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

Durations of asymptomatic, symptomatic, and care-seeking phases of tuberculosis disease with a Bayesian analysis of prevalence survey and notification data

This work was supported by the Wellcome Trust (206575/Z/17/Z to PM, 200901/Z/16/Z to ELC) and the UK MRC (MR/P022081/1 to PJD). This UK funded award (PJD) is part of the EDCTP2 programme supported by the European Union. KCH is supported by the European Research Council (757699) and UK FCDO (“Leaving no-one behind: transforming gendered pathways to health for TB”). This research has been partially funded by UK aid from the UK government (to KCH).Background Ratios of bacteriologically positive tuberculosis (TB) prevalence to notification rates are used to characterise typical durations of TB disease. However, this ignores the clinical spectrum of tuberculosis disease and potentially long infectious periods with minimal or no symptoms prior to care-seeking. Methods We developed novel statistical models to estimate progression from initial bacteriological positivity including smear conversion, symptom onset and initial care-seeking. Case-detection ratios, TB incidence, durations, and other parameters were estimated by fitting the model to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework using Markov chain Monte Carlo methods. Results Analysis across 11 national datasets found asymptomatic tuberculosis durations in the range 4–8 months for African countries; three countries in Asia (Cambodia, Lao PDR, and Philippines) showed longer durations of > 1 year. For the six countries with relevant data, care-seeking typically began half-way between symptom onset and notification. For Kenya and Blantyre, Malawi, individual-level data were available. The sex-specific durations of asymptomatic bacteriologically-positive tuberculosis were 9.0 months (95% credible interval [CrI]: 7.2–11.2) for men and 8.1 months (95% CrI: 6.2–10.3) for women in Kenya, and 4.9 months (95% CrI: 2.6–7.9) for men and 3.5 months (95% CrI: 1.3–6.2) for women in Blantyre. Age-stratified analysis of data for Kenya showed no strong age-dependence in durations. For Blantyre, HIV-stratified analysis estimated an asymptomatic duration of 1.3 months (95% CrI: 0.3–3.0) for HIV-positive people, shorter than the 8.5 months (95% CrI: 5.0–12.7) for HIV-negative people. Additionally, case-detection ratios were higher for people living with HIV than HIV-negative people (93% vs 71%). Conclusion Asymptomatic TB disease typically lasts around 6 months. We found no evidence of age-dependence, but much shorter durations among people living with HIV, and longer durations in some Asian settings. To eradicate TB transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions.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

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

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

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

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

Effects of coronavirus disease pandemic on tuberculosis notifications, Malawi

The coronavirus disease (COVID-19) pandemic might affect tuberculosis (TB) diagnosis and patient care. We analyzed a citywide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi did not have an official COVID-19 lockdown but closed schools and borders on March 23, 2020. In an interrupted time series analysis, we noted an immediate 35.9% reduction in TB notifications in April 2020; notifications recovered to near prepandemic numbers by December 2020. However, 333 fewer cumulative TB notifications were received than anticipated. Women and girls were affected more (30.7% fewer cases) than men and boys (20.9% fewer cases). Fear of COVID-19 infection, temporary facility closures, inadequate personal protective equipment, and COVID-19 stigma because of similar symptoms to TB were mentioned as reasons for fewer people being diagnosed with TB. Public health measures could benefit control of both TB and COVID-19, but only if TB diagnostic services remain accessible and are considered safe to attend.Peer reviewe

Pattern of abnormalities amongst chest X-rays of adults undergoing computer-assisted digital chest X-ray screening for tuberculosis in Peri-Urban Blantyre, Malawi: A cross-sectional study.

BACKGROUND: The prevalence of diseases other than tuberculosis (TB) detected during chest X-ray screening is poorly described in sub-Saharan Africa. Computer-assisted digital chest X-ray technology is available for TB screening and has the potential to be a screening tool for non-communicable diseases as well. Low- and middle-income countries are in a transition period where the burden of non-communicable diseases is increasing, but health systems are mainly focused on addressing infectious diseases. METHODS: Participants were adults undergoing computer-assisted chest X-ray screening for tuberculosis in a community-wide tuberculosis prevalence survey in Blantyre, Malawi. Adults with abnormal radiographs by field radiographer interpretation were evaluated by a physician in a community-based clinic. X-ray classifications were compared to classifications of a random sample of normal chest X-rays by radiographer interpretation. Radiographic features were classified using WHO Integrated Management for Adult Illnesses (IMAI) guidelines. All radiographs taken at the screening tent were analysed by the Qure.ai qXR v2.0 software. RESULTS: 5% (648/13,490) of adults who underwent chest radiography were identified to have an abnormal chest X-ray by the radiographer. 387 (59.7%) of the participants attended the X-ray clinic, and another 387 randomly sampled normal X-rays were available for comparison. Participants who were referred to the community clinic had a significantly higher HIV prevalence than those who had been identified to have a normal CXR by the field radiographer (90 [23.3%] vs. 43 [11.1%] p-value < 0.001). The commonest radiographic finding was cardiomegaly (20.7%, 95% CI 18.0-23.7). One in five (81/387) chest X-rays were misclassified by the radiographer. The overall mean Qure.ai qXR v2.0 score for all reviewed X-rays was 0.23 (SD 0.20). There was a high concordance of cardiomegaly classification between the physician and the computer-assisted software (109/118, 92.4%). CONCLUSION: There is a high burden of cardiomegaly on a chest X-ray at a community level, much of which is in patients with diabetes, heart disease and high blood pressure. Cardiomegaly on chest X-ray may be a potential tool for screening for cardiovascular NCDs at the primary care level as well as in the community

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