Adjunctive therapy for severe malaria: a review and critical appraisal

Abstract

BackgroundDespite recent efforts and successes in reducing the malaria burden globally, this infection still accounts for an estimated 212 million clinical cases, 2 million severe malaria cases, and approximately 429,000 deaths annually. Even with the routine use of effective anti-malarial drugs, the case fatality rate for severe malaria remains unacceptably high, with cerebral malaria being one of the most life-threatening complications. Up to one-third of cerebral malaria survivors are left with long-term cognitive and neurological deficits. From a population point of view, the decrease of malaria transmission may jeopardize the development of naturally acquired immunity against the infection, leading to fewer total cases, but potentially an increase in severe cases. The pathophysiology of severe and cerebral malaria is not completely understood, but both parasite and host determinants contribute to its onset and outcomes. Adjunctive therapy, based on modulating the host response to infection, could help to improve the outcomes achieved with specific anti-malarial therapy.Results and conclusionsIn the last decades, several interventions targeting different pathways have been tested. However, none of these strategies have demonstrated clear beneficial effects, and some have shown deleterious outcomes. This review aims to summarize evidence from clinical trials testing different adjunctive therapy for severe and cerebral malaria in humans. It also highlights some preclinical studies which have evaluated novel strategies and other candidate therapeutics that may be evaluated in future clinical trials.

New insights into microvascular injury to inform enhanced diagnostics and therapeutics for severe malaria

“…These approaches are challenging both in identifying who would benefit, especially early enough in the course of illness, and in how to administer in a low resource-setting, due to their cost and potential storage requirements [19]. We direct the reader to more in-depth reviews looking at cytoadherence adjunctive therapies [2,19]. Since parasite biomass is also a predictor of progression to SM [28], whole blood transfusions and automated erythrocyte exchange, to decrease parasitemia, have been used as putative adjunctive therapies, although no randomized clinical trials have confirmed their superiority over the standard of care (reviewed in [39]).…”

“…Since parasite biomass is also a predictor of progression to SM [28], whole blood transfusions and automated erythrocyte exchange, to decrease parasitemia, have been used as putative adjunctive therapies, although no randomized clinical trials have confirmed their superiority over the standard of care (reviewed in [39]). Additionally, due to cost and availability, these strategies are often untenable in most low-resource settings [2]. If parasite phenotypes are reproducibly found to predict progression to SM, then parasite isolate genotyping could be exploited to risk-stratify malaria patients [28].…”

“…Although, large knowledge gaps still exist in our understanding of its pathobiology, there is a consensus that the onset and outcome of SM depends on a complex interaction between both pathogen and host determinants [1]. The SM pathogenesis paradigm argues that the combination of microvascular sequestration of infected erythrocytes (IE), together with infection-induced; immune and endothelial activation, dysregulation of coagulation cascades and microvascular occlusion and injury, ultimately culminates in the breakdown of endothelial barriers including the blood-brain barrier (BBB), multi-organ dysfunction and death [2] (Figure 1).…”

Powerful solution for experimental cerebral malaria treatment: artesunate and tetramethylpyrazine

“…Adjunctive therapy is defined as an additional treatment that modifies the pathological processes caused by malaria to improve its clinical outcomes and/or decline mortality, along with the prevention of long-term neurocognitive impairment [13]. Over the past decades, dozens of CM interventions for different pathways have been evaluated based on immunomodulation, neuroprotection, regulation of gaseous signalling molecules and improvement of endothelial dysfunction [14]. In fact, more than 17 clinical trials have so far examined 11 treatments; however, no method has been proven effective in treating CM in children [15, 16].…”

Signatures of divergent antimalarial treatment responses in peripheral blood from infants and adults in Malawi

“…Infants face multiple barriers to overcoming malaria infection, including suboptimal innate immune responses to natural infection and poor antimalarial treatment efficacy, which in some cases results in serious outcomes, such as severe malarial anemia (SMA) or cerebral malaria (CM). Studies have shown that SMA and CM are driven by proinflammatory cytokine secretion and immunopathology, suggesting immunomodulation as a potential avenue for adjunctive therapy to prevent severe outcomes in infants [16, 17, 18, 19]. Although SMA and CM have been a major focus of research in infants, we were interested in identifying age-specific markers of treatment response in uncomplicated malaria (UM)—an area that is arguably less well studied and yet remains critical to understanding phenotypic variation in the majority of malaria-infected and treated infants.…”