Increased serum levels of interleukin-6 in erythema nodosum leprosum suggest its use as a biomarker.

BACKGROUND: Erythema nodosum leprosum (ENL) is a frequent complication of multibacillary leprosy that can result in significant morbidity, including peripheral nerve damage and physical disability. The identification of possible serum markers could be a valuable tool for the early detection of ENL. AIMS: The purpose of this study was to evaluate selected serum mediators involved in the innate and adaptive immune responses to identify possible immunomarkers for ENL. METHODS: The levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, interleukin-17, interferon-γ, tumor necrosis factor, nitric oxide and anti-phenolic glycolipid-I antibodies were measured in the sera of leprosy patients with ENL [at the beginning of reaction (M0) and 1 month later (M1)], and then compared with the levels of the same markers in patients with untreated multibacillary leprosy without ENL (controls with leprosy: CTRL) and healthy individuals (healthy controls: CTRH). RESULTS: Significantly higher levels of serum interleukin-6 were observed in M0 than in CTRL. In addition, pairwise comparisons showed higher levels of interleukin-6 in M0 compared to M1. Levels of tumor necrosis factor were higher in M0 than in CTRL, with no significant difference between M0 and M1. There were no differences in the levels of interleukin-2, interleukin-4, interleukin-10, interleukin-17 or interferon-γ between groups. The CTRL group had higher levels of nitric oxide compared to M0 and M1. High levels of anti-phenolic glycolipid-I were observed in M0, M1 and CTRL than in CTRH. LIMITATIONS: Three patients were not assessed at M1, decreasing the number of evaluated patients from 14 to 11. CONCLUSION: High-serum levels of interleukin-6 were observed during ENL, primarily in patients with more severe reactions; levels decreased after specific therapy, suggesting a role for this cytokine in pathogenesis and its utility as an ENL biomarker. Further studies should explore whether interleukin-6 could also be used as a predictive marker for ENL or as a specific target for its treatment.

Association of MICA and HLA-B 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 case-control and a family-based study in two endemic populations in Brazil. MICA and HLA-B alleles were evaluated in 409 leprosy patients and in 419 healthy contacts by PCR-SSOP-Luminex-based 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 Chi-square or Fisher's exact test together with a multivariate analysis. Family-based association was assessed by transmission disequilibrium test (TDT) software FBAT 2.0.4. We found associations between the haplotype MICA*002-HLA-B*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 (MICA-A4 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 HLA-B variants were found associated with leprosy per se in the Colônia do Prata population. Linkage disequilibrium analysis revealed perfect linkage disequilibrium (LD) between HLA-B 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 HLA-B. Our findings contribute the knowledge pool of the immunogenetics of Hansen's disease and reveals a new association of the MICA*029 allele.

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).

Increased serum levels of interleukin-6 in erythema nodosum leprosum suggest its use as a biomarker

Background: Erythema nodosum leprosum (ENL) is a frequent complication of multibacillary leprosy that can result in significant morbidity, including peripheral nerve damage and physical disability. The identification of possible serum markers could be a valuable tool for the early detection of ENL. Aims: The purpose of this study was to evaluate selected serum mediators involved in the innate and adaptive immune responses to identify possible immunomarkers for ENL.Methods: The levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, interleukin-17, interferon-γ, tumor necrosis factor, nitric oxide and anti-phenolic glycolipid-I antibodies were measured in the sera of leprosy patients with ENL [at the beginning of reaction (M0) and 1 month later (M1)], and then compared with the levels of the same markers in patients with untreated multibacillary leprosy without ENL (controls with leprosy: CTRL) and healthy individuals (healthy controls: CTRH).Results: Significantly higher levels of serum interleukin­6 were observed in M0 than in CTRL. In addition, pairwise comparisons showed higher levels of interleukin-6 in M0 compared to M1. Levels of tumor necrosis factor were higher in M0 than in CTRL, with no significant difference between M0 and M1. There were no differences in the levels of interleukin-2, interleukin-4, interleukin-10, interleukin-17 or interferon-γ between groups. The CTRL group had higher levels of nitric oxide compared to M0 and M1. High levels of anti-phenolic glycolipid-I were observed in M0, M1 and CTRL than in CTRH.Limitations: Three patients were not assessed at M1, decreasing the number of evaluated patients from 14 to 11. Conclusion: High-serum levels of interleukin-6 were observed during ENL, primarily in patients with more severe reactions; levels decreased after specific therapy, suggesting a role for this cytokine in pathogenesis and its utility as an ENL biomarker. Further studies should explore whether interleukin-6 could also be used as a predictive marker for ENL or as a specific target for its treatment.

A qualitative study exploring the parceived impact of race on leprosy-affected persons' experiences of diagnosis and treatment of leprosy in Southeast Brazil

Leprosy is a chronic, yet curable, infectious disease that causes severe morbidity in Brazil with an annual incidence of 33,000 new cases. Recent studies in Brazil showed a correlation between leprosy and the percentage of non-whites affected. Racial discrimination has been documented as a barrier to accessing healthcare. This study seeks to explore whether patients perceive race to have impacted on their leprosy care. A qualitative study was undertaken. 20 semi-structured interviews were conducted with patients' at Instituto Lauro de Souza Lima (ILSL), Brazil. Thematic analysis was used to analyse the data. 4 main themes were generated: racism is part of Brazilian culture, difficulties associated with the diagnosis of Leprosy, barriers to accessing treatment, and a lack of health education. Participants felt that racism infiltrates all aspects of Brazilian society, with isolated incidents in healthcare settings. Racism is known to be associated with socioeconomic inequalities. Leprosy control continues to be hindered by various social determinants of health. This, in turn, affects patients' access to leprosy treatment and care. This study may inform the continuing development of equitable leprosy control strategies in Brazil.

The long-term impact of the leprosy post-exposure prophylaxis (LPEP) program on leprosy incidence: a modelling study

The Leprosy Post-Exposure Prophylaxis (LPEP) program explored the feasibility and impact of contact tracing and the provision of SDR to eligible contacts of newly diagnosed leprosy patients in states or districts of Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. This study investigated the long-term impact of the LPEP program on the leprosy new case detection rate (NCDR). Our results show that LPEP could reduce the NCDR beyond the impact of the routine leprosy control programme and that many new cases could be prevented. The benefit of LPEP increases gradually over time. LPEP could accelerate the time of reaching predicted NCDR levels of 2040 under routine program by up to six years. Furthermore, we highlighted how the impact varies between countries due to differences in the number of contacts per index patient screened and differences in leprosy epidemiology and national control programme. Generally, including both household contacts and neighbours (> 20 contacts per index patient) would yield the highest impact.

Neurophysiological comparative response to clinical and surgical treatment of the ulnar neuropathy in leprosy / Padrões neurofisiológicos da resposta tardia ao tratamento clínico e cirúrgico da neuropatia ulnar na hanseníase

Leprosy neuropathy may develop into subacute and chronic inflammatory scenarios, called reactions, which may cause entrapments in the anatomic tunnels. Objective: This study describes the late nerve conduction findings in patients with ulnar neuropathy at the elbow that were submitted to clinical and surgery treatments. Methods: A total of 27 nerves of 21 patients with borderline leprosy during type 1 (reversal) reaction were selected in a non- competing retrospective cohort for three years. The nerves with treated clinically active neuropathy (Group A1) were randomized for inclusion of surgical treatment (Group A2) after one month of clinical treatment without clear signs of clinical and neurophysiological improvement. Fifteen nerves were randomly chosen for surgery while 12 were clinically treated, after steroids treatment without expected response. Nerve conduction was measured before and after treatment on four occasions. Results: The authors observed significant improvement in the following variables in the surgically treated nerves: compound motor action potential amplitude (CMAP) at elbow and above elbow and conduction velocity (CV) along the forearm. Conclusion: The improvement of CMAP amplitudes and conduction velocity (CV) along the forearm express the late effect of nerve decompression. Persistence of temporal dispersion (TD) along the elbow was related to the new reaction or to incomplete surgical solution. However, moderate reduction in CV along the elbow, without TD, was considered an indication of na expected partial remyelination. Previous gradation of the nerve lesion based on the CMAP amplitude was related to the most severe results

A neuropatia de hanseníase pode desenvolver quadros inflamatórios subagudos e crônicos denominados reações, os quais podem evoluir para compressões nos túneis anatômicos. Objetivo: Descrever os achados de condução nervosa (CN) tardios em pacientes com neuropatia ulnar no cotovelo submetidos aos tratamentos clínico e cirúrgico. Método: Vinte e sete nervos de 21 pacientes foram selecionados em uma coorte retrospectiva não-concorrente por um a três anos, sendo formados dois grupos. Após o tratamento clínico sem sinais inequívocos de melhora os nervos foram randomizados para manter o tratamento clinico (Grupo A1) ou adicionar a descompressão do nervo (Grupo A2). Resultados: Os autores observaram melhora significativa nas seguintes variáveis no Grupo A2, tratado com a adição da descompressão cirúrgica, amplitude do potencial de ação motor composto (PAMC) no cotovelo e acima do cotovelo e velocidade de condução (VC) ao longo do antebraço. Conclusão: O ganho em amplitudes dos PAMCs no cotovelo e acima do cotovelo e da velocidade de condução (VC) ao longo do antebraço são a expressão do efeito tardio da descompressão do nervo ulnar. A persistência de dispersão temporal (DT) através do cotovelo foi relacionada a nova reação ou solução cirúrgica incompleta. Entretanto, a persistência de redução moderada da VC através do cotovelo sem a DT foi discutida e considerada como remielinização parcial esperada. A graduação previa da lesão do nervo baseada na amplitude dos PAMCs apresentou relação direta aos resultados menos favoráveis

Emergence and transmission of drug-/multidrug-resistant Mycobacterium leprae in a former leprosy colony in the Brazilian Amazon

BACKGROUND: Leprosy has been treated with multidrug therapy (MDT) distributed for free across the globe and regarded as highly efficient. However, the impossibility to grow M. leprae in axenic media has historically impaired assessment of M. leprae resistance, a parameter only recently detectable through molecular methods. METHODS: A systematic, population-based search for M. leprae resistance in suspected leprosy relapse cases and contacts was performed in Prata Village, an isolated, hyper-endemic former leprosy colony located in the Brazilian Amazon. Results led to an extended active search involving the entire Prata population. Confirmed leprosy cases were investigated for bacterial resistance using a combination of in vivo testing and direct sequencing of resistance genes folP1, rpoB and gyrA. Molecular epidemiology analysis was performed using data from 17 variable number tandem repeats (VNTR). RESULTS: M. leprae was obtained from biopsies of 37 leprosy cases (18 relapses and 19 new); 16 (43.24%) displayed drug-resistance variants. Multi-drug resistance to rifampicin and dapsone was observed in 8 relapses and 4 new cases. Single resistance to rifampicin was detected in one new case. Resistance to dapsone was present in two relapses and one new case. Combined molecular resistance and VNTR data revealed evidence of intra-familial primary transmission of resistant M. leprae. CONCLUSIONS: A comprehensive, population-based systematic approach to investigate M. leprae resistance in a unique population revealed an alarming scenario of emergence and transmission of resistant strains. These findings may be used for the development of new strategies for surveillance of drug resistance in other populations.

Leprosy survey among rural communities and wild armadillos from Amazonas state, Northern Brazil

There is evidence that in southern US, leprosy is a zoonosis infecting wild Dasypus novemcinctus armadillos but the extent of this finding is unknown. This ecological study investigated leprosy in rural communities and in wild armadillos from the Brazilian Amazon. The study area was the Mamia´ Lake of Coari municipality, Amazonas State, Northern region, a hyper endemic leprosy area where residents live on subsistence farming, fishing and armadillo hunting and its meat intake are frequent. The leprosy survey was conducted in sixteen communities by a visiting team of specialists. Local partakers provided wild armadillos to investigate M. leprae infection. Volunteers had complete dermato-neurological examination by a dermatologist with expertise in leprosy diagnosis, suspect skin lesions were biopsied for histopathology (Hematoxylin-eosin/HE, Fite-Faraco/FF staining); slit skin smears were collected. Armadillos' tissue fragments (skins, spleens, livers, lymph nodes, adrenal glands, others) were prepared for histopathology (HE/FF) and for M. leprae repetitive elementRLEP-qPCR. Among 176 volunteers, six new indeterminate leprosy cases were identified (incidence = 3.4%). Suspect skin sections and slit skin smears were negative for bacilli. Twelve wild D. novemcinctus were investigated (48 specimens/96 slides) and histopathological features of M. leprae infection were not found, except for one skin presenting unspecific inflammatory infiltrate suggestive of indeterminate leprosy. Possible traumatic neuroma, granuloma with epithelioid and Langhans cells, foreign-body granuloma were also identified. Granulomatous/non-granulomatous dermatitides were periodic-acid-Schiff/ PAS negative for fungus. M. leprae-RLEP-qPCR was negative in all armadillos' tissues; no bacillus was found in histopathology. Our survey in rural communities confirmed the high endemicity for leprosy while one armadillo was compatible with paucibacillary M. leprae infection. At least in the highly endemic rural area of Coari, in the Brazilian Amazon region where infectious sources from untreated multibacillary leprosy are abundant, M. leprae infected armadillos may not represent a major source of infection nor a significant public health concern.

Digitalização e publicação online da Revista Leprosy Review de 1928-2001 - relato de experiência / Scanning and online publication of the Leprosy Review Journal from 1928-2001 - experience report

Trata-se de um relato de experiência cujo objetivo é compartilhar o processo de execução da digitalização e disponibilização em meio eletrônico da Revista Leprosy Review e de dar visibilidade aos estudos sobre hanseníase em âmbito nacional e internacional. Constitui-se de um relato baseado na observação dos profissionais envolvidos na execução do projeto. Os resultados obtidos evidenciam que os principais objetivos do projeto foram alcançados, pois a revista já está operando em meio eletrônico em caráter de acesso aberto e as etapas foram concluídas dentro dos critérios estabelecidos inicialmente no projeto (AU)

This is an experience report which main goal is to share the process of scanning and electronic availability of Leprosy Review Journal, and aims to give visibility to studies on leprosy on national and international levels. It is a report based on the observation of the professionals involved in the execution of the project. The results show that the main objectives of the project were achieved, since the journal is already operating online, in open access and has satisfactory levels of access. The stages of the project were completed within the criteria established initially (AU)

Early detection of M. leprae by qPCR in untreated patients and their contacts: results for nasal swab and palate mucosa scraping

To verify if the hard palate mucosa can be a site of relevance in the early molecular detection of Mycobacterium leprae in leprosy cases and their household contacts and if there is a correlation of results in nasal swab with those of the scraping of the palate mucosa. The quantitative polymerase chain reaction technique was used. Sample included 78 patients with untreated leprosy (G1), their 54 household contacts (G2), and 80 healthy individuals for the negative control (G3). The presence of M. leprae in both G1 and G2 was observed with the nasal swab and the palate mucosa scrapings methods, and it was shown that the sensitivity between the qPCR exams for RLEP and 85B genes is equivalent, with no statistically significant differences (G1 positivity of 35% in the hard palate mucosa and 44% for the nasal one, p = 0.3731 and for G2 of 31 and 38%, respectively, p = 0.6774). Results support the fact that the buccal mucosa and nasal mucosa may be important sites of primary infection of leprosy with repercussion in the transmission chain and that asymptomatic household contacts are heavily harbored by the causative agent of leprosy, which has a critical significance in the prevention and control action of this disease, since the evaluation of these sites arises as of importance in the early detection of M. leprae. Close monitoring and chemoprophylaxis of household contacts appear to be critical to attain interruption of the transmission of leprosy in endemic countries

Multidrug therapy for leprosy: a game changer on the path to elimination

Leprosy is present in more than 100 countries, where it remains a major cause of peripheral neuropathy and disability. Attempts to eliminate the disease have faced various obstacles, including characteristics of the causative bacillus Mycobacterium leprae: the long incubation period, limited knowledge about its mode of transmission, and its poor growth on culture media. Fortunately, the leprosy bacillus is sensitive to several antibiotics. The first antibiotic to be widely used for leprosy treatment was dapsone in the 1950s, which had to be taken over several years and was associated with increasing bacterial resistance. Therefore, in 1981, WHO recommended that all registered patients with leprosy should receive combination therapy with three antibiotics: rifampicin, clofazimine, and dapsone. Global implementation of this highly effective multidrug therapy took about 15 years. In 1985, 5·3 million patients were receiving multidrug therapy; by 1991, this figure had decreased to 3·1 million (a decrease of 42%) and, by 2000, to 597 232 (a decrease of almost 90%). This reduction in the number of patients registered for treatment was due to shortening of the treatment regimen and achievement of 100% coverage with multidrug therapy. This achievement, which owed much to WHO and the donors of the multidrug therapy components, prompted WHO in 1991 to set a global target of less than one case per 10 000 population by 2000 to eliminate the disease as a public health problem. All but 15 countries achieved this target. Since 2000, about 250 000 new cases of leprosy have been detected every year. We believe an all-out campaign by a global leprosy coalition is needed to bring that figure down to zero.

Higienização bucal em pacientes com deformidades nas mãos: uso de adaptador para escova dental

Avaliar o efeito do uso de uma adaptação para escova dental em indivíduos afetados pela hanseníase com garra e avaliar sua contribuição na higiene bucal. Sujeitos e método: estudo realizado no Instituto Lauro de Souza Lima, com amostra de dez pacientes com idade acima de 18 anos, apresentando garra ulnar, ou garra ulnar mediano no membro dominante, entre 2013 e 2016. Foram realizadas a identificação dos pacientes, de seu perfil social e da forma clínica da hanseníase e a análise da higienização bucal pelo Índice de Higiene Oral Simplificado (IHO-S). Cada componente desse índice é avaliado em uma escala de 0 a 3. O resultado do IHO-S é dado pela média dos pontos de cada dente, assim classificados: 0 a 1 ­ higiene satisfatória; 1,1 a 2 ­ higiene regular; 2,1 a 3 ­ higiene deficiente. Resultados: o IHO-S dos pacientes foi medido em três momentos: antes da entrega do adaptador; uma semana de uso contínuo do adaptador, 15 dias de uso contínuo do adaptador. Observaram-se valores menores da média e mediana do IHO-S com o uso do adaptador, de acordo com o tempo. O teste estatístico ANOVA confirmou a diferença significativa entre os grupos (p = 0,002196). O teste Tukey registrou a diferença do 1o momento em relação ao 2o (p = 0,02509) e ao 3o (p = 0,002199); não houve diferença estatística significativa entre o 2o e o 3o momentos. O teste de Kruskal-Wallis confirmou a diferença significativa entre os grupos (p = 0,005887). Conclusões: a tecnologia assistiva pode gerar melhora na capacidade funcional. Mesmo considerando o pequeno universo deste estudo, conclui-se que as adaptações podem contribuir para a melhora da qualidade de vida e também para a melhor qualidade da higiene bucal de tal população.

Factors contributing to the delay in diagnosis and continued transmission of leprosy in Brazil - an explorative, quantitative, questionnaire based study

BACKGROUND: Leprosy is a leading cause of preventable disability worldwide. Delay in diagnosis of patients augments the transmission of infection, and allows progression of disease and more severe disability. Delays in diagnosis greater than ten years have been reported in Brazil. To reduce this delay, it is important to identify factors that hinder patients from presenting to doctors, and those that delay doctors from diagnosing patients once they have presented. This study aimed to explore factors associated with the delayed diagnosis of leprosy in Brazil. METHODOLOGY/ PRINCIPAL FINDINGS: This is an exploratory study using a self-constructed questionnaire delivered to patients attending three leprosy referral clinics across three states in Brazil. Data were analysed to determine associations between variables and the time taken for participants to present to the health-service, and between variables and the time taken for doctors to diagnose participants once they had presented. Participants who suspected they had leprosy but feared community isolation were 10 times more likely to wait longer before consulting a doctor for their symptoms (OR 10.37, 95% CI 2.18-49.45, p = 0.003). Participants who thought their symptoms were not serious had a threefold greater chance of waiting longer before consulting than those who did (OR 3.114, 95% CI 1.235-7.856, p = 0.016). Forty-two point six per cent of participants reported initially receiving a diagnosis besides leprosy. These had a three times greater chance of receiving a later diagnosis of leprosy compared to those not misdiagnosed or not given a diagnosis (OR 2.867, 95% CI 1.288-6.384, p = 0.010). CONCLUSIONS/ SIGNIFICANCE: This study implies a need for patient education regarding leprosy symptoms and the reduction of stigma to encourage patients to present. The high rate of misdiagnosis reported suggests a need to increase clinician suspicion of leprosy. Further education regarding disease symptoms in medical school curriculums may be advisable.