Enhanced tuberculosis diagnosis with computer-aided chest X-ray and urine LAM in adults with HIV admitted to hospital (CASTLE study): A cluster randomised trial.

BACKGROUND: People with HIV (PHIV) admitted to hospital have high mortality, with tuberculosis (TB) being the major cause of death. Systematic use of new TB diagnostics could improve TB diagnosis and might improve outcomes. METHODS: We conducted a cluster randomised trial among adult PHIV admitted to Zomba Central Hospital, Malawi. Admission-days were randomly assigned to: enhanced TB diagnostics using urine lipoarabinomannan (LAM) antigen tests (SILVAMP-LAM, Fujifilm, Japan and Determine-LAM, Alere/Abbot, USA), digital chest X-ray with computer aided diagnosis (dCXR-CAD, CAD4TBv6, Delft, Netherlands), plus usual care ("enhanced TB diagnostics"); or usual care alone ("usual care"). The primary outcome was TB treatment initiation during admission. Secondary outcomes were 56-day mortality, TB diagnosis within 24-hours, and undiagnosed TB at discharge, ascertained by culture of one admission sputum sample. FINDINGS: Between 2 September 2020 and 15 February 2022, we recruited 419 people. Four people were excluded post-recruitment, leaving 415 adults recruited during 207 randomly assigned admission-days in modified intention-to-treat analysis. At admission, 90.8% (377/415) were taking antiretroviral therapy (ART) with median (IQR) CD4 cell count 240 cells/mm3. In the enhanced diagnostic arm, median CAD4TBv6 score was 60 (IQR: 51-71), 4.4% (9/207) had SILVAMP-LAM-positive and 14.4% (29/201) had Determine-LAM positive urine with three samples positive by both urine tests. TB treatment was initiated in 46/208 (22%) in enhanced TB diagnostics arm and 24/207 (12%) in usual care arm (risk ratio [RR] 1.92, 95% CI 1.20-3.08). There was no difference in mortality by 56 days (enhanced TB diagnosis: 54/208, 26%; usual care: 52/207, 25%; hazard ratio 1.05, 95% CI 0.72-1.53); TB treatment initiation within 24 hours (enhanced TB diagnosis: 8/207, 3.9%; usual care: 5/208, 2.4%; RR 1.61, 95% CI 0.53-4.71); or undiagnosed microbiological-confirmed TB at discharge (enhanced TB diagnosis, 0/207 (0.0%), usual care arm 2/208 (1.0%) (p = 0.50). INTERPRETATION: Urine SILVAMP-LAM/Determine-LAM plus dCXR-CAD diagnostics identified more hospitalised PHIV with TB than usual care. The increase in TB treatment appeared mainly due to greater use of Determine-LAM, rather than SILVAMP-LAM or dCXR-CAD. Poor concordance between Determine-LAM and SILVAMP-LAM urine tests requires further investigation. Inpatient mortality for adults with HIV remains unacceptability high.

Reduction in mortality from HIV-related CNS infections in routine care in Africa (DREAMM): a before-and-after, implementation study.

BACKGROUND: Four decades into the HIV epidemic, CNS infection remains a leading cause of preventable HIV-related deaths in routine care. The Driving Reduced AIDS-associated Meningo-encephalitis Mortality (DREAMM) project aimed to develop, implement, and evaluate pragmatic implementation interventions and strategies to reduce mortality from HIV-related CNS infection. METHODS: DREAMM took place in five public hospitals in Cameroon, Malawi, and Tanzania. The main intervention was a stepwise algorithm for HIV-related CNS infections including bedside rapid diagnostic testing and implementation of WHO cryptococcal meningitis guidelines. A health system strengthening approach for hospitals was adopted to deliver quality care through a co-designed education programme, optimised clinical and laboratory pathways, and communities of practice. DREAMM was led and driven by local leadership and divided into three phases: observation (including situational analyses of routine care), training, and implementation. Consecutive adults (aged ≥18 years) living with HIV presenting with a first episode of suspected CNS infection were eligible for recruitment. The primary endpoint was the comparison of 2-week all-cause mortality between observation and implementation phases. This study completed follow-up in September, 2021. The project was registered on ClinicalTrials.gov, NCT03226379. FINDINGS: From November, 2016 to April, 2019, 139 eligible participants were enrolled in the observation phase. From Jan 9, 2018, to March 25, 2021, 362 participants were enrolled into the implementation phase. 216 (76%) of 286 participants had advanced HIV disease (209 participants had missing CD4 cell count), and 340 (69%) of 494 participants had exposure to antiretroviral therapy (ART; one participant had missing ART data). In the implementation phase 269 (76%) of 356 participants had a probable CNS infection, 203 (76%) of whom received a confirmed microbiological or radiological diagnosis of CNS infection using existing diagnostic tests and medicines. 63 (49%) of 129 participants died at 2 weeks in the observation phase compared with 63 (24%) of 266 in the implementation phase; and all-cause mortality was lower in the implementation phase when adjusted for site, sex, age, ART exposure (adjusted risk difference -23%, 95% CI -33 to -13; p<0·001). At 10 weeks, 71 (55%) died in the observation phase compared with 103 (39%) in the implementation phase (-13%, -24 to -3; p=0·01). INTERPRETATION: DREAMM substantially reduced mortality from HIV-associated CNS infection in resource-limited settings in Africa. DREAMM scale-up is urgently required to reduce deaths in public hospitals and help meet Sustainable Development Goals. FUNDING: European and Developing Countries Clinical Trials Partnership, French Agency for Research on AIDS and Viral Hepatitis. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section.

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 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.

Risk factors for esophageal cancer in a high-incidence area of Malawi.

PURPOSE: To explore associations of nutritional, infectious, and lifestyle factors with esophageal cancer (EC) occurrence in a high-risk area of Malawi. METHODS: This case-control study was performed with 227 patients undergoing endoscopy for dysphagia or other upper gastrointestinal complaints. Data on clinicopathological characteristics and risk factors were collected using a questionnaire developed for this study specifically. Ninety-eight blood samples were collected and the prevalence of antibodies against human immunodeficiency virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, and Helicobacter pylori were determined serologically. RESULTS: The tumor and control groups comprised 157 (69.2%) and 70 (31.8%) patients, respectively. Patients with tumors were significantly older than controls (55.5 vs. 43.5 years, p < 0.001). The male/female ratio did not differ between groups (59% and 54% male, respectively; p = 0.469). EC was associated with smoking (p < 0.001), and alcohol consumption (p = 0.020), but 43% of patients with tumors did not smoke or drink. EC was associated with the consumption of hot food and tea (p = 0.003) and smoked fish (p = 0.011). EC was not associated with any serologically investigated infectious agents. In an age adjusted binary logistic regression analysis of all nutritive factors, only locally made alcohol was significant [odds ratio (OR), 9.252; 95% confidence interval (CI), 1.455-58.822; p = 0.018]. CONCLUSIONS: Apart from alcohol consumption and smoking, the consumption of hot food or tea and smoked fish are associated with EC. Locally distilled alcohol consumption increases the EC risk in Malawi.

Decentralising diabetes care from hospitals to primary health care centres in Malawi.

BACKGROUND: Non-communicable diseases (NCDs) such as diabetes and hypertension have become a prominent public health concern in Malawi, where health care services for NCDs are generally restricted to urban centres and district hospitals, while the vast majority of Malawians live in rural settings. Whether similar quality of diabetes care can be delivered at health centres compared to hospitals is not known. METHODS: We implemented a pilot project of decentralized diabetes care at eight health centres in four districts in Malawi. We described differences between district hospitals and rural health centres in terms of patient characteristics, diabetes complications, cardiovascular risk factors, and aspects of the quality of care and used multivariate logistic regression to explore factors associated with adequate diabetes and blood pressure control. RESULTS: By March 2019, 1339 patients with diabetes were registered of whom 286 (21%) received care at peripheral health centres. The median duration of care of patients in the diabetes clinics during the study period was 8.8 months. Overall, HIV testing coverage was 93.6%, blood pressure was recorded in 92.4%; 68.5% underwent foot examination of whom 35.0% had diabetic complications; 30.1% underwent fundoscopy of whom 15.6% had signs of diabetic retinopathy. No significant differences in coverage of testing for diabetes complications were observed between health facility types. Neither did we find significant differences in retention in care (72.1 vs. 77.6%; p=0.06), adequate diabetes control (35.0% vs. 37.8%; p=0.41) and adequate blood pressure control (51.3% vs. 49.8%; p=0.66) between hospitals and health centres. In multivariate analysis, male sex was associated with adequate diabetes control, while lower age and normal body mass index were associated with adequate blood pressure control; health facility type was not associated with either. CONCLUSION: Quality of care did not appear to differ between hospitals and health centres, but was insufficient at both levels.

Age estimation of Malawian adults from dental radiographs.

BACKGROUND: Previous studies have shown that with advancing age the size of the dental pulp cavity is reduced as a result of secondary dentine deposit, so that measurements of this reduction can be used as an indicator of age. Age estimation is one of the indicators used in forensic identification and teeth are biological markers for human age estimation. METHODOLOGY: We measured the height (mm) of the crown (CH = Coronal Height) and the height (mm) of the coronal pulp cavity (CPCH = Coronal pulp cavity height) of premolars and molars of 134 adult Malawians (77 males, 57 females) aged 20 - 80 years from dental radiographs. The Tooth-Coronal Index (TCI) was computed for each tooth and regressed on real age. RESULT: The correlation coefficients ranged from r -0.650 to -0.799 and were significant in both gender, in premolars and molars (P < 0.01). The equations obtained allowed estimation of age with an error of +/- 5 years in our studied population, the molar equation estimated age better for males while the premolar equation was for female and combined samples. The percentage accuracy levels of our sample population were higher than Caucasians previously reported using similar methods. CONCLUSION: Our study demonstrates the potential value of this method of age estimation which is precise, simple, non invasive and applicable to both living individuals and skeletal materials of unknown age.