Clofazimine-induced cutaneous hyperpigmentation as a source of stigma in the treatment of leprosy: A cross-sectional study.

OBJECTIVES: Cutaneous hyperpigmentation is one of the main adverse effects encountered in patients undergoing leprosy treatment with multidrug therapy (WHO-MDT). This adverse effect has been described as intolerable and capable of contributing to social stigma. The objectives of this study were to quantify the variation in skin colour induced by clofazimine during and after treatment and to assess the related stigma. METHODS: This observational cross-sectional study objectively measured skin colour in 51 patients by reading the individual typology angle (ITA°) with a spectrophotometer, followed by the application of the Stigma Scale of the Explanatory Model Interview Catalogue (EMIC). RESULTS: Skin hyperpigmentation was observed in 100% of the individuals. They showed more negative ITA° values in lesion areas than non-lesion areas, particularly in sun-exposed regions. Clofazimine-induced cutaneous hyperpigmentation was not homogeneous and seemed to follow the lesion locations. The mean EMIC score was 18.8 points. CONCLUSION: All patients presented skin hyperpigmentation caused by clofazimine, detectable through spectrophotometry. Hyperpigmentation strongly impacted the social domain, indicating the intersectionality of disease and skin colour stigma, contributing to the social isolation of these patients. Health authorities should consider the negative impact of clofazimine on treatment adherence.

An Overview of Treatment Guidelines and Methods of Synthesis of Drugs Used in Leprosy Chemotherapy.

Leprosy is a Neglected Tropical Disease (NTDs) caused by Mycobacterium leprae (M. leprae). The treatment is considered effective, however, the high dose Multidrug Therapy (MDT) for a long period and its adverse effects result in the abandonment of the treatment by patients. Indeed, antimicrobial resistance is still an obstacle that must be overcome in the treatment of leprosy. In the present article, we reviewed the WHO guidelines for the chemotherapy of leprosy and the methods of synthesis of these drugs.

Perfil clínico-epidemiológico de pacientes diagnosticados com hanseníase / Clinical-epidemiological profile of patients diagnosed with leprosy / Perfil clínico-epidemiológico de los pacientes diagnosticados de lepra

hanseníase no Brasil ainda apresenta como um problema de saúde pública. A posição epidemiológica da doença no país é considerada diversificada devido ao alto coeficiente e variação de prevalência nas diversas regiões do país. O objetivo desse estudo é conhecer o perfil epidemiológico da população acometida pela hanseníase na cidade de General Carneiro, no interior do Mato Grosso, durante os anos de 2006 e 2021. A coleta de dados foi realizada nos meses de julho e agosto do ano de 2021. Trata-se de uma pesquisa retrospectiva, documental do tipo descritiva, com abordagem quantitativa. No período em estudo notificou-se 50 casos, sendo 62% do sexo masculino, com faixa etária entre 48 a 69 anos de idade, de cor branca, com predominância da forma dimorfa. Os resultados demonstram que a cidade de General Carneiro, está com o número de casos de hanseníase na média do preconizado pela Organização Mundial de Saúde e também, inferior à média brasileira.

Leprosy in Brazil still presents as a public health problem. The epidemiological position of the disease in the country is considered diversified due to the high coefficient and variation in prevalence in different regions of the country. The aim of this study is to know the epidemiological profile of the population affected by leprosy in the city of General Carneiro, in the interior of Mato Grosso, during the years 2006 and 2021. Data collection was carried out in July and August of 2021 This is a retrospective, descriptive documentary research with a quantitative approach. During the study period, 50 cases were reported, 62% male, aged between 48 and 69 years old, white, with a predominance of the borderline form. The results show that the city of General Carneiro has the number of cases of leprosy in the average recommended by the World Health Organization and also below the Brazilian average.

La lepra en Brasil sigue siendo un problema de salud pública. La posición epidemiológica de la enfermedad en el país se considera diversificada debido al alto coeficiente y a la variación de la prevalencia en diferentes regiones del país. El objetivo de este estudio es conocer el perfil epidemiológico de la población afectada por la lepra en la ciudad de General Carneiro, en el interior de Mato Grosso, durante los años 2006 y 2021. La recogida de datos se realizó en julio y agosto del año 2021. Se trata de una investigación retrospectiva, documental y descriptiva, con un enfoque cuantitativo. En el período de estudio se notificaron 50 casos, siendo el 62% de sexo masculino, con una edad entre 48 y 69 años, de color blanco, con predominio de la forma dimorfa. Los resultados muestran que la ciudad de General Carneiro, está con el número de casos de lepra en la media recomendada por la Organización Mundial de la Salud y también por debajo de la media brasileña.

Undernutrition, food insecurity, and leprosy in North Gondar Zone, Ethiopia: A case-control study to identify infection risk factors associated with poverty.

BACKGROUND: Ethiopia has over 3,200 new cases of leprosy diagnosed every year. Prevention remains a challenge as transmission pathways are poorly understood. Susceptibility and disease manifestations are highly dependent on individual host-immune response. Nutritional deficiencies, such as protein-energy malnutrition, have been linked to reduced cell-mediated immunity, which in the case of leprosy, could lead to a higher chance of active leprosy and thus an increased reservoir of transmissible infection. METHODOLOGY/PRINCIPAL FINDINGS: Between June and August 2018, recently diagnosed patients with leprosy and individuals without known contact with cases were enrolled as controls in North Gondar regional health centers. Participants answered survey questions on biometric data, demographics, socioeconomic situation, and dietary habits. Descriptive statistics, univariate, and multivariate logisitic regression examined associations between undernutrition, specifically body mass index (BMI), middle upper arm circumference (MUAC), and leprosy. Eighty-one participants (40 cases of leprosy, 41 controls) were enrolled (75% male) with an average age of 38.6 years (SD 18.3). The majority of cases were multibacillary (MB) (90%). There was a high prevalence of undernutrition with 24 (29.6%) participants underweight (BMI <18.5) and 17 (21%) having a low MUAC. On multivariate analysis, underweight was significantly associated with leprosy (aOR = 9.25, 95% CI 2.77, 30.81). Also found to be associated with leprosy was cutting the size of meals/skipping meals (OR = 2.9, 95% CI 1.0, 8.32) or not having enough money for food (OR = 10, 95% CI 3.44 29.06). CONCLUSIONS/SIGNIFICANCE: The results suggest a strong association between leprosy and undernutrition, while also supporting the framework that food insecurity may lead to undernutrition that then could increase susceptibility to leprosy. In conclusion, this study highlights the need to study the interplay of undernutrition, food insecurity, and the manifestations of leprosy.

Leprosy detection rate in patients under immunosuppression for the treatment of dermatological, rheumatological, and gastroenterological diseases: a systematic review of the literature and meta-analysis.

BACKGROUND: Recently developed immunosuppressive drugs, especially TNF antagonists, may enhance the risk of granulomatous infections, including leprosy. We aimed to evaluate the leprosy detection rate in patients under immunosuppression due to rheumatological, dermatological and gastroenterological diseases. METHODS: We performed a systematic review of the literature by searching the PubMed, EMBASE, LILACS, Web of Science and Scielo databases through 2018. No date or language restrictions were applied. We included all articles that reported the occurrence of leprosy in patients under medication-induced immunosuppression. RESULTS: The search strategy resulted in 15,103 articles; finally, 20 articles were included, with 4 reporting longitudinal designs. The detection rate of leprosy ranged from 0.13 to 116.18 per 100,000 patients/year in the USA and Brazil, respectively. In the meta-analysis, the detection rate of cases of leprosy per 100,000 immunosuppressed patients with rheumatic diseases was 84 (detection rate = 0.00084; 95% CI = 0.0000-0.00266; I2 = 0%, p = 0.55). CONCLUSION: Our analysis showed that leprosy was relatively frequently detected in medication-induced immunosuppressed patients suffering from rheumatological diseases, and further studies are needed. The lack of an active search for leprosy in the included articles precluded more precise conclusions. TRIAL REGISTRATION: This review is registered in PROSPERO with the registry number CRD42018116275 .

Association of PTPN22-C1858T Polymorphism With Susceptibility to Mycobacterium tuberculosis and Mycobacterium leprae Infection: A Meta-Analysis.

It was previously published that single-nucleotide polymorphism rs2476601 (PTPN22 [protein tyrosine phosphatase non-receptor type 22]-C1858T) might be related to increased sensibility to Mycobacterium tuberculosis and M. leprae infection. However, the results were inconclusive despite a high degree of similarity between both parameters. Herein, we carried out this meta-analysis to systematically summarize and articulate the correlation between PTPN22-C1858T polymorphism and mycobacterial infection. The susceptibility of PTPN22-C1858T carriers with autoimmune conditions receiving immunosuppressive therapy to M. tuberculosis and M. leprae infection was determined. A systematic retrieval of studies on relevance of PTPN22-C1858T polymorphism to susceptibility of M. tuberculosis or M. leprae infection was performed in Chinese National Knowledge Infrastructure, PubMed and Embase databases. We regarded Odds ratios (ORs) and 95% confidence intervals (CIs) as the determined effect size. Finally, four and two case-control studies on tuberculosis and leprosy, respectively, were included. In all genetic models, without indicated association between PTPN22-C1858T polymorphism and tuberculosis's susceptibility. [C versus T: OR = 0.22 (95% CI: 0.09-0.50, PH = 0.887); CT versus CC: OR = 0.21 (95% CI: 0.09-0.49, PH = 0.889); TT+CT versus CC: OR = 0.21 (95% CI: 0.09-0.49, PH = 0.889)]. A significantly increased risk of leprosy was perceived in patients with the PTPN22-C1858T polymorphism [C versus T: OR = 2.82 (95% CI: 1.02-7.81, PH = 0.108)]. While the PTPN22-C1858T polymorphism is irrelevant to higher susceptibility to the infection of M. tuberculosis in Caucasians and Asians, it is relevant to increased susceptibility to the infection of M. leprae. However, the results of M. leprae are supposed to interpreted with prudence owing to the limited quantity of studies and heterogeneity. Further well-designed studies with sufficient populations are required to verify our conclusions.

Mycobacterium leprae induces a tolerogenic profile in monocyte-derived dendritic cells via TLR2 induction of IDO.

The enzyme IDO-1 is involved in the first stage of tryptophan catabolism and has been described in both microbicidal and tolerogenic microenvironments. Previous data from our group have shown that IDO-1 is differentially regulated in the distinctive clinical forms of leprosy. The present study aims to investigate the mechanisms associated with IDO-1 expression and activity in human monocyte-derived dendritic cells (mDCs) after stimulation with irradiated Mycobacterium leprae and its fractions. M. leprae and its fractions induced the expression and activity of IDO-1 in human mDCs. Among the stimuli studied, irradiated M. leprae and its membrane fraction (MLMA) induced the production of proinflammatory cytokines TNF and IL-6 whereas irradiated M. leprae and its cytosol fraction (MLSA) induced an increase in IL-10. We investigated if TLR2 activation was necessary for IDO-1 induction in mDCs. We observed that in cultures treated with a neutralizing anti-TLR2 antibody, there was a decrease in IDO-1 activity and expression induced by M. leprae and MLMA. The same effect was observed when we used a MyD88 inhibitor. Our data demonstrate that coculture of mDCs with autologous lymphocytes induced an increase in regulatory T (Treg) cell frequency in MLSA-stimulated cultures, showing that M. leprae constituents may play opposite roles that may possibly be related to the dubious effect of IDO-1 in the different clinical forms of disease. Our data show that M. leprae and its fractions are able to differentially modulate the activity and functionality of IDO-1 in mDCs by a pathway that involves TLR2, suggesting that this enzyme may play an important role in leprosy immunopathogenesis.

Association of IL-10 Gene Polymorphism With IL-10 Secretion by CD4 and T Regulatory Cells in Human Leprosy.

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Cytokines are known to play vital role as a peacekeeper during inflammatory and other immunocompromised conditions such as leprosy. This study has tried to bridge the gap of information on cytokine gene polymorphisms and its potential role in the pathogenesis of leprosy. Interleukin-10 (IL-10) is an immunosuppressive cytokine, found to be elevated in leprosy that accounted for the suppression of host's immune system by regulating the functions of other immune cells. T helper cells and T regulatory (Tregs) cells are the major source of IL-10 in lepromatous leprosy patients. In this study, we have documented the association of IL-10 cytokine gene polymorphism with the disease progression. A total of 132 lepromatous leprosy patients and 120 healthy controls were analyzed for IL-10 cytokine gene polymorphisms using PCR-SSP assay and flow cytometry was used to analyze IL-10 secretion by CD4 and Tregs in various genotype of leprosy patients. The frequencies of IL-10 (-819) TT and IL-10 (-1082) GG genotypes were significantly higher in leprosy patients as compared to healthy controls. This observation advocates that these genotypes were associated with the susceptibility and development of the disease. In addition, flow cytometry analysis demonstrated an increased number of IL-10 producing CD4 and Treg cells in IL-10 (819) TT genotype compared to CT and CC genotypes. These observations were further supported by immunohistochemical studies. Therefore, we can conclude that IL-10 cytokine gene polymorphisms by affecting its production can determine the predilection and progression of leprosy in the study population.

Differential Expression of IFN-γ, IL-10, TLR1, and TLR2 and Their Potential Effects on Downgrading Leprosy Reaction and Erythema Nodosum Leprosum.

Leprosy reactions are acute immunological events that occur during the evolution of chronic infectious disease causing neural damage and disabilities. A study using blood samples of 17 leprosy reaction patients and 17 reaction-free was carried out by means of associations between antigens, receptors, and expression of cytokines, using path analysis providing new insights into the immunological mechanisms involved in triggering leprosy reactions. Toll-like receptors (TLR) such as TLR1 and TLR2, presented balanced expression in the reaction-free multibacillary (MB) group (TLR1: 1.01 ± 0.23, TLR2: 1.22 ± 0.18; p = 0.267). On the other hand, downgrading type 1 reaction (T1R) (TLR1: 1.24 ± 0.17, TLR2: 2.88 ± 0.37; p = 0.002) and erythema nodosum leprosum (ENL) (TLR1: 1.93 ± 0.17, TLR2: 2.81 ± 0.15; p = 0.004) revealed an unbalance in relation to the expression of these receptors. When the path analysis was approached, it was noted that interleukin 10 (IL-10) expression showed a dependence relation with phenolic glycolipid I (PGL-I) in downgrading T1R (direct effect = 0.503 > residual effect = 0.364), whereas in ENL, such relationship occurred with lipoarabinomannan (LAM) (direct effect = 0.778 > residual effect = 0.280). On the contrary, in the reaction-free leprosy group, interferon-gamma (IFN-γ) levels were dependent on the association between TLR2 and TLR1 (0.8735). The high TLR2 expression associated with IL-10 levels, in the leprosy reaction groups, may be hypothetically related to the formation of TLR2/2 homodimers and/or TLR2/6 heterodimers linked to evasion mechanisms in downgrading reactions and pathophysiology of ENL.

Vitamin D Receptor Gene Polymorphisms Are Associated With Leprosy in Southern Brazil.

Vitamin D, together with its nuclear receptor (VDR), plays an important role in modulating the immune response, decreasing the inflammatory process. Some polymorphisms of the VDR gene, such as BsmI (G>A rs1544410), ApaI (G>T rs7975232), and TaqI (T>C rs731236) could affect its stability and mRNA transcription activity, while FokI T>C (rs2228570) gives a truncated protein with three fewer amino acids and more efficiency in binding vitamin D. This study evaluated these four polymorphisms in the immunopathogenesis of leprosy in 404 patients and 432 control individuals without chronic or infectious disease in southern Brazil. When analyzing differences in the allele and genotype frequency of polymorphisms between patients (leprosy per se, multibacillary, and paucibacillary clinical forms) and controls, we found no statistically significant association. Regarding haplotype analysis, the bAt haplotype was associated with protection from leprosy per se (P = 0.004, OR = 0.34, CI = 0.16-0.71) and from the multibacillary clinical form (P = 0.005, OR = 0.30, CI = 0.13-0.70). In individuals aged 40 or more years, this haplotype has also showed protection against leprosy per se and multibacillary (OR = 0.26, CI = 0.09-0.76; OR = 0.26, CI = 0.07-0.78, respectively), while the BAt haplotype was a risk factor for leprosy per se in the same age group (OR = 1.34, CI = 1.04-1.73). In conclusion, despite having found no associations between the VDR gene polymorphisms with the development of leprosy, the haplotypes formed by the BsmI, ApaI, and TaqI polymorphisms were associated with leprosy per se and the multibacillary clinical form.

Leprosy presenting as remitting seronegative symmetrical synovitis with pitting oedema syndrome - a case report.

BACKGROUND: Leprosy typically manifests with skin and peripheral nerve involvement. Musculoskeletal complaints are the third most common, and can be the sole presenting manifestation. They range from arthralgia/arthritis in reactional states to full mimics of systemic rheumatic diseases. Remitting Seronegative Symmetrical Synovitis with Pitting Oedema syndrome has only been described once in a patient with already diagnosed Leprosy. CASE REPORT: A 68-year-old male, from an endemic region of familial amyloid polyneuropathy, presented with an inaugural Remitting Seronegative Symmetrical Synovitis with Pitting Oedema like syndrome, more that 20 years after travelling to Leprosy endemic areas. Arthritis would resurface whenever oral prednisone was tapered, so methotrexate was started, controlling the complaints. Only one year later, after the appearance of peripheral neuropathy and skin lesions, it was possible to diagnose Leprosy, through the identification of Mycobacterium leprae bacilli in a peripheral nerve biopsy. CONCLUSION: This report is an example of the heterogeneity of manifestations of Leprosy, namely rheumatic, and the challenge of diagnosing it when typical complaints are absent. It is also a reminder that this disease should be considered whenever a patient with a combination of skin/neurologic/rheumatic complaints has travelled to endemic countries in the past.

Underlying mechanisms of leprosy recurrence in the Western Amazon: a retrospective cohort study.

BACKGROUND: The multidrug therapy (MDT) for leprosy treatment adopted by Brazil in the 1990s was important for reducing leprosy in the country; however, recurrent cases remained problematic. Mechanisms involved in leprosy recurrence are heterogeneous and can be sorted into three groups: insufficient therapy, bacillary persistence and new infections. This study aimed to analyse the time interval of leprosy recurrence in relation to the therapeutic scheme in the state of Acre. The hypotheses were as follows: 1) treatments (a) rifampicin, ofloxacin and minocycline (ROM) and (b) dapsone (DDS) have a short leprosy recurrence time, 2) treatments based on MDT have a long leprosy recurrence time, 3) there is a dose-response relationship between MDT and the time interval between leprosy episodes. METHODS: This retrospective cohort study included 201 patients with a second episode of clinical leprosy at the reference centers for leprosy control in the state of Acre. Exposure was the type of therapeutic scheme as follows: 1) ROM, 2) DDS, 3) MDT0-9 doses, 4) MDT10-19 doses, 5) MDT20-29 doses, and 6) MDT30+ doses. Outcome was the time interval between release from treatment and a diagnosis of a recurrent leprosy case. Incidence rate ratios and relative risk Poisson regressions adjusted by age and sex were calculated with 95% confidence intervals. RESULTS: The 201 patients studied during this retrospective follow-up resulted in a total of 224 cases of recurrent leprosy. Incidence rate ratios within this therapeutic scheme were as follows: 3.3 (2.39, 4.2; ROM/MDT30+), 1.12 (0.33, 1.92; DDS/MDT30+), 2.17 (1.39, 2.94; MDT0-9/MDT30+), 1.94 (1.13, 2.75; MDT10-19/MDT30+) and 1.26 (0.47, 2.05; MDT20-29/MDT30+). Relative risk Poisson regressions showed a protective effect of MDT30+ in comparison with ROM (0.22; 0.07, 0.72), MDT0-9 (0.42; 0.21, 0.85), and MDT10-19 (0.44; 0.21, 0.92). No differences among MDT30+ and DDS (0.71; 0.36, 1.41) and MDT20-29 (0.76; 0.38, 1.49) were observed. CONCLUSIONS: New infection is an important-yet neglected-mechanism in leprosy recurrence in the state of Acre and can challenge the leprosy elimination plan in Brazil. MDT with few doses might be associated with leprosy recurrence due to insufficient therapy or bacillary persistence.

Expressão diferencial de biomarcadores imunológicos de infecção subclínica em casos multibacilares de hanseníase e seus contatos domiciliares / Differential expression of immunological biomarkers of subclinical infection in multibacillary leprosy cases and their home contacts

A hanseníase é uma doença infectocontagiosa, causada pelo bacilo Mycobacterium leprae, com sintomatologia dermatoneurológica. Várias estratégias têm sido adotadas para o controle da hanseníase, porém o diagnóstico da hanseníase é essencialmente clínico. O desafio atual é identificar biomarcadores que possibilitem a identificação de parâmetros imunológicos de infecção subclínica e, em última análise, o diagnóstico precoce da hanseníase em indivíduos infectados e assintomáticos, para realização de imunoprofilaxia de forma oportuna quebrando, assim, a cadeia de transmissão do bacilo. Aprofundar nas diferenças entre casos índice multibacilares e seus contatos domiciliares foi a estratégia deste estudo, através da avaliação conjunta de parâmetros imunológicos gerais e específicos. Objetivo: o objetivo deste trabalho foi avaliar o perfil da resposta imune inata e adaptativa de casos multibacilares de hanseníase e seus contatos domiciliares para a identificação de parâmetros imunológicos de infecção subclínica. Metodologia: Para mensurar a expressão de moléculas de superfície foi realizada imunofenotipagem por citometria de fluxo. Para dosar os níveis de citocinas e quimiocinas séricas as foi utilizada a técnica de Cytometric Bead Array (CBA). Os níveis de IgM anti PGL-1 de foram mensurados pela técnica de ELISA. Resultados: Os níveis de IgM/IgG anti PGL-1, de linfócitos ativados T CD4+ e CD8+ e a frequência de monócitos circulantes estavam mais elevados em casos índice em relação aos seus contatos. A frequência de linfócitos T estava menor em casos índice MB. A distância imunológica entre casos e contatos domiciliares não foi significativa quando se avaliou em conjunto todos os parâmetros imunológicos. Conclusão: Nós inferimos, a partir dos parâmetros diferencialmente expressos em casos índice MB e contatos domiciliares, que a elevação da resposta humoral específica, o maior nível de ativação de linfócitos (com provável proliferação e diferenciação em células T efetoras e/ou de memória), a maior frequência de monócitos em trânsito no sangue periférico, podem ser opções de biomarcadores preditores de infecção subclínica em contatos domiciliares.(AU)

Leprosy is an infectious disease caused by the bacillus Mycobacterium leprae, with dermatoneurological symptoms. Several strategies have been adopted for leprosy control, but the diagnosis of leprosy is essentially clinical. The current challenge is to identify biomarkers that enable the identification of immunological parameters of subclinical infection and, ultimately, the early diagnosis of leprosy in infected and asymptomatic individuals, to perform immunoprophylaxis in a timely manner, thus breaking the bacillus transmission chain. Deepening the differences between multibacillary index cases and their household contacts was the strategy of this study, through the joint evaluation of general and specific immunological parameters. Objective: The aim of this study was to evaluate the profile of the innate and adaptive immune response of multibacillary leprosy cases and their household contacts for the identification of immunological parameters of subclinical infection. Methodology: To measure the expression of surface molecules, immunophenotyping was performed by flow cytometry. To measure serum cytokine and chemokine levels, the Cytometric Bead Array (CBA) technique was used. Anti-PGL-1 IgM/IgG levels were measured by ELISA. Results: Anti-PGL-1 IgM/IgG levels, CD4 + and CD8 + activated T lymphocytes and the frequency of circulating monocytes were higher in index cases compared to their contacts. The frequency of T lymphocytes was lower in MB index cases. The immunological distance between cases and home contacts was not significant when all immunological parameters were evaluated together. Conclusion: We infer from the differentially expressed parameters in MB index cases and household contacts that the elevation of specific humoral response, the highest level of lymphocyte activation (with probable proliferation and differentiation in effector and / or memory T cells), the higher frequency of peripheral blood transit monocytes, may be predictive biomarker options for subclinical infection in household contacts.

Underlying mechanisms of leprosy recurrence in the Western Amazon: a retrospective cohort study

BACKGROUND: The multidrug therapy (MDT) for leprosy treatment adopted by Brazil in the 1990s was important for reducing leprosy in the country; however, recurrent cases remained problematic. Mechanisms involved in leprosy recurrence are heterogeneous and can be sorted into three groups insufficient therapy, bacillary persistence and new infections. This study aimed to analyse the time interval of leprosy recurrence in relation to the therapeutic scheme in the state of Acre. The hypotheses were as follows 1) treatments (a) rifampicin, ofloxacin and minocycline (ROM) and (b) dapsone (DDS) have a short leprosy recurrence time, 2) treatments based on MDT have a long leprosy recurrence time, 3) there is a dose-response relationship between MDT and the time interval between leprosy episodes. METHODS: This retrospective cohort study included 201 patients with a second episode of clinical leprosy at the reference centers for leprosy control in the state of Acre. Exposure was the type of therapeutic scheme as follows 1) ROM, 2) DDS, 3) MDT0-9 doses, 4) MDT10-19 doses, 5) MDT20-29 doses, and 6) MDT30+ doses. Outcome was the time interval between release from treatment and a diagnosis of a recurrent leprosy case. Incidence rate ratios and relative risk Poisson regressions adjusted by age and sex were calculated with 95% confidence intervals. RESULTS: The 201 patients studied during this retrospective follow-up resulted in a total of 224 cases of recurrent leprosy. Incidence rate ratios within this therapeutic scheme were as follows 3.3 (2.39, 4.2; ROM/MDT30+), 1.12 (0.33, 1.92; DDS/MDT30+), 2.17 (1.39, 2.94; MDT0-9/MDT30+), 1.94 (1.13, 2.75; MDT10-19/MDT30+) and 1.26 (0.47, 2.05; MDT20-29/MDT30+). Relative risk Poisson regressions showed a protective effect of MDT30+ in comparison with ROM (0.22; 0.07, 0.72), MDT0-9 (0.42; 0.21, 0.85), and MDT10-19 (0.44; 0.21, 0.92). No differences among MDT30+ and DDS (0.71; 0.36, 1.41) and MDT20-29 (0.76; 0.38, 1.49) were observed. CONCLUSIONS: New infection is an important-yet neglected-mechanism in leprosy recurrence in the state of Acre and can challenge the leprosy elimination plan in Brazil. MDT with few doses might be associated with leprosy recurrence due to insufficient therapy or bacillary persistence.

γδ T cells are associated with inflammation and immunopathogenesis of leprosy reactions.

BACKGROUND: Leprosy reactions appear episodically in leprosy patients, which lead to high inflammation, morbidity and peripheral nerve damage. The role of Th17 cell has been well studied in leprosy reactions but the role of γδ or unconventional T cells which is an other major source of IL-17 in many diseases, not studied in leprosy reactional episodes. OBJECTIVE: The aim of the present study to elucidate the role of γδ T cells in leprosy reactions. METHODOLOGY: A total of 40 untreated non-reaction and reactions patients were recruited. PBMCs were isolated and stimulated with M. leprae sonicated antigen (MLSA) for 48 h and immuno-phenotyping was done using flow cytometry. Moreover, γδ T cells were isolated by Magnetic beads technology and mRNA expression of IL-17, IFN-γ, TGF-ß and FOXP3 were analyzed by real-time PCR (qPCR) and cytokine was estimated in the culture supernatant by ELISA. RESULTS: γδ T cells were significantly increased in both Reversal reaction (RR) and Erythema nodosum leprosum (ENL) reaction patients. These cells produced significant amount of IL-17 and IFN-γ. Furthermore, CD3+TCRγδ+ T cells expressed transient FOXP3 with a low amount of TGF-ß in both reactions as compared to stable patients. Moreover, low TGF-ß producing TCR-γδ cells were associated with low phosphorylation of STAT5A. CONCLUSION: This study will add to our understanding of the immunological features that mediate and regulate the pathogenesis of leprosy and may helpful to reduce the immuno-pathogenesis of leprosy reaction by targeting these cells.

Nerve Growth Factor and Pathogenesis of Leprosy: Review and Update.

Neurotrophins are a family of proteins that regulate different aspects of biological development and neural function and are of great importance in neuroplasticity. This group of proteins has multiple functions in neuronal cells, as well as in other cellular populations. Nerve growth factor (NGF) is a neurotrophin that is endogenously produced during development and maturation by multiple cell types, including neurons, Schwann cells, oligodendrocytes, lymphocytes, mast cells, macrophages, keratinocytes, and fibroblasts. These cells produce proNGF, which is transformed by proteolytic cleavage into the biologically active NGF in the endoplasmic reticulum. The present review describes the role of NGF in the pathogenesis of leprosy and its correlations with different clinical forms of the disease and with the phenomena of regeneration and neural injury observed during infection. We discuss the involvement of NGF in the induction of neural damage and the pathophysiology of pain associated with peripheral neuropathy in leprosy. We also discuss the roles of immune factors in the evolution of this pathological process. Finally, we highlight avenues of investigation for future research to broaden our understanding of the role of NGF in the pathogenesis of leprosy. Our analysis of the literature indicates that NGF plays an important role in the evolution and outcome of Mycobacterium leprae infection. The findings described here highlight an important area of investigation, as leprosy is one of the main causes of infection in the peripheral nervous system.

Spatial analysis of reported new cases and local risk of leprosy in hyper-endemic situation in Northeastern Brazil.

OBJECTIVE: To analyse the spatial distribution of the incidence of leprosy and identify areas at risk for occurrences of hyper-endemic disease in Northeastern Brazil. METHODS: Ecological study using municipalities as the analysis unit. Data on new cases of leprosy came from the Health Hazard Notification System (SINAN). This study focused on Pernambuco and covered the years 2005 to 2014. Indicators for monitoring were calculated per 100 000 inhabitants. The local empirical Bayes method was used to minimise rate variance, and spatial autocorrelation maps were used for spatial pattern analysis (box maps and Moran maps). RESULTS: A total of 28 895 new cases were registered in the study period. The average incidence was 21.88/100 000; the global Moran's I index was 0.36 (P < 0.01), thus indicating the existence of spatial dependence; and the Moran map identified 20 municipalities with high priority for attention. The average incidence rate among individuals under 15 years of age was 8.78/100 000; the global Moran's I index showed the presence of positive spatial autocorrelation (0.43; P < 0.01), and the Moran map showed a main cluster of 15 hyper-endemic municipalities. The average rate of grade 2 physical disability at the time of diagnosis was 1.12/100 000; the global Moran index presented a positive spatial association (0.17; P < 0.01); and the Moran map located clusters of municipalities (high-high) in three mesoregions. CONCLUSION: Application of different spatial analysis methods made it possible to locate areas that would not have been identified by epidemiological indicators alone.

Social determinants of leprosy in a hyperendemic State in North Brazil.

OBJECTIVE: To identify the socioeconomic, demographic, operational, and health service-related factors associated with the occurrence of leprosy in a hyperendemic State in North Brazil. METHODS: This is an ecological study based on secondary data from the Sistema de Informações de Agravos de Notificação in municipalities of the State of Tocantins from 2001 to 2012. Units of analysis were the 139 municipalities of the State. Negative binomial log linear regression models were used to estimate incidence rate ratios. RESULTS: In bivariate analysis, the incidence rate ratios were significantly higher for municipalities with higher income ratio of the poorest 20.0% (1.47; 95%CI 1.19-1.81) and better Municipal Human Development Index (1.53; 95%CI 1.14-2.06). In multivariate analysis, the incidence rate ratios were significantly higher in municipalities with higher proportion of immigrants (1.31; 95%CI 1.11-1.55) and higher proportion of households with waste collection (1.37; 95%CI 1.11-1.69). There was a significant reduction in the incidence rate ratio with increased coverage of the Bolsa Família Program (0.98; 95%CI 0.96-0.99). CONCLUSIONS: Control programs need to focus on activities in municipalities of greater social vulnerability with intersectoral investment for the improvement of the living conditions of the population. OBJETIVO: Identificar fatores socioeconômicos, demográficos, operacionais e de serviços de saúde associados à ocorrência da hanseníase em um estado hiperendêmico do norte do Brasil. MÉTODOS: Estudo ecológico com dados secundários do Sistema de Informações de Agravos de Notificação em municípios do estado do Tocantins de 2001 a 2012. As unidades de análise foram os 139 municípios do estado. Modelos de regressão log linear binomial negativa foram utilizados para estimar as razões de taxas de incidência. RESULTADOS: Na análise bivariada, a razão de taxa de incidência foi significativamente maior para os municípios com maior razão de renda dos 20,0% mais pobres (1,47; IC95% 1,19-1,81) e melhor Índice de Desenvolvimento Humano Municipal (1,53; IC95% 1,14-2,06). Na múltipla, a razão de taxa de incidência foi significativamente superior em municípios com maior concentração de imigrantes (1,31; IC95% 1,11-1,55) e proporção de domicílios com coleta de lixo (1,37; IC95% 1,11-1,69). Houve redução significativa da razão de taxa de incidência com o aumento da cobertura do programa bolsa família (0,98; IC95% 0,96-0,99). CONCLUSÕES: Os programas de controle precisam focar as atividades em municípios de maior vulnerabilidade social com investimentos intersetoriais para a melhoria das condições de vida da população.