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.

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.

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.

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.

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.

Anticeramide antibody and butyrylcholinesterase in peripheral neuropathies.

Ceramide is a glycosphingolipid, a component of nerve and non neuronal cell membrane and plays a role in maintaining the integrity of neuronal tissue. Butyrylcholinesterase (BChE) is a multifunctional enzyme, its involvement in neurodegenerative diseases has been well established. Anticeramide antibody (Ab-Cer) and enzyme BChE have been implicated in peripheral neuropathies. The present study investigates whether there is an association between Ab-Cer and BChE activities and peripheral neuropathies. Patients included: human immunodeficiency virus associated peripheral neuropathy (HIV-PN, n=39), paucibacillary leprosy (PB-L, n=36), multibacillary leprosy (MB-L, n=52), diabetic neuropathy (DN, n=22), demyelinating sensory motor polyneuropathy (DSMN, n=13) and chronic inflammatory demyelinating polyneuropathy (CIDP, n=10). Plasma Ab-Cer was measured by indirect enzyme linked immune assay (ELISA) and BChE activity in plasma was measured by colorimetric method. Ab-Cer levels were significantly elevated in MB-L and DN as compared to healthy subjects (HS). BChE levels were significantly higher in MB-L and DN as well as in HIV and HIV-PN. There is no significant difference in either Ab-Cer or BChE levels in DSMN and CIDP. Elevated plasma Ab-Cer and BChE levels may be considered significant in the pathogenesis of neuropathies. The variation in concurrent involvement of both the molecules in the neuropathies of the study, suggest their unique involvement in neurodegenerative pathways.

High levels of plasma interferon gamma and +874T/A gene polymorphism is associated with HIV-TB co-infection.

OBJECTIVE: Tuberculosis (TB) is one of the most frequent opportunistic infections in HIV patients leading to increased morbidity and death rate. This study was carried out to investigate the role of the cytokines IFN-γ and TNF-α level and their single nucleotide polymorphisms (SNPs) in HIV-TB co-infection. METHODS: 247 HIV-TB (124 HIV-pulmonary TB, 123 HIV-extra pulmonary TB), 126 HIV positive individuals without tuberculosis and 129 healthy subjects (HS) were included to measure plasma levels of IFN-γ and TNF-α by sandwich ELISA and One way ANOVA statistical analysis was carried out among the groups. The SNPs of TNF-α-308 G/A, -238 G/A and IFN-γ+874 T/A were also investigated using amplification refractory mutation system polymerase chain reaction (ARMS-PCR). The frequencies between the groups were compared by Pearson's chi square statistical analysis. RESULTS: Plasma IFN-γ and TNF-α were significantly elevated in HIV-TB and TB (p<0.05) as compared to those in HS group. There was significant association between IFN-γ+874 'A' allele and AA genotype in HIV-TB groups compared to HS and HIV (p<0.05) and no such association was found for TNF-α-308 and -238. The plasma cytokine levels of TNF-α and IFN-γ reveals no significant association with levels of IFN-γ+874 T/A, TNF-α -308 G/Aand-238 G/A genotypes in any of the study groups. CONCLUSION: In conclusion, the present study revealed elevated plasma IFN-γ and its +874 'A' allele are associated with HIV-TB co-infection indicating 1.6 times increased risk for TB susceptibility. Elevated TNF-α levels in TB and HIV-TB suggest its involvement in TB pathogenesis.

Detection of Tuberculosis in HIV Co-infected Individuals: Use of Multiple ELISA Responses to 38kDa, Lipoarabinomannan and ESAT- 6 of M. tuberculosis.

INTRODUCTION: There is a constant search for more sensitive and specific laboratory markers for tuberculosis (TB) infection. The early detection of TB in HIV co infected individuals is a diagnostic challenge. This is further compounded in those harbouring extrapulmonary disease. AIM: To evaluate the use of multiple Enzyme Linked Immunosorbent Assays (ELISA) quantifying antibody responses to 38kDa, LAM and ESAT-6 M.tb antigens in detection of TB in patients with TB and HIV-TB co-infection. MATERIALS AND METHODS: This is a cross-sectional study carried out in Hyderabad, India. Patient groups included 124 HIV-TB {62 with pulmonary TB (PTB) and 62 with extrapulmonary TB (ETB)}, 39 TB, 56 HIV and 57 healthy subjects (HS). A combination of anti 38kDa and LAM ELISAs measuring IgG, IgM and IgA levels and another ELISA measuring anti ESAT-6 combined antibody levels of IgG, IgM and IgA were evaluated. One-way ANOVA was performed to compare antibody responses among groups. To assess the efficacy of multiple ELISAs in detecting TB, concomitant seropositivity of an individual for all four ELISAs were evaluated for sensitivity and specificity. RESULTS: A single ELISA carried out to detect TB in HIV patients showed a sensitivity ranging from 39% to 72%. The sensitivities of concomitant evaluation of multiple ELISAs were 92% for any single, 72% for any two, 44% for any three and 14% for any four. Based on the specificities, a simple algorithm for TB detection can be deduced. When four ELISAs are positive (specificity 100%) in a patient-confirmed TB; when three ELISAs are positive (specificity 98%) - probably TB; when two ELISAs are positive (specificity 95%) - possibly TB; and when one ELISA is positive (specificity 70%) - suspicion of TB. CONCLUSION: The present study establishes the value of combining two or more M.tb antigen based ELISAs to enhance the sensitivity and specificity of TB detection in patients with tuberculosis as well as in those co-infected with HIV.

Pure neuritic leprosy: Current status and relevance.

Pure neuritic leprosy has always been an enigma due to its clinical and management ambiguities. Although only the Indian Association of Leprologist's classification recognizes 'pure neuritic leprosy' as a distinct sub group of leprosy, cases nonetheless are reported from various countries of Asia, Africa, South America and Europe, indicating its global relevance. It is important to maintain pure neuritic leprosy as a subgroup as it constitutes a good percentage of leprosy cases reported from India, which contributes to more than half of global leprosy numbers. Unfortunately, a high proportion of these patients present with Grade 2 disability at the time of initial reporting itself due to the early nerve involvement. Although skin lesions are absent by definition, when skin biopsies were performed from the skin along the distribution of the affected nerve, a proportion of patients demonstrated leprosy pathology, revealing sub-clinical skin involvement. In addition on follow-up, skin lesions are noted to develop in up to 20% of pure neuritic leprosy cases, indicating its progression to manifest cutaneous disease. Over the decades, the confirmation of diagnosis of pure neuritic leprosy has been subjective, however, with the arrival and use of high-resolution ultrasonography (HRUS) for nerve imaging, we have a tool not only to objectively measure and record the nerve thickening but also to assess the morphological alterations in the nerve including echo texture, fascicular pattern and vascularity. Management of pure neuritic leprosy requires multidrug therapy along with appropriate dose of systemic corticosteroids, for both acute and silent neuritis. Measures for pain relief, self-care of limbs and physiotherapy are important to prevent as well as manage disabilities in this group of patients.

Imaging techniques in leprosy clinics.

Leprosy is the most common treatable peripheral nerve disorder worldwide, with periods of acute neuritis leading to functional impairment of limbs and stigmatizing deformities. The nerve involvement in leprosy reactions, if recognized early and promptly treated with steroids and nerve release surgery, can be reversible. Currently, the nerve assessment in leprosy relies mainly on clinical assessment and nerve conduction studies. High-resolution ultrasonography (HRUS) of peripheral nerves is finding wider application in the differential diagnosis of peripheral neuropathy. HRUS provides a noninvasive tool that gives information on location and degree of nerve enlargement, nerve morphologic alterations, echo texture, fascicular pattern, and vascularity of the nerve, which mirrors the histologic changes. HRUS is amenable to studying structural changes in nerve sites that cannot be biopsied for histopathologic examination and is more cost effective than magnetic resonance imaging. So far other there are only five studies available on the sonographic findings in leprosy. These findings are reviewed and the technique of HRUS is described in this paper, with a recommendation of a standard protocol and proforma.

Imaging techniques in leprosy clinics

Leprosy is the most common treatable peripheral nerve disorder worldwide, with periods of acute neuritis leading to functional impairment of limbs and stigmatizing deformities. The nerve involvement in leprosy reactions, if recognized early and promptly treated with steroids and nerve release surgery, can be reversible. Currently, the nerve assessment in leprosy relies mainly on clinical assessment and nerve conduction studies. High-resolution ultrasonography (HRUS) of peripheral nerves is finding wider application in the differential diagnosis of peripheral neuropathy. HRUS provides a noninvasive tool that gives information on location and degree of nerve enlargement, nerve morphologic alterations, echo texture, fascicular pattern, and vascularity of the nerve, which mirrors the histologic changes. HRUS is amenable to studying structural changes in nerve sites that cannot be biopsied for histopathologic examination and is more cost effective than magnetic resonance imaging. So far other there are only five studies available on the sonographic findings in leprosy. These findings are reviewed and the technique of HRUS is described in this paper, with a recommendation of a standard protocol and proforma.

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.

Relationship of long-term highly active antiretroviral therapy on salivary flow rate and CD4 Count among HIV-infected patients.

OBJECTIVES: To determine if long-term highly active antiretroviral therapy (HAART) therapy alters salivary flow rate and also to compare its relation of CD4 count with unstimulated and stimulated whole saliva. MATERIALS AND METHODS: A cross-sectional study was performed on 150 individuals divided into three groups. Group I (50 human immunodeficiency virus (HIV) seropositive patients, but not on HAART therapy), Group II (50 HIV-infected subjects and on HAART for less than 3 years called short-term HAART), Group III (50 HIV-infected subjects and on HAART for more than or equal to 3 years called long-term HAART). Spitting method proposed by Navazesh and Kumar was used for the measurement of unstimulated and stimulated salivary flow rate. Chi-square test and analysis of variance (ANOVA) were used for statistical analysis. RESULTS: The mean CD4 count was 424.78 ± 187.03, 497.82 ± 206.11 and 537.6 ± 264.00 in the respective groups. Majority of the patients in all the groups had a CD4 count between 401 and 600. Both unstimulated and stimulated whole salivary (UWS and SWS) flow rates in Group I was found to be significantly higher than in Group II (P < 0.05). Unstimulated salivary flow rate between Group II and III subjects were also found to be statistically significant (P < 0.05). ANOVA performed between CD4 count and unstimulated and stimulated whole saliva in each group demonstrated a statistically significant relationship in Group II (P < 0.05). There were no significant results found between CD4 count and stimulated whole saliva in each groups. CONCLUSION: The reduction in CD4 cell counts were significantly associated with salivary flow rates of HIV-infected individuals who are on long-term HAART.