Introduction
  Leishmaniasis is a protozoal parasitic disease transmitted by a tiny blood-sucking insect roughly one-third the size of a mosquito and called phlebotomine sandfly. As sandflies feeding on human blood do not inhabit Japan, no outbreaks will immediately occur any even though pathogenic insects might be brought into the country as imported cases. However, co-infection by Leishmania and HIV/AIDS, which has been occurring primarily in Spain since the early 1980s, is spreading among intravenous drug addicts all over the world. Since it is a directly transmitted infection from person to person via the sharing of needles without necessitating the presence of sandflies, similar cases may possibly occur in Japan too in the future. American soldiers stationed in leishmaniasis endemic areas in Iraq (a country on which the world's attention is currently focused) have been bitten by infected sandflies and many patients have been reported. Therefore, there is also a risk of infection among the Japanese Self-Defense forces present in Iraq. Leishmaniasis is a typical zoonotic infectious disease. The transmission cycle continues between wild animals and sandflies in the natural world. Therefore, outbreaks occur when humans penetrate this transmission cycle for some reason, such as wars, construction of dams or roads, plantations, and the like. On the other hand, the geographic coverage of areas endemic for this disease is increasing due to various factors such as the migration of persons and animals on a global scale following internationalization, weather fluctuations, etc. Hunting dogs imported in 2000~2002 were infected by Leishmania in the suburbs of New York. Since was found that sandflies were found in this same region in 2004, there is a risk of infection not only for dogs but also for humans. In this article, we will briefly introduce the current status of leishmaniasis, the control measures and recent topics.
Description of Leishmania and sandfly vectors
  The Leishmania belongs to the family of Tripanosomatidae, order of Kinetoplastida. During its history life, this protozoan has two forms, namely the amastigote form during the period it has no flagellae, and the promastigote form during the period it has long flagellae. The former lives inside the reticuloendothelial cells of humans and mammals, particularly in macrophages, while the latter multiply extracellularly inside the gut of sandfly vectors. The multiplication pattern is binary fission for both forms. There exist approximately twenty currently known species of Leishmania pathogenic for humans. These protozoa elicit various clinical symptoms depending upon the species, the host (patient) immunity or the physiological difference. The causative agent is the protozoa of subspecies Leishmania in the Old World, whereas two subgenera, Leishmania (Leishmania) and Leishmania (Viannia) Leishmania, are involved in the New World. Generally, the species of the New World are not distributed in the Old World. Over 500 species of sandflies are known in the world, of which no less than 70 feed on human blood. Furthermore, there exist approximately thirty species transmitting human parasitic protozoa. These sandfly vectors belong to genus Phlebotomus in the Old World and to genus Lutzomyia in the New World.
Route of infection and forms of the disease (clinical symptoms)
  The infection caused by the Leishmania begins when promastigote penetrate into the human body for sucking the blood meal. As mentioned earlier, leishmaniasis is a typical zoonosis. In endemic regions, in addition to humans, domesticated animals and wild animals play the role of reservoir hosts (infection source). Therefore in must endemic areas, sandflies ingest protozoa together with blood when they suck the blood of carrier hosts. Then the infection (zoonotic infection) occurs through to humans by sandfly blood-sucking activity. However, in certain endemic regions, the carrier are not present and person-to-person infection transmitted via sandflies (anthroponotic infection) is observed. In addition, in co-infection of HIV/AIDS and Leishmania as mentioned above, direct infection occurs from person to person through shared needles. Leishmaniasis presents various pathological forms, and it is grossly divided into the visceral type and the cutaneous type. These disease forms may be further classified into six types. We will introduce them in the following.
1) Visceral leishmaniasis (visceral type): it is the most serious form with a lethality of 90% and more if it is left untreated. The pathogens are L. (L.) donovani and L.(L.) infantum (=L (L.) chagasi). This Pathological form is also called kala-azar (black fever) or Dum-Dum fever. It is characterized by splenomegaly, enlarged liver, enlarged lymph nodes, leucopenia-thrombocytopenia, hypergammaglobulinemia, intermittent fever, etc.
2) Cutaneous leishmaniasis (cutaneous type): single or multiple (sometimes several hundreds) ulcerous and nodular lesions are observed. This form is mainly caused by L.(L.) tropica and L. (L.) major in Asia and the African regions of the Old World. In the New World, this dermal form is observed in a wide area ranging from southern Texas in the United States to northern Argentina. Many types of pathogens are involved; they belong to the L. (L.) mexicana complex and to the L. (V.) braziliensis complex.
3) Mucocutaneous leishmaniasis (mucosal dermal type): the pathogens are mainly L. (V.) braziliensis in the New World and L. (L.) aethiopica in the Old World. In this form, in general after the lesions of the cutaneous type have clinically healed several years to over ten years (on average around six years), the nasal mucosa and the oral cavity mucous tissues are damaged, and nasal septum deficiency and lip deficiency, invasion and destruction of the tissues of the pharynx and larynx region and allophasis occur. There are also cases of death following a secondary infection.
4) Diffuse cutaneous leishmaniasis (diffuse dermal type): in this pathological form, leprosy tubercle-like lesions spread all over the body. The patients have a specific anergy to Leishmania antigen and they develop resistance to the currently available drugs. The pathogens are L. (L.) mexicana and L. (L.) amazonensis in the New World. The subgenus Viannia is not involved. In the Old World, notably in Africa, L. (L.) aethiopica is the pathogen.
5) Disseminated cutaneous leishmaniasis (disseminated dermal type): since ulcerous lesions spread all over the body in this pathological form, it is oftentimes confused with the diffuse dermal type. However, the nodular lesions never turn into ulcers in case of the latter. Besides the former (disseminated dermal type) responds well to antimony compounds, whereas the latter develops resistance.
6) Kala-azar cutaneous leishmaniasis (kala-azar cutaneous type): this type consists of nodular lesions appearing due to incomplete treatment or other reasons, after the visceral type has clinically healed. This form also tends to be confused with the diffuse dermal type. Since an extremely high number of protozoa are present in the focal region, the patients play the role of infection source (reservoir hosts) in endemic areas. For this reason, this pathological form should be also taken into account in terms of prevention measures. A form of this disease that does not go through the clinical healing of the visceral type has been observed with interest in Sudan (Africa) in recent years.
Epidemiology
  Leishmaniasis is one of the diseases targeted by the World Health Organization (WHO) (malaria, leishmaniasis, trypanosomiasis, filariasis, schistomiasis, Hansen's disease, Dengue fever, tuberculosis). There are 12 million infected persons in 88 countries on four continents (Asia, Africa, Central and South America, southern Europe). The annual number of patients is 500,000 for the visceral form and 1~1.5 million for the cutaneous form. The number of fatalities is approximately 60,000 per year. Three hundred and fifty million people on the globe are at risk for infection. In case of the visceral form, over 90% of the patients are cases originating from India, Bangladesh, Nepal, Sudan and Brazil. The visceral form is frequent notably in India, Bangladesh and Nepal, and 60% of the world's cases are observed in those countries. In case of the cutaneous form, over 90% of the patients are found in Iran, Afghanistan, Syria, Saudi Arabia, Brazil, Peru and Pakistan. Amongst those countries, endemic regions that draw the attention in particular are Afghanistan and Pakistan for the cutaneous form. In Kabul, the capital of Afghanistan, 2.7% of the population of approximately 2.5 million people are infected by the cutaneous form, and an NGO of Holland is in charge of the control measures. On the other hand, in Pakistan, infections caused by refugees from Afghanistan and by the migration of seasonal workers from the north have been spreading in recent years, in addition to the regions usually endemic for the visceral and cutaneous forms in the north-western region of the country. For this reason, the authors also launched a fact-finding survey and control measures several years ago. In the province of Shind where the Mohenjo Daro archaeological site is located, there were around 300 cases of cutaneous type in 2001, whereas, the number of cases was only a little more than a dozen in 1996.
  There are various factors for outbreaks, such as large displacements of people in search for food, clothing and shelter due to the confusion caused by war and internal conflicts, urbanization, deforestation, irrigation projects and changes in the raining pattern due to weather anomalies. Other factors that have been pointed out include opportunistic infections of the hosts (patients), such as HIV infection, malnutrition and genetic factors. Co-infection with leishmania is spreading in Africa where HIV/AIDS infection has become a problem all over the continent. In addition, since HIV and the protozoa are distributed locally in the same places in that area, there is a risk for large-scale co-infection outbreaks. On the other hand, on a global scale, with the addition of human-induced factors to those linked with the natural environment, infections are also spreading to areas so far considered non-endemic for leishmaniasis. As mentioned in the above, hunting dogs imported for fox hunting have been infected with the visceral-type pathogen L. (L.) infantum in New York suburbs, and human outbreaks have been reported. Also US troops stationed in Iraq have been infected with this disease, and view of the much-feared so-called "Baghdad boil", there is an urgent need for control measures in camps and other locations. Should these soldiers bring back infected dogs from Iraq to their country in future, the same situation that happened in New York suburbs might occur. The other countries having troops deployed in Iraq may be in a similar position.
  Incidentally leishmaniasis is a parasitic disease unfamiliar in Japan. However, before and after World War II, from 1936 through the 1950s, over 400 cases of visceral type leishmaniasis (kara-azar) were reported primarily amid persons who returned to Japan after contracting the infection abroad. Many of the infected persons were returnees from China. On the other hand, patients with the cutaneous form and the mucocutaneous form were primarily Brazilian immigrants and returnees including second-generation individuals. In case of the mucocutaneous form, many individuals had contracted the disease upon returning to Japan after being infected locally with the cutaneous form and healing clinically. Several cases have been reported annually in recent years amidst people who worked in the Near and Middle East countries and travelers to those areas.
  We will introduce here a shocking Kara-azar case that occurred over ten years ago. A Japanese female patient was diagnosed as malignant lymphoma in the United States. That person underwent a splenectomy and was given steroids. She was born in the US and raised in Japan. She returned to the US at the age of fifteen. After going to India for research when she was 28 years old and staying there for two and a half years, she went back to the US. A short while after, she ran a high grade fever hovering around 40Ž, and she was admitted to the Boston Medical Care Center. Since the patient had a history of tuberculosis, she was diagnosed with relapse and treated with antituberculous agents. Nonetheless since her condition did not improve, she underwent a biopsy of the liver and a puncture of the bone marrow. As a result, she was suspected of having malignant lymphoma. After a splenectomy and a treatment with Predonisone, the fever abated and her pancytopenia improved and she was discharged from the hospital. Afterward the patient returned to Japan and was examined in a certain university-affiliated hospital located in Tokyo. Protozoa were detected in her bone marrow puncture fluid and she was diagnosed with kara-azar. She healed completely after the administration of antimonial drugs. This case suggests that it is necessary to permanently be alert to tropical diseases including leishmaniasis even in industrialized countries such as the United States, Japan, etc.
Treatment
  Antimony compounds such as Glucantime and Pentostam have been used as first-choice drugs for fifty years for all forms of leishmaniasis. However, since these agents have to be injected intramuscularly or intravenously and elicit strong adverse reactions, they are not appropriate for treatment in endemic regions and countries where medical care facilities are inadequate. Besides due to the emergence of drug resistance, second-choice drugs with even stronger adverse reactions (Amphotericin B, etc.) have to be used in certain regions. Therefore expectations are pinned on the development of easy-to-use and effective drugs. Recently an oral drug called Miltefosine has finally become available, and extensive studies centered around the WHO are ongoing in India and in other areas. This drug is originally an alkyl-phospholipid compound developed for the treatment of metastatic skin cancer. Though it shows a remarkable response to the visceral form, its efficacy in the cutaneous form and the mucocutaneous form varies with the species of pathogen and the endemic region (country). Besides since the half-live of Miltefosine is long and since it has to be administered orally for a long course of treatment, there will be sooner or later a risk of emergence of resistant strains. Since its adverse reactions are strong, the development of a new oral agent is awaited. Incidentally therapy associating first and second choice drugs with INF and IL-2 is being tried, but its use in endemic regions poses problems due to its cost and other reasons. In addition of treatment with perilesional injection of antimony compounds, the antifungal agents Ketoconazole, Itraconazole, Fluconazole, etc. in the form of liniments and oral drugs are also used for the cutaneous form.
Prevention and control measures
  Various control measures are being considered as is the case with other insect-borne diseases, such as malaria, etc. The major actions concern the vectors, the reservoir hosts and animals (source of infection) and the improvement of the environment. However, these measures are only implemented sporadically, and unfortunately no effective and efficient method has been found yet. Besides, the control measures differ with the form of the disease and the mode of transmission in each endemic region (forests, urban areas, proximity of human habitations, etc.) or with the mode of infection (zoonotic infection or anthroponotic infection). With the simple cutaneous form, the lesions heal in many cases spontaneously within several months to several years, leaving specific permanent scars, and lifelong immunity is acquired. A procedure called "leishmanization" was used many years ago in the southern regions of the former Soviet Union. In these cases, the viable protozoa were inoculated into the buttocks in order to avoid the formation of scars on the face and on other exposed regions of the body. This live vaccine was inoculated to several millions of soldiers and civilians during the Iran-Iraq war in the 1990s. However, no practical vaccine has been so far developed for parasitic ailments including malaria. In case of leishmaniasis, a practical vaccine could be launched very rapidly before other parasitic diseases, since an extremely strong protective immunity is acquired. In recent years, immunotherapy in which BCG, alum and other adjuvants are added to leishmania antigen is being studied primarily by the WHO, and a certain level of efficacy has been obtained. As regards the control measures addressed to the vectors, the point is to avoid sandfly's sucking blood meals through the utilization of insect repellents and insecticides, as in case of other insect-borne diseases. Trials on the usage of insecticide-impregnated mosquito nets, a measure implemented to control malaria, are also underway. However, it is not easy to thoroughly implement the usage of mosquito nets in tropical and subtropical highly hot and humid areas. Control measures are extremely difficult in case of leishmaniasis, since the reservoir hosts are domesticated animals and numerous species of wild animals. For this reason, the WHO has classified this disease as an infection belonging to Category One in which the control measures are the most difficult. The control of the vectors and of the reservoir hosts is next to impossible except in certain endemic regions in the proximity of human habitations.
Conclusion
  Leishmaniasis is a disease with multiple forms and involving numerous species of pathogens, sandfly vectors and reservoir animals. Its mode of transmission is also complex. It may be divided into the forest type, rural area type and urban area type, and it can be classed further into indoor type, human habitation proximity type and work site proximity type. Of these types, the forest type is the most difficult and the urban community type is comparatively easy in terms of preventive measures. However, in fact no effective control method addressed to the eradication of this disease has been initiated. In addition many problems need to be solved in the area of patient treatment, such as the drug resistance and adverse reactions. However, the good news is that in a patient with leishmaniasis, a strong protective immunity, namely a "non-recidive" phenomenon, was found. This suggests the possibility that an effective immunotherapy and/or vaccine will be available in the near future. In recent years, there have been expectations also on the development of a vaccine based upon a rapidly advancing new concept featuring the utilization of a substance originating from the salivary glands of insect vectors, a method using a molecular biology technique. One must say that the eradication of many parasitic diseases endemic in remote tropical regions will be extremely difficult without the advent of an effective vaccine, since medical care facilities are inadequate. On the other hand, the development of easy-to-use, efficacious and low-priced oral drugs and the implementation of measures for the control of the vectors and the reservoir hosts from a new perspective better adapted to each endemic region should be studied as rapidly as possible.