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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.

Structured summaryBackgroundPulmonary tuberculosis (PTB) due toMycobacterium tuberculosis(Mtb) can be challenging to diagnose because of difficulty obtaining samples, and suboptimal sensitivity of existing tests. We investigated the performance characteristics and diagnostic accuracy of upper respiratory tract tests for diagnosing PTB and hypothesised they would have sufficient accuracy and utility to improve PTB diagnosis.MethodsA systematic review and meta-analysis was conducted by searching MEDLINE, Cinahl, Web of Science, Global Health, and Global Health Archive databases up to 31/01/2021, a second search was conducted for the period 1/1/2021 - 27/5/2022 (subsequently extended to 6/12/2022) to identify studies that reported on the accuracy of upper respiratory tract sampling for TB diagnosis compared to microbiological reference standards. We used a random-effects meta-analysis with a bivariate hierarchical model to estimate pooled sensitivity and specificity, stratified by sampling method. Bias was assessed using QUADAS- 2 criteria. Study registered with PROSPERO (CRD42021262392).Findings10,159 titles were screened for inclusion, 274 studies were assessed for full text review, and 71, comprising 119 test comparisons published between 1933 and 2022 were included in the systematic review (53 in meta-analysis). For laryngeal swabs, pooled sensitivity was 57.8% (95% CI 50.5-65.0%), specificity was 93.8% (95% CI 88.4-96.8%) and diagnostic odds ratio (DOR) was 20.7 (95% CI 11.1-38.8). Nasopharyngeal aspirate sensitivity was 65.2% (95% CI 52.0-76.4%), specificity was 97.9% (95% CI 96.0-99.0%) and DOR was 91.0 (95% CI 37.8-218.8). Oral swabs sensitivity was 56.7% (95% CI 44.3-68.2%), specificity was 91.3% (95% CI 81.0-96.3%), and DOR was 13.8 (95% CI 5.6-34.0).InterpretationUpper respiratory tract sampling holds promise to expand access to TB diagnosis, including for people who can’t produce sputum. Exploring historical methods using modern microbiological techniques may further increase the options for alternative sample types.Prospective studies are needed to optimise accuracy and utility of sampling methods in clinical practice.FundingHRS is funded by the MRC through the MRC DTP programme at LSTM [Grant number MR/N013514/1].Research in contextEvidence before this studyGlobally in 2021, an estimated 4.2 million of 10.6 million people with incident tuberculosis (TB) disease went undiagnosed, emphasising the urgent need for new diagnostic methodologies. Most TB diagnostics are performed on sputum samples, but people who need TB tests are often unable to produce sputum. Upper respiratory tract sampling for TB diagnosis was widely used historically and holds promise to expand non-sputum-based diagnosis.Added value of this studyWe systematically reviewed and synthesised through meta-analysis diagnostic accuracy evaluations of upper respiratory tract sampling for TB. Historically, upper respiratory tract sampling for TB diagnosis was commonly used, with 39/71 studies conducted before 1970, although in recent years there has been a resurgence of interest in oral sampling. We show that upper respiratory tract samples have acceptable sensitivity and specificity compared to sputum culture, and, if testing is optimised using newer molecular and culture-based methods, may be capable of meeting WHO target produce profiles.Implications of all the available evidenceUpper respiratory tract sampling methodologies for TB (oral sampling, and sampling from the larynx and nasopharynx) may hold promise to expand access to TB diagnosis, including for people who can’t produce sputum. These sampling strategies can be optimised using modern microbiological techniques to increase access to diagnostics for TB.

Seasonal trends in tuberculosis (TB) notifications have been observed in several countries but are poorly understood. Explanatory factors may include weather, indoor crowding, seasonal respiratory infections and migration. Using enhanced citywide TB surveillance data collected over nine years in Blantyre, Malawi, we set out to investigate how weather and seasonality affect temporal trends in TB case notification rates (CNRs) across different demographic groups. We used data from prospective enhanced surveillance between April 2011 and December 2018, which systematically collected age, HIV status, sex and case notification dates for all registering TB cases in Blantyre. We retrieved temperature and rainfall data from the Global Surface Summary of the Day weather station database. We calculated weekly trends in TB CNRs, rainfall and temperature, and calculated 10-week moving averages. To investigate the associations between rainfall, temperature and TB CNRs, we fitted generalized linear models using a distributed lag nonlinear framework. The estimated Blantyre population increased from 1,068,151 in April 2011 to 1,264,304 in December 2018, with 15,908 TB cases recorded. Overall annual TB CNRs declined from 222 to 145 per 100,000 between 2012 and 2018, with the largest declines seen in HIV-positive people and adults aged over 20 years old. TB CNRs peaks occurred with increasing temperature in September and October before the onset of increased rainfall, and later in the rainy season during January-March, after sustained rainfall. When lag between a change in weather and TB case notifications was accounted for, higher average rainfall was associated with an equivalent six weeks of relatively lower TB notification rates, whereas there were no changes in TB CNR associated with change in average temperatures. TB CNRs in Blantyre have a seasonal pattern of two cyclical peaks per year, coinciding with the start and end of the rainy season. These trends may be explained by increased transmission at certain times of the year, by limited healthcare access, by patterns of seasonal respiratory infections precipitating cough and care-seeking, or by migratory patterns related to planting and harvesting during the rainy season.

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.

Background The global annual estimate for cryptococcal disease-related deaths exceeds 180,000, with three fourth occurring in sub-Saharan Africa. The World Health Organization (WHO) recommends cryptococcal antigen (CrAg) screening in all HIV patients with CD4 count Methods A prospective cohort study design was used to screen consecutive adult (18 years or older) HIV patients at Connaught Hospital in Freetown, Sierra Leone with CD4 count below 100 cells/mm3 from January to April 2018. Participants received a blood CrAg lateral flow assay (IMMY, Oklahoma, USA). All participants with a positive serum CrAg had lumbar puncture and cerebrospinal fluid (CSF) CrAg assay, and those with cryptococcal diseases had fluconazole monotherapy with 8 weeks followed up. Data were entered into Excel and analysed in Stata version 13.0. Proportions, median and interquartile ranges were used to summarise the data. Fisher’s exact test was used to compare categorical variables. Results A total of 170 patients, with median age of 36 (IQR 30–43) and median CD4 count of 45 cells/mm3 (IQR 23–63) were screened. At the time of enrolment, 54% were inpatients, 51% were newly diagnosed with HIV, and 56% were either ART-naïve or newly initiated (≤ 30 days). Eight participants had a positive blood CrAg, giving a prevalence of 4.7% (95% CI: 2.4–9.2%). Of those with a positive CrAg, CSF CrAg was positive in five (62.5%). Five (62.5%) CrAg-positive participants died within the first month, while the remaining three were alive and established on ART at 8 weeks. Conclusion A substantial prevalence of cryptococcal antigenaemia and poor outcome of cryptococcal disease were demonstrated in our study. The high mortality suggests a need for the HIV programme to formulate and implement policies on screening and pre-emptive fluconazole therapy for all adults with advanced HIV in Sierra Leone, and advocate for affordable access to effective antifungal therapies.

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.

Background HIV testing services (HTS) are the first steps in reaching the UNAIDS 95-95-95 goals to achieve and maintain low HIV incidence. Evaluating the effectiveness of different demand creation interventions to increase uptake of efficient and effective HTS is useful to prioritize limited programmatic resources. This review was undertaken to inform World Health Organization (WHO) 2019 HIV testing guidelines and assessed the research question, “Which demand creation strategies are effective for enhancing uptake of HTS?” focused on populations globally. Methods and findings The following electronic databases were searched through September 28, 2021: PubMed, PsycInfo, Cochrane CENTRAL, CINAHL Complete, Web of Science Core Collection, EMBASE, and Global Health Database; we searched IAS and AIDS conferences. We systematically searched for randomized controlled trials (RCTs) that compared any demand creation intervention (incentives, mobilization, counseling, tailoring, and digital interventions) to either a control or other demand creation intervention and reported HTS uptake. We pooled trials to evaluate categories of demand creation interventions using random-effects models for meta-analysis and assessed study quality with Cochrane’s risk of bias 1 tool. This study was funded by the WHO and registered in Prospero with ID CRD42022296947. We screened 10,583 records and 507 conference abstracts, reviewed 952 full texts, and included 124 RCTs for data extraction. The majority of studies were from the African (N = 53) and Americas (N = 54) regions. We found that mobilization (relative risk [RR]: 2.01, 95% confidence interval [CI]: [1.30, 3.09], p < 0.05; risk difference [RD]: 0.29, 95% CI [0.16, 0.43], p < 0.05, N = 4 RCTs), couple-oriented counseling (RR: 1.98, 95% CI [1.02, 3.86], p < 0.05; RD: 0.12, 95% CI [0.03, 0.21], p < 0.05, N = 4 RCTs), peer-led interventions (RR: 1.57, 95% CI [1.15, 2.15], p < 0.05; RD: 0.18, 95% CI [0.06, 0.31], p < 0.05, N = 10 RCTs), motivation-oriented counseling (RR: 1.53, 95% CI [1.07, 2.20], p < 0.05; RD: 0.17, 95% CI [0.00, 0.34], p < 0.05, N = 4 RCTs), short message service (SMS) (RR: 1.53, 95% CI [1.09, 2.16], p < 0.05; RD: 0.11, 95% CI [0.03, 0.19], p < 0.05, N = 5 RCTs), and conditional fixed value incentives (RR: 1.52, 95% CI [1.21, 1.91], p < 0.05; RD: 0.15, 95% CI [0.07, 0.22], p < 0.05, N = 11 RCTs) all significantly and importantly (≥50% relative increase) increased HTS uptake and had medium risk of bias. Lottery-based incentives and audio-based interventions less importantly (25% to 49% increase) but not significantly increased HTS uptake (medium risk of bias). Personal invitation letters and personalized message content significantly but not importantly ( Conclusions Mobilization, couple- and motivation-oriented counseling, peer-led interventions, conditional fixed value incentives, and SMS are high-impact demand creation interventions and should be prioritized for programmatic consideration. Reduced duration counseling and video-based interventions are an efficient and effective alternative to address staffing shortages. Investment in demand creation activities should prioritize those with undiagnosed HIV or ongoing HIV exposure. Selection of demand creation interventions must consider risks and benefits, context-specific factors, feasibility and sustainability, country ownership, and universal health coverage across disease areas.

Background Suboptimal tuberculosis (TB) diagnostics and HIV contribute to the high global burden of TB. We investigated costs and yield from systematic HIV-TB screening, including computer-aided digital chest X-ray (DCXR-CAD). Methods and findings In this open, three-arm randomised trial, adults (≥18 years) with cough attending acute primary services in Malawi were randomised (1:1:1) to standard of care (SOC); oral HIV testing (HIV screening) and linkage to care; or HIV testing and linkage to care plus DCXR-CAD with sputum Xpert for high CAD4TBv5 scores (HIV-TB screening). Participants and study staff were not blinded to intervention allocation, but investigator blinding was maintained until final analysis. The primary outcome was time to TB treatment. Secondary outcomes included proportion with same-day TB treatment; prevalence of undiagnosed/untreated bacteriologically confirmed TB on day 56; and undiagnosed/untreated HIV. Analysis was done on an intention-to-treat basis. Cost-effectiveness analysis used a health-provider perspective. Between 15 November 2018 and 27 November 2019, 8,236 were screened for eligibility, with 473, 492, and 497 randomly allocated to SOC, HIV, and HIV-TB screening arms; 53 (11%), 52 (9%), and 47 (9%) were lost to follow-up, respectively. At 56 days, TB treatment had been started in 5 (1.1%) SOC, 8 (1.6%) HIV screening, and 15 (3.0%) HIV-TB screening participants. Median (IQR) time to TB treatment was 11 (6.5 to 38), 6 (1 to 22), and 1 (0 to 3) days (hazard ratio for HIV-TB versus SOC: 2.86, 1.04 to 7.87), with same-day treatment of 0/5 (0%) SOC, 1/8 (12.5%) HIV, and 6/15 (40.0%) HIV-TB screening arm TB patients (p = 0.03). At day 56, 2 SOC (0.5%), 4 HIV (1.0%), and 2 HIV-TB (0.5%) participants had undiagnosed microbiologically confirmed TB. HIV screening reduced the proportion with undiagnosed or untreated HIV from 10 (2.7%) in the SOC arm to 2 (0.5%) in the HIV screening arm (risk ratio [RR]: 0.18, 0.04 to 0.83), and 1 (0.2%) in the HIV-TB screening arm (RR: 0.09, 0.01 to 0.71). Incremental costs were US$3.58 and US$19.92 per participant screened for HIV and HIV-TB; the probability of cost-effectiveness at a US$1,200/quality-adjusted life year (QALY) threshold was 83.9% and 0%. Main limitations were the lower than anticipated prevalence of TB and short participant follow-up period; cost and quality of life benefits of this screening approach may accrue over a longer time horizon. Conclusions DCXR-CAD with universal HIV screening significantly increased the timeliness and completeness of HIV and TB diagnosis. If implemented at scale, this has potential to rapidly and efficiently improve TB and HIV diagnosis and treatment. Trial registration clinicaltrials.gov NCT03519425., In a randomised trial, Peter MacPherson and colleagues investigate the costs, timeliness, and completeness of computer-aided X-ray screening for tuberculosis and HIV testing in adults with cough in Malawi., Author summary Why was this study done? Tuberculosis (TB), one of the leading infectious killers worldwide, remains challenging to diagnose in low-resource settings, and patients frequently face multiple health centre visits at high cost before TB is diagnosed and treatment started. HIV is a major risk factor for TB. Robust digital X-ray equipment can now be deployed at a primary care level in sub-Saharan Africa, and automated computer software packages that can interpret chest X-rays providing a probabilistic score for pulmonary TB have accuracy similar to, or greater than, expert human readers. We therefore set out to investigate whether offering adults with cough attending primary care in Blantyre, Malawi universal HIV testing and linkage to antiretroviral therapy (ART)—either alone or combined with computer-aided digital chest X-ray (DCXR-CAD) and subsequent sputum Xpert confirmation—could improve the timeliness and completeness of HIV and TB diagnosis and treatment compared to current standard approaches (health worker–directed TB and HIV screening). What did the researchers do and find? A total of 1,462 adults attending a primary clinic in Blantyre, Malawi with cough were randomly allocated to receive either standard of care (SOC) health worker–directed HIV-TB screening; oral HIV testing and linkage to treatment (HIV screening); or oral HIV testing and linkage to treatment with additional digital chest X-ray screening for TB interpreted by computer-aided diagnosis software (CAD4TBv5), with sputum Xpert testing for participants with a CAD4TBv5 score above 45 (HIV/TB screening). Participants were followed for 56 days to investigate initiation of TB treatment, missed TB and HIV diagnosis, and cost-effectiveness. Median time to TB treatment initiation was shorter (1 day) in the HIV-TB screening arm compared to the SOC arm (11 days) and HIV screening arm (6 days). HIV screening reduced undiagnosed/untreated HIV from 10 (2.7%) in the SOC arm to 2 (0.5%) in the HIV screening arm and 1 (0.2%) in the HIV-TB screening arm. Over the trial follow-up period (56 days), oral HIV testing and linkage to care were likely to be cost-effective, but digital chest X-ray with computer-aided interpretation was not. What do these findings mean? Digital chest X-ray screening with computer-aided interpretation for TB with universal HIV screening increased the timeliness and completeness of HIV and TB diagnosis. If implemented at scale, these interventions have the potential to rapidly and efficiently improve TB and HIV diagnosis and treatment.

Background: HIV and tuberculosis are frequently diagnosed concurrently. In March 2021, World Health Organization recommended that antiretroviral therapy (ART) should be started within two weeks of tuberculosis treatment start, at any CD4 count. We assessed whether earlier ART improved outcomes in people with newly diagnosed HIV and tuberculosis. Methods: We did a systematic review by searching nine databases for trials that compared earlier ART to later ART initiation in people with HIV and tuberculosis. We included studies published from database inception to 12 March 2021. We compared ART within four weeks versus ART more than four weeks after TB treatment, and ART within two weeks versus ART between two and eight weeks, and stratified analysis by CD4 count. The main outcome was death; secondary outcomes included IRIS and AIDS‐defining events. We pooled effect estimates using random effects meta‐analysis. Results and discussion: We screened 2468 abstracts, and identified nine trials. Among people with all CD4 counts, there was no difference in mortality by earlier ART (≤4 week) versus later ART (>4 week) (risk difference [RD] 0%, 95% confidence interval [CI] −2% to +1%). Among people with CD4 count ≤50 cells/mm3, earlier ART (≤4 weeks) reduced risk of death (RD −6%, −10% to −1%). Among people with all CD4 counts earlier ART (≤4 weeks) increased the risk of IRIS (RD +6%, 95% CI +2% to +10%) and reduced the incidence of AIDS‐defining events (RD −2%, 95% CI −4% to 0%). Results were similar when trials were restricted to the four trials which permitted comparison of ART within two weeks to ART between two and eight weeks. Trials were conducted between 2004 and 2014, before recommendations to treat HIV at any CD4 count or to rapidly start ART in people without TB. No trials included children or pregnant women. No trials included integrase inhibitors in ART regimens. Discussion: Earlier ART did not alter risk of death overall among people living with HIV who had TB disease. For logistical and patient preference reasons, earlier ART initiation for everyone with TB and HIV may be preferred to later ART.

OBJECTIVE: To investigate trends in population incidence of HIV-positive hospital admission and risk of in-hospital death among adults living with HIV between 2012 and 2019 in Blantyre, Malawi. DESIGN: Population cohort study using an existing electronic health information system ('SPINE') at Queen Elizabeth Central Hospital and Blantyre census data. METHODS: We used multiple imputation and negative binomial regression to estimate population age-specific and sex-specific admission rates over time. We used a log-binomial model to investigate trends in risk of in-hospital death. RESULTS: Of 32 814 adult medical admissions during Q4 2012--Q3 2019, HIV status was recorded for 75.6%. HIV-positive admissions decreased substantially between 2012 and 2019. After imputation for missing data, HIV-positive admissions were highest in Q3 2013 (173 per 100 000 adult Blantyre residents) and lowest in Q3 2019 (53 per 100 000 residents). An estimated 10 818 fewer than expected people with HIV (PWH) [95% confidence interval (CI) 10 068-11 568] were admitted during 2012-2019 compared with the counterfactual situation where admission rates stayed the same throughout this period. Absolute reductions were greatest for women aged 25-34 years (2264 fewer HIV-positive admissions, 95% CI 2002-2526). In-hospital mortality for PWH was 23.5%, with no significant change over time in any age-sex group, and no association with antiretroviral therapy (ART) use at admission. CONCLUSION: Rates of admission for adult PWH decreased substantially, likely because of large increases in community provision of HIV diagnosis, treatment and care. However, HIV-positive in-hospital deaths remain unacceptably high, despite improvements in ART coverage. A concerted research and implementation agenda is urgently needed to reduce inpatient deaths among PWH.

Background\ud 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.\ud Methods\ud 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.\ud Results\ud 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.\ud Interpretation\ud 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.\ud Funding\ud WHO Global TB Programme.

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.

Objectives: Tuberculosis symptoms are very common among people living with HIV (PLHIV) initiating antiretroviral therapy (ART), are not specific for tuberculosis disease and may result in delayed ART start. The risks and benefits of same‐day ART initiation in PLHIV with tuberculosis symptoms are unknown. Methods: We systematically reviewed nine databases on 12 March 2020 to identify studies that investigated same‐day ART initiation among PLHIV with tuberculosis symptoms and reported both their approach to TB screening and clinical outcomes. We extracted and summarized data about TB screening, numbers of people starting same‐day ART and outcomes. Results: We included four studies. Two studies deferred ART for everyone with any tuberculosis symptoms (one or more of cough, fever, night sweats or weight loss) and substantial numbers of people had deferred ART start (28% and 39% did not start same‐day ART). Two studies permitted some people with tuberculosis symptoms to start same‐day ART, and fewer people deferred ART (2% and 16% did not start same‐day). Two of the four studies were conducted sequentially; proven viral load suppression at 8 months was 31% when everyone with tuberculosis symptoms had ART deferred, and 44% when the algorithm was changed so that some people with tuberculosis symptoms could start same‐day ART. Conclusions: Although tuberculosis symptoms are very common in people starting ART, there is insufficient evidence about whether presence of tuberculosis symptoms should lead to ART start being deferred or not. Research to inform clear guidelines would help to maximise the benefits of same‐day ART.

Background: Hospital admission and discharge data from Southern and Eastern Africa are sparse but suggest that, despite impressive progress in population coverage of HIV testing and antiretroviral therapy (ART) programmes, many hospital admissions remain attributable to HIV. Methods: An inpatient electronic health information system (‘SPINE’) in Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi recorded data from all adult medical admissions. We combined these with Malawi census data to investigate trends in admission rates for Blantyre residents between 2012 and 2019. Multiple imputation and negative binomial regression was used to estimate population age- and sex-specific admission rates over time. A log-binomial model was used to investigate trends in risk of in-hospital death. Results: Of 32,814 medical admissions during Q4.2012-Q3.2019, HIV status was recorded for 75.6%. ART coverage among hospitalised people living with HIV (PLHIV) increased from 66.0% in Q4.2012 to 92.5% in Q3.2019. After imputation for missing data, HIV-positive admissions per 100,000 Blantyre residents decreased substantially from peak Q3.2014 rates of 110 to 43 per 100,000 residents per quarter-year in Q3.2019. An estimated 10,818 fewer than expected PLHIV (95%CI 10,068-11,568) were admitted after 2012-2019 compared to the counterfactual situation where admission rates stayed the same throughout this period. Absolute reductions were greatest for women aged 25-34 years (2,264 fewer HIV-positive admissions, 95%CI 2,002-2,526). In-hospital mortality for PLHIV was 23.5%, with no significant change over time in any age-sex group, and no association with ART at admission. Discussion: Rates of admission for PLHIV decreased substantially, likely due to large increases in community provision of HIV diagnosis, treatment and care. However, HIV-positive in-hospital deaths remain unacceptably high, despite improvements in ART coverage. A concerted research and implementation agenda is urgently needed to reduce inpatient deaths among PLHIV. Funding Statement: SPINE received funding from Wellcome Core Grant to the Malawi-Liverpool-Wellcome Trust (reference 206545). RMB and PM are funded by Wellcome (203905/Z/16/Z and 206575/Z/17/Z, respectively). Declaration of Interests: MISSING Ethics Approval Statement: Use of anonymous electronic data (from SPINE project) was approved by QECH hospital research committee. Individual patient consent for anonymised secondary analysis was not sought.

Background To determine if tuberculosis (TB) screening improves patient outcomes, we conducted two systematic reviews to investigate the effect of TB screening on diagnosis, treatment outcomes, deaths (clinical review assessing 23 outcome indicators); and patient costs (economic review). Methods Pubmed, EMBASE, Scopus and the Cochrane Library were searched between 1/1/1980-13/4/2020 (clinical review) and 1/1/2010-14/8/2020 (economic review). As studies were heterogeneous, data synthesis was narrative. Findings Clinical review: of 27,270 articles, 18 (n=3 trials) were eligible. Nine involved general populations. Compared to passive case finding (PCF), studies showed lower smear grade (n=2/3) and time to diagnosis (n=2/3); higher pre-treatment losses to follow-up (screened 23% and 29% vs PCF 15% and 14%; n=2/2); and similar treatment success (range 68-81%; n=4) and case fatality (range 3-11%; n=5) in the screened group. Nine reported on risk groups. Compared to PCF, studies showed lower smear positivity among those culture-confirmed (n=3/4) and time to diagnosis (n=2/2); and similar (range 80-90%; n=2/2) treatment success in the screened group. Case fatality was lower in n=2/3 observational studies; both reported on established screening programmes. A neonatal trial and post-hoc analysis of a household contacts trial found screening was associated with lower all-cause mortality. Economic review: From 2841 articles, six observational studies were eligible. Total costs (n=6) and catastrophic cost prevalence (n=4; range screened 9-45% vs PCF 12-61%) was lower among those screened. Interpretation We found very limited patient outcome data. Collecting and reporting this data must be prioritised to inform policy and practice. Funding WHO and EDCTP.

Purpose: Neonatal sepsis caused by Streptococcus agalactiae [group B streptococcus (GBS)] is a life-threatening condition, which is preventable if colonized mothers are identified and given antibiotic prophylaxis during labour. Conventional culture is time consuming and unreliable, and many available non-culture diagnostics are too complex to implement routinely at point of care. Loop-mediated isothermal amplification (LAMP) is a method that, enables the rapid and specific detection of target nucleic acid sequences in clinical materials without the requirement for extensive sample preparation.Methodology: A prototype LAMP assay targeting GBS sip gene is described.Results: The assay was 100 % specific for GBS, with a limit of detection of 14 genome copies per reaction. The clinical utility of the LAMP assay for rapid direct molecular detection of GBS was determined by testing a total of 157 vaginal swabs with minimal sample processing using a rapid lysis solution. Compared to a reference quantitative real-time PCR assay, the direct LAMP protocol had a sensitivity and specificity of 95.4 and 100 %, respectively, with positive and negative predictive values of 100 and 98.3 %, respectively. Positive and negative likelihood ratios were infinity and 0.05, respectively. The direct LAMP method required a mean time of 45 min from the receipt of a swab to generation of a confirmed result, compared to 2 h 30 min for the reference quantitative real-time PCR test.Conclusion: The direct LAMP protocol described is easy to perform, facilitating rapid and accurate detection of GBS in vaginal swabs. This test has a potential for use at point of care.

Background The global annual estimate for cryptococcal disease related deaths exceeds 180,000, with three fourth occurring in sub-Saharan Africa. The World Health Organization (WHO) recommends cryptococcal antigen (CrAg) screening in all HIV patients with CD4 count

We summarise recent emerging evidence around tuberculosis (TB) transmission and its role in tuberculosis epidemiology, and in novel TB screening and diagnostic tests that will likely become available in low-resource settings in the near future. Little consideration has been paid to how these novel new tests will be implemented, nor what the consequences for individuals, communities and health systems will be. In particular, because of low specificity and consequent false-positive diagnoses, and the low percentage of people who “screen positive” that will go onto develop active pulmonary disease, there is significant potential for inappropriate initiation of TB treatment, as well as stigmatisation, loss of livelihoods and in some setting institutionalisation, with uncertain benefit for individual health or community transmission. We use analogy to prompt consideration of how and where new TB screening tests could be implemented in TB screening programmes in low-resource settings. Acceptance and confidence in TB screening programmes depends on well-functioning public health programmes that use screening algorithms that minimise harms and balance population benefits with autonomy and respect for individuals. Before new TB screening tests and algorithms are introduced, more evidence for their effectiveness, costs, benefits and harms under real-world conditions are required.

Coronavirus disease 2019 (COVID-19) is now established in Africa, with more than 63 000 cases and 2200 deaths in 53 countries, as of May 11, 2020.1 Fragile health systems leave African countries vulnerable to the anticipated surge in severely ill patients with COVID-19, despite much younger populations.

Introduction Hepatitis B is a serious public health problem across sub-Saharan Africa. Sierra Leone has no national hepatitis B strategy plan or high quality estimates of prevalence. Healthcare workers are perceived as an at-risk group for hepatitis B. We assessed the prevalence of hepatitis B among healthcare workers at two hospital sites in Freetown, Sierra Leone. Methods In October 2017, healthcare workers were offered voluntary testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), hepatitis B e antigen (HBeAg) and hepatitis B e antibody (anti-HBe) using rapid lateral flow assay for all samples, followed by Enzyme Immunosorbent Assay to confirm positive results. Participants completed a questionnaire about knowledge, attitudes and practices concerning hepatitis B. HBsAg positive participants were invited to a clinic for further assessment. Results Overall, 447 participants were tested for hepatitis B. Most (90.6%, 405/447) participants were nurses, 72.3% (323/447) were female and 71.6% (320/447) were 30 years or older. The prevalence of chronic hepatitis B (HBsAg positivity) was 8.7% (39 / 447, 95% CI 6.3–11.7%). There was no significant difference in prevalence by sex, age group, site of work or type of job. None of the 66.7% (26 / 39) of participants with chronic hepatitis B who attended the clinic met the 2015 WHO criteria to start treatment for hepatitis B on the basis of cirrhosis. Most participants (96.9% 432 / 446) stated that they were worried about their risk of hepatitis B at work. Conclusions Hepatitis B is highly prevalent among healthcare workers in Sierra Leone. It is unclear whether this reflects high community prevalence or is due to occupational risk. No participants with chronic hepatitis B needed to start treatment. In order to achieve the WHO target of elimination of viral hepatitis by 2030, introduction of birth dose vaccine for infants and catch-up vaccines for healthcare workers and healthcare students, together with a national hepatitis B screen and treat programme is advisable for Sierra Leone.

We report the range of minimum inhibitory concentrations for six antimicrobial drugs in 228 clinical Mycobacterium tuberculosis (MTB) isolates from three distinct groups of patients (unselected patients, patients at high risk of drug-resistant TB and HIV-positive patients) in Lima, Peru. These data highlight the challenges of and discriminatory characteristics required for MTB drug susceptibility testing.

BackgroundSleep-disordered breathing is a common and serious feature of many paediatric conditions and is particularly a problem in children with Down syndrome. Overnight pulse oximetry is recommended as an initial screening test, but it is unclear how overnight oximetry results should be interpreted and how many nights should be recorded.MethodsThis retrospective observational study evaluated night-to-night variation using statistical measures of repeatability for 214 children referred to a paediatric respiratory clinic, who required overnight oximetry measurements. This included 30 children with Down syndrome. We measured length of adequate trace, basal SpO2, number of desaturations (>4% SpO2 drop for >10 s) per hour (‘adjusted index’) and time with SpO2Results132 out of 214 (62%) children had three technically adequate nights’ oximetry, including 13 out of 30 (43%) children with Down syndrome. Intraclass correlation coefficient for adjusted index was 0.54 (95% CI 0.20 to 0.81) among children with Down syndrome and 0.88 (95% CI 0.84 to 0.91) for children with other diagnoses. Negative predictor value of a negative first night predicting two subsequent negative nights was 0.2 in children with Down syndrome and 0.55 in children with other diagnoses.ConclusionsThere is substantial night-to-night variation in overnight oximetry readings among children in all clinical groups undergoing overnight oximetry. This is a more pronounced problem in children with Down syndrome. Increasing the number of attempted nights’ recording from one to three provides useful additional clinical information.

Sub-optimal recovery of bacterial DNA from whole blood samples can limit the sensitivity of molecular assays to detect pathogenic bacteria. We compared 3 different pre-lysis protocols (none, mechanical pre-lysis and achromopeptidasepre-lysis) and 5 commercially available DNA extraction platforms for direct detection of Group B Streptococcus (GBS) in spiked whole blood samples, without enrichment culture. DNA was extracted using the QIAamp Blood Mini kit (Qiagen), UCP Pathogen Mini kit (Qiagen), QuickGene DNA Whole Blood kit S (Fuji), Speed Xtract Nucleic Acid Kit 200 (Qiagen) and MagNA Pure Compact Nucleic Acid Isolation Kit I (Roche Diagnostics Corp). Mechanical pre-lysis increased yields of bacterial genomic DNA by 51.3 fold (95% confidence interval; 31.6–85.1, p < 0.001) and pre-lysis with achromopeptidase by 6.1 fold (95% CI; 4.2–8.9, p < 0.001), compared with no pre-lysis. Differences in yield dueto pre-lysis were 2–3 fold larger than differences in yield between extraction methods. Including a pre-lysis step can improve the limits of detection of GBS using PCR or other molecular methods without need for culture.

Challenges to peptide-based therapies include rapid clearance, ready degradation by hydrolysis/proteolysis, and poor intestinal uptake and/or a need for blood brain barrier transport. This work evaluates the efficacy of conjugation of vitamin B12 (B12) on sc administered peptide tyrosine tyrosine (PYY)(3-36) function. In the current experiments, a B12-PYY(3-36) conjugate was tested against native PYY(3-36), and an inactive conjugate B12-PYYC36 (null control) in vitro and in vivo. In vitro experiments demonstrated similar agonism for the neuropeptide Y2 receptor by the B12-PYY(3-36) conjugate (EC50 26.5 nM) compared with native PYY(3-36) (EC50 16.0 nM), with the null control having an EC50 of 1.8 μM. In vivo experiments were performed in young adult male Sprague Dawley rats (9 wk). Daily treatments were delivered sc in five 1-hour pulses, each pulse delivering 5-10 nmol/kg, by implanted microinfusion pumps. Increases in hindbrain Fos expression were comparable 90 minutes after B12-PYY(3-36) or PYY3-36 injection relative to saline or B12-PYYC36. Food intake was reduced during a 5-day treatment for both B12-PYY(3-36)- (24%, P = .001) and PYY(3-36)-(13%, P = .008) treated groups relative to baseline. In addition, reduction of food intake after the three dark cycle treatment pulses was more consistent with B12-PYY(3-36) treatment (-26%, -29%, -27%) compared with the PYY(3-36) treatment (-3%, -21%, -16%), and B12-PYY(3-36) generated a significantly longer inhibition of food intake vs. PYY(3-36) treatment after the first two pulses (P = .041 and P = .036, respectively). These findings demonstrate a stronger, more consistent, and longer inhibition of food intake after the pulses of B12-PYY(3-36) conjugate compared with the native PYY(3-36).

On 1 February 2016 the World Health Organization declared a Public Health Emergency of International Concern following reports of large clusters of microcephaly and Guillain-Barre Syndrome associated with an increase in cases of Zika virus (ZIKV) infection in French Polynesia (2014) and Brazil (2015– 2016).1 The Committee emphasised that there was ‘... no public health justification for restrictions on travel or trade’ and the main interventions were to control mosquito populations and prevent bites in pregnant women. Why has this happened and how might it affect patients attending primary care in the UK? ZIKV was first isolated from a Rhesus monkey in Uganda in 1947.2 The following year it was identified in Aedes mosquitoes, which differ from malaria-transmitting Anopheles mosquitoes by biting during the day. ZIKV has been found throughout Africa and South East Asia where infection is asymptomatic or produces a mild febrile illness and rash which goes undiagnosed. The first outbreak was not recorded until 2007 when three-quarters of the population of Yap Island in Micronesia became infected.3 The current epidemic of ZIKV infection began in early 2015 in northeastern Brazil. Since then ZIKV transmission has been confirmed in 35 countries.4 One theory is that ZIKV was carried to Brazil by infected Pacific Islanders visiting an international canoeing event in Rio de Janeiro in August 2014. In September 2015 clinicians working in Pernambuco state noticed an increase in newborn babies with microcephaly. The Ministry of Health quickly established a register and within 3 months recorded 4180 suspected cases, including 68 deaths, compared to a total of 147 reports in …

Background The prevalence of asymptomatic tuberculosis (TB) in recently diagnosed HIV-1-infected persons attending pre-antiretroviral therapy (ART) clinics is not well described. In addition, it is unclear if the detection of Mycobacterium tuberculosis in these patients clearly represents an early asymptomatic phase leading to progressive disease or transient excretion of bacilli. Objective To describe the prevalence and outcome of subclinical TB disease in HIV-1-infected persons not eligible for ART. Methods The study was conducted in 274 asymptomatic ART-naive HIV-1-infected persons in Khayelitsha Day Hospital, Cape Town, South Africa. All participants were screened for TB using a symptom screen and spoligotyping was performed to determine genotypes. Results The prevalence of subclinical TB disease was 8.5% (95% CI 5.1% to 13.0%) (n=18; median days to culture positivity 17 days), with 22% of patients being smear-positive. Spoligotyping showed a diverse variety of genotypes with all paired isolates being of the same spoligotype, effectively excluding cross-contamination. 56% of patients followed up developed symptoms 3 days to 2 months later. All were well and still in care 6–12 months after TB diagnosis; 60% were started on ART. A positive tuberculin skin test (OR 4.96, p=0.064), low CD4 count (OR 0.996, p=0.06) and number of years since HIV diagnosis (OR 1.006, p=0.056) showed trends towards predicting TB disease. Conclusion This study found a high prevalence but good outcome (retained in care) of subclinical TB disease in HIV-1-infected persons. The results suggest that, in high HIV/TB endemic settings, a positive HIV-1 test should prompt TB screening by sputum culture irrespective of symptoms, particularly in those with a positive tuberculin skin test, longer history of HIV infection and low CD4 count. Operational difficulties in resource-constrained settings with respect to screening with TB culture highlight the need for rapid and affordable point-of-care tests to identify persons with clinical and subclinical TB disease.