Malaria

artReview

The pathophysiology of vivax malaria
Nicholas M. Anstey1,2, Bruce Russell1,3,4, Tsin W. Yeo1 and Ric N. Price1,2,5
1 2

International Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, 0810, Australia Division of Medicine, Royal Darwin Hospital, Darwin, 0810, Australia 3 Singapore Immunology Network, A*Star, Biopolis, 138648, Singapore 4Division of Bioengineering, National University of Singapore, 138648, Singapore 5 Centre for Vaccinology & Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK

Long considered a benign infection, Plasmodium vivax is now recognized as a cause of severe and fatal malaria, despite its low parasite biomass, the increased deformability ofvivax-infected red blood cells and an apparent paucity of parasite sequestration. Severe anemia is associated with recurrent bouts of hemolysis of predominantly uninfected erythrocytes with increased fragility, and lung injury is associated with inflammatory increases in alveolar-capillary membrane permeability. Although rare, vivax-associated coma challenges our understanding of pathobiology caused byPlasmodium spp. Host and parasite factors contribute to the risk of severe disease, and comorbidities might contribute to vivax mortality. In this review, we discuss potential mechanisms underlying the syndromes of uncomplicated and severe vivax malaria, identifying key areas for future research. Vivax malaria: neglected and not benign Plasmodium falciparum is responsible for the majority of severe andfatal malaria, thus overshadowing the public health importance and pathogenesis of vivax malaria [1,2]. However, outside of Africa, Plasmodium vivax accounts for almost half of malaria cases, with up to 390 million clinical infections each year [2]. In recent decades, P. vivax has usually been considered a benign infection; reports of severe vivax malaria have been confined to case reports and smallcase series [3]. Large studies from both halves of the island of New Guinea (Indonesian Papua [4,5] and Papua New Guinea, or PNG [6]) now show a strong association between P. vivax infection, severe disease and death [4–6]. These reports raise three major questions. How important a problem is severe and fatal vivax malaria outside of New Guinea? What proportion of severe disease and mortalityassociated with vivax infection is actually attributable to P. vivax? And what is the underlying pathogenesis of severe disease and death in vivax malaria? Some syndromes, such as severe vivax anemia, evoke several plausible mechanisms, whereas others (e.g. vivax coma) challenge our current understanding of pathogenesis caused by Plasmodium spp. Because it has a longer evolutionary history ofparasitizing primates than P. falciparum, P. vivax is probably better adapted to survival and replication without killing the host. This review compares the pathobiology of P. vivax with P. falciparum and discusses the potential mechanCorresponding author: Anstey, N.M. (anstey@menzies.edu.au).

isms underlying the syndromes of uncomplicated and severe vivax malaria (Table 1) and the potential host andparasite factors that contribute to these. Comparative pathobiology of P. vivax Parasite biomass Plasmodium falciparum invades red blood cells (RBCs) of all ages, progressing to high parasite burdens if uninhibited by treatment or host immunity. Conversely, P. vivax has a preference for infecting young RBCs, a property that seems to limit its reproductive capacity. Parasitemias in vivax malariararely exceed 2% of circulating RBCs [7], and high parasite burdens are not a feature of severe disease. Why does P. vivax evoke a greater inflammatory response than P. falciparum? A major feature that distinguishes P. vivax from P. falciparum is its lower pyrogenic threshold (the level of parasitemia associated with fever) [2,8]. Organ-specific studies have also shown that the inflammatory response...