RESUMO
INTRODUCTION: Leprosy is an ancient and chronic infectious disease caused by 2 mycobacteria (Mycobacterium leprae and Mycobacterium lepromatosis). Recently, our research group observed that HES-1, an innate cellular component of the Notch signaling pathway, is related to the pathogenesis of leprosy. Therefore, it could be helpful in its detection. OBJECTIVE: To determine the expression of HES-1 in the skin of patients with paucibacillary (PB) leprosy. METHODS: A cross-sectional, descriptive, observational study was conducted. Forty-five skin samples from patients with leprosy were evaluated (30 samples from MB leprosy and 15 from PB leprosy) using immunohistochemistry of HES-1 and S-100. RESULTS: PB leprosy biopsies revealed a reduction of HES-1 in 66.7% of the epidermis, 80% of the eccrine glands, and 62.5% of the hair follicles of these patients, with statistical differences in the control group (P < 0.0001). Besides, HES-1 showed similar utility to S-100 immunostaining in detecting the MB and PB leprosy. CONCLUSIONS: HES-1 is a transcriptional factor also reduced in PB patients' epidermis and skin appendages. Finally, our data show that HES-1 could be a biomarker in diagnosing PB and MB leprosy.
Assuntos
Hanseníase Multibacilar , Hanseníase Paucibacilar , Hanseníase , Humanos , Fatores de Transcrição , Fatores de Transcrição HES-1 , Estudos Transversais , Sensibilidade e Especificidade , Mycobacterium leprae , Hanseníase Multibacilar/microbiologiaRESUMO
Mannose-binding lectin (MBL) is a serum protein of innate immunity, with a central role in the activation of the complement system through the lectin pathway. This protein is encoded by MBL2 gene, and single-nucleotide polymorphisms located at exon 1, such as rs5030737 C>T (D variant), rs1800450 G>A (B variant), and rs1800451 G>A (C variant), may change the MBL structure and the serum concentration. MBL2 polymorphisms have been associated with several infectious diseases, including leprosy. Host immune response has a major impact on the clinical manifestation of leprosy since only a few individuals infected with Mycobacterium leprae will develop the disease. Therefore, the aim of this study was to evaluate the influence of MBL2 exon 1 polymorphisms (rs5030737, rs1800450, and rs1800451) on the MBL levels and leprosy immunopathogenesis. This case-control study included 350 leprosy patients from Southern Brazil, with 279 classified as multibacillary (MB) and 71 as paucibacillary (PB). The control group consisted of 350 non-consanguineous individuals, who were not diagnosed with leprosy or other infectious and autoimmune diseases. Genotyping was performed by PCR-sequence specific primers, and the MBL serum concentrations were evaluated by ELISA. MBL2 exon 1 polymorphisms were analyzed individually and grouped as genotypes, considering "A" as the wild allele and "O" as the presence of at least one polymorphism (D, B, or C variants). Differences were not observed in the distribution of genotypic and allelic frequencies between leprosy per se patients and controls. However, in a haplotypic analysis, the TGG haplotype presented a risk for development of leprosy per se in women when compared to the wild haplotype (CGG) (OR = 2.69). Comparing patients with MB and PB, in a multivariate analysis, the B variant was associated with the susceptibility of developing the MB form of leprosy (OR = 2.55). Besides that, the CAG haplotype showed an increased susceptibility to develop MB leprosy in women compared to men. It was observed that the A/O genotype in women was associated with a susceptibility to leprosy development per se (OR = 1.66) and progression to MB leprosy (OR = 3.13). In addition, the MBL serum concentrations were in accordance with the genotyping analysis. In summary, our data suggest that MBL2 exon 1 polymorphisms are associated with an increased risk to leprosy development and progression.
Assuntos
Hanseníase Multibacilar/genética , Lectina de Ligação a Manose/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Brasil , Estudos de Casos e Controles , Éxons , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hanseníase Multibacilar/diagnóstico , Hanseníase Multibacilar/microbiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Medição de Risco , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND: Dermatological diseases have a negative impact on quality of life (QoL), affecting mental and physical health. Leprosy patients usually present with a worse QoL compared with those affected by other conditions. Reactions, neural damage, and pain are some of the consequences that contribute to the lower QoL. However, due to the wide spectrum of the disease, symptoms vary according to leprosy's subtype. This study aimed to compare the QoL between paucibacillary and multibacillary leprosy patients. Individuals were also compared considering the presence of reactions and a correlation between questionnaires was performed. METHODS: A total of 104 patients with leprosy aged 18 years old and over were selected. QoL was assessed by the Brazilian-Portuguese validated versions of the Medical Outcomes Study 36-item short-form health survey (SF-36) and the Dermatology Life Quality Life Index (DLQI). RESULTS: Multibacillary patients showed a more impaired physical function, worse bodily pain, lower score of SF-36, and higher interference of skin on the performance of daily activities when compared to the paucibacillary group. Individuals without reactions presented lower bodily pain and less effect of the skin on clothing choices compared to those with reactions. The SF-36 domains exhibited weak correlations with most DLQI questions, and the linear regression model showed that 32% of changes in QoL were related to the skin aspect. CONCLUSIONS: Multibacillary leprosy patients have a worse QoL when compared to paucibacillary patients. Reactions played a small role in the QoL of our cohort of patients.
Assuntos
Hanseníase Multibacilar/psicologia , Hanseníase Paucibacilar/psicologia , Dor/psicologia , Qualidade de Vida , Adulto , Brasil , Feminino , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Hanseníase Multibacilar/complicações , Hanseníase Multibacilar/diagnóstico , Hanseníase Multibacilar/microbiologia , Hanseníase Paucibacilar/complicações , Hanseníase Paucibacilar/diagnóstico , Hanseníase Paucibacilar/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/isolamento & purificação , Dor/diagnóstico , Dor/etiologia , Medição da Dor , Índice de Gravidade de Doença , Pele/microbiologia , Pele/patologiaRESUMO
BACKGROUND: Erythema nodosum leprosum may appear before, during or after treatment of leprosy and is one of the main factors for nerve damage in patients. When it occurs or continues to occur after treatment, it may indicate disease recurrence and a new treatment may be instituted again. OBJECTIVE: To evaluate the retreatment of patients with multibacillary leprosy who underwent standard treatment with multidrug therapy, but developed or continued to present reactions of erythema nodosum leprosum and/or neuritis 3-5 years after its end. METHOD: For this objective, a new treatment was performed in 29 patients with multibacillary leprosy who maintained episodes of erythema nodosum and/or neuritis 3-5 years after conventional treatment. RESULTS: In general, we observed that 27 (93.10%) had no more new episodes after a follow up period of eight months to five years. In five of these patients the reason for the retreatment was the occurrence of difficult-to-control neuritis, and that has ceased to occur in all of them. STUDY LIMITATIONS: Small number of patients.. CONCLUSION: In the cases observed, retreatment was an effective measure to prevent the occurrence of erythema nodosum leprosum and/or persistent neuritis.
Assuntos
Eritema Nodoso/tratamento farmacológico , Hanseníase Virchowiana/tratamento farmacológico , Hanseníase Multibacilar/tratamento farmacológico , Neurite (Inflamação)/tratamento farmacológico , Eritema Nodoso/microbiologia , Feminino , Humanos , Hansenostáticos/uso terapêutico , Hanseníase Virchowiana/microbiologia , Hanseníase Multibacilar/microbiologia , Masculino , Neurite (Inflamação)/microbiologia , Recidiva , Retratamento , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The annual new-case detection rate for leprosy, while generally stable over the last decade, shows that transmission rates have remained stagnant despite the successful worldwide administration of multidrug therapy since the 1980s. As such, novel control strategies are urgently needed. Focusing on managing leprosy patient contacts, the most susceptible to contracting the disease, has been seen as a potential strategy in limiting the spread of leprosy as shown by a number of recent epidemiological studies. Immunoprophylaxis with Bacillus Calmette-Guérin (BCG) has been seen as an effective preventive measure due to its ability to stimulate the development of cellular immunity which is essential in controlling the disease, especially in its multibacillary (MB) forms. The association of immunoprophylaxis with chemoprophylaxis in a single dose of rifampicin has been shown to be a promising preventive strategy, although a variety of studies have found instances of early case detection just a few months after BCG vaccination. METHODS/DESIGN: The present study is a phase IV chemoprophylactic clinical trial consisting of administration of a single dose of rifampicin in MB leprosy patient contacts under care at the Souza Araújo Outpatient Clinic/FIOCRUZ as part of a randomized (2:1), double-blind, placebo-controlled study. It is comprised of two groups: 1) rifampicin + BCG; and 2) placebo + BCG. DISCUSSION: The aim is to evaluate whether the use of chemoprophylaxis with a single dose of rifampicin in MB leprosy patient contacts prior to the BCG vaccine would be able to prevent the onset of leprosy in those cases that may occur just a few months after vaccination. Contact subclinical infections (polymerase chain reaction) and the immunological parameters (anti-PGL-1, anti-LID-1, and IFN-γ) will be evaluated and the results will be compared after 12 months of follow-up. TRIAL REGISTRATION: The Brazilian Registry of Clinical Trials (ReBEC), RBR-69QK5P . Retrospectively registered on 1 June 2017.
Assuntos
Vacina BCG/administração & dosagem , Busca de Comunicante , Hansenostáticos/administração & dosagem , Hanseníase Multibacilar/prevenção & controle , Rifampina/administração & dosagem , Adolescente , Adulto , Idoso , Vacina BCG/efeitos adversos , Brasil , Criança , Pré-Escolar , Ensaios Clínicos Fase IV como Assunto , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Lactente , Hansenostáticos/efeitos adversos , Hanseníase Multibacilar/imunologia , Hanseníase Multibacilar/microbiologia , Hanseníase Multibacilar/transmissão , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Rifampina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Vacinação , Adulto JovemRESUMO
Abstract: Background: Erythema nodosum leprosum may appear before, during or after treatment of leprosy and is one of the main factors for nerve damage in patients. When it occurs or continues to occur after treatment, it may indicate disease recurrence and a new treatment may be instituted again. Objective: To evaluate the retreatment of patients with multibacillary leprosy who underwent standard treatment with multidrug therapy, but developed or continued to present reactions of erythema nodosum leprosum and/or neuritis 3-5 years after its end. Method: For this objective, a new treatment was performed in 29 patients with multibacillary leprosy who maintained episodes of erythema nodosum and/or neuritis 3-5 years after conventional treatment. Results: In general, we observed that 27 (93.10%) had no more new episodes after a follow up period of eight months to five years. In five of these patients the reason for the retreatment was the occurrence of difficult-to-control neuritis, and that has ceased to occur in all of them. Study limitations: Small number of patients.. Conclusion: In the cases observed, retreatment was an effective measure to prevent the occurrence of erythema nodosum leprosum and/or persistent neuritis.
Assuntos
Humanos , Masculino , Feminino , Hanseníase Virchowiana/tratamento farmacológico , Eritema Nodoso/tratamento farmacológico , Hanseníase Multibacilar/tratamento farmacológico , Neurite (Inflamação)/tratamento farmacológico , Recidiva , Fatores de Tempo , Hanseníase Virchowiana/microbiologia , Resultado do Tratamento , Retratamento , Eritema Nodoso/microbiologia , Hanseníase Multibacilar/microbiologia , Hansenostáticos/uso terapêutico , Neurite (Inflamação)/microbiologiaRESUMO
Leprosy is a chronic disease caused by M. leprae infection that can cause severe neurological complications and physical disabilities. A leprosy-specific vaccine would be an important component within control programs but is still lacking. Given that multifunctional CD4 T cells [i.e., those capable of simultaneously secreting combinations of interferon (IFN)-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)] have now been implicated in the protective response to several infections, we tested the hypothesis if a recombinant M. leprae antigen-specific multifunctional T cells differed between leprosy patients and their healthy contacts. We used whole blood assays and peripheral blood mononuclear cells to characterize the antigen-specific T cell responses of 39 paucibacillary (PB) and 17 multibacillary (MB) leprosy patients and 31 healthy household contacts (HHC). Cells were incubated with either crude mycobacterial extracts (M. leprae cell sonicate-MLCS) and purified protein derivative (PPD) or recombinant ML2028 protein, the homolog of M. tuberculosis Ag85B. Multiplex assay revealed antigen-specific production of IFN-γ and IL-2 from cells of HHC and PB, confirming a Th1 bias within these individuals. Multiparameter flow cytometry then revealed that the population of multifunctional ML2028-specific T cells observed in HHC was larger than that observed in PB patients. Taken together, our data suggest that these multifunctional antigen-specific T cells provide a more effective response against M. leprae infection that prevents the development of leprosy. These data further our understanding of M. leprae infection/leprosy and are instructive for vaccine development.
Assuntos
Antígenos de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Hanseníase Multibacilar/imunologia , Hanseníase Paucibacilar/imunologia , Mycobacterium leprae/imunologia , Vacinas/imunologia , Adulto , Idoso , Antígenos de Bactérias/genética , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Feminino , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-2/imunologia , Interleucina-2/metabolismo , Hanseníase Multibacilar/microbiologia , Hanseníase Multibacilar/prevenção & controle , Hanseníase Paucibacilar/microbiologia , Hanseníase Paucibacilar/prevenção & controle , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/fisiologia , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Vacinas/uso terapêutico , Adulto JovemRESUMO
Diffuse multibacillary leprosy of Lucio and Latapí is mainly reported in Mexico and Central America. We report a case in a 65-year-old man in Peru. He also had Lucio's phenomenon, characterized by vascular thrombosis and invasion of blood vessel walls by leprosy bacilli, causing extensive skin ulcers.
Assuntos
Hanseníase Multibacilar/diagnóstico , Mycobacterium leprae/isolamento & purificação , Idoso , Humanos , Hanseníase Multibacilar/microbiologia , Hanseníase Multibacilar/patologia , Masculino , Peru , Pele/microbiologia , Pele/patologiaRESUMO
BACKGROUND: Studies investigating the nutritional status of patients with leprosy and plantar ulcers are sparse. Therefore, the objective of this study was to describe the protein profile of leprosy patients with plantar ulcers from the Eastern Amazon region. METHODS: A case record form was created for 75 patients with leprosy (31 with plantar ulcers and 44 without plantar ulcers) with the following data: sociodemographic characteristics, clinical form of leprosy, presence or absence of plantar ulcers, and nutritional assessment using anthropometry consisting of the measurement of body mass index, arm circumference, arm muscle circumference, and triceps skinfold. Levels of blood albumin, transferrin, and C-reactive protein (CRP) were also measured. Data regarding protein intake were obtained using a Food Frequency Questionnaire. RESULTS: Plantar ulcers occurred more frequently in male patients (67.7%), patients aged 40-49 years (mean ± SD: 47.3 ± 8.0 years), and patients receiving 300 or 600 USD (71.0%). The mean weight and height of patients were 71.6 ± 11.4 kg and 1.62 ± 0.1 m, respectively. High levels of CRP were detected in 51.6% of leprosy patients with plantar ulcers and only 9.1% of patients without plantar ulcers (P < 0.001). Nutritional depletion of transferrin was observed in 14.3% of patients with paucibacillary leprosy and 44.3% of patients with multibacillary leprosy (P = 0.0447). Most patients had normal levels of serum albumin (74.2% with plantar ulcers and 77.3% without plantar ulcers). CONCLUSIONS: Most leprosy patients with plantar ulcers have normal levels of serum albumin and transferrin and high CRP levels, which indicates the presence of an inflammatory process. Our findings suggest the need to monitor patients with leprosy to prevent the occurrence of plantar ulcers and to provide adequate treatment for patients with existing plantar ulcers.
Assuntos
Proteínas Alimentares/análise , Úlcera do Pé/metabolismo , Hanseníase Multibacilar/metabolismo , Hanseníase Paucibacilar/metabolismo , Estado Nutricional , Adulto , Brasil , Feminino , Úlcera do Pé/etiologia , Humanos , Hanseníase Multibacilar/microbiologia , Hanseníase Paucibacilar/microbiologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
It is well established that helper T cell responses influence resistance or susceptibility to Mycobacterium leprae infection, but the role of more recently described helper T cell subsets in determining severity is less clear. To investigate the involvement of Th17 cells in the pathogenesis of leprosy, we determined the immune profile with variant presentations of leprosy. Firstly, IL-17A, IFN-γ and IL-10 were evaluated in conjunction with CD4+ T cell staining by confocal microscopy of lesion biopsies from tuberculoid (TT) and lepromatous leprosy (LL) patients. Secondly, inflammatory cytokines were measured by multiplex assay of serum samples from Multibacillary (MB, n = 28) and Paucibacillary (PB, n = 23) patients and household contacts (HHC, n = 23). Patients with leprosy were also evaluated for leprosy reaction occurrence: LR+ (n = 8) and LR- (n = 20). Finally, peripheral blood mononuclear cells were analysed by flow cytometry used to determine the phenotype of cytokine-producing cells. Lesions from TT patients were found to have more CD4+ IL-17A+ cells than those from LL patients. Higher concentrations of IL-17A and IL-1ß were observed in serum from PB than MB patients. The highest serum IFN-γ concentrations were, however, detected in sera from MB patients that developed leprosy reactions (MB LR+ ). Together, these results indicate that Th1 cells were associated with both the PB presentation and also with leprosy reactions. In contrast, Th17 cells were associated with an effective inflammatory response that is present in the PB forms but were not predictive of leprosy reactions in MB patients.
Assuntos
Mediadores da Inflamação/imunologia , Hanseníase Paucibacilar/imunologia , Hanseníase/imunologia , Mycobacterium leprae/imunologia , Células Th1/imunologia , Células Th17/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Criança , Busca de Comunicante , Feminino , Citometria de Fluxo , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Interferon gama/sangue , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-17/sangue , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Hanseníase/sangue , Hanseníase/microbiologia , Hanseníase Multibacilar/sangue , Hanseníase Multibacilar/imunologia , Hanseníase Multibacilar/microbiologia , Hanseníase Paucibacilar/sangue , Hanseníase Paucibacilar/microbiologia , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Mycobacterium leprae/fisiologia , Células Th1/metabolismo , Células Th17/metabolismo , Adulto JovemRESUMO
Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Proteínas de Transporte de Cátions/genética , Predisposição Genética para Doença/genética , Hanseníase/genética , Polimorfismo Genético/genética , Brasil , Estudos de Casos e Controles , Frequência do Gene , Modelos Logísticos , Hanseníase Multibacilar/genética , Hanseníase Multibacilar/microbiologia , Hanseníase Paucibacilar/genética , Hanseníase Paucibacilar/microbiologia , Hanseníase/microbiologiaRESUMO
Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.
Assuntos
Proteínas de Transporte de Cátions/genética , Predisposição Genética para Doença/genética , Hanseníase/genética , Polimorfismo Genético/genética , Adulto , Idoso , Brasil , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Hanseníase/microbiologia , Hanseníase Multibacilar/genética , Hanseníase Multibacilar/microbiologia , Hanseníase Paucibacilar/genética , Hanseníase Paucibacilar/microbiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
INTRODUCTION: There is no information in Colombia on Mycobacterium leprae primary and secondary drug resistance in regards to the WHO-multidrug therapy regime. On the other hand, public health authorities around the world have issued various recommendations, one of which prompts for the immediate organization of resistance surveillance through simple molecular methods. OBJECTIVE: To determine the prevalence of Mycobacterium leprae drug resistance to rifampicin, ofloxacin and dapsone in untreated and previously treated patients at the Centro Dermatológico Federico Lleras Acosta during the 1985-2004 period. MATERIALS AND METHODS: We conducted a retrospective study which included multibacillary patient biopsies through elective sampling: 381 of them from new patients and 560 from previously treated patients. Using a microtome, we obtained six slides from each skin biopsy preserved in paraffin, and we extracted M. leprae DNA. We amplified three molecular targets through PCR and obtained the patterns of drug resistance to dapsone, rifampicin and ofloxacin by reverse hybridization. Finally, we collected epidemiological, clinical and demographical data for analyses. RESULTS: From 941 samples under study, 4.14% of them were resistant to one or more drugs, and 5.77 and 3.04% had resistant genotypes in new and previously treated patients, respectively. Total resistance for each drug was 0.43% for dapsone, 3.19% for rifampicin and 1.17% for ofloxacin. We found statistically significant differences for rifampicin and for the total population when comparing the results from untreated versus previously treated patients. Two thirds of the resistant samples were resistant to rifampicin alone or combined. CONCLUSIONS: The standard multidrug therapy schemes continue being effective for leprosy cases; however, it is necessary to guarantee adherence and regularity. Surveillance to drug resistance in new and previously treated leprosy cases should be established.
Assuntos
Farmacorresistência Bacteriana Múltipla , Hansenostáticos/farmacologia , Hanseníase Multibacilar/microbiologia , Mycobacterium leprae/efeitos dos fármacos , Adolescente , Adulto , Proteínas de Bactérias/genética , Biópsia , Criança , Colômbia/epidemiologia , DNA Bacteriano/genética , Dapsona/farmacologia , Farmacorresistência Bacteriana/genética , Farmacorresistência Bacteriana Múltipla/genética , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Hansenostáticos/administração & dosagem , Hansenostáticos/uso terapêutico , Hanseníase Multibacilar/epidemiologia , Hanseníase Multibacilar/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/genética , Mycobacterium leprae/isolamento & purificação , Ofloxacino/farmacologia , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Rifampina/farmacologia , Adulto JovemRESUMO
Introduction: There is no information in Colombia on Mycobacterium leprae primary and secondary drug resistance in regards to the WHO-multidrug therapy regime. On the other hand, public health authorities around the world have issued various recommendations, one of which prompts for the immediate organization of resistance surveillance through simple molecular methods. Objective: To determine the prevalence of Mycobacterium leprae drug resistance to rifampicin, ofloxacin and dapsone in untreated and previously treated patients at the Centro Dermatológico Federico Lleras Acosta during the 1985-2004 period. Materials and methods: We conducted a retrospective study which included multibacillary patient biopsies through elective sampling: 381 of them from new patients and 560 from previously treated patients. Using a microtome, we obtained six slides from each skin biopsy preserved in paraffin, and we extracted M. leprae DNA. We amplified three molecular targets through PCR and obtained the patterns of drug resistance to dapsone, rifampicin and ofloxacin by reverse hybridization. Finally, we collected epidemiological, clinical and demographical data for analyses. Results: From 941 samples under study, 4.14% of them were resistant to one or more drugs, and 5.77 and 3.04% had resistant genotypes in new and previously treated patients, respectively. Total resistance for each drug was 0.43% for dapsone, 3.19% for rifampicin and 1.17% for ofloxacin. We found statistically significant differences for rifampicin and for the total population when comparing the results from untreated versus previously treated patients. Two thirds of the resistant samples were resistant to rifampicin alone or combined. Conclusions: The standard multidrug therapy schemes continue being effective for leprosy cases; however, it is necessary to guarantee adherence and regularity. Surveillance to drug resistance in new and previously treated leprosy cases should be established.
Introducción. Colombia no dispone de información sobre farmacorresistencia primaria y secundaria de Mycobacterium leprae al esquema de terapia múltiple de la Organización Mundial de la Salud (OMS) y las autoridades de salud pública del mundo han emitido varias recomendaciones, entre las cuales está organizar de inmediato la vigilancia a la resistencia empleando métodos moleculares simples. Objetivo. Determinar la prevalencia de la resistencia de M. leprae a rifampicina, ofloxacina y dapsona en pacientes del Centro Dermatológico Federico Lleras Acosta con tratamiento previo y sin él durante el período de 1985 a 2004. Materiales y métodos. Se realizó un estudio retrospectivo. Mediante muestreo electivo se incluyeron biopsias de pacientes multibacilares: 381 de pacientes nuevos y 560 de pacientes previamente tratados. Se obtuvieron con micrótomo seis cortes de cada biopsia de piel incluida en parafina, y se realizó la extracción de ADN de M. leprae. Se llevó a cabo la amplificación de tres blancos moleculares mediante PCR y se obtuvieron los patrones de resistencia a los medicamentos dapsona, rifampicina y ofloxacina por hibridación inversa. Se recolectaron datos epidemiológicos, clínicos y demográficos para llevar a cabo los análisis. Resultados. De las 941 muestras estudiadas, 4,14 % era resistente a uno o más fármacos, y se detectaron 5,77 y 3,04 % con genotipos resistentes en pacientes nuevos y previamente tratados, respectivamente. La resistencia total para cada fármaco fue de 0,43 % a dapsona, 3,19 % a rifampicina y 1,17 % a ofloxacina. Se encontró una diferencia estadísticamente significativa para rifampicina y para la población total al comparar los resultados de los pacientes no tratados con los de los pacientes tratados previamente. Dos tercios de las muestras resistentes lo fueron a rifampicina sola o combinada. Conclusiones. Los esquemas de terapia múltiple estándar siguen siendo efectivos para los casos de lepra; sin embargo, es necesario garantizar el cumplimiento y la regularidad y establecer la vigilancia de la farmacorresistencia en pacientes nuevos y previamente tratados.
Assuntos
Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Farmacorresistência Bacteriana Múltipla , Hansenostáticos/farmacologia , Hanseníase Multibacilar/microbiologia , Mycobacterium leprae/efeitos dos fármacos , Biópsia , Proteínas de Bactérias/genética , Colômbia/epidemiologia , DNA Bacteriano/genética , Quimioterapia Combinada , Dapsona/farmacologia , Farmacorresistência Bacteriana/genética , Farmacorresistência Bacteriana Múltipla/genética , Genótipo , Hansenostáticos/administração & dosagem , Hansenostáticos/uso terapêutico , Hanseníase Multibacilar/epidemiologia , Hanseníase Multibacilar/patologia , Mycobacterium leprae/genética , Mycobacterium leprae/isolamento & purificação , Ofloxacino/farmacologia , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Rifampina/farmacologiaRESUMO
In leprosy, the nasal mucosa is considered as the principal route of transmission for the bacillus Mycobacterium leprae. The objective of this study was to identify M. leprae in the oral mucosa of 50 untreated leprosy patients, including 21 paucibacillary (PB) and 29 multibacillary (MB) patients, using immunohistochemistry (IHC), with antibodies against bacillus Calmette-Guérin (BCG) and phenolic glycolipid antigen-1 (PGL-1), and polymerase chain reaction (PCR), with MntH-specific primers for M. leprae, and to compare the results. The material was represented by 163 paraffin blocks containing biopsy samples obtained from clinically normal sites (including the tongue, buccal mucosa and soft palate) and visible lesions anywhere in the oral mucosa. All patients and 158 available samples were included for IHC study. Among the 161 available samples for PCR, 110 had viable DNA. There was viable DNA in at least one area of the oral mucosa for 47 patients. M. leprae was detected in 70% and 78% of patients using IHC and PCR, respectively, and in 94% of the patients by at least one of the two diagnostic methods. There were no differences in detection of M. leprae between MB and PB patients. Similar results were obtained using anti-BCG and anti-PGL-1 antibodies, and immunoreactivity occurred predominantly on free-living bacteria on the epithelial surface, with a predilection for the tongue. Conversely, there was no area of predilection according to the PCR results. M. leprae is present in the oral mucosa at a high frequency, implicating this site as a potential means of leprosy transmission.
Assuntos
Hanseníase Multibacilar/microbiologia , Hanseníase Paucibacilar/microbiologia , Mucosa Bucal/microbiologia , Mycobacterium leprae/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Bactérias/genética , Proteínas de Transporte de Cátions/genética , Estudos Transversais , Feminino , Humanos , Imuno-Histoquímica , Hanseníase Multibacilar/epidemiologia , Hanseníase Multibacilar/transmissão , Hanseníase Paucibacilar/epidemiologia , Hanseníase Paucibacilar/transmissão , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/genética , Mycobacterium leprae/imunologia , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: Operational classification of leprosy based on the number of skin lesions was conceived to screen patients presenting severe forms of the disease to enable their reception of a more intense multidrug regimen without having to undergo lymph smear testing. We evaluated the concordance between operational classification and bacilloscopy to define multibacillary and paucibacillary leprosy. METHODS: We selected 1,213 records of individuals with leprosy, who were untreated (new cases) and admitted to a dermatology clinic in Recife, Brazil, from 2000 to 2005, and who underwent bacteriological examination at diagnosis for ratification of the operational classification. RESULTS: Compared to bacilloscopy, operational classification demonstrated 88.6% sensitivity, 76.9% specificity, a positive predictive value of 61.8%, and a negative predictive value of 94.1%, with 80% accuracy and a moderate kappa index. Among the bacilloscopy-negative cases, 23% had more than 5 skin lesions. Additionally, 11% of the bacilloscopy-positive cases had up to 5 lesions, which would have led to multibacillary cases being treated as paucibacillary leprosy if the operational classification had not been confirmed by bacilloscopy. CONCLUSIONS: Operational classification has limitations that are more obvious in borderline cases, suggesting that in these cases, lymph smear testing is advisable to enable the selection of true multibacillary cases for more intense treatment, thereby contributing to minimization of resistant strain selection and possible relapse.
Assuntos
Técnicas Bacteriológicas/métodos , Hanseníase Multibacilar/microbiologia , Hanseníase Paucibacilar/microbiologia , Mycobacterium leprae/isolamento & purificação , Doenças Negligenciadas/microbiologia , Pele/microbiologia , Adolescente , Adulto , Brasil , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Hanseníase Multibacilar/classificação , Hanseníase Paucibacilar/classificação , Masculino , Pessoa de Meia-Idade , Doenças Negligenciadas/classificação , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
INTRODUCTION: Operational classification of leprosy based on the number of skin lesions was conceived to screen patients presenting severe forms of the disease to enable their reception of a more intense multidrug regimen without having to undergo lymph smear testing. We evaluated the concordance between operational classification and bacilloscopy to define multibacillary and paucibacillary leprosy. METHODS: We selected 1,213 records of individuals with leprosy, who were untreated (new cases) and admitted to a dermatology clinic in Recife, Brazil, from 2000 to 2005, and who underwent bacteriological examination at diagnosis for ratification of the operational classification. RESULTS: Compared to bacilloscopy, operational classification demonstrated 88.6% sensitivity, 76.9% specificity, a positive predictive value of 61.8%, and a negative predictive value of 94.1%, with 80% accuracy and a moderate kappa index. Among the bacilloscopy-negative cases, 23% had more than 5 skin lesions. Additionally, 11% of the bacilloscopy-positive cases had up to 5 lesions, which would have led to multibacillary cases being treated as paucibacillary leprosy if the operational classification had not been confirmed by bacilloscopy. CONCLUSIONS: Operational classification has limitations that are more obvious in borderline cases, suggesting that in these cases, lymph smear testing is advisable to enable the selection of true multibacillary cases for more intense treatment, thereby contributing to minimization of resistant strain selection and possible relapse.
INTRODUÇÃO: A classificação operacional da hanseníase baseada no número de lesões de pele foi concebida para selecionar pacientes que apresentam formas graves da doença para receber regime terapêutico mais intenso com múltiplas drogas sem o exame de baciloscopia da linfa. Nós avaliamos a concordância entre a classificação operacional e a baciloscopia para a definição de hanseníase multibacilar e paucibacilar. MÉTODOS: Nós selecionamos 1.213 registros de indivíduos com hanseníase não tratada (casos novos), atendidos em um Ambulatório de Dermatologia, em Recife, Brasil, no período de 2000 a 2005, que foram submetidos a exame bacteriológico ao diagnóstico para a ratificação da classificação operacional. RESULTADOS: Comparando com a baciloscopia, a classificação operacional baseada no número de lesões cutâneas mostrou sensibilidade de 88,6%, especificidade 76,9%, valor preditivo positivo de 61,8% e valor preditivo negativo de 94,1%, com uma precisão de 80% e um moderado índice kappa. Entre os casos com baciloscopia negativa, 23% tinham mais de cinco lesões de pele, recebendo um tratamento mais intensivo. Além disso, 11% dos casos baciloscopia positiva tinham até cinco lesões, o que induziriam casos multibacilares de serem tratados com hanseníase paucibacilar se a classificação operacional não tivesse sido confirmada pela baciloscopia. CONCLUSÕES: Concluímos que a classificação operacional tem limitações mais visíveis nos casos borderline, sugerindo que, nestes casos, o esfregaço seria aconselhável por permitir que os verdadeiros casos multibacilares fossem selecionados para um tratamento mais intenso, contribuindo para minimizar a seleção de cepas resistentes e uma possível recidiva.
Assuntos
Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Técnicas Bacteriológicas/métodos , Hanseníase Multibacilar/microbiologia , Hanseníase Paucibacilar/microbiologia , Mycobacterium leprae/isolamento & purificação , Doenças Negligenciadas/microbiologia , Pele/microbiologia , Brasil , Estudos Transversais , Hanseníase Multibacilar/classificação , Hanseníase Paucibacilar/classificação , Doenças Negligenciadas/classificação , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: To determine the frequency and factors associated with relapse in multibacillary leprosy. DESIGN: We performed a retrospective cohort study on multibacillary leprosy patients treated at Centro Dermatologico Federico Lleras Acosta between January 1994 and December 2004. By survival analysis we studied the incidence density for recurrence and bacillary index conversion. The assessment of risk factors associated with the occurrence of relapse was constructed using a Cox regression model. RESULTS: We included 299 cases of which 243 received WHO-MB MDT on a regular basis, and followed them up to assess the frequency of relapses. We obtained 490 person-years of follow-up and an incidence density of 6.70 relapses/100 patient-years that was higher than most of the data reported in the literature. The relapse rate was 9.80 per 100 person-years when the initial bacillary index was > or = 2.0 and 5.60 relapses/100 patient-years when it was < 2 (P = 0.03). The relapse rate increased to 7.70/100 patient-years among those treated with WHO-MB 24 month fixed-dose, and it reduced to 5.70/100 patient-years when treated until smear negative. The variables that showed association with relapse were: initial bacillary index > or = 2.0, antireactional treatment and clinical classification of lepromatous leprosy. For each variable, the risk was four to five times more likely to present relapse. We also found that 21 patients' BI became negative per 100 treated for 1 year with WHO-MB MDT. CONCLUSIONS: We found a high relapse rate associated with initial high bacillary index in the Colombian population. Among the patients who received MDT on a regular basis 33 out of 165 (20%) relapsed.
Assuntos
Hansenostáticos/uso terapêutico , Hanseníase Multibacilar/tratamento farmacológico , Hanseníase Multibacilar/prevenção & controle , Mycobacterium leprae/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Colômbia/epidemiologia , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Incidência , Hansenostáticos/farmacologia , Hanseníase Multibacilar/epidemiologia , Hanseníase Multibacilar/microbiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/isolamento & purificação , Estudos Retrospectivos , Fatores de Risco , Prevenção Secundária , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Organização Mundial da Saúde , Adulto JovemRESUMO
UNLABELLED: Recently antimicrobials of the fluoroquinolone class (pefloxacin and ofloxacin) were found far more effective against Mycobacterium leprae in studies with both mice and patients than dapsone and clofazimine. As multicentre trial participants, we evaluated the therapeutic efficacy, in terms of rate of relapse, of two new multidrug regimens containing ofloxacin, comparing them to 1 year and 2 years of standard WHO-MDT regimen in multibacillary (MB) leprosy patients. A total of 198MB patients were recruited to participate in a randomized, double-blind trial. Among those, 53 patients were treated with 1 year of WHO-MDT (a regimen including dapsone, clofazimine, and rifampin), 55 patients received 1 year of WHO-MDT plus an initial 1 month of daily ofloxacin, 63 patients were treated with 1 month of daily rifampin and daily ofloxacin, whereas 27 were treated with 2 years of WHO-MDT. Patients were regularly monitored for signs of relapse, in at least 7 years follow-up after being released from treatment. RESULTS: Relapse occurred in those treated with 1-month regimen alone at a significant higher rate (P < 0.001): 388%, whereas in the other three regimens that included WHO-MDT it ranged from 0 to 5%. This study found that a short-course treatment for MB patients with rifampicin-ofloxacin combination had a higher failure rate. The addition of one month of daily ofloxacin to 12 months MB WHO-MDT did not increase its efficacy.
Assuntos
Hansenostáticos/uso terapêutico , Hanseníase Multibacilar/tratamento farmacológico , Mycobacterium leprae/efeitos dos fármacos , Ofloxacino/uso terapêutico , Adolescente , Adulto , Animais , Brasil/epidemiologia , Clofazimina/farmacologia , Clofazimina/uso terapêutico , Dapsona/farmacologia , Dapsona/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hansenostáticos/efeitos adversos , Hanseníase Multibacilar/epidemiologia , Hanseníase Multibacilar/microbiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Ofloxacino/efeitos adversos , Prevalência , Rifampina/farmacologia , Rifampina/uso terapêutico , Prevenção Secundária , Pele/microbiologia , Fatores de Tempo , Resultado do Tratamento , Organização Mundial da Saúde , Adulto JovemRESUMO
Leprosy still is an important public health problem in several parts of the world including Brazil. Unlike the diseases caused by other mycobacteria, the incidence and clinical presentation of leprosy seems little affected in immunosuppressed patients. We report the first case, to our knowledge, of a liver transplant patient who developed multi-bacillary leprosy. The patient presented with papules and infiltrated plaques with loss of sensation suggestive of leprosy 3.5 years after living-related liver transplantation for autoimmune hepatitis. A skin biopsy showing non-caseating macrophagic granulomas, neuritis, and intact acid-fast bacilli on Fite-Faraco stain, confirmed the diagnosis of borderline lepromatous leprosy. The donor of the liver did not show any evidence of leprosy. During follow-up, the patient presented 2 episodes of upgrading leprosy type I reactions, 1 mild before leprosy treatment, and 1 moderate 3 months after receiving standard multi-drug treatment (rifampicin, clofazimine, and dapsone). These reactions were accompanied by increase in liver function tests, especially of canalicular enzymes. This reaction occurred despite the patient's triple immunosuppression regimen. The moderate reaction was successfully treated with further immunosuppression (prednisone, 0.5 mg/kg). Currently, the patient is asymptomatic, off leprosy medication, with routine liver transplant follow-up. The dilemmas in diagnosis and management of such a case are discussed and the literature on leprosy in transplant recipients is reviewed.