Severe Plasmodium vivax malaria: fact or fiction?

TO THE EDITOR—Lacerda and colleagues should be congratulated for their excellent and timely autopsy study of patients who died with a diagnosis of Plasmodium vivax malaria in a tertiary care hospital in the Brazilian Amazon [1]. There have been increasing reports in the medical literature of single cases, case series, hospital-based studies, and reviews of severe and sometimes fatal malaria caused by P. vivax [2–25]. Autopsy studies are still essential to exclude confounding factors such as parasitological misdiagnosis, concurrent infections, and underlying diseases that can bias the majority of the published studies on severe P. vivax malaria [4, 7, 8, 15–22, 25]. However, the abovementioned reports have questioned the paradigm of benign P. vivax malaria and should prompt at least 2 questions: (1) Is an increasingly virulent P. vivax responsible for the emergence of the “new” severe clinical picture? (2) What are the characteristics of P. vivax malaria when it is severe or associated with numerous complications? In the outstanding book, “BruceChwatt’s Essential Malariology,” Warrell notes other conditions that are connected to P. vivax malaria: “. severe vivax malaria has been described in the past (for example in Europe) possibly related to malnutrition and other intercurrent diseases”;. ”Mild anemia is a common result of vivax malaria but it may become severe and even life-threatening in children and debilitated patients after relapsing infections. Thrombocytopenia is common” [26]. In agreement with the above cited statements, Poespoprodjo and coworkers showed in a prospective study conducted in Papua New Guinea that young infants with P. vivax malaria had a greater risk of severe anemia (OR 2.4) than those with P. falciparum, strikingly high parasitemia (geometric mean parasite count of 5814/μL), and a higher prevalence of malnutrition (18%), in comparison with the overall prevalence observed in the same region during the first year of life (8%) [27]. Severe anemia is by far the most frequently encountered complication of the disease that is noted across all studies of severe P. vivax malaria (10.7%, 817/76 152), but it is difficult to ascertain if it is exclusively the consequence of the observed malaria attack or if it is due to the additive effects of repeated malaria infections, hookworm infestation, and malnutrition. Cerebral involvement during the course of P. vivax malaria has been described as early as 1921, according to a literature review performed in 2002 that presented 40 cases that were reported up to 1996 [3]. All the studies that are presented in Table 1 were used to calculate the cumulative rate of cerebral malaria, which is 3% (226/75517) [5, 7–10, 14– 17, 19–25]. However, a prospective study done in Papua New Guinea using a stringent definition demonstrated that P. vivax-associated coma is 23 times less frequent in comparison with P. falciparum and not associated with death [16]. Deaths occurring among patients with P. vivax malaria can be inferred from studies conducted when malariotherapy (ie, the deliberate infection by P. vivax) was used to treat neurosyphilis. Mortality rates have been quoted at 3.4% to 5.4%, “although researchers believed that only a small portion of overall deaths could be attributed to the therapy rather than to the poor state of health of patients receiving it” [28]. If we consider all the studies regarding severe vivax malaria reported in recent years (Table 1), the overall case fatality rate is 1.2% (90/ 74539) [5, 7–10, 14–17, 19–25]; however, as demonstrated in the study by Lacerda et al, death could be directly attributed to P. vivax in only 4 patients (23.5%), and all the remaining patients had comorbidities or severe concurrent illnesses [1]. Thus, assuming the possibility that 23.5% of deaths are directly caused by P. vivax, the case fatality rate in published cases is 0.03% (21/74 539), a figure that is still probably an overestimate because in the majority of the studies, concurrent illnesses were not excluded. In conclusion, we believe that P. vivax malaria can indeed run a course with numerous complications. This phenomenon is certainly not new at all, but it has recently been rediscovered, as suggested in a clever editorial by Rogerson and Carter [29]. The frequency of severe and fatal P. vivax malaria is still low, although it is probably perceived as higher due to increasing reports of such cases that have been generated as a result of a renewed interest in this parasite. Future studies should address in greater detail the role of malnutrition, concurrent infections, underlying diseases, and mixed malaria infections in patient with severe P. vivax malaria.