Plasmodium vivax

“ Abstract Traditionally, infection with Plasmodium vivax was thought to be benign and self-limiting, however, recent evidence has demonstrated that infection with P. vivax can also result in severe illness and death. Research into P. vivax has been relatively neglected and much remains unknown regarding the biology, pathogenesis and epidemiology of this parasite. ”

“ There is uncertainty over the true epidemiology of relapse patterns over a large proportion of the P. vivax endemic world. Despite a resurgence of interest in malaria, and the belated recognition of the importance of Plasmodium vivax, this large knowledge gap seems to have gone unnoticed. It is quite possible that long-latency phenotypes are present in many tropical areas (Figure 17) . Defining these patterns is an essential prerequisite for therapeutic assessments, control and elimination planning, and the evaluation of novel interventions such as vaccines. ”

“ Plasmodium vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites) which can be prevented only by 8-aminoquinoline anti-malarials. Tropical P. vivax relapses at three week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics P. vivax infections are characterized either by a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months. ”

“ Investigating the genetic diversity of Plasmodium vivax populations is essential from both a public health perspective, and
to help achieve malaria control and elimination. Detection and analysis of individual clones within populations has not only provided a greater understanding of genetic diversity, but also of P. vivax prevalence and incidence [63] , [37] , [64] , [65] . Prevalence is one indicator of transmission and the main malariometric measurement in investigations including the global Malaria Atlas Project (MAP) [ [66] . ”

“ In the genus Plasmodium, four species are traditionally regarded as human parasites: Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, and Plasmodium falciparum. These species are remotely related to each other, suggesting that adaptation to humans has occurred several times independently during the history of the genus. ”

“ There is substantial stage-specificity of antigen expression by Plasmodium parasites so that candidate vaccines for one stage of the life cycle (figure 1) are unlikely to impact on another stage. Finally, malaria vaccine developers are faced with target species P. falciparum and Plasmodium vivax that will not infect small animals or old world macaques, so excluding the most widely used animal models for straightforward vaccine evaluation. There are many other malaria parasites that infect these species but these differ substantially from human parasites. ”

“ Malaria infection during pregnancy is a major public health problem in subtropical regions throughout the world. An estimated 125.2 million pregnancies occurred in areas with Plasmodium falciparum and/or Plasmodium vivax transmission in 2007, of which approximately 30.3 million occurred in Africa [1] , [2] . Of the five human malaria species, P. falciparum causes the most severe effects during pregnancy, and P. vivax is associated with maternal anaemia and low birth weight [3] , [4] . ”

“ Etiology.—There are at least three species of animal parasites which produce human malaria, Plasmodium vivax, the cause of benign tertian, P. malariae of quartan and P. falciparum of aestivo-autumnal. These parasites belong to the haemamoeba type of the order Haemosporidia, of the class Sporozoa and of the phylum Protozoa.
This type of Haemosporidia is characterized by invasion of red cells, amoeboid movement, pigment production and the extrusion of flagellum-like processes from the male sporont after the blood is taken from the animal and allowed to cool. ”

“ This is also supported by the rarity of finding patients or healthy subjects with gametocytes of both species in the blood at the same time. Development rates in the mosquito are also slightly different (P. vivax being more rapid) . Although space-time clustering of infections may occur in low transmission areas it is implausible that over 20% of P. falciparum inoculations would be associated with a separate P. vivax inoculation within one or two days, particularly when individuals receive on average less than one infectious bite per year. ”

“ In the absence of a continuous in vitro culture system and defined markers to identify drug resistance, genotyping is currently used to monitor treatment efficacy, and the emergence of resistant P. vivax strains. An understanding of haplotype frequency within a given population is therefore essential [75] . With respect to P. vivax parasites detected following drug treatment, there are three possible sources: re-infection with a new clone, recrudescence of a drug resistant clone, or relapse as a result of reactivation of liver hypnozoites [76] . ”

“ Porous land borders between malaria endemic countries, specifically throughout Southeast Asia and the Middle East, are potential barriers to the successful implementation of malaria elimination campaigns [68] , [70] . Migration of infected individuals resulting in importation of Plasmodium spp. and subsequent transmission by local vectors has contributed to the global spread of malaria [71] . Migration of infected individuals may seriously confound containment of P. vivax, as individuals can be unaware of their infection status due to long incubation periods. ”

“ Higher rates of vivax relapse in indigenous compared with artificial infection would also be explained by the ALH hypothesis. The incidence and number of relapses depends on the number of sporozoites inoculated. If all relapses derived from the inoculated infection then artificial infections which follow inoculations with 5-10 times more sporozoites should have higher, not lower rates of relapse. Relapse rates were particularly high in soldiers who were immunologically naïve and underwent intense exposure. ”

“ Wolf, RH; et al. (1986) , Observations on early and late post-sporozoite tissue stages in primate malaria. IV. Pre-erythrocytic schizonts and/or hypnozoites of Chesson and North Korean strains of Plasmodium vivax in the chimpanzee, vol. 10, pp. 263–74, 3513645 KrotoskiWAGarnhamPCCogswellFBCollinsWEBrayRSGwaszRWKillick-KendrickRWolfRHSindenRHollingdaleMLowrieRCKoontzLCStanfillPS, pmid:3513645 1 2 Garnham, PC (1988) , Swellengrebel lecture. Hypnozoites and 'relapses' in Plasmodium vivax and in vivax-like malaria, vol. ”

“ Following reports of increasing P. vivax genetic diversity in Korea [73] , Choi and colleagues used genotyping to successfully distinguish between autochthonous and imported P. vivax cases, identifying that the imported infections originated in neighbouring Asian countries. Imported infections also pose a risk in non-endemic regions of endemic countries. Many South American countries are geographically heterogeneous with regard to malaria transmission, and imported cases can result in serious illness and death amongst non-immune populations [74] . ”

“ In East Asia and Oceania a similar pattern pertains today. In East Asia a remarkably high proportion (20-50%) of symptomatic infections with P. falciparum are followed by an infection with P. vivax [121] - [122] . In Ethiopia where early relapse rates in vivax malaria are much lower, this proportion is also lower; 7% [ [123] . The intervals between the onset of treatment for the acute P. falciparum infection and the subsequent P. vivax infection are very similar to the intervals between acute vivax malaria and the first relapse (Figure 20) . ”

“ The unique biology of P. vivax is likely to be responsible for the apparent paradox of multiple clone infection in a low transmission setting. The latent hypnozoite stage of the P. vivax lifecycle increases the likelihood of superinfection with a second clone, potentially resulting in the reactivation of heterologous hypnozoites and an increased likelihood of meiotic recombination, ultimately increasing genetic diversity within the population [2] , [25] . ”

“ Fig. 5.—Plasmodium vivax. Mature schizont and merocyte. Found in the blood just before and at onset of chill. X 2200. (MacNeal after Doflein.)
Malignant tertian blood tends to show rather marked vacuolation of the red cells and these central vacuoles have a resemblance to young ring forms. The malarial parasites are most often peripherally placed and they do not enlarge and diminish in size on focusing up and down as do the vacuoles.
Fig. 6.—Plasmodium malariae. (Quartan.) Development of nonsexual parasite in blood of man. X 2200. (From MacNeal after Doflein.) ”

“ It also suggests that relapses are probably partially suppressed in older patients. Thus both the proportion of infections which relapse and the number of symptomatic relapses per mosquito sporozoite inoculation decline with age. It is likely that immunity and therefore age is a significant confounder in epidemiological assessments based on passive case reporting in many P. vivax endemic areas. In many areas adults are more likely to present to malaria clinics than children. In India the peak age of malaria presentation is often in young adults (and often with a predominance of young males) . ”

“ There are few data on temporal patterns of relapse in travellers in recent years, although studies in Eritrean immigrants to Israel, Turkish immigrants to Germany, and US soldiers returning from Somalia suggest the presence of long-latency phenotypes in the countries of origin [ [93] - [94] . Most travellers receive radical treatment for vivax malaria in temperate countries, which may be more effective against the long incubation or long-latency infections than against the tropical frequent relapse phenotypes. ”

“ Yet in the indigenous population living in transmission areas a significant degree of immunity should have been gained (by both sexes) by early adulthood which reduces the number of relapses. Usually in endemic areas it is children who bear the brunt of malaria. This applies to both falciparum and vivax malaria when malaria is uncontrolled, but with increasing control falciparum declines more rapidly than vivax, and their epidemiology separates. The paucity of data from children may contribute to the low apparent relapse rates reported from the Indian sub-continent. ”

“ In malaria, recrudescence is necessary for onward transmission of a de-novo resistant mutant parasites' progeny [ [143] . In P. vivax malaria the de-novo recrudescent infection is effectively in a race with the relapse-either of heterologous or drug sensitive homologous (sibling) parasites. Resistant parasites will only be transmitted if their progeny reach transmissible parasite densities before the relapse does. If the de-novo resistance is high grade then the resistant parasites may expand in numbers rapidly and may not be impeded by the relapse. ”

“ In conclusion, the recent data gathered from great apes in Africa have shown that a large diversity of Plasmodium species circulates among our relatives and have provided new insights into the evolutionary history of the malaria parasites of humans, particularly P. falciparum. These discoveries not only dramatically change our view on the evolution of the P. falciparum lineage, but also question the evolution and origin of the other human Plasmodium species (P. ovale, P. malariae, and P. vivax) . ”

“ McCutchan, TF & Su, XZ (2008) , Local adaptation and vector-mediated population structure in Plasmodium vivax malaria, vol. 25, pp. 1245–1252, 10.1093/molbev/msn07318385220 JoyDAGonzalez-CeronLCarltonJMGueyeAFayMMcCutchanTFSuXZ, pmid:18385220, DOI 10.1093/molbev/msn073 ↑ Sutton, PL; Neyra, V; Hernandez, JN & Branch, OH (2009) , Plasmodium falciparum and Plasmodium vivax infections in the Peruvian Amazon: propagation of complex, multiple allele-type infections without super-infection, vol. ”

“ Interest in the long-latency phenotype revived during the early 1950s as P. vivax malaria which had a long-latency was an important problem in soldiers fighting in the Korean war [61] . During this period patients who had received very heavy inoculations, typically soldiers from the Second World War, would return to clinics for many years complaining of recurrences of malaria. The long latencies and the long relapse intervals in some infections and the multiple relapses in others despite anti-malarial treatment gave rise to the old saw that "you never got rid of malaria". ”

“ A very wide range of treatments were used in a very diverse range of patient groups.P. vivax relapse rates following treatments which included 8-aminoquinolines (mainly plasmoquine or primaquine) . Otherwise as for Figure 13Proportions of P. vivax relapses in 222 US servicemen who had fought in the South Pacific in the Second World War [62] . Without radical treatment the proportion of patients who experience one relapse, the proportion of these patients who have a second relapse, and the proportion of these who have a third and so on, is constant (Table 1) . ”

“ Not only useful in the context of molecular epidemiology studies, identifying and managing multiple clone infections may have additional public health implications, as increasing, or high levels of multiple clone P. vivax infections may drive increases in parasite virulence and fitness, as parasite clones compete for both resources within the infected host and survival against antimalarial interventions [19] . ”