Marília Brasil Xavier

A Major Gene Controls Leprosy Susceptibility in a Hyperendemic Isolated Population from North of Brazil

BACKGROUND Leprosy is a chronic infectious disease that affects 250,000 new individuals/year worldwide. Genetic analysis has been successfully applied to the identification of host genetic factors affecting susceptibility to leprosy; however, a consensus regarding its mode of inheritance is yet to be achieved. METHODS We conducted a complex segregation analysis (CSA) on leprosy using data from the Prata Colony, an isolated, highly endemic former leprosy community located at the outskirts of the Brazilian Amazon. The colony offers large multiplex, multigenerational pedigrees composed mainly by descendents of a small number of original leprosy-affected families. Our enrollment strategy was complete ascertainment leading to the inclusion of the whole colony (2005 individuals, 225 of whom were affected) distributed in 112 pedigrees. CSA was performed using REGRESS software. RESULTS CSA identified a best-fit codominant model, with a major gene accounting for the entire familial effect observed. The frequency of predisposing allele was estimated at 0.22. Penetrance for homozygous individuals for the predisposing allele >30 years old ranged from 56% to 85%, depending on sex. CONCLUSIONS A strong major gene effect in the isolated, hyperendemic Prata Colony indicates enrichment of genetic risk factors, suggesting a population particularly suitable for leprosy gene identification studies.

HIV and lacaziosis, Brazil.

To the Editor: Jorge Lobo disease (lacaziosis) is a chronic deep mycosis for which prognosis is good in terms of survival but unclear in terms of regression of the lesions (1). No involvement of internal organs or mucous membranes is observed. The causative agent is Lacazia loboi (2), a fungus of uncertain phylogeny, which causes an inflammatory infiltrate accompanied by the formation of a granuloma in which giant cells phagocytose a larger number of fungi (3,4). Pecher and Funchs suggested that patients with lacaziosis have a cellular immunodeficiency (5). The disease is more frequent in men and persons 21–40 years of age. It is found exclusively in Latin America; only 1 case has been diagnosed in Europe, and that was due to accidental contamination with material from a dolphin (4). Trauma and injuries or sites of insect bites facilitate penetration of the fungus. Lesion progression is slow, with new lesions arising by contiguity with other lesions or through the lymphatic route (6,7). Clinically, lacaziosis manifests as keloidal lesions of solid consistency and variable size that contain small scales and crusts (6). The lesions are most frequently located in the auricle and on the upper and lower limbs. Cutaneous dissemination of the disease is observed in a relatively small number of cases. We describe a patient with Jorge Lobo disease. The patient was a 59-year-old man, a storeroom employee, who was seen at the Tropical Medical Center in Belem, Brazil, in April 2004. A papula had developed near his right knee in 1992 after a wood splinter had penetrated the skin. The lesion increased in size, and a histopathologic diagnosis of Jorge Lobo disease was made. The lesion was then surgically removed. Approximately 2 years later, the lesion recurred. The patient then went to a dermatology service and was treated with clofazimine, after which the lesion disappeared. However, the lesion reappeared 1 year later. HIV serologic analysis was performed in 2002, and the results were positive. The patient then began treatment for HIV infection. He is currently being monitored at the specialized referral unit in Belem. He does not have any opportunistic infections and is not taking any antiretroviral drugs. The patient came to the dermatology service of the Tropical Medical Center, where dermatologic and histopathologic examinations were conducted and CD cell counts and HIV viral load were measured. Dermatologic aspects of the lesion included an erythematous-infiltrated, hypertrophic plaque with a verrucous surface ≈4 cm long in the distal third of the medical aspect of the right thigh (Figure). A punch biopsy specimen of brown smooth skin 0.35 cm in diameter in an epidermal disk was fixed in formalin. Microscopy of skin sections containing epidermis showed compact keratinization, parakeratotic foci, and irregular hyperplasia with a pseudoepitheliomatous area. A highly dense, nodular, diffuse inflammatory infiltrate was observed at all levels of the dermis. It consisted of macrophages and numerous multinucleated cells, most of them of the foreign body type. Fibroplasia was also noted. Abundant, round parasitic elements surrounded by a double membrane and containing a basophilic nucleus were found in tissues, as well as other anucleated, intracellular, and free parasites that formed chains of >2 cells (Figure A1). Jorge Lobo disease was diagnosed. Laboratory results showed 146 CD4 cells/μL, 251 CD8 cells/μL, a CD4:CD8 ratio of 0.42, and 60,000 copies of HIV viral RNA/mL. Figure Erythematous-infiltrated, hypertrophic plaque with a verrucous surface ≈4 cm long in the distal third of the medical aspect of the right thigh of the patient. Since a cytotoxic response is observed in Jorge Lobo disease (7), HIV infection may increase the susceptibility to infection with L. loboi. Patients with AIDS show a predisposition to diverse fungal infections that classically affect different organs and systems. An association between Jorge Lobo disease and AIDS has not been reported. However, since Jorge Lobo disease is restricted to specific areas of the world and the number of AIDS cases is increasing, especially in Latin America, a possible correlation between HIV infection and Jorge Lobo disease should be considered because of the associated cellular immunodeficiency. The patient showed no signs of other opportunistic infections classically associated with AIDS, and he was not taking any antiretroviral drugs. His initial infection manifested as cutaneous lesions that occur in Jorge Lobo disease. Despite the cellular immunodeficiency, we did not observe atypical dissemination of the lesions. Further studies should be conducted to evaluate the relationship between the cellular immunosuppression of AIDS and secondary infection with L. loboi. In addition, epidemiologic studies are needed to determine the association of AIDS with Jorge Lobo disease.

Exposição humana ao metilmercúrio em comunidades ribeirinhas da Região do Tapajós, Pará, Brasil

Avaliou-se a exposicao humana ao metilmercurio e ao mercurio total em comunidades ribeirinhas do rio Tapajos e da regiao metropolitana de Belem, no Estado do Para, Brasil, atraves da determinacao de mercurio total e metilmercurio em amostras de cabelo nos anos de 1994 e 1995. Observou-se que as concentracoes medias de mercurio total variaram de 2 ± 1µg/g-1 a 20,5 ± 12,1µg/g-1, enquanto que as concentracoes medias de metilmercurio variaram de 1,4 ± 0,7µg/g-1 a 18,5 ± 11µg/g-1. Estes resultados confirmam a contaminacao mercurial na regiao do rio Tapajos, admitem a possibilidade do aparecimento de sinais e sintomas de intoxicacao mercurial e recomendam a manutencao da monitorizacao do mercurio total e do metilmercurio nas amostras de cabelo, bem como a necessidade de estudos clinico-epidemiologicos para implantacao de medidas de prevencao e controle da intoxicacao mercurial.

A Major Gene Effect Controls Resistance to Caries

Despite recent advances revealing genetic factors influencing caries susceptibility, questions regarding the model of inheritance involved are yet to be addressed. We conducted a Complex Segregation Analysis on decayed teeth in a sample of homogenous, isolated families recruited from the Brazilian Amazon. A dominant, major gene effect controlling resistance to phenotype was detected. The frequency of the resistance allele “A” was 0.63; mean numbers of decayed teeth were 1.53 and 9.53 for genotypes AA/AB and BB, respectively. These results represent a step toward a description of the exact nature of the genetic risk factors controlling human susceptibility to caries.

CD1a and factor XIIIa immunohistochemistry in leprosy: a possible role of dendritic cells in the pathogenesis of Mycobacterium leprae infection.

Leprosy is a curable chronic granulomatous infectious disease caused by the bacillus Mycobacterium leprae. This organism has a high affinity for skin and peripheral nerve cells. In the evolution of infections, the immune status of patients determines the disease expression. Dendritic cells are antigen-presenting cells that phagocytose particles and microorganisms. In skin, dendritic cells are represented by epidermal Langerhans cells and dermal dendrocytes, which can be identified by expression of CD1a and factor XIIIa (FXIIIa). In the present study, 29 skin samples from patients with tuberculoid (13 biopsies) and lepromatous (16 biopsies) leprosy were analyzed by immunohistochemistry using antibodies to CD1a and FXIIIa. Quantitative analysis of labeling pattern showed a clear predominance of dendritic cells in tuberculoid leprosy. Difference between the number of positive cells of immunohistochemistry for the CD1a and FXIIIa staining observed in this study indicates a role for dendritic cells in the cutaneous response to leprosy. Dendritic cells may be a determinant of the course and clinical expression of the disease.

Clinical, epidemiological and mycological report on 65 patients from the Eastern Amazon region with chromoblastomycosis

BACKGROUND Chromoblastomycosis is a chronic fungal infection caused by fungi from the Dematiaceae family. According to several studies, Fonsecaea pedrosoi is the most common of these fungi. The infection is more common in tropical countries, with the Brazilian state of Pará having one of the largest infected populations worldwide. The disease is difficult to treat and recurrences are common. OBJECTIVES To describe the epidemiological and mycological aspects of cases of chromoblastomycosis and its clinical forms in the state of Pará, Brazil. METHODS Mycological exams (direct mycological examinations, culture and microculture) were performed and a clinical/epidemiological evaluation was made of 65 patients receiving care at the Dermatology Department of the Federal University of Pará between 2000 and 2007. The clinical classification proposed by Carrión in 1950 was used in this study. RESULTS The majority of the patients were male (93.8%), agricultural workers (89.2%) of 45 to 55 years of age, and the majority of lesions (55.4%) were of the verrucous type, located principally on the lower limbs (81.5%). In the majority of the cases investigated (61.5%), the infection had been present for a long time, with a mean duration of 11 years. Direct mycological examination was performed in 86.2% of the patients (n=56). Of these, 96.4% (n=54) tested positive. Culture and microculture were performed in vitro in 47 cases of those that tested positive at direct microscopy, results showing Fonsecaea pedrosoi to be the only agent present in this sample. CONCLUSION This study highlighted the extent to which chromoblastomycosis still affects the quality of life of the local population, principally individuals working in agriculture. This is a chronic disease for which there is no effective treatment. The importance of continuing to investigate this disease should be emphasized, as further studies may lead to new clinical or epidemiological findings.

Deteccção do DNA de Mycobacterium leprae em secreção nasal

Studies have demonstrated high sensibility of the polimerase chain reaction (PCR) technique in the identification of the Mycobacterium leprae DNA . This study aimed to evalue the PCR sensibility at the detection of the M. leprae DNA in nasal swab of leprosy patients and to compare the results with the bacilloscopy and multibacillary (MBs) and paucibacilares (PBs) forms. Nasal secretion samples of 24 leprosy patients were collected, and were preserved in one and two lises solution. The PCR results were highly significant (p <0.0000) and they revealed grater sensibility than bacilloscopy, in several clinical forms. Nevertheless, still different studies are necessary, testing new markers and preservatives, with the purpose of lifting up the sensibility of this technique, in nasal secretion samples.

Leprosy Reactions in Patients Coinfected with HIV: Clinical Aspects and Outcomes in Two Comparative Cohorts in the Amazon Region, Brazil

Background Leprosy, caused by Mycobacterium leprae, can lead to scarring and deformities. Human immunodeficiency virus (HIV), a lymphotropic virus with high rates of replication, leads to cell death in various stages of infection. These diseases have major social and quality of life costs, and although the relevance of their comorbidity is recognized, several aspects are still not fully understood. Methodology/Principal Findings Two cohorts of patients with leprosy in an endemic region of the Amazon were observed. We compared 40 patients with leprosy and HIV (Group 1) and 107 leprosy patients with no comorbidity (Group 2) for a minimum of 2 years. Group 1 predominantly experienced the paucibacillary classification, accounting for 70% of cases, whereas Group 2 primarily experienced the multibacillary classification (80.4% of cases). There was no significant difference in the prevalence of leprosy reactions among the two groups (37.5% for Group 1 vs. 56.1% for Group 2), and the most frequent reaction was Type 1. The appearance of Group 1 patients’ reversal reaction skin lesions was consistent with each clinical form: typically erythematous and infiltrated, with similar progression as those patients without HIV, which responded to prednisone. Patients in both groups primarily experienced a single episode (73.3% in Group 1 and 75% in Group 2), and Group 1 had shorter reaction periods (≤3 months; 93.3%), moderate severity (80%), with 93.3% of the patients in the state of acquired immune deficiency syndrome, and 46.7% presenting the reaction at the time of the immune reconstitution inflammatory syndrome. Conclusions/Significance This study used a large sample and makes a significant contribution to the clinical outcomes of patients in the reactive state with comorbid HIV and leprosy. The data indicate that these diseases, although concurrent, have independent courses.

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.

Plasmacytoid dendritic cells in cutaneous lesions of patients with chromoblastomycosis, lacaziosis, and paracoccidioidomycosis: a comparative analysis

Plasmacytoid dendritic cells (pDCs) are characterized by expression of CD123 and BDCA-2 (Blood Dendritic Cell Antigen 2) (CD303) molecules, which are important in innate and adaptive immunity. Chromoblastomycosis (CBM), lacaziosis or Jorge Lobos disease (JLD), and paracoccidioidomycosis (PCM), are noteworthy in Latin America due to the large number of reported cases. The severity of lesions is mainly determined by the hosts immune status and in situ responses. The dendritic cells studied in these fungal diseases are of myeloid origin, such as Langerhans cells and dermal dendrocytes; to our knowledge, there are no data for pDCs. Forty-three biopsies from patients with CBM, 42 from those with JLD and 46 diagnosed with PCM, were evaluated by immunohistochemistry. Plasmacytoid cells immunostained with anti-CD123 and anti-CD303 were detected in 16 cases of CBM; in those stained with anti-CD123, 24 specimens were obtained from PCM. We did not detect the presence of pDCs in any specimen using either antibody in JLD. We believe that, albeit a secondary immune response in PCM and CBM, pDCs could act as a secondary source of important cytokines. The BDCA-2 (CD303) is a c-type lectin receptor involved in cell adhesion, capture, and processing of antigens. Through the expression of the c-lectin receptor, there could be an interaction with fungi, similar to other receptors of this type, namely, CD207 in PCM and CD205 and CD209 in other fungal infections. In JLD, the absence of expression of CD123 and CD303 seems to indicate that pDCs are not involved in the immune response.