Browsing by Subject "Severe malarial anemia"
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Item Delayed iron improves iron status without altering malaria risk in severe malarial anemia(Oxford University Press, 2020-05) Cusick, Sarah E.; Opoka, Robert O.; Ssemata, Andrew S.; Georgieff, Michael K.; John, Chandy C.; Pediatrics, School of MedicineBackground: WHO guidelines recommend concurrent iron and antimalarial treatment in children with malaria and iron deficiency, but iron may not be well absorbed or utilized during a malaria episode. Objectives: We aimed to determine whether starting iron 28 d after antimalarial treatment in children with severe malaria and iron deficiency would improve iron status and lower malaria risk. Methods: We conducted a randomized clinical trial on the effect of immediate compared with delayed iron treatment in Ugandan children 18 mo-5 y of age with 2 forms of severe malaria: cerebral malaria (CM; n = 79) or severe malarial anemia (SMA; n = 77). Asymptomatic community children (CC; n = 83) were enrolled as a comparison group. Children with iron deficiency, defined as zinc protoporphyrin (ZPP) ≥ 80 µmol/mol heme, were randomly assigned to receive a 3-mo course of daily oral ferrous sulfate (2 mg · kg-1 · d-1) either concurrently with antimalarial treatment (immediate arm) or 28 d after receiving antimalarial treatment (delayed arm). Children were followed for 12 mo. Results: All children with CM or SMA, and 35 (42.2%) CC, were iron-deficient and were randomly assigned to immediate or delayed iron treatment. Immediate compared with delayed iron had no effect in any of the 3 study groups on the primary study outcomes (hemoglobin concentration and prevalence of ZPP ≥ 80 µmol/mol heme at 6 mo, malaria incidence over 12 mo). However, after 12 mo, children with SMA in the delayed compared with the immediate arm had a lower prevalence of iron deficiency defined by ZPP (29.4% compared with 65.6%, P = 0.006), a lower mean concentration of soluble transferrin receptor (6.1 compared with 7.8 mg/L, P = 0.03), and showed a trend toward fewer episodes of severe malaria (incidence rate ratio: 0.39; 95% CI: 0.14, 1.12). Conclusions: In children with SMA, delayed iron treatment did not increase hemoglobin concentration, but did improve long-term iron status over 12 mo without affecting malaria incidence.This trial was registered at clinicaltrials.gov as NCT01093989.Item Elevated Plasma Soluble ST2 Levels are Associated With Neuronal Injury and Neurocognitive Impairment in Children With Cerebral Malaria(Case Western Reserve University, 2022-06-23) Fernander, Elizabeth M.; Adogamhe, Pontian; Datta, Dibyadyuti; Bond, Caitlin; Zhao, Yi; Bangirana, Paul; Conroy, Andrea L.; Opoka, Robert O.; John, Chandy C.; Pediatrics, School of MedicineBackground: Murine experimental cerebral malaria studies suggest both protective and deleterious central nervous system effects from alterations in the interleukin-33 (IL-33)/ST2 pathway. Methods: We assessed whether soluble ST2 (sST2) was associated with neuronal injury or cognitive impairment in a cohort of Ugandan children with cerebral malaria (CM, n=224) or severe malarial anemia (SMA, n=193). Results: Plasma concentrations of sST2 were higher in children with CM than in children with SMA or in asymptomatic community children. Cerebrospinal fluid (CSF) sST2 levels were elevated in children with CM compared with North American children. Elevated plasma and CSF ST2 levels in children with CM correlated with increased endothelial activation and increased plasma and CSF levels of tau, a marker of neuronal injury. In children with CM who were ≥5 years of age at the time of their malaria episode, but not in children <5 years of age, elevated risk factor-adjusted plasma levels of sST2 were associated with worse scores for overall cognitive ability and attention over a 2-year follow-up. Conclusions: The study findings suggest that sST2 may contribute to neuronal injury and long-term neurocognitive impairment in older children with CM.Item Impact of Oxidative Stress on Risk of Death and Readmission in African Children With Severe Malaria: A Prospective Observational Study(Oxford University Press, 2022) Blatt, Daniel B.; Hanisch, Benjamin; Co, Katrina; Datta, Dibyadyuti; Bond, Caitlin; Opoka, Robert O.; Cusick, Sarah E.; Michelow, Ian C.; John, Chandy C.; Pediatrics, School of MedicineBackground: We hypothesized that oxidative stress in Ugandan children with severe malaria is associated with mortality. Methods: We evaluated biomarkers of oxidative stress in children with cerebral malaria (CM, n = 77) or severe malarial anemia (SMA, n = 79), who were enrolled in a randomized clinical trial of immediate vs delayed iron therapy, compared with community children (CC, n = 83). Associations between admission biomarkers and risk of death during hospitalization or risk of readmission within 6 months were analyzed. Results: Nine children with CM and none with SMA died during hospitalization. Children with CM or SMA had higher levels of heme oxygenase-1 (HO-1) (P < .001) and lower superoxide dismutase (SOD) activity than CC (P < .02). Children with CM had a higher risk of death with increasing HO-1 concentration (odds ratio [OR], 6.07 [95% confidence interval {CI}, 1.17-31.31]; P = .03) but a lower risk of death with increasing SOD activity (OR, 0.02 [95% CI, .001-.70]; P = .03). There were no associations between oxidative stress biomarkers on admission and risk of readmission within 6 months of enrollment. Conclusions: Children with CM or SMA develop oxidative stress in response to severe malaria. Oxidative stress is associated with higher mortality in children with CM but not with SMA.Item What causes severe malaria and its complications in children? Lessons learned over the past 15 years(BMC, 2019-03-07) Conroy, Andrea L.; Datta, Dibyadyuti; John, Chandy C.; Pediatrics, School of MedicineOver the past 15 years, malaria mortality has reduced by approximately 50%. However, malaria still causes more than 400,000 deaths annually, most of which occur in African children under 5 years of age. Significant advances in understanding the pathogenesis of the disease provide a basis for future work to prevent severe malaria and its complications. Herein, we provide an overview of advances in our understanding of severe malaria in African children over the past 15 years, highlighting key complications and identifying priorities to further reduce malaria-associated mortality.Item Whole-Blood Transcriptional Signatures Composed of Erythropoietic and NRF2-Regulated Genes Differ Between Cerebral Malaria and Severe Malarial Anemia(Oxford University Press, 2019-01-01) Nallandhighal, Srinivas; Park, Gregory S.; Ho, Yen-Yi; Opoka, Robert O.; John, Chandy C.; Tran, Tuan M.; Medicine, School of MedicineBackground Among the severe malaria syndromes, severe malarial anemia (SMA) is the most common, whereas cerebral malaria (CM) is the most lethal. However, the mechanisms that lead to CM and SMA are unclear. Methods We compared transcriptomic profiles of whole blood obtained from Ugandan children with acute CM (n = 17) or SMA (n = 17) and community children without Plasmodium falciparum infection (n = 12) and determined the relationships among gene expression, hematological indices, and relevant plasma biomarkers. Results Both CM and SMA demonstrated predominantly upregulated enrichment of dendritic cell activation, inflammatory/Toll-like receptor/chemokines, and monocyte modules, but downregulated enrichment of lymphocyte modules. Nuclear factor, erythroid 2 like 2 (Nrf2)-regulated genes were overexpressed in children with SMA relative to CM, with the highest expression in children with both SMA and sickle cell disease (HbSS), corresponding with elevated plasma heme oxygenase-1 in this group. Erythroid and reticulocyte-specific signatures were markedly decreased in CM relative to SMA despite higher hemoglobin levels and appropriate increases in erythropoietin. Viral sensing/interferon-regulatory factor 2 module expression and plasma interferon-inducible protein-10/CXCL10 negatively correlated with reticulocyte-specific signatures. Conclusions Compared with SMA, CM is associated with downregulation of Nrf2-related and erythropoiesis signatures by whole-blood transcriptomics. Future studies are needed to confirm these findings and assess pathways that may be amenable to interventions to ameliorate CM and SMA.