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Determinants of relapse periodicity in Plasmodium vivax malaria White White Malaria Journal 2011, 10:297 (11 October 2011) White Malaria Journal 2011, 10:297 REVIEW Open Access D
  Determinants of relapse periodicity inPlasmodium vivax malaria White White  Malaria Journal   2011,  10 :297 (11 October 2011)  REVIEW Open Access Determinants of relapse periodicity in Plasmodium vivax   malaria Nicholas J White Abstract Plasmodium vivax   is a major cause of febrile illness in endemic areas of Asia, Central and South America, and thehorn of Africa.  Plasmodium vivax   infections are characterized by relapses of malaria arising from persistent liverstages 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 intemperate regions and parts of the sub-tropics  P. vivax   infections are characterized either by a long incubation or along-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 controland elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinantof both the timing and the number of relapses. The intervals between relapses display a remarkable periodicitywhich has not been explained. Evidence is presented that the proportion of patients who have successive relapsesis relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivaxmalaria is the systemic febrile illness itself. It is proposed that in endemic areas a large proportion of thepopulation harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparummalaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologousgenotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificialinfection studies, and, by facilitating recombination between different genotypes, contributes to  P. vivax   geneticdiversity particularly in low transmission settings. Long-latency  P. vivax   phenotypes may be more widespread andmore prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination. Introduction In endemic areas of Asia, Oceania, Central and SouthAmerica, and in the horn of Africa  Plasmodium vivax malaria is a major cause of morbidity. It is an importantcontributor to early pregnancy loss and reduced birthweight which increases mortality in infancy [1,2].  Plas-modium vivax  is a sophisticated and resilient malariaparasite which was once prevalent over much of theinhabited world. It has receded from North America,Europe and Russia, but in the tropics vivax malariaremains a major cause of childhood illness. In mostendemic areas,  P. vivax  cohabits with  Plasmodium falci- parum . Mixed infections with the two species are com-mon.  P. vivax  is more difficult to control and eliminatethan  P. falciparum  because of its tendency to relapseafter resolution of the primary infection. In endemicareas relapse of vivax malaria is a major cause of malariain young children, and an important source of malariatransmission. Relapse also occurs in  Plasmodium ovale infections and in several of the simian malarias, notably   Plasmodium cynomolgi , which has often been used as ananimal model of vivax malaria. The factors which con-trol relapse and determine their remarkable periodicity are not known. History The history of clinical research on vivax malaria con-tains a wealth of valuable information that is not widely known or recognised. Most studies were conducted overfifty years ago and are not readily accessible to the mod-ern reader. Indeed more may have been forgotten thanhas been learned about vivax malaria in recent years.The tendency of malaria infections to recur was well Correspondence: nickw@tropmedres.acMahidol Oxford Tropical Medicine Research Unit, Faculty of TropicalMedicine, Mahidol University, 420/6 Rajvithi Rd, Bangkok, 10400, Thailand White  Malaria Journal   2011,  10 :297 © 2011 White; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (, which permits unrestricted use, distribution, and reproduction inany medium, provided the srcinal work is properly cited.  known since Roman times. From the 1630s onwards aspecific treatment (Cinchona bark) was available foragues (although for most of those infected it was unaf-fordable). This treatment was often followed by frequentrelapses of the periodic fever, and so opinions differedwidely on its efficacy. Following Laveran ’ s discovery of the blood parasite that caused malaria in 1880 [3],understanding of malaria epidemiology, pathology, andtreatment was placed on a rational basis. In 1885, Golgiin Pavia distinguished the parasites responsible for ter-tian and quartan fevers [4]. In 1890,  P. vivax  was identi-fied as a separate species by Grassi and Feletti [5],although debate continued into the early 1920s as towhether there were indeed separate human malaria spe-cies, or just one single polymorphic species [6]. Studiesof the time often tended to consider the responses of the benign (vivax) and malignant (falciparum) tertianmalarias together. The Dutch physician Pel is generally credited with the first postulation of an exoerythrocyticstage of malaria in 1886 [7]. In 1897, the American phy-sician WS Thayer gave a very clear description of along-latency relapse of malaria 21 months after theinitial attack in a physician who had probably not beenre-exposed between the two events [8]. Thayer andBignami (in Italy) [9] both surmised that relapses of malaria resulted from a  “ spore ”  deposited in the internal viscera which remained inert  “ only to be set free as aresult of some insult, the nature of which is still notappreciable to us ”  [8]. Self-experimentation then pro- vided remarkably accurate descriptions of long latenciesin vivax malaria. In 1900 in London Sir Patrick Mansonwas investigating the mosquito transmission theory pro-posed by his protégé Ronald Ross. Upon requestBignami and Bastianelli kindly provided him with  P.vivax  infected anopheline mosquitoes that had been fedon malaria patients in the Ospedale Spirito Santo inRome. The mosquitoes were taken to the BritishEmbassy in Rome, and thereafter by the  “ Indian mail ” ,and duly arrived in London 48 hours later. His sonPatrick Thorburn Manson, and George Warren (alaboratory technician) both volunteered to be bitten.Acute attacks of malaria followed after a two-week incu-bation period, in September 1900. These were treatedsuccessfully with quinine [10]. On June 1st the following year, after a latent period of nine months, the youngerManson experienced a sudden onset of rigors. Relapseof his vivax malaria was confirmed by microscopy [11].Meanwhile in India, at the end of 1900, Major CFFearnside infected himself with mosquitoes which hadfed on vivax malaria patients in the Madras jail. His pri-mary attack of malaria began on January 14th, he suf-fered a relapse on March 11 1901, and a second relapsefollowed on November 11th apparently without the pos-sibility of interim reinfection [12]. These preciseobservations describing latencies of some eight to ninemonths were complemented by Korteweg ’ s detailed andpainstaking prospective epidemiological observationsover more than two decades in the village of Wormev-eer in The Netherlands. Celli had long surmised thatthe spring wave of benign tertian (  P. vivax ) malaria inNorthern Italy resulted from relapse [13,14] but it was Korteweg who provided convincing evidence that the vivax malaria which emerged in the early summer hadbeen acquired in the autumn of the previous year[15-19] (Figure 1). The considerable vivax malaria experience of the First World War (in the Balkans,Mesopotamia, and the Jordan valley), the secondary cases in England which followed the year after thereturn of infected soldiers, studies in American soldiersserving in Panama and the Philippines, studies in Britishsoldiers serving in India, studies in Japanese soldierswho had invaded China, and further epidemiologicalobservations and individual case reports in Europe andthe United States all pointed to a disease which couldrelapse within two months of stopping quinine treat-ment, but also tended to relapse some eight to tenmonths later (Figure 2). Until the 1920s it was commonto recommend an eight-week course of quinine treat-ment for malaria [20]. Despite this protracted treatmentrelapses were common, but whether these resulted frompersistence of the blood stage infection (i.e. recrudes-cence), or derived from a latent tissue stage wasunresolved. Early observations on relapse In 1913, Bignami proposed that relapses of malaria allderived from persistence of small numbers of parasitesin the blood [21]. Although this theory explained thelate recurrences of   Plasmodium malariae  infections inman, it did not explain several features of   P. vivax  and  P. ovale  infections. A much clearer understanding of relapse in  P. vivax  malaria was to come from JuliusWagner-Jauregg ’ s discovery that malaria could cure neu-rosyphilis. Between the 1920s and the 1950s thousandsof patients confined in mental hospitals with neurosy-philis were treated with malaria (malaria therapy). Gen-eral paralysis of the insane was then a uniformly lethalcondition, and at least half the malaria therapy treatedpatents were improved and over one fifth were cured. Itwas a remarkable period, unique in the history of medi-cine, when, as Henry Dale put it,  “ Man was the experi-mental animal ” . The majority of the malaria therapy experience was with a relatively small number of para-site  “ strains ”  transmitted either by blood passage, ormore usually by the bites of several infected anophelinemosquitoes. On the 8th September 1922 Professor War-rington Yorke and JWS MacFie inoculated blood from apatient with simple tertian malaria (  P. vivax) , which had White  Malaria Journal   2011,  10 :297 2 of 35  been acquired in India, into a patient with neurosyphilisat the Whittingham Mental Hospital near Liverpool[22,23]. This  “ strain ”  was then used to infect multiplepatients initially by blood passage, and later by mosquitotransmitted infections. It soon became apparent thatrecurrences of   P. vivax  (and  P.ovale ) malaria followed adifferent temporal pattern to those of   P. falciparum [24-26]. Recurrences of vivax malaria commonly  occurred many months after apparently successful treat-ment of the primary infection. Furthermore whereasrecurrence in blood transmitted vivax malaria could beprevented by curing the blood stage infection, recur-rence in mosquito transmitted vivax malaria could notbe [17,22-24]. This pointed to an exoerythrocytic stage of malaria, but its anatomical location remained elusive.The Dutch malariologists were able to show that theirindigenous  P. vivax  could have a short incubation per-iod if patients were bitten by a large number of infectedmosquitoes, but, in a further example of courageousself-experimentation, they proved that bites by one ortwo infected mosquito were followed by vivax malaria 8to 9 months later [26,27] (Figure 3). The Northern Eur- opean and Russian  “ strains ”  of   P. vivax  therefore provedunsatisfactory for malaria therapy because blood passagewas required to ensure an acute illness within weeks[17,20,22-29] whereas mosquito infection, even with multiple infected anophelines, often failed to produce anearly febrile illness. Importantly it was also noted in TheNetherlands that relapse rates in naturally acquiredinfections were higher than with mosquito-transmittedmalaria therapy with local  “ strains ”  [17]. The mostwidely used parasite used for malaria therapy in Europe Malaria   casesMonth 0201510525 Luxemburger   et   al   Trans   R   Soc   Trop   M1996;   90 :   105  11    A.atroparvus Delayed   primaryillnessRelapse   and   early   primary   illness J F M NM A O DSAJ J Figure 1  Long-latency  P. vivax   in the Netherlands; The mean monthly number of malaria cases in the village of Wormerveer, TheNetherlands, 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 casesderived from inoculations the previous year (pink curve) and, by subtraction, that this was followed by relapses and primary cases with a shortincubation period in the late summer and autumn (blue curve) [19]. White  Malaria Journal   2011,  10 :297 3 of 35
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