capreomycin conferring mutations was extremely high in XDR-TB isolates. In those with capreomycin resistance there appeared to be no therapeutic benefit of using capreomycin. These data inform susceptibility testing and the design of treatment regimens for XDR-TB in TB endemic settings.