T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2–specific (SARS-CoV-2–specific) CD4 + T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non–COVID-19 patients. We showed that SARS-CoV-2–specific CD4 + T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1–mediated CD4 + T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2–specific CD4 + T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis –specific CD4 + T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2–specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.

Objectives To describe the presentation and outcome of SARS–CoV2 infection in an African setting of high non–communicable co–morbidity and also HIV–1 and tuberculosis prevalence. Design Case control analysis with cases stratified by HIV–1 and tuberculosis status. Setting A single–centre observational case–control study of adults admitted to a South African hospital with proven SARS–CoV–2 infection or alternative diagnosis. Participants 104 adults with RT–PCR–proven SARS–CoV2 infection of which 55 (52.9%) were male and 31 (29.8%) HIV–1 co–infected. 40 adults (35.7% male, 30.9% HIV–1 co–infected) admitted during the same period with no RT–PCR or serological evidence of SARS–CoV2 infection and assigned alternative diagnoses. Additional in vitro data from prior studies of 72 healthy controls and 118 HIV–1 uninfected and infected persons participants enrolled to a prior study with either immune evidence of tuberculosis sensitization but no symptoms or microbiologically confirmed pulmonary tuberculosis. Results Two or more co–morbidities were present in 57.7% of 104 RT–PCR proven COVID–19 presentations, the commonest being hypertension (48%), type 2 diabetes mellitus (39%), obesity (31%) but also HIV–1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS–CoV–2, clinical features could be dominated by either SARS–CoV–2 or tuberculosis: lymphopenia was exacerbated, and some markers of inflammation (D–dimer and ferritin) elevated in singly SARS–CoV–2 infected patients were even further elevated (p less than 0.05). HIV–1 and SARS–CoV2 co–infection resulted in lower absolute number and proportion of CD4 lymphocytes, with those in the lowest peripheral CD4 percentage strata exhibiting absent or lower antibody responses against SARS–CoV2. Death occurred in 30/104 (29%) of all COVID–19 patients and in 6/15 (40%) of patients with coincident SARS–CoV–2 and tuberculosis. Conclusions In this South African setting, HIV–1 and tuberculosis are common co–morbidities in patients presenting with COVID–19. In environments in which tuberculosis is common, SARS–CoV–2 and tuberculosis may co–exist with clinical presentation being typical of either disease. Clinical suspicion of exacerbation of co–existent tuberculosis accompanying SARS–CoV–2 should be high.

Background Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis. Materials and methods We performed a randomized parallel group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR). Results Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; intravenous, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 - 253). Rifampicin geometric mean AUC0-24 was 42.9 μg·h/mL (95% CI, 24.5 – 75.0) for standard dose; 295.2 μg·h/mL (95% CI, 189.9 – 458.8) for high dose oral; and 206.5 μg·h/mL (95% CI, 154.6 – 275.8) for intravenous administration. Rifampicin AUC0-24 GMR was 1.44 (90% CI, 0.84 - 2.21) and Cmax GMR was 0.89 (90% CI, 0.63 – 1.23) for high dose oral with respect to intravenous dosing. Conclusions Plasma rifampicin AUC0-24 was higher after an oral 35 mg/kg dose compared with intravenous administration at 20 mg/kg dose over the first few days of TB treatment. Findings support oral rifampicin dosing in future tuberculous meningitis trials.