Patologia da hanseníase e a importância do diagnóstico histopatológico: uma entrevista com Dr. Cleverson Teixeira Soares / Pathology of leprosy and the importance of histopathological diagnosis: an interview with Dr. Cleverson Teixeira Soares

A revista Hansenologia Internationalis tem a honra de entrevistar o Dr. Cleverson Teixeira Soares, médico patologista, responsável pelo Laboratório de Anatomia Patológica do Instituto Lauro de Souza Lima, Bauru, São Paulo, Brasil. Dr. Cleverson é autor do livro Histopathological Diagnosis of Leprosy, publicado em 2021 pela editora Bentham Books, além de relevante publicação de artigos, em periódicos científicos nacionais e internacionais, com impacto nas áreas de patologia e hansenologia. Ele descreve sobre sua trajetória profissional, os desafios para o entendimento da hanseníase em suas múltiplas formas clínicas e como a patologia clássica e molecular tem contribuído para a construção do conhecimento sobre esta doença tão complexa.

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

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

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

Histoid leprosy presenting as a large tumor

Abstract Histoid leprosy is a rare form of multibacillary leprosy, characterized by the presence of papules, plaques, or nodules whose appearance is keloid-like, skin colored, or erythematous. Fusiform cells are the main histopathological feature. Due to the fact that it can simulate other dermatological lesions, for example, dermatofibroma and neurofibroma, it constitutes a diagnostic challenge for clinicians and pathologists. It is a bacilliferous form of leprosy, and it plays an important role in disease transmission. A case of a patient with histoid leprosy living in the Northeast Region of Brazil is reported.

Disabilities in leprosy: an open, retrospective analyses of institutional records

Abstract Background and objectives: Leprosy remains a leading cause of peripheral neuropathy and disability in the world. Primary objective of the study was to determine the incidence of deformities present at a time of diagnosis and new deformities that patients develop over follow up period. Material and methods: An open, retrospective cohort study was performed at a tertiary medical center in western India. Recruitment phase of the study was of 2 years (2009-2010) followed by observation/follow up phase of 7 years till 31st December 2017. New patients with leprosy and released from treatment cases who presented with deformity as defined by WHO disability grade (1998) and subsequently developing new deformities during the follow up period of up to 7 years were included in the study. Results: The study included 200 leprosy patients. Of the total 254 deformities, 168 (66.14%) deformities were noticed at the moment of diagnosis, 20 (7.87%) deformities occurred during the follow up phase. Of all patients, 21.25% had Grade 1 deformity and 6.31% had Grade 2 or more severe deformity. Deformities of hand were most common in 44.48%, followed by feet 39.76%, and face 15.74% respectively. Limitation of study: Mode of inclusion of patient was self-reporting during follow up phase so there is possible under reporting of the disabilities. Conclusion: New deformities continue to develop in certain forms of leprosy even after release from treatment. Long-term & regular follow up of patients who have been released from treatment is required.

Expression of NLRP3 inflammasome in leprosy indicates immune evasion of Mycobacterium leprae

BACKGROUND Leprosy is an infectious-contagious disease caused by Mycobacterium leprae that remain endemic in 105 countries. This neglected disease has a wide range of clinical and histopathological manifestations that are related to the host inflammatory and immune responses. More recently, the inflammasome has assumed a relevant role in the inflammatory response against microbiological agents. However, the involvement of inflammasome in leprosy remains poorly understood. OBJECTIVES The aim is to associate biomarkers of inflammasome with the different immunopathological forms of leprosy. METHODS We performed an observational, cross-sectional, and comparative study of the immunophenotypic expression of inflammasome-associated proteins in immunopathological forms of leprosy of 99 skin lesion samples by immunohistochemistry. The intensity and percentage of NLRP3, Caspase-1, Caspases-4/5, interleukin-1β and interleukin-18 immunoreactivities in the inflammatory infiltrate of skin biopsies were evaluated. FINDINGS Strong expression of NLRP3 and inflammatory Caspases-4/5 were observed in lepromatous leprosy (lepromatous pole). In addition, were observed low expression of caspase-1, interleukin-1β, and interleukin-18 in tuberculoid and lepromatous leprosy. The interpolar or borderline form showed immunophenotype predominantly similar to the lepromatous pole. MAIN CONCLUSIONS Our results demonstrate that the NLRP3 inflammasome is inactive in leprosy, suggesting immune evasion of M. leprae.

La Lepra: una enfermedad vigente / Leprosy: an ongoing disease

El libro resalta que la lepra continúa siendo una enfermedad presente en Colombia y que aún constituye un problema de salud pública importante por los costos sociales, económicos y de sufrimiento humano que conlleva. Sabiendo que la literatura sobre el tema es escasa en nuestro medio, este libro surge como una herramienta de consulta creada para médicos y otros profesionales de salud, con la certeza de que es preciso mejorar la oportunidad del diagnóstico. Siendo fundamental que, durante su proceso formativo, todos los profesionales de la salud adquieran conocimientos sobre dicha enfermedad, que cada día se hace más visible por sus secuelas y diagnóstico tardío.

The book highlights the fact that leprosy continues to be a disease present in Colombia and that it is still a major public health problem due to the social, economic and human suffering costs it entails. Knowing that the literature on the subject is scarce in our country, this book is intended as a reference tool for doctors and other health professionals, in the knowledge that it is necessary to improve the timeliness of diagnosis. It is essential that, during their training process, all health professionals acquire knowledge about this disease, which is becoming more and more visible every day due to its sequelae and late diagnosis.

Epidemiological, clinical and immune factors that influence the persistence of antiphospholipid antibodies in leprosy

Abstract Introduction: Antiphospholipid antibodies (aPL) are described in individuals with leprosy without the clinical features of antiphospholipid antibody syndrome (APS), a condition involving thromboembolic phenomena. We have described the persistence of these antibodies for over 5 years in patients with leprosy after specific treatment. Objectives: To determine whether epidemiological, clinical and immunological factors played a role in the longterm persistence of aPL antibodies in leprosy patients after multidrug therapy (MDT) had finished. Methods: The study sample consisted of 38 patients with a diagnosis of leprosy being followed up at the Dermatology and Venereology Outpatient Department at the Alfredo da Matta Foundation (FUAM) in Manaus, AM. ELISA was used to detect anticardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies. Patients were reassessed on average of 5 years after specific treatment for the disease (MDT) had been completed. Results: Persistence of aPL antibodies among the 38 leprosy patients was 84% (32/38), and all had the IgM isotype. Mean age was 48.1 ± 15.9 years, and 23 (72.0%) were male. The lepromatous form (LL) of leprosy was the most common (n = 16, 50%). Reactional episodes were observed in three patients (9.4%). Eighteen (47.37%) were still taking medication (prednisone and/or thalidomide). Mean IgM levels were 64 U/mL for aCL and 62 U/mL for anti-β2GPI. In the multivariate binary logistic regression the following variables showed a significant association: age (p = 0.045, OR = 0.91 and CI 95% 0.82-0.98), LL clinical presention (p = 0.034; OR = 0.02 and CI 95% = 0.0-0.76) and bacterial index (p = 0.044; OR = 2.74 and CI 95% = 1.03-7.33). We did not find association between prednisone or thalidomide doses and positivity for aPL (p = 0.504 and p = 0.670, respectively). No differences in the variables vascular thrombosis, pregnancy morbidity, diabetes, smoking and alcoholism were found between aPL-positive and aPL-negative patients. Conclusion: Persistence of positivity for aPL antibodies was influenced by age, clinical presentation and bacterial index. However, further studies are needed to elucidate the reason for this persistence, the role played by aPL antibodies in the disease and the B cell lineages responsible for generation of these antibodies.

De novo histoid leprosy in a Colombian patient with multiple skin nodules on the ears and extremities

Abstract Histoid leprosy is an uncommon form of lepromatous leprosy with distinct clinical, histopathological, immunological, and bacteriological features. This variant usually occurs in multibacillary patients who have irregular or inadequate treatment. Herein, we report a case of de novo histoid leprosy diagnosed in a patient from Cali, Colombia. In endemic areas, histoid leprosy should be in the differential diagnosis of any patient presenting with skin nodules. Early diagnosis and appropriate treatment are recommended for mitigating the impact of histoid leprosy cases, which are important reservoirs of Mycobacterium leprae.

Leprosy: current situation, clinical and laboratory aspects, treatment history and perspective of the uniform multidrug therapy for all patients

Abstract: In this review, the most relevant and current epidemiological data, the main clinical, laboratory and therapeutical aspects of leprosy are presented. Detailed discussion of the main drugs used for leprosy treatment, their most relevant adverse effects, evolution of the therapeutic regimen, from dapsone as a monotherapy to the proposed polychemotherapy by World Health Organization (WHO) can be found in this CME. We specifically highlight the drug acceptability, reduction in treatment duration and the most recent proposal of a single therapeutic regimen, with a fixed six months duration, for all clinical presentations, regardless of their classification.

qPCR detection of Mycobacterium leprae in biopsies and slit skin smear of different leprosy clinical forms

Abstract Leprosy, whose etiological agent is Mycobacterium leprae, is a chronic infectious disease that mainly affects the skin and peripheral nervous system. The diagnosis of leprosy is based on clinical evaluation, whereas histopathological analysis and bacilloscopy are complementary diagnostic tools. Quantitative PCR (qPCR), a current useful tool for diagnosis of infectious diseases, has been used to detect several pathogens including Mycobacterium leprae. The validation of this technique in a robust set of samples comprising the different clinical forms of leprosy is still necessary. Thus, in this study samples from 126 skin biopsies (collected from patients on all clinical forms and reactional states of leprosy) and 25 slit skin smear of leprosy patients were comparatively analyzed by qPCR (performed with primers for the RLEP region of M. leprae DNA) and routine bacilloscopy performed in histological sections or in slit skin smear. Considering clinical diagnostic as the gold standard, 84.9% of the leprosy patients were qPCR positive in skin biopsies, resulting in 84.92% sensitivity, with 84.92 and 61.22% positive (PPV) and negative (NPV) predictive values, respectively. Concerning bacilloscopy of histological sections (BI/H), the sensitivity was 80.15% and the PPV and NPV were 80.15 and 44.44%, respectively. The concordance between qPCR and BI/H was 87.30%. Regarding the slit skin smear, 84% of the samples tested positive in the qPCR. Additionally, qPCR showed 100% specificity, since all samples from different mycobacteria, from healthy individuals, and from other granulomatous diseases presented negative results. In conclusion, the qPCR technique for detection of M. leprae using RLEP primers proved to be specific and sensitive, and qPCR can be used as a complementary test to diagnose leprosy irrespective of the clinical form of disease.

The involvement of endothelial mediators in leprosy

Leprosy is a chronic infectious disease that requires better understanding since it continues to be a significant health problem in many parts of the world. Leprosy reactions are acute inflammatory episodes regarded as the central etiology of nerve damage in the disease. The activation of endothelium is a relevant phenomenon to be investigated in leprosy reactions. The present study evaluated the expression of endothelial factors in skin lesions and serum samples of leprosy patients. Immunohistochemical analysis of skin samples and serum measurements of VCAM-1, VEGF, tissue factor and thrombomodulin were performed in 77 leprosy patients and 12 controls. We observed significant increase of VCAM-1 circulating levels in non-reactional leprosy (p = 0.0009). The immunostaining of VEGF and tissue factor was higher in endothelium of non-reactional leprosy (p = 0.02 for both) than healthy controls. Patients with type 1 reaction presented increased thrombomodulin serum levels, compared with non-reactional leprosy (p = 0.02). In type 2 reaction, no significant modifications were observed for the endothelial factors investigated. The anti-inflammatory and antimicrobial activities of the endotfhelial factors may play key-roles in the pathogenesis of leprosy and should be enrolled in studies focusing on alternative targets to improve the management of leprosy and its reactions.

Lepra histioide de Wade: a propósito de 2 casos / Wade histoid leprosy: report of two cases

Presentamos dos casos de lepra histioide de Wade con manifestaciones clínicas e histopatológicas características. Debido a la escasa frecuencia de esta patología realizamos una revisión bibliográfica del tema (AU)

Histoid leprosy with giant lesions of fingers and toes / Lepra histioide con lesiones gigantes de los dedos de manos y pies

This work was conducted at the Facultad de Medicina, Universidad de La Sabana, and at the Facultad de Medicina, Universidad Surcolombiana. Histoid leprosy, a clinical and histological variant of multibacillary leprosy, may offer a challenging diagnosis even for experts. An 83-year-old woman presented with papular, nodular and tumor-like lesions of 3 years of evolution, affecting fingers, toes, hands, thighs and knees, and wide superficial ulcers in her lower calves. Cutaneous lymphoma was suspected. A biopsy of a nodule of the knee showed a diffuse dermal infiltrate with microvacuolated histiocytes, moderate numbers of lymphocytes and plasma cells. Cutaneous lymphoma was suggested. Immunohistochemistry (IHC) showed prominent CD68-positive macrophages, as well as CD3, CD8 and CD20 positive cells. Additional sections suggested cutaneous leishmaniasis. New biopsies were sent with the clinical diagnoses of cutaneous lymphoma, Kaposi´s sarcoma or lepromatous leprosy, as the patient had madarosis. These biopsies showed atrophic epidermis, a thin Grenz zone and diffuse inflammation with fusiform cells and pale vacuolated macrophages. ZiehlNeelsen stain showed abundant solid phagocytized bacilli with no globii formation. Abundant bacilli were demonstrated in the first biopsy. Histoid leprosy was diagnosed. The patient received the WHO multidrug therapy with excellent results. We concluded that Ziehl Neelsen staining should be used in the presence of a diffuse dermal infiltrate with fusiform and vacuolated histiocytes, which suggests a tumor, and an IHC particularly rich in CD68-positive macrophages; this will reveal abundant bacilli if the lesion is leprosy. A good clinical pathological correlation is essential to establish a proper diagnosis and management of the patient.

La lepra histioide es una forma de lepra multibacilar de diagnóstico clínico e histológico difícil incluso para expertos. Una mujer de 83 años se presentó a consulta con pápulas, nódulos y tumores de tres años de evolución en los dedos de manos y pies, y en manos, muslos y rodillas, así como úlceras superficiales extensas en la porción inferior de las pantorrillas, ante lo cual se sospechó linfoma cutáneo. La biopsia de un nódulo de la rodilla mostró infiltrado dérmico difuso con histiocitos microvacuolados y algunos linfocitos y plasmocitos. Se sugirió la posibilidad de un linfoma cutáneo. La inmunohistoquímica demostró macrófagos prominentes positivos para CD68 y células CD3, CD8 y CD20. Con base en los cortes adicionales de la biopsia, se sugirió la presencia de leishmaniasis cutánea. Se tomaron nuevas biopsias con las sugerencias diagnósticas de linfoma cutáneo, sarcoma de Kaposi o lepra lepromatosa, pues la paciente presentaba madarosis. Estas mostraron epidermis atrófica, una delgada zona subepidérmica de colágeno denso y dermatitis difusa con células fusiformes y algunos macrófagos vacuolados. La coloración de Ziehl-Neelsen reveló la presencia de bacilos abundantes en los macrófagos, sin tendencia a formar globias. En la primera biopsia se demostraron abundantes bacilos. Se diagnosticó lepra histioide. La paciente recibió quimioterapia antileprosa (Organización Mundial de la Salud) con resultados excelentes. Se concluyó que un infiltrado dérmico difuso con histiocitos fusiformes y algunos vacuolados, que sugiere un tumor fusocelular, cuya inmunohistoquímica sea particularmente rica en células positivas para CD68, debe teñirse con Ziehl-Neelsen, lo que revelará abundantes bacilos si la lesión es de lepra. La adecuada correlación clínico-patológica es necesaria para establecer el diagnóstico y el manejo preciso del paciente.

Comparison between histopathologic features of leprosy in reaction lesions in HIV coinfected and non-coinfected patients*

BACKGROUND: Leprosy and HIV are diseases that have a major impact on public health in Brazil. Patients coinfected with both diseases, appear to be at higher risk to develop leprosy reactions. OBJECTIVE: The aim of this study is to describe the histopathological aspects of cutaneous lesions during reactional states in a group of patients with HIV-leprosy coinfection, compared to patients with leprosy, without coinfection. METHODS: Two groups were established: group 1 comprised of 40 patients coinfected with HIV-leprosy; group 2, comprised of 107 patients with leprosy only. Patients presenting reactional states of leprosy had their lesions biopsied and comparatively evaluated. RESULTS: Reversal reaction was the most frequent feature in both groups, with dermis edema as the most common histopathological finding. Giant cells were seen in all group 1 histopathological examinations. Dermis edema was the most common finding in patients with erythema nodosum leprosum. CONCLUSION: Few histopathological differences were found in both groups, with reversal reaction as the most significant one, although this fact should be analyzed considering the predominant BT clinical form in the coinfected group and BB form in the group without HIV. Larger prospective studies in patients with HIV-leprosy coinfection are needed to confirm and broaden these results. .

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. .

Leprosy nephroptthy: a review of clinical and histopathological features / Nefropatia da hanseníase: revisão dos aspectos clínicos e histopatológicos

Leprosy is a chronic disease caused by Mycobacterium leprae, highly incapacitating, and with systemic involvement in some cases. Renal involvement has been reported in all forms of the disease, and it is more frequent in multibacillary forms. The clinical presentation is variable and is determined by the host immunologic system reaction to the bacilli. During the course of the disease there are the so called reactional states, in which the immune system reacts against the bacilli, exacerbating the clinical manifestations. Different renal lesions have been described in leprosy, including acute and chronic glomerulonephritis, interstitial nephritis, secondary amyloidosis and pyelonephritis. The exact mechanism that leads to glomerulonephritis in leprosy is not completely understood. Leprosy treatment includes rifampicin, dapsone and clofazimine. Prednisone and non-steroidal anti-inflammatory drugs may be used to control acute immunological episodes.

A hanseníase é doença crônica causada pelo Mycobacterium leprae, altamente incapacitante e com envolvimento sistêmico em alguns casos. O envolvimento renal tem sido relatado em todas as formas da doença, sendo mais frequente nas formas multibacilares. A apresentação clínica é variável e determinada pela reação do sistema imunológico do hospedeiro ao bacilo. Durante o curso da doença podem ocorrer os chamados estados reacionais, nos quais o sistema imune reage contra o bacilo, exacerbando as manifestações clínicas. Diferentes lesões renais tem sido descritas na hanseníase, incluindo glomerulonefrites, nefrite intersticial, amiloidose secundária e pielonefrite. O mecanismo exato que leva à glomerulonefrite na hanseníase ainda não está completamente esclarecido. O tratamento da hanseníase inclui o uso de rifampicina, dapsona e clofazimina. Prednisona e antiinflamatórios não-hormonais podem ser usados no controle dos episódios imunológicos agudos.

Leprosy: type 1 reaction precipitated by doxorubicin and cisplatin

Type 1 reaction [T1R] in leprosy is common and characterized by increased inflammation in skin lesions or nerve. Besides antileprotic therapy, T1Rs are associated with intercurrent infection, pregnancy and drugs. Also, T1Rs may be a presenting feature of leprosy. We report a case of T1R in leprosy presenting as drug reaction during cancer chemotherapy with doxorubicin and cisplatin. We propose to explain this unusual occurrence by highlighting the increased production and expression of TNF-alpha by these drugs. Thus, physicians using these drugs should keep this unusual adverse effect in mind

Leprosy: review of the epidemiological, clinical, and etiopathogenic aspects - Part 1

Leprosy is caused by Mycobacterium leprae and has been known since biblical times. It is still endemic in many regions of the world and a public health problem in Brazil. The prevalence rate in 2011 reached 1.54 cases per 10,000 inhabitants in Brazil. The mechanism of transmission of leprosy consists of prolonged close contact between susceptible and genetically predisposed individuals and untreated multibacillary patients. Transmission occurs through inhalation of bacilli present in upper airway secretion. The nasal mucosa is the main entry or exit route of M. leprae. The deeper understanding of the structural and biological characteristics of M. leprae, the sequencing of its genome, along with the advances in understanding the mechanisms of host immune response against the bacilli, dependent on genetic susceptibility, have contributed to the understanding of the pathogenesis, variations in the clinical characteristics, and progression of the disease. This article aims to update dermatologist on epidemiological, clinical, and etiopathogenic leprosy aspects.