The current status of neglected tropical diseases in Japan: A scoping review.

Little attention has been paid to neglected tropical diseases (NTDs) in high-income countries and no literature provides an overview of NTDs in Japan. This scoping review aims to synthesize the latest evidence and information to understand epidemiology of and public health response to NTDs in Japan. Using three academic databases, we retrieved articles that mentioned NTDs in Japan, written in English or Japanese, and published between 2010 and 2020. Websites of key public health institutions and medical societies were also explored. From these sources of information, we extracted data that were relevant to answering our research questions. Our findings revealed the transmission of alveolar echinococcosis, Buruli ulcer, Chagas disease, dengue, foodborne trematodiases, mycetoma, scabies, and soil-transmitted helminthiasis as well as occurrence of snakebites within Japan. Other NTDs, such as chikungunya, cystic echinococcosis, cysticercosis, leishmaniasis, leprosy, lymphatic filariasis, rabies, and schistosomiasis, have been imported into the country. Government agencies tend to organize surveillance and control programs only for the NTDs targeted by the Infectious Disease Control Law, namely, echinococcosis, rabies, dengue, and chikungunya. At least one laboratory offers diagnostic testing for each NTD except for dracunculiasis, human African trypanosomiasis, onchocerciasis, and yaws. No medicine is approved for treatment of Chagas disease and fascioliasis and only off-label use drugs are available for cysticercosis, opisthorchiasis, human African trypanosomiasis, onchocerciasis, schistosomiasis, and yaws. Based on these findings, we developed disease-specific recommendations. In addition, three policy issues are discussed, such as lack of legal frameworks to organize responses to some NTDs, overreliance on researchers to procure some NTD products, and unaffordability of unapproved NTD medicines. Japan should recognize the presence of NTDs within the country and need to address them as a national effort. The implications of our findings extend beyond Japan, emphasizing the need to study, recognize, and address NTDs even in high-income countries.

Hansen's disease (leprosy) in Japan, 1947-2020: an epidemiologic study during the declining phase to elimination.

OBJECTIVES: Leprosy, or Hansen's disease was a major public health problem in Japan in the early 20th century. Today, the number of new cases has decreased significantly. We aimed to investigate the trends of leprosy in Japan over the past 73 years and the challenges faced in recent years. METHODS: We assessed the data on newly registered cases of leprosy from 1947 to 2020. RESULTS: A total of 10,796 newly registered cases of leprosy were reported during the study period, of which 7573 were registered in mainland Japan, 2962 in Okinawa, and 250 were of foreign origin. Most autochthonous cases were born before 1950 in mainland Japan and before 1975 in Okinawa. The number of nonautochthonous cases surpassed that of autochthonous cases in 1992. Nonautochthonous cases originated from 26 countries, particularly Brazil and the Philippines. Three cases of antimicrobial resistance have been detected among nonautochthonous cases since 2004. CONCLUSION: Our data suggest that ongoing transmission of leprosy likely ceased in the 1940s in mainland Japan and in the 1970s in Okinawa. With the recent rise of nonautochthonous cases with globalization, continuous surveillance and efforts to maintain leprosy services within the country are necessary even after reaching the state of elimination.

Newly or switching effect of a selective EP2 agonist on intraocular pressure in Japanese patients with open-angle glaucoma.

PURPOSE: To evaluate omidenepag isopropyl (OMDI) for its efficacy in intraocular pressure control (IOP) and adverse reactions following administrations in Japanese patients with open-angle glaucoma (OAG) over a 3-month period. STUDY DESIGN: Retrospective observational study. SUBJECTS AND METHODS: Group 1 included untreated OAG patients, Group 2 included OAG patients treated with prostaglandin F (FP) receptor agonists (monotherapy) and Group 3 included OAG patients treated with multidrug therapy, including FP receptor agonists. OMDI was newly administered in Group 1, and FP receptor agonists were switched to OMDI in Group 2. In Group 3, all other ocular hypotensive medications were continued except FP receptor agonists. IOP changes were examined, and adverse reactions were retrieved from the medical records. RESULTS: Group 1 included 32 eyes, Group 2, 20 eyes and Group 3, 17 eyes. In Group 1, the baseline IOP was 15.7 mmHg (95% confidence interval [CI] 14.7-16.8 mmHg). After eyedrop treatment, the IOP was 14.1 mmHg (P < 0.001) at 1 month and 13.7 mmHg (P < 0.001) at 3 months. By contrast, in Group 2 and Group 3, switching FP receptor agonists to OMDI did not result in significant IOP changes (P ≥ 0.71). Six patients developed adverse reactions (hyperemia, headache, ocular pain, and swollen eyelids). CONCLUSIONS: New administration of OMDI significantly reduced the IOP. Furthermore, the IOP did not change after switching from FP receptor agonists to OMDI, including multidrug therapy. OMDI can be used as a first-line drug and is comparable to FP receptor agonists in Japanese patients with OAG.

[A Study on the Entering and Out-going Trends at Japan's National Hansen's Disease Sanatoriums].

A Hansen's disease (HD) policy began in Japan with the enactment of the No. 11 Act on Leprosy (1907 law No. 11), which was the first leprosy prevention law in Japan in 1907. Results of the law included the enforcement of regulations of the stated law and the establishment of Prefectural Allied (National) HD Sanatoriums in 1909. This policy continued until the "leprosy prevention law" abolition in 1996, and about 35,000 people were placed in isolation; however, its entering and out-going trends are not clear yet. The purpose of this research is to clarify the actual condition of the Japanese HD policy. We added up the number of individuals entering and leaving the sanatorium from 1909 to 2010. This information was collected from annual reports and the internal material from each national sanatorium. In the results, the number of general residents (new, re-entering, transferring from other sanatoriums) and the number of general out-going persons (transferring to another sanatorium, formal discharge, informal discharge including escape and wrong diagnosis, and others) were all totaled as the running number during the 102 year span, in addition to being added to the deaths. The results show that the number of general residents was 56,575 people and the number of general out-going persons was 54,047 people (death: 25,200 people; change of sanatorium: 4,350 people; formal discharge: 7,124 people; informal discharge including escape: 12,378 people; wrong diagnosis: 310 people; others: 4,685 people). Based on the details of each leprosy prevention law, the results for the first "1907 law No. 11" show that the number of general residents was 12,673 people and the number of general out-going persons was 9,070 people. The "1931 leprosy prevention law" results show that the number of general residents was 31,232 people and the number of general out-going persons was 23,354 people. The "1953 leprosy prevention law" results show that the number of general inmates was 12,098 people and the number of general out-going persons was 18,159 people. The "1996 law about repeal of leprosy prevention law" results show that the number of general residents was 572 people and the number of general out-going persons was 3,464 people. We can clarify the number of general residents and the number of general out-going persons in the National HD Sanatoriums in Japan.

[On the present and future of Japanese Leprosariums--the case of Oshima-seishoen Sanatorium].

In all thirteen national sanatorium in Japan, the number of patients have gradually declined year by year. Although it has been long discussed about maintenance and utilization of facilities in the future, clear and specific plans are still not sufficient. Especially Oshima-seishoen sanatorium, Oshima island is an isolated island located off the coast of Takamatsu port. It is very different from the other Leprosy sanatoriums in that there are no general population other than patients and officials of the sanatorium. So it is very difficult to have outlooks of the future of this sanatorium. In the conversation with the patients, two serious concerns have been raised. Whether patients will be provided support and treatment throughout life. The other one is whether the government would manage the ossuary permanently under the responsibility for the isolation policy of leprosy patients. These two points are also written in promotion measures of Oshima formulated by "Meeting to consider the future of Oshima", that was established in 2013 proposed by Takamatsu city authorities. In the situation of aging of patients accelerating, I considered that to promise these two points are the top priority.

[Current status of dementia in admitions to national leprosariums nationwide].

The purpose of this study was to get an overview of the following aspects of people admitted to 13 national leprosariums in Japan: the prevalence of dementia, medical and nursing systems, and facilities and equipment. Subjects included 1733 people admitted to wards for patients or disabled people in these leprosariums. Subjects were examined for cognitive function using Nishimura's behavioral rating scale for the mental states of the elderly (NMS), and for the prevalence of behavioral and psychological symptoms of dementia (BPSD). We also investigated medical and nursing systems, facilities and equipment, and status of nursing education. The results showed that, 288 subjects (16.6%) had a diagnosis of dementia. According to the NMS, 47.5% of the subjects were categorized as mild to severe dementia, while cognitive dysfunction was observed in 63.5% if borderline cases were included. Non-specialist physicians managed 30.8% of the subjects in 4 institutions, and there were no certified nurses specialized in dementia management. Results from this study suggest that there is need for the placement of dementia specialists', improvement of specialized medical services, and human resource development of specialized nurses in leprosariums where many elderly people live.

Characteristic mutations found in the ML0411 gene of Mycobacterium leprae isolated in Northeast Asian countries.

Genome analysis of Mycobacterium leprae strain Kyoto-2 in this study revealed characteristic nucleotide substitutions in gene ML0411, compared to the reference genome M. leprae strain TN. The ML0411 gene of Kyoto-2 had six SNPs compared to that of TN. All SNPs in ML0411 were non-synonymous mutations that result in amino acid replacements. In addition, a seventh SNP was found 41 bp upstream of the start codon in the regulatory region. The seven SNP sites in the ML0411 region were investigated by sequencing in 36 M. leprae isolates from the Leprosy Research Center in Japan. The SNP pattern in 14 of the 36 isolates showed similarity to that of Kyoto-2. Determination of the standard SNP types within the 36 stocked isolates revealed that almost all of the Japanese strains belonged to SNP type III, with nucleotide substitutions at position 14676, 164275, and 2935685 of the M. leprae TN genome. The geographical distribution pattern of east Asian M. leprae isolates by discrimination of ML0411 SNPs was investigated and interestingly turned out to be similar to that of tandem repeat numbers of GACATC in the rpoT gene (3 copies or 4 copies), which has been established as a tool for M. leprae genotyping. All seven Korean M. leprae isolates examined in this study, as well as those derived from Honshu Island of Japan, showed 4 copies of the 6-base tandem repeat plus the ML0411 SNPs observed in M. leprae Kyoto-2. They are termed Northeast Asian (NA) strain of M. leprae. On the other hand, many of isolates derived from the Okinawa Islands of Japan and from the Philippines showed 3 copies of the 6-base tandem repeat in addition to the M. leprae TN ML0411 type of SNPs. These results demonstrate the existence of M. leprae strains in Northeast Asian region having characteristic SNP patterns.

[Conjugal leprosy infection in Japan--case report and review].

The authors reported a conjugal leprosy infection observed in Japan. The husband, index case, first noticed sensory disturbance at the lower right leg in his forties. He developed edematous swelling with redness of the right hand and forearm at the age of 72 (1989), and then developed multiple erythema and hypesthesia at the extremities. He was diagnosed as BL type leprosy (reactional stage) and treated with multi-drug therapy. His 71-year-old wife developed a few erythema at the right forearm in 1993. She was classified as BT type. The duration of their marriage life was over forty years. The couple did not have consanguinity. No other leprosy patients were found in their lineage. From their clinical courses the authors concluded that the husband infected his wife. According to Japanese literatures, the frequency of conjugal leprosy among new patients in Japan was approximately 1%. There were worldwide observations that the husband often infected the wife, and mostly the index case was multibacillary and the secondary case paucibacillary. The authors reviewed definition and frequency of conjugal leprosy, factors in conjugal infection and leprosy infection among the adults.

SNP genotypes of Mycobacterium leprae isolates in Thailand and their combination with rpoT and TTC genotyping for analysis of leprosy distribution and transmission.

Based on the discovery of three single nucleotide polymorphisms (SNPs) in Mycobacterium leprae, it has been previously reported that there are four major SNP types associated with different geographic regions around the world. Another typing system for global differentiation of M. leprae is the analysis of the variable number of short tandem repeats within the rpoT gene. To expand the analysis of geographic distribution of M. leprae, classified by SNP and rpoT gene polymorphisms, we studied 85 clinical isolates from Thai patients and compared the findings with those reported from Asian isolates. SNP genotyping by PCR amplification and sequencing revealed that all strains like those in Myanmar were SNP type 1 and 3, with the former being predominant, while in Japan, Korea, and Indonesia, the SNP type 3 was found to be more frequent. The pattern of M. leprae distribution in Thailand and Myanmar is quite similar, except that SNP type 2 was not found in Thailand. In addition, the 3-copy hexamer genotype in the rpoT gene is shared among the isolates from these two neighboring countries. On the basis of these two markers, we postulate that M. leprae in leprosy patients from Myanmar and Thailand has a common historical origin. Further differentiation among Thai isolates was possible by assessing copy numbers of the TTC sequence, a more polymorphic microsatellite locus.

[Leprosy outpatient clinic in Aichi Prefecture, Japan].

Until the Japanese Leprosy Prevention Law was abolished in 1996, leprosy patients, regardless of their severity, had to be treated by accredited doctors. The majority of them had to be confined in a sanatorium to be treated, since only few hospitals/sanatoria had outpatient clinics for leprosy patients. This de facto confinement limited their occupational, social, financial, and family options, but no clear criteria/guidelines allowing discharge existed. The importance of leprosy outpatient clinics was almost never debated until 1962, when Tofu Association (a foundation established in 1952 to support the confined patients) and the National Suruga Sanatorium planned the opening of the clinic. This clinic looked after total of 4,977 patients until the abolishment of the Law. Since 1996, 349 persons consulted the clinic as of 2010. The importance of the continuation of these clinics is beyond dispute, even in low-endemic countries. However, the diminishing number of patients and demands in this country makes the management difficult. Thus, coordination with the local clinics and dermatologists is inevitable.

Molecular epidemiology of a hepatitis C virus outbreak in a leprosy sanatorium in Japan.

The hepatitis C virus (HCV) outbreak that occurred between 1940 and 1999 in a closed leprosy sanatorium located on a small island in Japan was analyzed. The analysis of 318 nucleotides in the NS5B region of HCV allowed us to establish the existence of at least three different HCV strains in this sanatorium.

[Survey of newly diagnosed Japanese leprosy patients].

We aimed to elucidate the patterns and trends of autochthonous leprosy in Japan from 1964 to 2009, to compare them with the findings from other studies of leprosy in decline. Data on registered leprosy cases in Japan in the period 1964-2009 were analysed with reference to trends in case detection, geographical distribution, age at diagnosis, sex, classification and family history. A consistent decline in leprosy case detection was observed in all areas of the country over the period 1964-2009. Highest incidence was consistently in Okinawa. Autochthonous leprosy has not been reported in anyone born in Japan since 1980. Increasing average age and a shift towards lower latitudes were demonstrated throughout the period. Analyses of data on autochthonous cases revealed patterns similar to those reported in other countries with declining leprosy. Okinawa has had the highest incidence of leprosy in all of Japan since the first national survey in 1900. Several possible explanations include the difference of leprosy control history between Okinawa and the rest of Japan, Okinawa's unique geographical condition, large-scale problem of stigma and discrimination against leprosy patients and delayed improvement of socio-economic conditions.

Clinical and immunological assessment of periodontal disease in Japanese leprosy patients.

Periodontitis is a chronic inflammatory disease caused by the infection of periodontopathic bacteria in dental plaque. However, an individual's susceptibility to this disease appears to be associated with multiple genetic factors, as seen in the case of leprosy. In order to gain a better understanding of the pathophysiology of periodontal disease in subjects with leprosy, we investigated the clinical features of periodontitis and the immunological responses against periodontopathic bacteria in 382 subjects with a history of leprosy and 451 age-matched control subjects. The prevalence of periodontitis and the degree of periodontal pocket depth were found to be significantly higher in leprosy patients than in age-matched controls. Furthermore, a comparison of the clinical parameters of lepromatous leprosy (L-lep) and tuberculoid leprosy (T-lep) patients showed that the probing pocket depth of L-lep patients with periodontal disease was significantly higher than that for T-lep patients. In contrast, serum IgG titers against Porphyromonas gingivalis in L-lep patients were significantly lower than in T-lep patients. These results imply that L-lep patients show more severe periodontal disease than T-lep patients or age-matched control subjects, and that low humoral immunity against P. gingivalis might be one of the genetic factors determining periodontal disease susceptibility in leprosy patients.

[Tendencies of prescriptions for neuralgic pain in National Suruga Sanatorium (leprosy), Japan during last 11 years].

The number of ex-leprosy patients has reduced rapidly who were forced to be admitted under leprosy prevention/segregation law and are staying at national sanatoriums with different disabilities due to different physical and social reasons for long time in Japan. Most of them have been of clinically cured status for decades after effective chemotherapy. Some have still been suffering from acute or chronic neuralgic pains which are supposed to be long standing consequences of nerve damage of leprosy and getting medications for long period. Pharmacy department of National Suruga Sanatorium has studied the amount of prescriptions of some medicines for last 11 years, which were thought to be prescribed for pain including neuralgic pain. There seem to be some tendencies of medications during last decade. VitaminB12 (Mecobalamine) is one of the commonest drugs for neuralgic pain at this sanatorium and the amount of prescription had almost been unchanged through the years. Prescription of non-steroid anti-inflammatory drugs (NSAIDs) increased year by year, which may reflect the increasing age of ex-patients who need more pain killers for their painful joints or back. Loxoprofen is the most popular pain killer here and increased by ten times for last decade. The number of prescription for Pentazocine and Hydroxyzine Hydrochloride injection increased for last several years, which reflects a few patients who were still suffering from severe chronic neuralgia for years. It is desirable that a standard regimen for chronic neuralgic pain as a consequence of nerve impairment in leprosy will be developed as soon as possible.

The decline of leprosy in Japan: patterns and trends 1964-2008.

OBJECTIVE: Our purpose was to elucidate the patterns and trends of autochthonous leprosy in Japan from 1964 to 2008, to compare them with the findings from other studies of leprosy in decline, and to determine whether M. leprae transmission persists in Japan. DESIGN: Data on registered leprosy cases in Japan in the period 1964-2008 were analysed with reference to trends in case detection, geographical distribution, age at diagnosis, sex, classification, family history and broad correlation with socioeconomic conditions. RESULTS: A consistent decline in leprosy case detection was observed in all areas of the country over the period 1964-2008. Highest incidence was consistently in Okinawa, the southernmost part of Japan. Autochthonous leprosy has not been reported in anyone born in Japan since 1980. Increasing average age and a shift towards lower latitudes were demonstrated throughout the period. There was an inverse association between regional measures of wealth and leprosy incidence. CONCLUSIONS: Leprosy has declined throughout the past century in Japan. Autochthonous transmission has probably stopped in mainland Japan, but may still occur at a low level in Okinawa, the country's southernmost region. Analyses of data on autochthonous cases revealed patterns similar to those reported in other countries with declining leprosy. Detailed comparisons between countries with very low leprosy incidence may help us to better understand the epidemiology of leprosy.

Prevalence and characteristics of depression in a Japanese leprosarium from the viewpoints of social stigmas and ageing. A preliminary report.

OBJECTIVE: To investigate the prevalence and characteristics of depressed patients living in a Japanese leprosarium who have been isolated by national law and are now becoming very elderly. METHODS: We surveyed the prevalence of depressed patients living in the National Tamazenshouen Sanatorium, a major leprosarium in Japan. We also investigated the characteristics of patients who had suffered a depressive episode during the last 5 years (2000-2004). The characteristics of residents who committed suicide were also studied. RESULTS: At the time of the investigation, 48 out of 385 (12.5%) patients were depressed or had experienced a depressive episode. Forty-one residents had committed suicide since the leprosarium was established in 1907. Somatic symptoms and depressive moods were the predominant symptoms and were not limited to symptoms unique to leprosy. The period of isolation was not statistically correlated with the GDS-SF or PGC morale scale scores. CONCLUSION: The findings of this study emphasize the importance of consultation psychiatric for elderly leprosy residents and could be used as a reference for treatment in countries with ageing leprosy residents.

[Recent condition of new leprosy patients in Japan].

Most of 148 newly registered leprosy patients in the past 10 years from 1995 to 2004 in Japan had received some examinations, such as histopathology test (85%), skin smear test (84%), estimation of PGL-I antibody titer (55%) or detection M. leprae with PCR method (41%). 17% of newly patients should receive wrong therapy, if they had not had aforesaid clinical examinations in addition to count skin lesions. Improvement of technical level at skin smear test should be required for accurate treatment program in Japan. In Japanese patients, the number has been decreasing year by year; epidemiological condition was different between in Okinawa prefecture and in others, about ratio of sex, kind of type and age group.