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.

Focused cardiac ultrasound: Competency among pre-internship medical officers in diagnosing cardiac causes of dyspnea.

BACKGROUND: Differentiating cardiovascular causes of dyspnea in resource-limited healthcare settings can be challenging. The use of easy-to-train, point-of-care, focused cardiac ultrasound (FoCUS) protocols may potentially alleviate this challenge. RESEARCH QUESTION: Can novices attain competency in FoCUS use after training using the cardiac ultrasound for resource-limited settings (CURLS) protocol? METHODS: A quasi-experimental study was conducted at the Kenyatta National Hospital in Nairobi, Kenya. Forty-five graduate medical pre-interns, novices in cardiac ultrasound, received simulated didactic and hands-on FoCUS skills training using the CURLS protocol and 2018 European Association of Cardiovascular Imaging (EACVI) FoCUS training and competence assessment recommendations. Competency was assessed in image interpretation, image acquisition, and image quality. RESULTS: Aggregate image interpretation competency was attained by n = 38 (84%) of trainees with a median score of 80%. The proportion of trainees attaining category-specific image interpretation competency was as follows: pericardial effusion n = 44 (98%), left atrial enlargement n = 40 (89%), cardiomyopathy n = 38 (84%), left ventricular hypertrophy n = 37 (82%), and right ventricular enlargement n = 29 (64%). Image acquisition skills competency was attained by n = 36 (80%) of trainees. Three-quarters of trainee-obtained images were of good quality. CONCLUSION: Majority of the trainees attained competency. Training constraints limit the generalizability of our findings.

Respiratory symptoms and lung function in patients treated for pulmonary tuberculosis in Malawi: a prospective cohort study.

RATIONALE: Pulmonary tuberculosis (PTB) can cause post-TB lung disease (PTLD) associated with respiratory symptoms, spirometric and radiological abnormalities. Understanding of the predictors and natural history of PTLD is limited. OBJECTIVES: To describe the symptoms and lung function of Malawian adults up to 3 years following PTB-treatment completion, and to determine the evolution of PTLD over this period. METHODS: Adults successfully completing PTB treatment in Blantyre, Malawi were followed up for 3 years and assessed using questionnaires, post-bronchodilator spirometry, 6 min walk tests, chest X-ray and high-resolution CT. Predictors of lung function at 3 years were identified by mixed effects regression modelling. MEASUREMENT AND MAIN RESULTS: We recruited 405 participants of whom 301 completed 3 years follow-up (mean (SD) age 35 years (10.2); 66.6% males; 60.4% HIV-positive). At 3 years, 59/301 (19.6%) reported respiratory symptoms and 76/272 (27.9%) had abnormal spirometry. The proportions with low FVC fell from 57/285 (20.0%) at TB treatment completion to 33/272 (12.1%), while obstruction increased from and 41/285 (14.4%) to 43/272 (15.8%) at 3 years. Absolute FEV1 and FVC increased by mean 0.03 L and 0.1 L over this period, but FEV1 decline of more than 0.1 L was seen in 73/246 (29.7%). Higher spirometry values at 3 years were associated with higher body mass index and HIV coinfection at TB-treatment completion. CONCLUSION: Spirometric measures improved over the 3 years following treatment, mostly in the first year. However, a third of PTB survivors experienced ongoing respiratory symptoms and abnormal spirometry (with accelerated FEV1 decline). Effective interventions are needed to improve the care of this group of patients.

A clinical and molecular epidemiological survey of hepatitis C in Blantyre, Malawi, suggests a historic mechanism of transmission.

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. There are no previous representative community HCV prevalence studies from Southern Africa, and limited genotypic data. Epidemiological data are required to inform an effective public health response. We conducted a household census-based random sampling serological survey, and a prospective hospital-based study of patients with cirrhosis and hepatocellular carcinoma (HCC) in Blantyre, Malawi. We tested participants with an HCV antigen/antibody ELISA (Monolisa, Bio-Rad), confirmed with PCR (GeneXpert, Cepheid) and used line immunoassay (Inno-LIA, Fujiribio) for RNA-negative participants. We did target-enrichment whole-genome HCV sequencing (NextSeq, Illumina). Among 96,386 censused individuals, we randomly selected 1661 people aged ≥16 years. Population-standardized HCV RNA prevalence was 0.2% (95% CI 0.1-0.5). Among 236 patients with cirrhosis and HCC, HCV RNA prevalence was 1.9% and 5.0%, respectively. Mapping showed that HCV RNA+ patients were from peri-urban areas surrounding Blantyre. Community and hospital HCV RNA+ participants were older than comparator HCV RNA-negative populations (median 53 vs 30 years for community, p = 0.01 and 68 vs 40 years for cirrhosis/HCC, p < 0.001). Endemic HCV genotypes (n = 10) were 4v (50%), 4r (30%) and 4w (10%). In this first census-based community serological study in Southern Africa, HCV was uncommon in the general population, was centred on peri-urban regions and was attributable for <5% of liver disease. HCV infection was observed only among older people, suggesting a historic mechanism of transmission. Genotype 4r, which has been associated with treatment failure with ledipasvir and daclatasvir, is endemic.

Computer-aided X-ray screening for tuberculosis and HIV testing among adults with cough in Malawi (the PROSPECT study): A randomised trial and cost-effectiveness analysis.

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.

'If not TB, what could it be?' Chest X-ray findings from the 2016 Kenya Tuberculosis Prevalence Survey.

BACKGROUND: The prevalence of diseases other than TB detected during chest X-ray (CXR) screening is unknown in sub-Saharan Africa. This represents a missed opportunity for identification and treatment of potentially significant disease. Our aim was to describe and quantify non-TB abnormalities identified by TB-focused CXR screening during the 2016 Kenya National TB Prevalence Survey. METHODS: We reviewed a random sample of 1140 adult (≥15 years) CXRs classified as 'abnormal, suggestive of TB' or 'abnormal other' during field interpretation from the TB prevalence survey. Each image was read (blinded to field classification and study radiologist read) by two expert radiologists, with images classified into one of four major anatomical categories and primary radiological findings. A third reader resolved discrepancies. Prevalence and 95% CIs of abnormalities diagnosis were estimated. FINDINGS: Cardiomegaly was the most common non-TB abnormality at 259 out of 1123 (23.1%, 95% CI 20.6% to 25.6%), while cardiomegaly with features of cardiac failure occurred in 17 out of 1123 (1.5%, 95% CI 0.9% to 2.4%). We also identified chronic pulmonary pathology including suspected COPD in 3.2% (95% CI 2.3% to 4.4%) and non-specific patterns in 4.6% (95% CI 3.5% to 6.0%). Prevalence of active-TB and severe post-TB lung changes was 3.6% (95% CI 2.6% to 4.8%) and 1.4% (95% CI 0.8% to 2.3%), respectively. INTERPRETATION: Based on radiological findings, we identified a wide variety of non-TB abnormalities during population-based TB screening. TB prevalence surveys and active case finding activities using mass CXR offer an opportunity to integrate disease screening efforts. FUNDING: National Institute for Health Research (IMPALA-grant reference 16/136/35).

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.

Etiology and Risk Factors for Mortality in an Adult Community-acquired Pneumonia Cohort in Malawi.

Rationale: In the context of rapid antiretroviral therapy rollout and an increasing burden of noncommunicable diseases, there are few contemporary data describing the etiology and outcome of community-acquired pneumonia (CAP) in sub-Saharan Africa.Objectives: To describe the current etiology of CAP in Malawi and identify risk factors for mortality.Methods: We conducted a prospective observational study of adults hospitalized with CAP to a teaching hospital in Blantyre, Malawi. Etiology was defined by blood culture, Streptococcus pneumoniae urinary antigen detection, sputum mycobacterial culture and Xpert MTB/RIF, and nasopharyngeal aspirate multiplex PCR.Measurements and Main Results: In 459 patients (285 [62.1%] males; median age, 34.7 [interquartile range, 29.4-41.9] yr), 30-day mortality was 14.6% (64/439) and associated with male sex (adjusted odds ratio, 2.60 [95% confidence interval, 1.17-5.78]), symptom duration greater than 7 days (2.78 [1.40-5.54]), tachycardia (2.99 [1.48-6.06]), hypoxemia (4.40 [2.03-9.51]), and inability to stand (3.59 [1.72-7.50]). HIV was common (355/453; 78.4%), frequently newly diagnosed (124/355; 34.9%), but not associated with mortality. S. pneumoniae (98/458; 21.4%) and Mycobacterium tuberculosis (75/326; 23.0%) were the most frequently identified pathogens. Viral infection occurred in 32.6% (148/454) with influenza (40/454; 8.8%) most common. Bacterial-viral coinfection occurred in 9.1% (28/307). Detection of M. tuberculosis was associated with mortality (adjusted odds ratio, 2.44 [1.19-5.01]).Conclusions: In the antiretroviral therapy era, CAP in Malawi remains predominantly HIV associated, with a large proportion attributable to potentially vaccine-preventable pathogens. Strategies to increase early detection and treatment of tuberculosis and improve supportive care, in particular the correction of hypoxemia, should be evaluated in clinical trials to address CAP-associated mortality.

Ischemic stroke as a complication of cryptococcal meningitis and immune reconstitution inflammatory syndrome: a case report.

BACKGROUND: Cryptococcal meningitis remains the leading cause of adult meningitis in Sub-Saharan Africa. Immune Reconstitution Inflammatory Syndrome (IRIS) following anti-retroviral therapy (ART) initiation is an important complication. Here we report the first documented case of a IRIS reaction presenting as an ischemic stroke. CASE PRESENTATION: A 38 year old newly diagnosed HIV-infected, ART naive Malawian male presented to a tertiary referral hospital in Blantyre, Malawi with a 2 week history of headache. A diagnosis of cryptococcal meningitis was made and the patient was started on 1200 mg fluconazole once daily and flucytosine 25 mg/kg four times daily as part of the Advancing Cryptococcal Treatment for Africa (ACTA) clinical trial. There was an initial clinical and microbiological response to anti-fungal treatment and anti-retroviral therapy was started at week 4. The patient re-presented 16 days later with recurrence of headache, fever, and a sudden onset of left sided weakness in the context of rapid immune reconstitution; peripheral CD4 count had increased from a baseline of 29 cells/µl to 198 cells/µl. Recurrence of cryptococcal meningitis was excluded through CSF examination and fungal culture. Magnetic Resonance Imaging (MRI) of the brain demonstrated multi-focal DWI (diffusion weighted imaging) positive lesions consistent with an ischemic stroke. Given the temporal relationship to ART initiation, these MRI findings in the context of sterile CSF with raised CSF protein and a rapid immune reconstitution, following an earlier favorable response to treatment is most consistent with a paradoxical Immune Reconstitution Inflammatory Syndrome. CONCLUSIONS: Stroke is an increasing cause of morbidity and mortality amongst HIV infected persons. Ischemic stroke is a recognized complication of cryptococcal meningitis in the acute phase and is thought to be mediated by an infectious vasculitis. This is the first time an ischemic stroke has been described as part of a paradoxical IRIS reaction. This report adds to the spectrum of clinical IRIS presentations recognized and highlights to clinicians the potential complications encountered at ART initiation in severely immunocompromised patients.

The Role of Human Immunodeficiency Virus-Associated Vasculopathy in the Etiology of Stroke.

Background: Human immunodeficiency virus (HIV) infection is a recognized risk factor for stroke among young populations, but the exact mechanisms are poorly understood. We studied the clinical, radiologic, and histologic features of HIV-related ischemic stroke to gain insight into the disease mechanisms. Methods: We conducted a prospective, in-depth analysis of adult ischemic stroke patients presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi, in 2011. Results: We recruited 64 HIV-infected and 107 HIV-uninfected patients. Those with HIV were significantly younger (P < .001) and less likely to have established vascular risk factors. Patients with HIV were more likely to have large artery disease (21% vs 10%; P < .001). The commonest etiology was HIV-associated vasculopathy (24 [38%]), followed by opportunistic infections (16 [25%]). Sixteen of 64 (25%) had a stroke soon after starting antiretroviral therapy (ART), suggesting an immune reconstitution-like syndrome. In this group, CD4+ T-lymphocyte count was low, despite a significantly lower HIV viral load in those recently started on treatment (P < .001). Conclusions: HIV-associated vasculopathy and opportunistic infections are common causes of HIV-related ischemic stroke. Furthermore, subtypes of HIV-associated vasculopathy may manifest as a result of an immune reconstitution-like syndrome after starting ART. A better understanding of this mechanism may point toward new treatments.

One hundred years of neglect in paediatric schistosomiasis.

Early in the history of schistosomiasis research, children under 5 years of age were known to be infected. Although this problem was recognized over 100 years ago, insufficient action has been taken to address this issue. Under current policy, such infected children only receive their first antiparasitic treatment (praziquantel - PZQ) upon entry into primary school as current mass drug administration programmes typically target school-aged children. For many infected children, they will wait up to 6 years before receiving their first medication and significant schistosomiasis-related morbidity may have already established. This inequity would not be accepted for other diseases. To unveil some of the reasons behind this neglect, it is paramount to understand the intricate historical relationship between schistosomiasis and British Imperial medicine, to underline its lasting influence on today's public health priorities. This review presents a perspective on the historical neglect of paediatric schistosomiasis, focusing on important gaps that persist from the early days after discovery of this parasite. Looking to end this inequity, we address several issues that need to be overcome to move forward towards the lasting success of schistosomiasis control and elimination efforts.

Implementation of NICE recommendations on abdomino-pelvic CT, following unprovoked venous thromboembolism, in a UK teaching hospital: no additional detection of occult malignancy and high numbers of incidental findings.

INTRODUCTION: NICE Clinical Guideline 144 recommends that patients with an unprovoked VTE, who do not have signs or symptoms of cancer on initial investigation, be considered for further investigation with an abdomino-pelvic CT to exclude occult malignancy. This study aimed to evaluate numbers of scans performed in a UK teaching hospital and outcomes, following this recommendation. METHODS: Retrospective review of CT scans performed before and after publication of the NICE guidance in 2012. CT reports and case notes were analysed. Type and stage of malignancy, treatment and other relevant findings were documented. For the 2014 data set, all incidental radiological findings and follow-up recommendations were reviewed. RESULTS: The annual number of CT scans requested for "unprovoked VTE", rose by 142% following publication of NICE Clinical Guideline 144. In the 2011 - 2012 data set, 21 patients were included, one of which was found to have a malignancy, which was clinically overt at the time of diagnosis i.e. not occult. Five patients (23.8%) had incidental findings requiring further investigation. In the 2014 - 2015 data set, 51 patients were included, five (9.8%) of which were found to have malignancy. In retrospect, all showed signs/symptoms of potential malignancy on initial investigation. No occult malignancies were detected in the patients correctly referred. Incidental findings warranting further investigation were reported in ten cases (19.6%). On review, follow-up advice was deemed incorrect in four of these. CONCLUSION: Addition of an abdomino-pelvic CT scan in patients with a first unprovoked VTE and no signs or symptoms of cancer on initial investigation, significantly increased the number of scans and incidental findings, but did not pick up any additional occult malignancies.

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.

The effect of a tuberculosis chest X-ray image reference set on non-expert reader performance.

OBJECTIVES: In low-resource settings, limitations in diagnostic accuracy of chest X-rays (CXR) for pulmonary tuberculosis (PTB) relate partly to non-expert interpretation. We piloted a TB CXR Image Reference Set (TIRS) to improve non-expert performance in an operational setting in Malawi. METHODS: Nineteen doctors and clinical officers read 60 CXR of patients with suspected PTB, at baseline and using TIRS. Two officers also used the CXR Reading and Recording System (CRRS). Correct treatment decisions were assessed against a "gold standard" of mycobacterial culture and expert performance. RESULTS: TIRS significantly increased overall non-expert sensitivity from 67.6 (SD 14.9) to 75.5 (SD 11.1, P = 0.013), approaching expert values of 84.2 (SD 5.2). Among doctors, correct decisions increased from 60.7 % (SD 7.9) to 67.1 % (SD 8.0, P = 0.054). Clinical officers increased in sensitivity from 68.0 % (SD 15) to 77.4 % (SD 10.7, P = 0.056), but decreased in specificity from 55.0 % (SD 23.9) to 40.8 % (SD 10.4, P = 0.049). Two officers made correct treatment decisions with TIRS in 62.7 %. CRRS training increased this to 67.8 %. CONCLUSION: Use of a CXR image reference set increased correct decisions by doctors to treat PTB. This tool may provide a low-cost intervention improving non-expert performance, translating into improved clinical care. Further evaluation is warranted. KEY POINTS: • Tuberculosis treatment decisions are influenced by CXR findings, despite improved laboratory diagnostics. • In low-resource settings, CXR interpretation is performed largely by non-experts. • We piloted the effect of a simple reference training set of CXRs. • Use of the reference set increased the number of correct treatment decisions. This effect was more marked for doctors than clinical officers. • Further evaluation of this simple training tool is warranted.

A 14-year follow-up of ultrasound-detected urinary tract pathology associated with urogenital schistosomiasis in women living in the Msambweni region of coastal Kenya.

BACKGROUND: Complications of urogenital schistosomiasis include acute inflammatory and chronic fibrotic changes within the urogenital tract. Disease burden of this neglected tropical disease is often underestimated, as only active, urine egg-patent Schistosoma infection is formally considered. Previous studies have focussed on short-term effects of praziquantel treatment on urinary tract pathology, demonstrating that acute inflammation is reversible. However, the reversibility of chronic changes is less well studied. METHODS: Our study compared, at two time points 14 y apart, urine egg-patent infection and urinary tract pathology in a cohort of women living in a highly endemic area having intermittent praziquantel treatment(s). In 2014 we matched 93 women to their findings in a previous study in 2000. RESULTS: Between 2000 and 2014 the rate of egg-patent infection decreased from 34% (95% confidence interval [CI] 25 to 44) to 9% (95% CI 3 to 14). However, urinary tract pathology increased from 15% (95% CI 8 to 22) to 19% (95% CI 11 to 27), with the greatest increase seen in bladder thickening and shape abnormality. CONCLUSIONS: Despite praziquantel treatment, fibrosis from chronic schistosomiasis outlasts the presence of active infection, continuing to cause lasting morbidity. We suggest that future efforts to eliminate persistent morbidity attributable to schistosomiasis should include intensified disease management.

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 ( p = 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) ( p = 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.

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.

Accuracy of computer-aided chest X-ray in community-based tuberculosis screening: Lessons from the 2016 Kenya National Tuberculosis Prevalence Survey.

Community-based screening for tuberculosis (TB) could improve detection but is resource intensive. We set out to evaluate the accuracy of computer-aided TB screening using digital chest X-ray (CXR) to determine if this approach met target product profiles (TPP) for community-based screening. CXR images from participants in the 2016 Kenya National TB Prevalence Survey were evaluated using CAD4TBv6 (Delft Imaging), giving a probabilistic score for pulmonary TB ranging from 0 (low probability) to 99 (high probability). We constructed a Bayesian latent class model to estimate the accuracy of CAD4TBv6 screening compared to bacteriologically-confirmed TB across CAD4TBv6 threshold cut-offs, incorporating data on Clinical Officer CXR interpretation, participant demographics (age, sex, TB symptoms, previous TB history), and sputum results. We compared model-estimated sensitivity and specificity of CAD4TBv6 to optimum and minimum TPPs. Of 63,050 prevalence survey participants, 61,848 (98%) had analysable CXR images, and 8,966 (14.5%) underwent sputum bacteriological testing; 298 had bacteriologically-confirmed pulmonary TB. Median CAD4TBv6 scores for participants with bacteriologically-confirmed TB were significantly higher (72, IQR: 58-82.75) compared to participants with bacteriologically-negative sputum results (49, IQR: 44-57, p<0.0001). CAD4TBv6 met the optimum TPP; with the threshold set to achieve a mean sensitivity of 95% (optimum TPP), specificity was 83.3%, (95% credible interval [CrI]: 83.0%-83.7%, CAD4TBv6 threshold: 55). There was considerable variation in accuracy by participant characteristics, with older individuals and those with previous TB having lowest specificity. CAD4TBv6 met the optimal TPP for TB community screening. To optimise screening accuracy and efficiency of confirmatory sputum testing, we recommend that an adaptive approach to threshold setting is adopted based on participant characteristics.

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.

Diagnostic point-of-care ultrasound in medical inpatients at Queen Elizabeth Central Hospital, Malawi: an observational study of practice and evaluation of implementation.

BACKGROUND: In less well-resourced settings, where access to radiology services is limited, point-of-care ultrasound (POCUS) can be used to assess patients and guide clinical management. The aim of this study was to describe ultrasound practice in the assessment of medical inpatients at Queen Elizabeth Central Hospital, Blantyre, Malawi, and evaluate uptake and impact of POCUS following the introduction of a training programme at the college of Medicine, Blantyre, Malawi. METHODS: : A weekly prospective record review of sequential adult medical inpatients who had received an ultrasound examination was conducted. RESULTS: Of 835 patients screened, 250 patients were included; 267 ultrasound examinations were performed, of which 133 (50%) were POCUS (defined as performed by a clinician at the bedside). The time from request to performance of examination was shorter for POCUS examinations than radiology department ultrasound (RDUS) (median 0 [IQR 0-2, range 0-11] vs 2 [IQR 1-4, range 0-15] d, p=0.002); 104/133 (78.2%) POCUS and 90/133 (67.7%) RDUS examinations were deemed to have an impact on management. CONCLUSION: Following the introduction of a training programme in POCUS, half of all ultrasound examinations were delivered as POCUS. POCUS was performed rapidly and impacted on patient management. POCUS may relieve the burden on radiology services in less well-resourced settings.