Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection

Abstract

Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P < 0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P = 0.0178, chi-square test). HIV-infected (HIV+) children with autopsy-confirmed CM were older than HIV-uninfected children (median age, 99 months versus 32 months, P = 0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV+ and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly (>9 times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly (>2-fold) greater in HIV+ children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV+ children exacerbates the pathological features associated with CM.Importance There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms causing coma and death are uncertain. Sub-Saharan Africa has a high HIV prevalence, with 3 million HIV-infected (HIV+) children, but the effects of HIV on CM pathogenesis and mortality are unknown. In a study of pediatric CM in Malawi, HIV prevalence was high and CM-attributed mortality was higher in HIV+ than in HIV-uninfected children. Brain pathology in children with fatal CM was notable not only for sequestered malaria parasites but also for intravascular accumulations of monocytes and platelets that were more severe in HIV+ children. Our findings raise the possibility that HIV+ children at risk for malaria may benefit from targeted malaria prophylaxis and that adjunctive treatments targeting inflammation and/or coagulation may improve CM outcomes.

Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria

“…As EPCR plays a central role in vascular homeostasis by facilitating the activation of the plasma protease protein C to activated protein C (APC) (Mosnier et al, 2007), it has been hypothesized that parasites may potentiate cerebral vascular dysfunction by inhibiting the protective APC-EPCR interaction (Gillrie et al, 2015; Petersen et al, 2015; Turner et al, 2013). Indeed, pediatric CM brain autopsies have revealed alterations in coagulation (fibrin deposits and platelet infiltrates) (Dorovini-Zis et al, 2011; Grau et al, 2003; Hochman et al, 2015; Moxon et al, 2015) and increased BBB permeability (Brown et al, 2001; Dorovini-Zis et al, 2011). However, the specific contribution of the CIDRα1-EPCR interaction to late stage disease mechanisms important for CM pathogenesis or fatality has been largely unaddressed.…”

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…More recent studies in pediatric patients have revealed the presence of some monocytes and platelets in the cerebral microvascular. 17,27,29 There is also a suggestion that there may be systemic neutrophil activation which may contribute to cerebral pathology through soluble mediators such as myeloperoxidase and elastase that are released. 30 In contrast to the findings in the brain, features consistent with acute lung injury are frequently found in the pulmonary microvasculature at autopsy of both adult and pediatric patients with severe falciparum malaria.…”

The immunological balance between host and parasite in malaria

“…In P. falciparum-infected patients with CM, massive iRBC cytoadherence is observed in the brain microvasculature (Silamut et al 1999;Milner et al 2014). The intravascular presence of leukocytes in the brain has long been debated; however, an increasing number of recent papers clearly show the presence of monocytes and platelets on brain autopsies from fatal CM patients alongside with iRBCs (Patnaik et al 1994;Hochman et al 2015). In mice with experimental CM, brain microvascular obstruction is mainly mediated by cytoad-…”

“…However, P. falciparum and P. vivax patients with severe malaria infections have significantly reduced ADAMTS13-activity (de Mast et al 2009;Larkin et al 2009;Lowenberg et al 2010;Barber et al 2015). Thus, the combination of endothelial activation with increased circulating amounts of active and UL-vWF, together with reduced vWF inactivation by ADAMTS13, may result in intravascular platelet aggregation, as observed in brains and lungs of severely ill patients and mice (Grau et al 1993(Grau et al , 2003Sun et al 2003;Wassmer et al 2004;von Zur Muhlen et al 2008;Hochman et al 2015) and in P. falciparum-infected placentas (Wassmer et al 2004). In P. vivax patients, platelet numbers are also positively correlated with ANG1 and negatively with ANG2 and the ANG2/ANG1 ratio .…”

“…Phagocytes clean up the iRBC content released during schizont rupture and thus prevent these components to cause damage to the vessel wall. Intravascular marginating and/or infiltrating phagocytes with or without ingested Hz are observed in brains, lungs and placenta of both mice (Curfs et al 1993;Senaldi et al 1994;Chen, Zhang and Sendo 2000;Pais and Chatterjee 2005;Coban et al 2007;Neres et al 2008;Van den Steen et al 2008Claser et al 2011;Hee et al 2011) and patients (Duarte et al 1985;Patnaik et al 1994;Ismail et al 2000;Ordi et al 2001, Clark et al 2003Medana and Turner 2006;Serghides et al 2006;Valecha et al 2009;Dorovini-Zis et al 2011, Lacerda et al 2012Souza et al 2013;Hochman et al 2015) with CM, malaria-associated acute lung injury (MA-ALI)/ARDS or PAM, respectively. Furthermore, tissue macrophages e.g.…”