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

Inequalities in the impact of COVID-19-associated disruptions on tuberculosis diagnosis by age and sex in 45 high TB burden countries

BACKGROUND: Tuberculosis remains a major public health priority and is the second leading cause of mortality from infectious disease worldwide. TB case detection rates are unacceptably low for men, the elderly and children. Disruptions in TB services due to the COVID-19 pandemic may have exacerbated these and other inequalities. METHODS: We modelled trends in age- and sex- disaggregated case notifications for all forms of new and relapse TB reported to the World Health Organization for 45 high TB, TB/HIV and MDR-TB burden countries from 2013 to 2019. We compared trend predicted notifications to observed notifications in 2020 to estimate the number of people with TB likely to have missed or delayed diagnosis. We estimated the risk ratio (RR) of missed or delayed TB diagnosis for children (aged < 15 years) or the elderly (aged ≥ 65 years) compared to adults (aged 15-64 years) and women compared to men (both aged ≥ 15 years) using a random-effects meta-analysis. RESULTS: An estimated 195,449 children (95% confidence interval, CI: 189,673-201,562, 37.8% of an expected 517,168), 1,126,133 adults (CI: 1,107,146-1,145,704, 21.8% of an expected 5,170,592) and 235,402 elderly (CI: 228,108-243,202, 28.5% of an expected 826,563) had a missed or delayed TB diagnosis in 2020. This included 511,546 women (CI: 499,623-523,869, 22.7%, of an expected 2,250,097) and 863,916 men (CI: 847,591-880,515, 23.0% of an expected 3,763,363). There was no evidence globally that the risk of having TB diagnosis missed or delayed was different for children and adults (RR: 1.09, CI: 0.41-2.91), the elderly and adults (RR: 1.40, CI: 0.62-3.16) or men and women (RR: 0.59, CI: 0.25-1.42). However, there was evidence of disparities in risk by age and/or sex in some WHO regions and in most countries. CONCLUSIONS: There is no evidence at an aggregate global level of any difference by age or sex in the risk of disruption to TB diagnosis as a result of the COVID-19 pandemic. However, in many countries, disruptions in TB services have been greater for some groups than others. It is important to recognise these context-specific inequalities when prioritising key populations for catch-up campaigns

Inequalities in the impact of COVID-19-associated disruptions on tuberculosis diagnosis by age and sex in 45 high TB burden countries

Background: Tuberculosis remains a major public health priority and is the second leading cause of mortality from infectious disease worldwide. TB case detection rates are unacceptably low for men, the elderly and children. Disruptions in TB services due to the COVID-19 pandemic may have exacerbated these and other inequalities. Methods: We modelled trends in age- and sex- disaggregated case notifications for all forms of new and relapse TB reported to the World Health Organization for 45 high TB, TB/HIV and MDR-TB burden countries from 2013 to 2019. We compared trend predicted notifications to observed notifications in 2020 to estimate the number of people with TB likely to have missed or delayed diagnosis. We estimated the risk ratio (RR) of missed or delayed TB diagnosis for children (aged < 15 years) or the elderly (aged ≥ 65 years) compared to adults (aged 15–64 years) and women compared to men (both aged ≥ 15 years) using a random-effects meta-analysis. Results: An estimated 195,449 children (95% confidence interval, CI: 189,673–201,562, 37.8% of an expected 517,168), 1,126,133 adults (CI: 1,107,146–1,145,704, 21.8% of an expected 5,170,592) and 235,402 elderly (CI: 228,108–243,202, 28.5% of an expected 826,563) had a missed or delayed TB diagnosis in 2020. This included 511,546 women (CI: 499,623–523,869, 22.7%, of an expected 2,250,097) and 863,916 men (CI: 847,591–880,515, 23.0% of an expected 3,763,363). There was no evidence globally that the risk of having TB diagnosis missed or delayed was different for children and adults (RR: 1.09, CI: 0.41–2.91), the elderly and adults (RR: 1.40, CI: 0.62–3.16) or men and women (RR: 0.59, CI: 0.25–1.42). However, there was evidence of disparities in risk by age and/or sex in some WHO regions and in most countries. Conclusions: There is no evidence at an aggregate global level of any difference by age or sex in the risk of disruption to TB diagnosis as a result of the COVID-19 pandemic. However, in many countries, disruptions in TB services have been greater for some groups than others. It is important to recognise these context-specific inequalities when prioritising key populations for catch-up campaigns

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

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

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

Effect of community-led delivery of HIV self-testing on HIV testing and antiretroviral therapy initiation in Malawi: A cluster-randomised trial

BACKGROUND: Undiagnosed HIV infection remains substantial in key population subgroups including adolescents, older adults, and men, driving ongoing transmission in sub-Saharan Africa. We evaluated the impact, safety, and costs of community-led delivery of HIV self-testing (HIVST), aiming to increase HIV testing in underserved subgroups and stimulate demand for antiretroviral therapy (ART). METHODS AND FINDINGS: This cluster-randomised trial, conducted between October 2018 and July 2019, used restricted randomisation (1:1) to allocate 30 group village head clusters in Mangochi district, Malawi to the community-led HIVST intervention in addition to the standard of care (SOC) or the SOC alone. The intervention involved mobilising community health groups to lead the design and implementation of 7-day HIVST campaigns, with cluster residents (≥15 years) eligible for HIVST. The primary outcome compared lifetime HIV testing among adolescents (15 to 19 years) between arms. Secondary outcomes compared: recent HIV testing (in the last 3 months) among older adults (≥40 years) and men; cumulative 6-month incidence of ART initiation per 100,000 population; knowledge of the preventive benefits of HIV treatment; and HIV testing stigma. Outcomes were measured through a post-intervention survey and at neighboring health facilities. Analysis used intention-to-treat for cluster-level outcomes. Community health groups delivered 24,316 oral fluid-based HIVST kits. The survey included 90.2% (3,960/4,388) of listed participants in the 15 community-led HIVST clusters and 89.2% (3,920/4,394) of listed participants in the 15 SOC clusters. Overall, the proportion of men was 39.0% (3,072/7,880). Most participants obtained primary-level education or below, were married, and reported a sexual partner. Lifetime HIV testing among adolescents was higher in the community-led HIVST arm (84.6%, 770/910) than the SOC arm (67.1%, 582/867; adjusted risk difference [RD] 15.2%, 95% CI 7.5% to 22.9%; p < 0.001), especially among 15 to 17 year olds and boys. Recent testing among older adults was also higher in the community-led HIVST arm (74.5%, 869/1,166) than the SOC arm (31.5%, 350/1,111; adjusted RD 42.1%, 95% CI 34.9% to 49.4%; p < 0.001). Similarly, the proportions of recently tested men were 74.6% (1,177/1,577) and 33.9% (507/1,495) in the community-led HIVST and SOC arms, respectively (adjusted RD 40.2%, 95% CI 32.9% to 47.4%; p < 0.001). Knowledge of HIV treatment benefits and HIV testing stigma showed no differences between arms. Cumulative incidence of ART initiation was respectively 305.3 and 226.1 per 100,000 population in the community-led HIVST and SOC arms (RD 72.3, 95% CI -36.2 to 180.8; p = 0.18). In post hoc analysis, ART initiations in the 3-month post-intervention period were higher in the community-led HIVST arm than the SOC arm (RD 97.7, 95% CI 33.4 to 162.1; p = 0.004). HIVST uptake was 74.7% (2,956/3,960), with few adverse events (0.6%, 18/2,955) and at US$5.70 per HIVST kit distributed. The main limitations include the use of self-reported HIV testing outcomes and lack of baseline measurement for the primary outcome. CONCLUSIONS: In this study, we found that community-led HIVST was effective, safe, and affordable, with population impact and coverage rapidly realised at low cost. This approach could enable community HIV testing in high HIV prevalence settings and demonstrates potential for economies of scale and scope. TRIAL REGISTRATION: Clinicaltrials.gov NCT03541382

Impact of COVID-19 on tuberculosis notifications in Blantyre Malawi: an interrupted time series analysis and qualitative study with healthcare workers.

COVID-19 may impact on tuberculosis (TB) diagnosis and care. We analysed a city-wide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi had no official “lockdown” but closed schools and borders on 23 March 2020. In interrupted time series analysis, there was an immediate 35.9% reduction in TB notifications (95% CI 22.0 to 47.3%) in April, which recovered to near pre-pandemic numbers by December 2020, but with 333 (95% CI 291 to 375) fewer cumulative notifications than anticipated. Women and girls were impacted (30.7% fewer cases, 95% CI 28.4 to 33.0%) more than men and boys (20.9% fewer, 95% CI 18.5 to 23.3). Fear of COVID-19 infection, temporary facility closure, inadequate protective equipment and COVID-19 stigma with similar presenting symptoms to TB were mentioned. Public health measures could benefit both TB and COVID-19, but only if diagnostic services remain accessible and are considered safe to attend

Prevalence of bacteriologically-confirmed pulmonary tuberculosis in urban Blantyre, Malawi 2019-20: substantial decline compared to 2013-14 national survey

Recent evidence shows rapidly changing tuberculosis (TB) epidemiology in Southern and Eastern Africa, with need for subdistrict prevalence estimates to guide targeted interventions. We conducted a pulmonary TB prevalence survey to estimate current TB burden in Blantyre city, Malawi. From May 2019 to March 2020, 115 households in middle/high-density residential Blantyre, were randomly-selected from each of 72 clusters. Consenting eligible participants (household residents ≥ 18 years) were interviewed, including for cough (any duration), and offered HIV testing and chest X-ray; participants with cough and/or abnormal X-ray provided two sputum samples for microscopy, Xpert MTB/Rif and mycobacterial culture. TB disease prevalence and risk factors for prevalent TB were calculated using complete-case analysis, multiple imputation, and inverse probability weighting. Of 20,899 eligible adults, 15,897 (76%) were interviewed, 13,490/15,897 (85%) had X-ray, and 1,120/1,394 (80%) sputum-eligible participants produced at least one specimen, giving 15,318 complete cases (5,895, 38% men). 29/15,318 had bacteriologically-confirmed TB (189 per 100,000 complete-case (cc) / 150 per 100,000 with inverse weighting (iw)). Men had higher burden (cc: 305 [95% CI:144–645] per 100,000) than women (cc: 117 [95% CI:65–211] per 100,000): cc adjusted odds ratio (aOR) 2.70 (1.26–5.78). Other significant risk factors for prevalent TB on complete-case analysis were working age (25–49 years) and previous TB treatment, but not HIV status. Multivariable analysis of imputed data was limited by small numbers, but previous TB and age group 25–49 years remained significantly associated with higher TB prevalence. Pulmonary TB prevalence for Blantyre was considerably lower than the 1,014 per 100,000 for urban Malawi in the 2013–14 national survey, at 150–189 per 100,000 adults, but some groups, notably men, remain disproportionately affected. TB case-finding is still needed for TB elimination in Blantyre, and similar urban centres, but should focus on reaching the highest risk groups, such as older men