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.

ABSTRACT:Hydroxyurea provides effective disease-modifying treatment for people with sickle cell anemia (SCA), especially when escalated to maximum tolerated dose (MTD), which has wide interpatient dosing variability due to pharmacokinetic (PK) differences. Whether hydroxyurea PK parameters differ among children with SCA in different global regions is unknown. We compared hydroxyurea PK parameters among children with SCA from 5 clinical trials: HUSTLE (United States), TREAT (United States), NOHARM (Uganda), REACH (Uganda and Kenya), and EXTEND (Jamaica). Key hydroxyurea PK parameters were determined using HdxSim, a validated hydroxyurea PK software program. The results were compared across regions by analysis of variance. PK profiles from 451 children with SCA (146 from the United States, 265 from Africa, and 40 from the Caribbean) were included. Children from Africa had slightly lower volumes of distribution, but absorption rate and clearance were similar across regions. The PK-recommended doses to achieve MTD were statistically different but clinically similar across the United States (26.6 ± 5.9 mg/kg per day), Africa (27.6 ± 6.5 mg/kg per day), and the Caribbean (25.2 ± 4.7 mg/kg per day) (P = .04). In multivariable regression, younger age and increased reticulocyte counts were associated with higher PK-recommended doses. Hydroxyurea PK parameters in children with SCA differ minimally across global populations, predicting clinically similar doses to achieve MTD. Individualized hydroxyurea dosing based on a PK-population model derived from US children with SCA can be used broadly to maximize the benefits of this critical medication in other global populations. These trials were registered at www.ClinicalTrials.gov as #NCT00305175 (HUSTLE), #NCT02286154 (TREAT), #NCT01976416 (NOHARM), #NCT01966731 (REACH), and #NCT02556099 (EXTEND).

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.

Objectives Severe malaria in childhood causes long-term cognitive and behavioral problems; however, its impact on health-related quality of life (HRQoL) remains understudied. We assessed HRQoL 4 to 20 years after cerebral malaria (CM), severe malarial anemia (SMA), or other severe malaria (OSM) in Uganda. Methods Participants from 3 longitudinal cohorts with CM, SMA, or OSM were included. Asymptomatic community children (CC) served as the reference group. HRQoL was assessed with a mean (SD) duration of 10.0 (3.3) years after enrollment using the EuroQol 5-Dimension 3-Level instrument (EQ-5D-3L) (age ≥12 years) and EQ-5D-Y-3L (age 8 to 11 years). Model-predicted EQ-5D-3L index and visual analog scale (VAS) scores (children ≥12 years) and EQ-5D-Y-3L VAS scores (children 8 to 11 years) were compared across groups using adjusted 2-part models with log transformation. Results Among the 479 study participants aged ≥12 years (187 CM, 133 SMA, and 159 CC), model-predicted EQ-5D-3L index and VAS scores were significantly lower in children with CM than SMA or CC, and VAS scores were higher in children with SMA than CC. Among the 313 children aged 8 to 11 years (39 CM, 76 SMA, 130 OSM, and 68 CC), model-predicted EQ-5D-Y-3L VAS scores were significantly lower in children with CM than in those with SMA, OSM, or CC and also lower in children with SMA than OSM or CC. Conclusions CM and, to a lesser extent, SMA in childhood are associated with long-term reduction in HRQoL. The chronic effects extend beyond cognition and behavior to affect overall HRQoL.

The gut microbiota shapes malaria immunity and disease severity, but the mechanisms underlying these effects remain unclear. In a murine model, susceptibility to Plasmodium yoelii hyperparasitemia was associated with elevated regulatory T cells and diminished IFN-γ. We demonstrate that the IgA-coated fraction of the microbiota is sufficient to transfer this susceptibility. Plasmodium infection disrupts the intestinal barrier regardless of microbiota composition. Mechanistically, barrier loss was associated with systemic adenosine persistence and an expansion of CD39+ plasmablasts in susceptible mice. Ugandan children with severe malaria exhibited a distinct purinergic immune signature compared to asymptomatic community children. Therapeutic reinforcement of the gut barrier or blockade of the downstream adenosine A2A receptor improved germinal centers and reduced disease severity in mice, independent of parasite burden, revealing a purinergic-dependent immunosuppression pathway that drives pathogenesis. This work defines an axis in which malaria-induced gut leakiness enables microbial-derived signals to trigger purinergic immunosuppression and severe disease.

Memory-like natural killer (NK) cells with enhanced antibody-dependent cellular cytotoxicity (ADCC) have correlated with protection from uncomplicated malaria in prior studies. However, the role of NK cells in severe malaria (SM) has not been characterized. In Ugandan sites with moderate and low malaria transmission, we evaluated NK cell (CD56bright, CD56dim, CD56neg) phenotype and ADCC function by flow cytometry in children <5 years of age with SM (n = 21) and control community children (CC, n = 19). Children with SM had similar total NK cell counts to CC. Children with SM had a higher proportion of LILRB1+ NK cells than CC. The level of malaria transmission in an area was related to NK cell function. In the low malaria transmission area only, children with SM had a higher proportion than CC of NK cells that degranulated, whereas children with SM from both low and moderate malaria transmission areas had lower IFN-γ production than CC. We next evaluated functional Boolean gating for degranulation and IFN-γ production (CD107a+/IFN-γ-, CD107a-/IFN-γ+, and CD107a+/IFN-γ+) in relation to memory-like and checkpoint/exhaustion NK cell markers in low and moderate malaria transmission SM and CC groups. We found there was a significant increase in degranulating only NK cells (CD107a+, IFN-γ-) in children with SM compared to CC solely in the low malaria transmission area. However, there was a significant decrease in NK cells that produced IFN-γ but did not degranulate (CD107a-, IFN-γ+) in children with SM compared to CC in both low and moderate transmission areas. Our data reveal compound functional differences in NK cells among children with SM living in areas of low versus moderate malaria transmission; however, a consistent finding is reduced NK cell IFN-γ production in SM, regardless of transmission intensity.

Background Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with long-term cognitive impairment in children, but little is known about cognitive impairment in children with other forms of severe malaria. Methods In this prospective cohort study of 600 Ugandan children 6 months to 4 years of age with 1 or more of the 5 most common forms of severe malaria (CM, respiratory distress, malaria with multiple seizures, SMA, or prostration), overall cognitive ability, attention, and associative memory were evaluated 12 months after hospital discharge. Age-adjusted z-scores for each domain were calculated from the scores of community children (CC) with no acute illness. Groups were compared using linear regression adjusted for potential confounding factors. Results Children with CM or SMA had significantly lower overall cognition scores than CC (mean difference [95% CI]: CM -0.66 [-1.12, -0.21], P = .001, SMA -0.71 [-1.05, -0.37], P < .001), and a greater proportion of children with CM (5/47, 10.6%) or SMA (17/140, 12.1%) had cognitive impairment (z-score < -2) than CC (2/104, 1.9%, P = .003 and 0.018, respectively). Cognition scores did not differ significantly between children with respiratory distress, multiple seizures or prostration and CC. Attention and associative memory scores did not differ significantly between children with any form of severe malaria and CC. Conclusions CM and SMA, but not other forms of severe malaria, are associated with long-term cognitive impairment in children <5 years of age.

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

OBJECTIVES:We examined how asymptomatic Plasmodium falciparum (Pf) infections and their treatment affect short-term cognitive trajectories among schoolchildren living in western Kenya and explored whether subclinical inflammation may contribute to this relationship. METHODS:In this prospective cohort study, 254 children aged 7-9 years underwent neurocognitive assessment and Pf detection by microscopy at baseline, 4, and 8 weeks. Microscopy-positive cases were treated. Haemoglobin, parasitaemia by quantitative PCR (PfqPCR), molecular force of Pf infection, and 21 plasma cytokines were measured longitudinally. Adjusted generalised linear mixed models were used to evaluate the associations between parasitaemia, treatment, and longitudinal changes in cognition. RESULTS:In pre-specified adjusted analyses, PfqPCR-detectable parasitaemia correlated with a decline in a composite cognitive score over time (adjusted β for interaction: -0.11, 95% CI -0.19--0.031), while treatment of microscopy-detectable infections correlated with improvement (0.082, 95% CI 0.0027-0.17). Higher levels of the inflammatory cytokine CXCL11/ITAC were associated with lower cognitive performance (adjusted β: -0.30, 95% CI -0.60--0.022), which was validated in an independent cross-sectional cohort (-0.18, 95% CI -0.34--0.019). CONCLUSIONS:Asymptomatic Pf parasitaemia may negatively influence short-term cognition in young schoolchildren living in an area of intense malaria transmission. Low-level inflammation may play a role in this effect.

Longitudinal studies follow up children over years to assess their cognitive functioning following exposure to possible cerebral insults. Assessment of similar cognitive domains from early childhood onwards is essential in determining their cognitive developmental trajectory over time. This study measured the predictive validity between cognitive test batteries for early and middle childhood in Ugandan children. Six hundred and thirty-six children (males = 351; 55.2%) ages 18 months to 12 years (mean = 3.82, standard deviation = 1.88) were assessed for overall cognition, attention and memory at baseline and at 6 and 12 months later. The Mullen Scales of Early Learning (MSEL), the Early Childhood Vigilance Test (ECVT) and the Color Object Association Test (COAT) were used to assess overall cognition, attention and memory respectively in children below five years. The Kaufman Assessment Battery for Children, Second Edition (KABC-II) assessed overall cognition and memory in children five years and older, while the Test of Variables of Attention (TOVA) assessed attention. Overall cognition scores for MSEL at baseline correlated with KABC-II cognition (0.71, p < 0.0001) at 12 months and ECVT at baseline correlated with TOVA at 12 months (r = 0.36, p = 0.001). Memory scores from COAT did not correlate with any memory scores from the KABC-II. In conclusion, cognitive ability and attention scores in early childhood are correlated with corresponding middle childhood scores 12 months later from these test batteries. These tests can be used in longitudinal studies of children from early childhood into adolescence.

Purpose Neurologic deficits may occur after severe malaria in childhood. This study sought to determine the perceptions and experiences of the caretakers of children with neurologic deficits after severe malaria in Uganda. Methods This was a thematic analysis informed by a phenomenological interest in lived experience which involved twenty-three in-depth interviews and four focus group discussions. Interviews were audio-taped, transcribed verbatim, and back-translated into English for those conducted in the local languages. Data were coded and analyzed using content thematic analysis. Results Neurologic deficits included motor, movement, cognitive, behavioral, and sensory deficits as well as epilepsy. Eight themes emerged which included: mixed perceptions about the deficits after severe malaria, difficulty in educating the impaired children, mistreatment by the community, mental and emotional distress, financial strain, misconceptions, misunderstandings and conflicts, limited access to specialized care services, and adaptation to a new way of life. Conclusion Caretakers have misconceptions about the cause of neurologic deficits in their children. Caretakers have negative experiences, however, they learn to cope with their children’s impairments. Health messaging and education campaigns targeting caretakers of children with neurologic deficits within communities should be conducted to provide awareness of the neurologic deficits of severe malaria.

Sickle cell anemia (SCA) causes childhood morbidity and mortality in Uganda and other countries in sub-Saharan Africa. Hydroxyurea is safe and effective, but not currently widely used in Uganda. We piloted a toolkit to support hydroxyurea use in two public health clinics: a regional referral hospital in a peri-urban area and a district hospital in a rural area. Implementation supports included a manual, expert training, and coaching over 2 years. We conducted key informant interviews and focus groups with national stakeholders, hospital leaders, healthcare workers, patient caregivers, and patients early in Year 1 and later in Year 2. Embedded research assistants at each clinic recorded observational data at least weekly throughout the study. Using rapid deductive qualitative analyses, the study team coded responses and observations according to constructs from the Consolidated Framework for Implementation Research (CFIR). Several key health system factors were critical for implementing hydroxyurea use: access to medication, laboratory monitoring capacity, and personnel and systems to support treatment. For the latter, executing the clinical registry and performing outreach was critical, so caregivers and patients return to clinic at proper intervals for laboratory monitoring, medication evaluation, and continued access to hydroxyurea. Several respondents requested a comprehensive national plan to address SCA, including effective medications. Supportive outer setting factors for hydroxyurea use in public health settings should include a national plan to improve hydroxyurea and laboratory monitoring access and costs, as well as staged roll-out of hydroxyurea to hospitals ready to provide personnel and system supports.

BACKGROUND:Neurologic sequelae occur after cerebral malaria (CM) but are less well described after non-cerebral severe malaria (NCSM). METHODS:In a prospective cohort study, we determined the presence, type and outcomes of neurologic sequelae (persistent neurologic deficits and/or development of epilepsy over 12-month follow-up) in Ugandan children admitted with CM (n = 54) or NCSM (severe malarial anemia, respiratory distress, malaria with multiple seizures, or prostration, n = 495). RESULTS:At hospital discharge, neurologic deficits were more frequent in children with CM (21/54 [38.9%]) than children with NCSM (45/495 [9.1%], P < 0.001). At 12-month follow-up, persistent neurologic deficits did not differ significantly between children with CM or NCSM (1/47 (2.1%) vs. 2/449 (0.4%), OR [95% CI], 5.8 [0.8, 44.7]). However, development of epilepsy, and consequently presence of neurologic sequelae, at 12-month follow-up were more frequent in children with CM than NCSM (3/47 (6.4%) vs. 3/449 (0.7%), OR [95% CI] 10.0 [2.2, 45.6], and 3/47 (6.4%) vs. 5/449 (1.1%), OR [95% CI] 6.4 [1.6, 25.1], respectively). Seven children with no neurologic deficits at discharge had new deficits at 12 months. CONCLUSION:Neurologic sequelae, particularly epilepsy, are more common in CM than other forms of severe malaria, but occur rarely in non-cerebral severe malaria. IMPACT:Long-term neurologic sequelae in children after forms of severe malaria other than cerebral malaria (e.g., severe malarial anemia, respiratory distress, malaria with multiple seizures, and prostration) are not well-characterized. In the present study, long-term neurologic sequelae (persistent neurological deficits and/or development of epilepsy after discharge over 12- month follow-up) were more common in children with cerebral malaria (6%) than in children with non-cerebral severe malaria (1%). Epilepsy was the primary driver of the differences between groups (cerebral malaria, 6%, non-cerebral severe malaria 0.7%). Long-term neurologic sequelae are rare in children with non-cerebral severe malaria.

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).

OBJECTIVES This study set out to describe imported pediatric malaria in the United States over an 8-year period, including patient demographics, clinical outcomes, and risk factors for severe disease. METHODS A retrospective descriptive study of pediatric patients treated for malaria at 9 hospitals in the United States from 2016 to 2023 was conducted to analyze patient demographics, clinical outcomes, and risk factors for severe malaria. RESULTS A total of 171 children were treated across the 9 US hospitals included in this study from 2016 to 2023. Most patients had traveled to West Africa to visit friends and relatives. Fever was the most common symptom recorded (90%), and most reported at least 1 abdominal symptom (66%). Thirty-two percent of patients were diagnosed with severe malaria. No deaths occurred. Delayed diagnoses were common (26%), occurred at similar rates across all hospitals in the study, and were a risk factor for severe malaria. CONCLUSIONS Delayed diagnoses of travel-acquired malaria were common for pediatric patients presenting to hospitals in the United States and are associated with higher risk for severe malaria, which is associated with longer hospitalizations and increased morbidity. Chemoprophylaxis against travel-acquired malaria and prompt diagnosis of imported cases are crucial to improving patient outcomes.