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.

Host-Related Laboratory Parameters for Leprosy Reactions.

Leprosy reactions are acute inflammatory episodes that complicate the course of a Mycobacterium leprae infection and are the major cause of leprosy-associated pathology. Two types of leprosy reactions with relatively distinct pathogenesis and clinical features can occur: type 1 reaction, also known as reversal reaction, and type 2 reaction, also known as erythema nodosum leprosum. These acute nerve-destructive immune exacerbations often cause irreversible disabilities and deformities, especially when diagnosis is delayed. However, there is no diagnostic test to detect or predict leprosy reactions before the onset of clinical symptoms. Identification of biomarkers for leprosy reactions, which impede the development of symptoms or correlate with early-onset, will allow precise diagnosis and timely interventions to greatly improve the patients' quality of life. Here, we review the progress of research aimed at identifying biomarkers for leprosy reactions, including its correlation with not only immunity but also genetics, transcripts, and metabolites, providing an understanding of the immune dysfunction and inflammation that underly the pathogenesis of leprosy reactions. Nevertheless, no biomarkers that can reliably predict the subsequent occurrence of leprosy reactions from non-reactional patients and distinguish type I reaction from type II have yet been found.

Relationship between Plantar Pressure and Sensory Disturbance in Patients with Hansen's Disease-Preliminary Research and Review of the Literature.

Orthoses and insoles are among the primary treatments and prevention methods of refractory plantar ulcers in patients with Hansen's disease. While dynamic plantar pressure and tactile sensory disturbance are the critical pathological factors, few studies have investigated whether a relationship exists between these two factors. In this study, dynamic pressure measured using F-scan system and tactile sensory threshold evaluated with monofilament testing were determined for 12 areas of 20 feet in patients with chronic Hansen's disease. The correlation between these two factors was calculated for each foot, for each clinical category of the foot (0-IV) and across all feet. A significant correlation was found between dynamic pressure and tactile sensation in Category II feet (n = 8, p = 0.016, r2 = 0.246, Spearman's rank test). In contrast, no significant correlation was detected for the entire foot or within the subgroups for the remainder of the clinical categories. However, the clinical manifestation of lesion areas showed high variability: (1) pressure concentrated, sensation lost; (2) margin of pressure concentration, sensation lost; (3) pressure concentrated, sensation severely disturbed but not lost; and (4) tip of the toe. These results may indicate that, even though there was a weak relationship between dynamic pressure and tactile sensation, it is important to assess both, in addition to the basics of orthotic treatment in patients with Hansen's disease presenting with refractory plantar ulceration.

The function of peroxisome proliferator-activated receptors PPAR-γ and PPAR-δ in Mycobacterium leprae-induced foam cell formation in host macrophages.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). In lepromatous leprosy (LL), skin macrophages, harboring extensive bacterial multiplication, gain a distinctive foamy appearance due to increased intracellular lipid load. To determine the mechanism by which M. leprae modifies the lipid homeostasis in host cells, an in vitro M. leprae infection system, using human macrophage precursor THP-1 cells and M. leprae prepared from the footpads of nude mice, was employed. RNA extracted from skin smear samples of patients was used to investigate host gene expressions before and after multidrug therapy (MDT). We found that a cluster of peroxisome proliferator-activated receptor (PPAR) target genes associated with adipocyte differentiation were strongly induced in M. leprae-infected THP-1 cells, with increased intracellular lipid accumulation. PPAR-δ and PPAR-γ expressions were induced by M. leprae infection in a bacterial load-dependent manner, and their proteins underwent nuclear translocalization after infection, indicating activation of PPAR signaling in host cells. Either PPAR-δ or PPAR-γ antagonist abolished the effect of M. leprae to modify host gene expressions and inhibited intracellular lipid accumulation in host cells. M. leprae-specific gene expressions were detected in the skin smear samples both before and after MDT, whereas PPAR target gene expressions were dramatically diminished after MDT. These results suggest that M. leprae infection activates host PPAR signaling to induce an array of adipocyte differentiation-associated genes, leading to accumulation of intracellular lipids to accommodate M. leprae parasitization. Certain PPAR target genes in skin lesions may serve as biomarkers for monitoring treatment efficacy.

Skin disease prevalence study in schoolchildren in rural Côte d'Ivoire: Implications for integration of neglected skin diseases (skin NTDs).

BACKGROUND: Early detection of several skin-related neglected tropical diseases (skin NTDs)-including leprosy, Buruli ulcer, yaws, and scabies- may be achieved through school surveys, but such an approach has seldom been tested systematically on a large scale in endemic countries. Additionally, a better understanding of the spectrum of skin diseases and the at-risk populations to be encountered during such surveys is necessary to facilitate the process. METHODS: We performed a school skin survey for selected NTDs and the spectrum of skin diseases, among primary schoolchildren aged 5 to 15 in Côte d'Ivoire, West Africa. This 2-phase survey took place in 49 schools from 16 villages in the Adzopé health district from November 2015 to January 2016. The first phase involved a rapid visual examination of the skin by local community healthcare workers (village nurses) to identify any skin abnormality. In a second phase, a specialized medical team including dermatologists performed a total skin examination of all screened students with any skin lesion and provided treatment where necessary. RESULTS: Of a total of 13,019 children, 3,504 screened positive for skin lesions and were listed for the next stage examination. The medical team examined 1,138 of these children. The overall prevalence of skin diseases was 25.6% (95% CI: 24.3-26.9%). The predominant diagnoses were fungal infections (n = 858, prevalence: 22.3%), followed by inflammatory skin diseases (n = 265, prevalence: 6.9%). Skin diseases were more common in boys and in children living along the main road with heavy traffic. One case of multi-bacillary type leprosy was detected early, along with 36 cases of scabies. Our survey was met with very good community acceptance. CONCLUSION: We carried out the first large-scale integrated, two-phase pediatric multi-skin NTD survey in rural Côte d'Ivoire, effectively reaching a large population. We found a high prevalence of skin diseases in children, but only limited number of skin NTDs. With the lessons learned, we plan to expand the project to a wider area to further explore its potential to better integrate skin NTD screening in the public health agenda.

Quantitative evaluation of maxillary bone deformation by computed tomography in patients with leprosy.

BACKGROUND: Facial deformation as a sequela of leprosy is caused not only by a saddle nose but also by regression of the maxilla, as well documented in paleopathological observations of excavated skeletal remains of patients with leprosy. However, maxillary changes in living patients have been evaluated only by the subjective visual grading. Here, we attempted to evaluate maxillary bone deformation in patients with leprosy using three-dimensional computed tomography (3D-CT). METHODS: Three-dimensional images centered on the maxilla were reconstructed using multiplanar reconstruction methods in former patients with leprosy (n = 10) and control subjects (n = 5); the anterior-posterior length of the maxilla (MA-P) was then measured. The difference between the MA-P of the patients and those of controls was evaluated after compensating for individual skull size. These findings were also compared with those from previous paleopathological studies. FINDINGS: Three former patients with lepromatous leprosy showed marked atrophy of the maxilla at the prosthion (-8.6, -11.1 and -17.9 mm) which corresponded with the visual appearance of the maxillary deformity, and these results were consistent with paleopathological findings of excavated skeletal remains. Additionally, the precise bone defects of the maxilla could be individually calculated for accurate reconstructive surgery. INTERPRETATION: We have successfully illustrated maxillary bone deformities in living patients with leprosy. This study also confirmed the maxillary regression described in paleopathological studies.

[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.

[Leprosy awareness-raising summer seminar: results of participant survey during 2012 and 2015].

In order to assess the effectiveness of this leprosy awareness-raising program, we surveyed 123 participants between 2012 and 2015. They were asked about their satisfaction with the program and what impact it had on them. In the past four years 80% to 100% have reported being "very satisfied" with the seminar. Many participants were grateful for the opportunity to be able to learn about leprosy from multiple perspectives and interact with people affected by leprosy. Interaction and sharing of opinions between participants were also regarded as important. These findings elucidated the importance of this seminar to provide opportunities for knowing the right information about leprosy, interacting with people affected by leprosy, coming to know of their experience and thoughts, and gaining exposure to other participants' opinions.

Mycobacterium haemophilum infection with prominent facial manifestation mimicking leprosy.

Mycobacterium haemophilum is a slow-growing non-tuberculous mycobacterium that is rarely known to cause human skin infection, particularly in immunocompromised patients. We recently experienced a 69-year-old Japanese woman with this infection who had been under immunosuppressive treatment for recalcitrant rheumatoid arthritis. The patient showed disseminated erythematous plaques and subcutaneous nodules on the face and extremities, and interestingly, the face manifested with a striking "facies leontina" appearance. Biopsy revealed abscess and granulomatous dermatitis with the involvement of peripheral nerve bundles and the presence of innumerable acid-fast bacilli, thus necessitating differentiation from lepromatous leprosy. M. haemophilum was identified by molecular characterization as well as by successful culture with iron supplements. Although drug susceptibility testing indicated responsiveness to multiple antibiotics administrated simultaneously for the treatment, it took over 6 months to achieve significant improvement, and we also employed concurrent oral potassium iodide administration and repeated surgical excision. This case highlights the importance of continuous combination therapy for successful outcome in this rare infection. Furthermore, application of potassium iodide for mycobacterial infection warrants further evaluation by accumulating more cases.

Paleopathological evidence and detection of Mycobacterium leprae DNA from archaeological skeletal remains of Nabe-kaburi (head-covered with iron pots) burials in Japan.

The Nabe-kaburi is a unique burial method, the purpose of which is shrouded in mystery. The burials were performed during the 15(th) to 18(th) centuries in eastern Japan, and involved covering the heads of the deceased with iron pots or mortars. The identification of leprosy-specific osteological lesions among some of the excavated remains has led to the suggestion that Nabe-kaburi burials were a reflection of the social stigma against certain infectious diseases, such as leprosy, tuberculosis or syphilis. However, molecular evidence for the presence of disease has been lacking. The goal of this study was to detect Mycobacterium leprae (M. leprae) DNA in archaeological human skeletal remains from Nabe-kaburi burials. The paleopathological data from three Nabe-kaburi burials were re-evaluated before small samples were taken from affected and control areas. DNA was extracted and used as a template to target the M. leprae-specific DNA using a combination of whole genome amplification, PCR analysis and DNA sequencing. M. leprae DNA fragments were detected in the two sets of skeletal remains that had also shown paleopathological evidence of leprosy. These findings provide definitive evidence that some of the Nabe-kaburi burials were performed for people affected by leprosy. Demonstration of the presence of M. leprae DNA, combined with archeological and anthropological examinations, will aid in solving the mystery of why Nabe-kaburi burials were performed in medieval Japan.

Leprosy as a model of immunity.

 Leprosy displays a spectrum of clinical manifestations, such as lepromatous and tuberculoid leprosy, and type I and II lepra reactions, which are thought to be a reflection of the host's immunological response against Mycobacterium leprae. Therefore, differential recognition of M. leprae, as well as its degraded components, and subsequent activation of cellular immunity will be an important factor for the clinical manifestation of leprosy. Although M. leprae mainly parasitizes tissue macrophages in the dermis and the Schwann cells of peripheral nerves, the presence of M. leprae in other organs, such as the liver, may also play important roles in the further modification of seesaw-like bipolar phenotypes of leprosy. Thus, leprosy is an exciting model for investigating the role of the human immune system in host defense and susceptibility to infection.

[Present leprosy situation in the world in 2012].

The epidemiological situation of leprosy is reported by the health division of each country to WHO. The reported data is collected by WHO and is immediately run on the Weekly Epidemiological Record. On this latest edition, data from the beginning of 2012 was reported. The Enhanced global strategy for further reducing the disease burden due to leprosy (plan period: 2011-2015) emphasizes reducing grade-2 disabilities among new cases. The sustained and committed efforts by the national programmes along with the continued support from national and international partners have led to a decline in the global burden of leprosy. It is important that all endemic countries continue to provide innovative solutions to address barriers to timely case detection and treatment completion, to ensure that the current declining trend is sustained.

[Guidelines for the treatment of Hansen's disease in Japan (third edition)].

ad hoc committee of Japanese Leprosy Association recommends revised standard treatment protocol of leprosy in Japan, which is a modification of World Health Organization's multidrug therapy (WHO/MDT, 2010). For paucibacillary (PB) leprosy, 6 months treatment by rifampicin and dapsone (MDT/PB) is enough. However, for high bacterial load multibacillary (MB) leprosy, 12 months treatment seems insufficient. Thus, (A) For MB with bacterial index (BI) > 3 before treatment, 2 years treatment by rifampicin, dapsone and clofazimine (MDT/MB) is necessary. When BI becomes negative and active lesion is lost within 2 years, no maintenance therapy is necessary. When BI is still positive, one year of MDT/MB is added (3 years in total), followed by maintenance therapy by dapsone and clofazimine until BI negativity and loss of active lesions. (B) For MB with BI < 3 or fresh MB (less than 6 months after the onset of the disease) with BI > 3, 1 year treatment by MDT/MB is necessary. When BI becomes negative and active lesion is lost within one year, no maintenance therapy is necessary. When BI is still positive or active lesion is remaining, additional therapy with MDT/MB for one more year is recommended. Brief summary of diagnosis, purpose of therapy, character of drugs, and prevention of deformity is also described.

Clofazimine modulates the expression of lipid metabolism proteins in Mycobacterium leprae-infected macrophages.

Mycobacterium leprae (M. leprae) lives and replicates within macrophages in a foamy, lipid-laden phagosome. The lipids provide essential nutrition for the mycobacteria, and M. leprae infection modulates expression of important host proteins related to lipid metabolism. Thus, M. leprae infection increases the expression of adipophilin/adipose differentiation-related protein (ADRP) and decreases hormone-sensitive lipase (HSL), facilitating the accumulation and maintenance of lipid-rich environments suitable for the intracellular survival of M. leprae. HSL levels are not detectable in skin smear specimens taken from leprosy patients, but re-appear shortly after multidrug therapy (MDT). This study examined the effect of MDT components on host lipid metabolism in vitro, and the outcome of rifampicin, dapsone and clofazimine treatment on ADRP and HSL expression in THP-1 cells. Clofazimine attenuated the mRNA and protein levels of ADRP in M. leprae-infected cells, while those of HSL were increased. Rifampicin and dapsone did not show any significant effects on ADRP and HSL expression levels. A transient increase of interferon (IFN)-ß and IFN-γ mRNA was also observed in cells infected with M. leprae and treated with clofazimine. Lipid droplets accumulated by M. leprae-infection were significantly decreased 48 h after clofazimine treatment. Such effects were not evident in cells without M. leprae infection. In clinical samples, ADRP expression was decreased and HSL expression was increased after treatment. These results suggest that clofazimine modulates lipid metabolism in M. leprae-infected macrophages by modulating the expression of ADRP and HSL. It also induces IFN production in M. leprae-infected cells. The resultant decrease in lipid accumulation, increase in lipolysis, and activation of innate immunity may be some of the key actions of clofazimine.