An MRI Ancillary Study of Malaria fever (RCT)
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Date
20-09-16
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Kamuzu University of Health Sciences
Abstract
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 began enrollment in Malawi in 2019 (R01NS102176) with expansion into
Zambia pending. In this clinical trial, the primary outcome is 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 this ancillary study, 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. Both
Zambia and Malawi have an unusually well-developed infrastructure for advanced imaging in the academic
centers where the RCT using aggressive antipyretic therapy will be conducted have MRI facilities. 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 MRI ancillary study when added to the Fever RCT will provide critical
insights that could inform future neuroprotective studies of malaria that might incorporate imaging to optimize
study design.
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Keywords
Malaria fever