Nail fold capillaroscopy in leprosy: Unveiling the microvascular changes.

BACKGROUND: Leprosy, a chronic infectious disease, is associated with various nail changes. Its etiopathogenesis is multifaceted, with microvascular damage being crucial. Nail fold capillaroscopy (NFC) emerges as a novel tool for detecting early vascular deficits in leprosy. The study aimed to assess and provide a complete clinical characterization of NFC changes in leprosy patients. METHODS: It is an observational cross-sectional study, done over a period of 1.5 year (January 2021 to august 2022) in a tertiary care hospital, encompassing 60 patients diagnosed with leprosy (18-60 years). After obtaining informed consent; detailed history, complete cutaneous and neurological examinations were conducted. All fingernails and toenails were examined for clinical changes. Subsequently, onychoscopy was performed using USB type of video-dermatoscope (Model AM7115MZT Dino-lite), a non-invasive tool. This was followed by NFC which was done for all fingernails and images were recorded by single operator, which were then assessed for quantitative and qualitive changes and statistical analysis was conducted using SPSS v20, with mean capillary density compared using Student's t-test, morphological change frequencies assessed by proportions, and group comparisons made using Chi-square or Fischer exact tests, with a significance threshold of p < 0.05. RESULTS: Among the 60 patients, 39 were in the lepromatous group, which included both borderline lepromatous (BL) and lepromatous leprosy (LL) patients, and 17 were in the tuberculoid group, which included borderline tuberculoid (BT) leprosy patients; 23.3 % had Type 1 reactions, and 18.3 % had Type 2 reactions. Nail fold capillaroscopy (NFC) showed microvasculature changes in 93.3 % of patients. The average capillary density was 6.8 ± 1.5 capillaries per mm, with the lepromatous group having a lower density (6.5 ± 1.09) compared to the tuberculoid group (7.0 ± 0.86). The most common NFC changes in the tuberculoid group were tortuous capillaries (70 %), capillary dropouts, and dilated capillaries (both 64.7 %). In the lepromatous group, capillary dropouts (82 %) were most frequent, followed by tortuous (69 %), receding (69 %), and dilated capillaries (66 %). A dilated and prominent subpapillary plexus was more common in the lepromatous group (35 %, p = 0.04). Patients with trophic changes in the lepromatous group had more capillary dropouts and bizarre capillaries. Capillary dropouts, dilated capillaries, and visible subpapillary venous plexus were more prevalent in patients with Type 2 reactions. CONCLUSION: NFC changes are prevalent in both tuberculoid and lepromatous leprosy, which may be an indicator of peripheral vascular compromise and trophic changes, especially in lepromatous leprosy. NFC can be an auxiliary tool for detecting microvascular abnormalities in leprosy patients.

Leprosy: Treatment and management of complications.

In the second article in this continuing medical education series, we review the treatment of leprosy, its immunologic reactions, and important concepts, including disease relapse and drug resistance. A fundamental understanding of the treatment options and management of neuropathic sequelae are essential to reduce disease burden and improve patients' quality of life.

Occult hepatitis B virus infection in patients with leprosy.

Leprosy patients may present with immune system impairment and have a higher hepatitis B virus (HBV) seroprevalence, justifying the investigation of occult HBV infection in these individuals. The aim of this study was to verify the frequency and the clinical factors associated with occult HBV infection in leprosy patients. Between 2015 and 2016, leprosy patients from a reference center in Brazil were interviewed to assess clinical data. Blood samples were collected for the screening of HBV serological markers using enzyme-linked immunosorbent assay. Patients with negative hepatitis B surface antigen (HBsAg) that had positive anti-HBc and/or anti-HBs were selected for HBV DNA detection using real-time polymerase chain reaction. SPSS was used for data analysis. Among 114 selected patients, six were identified with occult infection (5.3%) and five of them with multibacillary leprosy. Three patients with occult infection had a history of a type 2 reaction (P = 0.072; OR, 4.97; 95% CI, 0.87-28.52). Only two patients with occult infection had isolated anti-HBc, while three had isolated anti-HBs, including those with the highest HBV DNA titers. In conclusion, in leprosy patients with negative HBsAg and positive anti-HBc and/or anti-HBs, occult HBV infection occurs in 5.3% and can be found even in patients with isolated anti-HBs.

Soil-transmitted helminth infections and leprosy: a cross-sectional study of the association between two major neglected tropical diseases in Indonesia.

BACKGROUND: The clinical spectrum of leprosy is dependent on the host immune response against Mycobacterium leprae or the newly discovered Mycobacterium lepromatosis antigen. Helminth infections have been shown to affect the development of several diseases through immune regulation and thus may play a role in the clinical manifestations of leprosy and leprosy reactions. The purpose of this study is to determine the proportion of helminth infections in leprosy and its association with the type of leprosy and type 2 leprosy reaction (T2R). METHODS: History or episode of T2R was obtained and direct smear, formalin-ether sedimentation technique, and Kato-Katz smear were performed on 20 paucibacillary (PB) and 61 multibacillary (MB) leprosy participants. RESULTS: There are more helminth-positive participants in MB leprosy compared to PB (11/61 versus 0/20, p = 0.034) and in T2R participants compared to non-T2R (8/31 versus 3/50, p = 0.018). CONCLUSIONS: Our results suggest that soil-transmitted helminth infections may have a role in the progression to a more severe type of leprosy, as well as the occurrence of T2R. These findings could serve as a fundamental base for clinicians to perform parasitological feces examination in patients who have MB leprosy and severe recurrent reactions to rule out the possibility of helminth infection. Further secondary confirmation of findings are needed to support these conclusions.

Leprosy: diagnosis and management in a developed setting.

Leprosy remains an important global health concern, but little has been published about its diagnosis and management in developed settings. It has been postulated that delay in diagnosis is common in developed settings. We reviewed all the cases of leprosy seen at a major tertiary referral centre between 1999 and 2013 and demonstrated that delay in diagnosis is common, especially when patients present with symptoms of leprosy reactions rather than classical symptoms, such as hypo-pigmented hypo-aesthetic skin lesions and neuropathy.

Analysis of interleukin 7 and platelet-derived growth factor-BB mRNA expression as potential markers in erythema nodosum leprosum.

Erythema nodosum leprosum (ENL) is an immunological complication of leprosy characterized by acute inflammation of the skin, nerves, and other organs. Identifying laboratory parameters is important for early diagnosis of leprosy reactions. Various cytokine biomarkers have been examined and only a few studies have reported on angiogenesis in leprosy. This study aims to understand the pathomechanism of ENL by examining IL-7 and platelet-derived growth factor (PDGF)-BB mRNA expression that can be the development and consideration of new effective therapies to prevent reactions, recurrences, and defects in leprosy. The study used a cross-sectional analytic design. Sampling was done by peripheral blood from the patient and measuring mRNA expression with specific primers RT-PCR. The expression of mRNA IL-7 and PDGF-BB was significantly different between multibasilar patients without reaction and with ENL reaction, where there was an increased expression in ENL patients. This could be used as the development of potential biomarkers in ENL and development of new therapeutic intervention pathways in ENL.

Erythema nodosum leprosum necroticans: a case report of an atypical severe type 2 leprosy reaction and literature review.

Until now, leprosy remains a problem and challenge in the world because it can cause disability and morbidity in affected individuals, including problems due to the emergence of type 2 lepra reaction or erythema nodosum leprosum (ENL). The clinical picture of ENL can appear in an atypical and severe form, called ENL necroticans (ENN), which becomes a problem in diagnosis and therapy. We report a 17-year-old female with lepromatous leprosy and ENN who received therapy in the form of a combination of steroids and methotrexate. Four months after consuming this therapy, the ulcers on the patient's body improved, leaving atrophic and hypertrophic scars. ENN's unusual clinical presentation poses diagnostic difficulties in that its appearance does not follow the typical patterns, making it challenging to identify correctly. Furthermore, managing cases of ENN may necessitate supplementary treatment beyond steroids alone.

One Case of Tuberculosis-Like Leprosy with a Type I Leprosy Reaction.

Leprosy is a chronic infectious disease primarily affecting the skin and peripheral nerves and is caused by Mycobacterium leprae. Although effective control measures have significantly reduced its global incidence in recent years, its insidious onset and diverse skin manifestations pose considerable challenges to early diagnosis, particularly among young medical practitioners. This study reports a case of tuberculoid leprosy accompanied by a type I reaction (T1R) to leprosy, aiming to contribute to the broader understanding and management of the disease. The patient came from a leprosy-endemic region and had a family history of leprosy. They first presented with neuritis, characterised by numbness in the left upper limb, which is an early-stage symptom often overlooked. This case accentuates the importance of comprehensive examination techniques, including bacteriological and histological investigations, ultrasound and magnetic resonance imaging, to identify early nerve damage, which is critical for prompt diagnosis and intervention. According to World Health Organization data, approximately 200,000 new cases of leprosy are reported worldwide each year, with a prevalence rate of 0.2 cases per 10,000 individuals. The disease exhibits two clinical forms based on the host's immune response: tuberculoid leprosy in a well-immunised population and lepromatous leprosy in a poorly immunised host. The patient in this study demonstrated signs of tuberculoid leprosy, marked by isolated skin papules and plaques, and a T1R, a tissue-destructive, immune-driven inflammatory process. This case underscores the need for ongoing education and updated diagnostic tools to facilitate the early detection of leprosy, particularly in endemic areas. Moreover, attention must be given to the comprehensive care of patients, encompassing both physical and psychological aspects, to improve their quality of life and mitigate social discrimination and prejudice.

Immunopathogenesis of Type 1 and Type 2 Leprosy Reaction: An Update Review.

Leprosy reactions are acute exacerbations of the signs and symptoms of leprosy occurring during the natural course of the disease and during or after treatment. Left untreated or improperly managed, reactions can lead to severe nerve function impairment and subsequently to disabilities. In the present context of leprosy eradication efforts, leprosy reactions continue to pose a significant and enduring challenge. Type 1 leprosy reaction and type 2 leprosy reaction are substantial contributors to nerve impairment and the subsequent development of enduring impairments. The study of immunopathogenesis of leprosy reactions has emerged as a significant area of research due to its potential to identify critical targets for the early detection and management of these episodes. This study aims to reveal the pathogenesis of type 1 and 2 leprosy reactions so that they can form the basis for their treatment. The study used scientific journals from reputable platforms such as PubMed, Scopus, and Google Scholar to evaluate the pathogenesis of leprosy reaction type 1 and 2 in leprosy patients. This review indicates that the progression of leprosy nerve damage and sensitivity to reactions may be predicted using genetic and serum markers in the human host. A more profound comprehension of the molecular processes underlying leprosy reactions may offer a logical plan for early detection and leprosy reaction complication prevention.

Clinical, epidemiological, and laboratory prognostic factors in patients with leprosy reactions: A 10-year retrospective cohort study.

Introduction: Leprosy reactions, the main cause of neural damage, can occur up to 7 years after starting multidrug therapy. We aimed to approach the prognostic factors that may influence the leprosy reactions over the follow-up time. Methods: Retrospective cohort study, encompassing 10 years of data collection, composed of 390 patients, divided into 201 affected by reactions and 189 reaction-free individuals. Epidemiological, clinical, and laboratory variables were approached as prognostic factors associated with leprosy reactions. The association among variables was analyzed by a binomial test and survival curves were compared by the Kaplan-Meier and Cox proportional-hazards regression. Results: 51.5% (201/390) of patients were affected by leprosy reactions. These immunological events were associated with lepromatous leprosy (16.2%; 63/390; p < 0.0001) and multibacillary group (43%; 169/390; p < 0.0001). This study showed that survival curves for the prognostic factor anti-PGL-I, comparing positive and negative cases at diagnosis, differed in relation to the follow-up time (Log Rank: p = 0.0760; Breslow: p = 0.0090; Tarone-Ware: p = 0.0110). The median survival times (time at which 50% of patients were affected by leprosy reactions) were 5 and 9 months for those reactional cases with negative (26/51) and positive serology (75/150), respectively. The time-dependent covariates in the cox proportional-hazards regression showed anti-PGL-I as the main prognostic factor to predict leprosy reactions (hazard ratio=1.91; p = 0.0110) throughout the follow-up time. Conclusions: Finally, these findings demonstrated that anti-PGL-I serology at diagnosis is the most important prognostic factor for leprosy reactions after starting multidrug therapy, thus enabling prediction of this immunological event.

Evaluation of hematological parameters in patients with leprosy in Southern Nigeria.

Introduction: Leprosy is a chronic granulomatous infectious disease caused by Mycobacterium leprae that mostly result in immunological reactions that affect the skin, peripheral nervous system and mucosa of the upper respiratory tract. This study aimed to evaluate hematological parameters among subjects with leprosy and deduce biomarkers for onset of leprosy reaction. Methods: This was a cross-sectional study performed from September 1, 2018 to August 1, 2019. Sixty patients with leprosy (30 on multidrug therapy (MDT) and 30 that had completed MDT) and 30 apparently healthy controls were enrolled. Hematology auto-analyzer (Sysmex KX-21N by Sysmex Corporation Kobe, Japan) was used in sample analysis. ANOVA and Kruskal Wallis were used for mean comparison. Eta squared was used to assess effect size. Sensitivity and specificity were assessed using receiver operator characteristic (ROC) curve. Association was checked using bivariate logistics regression. Results: The majority (68.3%) of the patients with leprosy were males and a larger proportion were either farmers or unemployed. The prevalence of leprosy reaction in the studied population was 40%. The following parameters were significantly (p<0.05) reduced: red cell count, hemoglobin and hematocrit in patients with leprosy compared to controls. Total white cell count, absolute lymphocyte, neutrophil, monocyte and eosinophil counts were significantly elevated in patients with leprosy compared to controls. The hemoglobin and mean corpuscular volume of patients with leprosy on treatment were significantly higher compared to those who had completed treatment, while the mean corpuscular hemoglobin concentration was significantly reduced. Overall, 65% of patients with leprosy were anemic. Eosinophil count showed good biomarker potential for leprosy reaction onset with AUC 0.709. Sex and absolute eosinophil count were associated with leprosy reaction (OR=11.194; 95%CI: 1.775-70.586). Conclusions: This study has shown a high frequency of anemia in patients with leprosy, both those on treatment and those that had completed MDT, necessitating incorporation of post treatment plan in the management of leprosy. This study has reported absolute eosinophil as potential biomarker of leprosy reaction.

Case Report: A Case Series of Immunobiological Therapy (Anti-TNF-α) for Patients With Erythema Nodosum Leprosum.

Patients with leprosy may experience a chronic and severe type II leprosy reaction (ENL) erythema nodosum leprosum that may not respond to thalidomide and systemic immunosuppressants or may even cause serious adverse events. We here present four patients in whom anti-TNF-α therapy was used with successful results and compare our findings with other published cases. Four patients with chronic and severe ENL who did not respond to, at least, thalidomide and steroids (high doses) were followed up at two reference centers in Brazil. A thorough laboratory investigation was performed to exclude tuberculosis and other diseases before the start of immunobiological medication. Three patients were started on etanercept, and one patient was started on adalimumab. Of all patients, three developed severe adverse events resulting from the use of classical immunosuppressants for ENL (cataracts, deep vein thrombosis, diabetes, and osteoporosis). In all cases, a reduction in the number of ENL and, at least half of the immunosuppressant dose between 6 months and 2 years, were observed. Long-term follow-up of one patient revealed a dramatic reduction in hospital admissions due to ENL, from 12 instances in 1 year (before biologic therapy) to none (after biologic therapy), along with an improvement in condyloma acuminatum. In addition, no direct adverse events were observed with biologics. Treatment with anti-TNF-α therapy may be used as an alternative in patients with chronic and severe ENL who do not respond to traditional treatment (e.g., thalidomide, steroids, and other immunosuppressants). This treatment can help reduce the frequency of ENL, the immunosuppressive burden, and the number of hospital admissions.

The Type I Interferon Pathway Is Upregulated in the Cutaneous Lesions and Blood of Multibacillary Leprosy Patients With Erythema Nodosum Leprosum.

In leprosy patients, acute inflammatory episodes, known as erythema nodosum leprosum (ENL), are responsible for high morbidity and tissue damage that occur during the course of Mycobacterium leprae infection. In a previous study, we showed evidence implicating DNA-sensing via TLR9 as an important inflammatory pathway in ENL. A likely important consequence of TLR9 pathway activation is the production of type I interferons (IFN-I) by plasmacytoid dendritic cells (pDCs), also implicated in the pathogenesis of several chronic inflammatory diseases. In this study, we investigated whether the IFN-I pathway is activated during ENL. Blood samples and skin lesions from multibacillary patients diagnosed with ENL were collected and the expression of genes of the IFN-I pathway and interferon-stimulated genes were compared with samples collected from non-reactional multibacillary (NR) patients. Whole blood RNAseq analysis suggested higher activation of the IFN-I pathway in ENL patients, confirmed by RT-qPCR. Likewise, significantly higher mRNA levels of IFN-I-related genes were detected in ENL skin biopsies when compared to NR patient lesions. During thalidomide administration, the drug of choice for ENL treatment, a decrease in the mRNA and protein levels of some of these genes both in the skin and blood was observed. Indeed, in vitro assays showed that thalidomide was able to block the secretion of IFN-I by peripheral blood mononuclear cells in response to M. leprae sonicate or CpG-A, a TLR9 ligand. Finally, the decreased frequencies of peripheral pDCs in ENL patients, along with the higher TLR9 expression in ENL pDCs and the enrichment of CD123+ cells in ENL skin lesions, suggest the involvement of these cells as IFN-I producers in this type of reaction. Taken together, our data point to the involvement of the pDC/type I IFN pathway in the pathogenesis of ENL, opening new avenues in identifying biomarkers for early diagnosis and new therapeutic targets for the better management of this reactional episode.

Expansion and suppressive capacity of regulatory T cells isolated from patients across the leprosy spectrum: a pilot study.

Knowledge of the role of Tregs in the immunopathogenesis of the different clinical outcomes within the leprosy spectrum remains limited due to the lack of studies directly assessing their suppression capacity. We thus tested a protocol to expand Tregs from the peripheral blood of patients across the leprosy spectrum and analyzed their suppressive capacity in autologous TCD4+ responses. Results of these pilot assays show that Tregs can be expanded and exert suppressive capacity, but also that their rate of expansion and suppressive capacity are influenced by the patient's clinical classification, suggesting that they possibly retain some in vivo characteristics.

Use of methotrexate for leprosy reactions. Experience of a referral center and systematic review of the literature.

BACKGROUND: Patients with leprosy can present with systemic inflammatory complications called leprosy reactions (LR), which can be severe and cause a loss of nerve function. The treatment of choice is prolonged corticosteroid therapy, frequently associated with severe side effects. We have used methotrexate as a corticosteroid-sparing regimen with good results. METHODS: To evaluate the role of methotrexate in managing LR, we performed a systematic review of the literature including our cases. We evaluated studies, prospective and retrospective, in both adults and children, which included any dose/regimen of methotrexate for the treatment of LR type 1 or 2. RESULTS: The systematic search revealed 261 records that yield 21 patients including our 3 cases (19 adults/two children), who were treated with methotrexate for LR type 1 and 2. There were 14 males. Median age was 35 years (P25-P75 28 to 52). Patients showed lepromatous (7), borderline lepromatous (9) or borderline tuberculoid (3) leprosy, among the 19 cases in which the type of leprosy was specified. As for the type of LR, 15 patients showed erythema nodosum leprosum (ENL), five showed LR type 1 and one showed polyarthritis and previous ENL. Methotrexate at weekly doses ranging from 7.5 mg to 20 mg (median 15 mg per week), typically administered with low-dose corticosteroids, was effective and safe as a corticosteroid-sparing agent. CONCLUSIONS: Methotrexate could be a suitable ancillary treatment or alternative to corticosteroids, especially in populations who are more prone to its adverse events. However, this evidence is based only on case reports and short clinical series.

Reactive perforating leprosy: A rare case report of type 2 leprosy reaction.

Reactive perforating leprosy (RPL) is a rare clinical manifestation of type 2 leprosy reaction. A case of lepromatous leprosy (LL) with type 2 leprosy reaction presented as RPL in one patient was reported. A physical examination showed multiple punched-out ulcers with regular border, without undermined edge, and dermal base. The ulcers mostly covered with hemorrhagic crust, contained pus, and necrotic tissue. A histopathological examination revealed invagination of the epidermis, intracorneal abscess, and infiltration of foamy macrophages with lymphocytes in dermis that supported the diagnosis of LL with RPL. The patient was given multidrug therapy-multibacillary and 40 mg prednisone daily which tapered off and wound dressing. Clinical improvement was observed within 2 weeks of treatment, as some ulcers healed. Type 2 leprosy reaction can provide a variety of clinical manifestations, one of which is RPL.

Diagnostic value of neutrophil-to-lymphocyte ratio in patients with leprosy reactions.

INTRODUCTION: Leprosy reactions, classified as type 1 and type 2 reactions, are acute clinical conditions of exacerbation of localized or systemic inflammatory response inpatients with leprosy. No laboratory biomarker is available to predict the emergence of these reactions. Neutrophil-to-lymphocyte ratio (NLR) is an accurate biomarker for diagnosis and prognosis of various inflammatory and neoplastic diseases. OBJECTIVE: This study aimed to investigate the accuracy of the NLR in the diagnosis of leprosy reactions. MATERIALS AND METHODS: NLR was calculated for all patients and a receiver operating characteristic curve (ROC) were generated to identify the NLR cut-off point. RESULTS: A total of 123 patients with leprosy were included, 98 with leprosy reactions of which 56 (45.5%) had type 1 and 42 (34.1%) with type 2. Mean NLR was higher among patients with reactions than among those without. It was also statistically higher among patients with type 2 reactions than in those with type 1 reactions. Receiver operating characteristic curves were generated to identify the NLR cut-off point. The area under the ROC curve was 0.794 for diagnosis of any leprosy reaction and 0.796 for the diagnosis of type 2 reaction. The NLR cut-off points for diagnosis of any leprosy reaction and for type 2 reaction were 2.75 (sensitivity 61.0%, specificity 92.0%, accuracy 77.0%) and 2.95 (sensitivity 81.0%, specificity 74.0%, accuracy 78.0%), respectively. CONCLUSION: These results suggest that NLR could be a potential biomarker for diagnosis of leprosy reaction and useful for discriminating patients with type 2 reactions from those with type 1 leprosy reactions.

Th17 Cells and Cytokines in Leprosy: Understanding the Immune Response and Polarization

ABSTRACT While there are conflicting data concerning interleukin (IL)-17 levels in the serum of patients with leprosy compared with those in healthy controls, higher levels have been more evident in the tuberculoid clinical form of leprosy and type 1 reactions. This review aimed to highlight the role of Th17 cells and their cytokines in leprosy. Cytokines such as IL-1β and IL-23 induce Th17, while transforming growth factor beta and IL-10 inhibit Th17, indicating that the balance between Th17 and regulatory T cells is crucial for leprosy polarization. However, more comprehensive paired studies are required to better elucidate the role of Th17 cells in leprosy.

γδ T cells are associated with inflammation and immunopathogenesis of leprosy reactions.

BACKGROUND: Leprosy reactions appear episodically in leprosy patients, which lead to high inflammation, morbidity and peripheral nerve damage. The role of Th17 cell has been well studied in leprosy reactions but the role of γδ or unconventional T cells which is an other major source of IL-17 in many diseases, not studied in leprosy reactional episodes. OBJECTIVE: The aim of the present study to elucidate the role of γδ T cells in leprosy reactions. METHODOLOGY: A total of 40 untreated non-reaction and reactions patients were recruited. PBMCs were isolated and stimulated with M. leprae sonicated antigen (MLSA) for 48 h and immuno-phenotyping was done using flow cytometry. Moreover, γδ T cells were isolated by Magnetic beads technology and mRNA expression of IL-17, IFN-γ, TGF-ß and FOXP3 were analyzed by real-time PCR (qPCR) and cytokine was estimated in the culture supernatant by ELISA. RESULTS: γδ T cells were significantly increased in both Reversal reaction (RR) and Erythema nodosum leprosum (ENL) reaction patients. These cells produced significant amount of IL-17 and IFN-γ. Furthermore, CD3+TCRγδ+ T cells expressed transient FOXP3 with a low amount of TGF-ß in both reactions as compared to stable patients. Moreover, low TGF-ß producing TCR-γδ cells were associated with low phosphorylation of STAT5A. CONCLUSION: This study will add to our understanding of the immunological features that mediate and regulate the pathogenesis of leprosy and may helpful to reduce the immuno-pathogenesis of leprosy reaction by targeting these cells.