BACKGROUND:Paediatric acute kidney injury (AKI) is a complication of severe malaria, but its long-term outcomes remain poorly defined in low-income and middle-income countries. We aimed to evaluate the long-term association between paediatric AKI and kidney outcomes and mortality following severe malaria. METHODS:We pooled data from two prospective cohorts of Ugandan children (ie, those aged 6 months-12 years) admitted to hospital with severe malaria between 2008 and 2017. Children with stored admission blood samples available for creatinine measurement were included in the analysis. Surviving participants were enrolled in a follow-up study conducted from 2020 to 2023, when kidney function and survival were assessed, using Cox regression with age as the timescale to model mortality risk. Logistic regression was used to estimate the odds of chronic kidney disease (CKD), defined as two or more consecutive low estimated glomerular filtration rates 90 days or more apart, and long-term major adverse kidney events, defined as CKD or death. Adjusted analyses included the following enrolment characteristics: age, sex, height-for-age Z score, study site, study cohort, severe malaria group (ie, cerebral malaria, severe malarial anaemia, respiratory distress, complicated seizures, or prostration), and HIV status. FINDINGS:At enrolment, the median age was 2·5 years (IQR 1·8-3·5), 622 (57·8%) of 1077 were male and 455 (42·2%) were female, with Kidney Disease: Improving Global Outcomes-defined AKI occurring in 431 (40·0%) children. Over a median of 6·5 years (3·7-8·8), 147 (13·6%) of children died, with nearly half of deaths (71 of 147) occurring after hospital discharge. Adjusted odds of long-term major adverse kidney events were higher among children with AKI (adjusted odds ratio [aOR] 3·14, 95% CI 2·23-4·43), driven by a higher mortality risk (adjusted hazard ratio [aHR] 3·36, 95% CI 2·22-5·10) that remained elevated beyond 2 years after the acute episode (aHR 4·53, 1·80-11·37). AKI survivors had higher odds of chronic kidney disease over follow-up (odds ratio 1·77, 1·07-2·93), although not significant after adjustment (aOR 1·47, 95% CI 0·84-2·56; p=0·18). INTERPRETATION:In this paediatric population, AKI was associated with excess long-term mortality, suggesting AKI is a sentinel event that marks sustained vulnerability to death and highlights limitations of acute-care models in malaria-endemic settings. FUNDING:The US National Institute of Neurological Disorders and Stroke, the Fogarty International Center, the US National Institutes of Allergy and Infectious Diseases, and a Ralph W and Grace M Showalter Young Investigator Award.

The prevalence and clinical significance of mixed Plasmodium infections in children with severe Plasmodium falciparum (P. falciparum) malaria are not well characterized. In a cohort of 440 Ugandan children hospitalized with severe malaria who were diagnosed with Plasmodium species via microscopy, nested polymerase chain reaction (nPCR) testing was used to detect P. falciparum, Plasmodium ovale (P. ovale), Plasmodium malariae (P. malariae), and Plasmodium vivax (P. vivax) infections and assess their association with adverse clinical outcomes during hospitalization. Using nPCR testing, the Plasmodium 18S small-subunit ribosomal RNA gene was detected in 440 children. Plasmodium falciparum mono-infection was identified in 329 (74.8%) children, P. malariae mono-infection was detected in one (0.2%), P. falciparum and P. ovale mixed infections were detected in 100 (22.8%), P. falciparum and P. malariae mixed infection was detected in one (0.2%), and P. falciparum, P. ovale, and P. malariae triple infections were detected in nine (2.1%). Children with triple infections of P. falciparum, P. ovale, and P. malariae exhibited higher mortality rates than those with P. falciparum mono-infection (3/9 [33%] versus 23/329 [7%]; odds ratio = 7.0; 95% CI = 1.8-28; P = 0.005). They were also more likely to experience respiratory distress (6/9 [67%] versus 115/329 [35%]; P = 0.08). In the present study, a high proportion of children with severe falciparum malaria had mixed P. ovale infections, and P. falciparum, P. ovale, and P. malariae triple infections were associated with increased mortality. Improved detection and broader surveillance of non-falciparum malaria may help identify epidemiologic patterns associated with adverse outcomes in severe malaria.

Importance Despite existing prevention strategies, infections remain a major cause of morbidity and mortality in children in Africa with sickle cell anemia. Objective To determine the safety and effectiveness of daily zinc supplementation to prevent all-cause infection in children with sickle cell anemia in Uganda. Design, Setting, and Participants A randomized, double-blind, placebo-controlled trial of children aged 1.00 to 4.99 years with sickle cell anemia at Jinja Regional Referral Hospital in Jinja, Uganda, from February 10, 2025, to April 30, 2025, with 6 months of follow-up through November 7, 2025. Interventions Participants received zinc sulfate at 20 mg daily or placebo daily for 6 months. Main Outcomes and Measures The primary outcome was all-cause infections per 100 person-years, using standardized clinical criteria to define infections. Results Among 118 children screened for eligibility, 100 were randomly assigned to receive zinc supplementation (n = 50) or placebo (n = 50) (mean [SD] age, 36.0 [13.2] months; 45 female [45%]). At enrollment, 45 participants (45%) were receiving hydroxyurea therapy. All participants initiated or continued receiving hydroxyurea after enrollment. During the 6-month follow-up, there was complete ascertainment for all participants and no loss to follow-up. There were 80 all-cause infections in the zinc group and 124 in the placebo group, corresponding to a significantly lower infection rate in the zinc group than the placebo group (305.7 [95% CI, 242.4-380.4] infections per 100 person-years vs 480.7 [95% CI, 399.8-573.1] infections per 100 person-years; rate difference, −176.0 [95% CI, −300.8 to −51.3]; incidence rate ratio after adjustment for baseline age, sex, and hydroxyurea use, 0.62 [95% CI, 0.45-0.86]). No adverse events requiring discontinuation of the study intervention were observed in either group. Conclusions and Relevance Zinc supplementation at 20 mg per day reduced all-cause infection in children with sickle cell anemia younger than 5 years in Uganda. Multisite clinical trials are needed to validate these findings and to assess effectiveness in older children. Trial Registration ClinicalTrials.gov Identifier: NCT06561061

Importance:Despite existing prevention strategies, infections remain a major cause of morbidity and mortality in children in Africa with sickle cell anemia. Objective:To determine the safety and effectiveness of daily zinc supplementation to prevent all-cause infection in children with sickle cell anemia in Uganda. Design, Setting, and Participants:A randomized, double-blind, placebo-controlled trial of children aged 1.00 to 4.99 years with sickle cell anemia at Jinja Regional Referral Hospital in Jinja, Uganda, from February 10, 2025, to April 30, 2025, with 6 months of follow-up through November 7, 2025. Interventions:Participants received zinc sulfate at 20 mg daily or placebo daily for 6 months. Main Outcomes and Measures:The primary outcome was all-cause infections per 100 person-years, using standardized clinical criteria to define infections. Results:Among 118 children screened for eligibility, 100 were randomly assigned to receive zinc supplementation (n = 50) or placebo (n = 50) (mean [SD] age, 36.0 [13.2] months; 45 female [45%]). At enrollment, 45 participants (45%) were receiving hydroxyurea therapy. All participants initiated or continued receiving hydroxyurea after enrollment. During the 6-month follow-up, there was complete ascertainment for all participants and no loss to follow-up. There were 80 all-cause infections in the zinc group and 124 in the placebo group, corresponding to a significantly lower infection rate in the zinc group than the placebo group (305.7 [95% CI, 242.4-380.4] infections per 100 person-years vs 480.7 [95% CI, 399.8-573.1] infections per 100 person-years; rate difference, -176.0 [95% CI, -300.8 to -51.3]; incidence rate ratio after adjustment for baseline age, sex, and hydroxyurea use, 0.62 [95% CI, 0.45-0.86]). No adverse events requiring discontinuation of the study intervention were observed in either group. Conclusions and Relevance:Zinc supplementation at 20 mg per day reduced all-cause infection in children with sickle cell anemia younger than 5 years in Uganda. Multisite clinical trials are needed to validate these findings and to assess effectiveness in older children. Trial Registration:ClinicalTrials.gov Identifier: NCT06561061.

Importance:Cerebral malaria and severe malarial anemia are associated with cognitive impairment and decreased academic achievement 1 to 2 years after the initial episode. The extent to which impairment persists into later childhood and adolescence is unknown. Objective:To determine whether severe malaria in children is associated with long-term cognitive impairment or decreased academic achievement. Design, Setting, and Participants:Assessment of Ugandan children enrolled in 2 prior cohort studies of severe malaria; 1247 children completed the prior studies (2008-2018), of whom 958 were traceable (77%), and 939 (75%) enrolled in the present study (2020-2023). Data from 889 individuals younger than 18 years were analyzed. Exposures:Cerebral malaria (n = 184), severe malarial anemia (n = 249), other forms of severe malaria (respiratory distress, complicated seizures, or prostration, n = 239), and unaffected community children (n = 217). Main Outcomes and Measures:Descriptive analysis including age-adjusted z scores of overall cognitive ability, attention, and academic achievement (math, reading). Results:Participants (mean age, 11.1 [SD, 3.4] years; 44.2% female) were tested 4 to 15 years (mean, 8.4 [SD, 2.7] years) after their severe malaria episode. Compared with community children, children with a history of cerebral malaria or severe malarial anemia had lower scores in overall cognition (adjusted mean difference, -0.41 [Bonferroni-corrected 95% CI, -0.74 to -0.09] and -0.31 [95% CI, -0.61 to -0.01], respectively) and math (-0.46 [95% CI, -0.78 to -0.14] and -0.32 [95% CI, -0.61 to -0.03], respectively), while attention and reading scores did not differ significantly. Cognitive and academic scores were not significantly different between children with other forms of severe malaria and community children. In children with cerebral malaria or severe malarial anemia, acute kidney injury, hyperuricemia, and elevated plasma angiopoietin-2 levels at the time of the severe malaria episode were associated with worse z scores in overall cognitive ability (-0.44 [95% CI, -0.80 to -0.08], -0.45 [95% CI, -0.88 to -0.02], and -0.33 [95% CI, -0.63 to -0.03], respectively). In children with cerebral malaria or severe malarial anemia, acute kidney injury was additionally associated with lower z scores in reading (95% CI, -0.42 [95% CI, -0.79 to -0.05]) and math (95% CI, -0.39 [-0.74 to -0.04]). Conclusions and Relevance:Among survivors of a severe childhood malaria episode, cerebral malaria and severe malarial anemia in childhood are associated with cognitive impairment and decreased academic achievement in some metrics 4 to 15 years after the index episode.

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome diagnosed using composite clinical and laboratory criteria. Several features used to classify HLH overlap with manifestations of severe malaria, raising uncertainty about the specificity and prognostic significance of HLH classification in this context. We examined the frequency of HLH and its association with mortality in children with severe malaria. Methods We analyzed two cohorts of Ugandan children hospitalized with Plasmodium falciparum severe malaria (Cohort #1, n=461; Cohort #2, n=594). HLH was classified using the HLH-2004 criteria and the HScore. To address differences in laboratory availability, concordance analyses were performed using criteria assessed in both cohorts. Associations with in-hospital mortality were examined using logistic regression. Results Features included in HLH diagnostic criteria were common in both cohorts. Hyperferritinemia (≥500 ng/mL) was present in >75% of children, whereas hypofibrinogenemia was uncommon (<2%). Using complete criteria, the frequency of HLH classification varied between cohorts (HLH-2004: 3.5% vs 13.0%; HScore >169: 0% vs 17.8%), but was similar in concordance analyses. Classification by HLH-2004 criteria was not associated with mortality in either cohort. In Cohort #2, higher HScores were associated with increased unadjusted mortality (OR 3.04, 95%CI 1.57–5.86), although this association was attenuated after adjustment for markers of organ dysfunction (aOR 1.87, 95%CI 0.90–3.89). Conclusion Children with severe malaria frequently meet clinical and laboratory criteria used to classify HLH. However, HLH classification using current diagnostic frameworks was not independently associated with mortality, suggesting substantial overlap between HLH criteria and manifestations of severe malaria.

Introduction: Acute kidney injury (AKI) is a common complication of pediatric hospitalizations. We evaluated the prevalence of AKI in children hospitalized with acute malnutrition, examined how AKI definitions influence risk stratification, and assessed the performance of the STOP AKI risk score. Methods: We enrolled 185 Ugandan children hospitalized with acute malnutrition. AKI was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria based on serial creatinine measurements, with the nadir creatinine during hospitalization as baseline. Because children with malnutrition have low baseline creatinine levels, we evaluated whether applying minimum absolute creatinine thresholds improved identification of clinically meaningful AKI, defined by its association with mortality. Results: The median age was 1.2 years, and 13.5% of children died. KDIGO-defined AKI without a minimum creatinine threshold was not associated with mortality. Applying a minimum absolute creatinine threshold of 0.4 mg/dl to the KDIGO criteria identified AKI in 23.2% of participants and was independently associated with mortality (adjusted odds ratio [OR, aOR]: 4.06, 95% confidence interval [CI]: 1.39-11.84). A threshold of 0.5 mg/dl identified fewer children but predominantly severe AKI. Clinical risk factors included diarrhea, vomiting, and sepsis. The ISN STOP AKI risk score did not discriminate AKI risk (area under the receiver operating characteristic curve [AUROC]: 0.50, 95% CI: 0.40-0.60). Conclusion: AKI is common in children hospitalized with acute malnutrition and is strongly associated with mortality when clinically meaningful creatinine thresholds are applied. Existing AKI risk tools perform poorly in this population, thereby underscoring the need for adapted approaches to AKI identification in malnourished children.

BACKGROUND:Household air pollution (HAP) due to biomass fuel use is a risk factor for childhood pneumonia, a leading cause of under-five mortality globally. This study examined the relationship between HAP and disease severity in Ugandan children hospitalized with hypoxemic pneumonia. METHODS:We conducted a retrospective case-control study across 20 Ugandan hospitals. PM2.5 exposure was estimated using caregiver-reported fuel use, cooking duration, kitchen structure, and ventilation. Pneumonia severity was assessed clinically, and associations were analyzed using non-parametric tests. RESULTS:We included 735 children (median age 9 months, 42% female) hospitalized with hypoxemic pneumonia. Most households used firewood (84%) or charcoal (16%) for cooking. Other HAP sources included cigarette smoke (17%) and open-flame lighting (17%). The median estimated personal PM2.5 exposure was 145 µg/m³ (IQR 79-270), and 732 children (99.6%) exceeded the recommended WHO limit of 15 µg/m³. Chronic HAP-related symptoms included cough (57%), red eyes (41%), rhinorrhea (38%), difficulty breathing (22%), and wheeze (6.5%). Higher PM2.5 exposure was significantly associated with more frequent red eyes (p = 0.0073), rhinorrhea (p = 0.016), and difficulty breathing (p < 0.0001). The median SICK score was 3.9 (IQR 3.4-5.0). Higher scores correlated with higher PM2.5 exposure (τ = 0.15, p < 0.0001) and increased mortality risk (p = 0.0024). Higher PM2.5 exposure was also linked to WHO danger signs, lower SpO2 at admission, longer duration of oxygen therapy, and greater total oxygen volume administered over the hospital admission (p < 0.05 for all). CONCLUSION:Household PM2.5 exposure from biomass combustion is associated with greater pneumonia severity in hospitalized children under five. Reducing household air pollution through cleaner fuels, better ventilation, and behavioral changes may improve outcomes for a leading cause of child mortality globally.

HIV exposure in utero is associated with low birth weight (LBW), even in the absence of vertical transmission. To explore mechanism, we evaluated endothelial markers angiopoietin (Ang)-1 and Ang-2 among 294 uninfected Ugandan infants born to women with HIV (WWH). The median Ang-2/Ang-1 ratio was 0.051 [interquartile range (IQR) 0.023-0.19] among infants with LBW and 0.018 (IQR 0.010-0.037) among controls (P = 0.00011). Endothelial dysregulation may contribute to LBW among infants born to WWH.

Background Acute kidney injury (AKI) is a common complication of pediatric hospitalizations. We evaluated the prevalence of AKI in children hospitalized with acute malnutrition, examined how AKI definitions influence risk stratification, and assessed performance of the STOP AKI risk score. Methods We enrolled 185 Ugandan children hospitalized with acute malnutrition. AKI was defined using Kidney Disease: Improving Global Outcomes (KDIGO) criteria based on serial creatinine measurements, with the nadir creatinine during hospitalization as baseline. Because children with malnutrition have low baseline creatinine levels, we evaluated whether applying minimum absolute creatinine thresholds improved identification of clinically meaningful AKI, defined by its association with mortality. Results The median age was 1.2 years, and 13.5% of children died. KDIGO-defined AKI without a minimum creatinine threshold was not associated with mortality. Applying a minimum absolute creatinine threshold of 0.4 mg/dL to the KDIGO criteria identified AKI in 23.2% of participants and was independently associated with mortality (aOR 4.06, 95% CI 1.39–11.84). A threshold of 0.5 mg/dL identified fewer children but predominantly severe AKI. Clinical risk factors included diarrhea, vomiting, and sepsis. The International Society of Nephrology STOP AKI risk score did not discriminate AKI risk (AUROC 0.50, 95% CI 0.40–0.60). Conclusion AKI is common in children hospitalized with acute malnutrition and is strongly associated with mortality when clinically meaningful creatinine thresholds are applied. Existing AKI risk tools perform poorly in this population, underscoring the need for adapted approaches to AKI identification in malnourished children.

Historically, acute kidney injury (AKI) has been an underappreciated complication in children with severe malaria. We conducted an individual patient data meta-analysis to model the impact of AKI and its complications on inpatient mortality in African children hospitalized with malaria. Studies were identified using MEDLINE, EMBASE, Scopus, and PubMed with no language restrictions, as well as through outreach at scientific meetings. Investigators were contacted about participation in the study. Eligible studies included African children hospitalized with Plasmodium falciparum malaria, a serum creatinine measurement, and mortality assessed. The primary exposure was AKI, defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria based on serum creatinine. The primary outcome was all-cause in-hospital mortality, and dialysis requirement was a secondary outcome. Data were standardized and cleaned, and random-effects meta-analyses were conducted to generate pooled estimates. We included 18 studies involving 8 countries and 13,528 children aged 3 months to 16 years over a 33-year period with 951 deaths (7

BACKGROUND:The prevalence of iron deficiency (ID) among children exposed to HIV in utero is unclear, and an association with ID and neurobehavioral deficits has not been investigated. OBJECTIVES:We assessed iron status in Ugandan children aged 6 to 59 mo who were HIV-infected (HI), exposed to HIV but uninfected (HEU), or not exposed to HIV (HUU) and examined the relationship with neurobehavioral outcomes. METHODS:We enrolled children who were HI (n = 70), HEU (n = 70), or HUU (n = 70) and conducted assessments of cognition, attention, executive function, and socioemotional behavior. We used logistic regression to compare ID prevalence among the groups and tested for associations between iron status and neurobehavioral outcomes, using the HUU group to calculate age-adjusted Z-scores. RESULTS:More than 40% of children in each group had ID (plasma ferritin <12 or <30 μg/L if C-reactive protein >10 mg/L). Children who were HEU had a higher prevalence of ID than children who were HI (59.4% compared with 42%, P = 0.04) and a higher prevalence of ID with anemia (IDA) than children who were HUU (32.4% compared with 18.8%, P = 0.04). Overall, children with ID scored lower in fine motor {adjusted Z-score [95% confidence interval (CI)] for ID compared with not ID: -0.20 [-0.4, -0.03] compared with 0.07 [-0.09, 0.24]}, but there were no other differences by ID. Children with IDA, particularly those who were HI, had poorer socioemotional behavior, exhibiting poorer exploration quantity [adjusted odds ratio IDA compared with not IDA (95% CI): 0.39 (0.17, 0.92)], greater fear [4.5 (1.6, 12.1)], less positive affect [0.44 (0.23, 0.87)], and less adaptability [0.38 (0.17, 0.82)]. CONCLUSIONS:There is a significant burden of ID among Ugandan children, including those who are HI and HEU. IDA was associated with poorer socioemotional behavior, highlighting the need to study the safety and efficacy of early-life iron interventions to optimize neurobehavioral development in this population.

Background Acute kidney injury (AKI) is a common complication of severe malaria, arising from multiple pathophysiological processes. AKI is increasingly recognized as a critical contributor to morbidity and mortality in pediatric populations in Sub-Saharan Africa. This study assessed the prevalence of AKI and its associated factors among children diagnosed with severe malaria at St. Francis Hospital Nsambya. Methods This was a retrospective cross-sectional study in which the medical records of 198 children aged 2 months to 12 years admitted between 1 st January 2019 and 31 st December 2023 were reviewed. AKI was defined using the Kidney Disease Improving Global Outcomes (KDIGO) criteria based on fold change in admission creatinine from estimated baseline. A minimum creatinine value of 0.4mg/dL was required to be considered AKI. Logistic regression analysis was performed to assess factors associated with AKI. A p < 0.05 was considered statistically significant. Results The median (IQR) age of participants was 5 (2–7) years, and the majority were males 130 (65.7%). Overall, 1 in 2 children had AKI (49.5%) with 31.6% (198) participants having stage 3, 24.5% stage 2 AKI, and 15.3% required dialysis. Mortality was confined to children with AKI, with a mortality rate of 4.1% in AKI and highest in stage 3 AKI (9.7%). On multivariable analysis, younger age (aOR 0.6, 95% CI 0.51–0.71), higher BUN (aOR 1.1 per mg/dL, 95% CI 1.03–1.12), and lower hemoglobin levels (aOR 1.3, 95% CI 1.1–1.48) were independently associated with AKI. Conclusion This study found a high prevalence of AKI in children with severe malaria with younger children and children with lower hemoglobin most at risk. Routine early screening and close monitoring of renal function is recommended for all severe malaria cases in hyperendemic areas.

Abstract Objective To evaluate the performance of the point-of-care i-STAT device for creatinine measurement in Ugandan children with sickle cell anemia (SCA), and to determine the clinical impact of hydroxyurea-associated assay interference. Results description This secondary analysis was nested within a randomized clinical trial involving 248 Ugandan children with SCA. The mean age at enrollment was 32 months, and 115/248 (46.2%) initiated hydroxyurea during 12 months of follow-up as part of routine clinical care. At enrollment, creatinine values measured by i-STAT and reference laboratory testing were clinically comparable. At follow-up, children receiving hydroxyurea had significantly higher creatinine values measured by i-STAT than by reference laboratory testing (mean difference + 0.19 mg/dL; p = 0.006), with several i-STAT results falling within the clinically abnormal range. No such discrepancy was observed among children not receiving hydroxyurea. In a subset of samples, serum hydroxyurea concentrations measured by high-performance liquid chromatography accounted for 73% of the variability in i-STAT creatinine values. These findings demonstrate clinically meaningful interference of hydroxyurea with enzymatic point-of-care creatinine testing, which may result in misclassification of kidney function and inappropriate clinical decision-making in children with SCA receiving hydroxyurea. ClinicalTrials.gov identifier: NCT03528434 (date registered: May 7 th , 2018).

Soluble urokinase-type plasminogen activator receptor (suPAR) is an emerging critical illness biomarker. Circulating suPAR levels are elevated in severe malaria and are associated with mortality risk. The present study evaluated clinical predictors of elevated plasma suPAR (≥15 ng/mL). Elevated suPAR occurred in 22.1% of 1226 Ugandan children with severe malaria and was independently associated with severe acute kidney injury, hyperlactatemia, and coma, as well as biomarkers of immune and endothelial activation. An optimized clinical decision algorithm that prioritizes suPAR testing for children with clinical danger signs, including coma and kidney injury, could improve the identification of children at highest risk of death.

Severe malaria remains an important global cause of mortality, particularly in sub-Saharan Africa, where the majority of deaths occur in children under 5 years of age. Hyperkalemia in severe malaria has not been very well reported but is associated with increased mortality. Severe malaria has several features that predispose patients to hyperkalemia, including acute kidney injury, hemolysis, metabolic acidosis, and severe anemia requiring blood transfusion. Our objective is to discuss the epidemiology of hyperkalemia in severe malaria, provide an overview of potassium homeostasis, and discuss risk factors for elevated potassium levels in severe malaria, as well as management strategies considering the resource-limited settings where malaria is endemic.