Factors affecting tuberculosis health message recall 2 years after active case finding in Blantyre, Malawi.

SETTING: Urban slums, Blantyre, Malawi. OBJECTIVE: To explore tuberculosis (TB) community-wide active case finding (cwACF) recall and accompanying messaging 2 years after the intervention. DESIGN: This mixed-methods study used population-weighted random cluster sampling to select three cwACF-receiving and three non-cwACF-receiving neighbourhoods in Blantyre. Qualitative data were collected using 12 focus group discussions (community peer-group members) and five in-depth interviews (TB officers) with script guides based on the concepts of the Health Belief Model (HBM). Thematic analysis was used to explore transcripts employing deductive coding. Questionnaires completed by focus group participants were used to collect quantitative data, providing a 'knowledge score' evaluated through univariate/multivariate analysis, analysis of variance and multiple linear regression. RESULTS: Community peer-group participants (n = 118) retained high awareness and positive opinions of cwACF and recognised the relationship between early diagnosis and reduced transmission, considering cwACF to have prompted subsequent health-seeking behaviour. TB-affected individuals (personal/family: 47.5%) had significantly higher knowledge scores than unaffected individuals (P = 0.039), but only if resident in cwACF-receiving neighbourhoods (P = 0.005 vs. P = 0.582), implying effect modification between exposures, albeit statistically under-powered (P = 0.229). CONCLUSION: Consistent with epidemiological evidence and HBM theory, cwACF may have a permanent impact on knowledge and behaviour, particularly in communities with a high prevalence of TB-affected individuals. Behaviour change strategies should be explicitly included in cwACF planning and evaluation

High mortality and prevalence of HIV and tuberculosis in adults with chronic cough in Malawi: a cohort study.

BACKGROUND: Adults with suspected tuberculosis (TB) in health facilities in Africa have a high risk of death. The risk of death for adults with suspected TB at community-level is not known but may also be high. METHODS: Adults reporting cough of ⩾ 2 weeks (coughers) during a household census of 19,936 adults in a poor urban setting in Malawi were randomly sampled and age-frequency matched with adults without cough ⩾ 2 weeks (controls). At 12 months, participants were traced to establish vital status, offered human immunodeficiency virus (HIV) testing and investigated for TB if symptomatic (sputum for Xpert(®) MTB/RIF, smear microscopy and culture). RESULTS: Of 345 individuals with cough, 245 (71%) were traced, as were 243/345 (70.4%) controls. TB was diagnosed in 8.9% (16/178) of the coughers and 3.7% (7/187) of the controls (P = 0.039). HIV prevalence among coughers was 34.6% (56/162) and 18.8% (32/170) in controls (P = 0.005); of those who were HIV-positive, respectively 26.8% and 18.8% were newly diagnosed. The 12-month risk of death was 4.1% (10/245) in coughers and 2.5% (6/243) in controls (P = 0.317). CONCLUSION: Undiagnosed HIV and TB are common among adults with chronic cough, and mortality is high in this urban setting. Interventions that promote timely seeking of HIV and TB care are needed

Design and protocol for a cluster randomised trial of enhanced diagnostics for tuberculosis screening among people living with HIV in hospital in Malawi (CASTLE study)

BACKGROUND: People living with HIV (PLHIV) have a high risk of death if hospitalised in low-income countries. Tuberculosis has long been the leading cause of admission and death, in part due to suboptimal diagnostics. Two promising new diagnostic tools are digital chest Xray with computer-aided diagnosis (DCXR-CAD) and urine testing with Fujifilm SILVAMP LAM (FujiLAM). Neither test has been rigorously evaluated among inpatients. Test characteristics may be complementary, with FujiLAM especially sensitive for disseminated tuberculosis and DCXR-CAD especially sensitive for pulmonary tuberculosis, making combined interventions of interest. DESIGN AND METHODS: An exploratory unblinded, single site, two-arm cluster randomised controlled trial, with day of admission as the unit of randomisation. A third, smaller, integrated cohort arm (4:4:1 random allocation) contributes to understanding case-mix, but not trial outcomes. Participants are adults living with HIV not currently on TB treatment. The intervention (DCXR-CAD plus urine FujiLAM plus usual care) is compared to usual care alone. The primary outcome is proportion of participants started on tuberculosis treatment by day 56, with secondary outcomes of mortality (time to event) measured to to 56 days from enrolment, proportions with undiagnosed tuberculosis at death or hospital discharge and comparing proportions with enrolment-day tuberculosis treatment initiation. DISCUSSION: Both DCXR-CAD and FujiLAM have potential clinical utility and may have complementary diagnostic performance. To our knowledge, this is the first randomised trial to evaluate these tests among hospitalised PLHIV

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

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

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 intervention

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

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

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

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

Impact of community-wide tuberculosis active case finding and human immunodeficiency virus 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 human immunodeficiency virus (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 neighborhoods (“ACF areas”) in North-West Blantyre between April 2011 and August 2014. Many of these neighborhoods also had concurrent HIV testing interventions. The remaining neighborhoods in Blantyre City (“non-ACF areas”) provided a non-randomized 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. Results 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 3 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. Conclusions Tuberculosis ACF was associated with a rapid increase in people diagnosed with tuberculosis in Blantyre