High-Resolution Sonography as an Additional Diagnostic and Prognostic Tool to Monitor Disease Activity in Leprosy: A Two-Year Prospective Study.

PURPOSE: Early diagnosis and treatment of leprosy and leprosy reactions are essential to prevent stigmatizing deformities and disability. Although the incidence of leprosy has decreased enormously, grade 2 disability due to nerve injury has remained the same. New tools are needed to better diagnose and monitor leprosy reactions and associated neuritis and this study assessed whether high-resolution sonography (HRUS) can be used as such a tool. MATERIALS AND METHODS: During a prospective follow-up period of 2 years at regular intervals, we performed clinical examination to assess sensory and motor function and HRUS of the four main peripheral nerves in 57 patients, of whom 36 were with reactions and 21 were without reactions. Normative data of the cross-sectional area (CSA) of these nerves were obtained from 55 healthy subjects (HS). Color Doppler (CD) was used to study blood flow in the nerves. RESULTS: At the baseline visit and during follow-up, all four nerves were significantly thicker in patients with leprosy reactions in comparison to HS (p < 0.0001) and to a lesser extent also in comparison to patients without reactions ranging from a p-value of < 0.05 to < 0.0001 in the different nerves tested. During follow-up, the nerve size did not change significantly in patients without reactions, while it decreased significantly in patients with reactions. At baseline, endoneural blood flow was present only in patients with reactions. This occurred in 20 of the 36 (55 %) patients (49 nerves) and decreased to only 1 patient (2.7 %) at the end of the follow-up period. CONCLUSION: This prospective study demonstrates the ability of HRUS to monitor disease activity and the effect of treatment in patients with leprosy reactions by determining changes in nerve size and vascularity, which are indicators of peripheral nerve involvement and damage.

Association of tumor necrosis factor-alpha and interferon gamma gene polymorphisms and their plasma levels in leprosy, HIV and other peripheral neuropathies.

OBJECTIVE: Mycobacterium leprae and Human Immunodeficiency Virus (HIV) are causative agents known to be involved in nerve damage in leprosy and HIV-peripheral neuropathy (HIV-PN) respectively. Among other peripheral neuropathies the most common is diabetic neuropathy, which is metabolically induced. The proinflammatory cytokines TNF-α and IFN-γ have been implicated in the pathogenesis of peripheral neuropathy. The association between the plasma levels of these cytokines and their single nucleotide polymorphisms (SNPs) were investigated in leprosy neuropathy (LN), HIV-PN and other peripheral neuropathies (OPN). METHODS: Eighty-eight individuals with LN (PB=36; MB=52), 39 with HIV-PN, 52 patients with OPN, 101 HIV positive individuals without neuropathy (HIV) and 113 healthy subjects (HS) were included in the study. Plasma cytokine levels were measured by sandwich ELISA and one way ANOVA was carried out among the groups. SNPs of TNF-α- 308 G/A, -238 G/A and IFN-γ +874 T/A were investigated by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Their frequencies were compared between groups by Pearson's chi squared test. RESULTS: Plasma TNF-α and IFN-γ was significantly increased in LN (p<0.05), HIV-PN (p<0.05) and OPN (p<0.05) as compared to HS. A significant association was found between IFN-γ +874 A/A genotype in LN (p<0.05; OR=7.9), HIV-PN (p<0.05; OR=8.9) and OPN (p<0.05; OR=8.9) as compared to HS. CONCLUSION: Elevated levels of plasma TNF-α and IFN-γ and the association of IFN-γ +874 A/A genotype SNP in LN, HIV-PN and OPN suggests a common involvement of these cytokines in susceptibility/pathogenesis of peripheral neuropathy.

Serological responses to prednisolone treatment in leprosy reactions: study of TNF-α, antibodies to phenolic glycolipid-1, lipoarabinomanan, ceramide and S100-B.

BACKGROUND: Corticosteroids have been extensively used in the treatment of immunological reactions and neuritis in leprosy. The present study evaluates the serological response to steroid treatment in leprosy reactions and neuritis. METHODS: Seven serological markers [TNF-α, antibodies to Phenolic glycolipid-1 (PGL-1 IgM and IgG), Lipoarabinomannan (LAM IgG1 and IgG3), C2-Ceramide and S100 B] were analyzed longitudinally in 72 leprosy patients before, during and after the reaction. At the onset of reaction these patients received a standard course of prednisolone. The levels of the above markers were measured by Enzyme linked immunosorbent assay (ELISA) and compared with the individuals own value in the month prior to the reaction and presented as percentage increase. RESULTS: One month before the reaction individuals showed a varying increase in the level of different markers such as TNF-α (53%) and antibodies to Ceramide (53%), followed by to PGL-1 (51%), S100B (50%) and LAM (26%). The increase was significantly associated with clinical finding of nerve pain, tenderness and new nerve function impairment. After one month prednisolone therapy, there was a fall in the levels [TNF-α (60%), C2-Ceramide (54%), S100B (67%), PGL-1(47%) and LAM (52%)] with each marker responding differently to steroid. CONCLUSION: Reactions in leprosy are inflammatory processes wherein a rise in set of serological markers can be detected a month before the clinical onset of reaction, some of which remain elevated during their action and steroid treatment induces a variable fall in the levels, and this forms the basis for a variable individual response to steroid therapy.

Morphological changes of the epineurium in leprosy: a new finding detected by high-resolution sonography.

INTRODUCTION: From histopathological studies of peripheral nerves in leprosy, it is known that the epineurium can be thickened. We measured the epineurial thickness of the ulnar nerve by high resolution sonography (HRUS). METHODS: The epineurium of the ulnar nerve was measured above the elbow on transverse scan in 25 healthy controls and 26 leprosy patients. RESULTS: The mean epineurial thickness was 0.77 mm (95% confidence interval [CI] 0.66-0.88) in symptomatic ulnar nerves (n = 20), 0.58 mm (CI 0.51-0.65) in asymptomatic nerves (n = 30), and 0.49 mm (CI 0.44-0.54) in healthy controls (n = 25) (P = 0.0001). This thickening was related to the cross-sectional area of the ulnar nerve, but not with increased blood flow. CONCLUSIONS: The epineurium of the ulnar nerve can be measured with the use of HRUS, and it is often strikingly thickened in leprosy patients, especially in those with ulnar involvement.

Dermlep Study Part 3: Post-RFT Events in Leprosy Patients Presenting to Dermatologists.

Introduction: Presently the leprosy program has no defined surveillance protocols for patients who complete the fixed duration multidrug therapy and are released from treatment (RFT). Hence, the information about the post-RFT events in these patients is sparse and qualitative and quantitative data regarding their health care requirements is missing. During the DermLep survey carried out by the Indian Association of Dermatologists,Venereologists and Leprologists (IADVL), a number of patients presented to dermatologists during the post RFT period for a variety of symptoms. This paper analyses the events in these patients during the post RFT period. Results: Out of a total of 3701 leprosy patients who presented to 201 dermatologists across India during the DermLep survey, 708 (26.2%) were in the post RFT period (488 males; 220 females). Of these, 21% were PB and 79% MB patients as per their treatment records. Majority were in the age group of 31-59 years (55.5%); however, a significant proportion of them (20.7%) were elderly (>60 years). Majority of the patients (45.5%) presented within the first year of RFT with variable symptoms; 28% were between 1-5 years, 5.5% between 5-10 years; and 11.0% presented more than 10 years after RFT. Most common presenting complaint being persistent skin lesions as perceived by patients in 21.2%, followed by neuritis in 14.5%; trophic ulcers in 13.8%; deformities in 67 (11.8%); lepra reactions in 66 (11.6%); and recurrence of original symptoms in 6.7%. Conclusion: The DermLep Survey highlights the importance of 'post RFT' patients as an important subset of leprosy patients who visit dermatologists for various health related issues. The most common complaints in this subset were active/persistent skin lesions, lepra reactions and neuritis. In these patients, who are a sub-group of 'persons affected with leprosy' the disease related issues can persist for many years post RFT. Hence, it is important to provide services in the programme to monitor and manage these complications for the prevention of impairments, disability and the related social issues.

Antibodies to myelin P0 and ceramide perpetuate neuropathy in long standing treated leprosy patients.

Anti neural antibodies are known to play a role in the immunopathogenesis of nerve damage in leprosy and HIV/AIDS. Myelin Protein zero (P0) and ceramide are two nerve components which maintain the integrity of the peripheral nerve. The present study was undertaken to identify antibodies to myelin P0 and ceramide in the sera of treated leprosy patients, HIV positive individuals and healthy subjects using enzyme linked immunosorbant assay (ELISA). The results revealed that treated leprosy patients continue to have significantly elevated myelin P0 and ceramide antibody levels as compared to healthy subjects (P < 0.05). The elevated antibody response to myelin P0 and ceramide in leprosy patients indicate a low grade autoimmune activity that perpetuates nerve damage in treated leprosy. There was no significant difference in the myelin P0 and ceramide antibody levels between HIV positive and healthy subjects (P > 0.05) suggesting that these antibodies do not play a role in early HIV infection.

Changes in the size and number of skin lesions in PB leprosy on treatment and follow-up.

BACKGROUND: The increase in size of existing skin lesions and appearance of new skin lesions are considered important signs of clinical activity both in untreated and treated leprosy. To confirm such activity, the number and size of lesions need to be recorded methodically prior to therapy and on follow-up, especially in PB leprosy where clinical signs alone define the reactivation of the disease. However, no systematic follow-up studies are available on changes in size and number of skin lesions in PB leprosy before and after therapy. OBJECTIVES: To measure changes in the number and size of skin lesions in PB leprosy patients before starting MDT PB and after 18 months follow-up in order to evaluate their relevance in assessing clinical improvement and identifying possible relapses. DESIGN: In 32 untreated leprosy patients with 1-5 skin lesions, the number of skin lesions were recorded on body charts and their size measured using a grid chart method to arrive at total area of involvement in each patient prior to starting MDT PB and after 18 months. Skin smears and skin biopsies were performed at entry and follow-up to assist the clinical evaluation. RESULTS: Twenty three patients had single skin lesion (SSL), followed by three each with two and three skin lesions respectively, two with four and one with five skin lesions. The area of involvement ranged from six to 1686 sq cm. Few patients with SSL had higher areas of involvement than those who had multiple skin lesions. On follow-up at 18 months, in 14 (44%) patients skin lesions were not measurable, while in 18 (56%) they were measurable, with eight (25%) patients showing no change, three (9%) showing decrease and seven (22%) showing increase in area of involvement. Of the seven patients showing increase, in three it was due to the spread of existing skin lesions alone, in one it was due to a new skin lesion alone and in three due to the spread of existing skin lesions and the appearance of new skin lesions. New skin lesions were multiple (> 3) in two patients. T1R was observed in three out of four patients with new skin lesions, and this was persistent at 18 months in one patient. When histopathology at the entry and 18 month follow-up was compared, in one patient with persistent T1R with appearance of multiple new skin lesions, there was increase in GF from 10 to 40% with histological features of T1R and a BI of granuloma of 1+. CONCLUSIONS: In 32 treated patients of PB leprosy on 18 month follow-up for changes in size and number of skin lesions, of six patients showing increase in area of involvement of existing skin lesions, 3 (50%) developed new skin lesions, indicating persistent disease activity. The new lesions which were associated with T1R increased the total number of skin lesions to > 5 in two of these patients requiring a change of drug regimen from PB to MB MDT, with one of them fulfilling clinical and histopathological criteria for relapse of leprosy. Hence, although new lesions are known to occur as part of T1R in PB patients, they are events of great significance which need to be assessed in a methodical manner for their influence on classification and therapy of leprosy.

Updates on Management of Leprosy in the Context of COVID-19 Pandemic: Recommendations by IADVL SIG Leprosy.

The Special Interest Group (SIG) on leprosy thought it to be prudent to revisit its previous practice recommendations through this update. During this period, the pandemic course shifted to a 'second wave' riding on the 'delta variant'. While the number of cases increased manifold, so did the research on all aspects of the disease. Introduction of vaccination and data from various drug trials have an impact on current best practices on management of diseases including leprosy. The beneficial results of using steroids in management of COVID-19, gives elbow room regarding its usage in conditions like lepra reactions. On the other hand, the increase in cases of Mucormycosis again underlines applying due caution while recommending immunosuppressants to a patient already suffering from COVID-19. This recommendation update from SIG leprosy reflects current understanding about managing leprosy while the dynamic pandemic continues with its ebbs and flows.

The Dermlep Study Part 2: Results of a Nation-Wide Survey of Dermatologists' Access to Quality Leprosy Services at their Clinics and Hospitals in India.

INTRODUCTION: Dermatologists in India are trained and qualified to treat leprosy and there is evidence to suggest that they are involved in the diagnosis and management of a significant number of leprosy patients in the country. The present study evaluated the access to quality leprosy services at their clinics and hospitals to understand the extent of their role in providing comprehensive care to people affected by leprosy and how it can be organized further. METHODS: The DermLep Study was a pan-India questionnaire-based survey carried out to evaluate the role that dermatologists play in leprosy management in the country. It included as part-2 of the survey, 11 questions on the access of the dermatologist to various quality leprosy services available at the clinic or institution including skin smears, skin biopsy, multidrug therapy (MDT) blister packs, basic physiotherapy services, and reporting to the national program (NLEP). RESULTS: The dermatologists who participated in the survey included 101 private practitioners and 100 working in Government or private medical institutions. The key findings of the survey were that 78% of the participating dermatologists still encounter leprosy patients frequently in their clinics; 81.0% of them had access to skin smears; and 93.4% to skin biopsy. The World Health Organization (WHO) MDT regimen was followed by 79.0% of the dermatologists in the study, majority of whom were those working in medical colleges (88%); however overall, 87.4% extended the regimen beyond the fixed duration, mostly on a case to case basis. Thalidomide was available for 61.1% of them to treat type 2 reactions. Basic physiotherapy services were available with 70.2% of dermatologists surveyed; 58.9% dermatologists had access to MCR footwear; and RCS facility access known to 45.5% of them. About 83.5% of the dermatologists working in institutions were reporting their leprosy cases to the NLEP, whereas from a high percentage (71.4%) of dermatologists in private practice, cases were not captured in routine under NLEP. CONCLUSION: Dermatologists in India have the clinical skill, expertise, and access to most of the basic services, including skin smear and skin biopsy facilities needed to provide comprehensive care to leprosy patients in post-elimination era of integration of leprosy services. While dermatologists are already managing leprosy patients both at medical institutes and private clinics across India, their "structured" involvement at all levels in the national program will facilitate improved reporting and cataloging of cases seen by them. It will also elevate standards of leprosy care; create an effective public-private partnership and disease expertise; and assist develop a comprehensive, patient-tailored approach in the leprosy program in India.

The DermLep Study I: Results of Prospective Nation-Wide Survey of the Number & Profile of Leprosy Patients seen by Dermatologists in India.

INTRODUCTION: There is evidence to suggest that there is a mismatch between the number of reported cases of leprosy in India and the number of actual cases in the country. One reason could be that many patients are diagnosed and treated outside the NLEP network and dermatologists may be managing some of these patients not captured by official statistics. To estimate these missing numbers, the DermLep survey was carried out to study the number and profile of leprosy patients seen by dermatologists and their significance. METHODOLOGY: The DermLep survey was a questionnaire-based study to be filled in by participating dermatologists from all over India, both in private practice and in medical institutions. Participating dermatologists provided information on old and new leprosy patients seen in their clinic over a 3-month period. RESULTS: Total of 201 dermatologists from 20 states of India participated in the survey. 3701 leprosy patients (M: F ratio 2.1:1) were seen. Of them 46.62% (n = 1680) were new; 22.89% (n = 825) were under-treatment; and 19.65% (n = 708) were post RFT patients. Children <15 years constituted 4.29%, while elderly >60 years were 22.21%. As per WHO classification, MB were 73.36% and PB 28.46%. Of all patients 30.91% had lepra reactions, with T2R being more frequent. While 23.58% of all patients in the survey had G2D; in new patients 17.79%; and in post RFT patients 37% had G2D. Among the 1680 new cases seen, 59% were reported to NLEP by the dermatologists and 41% remained unreported mainly by the private dermatologists, among whom for 20% of the cases they mentioned "no access to register". Source of MDT was WHO-MDT in 60.09% of new cases and for rest of 39.91% it was private pharmacies where private dermatologists had no access to MDT blister packs. CONCLUSION: This survey suggests that a good number of new-untreated leprosy patients, treatment defaulters and post RFT cases are managed by dermatologists in India. About 40% of the new patients managed mainly by private dermatologists are not being reported to NLEP for various reasons, and these constitute the "missing numbers" from government statistics. If extrapolated to the large of number of practicing dermatologists in India, these numbers could be very significant. The high percentage of G2D noted in patients surveyed (23.58%) and post RFT patient issues observed need special attention. There is a need to develop access for dermatologists to confidentially report leprosy patients treated at their clinics to the NLEP.

Comparative study of uniform-MDT and WHO MDT in Pauci and Multi bacillary leprosy patients over 24 months of observation.

STUDY DESIGN: An open comparative study between WHO MDT and U-MDT regimen in all types of leprosy over 24 months of observation was carried out at Gandhi Hospital, Secunderabad, India. Periodic assessment of clinical and histopathological parameters at 6 monthly intervals was performed in both groups of patients for grading response to the treatment regimens. PATIENTS AND METHODS: One hundred and twenty-seven newly diagnosed, untreated leprosy patients classified into PB (< or = 5 skin lesions) and MB leprosy (> 5 skin lesions) were alternately allocated into Study (U-MDT for 6 months) and Control groups (WHO MDT) at entry. Out of the 127 patients included, 64 patients (M-44, F-20; PB leprosy 32 & MB leprosy 32) could be followed-up regularly. These 64 patients were clinically assessed and graded into Good, Moderate and Poor response at 6, 12 and 18 months of the study, and 44 of these patients were also assessed at 24 months of the study. Histopathological assessments were also done at the above intervals. RESULTS: PB PATIENTS: The control and study groups comprised of 14 and 18 patients respectively. When clinical grades were compared, the numbers of Moderate and Good responses were 78% and 61% at 6 months, 86% and 94% at 18 months and 82% and 100% at 24 months in the PB Control and Study groups respectively, suggesting better progressive improvement in the Study group compared to Control group, but the differences were not significant (At 6 months P = 02195, at 18 months 0.7305, at 24 months P = 0.3500) Histopathological assessment at 12 months, showed higher percentage of Good responses (100%) in the PB-Study group than in the PB-Control group (86%). MB PATIENTS: The MB Control and Study groups comprised of 22 and 10 patients respectively. In clinical improvement grades, Good responses in the Control group was 36%, 45% and 77% at 12, 18 and 24 months of study, whereas the Study group did not have a single Good response at 12 and 18 months with the Poor responses being 50%, 67% and 75% at 12, 18 and 24 months. These differences between the groups were significant at all periods of assessment. (At 12 months P = 0.0465, at 18 months P = 0.0014, at 24 months P = 0.0064). Histopathological assessment showed higher the percentage of Good responses in Control group (100%) compared to Study group (50%) at 18 months. CONCLUSION: U-MDT of 6 months duration was well tolerated and effective in patients with PB leprosy but was too short a regimen adequately to treat patients with MB leprosy.

Current Situation of Leprosy in India and its Future Implications.

The global leprosy situation has changed significantly over the last four decades after the introduction of multidrug therapy (MDT) in 1982 with a reduction in prevalence from over 5 million cases in the mid-1980s to less than 200,000 at the end of 2016. The programme in India also saw a reduction from a prevalence rate of 57.8/10,000 in 1983 to less than 1/10,000 by the end of 2005 when India declared to have reached the World Health Organization (WHO) target of elimination as a public health problem. Post 2005, major changes in the programme were made by the National leprosy eradication programme (NLEP) and the global leprosy programme, which may have affected the new case detection (NCD), disability, and child leprosy trends, which continue to show no appreciable regression. This article reviews the current global and Indian leprosy scenario to bring out its achievements and successes, including the impact of Leprosy Case Detection Campaigns (LCDC) on leprosy numbers. The basis and expected benefits of recent introduction of chemo and immune-prophylaxis in the programme are also discussed. It also discusses the shortcomings, the areas of concern, and the need for an inclusive strategy in the Indian leprosy programme that includes an intersectoral collaboration within the country for reaching the desired goal of leprosy eradication.

Insights from the sequence similarity of Zika virus proteins with the Human nerve proteins.

Massive peptide sharing between the Zika virus polyprotein and host tissue proteins could elicit significant host-pathogen interactions and cross-reactions leading to autoimmune diseases. This study found similarities in the Zika V proteins and human nerve tissue proteins. 63 human nerve proteins were screened for similarities with the Zika V of which Neuromodulin, Nestin, Galanin, Bombesin, Calcium-binding protein were found to have similarities to the Zika V poly protein C at different sequence regions. These sequence similarities could be significant in regulating pathogenic interactions/autoimmunity, as Polyprotein C is known to be a virulent factor.

Alteration of the cortisol-cortisone shuttle in leprosy type 1 reactions in leprosy patients in Hyderabad, India.

Regulation of inflammation in leprosy may be influenced by local concentrations of active cortisol and inactive cortisone, whose concentrations are regulated by enzymes in the cortisol-cortisone shuttle. We investigated the cortisol-cortisone shuttle enzymes in the skin of leprosy patients with type 1 reactions (T1R), which are characterised by skin and nerve inflammation. Gene expression of the shuttle enzymes were quantified in skin biopsies from 15 leprosy patients with new T1R before and during prednisolone treatment and compared with levels in skin biopsies from 10 borderline leprosy patients without reactions. Gene expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2, which converts cortisol to cortisone, is down-regulated in skin from T1R lesions. However expression levels of 11beta-HSD type 1, which converts cortisone to cortisol, were similar in skin with and without reactions and did not change during anti-leprosy drug treatment. Prednisolone treatment of patients with reactions is associated with an upregulation of 11beta-HSD2 expression in skin. The down regulation of 11beta-HSD2 at the beginning of a reaction may be caused by pro-inflammatory cytokines in the leprosy reactional lesion and may be a local attempt to down-regulate inflammation. However in leprosy reactions this local response is insufficient and exogenous steroids are required to control inflammation.

Histopathological and clinical findings in leprosy patients with chronic neuropathic pain: a study from Hyderabad, India.

BACKGROUND: Chronic neuropathic pain in leprosy patients after completion of multi-drug therapy (MDT) is an under-researched problem. The reason why some leprosy patients develop it is unknown. In this study we evaluated the role of ongoing inflammation and small-fibre neuropathy as possible contributing factors for neuropathic pain. METHODS: We assessed chronic neuropathic pain in 17 leprosy patients who had completed MDT and were attending a referral clinic in Hyderabad, India. All patients had a clinical assessment, intraepidermal nerve (IENF) assessment and quantitative sensory testing (QST), which included the testing of tactile and pinprick sensations using Semmes-Weinstein monofilaments and weighted needles method. Nine patients had a sural nerve biopsy (SNB). RESULTS: Thirteen patients had a glove and stocking pattern of neuropathy. All nerve biopsies showed inflammation with intraneural inflammation and perineural thickening, and intraneural acid fast bacilli were observed in five biopsies. IENF analysis of the skin biopsy specimens in 16/17 patients showed a statistically significant reduction in IENF density (P < 0.001, Mann Whitney test) compared to control skin biopsies. Complete depletion of intraepidermal nerves was observed in six patients. QST also showed marked abnormalities. In 11 patients total sensory loss for all modalities was found, and in the other six patients the sensory function was seriously impaired. DISCUSSION: There is evidence of ongoing intraneural inflammation in leprosy patients who have completed MDT. This may explain the occurrence of chronic neuropathic pain. Using IENF density measurement we have found significant small-fibre neuropathy in leprosy patients and the use of this tool could be expanded.