Unusual clinical spectra of childhood severe malaria during malaria epidemic in eastern Uganda: a prospective study.

BACKGROUND: In sub-Saharan Africa (SSA), malaria remains a public health problem despite recent reports of declining incidence. Severe malaria is a multiorgan disease with wide-ranging clinical spectra and outcomes that have been reported to vary by age, geographical location, transmission intensity over time. There are reports of recent malaria epidemics or resurgences, but few data, if any, focus on the clinical spectrum of severe malaria during epidemics. This describes the clinical spectrum and outcomes of childhood severe malaria during the disease epidemic in Eastern Uganda. METHODS: This prospective cohort study from October 1, 2021, to September 7, 2022, was nested within the 'Malaria Epidemiological, Pathophysiological and Intervention studies in Highly Endemic Eastern Uganda' (TMA2016SF-1514-MEPIE Study) at Mbale Regional Referral Hospital, Uganda. Children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the clinical WHO criteria for surveillance of severe malaria were enrolled on the study. Follow-up was performed until day 28. Data were collected using a customized proforma on social demographic characteristics, clinical presentation, treatment, and outcomes. Laboratory analyses included complete blood counts, malaria RDT (SD BIOLINE Malaria Ag P.f/Pan, Ref. 05FK60-40-1) and blood slide, lactate, glucose, blood gases and electrolytes. In addition, urinalysis using dipsticks (Multistix® 10 SG, SIEMENS, Ref.2300) at the bedside was done. Data were analysed using STATA V15.0. The study had prior ethical approval. RESULTS: A total of 300 participants were recruited. The median age was 4.6 years, mean of 57.2 months and IQR of 44.5 months. Many children, 164/300 (54.7%) were under 5 years, and 171/300 (57.0%) were males. The common clinical features were prostration 236/300 (78.7%), jaundice in 205/300 (68.3%), severe malarial anaemia in 158/300 (52.7%), black water fever 158/300 (52.7%) and multiple convulsions 51/300 (17.0%), impaired consciousness 50/300(16.0%), acidosis 41/300(13.7%), respiratory distress 26/300(6.7%) and coma in 18/300(6.0%). Prolonged hospitalization was found in 56/251 (22.3%) and was associated with acidosis, P = 0.041. The overall mortality was 19/300 (6.3%). Day 28 follow-up was achieved in 247/300 (82.3%). CONCLUSION: During the malaria epidemic in Eastern Uganda, severe malaria affected much older children and the spectrum had more of prostration, jaundice severe malarial anaemia, black water fever and multiple convulsions with less of earlier reported respiratory distress and cerebral malaria.

PARIST study protocol: a phase I/II randomised, controlled clinical trial to assess the feasibility, safety and effectiveness of paracetamol in resolving acute kidney injury in children with severe malaria.

BACKGROUND: Acute kidney injury (AKI) has in the past been considered a rare complication of malaria in children living in high-transmission settings. More recently, however, a growing number of paediatric case series of AKI in severe malaria studies in African children have been published (Artesunate vs Quinine in the Treatment of Severe P. falciparum Malaria in African children and Fluids Expansion as Supportive Therapy trials). The Paracetamol for Acute Renal Injury in Severe Malaria Trial (PARIST) therefore, aims to assess feasibility, safety and determine the effective dose of paracetamol, which attenuates nephrotoxicity of haemoproteins, red-cell free haemoglobin and myoglobin in children with haemoglobinuric severe malaria. METHODS: PARIST is a phase I/II unblinded randomised controlled trial of 40 children aged >6 months and <12 years admitted with confirmed haemoglobinuric severe malaria (blackwater fever), a positive blood smear for P. falciparum malaria and either serum creatinine (Cr) increase by ≥0.3 mg/dL within 48 hours or to ≥1.5 times baseline and elevated blood urea nitrogen (BUN) >20 mg/dL. Children will be randomly allocated on a 1:1 basis to paracetamol intervention dose arm (20 mg/kg orally 6-hourly for 48 hours) or to a control arm to receive standard of care for temperature control (ie, tepid sponging for 30 min if fever persists give rescue treatment). Primary outcome is renal recovery at 48 hours as indicated by stoppage of progression and decrease of Cr level below baseline, BUN (<20 mg/dL). Data analysis will be on the intention-to-treat principle and a per-protocol basis.Results from this phase I/II clinical trial will provide preliminary effectiveness data of this highly potential treatment for AKI in paediatric malaria (in particular for haemoglobinuric severe malaria) for a larger phase III trial. ETHICS AND DISSEMINATION: Ethical and regulatory approvals have been granted by the Mbale Hospital Institutional Ethics Review Committee (MRRH-REC OUT 002/2019), Uganda National Council of Science and Technology (UNCST-HS965ES) and the National drug Authority (NDA-CTC 0166/2021). We will be disseminating results through journals, conferences and policy briefs to policy makers and primary care providers. TRIAL REGISTRATION NUMBER: ISRCTN84974248.