Determinants of relapse periodicity in Plasmodium vivax malaria

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.

Prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in southeast Iran: implications for malaria elimination

“…Therefore, the dormant liver stage of P. vivax is responsible for a large proportion of P. vivax malaria cases and is the principal disease reservoir. In a review of more than 300 studies publishedbetween 1920 and 2010 regarding P. vivax relapse rates in patients with and without radical treatment, a total of ~17,000 (19.5%) relapses were reported in over 87,000 patients with acute P. vivax malaria, and the relapse rate ranged from zero to 100% [34]. Primaquine is the only licensed medicine for the treatment of P. vivax hypnozoites [20].…”

Diagnosis and Treatment of Plasmodium vivax Malaria

“…In equatorial regions, 50-80% of patients can have a relapse starting within 3 weeks of the initial infection (if a rapidly eliminated drug is used for treatment), whereas in patients infected by temperate strains, the risk of relapse may fall to 5-20%, recurrences occurring many months after the initial infection. 78 Major impediments to defining CQ resistance and common causes of misdiagnosis of CQ resistance and susceptibility come from multiple aspects (Table 3).…”

“…78 A better indication of PQ efficacy requires comparison with a control arm in which patients receive no PQ, thus controlling for background reinfection and relapse patterns. 105,106 There have been 18 published studies with control arms.…”

Biology of Malaria Transmission

“…To abrogate transmission of P. falciparum, we must be able to clear asexual and sexual stages from the human host, eventually rendering an individual noninfectious to mosquitoes. However, in the case of P. vivax, elimination is highly challenging because of the relapse of dormant liver-stage hypnozoites that can persist as a transmission reservoir for several months after the initial infection (White 2011;Dembélé et al 2014). Lack of sufficient knowledge on the infectivity of asymptomatic and symptomatic individuals harboring transmission parasite stages remains a major gap in understanding malaria transmission.…”