Single-Dose Rifapentine in Household Contacts of Patients with Leprosy.

BACKGROUND: Previous studies have suggested that a single dose of rifampin has protective effects against leprosy in close contacts of patients with the disease. Rifapentine was shown to have greater bactericidal activity against Mycobacterium leprae than rifampin in murine models of leprosy, but data regarding its effectiveness in preventing leprosy are lacking. METHODS: We conducted a cluster-randomized, controlled trial to investigate whether single-dose rifapentine is effective in preventing leprosy in household contacts of patients with leprosy. The clusters (counties or districts in Southwest China) were assigned to one of three trial groups: single-dose rifapentine, single-dose rifampin, or control (no intervention). The primary outcome was the 4-year cumulative incidence of leprosy among household contacts. RESULTS: A total of 207 clusters comprising 7450 household contacts underwent randomization; 68 clusters (2331 household contacts) were assigned to the rifapentine group, 71 (2760) to the rifampin group, and 68 (2359) to the control group. A total of 24 new cases of leprosy occurred over the 4-year follow-up, for a cumulative incidence of 0.09% (95% confidence interval [CI], 0.02 to 0.34) with rifapentine (2 cases), 0.33% (95% CI, 0.17 to 0.63) with rifampin (9 cases), and 0.55% (95% CI, 0.32 to 0.95) with no intervention (13 cases). In an intention-to-treat analysis, the cumulative incidence in the rifapentine group was 84% lower than that in the control group (cumulative incidence ratio, 0.16; multiplicity-adjusted 95% CI, 0.03 to 0.87; P = 0.02); the cumulative incidence did not differ significantly between the rifampin group and the control group (cumulative incidence ratio, 0.59; multiplicity-adjusted 95% CI, 0.22 to 1.57; P = 0.23). In a per-protocol analysis, the cumulative incidence was 0.05% with rifapentine, 0.19% with rifampin, and 0.63% with no intervention. No severe adverse events were observed. CONCLUSIONS: The incidence of leprosy among household contacts over 4 years was lower with single-dose rifapentine than with no intervention. (Funded by the Ministry of Health of China and the Chinese Academy of Medical Sciences; Chinese Clinical Trial Registry number, ChiCTR-IPR-15007075.).

Boletim Epidemiológico: análise descritiva da taxa de prevalência da hanseníase em dois cenários territoriais no Estado de Goiás / Epidemiological Bulletin: descriptive analysis of the prevalence rate of leprosy in two territorial scenarios in the State of Goiás

A hanseníase é uma doença infecto contagiosa causada pelo Mycobacterium leprae (bacilo de Hansen), manifestada por lesões na pele e comprometimento dos nervos periféricos, tendo as vias aéreas superiores como a principal via de eliminação do bacilo e a mais provável porta de entrada

Leprosy is a contagious infectious disease caused by Mycobacterium leprae (Hansen's bacillus), manifested by skin lesions and impairment of peripheral nerves, with the upper airways as the main route of elimination of the bacillus and the most likely gateway

Hanseníase em gêmeos de 3 anos em Mato Grosso, Brasil: a importância da baciloscopia no diagnóstico / Leprosy in 3-year-old twin children in Mato Grosso, Brazil: the importance of bacilloscopy in the diagnosis

Introdução: o diagnóstico clínico da hanseníase em crianças é particularmente difícil. Relato de Caso: crianças gêmeas bivitelinas, com três anos de idade, eram contactantes de pai com hanseníase Virchowiana. Os dois pacientes têm lesões cutâneas bem definidas e irregulares, anteriormente tratadas como micoses e uma cicatriz de BCG. Foram confirmados positivos para Mycobacterium por análise histopatológica da pele. Discussão: especialmente, com menos de cinco anos, os diagnósticos de hanseníase são raros e difíceis porque simulam outras doenças. Esses diagnósticos são alarmes epidemiológicos para áreas endêmicas e mostram a importância dos sintomas em crianças e o rastreamento nos contactantes dos pacientes.

Introduction: the clinical diagnosis of leprosy in children is particularly difficult. Case Report: fraternal twins, three years old, were in contact with a father with Virchowian leprosy. Both patients have well-defined and irregular skin lesions previously treated as mycoses and a BCG scar. They were confirmed positive for Mycobacterium by histopathological analysis of the skin. Discussion:especially, with less than five years, leprosy diagnoses are rare and difficult because they simulate other diseases. These diagnoses are epidemiological alarms for endemic areas and show the importance of symptoms in children and tracking of patients' contacts.

Detection of anti-M. leprae antibodies in children in leprosy-endemic areas: A systematic review.

BACKGROUND: Leprosy elimination primarily targets transmission of Mycobacterium leprae which is not restricted to patients' households. As interruption of transmission is imminent in many countries, a test to detect infected asymptomatic individuals who can perpetuate transmission is required. Antibodies directed against M. leprae antigens are indicative of M. leprae infection but cannot discriminate between active and past infection. Seroprevalence in young children, however, reflects recent M. leprae infection and may thus be used to monitor transmission in an area. Therefore, this literature review aimed to evaluate what has been reported on serological tests measuring anti-M. leprae antibodies in children without leprosy below the age of 15 in leprosy-endemic areas. METHODS AND FINDINGS: A literature search was performed in the databases Pubmed, Infolep, Web of Science and The Virtual Health Library. From the 724 articles identified through the search criteria, 28 full-text articles fulfilled all inclusion criteria. Two additional papers were identified through snowballing, resulting in a total of 30 articles reporting data from ten countries. All serological tests measured antibodies against phenolic glycolipid-I or synthetic derivatives thereof, either quantitatively (ELISA or UCP-LFA) or qualitatively (ML-flow or NDO-LID rapid test). The median seroprevalence in children in endemic areas was 14.9% and was stable over time if disease incidence remained unchanged. Importantly, seroprevalence decreased with age, indicating that children are a suitable group for sensitive assessment of recent M. leprae infection. However, direct comparison between areas, solely based on the data reported in these studies, was impeded by the use of different tests and variable cut-off levels. CONCLUSIONS: Quantitative anti-PGL-I serology in young children holds promise as a screening test to assess M. leprae infection and may be applied as a proxy for transmission and thereby as a means to monitor the effect of (prophylactic) interventions on the route to leprosy elimination.

Mycobacterium indicus pranii vaccine immunoprophylaxis in anti-phenolic glycolipid-1-positive leprosy contacts - A pilot study from a tertiary care center in North India.

BACKGROUND: Contacts of leprosy patients have an increased risk of infection with Mycobacterium leprae. Contact tracing and chemo- or immunoprophylaxis are important means of preventing leprosy transmission. AIMS: We aimed to evaluate the efficacy of immunoprophylaxis with Mycobacterium indicus pranii vaccine in reducing anti-phenolic glycolipid-1 titers in household contacts of leprosy patients. METHODS: This prospective single-center study was conducted in a tertiary care center in North India from January 2015 to December 2016. Contacts of leprosy patients (both paucibacillary and multibacillary) were screened for anti-phenolic glycolipid-1 antibodies with enzyme-linked immunosorbent assay. Those found positive were given immunoprophylaxis with a single dose of Mycobacterium indicus pranii vaccine, and anti-phenolic glycolipid-1 titers were evaluated at six and 12 months. All contacts were clinically followed for three years. RESULTS: Of the 135 contacts of 98 leprosy patients that were screened, 128 were recruited. Seventeen of these contacts were positive for anti-phenolic glycolipid-1 antibodies and were given Mycobacterium indicus pranii vaccine. Two contacts were lost to follow-up. After immunoprophylaxis, anti-phenolic glycolipid-1 titers were negative in all patients at all intervals, and no contact developed any clinical signs or symptoms of leprosy during the three-year follow-up. LIMITATIONS: The small number of contacts studied, the short follow-up period and the absence of a control group were limitations of this study. Dicussion: We could not find any papers on natural decline of PGL 1 titres in contacts, although in leprosy patients, these titres may even increase after completion of treatment. However the titres do correlate with bacterial load (reference: Int J Lepr Other Mycobact Dis. 1998 Sep;66(3):356-64) so if the tires decrease or become negative it may be considered as an indirect evidence of bacillary clearance. Hence we may suggest the protective efficacy. Furthermore, as the editor mentioned, considering the small number of positive patients, a control group was not possible in the present pilot study, but such studies may be carried out in the future. CONCLUSION: Immunoprophylaxis with Mycobacterium indicus pranii vaccine is effective and safe in preventing disease in contacts of leprosy patients. However, these findings need to be replicated in larger studies.

High-risk transmission clusters of leprosy in an endemic area in the Northeastern Brazil: A retrospective spatiotemporal modelling (2001-2019).

OBJECTIVES: To analyse and map the leprosy risk areas in the state of Alagoas, an endemic region in the Northeastern Brazil, between 2001 and 2019. METHODS: Ecological and time series study, using spatial analysis techniques. First, we analyse the epidemiological aspects of leprosy cases, using the data available in the Notifiable Diseases Information System; then, we used the segmented log-linear regression model to assess time trends. Spatial distribution was analysed by the Local Empirical Bayesian Estimator and by calculating the Global and Local Moran Index. Finally, spatiotemporal clusters were identified through scanning statistics, using the Kulldorf method of retrospective analysis. RESULTS: We observed that Alagoas showed an average new case detection rate of 14.43/100,000 inhabitants between 2001 and 2019, being classified as highly endemic. The area of highest risk was the 9th health region (state hinterland), with increasing time trend (Annual Percentage Change/APC = 7.2; p-value < 0.05). Several clusters of high risk of leprosy transmission were verified in Alagoas, including the state capital and hinterland municipalities. CONCLUSIONS: Our data indicate that active M. leprae transmission persists in Alagoas; that diagnosis is delayed and that there are high-risk areas, especially in inland municipalities.

Predictive nomogram for leprosy using genetic and epidemiological risk factors in Southwestern China: Case-control and prospective analyses.

BACKGROUND: There is a high incidence of leprosy among house-contacts compared with the general population. We aimed to establish a predictive model using these genetic factors along with epidemiological factors to predict leprosy risk of leprosy household contacts (HHCs). METHODS: Weighted genetic risk score (wGRS) encompassing genome wide association studies (GWAS) variants and five non-genetic factors were examined in a case-control design associated with leprosy risk including 589 cases and 647 controls from leprosy HHCs. We constructed a risk prediction nomogram and evaluated its performance by concordance index (C-index) and calibration curve. The results were validated using bootstrap resampling with 1000 resamples and a prospective design including 1100 HHCs of leprosy patients. FINDING: The C-index for the risk model was 0·792 (95% confidence interval [CI] 0·768-0·817), and was confirmed to be 0·780 through bootstrapping validation. The calibration curve for the probability of leprosy showed good agreement between the prediction of the nomogram and actual observation. HHCs were then divided into the low-risk group (nomogram score ≤ 81) and the high-risk group (nomogram score > 81). In prospective analysis, 12 of 1100 participants had leprosy during 63 months' follow-up. We generated the nomogram for leprosy in the validation cohort (C-index 0·773 [95%CI 0·658-0·888], sensitivity75·0%, specificity 66·8%). Interpretation The nomogram achieved an effective prediction of leprosy in HHCs. Using the model, the risk of an individual contact developing leprosy can be determined, which can lead to a rational preventive choice for tracing higher-risk leprosy contacts. FUNDING: The ministry of health of China, ministry of science and technology of China, Chinese academy of medical sciences, Jiangsu provincial department of science and technology, Nanjing municipal science and technology bureau.

Mycobacterium leprae transmission characteristics during the declining stages of leprosy incidence: A systematic review.

BACKGROUND: Leprosy is an infectious disease caused by Mycobacterium leprae. As incidence begins to decline, the characteristics of new cases shifts away from those observed in highly endemic areas, revealing potentially important insights into possible ongoing sources of transmission. We aimed to investigate whether transmission is driven mainly by undiagnosed and untreated new leprosy cases in the community, or by incompletely treated or relapsing cases. METHODOLOGY/PRINCIPAL FINDINGS: A literature search of major electronic databases was conducted in January, 2020 with 134 articles retained out of a total 4318 records identified (PROSPERO ID: CRD42020178923). We presented quantitative data from leprosy case records with supporting evidence describing the decline in incidence across several contexts. BCG vaccination, active case finding, adherence to multidrug therapy and continued surveillance following treatment were the main strategies shared by countries who achieved a substantial reduction in incidence. From 3950 leprosy case records collected across 22 low endemic countries, 48.3% were suspected to be imported, originating from transmission outside of the country. Most cases were multibacillary (64.4%) and regularly confirmed through skin biopsy, with 122 cases of suspected relapse from previous leprosy treatment. Family history was reported in 18.7% of cases, while other suspected sources included travel to high endemic areas and direct contact with armadillos. None of the countries included in the analysis reported a distinct increase in leprosy incidence in recent years. CONCLUSIONS/SIGNIFICANCE: Together with socioeconomic improvement over time, several successful leprosy control programmes have been implemented in recent decades that led to a substantial decline in incidence. Most cases described in these contexts were multibacillary and numerous cases of suspected relapse were reported. Despite these observations, there was no indication that these cases led to a rise in new secondary cases, suggesting that they do not represent a large ongoing source of human-to-human transmission.

Afectación familiar de la enfermedad de Hansen en Costa Rica / Impact of Hansen's disease on relatives of patients in Costa Rica

Resumen Objetivo: El contagio familiar de la enfermedad de Hansen es un hecho bien establecido; aunque la transmisibilidad es baja, los contactos intradomiciliarios de personas enfermas sin tratamiento son un grupo con alto riesgo. El objetivo del estudio fue identificar las características sociodemográficas, culturales y clínicas comunes en grupos familiares, con antecedente de enfermedad de Hansen, como insumo para mejorar el tratamiento de la lepra. Metodología: Se realizó un estudio cualitativo, empleando la técnica de entrevista en profundidad semiestructurada, basándose en una guía de entrevista elaborada, y tomando como referencia factores sociodemográficos, sociales y culturales relacionados con el diagnóstico y tratamiento. Se seleccionaron 25 personas adultas entre 23 y 88 años de edad, de ambos sexos atendidos por el sistema de salud público costarricense. Se utilizaron genogramas para identificar miembros de la familia con antecedentes de la enfermedad. Resultados: El estudio mostró que 12 participantes provenían de 3 grupos familiares; dos grupos con tres generaciones afectadas. Los participantes fueron diagnosticados en edades económicamente activas de vida. Además, realizan ocupaciones manuales, con niveles educativos bajos y de religión cristiana. Al momento de la entrevista conocían el antecedente familiar. La forma de presentación clínica en los tres grupos familiares fue Lepra lepromatosa. Se identificó un caso de lepra conyugal y una participante de 15 años de edad al diagnóstico. Conclusiones: El estudio identificó características sociodemográficas, culturales y clínicas comunes de grupos familiares, que evidenciaron la necesidad de fortalecer la vigilancia de contactos en familias con nuevos casos.

Abstract Aim: Leprosy transmission within family groups is a well-established fact. Although transmissibility is low, household contacts are high-risk population. The aim of the study was to identify common sociodemographic, cultural and clinical characteristics in family groups with history of Hansen's disease as an input to improve treatment. Methodology: A qualitative study was carried out, using in-depth semi-structured interview technique based on leprosy diagnosis and treatment in sociodemographic, social and cultural context. A total of 25 adults between 23 and 88 years of age included both sexes attended by Costa Rican public health care system were selected. Genograms were used to identify family history of disease. Results: The study shows that 12 participants came from 3 family groups; two of them with third affected generation. The participants were diagnosed in economically active periods of life, work in manual occupations, with low level of education and Christians. At the time of the interview, participants knew the family history. The clinical presentation form was lepromatouse leprosy. A conjugal leprosy and a 15-year-old participant at diagnosis were identified. Conclusions: The study identified common sociodemographic, cultural and clinical characteristics of family groups that demonstrate the need to strengthen contact surveillance efforts in families with new cases.

Leprosy incidence and risk estimates in a 33-year contact cohort of leprosy patients.

Reduction in incidence has been associated with the introduction of novel approaches, like chemo/immune-prophylaxis. Incidence determined through follow-up cohort studies can evaluate the implementation of these innovative policies towards control and prevention. We have assessed the incidence in our contacts cohort over past 33 years, considering the effect of demographic and clinical variables. Survival analysis was used to estimate the risk of leprosy. A total of 9024 contacts were evaluated, of which 192 developed leprosy, resulting in an overall incidence of 1.4/1000 person-years. The multivariate analysis showed that the major risk factors were (i) contact from MB index cases and (ii) consanguinity (iii) intra household contact. Lower risk was detected for contacts with BCG scar who were revaccinated. There was a significant decrease in accumulated risk between the 2011-2019 period compared with 1987, probably linked to the improvement in laboratory tools to monitor contacts, thereby providing early diagnosis of contacts at intake and reduction of transmission. Our findings suggest that a combination of contact surveillance and tracing, adequate neurodermatological examination, and availability of molecular tools is highly effective in supporting early diagnosis, while a second dose of the BCG vaccination can exert extra protection.

Zoonotic risk of Hansen's disease from community contact with wild armadillos: A systematic review and meta-analysis.

Understanding and quantifying the risk of Hansen's disease (HD) through zoonotic transmission of Mycobacterium leprae infection from wild armadillos is important because hunting, handling and consumption of these animals is widespread in communities where HD is endemic, posing a potential threat to the health of individuals and to HD elimination. We conducted a systematic review (PROSPERO CRD42019159891) of publications in MEDLINE, EMBASE, Global Health, Scopus, LILACS, Biblioteca Digital Brasileira de Teses e Dissertações, Catálogo de Teses e Dissertações de CAPES, and Biblioteca Virtual em Saúde up to 09/05/2020 using Mesh and text terms in English, Portuguese, Spanish and French. Random effects meta-analyses were performed including of subgroups by endemicity and type of exposure. Seven of the nine included studies were case-control, four from Brazil and three from the USA, comprising 1,124 cases and 2,023 controls in total. The other two studies, one from Brazil and one from Colombia, were cross-sectional. The overall summary estimate (odds ratio, OR) for the relative odds of HD comparing people who had direct contact with armadillos and/or had eaten armadillo meat with those who had not was OR = 2.60 (95% CI 1.78-3.80, p < .001) with a predictive interval of OR = 1.10-6.17. Summary odds ratios for specific exposures were as follows: indirect contact, OR = 1.39 (95% CI 1.02, 1.89) (p = .04); eating, OR = 2.29 (95% CI 1.13, 4.66) (p = .02); hunting, OR = 2.54 (95% CI 1.21, 5.33) (p = .01). Most of the included studies had moderate risk of bias. Crude estimates were reduced by up to 24% when adjusted for confounders (where reported). Direct contact with wild armadillos was strongly associated with an increased risk of HD, whilst evidence for an increased risk of HD from indirect contact was weaker. The fraction of HD in endemic countries attributable to zoonotic transmission from armadillos remains unknown, but the precautionary principle needs to be adopted to protect public health.

Estratégia estadual para enfrentamento da hanseníase: Goiás 2019 a 2023 / State Strategy to Combat Leprosy Goiás 2019 to 2023

A hanseníase é uma doença infecciosa, crônica, transmissível, de notificação compulsória e investigação obrigatória em todo o território nacional. Possui como agente etiológico o Mycobacterium leprae, uma bactéria que atinge principalmente a pele e os nervos periféricos, com capacidade de infectar grande número de indivíduos (alta infectividade), embora poucos adoeçam ­ baixa patogenicidade (BRASIL, 2019a, p. 9)

Leprosy is an infectious, chronic, communicable disease, of compulsory notification and mandatory investigation throughout the national territory. It has like etiological agent Mycobacterium leprae, a bacterium that mainly affects the skin and peripheral nerves, with the ability to infect a large number of individuals (high infectivity), although few get sick ­ low pathogenicity (BRASIL, 2019a, p. 9)

Association of MICA and HLA­B alleles with leprosy in two endemic populations in Brazil

Leprosy is a prevalent disease in Brazil, which ranks as the country with the second highest number of cases in the world. The disease manifests in a spectrum of forms, and genetic differences in the host can help to elucidate the immunopathogenesis. For a better understanding of MICA association with leprosy, we performed a case­control and a family­based study in two endemic populations in Brazil. MICA and HLA­B alleles were evaluated in 409 leprosy patients and in 419 healthy contacts by PCR­SSOP­Luminex­based technology. In the familial study, analysis of 46 families was completed by direct sequencing of all exons and 3'/5'untranslated regions, using the Ilumina MiSeq platform. All data were collected between 2006 and 2009. Statistical analysis was performed using the Chi­square or Fisher's exact test together with a multivariate analysis. Family­based association was assessed by transmission disequilibrium test (TDT) software FBAT 2.0.4. We found associations between the haplotype MICA*002­HLA­B*35 with leprosy in both the per se and the multibacillary (MB) forms when compared to healthy contacts. The MICA allele *008 was associated with the clinical forms of paucibacillary (PB). Additionally, MICA*029 was associated with the clinical forms of MB. The association of MICA*029 allele (MICA­A4 variant) with the susceptibility to the MB form suggests this variant for the transmembrane domain of the MICA molecule may be a risk factor for leprosy. Two MICA and nine HLA­B variants were found associated with leprosy per se in the Colônia do Prata population. Linkage disequilibrium analysis revealed perfect linkage disequilibrium (LD) between HLA­B markers rs2596498 and rs2507992, and high LD (R2 = .92) between these and the marker rs2442718. This familial study demonstrates that MICA association signals are not independent from those observed for HLA­B. Our findings contribute the knowledge pool of the immunogenetics of Hansen's disease and reveals a new association of the MICA*029 allele(AU).

Predição do risco de adoecimento por hanseníase em contatos de casos da doença de uma região endêmica brasileira / Risk prediction of illness due to leprosy in contacts of cases in an endemic Brazilian region

O objetivo deste estudo foi analisar os determinantes da infecção pelo Mycobacterium leprae e do adoecimento por hanseníase em contatos de casos da doença, residentes na Microrregião de Almenara, Minas Gerais, Brasil, a fim de compor um modelo de predição da hanseníase em contatos inseridos em regiões endêmicas. Trata-se de uma coorte retrospectiva de contatos domiciliares de casos de hanseníasecom período de acompanhamento de 1999 a 2018. Foi realizada coleta de dados com entrevista, aplicação de questionário semiestruturado, contendo informações sociodemográficas e de saúde, coleta de amostras biológicas e exame dermatoneurológico. As amostras biológicas subsidiaram a avaliação de polimorfismos genéticos e reatividade aos testes sorológicos. A escolha das variáveis explicativas incluídas nas análises se fundamentou no modelo teórico dos determinantes da hanseníase em contatos, elaborado a partir da realização de revisão sistemática. A análise de associação utilizou modelo de regressão logística por meio do método de estimação Generalized Estimating Equations. A construção do modelo de predição envolveu análise exploratória dos dados e aplicação de algoritmos de aprendizagem de máquina. Os determinantes da infecção pelo M. leprae foram: a cor de pele negra e parda, a presença de genótipos contendo o polimorfismo rs8057341 no gene NOD2 (Nucleotide-binding Oligomerization Domain Containing 2) e o convívio com caso apresentando incapacidades físicas no diagnóstico. Os determinantes do adoecimento por hanseníase foram: consanguinidade com o caso índice e a continuidade do convívio em intradomicílio ou peridomicílio após o diagnóstico do caso. A idade, o contato domiciliar e peridomiciliar, o convívio com mais de um caso e a presença de incapacidades físicas no diagnóstico foram determinantes para o risco à infecção e ao adoecimento em contatos. O genótipo heterozigoto contendo o polimorfismo rs2430561 no gene IFNG (Interferon-gama) foi fator protetor para a infecção e adoecimento em contatos. Os algoritmos de aprendizagem supervisionada Naive Bayes com discretização das variáveis numéricas, J48 e Random Forest tiveram os melhores desempenhos nos conjuntos de dados avaliados. Os determinantes do processo de infecção e adoecimento por hanseníase foram capazes de compor modelos de predição com a acurácia e sensibilidade superiores a 90% e indicam que a vigilância de contatos pode ser aprimorada pela utilização destas tecnologias nos serviços de Atenção Primária à Saúde, principalmente, em áreas de alta endemicidade.

This study aimed to investigate the determinants of Mycobacterium leprae infection and illness due to leprosy in contacts of cases of the disease in the Microregion of Almenara, Minas Gerais, Brazil, to support the construction of a leprosy prediction model in contacts of patients from endemic regions. We conducted a retrospective cohort of household contacts of leprosy patients with a follow-up period from 1999 to 2018. The researchers performed interviews using a semi-structured questionnaire containing sociodemographic and health questions, biological samples collection, and dermatological examination. Biological samples supported the evaluation of genetic polymorphisms and reactivity to serological tests. The choice of the explanatory variables included in the analysis was based on the theoretical model of the determinants of leprosy in contacts, developed from a systematic review. The association analysis used a logistic regression model using the Generalized Estimating Equations estimation method. The construction of the prediction model involved exploratory data analysis and applied machine learning algorithms. The determinants of M. leprae infection were: black and mixed skin color, homozygous and heterozygous genotypes containing the rs8057341 polymorphism in the NOD2 gene (Nucleotide-binding Oligomerization Domain Containing 2), and living with a leprosy patient with disabilities at diagnosis. The determinants of illness due to leprosy in contacts were: consanguinity with the index case and living in the same household or yard after the diagnosis of the leprosy patient. Age, living in the same household or lot, with more than one leprosy patient that presented disabilities at the diagnosis were determinants for the risk of infection and illness in contacts. The heterozygous genotype that carried the rs2430561 polymorphism in the IFNG gene (Interferon-gamma) was a protective factor for M. leprae infection and leprosy in contacts of patients. The supervised learning algorithms Naive Bayes with the discretization of numerical variables, J48 and Random Forest had the best performances in the evaluated datasets. The determinants of the process of infection and illness due to leprosy were able to compose prediction models with accuracy and sensitivity higher than 90%. These results indicate that using these technologies in Primary Health Care services can improve contact surveillance, especially in highly endemic areas.

Patients with skin smear positive leprosy in Bangladesh are the main risk factor for leprosy development: 21-year follow-up in the household contact study (COCOA).

BACKGROUND: Leprosy transmission is ongoing; globally and within Bangladesh. Household contacts of leprosy cases are at increased risk of leprosy development. Identification of household contacts at highest risk would optimize this process. METHODS: The temporal pattern of new case presentation amongst household contacts was documented in the COCOA (Contact Cohort Analysis) study. The COCOA study actively examined household contacts of confirmed leprosy index cases identified in 1995, and 2000-2014, to provide evidence for timings of contact examination policies. Data was available on 9527 index cases and 38303 household contacts. 666 household contacts were diagnosed with leprosy throughout the follow-up (maximum follow-up of 21 years). Risk factors for leprosy development within the data analysed, were identified using Cox proportional hazard regression. FINDINGS: The dominant risk factor for household contacts developing leprosy was having a highly skin smear positive index case in the household. As the grading of initial slit skin smear of the index case increased from negative to high positive (4-6), the hazard of their associated household contacts developing leprosy increases by 3.14 times (p<0.001). Being a blood relative was not a risk factor, no gender differences in susceptibility were found. INTERPRETATION: We found a dominance of a single variable predicting risk for leprosy transmission-skin smear positive index cases. A small number of cases are maintaining transmission in the household setting. Focus should be performing contact examinations on these households and detecting new skin smear positive index cases. Conducting slit-skin smears on new cases is needed for predicting risk; such services need supporting. If skin smear positive cases are sustaining leprosy infection within the household setting, the administration of single-dose rifampicin (SDR) to household contacts as the sole intervention in Bangladesh will not be effective.

Molecular epidemiology of leprosy: An update.

Molecular epidemiology investigations are notoriously challenging in the leprosy field mainly because the inherent characteristics of the disease as well as its yet uncultivated causative agents, Mycobacterium leprae and M. lepromatosis. Despite significant developments in understanding the biology of leprosy bacilli through genomic approaches, the exact mechanisms of transmission is still unclear and the factors underlying pathological variation of the disease in different patients remain as major gaps in our knowledge about leprosy. Despite these difficulties, the last two decades have seen the development of genotyping procedures based on PCR-sequencing of target loci as well as by the genome-wide analysis of an increasing number of geographically diverse isolates of leprosy bacilli. This has provided a foundation for molecular epidemiology studies that are bringing a better understanding of strain evolution associated with ancient human migrations, and phylogeographical insights about the spread of disease globally. This review discusses the advantages and drawbacks of the main tools available for molecular epidemiological investigations of leprosy and summarizes various methods ranging from PCR-based genotyping to genome-typing techniques. We also describe their main applications in analyzing the short-range and long-range transmission of the disease. Finally, we summarise the current gaps and challenges that remain in the field of molecular epidemiology of leprosy.

Autochthonous leprosy in Spain: Has the transmission of Mycobacterium leprae stopped?

BACKGROUND: The aim of this study is to explore whether transmission of M. leprae has ceased in Spain, based upon the patterns and trends of notified cases. METHODOLOGY: Data on new cases reported to the National Leprosy Registry between the years 2003-2018 were extracted. In absence of detailed travel history, cases were considered "autochthonous" or "imported" based on whether they were born within or outside of Spain. These data were analyzed by age, sex, clinical type, country of origin, and location of residence at time of notification. PRINCIPAL FINDINGS: Data were available on 61 autochthonous and 199 imported cases since 2003. There were clear declines in incidence in both groups, and more imported than autochthonous cases every year since 2006. Autochthonous cases were more frequently multibacillary and had older age at diagnosis compared to imported cases. All the autochthonous cases had been born before 1985 and were more than 25 years old at diagnosis. Male-to-female ratio increased with time for autochthonous cases (except for the last time period). The imported cases originated from 25 countries, half of them from Brasil and Paraguay. Autochthonous cases were mainly distributed in the traditionally endemic regions, especially Andalucía and the eastern Mediterranean coast. CONCLUSIONS: Autochthonous and imported cases have different epidemiologic patterns in Spain. There was a clear decline in incidence rates of autochthonous disease, and patterns consistent with those reported from other regions where transmission has ceased. Autochthonous transmission of M. leprae is likely to have now effectively stopped in Spain.

Post-exposure prophylaxis (PEP) efficacy of rifampin, rifapentine, moxifloxacin, minocycline, and clarithromycin in a susceptible-subclinical model of leprosy.

BACKGROUND: Subclinical infection with Mycobacterium leprae is one potential source of leprosy transmission, and post-exposure prophylaxis (PEP) regimens have been proposed to control this source. Because PEP trials require considerable investment, we applied a sensitive variation of the kinetic mouse footpad (MFP) screening assay to aid in the choice of drugs and regimens for clinical trials. METHODOLOGY/PRINCIPAL FINDINGS: Athymic nude mice were inoculated in the footpad (FP) with 6 x 103 viable M. leprae and treated by gastric gavage with a single dose of Rifampin (SDR), Rifampin + Ofloxacin + Minocycline (SD-ROM), or Rifapentine + Minocycline + Moxifloxacin (SD-PMM) or with the proposed PEP++ regimen of three once-monthly doses of Rifampin + Moxifloxacin (RM), Rifampin + Clarithromycin (RC), Rifapentine + Moxifloxacin (PM), or Rifapentine + Clarithromycin (PC). At various times post-treatment, DNA was purified from the FP, and M. leprae were enumerated by RLEP quantitative PCR. A regression analysis was calculated to determine the expected RLEP value if 99.9% of the bacilli were killed after the administration of each regimen. SDR and SD-ROM induced little growth delay in this highly susceptible murine model of subclinical infection. In contrast, SD-PMM delayed measurable M. leprae growth above the inoculum by 8 months. The four multi-dose regimens delayed bacterial growth for >9months post-treatment cessation. CONCLUSIONS/SIGNIFICANCE: The delay in discernable M. leprae growth post-treatment was an excellent indicator of drug efficacy for both early (3-4 months) and late (8-9 months) drug efficacy. Our data indicates that multi-dose PEP may be required to control infection in highly susceptible individuals with subclinical leprosy to prevent disease and decrease transmission.