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Background TB is a leading cause of morbidity among HIV positive individuals. Accurate algorithms are needed to achieve early TB diagnosis and treatment. We investigated the use of Xpert MTB/RIF Ultra in combination with chest radiography for TB diagnosis in ambulatory HIV positive individuals. Methods This was a randomised controlled trial with a 2-by-2 factorial design. Outpatient HIV clinic attendees with cough were randomised to four arms: Arm 1—Standard Xpert/no chest radiography (CXR); Arm 2—Standard Xpert/CXR; Arm 3—Xpert Ultra/no CXR; and Arm 4—Xpert Ultra/CXR. Participants were followed up at days 28 and 56 to assess for TB treatment initiation. Results We randomised 640 participants. Bacteriologically confirmed TB treatment initiation at day 28 were: Arm 1 (8.4% [14/162]), Arm 2 (6.9% [11/159]), Arm 3 (8.2% [13/159]) and Arm 4 (5.6% [9/160]) and between Xpert Ultra group (Arms 3 and 4) (6.9% [22/319]) vs Standard Xpert group (Arms 1 and 2) (7.8% [25/321]), risk ratio 0.89 (95% CI 0.51 to 1.54). By day 56, there were also similar all-TB treatment initiations in the x-ray group (Arms 2 and 4) (16.0% [51/319]) compared with the no x-ray group (Arms 1 and 3) (13.1% [42/321]), risk ratio 1.22 (95% CI 0.84 to 1.78); however, the contribution of clinically diagnosed treatment initiations were higher in x-ray groups (50.9% vs 19.0%). Conclusions Xpert Ultra performed similarly to Xpert MTB/RIF. X-rays are useful for TB screening but further research should investigate how to mitigate false-positive treatment initiations.

Equitable access to tuberculosis testing is vital for achieving global treatment targets, but access to diagnostic services is often worse in poorer communities. The SCALE survey to estimate TB prevalence in Blantyre city, Malawi, also recorded engagement with TB services. We explored variation in self-reported TB testing history between 72 community clusters - adjusting for sex, age and HIV status - and investigated whether residual differences could be explained by household poverty. We observed substantial variation between clusters in the prevalence of ever-testing for TB, with little correlation between neighbouring clusters. Participants in poorer households had, on average, lower odds of ever-testing, yet adjusting for poverty did not reduce cluster-level variation. We conclude that, despite a decade of increased active case finding efforts, access to TB testing is inconsistent across the population of Blantyre, likely reflecting health inequities that also apply to TB testing in many other settings.

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 TB prevalence survey to estimate current TB burden in Blantyre city, Malawi. From May 2019 to March 2020, 215 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 1,120/1,395 (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.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.

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.

BACKGROUND Finding individuals with drug-resistant (DR) tuberculosis (TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge systematic reviews assessing effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown. OBJECTIVE We assessed the available literature on DR-TB case-finding strategies using standard scoping review methodology. METHODS We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for TB symptoms, patients already diagnosed with TB or were laboratory-based. We searched the academic databases of Medline (PubMed), Embase (Ovid), The Cochrane Library, Africa-Wide Information (EBSCOhost), CINAHL (EBSCOhost), Epistemonikos and PROSPERO using no language or date restrictions. We screened titles, abstracts, and full text articles in duplicate. Data extraction and analyses were done in Excel. RESULTS We screened 3,028 titles and abstracts and 177 full-text articles. We identified six systematic reviews and 44 primary studies. Five reviews described yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible and DR-TB contacts and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described the following: 26 contact investigations; 11 outbreak investigations; 3 airline contact investigations; 2 epidemiological analyses; 1 public-private partnership programme; and an e-registry programme. Primary studies were all descriptive and included cross-sectional and retrospective reviews of programme data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information. CONCLUSIONS Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardisation of terminology, design, and reporting of DR-TB case-finding studies. CLINICALTRIAL NCT05022238

Summary Background Suboptimal diagnostics for pulmonary tuberculosis drive the use of the so-called trial of antibiotics, a course of broad-spectrum antibiotics without activity against Mycobacterium tuberculosis that is given to patients who are mycobacteriology negative but symptomatic, with the aim of distinguishing pulmonary tuberculosis from bacterial lower respiratory tract infection. The underlying assumption—that patients with lower respiratory tract infection will improve, whereas those with pulmonary tuberculosis will not—has an unclear evidence base for such a widely used intervention (at least 26·5 million courses are prescribed per year). We aimed to collate available evidence on the diagnostic performance of the trial of antibiotics. Methods In this systematic review and meta-analysis we searched the MEDLINE, Embase, and Global Health databases for studies published up to March 15, 2019, that investigated the sensitivity and specificity of the trial of antibiotics against mycobacteriology tests in adults (≥15 years) with tuberculosis symptoms. We used the QUADAS-2 tool to assess the risk of bias. We estimated pooled values for sensitivity and specificity of trial of antibiotics (as the index text) versus mycobacteriology tests (as the reference standard) using random-effects bivariate modelling, and we used the I2 statistic to assess heterogeneity between studies contributing to these estimates. This study is registered with PROSPERO, number CRD42017083915. Findings Of the 9410 articles identified by our search, eight studies were eligible for inclusion. The studies were from seven countries in Africa, South America, and Asia, and involved 2786 participants. Six studies used mycobacterial culture as the reference standard, and six used penicillins for the trial of antibiotics. The treatment duration, number of antimicrobial courses, and definition of what constituted response to treatment varied substantially between studies. The pooled sensitivity (67%, 95% CI 42–85) and specificity (73%, 58–85) of the trial of antibiotics versus mycobacteriology tests were below internationally defined minimum performance profiles for tuberculosis diagnostics and had substantial heterogeneity (I2 was 96% for sensitivity and 99% for specificity). Each included study failed on one or more domain of the QUADAS-2 tool. Interpretation Current policy and practice regarding the trial of antibiotics appear inappropriate, given the weak evidence base, poor diagnostic performance, potential contribution to the global antimicrobial resistance crisis, and adverse individual and public health consequences from the misclassification of tuberculosis status. Antibiotic strategies during tuberculosis investigations should instead optimise clinical outcomes, ideally guided by clinical trials in both inpatient and outpatient groups. Funding Helse Nord RHF, Wellcome Trust, and the UK Commonwealth Scholarship Commission.

Biometrics is the science of establishing the identity of an individual based on their physical attributes. Ethical concerns surrounding the appropriate use of biometrics have been raised, especially in resource-poor settings. A qualitative investigation was conducted to explore biometrics clients (n = 14), implementers (n = 12) and policy makers as well as bioethicists (n = 4) perceptions of the ethical aspects of implementing biometrics within the healthcare system in Malawi. Informed use, privacy and confidentiality as well as perceptions of benefits and harms were identified as major issues in the application of biometrics. Implementation of biometrics within the healthcare system in Malawi poses a range of potential ethical issues and practical challenges that impact on equitable uptake. There is a need for more research to explore the benefits and harms of biometrics in practice. Improved community engagement and sensitization should be a required component of biometrics introduction in Malawi.

People living with HIV (PLHIV) admitted to hospital have a high risk of death. We systematically appraised evidence for interventions to reduce mortality among hospitalised PLHIV in low- and middle-income countries (LMICs). Using a broad search strategy with terms for HIV, hospitals, and clinical trials, we searched for reports published between 1 Jan 2003 and 23 August 2021. Studies of interventions among adult HIV positive inpatients in LMICs were included if there was a comparator group and death was an outcome. We excluded studies restricted only to inpatients with a specific diagnosis (e.g. cryptococcal meningitis). Of 19,970 unique studies identified in search, ten were eligible for inclusion with 7,531 participants in total: nine randomised trials, and one before-after study. Three trials investigated systematic screening for tuberculosis; two showed survival benefit for urine TB screening vs. no urine screening, and one which compared Xpert MTB/RIF versus smear microscopy showed no difference in survival. One before-after study implemented 2007 WHO guidelines to improve management of smear negative tuberculosis in severely ill PLHIV, and showed survival benefit but with high risk of bias. Two trials evaluated complex interventions aimed at overcoming barriers to ART initiation in newly diagnosed PLHIV, one of which showed survival benefit and the other no difference. Two small trials evaluated early inpatient ART start, with no difference in survival. Two trials investigated protocol-driven fluid resuscitation for emergency-room attendees meeting case-definitions for sepsis, and showed increased mortality with use of a protocol for fluid administration. In conclusion, ten studies published since 2003 investigated interventions that aimed to reduce mortality in hospitalised adults with HIV, and weren’t restricted to people with a defined disease diagnosis. Inpatient trials of diagnostics, therapeutics or a package of interventions to reduce mortality should be a research priority. Trial registration: PROSPERO Number: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019150341.

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 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 noncommunicable 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%] versus 43 [11.1%] p-value

Ratios of bacteriologically-positive tuberculosis prevalence to notification rates are used to characterise typical durations of tuberculosis disease, but have not accounted for asymptomatic periods prior to care-seeking. We developed novel statistical models to estimate progression from initial bacteriological-positivity including smear conversion, symptom onset and initial care-seeking and fitted them to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework. Asymptomatic tuberculosis duration was in the range 4 – 8 months for African countries; three countries in Asia showed longer durations of > 1 year. Care-seeking typically began half-way between symptom onset and notification. Our method also estimated smear progression rates and case-detection ratios. We found evidence for higher case-detection ratios and much shorter durations of tuberculosis for people living with HIV. To eradicate tuberculosis transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions.

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.

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.

BackgroundTuberculosis (TB) control relies on early diagnosis and treatment. International guidelines recommend systematic TB screening at health facilities in high-burden settings, but implementation is challenging. To construct a TB diagnosis care cascade, we investigated screening guideline adherence and completion of TB testing steps in Blantyre, Malawi.MethodsA prospective cohort recruited adult (≥18) outpatients attending Bangwe acute-care primary clinic between 21/5/2018 and 6/9/2018. Entry interviews recording TB symptoms and demographic characteristics were linked to exit interviews by biometrics. Care cascades were constructed to estimate the proportion of patients progressing through each step of the diagnostic pathway. Multivariable logistic regression was used to investigate factors associated with being asked to submit sputum.ResultsOf 5,442 clinic attendances 2,397 (44%) had exit interviews. In clinically indicated participants (n=330) 203 (61.5%) were asked about cough, 39 (11.8%) were asked for sputum, 27 (8.2%) gave sputum and 1 (0.3%) 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 survey (20/day) outnumbered diagnostic capacity (8-12/day).ConclusionPatients were lost at every stage of the TB care cascade, with same day sputum submission achieved in only 8.2% if clinically indicated. Infection control strategies should be implemented, with reporting on early steps of the TB care cascade formalised. High-throughput interventions, such as digital CXR, that can optimise same-day TB screening are urgently needed to meet WHO End TB goals.SummaryWhat is already known?WHO guidelines recommend systematic screening for Tuberculosis at health facilities in high-burden settings, but implementation is challenging.Care cascades have been widely used by HIV programmes to evaluate care delivery but have only recently been applied to TB care. Care cascades help to define the steps of the cascade most in need of interventionWhat are the new findings?In this study, only 8.2% of those clinically indicated to test for TB (as per national guidelines in Malawi) did so, with patients lost at every step of the diagnosis care cascade.Failure to request sputum by clinicians despite elicited symptoms led to the biggest single gap in the diagnosis care cascade, followed by not asking about symptoms.If all patients attending the clinic were screened for TB as per the guidelines, the current testing facilities would only be able to process up to two thirds of the required samples.What do the new findings imply?Interventions focusing on health worker behaviour may have the greatest potential for retaining presumptive TB patients within the diagnosis cascadeWe must formalise and strengthen reporting on the early steps in the TB care cascade: a requirement to report numbers of screened presumptive TB cases would allow greater focus on these critical steps.If identification of presumptive TB patients is subsequently improved a novel high-throughput approach to triage testing using new diagnostics will be required for LMICs to increase capacity.

AlthoughMycobacterium tuberculosis (Mtb)strains exhibit genomic homology of >99%, there is considerable variation in the phenotype. The underlying mechanisms of phenotypic heterogeneity inMtbare not well understood but epigenetic variation is thought to contribute. At present the methylome ofMtbhas not been completely characterized. We completed methylomes of 18Mycobacterium tuberculosis(Mtb) clinical isolates from Malawi representing the largest number ofMtbgenomes to be completed in a single study using Single Molecule Real Time (SMRT) sequencing to date. We replicate and confirm four methylation disrupting mutations in lineages ofMtb. For the first time we report complete loss of methylation courtesy of C758T (S253L) mutation in theMamBgene of Indo-oceanic lineage ofMtb. We also conducted a genomic and methylome comparison of the Malawian samples against a global sample. We confirm that methylation inMtbis lineage specific although some unresolved issues still remain.

Introduction Over 40% of global tuberculosis case notifications are diagnosed clinically without mycobacteriological confirmation. Standard diagnostic algorithms include ‘trial-of-antibiotics’—empirical antibiotic treatment given to mycobacteriology-negative individuals to treat infectious causes of symptoms other than tuberculosis, as a ‘rule-out’ diagnostic test for tuberculosis. Potentially 26.5 million such antibiotic courses/year are prescribed globally for the 5.3 million/year mycobacteriology-negative patients, making trial-of-antibiotics the most common tuberculosis diagnostic, and a global-scale risk for antimicrobial resistance (AMR). Our systematic review found no randomised controlled trial (RCT) to support use of trial-of-antibiotic. The RCT aims to determine the diagnostic and clinical value and AMR consequences of trial-of-antibiotics. Methods and analysis A three-arm, open-label, RCT randomising (1:1:1) Malawian adults (≥18 years) seeking primary care for cough into: (a) azithromycin 500 mg one time per day for 3 days or (b) amoxicillin 1 g three times per day for 5 days or (c) standard-of-care (no immediate antibiotic). We will perform mycobacteriology tests (microscopy, Xpert MTB/RIF (Mycobacterium tuberculosis/rifampicin) and Mycobacterium tuberculosis culture) at baseline. We will use audiocomputer-assisted self-interview to assess clinical improvement at day 8. First primary outcome will be proportion of patients reporting day 8 improvement out of those with negative mycobacteriology (specificity). Second primary outcome will be day 29 incidence of a composite endpoint of either death or hospitalisation or missed tuberculosis diagnosis. To determine AMR impact we compare proportion of resistant nasopharyngeal Streptococcus pneumoniae isolates on day 29. 400 mycobacteriology-negative participants/arm will be required to detect a ≥10% absolute difference in diagnostic specificity with 80% power. We will estimate measures of effect by comparing outcomes in antibiotic arms (combined and individually) to standard-of-care. Ethics and dissemination The study has been reviewed and approved by Malawi College of Medicine Research and Ethics Committee, London School of Hygiene & Tropical Medicine (LSHTM) Research Ethics Committee and Regional Committee for Health and Research Ethics – Norway, and Malawi Pharmacy, Medicines and Poisons Board. We will present abstracts at relevant conferences, and prepare a manuscript for publication in a peer-reviewed journal. Trial registration number The clinical trial is registered with ClinicalTrials.gov, NCT03545373

Figure S3. Sensitivity analysis. X-axes are relative rates per unit increase in variable. Model k0 is model without spatial autocorrelation prior. Models k1 to k6 are models with kâ =â 1 to 6 nearest neighbour matrix spatial autocorrelation priors. k nearest neighbours calculated from Cartesian distances between pairs of Health Surveillance Assistant catchment area centroids (Additional file 2: Figure S2). WAIC: Widely applicable information criteria based on the posterior distribution of each model. (PDF 14 kb)

Background: Patients with tuberculosis (TB) symptoms in low-resource settings face convoluted diagnostic and treatment linkage pathways, incurring substantial health-seeking costs. In the context of a randomised trial looking at the impact of novel diagnostics such as computer-aided chest x-ray diagnosis (CAD4TB), we aimed to investigate the costs incurred by patients seeking TB diagnosis and whether optimised diagnostic interventions could result in a reduction in the cost faced by households. Methods: PROSPECT was a three-arm randomised trial conducted in a public primary health clinic in Blantyre, Malawi during 2018-2019 (trial arms: standard of care [SOC]; HIV testing [HIV]; HIV testing and CAD4TB [HIV/TB]). The direct and indirect costs incurred by 219 PROSPECT participants over the 56-day follow-up period were collected. Costs were deemed catastrophic if they exceeded 20% of annual household income. We compared mean costs and used generalised linear regression models to examine whether the interventions could result in a reduction in total costs. Results: The mean total cost incurred by all 219 participants was US$12.11 (standard error (SE): 1.86). The indirect and direct cost was US$8.47 (SE: 1.66) and US$3.64 (SE: 0.38), respectively. The mean total cost composed of 5.6% of the average annual household income. In total, 5% (9/180) of the participants with complete income data Open Peer Review Reviewer Status AWAITING PEER REVIEW Any reports and responses or comments on the article can be found at the end of the article. Page 1 of 13 Wellcome Open Research 2021, 6:153 Last updated: 02 JUL 2021 Corresponding author: Wala Kamchedzera (wala.kamchedzera@gmail.com) Author roles: Kamchedzera W: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; Maheswaran H: Conceptualization, Methodology, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; Squire SB: Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; Joekes E: Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; Pai M: Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; Nliwasa M: Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; G Lalloo D: Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; Webb EL: Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; Corbett EL: Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; MacPherson P: Conceptualization, Funding Acquisition, Methodology, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests: No competing interests were disclosed. Grant information: PM was supported by the Wellcome Trust (grant number: WT206575). WK was supported by Wellcome (grant number: 218333/Z/19/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2021 Kamchedzera W et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original data is properly cited. How to cite this article: Kamchedzera W, Maheswaran H, Squire SB et al. Economic costs of accessing tuberculosis (TB) diagnostic services in Malawi: an analysis of patient costs from a randomised controlled trial of computer-aided chest x-ray interpretation [version 1; peer review: awaiting peer review] Wellcome Open Research 2021, 6:153 https://doi.org/10.12688/wellcomeopenres.16683.1 First published: 15 Jun 2021, 6:153 https://doi.org/10.12688/wellcomeopenres.16683.1 incurred catastrophic costs. Compared to SOC, there was no statistically significant difference in the mean total cost faced by those in the HIV (ratio: 0.77, 95% CI: 0.51, 1.19) and HIV/TB arms (ratio: 0.85, 95% CI: 0.53, 1.37). Conclusions: Despite the absence of user fees, patients seeking healthcare with TB symptoms incurred catastrophic costs. The optimised TB diagnostic interventions that were investigated in the PROSPECT study did not significantly reduce costs. TB diagnosis interventions should be implemented alongside social protection policies whilst ensuring healthcare facilities are accessible by the poor

Background A sizeable fraction of tuberculosis (TB) cases go undiagnosed. By analysing data from enhanced demographic, microbiological and geospatial surveillance of TB registrations, we aimed to identify modifiable predictors of inequitable access to diagnosis and care. Methods Governmental community health workers (CHW) enumerated all households in 315 catchment areas during October–December 2015. From January 2015, government TB Officers routinely implemented enhanced TB surveillance at all public and private TB treatment registration centres within Blantyre (18 clinics in total). This included collection from registering TB patients of demographic and clinical characteristics, a single sputum sample for TB microscopy and culture, and geolocation of place of residence using an electronic satellite map application. We estimated catchment area annual TB case notification rates (CNRs), stratified by microbiological status. To identify population and area-level factors predictive of CHW catchment area TB case notification rates, we constructed Bayesian spatially autocorrelated regression models with Poisson response distributions. Worldpop data were used to estimate poverty. Results In total, the 315 CHW catchment areas comprised 753,489 people (range 162 to 13,066 people/catchment area). Between 2015 and 2017, 6077 TB cases (61% male; 99% HIV tested; 67% HIV positive; 55% culture confirmed) were geolocated, with 3723 (61%) resident within a CHW catchment area. In adjusted models, greater distance to the nearest TB registration clinic was negatively correlated with TB CNRs, which halved for every 3.2-fold (95% CI 2.24–5.21) increase in distance. Poverty, which increased with distance from clinics, was negatively correlated with TB CNRs; a 23% increase (95% CI 17–34%) in the mean percentage of the population living on less than US$2 per day corresponded to a halving of the TB case notification rates. Conclusions Using enhanced surveillance of TB cases in Blantyre, we show an ecological relationship consistent with an ‘inverse care law’ whereby poorer neighbourhoods and those furthest from TB clinics have lower relative CNRs. If confirmed as low case detection, then pro-poor strategies to facilitate equitable access to TB diagnosis and treatment are required. Electronic supplementary material The online version of this article (10.1186/s12916-019-1260-6) contains supplementary material, which is available to authorized users.

Background Antimicrobial resistance generates a huge health and economic burden and has the potential to become the leading cause of death globally, but its underlying drivers are yet to be fully described. The association between a microbe’s exposure to antimicrobials and subsequent development of, or selection for, resistance is well documented, as are the exacerbating microbial and human factors. However, the nature and extent of this risk, and how it varies by antimicrobial class and duration of treatment, is poorly defined. The goal of our systematic review and network meta-analysis is to determine the relationship between the duration of antimicrobial exposure and selection for resistance. We will use macrolides as the antimicrobial class of interest and Streptococcus pneumoniae carriage as an indicator organism. Our secondary outcomes include duration of symptoms, risk of treatment failure and recurrence, and descriptions of resistance mechanisms. Methods We will conduct a systematic review, selecting studies if they are published randomised controlled trials (RCTs) which report the relationship between taking a macrolide for any indication and incidence of resistant Streptococcus pneumoniae in patients of any age group. We will use a predefined search strategy to identify studies meeting these eligibility criteria in MEDLINE, Embase, Global Health and the Cochrane Central Register of RCTs. Two authors will independently screen titles and abstracts, review the full texts and undertake data extraction. We will use the Cochrane Collaboration’s tool to assess the quality of included RCTs. If feasible, we will perform pair-wise meta-analysis modelling to determine the relationship between the duration of macrolide treatment and development of macrolide resistant Streptococcus pneumoniae. If the identified studies meet the assumptions for a network meta-analysis (NMA), we will additionally model this relationship using indirect comparisons. Our protocol utilises reporting guidance by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the extensions for protocols (PRISMA-P) and network meta-analyses (PRISMA for NMA). Our review will also report to these standards. Discussion Establishing the relationship between the duration of antimicrobial exposure and development of, or selection for, resistance will inform the design of antimicrobial prescriptions, treatment guidelines and the behaviour of both physicians and patients. This work will therefore be a strong contribution towards the full realisation of current antimicrobial resistance stewardship strategies. Systematic review registration PROSPERO CRD42018089275 Electronic supplementary material The online version of this article (10.1186/s13643-018-0917-0) contains supplementary material, which is available to authorized users.

Search strategy for Embase and Global Health in Ovid Embase. (DOCX 18 kb)

Data extraction form. (DOCX 82 kb)

Data extraction form. The draft form includes the risk of bias assessment tool and documents the data which will be extracted from included studies. (DOCX 26 kb)

BackgroundChildren account for an estimated 1 million new cases of TB every year, representing roughly 7% of the total disease burden. Every year, around 2 09 000 children die from TB, half of those cases are in Africa. The main issue continues to be timely and accurate diagnosis, as treatment outcomes – even in the case of drug resistance – are significantly better than in adults.Clinical diagnosis in the absence of laboratory confirmation is hampered by non-specificity of symptoms. Diagnostics validation studies in children are difficult – in most studies, very few of the symptomatic children achieved microbiological disease confirmation, resulting in imprecise estimates for test sensitivity.Design/methodsWith the RaPaed TB study funded by EDCTP, we are preparing an improved diagnostic validation study design to improve on the traditional approach of a single-gate, double diagnostic study in the target population. The project will evaluate multiple new tests on the same patients, to determine algorithms of screening and confirmatory tests. Most novel tests in this study use non-sputum samples and are therefore more suitable for children.Allocation of patients to standardised groups will follow the recommendations of the NIH-convened consensus panel on case definitions of paediatric TB diagnostic studies. Using an endpoint review committee will allow blinded review of those new-positive cases, plus matched controls, and determine their likelihood of disease based on clinical data including follow-up, and X-ray. This will improve the quality of evaluation of false positive vs. true positive results of new tests and therefore improve the assessment of specificity.To improve on sensitivity assessment, the study includes partners with a high number of confirmed cases in past studies and plans to draw in cases of confirmed disease from other diagnostic facilities.ConclusionThis improved methodology will lead to more meaningful and applicable results of diagnostic validation studies.

Source at https://doi.org/10.1002/jia2.25162. Introduction: HIV and tuberculosis (TB) remain leading causes of preventable death in low- and middle-income countries(LMICs). The World Health Organization (WHO) recommends HIV testing for all individuals with TB symptoms, but implementation has been suboptimal. We conducted a systematic literature review and meta-analyses to estimate HIV and TB prevalence, and short-term (two to six months) mortality, among adults with TB symptoms at community- and facility level. Methods: We searched Embase, Global Health and MEDLINE databases, and reviewed conference abstracts for studies reporting simultaneous HIV and TB screening of adults in LMICs published between January 2003 and December 2017. Meta-analyses were performed to estimate prevalence of HIV, undiagnosed TB and mortality risk at different health system levels. Results: Sixty-two studies including 260,792 symptomatic adults were identified, mostly from Africa and Asia. Median HIV prevalence was 19.2% (IQR: 8.3% to 40.4%) at community level, 55.7% (IQR: 20.9% to 71.2%) at primary care level and 80.7% (IQR: 73.8% to 84.6%) at hospital level. Median TB prevalence was 6.9% (IQR: 3.3% to 8.4%) at community, 20.5%(IQR: 11.7% to 46.4%) at primary care and 36.4% (IQR: 22.9% to 40.9%) at hospital level. Median short-term mortality was 22.6% (IQR: 15.6% to 27.7%) among inpatients, 3.1% (IQR: 1.2% to 4.2%) at primary care and 1.6% (95% CI: 0.45 to 4.13,n=1 study) at community level. Conclusions: Adults with TB symptoms have extremely high prevalence of HIV infection, even when identified through community surveys. TB prevalence and mortality increased substantially at primary care and inpatient level respectively. Strategies to expand symptom-based TB screening combined with HIV and TB testing for all symptomatic individuals should be of the highest priority for both disease programmes in LMICs with generalized HIV epidemics. Interventions to reduce short-term mortality are urgently needed.

Background\ud Current tuberculosis diagnostics lack sensitivity, and are expensive. Highly accurate, rapid and cheaper diagnostic tests are required for point of care use in low resource settings with high HIV prevalence.\ud \ud Objective\ud To investigate the sensitivity and specificity, and cost of loop-mediated isothermal amplification (LAMP) assay for tuberculosis diagnosis in adults with chronic cough compared to Xpert® MTB/RIF, fluorescence smear microscopy.\ud \ud Methods\ud Between October 2013 and March 2014, consecutive adults at a primary care clinic were screened for cough, offered HIV testing and assessed for tuberculosis using LAMP, Xpert® MTB/RIF and fluorescence smear microscopy. Sensitivity and specificity (with culture as reference standard), and costs were estimated.\ud \ud Results\ud Of 273 adults recruited, 44.3% (121/273) were HIV-positive and 19.4% (53/273) had bacteriogically confirmed tuberculosis. The sensitivity of LAMP compared to culture was 65.0% (95% CI: 48.3% to 79.4%) with 100% (95% CI: 98.0% to 100%) specificity. The sensitivity of Xpert® MTB/RIF (77.5%, 95% CI: 61.5% to 89.2%) was similar to that of LAMP, p = 0.132. The sensitivity of concentrated fluorescence smear microscopy with routine double reading (87.5%, 95% CI: 73.2% to 95.8%) was higher than that of LAMP, p = 0.020. All three tests had high specificity. The lowest cost per test of LAMP was at batch size of 14 samples (US$ 9.98); this was lower than Xpert® MTB/RIF (US$ 13.38) but higher than fluorescence smear microscopy (US$ 0.65).\ud \ud Conclusion\ud The sensitivity of LAMP was similar to Xpert® MTB/RIF but lower than fluorescence smear microscopy; all three tests had high specificity. These findings support the Malawi policy that recommends a combination of fluorescence smear microscopy and Xpert® MTB/RIF prioritised for people living with HIV, already found to be smear-negative, or being considered for retreatment of tuberculosis.

Figure S1. Characteristics of Health Surveillance Assistant catchment areas, Blantyre, Malawi. A) Total population; B) population density per km2; C) Mean number of people per household; D) Mean proportion of population living in poverty; E) Cartesian distance from catchment area centroid to nearest TB registration centre; F) Ratio of male-to-female adults G) Proportion of population aged 15â years or older H) Sputum smear positive to negative ratio, on sample from routine clinic. Poverty estimates from Worldpop ( www.worldpop.org.uk ). Boundaries are Health Surveillance Assistant catchment areas. Black triangles are TB registration clinic. White areas in centre of maps are mountainous areas or business districts with few residents that were not enumerated in the census. The black triangle in the far north of maps is a health centre with a TB registration clinic located outside of Blantyre District that may be used by Blantyre residents; to increase accuracy of case notification rates, we captured TB registrations at this clinic. (PDF 933 kb)

Additional file 1 Table S1. Characteristics of adult acute clinic attendances by exit interview participation.

Additional file 1 Table S1. Characteristics of adult acute clinic attendances by exit interview participation.

Figure S2. Nearest neighbour structure of Blantyre Health Surveillance Assistant catchment areas. Blue lines indicate the nearest k neighbours to each 315 Health Surveillance Assistant catchment area, calculated as the Cartesian distance between pairs of Health Surveillance Assistant catchment area centroids. (PDF 37 kb)

Figure S4. Predicted and observed TB cases in 315 Blantyre Health Surveillance Assistant catchment areas. A: All TB cases. B: Microbiologically confirmed TB cases. X-axes are Health Surveillance catchment areas, ordered in decreasing frequency by number of TB cases registered through enhanced TB surveillance. Red points are observed numbers of cases, blue points are predicted values, estimated by the Bayesian spatial regression models. Transparency of blue fitted points are inversely proportional to absolute distance from observed value. Predicted numbers of TB cases estimated by fitting a Bayesian spatial regression model with Poisson response, a k = 6 nearest-neighbours conditional spatial autocorrelation structure, with linear terms fitted for health surveillance assistant catchment area log10 total population, log10 population density, adult M:F ratio, mean number of people per household, log10 Cartesian distance from geographical centroid to the nearest TB clinic, proportion of population aged 15 years or older, mean proportion living on less than US $2 per day, sputum smear positive to negative ratio, offset term for log10 HSA population size, and with weakly informative prior on the population-level effects intercept (Gaussian: mean = 0, sd = 10), and predictor intercept (Gaussian, mean = 0, sd = 10). (PDF 109 kb)

Figure S4. Predicted and observed TB cases in 315 Blantyre Health Surveillance Assistant catchment areas. A: All TB cases. B: Microbiologically confirmed TB cases. X-axes are Health Surveillance catchment areas, ordered in decreasing frequency by number of TB cases registered through enhanced TB surveillance. Red points are observed numbers of cases, blue points are predicted values, estimated by the Bayesian spatial regression models. Transparency of blue fitted points are inversely proportional to absolute distance from observed value. Predicted numbers of TB cases estimated by fitting a Bayesian spatial regression model with Poisson response, a k = 6 nearest-neighbours conditional spatial autocorrelation structure, with linear terms fitted for health surveillance assistant catchment area log10 total population, log10 population density, adult M:F ratio, mean number of people per household, log10 Cartesian distance from geographical centroid to the nearest TB clinic, proportion of population aged 15 years or older, mean proportion living on less than US $2 per day, sputum smear positive to negative ratio, offset term for log10 HSA population size, and with weakly informative prior on the population-level effects intercept (Gaussian: mean = 0, sd = 10), and predictor intercept (Gaussian, mean = 0, sd = 10). (PDF 109 kb)

Figure S2. Nearest neighbour structure of Blantyre Health Surveillance Assistant catchment areas. Blue lines indicate the nearest k neighbours to each 315 Health Surveillance Assistant catchment area, calculated as the Cartesian distance between pairs of Health Surveillance Assistant catchment area centroids. (PDF 37 kb)

Figure S1. Characteristics of Health Surveillance Assistant catchment areas, Blantyre, Malawi. A) Total population; B) population density per km2; C) Mean number of people per household; D) Mean proportion of population living in poverty; E) Cartesian distance from catchment area centroid to nearest TB registration centre; F) Ratio of male-to-female adults G) Proportion of population aged 15â years or older H) Sputum smear positive to negative ratio, on sample from routine clinic. Poverty estimates from Worldpop ( www.worldpop.org.uk ). Boundaries are Health Surveillance Assistant catchment areas. Black triangles are TB registration clinic. White areas in centre of maps are mountainous areas or business districts with few residents that were not enumerated in the census. The black triangle in the far north of maps is a health centre with a TB registration clinic located outside of Blantyre District that may be used by Blantyre residents; to increase accuracy of case notification rates, we captured TB registrations at this clinic. (PDF 933 kb)