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Relapses of Plasmodium vivax Infections
Abstract & Commentary
By Lin Chen, MD
Assistant Clinical Professor, Harvard Medical School; Director Travel Resource Center, Mount Auburn Hospital, Cambridge, MA
Dr. Lin H. Chen reports no financial relationship relevant to this field of study.
Synopsis: The majority of P. vivax relapses appear to be caused by activation of hypnozoites distinct from original infections. At times, P. vivax relapses may not be effectively treated with chloroquine and primaquine, particularly tropical strains. Better ways to predict and treat relapses are needed.
Sources: Imwong M, et al. Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites. J Infect Dis 2007;195:927-933. Chen N, et al. Relapses of Plasmodium vivax infection result from clonal hypnozoites activated at predetermined intervals. J Infect Dis 2007;195:934-941.
Imwong et al collected paired blood samples from 149 patients with vivax malaria in Thailand (n=36), Myanmar (n=75), and India (n=38), and compared parasite genotypes. The investigators amplified 2 antigenic markers and their results show that the majority of recurrent infections were caused by parasites that were genetically distinct from the P. vivax that caused the acute infections.
Among the 36 patients from Thailand in whom reinfection was excluded and recrudescence was considered unlikely, 78% of P. vivax parasites causing relapses were determined to be novel populations. Among the 75 patients from Myanmar and 38 patients from India, 75% and 63% of the parasites causing the recurrent infections respectively were such novel populations. The investigators conclude that heterologous hypnozoites of P. vivax are activated to cause the first relapses of vivax malaria.
Chen et al analyzed the patterns of relapse and molecular characterization of parasites collected from 71 Australian Defense Force personnel who presented with relapses of vivax malaria after exposure in East Timor. Six patients presented with clinical malaria in East Timor and had relapses after returning to Australia, and 3 had a second relapse. Sixty-five patients had their initial vivax attack after returning to Australia, including 13 patients with 1 relapse, 5 patients with 2 relapses, and 2 patients with 3 relapses. The 71 patients had relapse after presumptive anti-relapse therapy with primaquine, and 27% experienced a second relapse after chloroquine and primaquine (30 mg daily for 14 days). Furthermore, some relapses occurred more than 300 days after returning to Australia: 17% of the patients who had malaria attacks in East Timor and 6.8% of the patients who presented with initial malaria attacks in Australia.
Investigators genotyped the parasites and a comparison of 15 paired relapse samples found that among patients with >1 relapse, 71% demonstrated clonal allelic types that differed between the relapses. The investigators concluded that the activation of a single allelic type of hypnozoite causes each relapse. A mathematical model used to test the hypothesis that the hypnozoites operated under a biological clock found the model simulation to correlate with the temporal pattern observed in the malaria attacks.
P. vivax and P. ovale are Plasmodial species that produce hypnozoites, or dormant liver stages, that can manifest themselves clinically a long time after exposure and infection. P. vivax causes >75 million infections globally every year. P. vivax infections are usually considered less severe than those caused by P. falciparum. However, many severe complications have been reported. Outside of Africa, P. vivax causes >50% of malaria infections.1 The majority of vivax cases outside of Africa (80-90%) occur in Asia, the Middle East and the Western Pacific, and only 10-15% in Latin America. Although P. falciparum is predominant cause of malaria in Africa, P. vivax may cause up to 20% of malaria cases in Ethiopia and other parts of eastern and southern Africa, and Madagascar. Among reported cases of malaria in the United States from 2001-2004, almost all in travelers, P. vivax caused about 25% and P. ovale caused 2-4%.2,3 The proportion of malaria cases caused by P. vivax increases to 63-74% in Australia (Brisbane, Melbourne)4,5,6 reflecting the frequency of travel by Australians to vivax-dominant destinations in Asia.
The current first-line malaria chemoprophylaxis agents (chloroquine, mefloquine, doxycycline, atovaquone-proguanil) are active against blood stages. Use of these agents merely delays the first clinically apparent attack of malaria parasites, but does not prevent relapses caused by P. vivax and P. ovale. Primaquine is the only available antimalarial that is effective against hypnozoites. Although atovaquone-proguanil may have some activity against the liver stage of P. vivax, it does not reliably prevent vivax malaria relapse.7,8,9 In addition, resistance of vivax malaria to chloroquine has now been well documented.10,11
The biology of vivax malaria relapse remains poorly understood. The studies by Imwong et al and Chen et al involved relatively few patients, but are important in elucidating the biology of hypnozoites. To summarize the main points: 1) Each mosquito bite probably introduces multiple sporozoites that are genetically different from each other. 2) Some parasite genotypes seem to be capable of causing both primary attacks and relapses 3) Most P. vivax relapses appear to be caused by hypnozoites that are genetically distinct from the parasites causing the initial malaria episode. 4) The hypnozoites seem to be activated on a predetermined schedule. These findings may lead to ways to predict relapses, identify parasites that may cause relapses, and inactivate hypnozoites before they cause relapses.
Chen et al also documented multiple relapses and that such relapses can occur many months or years after the initial malaria infection. Since travelers and clinicians may be less likely to consider malaria when symptoms occur long after travel, travel medicine specialists need to inform patients traveling to areas with significant risk for P. vivax to consider this possibility. Patient education material would be helpful to bring awareness to the latency of P. vivax infections.12 Finally, the relapses after presumptive anti-relapse therapy with primaquine following treatment using chloroquine and primaquine illustrate the tolerance of tropical strains of P. vivax to primaquine.