The Topic of This Month Vol.22 No.1(No.251)
Hansen's disease, known as leprosy for centuries, is one of infectious diseases caused by an acid-fast bacterium, Mycobacterium leprae , which has not been cultured yet and is grown by inoculation into the footpads of nude mice. Neither subtype nor toxin production of M. leprae has been recognized. Roughly until 1955, when anti-leprosy drugs became available, leprosy patients used to develop deformities of appearances and extremities, and thereby suffered from prejudice and discrimination. Even nowadays, this line of hostility can still be seen.
The infection and classification of leprosy: Human infection occurs in youth when M. leprae is inhaled through the respiratory tract upon exposure to leprosy patients discharging a large number of bacilli. Symptoms may appear after an incubation period of several to ten-odd years. It is common to develop the disease in aged persons after incubation for presumably more than 20 years.
The types of leprosy differ from patient to patient depending on the specific immunity to M. leprae. The primary stage is called group I (indeterminate leprosy), followed by progress toward completion of the leprosy figures. The advanced forms can be classified into type TT (tuberculoid leprosy) with high cell-mediated immunity specific to M. leprae , type LL (lepromatous leprosy) with markedly deficient immunity, and group B (borderline leprosy) in-between. Group B can be subdivided into types BT, BL and BB. The disease is also classified into paucibacillary (PB) and multibacillary (MB) types according to the amount of the organisms in the body; this classification can be utilized for selecting the therapeutic methods. Type TT from which M. leprae is hardly detectable and type LL with abundant bacilli are classified into types PB and MB, respectively.
Legislation of leprosy: In Japan, the Law Concerning the Prevention of Leprosy was promulgated in 1907 followed by several amendments. The Leprosy Prevention Law was enacted in 1953, and leprosy patients have been subjected to treatments principally at leprosaria. Following the Leprosy Prevention Law, the leprosarium director was given the authority to keep order of the residents and to limit outing of infectious patients. When a physician diagnosed leprosy with a risk of transmission, the patient would mandatory be sent to a leprosarium. Most of patients stayed there for life. Because of negligible infectivity and availability of adequate treatments nowadays in Japan, the Leprosy Prevention Law was repealed in 1996 and the term leprosy was replaced by Hansen's disease. Newly-detected patients are now treated at general clinics and hospitals. Since medical care used to be limited to the leprosaria for many years, the staffs of general clinics and hospitals are not yet conformable with the handling of leprosy patients. To the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (the Infectious Diseases Control Law) enacted in 1999, given is a preamble, "realizing the seriousness of the resulting discrimination and prejudice against leprosy patients and other infectious diseases such as acquired immunodeficiency syndrome so far in Japan, we must not forget these misdirections in future". Due to the opinion of leprosarium residents and others, leprosy is not targeted for the National Epidemiological Surveillance of Infectious Diseases under the Infectious Diseases Control Law. The Japanese Leprosy Association is playing a main role in the surveillance of new leprosy patients.
Leprosy patients in Japan: About 30,000 leprosy cases were reported in 1900, which decreased to about 16,000 by 1919. From roughly 1955, due to the improvement of public health and appearance of remedies, new patients decreased rapidly. Recently, there are less than 10 new patients per year (Fig. 1), and in Okinawa Prefecture where there used to be a large number of patients, the decrease has been conspicuous. On the other hand, non-Japanese patients (imported cases) have been on the increase since roughly 1991, counting about 10 patients per year. The greater part of new Japanese patients are elderly (aged over 60 years) (Fig. 2). It is, therefore, anticipated that there will be no leprosy patients among Japanese in near future. Non-Japanese patients, however, appear among a large number of employees aged 20s - 30s from Brazil and the Philippines where leprosy is still endemic. In the nationwide 15 leprosaria, about 4,500 patients (average age 74 years) are still accommodated. Most of them are recovered but keep on staying there because of sequelae and age. Nowadays, patients may recover generally within a half to a few years, nevertheless more than 700 patients (former residents and outpatients) visit medical institutions for follow-up cares of relapses or sequelae as shown in Table 1.
Diagnosis of leprosy: Leprosy is diagnosed by all accounts of observations of skin lesions, peripheral neuropathy, microscopic detection of the organism, and histopathological findings.
The organisms are detected by (1) the skin smear test (tissue fluid taken by pricking the skin is smeared on a glass slide, subjected to acid-fast staining and examined under a microscope with oil immersion at a x1,000 magnifying power, at every institution), (2) skin and nerve are acid-fast stained to detect the organisms (at every institution), and (3) detection of genes specific to M. leprae by PCR (skin and blood) (practiced at the institutions described below). In case M. leprae is positive by skin smear or biopsy, leprosy will be diagnosed easily by taken the skin/nerve findings into account. If both are negative, diagnosis will be made by all accounts of the skin/nerve/histopathological findings with reference to the results of PCR (since PCR is affected by the sample condition and involves false positive or negative problems, the results are defined as merely "reference data" at present). M. leprae detections are shown in Table 2. For histopathological tests, in addition to HE staining and highly sensitive modified Ziehl-Neelsen staining, S100 and PGL-I immuno-stainings (PGL-I is an antigen specific to M. leprae ) will be performed. In addition, tests for serum anti-PGL-I antibody are used for auxiliary diagnosis and assessing the therapeutic effects. The lepromin test is no longer in use.
Since there are only limited leprosy patients in Japan, special tests (histopathology, PCR, and anti-PGL-I antibody tests) are performed only at the Leprosy Research Center, the National Institute of Infectious Diseases, the Department of Dermatology, Yokohama City University, and the Department of Dermatology, Ryukyu University.
Therapy of leprosy: The multidrug therapy (MDT) has been recommended by WHO; rifampin (RFP), dapsone (DDS), and clofazimine (CLF) are administered orally for half a year (PB cases) or a year (MB cases), respectively. In Japan, MDT has been modified by adding other drugs or prolonging the medication period.
Network for leprosy diagnoses and cares: There is a network for advising physicians and medical personnel who have had little chance to diagnose and treat leprosy on medical care, examination, and therapy. Physicians belonging to the Japanese Leprosy Association and having enough experiences in handling leprosy patients are registered.
Global situation: Owing to MDT pursued by WHO, more than 10 million leprosy patients worldwide were cured from 1985 to the end of 1999. The registered cases decreased to 750,000 by early 2000 and the prevalence was 1.25 per 10,000 population, which is an 86% reduction from 1985. After treatment for 6 months in PB cases and for one year in MB cases, they are regarded as cured and withdrawn from the WHO registration (see WHO Expert Committee on Leprosy 7th Report, 1998 for the diagnostic criteria in the WHO surveillance). The relapse rate is about 0.1% per year. Only few MDT-resistant cases have been found. Physical disability may be seen after peripheral nervous impairment (two to three million cases), and many have difficulty returning to and attaining social lives. In spite of the promotion of MDT by WHO, as many as 700,000 new patients are still registered every year, and that is presumably due to improved diagnosis and enhanced surveillance for many new cases including ones overlooked in the past. The countries with many yearly registered new leprosy patients are; India (about 527,000), Brazil (about 73,000), Indonesia (about 29,000), Bangladesh, Myanmar, Nepal, Nigeria (about 13,000 each), the Philippines (about 9,000), etc (see WHO, WER 75:226-231 and 361-368).
Future problems: The best methods to cure leprosy without leaving any sequela are early diagnosis and treatment. For this purpose, development of simpler tests is desired. Further development of research on anti-leprosy drugs capable of curing in a short period, combination of drugs, and vaccination is also required. Since there are still a great many leprosy patients mainly in Asia, Japan is anticipated as a major cooperator in leprosy control.