Clinical, health systems and neighbourhood determinants of tuberculosis case fatality in urban Blantyre, Malawi : a multilevel epidemiological analysis of enhanced surveillance data

We investigated whether household to clinic distance was a risk factor for death on tuberculosis (TB) treatment in Malawi. Using enhanced TB surveillance data, we recorded all TB treatment initiations and outcomes between 2015 and 2018. Household locations were geolocated, and distances were measured by a straight line or shortest road network. We constructed Bayesian multi-level logistic regression models to investigate associations between distance and case fatality. A total of 479/4397 (10.9%) TB patients died. Greater distance was associated with higher (odds ratio (OR) 1.07 per kilometre (km) increase, 95% credible interval (CI) 0.99–1.16) odds of death in TB patients registered at the referral hospital, but not among TB patients registered at primary clinics (OR 0.98 per km increase, 95% CI 0.92–1.03). Age (OR 1.02 per year increase, 95% CI 1.01–1.02) and HIV-positive status (OR 2.21, 95% CI 1.73–2.85) were also associated with higher odds of death. Model estimates were similar for both distance measures. Distance was a risk factor for death among patients at the main referral hospital, likely due to delayed diagnosis and suboptimal healthcare access. To reduce mortality, targeted community TB screening interventions for TB disease and HIV, and expansion of novel sensitive diagnostic tests are required.Peer reviewe

Clinical, health systems and neighbourhood determinants of tuberculosis case fatality in urban Blantyre, Malawi: a multilevel epidemiological analysis of enhanced surveillance data

Abstract We investigated whether household to clinic distance was a risk factor for death on tuberculosis (TB) treatment in Malawi. Using enhanced TB surveillance data, we recorded all TB treatment initiations and outcomes between 2015 and 2018. Household locations were geolocated, and distances were measured by a straight line or shortest road network. We constructed Bayesian multi-level logistic regression models to investigate associations between distance and case fatality. A total of 479/4397 (10.9%) TB patients died. Greater distance was associated with higher (odds ratio (OR) 1.07 per kilometre (km) increase, 95% credible interval (CI) 0.99–1.16) odds of death in TB patients registered at the referral hospital, but not among TB patients registered at primary clinics (OR 0.98 per km increase, 95% CI 0.92–1.03). Age (OR 1.02 per year increase, 95% CI 1.01–1.02) and HIV-positive status (OR 2.21, 95% CI 1.73–2.85) were also associated with higher odds of death. Model estimates were similar for both distance measures. Distance was a risk factor for death among patients at the main referral hospital, likely due to delayed diagnosis and suboptimal healthcare access. To reduce mortality, targeted community TB screening interventions for TB disease and HIV, and expansion of novel sensitive diagnostic tests are required.</jats:p

Neighbourhood prevalence-to-notification ratios for adult bacteriologically-confirmed tuberculosis reveals hotspots of underdiagnosis in Blantyre, Malawi

Funding: This work was supported by two grants from Wellcome Trust (ELC grant number WT200901/Z/16/Z) and (PM grant number 200901/Z/16/Z). JRC was funded by UK Medical Research Council (MRC) programme grant MC_UU_00004/07. PJD was supported by a fellowship from the MRC (MR/P022081/1); this UK funded award was part of the EDCTP2 programme supported by the European Union. RMB was funded by Wellcome Trust (203905/16/Z). KCH was supported by the European Research Council (757699) and UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). TC was supported by US NIH R01 R01AI147854.Local information is needed to guide targeted interventions for respiratory infections such as tuberculosis (TB). Case notification rates (CNRs) are readily available, but systematically underestimate true disease burden in neighbourhoods with high diagnostic access barriers. We explored a novel approach, adjusting CNRs for under-notification (P:N ratio) using neighbourhood-level predictors of TB prevalence-to-notification ratios. We analysed data from 1) a citywide routine TB surveillance system including geolocation, confirmatory mycobacteriology, and clinical and demographic characteristics of all registering TB patients in Blantyre, Malawi during 2015–19, and 2) an adult TB prevalence survey done in 2019. In the prevalence survey, consenting adults from randomly selected households in 72 neighbourhoods had symptom-plus-chest X-ray screening, confirmed with sputum smear microscopy, Xpert MTB/Rif and culture. Bayesian multilevel models were used to estimate adjusted neighbourhood prevalence-to-notification ratios, based on summarised posterior draws from fitted adult bacteriologically-confirmed TB CNRs and prevalence. From 2015–19, adult bacteriologically-confirmed CNRs were 131 (479/371,834), 134 (539/415,226), 114 (519/463,707), 56 (283/517,860) and 46 (258/578,377) per 100,000 adults per annum, and 2019 bacteriologically-confirmed prevalence was 215 (29/13,490) per 100,000 adults. Lower educational achievement by household head and neighbourhood distance to TB clinic was negatively associated with CNRs. The mean neighbourhood P:N ratio was 4.49 (95% credible interval [CrI]: 0.98–11.91), consistent with underdiagnosis of TB, and was most pronounced in informal peri-urban neighbourhoods. Here we have demonstrated a method for the identification of neighbourhoods with high levels of under-diagnosis of TB without the requirement for a prevalence survey; this is important since prevalence surveys are expensive and logistically challenging. If confirmed, this approach may support more efficient and effective targeting of intensified TB and HIV case-finding interventions aiming to accelerate elimination of urban TB.Peer reviewe

Community-based active case-finding interventions for tuberculosis : a systematic review

This work was made possible through grants provided by the WHO Global TB Programme. RMB, ELC, and PM hold Wellcome fellowships: 203905/Z/16/Z (RMB), 200901/Z/16/Z (ELC), and 206575/Z/17/Z (PM). MR, LT, and HA are funded by part of the European and Developing Countries Clinical Trials Partnership 2 programme supported by the EU (grant number RIA2016S-1632-TREATS). AES is supported by a National Institutes of Health (NIH) grant K23AI140918.Background Community-based active case-finding interventions might identify and treat more people with tuberculosis disease than standard case detection. We aimed to assess whether active case-finding interventions can affect tuberculosis epidemiology in the wider community. Methods We did a systematic review by searching PubMed, Embase, Scopus, and Cochrane Library for studies that compared tuberculosis case notification rates, tuberculosis disease prevalence, or tuberculosis infection prevalence or incidence in children, between populations exposed and unexposed to active case-finding interventions. We included studies published in English between Jan 1, 1980, and April 13, 2020. Studies of active case-finding in the general population, in populations perceived to be at high risk for tuberculosis, and in closed settings were included, whereas studies of tuberculosis screening at health-care facilities, among household contacts, or among children only, and studies that screened fewer than 1000 people were excluded. To estimate effectiveness, we extracted or calculated case notification rates, prevalence of tuberculosis disease, and incidence or prevalence of tuberculosis infection in children, and compared ratios of these outcomes between groups that were exposed or not exposed to active case-finding interventions. Results 27 883 abstracts were screened and 988 articles underwent full text review. 28 studies contributed data for analysis of tuberculosis case notifications, nine for prevalence of tuberculosis disease, and two for incidence or prevalence of tuberculosis infection in children. In one cluster-randomised trial in South Africa and Zambia, an active case-finding intervention based on community mobilisation and sputum drop-off did not affect tuberculosis prevalence, whereas, in a cluster-randomised trial in Vietnam, an active case-finding intervention based on sputum tuberculosis tests for everyone reduced tuberculosis prevalence in the community. We found inconsistent, low-quality evidence that active case-finding might increase the number of cases of tuberculosis notified in populations with structural risk factors for tuberculosis. Interpretation Community-based active case-finding for tuberculosis might be effective in changing tuberculosis epidemiology and thereby improving population health if delivered with high coverage and intensity. If possible, active case-finding projects should incorporate a well designed, robust evaluation to contribute to the evidence base and help elucidate which delivery methods and diagnostic strategies are most effective. Funding WHO Global TB Programme.Peer reviewe

Tuberculosis diagnosis cascade in Blantyre, Malawi : a prospective cohort study

Wellcome Trust. PM is funded by Wellcome (206575/Z/17/Z). ELC is funded by Wellcome (200901/Z/16/Z). ELW received salary funding from the UK Medical Research Council (grant number MR/K012126/1), this award is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union.Background Tuberculosis (TB) control relies on early diagnosis and treatment. International guidelines recommend systematic TB screening at health facilities, but implementation is challenging. We investigated completion of recommended TB screening steps in Blantyre, Malawi. Methods A prospective cohort recruited adult outpatients attending Bangwe primary clinic. Entry interviews were linked to exit interviews. The proportion of participants progressing through each step of the diagnostic pathway were estimated. Factors associated with request for sputum were investigated using multivariable logistic regression. Results Of 5442 clinic attendances 2397 (44%) had exit interviews. In clinically indicated participants (n = 445) 256 (57.5%) were asked about cough, 36 (8.1%) were asked for sputum, 21 (4.7%) gave sputum and 1 (0.2%) received same-day results. Significant associations with request for sputum were: any TB symptom (aOR:3.20, 95%CI:2.02–5.06), increasing age (aOR:1.02, 95%CI:1.01–1.04 per year) and for HIV-negative participants only, a history of previous TB (aOR:3.37, 95%CI:1.45–7.81). Numbers requiring sputum tests (26/day) outnumbered diagnostic capacity (8–12/day). Conclusions Patients were lost at every stage of the TB care cascade, with same day sputum submission following all steps of the diagnosis cascade achieved in only 4.7% if clinically indicated. Infection control strategies should be implemented, with reporting on early steps of the TB care cascade formalised. High-throughput screening interventions, such as digital CXR, that can achieve same-day TB diagnosis are urgently needed to meet WHO End TB goals.Peer reviewe

Do community-based active case-finding interventions have indirect impacts on wider TB case detection and determinants of subsequent TB testing behaviour? A systematic review

Funding: This work was made possible through grants provided by the WHO Global TB Programme. RMB, ELC, and PM hold Wellcome fellowships: 203905/Z/16/Z (RMB), 200901/Z/16/Z (ELC), and 206575/Z/17/Z (PM). MR, LT, and HA are funded by part of the European and Developing Countries Clinical Trials Partnership 2 programme supported by the EU (grant number RIA2016S-1632-TREATS). AES is supported by a National Institutes of Health (NIH) grant K23AI140918. WHO facilitated discussions among authors at the design stage and contributed to this manuscript but had no role in the conduct or writing of the WHO review.Community-based active case-finding (ACF) may have important impacts on routine TB case-detection and subsequent patient-initiated diagnosis pathways, contributing “indirectly” to infectious diseases prevention and care. We investigated the impact of ACF beyond directly diagnosed patients for TB, using routine case-notification rate (CNR) ratios as a measure of indirect effect. We systematically searched for publications 01-Jan-1980 to 13-Apr-2020 reporting on community-based ACF interventions compared to a comparison group, together with review of linked manuscripts reporting knowledge, attitudes, and practices (KAP) outcomes or qualitative data on TB testing behaviour. We calculated CNR ratios of routine case-notifications (i.e. excluding cases identified directly through ACF) and compared proxy behavioural outcomes for both ACF and comparator communities. Full text manuscripts from 988 of 23,883 abstracts were screened for inclusion; 36 were eligible. Of these, 12 reported routine notification rates separately from ACF intervention-attributed rates, and one reported any proxy behavioural outcomes. Two further studies were identified from screening 1121 abstracts for linked KAP/qualitative manuscripts. 8/12 case-notification studies were considered at critical or serious risk of bias. 8/11 non-randomised studies reported bacteriologically-confirmed CNR ratios between 0.47 (95% CI:0.41–0.53) and 0.96 (95% CI:0.94–0.97), with 7/11 reporting all-form CNR ratios between 0.96 (95% CI:0.88–1.05) and 1.09 (95% CI:1.02–1.16). One high-quality randomised-controlled trial reported a ratio of 1.14 (95% CI 0.91–1.43). KAP/qualitative manuscripts provided insufficient evidence to establish the impact of ACF on subsequent TB testing behaviour. ACF interventions with routine CNR ratios >1 suggest an indirect effect on wider TB case-detection, potentially due to impact on subsequent TB testing behaviour through follow-up after a negative ACF test or increased TB knowledge. However, data on this type of impact are rarely collected. Evaluation of routine case-notification, testing and proxy behavioural outcomes in intervention and comparator communities should be included as standard methodology in future ACF campaign study designs.Peer reviewe

Community-based active-case finding for tuberculosis: navigating a complex minefield

Community-based active case finding (ACF) for tuberculosis (TB) involves an offer of screening to populations at risk of TB, oftentimes with additional health promotion, community engagement and health service strengthening. Recently updated World Health Organization TB screening guidelines conditionally recommend expanded offer of ACF for communities where the prevalence of undiagnosed pulmonary TB is greater than 0.5% among adults, or with other structural risk factors for TB. Subclinical TB is thought to be a major contributor to TB transmission, and ACF, particularly with chest X-ray screening, could lead to earlier diagnosis. However, the evidence base for the population-level impact of ACF is mixed, with effectiveness likely highly dependent on the screening approach used, the intensity with which ACF is delivered, and the success of community- and health-system participation. With recent changes in TB epidemiology due to the effective scale-up of treatment for HIV in Africa, the impacts of the COVID-19 pandemic, and the importance of subclinical TB, researchers and public health practitioners planning to implement ACF programmes must carefully and repeatedly consider the potential population and individual benefits and harms from these programmes. Here we synthesise evidence and experience from implementing ACF programmes to provide practical guidance, focusing on the selection of populations, screening algorithms, selecting outcomes, and monitoring and evaluation. With careful planning and substantial investment, community-based ACF for TB can be an impactful approach to accelerating progress towards elimination of TB in high-burden countries. However, ACF cannot and should not be a substitute for equitable access to responsive, affordable, accessible primary care services for all

Impact of community-wide tuberculosis active case finding and HIV testing on tuberculosis trends in Malawi

BACKGROUND: Tuberculosis case-finding interventions are critical to meeting World Health Organization End TB strategy goals. We investigated the impact of community-wide tuberculosis active case-finding (ACF) alongside scale-up of HIV testing and care on trends in adult tuberculosis case notification rates (CNRs) in Blantyre, Malawi. METHODS: Five rounds of ACF for tuberculosis (1-2 weeks of leafleting, door-to-door enquiry for cough and sputum microscopy) were delivered to neighbourhoods ("ACF areas") in North-West Blantyre between April 2011 and August 2014. Many of these neighborhoods also had concurrent HIV testing interventions. The remaining neighbourhoods in Blantyre City ("non-ACF areas") provided a non-randomised comparator. We analyzed TB CNRs from January 2009 until December 2018. We used interrupted time series analysis to compare tuberculosis CNRs before ACF and after ACF, and between ACF and non-ACF areas. FINDINGS: Tuberculosis CNRs increased in Blantyre concurrently with start of ACF for tuberculosis in both ACF and non-ACF areas, with a larger magnitude in ACF areas. Compared to a counterfactual where pre-ACF CNR trends continued during ACF period, we estimated there were an additional 101 (95% confidence interval [CI] 42 to 160) microbiologically confirmed (Bac+) tuberculosis diagnoses per 100,000 person-years in the ACF areas in three and a half years of ACF. Compared to a counterfactual where trends in ACF area were the same as trends in non-ACF areas, we estimated an additional 63 (95% CI 38 to 90) Bac+ diagnoses per 100,000 person-years in the same period. INTERPRETATION: Tuberculosis ACF was associated with a rapid increase in people diagnosed with tuberculosis in Blantyre

Tuberculosis Immunoreactivity Surveillance in Malawi (Timasamala)—A protocol for a cross-sectional Mycobacterium tuberculosis immunoreactivity survey in Blantyre, Malawi

Tuberculosis (TB) transmission and prevalence are dynamic over time, and heterogeneous within populations. Public health programmes therefore require up-to-date, accurate epidemiological data to appropriately allocate resources, target interventions, and track progress towards End TB goals. Current methods of TB surveillance often rely on case notifications, which are biased by access to healthcare, and TB disease prevalence surveys, which are highly resource-intensive, requiring many tens of thousands of people to be tested to identify high-risk groups or capture trends. Surveys of “latent TB infection”, or immunoreactivity to Mycobacterium tuberculosis (Mtb), using tests such as interferon-gamma release assays (IGRAs) could provide a way to identify TB transmission hotspots, supplementing information from disease notifications, and with greater spatial and temporal resolution than is possible to achieve in disease prevalence surveys. This cross-sectional survey will investigate the prevalence of Mtb immunoreactivity amongst young children, adolescents and adults in Blantyre, Malawi, a high HIV-prevalence city in southern Africa. Through this study we will estimate the annual risk of TB infection (ARTI) in Blantyre and explore individual- and area-level risk factors for infection, as well as investigating geospatial heterogeneity of Mtb infection (and its determinants), and comparing these to the distribution of TB disease case-notifications. We will also evaluate novel diagnostics for Mtb infection (QIAreach QFT) and sampling methodologies (convenience sampling in healthcare settings and community sampling based on satellite imagery), which may increase the feasibility of measuring Mtb infection at large scale. The overall aim is to provide high-resolution epidemiological data and provide new insights into methodologies which may be used by TB programmes globally

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century