Prediction of the occurrence of leprosy reactions based on Bayesian networks.

Introduction: Leprosy reactions (LR) are severe episodes of intense activation of the host inflammatory response of uncertain etiology, today the leading cause of permanent nerve damage in leprosy patients. Several genetic and non-genetic risk factors for LR have been described; however, there are limited attempts to combine this information to estimate the risk of a leprosy patient developing LR. Here we present an artificial intelligence (AI)-based system that can assess LR risk using clinical, demographic, and genetic data. Methods: The study includes four datasets from different regions of Brazil, totalizing 1,450 leprosy patients followed prospectively for at least 2 years to assess the occurrence of LR. Data mining using WEKA software was performed following a two-step protocol to select the variables included in the AI system, based on Bayesian Networks, and developed using the NETICA software. Results: Analysis of the complete database resulted in a system able to estimate LR risk with 82.7% accuracy, 79.3% sensitivity, and 86.2% specificity. When using only databases for which host genetic information associated with LR was included, the performance increased to 87.7% accuracy, 85.7% sensitivity, and 89.4% specificity. Conclusion: We produced an easy-to-use, online, free-access system that identifies leprosy patients at risk of developing LR. Risk assessment of LR for individual patients may detect candidates for close monitoring, with a potentially positive impact on the prevention of permanent disabilities, the quality of life of the patients, and upon leprosy control programs.

National Health Survey reveals high percentage of signs and symptoms of leprosy in Brazil. / Pesquisa Nacional de Saúde revela alto percentual de sinais e sintomas de hanseníase no Brasil.

Leprosy is a debilitating, infectious, systemic or localized dermato-neurological disease caused by Mycobacterium lepra. In Brazil, the magnitude and high disabling power keep the disease as a public health problem. Skin spotting and numbness are pathognomonic signs and symptoms in leprosy. The Instituto Brasileiro de Geografia e Estatística (IBGE) 2019 National Health Survey (PNS-2019) considered the following question as a proxy to estimate its magnitude in the country. "Do you have a spot with numbness or part of the skin with numbness?". In Brazil, 1,921,289 adults reported having a patch or part of the skin with numbness, with no regional differences. As for the age group, the older, the higher the prevalence, for example, between 18 to 29 years old (235,445) and 30 to 39 years old (236,485), 0.7% had the condition, between 40 to 59 years old (827,887), 1.5% and among the elderly, 1.8% (621,472). Being able to estimate, in population-based surveys, with statistical representativeness, a reported morbidity such as leprosy is essential to support the formulation of public policies, notably those related to primary health care actions. In this way, the IBGE fulfills its constitutional role of portraying the reality of the Brazilian population and today it is the main external evaluator of the Unified Health System (SUS) and of public policies developed by the federal level.

A hanseníase é uma doença dermato-neurológica, infecciosa, sistêmica ou localizada, debilitante, causada por Mycobacterium leprae. No Brasil, a magnitude e o alto poder incapacitante mantêm a doença como um problema de saúde pública. Mancha na pele e dormência são sinais e sintomas patognomônicos na hanseníase. A Pesquisa Nacional de Saúde de 2019 (PNS-2019), do Instituto Brasileiro de Geografia e Estatística (IBGE), considerou a seguinte pergunta como proxy para estimar sua magnitude no país. "O(a) sr(a). tem mancha com dormência ou parte da pele com dormência?". No Brasil, 1.921.289 adultos referiram ter mancha ou parte da pele com dormência, sem diferenças regionais. Com relação ao grupo etário, quanto mais velho, maior a prevalência. Por exemplo, entre os de 18 a 29 anos (235.445) e de 30 a 39 anos (236.485), 0,7% possuía a condição, entre 40 e 59 anos (827.887), 1,5%, e entre os idosos, 1,8% (621.472). Poder estimar, em pesquisas de base populacional, com representatividade estatística, uma morbidade referida tal como a hanseníase é fundamental para apoiar a formulação de políticas públicas, notadamente as relativas às ações da atenção primária à saúde. Dessa forma, o IBGE cumpre seu papel constitucional de retratar a realidade da população brasileira e hoje é o principal avaliador externo do Sistema Único de Saúde (SUS) e das políticas públicas instituídas no âmbito federal.

Pesquisa Nacional de Saúde revela alto percentual de sinais e sintomas de hanseníase no Brasil / National Health Survey reveals high percentage of signs and symptoms of leprosy in Brazil

Resumo A hanseníase é uma doença dermato-neurológica, infecciosa, sistêmica ou localizada, debilitante, causada por Mycobacterium leprae. No Brasil, a magnitude e o alto poder incapacitante mantêm a doença como um problema de saúde pública. Mancha na pele e dormência são sinais e sintomas patognomônicos na hanseníase. A Pesquisa Nacional de Saúde de 2019 (PNS-2019), do Instituto Brasileiro de Geografia e Estatística (IBGE), considerou a seguinte pergunta como proxy para estimar sua magnitude no país. "O(a) sr(a). tem mancha com dormência ou parte da pele com dormência?". No Brasil, 1.921.289 adultos referiram ter mancha ou parte da pele com dormência, sem diferenças regionais. Com relação ao grupo etário, quanto mais velho, maior a prevalência. Por exemplo, entre os de 18 a 29 anos (235.445) e de 30 a 39 anos (236.485), 0,7% possuía a condição, entre 40 e 59 anos (827.887), 1,5%, e entre os idosos, 1,8% (621.472). Poder estimar, em pesquisas de base populacional, com representatividade estatística, uma morbidade referida tal como a hanseníase é fundamental para apoiar a formulação de políticas públicas, notadamente as relativas às ações da atenção primária à saúde. Dessa forma, o IBGE cumpre seu papel constitucional de retratar a realidade da população brasileira e hoje é o principal avaliador externo do Sistema Único de Saúde (SUS) e das políticas públicas instituídas no âmbito federal.

Abstract Leprosy is a debilitating, infectious, systemic or localized dermato-neurological disease caused by Mycobacterium lepra. In Brazil, the magnitude and high disabling power keep the disease as a public health problem. Skin spotting and numbness are pathognomonic signs and symptoms in leprosy. The Instituto Brasileiro de Geografia e Estatística (IBGE) 2019 National Health Survey (PNS-2019) considered the following question as a proxy to estimate its magnitude in the country. "Do you have a spot with numbness or part of the skin with numbness?". In Brazil, 1,921,289 adults reported having a patch or part of the skin with numbness, with no regional differences. As for the age group, the older, the higher the prevalence, for example, between 18 to 29 years old (235,445) and 30 to 39 years old (236,485), 0.7% had the condition, between 40 to 59 years old (827,887), 1.5% and among the elderly, 1.8% (621,472). Being able to estimate, in population-based surveys, with statistical representativeness, a reported morbidity such as leprosy is essential to support the formulation of public policies, notably those related to primary health care actions. In this way, the IBGE fulfills its constitutional role of portraying the reality of the Brazilian population and today it is the main external evaluator of the Unified Health System (SUS) and of public policies developed by the federal level.

A social network approach for the study of leprosy transmission beyond the household.

BACKGROUND: Mycobacterium leprae was the first microorganism directly associated with a disease, however, there are still important gaps in our understanding of transmission. Although household contacts are prioritized, there is evidence of the importance of extrahousehold contacts. The goal of this article is to contribute to our understanding of the transmission of leprosy ex-household. METHODS: We compare co-location data of 397 leprosy cases and 211 controls drawn from the Centro de Dermatologia Sanitária D. Libânia in Fortaleza, Brazil. We collected lifetime geolocation data related to residence, school attendance and workplace and developed novel methods to establish a critical distance (Rc) for exposure and evaluated the potential for transmission for residence, school and workplace. RESULTS: Our methods provide different threshold values of distance for residence, school and workplace. Residence networks demonstrate an Rc of about 500 m. Cases cluster in workplaces as well. Schools do not cluster cases. CONCLUSIONS: Our novel network approach offers a promising opportunity to explore leprosy transmission. Our networks confirm the importance of coresidence, provide a boundary and suggest a role for transmission in workplaces. Schools, on the other hand, do not demonstrate a clustering of cases. Our findings may have programmatic relevance.

[Factors associated with timing of lepra reactions in a cohort from 2008 to 2016 in Rondônia, Amazon Region, Brazil]. / Fatores associados ao tempo de ocorrência das reações hansênicas numa coorte de 2008 a 2016 em Rondônia, Região Amazônica, Brasil.

The clinical management of leprosy patients poses a specific challenge, namely lepra reactions. This non-concurrent cohort study aimed to analyze the timing of the first lepra reaction during and after polychemotherapy (PCT) and associated factors. A total of 1,621 patients were assessed (PB = 8.9% and MB = 91.1%) from 2008 to 2016, reported to the System of Reaction States in Leprosy (SisReação/RO) database. Reactions occurred predominantly during PCT (997; 61.5%) and less frequently only after PCT (624; 38.5%). Earliness of the reaction after diagnosis was analyzed with Kaplan-Meier survival curves, with comparison between the PB and MB groups using the Mantel-Cox log-rank test. Univariate and multivariate Cox regression models were constructed to identify factors associated with occurrence of lepra reactions (hazard ratio) and the corresponding 95%CI. The multivariate model included variables with p-values < 0.20 in the univariate analysis. PB patients developed reactions earlier than MB patients. Other characteristics were associated with earlier reactions: female gender and negative smear microscopy. In the aggregate period (during and after PCT), PB presented 24% higher risk of lepra reaction than MB patients, and negative smear microscopy increased this risk by 40% compared to positive smear microscopy. During and after PCT, PB presented 1.3 and 1.6 times the risk, respectively, of reactions when compared to MB patients. We thus recommend prioritizing surveillance of lepra reactions during and after PCT as measures to prevent physical disabilities and to improve quality of life for persons with leprosy.

O manejo clínico de pacientes com hanseníase apresenta um desafio particular que são as reações. O objetivo deste estudo de coorte não concorrente foi analisar o tempo e fatores associados à ocorrência da primeira reação durante e após o tratamento da poliquimioterapia (PQT). Avaliou-se 1.621 pacientes paucibacilares (PB = 8,9%) e multibacilares (MB = 91,1%) de 2008 a 2016 notificados no Sistema de Estados Reacionais em Hanseníase/Rondônia (SisReação/RO). Prevaleceu a ocorrência durante o tratamento da PQT = 997 (61,5%), e 624 (38,5%) somente após o PQT. A precocidade da reação, a partir do diagnóstico, foi analisada por meio de curvas de sobrevida de Kaplan-Meier e comparadas entre os grupos PB e MB, usando o teste de log-rank de Mantel-Cox; e foram construídos modelos de regressão de Cox univariada e multivariada para identificar os fatores associados à ocorrência da reação (hazard ratio) e os correspondentes IC95%. No modelo multivariado foram incluídas variáveis com valores de p < 0,2 na análise univariada. Os PB desenvolveram reação de forma mais precoce do que os MB. Outras características associaram-se à reação em menor tempo: sexo feminino e baciloscopia negativa. No período agregado (durante e após a PQT), os pacientes PB apresentaram risco 24% maior de reação do que os MB e aqueles com baciloscopia negativa aumentaram este risco em 40% comparado à baciloscopia positiva. Durante e após a PQT, os PB apresentaram 1,3 e 1,6 vezes maior risco de ocorrência da reação dos pacientes MB. Dessa forma, recomendamos priorizar ações de vigilância para reações hansênicas durante e após a PQT como medidas de prevenção de incapacidades físicas e de melhoria na qualidade de vida das pessoas acometidas pela hanseníase.

La gestión clínica de pacientes con hanseniasis presenta un desafío particular que son las reacciones. El objetivo de este estudio de cohorte no concurrente fue analizar el tiempo y factores asociados a la ocurrencia de la primera reacción durante y tras el tratamiento de la poliquimioterapia (PQT). Se evaluó a 1621 pacientes (PB = 8,9% y MB = 91,1%) de 2008 a 2016, notificados en el Sistema de Estados Reaccionarios en Lepra (SisReação/RO). Prevaleció la ocurrencia durante la PQT = 997 (61,5%), y 624 (38,5%) solamente tras la PQT. La precocidad de la reacción a partir del diagnóstico se analizó mediante curvas de supervivencia de Kaplan-Meier y se compararon entre los grupos PB y MB, usando el test de log-rank de Mantel-Cox; asimismo, se construyeron modelos de regresión univariada y multivariada de Cox para identificar los factores asociados con la ocurrencia de la reacción (cociente de riesgos) y los correspondientes IC95%. En el modelo multivariado se incluyeron las variables con valores de p < 0,2 en el análisis univariado. Los PB desarrollaron una reacción de forma más precoz que los MB. Otras características se asociaron a la reacción en menor tiempo: sexo femenino y baciloscopia negativa. En el período agregado (durante y tras PQT), los PB presentaron un riesgo un 24% mayor de reacción que los multibacilares y la baciloscopia negativa aumentó este riesgo en un 40%, comparado con la baciloscopia positiva. Durante y tras el tratamiento PQT, los PB presentaron 1,3 y 1,6 veces el riesgo de ocurrencia de la reacción de los pacientes MB. De esa forma, recomendamos priorizar acciones de vigilancia para reacciones hansénicas durante y tras PQT, como medidas de prevención de discapacidades físicas, así como de mejoría en la calidad de vida de personas afectadas por la hanseniasis.

Epidemiological characteristics and temporal trends of new leprosy cases in Brazil: 2006 to 2017.

Our study aims to describe trends in new case detection rate (NCDR) of leprosy in Brazil from 2006 to 2017 overall and in subgroups, and to analyze the evolution of clinical and treatment characteristics of patients, with emphasis on cases diagnosed with grade 2 physical disabilities. We conducted a descriptive study to analyze new cases of leprosy registered in the Brazilian Information System for Notificable Diseases (SINAN), from 2006-2017. We calculated the leprosy NCDR per 100,000 inhabitants (overall and for individuals aged < 15 and ≥ 15 years) by sex, age, race/ethnicity, urban/rural areas, and Brazilian regions, and estimated the trends using the Mann-Kendall non-parametric test. We analyzed the distributions of cases according to relevant clinical characteristics over time. In Brazil, there was a sharp decrease in the overall NCDR from 23.4/100,000 in 2006 to 10.3/100,000 in 2017; among children < 15 years, from 6.94 to 3.20/100,000. The decline was consistent in all Brazilian regions and race/ethnicity categories. By 2017, 70.2% of the cases were multibacillary, 30.5% had grade 1 (G1D) or 2 (G2D) physical disabilities at diagnosis and 42.8% were not evaluated at treatment completion/discharge; cases with G2D at diagnosis were mostly detected in urban areas (80%) and 5% of cases died during the treatment (leprosy or other causes). Although the frequency of leprosy NCDR decreased in Brazil from 2006 to 2017 across all evaluated population groups, the large number of cases with multibacillary leprosy, physical disabilities or without adequate evaluation, and among children suggest the need to reinforce timely diagnosis and treatment to control leprosy in Brazil.

Estimating underreporting of leprosy in Brazil using a Bayesian approach.

BACKGROUND: Leprosy remains concentrated among the poorest communities in low-and middle-income countries and it is one of the primary infectious causes of disability. Although there have been increasing advances in leprosy surveillance worldwide, leprosy underreporting is still common and can hinder decision-making regarding the distribution of financial and health resources and thereby limit the effectiveness of interventions. In this study, we estimated the proportion of unreported cases of leprosy in Brazilian microregions. METHODOLOGY/PRINCIPAL FINDINGS: Using data collected between 2007 to 2015 from each of the 557 Brazilian microregions, we applied a Bayesian hierarchical model that used the presence of grade 2 leprosy-related physical disabilities as a direct indicator of delayed diagnosis and a proxy for the effectiveness of local leprosy surveillance program. We also analyzed some relevant factors that influence spatial variability in the observed mean incidence rate in the Brazilian microregions, highlighting the importance of socioeconomic factors and how they affect the levels of underreporting. We corrected leprosy incidence rates for each Brazilian microregion and estimated that, on average, 33,252 (9.6%) new leprosy cases went unreported in the country between 2007 to 2015, with this proportion varying from 8.4% to 14.1% across the Brazilian States. CONCLUSIONS/SIGNIFICANCE: The magnitude and distribution of leprosy underreporting were adequately explained by a model using Grade 2 disability as a marker for the ability of the system to detect new missing cases. The percentage of missed cases was significant, and efforts are warranted to improve leprosy case detection. Our estimates in Brazilian microregions can be used to guide effective interventions, efficient resource allocation, and target actions to mitigate transmission.

Physical disabilities caused by leprosy in 100 million cohort in Brazil.

BACKGROUND: Leprosy continues to be an important cause of physical disability in endemic countries such as Brazil. Knowledge of determinants of these events may lead to better control measures and targeted interventions to mitigate its impact on affected individuals. This study investigated such factors among the most vulnerable portion of the Brazilian population. METHODS: A large cohort was built from secondary data originated from a national registry of applicants to social benefit programs, covering the period 2001-2015, including over 114 million individuals. Data were linked to the leprosy notification system utilizing data from 2007 until 2014. Descriptive and bivariate analyses lead to a multivariate analysis using a multinomial logistic regression model with cluster-robust standard errors. Associations were reported as Odds Ratios with their respective 95% confidence intervals. RESULTS: Among the original cohort members 21,565 new leprosy cases were identified between 2007 and 2014. Most of the cases (63.1%) had grade zero disability. Grades 1 and 2 represented 21 and 6%, respectively. Factors associated with increasing odds of grades 1 and 2 disability were age over 15 years old (ORs 2.39 and 1.95, respectively), less schooling (with a clear dose response effect) and being a multibacillary patient (ORs 3.5 and 8.22). Protective factors for both grades were being female (ORs 0.81 and 0.61) and living in a high incidence municipality (ORs 0.85 and 0.67). CONCLUSIONS: The findings suggest that the developing of physical disabilities remains a public health problem which increases the burden of leprosy, mainly for those with severe clinical features and worse socioeconomic conditions. Early diagnosis is paramount to decrease the incidence of leprosy-related disability and our study points to the need for strengthening control actions in non-endemic areas in Brazil, where cases may be missed when presented at early stages in disease. Both actions are needed, to benefit patients and to achieve the WHO goal in reducing physical disabilities among new cases of leprosy.

Fatores associados ao tempo de ocorrência das reações hansênicas numa coorte de 2008 a 2016 em Rondônia, Região Amazônica, Brasil / Factors associated with timing of lepra reactions in a cohort from 2008 to 2016 in Rondônia, Amazon Region, Brazil / Factores asociados al tiempo de ocurrencia de las reacciones hansénicas en una cohorte de 2008 a 2016 en Rondonia, Región Amazónica, Brasil

O manejo clínico de pacientes com hanseníase apresenta um desafio particular que são as reações. O objetivo deste estudo de coorte não concorrente foi analisar o tempo e fatores associados à ocorrência da primeira reação durante e após o tratamento da poliquimioterapia (PQT). Avaliou-se 1.621 pacientes paucibacilares (PB = 8,9%) e multibacilares (MB = 91,1%) de 2008 a 2016 notificados no Sistema de Estados Reacionais em Hanseníase/Rondônia (SisReação/RO). Prevaleceu a ocorrência durante o tratamento da PQT = 997 (61,5%), e 624 (38,5%) somente após o PQT. A precocidade da reação, a partir do diagnóstico, foi analisada por meio de curvas de sobrevida de Kaplan-Meier e comparadas entre os grupos PB e MB, usando o teste de log-rank de Mantel-Cox; e foram construídos modelos de regressão de Cox univariada e multivariada para identificar os fatores associados à ocorrência da reação (hazard ratio) e os correspondentes IC95%. No modelo multivariado foram incluídas variáveis com valores de p < 0,2 na análise univariada. Os PB desenvolveram reação de forma mais precoce do que os MB. Outras características associaram-se à reação em menor tempo: sexo feminino e baciloscopia negativa. No período agregado (durante e após a PQT), os pacientes PB apresentaram risco 24% maior de reação do que os MB e aqueles com baciloscopia negativa aumentaram este risco em 40% comparado à baciloscopia positiva. Durante e após a PQT, os PB apresentaram 1,3 e 1,6 vezes maior risco de ocorrência da reação dos pacientes MB. Dessa forma, recomendamos priorizar ações de vigilância para reações hansênicas durante e após a PQT como medidas de prevenção de incapacidades físicas e de melhoria na qualidade de vida das pessoas acometidas pela hanseníase.

The clinical management of leprosy patients poses a specific challenge, namely lepra reactions. This non-concurrent cohort study aimed to analyze the timing of the first lepra reaction during and after polychemotherapy (PCT) and associated factors. A total of 1,621 patients were assessed (PB = 8.9% and MB = 91.1%) from 2008 to 2016, reported to the System of Reaction States in Leprosy (SisReação/RO) database. Reactions occurred predominantly during PCT (997; 61.5%) and less frequently only after PCT (624; 38.5%). Earliness of the reaction after diagnosis was analyzed with Kaplan-Meier survival curves, with comparison between the PB and MB groups using the Mantel-Cox log-rank test. Univariate and multivariate Cox regression models were constructed to identify factors associated with occurrence of lepra reactions (hazard ratio) and the corresponding 95%CI. The multivariate model included variables with p-values < 0.20 in the univariate analysis. PB patients developed reactions earlier than MB patients. Other characteristics were associated with earlier reactions: female gender and negative smear microscopy. In the aggregate period (during and after PCT), PB presented 24% higher risk of lepra reaction than MB patients, and negative smear microscopy increased this risk by 40% compared to positive smear microscopy. During and after PCT, PB presented 1.3 and 1.6 times the risk, respectively, of reactions when compared to MB patients. We thus recommend prioritizing surveillance of lepra reactions during and after PCT as measures to prevent physical disabilities and to improve quality of life for persons with leprosy.

La gestión clínica de pacientes con hanseniasis presenta un desafío particular que son las reacciones. El objetivo de este estudio de cohorte no concurrente fue analizar el tiempo y factores asociados a la ocurrencia de la primera reacción durante y tras el tratamiento de la poliquimioterapia (PQT). Se evaluó a 1621 pacientes (PB = 8,9% y MB = 91,1%) de 2008 a 2016, notificados en el Sistema de Estados Reaccionarios en Lepra (SisReação/RO). Prevaleció la ocurrencia durante la PQT = 997 (61,5%), y 624 (38,5%) solamente tras la PQT. La precocidad de la reacción a partir del diagnóstico se analizó mediante curvas de supervivencia de Kaplan-Meier y se compararon entre los grupos PB y MB, usando el test de log-rank de Mantel-Cox; asimismo, se construyeron modelos de regresión univariada y multivariada de Cox para identificar los factores asociados con la ocurrencia de la reacción (cociente de riesgos) y los correspondientes IC95%. En el modelo multivariado se incluyeron las variables con valores de p < 0,2 en el análisis univariado. Los PB desarrollaron una reacción de forma más precoz que los MB. Otras características se asociaron a la reacción en menor tiempo: sexo femenino y baciloscopia negativa. En el período agregado (durante y tras PQT), los PB presentaron un riesgo un 24% mayor de reacción que los multibacilares y la baciloscopia negativa aumentó este riesgo en un 40%, comparado con la baciloscopia positiva. Durante y tras el tratamiento PQT, los PB presentaron 1,3 y 1,6 veces el riesgo de ocurrencia de la reacción de los pacientes MB. De esa forma, recomendamos priorizar acciones de vigilancia para reacciones hansénicas durante y tras PQT, como medidas de prevención de discapacidades físicas, así como de mejoría en la calidad de vida de personas afectadas por la hanseniasis.

Epidemiological characteristics and temporal trends of new leprosy cases in Brazil: 2006 to 2017 / Características epidemiológicas e tendências temporais de casos novos de hanseníase no Brasil: 2006 a 2017 / Características epidemiológicas y tendencias temporales de nuevos casos de lepra en Brasil: de 2006 a 2017

Abstract: Our study aims to describe trends in new case detection rate (NCDR) of leprosy in Brazil from 2006 to 2017 overall and in subgroups, and to analyze the evolution of clinical and treatment characteristics of patients, with emphasis on cases diagnosed with grade 2 physical disabilities. We conducted a descriptive study to analyze new cases of leprosy registered in the Brazilian Information System for Notificable Diseases (SINAN), from 2006-2017. We calculated the leprosy NCDR per 100,000 inhabitants (overall and for individuals aged < 15 and ≥ 15 years) by sex, age, race/ethnicity, urban/rural areas, and Brazilian regions, and estimated the trends using the Mann-Kendall non-parametric test. We analyzed the distributions of cases according to relevant clinical characteristics over time. In Brazil, there was a sharp decrease in the overall NCDR from 23.4/100,000 in 2006 to 10.3/100,000 in 2017; among children < 15 years, from 6.94 to 3.20/100,000. The decline was consistent in all Brazilian regions and race/ethnicity categories. By 2017, 70.2% of the cases were multibacillary, 30.5% had grade 1 (G1D) or 2 (G2D) physical disabilities at diagnosis and 42.8% were not evaluated at treatment completion/discharge; cases with G2D at diagnosis were mostly detected in urban areas (80%) and 5% of cases died during the treatment (leprosy or other causes). Although the frequency of leprosy NCDR decreased in Brazil from 2006 to 2017 across all evaluated population groups, the large number of cases with multibacillary leprosy, physical disabilities or without adequate evaluation, and among children suggest the need to reinforce timely diagnosis and treatment to control leprosy in Brazil.

Resumo: O estudo teve com objetivos descrever as tendências na taxa de detecção de casos novos (TDCN) de hanseníase no Brasil em 2006-2017, global e por subgrupos, e analisar a evolução das características clínicas e terapêuticas dos pacientes, com ênfase nos casos diagnosticados com incapacidade física grau 2. Realizamos um estudo descritivo par analisar casos novos de hanseníase registrados no Sistema de Informação de Agravos de Notificação (SINAN), 2006-2017. Calculamos a TDCN de hanseníase por 100.000 habitantes (global e para indivíduos < 15 e ≥ 15 anos de idade) por sexo, idade, raça/etnicidade, área urbana/rural e macrorregião do Brasil e estimamos as tendências com o teste não paramétrico de Mann-Kendall. Analisamos as distribuições de casos de acordo com características clínicas relevantes ao longo do tempo. No Brasil, houve uma queda marcante na TDCN global, de 23,4/100.000 em 2006 para 10,3/100.000 em 2017; entre crianças < 15 anos, de 6,94 para 3,20/100.000. A queda foi consistente em todas a regiões brasileiras e em todas as categorias de raça/etnicidade. Até 2017, 70,2% dos casos eram multibacilares, 30,5% apresentavam incapacidades físicas grau 1 (G1D) ou grau 2 (G2D) ao diagnóstico e 42,8% não foram avaliados ao encerramento do tratamento ou alta; os casos com G2D ao diagnóstico foram detectados majoritariamente nas áreas urbanas (80%), e 5% dos casos faleceram durante o tratamento (devido à hanseníase ou por outras causas). Embora a frequência da TDCN da hanseníase tenha diminuído no Brasil entre 2006 e 2017 em todos os grupos avaliados, o número grande de casos com hanseníase multibacilar, incapacidades físicas ou sem avaliação adequada e entre crianças sugere a necessidade de reforçar o diagnóstico e tratamento oportunos para controlar a hanseníase no Brasil.

Resumen: Se realizó este trabajo con el fin de describir la tendencia general y en subgrupos de la tasa de detección de nuevos casos de lepra (NCDR por sus siglas en inglés) en Brasil, entre 2006-2017, así como para analizar la evolución de las características clínicas y de tratamiento de los pacientes, con énfasis en los casos diagnosticados con un grado 2 de discapacidad física. Realizamos un estudio descriptivo para analizar los nuevos casos de lepra registrados en el Sistema Brasileño de Información de Enfermedades de Notificación (SINAN), 2006-2017. Calculamos la NCDR de lepra por cada 100.000 habitantes (general e individuos con una edad < 15 y ≥ 15 años) por sexo, edad, raza/etnicidad, áreas urbanas/rurales y regiones brasileñas, y estimamos las tendencias usando el test no paramétrico de Mann-Kendall. Analizamos las distribuciones de casos según las características clínicas relevantes a lo largo del tiempo. En Brasil, hubo una drástica disminución en general de NCDR de los 23,4/100.000 en 2006, a los 10,3/100.000 en 2017; entre niños < 15 años, desde los 6,94 a los 3,20/100.000. El decremento fue consistente en todas las regiones brasileñas y categorías de raza/etnicidad. En 2017, un 70,2% de los casos fueron multibacilares, un 30,5% tenían grado 1 (G1D) o 2 (G2D) discapacidad física en el diagnóstico y un 42,8% no fueron evaluados al completar el tratamiento/ser dados de alta; casos con G2D en el diagnóstico fueron en su mayoría detectados en áreas urbanas (80%) y un 5% de los casos murieron durante el tratamiento (lepra u otras causas). A pesar de la frecuencia de lepra los NCDR decrecieron en Brasil de 2006 a 2017, a través de todos los grupos de población evaluados, el elevado número de casos con lepra multibacilar, discapacidad física o sin una adecuada evaluación, y entre niños sugiere la necesidad de reforzar a tiempo el diagnóstico y tratamiento para controlar la lepra en Brasil.

Correction: Geographic and socioeconomic factors associated with leprosy treatment default: An analysis from the 100 Million Brazilian Cohort.

[This corrects the article DOI: 10.1371/journal.pntd.0007714.].

Conditional Cash Transfer Program and Leprosy Incidence: Analysis of 12.9 Million Families From the 100 Million Brazilian Cohort.

Leprosy is a neglected tropical disease predominately affecting poor and marginalized populations. To test the hypothesis that poverty-alleviating policies might be associated with reduced leprosy incidence, we evaluated the association between the Brazilian Bolsa Familia (BFP) conditional cash transfer program and new leprosy case detection using linked records from 12,949,730 families in the 100 Million Brazilian Cohort (2007-2014). After propensity score matching BFP beneficiary to nonbeneficiary families, we used Mantel-Haenszel tests and Poisson regressions to estimate incidence rate ratios for new leprosy case detection and secondary endpoints related to operational classification and leprosy-associated disabilities at diagnosis. Overall, cumulative leprosy incidence was 17.4/100,000 person-years at risk (95% CI: 17.1, 17.7) and markedly higher in "priority" (high-burden) versus "nonpriority" (low-burden) municipalities (22.8/100,000 person-years at risk, 95% confidence interval (CI): 22.2, 23.3, compared with 14.3/100,000 person-years at risk, 95% CI: 14.0, 14.7). After matching, BFP participation was not associated with leprosy incidence overall (incidence rate ratio (IRR)Poisson = 0.97, 95% CI: 0.90, 1.04) but was associated with lower leprosy incidence when restricted to families living in high-burden municipalities (IRRPoisson = 0.86, 95% CI: 0.77, 0.96). In high-burden municipalities, the association was particularly pronounced for paucibacillary cases (IRRPoisson = 0.82, 95% CI: 0.68, 0.98) and cases with leprosy-associated disabilities (IRRPoisson = 0.79, 95% CI: 0.65, 0.97). These findings provide policy-relevant evidence that social policies might contribute to ongoing leprosy control efforts in high-burden communities.

Incidence of and Factors Associated With Leprosy Among Household Contacts of Patients With Leprosy in Brazil.

Importance: Despite progress toward reducing global incidence, leprosy control remains a challenge in low- and middle-income countries. Objective: To estimate new case detection rates of leprosy among household contacts of patients with previously diagnosed leprosy and to investigate its associated risk factors. Design, Setting, and Participants: This population-based cohort study included families registered in the 100 Million Brazilian Cohort linked with nationwide registries of leprosy; data were collected from January 1, 2007, through December 31, 2014. Household contacts of patients with a previous diagnosis of leprosy from each household unit were followed up from the time of detection of the primary case to the time of detection of a subsequent case or until December 31, 2014. Data analysis was performed from May to December 2018. Exposures: Clinical characteristics of the primary case and sociodemographic factors of the household contact. Main Outcomes and Measures: Incidence of leprosy, estimated as the new case detection rate of leprosy per 100 000 household contacts at risk (person-years at risk). The association between occurrence of a subsequent leprosy case and the exposure risk factors was assessed using multilevel mixed-effects logistic regressions allowing for state- and household-specific random effects. Results: Among 42 725 household contacts (22 449 [52.5%] female; mean [SD] age, 22.4 [18.5] years) of 17 876 patients detected with leprosy, the new case detection rate of leprosy was 636.3 (95% CI, 594.4-681.1) per 100 000 person-years at risk overall and 521.9 (95% CI, 466.3-584.1) per 100 000 person-years at risk among children younger than 15 years. Household contacts of patients with multibacillary leprosy had higher odds of developing leprosy (adjusted odds ratio [OR], 1.48; 95% CI, 1.17-1.88), and the odds increased among contacts aged 50 years or older (adjusted OR, 3.11; 95% CI, 2.03-4.76). Leprosy detection was negatively associated with illiterate or preschool educational level (adjusted OR, 0.59; 95% CI, 0.38-0.92). For children, the odds were increased among boys (adjusted OR, 1.70; 95% CI, 1.20-2.42). Conclusions and Relevance: The findings in this Brazilian population-based cohort study suggest that the household contacts of patients with leprosy may have increased risk of leprosy, especially in households with existing multibacillary cases and older contacts. Public health interventions, such as contact screening, that specifically target this population appear to be needed.

Effect of a conditional cash transfer programme on leprosy treatment adherence and cure in patients from the nationwide 100 Million Brazilian Cohort: a quasi-experimental study.

BACKGROUND: Indirect financial costs and barriers to health-care access might contribute to leprosy treatment non-adherence. We estimated the association of the Brazilian conditional cash transfer programme, the Programa Bolsa Família (PBF), on leprosy treatment adherence and cure in patients in Brazil. METHODS: In this quasi-experimental study, we linked baseline demographic and socioeconomic information for individuals who entered the 100 Million Brazilian Cohort between Jan 1, 2007, and Dec 31, 2014, with the PBF payroll database and the Information System for Notifiable Diseases, which includes nationwide leprosy registries. Individuals were eligible for inclusion if they had a household member older than 15 years and had not received PBF aid or been diagnosed with leprosy before entering the 100 Million Brazilian Cohort; they were excluded if they were partial receivers of PBF benefits, had missing data, or had a monthly per-capita income greater than BRL200 (US$50). Individuals who were PBF beneficiaries before leprosy diagnosis were matched to those who were not beneficiaries through propensity-score matching (1:1) with replacement on the basis of baseline covariates, including sex, age, race or ethnicity, education, work, income, place of residence, and household characteristics. We used logistic regression to assess the average treatment effect on the treated of receipt of PBF benefits on leprosy treatment adherence (six or more multidrug therapy doses for paucibacillary cases or 12 or more doses for multibacillary cases) and cure in individuals of all ages. We stratified our analysis according to operational disease classification (paucibacillary or multibacillary). We also did a subgroup analysis of paediatric leprosy restricted to children aged up to 15 years. FINDINGS: We included 11 456 new leprosy cases, of whom 8750 (76·3%) had received PBF before diagnosis and 2706 (23·6%) had not. Overall, 9508 (83·0%) patients adhered to treatment and 10 077 (88·0%) were cured. After propensity score matching, receiving PBF before diagnosis was associated with adherence to treatment (OR 1·22, 95% CI 1·01-1·48) and cure (1·26, 1·01-1·58). PBF receipt did not significantly improve treatment adherence (1·37, 0·98-1·91) or cure (1·12, 0·75-1·67) in patients with paucibacillary leprosy. For patients with multibacillary disease, PBF beneficiaries had better treatment adherence (1·37, 1·08-1·74) and cure (1·43, 1·09-1·90) than non-beneficiaries. In the propensity score-matched analysis in 2654 children younger than 15 years with leprosy, PBF exposure was not associated with leprosy treatment adherence (1·55, 0·89-2·68) or cure (1·57, 0·83-2·97). INTERPRETATION: Our results suggest that being a beneficiary of the PBF, which facilitates cash transfers and improved access to health care, is associated with greater leprosy multidrug therapy adherence and cure in multibacillary cases. These results are especially relevant for patients with multibacillary disease, who are treated for a longer period and have lower cure rates than those with paucibacillary disease. FUNDING: CONFAP/ESRC/MRC/BBSRC/CNPq/FAPDF-Doenças Negligenciadas, the UK Medical Research Council, the Wellcome Trust, and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brazil (CAPES).

Human Genetic Susceptibility of Leprosy Recurrence.

Host genetic susceptibility to leprosy has been intensively investigated over the last decades; however, there are no studies on the role of genetic variants in disease recurrence. A previous initiative identified three recurrent cases of leprosy for which none of the M. leprae strains, as obtained in the first and the second diagnosis, had any known genomic variants associated to resistance to Multidrug therapy; in addition, whole genome sequencing indicated that the same M. leprae was causing two out of the three recurrences. Thus, these individuals were suspected of being particularly susceptible to M. leprae infection, either as relapse or reinfection. To verify this hypothesis, 19 genetic markers distributed across 11 loci (14 genes) classically associated with leprosy were genotyped in the recurrent and in three matching non-recurrent leprosy cases. An enrichment of risk alleles was observed in the recurrent cases, suggesting the existence of a particularly high susceptibility genetic profile among leprosy patients predisposing to disease recurrence.

Geographic and socioeconomic factors associated with leprosy treatment default: An analysis from the 100 Million Brazilian Cohort.

BACKGROUND: Although leprosy is largely curable with multidrug therapy, incomplete treatment limits therapeutic effectiveness and is an important obstacle to disease control. To inform efforts to improve treatment completion rates, we aimed to identify the geographic and socioeconomic factors associated with leprosy treatment default in Brazil. METHODOLOGY/PRINCIPAL FINDINGS: Using individual participant data collected in the Brazilian national registries for social programs and notifiable diseases and linked as part of the 100 Million Brazilian Cohort, we evaluated the odds of treatment default among 20,063 leprosy cases diagnosed and followed up between 2007 and 2014. We investigated geographic and socioeconomic risk factors using a multivariate hierarchical analysis and carried out additional stratified analyses by leprosy subtype and geographic region. Over the duration of follow-up, 1,011 (5.0%) leprosy cases were observed to default from treatment. Treatment default was markedly increased among leprosy cases residing in the North (OR = 1.57; 95%CI 1.25-1.97) and Northeast (OR = 1.44; 95%CI 1.17-1.78) regions of Brazil. The odds of default were also higher among cases with black ethnicity (OR = 1.29; 95%CI 1.01-1.69), no income (OR = 1.41; 95%CI 1.07-1.86), familial income ≤ 0.25 times Brazilian minimum wage (OR = 1.42; 95%CI 1.13-1.77), informal home lighting/no electricity supply (OR = 1.53; 95%CI 1.28-1.82), and household density of > 1 individual per room (OR = 1.35; 95%CI 1.10-1.66). CONCLUSIONS: The findings of the study indicate that the frequency of leprosy treatment default varies regionally in Brazil and provide new evidence that adverse socioeconomic conditions may represent important barriers to leprosy treatment completion. These findings suggest that interventions to address socioeconomic deprivation, along with continued efforts to improve access to care, have the potential to improve leprosy treatment outcomes and disease control.

Socioeconomic determinants of leprosy new case detection in the 100 Million Brazilian Cohort: a population-based linkage study.

BACKGROUND: Although leprosy is recognised as a disease of poverty, there is little evidence on the specific socioeconomic factors associated with disease risk. To inform targeted strategies for disease elimination, we investigated socioeconomic markers of leprosy risk in Brazil. METHODS: Socioeconomic data from the 100 Million Brazilian Cohort were linked to the Brazilian national disease registry (Sistema de Informação de Agravos de Notificação) for leprosy from Jan 1, 2007, to Dec 31, 2014. Using Poisson regression, we assessed the association of socioeconomic factors with risk of incident leprosy in the full cohort and in children (aged 0-15 years), by leprosy subtype and region of residence. FINDINGS: In an analysis of 23 899 942 individuals including 18 518 patients with leprosy, increased levels of deprivation were associated with an increased risk of leprosy in Brazil. Directions of effect were consistent in children younger than 15 years and across disease subtypes. Individuals residing in regions with the highest poverty in the country (central-west, north, and northeast regions) had a risk of leprosy incidence five-to-eight times greater than did other individuals. Decreased levels of income and education and factors reflecting unfavourable living conditions were associated with an up to two-times increase in leprosy incidence (incidence rate ratio 1·46, 95% CI 1·32-1·62, for lowest vs highest quartile of income per capita; 2·09, 95% CI 1·62-2·72, for lowest vs highest level of education). INTERPRETATION: Within the poorest half of the Brazilian population, the most deprived individuals have the greatest risk of leprosy. Strategies focusing on early detection and treatment in the poorest populations could contribute substantially to global disease control. FUNDING: Medical Research Council, Wellcome Trust, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazil), the Conselho Nacional das Fundações Estaduais de Amparo à Pesquisa, Economic and Social Research Council, Biotechnology and Biological Sciences Research Council, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and Fundação de Apoio à Pesquisa do Distrito Federal.