Malaria had disappeared in the Republic of Korea, but it has re-emerged since 1993. Until the late 1990s, it was mostly found in soldiers on active duty. However, the rate of civilians infected gradually increased, accounting for more than half of all malaria patients since 2002 [1]. In the beginning of its re-emergence, malaria occurred mostly in areas such as Paju and Yunchun, but recently it has been more prevalent in the westerm parts of Gyeonggi-do such as Ganghwa County, Gimpo, Incheon, Paju, and Goyangi [2].

Indigenous vivax malaria is not a common cause of death, but a recurrence can be caused by hypnozoites in the hepatocyte. Since most malarial medications, including chloroquine, cannot kill hypnozoites, primaquine is administered to prevent future recurrences of vivax malaria. The adequate dosage of primaquine differs depending on outbreak regions and reports [3-6].

Although a few studies targeting civilians in the Republic of Korea have been conducted since the re-emergence of malaria, most of the studies analyzed a small group of patients [7, 8]. This study is aimed at analyzing clinical features of vivax malaria and characteristics of recurred malarial patients who were treated at a hospital located in the northwestern part of Gyeonggi province where malaria is prevalent.

This study was conducted in a university-affiliated hospital located in Goyang of Gyeonggi province. Patients over 15 years old diagnosed as vivax malaria by peripheral blood smear between January 2005 and December 2009 were enrolled. We retrospectively reviewed the medical records of patients and collected information including sex, age, weight, hospitalization history, residence, date of symptom onset and diagnosis, fever pattern, previous history of malaria, whether or not patients had participated in military service, underlying diseases, results of blood test and radiology, recurrence, occurrence of complications, and administered doses and period of chloroquine and primaquine. For the recurrent cases, only the first diagnosis was included for the analysis of clinical characteristics. However, all episodes were counted for analysis of monthly and yearly distribution of vivax malaria regardless of recurrence.

Statistical analysis was processed using SAS Enterprise Guide Version 4.1 (SAS Institute Inc., Cary, North Carolina, USA). The normality of the samples was confirmed by performing a Shapiro-Wilk test. Comparisons of clinical characteristics between the first and recurrent episodes of vivax malaria in recurrent patients were performed by paired t-test for samples normally distributed and Wilcoxon signed rank test for samples not normally distributed. For all statistical analyses a P-value less than 0.05 (two-sided) was considered statistically significant.

Whereas the average incubation period of vivax malaria that occurs in tropical areas is about 2 weeks, the incubation period of vivax malaria in the Republic of Korea is known to vary from as short as 2 weeks to as long as 6-12 months [1, 9]. Most studies define May through October as the period of high risk for the occurrence of vivax malaria, with a peak in July and August [10-12]. Cases are seen even in late fall through late spring when mosquito vectors are not active, and it is assumed that such cases are attributed to a long incubation period since infection in the previous year [9-10]. In our study, most cases (94.9%, 334/352) were found between May and October with a peak in July and August, and cases were sporadically seen in late fall through late spring.

Vivax malaria seldom causes severe complications or death; however, recurrent episodes originating from hypnozoites of Plasmodium vivax occur after a certain amount of time even though parasites disappeared completely in blood. Therefore, administering chloroquine for 3 days and 15 or 30 mg of primaquine which works on hypnozoites, for 2 weeks is recommended as a standard treatment to prevent relapses of vivax malaria [1, 4, 13]. In our study, the rate of recurrence was 3.2%. Possible causes of recurrent episodes include resistance to chloroquine, recrudescence, resistance to primaquine, inadequate primaquine dose, low compliance with medication, and reinfection [14]. In the Republic of Korea, it is extremely difficult to make a distinction between recrudescence, relapse, and reinfection, since reinfection is always possible during malaria season. Additionally, there is no method to distinguish what, among recrudescence, relapse, and reinfection, causes recurrent episodes [15]. However, the time between the initial episode and a recurrent episode can be a clue to differentiate causes of recurrent episodes. In general, recrudescence, caused by failing to block the intra-erythrocyte life cycle of P. vivax, occurs within 4-5 weeks of treatment whereas relapse caused by extra-erythrocyte life cycle takes longer to occur than recrudescence [9]. If recurrence occurs after a period of 2-3 months, it is more likely to be related to primaquine administration rather than chloroquine resistance [14]. In this study, one patient after 32 days, 4 patients within 3 months, and 6 patients after 3 months of treatment respectively experienced recurrences, and all of those episodes were detected during malaria season, between May and October. Therefore, the possibility of reinfection cannot be ruled out. Chloroquine resistance has not been known to be a serious issue yet in the Republic of Korea; however, military cases that did not respond to a prophylactic dose of chloroquine have been found since 2000 and there were a few reports about chloroquine resistance to the treatment dosage [10, 16]. Moreover, some cases of early recurrence were detected in our study, and therefore, continuous monitoring of the changes in susceptibility to chloroquine is needed.

Inappropriate dosages and compliance of primaquine is reported as one of risk factors for recurrence of vivax malaria, and there are several reports to propose that the dosage of primaquine should be adjusted according to weight [4, 17]. Baird et al. reported that 26 out of 103 patients experienced recurrence when 15 mg of primaquine was administered for 14 days, whereas only 1 out of 36 experienced recurrence when 22.5 or 30 mg was administered for 14 days. Also, they recommended that a dosage of more than 0.5 mg/kg of primaquine should be administered to those who weigh more than 70 kg [4]. Schwartz et al. reported that administering subtherapeutic dose of primaquine to the obese was a cause of primaquine treatment failure, but recurrence did not occur when more than 3.5 mg/kg dose was administered. In addition, Takechi et al. reported that the rate of recurrence was high when the primaquine dose is less than 2.75 mg/kg [17, 18]. Besides age and sex, additionally in the cases where parasitemia is high at the time of diagnosis, the time elapsed from the onset of symptoms to the hospital visit is short, and that gametocyte exists at the time of hospitalization have been reported as factors related to recurrence [18-19]. Since primaquine needs to be administered for 14 days and the main symptoms of malaria, including fever, improve during this time, medication adherence can be expected to play a critical role in preventing recurrence. Takechi et al. reported that a group treated with directly-observed therapy (DOT) had lower rates of re-appearance of P. vivax by comparing with self-administration group ; 15% of the self-administration patients failed to take the medication more than once [18].

In this study, decreased platelet counts, which commonly accompanies vivax malaria, was present more significantly in the first episode in comparison with the recurrent episode (P=0.010), and the time elapsed from the onset of symptoms to treatment as malaria was significantly shorter in the recurrent episode (P=0.046). It is thought that the recurrent patients tend to visit the hospital earlier due to their previous experiences and learning from them, and malaria was also diagnosed more easily by doctors because of the patients' previous histories. Our study was not able to analyze risk factors that cause recurrence since it was not a prospective study and the number of recurrent patients was too small. However, 6 (54.6%) out of 11 recurrent patients weighed over 70 kg, and the primaquine dosage (3.01 mg/kg) administered to recurrent patients tended to be less than that of the non-recurrent group (3.39 mg/kg) even though it is not statistically significant (P=0.057). Therefore, prospective studies on larger numbers of patients examining the influence of primaquine dosage for recurrence in the Republic of Korea are needed.

Our study was conducted with the largest number of recurred patients since the reappearance of vivax malaria in the Republic of Korea. Nevertheless, there are some limitations of this study. This study was not performed as a cohort study, targeting only patients who had visited the hospital, and therefore there is a possibility that those who had visited other hospitals or public health centers for recurrent episode were excluded. In addition, considering the fact that some patients were not included in the analysis of recurrent patients even though they had had a history of vivax malaria, this study may underestimate the rate of recurrence. Although risk factors attributed to recurrence were not analyzed due to the small number of patients and the low rate of recurrence, large prospective studies should be considered to evaluate risk factors related to recurrence of vivax malaria and determine appropriate dosages of primaquine.