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Tuberculosis (TB) remains the leading cause of hospitalization and in-hospital mortality in HIV-positive adults. Using data from hospital and clinic files, research databases, and autopsy, we describe causes and outcomes of admissions, and assess investigations for TB among adults with advanced HIV who were hospitalized after enrollment into the TB Fast Track trial in South Africa (2013–2015). A total of 251 adults [median CD4 count, 37.5 cells/μL; interquartile range, 14–68 cells/µL; 152 (60.6%) on antiretroviral therapy] experienced 304 admissions. Ninety-five of 251 of the first admissions (37.8%) were TB related; the next most common causes were AIDS-related illnesses (41 of 251, 16.3%) and surgical causes (21 of 251, 8.4%). Of those admitted with previously undiagnosed TB, 60% had CD4 counts less than 50 cells/µL. Overall, 137 of 251 individuals died as inpatients or within 90 days of their first discharge. Case fatality rates were particularly high for those admitted with TB (66%) and bacterial infections (80%). In 144 admissions for whom anti-TB treatment had not been started before admission, a sputum-based TB investigation was recorded in only 12 of 57 admissions (21.1%) in whom one or more TB symptom was recorded (24 of 57 started on treatment), and 6 of 87 admissions (6.9%) in whom no TB symptoms were recorded (14 of 87 started on treatment). Hospitalized adults with advanced HIV are at high risk of death. TB was a common cause of hospitalization but was under-investigated, even in those with symptoms. In addition to early identification of TB and other AIDS-related illnesses during hospitalization of adults with advanced HIV, improved pre-hospital management strategies are needed to interrupt disease progression and reduce poor outcomes in this already vulnerable population.

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.

BackgroundElevated rates of tuberculosis in healthcare workers demonstrate the high rate of Mycobacterium tuberculosis (Mtb) transmission in health facilities in high-burden settings. In the context of a project taking a whole systems approach to tuberculosis infection prevention and control (IPC), we aimed to evaluate the potential impact of conventional and novel IPC measures on Mtb transmission to patients and other clinic attendees.MethodsAn individual-based model of patient movements through clinics, ventilation in waiting areas, and Mtb transmission was developed, and parameterised using empirical data from eight clinics in two provinces in South Africa. Seven interventions—codeveloped with health professionals and policy-makers—were simulated: (1) queue management systems with outdoor waiting areas, (2) ultraviolet germicidal irradiation (UVGI) systems, (3) appointment systems, (4) opening windows and doors, (5) surgical mask wearing by clinic attendees, (6) simple clinic retrofits and (7) increased coverage of long antiretroviral therapy prescriptions and community medicine collection points through the Central Chronic Medicine Dispensing and Distribution (CCMDD) service.ResultsIn the model, (1) outdoor waiting areas reduced the transmission to clinic attendees by 83% (IQR 76%–88%), (2) UVGI by 77% (IQR 64%–85%), (3) appointment systems by 62% (IQR 45%–75%), (4) opening windows and doors by 55% (IQR 25%–72%), (5) masks by 47% (IQR 42%–50%), (6) clinic retrofits by 45% (IQR 16%–64%) and (7) increasing the coverage of CCMDD by 22% (IQR 12%–32%).ConclusionsThe majority of the interventions achieved median reductions in the rate of transmission to clinic attendees of at least 45%, meaning that a range of highly effective intervention options are available, that can be tailored to the local context. Measures that are not traditionally considered to be IPC interventions, such as appointment systems, may be as effective as more traditional IPC measures, such as mask wearing.

Background 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. Methods and findings 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. Conclusions 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. Trial registration Systematic review registration: PROSPERO 85226., Author summary Why was this study done? Though cited in many countries’ national guidance, the evidence that individuals with pulmonary tuberculosis (TB) are rendered non-infectious by 2 weeks of effective TB treatment is challenged. This systematic review was commissioned by the World Health Organization to provide evidence to inform TB infection prevention and control guidelines. We sought to synthesise the available data on the clearance of potentially infectious TB bacteria from the sputum of patients after starting effective treatment. What did the researchers do and find? We performed systematic searches of literature databases to identify relevant articles, using predetermined inclusion criteria. Extracted data were synthesised using narrative summaries and meta-analyses. A minority of patients had clearance of TB bacteria from sputum at 2 weeks of effective treatment, as assessed by either sputum smear or culture. As expected, the proportion having cleared TB bacteria from sputum increased over time; however, at 2 months of treatment 12% and 41% of patients still had viable TB bacteria present, as assessed by solid and liquid culture, respectively. What do these findings mean? The presence of viable TB bacteria in the sputum of pulmonary TB patients beyond 2 weeks of effective treatment suggests individuals may be infectious for longer than this interval. TB transmission requires the presence of viable mycobacteria in sputum and a mechanism for aerosol or droplet spread. Understanding how other factors, such as the presence of cough, change during treatment is also important for TB infection prevention and control.

Background 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. Results 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. Conclusions 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.

Maintaining adherence to treatment for tuberculosis (TB) is essential if the disease is to be eliminated. As part of formative research to develop an intervention to improve adherence, we documented the lived experiences of adults receiving anti-TB treatment (ATT) in three UK cities and examined how personal, social, and structural circumstances interacted to impact on individuals’ adherence to treatment. Using a topic guide that explored social circumstances and experiences of TB care, we conducted in-depth interviews with 18 adults (six women) who were being or had been treated for TB (patients) and four adults (all women) who were caring for a friend, relative, or partner being treated for TB (caregivers). We analysed transcripts using an adapted framework method that classified factors affecting adherence as personal, social, structural, health systems, or treatment-related. Eleven of 18 patients were born outside the UK (in South, Central, and East Asia, and Eastern and Southern Africa); among the seven who were UK-born, four were Black, Asian, or Minority Ethnic and three were White British. TB and its treatment were often disruptive: in addition to debilitating symptoms and side effects of ATT, participants faced job insecurity, unstable housing, stigma, social isolation, worsening mental health, and damaged relationships. Those who had a strong support network, stable employment, a routine that could easily be adapted, a trusting relationship with their TB team, and clear understanding of the need for treatment reported finding it easier to adhere to ATT. Changes in circumstances sometimes had dramatic effects on an individual’s ability to take ATT; participants described how the impact of certain acute events (e.g., the onset of side effects or fatigue, episodes of stigmatisation, loss of income) were amplified by their timing or through their interaction with other elements of the individual’s life. We suggest that the dynamic and fluctuating nature of these factors necessitates comprehensive and regular review of needs and potential problems, conducted before and during ATT; this, coupled with supportive measures that consider (and seek to mitigate) the influence of social and structural factors, may help improve adherence.

Summary: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is transmitted mainly by aerosol in particles

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., Digital adherence technologies (DATs) provide a wealth of information on dose-by-dose anti-TB medication-taking. Studies of DAT data should place nonadherence in standardised taxonomic frameworks in order to best inform intervention and regimen design. https://bit.ly/3jq1D8a

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.

BACKGROUND: In South Africa, it is generally estimated that only 0.5–0.6% of people's contacts occur in clinics. Both people with infectious tuberculosis and people with increased susceptibility to disease progression may spend more time in clinics, however, increasing the importance of clinic-based transmission to overall disease incidence.METHODS: We developed an illustrative mathematical model of Mycobacterium tuberculosis transmission in clinics and other settings. We assumed that 1% of contact time occurs in clinics. We varied the ratio of clinic contact time of human immunodeficiency virus (HIV) positive people compared to HIV-negative people, and of people with infectious TB compared to people without TB, while keeping the overall proportion of contact time occurring in clinics, and each person's total contact time, constant.RESULTS: With clinic contact rates respectively 10 and 5 times higher in HIV-positive people and people with TB, 10.7% (plausible range 8.5–13.4%) of TB resulted from transmission in clinics. With contact rates in HIV-positive people and people with TB respectively 5 and 2 times higher, 5.3% (plausible range 4.3–6.3%) of all TB was due to transmission in clinics.CONCLUSION: The small amount of contact time that generally occurs in clinics may greatly underestimate their contribution to TB disease in high TB-HIV burden settings.

Current estimates of the burden of tuberculosis (TB) disease and cause-specific mortality in human immunodeficiency virus (HIV) positive people rely heavily on indirect methods that are less reliable for ascertaining individual-level causes of death and on mathematical models. Minimally invasive autopsy (MIA) is useful for diagnosing infectious diseases, provides a reasonable proxy for the gold standard in cause of death ascertainment (complete diagnostic autopsy) and, used routinely, could improve cause-specific mortality estimates. From our experience in performing MIAs in HIV-positive adults in private mortuaries in South Africa (during theLes estimations actuelles du poids de la tuberculose (TB) maladie et de la mortalité qui lui est due parmi les patients positifs à l'infection par le virus de l'immunodéficience humaine (VIH) dépendent beaucoup de méthodes indirectes, qui sont moins fiables pour vérifier les causes de décès au niveau individuel et de modèles mathématiques. Une autopsie peu invasive (MIA) est utile au diagnostic de maladies infectieuses, fournit une approximation raisonnable de l'étalon or de la vérification de la cause du décès c'est-à-dire une autopsie diagnostique complète. Si elle est utilisée en routine, elle pourrait améliorer les estimations de mortalité spécifique d'une cause. A partir de nos expériences de MIA sur des adultes positifs au VIH dans des morgues privées d'Afrique du Sud (au cours de l'étudeLas estimaciones actuales de morbilidad por tuberculosis (TB) y de mortalidad por causas específicas en las personas positivas frente al virus de la inmunodeficiencia humana (VIH) se fundamentan en su mayor parte en métodos indirectos que son menos fiables para determinar las causas de muerte individuales y en modelizaciones matemáticas. La autopsia mínimamente invasiva (MIA) es útil en el diagnóstico de las enfermedades infecciosas, ofrece un sustituto aceptable al método de referencia para determinar la causa de muerte (que es la autopsia diagnóstica completa), y cuando se usa de manera sistemática, mejora las estimaciones de la mortalidad por causas específicas. A partir de su experiencia con la MIA en adultos con infección por el VIH en empresas fúnebres privadas en Suráfrica (durante el estudio

BACKGROUND: 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). METHODS AND FINDINGS: 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). CONCLUSIONS: 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.

Background: Adults being investigated for TB in South Africa experience high mortality, yet causes of death (CoD) are not well defined. We determined CoD in this population using verbal autopsy (VA), and compared HIV- and TB-associated CoD using physician-certified verbal autopsy (PCVA) and InterVA-4 software. Methods: All contactable consenting caregivers of participants who died during a trial comparing Xpert MTB/RIF to smear microscopy were interviewed using the WHO VA tool. CoD were assigned using PCVA and InterVA-4. Kappa statistic (K) and concordance correlation coefficient (CCC) were calculated for comparison. Results: Among 231 deaths, relatives of 137 deceased were interviewed. Of the 137 deceased 76 (55.4%) were males, median age 41 years (IQR 33-50). PCVA assigned 70 (51.1%) TB immediate CoD (44 [62.8%] pulmonary TB; 26 [37.1%] extra-pulmonary TB); 21 (15.3%) HIV/AIDS-related; and 46 (33.5%) other CoD. InterVA-4 assigned 48 (35.0%) TB deaths; 49 (35.7%) HIV/AIDS-related deaths; and 40 (29.1%) other CoD. Agreement between PCVA and InterVA-4 CoD was slight at individual level (K=0.20; 95% CI 0.10-0.30) and poor at population level (CCC 0.67; 95% CI 0.38-0.99). Conclusions: TB and HIV are leading CoD among adults being investigated for TB. PCVA and InterVA agreement at individual level was slight and poor at population level. VA methodology needs further development where TB and HIV are common.