Predictors of mortality among low birth weight neonates after hospital discharge in a low-resource setting: A case study in Uganda.

BACKGROUND: Most neonatal deaths occur among low birth weight infants. However, in resource-limited settings, these infants are commonly discharged early which further exposes them to mortality. Previous studies on morbidity and mortality among low birth weight infants after early discharge mainly focused on very low birth weight infants, and none described post-discharge neonatal mortality. This study aimed to determine the proportion and predictors of mortality among low birth weight neonates discharged from the Special Care Baby Unit at Mulago National Referral Hospital in Uganda. METHODS: This was a prospective cohort study of 220 low birth weight neonates discharged from the Special Care Baby Unit at Mulago National Referral Hospital. These were followed up to 28 completed days of life, or death, whichever occurred first. Proportions were used to express mortality. To determine the predictors of mortality, Cox hazards regression was performed. RESULTS: Of the 220 enrolled participants, 216 (98.1%) completed the follow-up. The mean gestational age of study participants was 34 ±3 weeks. The median weight at discharge was 1,650g (IQR: 1,315g -1,922g) and 46.1% were small for gestational age. During follow-up, 14/216 (6.5%) of neonates died. Mortality was highest (7/34, 20.6%) among neonates with discharge weights less than 1,200g. The causes of death included presumed neonatal sepsis (10/14, 71.4%), suspected aspiration pneumonia (2/14, 14.3%), and suspected cot death (2/14, 14.3%). The median time to death after discharge was 11 days (range 3-16 days). The predictors of mortality were a discharge weight of less than 1,200g (adj HR: 23.47, p <0.001), a 5-minute Apgar score of less than 7 (adj HR: 4.25, p = 0.016), and a diagnosis of neonatal sepsis during admission (adj HR: 7.93, p = 0.009). CONCLUSION: Post-discharge mortality among low birth weight neonates at Mulago National Referral Hospital is high. A discharge weight of less than 1,200g may be considered unsafe among neonates. Caregiver education about neonatal danger signs, and measures to prevent sepsis, aspiration, and cot death should be emphasized before discharge and during follow-up visits.

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.

Doxycycline for the treatment of nodding syndrome: a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Nodding syndrome is a poorly understood neurological disorder that predominantly occurs in Africa. We hypothesised that nodding syndrome is a neuroinflammatory disorder, induced by antibodies to Onchocerca volvulus or its Wolbachia symbiont, cross-reacting with host neuronal proteins (HNPs), and that doxycycline can be used as treatment. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, we recruited participants from districts affected by nodding syndrome in northern Uganda. We included children and adolescents aged 8-18 years with nodding syndrome, as defined by WHO consensus criteria. Participants were randomly assigned (1:1) to receive either 100 mg doxycycline daily or placebo for 6 weeks via a computer-generated schedule stratified by skin microscopy results, and all parties were masked to group assignment. Diagnoses of O volvulus and antibodies to HNPs were made using luciferase immunoprecipitation system assays and immunohistochemistry. The primary outcome was change in the proportion with antibodies to HNPs, assessed at 24 months. All participants were included in safety analyses, and surviving participants (those with samples at 24 months) were included in primary analyses. Secondary outcomes were: change in concentrations of antibodies to HNPs at 24 months compared with baseline; proportion of participants testing positive for antibodies to O volvulus-specific proteins and concentrations of Ov16 or OVOC3261 antibodies at 24 months compared with baseline; change in seizure burden, proportion achieving seizure freedom, and the proportions with interictal epileptiform discharges on the diagnostic EEG; overall quality of life; disease severity at 24 months; and incidence of all-cause adverse events, serious adverse events, and seizure-related mortality by 24 months. This trial is registered with ClinicalTrials.gov, NCT02850913. FINDINGS: Between Sept 1, 2016, and Aug 31, 2018, 329 children and adolescents were screened, of whom 240 were included in the study. 140 (58%) participants were boys and 100 (42%) were girls. 120 (50%) participants were allocated to receive doxycycline and 120 (50%) to receive placebo. At recruitment, the median duration of symptoms was 9 years (IQR 6-10); 232 (97%) participants had O volvulus-specific antibodies and 157 (65%) had autoantibodies to HNPs. The most common plasma autoantibodies were to human protein deglycase DJ-1 (85 [35%] participants) and leiomodin-1 (77 [32%] participants) and, in cerebrospinal fluid (CSF), to human DJ-1 (27 [11%] participants) and leiomodin-1 (14 [6%] participants). On immunohistochemistry, 46 (19%) participants had CSF autoantibodies to HNPs, including leiomodin-1 (26 [11%]), γ-aminobutyric acid B receptors (two [<1%]), CASPR2 (one [<1%]), or unknown targets (28 [12%]). At 24 months, 161 (72%) of 225 participants had antibodies to HNPs compared with 157 (65%) of 240 at baseline. 6 weeks of doxycycline did not affect the concentration of autoantibodies to HNPs, seizure control, disease severity, or quality of life at the 24-month follow-up but substantially decreased Ov16 antibody concentrations; the median plasma signal-to-noise Ov16 ratio was 16·4 (95% CI 6·4-38·4), compared with 27·9 (8·2-65·8; p=0·033) for placebo. 14 (6%) participants died and, other than one traffic death, all deaths were seizure-related. Acute seizure-related hospitalisations (rate ratio [RR] 0·43 [95% CI 0·20-0·94], p=0·028) and deaths (RR 0·46 [0·24-0·89], p=0·028) were significantly lower in the doxycycline group. At 24 months, 96 (84%) of 114 participants who received doxycycline tested positive for antibodies to Ov16, compared with 97 (87%) of 111 on placebo (p=0·50), and 74 (65%) participants on doxycycline tested positive for antibodies to OVOC3261, compared with 57 (51%) on placebo (p=0·039). Doxycycline was safe; there was no difference in the incidence of grade 3-5 adverse events across the two groups. INTERPRETATION: Nodding syndrome is strongly associated with O volvulus and the pathogenesis is probably mediated through an O volvulus induced autoantibody response to multiple proteins. Although it did not reverse disease symptoms, doxycycline or another prophylactic antibiotic could be considered as adjunct therapy to antiseizure medication, as it might reduce fatal complications from acute seizures and status epilepticus induced by febrile infections. FUNDING: Medical Research Council (UK). TRANSLATION: For the Luo translation of the abstract see Supplementary Materials section.

Ketogenic dietary therapy utilization in Kenya: A qualitative exploration of dietitian's perceptions.

This study utilized a qualitative design to explore dietitians' perceptions regarding Ketogenic Diet Therapy (KDT) for patients with drug-resistant epilepsy in Kenya. Dietitians from Kenya were selected and consented. Audio-recorded interviews were conducted, followed by thematic analysis of verbatim transcripts to identify recurring patterns. The study enrolled 18 dietitians, fourteen of whom correctly described their understanding of KDT for managing drug-resistant epilepsy. There was a lack of confidence in their capacity to initiate the KDT with all expressing the need for further training and facilitation. Only one dietitian reported having initiated and maintained KDT. There was an overall positive view regarding KDT and willingness to implement KDT for patients with drug-resistant epilepsy. Dietitians expressed concerns regarding the availability of national policies, inadequate staffing to support families who require KDT, and the cost of implementing this intervention. Dietitians expressed interest in virtual training to enhance their understanding of KDT. Dietitians in Kenya are mostly aware of KDT utilization for the management of drug-resistant epilepsy. However, they cited poor capability and various barriers to implementation. There is a need for policies to facilitate KDT as a treatment option for the benefit of patients with drug-resistant epilepsy.

Bi-isotype immunoglobulins enhance antibody-mediated neutrophil activity against Plasmodium falciparum parasites.

Background: Malaria remains a major global health priority, and monoclonal antibodies (mAbs) are emerging as potential new tools to support efforts to control the disease. Recent data suggest that Fc-dependent mechanisms of immunity are important mediators of protection against the blood stages of the infection, but few studies have investigated this in the context of mAbs. We aimed to isolate mAbs agnostic to cognate antigens that target whole merozoites and simultaneously induce potent neutrophil activity measured by the level of reactive oxygen species (ROS) production using an antibody-dependent respiratory burst (ADRB) assay. Methods: We used samples from semi-immune adults living in coastal Kenya to isolate mAbs that induce merozoite-specific ADRB activity. We then tested whether modifying the expressed IgG1 isotype to an IgG-IgA Fc region chimera would enhance the level of ADRB activity. Results: We isolated a panel of nine mAbs with specificity to whole merozoites. mAb J31 induced ADRB activity in a dose-dependent fashion. Compared to IgG1, our modified antibody IgG-IgA bi-isotype induced higher ADRB activity across all concentrations tested. Further, we observed a negative hook effect at high IgG1 mAb concentrations (i.e., >200 µg/mL), but this was reversed by Fc modification. We identified MSP3.5 as the potential cognate target of mAb J31. Conclusions: We demonstrate an approach to engineer mAbs with enhanced ADRB potency against blood-stage parasites.

Prevalence and risk factors of gross neurologic deficits in children after severe malaria: a systematic review protocol.

Background: Children exposed to severe malaria may recover with gross neurologic deficits (GND). Several risk factors for GND after cerebral malaria (CM), the deadliest form of severe malaria, have been identified in children. However, there is inconsistency between previously reported and more recent findings. Although CM patients are the most likely group to develop GND, it is not clear if other forms of severe malaria (non-CM) may also contribute to the malaria related GND. The aim of this systematic review is to synthesize evidence on the prevalence and risk factors for GND in children following CM and map the changes in patterns over time. In addition, this review will synthesize evidence on the reported prevalence and risk factors of gross neurologic deficits following other forms of severe malaria. Methods: The systematic review will be conducted according to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P). Relevant research articles will be identified using relevant search terms from the following databases: MEDLINE, Embase, Web of Science and Global Index Medicus (GIM). The articles will be screened at title and abstract, then at full text for inclusion using a priori eligibility criteria. Data extraction will be done using a tool developed and optimized in Excel spreadsheet. Risk of bias assessment will be done using appropriate tools including ROBINS-E ('Risk Of Bias In Non-randomized Studies of Exposure') tool, while publication bias will be assessed using funnel plot. A random-effects meta-analysis and structured narrative synthesis of the outcomes will be performed and results presented. Discussion: Findings from this systematic review will inform policy makers on planning, design and implementation of interventions targeting the treatment and rehabilitation of GND following severe malaria in children. Systematic review registration: The protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42022297109.

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.

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.

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.

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.

Neurofilament light chain: A potential biomarker for cerebrovascular disease in children with sickle cell anaemia.

Cerebrovascular injury frequently occurs in children with sickle cell anaemia (SCA). Limited access to magnetic resonance imaging and angiography (MRI-MRA) in sub-Saharan Africa impedes detection of clinically unapparent cerebrovascular injury. Blood-based brain biomarkers of cerebral infarcts have been identified in non-SCA adults. Using plasma samples from a well-characterized cross-sectional sample of Ugandan children with SCA, we explored relationships between biomarker levels and MRI-detected cerebral infarcts and transcranial Doppler (TCD) arterial velocity. Testing was performed using a 4-plex panel of brain injury biomarkers, including neurofilament light chain (NfL), a central nervous system neuron-specific protein. Mean biomarker levels from the SCA group (n = 81) were similar to those from non-SCA sibling controls (n = 54). Within the SCA group, NfL levels were significantly higher in those with MRI-detected infarcts compared to no infarcts, and higher with elevated TCD velocity versus normal velocity. Elevated NfL remained strongly associated with MRI-detected infarcts after adjusting for sex and age. All non-SCA controls and SCA participants lacking MRI-detected infarcts had low NfL levels. These data suggest potential utility of plasma-based NfL levels to identify children with SCA cerebrovascular injury. Replication and prospective studies are needed to confirm these novel findings and the clinical utility of NfL versus MRI imaging.

Admission Clinical and EEG Features Associated With Mortality and Long-term Neurologic and Cognitive Outcomes in Pediatric Cerebral Malaria.

BACKGROUND AND OBJECTIVES: For children with cerebral malaria, mortality is high, and in survivors, long-term neurologic and cognitive dysfunctions are common. While specific clinical factors are associated with death or long-term neurocognitive morbidity in cerebral malaria, the association of EEG features with these outcomes, particularly neurocognitive outcomes, is less well characterized. METHODS: In this prospective cohort study of 149 children age 6 months to 12 years who survived cerebral malaria in Kampala, Uganda, we evaluated whether depth of coma, number of clinical seizures, or EEG features during hospitalization were associated with mortality during hospitalization, short-term and long-term neurologic deficits, or long-term cognitive outcomes (overall cognition, attention, memory) over the 2-year follow-up. RESULTS: Higher Blantyre or Glasgow Coma Scores (BCS and GCS, respectively), higher background voltage, and presence of normal reactivity on EEG were each associated with lower mortality. Among clinical and EEG features, the presence of >4 seizures on admission had the best combination of negative and positive predictive values for neurologic deficits in follow-up. In multivariable modeling of cognitive outcomes, the number of seizures and specific EEG features showed independent association with better outcomes. In children younger than 5 years throughout the study, seizure number and presence of vertex sharp waves were independently associated with better posthospitalization cognitive performance, faster dominant frequency with better attention, and higher average background voltage and faster dominant background frequency with better associative memory. In children younger than 5 years at CM episode but 5 years or older at cognitive testing, seizure number, background dominant frequency, and the presence of vertex sharp waves were each associated with changes in cognition, seizure number and variability with attention, and seizure number with working memory. DISCUSSION: In children with cerebral malaria, seizure number is strongly associated with the risk of long-term neurologic deficits, while seizure number and specific EEG features (average background voltage, dominant rhythm frequency, presence of vertex sharp waves, presence of variability) are independently associated with cognitive outcomes. Future studies should evaluate the predictive value of these findings.

Cerebrospinal fluid biomarkers provide evidence for kidney-brain axis involvement in cerebral malaria pathogenesis.

Introduction: Cerebral malaria is one of the most severe manifestations of malaria and is a leading cause of acquired neurodisability in African children. Recent studies suggest acute kidney injury (AKI) is a risk factor for brain injury in cerebral malaria. The present study evaluates potential mechanisms of brain injury in cerebral malaria by evaluating changes in cerebrospinal fluid measures of brain injury with respect to severe malaria complications. Specifically, we attempt to delineate mechanisms of injury focusing on blood-brain-barrier integrity and acute metabolic changes that may underlie kidney-brain crosstalk in severe malaria. Methods: We evaluated 30 cerebrospinal fluid (CSF) markers of inflammation, oxidative stress, and brain injury in 168 Ugandan children aged 18 months to 12 years hospitalized with cerebral malaria. Eligible children were infected with Plasmodium falciparum and had unexplained coma. Acute kidney injury (AKI) on admission was defined using the Kidney Disease: Improving Global Outcomes criteria. We further evaluated blood-brain-barrier integrity and malaria retinopathy, and electrolyte and metabolic complications in serum. Results: The mean age of children was 3.8 years (SD, 1.9) and 40.5% were female. The prevalence of AKI was 46.3% and multi-organ dysfunction was common with 76.2% of children having at least one organ system affected in addition to coma. AKI and elevated blood urea nitrogen, but not other measures of disease severity (severe coma, seizures, jaundice, acidosis), were associated with increases in CSF markers of impaired blood-brain-barrier function, neuronal injury (neuron-specific enolase, tau), excitatory neurotransmission (kynurenine), as well as altered nitric oxide bioavailability and oxidative stress (p < 0.05 after adjustment for multiple testing). Further evaluation of potential mechanisms suggested that AKI may mediate or be associated with CSF changes through blood-brain-barrier disruption (p = 0.0014), ischemic injury seen by indirect ophthalmoscopy (p < 0.05), altered osmolality (p = 0.0006) and through alterations in the amino acids transported into the brain. Conclusion: In children with cerebral malaria, there is evidence of kidney-brain injury with multiple potential pathways identified. These changes were specific to the kidney and not observed in the context of other clinical complications.

Dihydroartemisinin-piperaquine or sulphadoxine-pyrimethamine for the chemoprevention of malaria in children with sickle cell anaemia in eastern and southern Africa (CHEMCHA): a protocol for a multi-centre, two-arm, double-blind, randomised, placebo-controlled superiority trial.

BACKGROUND: An estimated 300,000 babies are born with sickle cell anaemia (SCA) annually. Affected children have chronic ill health and suffer premature death. Febrile illnesses such as malaria commonly precipitate acute crises in children with SCA. Thus, chemoprophylaxis for malaria is an important preventive strategy, but current regimes are either sub-optimally effective (e.g. monthly sulphadoxine-pyrimethamine, SP) or difficult to adhere to (e.g. daily proguanil). We propose dihydroartemisinin-piperaquine (DP) as the agent with the most potential to be used across Africa. METHODS: This will be a randomised, double-blind, parallel-group superiority trial of weekly single-day courses of DP compared to monthly single-day courses of SP in children with SCA. The study will be conducted in eastern (Uganda) and southern (Malawi) Africa using randomisation stratified by body weight and study centre. Participants will be randomised using an allocation of 1:1 to DP or SP. We will investigate the efficacy, safety, acceptability and uptake and cost-effectiveness of malaria chemoprevention with weekly courses of DP vs monthly SP in 548 to 824 children with SCA followed up for 12-18 months. We will also assess toxicity from cumulative DP dosing and the development of resistance. Participant recruitment commenced on 30 April 2021; follow-up is ongoing. DISCUSSION: At the end of this study, findings will be used to inform regional health policy. This manuscript is prepared from protocol version 2.1 dated 1 January 2022. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov, NCT04844099 . Registered on 08 April 2021.

Severe Malaria and Academic Achievement.

BACKGROUND: Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with neurocognitive impairment in childhood but their effects on long-term academic achievement are not known. METHODS: Ugandan children 5 to 12 years old who participated in a previous study evaluating cognitive outcomes after CM (n = 73) or SMA (n = 56), along with community children (CC, n = 100) from the same household or neighborhood, were on average enrolled 67.1 months (range, 19-101 months) after the severe malaria episode or previous study enrollment. Academic achievement in word reading, sentence comprehension, spelling, and math computation was evaluated using the Wide Range Achievement Test, Fourth Edition. Age-adjusted z-scores for academic achievement outcomes were calculated from CC scores. RESULTS: After adjustment for age and time from enrollment, reading scores were lower (mean difference from CC [95% confidence interval]) in children with CM (-0.15 [-0.27 to -0.03], P = .02) or SMA (-0.15 [-0.28 to -0.02], P = .02) than CC. Postdischarge malaria episodes were associated with worse spelling and reading scores in CM and worse spelling scores only in SMA. Pathway analysis showed that incidence of postdischarge uncomplicated malaria contributed significantly to the association of CM or SMA with poorer reading scores. CONCLUSION: Children with CM or SMA have poorer long-term reading skills. Postdischarge malaria episodes contribute significantly to this association. Postdischarge malaria chemoprevention should be assessed as an intervention to improve long-term academic achievement in children with severe malaria.

Viral, Bacterial, Metabolic, and Autoimmune Causes of Severe Acute Encephalopathy in Sub-Saharan Africa: A Multicenter Cohort Study.

OBJECTIVES: To assess whether viral, bacterial, metabolic, and autoimmune diseases are missed by conventional diagnostics among children with severe acute encephalopathy in sub-Saharan Africa. STUDY DESIGN: One hundred thirty-four children (6 months to 18 years) presenting with nontraumatic coma or convulsive status epilepticus to 1 of 4 medical referral centers in Uganda, Malawi, and Rwanda were enrolled between 2015 and 2016. Locally available diagnostic tests could be supplemented in 117 patients by viral, bacterial, and 16s quantitative polymerase chain reaction testing, metagenomics, untargeted metabolomics, and autoimmune immunohistochemistry screening. RESULTS: Fourteen (12%) cases of viral encephalopathies, 8 (7%) cases of bacterial central nervous system (CNS) infections, and 4 (4%) cases of inherited metabolic disorders (IMDs) were newly identified by additional diagnostic testing as the most likely cause of encephalopathy. No confirmed cases of autoimmune encephalitis were found. Patients for whom additional diagnostic testing aided causal evaluation (aOR 3.59, 90% CI 1.57-8.36), patients with a viral CNS infection (aOR 7.91, 90% CI 2.49-30.07), and patients with an IMD (aOR 9.10, 90% CI 1.37-110.45) were at increased risk for poor outcome of disease. CONCLUSIONS: Viral and bacterial CNS infections and IMDs are prevalent causes of severe acute encephalopathy in children in Uganda, Malawi, and Rwanda that are missed by conventional diagnostics and are associated with poor outcome of disease. Improved diagnostic capacity may increase diagnostic yield and might improve outcome of disease.

Projected health impact of post-discharge malaria chemoprevention among children with severe malarial anaemia in Africa.

Children recovering from severe malarial anaemia (SMA) remain at high risk of readmission and death after discharge from hospital. However, a recent trial found that post-discharge malaria chemoprevention (PDMC) with dihydroartemisinin-piperaquine reduces this risk. We developed a mathematical model describing the daily incidence of uncomplicated and severe malaria requiring readmission among 0-5-year old children after hospitalised SMA. We fitted the model to a multicentre clinical PDMC trial using Bayesian methods and modelled the potential impact of PDMC across malaria-endemic African countries. In the 20 highest-burden countries, we estimate that only 2-5 children need to be given PDMC to prevent one hospitalised malaria episode, and less than 100 to prevent one death. If all hospitalised SMA cases access PDMC in moderate-to-high transmission areas, 38,600 (range 16,900-88,400) malaria-associated readmissions could be prevented annually, depending on access to hospital care. We estimate that recurrent SMA post-discharge constitutes 19% of all SMA episodes in moderate-to-high transmission settings.

Comparison of Structural Changes in Nodding Syndrome and Other Epilepsies Associated With Onchocerca volvulus.

BACKGROUND AND OBJECTIVE: Nodding syndrome (NS) is a unique childhood-onset epileptic disorder that occurs predominantly in several regions of sub-Saharan Africa. The disease has been associated with Onchocerca volvulus (Ov)-induced immune responses and possible cross-reactivity with host proteins. The aim of this study was to compare structural changes in the brain on MRI between NS and other forms of onchocerciasis-associated epilepsies (OAEs) and to relate structural changes to the Ov-induced immune responses and level of disability. METHODS: Thirty-nine children with NS and 14 age-matched participants with other forms of OAE from an endemic region in Uganda underwent detailed clinical examination, serologic evaluation (including Ov-associated antibodies to Ov-16 and Hu-leiomodin-1) and quantitative volumetric analysis of brain MRIs (1.5 T scanner) using Neuroreader, a cloud-based software. RESULTS: Cerebral and cerebellar atrophy were the predominant features in both NS and OAE. On quantitative volumetric analysis, participants with NS had larger ventricular volumes compared with participants with OAE, indicative of increased global cortical atrophy (pcorr = 0.036). Among children with NS, severe disability correlated with higher degree of atrophy in the gray matter volume (pcorr = 0.009) and cerebellar volume (pcorr = 0.009). NS cases had lower anti-Ov-16 IgG signal-to-noise ratios than the OAE cases (p < 0.01), but no difference in the levels of the Hu-leiomodin-1 antibodies (p = 0.64). The levels of Ov-associated antibodies did not relate to the degree of cerebral or cerebellar atrophy in either NS or OAE cases. DISCUSSION: This is the first study to show that cerebral and cerebellar atrophy correlated with the severity of NS disability, providing an imaging marker for these endemic epileptic disorders that until now have remained poorly characterized. Both NS and OAE have cerebral and cerebellar atrophy, and the levels of Ov-associated antibodies do not seem to be related to the structural changes on MRI.

Economic evaluation of postdischarge malaria chemoprevention in preschool children treated for severe anaemia in Malawi, Kenya, and Uganda: A cost-effectiveness analysis.

Background: Children hospitalised with severe anaemia in malaria-endemic areas are at a high risk of dying or being readmitted within six months of discharge. A trial in Kenya and Uganda showed that three months of postdischarge malaria chemoprevention (PDMC) with monthly dihydroartemisinin-piperaquine (DP) substantially reduced this risk. The World Health Organization recently included PDMC in its malaria chemoprevention guidelines. We conducted a cost-effectiveness analysis of community-based PDMC delivery (supplying all three PDMC-DP courses to caregivers at discharge to administer at home), facility-based PDMC delivery (monthly dispensing of PDMC-DP at the hospital), and the standard of care (no PDMC). Methods: We combined data from two recently completed trials; one placebo-controlled trial in Kenya and Uganda collecting efficacy data (May 6, 2016 until November 15, 2018; n=1049), and one delivery mechanism trial from Malawi collecting adherence data (March 24, 2016 until October 3, 2018; n=375). Cost data were collected alongside both trials. Three Markov decision models, one each for Malawi, Kenya, and Uganda, were used to compute incremental cost-effectiveness ratios expressed as costs per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were performed to account for uncertainty. Findings: Both PDMC strategies were cost-saving in each country, meaning less costly and more effective in increasing health-adjusted life expectancy than the standard of care. The estimated incremental cost savings for community-based PDMC compared to the standard of care were US$ 22·10 (Malawi), 38·52 (Kenya), and 26·23 (Uganda) per child treated. The incremental effectiveness gain using either PDMC strategy varied between 0·3 and 0·4 QALYs. Community-based PDMC was less costly and more effective than facility-based PDMC. These results remained robust in sensitivity analyses. Interpretation: PDMC under implementation conditions is cost-saving. Caregivers receiving PDMC at discharge is a cost-effective delivery strategy for implementation in malaria-endemic southeastern African settings. Funding: Research Council of Norway.