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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 55  |  Issue : 1  |  Page : 1-8

Epidemiology, drug resistance, and pathophysiology of Plasmodium vivax malaria


1 Department of Biochemistry, K.S. Hegde Medical Academy, NITTE University, Mangaluru, Karnataka, India
2 Department of Biochemistry, Kuvempu University, Shankaraghatta, Karnataka, India
3 Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA

Date of Submission07-Jun-2017
Date of Acceptance21-Feb-2018
Date of Web Publication18-Jun-2018

Correspondence Address:
D Channe Gowda
Department of Biochemistry and Molecular Biology, The Penn State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9062.234620

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  Abstract 


Malaria, caused by the protozoan parasites of the genus Plasmodium, is a major health problem in many countries of the world. Five parasite species namely, Plasmodium falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi, cause malaria in humans. Of these, P. falciparum and P. vivax are the most prevalent and account for the majority of the global malaria cases. In most areas of Africa, P. vivax infection is essentially absent because of the inherited lack of Duffy antigen receptor for chemokines on the surface of red blood cells that is involved in the parasite invasion of erythrocytes. Therefore, in Africa, most malaria infections are by P. falciparum and the highest burden of P. vivax infection is in Southeast Asia and South America. Plasmodium falciparum is the most virulent and as such, it is responsible for the majority of malarial mortality, particularly in Africa. Although, P. vivax infection has long been considered to be benign, recent studies have reported life-threatening consequences, including acute respiratory distress syndrome, cerebral malaria, multi-organ failure, dyserythropoiesis and anaemia. Despite exhibiting low parasite biomass in infected people due to parasite’s specificity to infect only reticulocytes, P. vivax infection triggers higher inflammatory responses and exacerbated clinical symptoms than P. falciparum, such as fever and chills. Another characteristic feature of P. vivax infection, compared to P. falciparum infection, is persistence of the parasite as dormant liver-stage hypnozoites, causing recurrent episodes of malaria. This review article summarizes the published information on P. vivax epidemiology, drug resistance and pathophysiology.

Keywords: Clinical manifestations; drug resistance; epidemiology; pathogenesis; severe malaria


How to cite this article:
Dayananda KK, Achur RN, Gowda D C. Epidemiology, drug resistance, and pathophysiology of Plasmodium vivax malaria. J Vector Borne Dis 2018;55:1-8

How to cite this URL:
Dayananda KK, Achur RN, Gowda D C. Epidemiology, drug resistance, and pathophysiology of Plasmodium vivax malaria. J Vector Borne Dis [serial online] 2018 [cited 2018 Dec 18];55:1-8. Available from: http://www.jvbd.org/text.asp?2018/55/1/1/234620




  Introduction Top


Plasmodium vivax is the most widespread human malaria parasite species found in many parts of the tropical and subtropical regions of the world, except sub Saharan Africa. Nearly, 2.5 billion people are at risk of P. vivax infection in 94 countries in the world, and 16 million clinical cases occur annually[1],[2]. The highest burden of P vivax infection is seen in Southeast Asia and South America[3]. In most parts of Africa, P. vivax infection is absent because of the inherited lack of Duffy antigen receptor for chemokines on the surface of red blood cells (RBCs) in the majority of people[4]. However, there are few reports describing prevalence of submicroscopic P. vivax infection in certain parts of Africa, suggesting that either the parasite is evolving to use alternative receptors for eryth- rocyte invasion or population in those regions express low levels of Duffy antigen receptors[5],[6]. The geographical dis- tribution of P. vivax malaria often overlaps with that of falciparum malaria, except in some regions of Southeast Asia, for example South Korea, where P. vivax is almost exclusively prevalent[7].

In infected individuals, while P. falciparum infection tends to show higher mean parasitaemia index, P. vivax infection generally exhibit low parasitaemia index due to its preference to invade reticulocytes rather than erythro- cytes[8],[9]. Determining the exact burden of P. vivax infection requires a more sensitive diagnostic tool since it is difficult to detect P. vivax in infected asymptomatic individuals and in mixed species infections by conventional light microscopy. The current rapid diagnostic tests that rely on detecting lactate dehydrogenase or aldolase are also not sufficiently sensitive in detecting P. vivax. This technique is unable to detect parasites if parasitaemia is lower than 200 parasites per μl blood[10]. The PCR-based detection methods are more sensitive, but they are not practicable in routine diagnostic procedures especially in rural settings. Therefore, more sensitive and simple P vivax specific diagnostic assays are needed for routine clinical diagnosis. Immunological assays may be attractive alternatives since they can be used to diagnose asymptomatic carriers and individuals recently exposed to P. vivax[11].

Population studies from many parts of the world have shown that individuals exposed to multiple infections and experienced clinical episodes of P vivax or P. falciparum acquires clinical immunity to P. vivax more rapidly than to P. falciparum, irrespective of overall transmission in- tensity[12]. However, the mechanisms underlying the more rapid acquisition of immunity to P. vivax remain poorly understood. In high endemic areas, morbidity associated with P. vivax infection peaks at a much younger age than P. falciparum infection[12]. Thus, in these regions, adolescents and adults with P. vivax infection are more likely to be asymptomatic than their P. falciparum-infected counterparts. In P. vivax low-transmission settings, however, the risk of developing severe disease is independent of age[13],[14].

A distinctive characteristic feature of P. vivax compared to other human malaria parasites is the persistent presence of dormant parasites (liver-stage hypnozoites), which initiate blood stage infection and cause malaria episodes several months or even one to two years after initial infection. The hypnozoites can remain dormant up to 2 yr after an initial inoculation of sporozoites through mosquito bite[15]. Usually parasite strains in temperate and subtropical regions exhibit longer dormant period between the primary infection and relapse (8–10 months or longer), whereas those in tropical regions generally exhibit shorter relapse intervals (around 3-6 wk)[16]. Thus, relapse pattern varies from region to region and the exact mechanism of how hypnozoite relapses are triggered, and the source of this phenotypic variation, remains unknown[15],[17]. Frequent relapses that occur at 2–3 wk intervals induce early disease tolerance, characterized by high threshold for fever, and sometimes asymptomatic infections[18]. However, frequent recurrent episodes result in inadequate time for patients to recover from haematological damages, leading to severe anaemia[19]. Currently, primaquine, an 8-aminoquinoline antimalarial agent, is the drug of choice to kill liver hyp- nozoites and prevent relapse. However, the drug is highly toxic to people having glucose-6-phosphate dehydroge- nase (G6PD) deficiency as it causes fatal haemolysis[20].

Drug resistance

In recent years, antimalarial resistance has been a major concern in treating malaria. For many years, chloro- quine (CQ) was the drug of choice in treating both P. vivax and P. falciparum infections since the drug is cheap and effective. However, currently in most endemic areas, parasites have developed resistance to this drug[21]. Resistance to CQ in P. vivax was first reported in Papua New Guinea in 1989 and subsequently resistance was also seen in most endemic places in Southeast Asia. Highest prevalence of CQ-resistance in P. vivax was reported in Northeastern coast of Indonesian Papua[22]. Resistance to CQ and failure of primaquine as anti-relapse drug for P. vivax malaria have also been reported in some parts of Southwestern and Northeastern regions of India[23],[24]. Since, the blood stage P. vivax infection, could be due to either recrudescence of CQ-resistant strains or reinfection, it is difficult to determine primaquine resistance in many cases. In India, very little information is available on the molecular mechanisms and epidemiology of P. vivax resistance to CQ and primaquine. In many regions of the world, where CQ resistance in P. vivax is seen, artemisinin combination therapy along with primaquine is used as an alternative treatment strategy[25]. Effective artemisinin combination therapies such as dihydroartemisinin-piperaquine and artesunate-mefloquine provide greater post-exposure prophylaxis against early recurrence of infection in P. vivax[26].

Compared to P. falciparum, the molecular basis of an- ti-malarial drug resistance to P. vivax has not been studied extensively, mainly because of difficulty in establishing in vitro culture. However, in recent years, many laboratories around the world have reported methods for conducting in vitro P. vivax drug susceptibility studies[27],[28]. Anti-malarial drug resistance appears to be mainly due to mutations in genes encoding essential enzymes or transporters involved in parasite development or its nutritional needs. The P. vivax multidrug resistance (Pvmdr) and putative transporter protein (Pvcrt-o), which are orthologous to Pfmdr1 and Pfcrt genes, have been identified as chlo- roquine resistance markers in P. vivax. The mutant alleles of both genes were suggested to be associated with chlo- roquine resistance in P. vivax in Southeast Asia based on in vivo and in vitro studies[29],[30]. There are reports suggesting that genotypic variations in P. vivax dihydrofolate reduc- tase gene (Pvdhfr) and dihyropteroate synthetase (Pvdhps) have also been associated with drug resistance[16],[31]. The Y976F and F1076L mutations in Pvmdr1 gene have been reported to be associated with chloroquine resis- tance[29], and point mutations at F57L/I, S58R, T61M, and S117T/N codons of Pvdhfr gene have been linked to pyrimethamine resistance and treatment failure in P. vivax. Whole sequence analysis of Pvmdr1 and Pvcrt- o in P. vivax field isolates has revealed that Pvmdr1 gene contained 24 single nucleotide polymorphisms (SNPs), whereas Pvcrt-o gene contained five SNPs and lysine insertion at the amino acid position 10[32]. Recently, mutations in the PF3D7 1343700 kelch propeller domain (K13-propeller) of Pfk13 gene have been shown to be associated with artemisinin resistance in P. falciparum, which is demonstrated as delayed parasite clearance post artemisinin treatment[33],[34]. Similar mutations mediating artemisinin resistance in the Pfk13 orthologue of P vivax, i.e. Pvk12 (mutation V552I) have been identified in Cambodia at a very low frequency[35].

Pathophysiology

Malaria illnesses are generally associated with periodic fever, chills, shivering, headache, nausea, vomiting, and many other clinical conditions. However, in the case of P. falciparum, clinical complications such as severe anaemia, respiratory distress, cerebral malaria and other organ dysfunction are also common[10]. It has long been believed that P. vivax infections are relatively benign and cause mild clinical symptoms, and parasites do not sequester in the deep capillaries of organs[36]. However, recent studies have suggested the possibility of parasite sequestration in organs as evidenced by the P. vivax infection-associated severe illnesses and deaths[37].

Clinical symptoms of malarial infections are seen soon after the initiation of the blood stage infection, in which merozoite forms of parasites invade RBCs[38]. Unlike P. falciparum, which invades RBCs and parasitae- mia can exceed 20-30%, P. vivax exhibits exclusive specificity to invade reticulocytes[39]. This distinctive property of P vivax results in lower parasite biomass due to relatively low reticulocytes in the blood compared to RBCs, rarely exceeding 2–3% parasitaemia, even in situations when infections causing severe diseases. In spite of having lower pyrogenic threshold than P. falci- parum, cytokine production, endothelial activation, and pulmonary inflammatory responses are higher in P. vivax infection compared to P. falciparum infection[40],[41]. The main reason for this phenomenon might be the presence of higher GC content in P. vivax genome , which is approximately two times higher than that of P. falciparum, and thus having higher contents of CpG motifs, which are recognised by Toll-like receptor 9 leading to cell activation and inflammatory responses[42],[43],[44],[45]. Lipids found in the cholesterol/triglyceride fractions of plasma at the time of paroxysmal fever have also been proposed as a putative malaria toxin unique to P. vivax, and they may also contribute to the pyrogenicity of P. vivax[46]. It has been suggested that the cholesterol/triglyceride fractions of P. vivax exhibit greater inflammatory response-inducing activity than glycosylphosphatidylinositol anchors[46],[47]. Several clinical conditions seen in P. vivax malaria are due to imbalance in pro- and anti-inflammatory cytokine production, resulting in greater concentrations of both pro- and anti-inflammatory cytokines than in falciparum malaria[48]. Plasma concentrations of the pro-inflammatory cytokines, TNF-α and IFN-γ have been shown to be directly related to disease severity, whereas plasma concentrations of IL-10 have been shown to be inversely related to disease severity[49]. Also, plasma concentration of superoxide dismutase, an enzyme produced during oxidative stress, has also been shown to be associated with P. vivax disease severity[50].

Parasite sequestration and severe malaria

Severe P. falciparum pathology is associated with the sequestration of parasites in microvascular endo- thelia through the binding of parasite-infected RBCs to endothelial cell receptors, such as CD36, ICAM-1, and VCAM-1 in organs, causing microvascular obstruction, hypoxia, and inflammation[51],[52]. High levels of inflammatory responses at sites of sequestration contribute to tissue disruption and single- or multi-organ dysfunction and mortality. Sequestration of parasites usually does not occur to a substantial degree in P. vivax malaria and therefore, organ dysfunction and mortality are not frequent as compared to P. falciparum[42]. Autopsy studies of P. vivax infected severe malaria cases showed little evidence for microvascular accumulation of P vivax-infected RBCs[53]. However, other studies have shown that P. vivax-infect- ed RBCs bind to endothelial cells via receptors, such as ICAM-1, with a similar strength but a 10-fold lower frequency than P. falciparum-infected RBCs[54]. Further, it has been reported that P. vivax-infected RBCs bind to glycosaminoglycans, such as chondroitin sulfate-A and hyaluronic acid[55]. Indirect physiological studies, partitioning pulmonary gas transfer in adults with P. vivax malaria, have shown the impairment of pulmonary capillary vascular functions, suggesting sequestration of parasitized RBCs in the lung[40]. Autopsy of Brazilian P. vivax-in- fected people having acute respiratory distress syndrome (ARDS) showed parasitized RBCs in alveolar capillaries even after parasites from peripheral blood were cleared by antimalarial drug treatment[53].

Thus, it seems that in some circumstances, moderate levels of cytoadherence to endothelial cells occur, contributing to inflammatory responses in affected organs, such as the lung. Rosetting/autoagglutination, i.e. adherence of non-infected RBCs to infected RBCs and thus cell clumping together is an important phenomenon of cytoadherence and pathophysiology in P. falciparum malaria[56],[57],[58]. The rosetting is initiated by the binding of infected RBCs to CD36 and P-selectin on platelets. However, this mechanism is not seen in P. vivax malaria[58],[59]. In P. falciparum infection, decreased nitric oxide bioavail- ability, and endothelial activation and dysfunction are significant contributors to impaired microvascular perfusions and complications[60],[61]. The levels of endothelial activation markers, ICAM-1, E-selectin and angiopoietin-2, are as high in uncomplicated vivax malaria as they are in falciparum malaria[62],[63].

However, their significance in severe vivax malaria is not known. Autopsies of brain and lung sections in severe cases of P. vivax have demonstrated endothelial activation[64]. Since, P. vivax show limited ability to cy- toadhere, pathogenic consequences of endothelial activation and sequestration of parasitized RBCs are likely much less in vivax malaria than in falciparum malaria. However, other consequences of endothelial activation and altered thrombostasis in P. vivax infection are imperative. Plasmodium vivax infection is associated with elevated thrombomodulin, von Willebrand factor, procoagulant activity, thrombotic microangiopathy, and reduced levels of metalloproteinases[65],[66],[67]. These altered hemostatic pathways could result in intravascular coagulation and endothelial inflammation through increased formation of large von Willebrand factor and platelet aggregates[67]. Moreover, malaria parasite-infected RBCs exhibit greater rigidity and lower deformability than normal RBCs[68]. Compared to P. falciparum-infected RBCs, P. vivax-infected RBCs show lower levels of de- formability[69],[70]. This enables P. vivax to pass through the narrow inter-endothelial slits of the splenic sinusoids resulting in inefficient trapping of P. vivax-infected RBCs and splenic clearance[71]. However, low deformability may contribute to increased fragility of P. vivax-infected RBCs[70].

Severe malarial anaemia (SMA)

Severe malarial anaemia is defined as a haemoglobin concentration of < 50 g/l (5 g/dL) and the presence of high parasitaemia (>10,000 parasites/μl)[72]. Anaemia is the most common clinical condition of P. vivax infection in both adults and children in endemic areas, where transmission is intense and relapses are frequent[73],[74]. P vivax-associated anaemia is complex and confounded by coinfection of P. falciparum. The likely mechanisms involved in severe malaria anaemia is a cumulative of loss of RBCs due to infection, lysis of uninfected RBCs in the circulation, and impaired RBC production[42],[75]. In P. vivax infections, ~34 uninfected RBCs are removed for every infected RBCs in the circulation[75],[76], whereas in P.

falciparum infections, about eight uninfected RBCs are lysed for every infected RBC[77],[78]. Thus, compared to P. falciparum infections, lysis of uninfected RBCs is higher in P. vivax infections, contributing to greater loss of RBCs and severe anaemia. However, mechanisms that underlie the higher loss of RBCs in P. vivax infections despite having lower parasitaemia index compared to P. falciparum infections are not well understood. Higher inflammatory responses to P. vivax parasitaemias in the spleen, where the majority of extravascular haemolysis occurs, seem to be an important factor[41],[75]. Consistent with this prediction, higher inflammatory responses in P. vivax infections have been shown to be associated with greater oxidative stress in RBCs[75],[79]. Although, malaria-related clearance of uninfected RBCs has been shown to persist for at least 5 wk after antimalarial treatment[80], over 80% of P. vivax infections results in relapse at 3–4 wk intervals and recurrent episodes leads to anaemia progressively due to haemolysis and dyserythropoiesis, before haematologi- cal recovery from the preceding infection takes place[81],[82]. Inflammatory cytokine contributing to dyserythropoiesis is likely due to either direct toxicity of P. vivax on eryth- roblasts or enhanced bone marrow phagocyte activity in vivax malaria[83],[84].

Acute respiratory distress syndrome (ARDS)

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has been reported in complicated malarial cases worldwide. This condition is associated with deep breathing, respiratory distress, pulmonary oedema, airway obstruction, impaired function of the alveoli, decreased gas exchange, and an increase in pulmonary activ- ity[85]. In both falciparum and vivax malaria, the majority of ARDS occurs in young children[19],[86]. An autopsy study in ARDS cases from P. vivax prior to antimalarial treatment has showed heavy infiltrates of intravascular mononucle- ar cells, endothelial and alveolar damages, and absence of parasite sequestration in the pulmonary vasculature[64]. Another autopsy study from Brazil has reported an infiltration of neutrophils in alveolar capillaries even after parasites were cleared from peripheral blood by antima- larial drug treatment[53]. Thus, it seems that inflammatory mediators cause ARDS in P. vivax infections[87],[88].

Pregnancy-associated malaria

Pregnancy-associated malaria (PAM) is associated with high morbidity and mortality, causing 75,000200000 infant deaths globally each year[89]. Pregnant women are more susceptible to malaria infections because of their somewhat compromised immune status, especially during the first and second trimesters of pregnancy[90],[91].

PAM-associated severe pathological conditions are mainly attributed to P. falciparum infections because of parasite’s ability to massively sequester in the placenta[92]. Placental malaria presents a wide-spectrum of clinical conditions, including severe anemia, intrauterine growth retardation, low birth weight, preterm delivery, miscarriage, perinatal mortality, and death in the mother[93],[94]. The sequestration of parasite-infected RBCs in the intervil- lous space of placenta and the adherence of infected RBCs to the syncytiotrophoblast cell layer are the contributors to PAM pathogenesis[91]. The sequestration and adherence of infected RBCs are mediated by the binding of VAR2CSA, a variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of infected RBCs to chondroitin sulphate-A in the placenta[95],[96],[97]. Accumulation of parasite in the placenta results in the enhanced deposition of haemozoin and fibrin as well as increased leukocyte infiltration. This results in alteration of intervillous and perivillous spaces, trophoblast cell membrane dysfunction and compromised nutrient and oxygen transport to the developing foetus[98]. Production of cytokines, such as IL-1, IFN-γ, TNF-α and IL-2, leads to inflammation in the placenta[99],[100]. Additionally, complement immune activation plays a pathogenetic role during PAM[101].

For P. vivax infections, however, there are only few studies on clinical outcomes of PAM. Of these studies, the majority has been conducted in the Asia-Pacific re- gion[102],[103],[104]. Compared to PAM caused by P. falciparum, P. vivax-associated PAM appears to be less severe. An histo- pathological study of P. vivax-infected placentas showed the accumulation of parasitized RBCs and malarial pigment deposits in intervillous spaces, but there were no significant tissue changes[105]. An epidemiological study from Brazil has showed P. vivax infection contributing to low birth weight, abortion, and premature delivery; maternal anaemia might have contributed to low birth weights[91]. In addition, an observational case control study from Brazil has reported that women with P. vivax infections during pregnancy harboured parasites and infiltrated immune cells in the placenta[106]. Thus, systemic and placental inflammatory responses and microvascular dysfunction from vivax malaria may cause deleterious utero-placental hemodynamic effects and foetal growth restriction[9],[105],[107]


  Conclusion Top


Although, in the past, P. vivax infections were thought to be mostly benign and rarely life threatening, parasites are becoming increasingly virulent, causing fetal illnesses. The molecular mechanisms for this shift in patho- physiology of P. vivax infection still remain poorly understood. It is possible that drug resistance and evolving alterations in parasite’s genomic make up, and changes in host responses due to altered microbiomes have resulted in dysregulated immune responses, contributing to severity of infections. In any event, there is a critical gap in the current knowledge on P. vivax biology, pathophysiology and immunity. Coordinated multidisciplinary efforts are essential to bridge this knowledge gap.

Conflict of interest

The authors declare that they have no conflict of interests.


  Acknowledgements Top


This work was supported by the grant D43 TW008268 from the Fogarty International Center, National Institutes of Health, under Global Infectious Diseases Program.



 
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