Research Article: Plasmodium vivax and Mixed Infections Are Associated with Severe Malaria in Children: A Prospective Cohort Study from Papua New Guinea

Date Published: June 17, 2008

Publisher: Public Library of Science

Author(s): Blaise Genton, Valérie D’Acremont, Lawrence Rare, Kay Baea, John C Reeder, Michael P Alpers, Ivo Müller, Stephen Rogerson

Abstract: BackgroundSevere malaria (SM) is classically associated with Plasmodium falciparum infection. Little information is available on the contribution of P. vivax to severe disease. There are some epidemiological indications that P. vivax or mixed infections protect against complications and deaths. A large morbidity surveillance conducted in an area where the four species coexist allowed us to estimate rates of SM among patients infected with one or several species.Methods and FindingsThis was a prospective cohort study conducted within the framework of the Malaria Vaccine Epidemiology and Evaluation Project. All presumptive malaria cases presenting at two rural health facilities over an 8-y period were investigated with history taking, clinical examination, and laboratory assessment. Case definition of SM was based on the World Health Organization (WHO) criteria adapted for the setting (i.e., clinical diagnosis of malaria associated with asexual blood stage parasitaemia and recent history of fits, or coma, or respiratory distress, or anaemia [haemoglobin < 5 g/dl]). Out of 17,201 presumptive malaria cases, 9,537 (55%) had a confirmed Plasmodium parasitaemia. Among those, 6.2% (95% confidence interval [CI] 5.7%–6.8%) fulfilled the case definition of SM, most of them in children <5 y. In this age group, the proportion of SM was 11.7% (10.4%–13.2%) for P. falciparum, 8.8% (7.1%–10.7%) for P. vivax, and 17.3% (11.7%–24.2%) for mixed P. falciparum and P. vivax infections. P. vivax SM presented more often with respiratory distress than did P. falciparum (60% versus 41%, p = 0.002), but less often with anaemia (19% versus 41%, p = 0.0001).ConclusionP. vivax monoinfections as well as mixed Plasmodium infections are associated with SM. There is no indication that mixed infections protected against SM. Interventions targeted toward P. falciparum only might be insufficient to eliminate the overall malaria burden, and especially severe disease, in areas where P. falciparum and P. vivax coexist.

Partial Text: Most of the research and published literature on malaria focuses on P. falciparum and much less on P. vivax [1,2]. This focus is due to the very high burden of mortality attributed to the falciparum species in Africa [3]. However, there is growing evidence that P. vivax is responsible for a significant burden of disease worldwide accounting for half of all malaria cases in Asia and Latin America [4]. As the term “benign tertian malaria” implies, vivax malaria is usually an uncomplicated disease that runs a benign course and is rarely fatal. This clinical paradigm has been challenged recently [5] by numerous reports of symptoms and signs of severe disease, and even deaths due to P. vivax monoinfections [6–9]. However, most of the published literature consists of case reports or small descriptive clinical series lacking denominators. The relative contribution of P. vivax versus P. falciparum to severe morbidity has not been properly assessed, except for one study in Thailand that found very little severe disease and no death due to P. vivax [10]. This Thai study suggested, rather, a protecting effect of vivax, as had a study from Vanuatu [11,12]. It is only recently that severe disease due to P. vivax has received more attention with a recent report from a hospital in northeastern Indonesian New Guinea (Papua) where they found 36 severe malaria (SM) cases among 1,135 P. vivax infected patients (3.2%) [13].

A total of 73,620 patients were registered in the 8-y period of the morbidity surveillance from 1997 to 2004. Among those, 17,201 cases were diagnosed as presumptive malaria cases and investigated further by the research nurse. A total of 9,537 of those patients (55%) had asexual Plasmodium parasitaemia. Among those, 6,886 (72%) had pure P. falciparum, 1,946 (20%) P. vivax, 328 (3%) P. malariae, 27 (0.3%) P. ovale, and 350 (4%) mixed infections (314 P. falciparum and P. vivax; 21 P. falciparum and P. malariae; ten P. vivax and P. malariae; three P. falciparum and P. ovale; one P. malariae and P. ovale; and one P. falciparum, P. vivax, and P. malariae). The age-specific parasite prevalence and species distribution among all presumptive malaria cases is shown in Figure 1. The highest parasite prevalence was found in children aged 5 to < 10 y (peak age 7 y). On the other hand, the highest proportion of P. vivax was seen in children 2 to < 5 y (peak age 2 y), with up to 20% parasitaemic. The present study shows that in a rural area of PNG where all four species of Plasmodium coexist, P. vivax is responsible for 21% of all SM cases, P. falciparum for 71%, and mixed P. vivax and P. falciparum infections for 5%. A feature of this clinico-epidemiological report is the simultaneous presence of P. falciparum as an internal control for P. vivax, so that the relative proportions of severe disease can be determined, regardless of its definition. The proportion of patients < 5 y who presented with SM among all P. vivax infected children was as high as 9%. The corresponding value for P. falciparum was 12%. Since the evaluators and the defining criteria for uncomplicated and severe malaria were strictly the same, we can be confident that the relative values (P. vivax versus P. falciparum) are correct. Moreover, the absolute value for the proportion of severe cases among all P. falciparum-infected children (12%) was lower than those found in numerous other studies of clinical malaria, the main reason being that our study took place in a peripheral health facility and not in a referral hospital as most, if not all, other studies [26–28]. It is clear that this absolute value depends entirely on the criteria used to define SM and on the population from which the cases are selected. Since we were working in a setting that did not allow us to measure certain parameters included in the WHO definition, such as glycemia or creatininemia, we probably slightly underestimated the true proportion of severe malaria caused by both species. Whichever definition is used, the relative contribution of P. vivax to the overall burden of SM morbidity is considerable in this region, and especially in children <2 y, where the proportion of P. vivax parasitaemic children presenting with severe disease reached a worrying rate of 14% (versus 18% for P. falciparum). These data on severe vivax malaria are in line with those reported in a joint paper from a hospital in Papua, Indonesia, also published in this issue of the journal [28]. In that setting, severe disease was present in 23% of the patients with malaria, with rates similar for P. falciparum and P. vivax (22%), but significantly higher in patients with mixed infections (34%). These two observational studies, although both originating from the same region of the world, add to the growing realization that P. vivax is not benign. They are the first studies, to our knowledge, to incorporate denominators that allow assessing the relative magnitude of the problem when compared to that of P. falciparum. Source: http://doi.org/10.1371/journal.pmed.0050127

 

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