Introduction
Malaria is a major global infectious disease caused by parasitic protozoans of the genus Plasmodium. Of the five Plasmodium species that infect humans, Plasmodium falciparum and Plasmodium vivax cause the majority of cases, and P. falciparum is the most virulent and responsible for the majority of deaths.1 Despite recent reductions in the overall malaria case incidence, malaria remains a leading cause of morbidity and mortality in the developing world. In 2012, there were an estimated 207 million cases of malaria and over 600,000 deaths.1 The majority of malaria deaths (90%) occur in children in Africa, where falciparum malaria accounts for as many as one in six childhood deaths and is the biggest killer of African children between the ages of 1 and 4 years.2,3 Outside Africa, there are a variety of transmission settings where P. falciparum, P. vivax, or both are present. In lower transmission settings in South America, India, and southeast Asia, adult populations are at higher risk for severe malaria.
Malaria is a complex disease, and the spectrum of disease manifestations differs between children and adults.4 Symptoms can range from none, in individuals with asymptomatic parasitemia, to mild, in patients with undifferentiated fever, to severe, in patients with life-threatening anemia, metabolic acidosis, cerebral malaria (CM), and multiorgan system involvement.5 Only a small minority of infections, less than 1–2%, leads to severe malaria.6 Because pathogenetic mechanisms are complex and poorly understood, current treatment primarily relies on antimalarial drugs and supportive care. Here we focus on recent advancements in understanding the molecular pathogenesis of CM and the variable presentations between children and adults.
Several pathogenetic mechanisms have been proposed for CM including mechanical microvascular obstruction by sequestered infected erythrocytes (IEs),7 activation of immune cells and release of pro-inflammatory cytokines,8,9 endothelial dysfunction,10 dysregulation of coagulation pathways,11,12 blood–brain barrier (BBB) permeability,13 and brain swelling.14 Furthermore, autopsy studies have subdivided pediatric cases into two different groups based on histopathological patterns. The CM1 group has sequestration only, while CM2 group has sequestration plus vascular pathology (ring hemorrhages, fibrin-platelet thrombi, and monocytes).15,16 Ring hemorrhages and cerebral thrombosis are also described in a proportion of adult cases,17 but whether there is an equivalent CM1/CM2 dichotomy in adults is less clear. Recent findings implicate a specific subset of parasites that adhere to endothelial protein C receptor (EPCR) in severe childhood malaria.18 As EPCR plays a key role in regulating coagulation and endothelial cytoprotective and barrier properties,19 this raises the possibility there may be linkages between IE cytoadhesion and microvascular complications in CM.20 However, the precise molecular processes that account for the pathophysiological differences between CM1, CM2, and adult CM are poorly understood. Elucidating key pathogenetic mechanisms in CM and severe malaria may suggest new treatment options to improve patient outcomes.
Unlike P. falciparum, P. vivax rarely causes severe disease in healthy travelers and is a less deadly parasite.21 Factors that may contribute to the lower virulence are that P. vivax only infects reticulocytes and the absence of the cytoadhesion protein family responsible for sequestration in P. falciparum infections.21,22 These differences limit the blood-stage parasite burden and spectrum of cytoadhesion-based complications. Another distinction is that P. vivax has dormant liver hypnozoite stages, which can reactivate and lead to blood-stage relapses. Relapses contribute to vivax morbidity, but the mechanisms leading to severe vivax disease remain to be elucidated. This review covers recent findings on the pathological pathways in pediatric and adult CM, as well as severe malaria cases in low-transmission settings in South America and India because of P. vivax infections, highlighting progress and outstanding questions in severe malaria pathophysiology in the context of the pathogenesis research activities within the International Centers of Excellence for Malaria Research (ICEMR) program.
Severe Falciparum Malaria in Children and Adults
The clinical presentations of severe falciparum malaria differ between children and adults.5 In particular, adults have a higher mortality rate and more multiorgan system involvement than children. A recent large multicenter comparison of artesunate versus quinine in the treatment of severe malaria in adults and children reported adult and pediatric mortality rates of 18.5%23 and 9.7%, respectively.24 The major organs affected in adult severe malaria are brain (CM), lungs (acute respiratory distress syndrome [ARDS]), liver (jaundice), and kidneys (acute renal failure) (Figure 1). Although the overall mortality of adult CM is about 15–20%, the risk of death depends on associated vital organ dysfunction and is increased 3-fold in the presence of acidosis and renal failure.25 In children, the three major disease complications are CM, severe anemia, and acidosis, but ARDS and renal failure are rare (Figure 1).26 Although the three disease syndromes can occur singly or as overlapping syndromes, severe malaria anemia commonly affects younger children, and CM and metabolic acidosis are more commonly found in slightly older children.27 CM and metabolic acidosis are each associated with high mortality rates in children (12% and 14%, respectively), and the presence of both increases the risk of death.28 The severity of disease may be exacerbated by both higher parasite burdens and the tissue-specific patterns of IE sequestration. Thus, there is significant research effort to understand factors that contribute to parasite blood-stage multiplication potential and cerebral homing of IEs.
