Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria

Andrea L. Conroy, Robert O. Opoka, Paul Bangirana, Ruth Namazzi, Allen E. Okullo, Michael K. Georgieff, Sarah Cusick, Richard Idro, John M. Ssenkusu, Chandy C. John

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM.

METHODS: From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up.

RESULTS: 346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07-0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine.

CONCLUSIONS: Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.

Original languageEnglish (US)
Article number168
JournalBMC medicine
Volume19
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke, the Eunice Kennedy Shriver National Institute of Child Health and Development, and the Fogarty International Center (grants R01NS055349, U01 HD064698 and D43 TW010928). The funders had no role in the design of the study, data collection and analysis, interpretation of data, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Artemisinin
  • Artesunate
  • Behavior
  • Cerebral malaria
  • Children
  • Hospital readmission
  • Inflammation
  • Long-term
  • Mortality
  • Neurologic deficit
  • Pediatric
  • Quinine
  • Severe anemia
  • Severe malaria

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