Role of histopathological, serological and molecular findings for the early diagnosis of treatment failure in leprosy.

BACKGROUND: Treatment failure (TF) in leprosy following multidrug therapy (MDT) presents a significant challenge. The current World Health Organization (WHO) fixed-duration MDT regimen, based on lesion count, might not be adequate. Leprosy lacks clear-cut objective cure criteria, and the predictive value of post-MDT histopathological findings remains uncertain. This study aims to identify predictive factors for TF among leprosy patients who have completed the WHO-recommended MDT. METHODS: An analysis was conducted on 80 individuals from a national leprosy reference center, comprising 40 TF cases (with a mean relapse at 13.0 months) and 40 controls (with a mean of 113.1 months without disease signs). Various epidemiological and clinical-laboratory parameters were assessed post-MDT. RESULTS: In skin samples, the presence of foamy granuloma (OR = 7.36; 95%CI2.20-24.60; p = 0.0012) and histological bacillary index (hBI) ≥ 1+ (OR = 1.55; 95%CI1. 22-1.99; p = 0.0004) were significantly associated with TF, with odds ratios of 7.36 and 1.55, respectively. Individuals who experienced TF had a mean hBI of 3.02+ (SD ± 2.02), while the control group exhibited a mean hBI of 1.8+ (SD ± 1.88). An hBI ≥ 3 + showed a sensitivity of 73% and a specificity of 78% for TF detection (AUC: 0.75; p = 0.0001). Other histopathological features like epithelioid granulomas, and skin changes did not show significant associations (p > 0.05). Additionally, higher anti-phenolic glycolipid-I (anti-PGL-I) ELISA index (EI) levels were linked to a 1.4-fold increased likelihood for TF (OR = 1.4; 95%CI1.13-1.74; p = 0.0019). A mean EI of 4.48 (SD ± 2.80) was observed, with an EI ≥ 3.95 showing a sensitivity of 79% and a specificity of 59% for TF detection (AUC: 0.74; p = 0.0001). Moreover, the presence of Mycobacterium leprae (M. leprae) DNA in real-time polymerase chain reaction (qPCR) was associated with a 3.43-fold higher likelihood of TF. Multivariate regression analysis indicated that concurrent presentation of neural/perineural lymphocytic infiltrate, foamy granuloma, hBI ≥ 1+, and EI ≥ 1 markedly increased the likelihood of TF by up to 95.41%. CONCLUSION: Persistence of nerve-selective lymphocytic infiltrate, foamy granulomas, and bacilli in skin biopsies, and elevated EI post-MDT, may serve as predictive factors for identifying individuals at higher probability of TF.

Severe postural hypotension and sinus bradycardia with thalidomide in patients with erythema nodosum leprosum.

Two men in their 60s and 40s were diagnosed with erythema nodosum leprosum based on the development of recurrent painful ulcers and nodules, respectively, for the previous 6 months. Thalidomide 100 mg four times a day, along with MB-MDT, was started in both patients. Both patients experienced severe dizziness on rising from a seated posture soon after initiation of thalidomide and a decrease in blood pressure and heart rate. Cardiovascular/neurology examination and routine blood investigations were normal. An autonomic nervous system assessment indicated bradycardia, postural hypotension and decreased cardiac autonomic function. The dosage of thalidomide was then gradually reduced over 4-5 days to 100 mg/day following a suspicion that thalidomide was the cause of postural hypotension. The dizziness subsided, and blood pressure and heart rate returned to normal.We concluded that thalidomide was the culprit behind bradycardia and dose- dependent postural hypotension.

Self-healing in leprosy: A systematic review.

BACKGROUND: Leprosy, caused by Mycobacterium leprae, affects multiple body systems and can lead to preventable disability if untreated. While multidrug therapy (MDT) has been available since 1982, historical evidence suggests that untreated leprosy can resolve spontaneously. Nevertheless, the prevalence of self-healing worldwide, as well as factors determining self-healing, remain unclear. METHODS: A systematic review was conducted in 2023 with data from PubMed, Infolep, and Web of Sciences data bases, along with a google search. Data extraction and analysis followed PRISMA guidelines and were summarized in a separate Excel sheet. Included were English-language studies on self-healing in leprosy, regardless the year of publication. RESULTS: We included six studies spanning from 1938 to 1978 exploring the incidence of self-healing in different countries and continents. Children, paucibacillary (PB) cases, and possibly males showed a higher probability of self-healing with an average healing time of two years. DISCUSSION/CONCLUSION: Recent research on self-healing in leprosy is scarce and evidence limited. This is primarily due to ethical concerns regarding withholding effective treatment of diagnosed patients, and because of the absence of an agreed definition of self-healing. Nevertheless, self-healing appears to be a plausible phenomenon influenced by geographic and demographic factors, and the type of leprosy. We recommend further research on self-healing in leprosy, as it provides insight into the human immune system and the determinants of this phenomenon. More insight could help adapt clinical practices and public health strategies, thereby contributing to an effective management and control of this disease.

An update of the diagnosis, treatment, and prevention of leprosy: A narrative review.

Leprosy is an infectious disease that remains a public health concern. It is caused by acid-fast Bacillus leprae, which primarily affects the skin and peripheral nerves, potentially leading to long-term disability and stigma. However, current and previous efforts have focused on developing better diagnostic and therapeutic interventions for leprosy, and its prevention needs to be addressed. In this review, we organize the currently published papers and provide updates on the global epidemiology, diagnosis, treatment, and prevention of leprosy. Several online databases, including MEDLINE (National Library of Medicine, Bethesda, MD), PubMed, EMBASE, Web of Science, and Google Scholar, were searched to collect relevant published papers. As a public health issue, the World Health Organization set the goal of leprosy elimination with a prevalence of <1 case per 10,000 people, which was achieved in 2000 and in most countries by 2010, mainly owing to the treatment of leprosy using drugs starting in 1980 and no-cost access for patients since 1995. Although diagnostic and therapeutic techniques have improved, the new occurrence of leprosy remains a critical global disease burden. With continuous technological improvements in diagnosing and treating leprosy, obtaining more relevant healthcare knowledge and preventing leprosy disability are crucial.

Case Report: Recurrent Type 2 Leprosy Reaction Associated with Multiple Nerve Function Impairments Refractory to Steroids: A Therapeutic Challenge.

Nerve function impairment (NFI) in leprosy results in serious deformities of the face, hands, and feet and contributes significantly to the stigma associated with the disease. Most literature on NFI focuses on either type 1 reaction-associated NFI, or the silent neuropathy, whereas NFI associated with type 2 reaction (T2R) is less well researched. The latter, however, can be more refractory to conventional treatment, not solely owing to its recurrent nature. We present a therapeutically challenging case of a 31-year-old male with borderline lepromatous leprosy with recurrent T2R associated with recurrent and progressive sensorimotor NFI, largely unresponsive to oral steroids and multibacillary, multidrug therapy.

Dapsone Use in Dermatology.

Dapsone, initially synthesized for textile dyeing, gained recognition in the 1930s for its antibacterial properties, leading to its utilization in dermatology for leprosy and dermatitis herpetiformis. Despite US Food and Drug Administration (FDA) approval for these conditions, dapsone's off-label uses have expanded, making it a valuable option in various dermatologic conditions. This review seeks to highlight the common uses of dapsone in its FDA indications and off-label indications. Diseases in which dapsone is considered first-line therapy or adjunctive therapy are reviewed, with highlights from the resources included. An overview of dapsone's pharmacokinetics, pharmacodynamics, indications, dosages, and safety profile are also reviewed. Dapsone's versatility and safety profile make it a cost-effective treatment option in dermatology, particularly for patients with limited access to specialized medications. Ongoing clinical trials are also described exploring dapsone's efficacy in novel dermatologic uses. Dapsone has been a valuable adjunctive therapy across various dermatologic conditions for years and evidence for its use continues to expand.

Near fatal case of Lucio leprosy with Lucio phenomenon with pleomorphic features and its successful management from a non-endemic area.

Lucio leprosy is a diffuse non-nodular form of lepromatous leprosy. Lucio phenomenon is a type of reactional state which occurs in untreated cases due to the bacillary invasion of endothelial cells. We hereby describe a histopathologically confirmed case of Lucio leprosy with Lucio phenomenon. The patient presented with pleomorphic clinical features and started taking antileprosy treatment and systemic steroids. After few days of admission, she developed deep ulcers exposing the fascia. She also developed cardiogenic shock secondary to septicaemia. She was managed with inotropes and broad-spectrum antibiotics. The patient was given appropriate wound care and the ulcers healed within a period of 3 months and antileprosy drugs were continued. Our patient is a de novo case of Lucio leprosy with Lucio phenomenon and pleomorphic clinical features who developed near fatal septic shock. She was managed successfully. Despite the extensive disease manifestation, all the wounds healed completely.

A case report and literature review: Mycobacterium leprae infection diagnosed by metagenomic next-generation sequencing of cerebrospinal fluid.

BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae) that is responsible for deformities and irreversible peripheral nerve damage and has a broad spectrum of clinical and serological manifestations. Leprosy primarily affects the peripheral nerves and rarely presents with central nervous system involvement. Diagnosing leprosy can still be difficult in some cases, especially when the infection involves uncommon clinical manifestations and extracutaneous sites. Delayed diagnosis and treatment of leprosy may lead to irreversible damage and death. CASE PRESENTATION: We report a case of a 30-year-old female presenting with "repeated high fever with symptoms of headache for 14 days". On the day of admission, physical signs of lost eyebrows and scattered red induration patches all over her body were observed. The patient's diagnosis was based on the clinical characteristics using a combination of metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) and slit-skin smear. After confirming Listeria meningitis and multibacillary leprosy with erythema nodosum leprosum (ENL), a type 2 reaction, she was treated with ampicillin sodium, dapsone, rifampicin, clofazimine, methylprednisolone, and thalidomide. At the 1-year follow-up, the frequency and severity of headaches have significantly decreased and a good clinical response with improved skin lesions was found. CONCLUSION: This case highlights the importance of considering leprosy, which is a rare and underrecognized disease, in the differential diagnosis of skin rashes with rheumatic manifestations, even in areas where the disease is not endemic, and physicians should be alerted about the possibility of central nervous system infections. In addition, mNGS can be used as a complementary diagnostic tool to traditional diagnostic methods to enhance the diagnostic accuracy of leprosy.

Feasibility and accuracy of mobile QT interval monitoring strategies in bedaquiline-enhanced prophylactic leprosy treatment.

Some anti-mycobacterial drugs are known to cause QT interval prolongation, potentially leading to life-threatening ventricular arrhythmia. However, the highest leprosy and tuberculosis burden occurs in settings where electrocardiographic monitoring is challenging. The feasibility and accuracy of alternative strategies, such as the use of automated measurements or a mobile electrocardiogram (mECG) device, have not been evaluated in this context. As part of the phase II randomized controlled BE-PEOPLE trial evaluating the safety of bedaquiline-enhanced post-exposure prophylaxis (bedaquiline and rifampicin, BE-PEP, versus rifampicin, SDR-PEP) for leprosy, all participants had corrected QT intervals (QTc) measured at baseline and on the day after receiving post-exposure prophylaxis. The accuracy of mECG measurements as well as automated 12L-ECG measurements was evaluated. In total, 635 mECGs from 323 participants were recorded, of which 616 (97%) were of sufficient quality for QTc measurement. Mean manually read QTc on 12L-ECG and mECG were 394 ± 19 and 385 ± 18 ms, respectively (p < 0.001), with a strong correlation (r = 0.793). The mean absolute QTc difference between both modalities was 11 ± 10 ms. Mean manual and automated 12L-ECG QTc were 394 ± 19 and 409 ± 19 ms, respectively (n = 636; p < 0.001), corresponding to moderate agreement (r = 0.655). The use of a mECG device for QT interval monitoring was feasible and yielded a median absolute QTc error of 8 ms. Automated QTc measurements were less accurate, yielding longer QTc intervals.

Characteristics, clinical manifestations and management of leprosy in KwaZulu-Natal, South Africa: A 20-year retrospective study.

BACKGROUND: Although leprosy, a neglected tropical disease, has been eliminated (<1 case per 10 000 population) in South Africa (SA) since 1926, according to the World Health Organization, new cases continue to be reported. The management of leprosy poses several challenges, including patient adherence, education and insufficient training of healthcare practitioners. OBJECTIVES: To describe the biographical profile, clinical manifestations and treatment outcomes in patients with leprosy in KwaZulu-Natal Province. METHODS: This retrospective study aimed to analyse the clinical data of leprosy patients in SA from 2002 to 2022. Data collected included patient demographics, comorbidities, cutaneous and neurological manifestations of leprosy, complications, treatment and adverse reactions. Descriptive statistics were used to summarise the data. RESULTS: The study analysed the clinical data of 194 leprosy patients from 2002 to 2022. The majority of patients were male and middle aged, with a disproportionate representation of black South Africans. Regarding socioeconomic status, 80% were unemployed and 40% were social grant recipients. Most cases were clustered in urban centres and diagnosed at secondary care facilities, with 15% being HIV positive. The majority of patients (90%) were classified as having multibacillary leprosy. Common symptoms included upper respiratory tract involvement, hair loss and painful nerves, with the face and limbs being most frequently affected. Cutaneous morphology predominantly included plaques and hypopigmented patches, while neurological signs included ulnar nerve tenderness, muscle weakness and sensory deficits. Debilitating neurological complications were found in one-fifth of patients. Despite initiation of multidrug therapy in most patients, a significant proportion (27.3%) did not complete the full course of treatment, and treatment reactions were noted in 33.5% of patients. CONCLUSION: These findings emphasise the urgent need for enhanced patient and healthcare worker education, particularly in primary healthcare settings, to improve adherence to treatment, advocate for prophylactic measures and prevent new cases. Achieving leprosy-free status in SA requires the collaboration of many role-players to address these challenges and improve healthcare practices.

Case Report: Nonalcoholic Hepatic Steatosis Associated with Type-2 Leprosy Reaction.

Leprosy reactions are complex immune events, generating disabling consequences and threatening the lives of those who experience them. This case report addresses the episode of a 28-year-old female patient who suffered a severe type-2 leprosy reaction, characterized by significant hepatic involvement, specifically, nonalcoholic hepatic steatosis. This case report underscores the importance of maintaining a high level of clinical suspicion, early recognition, accurate diagnosis, and immediate addressing of these types of reactions that may arise in the context of leprosy.

Leprosy Presenting as Distal Acquired Demyelinating Symmetric Variant of Chronic Inflammatory Demyelinating Polyneuropathy: An Atypical Manifestation of Hansan's Disease.

Leprosy, caused by the bacterium Mycobacterium leprae, is known to primarily affect the skin and peripheral nerves. We present a rare case of leprosy initially manifesting as demyelinating polyneuropathy. A 46-year-old female presented with progressive weakness, tingling, and numbness in her extremities. Nerve conduction studies revealed evidence of demyelination, prompting further investigations. Skin slit-skin smears confirmed the diagnosis of leprosy, with the presence of acid-fast bacilli. The patient was subsequently started on multidrug therapy, leading to significant clinical improvement. This case highlights the importance of considering leprosy as a differential diagnosis in patients presenting with demyelinating polyneuropathy, especially in endemic regions.

MIP vaccine in leprosy: A scoping review and future horizons.

Mycobacterium Indicus Pranii (MIP) vaccine is a killed vaccine developed in India for leprosy with immunotherapeutic as well as immunoprophylactic effects. MIP, earlier known as Mycobacterium welchii, is a rapidly growing non-pathogenic mycobacterium. The novelty of this bacterium is due to its translational application as an immunotherapeutic agent. When administered intradermally, the vaccine induces cell-mediated immunity in the host towards Mycobacterium leprae. It leads to faster clinical and histopathological improvement, rapid bacillary clearance, and also lepromin conversion in anergic leprosy patients. The beneficial role of the MIP vaccine in augmenting the therapeutic efficacy of Multidrug Therapy (MDT), particularly in highly bacillated leprosy patients, is well documented in various studies from India. The role of the vaccine in reactional states is controversial, with varied results in different studies. Overall, it is found to decrease the frequency of type 2 lepra reactions and is useful in recalcitrant erythema nodosum leprosum. Even though there may be an increased likelihood of type 1 reactions, no additional nerve function impairment is attributed to the vaccine in various studies. In household contacts of leprosy who are administered MIP, it is noted to confer protection from disease lasting up to 10 years. It may prove to be a cost-effective strategy in national leprosy programmes. Apart from local injection site reactions, the vaccine is relatively safe, but it is not recommended in pregnancy and lactation. This article provides an overview of the MIP vaccine's clinical application in the context of leprosy spanning over 40 years. It also considers the vaccine's possible future applications in the management of disease-related complications and achieving the long-term goal of zero leprosy.

Whole blood transcriptomics reveals the enrichment of neutrophil activation pathways during erythema nodosum leprosum reaction.

Introduction: Patients with the multibacillary form of leprosy can develop reactional episodes of acute inflammation, known as erythema nodosum leprosum (ENL), which are characterized by the appearance of painful cutaneous nodules and systemic symptoms. Neutrophils have been recognized to play a role in the pathogenesis of ENL, and recent global transcriptomic analysis revealed neutrophil-related processes as a signature of ENL skin lesions. Methods: In this study, we expanded this analysis to the blood compartment, comparing whole blood transcriptomics of patients with non-reactional lepromatous leprosy at diagnosis (LL, n=7) and patients with ENL before administration of anti-reactional treatment (ENL, n=15). Furthermore, a follow-up study was performed with patients experiencing an ENL episode at the time of diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Validation in an independent cohort (ENL=8; LL=7) was performed by RT-qPCR. Results: An enrichment of neutrophil activation and degranulation-related genes was observed in the ENL group, with the gene for the neutrophil activation marker CD177 being the most enriched gene of ENL episode when compared to its expression in the LL group. A more pro-inflammatory transcriptome was also observed, with increased expression of genes related to innate immunity. Validation in an independent cohort indicated that S100A8 expression could discriminate ENL from LL. Supernatants of blood cells stimulated in vitro with Mycobacterium leprae sonicate showed higher levels of CD177 compared to the level of untreated cells, indicating that the leprosy bacillus can activate neutrophils expressing CD177. Of note, suggestive higher CD177 protein levels were found in the sera of patients with severe/moderate ENL episodes when compared with patients with mild episodes and LL patients, highlighting CD177 as a potential systemic marker of ENL severity that deserves future confirmation. Furthermore, a follow-up study was performed with patients at the time of ENL diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Enrichment of neutrophil pathways was sustained in the transcriptomic profile of patients undergoing treatment; however, important immune targets that might be relevant to the effect of thalidomide at a systemic level, particularly NLRP6 and IL5RA, were revealed. Discussion: In conclusion, our study reinforces the key role played by neutrophils in ENL pathogenesis and shed lights on potential diagnostic candidates and novel therapeutic targets that could benefit patients with leprosy.

Rare Variant of Leprosy Reaction (Lucio Phenomenon): A Case Series.

ABSTRACT: Lucio phenomenon (LP) is a variant of type two leprosy, characterized by necrotizing erythema, frequently found in neglected leprosy patient who experience delayed diagnosis or inappropriate treatment. Indonesia is in the third place for highest leprosy cases worldwide. Nonetheless, LP is less common, regardless being an endemic country. In this serial case, we describe the three cases of LP in lepromatous leprosy patients in Denpasar, Bali. All three cases came to our hospital with chronic wounds complained up to a year, accompanied by swollen leg, blisters, tingling sensation, and other symptoms. They had received no suitable treatment, proving LP as a neglected case in primary health care. After a period of treatment, however, patient lesions improved clinically with no physical disability. With this case series, a better understanding toward LP initial complains together with its natural history and further examination could be achieved; thus, improving the early diagnosis and management of LP.