Early morning urine collection to improve the sensitivity of LAM in hospitalised TB/HIV co-infected patients

Point-of-care detection of urine lipoarabinomannan (LAM) is a low-cost rapid TB diagnostic for use in HIV co-infected patients. However, its sensitivity in these patients is suboptimal. Strategies to improve its performance is a need. The hypothesis was that early morning urine (EMU), rather than random urine sampling, would improve LAM's sensitivity. Methods Recruitment process conducted between June 2012 and February 2014 for HIV-infected patients from four hospitals in Cape Town, South Africa presenting with possible TB (all patients initiated on TB treatment). Fresh random and early morning urine (EMU) samples (~10-30 ml) collected in sterile containers. Following the manufacturer's instructions, an Alere Determine® TB Lateral flow assay performed on each sample, using both grade 1 and 2 cut-points. A single sputum Xpert MTB/RIF and/or liquid TB culture was a reference standard. Those designated probable TB patients were sputum Xpert MTB/RIF and/ TB culture negative, but started on TB treatment

Linezolid interruption in patients with fluoroquinolone-resistant tuberculosis receiving a bedaquiline-based treatment regimen.

BACKGROUND: Treatment outcomes of patients with extensively drug-resistant tuberculosis (XDR-TB) are suboptimal and treatment options remain limited. Linezolid is associated with improved outcomes but also substantial toxicity, and details about the relationship between these are lacking from resource-poor HIV-endemic settings. METHODS: This was a prospective follow-up study of 63 South African XDR-TB patients (58.7% HIV-infected; median CD4 131 cells/μl) between 2014 and 2018. The frequency and severity of linezolid-associated adverse events and the impact on treatment outcomes were compared between linezolid interrupters and non-interrupters. RESULTS: Twenty-two patients (34.9%) discontinued or underwent dose reduction due to presumed linezolid-associated toxicity. Anaemia (77.3% vs. 7.3%; p< 0.001), peripheral neuropathy (63.6% vs. 14.6%; p= 0.003), and optic neuritis (18.2% vs. 9.8%; p= 0.34) occurred more frequently in linezolid interrupters than in non-interrupters. Anaemia, peripheral neuropathy, and optic neuritis occurred at a median of 5, 18, and 23 weeks, respectively, after treatment initiation. Linezolid interruption was not associated with unfavourable outcomes but was strongly associated with HIV co-infection (adjusted hazard ratio 4.831, 95% confidence interval 1.526-15.297; p= 0.007) and bacterial load (culture days to positivity; adjusted hazard ratio 0.824, 95% confidence interval 0.732- 0.927; p= 0.001). CONCLUSIONS: Linezolid-related treatment interruption is common, is strongly associated with HIV co-infection, and system-specific toxicity occurs within predictable time frames. These data inform the clinical management of patients with drug-resistant TB

A Human Lung Challenge Model to Evaluate the Safety and Immunogenicity of PPD and Live Bacillus Calmette-Guérin.

Rationale: A human model to better understand tuberculosis immunopathogenesis and facilitate vaccine development is urgently needed.Objectives: We evaluated the feasibility, safety, and immunogenicity of live bacillus Calmette-Guérin (BCG) in a lung-oriented controlled human infection model.Methods: We recruited 106 healthy South African participants with varying degrees of tuberculosis susceptibility. Live BCG, sterile PPD, and saline were bronchoscopically instilled into separate lung segments (n = 65). A control group (n = 34) underwent a single bronchoscopy without challenge. The primary outcome was safety. Cellular and antibody immune signatures were identified in BAL before and 3 days after challenge using flow cytometry, ELISA, RNA sequencing, and mass spectrometry.Measurements and Main Results: The frequency of adverse events was low (9.4%; n = 10), similar in the challenge versus control groups (P = 0.8), and all adverse events were mild and managed conservatively in an outpatient setting. The optimal PPD and BCG dose was 0.5 TU and 104 cfu, respectively, based on changes in BAL cellular profiles (P = 0.02) and antibody responses (P = 0.01) at incremental doses before versus after challenge. At 104 versus 103 cfu BCG, there was a significant increase in number of differentially expressed genes (367 vs. 3; P < 0.001) and dysregulated proteins (64 vs. 0; P < 0.001). Immune responses were highly setting specific (in vitro vs. in vivo) and compartment specific (BAL vs. blood) and localized to the challenged lung segments.Conclusions: A lung-oriented mycobacterial controlled human infection model using live BCG and PPD is feasible and safe. These data inform the study of tuberculosis immunopathogenesis and strategies for evaluation and development of tuberculosis vaccine candidates

The utility of high-flow nasal oxygen for severe COVID-19 pneumonia in a resource-constrained setting: A multi-centre prospective observational study.

BACKGROUND: The utility of heated and humidified high-flow nasal oxygen (HFNO) for severe COVID-19-related hypoxaemic respiratory failure (HRF), particularly in settings with limited access to intensive care unit (ICU) resources, remains unclear, and predictors of outcome have been poorly studied. METHODS: We included consecutive patients with COVID-19-related HRF treated with HFNO at two tertiary hospitals in Cape Town, South Africa. The primary outcome was the proportion of patients who were successfully weaned from HFNO, whilst failure comprised intubation or death on HFNO. FINDINGS: The median (IQR) arterial oxygen partial pressure to fraction inspired oxygen ratio (PaO2/FiO2) was 68 (54-92) in 293 enroled patients. Of these, 137/293 (47%) of patients [PaO2/FiO2 76 (63-93)] were successfully weaned from HFNO. The median duration of HFNO was 6 (3-9) in those successfully treated versus 2 (1-5) days in those who failed (p<0.001). A higher ratio of oxygen saturation/FiO2 to respiratory rate within 6 h (ROX-6 score) after HFNO commencement was associated with HFNO success (ROX-6; AHR 0.43, 0.31-0.60), as was use of steroids (AHR 0.35, 95%CI 0.19-0.64). A ROX-6 score of ≥3.7 was 80% predictive of successful weaning whilst ROX-6 ≤ 2.2 was 74% predictive of failure. In total, 139 patents (52%) survived to hospital discharge, whilst mortality amongst HFNO failures with outcomes was 129/140 (92%). INTERPRETATION: In a resource-constrained setting, HFNO for severe COVID-19 HRF is feasible and more almost half of those who receive it can be successfully weaned without the need for mechanical ventilation

Long-term outcomes of the global tuberculosis and COVID-19 co-infection cohort

Background: Longitudinal cohort data of patients with tuberculosis (TB) and coronavirus disease 2019 (COVID-19) are lacking. In our global study, we describe long-term outcomes of patients affected by TB and COVID-19. Methods: We collected data from 174 centres in 31 countries on all patients affected by COVID-19 and TB between 1 March 2020 and 30 September 2022. Patients were followed-up until cure, death or end of cohort time. All patients had TB and COVID-19; for analysis purposes, deaths were attributed to TB, COVID-19 or both. Survival analysis was performed using Cox proportional risk-regression models, and the log-rank test was used to compare survival and mortality attributed to TB, COVID-19 or both. Results: Overall, 788 patients with COVID-19 and TB (active or sequelae) were recruited from 31 countries, and 10.8% (n=85) died during the observation period. Survival was significantly lower among patients whose death was attributed to TB and COVID-19 versus those dying because of either TB or COVID-19 alone (p&lt;0.001). Significant adjusted risk factors for TB mortality were higher age (hazard ratio (HR) 1.05, 95% CI 1.03-1.07), HIV infection (HR 2.29, 95% CI 1.02-5.16) and invasive ventilation (HR 4.28, 95% CI 2.34-7.83). For COVID-19 mortality, the adjusted risks were higher age (HR 1.03, 95% CI 1.02-1.04), male sex (HR 2.21, 95% CI 1.24-3.91), oxygen requirement (HR 7.93, 95% CI 3.44-18.26) and invasive ventilation (HR 2.19, 95% CI 1.36-3.53). Conclusions: In our global cohort, death was the outcome in &gt;10% of patients with TB and COVID-19. A range of demographic and clinical predictors are associated with adverse outcomes

Risk factors for Coronavirus disease 2019 (Covid-19) death in a population cohort study from the Western Cape province, South Africa

Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector “active patients” (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates.Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70–2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81–4.04] and 1.51 [95% CI, 1.18–1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96–2.86); population attributable fraction 8.5% (95% CI, 6.1–11.1)

Early morning urine collection to improve urinary lateral flow LAM assay sensitivity in hospitalised patients with HIV-TB co-infection

Urine LAM testing has been approved by the WHO for use in hospitalised patients with advanced immunosuppression. However, sensitivity remains suboptimal. We therefore examined the incremental diagnostic sensitivity of early morning urine (EMU) versus random urine sampling using the Determine® lateral flow lipoarabinomannan assay (LF-LAM) in HIV-TB co-infected patients.Consenting HIV-infected inpatients, screened as part of a larger prospective randomized controlled trial, that were treated for TB, and could donate matched random and EMU samples were included. Thus paired sample were collected from the same patient, LF-LAM was graded using the pre-January 2014, with grade 1 and 2 manufacturer-designated cut-points (the latter designated grade 1 after January 2014). Single sputum Xpert-MTB/RIF and/or TB culture positivity served as the reference standard (definite TB). Those treated for TB but not meeting this standard were designated probable TB.123 HIV-infected patients commenced anti-TB treatment and provided matched random and EMU samples. 33% (41/123) and 67% (82/123) had definite and probable TB, respectively. Amongst those with definite TB LF-LAM sensitivity (95%CI), using the grade 2 cut-point, increased from 12% (5-24; 5/43) to 39% (26-54; 16/41) with random versus EMU, respectively (p = 0.005). Similarly, amongst probable TB, LF-LAM sensitivity increased from 10% (5-17; 8/83) to 24% (16-34; 20/82) (p = 0.001). LF-LAM specificity was not determined.This proof of concept study indicates that EMU could improve the sensitivity of LF-LAM in hospitalised TB-HIV co-infected patients. These data have implications for clinical practice