Quantitative Assessment of Multiorgan Sequestration of Parasites in Fatal Pediatric Cerebral Malaria

Abstract

Children in sub-Saharan Africa continue to acquire and die from cerebral malaria, despite efforts to control or eliminate the causative agent, Plasmodium falciparum. We present a quantitative histopathological assessment of the sequestration of parasitized erythrocytes in multiple organs obtained during a prospective series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi, on pediatric patients who died from cerebral malaria and controls. After the brain, sequestration of parasites was most intense in the gastrointestinal tract, both in patients with cerebral malaria and those with parasitemia in other organs. Within cases of histologically defined cerebral malaria, which includes phenotypes termed "sequestration only" (CM1) and "sequestration with extravascular pathology" (CM2), CM1 was associated with large parasite numbers in the spleen and CM2 with intense parasite sequestration in the skin. A striking histological finding overall was the marked sequestration of parasitized erythrocytes across most organs in patients with fatal cerebral malaria, supporting the hypothesis that the disease is, in part, a result of a high level of total-body parasite sequestration.

Cerebral malaria is associated with differential cytoadherence to brain endothelial cells

“…The overall mortality rate for CM in children is 15-25%, with a recent MRI study showing that brain swelling is strongly associated with fatal outcome in CM . What is clear is that the pathogenesis is multifactorial, with a role for the immune response to the Plasmodium infection (Hunt & Grau, 2003;Ioannidis et al, 2014;Dieye et al, 2016;Mandala et al, 2017;Wolf et al, 2017) and obstruction of the microvasculature by sequestration and rosetting (Rowe et al, 2009;Craig et al, 2012;Ponsford et al, 2012;White et al, 2013;Milner et al, 2015), leading to endothelial dysfunction. What is clear is that the pathogenesis is multifactorial, with a role for the immune response to the Plasmodium infection (Hunt & Grau, 2003;Ioannidis et al, 2014;Dieye et al, 2016;Mandala et al, 2017;Wolf et al, 2017) and obstruction of the microvasculature by sequestration and rosetting (Rowe et al, 2009;Craig et al, 2012;Ponsford et al, 2012;White et al, 2013;Milner et al, 2015), leading to endothelial dysfunction.…”

“…The pathology of CM has been studied extensively (Idro et al, 2005;Hawkes et al, 2013) but also debated for many decades, as discussed in numerous reviews (Shikani et al, 2012;Cunnington et al, 2013;Storm & Craig, 2014;Wassmer & Grau, 2017). What is clear is that the pathogenesis is multifactorial, with a role for the immune response to the Plasmodium infection (Hunt & Grau, 2003;Ioannidis et al, 2014;Dieye et al, 2016;Mandala et al, 2017;Wolf et al, 2017) and obstruction of the microvasculature by sequestration and rosetting (Rowe et al, 2009;Craig et al, 2012;Ponsford et al, 2012;White et al, 2013;Milner et al, 2015), leading to endothelial dysfunction. Sequestration of P. falciparuminfected erythrocytes (IE) in brain microvasculature is a hallmark of human CM as shown in post-mortem studies (Pongponratn et al, 1991;Taylor et al, 2004), but whether this sequestration is due to differential binding of IE to brain endothelium has been harder to demonstrate.…”

CD8+ T Cells Induce Fatal Brainstem Pathology during Cerebral Malaria via Luminal Antigen-Specific Engagement of Brain Vasculature

“…Human cerebral malaria (HCM) is one of several clinical manifestations of severe P . falciparum infection and is diagnosed by coma and parasitemia in the absence of meningitis, hyperglycemia, and postictal state [2]. HCM is fatal in 15–30% of affected individuals [3, 4], while an additional 10% of survivors suffer long-term neurological sequelae such as ataxia, hemiplegia, and cognitive impairment [5].…”

“…At the cellular and molecular level, HCM is associated with an increase in systemic pro-inflammatory cytokines [11, 12], endothelial cell (EC) activation [13], and sequestration of parasite-infected red blood cells (iRBCs) [2] and leukocytes [8] within the brain vasculature. These conditions are hypothesized to contribute to the observed BBB disruption and cerebral edema as well as ischemia throughout the CNS [14].…”

The immunological balance between host and parasite in malaria

“…Although it also occurs in patients with uncomplicated or asymptomatic infections, high organ-specific parasite loads are associated with severe disease as demonstrated in brains and lungs of patients who died from CM or MA-ARDS and in placentas from women with P. falciparum-associated PAM (Walter, Garin and Blot 1982;Corbett et al 1989;Silamut et al 1999;Ismail et al 2000;Pongponratn et al 2003;Taylor et al 2004). Furthermore, in CM high parasite loads are also found in several other organs besides the brain, including lungs, intestine, kidneys and skin, indicating that CM is characterized by a high total parasite biomass (Seydel et al 2006;Milner et al 2014Milner et al , 2015. The parasite load in P. vivax-infections is much lower than with P. falciparum, but with both parasites total parasite biomass is associated with severe disease (Barber et al 2015).…”