Malaria, typhoid fever, dengue fever, hepatitis A are representative infectious diseases that should be taken into consideration when examining patients developing fever on returning to Japan after traveling to tropical and subtropical areas. Amid those diseases, falciparum malaria is an important disease that may become lethal if it is missed out. Therefore early diagnosis and treatment are capital. ((We advise people who traveled to malaria endemic regions to go immediately to a hospital in case they develop fever of 38~39 C. Indeed individuals with no history of malaria will run high-grade fever at high rate in case they contract malaria.)
  The number of imported malaria cases in Japan was reportedly 103~132 per year during eleven years from 1990 to 2000 (reference document 1). The number of malaria cases treated in the Research Hospital of Medical Science of the University of Tokyo (called "our hospital" in the following) during ten years from 1992 to 2001, practically the same time frame, was 170 (153 subjects, without 17 cases of recrudescence and relapse of malaria). This corresponds to 15% of the total cases in Japan. Since the trends of the malaria patients of our hospital likely reflect the trends of imported malaria throughout Japan in the species of protozoan, area of infection, purpose of traveling that led to the infection , method of treatment, etc., we will introduce the results of our survey based on medical records(reference document 2).
Current status of imported malaria cases that emerged from the survey based on medical records in our hospital
  The ratio taken up by fatal falciparum malaria among the four species of imported malaria showed slightly increasing during the ten years of our survey (however, this increase is not statistically significant.). The ratio averages 52.3%. This figure is lower than the percentage found in European countries (about 80% for France, and 60% for England), and higher than that noted in the United States (approximately 40%). The high frequency of falciparum malaria in the European countries is apparently due to the high risk of infection for immigrants of African origin returning to their homes on the African continent where falciparum malaria is highly endemic in order to visit friends and relatives.
  Classed by assumed area of infection, 74.4% of the patients contracting the infection in Africa were cases of falciparum malaria, while vivax malaria was the primary plasmodium species in the other regions (Figure 1). One may also see from the figure that almost half of all the malaria cases were contracted in Africa.
  Classed by purpose of travel, the rate of infection of individuals traveling for business was as high as, 70%. This ratio has remained roughly flat throughout the ten years of our survey. The rate of infection of people traveling for sightseeing (28%) did not rise contrarily to our predictions. The assumed reason is that whereas many tourists stay in safe urban areas for only a short period, people traveling for their work tend to remain a long time in high risk regions. Although it needs further investigation, the number of malaria cases imported into Japan may be reduced by thoroughly implementing measures to prevent people staying in foreign countries for business from becoming infected with malaria.
  As far as the treatment of falciparum malaria is concerned, mefloquine was used in 82.5% of the cases, while atovaquone/proguanil compound (malarone) and artesunate were also administered to some patients. Chloroquine was often used for the other forms of malaria. The mortality rate for falciparum malaria in our hospital was fortunately zero during these ten years. The mortality rate for falciparum malaria for all the cases in Japan is estimated to be 3%. The fatal case is presumably due to the unfavorable prognosis for patients because of the delay in getting a definitive diagnosis after contracting the disease. The time elapsed from the onset of malaria in all the subjects treated in our hospital to the examination in medical institutions was 4.7 days on average and the median was 3.0 days (25 percentile 2.0 days, 75 percentile 5.0 days). The difference between the average and the median is due to patients who finally consulted a medical institution after one week or more elapsed. (Considering the aggravation of the symptoms of falciparum malaria, the time up to the examination should be shortened. As we mentioned earlier, "we advise people who traveled to malaria endemic regions to go immediately to a hospital in case they develop a fever of 38\39 C.")
  Amid 36 patients who received primaquine for the prevention of relapse after treatment of vivax malaria with chloroquine, eight eventually relapsed despite these preventative measures. Six of them had been infected in Oceania (of whom five had been to Papua New Guinea). The current administration dose of primaquine for the prevention of relapse was reportedly decided based upon the experience of the US Army during the Korean War. Our impression is that the dose is insufficient for the treatment of the tissue form in the Oceanian region.
Recent trends particularly regarding treatment and prevention
  We have introduced above the current status regarding the cases of imported malaria from 1992 to 2001 treated in our hospital. The incidence of imported malaria is seemingly decreasing all over Japan, since the number of travelers taking mefloquine for the prevention of malaria has increased following its approval in Japan in 2001.
  Mefloquine is also generally employed for the treatment of falciparum malaria. However, its resistance to falciparum malaria in the border areas of Thailand-Myanmar and Thailand-Cambodia has been pointed out, and precautions are now required. Besides quinine intravenous drip has been conventionally used in falciparum malaria cases requiring emergency measures due to symptom aggravation. However, the administration of rapid-acting artemisinin derivatives (artesunate suppositories and injectable medications) has also been recommended in recent years. Similarly a combination of artemether, an artemisinin derivative, with long-acting lumefantrine is now employed for the treatment. Since all the therapeutic agents mentioned here except for mefloquine are stored by the Orphan Drug Research Team (Tropical Disease Drug Research Team), information is available by consulting their homepage, http:www.ims.u-tokyo.ac.jp/didai/orphan/index.html.
  Whatever the case may be, an early accurate diagnosis and treatment initiation are most important (notably in case of falciparum malaria). When no elevation in the leukocyte count and a decrease in cholesterol are observed despite a decrease in blood platelets and CRP elevation in patients with high-grade fever after returning from endemic regions, malaria should be strongly suspected. Blood smear specimens should be prepared, and the presence of plasmodium in the erythrocytes should be checked.
  We will conclude with additional remarks on the chemoprophylaxis of malaria. Available in general medical facilities since October 2001, mefloquine has been prescribed in our hospital to about 25 subjects a year. However, this agent tends to elicit psychoneurotic adverse reactions. A survey of the individuals who took this medication in our hospital showed that at least 30% of them developed dizziness and nausea, and less than 20% experienced nightmares and headache (reference document 3). Some of these subjects had to postpone their travel due to adverse reactions. These adverse reactions seem to be the most potent during the first administration (during the initial elevation of blood concentration). We recommend the initiation of prophylactic medication (one tablet weekly) two to three weeks before traveling if possible, so that traveling will not be made uncomfortable due to adverse reactions. We think that it would be desirable to have access to new anti-malaria drugs in Japan in the future. (The drugs stored by the abovementioned Orphan Drug Research Team are all for treatment and they are not prescribed for prophylaxis.)
Reference literature