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

ABSTRACT

Severe malaria (SM) has high mortality and morbidity rates despite treatment with potent antimalarials. Disease onset and outcome is dependent upon both parasite and host factors. Infected erythrocytes bind to host endothelium contributing to microvascular occlusion and dysregulated inflammatory and immune host responses, resulting in endothelial activation and microvascular damage. This review focuses on the mechanisms of host endothelial and microvascular injury. Only a small percentage of malaria infections (≤1%) progress to SM. Early recognition and treatment of SM can improve outcome, but we lack triage tools to identify SM early in the course of infection. Current point-of-care pathogen-based rapid diagnostic tests do not address this critical barrier. Immune and endothelial activation have been implicated in the pathobiology of SM. We hypothesize that measuring circulating mediators of these pathways at first clinical presentation will enable early triage and treatment of SM. Moreover, that host-based interventions that modulate these pathways will stabilize the microvasculature and improve clinical outcome over that of antimalarial therapy alone.

KEYWORDS:

• Severe malaria (SM)
• host innate response
• severity markers
• adjunctive therapy
• microvascular injury
• risk-stratification

Disclosure statement

Kevin Kain is a named inventor on patents held by his institution linked to Angiopoietins and TREM-1 as infection severity markers as well as therapies linked to these pathways.

Additional information

Funding

This work was supported in part by grants from the Canadian Institutes of Health Research (CIHR FDN 148439 to KCK) and the Canada Research Chairs program (KCK);CIHR FDN [148439].