Low prevalence of soil transmitted helminth infection in Ugandan children hospitalized with severe malaria.

Co-infection by intestinal helminths and Plasmodium spp. may be common in endemic communities. Several studies have identified a relationship between helminth infection, Plasmodium spp. infection and malaria severity. However, the relationship is not well defined, and results are inconclusive. We analyzed 202 stool samples from a cohort of children with severe malaria enrolled in two hospitals in Uganda from 2014-2017 and asymptomatic community children from the same household or neighborhood and enrolled at the same time, all 6 months to 48 months of age. We investigated if intestinal helminth infection modified risk of severe malaria. We extracted nucleic acids from stool and tested them for six helminth species (Anyclostoma duodenale, Ascaris lumbricoides, Necator americanus, Strongyloides stercolaris, Trichuris trichiura, Shistosoma mansoni) using highly sensitive quantitative PCR. We found a low prevalence of infection by ≥1 intestinal helminth species in children with severe malaria (5.1%, n=9/177) and community control children (4.0%, n=1/25). Infection by ≥1 of the helminths assessed was not associated with severe malaria (aRR = 1.0, 95% Confidence Interval = 0.82, 1.3, p = 0.78). In 2003 Uganda instituted a national deworming program, with anti-helminth medication provided twice annually to children 6 months to 5 years of age. In these areas of Uganda, the national deworming campaign has been highly successful, as stool-based helminth infection was rare even when using highly sensitive methods of detection and was not a major contributor to risk of severe malaria.

Is fat mass a better predictor of 6-month survival than muscle mass among African children aged 6-59 months with severe pneumonia?

BACKGROUND: Pneumonia remains the leading cause of mortality among children under 5 years. Poor nutritional status increases pneumonia mortality. Nutritional status assessed by anthropometry alone does not provide information on which body composition element predicts survival. Body composition proxy measures including arm-fat-area (AFA), arm-muscle-area (AMA), and arm-muscle-circumference (AMC) could be useful predictors. OBJECTIVE: To compare the ability of fat and muscle mass indices to predict 6-month survival among children with severe pneumonia. METHODS: This prospective cohort study was nested in the COAST-Nutrition trial (ISRCTN10829073, 06/06/2018) conducted between June 2020 and October 2022 in Uganda and Kenya. We included children aged 6-59 months hospitalized for severe pneumonia with hypoxemia. Children with severe malnutrition, known chronic lung or cardiac diseases were excluded. Anthropometry and clinical status were assessed at enrolment and at follow-up to day 180. We examined Receiver Operator Characteristic (ROC) curves of fat and muscle mass indices with 6-month survival as the outcome, and compared the areas under the curve (AUCs) using chi-square tests. Cox survival analysis models assessed time-to-mortality. RESULTS: We included 369 participants. The median age was 15-months (IQR 9, 26), and 59.4% (219/369) of participants were male. The baseline measurements were: median MUAC 15.0 cm (IQR 14.0,16.0); arm-fat-area 5.6cm2 (IQR 4.7, 6.8); arm-muscle-area 11.4cm2 (IQR 10.0, 12.7); and arm-muscle-circumference 12.2 cm (IQR 11.5, 12.9). Sixteen (4.3%) participants died and 4 (1.1%) were lost-to-follow-up. The AUC for Arm-Fat-Area was not significantly higher than that for Arm-Muscle-Area and Arm-Muscle-Circumference [AUC 0.77 (95%CI 0.64-0.90) vs. 0.61 (95%CI 0.48-0.74), p = 0.09 and 0.63 (95%CI 0.51-0.75), p = 0.16 respectively], but was not statistically different from MUAC (AUC 0.73 (95%CI 0.62-0.85), p = 0.47). Increase in Arm-Fat-Area and Arm-Muscle-Circumference significantly improved survival [aHR 0.40 (95%CI 0.24-0.64), p = < 0.01 and 0.59 (95%CI 0.36-1.06), p = 0.03 respectively]. Survival prediction using Arm-Fat-Area was not statistically different from that of MUAC (p = 0.54). CONCLUSIONS: Muscle mass did not predict 6-month survival better than fat mass in children with severe pneumonia. Fat mass appears to be a better predictor. Effects of fat and muscle could be considered for prognosis and targeted interventions.

Elevated levels of PDGF-BB and VEGF are associated with a decreased risk of readmission or death in children with severe malarial anemia.

BACKGROUND: Children with severe malarial anemia (SMA) typically have low in-hospital mortality but have a high risk of post-discharge readmission or death. We hypothesized that the dysregulation of hematopoiesis, vascular growth factors, and endothelial function that occurs in SMA might affect risk of readmission or death. METHODS: Plasma was obtained from children 18 months to 12 years old with SMA (N=145) in Kampala, Uganda on admission, and outcomes were assessed over 12-month follow-up. Admission plasma levels of ten biomarkers of vascular growth, hematopoiesis, and endothelial function were compared to risk of readmission or death over 12-month follow-up. RESULTS: Over 12-month follow-up, 19 of 145 children with SMA were either readmitted or died: 15 children were readmitted (13 with malaria) and 4 children died. In multivariable analyses adjusted for age and sex, elevated plasma levels of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor (VEGF) on admission were independently associated with a decreased risk of all-cause readmission or death (adjusted hazard ratios [95% confidence intervals], 0.28 [0.16-0.51] and 0.19 [0.08-0.48], respectively) and a decreased risk of readmission due to severe malaria (0.27 [0.15, 0.51] and 0.16 [0.05, 0.47]) but not with risk of uncomplicated malaria (1.01 [0.53, 1.95] and 2.07 [0.93-4.64]). CONCLUSIONS: In children with severe malarial anemia, elevated plasma levels of PDGF-BB and VEGF, two factors that promote angiogenesis, are associated with a decreased risk of readmission or death in the year following admission, primarily driven by a decrease in the risk of recurrent severe malaria.

Peripheral Perfusion Index in Ugandan Children With Plasmodium falciparum Severe Malaria: Secondary Analysis of Outcomes in a 2014-2017 Cohort Study.

OBJECTIVES: Continuous, noninvasive tools to monitor peripheral perfusion, such as perfusion index (PI), can detect hemodynamic abnormalities and assist in the management of critically ill children hospitalized with severe malaria. In this study of hospitalized children with severe malaria, we aimed to assess whether PI correlates with clinical markers of perfusion and to determine whether combining PI with these clinical measures improves identification of children with greater odds of mortality. DESIGN: Post hoc analysis of a prospective, multicenter, cohort study conducted between 2014 and 2017. SETTING: Two referral hospitals in Central and Eastern Uganda. PATIENTS: Six hundred children younger than 5 years old with severe malaria and 120 asymptomatic community children. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PI was measured at 6-hour intervals for the first 24 hours of hospitalization. We compared PI to standard clinical perfusion measures such as capillary refill time, presence of cold peripheral limbs, or temperature gradient. Admission PI was highly correlated with clinical measures of perfusion. Admission PI was lower in children with severe malaria compared with asymptomatic community children; and, among the children with severe malaria, PI was lower in those with clinical features of poor perfusion or complications of severe malaria, such as shock and hyperlactatemia (all p < 0.02). Among children with severe malaria, lower admission PI was associated with greater odds of mortality after adjustment for age, sex, and severe malaria criteria (adjusted odds ratio, 2.4 for each log decrease in PI [95% CI, 1.0-5.9]; p = 0.045). Diagnostically, the presence of two consecutive low PI measures (< 1%) predicted mortality, with a sensitivity of 50% and a specificity of 76%. CONCLUSIONS: In severe malaria, PI correlates with clinical complications (including shock and elevated serum lactate) and may be useful as an objective, continuous explanatory variable associated with greater odds of later in-hospital mortality.

Circulating immune complexes and G6PD deficiency predict readmissions for blackwater fever and severe anemia in children with severe malaria in Eastern Uganda.

BACKGROUND: Recently, there has been an unexplained increase in the incidence of blackwater fever (BWF) in Eastern Uganda. In this study, we evaluate the association between immune complexes, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and the occurrence and recurrence of BWF in children with severe malaria (SM). METHODS: Between 2014 and 2017, children aged six months to <4 years hospitalized with SM and community children (CC) were recruited at two hospitals in Central and Eastern Uganda. We measured serum circulating immune complexes (cIC) and their relationship to SM complications and post-discharge outcomes and evaluated effect mediation through G6PD deficiency. RESULTS: 557 children with SM and 101 CC were enrolled. The mean age of children was 2.1 years. Children with SM had higher cIC levels than CC, p<0.001. After controlling for age, sex, and site, cIC were associated with severe anemia, jaundice, and BWF (adjusted odds ratio, 95% confidence interval: 7.33 (3.45, 15.58), p<0.0001; 4.31 (1.68, 11.08), p=0.002; and 5.21 (2.06, 13.18), p<0.0001), respectively. cIC predicted readmissions for SM, severe anemia, and BWF (adjusted incidence rate ratios (95% confidence interval): 2.11 (1.33, 3.34), p=0.001; 8.62 (2.80, 26.59), p<0.0001; and 7.66 (2.62, 22.45), p<0.0001), respectively. The relationship was most evident in males where the frequency of the G6PD African allele (A-) was 16.8%. G6PD deficiency was associated with increases in cIC in males (p=0.01) and mediation analysis suggested G6PD deficiency contributes to recurrent severe anemia and BWF via increased cIC. CONCLUSIONS: Immune complexes are associated with hemolytic complications and predict recurrences in SM survivors.

Academic achievement in Ugandan children with sickle cell anaemia: A cross-sectional study.

Objective: Academic achievement in school-age children is crucial for advancing learning goals. Children with sickle cell anaemia (SCA) in Sub-Saharan Africa may be at risk of disease-associated school difficulties. Limited data exist on the academic achievement of children with SCA in the region. This study aimed to assess academic achievement of children with SCA in Uganda compared to siblings without SCA. Design and setting: A cross-sectional study conducted at Mulago Hospital SCA Clinic in Uganda. Participants: School-going children (6-12 years) with SCA and age-matched sibling controls without SCA. Outcome measures: Academic achievement was tested using the Wide Range Achievement Test, Fourth Edition (WRAT4). Outcome measures were spelling, mathematical computation, word reading, and sentence comprehension by age-normalized Z-scores on the WRAT4 test. Results: Among 68 SCA and 69 control, the mean age (standard deviation) was 9.44 (2.04) and 9.42 (2.02) years and males were 55.9% and 46.4% respectively. Mean haemoglobin was 7.9 (SD 0.89)g/dL in the SCA group versus 12.8 (SD 0.89)g/dL in the controls, (p<0.001). Children with SCA scored lower in spelling, (mean difference [95% confidence interval] - 0.36 [-0.02 to -0.69], p=0.04) and mathematical computation, (mean difference [95% confidence interval] -0.51 [-0.17 to -0.85], p=0.003) than the controls. In the SCA group, lower scores in spelling correlated with age, while males performed better than females in mathematical computation. Conclusion: School-aged children with SCA are at risk of poor performance in spelling and mathematical computation. Our findings support the need for educational evaluation and possible support, especially in these two areas.

The Ugandan sickle Pan-African research consortium registry: design, development, and lessons.

BACKGROUND: Sub-Saharan Africa bears the highest burden of sickle cell disease (SCD) globally with Nigeria, Democratic Republic of Congo, Tanzania, Uganda being the most affected countries. Uganda reports approximately 20,000 SCD births annually, constituting 6.67% of reported global SCD births. Despite this, there is a paucity of comprehensive data on SCD from the African continent. SCD registries offer a promising avenue for conducting prospective studies, elucidating disease severity patterns, and evaluating the intricate interplay of social, environmental, and genetic factors. This paper describes the establishment of the Sickle Pan Africa Research Consortium (SPARCo) Uganda registry, encompassing its design, development, data collection, and key insights learned, aligning with collaborative efforts in Nigeria, Tanzania, and Ghana SPARCo registries. METHODS: The registry was created using pre-existing case report forms harmonized from the SPARCo data dictionary and ontology to fit Uganda clinical needs. The case report forms were developed with SCD data elements of interest including demographics, consent, baseline, clinical, laboratory and others. That data was then parsed into a customized REDCap database, configured to suit the optimized ontologies and support retrieval aggregations and analyses. Patients were enrolled from one national referral and three regional referral hospitals in Uganda. RESULTS: A nationwide electronic patient-consented registry for SCD was established from four regional hospitals. A total of 5,655 patients were enrolled from Mulago National Referral Hospital (58%), Jinja Regional Referral (14.4%), Mbale Regional Referral (16.9%), and Lira Regional Referral (10.7%) hospitals between June 2022 and October 2023. CONCLUSION: Uganda has been able to develop a SCD registry consistent with data from Tanzania, Nigeria and Ghana. Our findings demonstrate that it's feasible to develop longitudinal SCD registries in sub-Saharan Africa. These registries will be crucial for facilitating a range of studies, including the analysis of SCD clinical phenotypes and patient outcomes, newborn screening, and evaluation of hydroxyurea use, among others. This initiative underscores the potential for developing comprehensive disease registries in resource-limited settings, fostering collaborative, data-driven research efforts aimed at addressing the multifaceted challenges of SCD in Africa.

Heparin-Binding Protein Stratifies Mortality Risk Among Ugandan Children Hospitalized With Respiratory Distress.

Background: Current prognostic tools do not reliably and objectively identify children with pneumonia at risk of a severe or life-threatening episode. Heparin-binding protein (HBP) is a host immune protein that is released in response to infection. We hypothesized that measuring HBP concentrations at hospital admission could help risk-stratify children with pneumonia and identify those at higher risk of an adverse prognosis. Methods: We evaluated the prognostic accuracy of HBP for predicting in-hospital mortality among children with respiratory distress, and whether HBP could improve the accuracy of validated composite clinical severity scores. Results: Of 778 Ugandan children under 5 years of age and presenting with clinically defined pneumonia, 60 (7.7%) died during hospital admission. HBP concentrations at presentation were significantly higher in children with fatal outcomes (median, 76 ng/mL [interquartile range {IQR}, 41-150]) compared to children who survived (median, 31 ng/mL [IQR, 18-57]) (P < .001). Children with HBP >41 ng/mL on admission had an elevated risk of death (hazard ratio, 5.3 [95% confidence interval {CI}, 2.9-9.5]; P < .0001). In receiver operating characteristic (ROC) curve analysis, HBP concentrations distinguished between fatal and nonfatal outcomes (area under the ROC curve, 0.75 [95% CI, .66-.84]) and significantly improved the prediction provided by the Respiratory Index of Severity in Children, a composite clinical severity score (P = .0026). Conclusions: Measuring HBP at presentation could help identify children at risk of severe and fatal pneumonia. Adding HBP to clinical scores could improve the recognition and triage of children with pneumonia at risk of death.

Neurocognitive impairment in Ugandan children with sickle cell anemia compared to sibling controls: a cross-sectional study.

Introduction: The neurocognitive functions in Ugandan children aged 1-12 years with sickle cell anemia (SCA) were compared to their non-SCA siblings to identify risk factors for disease-associated impairment. Methods: This cross-sectional study of the neurocognitive functions in children with SCA (N = 242) and non-SCA siblings (N = 127) used age- and linguistically appropriate standardized tests of cognition, executive function, and attention for children ages 1-4 and 5-12. Test scores were converted to locally derived age-normalized z-scores. The SCA group underwent a standardized stroke examination for prior stroke and transcranial Doppler ultrasound to determine stroke risk by arterial flow velocity. Results: The SCA group was younger than their siblings (mean ages 5.46 ± 3.0 vs. 7.11 ± 3.51 years, respectively; p < 0.001), with a lower hemoglobin concentration (7.32 ± 1.02 vs. 12.06 ± 1.42, p < 0.001). The overall cognitive SCA z-scores were lower, -0.73 ± 0.98, vs. siblings, -0.25 ± 1.12 (p < 0.001), with comparable findings for executive function of -1.09 ± 0.94 vs. -0.84 ± 1.26 (p = 0.045), respectively. The attention z-scores for ages 5-12 for the SCA group and control group were similar: -0.37 ± 1.4 vs. -0.11 ± 0.17 (p = 0.09). The overall differences in SCA status were largely driven by the older age group, as the z-scores in the younger subsample did not differ from controls. Analyses revealed the strongest predictors of poor neurocognitive outcomes among the SCA sample to be the disease, age, and prior stroke (each p < 0.001). The impacts of anemia and SCA were indistinguishable. Discussion: Neurocognitive testing in children with SCA compared to non-SCA siblings revealed poorer SCA-associated functioning in children older than age 4. The results indicate the need for trials assessing the impact of disease modification on children with SCA.

Pharmacokinetic-Guided Hydroxyurea to Reduce Transfusions in Ugandan Children with Sickle Cell Anemia: Study Design of the Alternative Dosing And Prevention of Transfusions Trial.

INTRODUCTION: People with sickle cell anemia (SCA) may require frequent blood transfusions to treat acute and chronic complications. Hydroxyurea is a life-saving treatment for SCA that could also decrease the need for blood transfusions. Inadequate medication access and challenges in dose optimization limit the widespread use of hydroxyurea in Africa. If feasible, pharmacokinetic (PK) dosing might improve dose determination to minimize toxicities and maximize clinical benefits. The Alternative Dosing And Prevention of Transfusions (ADAPT, NCT05662098) trial will analyze the impact of hydroxyurea on transfusion rate and serve as a pilot study to evaluate the feasibility of PK-guided hydroxyurea dosing in Uganda. METHODS: Herein we describe the rationale and design of ADAPT, a prospective cohort study of ∼100 children with SCA in Jinja, Uganda. The primary hypothesis is that hydroxyurea will decrease blood transfusion use by ≥ 50%, comparing the transfusion incidence rate ratio between a 3-month pretreatment and a 12-month treatment period. A key secondary hypothesis is that our PK-dosing approach will generate a suitable hydroxyurea dose for ≥80% of participants. Every ADAPT participant will undergo hydroxyurea PK testing, and if a dose is generated within 15-35 mg/kg/day, participants will start on their individualized dose. If not, they will start on a default dose of 20 mg/kg/day. Hydroxyurea dose optimization will occur with periodic dose adjustments. CONCLUSION: Overall, demonstrating the reduction in blood transfusion utilization with hydroxyurea treatment would provide leverage to increase hydroxyurea access, and PK-guided hydroxyurea dosing should optimize the safe and effective treatment of SCA across sub-Saharan Africa.

Nutritional supplementation in children with severe pneumonia in Uganda and Kenya (COAST-Nutrition): a phase 2 randomised controlled trial.

Background: Severe pneumonia in African children results in poor long-term outcomes (deaths/readmissions) with undernutrition as a key risk factor. We hypothesised additional energy/protein-rich Ready-to-Use Therapeutic Foods (RUTF) would meet additional nutritional requirements and improve outcomes. Methods: COAST-Nutrition was an open-label Phase 2 randomised controlled trial in children (aged 6 months-12 years) hospitalised with severe pneumonia (and hypoxaemia, SpO2 <92%) in Mbale, Soroti, Jinja, Masaka Regional Referral Hospitals, Uganda and Kilifi County Hospital, Kenya (ISRCTN10829073 (registered 6th June 2018) PACTR202106635355751 (registered 2nd June 2021)). Children were randomised (ratio 1:1) to enhanced nutritional supplementation with RUTF (plus usual diet) for 56 days vs usual diet (control). The primary outcome was change in mid-upper arm circumference (MUAC) at 90 days as a composite with mortality. Secondary outcomes include anthropometric status, mortality, and readmissions at Days 28, 90 and 180. Findings: Between 12 August 2018 and 22 April 2022, 846 eligible children were randomised, 424 to RUTF and 422 to usual diet, and followed for 180-days [12 (1%) lost-to-follow-up]. RUTF supplement was initiated in 417/419 (>99%). By Day 90, there was no significant difference in the composite endpoint (probabilistic index 0.49, 95% CI 0.45-0.53, p = 0.74). Respective 90-day mortality (13/420 3.1% vs 14/421 3.3%) and MUAC increment (0.54 (SD 0.85) vs 0.55 (SD 0.81)) were similar between arms. There was no difference in any anthropometric secondary endpoints to Day 28, 90 or 180 except skinfold thickness at Day 28 and Day 90 was greater in the RUTF arm. Serious adverse events were higher in the RUTF arm (n = 164 vs 108), mainly due to hospital readmission for acute illness (54/387 (14%) vs 37/375 (10%). Interpretation: Our study suggested that nutritional supplementation with RUTF did not improve outcomes to 180 days in children with severe pneumonia. Funding: This trial is part of the EDCTP2 programme (grant number RIA-2016S-1636-COAST-Nutrition) supported by the European Union, and UK Joint Global Health Trials scheme: Medical Research Council, Department for International Development, Wellcome Trust (grant number MR/L004364/1, UK).

Solar-powered O2 delivery for the treatment of children with hypoxaemia in Uganda: a stepped-wedge, cluster randomised controlled trial.

BACKGROUND: Supplemental O2 is not always available at health facilities in low-income and middle-income countries (LMICs). Solar-powered O2 delivery can overcome gaps in O2 access, generating O2 independent of grid electricity. We hypothesized that installation of solar-powered O2 systems on the paediatrics ward of rural Ugandan hospitals would lead to a reduction in mortality among hypoxaemic children. METHODS: In this pragmatic, country-wide, stepped-wedge, cluster randomised controlled trial, solar-powered O2 systems (ie, photovoltaic cells, battery bank, and O2 concentrator) were sequentially installed at 20 rural health facilities in Uganda. Sites were selected for inclusion based on the following criteria: District Hospital or Health Centre IV with paediatric inpatient services; supplemental O2 on the paediatric ward was not available or was unreliable; and adequate space to install solar panels, a battery bank, and electrical wiring. Allocation concealment was achieved for sites up to 2 weeks before installation, but the study was not masked overall. Children younger than 5 years admitted to hospital with hypoxaemia and respiratory signs were included. The primary outcome was mortality within 48 h of detection of hypoxaemia. The statistical analysis used a linear mixed effects logistic regression model accounting for cluster as random effect and calendar time as fixed effect. The trial is registered at ClinicalTrials.gov, NCT03851783. FINDINGS: Between June 28, 2019, and Nov 30, 2021, 2409 children were enrolled across 20 hospitals and, after exclusions, 2405 children were analysed. 964 children were enrolled before site randomisation and 1441 children were enrolled after site randomisation (intention to treat). There were 104 deaths, 91 of which occurred within 48 h of detection of hypoxaemia. The 48 h mortality was 49 (5·1%) of 964 children before randomisation and 42 (2·9%) of 1440 (one individual did not have vital status documented at 48 h) after randomisation (adjusted odds ratio 0·50, 95% CI 0·27-0·91, p=0·023). Results were sensitive to alternative parameterisations of the secular trend. There was a relative risk reduction of 48·7% (95% CI 8·5-71·5), and a number needed to treat with solar-powered O2 of 45 (95% CI 28-230) to save one life. Use of O2 increased from 484 (50·2%) of 964 children before randomisation to 1424 (98·8%) of 1441 children after randomisation (p<0·0001). Adverse events were similar before and after randomisation and were not considered to be related to the intervention. The estimated cost-effectiveness was US$25 (6-505) per disability-adjusted life-year saved. INTERPRETATION: This stepped-wedge, cluster randomised controlled trial shows the mortality benefit of improving O2 access with solar-powered O2. This study could serve as a model for scale-up of solar-powered O2 as one solution to O2 insecurity in LMICs. FUNDING: Grand Challenges Canada and The Women and Children's Health Research Institute.

Hydroxyurea Therapy for Neurological and Cognitive Protection in Pediatric Sickle Cell Anemia in Uganda (BRAIN SAFE II): Protocol for a single-arm open label trial.

Background: Children with sickle cell anemia (SCA) in Sub-Saharan Africa are at high risk of sickle cerebrovascular injury (SCVI). Hydroxyurea, a commonly used disease-modifying therapy, may prevent or decrease SCVI for reduced incident stroke, stroke risk and potentially cognitive dysfunction. We aim to test the impact of daily hydroxyurea therapy on these outcomes in Ugandan children with SCA. We hypothesize that hydroxyurea therapy over 36 months will prevent, stabilize or improve these complications of SCA. Methods: The BRAIN SAFE II study is an open-label, single-arm trial of daily hydroxyurea for 270 children with SCA (HbSS) in Uganda, ages 3-9 years. Following baseline assessments, participants began hydroxyurea therapy and clinically followed per local guidelines. Standard hydroxyurea dose is escalated to maximum tolerated dose (MTD). SCVI is assessed by cerebral arterial velocity using Doppler ultrasound, with cognitive function determined by formal neurocognitive testing (primary outcomes). Structural SCVI is assessed by magnetic resonance imaging (MRI) and angiography (MRA) in a sub-sample of 90 participants ages ≥5 years, along with biomarkers of anemia, inflammation and malnutrition (secondary outcomes). At trial midpoint (18 months) and completion (36 months), primary outcomes will be compared to participants' baseline to determine hydroxyurea impact and relationships to secondary outcomes. Conclusion: This open-label, single-arm trial will examine the impact of hydroxyurea on preventing or ameliorating SCA SCVI in children, assessed by reducing incident stroke, stroke risk and neurocognitive dysfunction. Trial results will provide important insight into the role of hydroxyurea therapy on critical manifestations of SCVI in children with SCA.

Hydroxyurea reduces infections in children with sickle cell anemia in Uganda.

ABSTRACT: After starting hydroxyurea treatment, Ugandan children with sickle cell anemia had 60% fewer severe or invasive infections, including malaria, bacteremia, respiratory tract infections, and gastroenteritis, than before starting hydroxyurea treatment (incidence rate ratio, 0.40 [95% confidence interval, 0.29-0.54]; P < .001).

Neurocognitive Impairment in Ugandan Children with Sickle Cell Anemia Compared to Sibling Controls: A cross-sectional study.

Introduction: Neurocognitive function in Ugandan children aged 1-12 years with sickle cell anemia (SCA) were compared to their non-SCA siblings to identify risk factors for disease-associated impairment. Methods: This cross-sectional neurocognitive function study of children with SCA (N=242) and non-SCA siblings (N=127) used age- and linguistically-appropriate standardized tests of cognition, executive function and attention for children ages 1-4 and 5-12 years. Test scores were converted to locally derived age-normalized z-scores. The SCA group underwent standardized stroke examination for prior stroke and transcranial doppler ultrasound (TCD) to determine stroke risk by arterial flow velocity. Results: The SCA group was younger than siblings (mean ages 5.46±3.0 versus 7.11±3.51 years, respectively; p <.001), with lower hemoglobin concentration (7.32±1.02 vs. 12.06±1.42, p <.001). Overall cognitive SCA z-scores were lower: -0.73 ±0.98 vs. siblings -0.25 ±1.12 (p<.001), with comparable findings for executive function of -1.09±0.94 versus -0.84±1.26 (p=0.045), respectively. Attention z-scores for ages 5-12 for the SCA group and controls were similar: -0.37±1.4 vs. -0.11±0.17 (p=.09). Overall differences by SCA status were largely driven by the older age group, as z-scores in the younger sub-sample did not differ from controls. Analyses revealed the strongest predictors of poor neurocognitive outcomes among the SCA sample to be the disease, age and prior stroke (each p<.001). Impact from anemia and SCA were indistinguishable. Discussion: Neurocognitive testing in children with SCA compared to non-SCA siblings revealed poorer SCA-associated functioning in children older than age 4. Results indicate need for trials assessing impact from disease modification for children with SCA.

sTREM-1: A Biomarker of Mortality in Severe Malaria Impacted by Acute Kidney Injury.

BACKGROUND: Malaria is an important cause of mortality in African children. Identification of biomarkers to identify children at risk of mortality has the potential to improve outcomes. METHODS: We evaluated 11 biomarkers of host response in 592 children with severe malaria. The primary outcome was biomarker performance for predicting mortality. Biomarkers were evaluated using receiver operating characteristic (ROC) curve analysis comparing the area under the ROC curve (AUROC). RESULTS: Mortality was 7.3% among children in the study with 72% of deaths occurring within 24 hours of admission. Among the candidate biomarkers, soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) had the highest AUROC (0.78 [95% confidence interval, .70-.86]), outperforming several other biomarkers including C-reactive protein and procalcitonin. sTREM-1 was the top-performing biomarker across prespecified subgroups (malaria definition, site, sex, nutritional status, age). Using established cutoffs, we evaluated mortality across sTREM-1 risk zones. Among children with acute kidney injury, 39.9% of children with a critical-risk sTREM-1 result had an indication for dialysis. When evaluated relative to a disease severity score, sTREM-1 improved mortality prediction (difference in AUROC, P = .016). CONCLUSIONS: sTREM-1 is a promising biomarker to guide rational allocation of clinical resources and should be integrated into clinical decision support algorithms, particularly when acute kidney injury is suspected.

Post-discharge malaria chemoprevention in children admitted with severe anaemia in malaria-endemic settings in Africa: a systematic review and individual patient data meta-analysis of randomised controlled trials.

BACKGROUND: Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality or readmission after hospital discharge. We conducted a systematic review and individual patient data meta-analysis to determine the efficacy of monthly post-discharge malaria chemoprevention in children recovering from severe anaemia. METHODS: This analysis was conducted according to PRISMA-IPD guidelines. We searched multiple databases on Aug 28, 2023, without date or language restrictions, for randomised controlled trials comparing monthly post-discharge malaria chemoprevention with placebo or standard of care among children (aged <15 years) admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. The investigators from all eligible trials shared pseudonymised datasets, which were standardised and merged for analysis. The primary outcome was all-cause mortality during the intervention period. Analyses were performed in the modified intention-to-treat population, including all randomly assigned participants who contributed to the endpoint. Fixed-effects two-stage meta-analysis of risk ratios (RRs) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data (readmissions or clinic visits) were analysed using one-stage mixed-effects Prentice-Williams-Peterson total-time models to obtain hazard ratios (HRs). This study is registered with PROSPERO, CRD42022308791. FINDINGS: Our search identified 91 articles, of which 78 were excluded by title and abstract, and a further ten did not meet eligibility criteria. Three double-blind, placebo-controlled trials, including 3663 children with severe anaemia, were included in the systematic review and meta-analysis; 3507 (95·7%) contributed to the modified intention-to-treat analysis. Participants received monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (mean 3·1 courses per child [range 1-6]; n=1085; The Gambia), monthly artemether-lumefantrine given at the end of weeks 4 and 8 post discharge (n=1373; Malawi), or monthly dihydroartemisinin-piperaquine given at the end of weeks 2, 6, and 10 post discharge (n=1049; Uganda and Kenya). During the intervention period, post-discharge malaria chemoprevention was associated with a 77% reduction in mortality (RR 0·23 [95% CI 0·08-0·70], p=0·0094, I2=0%) and a 55% reduction in all-cause readmissions (HR 0·45 [95% CI 0·36-0·56], p<0·0001) compared with placebo. The protective effect was restricted to the intervention period and was not sustained after the direct pharmacodynamic effect of the drugs had waned. The small number of trials limited our ability to assess heterogeneity, its sources, and publication bias. INTERPRETATION: In malaria-endemic Africa, post-discharge malaria chemoprevention reduces mortality and readmissions in recently discharged children recovering from severe anaemia. Post-discharge malaria chemoprevention could be a valuable strategy for the management of this group at high risk. Future research should focus on methods of delivery, options to prolong the protection duration, other hospitalised groups at high risk, and interventions targeting non-malarial causes of post-discharge morbidity. FUNDING: The Research-Council of Norway and the Bill-&-Melinda-Gates-Foundation through the Worldwide-Antimalarial-Research-Network.

Blood biomarkers of neuronal injury in paediatric cerebral malaria and severe malarial anaemia.

Persistent neurodisability is a known complication in paediatric survivors of cerebral malaria and severe malarial anaemia. Tau, ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein have proven utility as biomarkers that predict adverse neurologic outcomes in adult and paediatric disorders. In paediatric severe malaria, elevated tau is associated with mortality and neurocognitive complications. We aimed to investigate whether a multi-analyte panel including ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein can serve as biomarkers of brain injury associated with mortality and neurodisability in cerebral malaria and severe malarial anaemia. In a prospective cohort study of Ugandan children, 18 months to 12 years of age with cerebral malaria (n = 182), severe malarial anaemia (n = 158), and asymptomatic community children (n = 118), we measured admission blood levels of ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein. We investigated differences in biomarker levels, associations with mortality, blood-brain barrier integrity, neurodeficits and cognitive Z-scores in survivors up to 24-month follow-up. Admission ubiquitin C-terminal hydrolase-L1 levels were elevated >95th percentile of community children in 71 and 51%, and neurofilament-light chain levels were elevated >95th percentile of community children in 40 and 37% of children with cerebral malaria and severe malarial anaemia, respectively. Glial fibrillary acidic protein was not elevated in disease groups compared with controls. In cerebral malaria, elevated neurofilament-light chain was observed in 16 children who died in hospital compared with 166 survivors (P = 0.01); elevations in ubiquitin C-terminal hydrolase-L1 levels were associated with degree of blood-brain barrier disruption (P = 0.01); and the % predictive value for neurodeficits over follow-up (discharge, 6-, 12-, and 24 months) increased for ubiquitin C-terminal hydrolase-L1 (60, 67, 72, and 83), but not neurofilament-light chain (65, 68, 60, and 67). In cerebral malaria, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse memory scores in children <5 years at malaria episode who crossed to over 5 years old during follow-up cognitive testing [ß -1.13 (95% confidence interval -2.05, -0.21), P = 0.02], and elevated neurofilament-light chain was associated with worse attention in children ≥5 years at malaria episode and cognitive testing [ß -1.08 (95% confidence interval -2.05, -1.05), P = 0.03]. In severe malarial anaemia, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse attention in children <5 years at malaria episode and cognitive testing [ß -0.42 (95% confidence interval -0.76, -0.07), P = 0.02]. Ubiquitin C-terminal hydrolase-L1 and neurofilament-light chain levels are elevated in paediatric cerebral malaria and severe malarial anaemia. In cerebral malaria, elevated neurofilament-light chain is associated with mortality whereas elevated ubiquitin C-terminal hydrolase-L1 is associated with blood-brain barrier dysfunction and neurodeficits over follow-up. In cerebral malaria, both markers are associated with worse cognition, while in severe malarial anaemia, only ubiquitin C-terminal hydrolase-L1 is associated with worse cognition.

Apolipoprotein-E4: risk of severe malaria and mortality and cognitive impairment in pediatric cerebral malaria.

BACKGROUND: The relationship of apolipoprotein-E4 (APOE4) to mortality and cognition after severe malaria in children is unknown. METHODS: APOE genotyping was performed in children with cerebral malaria (CM, n = 261), severe malarial anemia (SMA, n = 224) and community children (CC, n = 213). Cognition was assessed over 2-year follow-up. RESULTS: A greater proportion of children with CM or SMA than CC had APOE4 (n = 162, 31.0%; n = 142, 31.7%; n = 103, 24.2%, respectively, p = 0.02), but no difference was seen in APOE3 (n = 310, 59.4%; n = 267, 59.6%; n = 282, 66.2%, respectively, p = 0.06), or APOE2 (n = 50, 9.6%; n = 39, 8.7%; and n = 41, 9.6%, respectively, p = 0.87). APOE4 was associated with increased mortality in CM (odds ratio, 2.28; 95% CI, 1.01, 5.11). However, APOE4 was associated with better long-term cognition (ß, 0.55; 95% CI, 0.04, 1.07, p = 0.04) and attention (ß 0.78; 95% CI, 0.26, 1.30, p = 0.004) in children with CM < 5 years old, but worse attention (ß, -0.90; 95% CI, -1.69, -0.10, p = 0.03) in children with CM ≥ 5 years old. Among children with CM, risk of post-discharge malaria was increased with APOE4 and decreased with APOE3. CONCLUSIONS: APOE4 is associated with higher risk of CM or SMA and mortality in children with CM, but better long-term cognition in CM survivors <5 years of age.

Attitudes, Practices and Understanding of health workers and caregivers regarding the relationship between severe pneumonia and malnutrition in children: A Qualitative Study.

Background: Severe Pneumonia is still the leading cause of morbidity and mortality among children worldwide. Many children with severe pneumonia are reported to die in hospital as well as following discharge due to malnutrition. Severe pneumonia is a catabolic illness, which predisposes to severe malnutrition. WHO and United Nations Children's Fund (UNICEF), recommend 'continued' feeding but do not give any specific recommendations for nutritional support. This could influence health workers' and caregivers' attitudes, practices and understanding regarding the topic. This study aimed to explore the attitudes, practices and understanding of health workers regarding the relationship between severe pneumonia and malnutrition. Methods: We conducted an exploratory qualitative study among health workers and caregivers of children hospitalized with severe pneumonia at Mulago National Referral Hospital in Uganda. Data were collected using focus-groups involving caregivers and key informant interviews with health workers and analysed using the content-thematic analysis approach. Both manual coding and Atlas Ti software were used to support the analysis. Results: Some of the health workers and caregivers were aware of the relationship between severe pneumonia and malnutrition to various degrees, citing reduced appetite, difficulty in breathing and persistent vomiting as pathways to malnutrition in patients with severe pneumonia, which called for a balanced diet and more frequent breastfeeding. Suppressed immunity in malnourished children was mentioned as the pathway to severe pneumonia. Some caregivers confessed not knowing anything about the relationship between the two conditions. Conclusion: Attitudes, practices and understanding regarding the deadly relationship between severe pneumonia and malnutrition among care givers could further be improved by health education and mass sensitization. Clarifying practice guidelines could further enhance attitudes and practices of health workers to reduce preventable pneumonia deaths.