Background
Malaria is one of the most important health problems in developing countries. It is estimated that about half of the world’s population are at risk of malaria [
1,
2].
P. falciparum and
P. vivax have worldwide distribution, with
P. falciparum being the more pathogenic. Few years back, it was indicated that about 1–3 million mortality per year, mainly in children and pregnant women, are due to severe malaria caused by
P. falciparum [
3]. However, according to the latest report released by WHO [
4] there were an estimated 584,000 deaths globally. The same report showing reduction of malaria mortality rates among children in Africa by an estimation of 47 % globally since 2000 and by 54 % in the WHO African Region [
4].
In Ethiopia malaria is unstable and seasonal. This is because of the country’s heterogeneous topography and climatic factors [
5,
6]. Areas at altitudes between 1600 and 2000 m above sea level (masl) are epidemic-prone hypo-endemic zones of malaria [
7]. However, malaria epidemics are expanding to areas as high as 2500 masl [
8]. On the other hand, although
P. vivax is a rare parasite in most parts of Africa, it is an important parasite in Ethiopia. In some areas of the country the prevalence rate even exceeds 70 % of total malaria infections. This was previously reported due to the high Duffy positivity trait of most population of Ethiopia, but recently contradictory reports are coming [
9‐
11]. In addition, chloroquine resistance pattern of
P. vivax parasite is increasing in the country [
12]. Recently severe life threatening malaria symptoms
, frequently associated with
P. falciparum, has been reported from Asia, South America and Africa for
P. vivax [
13‐
18]. Thus, the current study was aimed to assess incidence of severe malaria symptoms due to
P. vivax infection in one of malaria endemic areas of Ethiopia.
Discussion
The overall prevalence of malaria during the study period (2014/15) was 29.8 %, (declined by 3.3 % from the 33.1 % prevalence documented in 2005 by the two local health facilities 2013) (Unpublished data). The overall prevalence of malaria observed during the study period was slightly lower than the recent report from southern part of Ethiopia (31.9 %) [
16] and much lower than report from Nigeria (81.9 %) [
23]. The possible explanation for the observed discrepancy could be due to the intense and diverse malaria control strategies undertaken in most parts of the country [
22].
P. vivax mono-infection has been associated with severe and fatal disease in endemic areas [
13,
24,
25]. The observed severe malaria symptoms in this study (14.3 %) was almost similar to reports from southern Ethiopia (13.67 %) and Tertiary care center of central India among hospitalized patients (17.2 %) due to
P. vivax malaria [
16,
18], but lower than report from Eastern Sudan’s New Halfa Hospital (27.8 %) [
26]. The most commonly encountered severe malaria manifestations of
P.vivax mono infection in this study were prostration, followed by severe anemia, persistent vomiting, hyperpyrexia, respiratory distress, and hypoglycemia. As observed in our study, severe malaria symptoms commonly detected in
P. vivax infected patients is severe anemia [
24]. This could be due to continuous presence of the parasite in liver as hypnozoite stage, infecting and destroying young RBCs [
25]. Also, for every infected RBC destroyed during
P. vivax infection, 32 non-infected RBCs are removed from the circulation, compared to the loss of 8 RBCs for every infected erythrocyte in
P. falciparum malaria [
27]. Other assumption is that anemia might occur as a result of rigor inflammatory reactions [
28] and phagocytosis of non-parasitized red blood cells, increased splenic clearance, and dyserythropoiesis in bone marrow [
29]. To this effect severe anemia caused by
P. vivax is responsible for 87 % of severe diseases compared to 73 % of severe malaria complications that occur due to
P. falciparum [
13]. In this study, significant number of severe anemia patients was children aged less than 5 years. The high susceptibility of young children to severe anemia could be due to relatively faster attainment of immunity to
P. vivax than to
P. falciparum [
30‐
32].
Frequency of respiratory distress due to
P. vivax mono infection observed in this study (10.9 %) was higher than report from India (6.8 %) [
18], but comparable with other report from adults living in malaria-endemic areas in Bikaner, Northwestern India (10 %) [
14]. The possible mechanism of pathogenesis of respiratory distress in
P. vivax malaria has been proposed to be severe alveolar capillary dysfunction like in
P. falciparum [
33]. This is evidenced by the comparable clinical manifestations of acute respiratory distress syndromes (ARDS) in
P. vivax and
P. falciparum infected patients [
34‐
36].
Most of these symptoms are largely attributed to production of various cytokines such as TNF- α produced in response to the parasite and toxin products released during rupture of infected RBCs [
37]. Also, hemozoin released from infected RBCs (iRBCs) leading to the release of pro-inflammatory cytokines that inturn induce COX-2 (cyclooxygenase-2) up-regulating prostaglandins leading to the induction of fever [
38,
39]. As there is an evidence for rigor inflammatory reactions due to pro-inflammatory response and cytokines activation during
P. vivax infection [
28], the hyperpyrexia and persistent vomiting observed in this study could be due to the intense inflammatory reaction caused by
P. vivax.
Differences in parasite load did not affect the incidence of severe malaria symptoms among assessed patients. This was in consistence with earlier report made by Price et al. [
40], which explained that
P. vivax is capable of inducing fever at levels of parasitemia lower than those causing fever in
P. falciparum infection [
40]. WHO also reported that in western Thailand, a region of low endemicity, the pyrogenic density for
P. vivax was 180 parasites/μL compared to 1000 parasites/μL observed in
P. falciparum infection [
41]. This is mainly because of the fact that
P. vivax has a tendency to achieve and maintain lower density parasitemia as it only invades young RBCs [
42]. In addition, patients with
P. vivax infections also tend to present all parasite stages that could be visible on the peripheral blood film [
4,
43]. Hypothesis given for the lower parasitemia caused by
P. vivax may be due to the presence of the same parasite in haemopoietic tissue than in the vascular sinus [
35]. Thus, parasite load of
P. vivax in peripheral blood could expand rigorously without its detection [
44].
Naturally,
P. vivax causes an acute febrile illness with no complications or death. However, recently reports on complications due to
P. vivax are globally increasing [
29,
45,
46]. The exact causes of changes in the clinical profile of
P. vivax infection are uncertain. It is assumed that, it may be due to genetic alterations of the parasite or change in vector and its biting habits, indiscriminate use of anti-malarial drugs, delayed treatment, or due to declining efficacy of chloroquine or rise in chloroquine- resistant
P. vivax strains [
47‐
49]. In addition, prolonged existence of hypnozoite reservoir in patient’s liver could cause recurrent infection even after patients successfully treated [
50]. The increasing evidence on severe malaria complications associated with
P. vivax has implication on the current global target of malaria eradication. Using knowledge and long experience accumulated over periods on
P. falciparum, all concerned bodies including policy makers, researchers and others working in the same field should characterize clinical epidemiology and economic burden of
P. vivax in different geographical areas for better management of burdens due to P.vivax infection.
Study limitation
The lack of confirmation of absence of mixed infection due to P.vivax and P.falciparium using PCR is a major limitation of this study.
Acknowledgements
The authors would like to thank officials, health personnel of the two health facilities in Mendi Town for their cooperation and support during data collection. The study participants were greatly acknowledged for their willingness to participate in the study.