Correction: Association of NOD2 and IFNG single nucleotide polymorphisms with leprosy in the Amazon ethnic admixed population.

[This corrects the article DOI: 10.1371/journal.pntd.0008247.].

Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations.

Pyruvate kinase (PK), encoded by the PKLR gene, is a key player in glycolysis controlling the integrity of erythrocytes. Due to Plasmodium selection, mutations for PK deficiency, which leads to hemolytic anemia, are associated with resistance to malaria in sub-Saharan Africa and with susceptibility to intracellular pathogens in experimental models. In this case-control study, we enrolled 4,555 individuals and investigated whether PKLR single nucleotide polymorphisms (SNPs) putatively selected for malaria resistance are associated with susceptibility to leprosy across Brazil (Manaus-North; Salvador-Northeast; Rondonópolis-Midwest and Rio de Janeiro-Southeast) and with tuberculosis in Mozambique. Haplotype T/G/G (rs1052176/rs4971072/rs11264359) was associated with leprosy susceptibility in Rio de Janeiro (OR = 2.46, p = 0.00001) and Salvador (OR = 1.57, p = 0.04), and with tuberculosis in Mozambique (OR = 1.52, p = 0.07). This haplotype downregulates PKLR expression in nerve and skin, accordingly to GTEx, and might subtly modulate ferritin and haptoglobin levels in serum. Furthermore, we observed genetic signatures of positive selection in the HCN3 gene (xpEHH>2 -recent selection) in Europe but not in Africa, involving 6 SNPs which are PKLR/HCN3 eQTLs. However, this evidence was not corroborated by the other tests (FST, Tajima's D and iHS). Altogether, we provide evidence that a common PKLR locus in Africans contribute to mycobacterial susceptibility in African descent populations and also highlight, for first, PKLR as a susceptibility gene for leprosy and TB.

Lagoftalmo na hanseníase: experiência clínica em centro de referência amazonense / Lagophthalmos in leprosy: clinical experience in an Amazon reference center

RESUMO Objetivo: O presente trabalho teve por objetivo caracterizar o perfil epidemiológico e clínico de pacientes com lagoftalmo associado à hanseníase, atendidos no ambulatório de oftalmologia da Fundação Alfredo da Matta, Manaus, Amazonas. Métodos: Trata-se de estudo retrospectivo realizado por meio da análise dos prontuários clínicos dos pacientes incluídos no estudo. Sexo, idade, forma clínica, grau de incapacidade no diagnóstico e desfecho foram obtidos dos prontuários. Início, tipo de comprometimento (unilateral ou bilateral), grau de intensidade do lagoftalmo e alterações oculares associadas também foram compilados. Resultados: Foram incluídos 65 pacientes; 66,1% eram do sexo masculino e 53,8% tinham idade superior a 60 anos. Em relação à classificação operacional da hanseníase, a maioria dos pacientes (81,5%) era multibacilar: 33,8% na forma de hanseníase borderline e 47% virchowiana. 36,9% casos apresentavam sequelas oculares associadas ao lagoftalmo: opacidade corneana, epífora, ceratopatia em faixa, e neovascularização corneana.41,6% evoluíram para a cegueira. O lagoftalmo foi conduzido de forma clínica em 23 pacientes e a abordagem cirúrgica foi indicada em 42. Em relação ao tratamento cirúrgico consistiu principalmente no implante de peso de ouro e na cantoplastia de Tessier. Discussão: O lagoftalmo nessa casuística acometeu mais homens idosos, esteve relacionado à forma multibacilar, com hanseníase do tipo virchowiano como relatado na literatura. O diagnóstico de lagoftalmo foi tardio na maioria dos casos, explicando o grande número de sequelas incluindo a cegueira. Conclusão: O presente estudo reforça a necessidade de acompanhamento oftalmológico precoce para que as potenciais e graves sequelas associadas a essa condição sejam evitadas.

ABSTRACT Objective: The present study aimed to characterize the epidemiological and clinical profile of patients with lagophthalmos associated with leprosy, seen at the ophthalmology outpatient clinic of Fundação Alfredo da Matta, Manaus, Amazonas. Methods: This is a retrospective study carried out by analyzing the medical records of the patients included in the study. Sex, age, clinical form, degree of disability in diagnosis and outcome were obtained from medical records. Onset, type of impairment (unilateral or bilateral), degree of intensity of lagophthalmos and associated eye changes were also compiled. Results: 65 patients were included; 66.1% were male and 53.8% were older than 60 years. Regarding the operational classification of leprosy, most patients (81.5%) were multibacillary: 33.8% in the form of borderline leprosy and 47% virchowian. 36.9% of cases had ocular sequelae associated with lagophthalmos: corneal opacity, epiphora, band keratopathy, and corneal neovascularization.41.6% progressed to blindness. Lagophthalmos was performed clinically in 23 patients and the surgical approach was indicated in 42. Regarding surgical treatment, it consisted mainly of gold weight implantation and Tessier's canthoplasty. Discussion: Lagophthalmos in this sample affected more elderly men, was related to the multibacillary form, with leprosy-like leprosy as reported in the literature. The diagnosis of lagophthalmos was delayed in most cases, explaining the large number of sequelae including blindness. Conclusion: The present study reinforces the need for early eye care so that the potential and serious sequelae associated with this condition are avoided.

Case for diagnosis. Infiltrated areas on the trunk

Abstract Leprosy is an infectious disease with chronic evolution, caused by Mycobacterium leprae, an acid-fast bacillus that mainly affects the skin and peripheral nervous tissue. Many of the clinical manifestations of leprosy can mimic connective tissue diseases. The authors present the case of a 49-year-old woman who had been treated for four years for systemic lupus erythematosus in a rheumatological service. Skin biopsy of a plaque on the inguinal region was compatible with borderline lepromatous leprosy associated with a type 1 lepra reaction. The patient is undergoing treatment with multibacillary multidrug therapy, showing clinical improvement.

Case for diagnosis. Infiltrated areas on the trunk.

Leprosy is an infectious disease with chronic evolution, caused by Mycobacterium leprae, an acid-fast bacillus that mainly affects the skin and peripheral nervous tissue. Many of the clinical manifestations of leprosy can mimic connective tissue diseases. The authors present the case of a 49-year-old woman who had been treated for four years for systemic lupus erythematosus in a rheumatological service. Skin biopsy of a plaque on the inguinal region was compatible with borderline lepromatous leprosy associated with a type 1 lepra reaction. The patient is undergoing treatment with multibacillary multidrug therapy, showing clinical improvement.

Case for diagnosis. Keloidal cord-like lesion on the leg

Abstract We report a 74-year-old male presented to an outpatient dermatology clinic in Manaus, Amazonas, with a one-year history of pruritic, keloidal lesions on his left lower extremity. Histopathology showed round structures in reticular dermis. Grocott methenamine silver stain revealed numerous round yeasts with thick double walls, occurring singly or in chains connected by tubular projections. The diagnosis was lobomycosis. Although the keloidal lesions presented by this patient are typical of lobomycosis, their linear distribution along the left lower limb is unusual.

Association of NOD2 and IFNG single nucleotide polymorphisms with leprosy in the Amazon ethnic admixed population.

Leprosy is a chronic infectious disease, caused by Mycobacterium leprae, which affects skin and peripheral nerves. Polymorphisms in genes associated with autophagy, metabolism, innate and adaptive immunity confer susceptibility to leprosy. However, these associations need to be confirmed through independent replication studies in different ethnicities. The population from Amazon state (northern Brazil) is admixed and it contains the highest proportion of Native American genetic ancestry in Brazil. We conducted a case-control study for leprosy in which we tested fourteen previously associated SNPs in key immune response regulating genes: TLR1 (rs4833095), NOD2 (rs751271, rs8057341), TNF (rs1800629), IL10 (rs1800871), CCDC122/LACC1 (rs4942254), PACRG/PRKN (rs9356058, rs1040079), IFNG (rs2430561), IL6 (rs2069845), LRRK2 (rs7298930, rs3761863), IL23R (rs76418789) and TYK2 (rs55882956). Genotyping was carried out by allelic discrimination in 967 controls and 412 leprosy patients. Association with susceptibility was assessed by logistic regression analyses adjusted for the following covariates: gender, age and ancestry. Genetic ancestry was similar in case and control groups. Statistically significant results were only found for IFNG and NOD2. The rs8057341 polymorphism within NOD2 was identified as significant for the AA genotype (OR = 0.56; 95% CI, 0.37-0.84; P = 0.005) and borderline for the A allele (OR = 0.76; 95% CI, 0.58-1.00; P = 0.053) and carrier (OR = 0.76; 95% CI, 0.58-1.00; P = 0.051). The rs2430561 SNP in IFNG was associated with disease susceptibility for the AT genotype (OR = 1.40; 95% CI, 1.06-1.85; P = 0.018) and carrier (OR = 1.44; 95% CI, 1.10-1.88; P = 0.008). We confirmed that NOD2 and IFNG are major players in immunity against M.leprae in the Amazon ethnic admixed population.

What is your diagnosis? Keloidal cord-like lesion on the leg.

We report a 74-year-old male presented to an outpatient dermatology clinic in Manaus, Amazonas, with a one-year history of pruritic, keloidal lesions on his left lower extremity. Histopathology showed round structures in reticular dermis. Grocott methenamine silver stain revealed numerous round yeasts with thick double walls, occurring singly or in chains connected by tubular projections. The diagnosis was lobomycosis. Although the keloidal lesions presented by this patient are typical of lobomycosis, their linear distribution along the left lower limb is unusual.

Performance of serological tests PGL1 and NDO-LID in the diagnosis of leprosy in a reference Center in Brazil.

BACKGROUND: Early detection of leprosy and multidrug therapy are crucial to achieve zero transmission and zero grade II incapacities goals of World Health Organization. Leprosy is difficult to diagnose because clinical forms vary and there are no gold standard methods to guide clinicians. The serological rapid tests aid the clinical diagnosis and are available for field use. They are easy to perform, do not require special equipment or refrigeration and are cheaper than the molecular tests. METHODS: We evaluated the performance of two rapid serological tests (PGL1 and NDO-LID) in the discrimination of leprosy cases from healthy individuals at the Alfredo da Matta Foundation, a reference center for the disease in Manaus, Amazonas, Brazil. PGL1 and NDO-LID rapid tests are capable of detecting specific antibodies of M. leprae, IgM and IgM/IgG, respectively. A total of 530 healthy subjects and 171 patients (50 with paucibacillary and 121 multibacillary leprosy) were included in the study. RESULTS: Among the paucibacillary leprosy patients, the sensitivity was 34.0 and 32.0% for the NDO-LID and PGL1, respectively. In multibacillary leprosy patients, the NDO-LID sensitivity was 73.6% and the PGL1 was 81.0%. Serological tests demonstrated specificities of 75.9% for PGL-1 and 81.7% for NDO-LID. The positive predictive value (PPV), negative predictive value (NPV) and accuracy in multibacillary patients were 47.9, 93.1, and 80.2% respectively for the NDO-LID, and 43.4, 94.6 76.8% for PGL1. CONCLUSIONS: The tests showed limited capacity in the diagnosis of the disease, however, the high negative predictive value of the tests indicates a greater chance of true negatives in this group favoring exclusion of leprosy. This characteristic of the ML flow test is important in aiding clinical Diagnosis, especially in a region endemic to the disease and with other confounding skin conditions.

Atypical crusted scabies in a patient with chronic liver disease caused by hepatitis B and D viruses.

Crusted scabies is a less common variant of scabies that is highly contagious, difficult to treat and involves infestation by Sarcoptes scabiei var. hominis. The classical clinical presentation includes crusted, scaly and generally non-pruritic lesions usually located on the head, neck, palmar, plantar and periungual region. It was first described in Norway in 1848 in patients with leprosy who presented with crusted lesions. In this study, we report the case of a patient with crusted scabies with florid clinical manifestations and chronic liver disease due to hepatitis B and delta virus infection.

Atypical crusted scabies in a patient with chronic liver disease caused by hepatitis B and D viruses

Abstract: Crusted scabies is a less common variant of scabies that is highly contagious, difficult to treat and involves infestation by Sarcoptes scabiei var. hominis. The classical clinical presentation includes crusted, scaly and generally non-pruritic lesions usually located on the head, neck, palmar, plantar and periungual region. It was first described in Norway in 1848 in patients with leprosy who presented with crusted lesions. In this study, we report the case of a patient with crusted scabies with florid clinical manifestations and chronic liver disease due to hepatitis B and delta virus infection.

Leprosy among schoolchildren in the Amazon region: A cross-sectional study of active search and possible source of infection by contact tracing.

BACKGROUND: The high rate of leprosy cases among children under 15 years of age in Brazil indicates ongoing transmission within the community. The identification of the new leprosy cases among contacts can help identify the source of infection and interrupt the transmission chain. This study aims to determine the detection rate of previously undiagnosed cases of leprosy among schoolchildren who are under 15 years of age living in Manaus, Amazonas, Brazil, and their possible source of infection by contact tracing. METHODOLOGY/PRINCIPAL FINDINGS: This was a school-based, cross-sectional study in which the identification of active leprosy cases was conducted in 277 out of 622 randomly selected public schools in Manaus, Amazonas, Brazil. Suspected cases of leprosy were referred to the Alfredo da Matta Foundation, a reference center for leprosy in Manaus. A total of 34,547 schoolchildren were examined, and 40 new leprosy cases were diagnosed. Among new cases, 57.5% were males, and 80.0% demonstrated paucibacillary leprosy. A total of 196 of 206 registered contacts were screened, and 52.5% of the newly diagnosed children's cases had at least one positive household contact. In these contacts, grandparents (52.4%) were the most common co-prevalent cases, while 14.3% were uncles, 9.5% were parents and 9.5% were granduncles. Seven contacts (5.0%), including four siblings of child patients were newly diagnosed. Our data indicate that the prevalence is 11.58 per 10,000, which is 17 times higher than the registered rate. CONCLUSIONS/SIGNIFICANCE: This study suggests that the detection rate of leprosy among schoolchildren may have remained unchanged over the past thirty years. It also indicates that that active case finding is necessary for reaching the World Health Organization's goals of zero detection among children, especially in endemic areas where the prevalence of leprosy is obscure. Moreover, we assert that all children must have their household contacts examined in order to identify the possible source of infection and interrupt the disease's transmission. Novel strategies to reinforce contact tracing associated with large-scale strategies of chemo- and immune-prophylaxis should be expanded to prevent the perpetuation of the disease cycle.

A historical overview of leprosy epidemiology and control activities in Amazonas, Brazil.

Leprosy is an ancient infectious disease caused by Mycobacterium leprae. According to comparative genomics studies, this disease originated in Eastern Africa or the Near East and spread with successive human migrations. The Europeans and North Africans introduced leprosy into West Africa and the Americas within the past 500 years. In Brazil, this disease arrived with the colonizers who disembarked at the first colonies, Rio de Janeiro, Salvador and Recife, at the end of the sixteenth century, after which it was spread to the other states. In 1854, the first leprosy cases were identified in State of Amazonas in the north of Brazil. The increasing number of leprosy cases and the need for treatment and disease control led to the creation of places to isolate patients, known as leprosaria. One of them, Colonia Antônio Aleixo was built in Amazonas in 1956 according to the most advanced recommendations for isolation at that time and was deactivated in 1979. The history of the Alfredo da Matta Center (AMC), which was the first leprosy dispensary created in 1955, parallels the history of leprosy in the state. Over the years, the AMC has become one of the best training centers for leprosy, general dermatology and sexually transmitted diseases in Brazil. In addition to being responsible for leprosy control programs in the state, the AMC has carried out training programs on leprosy diagnosis and treatment for health professionals in Manaus and other municipalities of the state, aiming to increase the coverage of leprosy control activities. This paper provides a historical overview of leprosy in State of Amazonas, which is an endemic state in Brazil.

A historical overview of leprosy epidemiology and control activities in Amazonas, Brazil

Leprosy is an ancient infectious disease caused by Mycobacterium leprae. According to comparative genomics studies, this disease originated in Eastern Africa or the Near East and spread with successive human migrations. The Europeans and North Africans introduced leprosy into West Africa and the Americas within the past 500 years. In Brazil, this disease arrived with the colonizers who disembarked at the first colonies, Rio de Janeiro, Salvador and Recife, at the end of the sixteenth century, after which it was spread to the other states. In 1854, the first leprosy cases were identified in State of Amazonas in the north of Brazil. The increasing number of leprosy cases and the need for treatment and disease control led to the creation of places to isolate patients, known as leprosaria. One of them, Colonia Antônio Aleixo was built in Amazonas in 1956 according to the most advanced recommendations for isolation at that time and was deactivated in 1979. The history of the Alfredo da Matta Center (AMC), which was the first leprosy dispensary created in 1955, parallels the history of leprosy in the state. Over the years, the AMC has become one of the best training centers for leprosy, general dermatology and sexually transmitted diseases in Brazil. In addition to being responsible for leprosy control programs in the state, the AMC has carried out training programs on leprosy diagnosis and treatment for health professionals in Manaus and other municipalities of the state, aiming to increase the coverage of leprosy control activities. This paper provides a historical overview of leprosy in State of Amazonas, which is an endemic state in Brazil.

T regulatory cells (TREG)(TCD4+CD25+FOXP3+) distribution in the different clinical forms of leprosy and reactional states.

BACKGROUND: Leprosy is characterized histologically by a spectrum of different granulomatous skin lesions, reflecting patients' immune responses to Mycobacterium leprae. Although CD4+CD25+ FoxP3+ T regulatory cells are pivotal in the immuneregulation, presence, frequency, and distribution of Tregs in leprosy, its reactional states have been investigated in few studies. OBJECTIVES: This study aimed to verify the frequency and distribution of regulatory T cells in different clinical forms and reactional states of leprosy. METHODS: We performed an immunohistochemical study on 96 leprosy cases [Indeterminate (I): 9 patients; tuberculoid tuberculoid: 13 patients; borderline tuberculoid: 26 patients; borderline borderline: 3 patients; borderline lepromatous: 8 patients; lepromatous lepromatous: 27 patients; reversal reaction: 8 patients; and erythema nodosum leprosum: 2 patients]. RESULTS: FoxP3-positive cells were present in 100% of the cases with an average density of 2.82% of the infiltrate. Their distribution was not related to granulomatous structures or special locations. There was a statistically significant increment of FoxP3 expression in patients with leprosy reversal reactions when compared with patients presenting with type I leprosy (P= 0.0228); borderline tuberculoid leprosy (P = 0.0351) and lepromatous leprosy (P = 0.0344). CONCLUSIONS: These findings suggest that Tregs play a relevant role in the etiopathogenesis of leprosy, mainly in type I leprosy reaction.

T regulatory cells (TREG)(TCD4+CD25+FOXP3+) distribution in the different clinical forms of leprosy and reactional states

BACKGROUND: Leprosy is characterized histologically by a spectrum of different granulomatous skin lesions, reflecting patients' immune responses to Mycobacterium leprae. Although CD4+CD25+ FoxP3+ T regulatory cells are pivotal in the immuneregulation, presence, frequency, and distribution of Tregs in leprosy, its reactional states have been investigated in few studies. OBJECTIVES: This study aimed to verify the frequency and distribution of regulatory T cells in different clinical forms and reactional states of leprosy. METHODS: We performed an immunohistochemical study on 96 leprosy cases [Indeterminate (I): 9 patients; tuberculoid tuberculoid: 13 patients; borderline tuberculoid: 26 patients; borderline borderline: 3 patients; borderline lepromatous: 8 patients; lepromatous lepromatous: 27 patients; reversal reaction: 8 patients; and erythema nodosum leprosum: 2 patients]. RESULTS: FoxP3-positive cells were present in 100% of the cases with an average density of 2.82% of the infiltrate. Their distribution was not related to granulomatous structures or special locations. There was a statistically significant increment of FoxP3 expression in patients with leprosy reversal reactions when compared with patients presenting with type I leprosy (P= 0.0228); borderline tuberculoid leprosy (P = 0.0351) and lepromatous leprosy (P = 0.0344). CONCLUSIONS: These findings suggest that Tregs play a relevant role in the etiopathogenesis of leprosy, mainly in type I leprosy reaction. .

Clinical aspects of leprosy.

Leprosy is a chronic, infectious disease caused by Mycobacterium leprae. It mainly affects the peripheral nervous system, skin, and certain other tissues such as the reticulo-endothelial system, bones and joints, mucous membranes, eyes, testes, muscles, and adrenals. Leprosy clinical presentation varies from few to widespread lesions. In most patients, early leprosy presents as macular and hypopigmented lesions. This initial clinical presentation is known as indeterminate leprosy and occurs in individuals who have not developed cell-mediated immunity against M. leprae yet. The number of lesions depends on the genetically determined cellular immunity of the patient. Individuals presenting a vigorous cellular immune response and limited humoral immune responses to M. leprae, usually present few skin lesions. Without treatment, those patients tend to evolve into the polar tuberculoid or borderline tuberculoid form of leprosy. Due to the inability to mount an effective cellular-mediated response to M. leprae and the consequent hematogenous spread of the bacilli, some patients may present with numerous and symmetrically distributed hypochromic lesions. Without treatment these patients evolve to a nonresistant form of leprosy, polar lepromatous.