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Existing literature on factors triggering leprosy reactions is based only on case reports and case series, and thus probably gives a biased view. We undertook a case-control study to investigate such purported trigger factors in 42 leprosy reaction patients and 40 non-reactional controls, and the cost of investigations required for the same. Detailed history, clinical evaluation and investigations for triggers were carried out. Infections (typhoid, dental caries) were the most common triggers found, followed by pregnancy. Trigger factors were commoner in the type 2 reaction (T2R) group compared to type 1 (T1R) reaction group. There was however no statistical difference between the two groups. The average estimated cost of investigations was higher in the reactional group and this difference was statistically significant. Hence, except for essential investigations required for initiating steroids, an extensive battery of investigations is unjustified unless the medical history suggests a definitive infective trigger., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Tropical diseases prevalent in leprosy-endemic areas may alter the immunological patient response and also complicate the presentation of leprosy reactional episodes. The introduction of anti-malarial drugs in our case produced a subsidence of reaction. With dwindling manpower skilled in leprosy, the reactional episodes are very often treated with non-steroidal anti-inflammatory drugs, steroids and thalidomide, neglecting the possibility of other co-existing infections, tropical or other. Our case emphasises the importance of history, examination and balanced investigation in the context of tropical diseases in endemic areas before injudicious intervention., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Pure Neural Leprosy (PNL) is a form of this long time known disease that affects only the peripheral nervous system. Since it is a rare form of the disease, its pathophisiology is still poorly understood., Objective: Describe the cytokines profile in patients with PNL., Methods: 30 Patients diagnosed with PNL in the Souza Araujo Outpatient Clinic and with cytokines evaluated were selected. They were evaluated by neurologists and diagnosed after a nerve biopsy. Serum levels of IL-1 β, IL-6, IL-10, IL-17, TNF, CCL-2/MCP-1, IFN-ϒ, CXCL-10/IP-10 and TGF-β were evaluates at the moment of the diagnosis., Results: Neural thickening was a common clinical finding in this groups of patients. Small and medium sensitive fibers signs and symptoms were present in 92% of the patients and motor involvement in 53%. 43% of patients presented neuropathic pain and no one had neuritis TGF-beta, IL-17, CCl-2 and IP-10. CCL-2 levels were associated with demyelinating patters and IP-10 and IL-1o were associated with axonal patterns at NCS., Discussion: PNL patients' cytokine profile appears to be different of other clinical forms of leprosy, with the presence of cytokines described in both tuberculoid and lepromatous leprosy. High levels of CCl-2 may be related to the presence of silent neuritis as well as the presence of IL-10. PNL is unique a form of leprosy, therefore, understanding its immunological profiles essential to better understand the disease itself., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pitta, Angst, Pinheiro, Vieira, Spitz, Andrade, Carvalho, Hacker, Sarno and Jardim.)

Objective: Hansen's disease (HD) is a chronic granulomatous infection endemic in the tropics. Its main clinical manifestations involve the cutaneous, nervous, and musculoskeletal systems. Leprosy reactions (LR) are systemic inflammatory and immune-mediated complications of HD. These include reversal reactions (RR), erythema nodosum leprosum (ENL), and Lucio phenomenon. These reactions significantly increase disease-related morbidity and disability. We aimed to determine the number and type of LR, their association to hosts' immune responses (Ridley Jopling classification), timing of development, and treatment of HD patients in Puerto Rico., Methods: A retrospective medical record review was performed on 291 HD patients containing LR status data available from the Dermatology Service at the Hispanic Alliance for Clinical & Translational Research., Results: Our data revealed that 83 (29%) patients developed LR, of which 31% had RR and 69% had ENL. Most LR were observed in patients in the lepromatous border (97%): Borderline lepromatous leprosy (BL) and Lepromatous Leprosy (LL). Most patients with RR and ENL had a single episode (83% and 62%, respectively), and those that received multi-drug therapy (MDT) had a reaction onset occurring most frequently within the first year of MDT and after the first year of MDT, respectively. Prednisone was the first line treatment used to manage both types of LR., Conclusion: Most lepromatous reactions occur within the lepromatous border. ENL was the most common LR. Prompt recognition and management of these immunologic reactions is essential to prevent long term nerve function impairment.

Leprosy is a disease caused by Mycobacterium leprae (ML) with diverse clinical manifestations, which are strongly correlated with the host's immune response. Skin lesions may be accompanied by peripheral neural damage, leading to sensory and motor losses, as well as deformities of the hands and feet. Both innate and acquired immune responses are involved, but the disease has been classically described along a Th1/Th2 spectrum, where the Th1 pole corresponds to the most limited presentations and the Th2 to the most disseminated ones. We discuss this dichotomy in the light of current knowledge of cytokines, Th subpopulations and regulatory T cells taking part in each leprosy presentation. Leprosy reactions are associated with an increase in inflammatory activity both in limited and disseminated presentations, leading to a worsening of previous symptoms or the development of new symptoms. Despite the efforts of many research groups around the world, there is still no adequate serological test for diagnosis in endemic areas, hindering the eradication of leprosy in these regions.

Mycobacterium leprae is known to cause leprosy, a neurological and dermatological disease. In the past 20 years, 16 million leprosy cases have been recorded and more than 200,000 new cases were registered each year, indicating that the disease is still progressing without hindrance. M. leprae, an intracellular bacterium, infects the Schwann cells of the peripheral nervous system. Several types of leprosy have been described, including indeterminate, tuberculoid, borderline tuberculoid, mid-borderline, borderline lepromatous and lepromatous, and three different forms of leprosy reactions, namely type 1, 2 and 3, have been designated. Microscopic detection, serological diagnostic test, polymerase chain reaction and flow tests are employed in the diagnosis of leprosy. The recommended treatment for leprosy consists of rifampicin, dapsone, clofazimine, ofloxacin and minocycline and vaccines are also available. However, relapse may occur after treatment has been halted and hence patients must be educated on the signs of relapse to allow proper treatment and reduce severity. In this review, we depict the current understanding of M. leprae pathogenicity, clinical aspects and manifestations. Transmission of leprosy, diagnosis and treatment are also discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The chronic aspects of leprosy are discussed here. They are a consequence of the peripheral nerve damage that affects many patients during their lifetime with leprosy. The peripheral nerve damage leaves people unable to feel and with weakness in their hands and feet. They are at risk of damaging their hands and feet, causing the disabilities and deformities that characterise late leprosy. More than 200 000 new leprosy patients are diagnosed globally each year. Better data are needed from cohort studies to estimate the number of patients developing nerve damage and modelling studies are needed to estimate the number of patients who develop disabilities. For some of them, this will be a lifelong disability. Nerve damage is caused by inflammation in leprosy-affected nerves. Patients with nerve damage of <6-mo duration need treatment with steroids. About 66% of multibacillary patients will develop nerve damage. Plastic graded monofilaments can be used to detect nerve damage in leprosy and diabetic clinics. Assessing nerve damage and treating patients with steroids in leprosy programmes needs to be strengthened. The World Health Organization has a successful programme for supplying antibiotics for treating leprosy infection to national leprosy programmes. They should take responsibility for providing steroids to national programmes since this is a core part of the treatment for >66% of multibacillary patients. Patients need to be asked about neuropathic pain symptoms and treated if necessary. Treated leprosy patients are at risk of developing ulcers in their feet. Treatment and prevention needs to be improved through health education, providing protective footwear and patient empowerment., (© The Author(s) 2019. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Understanding host immune pathways associated with tissue damage during reactions are of upmost importance to the development of immune intervention strategies. The participation of monocytes in leprosy reactions was evaluated by determining the frequency of monocyte subsets and the degree of cellular activation through the expression of MHCII and the co-stimulatory molecules CD40, CD80, CD86. Leprosy subjects with or without reactions were included in this cross-sectional study. Peripheral blood mononuclear cell were isolated and stained ex vivo to determine monocyte subsets and the degree of cellular activation by flow cytometry. Intermediate monocytes were increased in leprosy patients with reactions when compared to patients without reactions. Although no difference was detected in the frequency of monocyte subsets between type 1 and 2 reactions, the expression of CD80 was increased in monocytes from patients with type 1 reactions and CD40 was higher in paucibacillary subjects presenting type 1 reactions. Moreover, CD86 and MHC II expression were higher in intermediate monocytes when compared to the other subsets in leprosy reaction types 1 and 2. Intermediate monocyte activation with CD86 and MHCII expression is involved with both type 1 and 2 reactions, whereas CD80 and CD40 expression is related to type 1 reactions., (Copyright © 2018 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Background: Erythema nodosum leprosum is an immune-mediated complication of leprosy which causes significant morbidity. Biomarkers in the pathogenesis of erythema nodosum leprosum are not yet fully determined., Aim: To determine macrophage migration inhibitory factor levels in the sera of leprosy patients with erythema nodosum leprosum and to correlate the same with clinical parameters., Methods: This cross-sectional study included 37 consecutive leprosy patients with active erythema nodosum leprosum and 31 age- and sex-matched controls. Detailed clinical history and examination findings were recorded including the severity and frequency of erythema nodosum leprosum. Slit skin smears and histopathologic examination were done in all patients at baseline. Serum macrophage migration inhibitory factor levels were determined using an enzyme-linked immunosorbent assay., Results: Most of our patients were males (78.4%) and suffering from lepromatous leprosy (27, 73%) with a mean initial bacillary index of 3.38 ± 1.36. Recurrent and chronic patterns of erythema nodosum leprosum were seen in 15 (40.5%) and 6 (16.3%) patients, respectively. Most (86.5%) of our patients presented with moderate to severe erythema nodosum leprosum. The mean serum macrophage migration inhibitory factor level was 21.86 ± 18.7 ng/ml among patients while it was 11.78 ± 8.4 ng/ml in the control group (P < 0.01). There were no statistically significant correlations of macrophage migration inhibitory factor levels with erythema nodosum leprosum frequency or severity., Limitation: Serum macrophage migration inhibitory factor levels in leprosy patients with no erythema nodosum leprosum and in patients with other inflammatory and autoimmune conditions were not assessed. Hence, this study falls short of providing the predictive value and specificity of higher macrophage migration inhibitory factor concentrations in serum as a biomarker of erythema nodosum leprosum., Conclusion: Macrophage migration inhibitory factor levels are elevated in erythema nodosum leprosum patients as compared to controls. A larger sample size and macrophage migration inhibitory factor gene polymorphism analysis will be needed to elucidate the role of this pro-inflammatory cytokine in erythema nodosum leprosum., Competing Interests: There are no conflicts of interest

Leprosy causes the most common peripheral neuropathy of infectious etiology, posing an important public health problem worldwide. Understanding the molecular and immunological mechanisms of nerve damage induced by M. leprae is mandatory to develop tools for early diagnosis and preventive measures. The phenolic glycolipid 1 (PGL-1) and lipoarabinomannan (LAM) antigens are major components of the bacterial surface and are implicated on leprosy immunopathogenesis and neural damage. Although the anti-PGL-1 serum IgM is highly used for operational classification of patients, the anti-LAM salivary IgA (sIgA) has not been investigated as diagnostic or prognostic marker in leprosy. Our aim was to assess the presence of anti-LAM sIgA in leprosy patients and their contacts in order to demonstrate whether such expression was associated with leprosy reactions. Distinct patterns of anti-LAM slgA were observed among groups, which were stratified into treatment-naïve patients (116), patients who completed multidrug therapy-MDT (39), household contacts (111), and endemic controls (11). Both anti-LAM sIgA and anti-PGL-I serum IgM presented similar prognostic odds toward leprosy reactions [(odds ratio) OR = 2.33 and 2.78, respectively]. Furthermore, the anti-LAM sIgA was highly correlated with multibacillary (MB) forms (OR = 4.15). Contrarily, among contacts the positive anti-LAM sIgA was highly correlated with those with positive Mitsuda test, suggesting that the presence of anti-LAM slgA may act as an indicator of cellular immunity conferred to contacts. Our data suggest that anti-LAM slgA may be used as a tool to monitor patients undergoing treatment to predict reactional episodes and may also be used in contacts to evaluate their cellular immunity without the need of Mitsuda tests.

Background: Leprosy is a complex infectious and neurological disease caused by Mycobacterium leprae. Nerve damage is related to immunological hypersensitivity responses known as leprosy reactions (LRs). Diagnostic tools to predict LRs are not available. We hypothesized that natural octyl disaccharide-leprosy IDRI diagnostic (NDO-LID) would be helpful as an indicator of LRs and neuritis., Methods: To assess the utility of NDO-LID in indicating reactions, ELISA were used to detect specific antibodies in serum samples from 80 Colombian leprosy patients (40 with and 40 without history of LRs). Responses were detected using a range of detection reagents detecting IgG, IgM or both isotypes., Results: Patients with a history of LRs had an increased seropositivity rate for anti-NDO-LID antibodies compared to patients without (anti-NDO-LID protein A [p=0.02], IgG anti-NDO-LID [p=0.01] and IgM anti-NDO-LID [p=0.01]). Further analyses of patients with a history of LRs indicated that both seropositivity rate and magnitude of responses were elevated among patients with neuritis versus those without neuritis (anti-NDO-LID protein A [p=0.03], IgG anti-NDO-LID [p=0.001] and IgM anti-NDO-LID [p=0.06])., Conclusions: Our data indicate that testing for serum anti-NDO-LID antibodies can be a useful screen to identify patients at risk of developing LRs and neuritis., (© The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Leprosy, a chronic mycobacterial infection caused by Mycobacterium leprae, is an infectious disease that has ravaged human societies throughout millennia. This ancestral pathogen causes disfiguring cutaneous lesions, peripheral nerve injury, ostearticular deformity, limb loss and dysfunction, blindness and stigma. Despite ongoing efforts in interrupting leprosy transmission, large numbers of new cases are persistently identified in many endemic areas. Moreover, at the time of diagnosis, most newly identified cases have considerable neurologic disability. Many challenges remain in our understanding of the epidemiology of leprosy including: (a) the precise mode and route of transmission; (b) the socioeconomic, environmental, and behavioral factors that promote its transmission; and, ((c) strategies to achieve early diagnosis and prevent neurologic impairment to reduce the large burden of disability among newly identified cases; and among those who endure long-term disability in spite of completing multidrug therapy.)

Leprosy remains a significant neglected tropical disease despite the goal of elimination having been achieved in various endemic nations over the past two decades. Reactional episodes complicate the disease course, resulting in deformities and disability. The main aim of treatment is to kill Mycobacterium leprae and decrease the bacterial load, which could help prevent further bacilli transmission. A major concern in breaking the chain of transmission and possibly for recurrent reactions is the role of drug‐resistant bacilli. Though some data is available on the background prevalence of drug resistance in leprosy, there is a paucity of studies that look for resistance specifically in leprosy reactions. Administration of long‐term steroids or immunosuppressants for chronic and recurrent responses in the presence of drug resistance has the twin effect of perpetuating the multiplication of resistant bacilli and encouraging the dissemination of leprosy. The increasing trend of prescribing second‐line drugs for leprosy or type 2 reactions without prior assessment of drug resistance can potentially precipitate a severe public health problem as this can promote the development of resistance to second‐line drugs as well. A comprehensive multicenter study, including drug resistance surveillance testing in cases of reactions, is necessary, along with the current measures to stop the spread of leprosy. Here, we have detailed the history of drug resistance in leprosy, given pointers on when to suspect drug resistance, described the role of resistance in reactions, methods of resistance testing, and the management of resistant cases with second‐line therapy. [ABSTRACT FROM AUTHOR]

Background The clinical management of leprosy is complicated by leprosy reactions (LR) causing irreversible nerve damage and disabilities. LR often require long-term use of corticosteroids causing serious side effects. Adjunct host-directed therapy (HDT) is a potentially attractive strategy in leprosy to prevent LR and associated immunopathology, modulate immunological memory that protects against recurrence, and thereby reduce nerve damage, disability and corticosteroid-associated morbidities. Metformin, a well-tolerated, safe and cheap anti-hyperglycaemic drug, is repurposed as HDT in auto-immune and infectious diseases, like tuberculosis (TB). Metformin use in people with diabetes is associated with reduced risks of TB-infection, progression to active TB, treatment failure and TB-mortality. Given the similarities both mycobacteria share, we hypothesize that among persons with multibacillary (MB) leprosy, adjunctive metformin may prevent/mitigate LR. Methods We will perform a double-blind controlled proof-of-concept trial in which people with newly diagnosed multibacillary leprosy will be randomized (1:1) to metformin hydrochloride 1000mg extended release once daily versus placebo for 24 weeks in addition to standard-of-care WHO MB multidrug therapy (MDT) during 48 weeks. We aim to enrol 166 participants aged between 18 and 65 years, across five clinical sites in two leprosy endemic areas in Indonesia. Primary outcomes are the proportion of participants experiencing a LR and the frequency of (serious) adverse events. Secondary outcomes are the severity and time to first LR, the cumulative corticosteroid usage, and quality of life. The total study follow-up is 48 weeks. Discussion LR signify the most important cause of irreversible nerve damage leading to anatomical deformities and disabilities, imposing a social and financial burden on those affected. Our study aims to evaluate the efficacy, tolerability and safety of adjunct metformin added to MDT in persons with multibacillary leprosy, and explore its effects on clinical and immunological outcomes. ClinicalTrials.gov registration NCT05243654 (17/02/2022)

Abstract Leprosy reactions often require prolonged high-dose steroids or immunosuppressive drugs, putting patients at risk of Pneumocystis jirovecii pneumonia (PJP). However, no PJP cases are reported, possibly due to dapsone treatment for leprosy. In patients with leprosy reactions not receiving dapsone because of toxicity or resistance and requiring long-term immunosuppression, PJP prophylaxis should be considered.

Background: Leprosy is a major public health problem in India, which affects many people every year and has significantly high new case detection rates in certain districts and blocks. According to the National Leprosy Elimination Program (NLEP) report of March 2019, there were a total of 1.14 lakhs new cases of leprosy in India with an Annual New Case Detection Rate (ANCDR) of 8.1 per 100,000 population. Aim: The present study aimed at determining the epidemiological and clinical profile of leprosy patients from a tertiary level teaching hospital in South Rajasthan. Materials and Methods: A retrospective, record-based study was carried out on patients registered in the leprosy clinic of a tertiary level teaching hospital of South Rajasthan during a period of ten years (2010-2019). Data regarding the demographic profile, clinical features, treatment given, and complications were analysed. Results: A total of 1372 patients registered in the leprosy clinic during a period of 10 years were evaluated. There were 1007 (73.4%) males and 365 (26.6%) females with a male-female ratio of 2.76:1. The majority of patients 671 (48.9%) belonged to the middle age group (21-40 years). Multibacillary leprosy was the most common clinical type seen in 1109 patients (80.8%). Borderline leprosy was the most common morphological type, determined in 625 (45.6%) patients, of which BL (21.0%) was the most common group. 16.7% patients presented with leprosy reaction at the time of initial diagnosis. Type 1 reaction was seen in 91(6.6%) and type 2 reaction in 138 (10.1%) patients. Grade I disability was observed in 347 (25.3%) patients whereas grade II disability was seen in 456 (33.2%) patients. 54 patients (3.9%) had a definite history of contact in the family. 28 patients defaulted during the study period. Yearly trend of epidemiological and operational parameters was observed, and the parameters were compared with the national data. Conclusion: Persistent high proportion of multibacillary cases and grade 2 disability indicates that leprosy continues to be a significant health care problem despite statistical elimination. There is a clear need to strengthen early detection, treatment and regular follow-up of these cases in both high and low endemic settings. [ABSTRACT FROM AUTHOR]

Leprosy reactions often require prolonged high-dose steroids or immunosuppressive drugs, putting patients at risk of Pneumocystis jirovecii pneumonia (PJP). However, no PJP cases are reported, possibly due to dapsone treatment for leprosy. In patients with leprosy reactions not receiving dapsone because of toxicity or resistance and requiring long-term immunosuppression, PJP prophylaxis should be considered. [ABSTRACT FROM AUTHOR]

IntroductionLeprosy reactions (LR) are severe episodes of intense activation of the host inflammatory response of uncertain etiology, today the leading cause of permanent nerve damage in leprosy patients. Several genetic and non-genetic risk factors for LR have been described; however, there are limited attempts to combine this information to estimate the risk of a leprosy patient developing LR. Here we present an artificial intelligence (AI)-based system that can assess LR risk using clinical, demographic, and genetic data.MethodsThe study includes four datasets from different regions of Brazil, totalizing 1,450 leprosy patients followed prospectively for at least 2 years to assess the occurrence of LR. Data mining using WEKA software was performed following a two-step protocol to select the variables included in the AI system, based on Bayesian Networks, and developed using the NETICA software.ResultsAnalysis of the complete database resulted in a system able to estimate LR risk with 82.7% accuracy, 79.3% sensitivity, and 86.2% specificity. When using only databases for which host genetic information associated with LR was included, the performance increased to 87.7% accuracy, 85.7% sensitivity, and 89.4% specificity.ConclusionWe produced an easy-to-use, online, free-access system that identifies leprosy patients at risk of developing LR. Risk assessment of LR for individual patients may detect candidates for close monitoring, with a potentially positive impact on the prevention of permanent disabilities, the quality of life of the patients, and upon leprosy control programs.

Background: Leprosy is a neglected tropical disease caused by chronic granulomatous infection of Mycobacterium leprae. Indonesia ranks third in new case findings, with 84% of the case being multibacillary (MB) leprosy. MB leprosy cases have a higher risk of leprosy reactions and physical disabilities that decrease quality of life. Purpose: To determine the demographic, clinical characteristics, and white blood analysis of newly diagnosed MB leprosy patients, especially concerning leprosy reactions. Methods: This is a descriptive retrospective study with a cross-sectional design that describe the following data: domicile, gender, age, treatment status, disabilities, body mass index (BMI); bacterial index (BI), morphological index (MI), white blood cell (WBC) and differential counts, and thrombocyte count. Result: This study included 176 adult MB cases, predominantly male aged 20–39 years old with average BMI, lived in Surabaya with negative history of multi-drug therapy, disability, BI, nor MI. The grade 2 disability (G2D) percentage in this study setting than in Indonesia (10.7% vs. 6.43%). The WBCs, especially neutrophil count, was higher in T2R group. Monocyte and lymphocyte counts were relatively similar. There was an increase in thrombocyte count in leprosy reaction groups. Conclusion: MB leprosy in the endemic area, which is more commonly found in productive-aged male, displayed higher G2D than global Indonesia population. Thus denotes the importance of active case findings. The difference in blood analysis characteristics between MB leprosy with and without reactions may serve as the foundation for future study.

IntroductionLeprosy reactions are complications that can occur before, during, or after multidrug therapy (MDT) and are considered a major cause of nerve damage. Neuritis is an inflammatory process that causes nerve function impairment associated with pain and tenderness along the nerve. Neuritis can be found in both type 1 and type 2 reactions and may also be the sole manifestation of a leprosy reaction. The objective of this study is to describe the incidence of leprosy reactions and its association with neuropathic pain in pure neural leprosy (PNL) patients.MethodsWe selected 52 patients diagnosed with PNL and 67 patients with other clinical forms of leprosy. During the MDT the patients visited the clinic monthly to take their supervised dose. The patients were instructed to return immediately if any new neurological deficit or skin lesions occurred during or after the MDT.ResultsOf the PNL patients, 23.1% had a leprosy reaction during or after the MDT, while this was 59.7% for patients with the other clinical forms of leprosy. There was an association between having PNL and not having any reaction during and after the MDT, as well as having PNL and having neuritis after the MDT.There was also an association between having previous neuritis and having neuropathic pain in the other clinical forms of leprosy group, although this association was not present in the PNL group.DiscussionOur data suggest that PNL is a different form of the disease, which is immunologically more stable. In addition, PNL patients have more neuritis than the classical leprosy skin reactions. In PNL there was no association between acute neuritis and neuropathic pain, suggesting that these patients may have had silent neuritis. Understanding and identifying neuritis is essential to reduce disability and the impact on public health.

Leprosy reactions are acute inflammatory episodes that complicate the course of a Mycobacterium leprae infection and are the major cause of leprosy-associated pathology. Two types of leprosy reactions with relatively distinct pathogenesis and clinical features can occur: type 1 reaction, also known as reversal reaction, and type 2 reaction, also known as erythema nodosum leprosum. These acute nerve-destructive immune exacerbations often cause irreversible disabilities and deformities, especially when diagnosis is delayed. However, there is no diagnostic test to detect or predict leprosy reactions before the onset of clinical symptoms. Identification of biomarkers for leprosy reactions, which impede the development of symptoms or correlate with early-onset, will allow precise diagnosis and timely interventions to greatly improve the patients' quality of life. Here, we review the progress of research aimed at identifying biomarkers for leprosy reactions, including its correlation with not only immunity but also genetics, transcripts, and metabolites, providing an understanding of the immune dysfunction and inflammation that underly the pathogenesis of leprosy reactions. Nevertheless, no biomarkers that can reliably predict the subsequent occurrence of leprosy reactions from non-reactional patients and distinguish type I reaction from type II have yet been found.

Background: The 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). Methods: This 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. Results: More 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). Conclusions: MB 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. [ABSTRACT FROM AUTHOR]

Introduction Leprosy is a chronic disease that affects skin and peripheral nerves. Disease complications include reactional episodes and physical impairment. One World Health Organization (WHO) goal of leprosy programs is to decrease the number of grade 2 impairment diagnoses by 2015. This study aims to evaluate clinical factors associated with the occurrence of leprosy reactions and physical impairment in leprosy patients. Methods We conducted a retrospective study of data from medical records of patients followed in two important centers for the treatment of leprosy in Aracaju, Sergipe, Brazil, from 2005 to 2011. We used the chi-square test to analyze associations between the following categorical variables: gender, age, operational classification, clinical forms, leprosy reactions, corticosteroid treatment, and physical impairment at the diagnosis and after cure. Clinical variables associated with multibacillary leprosy and/or reactional episodes and the presence of any grade of physical impairment after cure were evaluated using the logistic regression model. Results We found that men were more affected by multibacillary forms, reactional episodes, and grade 2 physical impairment at diagnosis. Leprosy reactions were detected in a total of 40% of patients and all were treated with corticosteroids. However, physical impairment was observed in 29.8% of the patients analyzed at the end of the treatment and our multivariate analysis associated a low dose and short period of corticosteroid treatment with persistence of physical impairments. Conclusions Physical impairment should receive an increased attention before and after treatment, and adequate treatment should be emphasized.

INTRODUÇÃO: As reações são frequentes e importantes no contexto da hanseníase, representando uma significativa parcela de pacientes com incapacidades e submetidos ao retratamento da hanseníase. A caracterização clínico-epidemiológica dos padrões reacionais é primordial para o manejo dos pacientes. O objetivo desse trabalho é descrever as características epidemiológicas e clínicas das reações hansênicas em indivíduos paucibacilares e multibacilares. MÉTODOS: Estudo transversal onde foram avaliados 201 pacientes com história de quadro reacional, atendidos em dois centros de referência para tratamento da hanseníase. Variáveis como baciloscopia inicial, sexo, idade, fototipo, procedência, forma clínica, tipo de tratamento e de reação, índice baciloscópico final e período de surgimento da reação em relação ao tratamento foram avaliados. A análise estatística foi realizada usando-se frequências simples. Para cálculo dos fatores de risco para as formas multibacilares, foram realizadas análises univariada e multivariada. RESULTADOS: Sexo masculino, idade entre 30-44 anos, fototipo V, a forma clínica borderline, tratamento regular, reação tipo I, neurite, presença de 10 a 20 nódulos e surgimento da reação hansênica durante o tratamento foram os achados mais frequentes. CONCLUSÕES: Predominaram os indivíduos do sexo masculino que se associaram a um maior risco de desenvolvimento da forma multibacilar. As reações hansênicas foram mais frequentes durante o tratamento, os pacientes multibacilares foram mais propensos ao retratamento da hanseníase e aqueles com reações tipo I e II, apresentaram maior frequência de neurite, linfadenopatia, artrite e irite do que aqueles com reação isolada.INTRODUCTION: Significant reactions frequently occur among leprosy cases, and thus a significant proportion of leprosy patients present disabilities and undergo leprosy retreatment. Clinical-epidemiological characterization of reaction patterns is essential for managing such patients. Objective to describe the epidemiological and clinical characteristics of leprosy reactions among paucibacillary and multibacillary individuals. METHODS: In this cross-sectional study, 201 patients with histories of reactions who were attended at two reference centers for leprosy treatment were evaluated. Variables such as initial bacilloscopy, sex, age, skin phototype, origin, clinical presentation, type of treatment, type of reaction, final bacilloscopy index and time of reaction onset in relation to the treatment were evaluated. Statistical analysis was performed using simple frequencies. To calculate risk factors for multibacillary forms, univariate and multivariate analyses were performed. RESULTS: Male sex, age between 30 and 44 years, phototype V, borderline clinical form, regular treatment, type I reaction, neuritis, presence of 10 to 20 nodules and onset of the leprosy reaction during the treatment were the most frequent findings. CONCLUSIONS: Male patients predominated and were associated with greater risk of developing the multibacillary forms. Leprosy reactions occurred most frequently during the treatment. Multibacillary patients were more likely to need leprosy retreatment, and those with type I and type II reactions presented greater frequency of neuritis, lymphadenopathy, arthritis and iritis than did those with isolated reactions.

Background. Hansen's disease (HD), or leprosy, is uncommon in the United States. We sought to describe the characteristics of patients with HD in a US clinic, including an assessment of delays in diagnosis and HD reactions, which have both been associated with nerve damage. Methods. A retrospective chart review was conducted on patients seen at an HD clinic in the southern United States between January 1, 2002 and January 31, 2014. Demographic and clinical characteristics were summarized, including delays in diagnosis, frequency of reactions, and other complications including peripheral neuropathy. Results. Thirty patients were seen during the study time period. The majority of patients were male (73%) and had multibacillary disease (70%). Brazil, Mexico, and the United States were the most frequent of the 14 countries of origin. Hansen's disease "reactions", severe inflammatory complications, were identified among 75% of patients, and nerve damage was present at diagnosis in 36% of patients. The median length of time between symptom onset and diagnosis was long at 12 months (range, 1-96), but no single factor was associated with a delay in diagnosis. Discussion. The diagnosis of HD was frequently delayed among patients referred to our US clinic. The high frequency of reactions and neuropathy at diagnosis suggests that further efforts at timely diagnosis and management of this often unrecognized disease is needed to prevent the long-term sequelae associated with irreversible nerve damage. [ABSTRACT FROM AUTHOR]

Background: Post-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis (VL), which may occur after or during treatment. It has been frequently reported from India and the Sudan, but its occurrence in South America has been rarely reported. It may mimic leprosy and its differentiation may be difficult, since both diseases may show hypo-pigmented macular lesions as clinical presentation and neural involvement in histopathological investigations. The co-infection of leprosy and VL has been reported in countries where both diseases are endemic. The authors report a co-infection case of leprosy and VL, which evolved into PKDL and discuss the clinical and the pathological aspects in the patient and review the literature on this disease.Case Presentation: We report an unusual case of a 53-year-old female patient from Alagoas, Brazil. She presented with leprosy and a necrotizing erythema nodosum, a type II leprosy reaction, about 3 month after finishing the treatment (MDT-MB) for leprosy. She was hospitalized and VL was diagnosed at that time and she was successfully treated with liposomal amphotericin B. After 6 months, she developed a few hypo-pigmented papules on her forehead. A granulomatous inflammatory infiltrate throughout the dermis was observed at histopathological examination of the skin biopsy. It consisted of epithelioid histiocytes, lymphocytes and plasma cells with the presence of amastigotes of Leishmania in macrophages (Leishman's bodies). The diagnosis of post-kala-azar dermal leishmaniasis was established because at this time there was no hepatosplenomegaly and the bone marrow did not show Leishmania parasites thus excluding VL. About 2 years after the treatment of PKDL with liposomal amphotericin B the patient is still without PKDL lesions.Conclusion: Post-kala-azar dermal leishmaniasis is a rare dermal complication of VL that mimics leprosy and should be considered particularly in countries where both diseases are endemic. A co-infection must be seriously considered, especially in patients who are non-responsive to treatment or develop persistent leprosy reactions as those encountered in the patient reported here. [ABSTRACT FROM AUTHOR]

Abstract: This review focuses on nerve damage in leprosy. We present evidence to support the argument that leprosy is best seen as a chronic neurological condition rather than a simple skin disease. Nerve damage affects small dermal nerves and peripheral nerve trunks. Perineural inflammation is a characteristic and hallmark of early leprosy. T cell-mediated inflammation is the main pathological process in leprosy nerve damage. The level of nerve damage in leprosy is high with up to 60% of multibacillary patients having clinically apparent nerve damage at the time of diagnosis; 30% of patents may develop further nerve damage during treatment and 10% may develop new nerve damage after drug treatment. Since the nerve damage is immune mediated, the antibiotics used to treat Mycobacterium leprae infection have little effect on the accompanying nerve damage. This requires treatment with immunosuppressants to stop the inflammation. Treatment of nerve damage with steroids can be effective but about 50% of patients relapse and require a further course of steroids. Research is needed to refine steroid regimens to be used and define appropriate alternatives. Neuropathic pain is now being recognised as another late complication for leprosy patients. There are also service challenges relating to how best to identify patients who need steroid treatment and how to manage patients with established neuropathy who may require health services for many years. [Copyright &y& Elsevier]

Leprosy was supposed to be eliminated by WHO at the global level by the end of the year 2000; however, it still remains a significant public health problem at a national level in six countries, where India alone accounts for 64% of prevalence and 78% of new case detection, worldwide. The global registered prevalence of leprosy at the beginning of 2006 was 219 826 cases. The number of new cases reported during 2005 was 296 499. The clinical diagnosis of leprosy continues to be based on patients having one or more of the three cardinal signs: hypopigmented or reddish anesthetic skin lesion(s); involvement of the peripheral nerves, as demonstrated by definite thickening with loss of sensation in the area of distribution; and a positive skin smear for acid-fast bacilli. Multidrug therapy (MDT) for leprosy has proved to be highly effective, with low relapse rates resulting in a dramatic decrease in the global prevalence rate to less than one case per 10 000 by the end of the year 2000. It was thought to be worthwhile to review the progress made in the treatment of this neglected tropical disease from the time diaminodiphenylsulfone (dapsone) monotherapy was introduced in its management, to the rapidly changing situation following the advent of WHO-recommended MDT and subsequently to short-course newer drug regimens with the prime objective to eliminate/eradicate leprosy from the world. Several permutations and combinations of drugs were utilized, the outline of which are succinctly depicted in the following account. Furthermore, a synopsis of the role of immunoprophylaxis therapy has briefly been reviewed to arrive at the possible current status. It is expected that this article is not only essential at this point in time but is also likely to make clear the intricacies surrounding its management. [ABSTRACT FROM AUTHOR]

Leprosy, also known as Hansen's disease, an ancient affliction of mankind, is still endemic in some countries. The fear and stigma associated with the disease arised from the unsightly deformities due to nerve damage and anesthesia. Historically, mono- and multidrug therapies have been used in a range of combinations for various durations with variable results and degrees of compliance. WHO-recommended multidrug therapy has proved to be the most important landmark in the chemotherapy of leprosy with a tremendous success in the control of the disease, significant fall in the number of patients worldwide and acceptable relapse rates. Research for more effective and bactericidal drugs is in progress. Intensive short-course regimens and uniform schedules all along the spectrum are being evaluated in field trials. Care of patients with nerve function impairment, reactions, relapses and prevention of disabilities and rehabilitation will remain an imperative task for healthcare providers even in the post-elimination era. Integration of leprosy with general health services in all endemic countries poses a challenge for early diagnosis and proper management of disease, including reactions, prevention of disabilities, imparting quality training to primary healthcare workers and maintaining required expertise at the referral level. It is hoped that the newer and more effective patient-friendly regimens combined with the positive approach of national and international agencies could lead to leprosy becoming a historical disease. [ABSTRACT FROM AUTHOR]

Objective To review the history of the treatment of leprosy and leprosy reactions after World War II. Methods Treatments based on experience and clinical evidence are compared with those advised by the WHO in their quest to eliminate leprosy by the year 2000, later extended to 2005. Results Leprosy is not eliminated. Analyses of data on reaction treatment suggest that the treatment regimens for leprosy reactions as advised by the WHO may lead to more impairment among leprosy patients than the ‘old’ established regimes. Conclusion WHO policies to eliminate leprosy may have jeopardized the proper treatment of leprosy for years to come. [ABSTRACT FROM AUTHOR]

Leprosy remains an endemic infectious disease in many countries. Typical clinical manifestations involve skin and nerves, but bone and joint involvement can be observed. There are either classical rheumatic manifestations (directly due to Hansen bacillus or linked to complications due to nervous involvement), or inflammatory manifestations, which can be acute or chronic, occur during leprosy reactions or not, and which physiopathology remains unclear. Because of their clinical, radiological and biological features, these inflammatory manifestations may mimick some systemic diseases, raising diagnosis difficulties in areas where leprosy is rare. [Copyright &y& Elsevier]

It is well known that reactions are commonplace occurrences during the course of leprosy disease. Stigmatization may even be attributable to reactions which are also responsible for the worsening of neural lesions. A cohort of 162 newly-diagnosed baciloscopically positive patients from the Leprosy Care Outpatient Clinic of the Oswaldo Cruz Foundation (FIOCRUZ) was selected for this study. While 46% of the multibacillary (MB) patients submitted to the 24 fixed-dose multidrug therapy (MDT) regimen suffered reactions during treatment, it was found that all MBs were susceptible and that constant attention and care were required at all times. Fourteen per cent were classified as BB, 52% as BL, and 33% as LL. None of the variables under study, such as, sex, age, clinical form, length of illness, length of dermatological lesions, baciloscopic index (BI), or degree of disability proved to be associate with reaction among the patients studied. Reversal Reaction (RR) occurred in 45%, and Erythema Nodosum Leprosum (ENL) occurred in 55%. Among BB patients who developed reactions (15 patients), 93% presented RR; while among the LL patients who developed reactions (34 patients), 91% presented ENL. Likewise, ENL was very frequent among those with disseminate lesions, while RR was most often observed in patients with segmentary lesions. RR was also most likely to occur during the initial months of treatment. It was demonstrated that the recurrence rate of ENL was significantly higher than that of RR. Neither grade of disability nor BI was shown to be associated with RR and ENL reaction. However, the RR rate was significantly higher among patients showing BI < 3, while ENL predominated among those patients with BI > 3.Reações são ocorrências comuns no curso da hanseníase e são responsáveis pelo agravamento das lesões neurais. Uma coorte de 162 pacientes recém-diagnosticados, baciloscopicamente positivos, em acompanhamento no Ambulatório de Hanseníase da Fundação Oswaldo Cruz (FIOCRUZ) foi selecionada para estudo. Observou-se que 46% dos pacientes multibacilares submetidos a 24 doses fixas de poliquimioterapia (PQT) apresentaram reações durante o tratamento; todos multibacilares eram suscetíveis e cuidados e atenção constantes eram necessários. Quatorze por cento foram classificados como BB, 52% como BL e 33% como LL. Nenhuma das variáveis em estudo, tais como: sexo, idade, forma clínica, tempo de doença, extensão das lesões dermatológicas, índice baciloscópico (IB), ou grau de incapacidade associaram-se a reação entre os pacientes estudados. Reação Reversa (RR) ocorreu em 45% e Eritema Nodoso Hansênico (ENH) em 55% dos casos. Entre os pacientes BB que desenvolveram reação (15 pacientes), 93% apresentaram RR, enquanto entre os pacientes LL que tiveram reação (34 pacientes), 91% apresentaram ENH. Por outro lado, ENH foi mais frequente entre aqueles com lesões difusas, enquanto RR foi mais frequente em pacientes com lesões localizadas. O RR ocorreu principalmente nos primeiros meses de tratamento. A taxa de recorrência do ENL foi significativamente maior que a do RR. Nenhum grau de incapacidade nem IB esteve associado com RR e ENL. Entretanto a taxa de RR foi significativamente maior entre pacientes mostrando IB < 3, enquanto que o ENH predominou entre os pacientes com IB > 3.

Abstract Background Caused by Mycobacterium leprae (ML), leprosy presents a strong immune-inflammatory component, whose status dictates both the clinical form of the disease and the occurrence of reactional episodes. Evidence has shown that, during the immune-inflammatory response to infection, the growth hormone/insulin-like growth factor-I (GH/IGF-I) plays a prominent regulatory role. However, in leprosy, little, if anything, is known about the interaction between the immune and neuroendocrine systems. Methods In the present retrospective study, we measured the serum levels of IGF-I and IGBP-3, its major binding protein. These measurements were taken at diagnosis in nonreactional borderline tuberculoid (NR BT), borderline lepromatous (NR BL), and lepromatous (NR LL) leprosy patients in addition to healthy controls (HC). LL and BL patients who developed reaction during the course of the disease were also included in the study. The serum levels of IGF-I, IGFBP-3 and tumor necrosis factor-alpha (TNF-α) were evaluated at diagnosis and during development of reversal (RR) or erythema nodosum leprosum (ENL) reaction by the solid phase, enzyme-labeled, chemiluminescent-immunometric method. Results The circulating IGF-I/IGFBP-3 levels showed significant differences according to disease status and occurrence of reactional episodes. At the time of leprosy diagnosis, significantly lower levels of circulating IGF-I/IGFBP-3 were found in NR BL and NR LL patients in contrast to NR BT patients and HCs. However, after treatment, serum IGF-I levels in BL/LL patients returned to normal. Notably, the levels of circulating IGF-I at diagnosis were low in 75% of patients who did not undergo ENL during treatment (NR LL patients) in opposition to the normal levels observed in those who suffered ENL during treatment (R LL patients). Nonetheless, during ENL episodes, the levels observed in RLL sera tended to decrease, attaining similar levels to those found in NR LL patients. Interestingly, IGF-I behaved contrary to what was observed during RR episodes in R BL patients. Conclusions Our data revealed important alterations in the IGF system in relation to the status of the host immune-inflammatory response to ML while at the same time pointing to the circulating IGF-I/IGFBP-3 levels as possible predictive biomarkers for ENL in LL patients at diagnosis.

Abstract INTRODUCTION: The occurrence of leprosy reactions, a common event during treatment, may be mostly related to the action of multidrug therapy on Mycobacterium leprae. The clinical and laboratory monitoring of patients with reactions is important, since collecting data that assists in predicting the risk of reactions may help to prevent disability. METHODS: This was a sectional study, in order to correlate clinical and laboratory diagnosis with the number of reactions during treatment. Spearman's correlation was used to verify the degree of association between the assessed variables. RESULTS: This study was conducted with 211 patients with leprosy reactions during treatment of M. leprae. The borderline tuberculoid group was the most prevalent clinical form (74/211; 35.1%) and the type one reaction showed the highest frequency (136/211; 64.5%). It was observed that 73.5% (155/211) of reactions occurred within 3 months of the initiation of multidrug therapy. The diagnostic values, including the bacterial indices (BIs) of dermal smears (r = 0.21, p < 0.05) and skin biopsies (r = 0.20; p < 0.05), showed a positive correlation with the number of reactions during treatment. CONCLUSIONS: This research showed a positive correlation between bacillary load markers and the number of leprosy reactions. This study provided scientific support to future research aiming to elucidate the influence of antigenic load on the number of leprosy reactions during treatment.