An autopsy study exploring the spectrum of disease in individuals with advanced HIV in primary care clinics in South Africa

Background and methods: Tuberculosis (TB) remains the leading reported cause of mortality among HIV-positive individuals in low- and middle-income countries (LMIC), but disease prevalence and cause-specific mortality data are based on estimates; reliable data are needed to track progress towards targets for reductions in TB and HIV-related deaths. The aim of this work was to estimate disease prevalence and causes of death (CoD) among people dying after enrolment to three large studies of TB and HIV in South Africa. Literature was systematically reviewed for autopsy studies estimating disease prevalence in HIV-positive adults; studies validating verbal autopsy (VA) for HIV and TB deaths; and studies directly estimating CoD in HIV-positive adults in LMIC. Primary data were collected concerning HIV-positive decedents from three parent studies and HIV-negative controls. Minimally-invasive autopsy (MIA), involving tissue biopsy, fluid aspiration, and bronchoalveolar lavage was conducted in a subset of HIV-positive decedents. CoD were assigned, through structured review of clinical and research data (“reference-standard”) and VA data, collected using the World Health Organization (WHO) 2012 instrument and interpreted using physician-certified (PCVA) and computer-coded VA (CCVA) methods (InterVA-4 and SmartVA-Analyze). VA-assigned and reference-standard CoD were compared; agreement was measured at individual- and population-level. Results: MIA was conducted for 34 HIV-positive adults: 16 (47%) had evidence of TB at autopsy, 14/16 (88%) had evidence of extrapulmonary disease, and 6/16 (38%) had not been started on TB treatment; 23/34 (68%) had evidence of bacterial pneumonia and 20/34 (59%) had evidence of two or more concomitant infections. Most (94%) individuals who underwent MIA were assigned HIV-associated reference-standard CoD; this was underestimated by all three VA methods (PCVA 74% [chance-corrected concordance {CCC} 0.71], InterVA-4 47% [CCC 0.42], and SmartVA-Analyze 41% [CCC 0.31]). Reference-standard CoD were assigned, without MIA data, to 259 HIV-positive adults: 183 (71%) were assigned HIV-associated causes. Only the PCVA estimate was similar, at 80% (CCC 0.78); InterVA-4 and SmartVA-Analyze underestimated the HIV-associated mortality fraction (estimates 48% and 29%; CCC 0.48 and 0.20, respectively). An autopsy study exploring the spectrum of disease in individuals with advanced HIV in primary care clinics in South Africa Agreement between VA methods and the reference-standard was poor at individual level (overall CCC ≤0.22) and slightly better at population level (cause-specific mortality fraction [CSMF] accuracy 0.43–0.79). Only PCVA could estimate the HIV-associated TB mortality fraction, underestimating it when compared with a reference standard that included autopsy data (reference 41% vs. PCVA 32%; CCC 0.23) and overestimating it when compared with a reference standard without autopsy data (reference 27% vs. PCVA 42%; CCC 0.42). Among 356 HIV-positive and 103 HIV-negative adults with confirmed HIV status, the VA instrument was sensitive (84.3%) and specific (94.2%) in assigning HIV status; VA methods showed high specificity (all methods >89%) in assigning HIV-associated CoD; and both CCVA methods underestimated the likely true HIV-associated mortality fraction among confirmed HIV-positive decedents (InterVA-4 44.7% and SmartVA-Analyze 22.5%). Conclusions: TB remains a leading CoD among HIV-positive adults in LMIC. Changes are needed to disease classification systems and automated VA methods to allow for better estimation of HIV-associated mortality overall and mortality due to HIV-associated TB. Structured guidelines for assigning CoD in HIV-positive people in clinical settings and the use of MIA at sentinel surveillance sites may be useful additions to current methods

All nonadherence is equal but is some more equal than others? Tuberculosis in the digital era

Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization's recommendation of the direct observation of treatment in the 1990s. Recent advances in digital adherence technologies (DATs) have renewed discussion on how to best address nonadherence, as well as offering important information on dose-by-dose adherence patterns and their variability between countries and settings. Previous studies have largely focussed on percentage thresholds to delineate sufficient adherence, but this is misleading and limited, given the complex and dynamic nature of adherence over the treatment course. Instead, we apply a standardised taxonomy – as adopted by the international adherence community – to dose-by-dose medication-taking data, which divides missed doses into 1) late/noninitiation (starting treatment later than expected/not starting), 2) discontinuation (ending treatment early), and 3) suboptimal implementation (intermittent missed doses). Using this taxonomy, we can consider the implications of different forms of nonadherence for intervention and regimen design. For example, can treatment regimens be adapted to increase the “forgiveness” of common patterns of suboptimal implementation to protect against treatment failure and the development of drug resistance? Is it reasonable to treat all missed doses of treatment as equally problematic and equally common when deploying DATs? Can DAT data be used to indicate the patients that need enhanced levels of support during their treatment course? Critically, we pinpoint key areas where knowledge regarding treatment adherence is sparse and impeding scientific progress

Prevalence of Mycobacterium tuberculosis in sputum and reported symptoms among clinic attendees compared to a community survey in rural South Africa

BACKGROUND: Tuberculosis (TB) case finding efforts typically target symptomatic people attending health facilities. We compared the prevalence of Mycobacterium tuberculosis (Mtb) sputum culture-positivity among adult clinic attendees in rural South Africa with a concurrent, community-based estimate from the surrounding demographic surveillance area (DSA). METHODS: Clinic: Randomly-selected adults (≥18 years) attending two primary healthcare clinics were interviewed and requested to give sputum for mycobacterial culture. HIV and antiretroviral therapy (ART) status were based on self-report and record review. Community: All adult (≥15 years) DSA residents were invited to a mobile clinic for health screening, including serological HIV testing; those with ≥1 TB symptom (cough, weight loss, night sweats, fever) or abnormal chest radiograph were asked for sputum. RESULTS: Clinic: 2,055 patients were enrolled (76.9% female, median age 36 years); 1,479 (72.0%) were classified HIV-positive (98.9% on ART) and 131 (6.4%) reported ≥1 TB symptom. Of 20/2,055 (1.0% [95% CI 0.6-1.5]) with Mtb culture-positive sputum, 14 (70%) reported no symptoms. Community: 10,320 residents were enrolled (68.3% female, median age 38 years); 3,105 (30.3%) tested HIV-positive (87.4% on ART) and 1,091 (10.6%) reported ≥1 TB symptom. Of 58/10,320 (0.6% [95% CI 0.4-0.7]) with Mtb culture-positive sputum, 45 (77.6%) reported no symptoms.In both surveys, sputum culture positivity was associated with male sex and reporting >1 TB symptom. CONCLUSIONS: In both clinic and community settings, most participants with Mtb culture-positive sputum were asymptomatic. TB screening based only on symptoms will miss many people with active disease in both settings

A position statement and practical guide to the use of particulate filtering facepiece respirators (N95, FFP2, or equivalent) for South African health workers exposed to respiratory pathogens including Mycobacterium tuberculosis and SARS-CoV-2.

SUMMARY: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is transmitted mainly by aerosol in particles <10 µm that can remain suspended for hours before being inhaled. Because particulate filtering facepiece respirators ('respirators'; e.g. N95 masks) are more effective than surgical masks against bio-aerosols, many international organisations now recommend that health workers (HWs) wear a respirator when caring for individuals who may have COVID-19. In South Africa (SA), however, surgical masks are still recommended for the routine care of individuals with possible or confirmed COVID-19, with respirators reserved for so-called aerosol-generating procedures. In contrast, SA guidelines do recommend respirators for routine care of individuals with possible or confirmed tuberculosis (TB), which is also transmitted via aerosol. In health facilities in SA, distinguishing between TB and COVID-19 is challenging without examination and investigation, both of which may expose HWs to potentially infectious individuals. Symptom-based triage has limited utility in defining risk. Indeed, significant proportions of individuals with COVID-19 and/or pulmonary TB may not have symptoms and/or test negative. The prevalence of undiagnosed respiratory disease is therefore likely significant in many general clinical areas (e.g. waiting areas). Moreover, a proportion of HWs are HIV-positive and are at increased risk of severe COVID-19 and death. RECOMMENDATIONS: Sustained improvements in infection prevention and control (IPC) require reorganisation of systems to prioritise HW and patient safety. While this will take time, it is unacceptable to leave HWs exposed until such changes are made. We propose that the SA health system adopts a target of 'zero harm', aiming to eliminate transmission of respiratory pathogens to all individuals in every healthcare setting. Accordingly, we recommend: the use of respirators by all staff (clinical and non-clinical) during activities that involve contact or sharing air in indoor spaces with individuals who: (i) have not yet been clinically evaluated; or (ii) are thought or known to have TB and/or COVID-19 or other potentially harmful respiratory infections;the use of respirators that meet national and international manufacturing standards;evaluation of all respirators, at the least, by qualitative fit testing; andthe use of respirators as part of a 'package of care' in line with international IPC recommendations. We recognise that this will be challenging, not least due to global and national shortages of personal protective equipment (PPE). SA national policy around respiratory protective equipment enables a robust framework for manufacture and quality control and has been supported by local manufacturers and the Department of Trade, Industry and Competition. Respirator manufacturers should explore adaptations to improve comfort and reduce barriers to communication. Structural changes are needed urgently to improve the safety of health facilities: persistent advocacy and research around potential systems change remain essential

Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGO–Virgo run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate

Estimating ventilation rates in rooms with varying occupancy levels: Relevance for reducing transmission risk of airborne pathogens

BACKGROUND: In light of the role that airborne transmission plays in the spread of SARS-CoV-2, as well as the ongoing high global mortality from well-known airborne diseases such as tuberculosis and measles, there is an urgent need for practical ways of identifying congregate spaces where low ventilation levels contribute to high transmission risk. Poorly ventilated clinic spaces in particular may be high risk, due to the presence of both infectious and susceptible people. While relatively simple approaches to estimating ventilation rates exist, the approaches most frequently used in epidemiology cannot be used where occupancy varies, and so cannot be reliably applied in many of the types of spaces where they are most needed. METHODS: The aim of this study was to demonstrate the use of a non-steady state method to estimate the absolute ventilation rate, which can be applied in rooms where occupancy levels vary. We used data from a room in a primary healthcare clinic in a high TB and HIV prevalence setting, comprising indoor and outdoor carbon dioxide measurements and head counts (by age), taken over time. Two approaches were compared: approach 1 using a simple linear regression model and approach 2 using an ordinary differential equation model. RESULTS: The absolute ventilation rate, Q, using approach 1 was 2407 l/s [95% CI: 1632-3181] and Q from approach 2 was 2743 l/s [95% CI: 2139-4429]. CONCLUSIONS: We demonstrate two methods that can be used to estimate ventilation rate in busy congregate settings, such as clinic waiting rooms. Both approaches produced comparable results, however the simple linear regression method has the advantage of not requiring room volume measurements. These methods can be used to identify poorly-ventilated spaces, allowing measures to be taken to reduce the airborne transmission of pathogens such as Mycobacterium tuberculosis, measles, and SARS-CoV-2

Cryptococcal-related Mortality Despite Fluconazole Preemptive Treatment in a Cryptococcal Antigen Screen-and-Treat Program

Background Cryptococcal antigen (CrAg) screening and treatment with preemptive fluconazole reduces the incidence of clinically evident cryptococcal meningitis in individuals living with advanced human immunodeficiency virus (HIV) disease. However, mortality remains higher in CrAg-positive than in CrAg-negative patients with similar CD4+ T-lymphocyte counts. Methods We conducted a cohort study to investigate causes of morbidity and mortality during 6 months of follow-up among asymptomatic CrAg-positive and CrAg-negative (ratio of 1:2) patients living with HIV with CD4 counts <100 cells/µL attending 2 hospitals in Johannesburg, South Africa. When possible, minimally invasive autopsy (MIA) was performed on participants who died. Results Sixty-seven CrAg-positive and 134 CrAg-negative patients were enrolled. Death occurred in 17/67 (25%) CrAg-positive and 12/134 (9%) CrAg-negative participants (hazard ratio for death, adjusted for CD4 count, 3.0; 95% confidence interval, 1.4–6.7; P = .006). Cryptococcal disease was an immediate or contributing cause of death in 12/17 (71%) CrAg-positive participants. Postmortem cryptococcal meningitis and pulmonary cryptococcosis were identified at MIA in all 4 CrAg-positive participants, 3 of whom had negative cerebrospinal fluid CrAg tests from lumbar punctures (LPs) at the time of CrAg screening. Conclusions Cryptococcal disease was an important cause of mortality among asymptomatic CrAg-positive participants despite LPs to identify and treat those with subclinical cryptococcal meningitis and preemptive fluconazole for those without meningitis. Thorough investigation for cryptococcal disease with LPs and blood cultures, prompt ART initiation, and more intensive antifungals may reduce mortality among asymptomatic CrAg-positive patients identified through screening