Multibacillary Patients Research Articles

Chemoprophylaxis of leprosy with rifampicin in contacts of multibacillary patients: study protocol for a randomized controlled trial

BackgroundThe 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/designThe 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.DiscussionThe 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 registrationThe Brazilian Registry of Clinical Trials (ReBEC), RBR-69QK5P. Retrospectively registered on 1 June 2017.

Utility of immunoglobulin isotypes against LID-1 and NDO-LID for, particularly IgG1, confirming the diagnosis of multibacillary leprosy.

BACKGROUND Leprosy remains a health problem in many countries, with difficulties in diagnosis resulting in delayed treatment and more severe disabilities. Antibodies against several Mycobacterium leprae antigens have, however, shown value as diagnostic and/or prognostic markers.OBJECTIVES The objective of this study was to evaluate serum immunoglobulin (Ig) IgM and IgG subclass reactivity against three M. leprae specific antigens: NDO-HSA, a conjugate formed by natural octyl disaccharide bound to human serum albumin; LID-1, the fusion protein product of the ml0405 and ml2331 genes; and NDO-LID, a combination of LID-1 and NDO.METHODS Sera from healthy controls, paucibacillary (PB) and multibacillary (MB) leprosy patients, and their respective household contacts, were evaluated for the presence of antigen-specific IgM, IgG, and IgG subclass antibodies by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity of each ELISA were evaluated by receiver operating characteristic (ROC) curve analysis.FINDINGS Our data confirm that serum IgM antibodies against NDO-HSA and IgG antibodies against LID-1, as well as IgG/M antibodies against NDO-LID, are markedly increased in MB patients. For the first time, our data reveal a selective increase in IgG1 and IgG3 antibodies against LID-1 and NDO-LID in MB patients, demonstrating that these antibody isotypes are suitable for differentiation between MB and PB patients. ROC curve analysis indicates an improved capacity for diagnosing MB leprosy patients using the detection of IgG antibodies, particularly the IgG1 isotype, specific to LID-1 and NDO-LID over the performance levels attained with NDO-HSA.CONCLUSIONS Our findings indicate that serological tests based on the detection of antigen-specific IgG1 antibodies are a useful tool to differentiate MB from PB patients, and indicate the enhanced performance of the LID-1 and NDO-LID antigens in the serodiagnosis of leprosy.

Evaluation of the Visual Function of Patients in Treatment for Hanseníase

Introduction: Leprosy is a long-term infectious and contagious dermatoneurological disease whose etiologic agent is Mycobacterium leprae and manifests itself in the skin and peripheral nerves. This pathology can trigger serious eye complications by altering visual functional performance, impairing visual acuity through retinal lesions triggering blindness. Objective: of this study was to evaluate visual psychophysical performance in leprosy patients with normal or near normal visual acuity. Methodology: The Farnsworth – Munsell 100 Hue multi – paucibacillary test of thirty – one patients with leprosy (59 eyes), 19 men and 40 women, with a mean age of 31.28 ± 10 , 2 years of age, were compared to the control group composed of twenty-eight participants (56 eyes), 20 men and 36 women, with a mean age of 46.29 ± 11.81. Patient data were compared with the confidence interval and tolerance established by the controls. The Agostino-Pearson test and one-way ANOVA were applied in the statistical analyzes. Results and Discussion: Showed that there was statistical difference in Farnsworth – Munsell test between patients and controls. Patients presented higher number of errors than controls (p <0.01). For the sensitivity to spatial contrast of luminance, a spatial frequency difference of 0.5 cpx was found between patients and controls. There was no correlation between the therapeutic dosage of the drug and the psychosomatic performances. There was no difference between the psychophysical performance of pauci and multibacillary patients. The conclusion of this study showed that patients with leprosy present a compromised color vision and sensitivity to normal contrast when compared to controls. Further studies may be needed to quantify the specific color vision loss of patients with leprosy.

Evaluation of 16S rRNA qPCR for detection of Mycobacterium leprae DNA in nasal secretion and skin biopsy samples from multibacillary and paucibacillary leprosy cases

Mycobacterium leprae bacilli are mainly transmitted by the dissemination of nasal aerosols from multibacillary (MB) patients to susceptible individuals through inhalation. The upper respiratory tract represents the main entry and exit routes of M. leprae. Therefore, this study aimed to evaluate the sensitivity and specificity of real-time quantitative polymerase chain reaction (qPCR) in detecting M. leprae in nasal secretion (NS) and skin biopsy (SB) samples from MB and paucibacillary (PB) cases. Fifty-four NS samples were obtained from leprosy patients at the Dona Libânia National Reference Centre for Sanitary Dermatology in Ceará, Brazil. Among them, 19 MB cases provided both NS and SB samples. Bacilloscopy index assays were conducted and qPCR amplification was performed using specific primers for M. leprae 16S rRNA gene, generating a 124-bp fragment. Primer specificity was verified by determining the amplicon melting temperature (Tm = 79.5 °C) and detection limit of qPCR was 20 fg of M. leprae DNA. Results were positive for 89.7 and 73.3% of NS samples from MB and PB cases, respectively. SB samples from MB patients were 100% positive. The number of bacilli detected in NS samples were 1.39 × 103–8.02 × 105, and in SB samples from MB patients were 1.87 × 103–1.50 × 106. Therefore, qPCR assays using SYBR Green targeting M. leprae 16S rRNA region can be employed in detecting M. leprae in nasal swabs from leprosy patients, validating this method for epidemiological studies aiming to identify healthy carriers among household contacts or within populations of an endemic area.

Genotyping of Mycobacterium leprae for better understanding of leprosy transmission in Fortaleza, Northeastern Brazil.

Leprosy is endemic in large part of Brazil with 28,761 new patients in 2015, the second largest number worldwide and reaches 9/10.000 in highly endemic regions and 2.7/10.000 in the city of Fortaleza, Ceará, Northeast Brazil. For better understanding of risk factors for leprosy transmission, we conducted an epidemiologic study supplemented by 17 locus VNTR and SNP 1–4 typing of Mycobacterium leprae in skin biopsy samples from new multibacillary (MB) patients diagnosed at a reference center in 2009 and 2010. Among the 1,519 new patients detected during the study period, 998 (65.7%) were MB and we performed DNA extraction and genotyping on 160 skin biopsy samples, resulting in 159 (16%) good multilocus VNTR types. Thirty-eight of these patients also provided VNTR types from M. leprae in nasal swabs. The SNP-Type was obtained for 157 patients and 87% were of type 4. Upon consideration all VNTR markers, 156 different genotypes and three pairs with identical genotypes were observed; no epidemiologic relation could be observed between individuals in these pairs. Considerable variability in differentiating index (DI) was observed between the different markers and the four with highest DI [(AT)15, (TA)18, (AT)17 and (GAA)21] frequently demonstrated differences in copy number when comparing genotypes from both type of samples. Excluding these markers from analysis resulted in 83 genotypes, 20 of which included 96 of the patients (60.3%). These clusters were composed of two (n = 8), three (n = 6), four (n = 1), five (n = 2), six (n = 1), 19 (n = 1) and 23 (n = 23) individuals and suggests that recent transmission is contributing to the maintenance of leprosy in Fortaleza. When comparing epidemiological and clinical variables among patients within clustered or with unique M. leprae genotypes, a positive bacterial index in skin biopsies and knowledge of working with someone with the disease were significantly associated with clustering. A tendency to belong to a cluster was observed with later notification of disease (mean value of 3.4 months) and having disability grade 2. A tendency for lack of clustering was observed for patients who reported to have lived with another leprosy case but this might be due to lack of inclusion of household contacts in the study. Although clusters were spread over the city, kernel analysis revealed that some of the patients belonging to the two major clusters were spatially related to some neighborhoods that report poverty and high disease incidence in children. Finally, inclusion of genotypes from nasal swabs might be warranted. A major limitation of the study is that sample size of 160 patients from a two year period represents only 15% of the new patients and this could have weakened statistical outcomes. This is the first molecular epidemiology study of leprosy in Brazil and although the high clustering level suggests that recent transmission is the major cause of disease in Fortaleza; the existence of two large clusters needs further investigation.

ELISA-based assay of immunoglobulin G antibodies against mammalian cell entry 1A (Mce1A) protein: a novel diagnostic approach for leprosy.

BACKGROUNDLeprosy is a chronic infectious disease caused by the obligate intracellular bacillus Mycobacterium leprae. Because leprosy diagnosis is complex and requires professional expertise, new tools and methodologies are needed to detect cases in early stages and prevent transmission. The M. leprae genome contains mce1A, which encodes a putative mammalian cell entry protein (Mce1A). We hypothesised that the presence of Mce1A on the cell surface could be detected by the host's immune system.OBJECTIVEThe aim of this study was to evaluate antibody responses against the Mce1A protein in leprosy patients, household contacts of patients, and the general population to present an addition tool for leprosy diagnosis.METHODSA cross-sectional study involving 89 volunteers [55 leprosy cases, 12 household contacts (HHC) and 22 endemic controls (EC)] was conducted at Couto Maia Hospital, in Salvador, Bahia (BA), Brazil.RESULTSThe median anti-Mce1A IgA was significantly higher in multibacillary (MB) and paucibacillary (PB) cases than in EC (p < 0.0001). A similar trend was observed in IgM levels, which were significantly higher in both MB (p < 0.0001) and PB (p = 0.0006) groups compared to in EC individuals. The greatest differences were observed for IgG class-specific antibodies against Mce1A. The median levels of MB and PB were significantly higher compared to both controls HHC and EC (MB or PB vs EC, MB vs HHC p < 0.0001; PB vs HHC, p = 0.0013). Among leprosy cases, IgG enzyme-linked immunosorbent assay sensitivity and specificity were 92.7% and 97.1%, respectively. IgG positivity was confirmed in 92.1% and 94.1% of MB and PB patients, respectively.CONCLUSIONThis novel diagnostic approach presents an easy, non-invasive, and inexpensive method for leprosy screening, which may be applicable in endemic areas.

The impact of Erythema Nodosum Leprosum on health related quality of life in Rio de Janeiro

© Lepra. Objectives: Erythema nodosum leprosum (ENL - leprosy Type 2 reaction) is a severe immune-inflammatory complication of leprosy that frequently affects patients at any stage of the disease, even after release from multidrug therapy (MDT). Its effect on the patient's health related quality of life (HRQoL) was evaluated with the SF-36 in a group of 59 multibacillary patients at the Fiocruz leprosy outpatient clinic in Rio de Janeiro. Results: A total of 40 patients with ENL or a history of ENL, 19 patients with neuritis, Type 1 reaction or no reaction, of which six patients had never experienced reactions were recruited. Patients with acute ENL episode had significantly lower scores than patients with recurrent episodes in the mental health (P = 0·036) and the role physical (P = 0·03) domains. Patients with active ENL (new or on treatment) had the lowest scores on all domains of both physical and mental health components. They were significantly more affected in the bodily pain (P < 0·01), physical functioning (P = 0·037) and general health (P = 0·04) domains than patients with no reaction at the time of interview. In general, ENL patients have reduced quality of life, especially in the physical health component. Conclusion: Larger studies of HRQoL of people affected by leprosy are needed to give a more detailed picture of the impact of ENL. It is clear that leprosy, its complications and sequela affect HRQoL which should be routinely evaluated in the assessment of patients to improve care.

Field-friendly serological tests for determination of M. leprae-specific antibodies

Early detection of leprosy is key to reduce the ongoing transmission. Antibodies directed against M. leprae PGL-I represent a useful biomarker for detecting multibacillary (MB) patients. Since efficient leprosy diagnosis requires field-friendly test conditions, we evaluated two rapid lateral flow assays (LFA) for detection of Mycobacterium leprae-specific antibodies: the visual immunogold OnSite Leprosy Ab Rapid test [Gold-LFA] and the quantitative, luminescent up-converting phosphor anti-PGL-I test [UCP-LFA]. Test performance was assessed in independent cohorts originating from three endemic areas. In the Philippine cohort comprising patients with high bacillary indices (BI; average:4,9), 94%(n = 161) of MB patients were identified by UCP-LFA and 78%(n = 133) by Gold-LFA. In the Bangladeshi cohort, including mainly MB patients with low BI (average:1), 41%(n = 14) and 44%(n = 15) were detected by UCP-LFA and Gold-LFA, respectively. In the third cohort of schoolchildren from a leprosy hyperendemic region in Brazil, both tests detected 28%(n = 17) seropositivity. Both rapid tests corresponded well with BI(p < 0.0001), with a fairly higher sensitivity obtained with the UCP-LFA assay. However, due to the spectral character of leprosy, additional, cellular biomarkers are required to detect patients with low BIs. Therefore, the UCP-LFA platform, which allows multiplexing with differential biomarkers, offers more cutting-edge potential for diagnosis across the whole leprosy spectrum.

Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): Results of an open label, randomized and controlled clinical trial, among multibacillary patients.

BackgroundLeprosy control is based on early diagnosis and multidrug therapy. For treatment purposes, leprosy patients can be classified as paucibacillary (PB) or multibacillary (MB), according to the number of skin lesions. Studies regarding a uniform treatment regimen (U-MDT) for all leprosy patients have been encouraged by the WHO, rendering disease classification unnecessary.Methodology and findingsAn independent, randomized, controlled clinical trial conducted from 2007 to 2015 in Brazil, compared main outcomes (frequency of reactions, bacilloscopic index trend, disability progression and relapse rates) among MB patients treated with a uniform regimen/U-MDT (dapsone+rifampicin+clofazimine for six months) versus WHO regular-MDT/R-MDT (dapsone+rifampicin+clofazimine for 12 months). A total of 613 newly diagnosed, untreated MB patients with high bacterial load were included. There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups, with more than 25% disability progression in both groups. The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group.During active follow up, four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up (95% CI [0·81, 6·2] per 1000). During passive follow up three patients relapsed in U-MDT and one in R-MTD. As this period corresponds to passive follow up, sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year.ConclusionOur results on the first randomized and controlled study on U-MDT together with the results from three previous studies performed in China, India and Bangladesh, support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide.Trial registrationClinicalTrials.gov: NCT00669643

A 10 year retrospective analysis of Hansen’s disease patients in an urban leprosy centre of Himachal Pradesh

Background: Leprosy is a chronic disease caused by Mycobacterium leprae, which is a non culturable, slowly multiplying bacillus. The incubation period is variable and may take as long as twenty years for the symptoms to appear. It mainly affects the skin and peripheral nerves, but has a wide range of clinical presentations. The disease is associated with deformities and social stigma. Methods: Records of Hansen’s disease patients from January 2007 to December 2016 were taken and analysed retrospectively. A total of 288 patients were registered during this period. Results: Out of 288 registered patients, 78.8% were males and 21.2% were females. Maximum number of patients (62.15%) was in the age group of 20-40 years. Multibacillary patients constituted 86.11% and only13.88% were paucibacillary patients. 66.66% patients had grade 0 deformities, 22.56% had grade 1 deformities and 10.76% had grade 2 deformities. Conclusions: The study recommends that continuous efforts should be made for early detection of cases to prevent spread of disease in the community and to avoid development of deformities.

Distinct Roles of Th17 and Th1 Cells in Inflammatory Responses Associated with the Presentation of Paucibacillary Leprosy and Leprosy Reactions.

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-1β 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.

Elevated Pentraxin-3 Concentrations in Patients With Leprosy: Potential Biomarker of Erythema Nodosum Leprosum.

Leprosy, the leading infectious cause of disability worldwide, remains a major public health challenge in the most severely affected countries despite the sharp decline in new cases in recent years. The search for biomarkers is essential to achieve a better understanding of the molecular and cellular mechanisms underlying the disease. Pentraxin-3 (PTX3) analyses of sera from 87 leprosy patients with or without reactions were conducted via enzyme-linked immunosorbent assay. In situ identification of PTX3 in skin lesion was confirmed by quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and immunofluorescence assays. We found that PTX3 serum levels were higher in multibacillary patients when evaluated before the onset of acute erythema nodosum leprosum (ENL) and persistently elevated during reaction. Thalidomide treatment reduced PTX3 in the serum 7 days after starting treatment. In situ analyses have also demonstrated enhancement of PTX3 in ENL lesions and showed that treatment with thalidomide reduced its expression and the prominent neutrophilic infiltrate, a hallmark of the disease. In summary, our study provides in vivo evidence that PTX3 is enhanced during ENL but not in reversal reaction and provides a new molecular target in ENL pathogenesis.

In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy lesional skin.

Mycobacterium leprae (M. leprae) infection causes nerve damage and the condition worsens often during and long after treatment. Clearance of bacterial antigens including lipoarabinomannan (LAM) during and after treatment in leprosy patients is slow. We previously demonstrated that M. leprae LAM damages peripheral nerves by in situ generation of the membrane attack complex (MAC). Investigating the role of complement activation in skin lesions of leprosy patients might provide insight into the dynamics of in situ immune reactivity and the destructive pathology of M. leprae. In this study, we analyzed in skin lesions of leprosy patients, whether M. leprae antigen LAM deposition correlates with the deposition of complement activation products MAC and C3d on nerves and cells in the surrounding tissue. Skin biopsies of paucibacillary (n = 7), multibacillary leprosy patients (n = 7), and patients with erythema nodosum leprosum (ENL) (n = 6) or reversal reaction (RR) (n = 4) and controls (n = 5) were analyzed. The percentage of C3d, MAC and LAM deposition was significantly higher in the skin biopsies of multibacillary compared to paucibacillary patients (p = <0.05, p = <0.001 and p = <0.001 respectively), with a significant association between LAM and C3d or MAC in the skin biopsies of leprosy patients (r = 0.9578, p< 0.0001 and r = 0.8585, p<0.0001 respectively). In skin lesions of multibacillary patients, MAC deposition was found on axons and co-localizing with LAM. In skin lesions of paucibacillary patients, we found C3d positive T-cells in and surrounding granulomas, but hardly any MAC deposition. In addition, MAC immunoreactivity was increased in both ENL and RR skin lesions compared to non-reactional leprosy patients (p = <0.01 and p = <0.01 respectively). The present findings demonstrate that complement is deposited in skin lesions of leprosy patients, suggesting that inflammation driven by complement activation might contribute to nerve damage in the lesions of these patients. This should be regarded as an important factor in M. leprae nerve damage pathology.

Correlation between therapy and lipid profile of leprosy patients: is there a higher risk for developing cardiovascular diseases after treatment?

BackgroundThe impact of leprosy reduces health-related quality of life of affected patients, interfering with different factors such as nutrition. This study investigated the lipid profile, nutritional status, and risk for cardiovascular disease (CVD) in patients who underwent leprosy treatment in Brazil.MethodsEighty-four adult patients of both genders ranging in age from 20 to 60 years and diagnosed with paucibacillary (PB) or multibacillary (MB) leprosy were selected after undergoing multidrug treatment. The following data were collected: sociodemographic and clinical data; food intake; anthropometric measures (weight, height, and waist circumference); and lipid profile components (total cholesterol, high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], and triglycerides).ResultsAmong the study population, there was a predominance of males (65.48%) aged 50 to 60 years, patients with an income of 248–496 American dollars (63.10%), patients who completed elementary school (65.48%), inactive patients (76.19%), non-smokers (46.43%), and non-drinking patients (69.05%). The levels (mean ± standard deviation) of total cholesterol were 193.8 ± 29.4 mg/dL in the PB form and 203.5 ± 41.7 mg/dL in the MB form. The mean LDL-c was 116.9 ± 22.7 mg/dL in PB patients and 121 ± 31.3 mg/dL in MB patients. Mean triglyceride levels were 123.4 ± 45.2 mg/dL in the PB form and 147.4 ± 88.9 mg/dL in the MB form. The evaluation of nutritional status showed that 41.67% of the patients were eutrophic, while 55.96% had excess weight. Food intake was significantly associated with HDL-c in male patients (P = 0.0264) and with triglycerides in patients above the ideal weight (P = 0.0049).ConclusionsThe risk of acquiring CVDs was observed to be high due to patients’ excess weight and increased waist circumference. This study will guide clinicians in the adequate treatment of patients with leprosy in order to avoid adverse cardiovascular events.

Leprosy reactions in postelimination stage: the Bangladesh experience.

Leprosy reactions are immunologically mediated conditions and a major cause of disability before, during and after multidrug therapy (MDT). Little data have been published on the epidemiology of leprosy reactions in Bangladesh. To describe the pattern and prevalence of leprosy reactions in the postelimination stage. A descriptive retrospective cross-sectional study was carried out in Chittagong Medical College Hospital using the registered records of patients in the period between 2004 and 2013. Of the 670 patients with leprosy, 488 (73.38%) were males and 182 (27.37%) were females. The prevalence of reaction was in 300 (44.78%) patients with a male:female ratio of 3.55 : 1. The age-specific cumulative reaction cases at >40 years were 115 (38.33%) among all age groups. The prevalence of reaction was found to be in 166 (55.33%) patients for the reversal reaction, 49 (16.57%) for the erythema nodosum leprosum (ENL) and 85 (28.33%) for the neuritis. Borderline tuberculoid was most common (106, 35.33%)in the reversal reaction group, while lepromatous leprosy was most common (37, 12.33%) in ENL group. More than half of the patients (169, 56.33%) had reactions at the time of presentations, while 85 (28.33%) and 46 (15.33%) patients developed reaction during and after MDT, respectively. The reversal reaction group presented with ≥six skin lesions in 96 (57.83%) patients and ≥two nerve function impairments (NFIs) in 107 (64.46%) patients. The ENL was present chiefly as papulo-nodular lesions in 45 (91.84%) patients followed by pustule-necrotic lesions in four (8.16%), neuritis in 33 (67.35%), fever in 24 (48.98%), lymphadenitis in six (12.24%), arthritis in five (10.20%) and iritis in two (4.08%). Bacterial index ≥3 had been demonstrated in 34 (60.71%) patients in ENL group. The incidence of leprosy reaction seemed to be more than three times common in borderline tuberculoid (52.33%) group than in lepromatous leprosy (14%) group. Reactions with NFI and disability still occur among multibacillary patients during and after MDT. Early detection and management of leprosy reaction are very important in preventing disability and deformity, and patients should be educated to undergo regular follow-up examinations. Developing reinforced new therapies to curb leprosy reactions is crucial for improving leprosy healthcare services.

Can baseline ML Flow test results predict leprosy reactions? An investigation in a cohort of patients enrolled in the uniform multidrug therapy clinical trial for leprosy patients in Brazil.

BackgroundThe predictive value of the serology to detection of IgM against the Mycobacterium leprae-derived phenolic glycolipid-I/PGL-I to identify leprosy patients who are at higher risk of developing reactions remains controversial. Whether baseline results of the ML Flow test can predict leprosy reactions was investigated among a cohort of patients enrolled in The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR).MethodsThis was a descriptive study focusing on the main clinical manifestations of leprosy patients enrolled in the U-MDT/CT-BR from March 2007 to February 2012 at two Brazilian leprosy reference centers. For research purposes, 753 leprosy patients were categorized according to a modified Ridley-Jopling (R&J) classification and according to the development of leprosy reactions (reversal reaction/RR and erythema nodosum leprosum/ENL), and whether they had a positive or negative bacillary index/BI.ResultsMore than half of the patients (55.5 %) reported leprosy reaction: 18.3 % (138/753) had a RR and 5.4 % (41/753) had ENL. Leprosy reactions were more frequent in the first year following diagnosis, as seen in 27 % (205/753) of patients, while 19 % (142/753) developed reactions during subsequent follow-up. Similar frequencies of leprosy reactions and other clinical manifestations were observed in paucibacillary (PB) and multibacillary (MB) leprosy patients treated with U-MDT and regular MDT (R-MDT) (P = 0.43 and P = 0.61, respectively). Compared with PB patients, leprosy reactions were significantly more frequent in MB patients with a high BI, and more patients developed RR than ENL. However, RR and neuritis were also reported in patients with a negative BI. At baseline, the highest rate of ML Flow positivity was observed in patients with a positive BI, especially those who developed ENL, followed by patients who had neuritis and RR. Among reaction-free patients, 81.9 % were ML Flow positive, however, the differences were not statistically significant compared to reactional patients (P = 0.45).ConclusionsMB and PB patients treated with R-MDT and U-MDT showed similar frequencies of RR and other clinical manifestations. Positive ML Flow tests were associated with MB leprosy and BI positivity. However, ML Flow test results at baseline showed limited sensitivity and specificity for predicting the development of leprosy reactions.Electronic supplementary materialThe online version of this article (doi:10.1186/s40249-016-0203-0) contains supplementary material, which is available to authorized users.

Ultrasonography of Leprosy Neuropathy: A Longitudinal Prospective Study.

BackgroundPrevious studies have shown that leprosy multi-drug therapy (MDT) does not stop the progression of nerve function impairment. There are no prospective studies investigating the evolution of nerve anatomic abnormalities after treatment. We examined leprosy patients aiming to investigate the evolution of nerve ultrasonography (US) abnormalities and the risk factors for poor outcomes after MDT.Methodology/Principal findingsWe performed bilateral US of the ulnar (U), median (M) and common fibular (CF) nerves in 9 paucibacillary (PB) and 64 multibacillary (MB) patients before and after MDT. Forty-two patients had leprosy reactions (type 1, type 2, acute neuritis) during the study. We analyzed nerve maximum cross-sectional areas (CSA), echogenicity and Doppler signal. Poor outcomes included a post-treatment CSA above normal limits with a reduction of less than 30% (U, M) or 40% (CF) from the baseline, echogenicity abnormalities or intraneural Doppler in the post-treatment study. We found that PB and patients without reactions showed significant increases in CSA at CF, whereas MB and patients with reactions had CSA reduction in some nerves after treatment (p<0.05). Despite this reduction, we observed a greater frequency of poor CSA outcomes in the MB compared to the PB (77.8% and 40.6%; p>0.05) and in the patients with reactions compared to those without (66.7% and 38.7%; p<0.05). There was significantly higher odds ratio (7.75; 95%CI: 1.56–38.45) for poor CSA outcomes only for M nerve in patients with reactions. Poor echogenicity outcomes were more frequent in MB (59.4%) compared to PB (22.2%) (p<0.05). There was significant association between poor Doppler outcomes and neuritis. Gender, disease duration, and leprosy classification were not significant risk factors for poor outcomes in CSA, echogenicity or Doppler.Conclusions/SignificanceUS nerve abnormalities can worsen after treatment despite the leprosy classification or the presence of reactions.

Leprosy Drug Resistance Surveillance in Colombia: The Experience of a Sentinel Country.

An active search for Mycobacterium leprae drug resistance was carried out, 243 multibacillary patients from endemic regions of Colombia were included from 2004 to 2013 in a surveillance program. This program was a World Health Organization initiative for drug resistance surveillance in leprosy, where Colombia is a sentinel country. M. leprae DNA from slit skin smear and/or skin biopsy samples was amplified and sequenced to identify mutations in the drug resistance determining region (DRDR) in rpoB, folP1, gyrA, and gyrB, the genes responsible for rifampicin, dapsone and ofloxacin drug-resistance, respectively. Three isolates exhibited mutations in the DRDR rpoB gene (Asp441Tyr, Ser456Leu, Ser458Met), two in the DRDR folP1 gene (Thr53Ala, Pro55Leu), and one isolate exhibited mutations in both DRDR rpoB (Ser456Met) and DRDR folP1 (Pro55Leu), suggesting multidrug resistance. One isolate had a double mutation in folP1 (Thr53Ala and Thr88Pro). Also, we detected mutations outside of DRDR that required in vivo evaluation of their association or not with drug resistance: rpoB Arg505Trp, folP1 Asp91His, Arg94Trp, and Thr88Pro, and gyrA Ala107Leu. Seventy percent of M. leprae mutations were related to drug resistance and were isolated from relapsed patients; the likelihood of relapse was significantly associated with the presence of confirmed resistance mutations (OR range 20.1–88.7, p < 0.05). Five of these relapsed patients received dapsone monotherapy as a primary treatment. In summary, the current study calls attention to M. leprae resistance in Colombia, especially the significant association between confirmed resistance mutations and relapse in leprosy patients. A high frequency of DRDR mutations for rifampicin was seen in a region where dapsone monotherapy was used extensively.

Results of eight years follow up among multibacillary patients treated with Uniform Multidrug Therapy in China

Objective: To analyse the results of treatment among multibacillary (MB) patients 8 years after treatment with 6 months multidrug therapy (MDT). Methods: Newly detected and relapsed MB leprosy patients were treated with 6 months WHO-MDT. The patients were followed up for 8 years. The effectiveness of treatment was assessed by clinical status and bacteriological changes. Results: A total of 114 patients were recruited. Forty two patients dropped out from the study for various reasons. Only 72 patients remained for the final analysis. The mean Bacteriological Index (BI) of all patients decreased from 2.93 ± 1.39 before treatment, to 0 at the end of the eight year follow up period, with an average annual BI decrease of 0.42. The rate of smear negativity of all patients was 100% at the end of follow up. 38 (53%) patients experienced leprosy reactions during the study and one patient relapsed, giving a cumulative relapse rate of 1.3% or 0.035 per 100 patient-years. Conclusion: The finding that all MB cases with initially positive skin smears, who were treated with only 6 months of MB-MDT, became negative within 8 years showed that the response to this regimen is good in a majority of MB cases.

Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy.

Mycobacterium leprae infection gives rise to the immunologically and histopathologically classified spectrum of leprosy. At present, several tools for the stratification of patients are based on acquired immunity markers. However, the role of innate immunity, particularly the complement system, is largely unexplored. The present retrospective study was undertaken to explore whether the systemic levels of complement activation components and regulators can stratify leprosy patients, particularly in reference to the reactional state of the disease. Serum samples from two cohorts were analysed. The cohort from Bangladesh included multi-bacillary (MB) patients with (n = 12) or without (n = 46) reaction (R) at intake and endemic controls (n = 20). The cohort from Ethiopia included pauci-bacillary (PB) (n = 7) and MB (n = 23) patients without reaction and MB (n = 15) patients with reaction. The results showed that the activation products terminal complement complex (TCC) (P≤0·01), C4d (P≤0·05) and iC3b (P≤0·05) were specifically elevated in Bangladeshi patients with reaction at intake compared to endemic controls. In addition, levels of the regulator clusterin (P≤0·001 without R; P<0·05 with R) were also elevated in MB patients, irrespective of a reaction. Similar analysis of the Ethiopian cohort confirmed that, irrespective of a reaction, serum TCC levels were increased significantly in patients with reactions compared to patients without reactions (P≤0·05). Our findings suggests that serum TCC levels may prove to be a valuable tool in diagnosing patients at risk of developing reactions.