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Background Leprosy neuropathy is the most common peripheral neuropathy of infectious etiology worldwide; it is characterized as asymmetric and focal multiple mononeuropathy. Semmes-Weinstein monofilament (SWM) test is a simple method to assess sensory nerve function. Methods and findings In this prospective cohort study, a dermatologist carried out hands and feet tactile sensation test with SWM in 107 multibacillary leprosy patients at diagnosis and in 76 patients at the end of treatment from 2016 to 2019. At diagnosis, 81/107 (75.7%) patients had some degree of functional disability, and 46 (43%) of them had altered SWM-test in the hands and 94 (87.9%) of them in the feet. After one year of multibacillary multidrug therapy, the disability decreasing to 44/76 patients (57.9%) and decreasing of the percentual of patients with altered SWM-test to 18% for the hands, and to 28.7% for the feet. At the end of treatment, the number of SMW-test points presented improvement in the hands of 22 (28.9%) patients, and in the feet of 47 (61.8%). In the hands, by SWM-test, only the radial nerve point demonstrated a significant asymmetry, while in the feet, the difference between the sum of altered SWM-test points showed significant asymmetry between both sides, highlighting the tibial nerve for the establishment of asymmetric leprosy neuropathy. In Spearman’s correlation analysis, a positive correlation with statistical significance was observed between the number of hands and feet SWM altered points at diagnosis and the degree of disability at diagnosis (0.69) and at the end of the treatment (0.80). Conclusion The patterns of hands and feet tactile sensation at diagnosis and their consequent modifications with the anti-leprosy drugs define the bacterial etiology of neuropathy, an important tool for the clinical diagnosis and follow up of the disease, highlighting the tibial nerve findings, the most affected nerve among leprosy patients by SWM-test, with significant asymmetry and focality impairments.

The treatment of multibacillary cases of leprosy with multidrug therapy (MDT) comprises 12 doses of a combination of rifampicin, dapsone and clofazimine. Previous studies have described the immunological phenotypic pattern in skin lesions in multibacillary patients. Here, we evaluated the effect of MDT on skin cell phenotype and on the Mycobacterium leprae-specific immune response. An analysis of skin cell phenotype demonstrated a significant decrease in MRS1 (SR-A), CXCL10 (IP-10) and IFNG (IFN-γ) gene and protein expression after MDT release. Patients were randomized according to whether they experienced a reduction in bacillary load after MDT. A reduction in CXCL10 (IP-10) in sera was associated with the absence of a reduction in the bacillary load at release. Although IFN-γ production in response to M. leprae was not affected by MDT, CXCL10 (IP-10) levels in response to M. leprae increased in cells from patients who experienced a reduction in bacillary load after treatment. Together, our results suggest that CXCL10 (IP-10) may be a good marker for monitoring treatment efficacy in multibacillary patients.

Background Leprosy is curable with multidrug therapy and treatment in the early stages can prevent disability. However, local nerve damage can lead to injury and consequently recurring and disfiguring ulcers. The aim of this study is to evaluate the treatment of leprosy ulcers using an autologous blood product; leukocyte and platelet-rich fibrin (L-PRF) to promote healing. Methods This is a single-centre study in the Anandaban Hospital, The Leprosy Mission Nepal, Kathmandu, Nepal. Consenting patients (n=130) will be individually randomised in a single-blinded, controlled trial. Participants will be 18 years of age or older, admitted to the hospital with a clean, dry and infection-free chronic foot ulcer between 2 and 20 cm2 in size. If the ulcer is infected, it will be treated before enrolment into the study. The intervention involves the application of leukocyte and platelet-rich fibrin (L-PRF) matrix on the ulcer beds during twice-weekly dressing changes. Controls receive usual care in the form of saline dressings only during their twice-weekly dressing changes. Primary outcomes are the rate of healing assessed using standardised photographs by observers blind to allocated treatment, and time to complete re-epithelialization. Follow-up is at 6 months from randomisation. Discussion This research will provide valuable information on the clinical and cost-effectiveness of L-PRF in the treatment of leprosy ulcers. An additional benefit is the evaluation of the effects of treatment on quality of life for people living with leprosy ulcers. The results will improve our understanding of the scalability of this treatment across low-income countries for ulcer healing in leprosy and potentially other conditions such as diabetic ulcers. Trial registration ISRCTN14933421. Registered on 16 June 2020

BACKGROUND Leprosy relapse/recurrence is a serious concern particularly in a leprosy-endemic nation such as India. It is believed that bacilli persisting even after multidrug therapy can cause relapse; recently, however, drug resistance as a cause for recurrences and chronic erythema nodosum leprosum (ENL) has been speculated. AIM To study drug-resistance patterns in cases of leprosy relapse and chronic/recurrent (c/r)ENL. METHODS This cross-sectional study conducted over a period of 1 year included patients diagnosed as having leprosy relapse and those with c/rENL. Skin biopsy specimens were examined by conventional PCR for resistance testing for rifampicin, dapsone and ofloxacin, respectively targeting the rpoB, folP and gyrA genes of Mycobacterium leprae. RESULTS In total, 61 patients (25 smear-negative) were included in the study. Of these, 37 were diagnosed as having leprosy relapse and 24 as having c/rENL. Drug resistance to at least one drug was identified in 10 cases (16.4%). Rates of drug resistance were 5.4% (2 of 37) for dapsone, 10.8% (4 of 37) for rifampicin and 2.7% (1 of 37) for ofloxacin among cases of relapse, whereas it was 12.5% (3 of 24) and 8.3% (2 of 24) for dapsone and rifampicin respectively among those with c/rENL. Multidrug resistance was seen in 3.3% patients (2 of 61). CONCLUSION Drug-resistance rate among those with c/rENL was almost equalled that of relapse. Smear-negative leprosy relapse cases also had resistance to bactericidal drugs. These findings call for modifications in criteria for testing under leprosy drug-resistance surveillance and all cases of relapse and those with recalcitrant c/rENL should be tested.

INTRODUCTION One of the biggest drug disasters in history has not prevented thalidomide from being used to treat various clinical conditions. Currently, Brazil has a worrying scenario: high consumption of the drug and, cases of pregnant women using thalidomide, even after adopting restrictive legislation. AREAS COVERED This review of the literature and legislation sought to comparatively analyze the monitoring of thalidomide use in Brazil and other countries that use this drug. Finally, we discuss the differences between the countries. EXPERT OPINION This analysis allows us to think beyond the safe use of thalidomide, but the safety provided by any type of monitoring system. It seems that out-patients that use unsafe drugs are exposed to some degree of risk. To improve safety, more extensive improvements are needed than monitoring systems related to the use of thalidomide. Its safe use depends on a drastic reduction in the incidence of leprosy and Erythema Nodosum Leprosum in the world; investment in research and development of safe and effective therapeutic alternatives to thalidomide; improvement of health systems and their health surveillance systems, particularly in primary health care; awareness of health professionals and patients for greater responsibility in the use of medicines, especially thalidomide.

Background Vasoplegic syndrome (VPS) is defined as systemic hypotension due to profound vasodilatation and loss of systemic vascular resistance (SVR), despite normal or increased cardiac index, and characterized by inadequate response to standard doses of vasopressors, and increased morbidity and mortality. It occurs in 9%-44% of cardiac surgery patients after cardiopulmonary bypass (CPB). The underlying pathophysiology following CPB consists of resistance to vasopressors (inactivation of Ca2+ voltage gated channels) on the one hand and excessive activation of vasodilators (SIRS, iNOS, and low AVP) on the other. Use of angiotensin-converting enzyme inhibitor (ACE-I), calcium channel blockers, amiodarone, heparin, low cardiac reserve (EF 60-70 mmHg) are not achieved with nor-epinephrine and/or vasopressin. Aims The aims of this systematic review are to collect all the clinically relevant data to describe the VPS, its potential risk factors, pathophysiology after CPB, and to assess the efficacy, safety, and outcome of the therapeutic management with catecholamine and non-catecholamine vasopressors employed for refractory vasoplegia after cardiac surgery. Also, to elucidate the current and practical approach for management of VPS after cardiac surgery. Material and methods "PubMed," "Google," and "Medline" weresearched, and over 150 recent relevant articles including RCTs, clinical studies, meta-analysis, reviews, case reports, case series and Cochrane data were analyzed for this systematic review. The filter was applied specificallyusing key words like VPS after cardiac surgery, perioperative VPS following CPB, morbidity, and mortality in VPS after cardiac surgery, vasopressors for VPS that improve outcomes, VPS after valve surgery, VPS after CABG surgery, VPS following complex congenital cardiac anomalies corrective surgery, rescue therapy for VPS, adjuvant therapy for VPS, definition of VPS, outcome in VPS after cardiac surgery, etiopathology of VPS following CPB. This review did not require any ethical approval or consent from the patients. Results Despite the recent advances in therapy, the mortality remains as high as 30%-50%. NE has been recommended the most frequent used vasopressor for VPS. It restores and maintain the MAP and provides the outcome benefits. Vasopressin rescue therapy is an alternative approach, if catecholamines and fluid infusions fail to improve hemodynamics. It effectively increases vascular tone and lowers CO, and significantly decreases the 30 days mortality. Hence, suggested a first-line vasopressor agent in postcardiac surgery VPS. Terlipressin (1.3μg/kg/h), a longer acting and more specific vasoconstrictor prevents the development of VPS after CPB in patients treated with ACE-I. MB significantly reduces morbidity and mortality of VPS. The Preoperative MB (1%, 2mg/kg/30min, 1h before surgery) administration in high risk (on ACE-I) patients for VPS undergoing CABG surgery, provides 100% protection against VPS, and early of MB significantly reduces operative mortality, and recommended as a rescue therapy for VPS. Hydroxocobalamin (5 g) has been recommended as a rescue agent in VPS refractory to multiple vasopressors. A combination of ascorbic acid (6 g), hydrocortisone (200 mg/day), and thiamine (400 mg/day) as an adjuvant therapy significantly reduces the vasopressors requirement, and provides mortality and morbidity benefits. Conclusion Currently, the VPS is frequently encountered (9%-40%) in cardiac surgical patients with predisposing patient-specific risk factors and combined with inflammatory response to CPB. Multidrug therapy (NE, MB, AVP, ATII, terlipressin, hydroxocobalamin) targeting multiple receptor systems is recommended in refractory VPS. A combination of high dosage of ascorbic acid, hydrocortisone and thiamine has been used successfully as adjunctive therapyto restore the MAP. We also advocate for the early use of multiagent vasopressors therapy and catecholamine sparing adjunctive agents to restore the systemic perfusion pressure with a goal of preventing the progressive refractory VPS.

Leprosy may present kidney and endothelial abnormalities, being a risk factor for complications. However, the involvement of renal and vascular endothelia has been poorly investigated. We aimed to investigate if the levels of systemic endothelial biomarkers are associated with kidney abnormalities and the clinical forms of leprosy. This is a cross-sectional study with leprosy patients enrolled in January 2017 to December 2018, before the initiation of the multidrug therapy. Leprosy-associated clinical and epidemiological data were collected. Two groups were investigated: Paucibacillary (PB) and Multibacillary (MB) infections, for the comparisons. Serum and urine samples were obtained for laboratory analysis. In serum samples, were evaluated the endothelial biomarkers VCAM-1 and ICAM-1. In total, 101 leprosy patients were included, the mean age was 48±١٥ years and 71 (70%) were male. The multibacillary form occurred in 81 cases (80%), among which 22 had the Virchowian form. Serum creatinine was more elevated in the MB group than in PB patients. In addition, VCAM-1 was elevated in the MB group and was correlated with the bacteriological index (rho = 0.372, p 15 mg/g of creatinine, VCAM-1 showed a significant correlation with increased albuminuria and improved the correlation with the number of skin lesions (rho= 0.563, p=0.010). In conclusion, higher systemic VCAM-1 levels were associated with the multibacillary clinical form of leprosy and with increased albuminuria. Prospective studies are necessary to establish a cause-effect and evaluate the preventive role of these biomarkers to improve the clinical care.

Background: Leprosy (Hansen’s disease) is a neglected tropical disease affecting millions of people globally. The combined formulations of dapsone, rifampicin and clofazimine (multidrug therapy, MDT) is only supportive in the early stage of detection, while “reemergence” is a significant problem. Thus, there is still a need to develop newer antileprosy molecules either of natural or semi-synthetic origin. Objective: The review intends to present the latest developments in the disease prevalence, available therapeutic interventions and the possibility of identifying new molecules from phytoextracts. Methods: Literature on the use of plant extracts and their active components to treat leprosy was searched. Selected phytoconstituents were subjected to molecular docking study on both wild and mutant types of the Mycobacterium leprae. Since the M. leprae dihydropteroate synthase (DHPS) is not available in the protein data bank (PDB), it was modelled by the homology model method and validated with the Ramachandran plot along with other bioinformatics approaches. Two mutations were introduced at codons 53 (Thr to Ile) and 55 (Pro to Leu) for docking against twenty-five selected phytoconstituents reported from eight plants that recorded effective anti-leprosy activity. The chemical structure of phytochemicals and the standard dapsone structure were retrieved from the PubChem database and prepared accordingly for docking study with the virtual-screening platform of PyRx-AutoDock 4.1. Results: Based on the docking score (kcal/mol), most of the phytochemicals exhibited a higher docking score than dapsone. Asiaticoside, an active saponin (-11.3, -11.2 and -11.2 kcal/mol), was proved to be the lead phytochemical against both wild and mutant types DHPS. Some other useful phytoconstituents include echinocystic acid (-9.6, -9.5 and -9.5 kcal/mol), neobavaisoflavone (-9.2, -9.0 and -9.0 kcal/mol), boswellic acid (-8.90, -8.90 and -8.90 kcal/mol), asiatic acid (-8.9, -8.8 and -8.9 kcal/mol), corylifol A (-8.8, 8.0, and -8.0), etc. Overall, the computational predictions support the previously reported active phytoextracts of Centella asiatica (L.) Urban, Albizia amara (Roxb.) Boivin, Boswellia serrata Roxb. and Psoralea corylifolia L. to be effective against leprosy. Conclusion: A very small percentage of well-known plants have been evaluated scientifically for antileprosy activity. Further in vivo experiments are essential to confirm anti-leprosy properties of such useful phytochemicals.

Patient: Female, 22-year-old Final Diagnosis: Lepromatous leprosy co-infected with melioidosis • complicated by dapsone-induced methaemoglobinaemia and type 2 lepra reaction Symptoms: Cyanosis • fever • jaundice • pallor • skin rash Medication: — Clinical Procedure: — Specialty: Dermatology • Hematology • Infectious Diseases • General and Internal Medicine • Microbiology and Virology Objective: Unusual clinical course Background: Leprosy is an infection caused by Mycobacterium leprae. An extensive literature search did not reveal many reports of melioidosis in association with leprosy. Case Report: A 22-year-old woman, who was diagnosed with multibacillary leprosy, developed dapsone-induced methemoglobinemia and hemolytic anemia, complicated by melioidosis. Methemoglobinemia was treated with methylene blue and vitamin C. Two weeks of ceftazidime was initiated to treat melioidosis, and the patient was discharged on amoxicillin/clavulanic acid and doxycycline as melioidosis eradication therapy. However, she developed drug-induced hypersensitivity. Trimethoprim/sulfamethoxazole, as an alternative treatment for melioidosis eradication, was commenced and was successfully completed for 12 weeks. During the fifth month of multidrug therapy, the patient developed type II lepra reaction with erythema nodosum leprosum reaction, which was treated with prednisolone. Leprosy treatment continued with clofazimine and ofloxacin, and complete resolution of skin lesions occurred after 12 months of therapy. Conclusions: Our case highlighted the challenges posed in managing a patient with multibacillary leprosy with multiple complications. Clinicians should be aware that dapsone-induced methemoglobinemia and hemolysis might complicate the treatment of leprosy. Our case also highlighted the safety and efficacy of combining ofloxacin and clofazimine as a leprosy treatment regimen in addition to gradual steroid dose titration in the presence of type II lepra reaction.

Background Leprosy is an infectious disease caused by Mycobacterium leprae. As incidence begins to decline, the characteristics of new cases shifts away from those observed in highly endemic areas, revealing potentially important insights into possible ongoing sources of transmission. We aimed to investigate whether transmission is driven mainly by undiagnosed and untreated new leprosy cases in the community, or by incompletely treated or relapsing cases. Methodology/Principal findings A literature search of major electronic databases was conducted in January, 2020 with 134 articles retained out of a total 4318 records identified (PROSPERO ID: CRD42020178923). We presented quantitative data from leprosy case records with supporting evidence describing the decline in incidence across several contexts. BCG vaccination, active case finding, adherence to multidrug therapy and continued surveillance following treatment were the main strategies shared by countries who achieved a substantial reduction in incidence. From 3950 leprosy case records collected across 22 low endemic countries, 48.3% were suspected to be imported, originating from transmission outside of the country. Most cases were multibacillary (64.4%) and regularly confirmed through skin biopsy, with 122 cases of suspected relapse from previous leprosy treatment. Family history was reported in 18.7% of cases, while other suspected sources included travel to high endemic areas and direct contact with armadillos. None of the countries included in the analysis reported a distinct increase in leprosy incidence in recent years. Conclusions/Significance Together with socioeconomic improvement over time, several successful leprosy control programmes have been implemented in recent decades that led to a substantial decline in incidence. Most cases described in these contexts were multibacillary and numerous cases of suspected relapse were reported. Despite these observations, there was no indication that these cases led to a rise in new secondary cases, suggesting that they do not represent a large ongoing source of human-to-human transmission., Author summary Although leprosy remains a public health problem in many parts of the world, several countries have successfully controlled the Mycobacterium leprae transmission over recent decades and the case characteristics have been shown to change during periods of declining incidence. However, the potential for certain groups of individuals, such as untreated or relapsed leprosy patients with more severe forms of the disease, to act as sources of ongoing transmission remains unclear. In this systematic review, we aimed to evaluate leprosy case characteristics in low endemic settings, to identify possible sources of transmission and to describe the different control measures implemented. Together with socioeconomic improvement over time, the main strategies shared by many of the countries who achieved a substantial reduction in incidence over recent decades included BCG vaccination, active case finding, adherence to MDT and continued surveillance following treatment. By collecting information on cases in these settings, we found that the number of new cases reported remained low with no indication of a rise in new secondary cases, despite a high proportion of multibacillary disease and the presence of persistent cases of suspected relapse. This evidence suggests that such cases do not represent a large ongoing source of human-to-human transmission.

Background and Objectives: Hypertension affects at least 80% of hemodialysis patients. Inappropriate control of blood pressure is mentioned as one of the essential cardiovascular risk factors associated with development of cardiovascular events in dialysis populations. The aim of the cross-sectional, retrospective study was the evaluation of the antihypertensive treatment schedule and control of blood pressure in relation to the guidelines in the group of hemodialysis patients. Additionally, we assessed the level of decrease in blood pressure by each group of hypotensive agents. Materials and Methods: 222 patients hemodialyzed in a single Dialysis Unit in three distinct periods of time—2006, 2011, and 2016—with a diagnosis of hypertension were enrolled in the study. The analysis of the antihypertensive treatment was based on the medical files and it consisted of a comparison of the mean blood pressure results reported during the six consecutive hemodialysis sessions. Results: The mean values of blood pressure before hemodialysis were as follows: 134/77, 130/74, and 140/76 mmHg, after hemodialysis 124/74, 126/73, and 139/77 mmHg in 2006, 2011, and 2016 respectively. The goal of predialysis blood pressure control (&lt, 140/90) was achieved by up to 64.3% of participants in 2006 as compared to 49.4% in 2016. Additionally, the postdialysis goal (&lt, 130/90) reached 57.1% of the study population in 2006 as compared to 27.1% of patients in 2016. The differences in percentage of patients using single, double, triple, and multidrug therapy during observation were not statistically significant. The most often used drugs were ß-blockers, diuretics, and calcium channel blockers in all points of the study. Blockades of the renin–angiotensin–aldosterone system in 2006 and calcium channel blockers in 2011 and 2016 were the drugs with highest impact on lowering blood pressure. Conclusions: The goal of predialysis or postdialysis blood pressure control was achieved in a lower percentage of patients during the period of the study. Blockade of renin–angiotensin–aldosterone system and calcium channel blockers decrease the blood pressure significantly. It is necessary to achieve better control of blood pressure in prevention of cardiovascular incidents.

The World Health Organization has raised concerns about the increasing number of Hansen disease (HD) relapses worldwide, especially in Brazil, India, and Indonesia that report the highest number of recurrent cases. Relapses are an indicator of MDT effectiveness and can reflect Mycobacterium leprae persistence or re-infection. Relapse is also a potential marker for the development or progression of disability. In this research, we studied a large cohort of persons affected by HD treated with full fixed-dose multibacillary (MB) multidrug therapy (MDT) followed for up to 20 years and observed that relapses are a rare event. We estimated the incidence density of relapse in a cohort of patients classified to receive MB regime (bacillary index (BI) > 0), diagnosed between September 1997 and June 2017, and treated with twelve-dose MB-MDT at a HD reference center in Rio de Janeiro, Brazil. We obtained the data from the data management system of the clinic routine service. We linked the selected cases to the dataset of relapses of the national HD data to confirm possible relapse cases diagnosed elsewhere. We diagnosed ten cases of relapse in a cohort of 713 patients followed-up for a mean of 12.1 years. This resulted in an incidence rate of 1.16 relapse cases per 1000 person-year (95% CI = 0.5915–2.076). The accumulated risk was 0.025 in 20 years. The very low risk observed in this cohort of twelve-dose-treated MB patients reinforces the success of the current MDT scheme., Author summary People affected by Hansen disease that have many skin patches or lumps receive twelve-dose multibacillary multidrug therapy. After the fixed-dose regime, they are released from treatment and are considered cured. However, some of these people may have a recurrence of skin lesions or peripheral nerve problems after several years. Clinicians, scientists, and the World Health Organization are concerned about this problem, known as relapse, which seems to be increasing in countries where Hansen disease is common, especially in Brazil, India, and Indonesia. It is important to demonstrate regular proof that the therapy remains effective to treat people affected by Hansen disease. In this study, we showed that the recurrence of signs and symptoms of Hansen disease after the twelve-dose multibacillary treatment is rare. These findings are good evidence of the success of the current multibacillary scheme.

To clinically evaluate the oro-facial manifestations in lepromatous leprosy patients undergoing multidrug therapy in Central India. Two hundred patients from 2 leprosy treatment centers in Central India who satisfied the diagnostic criteria set by the WHO (2006–2010) committee on leprosy were included in the study. To avoid bias, only patients who started the multi-drug treatment regimen less than 1 year ago were included. All the patients were examined for the presence of oral and facial manifestations. To confirm that the oro-facial manifestations were not due to HIV co-infection, serological diagnostic tests including ELISA, Immunocomb, and Tri-dot were performed. Majority of the patients (n = 189) exhibited oral (n = 145) and/or facial (n = 147) manifestations. The most common oral lesions were found to be fissuring and depapillation of the tongue followed by fibrosis and loss of uvula. Among the facial manifestations, facial skin lesions and loss of eyebrows were most prevalent followed by sagging of facial skin and facies leonine. The facial manifestations of leprosy are quite common, readily recognizable, and relatively specific to the disease. Thus, the presence of facial manifestations, especially with co-existing oral lesions must prompt the clinician to mandate further investigations to confirm the diagnosis. As evidenced by the present study, facial manifestations and oral lesions are an integral part of leprosy. In addition to being a diagnostic parameter, facial manifestations and oral lesions could potentially be used to monitor the disease progression and treatment outcome.

Patients with lepromatous leprosy that have received treatment for many years usually get follow up biopsies for persistent skin lesions or positive bacilloscopy even if the values are lower than in the initial bacilloscopy. We report the case of a 48-year old woman with long-standing lepromatous leprosy of 15 years of evolution, with a bacterial index of 4 in the direct smear and the initial skin biopsy. The patient was treated with multidrug therapy for 32 months although the treatment recommended by the World Health Organization (WHO) is only for 12 months. A skin biopsy was taken to determine if there was an active disease. We observed a diffuse dermal inflammation with numerous foreign body giant cells and vacuolated macrophages (Virchow´s cells). These cells contained granular acid-fast material that was also positive with immunohistochemistry for BCG. There were fragmented bacilli and the BI was 2. These cells were also strongly positive for CD68. The biopsy was interpreted as a residual form of lepromatous leprosy that did not require further multidrug therapy. We have observed similar histological profiles in several cases. The lack of clinical data makes it a histological challenge. The accumulation of lipids in these giant cells is due to bacillary destruction and fusion of vacuolated macrophages. We discuss here the role of bacillary and host lipids in the pathogenesis of lepromatous leprosy. We concluded that there was no need to extend the 12-month multidrug therapy recommended by WHO.Los pacientes con lepra lepromatosa (LL) que han recibido tratamiento durante años, usualmente tienen seguimiento con biopsias de piel para lesiones persistentes o con baciloscopia positiva, con valores menores a los iniciales. Presentamos una mujer de 48 años con LL de 15 años de evolución, con índice bacilar (IB) 4 en el extendido directo y en la biopsia, que recibió terapia multidroga durante 32 meses, aunque el tratamiento recomendado por la Organización mundial de la salud (OMS) es de 12 meses. Se tomó una biopsia de piel para determinar si la enfermedad estaba activa. Se observó inflamación dérmica difusa con numerosas células gigantes tipo cuerpo extraño y macrófagos vacuolados (células de Virchow). Estas células, CD68 positivas, contenían material granular ácido-alcohol resistente, positivo con inmunohistoquímica para BCG. Se encontraron bacilos fragmentados y el IB fue de 2. Se interpretó como una forma residual de LL y que la paciente no requería MDT adicional. Este perfil histológico lo hemos observado en casos similares. Sin datos clínicos estas biopsias son un reto diagnóstico. La acumulación de lípidos en estas células gigantes se debe a la destrucción bacilar y a la fusión de macrófagos vacuolados. Revisamos el papel de los lípidos del bacilo y del huésped en la patogénesis de la LL. En estos casos no es necesario extender los 12 meses de MDT recomendados por la OMS. En el seguimiento de los pacientes se recomienda contar con los hallazgos clínicos, la baciloscopia, la biopsia anual de piel y los títulos IgM anti-glicolípido fenólico.

Today, the emergence of the phenomenon of drug or multidrug-resistance for community-associated diseases represents a major concern in the world. In these contexts, the chronic infectious disease, leprosy, grounded by a slow-growing bacterium called Mycobacterium leprae or Mycobacterium lepromatosis is a leadingcause of severe disfiguring skin sores and nerve damage in the arms, legs, and skin areas around the body. Even, over 200,000 new leprosy cases are being accounted every year along with the relapsed leprosy cases. Nonetheless, this has been considered a curable disease with a higher dose of multidrug therapy (MDT) for a long period of time. The prolonged action of a high dose of combination drugs administration may cause an adverse reaction that can significantly affect patient compliance, particularly the outbreak of multidrug-resistance in the infected person. To overcome these shortfalls or prevent the resistance-associated problems, researchers are diligently involved in the structural modifications of the clinically used anti-leprosy drugs or the allied compounds for the structure-antimycobacterial activity relationship study. This review article described the detailed synthesis and biological assays of different anti-leprosy compounds reported by several research groups.

Background Leprosy has been treated with multidrug therapy, which has been distributed for free across the globe and regarded as highly efficient. However, the impossibility of growing Mycobacterium leprae in axenic media has historically impaired assessments of M. leprae resistance, a parameter only recently detectable through molecular methods. Methods A systematic, population-based search for M. leprae resistance in suspected leprosy relapse cases and contacts was performed in Prata Village, an isolated, hyperendemic, former leprosy colony located in the Brazilian Amazon. Results led to an extended active search involving the entire Prata population. Confirmed leprosy cases were investigated for bacterial resistance using a combination of in vivo testing and direct sequencing of resistance genes folP1, rpoB, and gyrA. A molecular epidemiology analysis was performed using data from 17 variable number tandem repeats (VNTR). Results Mycobacterium leprae was obtained from biopsies of 37 leprosy cases (18 relapses and 19 new cases): 16 (43.24%) displayed drug-resistance variants. Multidrug resistance to rifampicin and dapsone was observed in 8 relapses and 4 new cases. Single resistance to rifampicin was detected in 1 new case. Resistance to dapsone was present in 2 relapses and 1 new case. Combined molecular resistance and VNTR data revealed evidence of intra-familial primary transmission of resistant M. leprae. Conclusions A comprehensive, population-based systematic approach to investigate M. leprae resistance in a unique population revealed an alarming scenario of the emergence and transmission of resistant strains. These findings may be used for the development of new strategies for surveillance of drug resistance in other populations., Our study, in a unique population, revealed the highest proportion of resistant Mycobacterium leprae isolates to single and multiple drugs ever reported and demonstrated intra-familial transmission of resistant M. leprae: immediate, strong attention to drug resistance in leprosy is suggested.

Lepromatous leprosy represents a cutaneous infection by the bacterium Mycobacterium leprae. Once considered a common, fatal disease, leprosy has become increasingly rare with modern, inexpensive antibiotics. Most healthcare workers will never encounter a case of leprosy due to the low prevalence of the disease. However, military physicians, through deployments and contact with foreign-born servicemembers, are one of the first lines of defense against this disease. With an unknown method of transmission and an insidiously slow replication, it can take years for the disease to fully manifest. There are multiple cutaneous manifestations associated with the infection that can mimic other infectious etiologies, stalling appropriate diagnosis and treatment. To determine which treatment course is recommended requires evaluation of disease dissemination and the level of host immune response. As the incidence of reported leprosy cases continues to decline, disease education on diagnosis and treatment is imperative to enhance early detection and intervention. Understanding the populations at risk for leprosy and its insidious presentation will aid the practitioner in minimizing disease burden for both U.S. servicemembers and our foreign partners.

Leishmaniasis is a vector-borne neglected tropical disease which manifests as visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and mucocutaneous leishmaniasis (MCL). The current drugs are toxic, duration of treatment is long, there is regional variation in efficacy, and emergence of resistance is common.This manuscript is based on literature derived from PubMed and reviews the current and emerging medications for the treatment of leishmaniasis. A single dose of liposomal amphotericin B (L-AmB) and multidrug therapy are the best options for VL in the Indian subcontinent (ISC), while a combination of pentavalent antimonials and paromomycin remains the treatment of choice for VL in Africa where efficacious and safe regimens are needed for HIV-VL coinfection. L-AmB at a total dose of 18-21 mg/kg is the recommended regimen for VL in the Mediterranean region, South America and for HIV-VL coinfection. Treatment of CL varies from observation, local or systemic therapy depending on severity of lesions, etiological species and its potential to develop into mucosal leishmaniasis.The monitoring of single-dose L-AmB and combination therapy in the ISC is essential. Effective short-course combination therapy is needed for the treatment of post-kala-azar dermal leishmaniasis and HIV-VL. Better evidence for treatment is still needed along with safer and shorter treatment options for CL and MCL.

Type 1 reactions, characterized by increasing lesion erythema, pain, and nerve damage, commonly complicate leprosy. Dapsone hypersensitivity syndrome (DHS) is a potentially fatal reaction occurring 6-8 weeks into dapsone therapy. We present a case of intercurrent Type 1 reaction and DHS in a multibacillary leprosy patient recently started on multidrug treatment.

In recent years, advances in medical diagnosis and treatment have greatly attracted our attention, whereas some rare diseases, such as leprosy, have not found a place in the medical education curriculum; their existence may even be forgotten. Although the prevalence and incidence rates for leprosy have been significantly reduced as a result of the control strategies of the World Health Organization, new cases still appear. A total of 214,783 new cases were reported from 143 countries during 2016, corresponding to the global new-case detection rate of 2.9 per 100,000 population. Leprosy proves to be a very interesting model due to its immunologic properties. It joins with syphilis, mycosis fungoides, cutaneous tuberculosis, and sarcoidosis as one of the great imitators. The diagnosis of leprosy can be simple and practical, but considering the diagnosis of leprosy in the differential diagnosis is the first requisite again.

Background Leprosy or Hansen's disease is a chronic infection caused by Mycobacterium leprae (M. leprae) or Mycobacterium lepromatosis (M. lepromatosis). In Europe, most of the leprosy cases are imported. However, occasionally a case is diagnosed in one of the old endemic foci. Leprosy is often not suspected because it is no longer emphasized in the medical curricula. Attention shifted from leprosy to tuberculosis and human immunodeficiency virus infections in the late 20th century, whereby the WHO leprosy programme was toned down in the conviction that leprosy was all but eliminated. The result of unawareness is a harmful doctor's delay. Material and methods This paper focusses on clinical diagnosis, complications and treatment based on literature and experience. Results It mentions the value of laboratory tests in classification, follow-up and detection of relapses. It discusses the etiopathology. Conclusion This is a position statement.

The Mycobacterium tuberculosis mec+-cysO-cysM gene cluster was shown to be part of a novel cysteine biosynthesis pathway in vitro, but little is known about its essentiality or role in M. tuberculosis physiology. In this study, we generate a knock out of the mec+-cysO-cysM gene cluster in M. tuberculosis and show that the gene cluster is not essential under a variety of conditions, suggesting redundancy in pathways for cysteine biosynthesis in M. tuberculosis. The cysteine biosynthesis gene cluster is essential for resistance for clofazimine, a peroxide-producing anti-leprosy drug. Therefore, although under most conditions the pathway is not essential, it likely has an important role in defense against oxidative stress in M. tuberculosis.

A subset of multibacillary (MB) leprosy patients manifest with clinical "nonresponsiveness" to the fixed-duration, World Health Organization multidrug therapy MB regimen (WHO-MDT-MBR). The aim of this retrospective study was to assess the effectiveness and safety of alternate anti-leprosy therapy (ALT) in such patients. This is an analysis of patients' records, registered in the leprosy clinic of our institute over a period of 6 years (2010-2015). The criteria for inadequate response/nonresponsiveness to treatment were as follows: 1) persistent/new lesions after completing ≥ 12 months of WHO-MDT-MBR (isolated reactions were ruled out histopathologically) and 2) persistent positive/increasing value of the morphological index (MI) and a 2 log increase in the bacteriological index (BI) after ≥ 12 months of WHO-MDT-MBR. Such cases were treated with ALT consisting of minocycline, clofazimine, and ofloxacin (24 months). Of 556 patients registered during the study period, 40.3% (224) were slit-skin smear (SSS) positive and 59.7% (332) were SSS negative. Of all, 35 patients (6.3%) satisfied the criteria for clinical nonresponsiveness. Of 224 SSS-positive patients, these 35 patients amounted to 15.6%. The mean BI and MI of these patients after completion of ≥ 12 months of WHO-MDT-MBR were 5.3 ± 0.6 and 14 ± 6.8%, respectively. After 6 months of treatment with ALT, MI became negative (0) in all these patients. After completion of ALT, the mean BI and MI became 1.7 ± 0.7 and 0%, respectively (P < 0.0001). There were 16 patients with corticosteroid-dependent recurrent/chronic erythema nodosum leprosum, who had excellent response with significant reduction in the number of reactional episodes and mean dose of prednisolone required (P < 0.0001). No serious adverse effects were noted. We conclude that ALT is safe and effective in the management of MB leprosy patients who are nonresponsive to 12 months of WHO-MDT-MBR.

Introduction: Antimicrobial resistance in leprosy is an emerging problem, and the quantitative impact of low bacilloscopic indexes (BIs) on the sensitivity of molecular tests is unknown. We aimed to evaluate the sensitivity of gene sequencing for the detection of mutations related to antimicrobial resistance in Mycobacterium leprae in patients with low BIs using an analytical model. Methods: Patients with leprosy were included and divided into two groups depending on their BIs (≥ 2+ and < 2+). The sensitivities of the two DNA extraction methods were compared after amplifying and sequencing the repetitive element (RLEP), folP1, rpoB and gyrA in M. leprae. Results: We included 56 patients with leprosy: 35 had BIs less than 2+ (22 had negative slit-skin smear [SSS] results) and 21 patients had BIs greater than or equal to 2+. The sensitivity of the amplification of the RLEP target and the gene sequencing of folP1, rpoB and gyrA was 50 to 70% lower in patients with a BI less than 2+ and was significantly reduced in patients with lower BIs for all targets (p < 0.001). One patient had a mutation in the folP1 gene, and 14 patients had mutations in the gyrA gene, but no mutations related to antimicrobial resistance were found. Conclusions: We can conclude that the sensitivity of molecular tests is directly related to the BI, but these tests can still detect up to 20% of the targets in patients with BIs < 2+. New strategies to improve the sensitivity for detecting antimicrobial resistance in leprosy patients and reasonable clinical criteria for follow-up and the introduction of alternative treatments must be developed.

The disease leprosy is caused by Mycobacterium leprae. The disease displays a spectrum of clinical manifestations relating to the stage of the infection and the pathogen-specific immune response. The most frequent M. leprae-specific hypersensitivity reactions are erythema nodosum leprosum (ENL) and type-1 (reversal) reaction (T1R). Omega-3 and omega-6 fatty acid-derived lipid mediators are involved in the regulation of these M. leprae-specific inflammatory and immune responses. Studies on lipid mediators showed their presence during different manifestations of leprosy-before and after multidrug therapy (MDT) and during T1R. This review aims to compare the lipid mediators at different stages of the disease. This review also presents new data on the significance of lipid mediators (cysteinyl leukotrienes and leukotriene B4, prostaglandin E2 and D2, lipoxin A4 and resolvin D1) on ENL.

Background The Leprosy Post-Exposure Prophylaxis (LPEP) program explored the feasibility and impact of contact tracing and the provision of single dose rifampicin (SDR) to eligible contacts of newly diagnosed leprosy patients in Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. As the impact of the programme is difficult to establish in the short term, we apply mathematical modelling to predict its long-term impact on the leprosy incidence. Methodology The individual-based model SIMCOLEP was calibrated and validated to the historic leprosy incidence data in the study areas. For each area, we assessed two scenarios: 1) continuation of existing routine activities as in 2014; and 2) routine activities combined with LPEP starting in 2015. The number of contacts per index patient screened varied from 1 to 36 between areas. Projections were made until 2040. Principal findings In all areas, the LPEP program increased the number of detected cases in the first year(s) of the programme as compared to the routine programme, followed by a faster reduction afterwards with increasing benefit over time. LPEP could accelerate the reduction of the leprosy incidence by up to six years as compared to the routine programme. The impact of LPEP varied by area due to differences in the number of contacts per index patient included and differences in leprosy epidemiology and routine control programme. Conclusions The LPEP program contributes significantly to the reduction of the leprosy incidence and could potentially accelerate the interruption of transmission. It would be advisable to include contact tracing/screening and SDR in routine leprosy programmes., Author summary The Leprosy Post-Exposure Prophylaxis (LPEP) program explored the feasibility and impact of contact tracing and the provision of SDR to eligible contacts of newly diagnosed leprosy patients in states or districts of Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. This study investigated the long-term impact of the LPEP program on the leprosy new case detection rate (NCDR). Our results show that LPEP could reduce the NCDR beyond the impact of the routine leprosy control programme and that many new cases could be prevented. The benefit of LPEP increases gradually over time. LPEP could accelerate the time of reaching predicted NCDR levels of 2040 under routine program by up to six years. Furthermore, we highlighted how the impact varies between countries due to differences in the number of contacts per index patient screened and differences in leprosy epidemiology and national control programme. Generally, including both household contacts and neighbours (> 20 contacts per index patient) would yield the highest impact.

Mycobacteroides abscessus (Mab) is an opportunistic environmental pathogen that can cause chronic pulmonary disease in the setting of structural lung conditions such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. These infections are often incurable and associated with rapid lung function decline. Mab is naturally resistant to most of the antibiotics available today, and current treatment guidelines require at least 1 year of daily multidrug therapy, which is often ineffective and is associated with significant toxicities. β-Lactams are the most widely used class of antibiotics and have a demonstrated record of safety and tolerability. Here, using a panel of recent clinical isolates of Mab, we evaluated the in vitro activities of dual-β-lactam combinations to identify new treatments with the potential to treat infections arising from a wide range of Mab strains. The Mab clinical isolates were heterogeneous, as reflected by the diversity of their genomes and differences in their susceptibilities to various drugs. Cefoxitin and imipenem are currently the only two β-lactams included in the guidelines for treating Mab disease, yet they are not used concurrently in clinical practice. However, this dual-β-lactam combination exhibited synergy against 100% of the isolates examined (n = 21). Equally surprising is the finding that the combination of two carbapenems, doripenem and imipenem, exhibited synergy against the majority of Mab isolates. In the setting of multidrug-resistant Mab disease with few therapeutic options, these combinations may offer viable immediate treatment options with efficacy against the broad spectrum of Mab strains infecting patients today.

Background Leprosy continues to be a public health problem in Brazil. Furthermore, detection rates in elderly people have increased, particularly those of multibacillary (L-Lep) patients, who are responsible for transmitting M. leprae. Part of the decline in physiological function during aging is due to increased oxidative damage and change in T cell subpopulations, which are critical in defense against the disease. It is not still clear how age-related changes like those related to oxidation affect elderly people with leprosy. The aim of this work was to verify whether the elderly leprosy patients have higher ROS production and how it can impact the evolution of leprosy. Methodology/Principal findings 87 leprosy patients, grouped according to age range and clinical form of leprosy, and 25 healthy volunteers were analyzed. Gene expression analysis of antioxidant and oxidative burst enzymes were performed in whole blood using Biomark’s microfluidic-based qPCR. The same genes were evaluated in skin lesion samples by RT-qPCR. The presence of oxidative damage markers (carbonylated proteins and 4-hydroxynonenal) was analyzed by a DNPH colorimetric assay and immunofluorescence. Carbonylated protein content was significantly higher in elderly compared to young patients. One year after multidrug therapy (MDT) discharge and M. leprae clearance, oxidative damage increased in young L-Lep patients but not in elderly ones. Both elderly T and L-Lep patients present higher 4-HNE in cutaneous lesions than the young, mainly surrounding memory CD8+ T cells. Furthermore, young L-Lep demonstrated greater ability to neutralize ROS compared to elderly L-Lep patients, who presented lower gene expression of antioxidant enzymes, mainly glutathione peroxidase. Conclusions/Significance We conclude that elderly patients present exacerbated oxidative damage both in blood and in skin lesions and that age-related changes can be an important factor in leprosy immunopathogenesis. Ultimately, elderly patients could benefit from co-supplementation of antioxidants concomitant to MDT, to avoid worsening of the disease., Author summary Leprosy, which has been reported throughout human history since Biblical times, still presents unclear aspects in regards to its pathogeny, and represents a public health concern, particularly in developing countries, where poor sanitary conditions of socially disfavored groups is a relevant contributing factor in maintaining disease dissemination. Although its signs and symptoms are primarily found in young adults, the increasing number of elderly individuals with leprosy is a recent phenomenon that requires clarification. Considering the specific biochemical profile of the elderly, as well as the influence thereof on their immune response to infection, this work demonstrates that elderly leprosy patients present increased levels of oxidative damage in blood and skin lesions when compared to younger patients. Such findings appear to be correlated with low gene expression of antioxidant enzymes, particularly among multibacillary patients. This work intends to contribute to a better understanding on the progress of leprosy in elderly groups.

Background Worldwide, around 210,000 new cases of leprosy are detected annually. To end leprosy, i.e. zero new leprosy cases, preventive interventions such as contact tracing and post-exposure prophylaxis (PEP) are required. This study aims to estimate the number of people requiring PEP to reduce leprosy new case detection (NCD) at national and global level by 50% and 90%. Methodology/Principal findings The individual-based model SIMCOLEP was fitted to seven leprosy settings defined by NCD and MB proportion. Using data of all 110 countries with known leprosy patients in 2016, we assigned each country to one of these settings. We predicted the impact of administering PEP to about 25 contacts of leprosy patients on the annual NCD for 25 years and estimated the number of contacts requiring PEP per country for each year. The NCD trends show an increase in NCD in the first year (i.e. backlog cases) followed by a significant decrease thereafter. A reduction of 50% and 90% of new cases would be achieved in most countries in 5 and 22 years if 20.6 and 40.2 million people are treated with PEP over that period, respectively. For India, Brazil, and Indonesia together, a total of 32.9 million people requiring PEP to achieve a 90% reduction in 22 years. Conclusion/Significance The leprosy problem is far greater than the 210,000 new cases reported annually. Our model estimates of the number of people requiring PEP to achieve significant reduction of new leprosy cases can be used by policymakers and program managers to develop long-term strategies to end leprosy., Author summary Leprosy is a chronic infectious disease affecting the skin and peripheral nerves. Despite efforts to end leprosy, the number of new leprosy cases remains stable at around 210,000. To interrupt transmission and reduce this number significantly, new strategies such as the provision of (prophylactic) treatment need to be implemented. This should be done by targeting those most at risk of developing leprosy, the contacts of new leprosy patients. Mathematical modeling can be applied to predict the impact of preventive treatment with post-exposure prophylaxis (PEP) on the incidence and the number of contacts requiring PEP at global and national level. In this study, the cumulative number of individuals requiring PEP was estimated at 40.2 million globally to reduce the incidence by 90% in 22 years. This number provides a more realistic reflection of the size of the leprosy problem worldwide. The estimates at national level are highly relevant to all countries where leprosy has been reported as it can support the policymakers and health program makers to design their elimination strategies. It also provides insight into the investment that is required to end leprosy globally and nationally.

Abstract: Leprosy is caused by extremely slow-growing and uncultivated mycobacterial pathogens, namely Mycobacterium leprae and M. lepromatosis. Nearly 95% of the new cases of leprosy recorded globally are found in India, Brazil, and 20 other priority countries (WHO, 2019), of which nearly two-third of the cases are reported in India alone. Currently, leprosy is treated with dapsone, rifampicin, and clofazimine, also known as multi-drug therapy (MDT), as per the recommendations of WHO since 1981. Still, the number of new leprosy cases recorded globally has remained constant in last one-decade, and resistance to multiple drugs has been documented in various parts of the world, even though relapses are rare in patients treated with MDT. Antimicrobial resistance testing against M. leprae or the evaluation of the anti-leprosy activity of new drugs remains a challenge as leprosy bacilli cannot grow in vitro. Besides, developing a new drug against leprosy through conventional drug development process is not economically attractive or viable for pharma companies. Therefore, a promising alternative is the repurposing of existing drugs/approved medications or their derivatives for assessing their anti-leprosy potential. It is an efficient method to identify novel medicinal and therapeutic properties of approved drug molecules. Any combinatorial chemotherapy that combines these repurposed drugs with the existing first-line (MDT) and second-line drugs could improve the bactericidal and synergistic effects against these notorious bacteria and can help in achieving the much-cherished goal of “leprosy-free world”. This review highlights novel opportunities for drug repurposing to combat resistance to current therapeutic approaches.

Background Leprosy is a treatable disease; however, the release from treatment after completion of multidrug therapy (MDT) often does not equal absence of health problems. Consequently, sequelae interfere with the patient’s perception of cure. The objective of this study was to analyze the factors associated with the perception of not being healed among people treated for leprosy in a highly endemic area in Brazil. Method A cross-sectional study of perceived cure of leprosy in the post-release from treatment period was conducted in Cáceres in the state of Mato Grosso, Brazil. The study included a total of 390 leprosy patients treated with MDT and released after completion of treatment from 1 January 2000 to 31 December 2017. The dependent variable was self-reported cure of leprosy; the independent variables included clinical, operational and socioeconomic variables. Results Out of the 390 former leprosy patients, 304 (77.9%) perceived themselves as cured and 86 (22.1%) considered themselves unhealed. Among the latter, 49 (57.0%) reported muscle weakness and joint pains. Individuals with complaints related to leprosy post-release from treatment had a 4.6 times higher chance to self-report as unhealed (OR 4.6; 95% CI 2.5–8.5). Patients with physical disabilities (PD) grade 1 and 2 at the time of the study had a 3.1 (OR 3.1; 95% CI 1.3–7.4) and 8.8 (OR 7.7; 95% CI 3.5–21.9) times higher likelihood to self-identify as unhealed, respectively. Conclusion Among successfully treated leprosy patients, a quarter self-report as unhealed of the disease. The factors associated with the perception of being unhealed are PD and complaints related to leprosy in the post-release from treatment phase.

Venous thromboembolism is a common complication of patients with hematologic malignancies, due both to release of procoagulant factors by tumor cells and to external factors, such us drugs. In multiple myeloma patients, the risk is increased by use of immunomodulants, especially when associated to multidrug therapy, during the induction phase. Prevention of venous thromboembolism in myeloma patients is highly recommended but specific guidelines are still lacking. The most common approach is to stratify the thrombotic risk according to individual, myeloma-related and therapy-related risk factors and to use aspirin for all patients, except those with two or more thrombotic risk factors who should be treated with traditional oral or parenteral anticoagulant. A more controversial approach indicates for prophylaxis either anticoagulant or aspirin, regardless of risk stratification. Recent trials investigate prophylaxis in myeloma patients with direct oral anticoagulants, based on studies showing efficacy and safety of this new class of drugs in the treatment and prophylaxis of thrombosis in patients with any malignancy. The results of these trials are encouraging but they need to be confirmed by larger studies. An international consensus about best prophylaxis to prevent venous thromboembolism in patients with multiple myeloma on treatment is still missing. Therefore, thrombosis in multiple myeloma remains an ongoing issue.

Background Slightly more than half the total number of childhood leprosy cases worldwide are from India. Aim To analyze the clinical and epidemiological trends of childhood leprosy over 20 years in a tertiary care hospital. Methods We retrieved the medical records of all children less than 15 years of age registered in the leprosy clinic between April 1998 and March 2018. We tabulated and analyzed data pertaining to demographic details along with clinical findings such as cutaneous lesions, nerves involved, sensory loss, deformities, reactions, smear status, histopathology and treatment. Results Out of total 1548 leprosy cases registered during the study period, 55 (3.55%) cases of childhood leprosy were diagnosed. Thirty five (63.6%) children were in the age group of 11–15 years and 83.7% were migrants from other states. Thirteen (23.6%) children reported contact with a diagnosed case of leprosy, mainly in close contacts. Fifty three (96.4%) children presented with cutaneous lesions while 2 (3.6%) had pure neural involvement. Borderline tuberculoid leprosy was the most common clinical presentation in 27 (49.1%) followed by borderline lepromatous leprosy in 11 (18%). Thickened peripheral nerve trunks were detected in 42 (76.4%), most commonly the ulnar nerve. Reactional episodes occurred in 12 (21.8%) cases (Type 1 reaction, 10 (18.2%); Type 2 reaction, 2 (3.6%)). Grade 2 disability was detected in 4 (7.3%). Multidrug therapy was started in all patients, multibacillary (MB) regimen in 42 (76.3%) patients and paucibacillary (PB) regimen in 13 (23.7%). Twenty five (45.4%) children defaulted from the treatment. On comparing the data of 2008-18 with that of the previous decade (1998–2007), there was a higher proportion of migrant cases as compared to local cases (3:1–11:1) and MB cases as compared to PB cases (2:1–6:1). The proportion of treatment defaulters declined from 60% to 36%. Limitations Relapse rate could not be calculated due to inadequate follow-up period. As it is a hospital-based retrospective study with no active surveys, these findings may not reflect trends in the community. Conclusion Childhood leprosy continues to be a significant problem. There is a clear need to strengthen early detection, treatment and regular follow-up of these cases in both high and low endemic settings.

Leprous neuropathy is treatable but still a source of disability worldwide. Multidrug therapy (MDT) and oral steroids are the main stay of treatment. Ulnar nerve, at the elbow, is commonly involved. Nerve decompression may be required in selected cases by an epineurotomy (internal neurolysis). The preferred surface of ulnar nerve for performing this procedure to minimize iatrogenic vascular compromise is a matter of debate. We describe the epineural vessel arrangement on the medial and lateral surface of ulnar nerve around the medial epicondyle while performing epineurotomy for leprous neuropathy. We enrolled patients of symptomatic leprous ulnar neuropathy of less than one year duration on MDT that did not respond to steroids, for surgical decompression. Ten patients underwent epineurotomy of ulnar nerves (N = 11) around medial epicondyle. The epineural vessels were classified as per Sunderland’s classification of arteriae nervorum. The number of epineural vessels was assessed on the medial and lateral surface of the ulnar nerve adjoining the medial epicondyle. The epineurotomy incision was placed over the surface of ulnar nerve having relatively less vessels. The mean number of epineural vessels on the medial surface was 9.72 (range; 7–14) and on the lateral surface were 4.72 (range; 3–6). The average number of vessels per cm2 of the medial and lateral surface of the nerve was 0.94 and 0.48, respectively. The most common type of epineural vessel was type 3 on both medial and lateral surface of the nerve. Lateral epineurotomy was performed in all 11 cases. All the patients had relief from neuropathic pain. The mean VAS score improved from 3.20 ± 0.89 to 0.50 ± 0.34 at 2 years follow-up (p = 0.02). The mean motor score improved from 9.31 ± 4.12 to 15.42 ± 3.10 and sensory score improved from 40.0 ± 30.70 to 85 ± 9.90 at two years follow-up (p

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). In lepromatous leprosy (LL), skin macrophages, harboring extensive bacterial multiplication, gain a distinctive foamy appearance due to increased intracellular lipid load. To determine the mechanism by which M. leprae modifies the lipid homeostasis in host cells, an in vitro M. leprae infection system, using human macrophage precursor THP-1 cells and M. leprae prepared from the footpads of nude mice, was employed. RNA extracted from skin smear samples of patients was used to investigate host gene expressions before and after multidrug therapy (MDT). We found that a cluster of peroxisome proliferator-activated receptor (PPAR) target genes associated with adipocyte differentiation were strongly induced in M. leprae-infected THP-1 cells, with increased intracellular lipid accumulation. PPAR-δ and PPAR-γ expressions were induced by M. leprae infection in a bacterial load-dependent manner, and their proteins underwent nuclear translocalization after infection, indicating activation of PPAR signaling in host cells. Either PPAR-δ or PPAR-γ antagonist abolished the effect of M. leprae to modify host gene expressions and inhibited intracellular lipid accumulation in host cells. M. leprae-specific gene expressions were detected in the skin smear samples both before and after MDT, whereas PPAR target gene expressions were dramatically diminished after MDT. These results suggest that M. leprae infection activates host PPAR signaling to induce an array of adipocyte differentiation-associated genes, leading to accumulation of intracellular lipids to accommodate M. leprae parasitization. Certain PPAR target genes in skin lesions may serve as biomarkers for monitoring treatment efficacy., Author summary Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). Lipid-enriched intracellular environment is important for the parasitization of M. leprae. During anti-leprosy treatment, chemotherapy-killed bacilli can remain in host tissues for a long time, making it difficult to determine the treatment efficacy by Zeihl-Nelson’s staining-based bacterial index (BI) test. In this study, we found that host peroxisome proliferator-activated receptor (PPAR) signaling is responsible for modification of intracellular lipid homeostasis to accommodate M. leprae parasitization in host macrophages. In skin smear samples of patients, M. leprae-derived gene expressions were detected both before and after anti-leprosy treatment, whereas human PPAR target gene expressions were dramatically diminished after the treatment. These results further our understanding of M. leprae intracellular parasitization, and suggest that PPAR signaling may be a novel therapeutic target for treating M. leprae infection and monitoring the expressions of certain PPAR target genes in skin lesions may be helpful to evaluate the treatment efficacy and recurrent infection.

Erythema nodosum leprosum (ENL), or type 2 lepra reaction, is a multi-system immune-mediated complication in patients with multibacillary leprosy, frequently associated with chronicity and recurrences. Management of ENL requires high doses of oral corticosteroids, which may not be universally effective and pose serious adverse effects. Thalidomide has proven to be a steroid-sparing agent and is useful in controlling the reactions. However, many centres do not employ it in outpatient settings due to adverse effects and teratogenicity risk. Hence, we studied the feasibility of treating ENLs and reported the therapeutic outcome.This is a five-year record-based analysis of ENL leprosy patients treated with thalidomide, includingdescriptive statistics of demographic variables. Clinical characteristics were stratified by treatment compliance status (yes/no). Incidence rates and rate ratios for recovery stratified by bacillary index, type of ENL presentation and MDT treatment status were calculated.Out of 102 ENL patients treated with thalidomide, 68 (66.7%) were compliant and improved. Among them, ENL recurrence was noted in 11(16.2%) patients. The commonest thalidomide side effect was pedal oedema (73.5%). Patients with bacillary index (BI) less than or equal to 4.0 had a 37% increase in the incidence of recovery. Patients with acute ENL were almost twice as likely to recover as those with chronic ENL. Also, the improvement was two and a half times greater among those who completed MDT as compared to those on MDT. The study showed that thalidomide treatment for patients with ENL is possible in outpatientclinics. We also successfully prevented pregnancies to a larger extent through counselling for contraception.We observed that early institution of thalidomide induces faster remission and prevents ENL recurrence., Author summary Erythema nodosum leprosum (ENL), is an immune-mediated condition of leprosy.It is a multi-system disorder which can occurbefore, during or after completion of multidrug therapy for leprosy.ENL is often characterised by chronicity and recurrence. Management of ENL requires long-term oral corticosteroids which are associated with adverse effects.Thalidomide is an alternative to steroids, but many centres donot use it in their outpatient clinics due to the significant concern of drug-producing birth defects.This study provides additional evidence of the feasibility of thalidomide treatment in ENL at outpatient settings.

Leprosy is a stigmatizing, chronic infection which degenerates the nervous system and often leads to incapacitation. Multi-drug therapy which consists of dapsone, rifampicin and clofazimine has been effective to combat this disease. In Indonesia, especially in Papua Island, leprosy is still a problem. Furthermore, there had been higher reports of Dapsone Hypersensitivity Syndrome (DHS) which also challenges leprosy elimination in certain aspects. Globally, DHS has a prevalence rate of 1.4% and a fatality rate up to 13%. The aim of this study is to validate HLA-B*13:01, a previously discovered biomarker for DHS in the Chinese population, as a biomarker for DHS in the Papua population.This is a case-control study of 34 leprosy patients who presented themselves with DHS (case subjects) and 52 leprosy patients without DHS (control subjects). Patients were recruited from 2 provinces: Papua and West Papua. DNA was extracted from 3 ml blood specimens. HLA-B alleles were typed using the gold-standard sequence based typing method. Results were then analysed using logistic regression and risk assessment was carried out. The results of HLA-typing showed that HLA-B*13:01 was the most significant allele associated with DHS, with odds ratio = 233.64 and P-value = 7.11×10−9, confirming the strong association of HLA-B*13:01 to DHS in the Papua population. The sensitivity of this biomarker is 91.2% and specificity is 96.2%, with an area under the curve of 0.95. HLA-B*13:01 is validated as a biomarker for DHS in leprosy patients in Papua, Indonesia, and can potentially be a good predictor of DHS to help prevent this condition in the future., Author summary Leprosy as a chronic infectious disease that affects the skin and nervous system is treated with a treatment cocktail, including rifampicin, clofazimine and dapsone. Unfortunately, one of these drugs, namely dapsone, may cause the patient to exhibit adverse symptoms that appear as skin hypersensitivity and may potentially lead to death up to 9.9% of the time. In a previous study, it has been established that this adverse drug reaction, which is called dapsone hypersensitivity syndrome (DHS), is associated with an allele in the human leukocyte antigen, HLA-B*13:01. In the light of validating the association of HLA-B*13:01 with DHS in a leprosy endemic area like Indonesia, we conducted a study involving leprosy patients who had DHS during the course of their multi-drug treatment as well as leprosy patients who managed to complete their course of treatment without exhibiting DHS. The results of this study validated the association of HLA-B*13:01 and DHS at a very significant level of evidence and the odds of people carrying at least one allele is 233.3-times the risk of non-carriers. This allele was also able to predict a person at risk of DHS 95% of the time. Thus, screening of HLA-B*13:01 to prevent DHS is warranted.