RESUMO
Mycobacterium leprae causes leprosy and is unique among mycobacterial diseases in producing peripheral neuropathy. This debilitating morbidity is attributed to axon demyelination resulting from direct interaction of the M. leprae-specific phenolic glycolipid 1 (PGL-1) with myelinating glia and their subsequent infection. Here, we use transparent zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage. We find that demyelination and axonal damage are not directly initiated by M. leprae but by infected macrophages that patrol axons; demyelination occurs in areas of intimate contact. PGL-1 confers this neurotoxic response on macrophages: macrophages infected with M. marinum-expressing PGL-1 also damage axons. PGL-1 induces nitric oxide synthase in infected macrophages, and the resultant increase in reactive nitrogen species damages axons by injuring their mitochondria and inducing demyelination. Our findings implicate the response of innate macrophages to M. leprae PGL-1 in initiating nerve damage in leprosy.
Assuntos
Antígenos de Bactérias/metabolismo , Modelos Animais de Doenças , Glicolipídeos/metabolismo , Hanseníase/microbiologia , Hanseníase/patologia , Macrófagos/imunologia , Mycobacterium leprae/fisiologia , Animais , Axônios/metabolismo , Axônios/patologia , Doenças Desmielinizantes , Larva/crescimento & desenvolvimento , Hanseníase/imunologia , Mycobacterium marinum/metabolismo , Bainha de Mielina/química , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Neuroglia/metabolismo , Neuroglia/patologia , Óxido Nítrico/metabolismo , Peixe-ZebraRESUMO
Differentiated cells possess a remarkable genomic plasticity that can be manipulated to reverse or change developmental commitments. Here, we show that the leprosy bacterium hijacks this property to reprogram adult Schwann cells, its preferred host niche, to a stage of progenitor/stem-like cells (pSLC) of mesenchymal trait by downregulating Schwann cell lineage/differentiation-associated genes and upregulating genes mostly of mesoderm development. Reprogramming accompanies epigenetic changes and renders infected cells highly plastic, migratory, and immunomodulatory. We provide evidence that acquisition of these properties by pSLC promotes bacterial spread by two distinct mechanisms: direct differentiation to mesenchymal tissues, including skeletal and smooth muscles, and formation of granuloma-like structures and subsequent release of bacteria-laden macrophages. These findings support a model of host cell reprogramming in which a bacterial pathogen uses the plasticity of its cellular niche for promoting dissemination of infection and provide an unexpected link between cellular reprogramming and host-pathogen interaction.
Assuntos
Interações Hospedeiro-Patógeno , Hanseníase/microbiologia , Hanseníase/patologia , Mycobacterium leprae , Células de Schwann/patologia , Células-Tronco/patologia , Animais , Movimento Celular , Sobrevivência Celular , Epigênese Genética , Transição Epitelial-Mesenquimal , Granuloma/microbiologia , Humanos , Hanseníase/genética , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Nus , Nervos Periféricos/patologia , Células de Schwann/microbiologiaRESUMO
BACKGROUND: Leprosy, a chronic infectious disease, is associated with various nail changes. Its etiopathogenesis is multifaceted, with microvascular damage being crucial. Nail fold capillaroscopy (NFC) emerges as a novel tool for detecting early vascular deficits in leprosy. The study aimed to assess and provide a complete clinical characterization of NFC changes in leprosy patients. METHODS: It is an observational cross-sectional study, done over a period of 1.5 year (January 2021 to august 2022) in a tertiary care hospital, encompassing 60 patients diagnosed with leprosy (18-60 years). After obtaining informed consent; detailed history, complete cutaneous and neurological examinations were conducted. All fingernails and toenails were examined for clinical changes. Subsequently, onychoscopy was performed using USB type of video-dermatoscope (Model AM7115MZT Dino-lite), a non-invasive tool. This was followed by NFC which was done for all fingernails and images were recorded by single operator, which were then assessed for quantitative and qualitive changes and statistical analysis was conducted using SPSS v20, with mean capillary density compared using Student's t-test, morphological change frequencies assessed by proportions, and group comparisons made using Chi-square or Fischer exact tests, with a significance threshold of p < 0.05. RESULTS: Among the 60 patients, 39 were in the lepromatous group, which included both borderline lepromatous (BL) and lepromatous leprosy (LL) patients, and 17 were in the tuberculoid group, which included borderline tuberculoid (BT) leprosy patients; 23.3 % had Type 1 reactions, and 18.3 % had Type 2 reactions. Nail fold capillaroscopy (NFC) showed microvasculature changes in 93.3 % of patients. The average capillary density was 6.8 ± 1.5 capillaries per mm, with the lepromatous group having a lower density (6.5 ± 1.09) compared to the tuberculoid group (7.0 ± 0.86). The most common NFC changes in the tuberculoid group were tortuous capillaries (70 %), capillary dropouts, and dilated capillaries (both 64.7 %). In the lepromatous group, capillary dropouts (82 %) were most frequent, followed by tortuous (69 %), receding (69 %), and dilated capillaries (66 %). A dilated and prominent subpapillary plexus was more common in the lepromatous group (35 %, p = 0.04). Patients with trophic changes in the lepromatous group had more capillary dropouts and bizarre capillaries. Capillary dropouts, dilated capillaries, and visible subpapillary venous plexus were more prevalent in patients with Type 2 reactions. CONCLUSION: NFC changes are prevalent in both tuberculoid and lepromatous leprosy, which may be an indicator of peripheral vascular compromise and trophic changes, especially in lepromatous leprosy. NFC can be an auxiliary tool for detecting microvascular abnormalities in leprosy patients.
Assuntos
Capilares , Angioscopia Microscópica , Unhas , Valor Preditivo dos Testes , Humanos , Adulto , Pessoa de Meia-Idade , Masculino , Feminino , Estudos Transversais , Unhas/irrigação sanguínea , Adulto Jovem , Adolescente , Capilares/diagnóstico por imagem , Capilares/patologia , Capilares/fisiopatologia , Microcirculação , Doenças da Unha/microbiologia , Doenças da Unha/diagnóstico por imagem , Doenças da Unha/patologia , Densidade Microvascular , Hanseníase/diagnóstico por imagem , Hanseníase/patologia , Hanseníase/microbiologia , Hanseníase/diagnósticoRESUMO
Leprosy is a skin disease and it is characterized by a disorder of the peripheral nervous system which occurs due to the infection of Schwann cells. In this research article, we have formulated a four-dimensional ODE-based mathematical model which consists of the densities of healthy Schwann cells, infected Schwann cells, M. leprae bacteria, and the concentration of multidrug therapy (MDT). This work primarily aims on exploring the dynamical changes and interrelations of the system cell populations during the disease progression. Also, evaluating a critical value of the drug efficacy rate of MDT remains our key focus in this article so that a safe drug dose regimen for leprosy can be framed more effectively and realistically. We have examined the stability scenario of different equilibria and the occurrence of Hopf-bifurcation for the densities of our system cell populations with respect to the drug efficacy rate of MDT to gain insight on the precise impact of the efficiency rate on both the infected Schwann cell and the bacterial populations. Also, a necessary transversality condition for the occurrence of the bifurcation has been established. Our analytical and numerical investigations in this research work precisely explores that the process of demyelination, nerve regeneration, and infection of the healthy Schwann cells are the three most crucial factors in the leprosy pathogenesis and to control the M. leprae-induced infection of Schwann cells successfully, a more flexible version of MDT regime with efficacy rate varying in the range η∈(0.025,0.059) for 100-120 days in PB cases and 300 days in MB cases obtained in this research article should be applied. All of our analytical outcomes have been verified through numerical simulations and compared with some existing clinical findings.
Assuntos
Hansenostáticos , Hanseníase , Humanos , Quimioterapia Combinada , Hansenostáticos/uso terapêutico , Hansenostáticos/farmacologia , Hanseníase/tratamento farmacológico , Hanseníase/microbiologia , Hanseníase/patologia , Mycobacterium leprae , Organização Mundial da SaúdeRESUMO
Disability in leprosy is a direct consequence of damage to the peripheral nervous system which is usually worse in patients with no skin manifestations, an underdiagnosed subtype of leprosy known as primary neural leprosy. We evaluated clinical, neurophysiological and laboratory findings of 164 patients with definite and probable primary neural leprosy diagnoses. To better understand the disease progression and to improve primary neural leprosy clinical recognition we compared the characteristics of patients with short (≤12 months) and long (>12 months) disease duration. Positive and negative symptoms mediated by small-fibres were frequent at presentation (â¼95%), and symptoms tend to manifest first in the upper limbs (â¼68%). There is a consistent phenotypic variability between the aforementioned groups. Deep sensory modalities were spared in patients evaluated within the first 12 months of the disease, and were only affected in patients with longer disease duration (â¼12%). Deep tendon reflexes abnormalities were most frequent in patients with longer disease duration (P < 0.001), as well as motor deficits (P = 0.002). Damage to large fibres (sensory and motor) is a latter event in primary neural leprosy. Grade-2 disability and nerve thickening was also more frequent in cases with long disease duration (P < 0.001). Primary neural leprosy progresses over time and there is a marked difference in clinical phenotype between patients with short and long disease duration. Patients assessed within the first 12 months of symptom onset had a non-length-dependent predominant small-fibre sensory neuropathy, whilst patients with chronic disease presented an asymmetrical all diameter sensory-motor neuropathy and patchily decreased/absent deep tendon reflexes.
Assuntos
Hanseníase Tuberculoide , Hanseníase , Doenças do Sistema Nervoso Periférico , Humanos , Hanseníase/complicações , Hanseníase/diagnóstico , Hanseníase/patologia , Hanseníase Tuberculoide/diagnóstico , Hanseníase Tuberculoide/patologia , Doenças do Sistema Nervoso Periférico/diagnósticoRESUMO
BACKGROUND: The lepromatous pole is a stigmatising prototype for patients with leprosy. Generally, these patients have little or no symptoms of peripheral nerve involvement at the time of their diagnosis. However, signs of advanced peripheral neuropathy would be visible during the initial neurological evaluation and could worsen during and after multidrug therapy (MDT). Disabilities caused by peripheral nerve injuries greatly affect these patients' lives, and the pathophysiological mechanisms underlying nerve damage remain unclear. OBJECTIVES: To evaluate the outcome of peripheral neuropathy in patients with lepromatous leprosy (LL) and persistent neuropathic symptoms years after completing MDT. METHODS: We evaluated the medical records of 14 patients with LL who underwent nerve biopsies due to worsening neuropathy at least four years after MDT. FINDINGS: Neuropathic pain developed in 64.3% of the patients, and a neurological examination showed that most patients had alterations in the medium- and large-caliber fibers at the beginning of treatment. Neurological symptoms and signs deteriorated despite complete MDT and prednisone or thalidomide use for years. Nerve conduction studies showed that sensory nerves were the most affected. MAIN CONCLUSIONS: Patients with LL can develop progressive peripheral neuropathy, which continues to develop even when they are on long-term anti-inflammatory and immunosuppressive therapy.
Assuntos
Hanseníase Virchowiana , Hanseníase , Doenças do Sistema Nervoso Periférico , Humanos , Hanseníase Virchowiana/complicações , Hanseníase Virchowiana/tratamento farmacológico , Hanseníase Virchowiana/patologia , Quimioterapia Combinada , Hansenostáticos/efeitos adversos , Hanseníase/patologia , Doenças do Sistema Nervoso Periférico/etiologiaRESUMO
Leprosy is a chronic disease caused by Mycobacterium leprae. Worldwide, more than 200,000 new patients are affected by leprosy annually, making it the second most common mycobacterial disease after tuberculosis. The MHC/HLA region has been consistently identified as carrying major leprosy susceptibility variants in different populations at times with inconsistent results. To establish the unambiguous molecular identity of classical HLA class I and class II leprosy susceptibility factors, we applied next-generation sequencing to genotype with high-resolution 11 HLA class I and class II genes in 1,155 individuals from a Vietnamese leprosy case-control sample. HLA alleles belonging to an extended haplotype from HLA-A to HLA-DPB1 were associated with risk to leprosy. This susceptibility signal could be reduced to the HLA-DRB1*10:01~ HLA-DQA1*01:05 alleles which were in complete linkage disequilibrium (LD). In addition, haplotypes containing HLA-DRB3~ HLA-DRB1*12:02 and HLA-C*07:06~ HLA-B*44:03~ HLA-DRB1*07:01 alleles were found as two independent protective factors for leprosy. Moreover, we replicated the previously associated HLA-DRB1*15:01 as leprosy risk factor and HLA-DRB1*04:05~HLA-DQA1*03:03 as protective alleles. When we narrowed the analysis to the single amino acid level, we found that the associations of the HLA alleles were largely captured by four independent amino acids at HLA-DRß1 positions 57 (D) and 13 (F), HLA-B position 63 (E) and HLA-A position 19 (K). Hence, analyses at the amino acid level circumvented the ambiguity caused by strong LD of leprosy susceptibility HLA alleles and identified four distinct leprosy susceptibility factors.
Assuntos
Aminoácidos/genética , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Hanseníase/patologia , Mutação , Adolescente , Adulto , Feminino , Haplótipos , Humanos , Hanseníase/genética , Masculino , Adulto JovemRESUMO
Leprosy is a chronic granulomatous disease that remains a serious public health problem in developing countries. According to the Madrid classification, leprosy presents in four clinical forms: two immunologically unstable forms (indeterminate and borderline) and two stable polar forms (tuberculoid and lepromatous). In leprosy, the relationship of cell death to clinical disease outcome remains unclear. Therefore, we investigated the extent of autophagy and different cell death mechanisms-such as apoptosis, necroptosis, and pyroptosis-in cutaneous lesions of patients with leprosy, as well as the role of these mechanisms in clinical disease progression. This cross-sectional analytical study included 30 patients with a confirmed diagnosis of leprosy, with 10 patients in each of the following groups: lepromatous (LL), tuberculoid (TT), and indeterminate (II) leprosy groups. For histopathological analysis, skin samples were subjected to haematoxylin-eosin staining and immunostaining for apoptotic and necroptotic markers. The results indicated that FasL expression was much higher in the LL form than in the TT and II forms. Similar results (higher expression in the LL form than in the TT and II forms) were observed for caspase 8, RIP1, and RIP3 expressions. MLKL, BAX, and caspase 3 expression levels were highest in the LL form, especially in globular foamy macrophages. Beclin-1 expression was highest in the TT form but was low in LL and II forms. Caspase 1 expression was highest in the LL form, followed by that in the TT and II forms. In conclusion, our study elucidates the role of different cell death mechanisms in the pathophysiology of various forms of leprosy and suggests measures that may be used to control the host response to infection and disease progression.
Assuntos
Hanseníase Virchowiana , Hanseníase , Apoptose , Estudos Transversais , Progressão da Doença , Humanos , Hanseníase/patologia , Mycobacterium lepraeRESUMO
Leprosy is an infectious disease caused by non-cultivable bacteria Mycobacterium leprae. Th17 cells play vital roles during pathogenesis of leprosy reactions and IL-23 is involved in Th17 cell differentiation. Although previous studies have reported the participation of IL-23 in leprosy patients in peripheral blood, the role of this cytokine in skin has not yet been described for the disease. In this study, we first evaluated IL-23 expression in the skin of patients with leprosy. Data showed that in keratinocytes, endothelial cells, and macrophages, IL-23 expression was markedly higher in patients compared to that in the normal skin controls. Also, leprosy patients presented higher percentage of IL-17A-producing IL-23R + CD4 T cells than healthy donors. IL-23R blocking induced markedly downregulated IL-17A secretion in leprosy patients but not in healthy donors. Furthermore, TGF-ß expression was significantly elevated after IL-23R blocking. Overall, this study establishes that Th17 cells produce IL-17A in an IL-23 dependent manner in the skin of leprosy patients and provides more focused treatment strategies for Mycobacterium leprae.
Assuntos
Hanseníase , Células Th17 , Células Endoteliais/metabolismo , Humanos , Interleucina-17/metabolismo , Interleucina-23 , Subunidade p19 da Interleucina-23 , Hanseníase/microbiologia , Hanseníase/patologia , Mycobacterium leprae/metabolismo , Células Th17/metabolismoRESUMO
Leprosy is still a considerable health threat in pockets of several low and middle income countries worldwide where intense transmission is witnessed, and often results in irreversible disabilities and deformities due to delayed- or misdiagnosis. Early detection of leprosy represents a substantial hurdle in present-day leprosy health care. The dearth of timely diagnosis has, however, particularly severe consequences in the case of inflammatory episodes, designated leprosy reactions, which represent the major cause of leprosy-associated irreversible neuropathy. There is currently no accurate, routine diagnostic test to reliably detect leprosy reactions, or to predict which patients will develop these immunological exacerbations. Identification of host biomarkers for leprosy reactions, particularly if correlating with early onset prior to development of clinical symptoms, will allow timely interventions that contribute to decreased morbidity. Development of a point-of-care (POC) test based on such correlates would be a definite game changer in leprosy health care. In this review, proteomic-, transcriptomic and metabolomic research strategies aiming at identification of host biomarker-based correlates of leprosy reactions are discussed, next to external factors associated with occurrence of these episodes. The vast diversity in research strategies combined with the variability in patient- and control cohorts argues for harmonisation of biomarker discovery studies with geographically overarching study sites. This will improve identification of specific correlates associated with risk of these damaging inflammatory episodes in leprosy and subsequent application to rapid field tests.
Assuntos
Anticorpos Antibacterianos/análise , Determinação de Ponto Final/métodos , Hanseníase/diagnóstico , Mycobacterium leprae/imunologia , Transcriptoma/imunologia , Anticorpos Antibacterianos/biossíntese , Biomarcadores/metabolismo , Ligante CD30/genética , Ligante CD30/imunologia , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/imunologia , Diagnóstico Tardio , Progressão da Doença , Humanos , Hanseníase/imunologia , Hanseníase/microbiologia , Hanseníase/patologia , Metaboloma/imunologia , Mycobacterium leprae/isolamento & purificação , Mycobacterium leprae/patogenicidade , Testes Imediatos , Biologia de Sistemas/métodos , Receptores Toll-Like/genética , Receptores Toll-Like/imunologiaRESUMO
BACKGROUND: Leprosy is a chronic granulomatous disease affecting skin and nerves with a range of clinical and immunological responses. OBJECTIVES: The study aimed to identify levels of IL-4 and antibodies to ceramide in the sera of leprosy patients and healthy subjects using enzyme linked immunosorbent assay (ELISA) to evaluate their possible role in disease severity and their correlation to nerve involvement and physical impairments. METHODS: This study included 25 patients with multibacillary leprosy, 25 with paucibacillary, and 25 healthy controls who were subjected to history taking, clinical examination, and identification of sites and morphology of skin lesions, nerve examination, eye examination, as well as sensory examination. Slit skin smear examination was used for diagnosing paucibacillary (PB) and multibacillary (MB) leprosy cases. Anti-ceramide antibody (ACA) and IL-4 titers were estimated and correlated with the type of leprosy, disease duration, nerve damage, and disabilities. RESULTS: Serum ACA and IL-4 levels were significantly higher in MB than its level in PB leprotic patients and controls. A significant positive correlation was established between nerve affection; physical impairments and serum levels of ACA and IL-4. CONCLUSION: Levels of ACA and IL-4 can impact nerve affection in leprotic patients and can serve as potential biomarkers of disease progression J Drugs Dermatol. 2022;21(3):284-291. doi:10.36849/JDD.5543.
Assuntos
Ceramidas/imunologia , Interleucina-4 , Hanseníase , Anticorpos , Estudos de Casos e Controles , Humanos , Hanseníase/diagnóstico , Hanseníase/imunologia , Hanseníase/patologia , Pele/patologiaRESUMO
Type-1 reactions (T1R) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the genewise enrichment of rare protein-altering variants in 7 genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Genewise enrichment of nonsynonymous variants was tested with both kernel-based (sequence kernel association test [SKAT]) and burden methods. Of the 7 genes tested 2 showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (PSKAT-O = 1.6 × 10-4). This genewise association was driven almost entirely by the gain-of-function variant R1628P (P = 0.004; odds ratio = 0.29). The second genewise association was found for the Parkin coding gene PRKN (formerly PARK2) where 7 rare variants were enriched in T1R-affected cases (PSKAT-O = 7.4 × 10-5). Mutations in both PRKN and LRRK2 are known causes of Parkinson's disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that amino acids in Parkin targeted by nonsynonymous T1R-risk mutations were also enriched for mutations implicated in PD (P = 1.5 × 10-4). Hence, neuroinflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping genetic control of pathogenicity.
Assuntos
Hanseníase , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Mutação , Doença de Parkinson , Ubiquitina-Proteína Ligases , Feminino , Humanos , Hanseníase/genética , Hanseníase/metabolismo , Hanseníase/patologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Masculino , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: A decision to diagnose certain skin diseases in patient undergoing psychotic break is challenging; this includes establishing the diagnosis of leprosy. Diagnosis of leprosy is established if there is at least one of the three cardinal signs of leprosy. Histopathological examination is not a gold standard, but remains useful in atypical or clinically suspicious cases. CASE PRESENTATION: We report for the first time, an interesting case of leprosy with atypical clinical manifestations in a psychotic homeless male with unknown history of present illness. Upon examination, hypopigmented macules, hyperpigmented macules, and plaques were observed, with unclear sensation impairment. Peripheral nerve thickening and acid-fast bacilli from slit-skin smear were not found. Histopathological examination from hypopigmented macule on the upper right limb showed no granulomatous reaction and other histopathological features of leprosy. Although the condition did not fulfill the cardinal signs of leprosy, we found lagophthalmos, claw hands, pseudomutilation of fingers and toes. Therefore, the diagnosis of suspected leprosy was established. The patient was hospitalized and attempts to administer oral rifampicin and clofazimine were made. Several days after treatment, annular erythematous macules appeared on the patient's face, abdomen, and back. Histopathological examination results on sample taken from erythematous macule and right sural nerve were consistent with the diagnosis of leprosy with reversal reaction. CONCLUSION: In certain conditions, histopathological examination of the skin and nerves are a highly rewarding test in establishing a diagnosis of leprosy.
Assuntos
Pessoas Mal Alojadas , Hanseníase/diagnóstico , Transtornos Psicóticos/complicações , Dermatopatias/diagnóstico , Diagnóstico Diferencial , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/complicações , Hanseníase/tratamento farmacológico , Hanseníase/patologia , Masculino , Dermatopatias/complicações , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Leprosy continues to be an important cause of physical disability in endemic countries such as Brazil. Knowledge of determinants of these events may lead to better control measures and targeted interventions to mitigate its impact on affected individuals. This study investigated such factors among the most vulnerable portion of the Brazilian population. METHODS: A large cohort was built from secondary data originated from a national registry of applicants to social benefit programs, covering the period 2001-2015, including over 114 million individuals. Data were linked to the leprosy notification system utilizing data from 2007 until 2014. Descriptive and bivariate analyses lead to a multivariate analysis using a multinomial logistic regression model with cluster-robust standard errors. Associations were reported as Odds Ratios with their respective 95% confidence intervals. RESULTS: Among the original cohort members 21,565 new leprosy cases were identified between 2007 and 2014. Most of the cases (63.1%) had grade zero disability. Grades 1 and 2 represented 21 and 6%, respectively. Factors associated with increasing odds of grades 1 and 2 disability were age over 15 years old (ORs 2.39 and 1.95, respectively), less schooling (with a clear dose response effect) and being a multibacillary patient (ORs 3.5 and 8.22). Protective factors for both grades were being female (ORs 0.81 and 0.61) and living in a high incidence municipality (ORs 0.85 and 0.67). CONCLUSIONS: The findings suggest that the developing of physical disabilities remains a public health problem which increases the burden of leprosy, mainly for those with severe clinical features and worse socioeconomic conditions. Early diagnosis is paramount to decrease the incidence of leprosy-related disability and our study points to the need for strengthening control actions in non-endemic areas in Brazil, where cases may be missed when presented at early stages in disease. Both actions are needed, to benefit patients and to achieve the WHO goal in reducing physical disabilities among new cases of leprosy.
Assuntos
Pessoas com Deficiência/estatística & dados numéricos , Hanseníase/diagnóstico , Adolescente , Adulto , Brasil/epidemiologia , Estudos de Coortes , Bases de Dados Factuais , Escolaridade , Feminino , Humanos , Incidência , Hanseníase/epidemiologia , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , População Rural , Adulto JovemRESUMO
OBJECTIVES: Median nerve enlargement in leprosy seems to be more proximal than in carpal tunnel syndrome (CTS), but this feature has not been studied systematically. The aim of the study was to compare the sites of median nerve enlargement in patients with leprosy with that of patients with CTS. MATERIALS AND METHODS: Transverse sections of the median nerve were recorded from wrist to the mid-forearm (at distal wrist crease and at 2-cm: M1, 4-cm: M2, 6-cm: M3, 8-cm: M4 and 10-cm: M5, proximal to the distal wrist crease in the forearm) in patients with leprosy, CTS and healthy subjects using high-resolution ultrasound. RESULTS: Twenty-six patients each with leprosy and CTS were compared with healthy controls. Patients with leprosy included 6 (23.1%), 7 (26.9%), 7 (26.9%) and 6 (23.1%) patients with borderline tuberculoid, borderline-borderline, borderline lepromatous and lepromatous leprosy, respectively. Cross-sectional area (CSA) of median nerve was increased in all patients with leprosy as compared to healthy controls at all points of measurement. CSA was higher among patients with leprosy as compared to CTS at all points except at the wrist. In patients with leprosy, the maximal enlargement was noted 2-cm (M1) proximal to the wrist crease with gradual tapering of the CSA proximally (p < .05). In contrast, in patients with CTS the median nerve was maximally enlarged at the distal wrist crease (p<.05). CONCLUSIONS: Median nerve enlargement 2-cm proximal to the distal wrist crease distinguishes leprosy from CTS. This important discriminating sign can be used at point-of-care to identify patients with leprosy.
Assuntos
Síndrome do Túnel Carpal/diagnóstico por imagem , Síndrome do Túnel Carpal/patologia , Hanseníase/patologia , Nervo Mediano/diagnóstico por imagem , Nervo Mediano/patologia , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , UltrassonografiaRESUMO
The presence of Mycobacterium lepromatosis and Mycobacterium leprae in Eurasian red squirrel (Sciurus vulgaris, ERS) carcasses throughout the British Isles, and leprosy as a disease, have recently been reported using histological and molecular diagnostic methods. In 2016, the first longitudinal study of ERS affected by leprosy was initiated. One of the main challenges was the reliable diagnosis of leprosy in live ERS, which is important for (a) welfare and case management and (b) surveillance or pretranslocation screening efforts. We explored diagnostic methods ranging from detailed clinical assessment and informative categorization of observed lesions, thermal imaging, serology (antiphenolic glycolipid-I antibody [αPGL-I] detection) to molecular methods (polymerase chain reaction [PCR]). For PCR the ear was established as the optimal sampling site. Based on the experiences from this 2-yr study we propose an objective categorization system for clinical lesions and a diagnostic framework for the combination of the diagnostic tools we found to be effective in live ERS: clinical assessment, αPGL-I serology, and PCR. Thermal imaging did not offer additional information for leprosy diagnostics in ERS. We propose an amended definition of leprosy lesions in ERS as "skin areas of local hair loss, in which a firm-rubbery, glossy swelling develops, that may ulcerate" and standardized terminology for describing ERS leprosy status. The information presented forms the basis of a consistent, reliable diagnostic and reporting system for leprosy cases in ERS.
Assuntos
Hanseníase/veterinária , Doenças dos Roedores/diagnóstico , Sciuridae/microbiologia , Animais , Hanseníase/diagnóstico , Hanseníase/epidemiologia , Hanseníase/patologia , Mycobacterium leprae/isolamento & purificação , Vigilância da População , Doenças dos Roedores/epidemiologia , Doenças dos Roedores/patologia , Reino Unido/epidemiologiaRESUMO
Due to multiple hypothesis testing with often limited sample size, microarrays and other-omics technologies can sometimes produce irreproducible findings. Complementary to better experimental design, reanalysis and integration of gene expression datasets may help overcome reproducibility issues by identifying consistent differentially expressed genes from independent studies. In this work, after a systematic search, nine microarray datasets evaluating host gene expression in leprosy were reanalyzed and the information was integrated to strengthen evidence of differential expression for several genes. Our results are relevant in prioritizing genes and pathways for further investigation, whether in functional studies or in biomarker discovery. Reanalysis of individual datasets revealed several differentially expressed genes (DEGs) in accordance with original reports. Then, five integration methods (P value and effect size based) were tested. In the end, random-effects model and ratio association were selected as the main methods to pinpoint DEGs. Overall, classic pathways were found corroborating previous findings and validating this approach. Also, we identified some novel DEG involved especially with skin development processes (AQP3, AKR1C3, CYP27B1, LTB, VDR) and keratinocyte biology (CSTA, DSG1, KRT14, KRT5, PKP1, IVL), both still poorly understood in leprosy context. In addition, here we provide aggregated evidence towards some gene candidates that should be prioritized in further leprosy research, as they are likely important in immunopathogenesis. Altogether, these data are useful in better understanding host responses to the disease and, at the same time, provide a list of potential host biomarkers that could be useful in complementing leprosy diagnosis based on transcriptional levels.
Assuntos
Algoritmos , Biomarcadores/análise , Biologia Computacional/métodos , Genoma Humano , Hanseníase/genética , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Hanseníase/patologia , Reprodutibilidade dos TestesRESUMO
Type 1 reactions (T1R) an inflammatory condition, of local skin patches in 30-40% leprosy patients during the course of MDT. IL-17A and IL-17F play an important role in regulating skin inflammation through neutrophils. In the present study, we have analyzed 18 of each T1R and Non-reactions (NR) patients through flow cytometry and qPCR. Interestingly we found that, CD3+CD4+ gated IL-17A+IL-17F+ cells were significantly high in T1R in both MLSA stimulated PBMCs and skin lesions as compared to NR leprosy patients. Hierarchical clustering analysis of gene expression showed that CXCL6, CXCL5, CCL20, CCL7, MMP13 and IL-17RB expression were significantly associated with IL-17A and IL-17F expression (Spearman r2â¯=â¯0.77 to 0.98), neutrophils and monocyte markers respectively. In this study, the inflammation noted in lesions of T1R is a different phenotype of Th17 which produce double positive IL-17A+IL17F+ and also contributes IL-17 producing neutrophils and thus would be useful for monitoring, diagnosis and treatment response before reactions episodes.
Assuntos
Citocinas/metabolismo , Interleucina-17/metabolismo , Hanseníase/imunologia , Mycobacterium leprae/imunologia , Neutrófilos/metabolismo , Células Th17/metabolismo , Adulto , Complexo CD3/metabolismo , Antígenos CD4/metabolismo , Quimiocina CCL20/genética , Quimiocina CCL20/metabolismo , Quimiocina CCL7/genética , Quimiocina CCL7/metabolismo , Quimiocina CXCL5/genética , Quimiocina CXCL5/metabolismo , Quimiocina CXCL6/genética , Quimiocina CXCL6/metabolismo , Citocinas/genética , Quimioterapia Combinada , Feminino , Citometria de Fluxo , Humanos , Inflamação/genética , Inflamação/metabolismo , Hanseníase/patologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Pessoa de Meia-Idade , Família Multigênica , Reação em Cadeia da Polimerase em Tempo RealRESUMO
In the second article in this continuing medical education series, we review the treatment of leprosy, its immunologic reactions, and important concepts, including disease relapse and drug resistance. A fundamental understanding of the treatment options and management of neuropathic sequelae are essential to reduce disease burden and improve patients' quality of life.
Assuntos
Hanseníase/complicações , Hanseníase/tratamento farmacológico , Antibacterianos/uso terapêutico , Efeitos Psicossociais da Doença , Farmacorresistência Bacteriana , Quimioterapia Combinada , Feminino , Humanos , Hanseníase/imunologia , Hanseníase/patologia , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Qualidade de Vida , RecidivaRESUMO
PURPOSE OF REVIEW: Ocular manifestations of leprosy do occur despite advances in the areas of leprosy research. Understanding the nuances in the domain shall guide the clinician for effective patient-centered care. RECENT FINDINGS: Despite the existence of microbiologic cure for leprosy, ocular manifestations of this disease do occur. Advances in genetic and genomic studies have better characterized the interaction that the bacteria has with the host. The ocular features vary with the spectrum of the disease. Its careful correlation can help to predict the bacillary load of the patient. Investigations are particularly relevant in multibacillary cases. The WHO suggests a treatment duration longer than the 2 years in ocular involvement. SUMMARY: The isolation of lepra bacilli from the iris biopsy in negative skin smear patients and multidrug therapy completion highlights the potential role of bactericidal agents in the planned intraocular treatment. Lepra reactions need careful titration of oral steroids and appropriate antibacterial agents. Advances in phacoemulsification with in the bag implantation of intraocular lenses is a game changer in the management of the most common cause of blindness of leprosy. Advances in vaccine research in leprosy are promising.