An MRI Ancillary Study of a Malaria Fever Randomized Controlled Trial (RCT)

Despite eradication efforts, ~400,000 African children sustained brain injuries as a result of CNS malaria in 2016. A higher maximum temperature (Tmax) during the acute malaria infection is an established risk factor for neurologic sequelae and a randomized controlled trial (RCT) of aggressive antipyretic therapy with acetaminophen and ibuprofen conducted in Malawi and Zambia began enrollment in 2019 (R01NS102176). In that clinical trial, the primary outcome was Tmax during the acute infection. However, the antipyretic therapies used in this RCT may offer neuroprotective effects without affecting Tmax--for example, neuroprotection through anti-inflammatory mechanisms. In An MRI Ancillary Study of Malaria FEVER RCT, we propose to use neuroimaging in the context of the RCT to further evaluate the potential neuroprotective effects of aggressive antipyretic therapy for CNS malaria and explore possible mechanisms for these effects. Comparing children allocated to aggressive antipyretic therapy vs. usual care on the prevalence of structural brain abnormalities after recovery from CNS malaria will facilitate the evaluation of non-fever pathways for neuroprotection. Brain MRIs will be obtained in children enrolled in the RCT at 1- and 12-months post recovery. Analyses will be completed comparing the odds of having any structural injury based upon RCT treatment allocation and based upon (Tmax) stratified by treatment allocation to assess changes specifically related to response to therapy in terms of fever reduction. Potential mechanisms of aggressive antipyretic-related injury will be evaluated including assessments for treatment-related CNS bleeds. Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury including in pediatric CNS malaria. Adding this MRI ancillary study to our fever RCT may elucidate mechanisms of treatment-associated injury and allow for early identification of neuroprotection from aggressive antipyretic use that would otherwise require long-term follow-up for cognitive and behavioral assessments. This study will provide critical insights that could inform future neuroprotective studies of malaria that might incorporate imaging to optimize study design. It will also add to our understanding of the long term impact of severe malaria on chronic kidney disease risk in children.