Malaria Treatment for Children: Antipyretic Therapy Reduces Fever, Seizures

Aggressive antipyretic therapy of acetaminophen and ibuprofen reduces clinical temperature levels and improves acute seizure outcomes with no prolongation of parasitemia, which suggests it’s an effective central nervous system (CNS) malaria treatment for children. These are the findings of a study published in JAMA Neurology.

Antipyretics have shown effectiveness in fever reduction in previous malaria studies; however, limited data are available on the effect of prophylactic antipyretics or 2 antipyretics with different mechanisms of action.

Researchers conducted a randomized double-blind placebo-controlled trial (ClinicalTrials.gov Identifier: NCT03399318) to compare fever and seizure outcomes among children with CNS malaria who received standard therapy vs aggressive antipyretic therapy.

Eligible participants were aged between 24 and 132 months and were diagnosed with malaria, as well as experienced symptoms of CNS malaria, including seizures or impaired consciousness.

Patients were randomly assigned 1:1 to receive standard therapy of 15 mg/kg of acetaminophen every 6 hours for temperatures of at least 38.5 °C or aggressive antipyretic therapy of 30 mg/kg followed by 15 mg/kg of acetaminophen plus 10 mg/kg of ibuprofen every 6 hours, regardless of temperature, for 72 hours. A 15 mg/kg dose of placebo was administered to patients in the antipyretics group who had a temperature of 38.5 °C or higher.

Primary study outcome was maximum temperature (Tmax) and secondary outcomes were seizure activity and parasite clearance.

From 2019 to 2022, 256 children (mean age, 4.3 years; boys, 55%; standard therapy, n=128; antipyretics, n=128) were included in the study. Mean clinical temperature at admission was 38.1 °C in both the groups.

Results of the analysis showed that adjusted mean Tmax was lower in the antipyretic vs standard therapy group (38.57 vs 39.19 °C; absolute difference, -0.62; 95% CI, -0.82 to -0.42; P <.001).

With regard to secondary outcomes, exposure to fever, as measured by area under the curve (AUC) temperatures of at least 38.5 °C, was lower in the antipyretic vs standard therapy group, as well as reduced frequency of multiple or prolonged seizures (8% vs 27%, respectively; odds ratio [OR], 0.26; 95% CI, 0.12-0.56; risk ratio, 0.34; 95% CI, 0.15-0.61).

Researchers did not observe differences in parasite clearance time between the 2 groups (hazard ratio, 0.94; 95% CI, 0.69-1.26).

A total of 15% of participants had severe adverse events, including neurologic impairment at hospital discharge, acute kidney injury, clinical bleeding, and death. Of 13 deaths, 10 were of patients in the standard therapy group and 3 from the antipyretics group (OR, 0.28; 95% CI, 0.07-1.05).

“[A]ggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia,” the researchers wrote.

However, they concluded, “Additional studies are needed to assess long-term neurological outcomes after aggressive antipyretic therapy.”

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of the author’s disclosures.