Results from our studies in Ugandan children with severe malaria suggest children with severe malaria other than cerebral malaria may have cognitive sequelae and that the functional areas, degree, and pathogenesis of cognitive impairment may differ by type of severe malaria. African countries plan to switch from quinine to artesunate for treatment of severe malaria because lower mortality has been documented with artesunate treatment. However, the effects of artesunate on neurodevelopment in children with severe malaria are unknown, as quinine has been used in all studies of neurodevelopment in severe malaria to date. Artesunate has effects that may be neuroprotective (e.g., more rapid parasite clearance, fewer seizures, less hypoglycemia than quinine), but high-dose artesunate has been associated with neurotoxicity in some animal studies. We propose to study the pathogenesis of developmental sequelae in the five most common types of severe malaria, in children treated with artesunate. The study's central hypothesis is that different types of severe malaria affect distinct pathogenic pathways leading to specific functional areas and levels of impairment. Our study has two primary aims.
Aim 1 is to establish the areas and level of neurodevelopmental function affected by the five major types of severe malaria in children treated with artesunate. To accomplish this aim, we will compare areas and age-adjusted level of neurologic, developmental, and behavioral impairment in children with severe malaria (cerebral malaria [CM], severe malarial anemia [SMA], repeated seizures, respiratory distress, prostration) treated with artesunate versus healthy children, 12 months after enrollment. Level of impairment in children with CM or SMA will be compared between children in the present (artesunate) and in past (quinine) studies.
Aim 2 is to identify immunologic, metabolic, and nutritional risk factors associated with neurodevelopmental impairment in children with severe malaria who are treated with artesunate. To accomplish this aim, we will compare the presence/level of risk factors in children with severe malaria to the level of neurologic, developmental, and behavioral deficits 12 months after enrollment. We will assess markers of endovascular and central nervous system inflammation, metabolic changes, and micronutrients that are affected by inflammation and associated with developmental impairment. We predict neurodevelopmental impairment will be present in all forms of severe malaria that level of impairment after artesunate treatment will be lower than after quinine treatment, and that specific immunologic, metabolic, and nutritional factors will be associated with risk of impairment. We expect this study will constitute a significant advance in the understanding of malaria-associated developmental impairment, and will provide a basis for interventions to prevent neurodevelopmental impairment in the millions of children who develop severe malaria every year.

Public Health Relevance

Identification of key factors associated with neurodevelopmental or behavioral impairment in severe malaria could lead to interventions that prevent brain injury and the loss of developmental potential in hundreds of thousands of children in sub-Saharan Africa.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055349-10
Application #
9412198
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hartman, Adam L
Project Start
2015-03-26
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Villaverde, Chandler; Namazzi, Ruth; Shabani, Estela et al. (2017) Clinical Comparison of Retinopathy-Positive and Retinopathy-Negative Cerebral Malaria. Am J Trop Med Hyg 96:1176-1184
John, Chandy C; Black, Maureen M; Nelson 3rd, Charles A (2017) Neurodevelopment: The Impact of Nutrition and Inflammation During Early to Middle Childhood in Low-Resource Settings. Pediatrics 139:S59-S71
Shabani, E; Ouma, B J; Idro, R et al. (2017) Elevated cerebrospinal fluid tumour necrosis factor is associated with acute and long-term neurocognitive impairment in cerebral malaria. Parasite Immunol 39:
Holmberg, Dag; Franzén-Röhl, Elisabeth; Idro, Richard et al. (2017) Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria. Malar J 16:303
Park, Gregory S; Opoka, Robert O; Shabani, Estela et al. (2017) Plasmodium falciparum Histidine-Rich Protein-2 Plasma Concentrations Are Higher in Retinopathy-Negative Cerebral Malaria Than in Severe Malarial Anemia. Open Forum Infect Dis 4:ofx151
Opoka, Robert O; Hamre, Karen E S; Brand, Nathan et al. (2017) High Postdischarge Morbidity in Ugandan Children With Severe Malarial Anemia or Cerebral Malaria. J Pediatric Infect Dis Soc 6:e41-e48
Shabani, Estela; Hanisch, Benjamin; Opoka, Robert O et al. (2017) Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria. BMC Med 15:183
Brand, Nathan R; Opoka, Robert O; Hamre, Karen E S et al. (2016) Differing Causes of Lactic Acidosis and Deep Breathing in Cerebral Malaria and Severe Malarial Anemia May Explain Differences in Acidosis-Related Mortality. PLoS One 11:e0163728
Conroy, Andrea L; Hawkes, Michael; McDonald, Chloe R et al. (2016) Host Biomarkers Are Associated With Response to Therapy and Long-Term Mortality in Pediatric Severe Malaria. Open Forum Infect Dis 3:ofw134
Ssenkusu, John Mbaziira; Hodges, James Steven; Opoka, Robert Opika et al. (2016) Long-term Behavioral Problems in Children With Severe Malaria. Pediatrics 138:

Showing the most recent 10 out of 32 publications