Design and protocol for a pragmatic randomised study to optimise screening, prevention and care for tuberculosis and HIV in Malawi (PROSPECT Study)

Background: Adults seeking diagnosis and treatment for tuberculosis (TB) and HIV in low-resource settings face considerable barriers and have high pre-treatment mortality. Efforts to improve access to prompt TB treatment have been hampered by limitations in TB diagnostics, with considerable uncertainty about how available and new tests can best be implemented. Design and methods: The PROSPECT Study is an open, three-arm pragmatic randomised study that will investigate the effectiveness and cost-effectiveness of optimised HIV and TB diagnosis and linkage to care interventions in reducing time to TB diagnosis and prevalence of undiagnosed TB and HIV in primary care in Blantyre, Malawi. Participants (≥ 18 years) attending a primary care clinic with TB symptoms (cough of any duration) will be randomly allocated to one of three groups: (i) standard of care; (ii) optimised HIV diagnosis and linkage; or (iii) optimised HIV and TB diagnosis and linkage. We will test two hypotheses: firstly, whether prompt linkage to HIV care should be prioritised for adults with TB symptoms; and secondly, whether an optimised TB triage testing algorithm comprised of digital chest x-ray evaluated by computer-aided diagnosis software and sputum GeneXpert MTB/Rif can outperform clinician-directed TB screening. The primary trial outcome will be time to TB treatment initiation by day 56, and secondary outcomes will include prevalence of undiagnosed TB and HIV, mortality, quality of life, and cost-effectiveness. Conclusions: The PROSPECT Study will provide urgently-needed evidence under “real-life” conditions to inform clinicians and policy makers on how best to improve TB/HIV diagnosis and treatment in Africa

Teleradiology usage and user satisfaction with the telemedicine system operated by Médecins Sans Frontières

Médecins Sans Frontières (MSF) began a pilot trial of store-and-forward telemedicine in 2010, initially operating separate networks in English, French, and Spanish; these were merged into a single, multilingual platform in 2013. We reviewed the pattern of teleradiology usage on the MSF telemedicine platform in the 4-year period from April 2010. In total, 564 teleradiology cases were submitted from 22 different countries. A total of 1114 files were uploaded with the 564 cases, the majority being of type JPEG (n = 1081, 97%). The median file size was 938 kb (interquartile range, IQR 163-1659). A panel of 14 radiologists was available to report cases, but most (90%) were reported by only 4 radiologists. The median radiologist response time was 6.1 h (IQR 3.0-20). A user satisfaction survey was sent to 29 users in the last 6 months of the study. There was a 28% response rate. Most respondents found the radiologist's advice helpful and all of them stated that the advice assisted in clarification of a diagnosis. Although some MSF sites made substantial use of the system for teleradiology, there is considerable potential for expansion. More promotion of telemedicine may be needed at different levels of the organization to increase engagement of staff

Evaluation of a chest radiograph reading and recording system for tuberculosis in a HIV-positive cohort.

Aim To assess the impact of introducing a chest radiograph reading and recording system (CRRS) with a short training session, on the accuracy and inter-reader variability of tuberculosis (TB) interpretation of chest radiographs (CXRs) by a group of non-expert readers in a human immunodeficiency virus (HIV)-positive cohort. Materials and methods A set of 139 CXRs was reviewed by a group of eight physicians pre- and post-intervention at two clinics in Shan State, Myanmar, providing HIV/TB diagnosis and treatment services. The results were compared against the consensus of expert radiologists for accuracy. Results Overall accuracy was similar pre- and post-intervention for most physicians with an average area under the receiver operating characteristic curve difference of 0.02 (95% confidence interval: –0.03, 0.07). The overall agreement among physicians was poor pre- and post-intervention (Fleiss κ=0.35 and κ=0.29 respectively). The assessment of agreement for specific disease patterns associated with active TB in HIV-infected patients showed that for intrinsically subtle findings, the agreement was generally poor but better for the more intrinsically obvious disease patterns: pleural effusion (Cohen’s kappa range = 0.37–0.67) and milliary nodular pattern (Cohen’s kappa range = 0.25–0.52). Conclusion This study demonstrated limited impact of the introduction of a CRRS on CXR accuracy and agreement amongst non-expert readers. The role in which CXRs are used for TB diagnosis in a HIV-positive cohort in similar clinical contexts should be reviewed

Prospective cohort study to identify prevalence, risk factors and outcomes of infection associated kidney disease in a regional hospital in Malawi

Objectives: Acute kidney injury (AKI) is a common and severe complication of community acquired infection, but data on impact in sub-Saharan Africa (SSA) are lacking. We determined prevalence, risk factors and outcomes of infection associated kidney disease in adults in Malawi. Design: A prospective cohort study of adults admitted to hospital with infection, from February 2021 to June 2021, collecting demographic, clinical, laboratory and ultrasonography data. Setting: Adults admitted to a regional hospital in Southern Region, Malawi. Primary and secondary outcome measures: The primary outcomes were prevalence of kidney disease and mortality by Cox proportional hazard model. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Secondary outcomes were risk factors for AKI identified by logistic regression and prevalence of chronic kidney disease at 3 months. Results: We recruited 101 patients presenting to hospital with infection. Median age was 38 years (IQR: 29–48 years), 88 had known HIV status of which 53 (60%) were living with HIV, and of these 42 (79%) were receiving antiretroviral therapy. AKI was present in 33/101 at baseline, of which 18/33 (55%) cases were severe (KDIGO stage 3). At 3 months, 28/94 (30%) participants had died, while 7/61 (11%) of survivors had chronic kidney disease. AKI was associated with older age (age: 60 years vs 40 years, OR: 3.88, 95% CI 1.82 to 16.64), and HIV positivity (OR: 4.08, 95% CI 1.28 to 15.67). Living with HIV was independently associated with death (HR: 3.97, 95% CI 1.07 to 14.69). Conclusions: Kidney disease is common among hospitalised adults with infection in Malawi, with significant kidney impairment identified at 3 months. Our study highlights the difficulty in diagnosing acute and chronic kidney disease, and the need for more accurate methods than creatinine based estimated glomerular filtration rate (eGFR) equations for populations in Africa. Patients with kidney impairment identified in hospital should be prioritised for follow-up

Design and protocol for a pragmatic randomised study to optimise screening, prevention and care for tuberculosis and HIV in Malawi (PROSPECT Study)

Background: Adults seeking diagnosis and treatment for tuberculosis (TB) and HIV in low-resource settings face considerable barriers and have high pre-treatment mortality. Efforts to improve access to prompt TB treatment have been hampered by limitations in TB diagnostics, with considerable uncertainty about how available and new tests can best be implemented. Design and methods: The PROSPECT Study is an open, three-arm pragmatic randomised study that will investigate the effectiveness and cost-effectiveness of optimised HIV and TB diagnosis and linkage to care interventions in reducing time to TB diagnosis and prevalence of undiagnosed TB and HIV in primary care in Blantyre, Malawi. Participants (≥ 18 years) attending a primary care clinic with TB symptoms (cough of any duration) will be randomly allocated to one of three groups: (i) standard of care; (ii) optimised HIV diagnosis and linkage; or (iii) optimised HIV and TB diagnosis and linkage. We will test two hypotheses: firstly, whether prompt linkage to HIV care should be prioritised for adults with TB symptoms; and secondly, whether an optimised TB triage testing algorithm comprised of digital chest x-ray evaluated by computer-aided diagnosis software and sputum GeneXpert MTB/Rif can outperform clinician-directed TB screening. The primary trial outcome will be time to TB treatment initiation by day 56, and secondary outcomes will include prevalence of undiagnosed TB and HIV, mortality, quality of life, and cost-effectiveness. Conclusions: The PROSPECT Study will provide urgently-needed evidence under “real-life” conditions to inform clinicians and policy makers on how best to improve TB/HIV diagnosis and treatment in Africa. Clinical trial registration: NCT03519425 (08/05/2018

Ultrasound appearance of the kidney among radiology department attendees of a tertiary centre in Malawi.

Background: Diagnostic and therapeutic decisions in nephrology in low-resource settings are frequently based on ultrasound assessment of kidney size. An understanding of reference values is critical, particularly given the rise of non-communicable disease and the expanding availability of point-of-care ultrasound. However, there is a paucity of normative data from African populations. We determined estimates of kidney ultrasound measures, including kidney size based on age, sex, and HIV status, among apparently healthy outpatient attendees of Queen Elizabeth Central hospital radiology department, Blantyre, Malawi. Methods: We performed a cross-sectional cohort study of 320 adults attending the radiology department between October 2021 and January 2022. Bilateral kidney ultrasound was performed on all participants using a portable Mindray DP-50 machine and a 5MHz convex probe. The sample was stratified by age, sex, and HIV status. Predictive linear modelling was used to construct reference ranges for kidney size estimating the central 95 percentiles of 252 healthy adults. Exclusion criteria for the healthy sample were known kidney disease, hypertension, diabetes, BMI > 35, heavy alcohol intake, smoking and ultrasonographic abnormalities. Results: There were 162/320 (51%) male participants. The median age was 47 (interquartile range [IQR] 34-59). Among people living with HIV 134/138 (97%) were receiving antiretroviral therapy. Men had larger average kidney sizes: mean 9.68 cm (SD 0.80 cm), compared to 9.46 cm (SD 0.87 cm) in women ( = 0.01). Average kidney sizes in people living with HIV were not significantly different from those who were HIV-negative, 9.73 cm (SD 0.93 cm) versus 9.58 cm (SD 0.93 cm) ( = 0.63). Conclusions: This is the first report of the apparently healthy kidney size in Malawi. Predicted kidney size ranges may be used for reference in the clinical assessment of kidney disease in Malawi

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

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 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.</ns4:p

Patient outcomes associated with post-tuberculosis lung damage in Malawi: a prospective cohort study.

BACKGROUND: Post-tuberculosis lung damage (PTLD) is a recognised consequence of pulmonary TB (pTB). However, little is known about its prevalence, patterns and associated outcomes, especially in sub-Saharan Africa and HIV-positive adults. METHODS: Adult (≥15 years) survivors of a first episode of pTB in Blantyre, Malawi, completed the St George's Respiratory Questionnaire, 6-minute walk test, spirometry and high-resolution CT (HRCT) chest imaging at TB treatment completion. Symptom, spirometry, health seeking, TB-retreatment and mortality data were collected prospectively to 1 year. Risk factors for persistent symptoms, pulmonary function decline and respiratory-related health-seeking were identified through multivariable regression modelling. RESULTS: Between February 2016 and April 2017, 405 participants were recruited. Median age was 35 years (IQR: 28 to 41), 77.3% (313/405) had had microbiologically proven pTB, and 60.3% (244/403) were HIV-positive. At pTB treatment completion, 60.7% (246/405) reported respiratory symptoms, 34.2% (125/365) had abnormal spirometry, 44.2% (170/385) had bronchiectasis ≥1 lobe and 9.4% (36/385) had ≥1 destroyed lobe on HRCT imaging. At 1 year, 30.7% (113/368) reported respiratory symptoms, 19.3% (59/305) and 14.1% (43/305) of patients had experienced declines in FEV1 or FVC of ≥100 mL, 16.3% (62/380) had reported ≥1 acute respiratory event and 12.2% (45/368) had symptoms affecting their ability to work. CONCLUSIONS: PTLD is a common and under-recognised consequence of pTB that is disabling for patients and associated with adverse outcomes beyond pTB treatment completion. Increased efforts to prevent PTLD and guidelines for management of established disease are urgently needed. Low-cost clinical interventions to improve patient outcomes must be evaluated

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

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

Screening for post-TB lung disease at TB treatment completion: Are symptoms sufficient?

Pulmonary TB survivors face a high burden of post-TB lung disease (PTLD) after TB treatment completion. In this secondary data analysis we investigate the performance of parameters measured at TB treatment completion in predicting morbidity over the subsequent year, to inform programmatic approaches to PTLD screening in low-resource settings. Cohort data from urban Blantyre, Malawi were used to construct regression models for five morbidity outcomes (chronic respiratory symptoms or functional limitation, ongoing health seeking, spirometry decline, self-reported financial impact of TB disease, and death) in the year after PTB treatment, using three modelling approaches: logistic regression; penalised regression with pre-selected predictors; elastic net penalised regression using the full parent dataset. Predictors included demographic, clinical, symptom, spirometry and chest x-ray variables. The predictive performance of models were examined using the area under the receiver-operator curve (ROC AUC) values. Key predictors were identified, and their positive and negative predictive values (NPV) determined. The presence of respiratory symptoms at TB treatment completion was the strongest predictor of morbidity outcomes. TB survivors reporting breathlessness had higher odds of spirometry decline (aOR 20.5, 95%CI:3–199.1), health seeking (aOR 10.2, 2.4–50), and symptoms or functional limitation at 1-year (aOR 16.7, 3.3–133.4). Those reporting activity limitation were more likely to report symptoms or functional limitation at 1-year (aOR 4.2, 1.8–10.3), or severe financial impact of TB disease (aOR2.3, 1.0–5.0). Models were not significantly improved by including spirometry or imaging parameters. ROC AUCs were between 0.65–0.77 for the morbidity outcomes. Activity limitation at treatment completion had a NPV value of 78–98% for adverse outcomes. Our data suggest that whilst challenging to predict the development of post-TB morbidity, the use of symptom screening tools at TB treatment completion to prioritise post-TB care should be explored. We identified little benefit from the additional use of spirometry or CXR imaging