The World Health Organization (WHO) aims to reduce tuberculosis (TB) deaths by 95% by 2035; tracking progress requires accurate measurement of TB mortality. International Classification of Diseases ...(ICD) codes do not differentiate between HIV-associated TB and HIV more generally. Verbal autopsy (VA) is used to estimate cause of death (CoD) patterns but has mostly been validated against a suboptimal gold standard for HIV and TB. This study, conducted among HIV-positive adults, aimed to estimate the accuracy of VA in ascertaining TB and HIV CoD when compared to a reference standard derived from a variety of clinical sources including, in some, minimally-invasive autopsy (MIA).
Decedents were enrolled into a trial of empirical TB treatment or a cohort exploring diagnostic algorithms for TB in South Africa. The WHO 2012 instrument was used; VA CoD were assigned using physician-certified VA (PCVA), InterVA-4, and SmartVA-Analyze. Reference CoD were assigned using MIA, research, and health facility data, as available. 259 VAs were completed: 147 (57%) decedents were female; median age was 39 (interquartile range IQR 33-47) years and CD4 count 51 (IQR 22-102) cells/μL. Compared to reference CoD that included MIA (n = 34), VA underestimated mortality due to HIV/AIDS (94% reference, 74% PCVA, 47% InterVA-4, and 41% SmartVA-Analyze; chance-corrected concordance CCC 0.71, 0.42, and 0.31, respectively) and HIV-associated TB (41% reference, 32% PCVA; CCC 0.23). For individual decedents, all VA methods agreed poorly with reference CoD that did not include MIA (n = 259; overall CCC 0.14, 0.06, and 0.15 for PCVA, InterVA-4, and SmartVA-Analyze); agreement was better at population level (cause-specific mortality fraction accuracy 0.78, 0.61, and 0.57, for the three methods, respectively).
Current VA methods underestimate mortality due to HIV-associated TB. ICD and VA methods need modifications that allow for more specific evaluation of HIV-related deaths and direct estimation of mortality due to HIV-associated TB.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Two weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous ...mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment.
For the main analysis, 2 systematic literature searches of OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted to identify studies with data on TB infectiousness (all studies to search date, 1 December 2017) and all randomised controlled trials (RCTs) for drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018). Included articles reported on patients receiving effective treatment for culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was sputum bacteriological conversion: the proportion of patients having converted by a defined time point or a summary measure of time to conversion, assessed by smear or culture. Any study design with 10 or more particpants was considered. Record sifting and data extraction were performed in duplicate. Random effects meta-analyses were performed. A narrative summary additionally describes the results of a systematic search for data evaluating infectiousness from humans to experimental animals (PubMed, all studies to 27 March 2018). Other evidence on duration of infectiousness-including studies reporting on cough dynamics, human tuberculin skin test conversion, or early bactericidal activity of TB treatments-was outside the scope of this review. The literature search was repeated on 22 November 2020, at the request of the editors, to identify studies published after the previous censor date. Four small studies reporting 3 different outcome measures were identified, which included no data that would alter the findings of the review; they are not included in the meta-analyses. Of 5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17 (39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12 (27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4 (9%) from Europe. Four studies reported data from multiple continents. Summary estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI 3%-24%, 1 single study N = 1), and 82% of patients at 2 months of treatment (95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88% at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N = 8). Significant heterogeneity was observed. Further interrogation of the data to explain this heterogeneity was limited by the lack of disaggregation of results, including by factors such as HIV status, baseline smear status, and the presence or absence of lung cavitation.
This systematic review found that most patients remained culture positive at 2 weeks of TB treatment, challenging the view that individuals are not infectious after this interval. Culture positivity is, however, only 1 component of infectiousness, with reduced cough frequency and aerosol generation after TB treatment initiation likely to also be important. Studies that integrate our findings with data on cough dynamics could provide a more complete perspective on potential transmission of Mycobacterium tuberculosis by individuals on treatment.
Systematic review registration: PROSPERO 85226.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Early mortality among HIV-positive adults starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis (TB) the leading cause of death. However, current methods ...to estimate TB-related deaths are inadequate and most autopsy studies do not adequately represent those attending primary health clinics (PHCs). This study aimed to determine the autopsy prevalence of TB and other infections in adults enrolled at South African PHCs in the context of a pragmatic trial of empiric TB treatment ("TB Fast Track").
Adults with CD4 ≤150 cells/μL, not on ART or TB treatment, were enrolled to TB Fast Track and followed up for at least six months. Minimally invasive autopsy (MIA) was conducted as soon as possible after death. Lungs, liver, and spleen were biopsied; blood, CSF, and urine aspirated; and bronchoalveolar lavage fluid obtained. Samples underwent mycobacterial, bacterial, and fungal culture; molecular testing (including Xpert® MTB/RIF); and histological examination. 34 MIAs were conducted: 18 (53%) decedents were female; median age was 39 (interquartile range 33-44) years; 25 (74%) deaths occurred in hospitals; median time from death to MIA was five (IQR 3-6) days. 16/34 (47%) had evidence of TB (14/16 88% with extrapulmonary disease; 6/16 38% not started on treatment antemortem); 23 (68%) had clinically important bacterial infections; four (12%) cryptococcal disease; three (9%) non-tuberculous mycobacterial disease; and two (6%) Pneumocystis pneumonia. Twenty decedents (59%) had evidence of two or more concurrent infections; 9/16 (56%) individuals with TB had evidence of bacterial disease and two (13%) cryptococcal disease.
TB, followed by bacterial infections, were the leading findings at autopsy among adults with advanced HIV enrolled from primary care clinics. To reduce mortality, strategies are needed to identify and direct those at highest risk into a structured pathway that includes expedited investigation and/or treatment of TB and other infections.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tuberculosis (TB) is a major public health concern in South Africa and TB-related mortality remains unacceptably high. Numerous clinical studies have examined the direct causes of TB-related ...mortality, but its wider, systemic drivers are less well understood. Applying systems thinking, we aimed to identify factors underlying TB mortality in South Africa and describe their relationships. At a meeting organised by the 'Optimising TB Treatment Outcomes' task team of the National TB Think Tank, we drew on the wide expertise of attendees to identify factors underlying TB mortality in South Africa. We generated a causal loop diagram to illustrate how these factors relate to each other.
Meeting attendees identified nine key variables: three 'drivers' (adequacy & availability of tools, implementation of guidelines, and the burden of bureaucracy); three 'links' (integration of health services, integration of data systems, and utilisation of prevention strategies); and three 'outcomes' (accessibility of services, patient empowerment, and socio-economic status). Through the development and refinement of the causal loop diagram, additional explanatory and linking variables were added and three important reinforcing loops identified. Loop 1, 'Leadership and management for outcomes' illustrated that poor leadership led to increased bureaucracy and reduced the accessibility of TB services, which increased TB-related mortality and reinforced poor leadership through patient empowerment. Loop 2, 'Prevention and structural determinants' describes the complex reinforcing loop between socio-economic status, patient empowerment, the poor uptake of TB and HIV prevention strategies and increasing TB mortality. Loop 3, 'System capacity' describes how fragmented leadership and limited resources compromise the workforce and the performance and accessibility of TB services, and how this negatively affects the demand for higher levels of stewardship.
Strengthening leadership, reducing bureaucracy, improving integration across all levels of the system, increasing health care worker support, and using windows of opportunity to target points of leverage within the South African health system are needed to both strengthen the system and reduce TB mortality. Further refinement of this model may allow for the identification of additional areas of intervention.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
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.
Asymptomatic cryptococcal antigenemia was a risk factor for mortality despite a screen-and-treat program with preemptive fluconazole treatment. Cryptococcal disease was a significant cause of death on the basis of clinical and autopsy evidence. Fluconazole monotherapy may be inadequate preemptive treatment.
Abstract
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 2 primary healthcare clinics were interviewed and requested to give sputum for mycobacterial culture. Human immunodeficiency virus (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: 2055 patients were enrolled (76.9% female; median age, 36 years); 1479 (72.0%) were classified HIV-positive (98.9% on ART) and 131 (6.4%) reported ≥1 TB symptom. Of 20/2055 (1.0% 95% CI, .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); 3105 (30.3%) tested HIV-positive (87.4% on ART) and 1091 (10.6%) reported ≥1 TB symptom. Of 58/10 320 (0.6% 95% CI, .4–.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.
In primary healthcare facilities and the surrounding community in rural South Africa, most people with Mycobacterium tuberculosisin sputum reported no symptoms. Tuberculosis case finding restricted to symptom screening in health facilities will miss many people with active disease.
Infection prevention and control (IPC) measures to reduce transmission of drug-resistant and drug-sensitive tuberculosis (TB) in health facilities are well described but poorly implemented. The ...implementation of TB IPC has been assessed primarily through quantitative and structured approaches that treat administrative, environmental, and personal protective measures as discrete entities. We present an on-going project entitled Umoya omuhle ("good air"), conducted in two provinces of South Africa, that adopts an interdisciplinary, 'whole systems' approach to problem analysis and intervention development for reducing nosocomial transmission of Mycobacterium tuberculosis (Mtb) through improved IPC. We suggest that TB IPC represents a complex intervention that is delivered within a dynamic context shaped by policy guidelines, health facility space, infrastructure, organisation of care, and management culture. Methods drawn from epidemiology, anthropology, and health policy and systems research enable rich contextual analysis of how nosocomial Mtb transmission occurs, as well as opportunities to address the problem holistically. A 'whole systems' approach can identify leverage points within the health facility infrastructure and organisation of care that can inform the design of interventions to reduce the risk of nosocomial Mtb transmission.
Abstract
Health system constraints are increasingly recognized as an important addition to model-based analyses of disease control interventions, as they affect achievable impact and scale. Enabling ...activities implemented alongside interventions to relax constraints and reach the intended coverage may incur additional costs, which should be considered in priority setting decisions. We explore the use of group model building, a participatory system dynamics modelling technique, for eliciting information from key stakeholders on the constraints that apply to tuberculosis infection prevention and control processes within primary healthcare clinics in South Africa. This information was used to design feasible interventions, including the necessary enablers to relax existing constraints. Intervention and enabler costs were then calculated at two clinics in KwaZulu-Natal using input prices and quantities from the published literature and local suppliers. Among the proposed interventions, the most inexpensive was retrofitting buildings to improve ventilation (US$1644 per year), followed by maximizing the use of community sites for medication collection among stable patients on antiretroviral therapy (ART; US$3753) and introducing appointments systems to reduce crowding (US$9302). Enablers identified included enhanced staff training, supervision and patient engagement activities to support behaviour change and local ownership. Several of the enablers identified by the stakeholders, such as obtaining building permissions or improving information flow between levels of the health systems, were not amenable to costing. Despite this limitation, an approach to costing rooted in system dynamics modelling can be successfully applied in economic evaluations to more accurately estimate the ‘real world’ opportunity cost of intervention options. Further empirical research applying this approach to different intervention types (e.g. new preventive technologies or diagnostics) may identify interventions that are not cost-effective in specific contexts based on the size of the required investment in enablers.
Abstract
Evidence is limited for infection prevention and control (IPC) measures reducing Mycobacterium tuberculosis (MTB) transmission in health facilities. This systematic review, 1 of 7 ...commissioned by the World Health Organization to inform the 2019 update of global tuberculosis (TB) IPC guidelines, asked: do triage and/or isolation and/or effective treatment of TB disease reduce MTB transmission in healthcare settings?
Of 25 included articles, 19 reported latent TB infection (LTBI) incidence in healthcare workers (HCWs; absolute risk reductions 1%–21%); 5 reported TB disease incidence in HCWs (no/slight high TB burden or moderate low burden reduction) and 2 in human immunodeficiency virus-positive in-patients (6%–29% reduction). In total, 23/25 studies implemented multiple IPC measures; effects of individual measures could not be disaggregated.
Packages of IPC measures appeared to reduce MTB transmission, but evidence for effectiveness of triage, isolation, or effective treatment, alone or in combination, was indirect and low quality. Harmonizing study designs and reporting frameworks will permit formal data syntheses and facilitate policy making.
Twenty-five articles were found. Most studies showed reduced latent tuberculosis infection or tuberculosis disease incidence after implementation of an intervention package, but evidence was weak for effectiveness of individual interventions. We make recommendations for future research to provide a better evidence base.
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