The Topic of This Month Vol.28 No.1(No.323)
Malarious areas are widely distributed globally and 40% of the world's population are living in more than 100 malarious countries. Travelers from non-malarious areas including Japan to malarious areas are on the increase and an estimated 30,000 imported malaria cases are occurring annually in the whole world.
Malaria in Japan as seen from the National Epidemiological Surveillance of Infectious Diseases (NESID): Malaria represents a category IV notifiable infectious disease in compliance with the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (the Infectious Diseases Control Law) and any physician who has diagnosed malaria is obliged to notify all of these cases (see http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-04-33.html for the criteria of notification). This topic article summarizes malaria cases reported since April 1999. During the era of the previous Communicable Disease Prevention Law in Japan, the annually reported number of malaria cases used to count approximately 50-80 (see IASR 22: 23-24, 2001). In comparison with this, an increase was seen in 1999 (April-December) and 2000, but after 2001, malaria cases have decreased year after year (Fig. 1). By causative Plasmodium species, falciparum malaria cases decreased until 2003, but slightly increased in 2004-2005.
A total of 678 malaria cases diagnosed during April 1999-December 2005 were identified and analyzed by gender and age (Fig. 2). There were more male cases than female ones. By age, the largest number was seen in those aged 20-29 years followed by those aged 30-39 years for all malaria cases. For falciparum malaria, the largest number was seen in those aged 30-39 years; however, for vivax malaria, it was in those aged 20-29 years. It must be noted that these figures can be influenced significantly by the age distribution of the travelers to malarious areas, which cannot be obtained from the NESID data. Malaria cases in children under 15 years of age counted 16, of which seven were due to falciparum malaria and all of the recent seven cases were contracted in Africa.
In NESID, deaths after notification of cases are reported only voluntarily, thus not necessarily reflecting the actual number of deaths; nevertheless, nine fatal cases were identified at the time of notification during April 1999-December 2005. Of these, five cases were due to falciparum malaria and for the remaining four cases, causative Plasmodium species were reported to be gunknownh.
In Fig. 3, the malarious areas were roughly grouped into Africa, Asia, Oceania, and Middle/South America and the proportions of the causative Plasmodium species of the reported cases are shown based on the reported suspected area of infection. Of malaria cases contracted in Africa, falciparum malaria accounted for the largest number of cases. Asia and Oceania showed nearly the same tendencies; vivax malaria accounting for the largest number, followed by falciparum malaria. In Middle and South Americas, vivax malaria accounted for the majority.
Next, suspected areas of infection were analyzed by causative Plasmodium species. As for falciparum malaria, Africa accounted for 74%, followed by Asia 16% and Oceania 8%. Of the falciparum malaria cases contracted in Africa, 60% were in West Africa and 24% in East Africa. As for vivax malaria, Asia accounted for 59%, followed by Oceania 18%. Of the vivax malaria cases contracted in Asia, 60% were in Southeast Asia and 37% in South Asia. Ovale and malariae malaria cases were very few in number; Africa accounting for 84% of ovale malaria cases.
Problems involved in imported malaria and their countermeasures: Although it is well known that the risk of infection with falciparum malaria is particularly high in sub-Saharan Africa, the present survey suggests a high risk of infection also in Papua New Guinea. In addition, more cases of vivax malaria than those of falciparum malaria were contracted in Papua New Guinea. To implement effective educational measures against imported malaria, evaluation of infection risks based on the incidence rates of malaria per given number of travelers to each area/country is necessary.
In NESID, the number of malaria cases reported after 2001 is on the yearly decrease. Although mefloquine became available for chemoprophylaxis since the end of 2001, its implementation appears to be suboptimal among Japanese travelers (see p. 4 of this issue). However, it is conceivable that chemoprophylaxis is increasingly implemented among travelers at particularly high risk for malaria, thus contributing to the yearly decrease in the number of reported cases. Furthermore, under the NESID, it is impossible to detect patients with malaria who have been cured or dead in the destination countries. Thus, it is difficult to evaluate the whole problem of malaria among Japanese travelers solely based on the number of cases reported under the NESID.
Although the number of cases whose causative Plasmodium species is unknown is decreasing recently, four such cases were found in 2006 (provisional data). This suggests that the diagnosis of falciparum malaria, the most dangerous type of malaria, is missed in some cases, which poses a grave concern in selecting appropriate treatment. In fact, among the above-described fatal cases, several were due to gunknownh Plasmodium species. Medical personnel should be aware that malaria, particularly falciparum malaria, tends to become severe or even fatal if the initiation of appropriate medical management is delayed even by a brief period.
Recently, severe cases are reported not only for falciparum malaria but also for vivax malaria although less frequently. In vivax malaria, cases with reduced susceptibility to primaquine, a drug used for preventing relapse, are increasing, and cases resistant to chloroquine, a therapeutic drug for acute stages, are also emerging. Thus, the importance of vivax malaria should never be underestimated.
Only three anti-malarial drugs have been licensed for treatment in Japan. However, the Research Group on Chemotherapy of Tropical Diseases is introducing other unlicensed drugs, aimed at facilitating immediate and appropriate treatment of the patients (see http://www.ims.u-tokyo.ac.jp/didai/orphan/index.html and p. 6 of this issue). Furthermore, this research group is accepting consultations from medical personnel on the diagnosis of malaria and other tropical diseases.
It has been recognized that those who were born and grew in a malarious area and immigrated to a non-malarious area, e.g., Europe or America, are at high risk for malaria when visiting their friends and relatives (VFR) in their home country. They sometimes accompany children who were born after they immigrated (see IASR 27: 281, 2006). They may have the misconception that the immunity having acquired earlier in their country of origin is still effective, leading to negligence of necessary preventive measures and appropriate medical attention when they fall ill. Such so-called VFR travelers are hardly detected under the NESID, but malaria cases are increasingly recognized in this population during recent years in Japan, including cases in children.
Future perspectives: Among the current antimalarial drugs, artemisinin (qinghaosu) and its derivatives are more highly evaluated because of their rapid killing activity against P. falciparum (see p. 7 of this issue). In fact, combination therapies with these drugs have been introduced for controlling malaria in endemic areas, and dramatic results are being obtained in some of these areas. However, production of artemisinin and its derivatives requires cultivation of the plants. The Faculty of Pharmaceutical Sciences, Okayama University, has developed synthetic chemical compounds containing peroxide, an active site of artemisinin and its derivatives. The excellent efficacy of these compounds was shown in Plasmodium -infected mice and further, their effects in Plasmodium -infected monkeys are also being studied (see p. 9 of this issue). Recently, the Research Institute for Microbial Diseases, Osaka University, is developing a novel malaria vaccine. The Phase I clinical trial has been completed with this vaccine, showing not only satisfactory safety but also a 100% seroconversion rate. This vaccine will be subjected to the Phase II clinical trial in the near future (see p. 10 of this issue).
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