Lepra Bubalorum, a Potential Reservoir of Mycobacterium leprae.

In 1926, a mycobacterial skin disease was observed in water buffaloes by researchers in Indonesia. The disease was designated as skin tuberculosis, though it was hypothesized that it might be a form of leprosy or a leprosy-like disease. In a follow-up study (Ph.D. thesis Lobel, 1934, Utrecht University, Netherlands) a similar nodular skin disease was described in Indonesian water buffaloes and named "lepra bubalorum" or "nodular leprosy." Two decades later Kraneveld and Roza (1954) reported that, so far, the diagnosis lepra bubalorum had been made in 146 cases in Indonesia. After a final series of research reports by Indonesian veterinarians in 1961, no subsequent cases were published. Based on information from these reports, it can be concluded that, even though evidence of nerve involvement in buffaloes was not reported, similarities exist between lepra bubalorum and Hansen's disease (leprosy), i.e., nodular skin lesions with a chronic course and microscopically granulomatous reactions with AFB in globi in vacuoles. This raises the question as to whether these historical cases might indeed have been caused by Mycobacterium leprae, Mycobacterium lepromatosis or another representative of the M. leprae complex. The future use of state-of-the-art molecular techniques may answer this question and may also help to answer the question whether water buffaloes should be considered as a potential natural reservoir of the causative pathogen of Hansen's disease.

Reservoirs and transmission routes of leprosy; A systematic review.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae) and the more recently discovered Mycobacterium lepromatosis (M. lepromatosis). The two leprosy bacilli cause similar pathologic conditions. They primarily target the skin and the peripheral nervous system. Currently it is considered a Neglected Tropical Disease, being endemic in specific locations within countries of the Americas, Asia, and Africa, while in Europe it is only rarely reported. The reason for a spatial inequality in the prevalence of leprosy in so-called endemic pockets within a country is still largely unexplained. A systematic review was conducted targeting leprosy transmission research data, using PubMed and Scopus as sources. Publications between January 1, 1945 and July 1, 2019 were included. The transmission pathways of M. leprae are not fully understood. Solid evidence exists of an increased risk for individuals living in close contact with leprosy patients, most likely through infectious aerosols, created by coughing and sneezing, but possibly also through direct contact. However, this systematic review underscores that human-to-human transmission is not the only way leprosy can be acquired. The transmission of this disease is probably much more complicated than was thought before. In the Americas, the nine-banded armadillo (Dasypus novemcinctus) has been established as another natural host and reservoir of M. leprae. Anthroponotic and zoonotic transmission have both been proposed as modes of contracting the disease, based on data showing identical M. leprae strains shared between humans and armadillos. More recently, in red squirrels (Sciurus vulgaris) with leprosy-like lesions in the British Isles M. leprae and M. lepromatosis DNA was detected. This finding was unexpected, because leprosy is considered a disease of humans (with the exception of the armadillo), and because it was thought that leprosy (and M. leprae) had disappeared from the United Kingdom. Furthermore, animals can be affected by other leprosy-like diseases, caused by pathogens phylogenetically closely related to M. leprae. These mycobacteria have been proposed to be grouped as a M. leprae-complex. We argue that insights from the transmission and reservoirs of members of the M. leprae-complex might be relevant for leprosy research. A better understanding of possible animal or environmental reservoirs is needed, because transmission from such reservoirs may partly explain the steady global incidence of leprosy despite effective and widespread multidrug therapy. A reduction in transmission cannot be expected to be accomplished by actions or interventions from the human healthcare domain alone, as the mechanisms involved are complex. Therefore, to increase our understanding of the intricate picture of leprosy transmission, we propose a One Health transdisciplinary research approach.

Biologics in Leprosy: A Systematic Review and Case Report.

Tumor necrosis factor (TNF)-α inhibitors increase susceptibility to tuberculosis, but the effect of biologics on susceptibility to leprosy has not been described. Moreover, biologics may play a role in treating erythema nodosum leprosum (ENL). The objectives of this systematic review were to determine whether the development of clinical leprosy is increased in patients being treated with biologics and to assess the use of biologics in treating leprosy reactions. A systematic literature review was completed of patients with leprosy who received treatment with biologics either before or after a diagnosis of leprosy was confirmed. All studies and case reports were included for qualitative evaluation. The search yielded 10 cases (including one duplicate publication) of leprosy diagnosed after initiation of TNF-α inhibitors and four case reports of refractory ENL successfully treated with infliximab or etanercept. An unpublished case of persistent ENL responsive to infliximab is also presented. These data demonstrate that the use of TNF-α inhibitors may be a risk factor for developing leprosy or reactivating subclinical infections. Leprosy can present with skin lesions and arthritis, so leprosy should be considered in patients presenting with these signs before starting treatment with these agents. Leprosy should be considered in patients who develop worsening eruptions and neurologic symptoms during treatment with TNF-α inhibitors. Finally, TNF-α inhibitors appear effective in some cases of refractory ENL.

Detection of Mycobacterium leprae DNA in soil: multiple needles in the haystack.

Leprosy is an infectious disease caused by Mycobacterium leprae affecting the skin and nerves. Despite decades of availability of adequate treatment, transmission is unabated and transmission routes are not completely understood. Despite the general assumption that untreated M. leprae infected humans represent the major source of transmission, scarce reports indicate that environmental sources could also play a role as a reservoir. We investigated whether M. leprae DNA is present in soil of regions where leprosy is endemic or areas with possible animal reservoirs (armadillos and red squirrels). Soil samples (n = 73) were collected in Bangladesh, Suriname and the British Isles. Presence of M. leprae DNA was determined by RLEP PCR and genotypes were further identified by Sanger sequencing. M. leprae DNA was identified in 16.0% of soil from houses of leprosy patients (Bangladesh), in 10.7% from armadillos' holes (Suriname) and in 5% from the habitat of lepromatous red squirrels (British Isles). Genotype 1 was found in Bangladesh whilst in Suriname the genotype was 1 or 2. M. leprae DNA can be detected in soil near human and animal sources, suggesting that environmental sources represent (temporary) reservoirs for M. leprae.

Plantar pressure and daily cumulative stress in persons affected by leprosy with current, previous and no previous foot ulceration.

Not only plantar pressure but also weight-bearing activity affects accumulated mechanical stress to the foot and may be related to foot ulceration. To date, activity has not been accounted for in leprosy. The purpose was to compare barefoot pressure, in-shoe pressure and daily cumulative stress between persons affected by leprosy with and without previous or current foot ulceration. Nine persons with current plantar ulceration were compared to 15 with previous and 15 without previous ulceration. Barefoot peak pressure (EMED-X), in-shoe peak pressure (Pedar-X) and daily cumulative stress (in-shoe forefoot pressure time integral×mean daily strides (Stepwatch™ Activity Monitor)) were measured. Barefoot peak pressure was increased in persons with current and previous compared to no previous foot ulceration (mean±SD=888±222 and 763±335 vs 465±262kPa, p<0.05). In-shoe peak pressure was only increased in persons with current compared to without previous ulceration (mean±SD=412±145 vs 269±70kPa, p<0.05). Daily cumulative stress was not different between groups, although persons with current and previous foot ulceration were less active. Although barefoot peak pressure was increased in people with current and previous plantar ulceration, it did not discriminate between these groups. While in-shoe peak pressure was increased in persons with current ulceration, they were less active, resulting in no difference in daily cumulative stress. Increased in-shoe peak pressure suggests insufficient pressure reducing footwear in persons with current ulceration, highlighting the importance of pressure reducing qualities of footwear.

Increased plantar foot pressure in persons affected by leprosy.

Although foot pressure has been reported to be increased in people affected by leprosy, studies on foot pressure and its determinants are limited. Therefore, the aim was to assess barefoot plantar foot pressure and to identify clinical determinants of increased plantar foot pressure in leprosy affected persons. Plantar pressure in both feet was assessed using the Novel EMED-X platform in 39 persons affected by leprosy. Peak pressure was determined for the total foot and four regions: hallux, metatarsal heads, midfoot and heel. Potential determinants were: age, weight, nerve function (Neuropathy Disability Score, Pressure Perception Threshold and Vibration Perception Threshold), toe and foot deformities, joint mobility, ankle muscle strength and callus. Increased peak pressure (>600kPa) was observed in 46% of the participants. The highest peak pressure (mean) was found in the metatarsal heads region (right 549 (SD 321)kPa; left 530 (SD 298)kPa). Multilevel regression analysis showed that Neuropathy Disability Score, amputation/absorption of toes and hallux valgus independently contributed to metatarsal heads peak pressure in persons affected with leprosy. To conclude, peak pressure is increased in people affected by leprosy. The highest peak pressure is found in the forefoot region and is significantly associated to Neuropathy Disability Score, toe amputation/absorption and hallux valgus. Screening for clinical characteristics can be used to identify individual persons affected by leprosy at risk of excessive pressure.

Foot impairments and limitations in walking activities in people affected by leprosy.

OBJECTIVE: To explore the relationships between perceived limitations in walking-related daily activities, walking ability (capacity), and the amount of daily walking (performance) in persons affected by leprosy and to identify their determinants. DESIGN: A cross-sectional study. SUBJECTS: Thirty-nine persons affected by leprosy. METHODS: Perceived limitations were assessed with the World Health Organization Disability Schedule II, domain "getting around". Walking capacity was assessed as covered distance in 6 min. Walking performance was recorded as mean strides/day with the Stepwatch(TM) 3 Activity Monitor. Potential determinants were sensory function, foot deformities, joint mobility, ankle muscle strength and co-morbidity. RESULTS: Perceived limitations in walking-related activities were significantly correlated with walking capacity (r = -0.47; p < 0.01) but not with walking performance, although walking capacity significantly correlated with walking performance (r = 0.38; p < 0.05). Various foot impairments independently contributed to reduced walking capacity and, to a lower degree, to perceived limitations in activities and performance. CONCLUSION: People affected by leprosy perceive limitations in walking-related activities that are determined by a reduced walking ability and the severity of foot impairments. Since perceived limitations in walking-related activities were not related to walking performance, perceived limitations are apparently weighted against the individual's needs.

Effects of impairments on activities and participation in people affected by leprosy in The Netherlands.

OBJECTIVE: To assess the prevalence of impairments and evaluate the relationships between impairments, activity limitations and participation restrictions in people affected by leprosy living in The Netherlands. DESIGN: A cross-sectional study. SUBJECTS: Eighty-two people affected by leprosy living in The Netherlands. METHODS: A postal questionnaire was performed. Impairments were inventoried with the Total Impairment Score. Activity limitations were assessed with the World Health Organization Disability Schedule II (WHODAS-II) and participation restrictions with the Impact on Participation and Autonomy (IPA) questionnaire. RESULTS: A high prevalence of impairments was found (83%), mostly in hands and feet. Activity limitations were substantial, and highest for the WHODAS-II domains "household/work" and "getting around". The severity of impairments correlated significantly with activity limitations. Eye and foot impairments independently contributed to the domains "household/work" and "getting around", explaining 34% and 40% of variance. Poor or very poor participation (IPA) was reported by 13-32% of persons, mostly in the "autonomy outdoors" and "family role" domains. These domains were associated with activity limitations and hand impairments CONCLUSIONS: People affected by leprosy in The Netherlands encounter limitations in activities and participation restrictions, which are related to the severity of impairments. The high prevalence of disability suggests rehabilitation care should be considered for a substantial proportion of people affected by leprosy.

['Rheumatoid arthritis' in a Surinamese man: leprosy]. / 'Reumatoïde artritis' bij een Surinaamse man: lepra.

Rheumatoid arthritis was diagnosed in a 65-year-old man from Suriname, on the basis of clinical and radiological findings. However, he was eventually diagnosed with leprosy. This emerged when the patient developed skin lesions and complained of increasing sensibility disorders during treatment for the alleged rheumatoid arthritis. He was treated with a combination therapy consisting of rifampicin, clofazimine, dapsone, and prednisone. The skin lesions and joint symptoms were resolved as a result of this, but the sensibility disorders persisted. As physicians are not sufficiently familiar with leprosy and the condition has many manifestations that can mimic more frequently occurring diseases, leprosy is often diagnosed at a later stage. This may result in irreversible damage, especially to the peripheral nerves, which may lead to disability. Therefore, for patients who originate from areas where leprosy is endemic and who suffer from joint complaints in combination with skin or sensibility disorders, the diagnosis of leprosy should be considered.

The potential role of magnetic resonance imaging in patients with Hansen's neuropathy of the feet: a preliminary communication.

A magnetic resonance imaging (MRI) protocol was performed in leprosy patients with a neuropathic foot and superficial ulcers and/or localized cellulitis but no clinical suspicion of osteomyelitis. The aim of the study was to determine if unsuspected osteomyelitis was present in this defined group of leprosy patients. A total of 15 neuropathic feet from 9 patients were included. Clinically and on MRI, the forefoot was predominantly affected. MRI findings of osteomyelitis were found in 4 feet. In feet with osteomyelitis, 3 had a superficial ulcer and 3 had clinical signs of localized cellulitis. A clinical diagnosis of cellulitis was confirmed on MRI in 2 feet.A striking discrepancy between clinical and MRI findings was found.This study shows that, compared with clinical evaluation, MRI is a sensitive method for the detection of unsuspected osteomyelitis in neuropathic feet with superficial ulcers and/or cellulitis. MRI findings in this group of patients may influence clinical decision making and may prevent further complications, because osteomyelitis requires more aggressive medical treatment. This preliminary communication should pave the wave for designed controlled studies so that patients with Hansen's neuropathy may get the best medical care.

Polymorphism N248S in the human Toll-like receptor 1 gene is related to leprosy and leprosy reactions.

We investigated the association between a polymorphism of a key innate immunity receptor, Toll-like receptor 1 (TLR1) N248S, and susceptibility to leprosy and its clinical presentation. TLR1 N248S has been shown elsewhere to diminish TLR1 signaling and subsequent leprosy disease. The homozygous genotype SS was more frequent (P=.012) and the heterozygous SN genotype was less frequent (P=.015) in patients with leprosy than in control subjects. Additional observed differences in allelic frequency in patients who experienced reversal reactions and/or erythema nodosum leprosum reactions indicates that altered TLR1 function, or at least a TLR1 N248S-linked trait, may affect the progression from infection to disease as well as the disease course and the risk of debilitating reactional episodes in this population.

The role of radiology in nerve function impairment and its musculoskeletal complications in leprosy.

Conventional techniques, such as plain radiography and bone-scintigraphy, were used in the past to evaluate skeletal changes in patients with leprosy. More recent publications focus on radiological imaging of affected nerves, and involve advanced modalities such as Computed Tomography (CT-scan), Ultrasonography (US), and Magnetic Resonance Imaging (MRI). US and MRI can play an especially important role in the evaluation of nerve involvement in newly diagnosed patients, and also during leprosy reactions. This is important, because when nerve involvement is diagnosed in time, it may be reversible with adequate treatment. Radiological modalities can also play an important role during the followup of patients with leprosy with nerve function impairment. Skeletal and soft-tissue abnormalities occur, even after treatment. The so-called neuropathic foot is a well known consequence. Because of nerve function impairment, there is a constant risk of developing ulcers and subsequent osteomyelitis, or neuro-osteoarthropathy (Charcot foot or tarsal disintegration), which can lead to the amputation of the affected limb. Different radiological modalities can be used during the evaluation and follow-up of patients with leprosy with a neuropathic foot. With this up-to-date review, we highlight the importance and potential role of radiological imaging techniques in leprosy.

Preventing nerve function impairment in leprosy: validation and updating of a prediction rule.

BACKGROUND: To validate and update a prediction rule for estimating the risk of leprosy-related nerve function impairment (NFI). METHODOLOGY/PRINCIPAL FINDINGS: Prospective cohort using routinely collected data, in which we determined the discriminative ability of a previously published rule and an updated rule with a concordance statistic (c). Additional risk factors were analyzed with a Cox proportional hazards regression model. The population consisted of 1,037 leprosy patients newly diagnosed between 2002 and 2003 in the health care facilities of the Rural Health Program in Nilphamari and Rangpur districts in northwest Bangladesh. The primary outcome was the time until the start of treatment. An NFI event was defined as the decision to treat NFI with corticosteroids after diagnosis. NFI occurred in 115 patients (13%; 95% confidence interval 11%-16%). The original prediction rule had adequate discriminative ability (c = 0.79), but could be improved by substituting one predicting variable: 'long-standing nerve function impairment at diagnosis' by 'anti-PGL-I antibodies'. The adjusted prediction rule was slightly better (c = 0.81) and identified more patients with NFI (80%) than the original prediction rule (72%). CONCLUSIONS/SIGNIFICANCE: NFI can well be predicted by using the risk variables 'leprosy classification' and 'anti-PGL-I antibodies'. The use of these two variables that do not include NFI offer the possibility of predicting NFI, even before it occurs for the first time. Surveillance beyond the treatment period can be targeted to those most likely to benefit from preventing permanent disabilities.

The relation between seroprevalence of antibodies against phenolic glycolipid-I among school children and leprosy endemicity in Brazil.

Leprosy control programs would benefit expressively from an easy method to estimate disease prevalence and to assess the effect of leprosy control measures on disease prevalence. Determination of the seroprevalence of antibodies to PGL-I through school children surveys might be a useful indicator of leprosy prevalence at the district level. To investigate whether seropositivity rates could be related to leprosy detection rates and whether seropositivity could be used as a proximal indicator to predict the leprosy incidence in other areas, 7,073 school children in three different leprosy-endemic states in Brazil were tested. The results show a widely varying distribution of seropositivity in the communities independent of the number of leprosy cases detected. Seroprevalence was significantly lower at private schools. No differences in the patterns of seropositivity between ELISA and dipstick were observed. No correlation between leprosy detection rate and seropositivity rates could be established.

A relação entre soroprevalência de anticorpos contra o glicolipídeo fenólico-I entre crianças em idade escolar e endemicidade da hanseníase no Brasil / The relation between seroprevalence of antibodies against phenolic glycolipid-I among school children and leprosy endemicity in Brazil

Os programas de controle da hanseníase se beneficiariam de um método fácil para estimar prevalência e avaliar o impacto das ações de controle na prevalência da doença. A determinação da soroprevalência de anticorpos contra PGL-I através de estudos com crianças em idade escolar foi sugerida como indicador útil da taxa de prevalência da hanseníase a nível municipal.Para investigar se a soropositividade estaria associada aos coeficientes de detecção da hanseníase e se poderia ser usada como indicador da prevalência em outras áreas, 7.073 crianças em três estados endêmicos de hanseníase no Brasil foram testadas. Resultados mostram uma considerável variação da distribuição de soropositividade nas comunidades, independente do número de casos de hanseníase detectados. A soroprevalência foi significativamente menor nos colégios. Nenhuma diferença na distribuição da soropositividade determinada por ELISA ou dipstick foi observada. Nenhuma correlação entre o coeficiente de detecção da hanseníase e soropositividade pôde ser estabelecida.

Leprosy control programs would benefit expressively from an easy method to estimate disease prevalence and to assess the effect of leprosy control measures on disease prevalence. Determination of the seroprevalence of antibodies to PGL-I through school children surveys might be a useful indicator of leprosy prevalence at the district level. To investigate whether seropositivity rates could be related to leprosy detection rates and whether seropositivity could be used as a proximal indicator to predict the leprosy incidence in other areas, 7,073 school children in three different leprosy-endemic states in Brazil were tested. The results show a widely varying distribution of seropositivity in the communities independent of the number of leprosy cases detected. Seroprevalence was significantly lower at private schools. No differences in the patterns of seropositivity between ELISA and dipstick were observed. No correlation between leprosy detection rate and seropositivity rates could be established.

Leprosy-specific B-cells within cellular infiltrates in active leprosy lesions.

Leprosy is a spectral disease with polar lepromatous and tuberculoid forms correlating with enhanced humoral and cell-mediated immunity, respectively, against Mycobacterium leprae and the borderline forms, borderline lepromatous, midborderline, and borderline tuberculoid showing in-between clinical and immunological characteristics. Histopathologically, the cellular infiltrates of leprosy lesions show predominantly the presence of interacting T-cells and antigen presenting cells like macrophages, whereas the presence of B-cells has only been sporadically reported. The present study demonstrates by immunohistochemical techniques the presence of B-cells, including plasma cells, in active lesions from lepromatous leprosy, skin smear negative borderline lepromatous, and paucibacillary borderline tuberculoid leprosy. Furthermore, the study demonstrates the in situ production of M leprae-specific antibodies from BT lesions using an organotypic skin explant culture model. Finally, analysis of the cytokine release profile in supernatants of lesional organotypic skin cultures showed a microenvironment conducive to the differentiation and maturation of B-cells. The results demonstrate the presence of different functionally active B-cell stages within lesions of patients with leprosy, including borderline tuberculoid patients, which could secrete anti-M leprae-specific antibodies. However, their role in leprosy pathology remains to be elucidated.

Risk factors for developing leprosy--a population-based cohort study in Indonesia.

We identified risk factors associated with increased yearly incidence rates of leprosy in five island populations. Age, sex, household size and Mycobacterium leprae-specific antibodies as well as contact factors were studied. Of 94 index patients (patients diagnosed in 2000), 43 (46%) were classified as multibacillary (MB), 17 (19%) were seropositive for PGL-1 [corrected] antibodies and 6 (7%) had M. leprae DNA in nasal swabs as determined by polymerase chain reaction (PCR) testing. All PCR positive patients were also seropositive. Forty-four of 4903 initially symptom free persons developed leprosy within 4 years, giving an incidence rate of 298 per 1000 person-years. Men had a 22 times higher risk [95% confidence interval (CI): 1.2-4.1] of developing leprosy than women. People living in households with more than 7 members had a 3.1 times higher risk (95% CI: 1.3-7.3) than households of 1-4 members. Persons who were seropositive in 2000 had a 3.8 times higher risk (95% CI: 1.1-12.6) than seronegative persons. Household contacts of MB patients had an adjusted hazard ratio (aHR) of 4.6 (95% CI: 1.6-12.9) and household contacts of PCR positive patients an aHR of 9.36 (95% CI: 2.5-34.9) compared with non-contacts. Patients with PCR positive nasal swabs, suggesting nasal excretion of M. leprae, are probably the patients with the highest transmission potential. Since all index patients who were PCR positive were also seropositive, serology seems an adequate tool to identify these patients. Preventing seropositive persons from becoming seropositive and infectious patients might break the chain of transmission.

Role of PGL-I antibody detection in the diagnosis of pure neural leprosy.

Pure neural leprosy (PNL) is difficult to diagnose because skin lesions and acid-fast bacilli (AFB) in slit smears are absent. At present, the gold standard for PNL diagnosis is the histopathological examination of a peripheral nerve biopsy. Even so, detection of bacteria is difficult and histological findings may be non-specific. Furthermore, nerve biopsy is an invasive procedure that is only possible in specialized centres. Therefore, there is a need for additional diagnostic methods that may help to confirm the clinical diagnosis of PNL. In the present study, an additional laboratory test, the ELISA for anti-phenolic glycolipid I (PGL-I) IgM antibodies, was performed on 103 individuals with clinical and neurophysiological signs of peripheral neuropathy, of which 67 were diagnosed as PNL patients and 36 remained as 'not diagnosed as PNL', as well as on a control group of 34 patients with other neurological diseases. An antibody response was present in 14/67 (21%) of the patients diagnosed as PNL as compared with 3/34 (9%) of controls. Anti-PGL-I positivity was observed in 5/8 (63%) of the AFB positive cases. Patients whose diagnosis was confirmed solely by Mycobacterium leprae PCR on the nerve sample had 4/25 (16%) seropositivity. In addition, anti-PGL-I antibodies were detected in 9/40 (23%) of the PNL patients who were PCR negative for M. leprae DNA. Moreover, two patients who showed clinical and eletrophysiological manifestations suggestive of PNL were diagnosed with the help of their positive test results in the anti-PGL-I ELISA. In conclusion, detection of antibodies against PGL-I in patients with peripheral neuropathy is useful as an additional laboratory test to help PNL diagnosis.