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Review
. 2011 Oct 11:10:297.
doi: 10.1186/1475-2875-10-297.

Determinants of relapse periodicity in Plasmodium vivax malaria

Nicholas J White  1
Affiliations
Review

Determinants of relapse periodicity in Plasmodium vivax malaria

Nicholas J White. Malar J. .

Abstract

Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa. 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. The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria control and elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses. The intervals between relapses display a remarkable periodicity which has not been explained. Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself. It is proposed that in endemic areas a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings. Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.

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Figures

Figure 1
Figure 1
Long-latency P. vivax in the Netherlands; The mean monthly number of malaria cases in the village of Wormerveer, The Netherlands, recorded by Korteweg from 1902 to 1923 (black line) [15-17,19]. Swellengrebel et al showed that malaria transmission usually occurred between the first week of August and the end of October [16]. From this it can be deduced that the initial wave of malaria cases derived from inoculations the previous year (pink curve) and, by subtraction, that this was followed by relapses and primary cases with a short incubation period in the late summer and autumn (blue curve) [19].
Figure 2
Figure 2
The temporal pattern of illness recurrence in patients with neurosyphilis artificially infected for malaria therapy with Plasmodium falciparum (87 patients) and the "Madagascar" strain of P. vivax (105 patients) studied by SP James and colleagues at the Horton Hospital, Epsom, England [24-26]between 1925 and 1930. The vivax relapses had a bimodal pattern with the majority having a long latent period (mode 28 weeks) before the relapse.
Figure 3
Figure 3
Combined results of the preliminary mosquito infection studies of James and Shute in the Horton Hospital, Epsom, England and the self experimentation of Shüffner, Korteweg, Swellengrebel-de Graaf, Swellengrebel, de Buck and de Moor in The Netherlands as illustrated by Shüffner et al [27]. This confirmed the 8 to 9 month interval from being bitten by one or two infected anopheline mosquitoes and developing vivax malaria
Figure 4
Figure 4
The family history between May 1925 and May 1933 of the "Madagascar strain" of Plasmodium vivax as used in malaria therapy at the Horton hospital [30]. The number within the circles refers to the number of patients infected with the "Madagascar strain" at each time and the number over the lines refers to the batch number of the infected mosquitoes. Overall 24,361 mosquitoes and 1739 patients were infected.
Figure 5
Figure 5
Boyd's 10 year experience with mosquito transmitted P. vivax malaria therapy in 375 patients studied at the Florida State Hospital [93]. Most infections were with the McCoy strain, and some were with other local "strains" which he considered to behave similarly. Infections which were allowed to continue until self termination did not relapse subsequently [31]. The median interval to relapse was approximately 9 months. Inset is the study of Coatney et al [71] describing 403 mosquito transmitted infections with the St Elizabeth strain of P. vivax.
Figure 6
Figure 6
Diagram of the different P. vivax phenotypes and the usual patterns of primary illness and relapse (after Bray and Garnham [69]). The thickness of the lines gives a rough approximation of proportions.
Figure 7
Figure 7
Schematic diagram by Hankey et al [79]of relapse patterns following Korean vivax malaria (upper panel) and tropical frequent relapse P. vivax (lower panel). Note the frequent relapse pattern after a long interval with Korean vivax malaria.
Figure 8
Figure 8
Relapse patterns in volunteers in the USA who were infected by a single mosquito bite with the Chesson strain of P. vivax studied by Coatney et al [75]. Some were rechallenged as indicated.
Figure 9
Figure 9
Relapse patterns of P.cynomolgi infections in Rhesus monkeys studied by Schmidt [82]. The infections were induced with different numbers of injected sporozoites as indicated and treated repetitively with chloroquine. Monkeys in groups A, B, C, and D were inoculated, respectively, with 5 × 106, 5 × 104, 5 × 102 and 5 sporozoites. Some monkeys were rechallenged and some were finally given radical treatment with primaquine in addition.
Figure 10
Figure 10
Lengthening intervals between sequential relapses in individual volunteers who were infected with the Chesson strain of P. vivax, each of whom was treated with quinine for 16 days [83]. Diamonds represent median values.
Figure 11
Figure 11
In infections of volunteers with the St Elizabeth strain of P. vivax [71], there was no evident relationship between the occurrence or duration of the primary illness and the long-latency interval before illness (left panel), whereas there was an inverse relationship between sporozoite inocula (assessed semi-quantitatively from sporozoite numbers in the salivary glands and number of infectious bites) and the latency interval.
Figure 12
Figure 12
Cumulative proportions of relapses in soldiers with vivax malaria acquired in the Pacific and treated subsequently with different anti-malarial drug regimens in Chicago. Regimens were quinine; 2 g/day for 14 days (N = 75), mepacrine 0.4 g/day for 7 days (N = 69), chloroquine 1.5 - 2 g/day for 4-7 days (N = 82), and quinine 2 g/day and plasmoquine 60 mg/day for 14 days (N = 72) [47].
Figure 13
Figure 13
P. vivax relapse rates without radical treatment in published studies conducted between 1920 and 2010. Each circle represents one study arm. The horizontal scale represents the study location from West (United States) to East (Pacific). A very wide range of treatments were used in a very diverse range of patient groups.
Figure 14
Figure 14
P. vivax relapse rates following treatments which included 8-aminoquinolines (mainly plasmoquine or primaquine). Otherwise as for Figure 13
Figure 15
Figure 15
Proportions of P. vivax relapses in 222 US servicemen who had fought in the South Pacific in the Second World War [76].
Figure 16
Figure 16
The proportions of patients experiencing successive P. vivax relapses taken from eight different clinical series: These were US soldiers with vivax malaria acquired in the South Pacific (2 series) [49,76], German soldiers who acquired vivax malaria in Greece [41], US soldiers with vivax malaria acquired in the Mediterranean area (two series)[45,47]and Italy[156], patients receiving malaria therapy with a local "strain" in Moscow [28], British patients receiving malaria therapy with the Madagascar strain [24,25], patients receiving malaria therapy with the McCoy strain in the United States [93], volunteers infected with the Chesson strain in the United States [75] and children followed prospectively in an evaluation of an ineffective malaria vaccine (SPf66) in northwestern Thailand [157]. Inset shows proportions on a log scale and numbers of patients studied.
Figure 17
Figure 17
Approximate historical distribution of P. vivax latency phenotypes. Areas where tropical "frequent relapse phenotypes" are prevalent are shown in pink. Areas where both frequent relapse and long-latency phenotypes have been reported are shown in purple, and areas where long-latency phenotypes were prevalent are shown in grey. Although both South America and India are generally considered to harbour frequent relapse phenotypes predominantly, there is evidence that long-latency phenotypes are present in both areas (particularly across the North of India), and without genotyping it may be difficult or impossible to distinguish the two phenotypes within an endemic area (Figure 22).
Figure 18
Figure 18
The epidemiology of vivax and falciparum malaria in an area of low seasonal transmission on the Western border of Thailand; age incidence profiles [106].
Figure 19
Figure 19
Numbers of US servicemen admitted to hospital in the USA each week with vivax malaria following their return from the Korean war. Exposure was predominantly in 1950. Figures taken from the Office of the US Surgeon General.
Figure 20
Figure 20
The median (IQR, range) Intervals between acute P. falciparum malaria (in green) and acute P. vivax malaria (in red) and the subsequent vivax malaria episode in patients studied in Thailand following different anti-malarial treatments. The figures in brackets are the number of patients studied [136-138]. * reinfection excluded.
Figure 21
Figure 21
Proposed mechanism and sequence of Plasmodium vivax relapse activation in a malaria endemic area. In an illustrated example, at the time of infection (sporozoite inoculation) the individual already has hypnozoites of two different genotypes acquired from two previous inoculations which are latent in the liver. The different genotypes are denoted by different colours (red and white). Half the newly acquired infection sporozoites (blue) develop into preerythrocytic schizonts and half become dormant as hypnozoites (the estimated proportions for tropical "strains") [59,69]. Illness associated with the blood stage infection activates a small fraction of the hypnozoites (inset shows a "classic" P. vivax fever pattern in relation to asexual parasite development). In this example there is one hypnozoite of each genotype and each is activated by the illness and each develops into a pre-erythrocytic schizonts. By chance the progeny of one of the preexisting latent hypnozoites reach pyrogenic densities before the progeny of the recently inoculated hypnozoite (inset shows the logarithmic growth of the three genotypically different infections-vertical axis shows number of parasites in the body). The consequent febrile illness then suppresses further multiplication of the blood stage infection so that the progeny of the other two prerythrocytic schizonts may not reach transmissible densities. The ensuing illness activates some of the remaining hypnozoites (the same fraction as were activated initially) and relapses continue until either the number of hypnozoites is exhausted or some fail to be activated. If there are some hypnozoites which fail to be activated these may be activated at a later date by a subsequent malaria infection.
Figure 22
Figure 22
Potential similarity of relapse patterns with the long-latency and frequent relapse P. vivax phenotypes. The different colours and symbols represent different genotypes in two hypothetical infections. The upper panel shows the relapse pattern where the frequent relapse phenotypes are prevalent. The patient has hypnozoites from three preceding inoculations present at the time of illness from the newly acquired (red) infection. These are sequentially activated as proposed in Figure 21. Three relapses occur with similar periodicities, and a later randomly activated relapse occurs 8 months later. In the lower panel the long-latency phenotypes are present. Activation occurs as above and the long-latency relapse emerges nine months later. The initial relapse patterns associated with the two different phenotypes are identical. This illustrates the difficulty in excluding the presence of long-latency phenotypes in malaria endemic areas.
Figure 23
Figure 23
Relapse pre-empts the emergence of de-novo anti-malarial drug resistance. De-novo drug resistance is a rare event and usually there is only one mutant resistant parasite which multiplies while the sibling drug sensitive parasite population declines (green) [160]. Only a highly resistant parasites' progeny (red line) can reach transmissible densities in blood (total numbers circa 100,000,000 in the body) before the relapse (comprising drug sensitive parasites) becomes patent and the consequent illness (and any treatment effect) suppresses multiplication. Slowly eliminated anti-malarial drugs reduce this protective effect by reducing multiplication of the relapse parasites more than multiplication of the de-novo resistant parasites.
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