An assessment of the reported impact of the COVID-19 pandemic on leprosy services using an online survey of practitioners in leprosy referral centres.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to governments implementing a variety of public health measures to control transmission and has affected health services. Leprosy is a communicable neglected tropical disease caused by Mycobacterium leprae and is an important health problem in low- and middle-income countries. The natural history of leprosy means that affected individuals need long-term follow-up. The measures recommended to reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can create barriers to health services. We evaluated the impact of the COVID-19 epidemic response on leprosy services and disease management. METHODS: We conducted a cross-sectional online survey with healthcare professionals in leprosy referral centres. RESULTS: Eighty percent of leprosy diagnostic services were reduced. All respondents reported that multidrug therapy (MDT) was available but two reported a reduced stock. Clinicians used alternative strategies such as telephone consultations to maintain contact with patients. However, patients were not able to travel to the referral centres. DISCUSSION: This study highlights the effects of the initial phase of the SARS-CoV-2 pandemic on leprosy services in a range of leprosy-endemic countries. Many services remained open, providing leprosy diagnosis, MDT and leprosy reaction medications. Centres developed innovative measures to counter the negative impacts of the COVID-19 pandemic.

Methotrexate and prednisolone study in erythema nodosum leprosum (MaPs in ENL) protocol: a double-blind randomised clinical trial.

INTRODUCTION: Erythema nodosum leprosum (ENL) is an immunological complication of leprosy. ENL results in morbidity and disability and if it is not treated can lead to death. The current treatment consists of thalidomide or high doses of oral corticosteroids for prolonged periods. Thalidomide is not available in many leprosy endemic countries. The use of corticosteroids is associated with morbidity and mortality. Identifying treatment regimens that reduce the use of corticosteroids in ENL is essential. Methotrexate (MTX) is used to treat many inflammatory diseases and has been used successfully to treat patients with ENL not controlled by other drugs, including prednisolone and thalidomide. We present the protocol of the 'MTX and prednisolone study in ENL' (MaPs in ENL) a randomised controlled trial (RCT) designed to test the efficacy of MTX in the management of ENL. METHODS AND ANALYSIS: MaPs in ENL is an international multicentre RCT, which will be conducted in leprosy referral centres in Bangladesh, Brazil, Ethiopia, India, Indonesia and Nepal. Patients diagnosed with ENL who consent to participate will be randomly allocated to receive 48 weeks of weekly oral MTX plus 20 weeks of prednisolone or 48 weeks of placebo plus 20 weeks of prednisolone. Participants will be stratified by type of ENL into those with acute ENL and those with chronic and recurrent ENL. The primary objective is to determine whether MTX reduces the requirement for additional prednisolone. Patients' reported outcome measures will be used to assess the efficacy of MTX. Participants will be closely monitored for adverse events. ETHICS AND DISSEMINATION: Results will be submitted for publication in peer-reviewed journals. Ethical approval was obtained from the Observational/Interventions Research Ethics Committee of the London School of Hygiene & Tropical Medicine (15762); The Leprosy Mission International Bangladesh Institutional Research Board (in process); AHRI-ALERT Ethical Review Committee, Ethiopia; Ethics Committee of the Managing Committee of the Bombay Leprosy Project; and The Leprosy Mission Trust India Ethics Committee; the Nepal Health and Research Council and Health Research Ethics Committee Dr. Soetomo, Indonesia. This study is registered at www.clinicaltrials.gov. This is the first RCT of MTX for ENL and will contribute to the evidence for the management of ENL.Trial registration numberNCT 03775460.

Clinical characteristics of neuropathic pain in leprosy and associated somatosensory profiles: a deep phenotyping study in India.

This study investigated the clinical characteristics and somatosensory profiles of patients suffering from leprosy in Mumbai, India. A cross-sectional deep profiling study was conducted in 86 patients with leprosy (with and without pain) using an extensive battery of phenotyping measures including structured clinical examination, psychological state (General Health Questionnaire [GHQ-12]), and a quality-of-life condition-specific instrument (Brief Pain Inventory-short form). Quantitative sensory testing was performed according to the protocol of the German Research Network on Neuropathic Pain (DFNS) to assess the somatosensory profiles in the ulnar nerve innervation territory of all participants (dorsum of the hand). Reference data from 50 healthy Indian subjects were within the range of published DFNS values. Somatosensory profiles in leprosy patients with clinically or electroneurographically diagnosed neuropathy (with and without pain) revealed a profile of sensory loss to thermal and tactile stimuli combined with preservation of vibration and deep pressure detection. Sensory gain phenomena were not generally observed in patients with leprosy. In the group of subclinical neuropathy, a high degree of impaired thermal sensation was found, which could be clinically deployed to enhance identification of leprosy neuropathy at an early stage. Quantitative sensory testing can effectively document leprosy-associated neuropathy but does not distinguish between patients with or without pain. Patients with leprosy and neuropathic pain reported a poor quality of life and less psychological well-being compared with the pain-free patients with leprosy neuropathy.

Effectiveness of 32 versus 20 weeks of prednisolone in leprosy patients with recent nerve function impairment: A randomized controlled trial.

BACKGROUND: While prednisolone is commonly used to treat recent nerve function impairment (NFI) in leprosy patients, the optimal treatment duration has not yet been established. In this "Treatment of Early Neuropathy in Leprosy" (TENLEP) trial, we evaluated whether a 32-week prednisolone course is more effective than a 20-week course in restoring and improving nerve function. METHODS: In this multi-centre, triple-blind, randomized controlled trial, leprosy patients who had recently developed clinical NFI (<6 months) were allocated to a prednisolone treatment regimen of either 20 weeks or 32 weeks. Prednisolone was started at either 45 or 60 mg/day, depending on the patient's body weight, and was then tapered. Throughout follow up, NFI was assessed by voluntary muscle testing and monofilament testing. The primary outcome was the proportion of patients with improved or restored nerve function at week 78. As secondary outcomes, we analysed improvements between baseline and week 78 on the Reaction Severity Scale, the SALSA Scale and the Participation Scale. Serious Adverse Events and the need for additional prednisolone treatment were monitored and reported. RESULTS: We included 868 patients in the study, 429 in the 20-week arm and 439 in the 32-week arm. At 78 weeks, the proportion of patients with improved or restored nerve function did not differ significantly between the groups: 78.1% in the 20-week arm and 77.5% in the 32-week arm (p = 0.821). Nor were there any differences in secondary outcomes, except for a significant higher proportion of Serious Adverse Events in the longer treatment arm. CONCLUSION: In our study, a 20-week course of prednisolone was as effective as a 32-week course in improving and restoring recent clinical NFI in leprosy patients. Twenty weeks is therefore the preferred initial treatment duration for leprosy neuropathy, after which likely only a minority of patients require further individualized treatment.

A leprosy clinical severity scale for erythema nodosum leprosum: An international, multicentre validation study of the ENLIST ENL Severity Scale.

OBJECTIVES: We wished to validate our recently devised 16-item ENLIST ENL Severity Scale, a clinical tool for measuring the severity of the serious leprosy associated complication of erythema nodosum leprosum (ENL). We also wished to assess the responsiveness of the ENLIST ENL Severity Scale in detecting clinical change in patients with ENL. METHODS: Participants, recruited from seven centres in six leprosy endemic countries, were assessed using the ENLIST ENL Severity Scale by two researchers, one of whom categorised the severity of ENL. At a subsequent visit a further assessment using the scale was made and both participant and physician rated the change in ENL using the subjective categories of "Much better", "somewhat better", "somewhat worse" and "much worse" compared with "No change" or "about the same". RESULTS: 447 participants were assessed with the ENLIST ENL Severity Scale. The Cronbach alpha of the scale and each item was calculated to determine the internal consistency of the scale. The ENLIST ENL Severity Scale had good internal consistency and this improved following removal of six items to give a Cronbach's alpha of 0.77. The cut off between mild ENL and more severe disease was 9 determined using ROC curves. The minimal important difference of the scale was determined to be 5 using both participant and physician ratings of change. CONCLUSIONS: The 10-item ENLIST ENL Severity Scale is the first valid, reliable and responsive measure of ENL severity and improves our ability to assess and compare patients and their treatments in this severe and difficult to manage complication of leprosy. The ENLIST ENL Severity Scale will assist physicians in the monitoring and treatment of patients with ENL. The ENLIST ENL Severity Scale is easy to apply and will be useful as an outcome measure in treatment studies and enable the standardisation of other clinical and laboratory ENL research.

ENLIST 1: An International Multi-centre Cross-sectional Study of the Clinical Features of Erythema Nodosum Leprosum.

Erythema nodosum leprosum (ENL) is a severe multisystem immune mediated complication of borderline lepromatous leprosy and lepromatous leprosy. ENL is associated with skin lesions, neuritis, arthritis, dactylitis, eye inflammation, osteitis, orchitis, lymphadenitis and nephritis. The treatment of ENL requires immunosuppression, which is often required for prolonged periods of time and may lead to serious adverse effects. ENL and its treatment is associated with increased mortality and economic hardship. Improved, evidence-based treatments for ENL are needed; however, defining the severity of ENL and outcome measures for treatment studies is difficult because of the multiple organ systems involved. A cross-sectional study was performed, by the members of the Erythema Nodosum Leprosum International STudy (ENLIST) Group, of patients with ENL attending seven leprosy referral centres in Brazil, Ethiopia, India, Nepal, the Philippines and the United Kingdom. We systematically documented the clinical features and type of ENL, its severity and the drugs used to treat it. Patients with chronic ENL were more likely to be assessed as having severe ENL. Pain, the most frequent symptom, assessed using a semi-quantitative scale was significantly worse in individuals with "severe" ENL. Our findings will determine the items to be included in a severity scale of ENL which we are developing and validating. The study also provides data on the clinical features of ENL, which can be incorporated into a definition of ENL and used for outcome measures in treatment studies.

Interesting and unusual clinical presentations in leprosy at a referral center.

BACKGROUND: Leprosy is a disease of declining global endemicity but is still an important health-care problem in India. Pure neural leprosy is an important subset of presentations of leprosy in India. Leprosy is a known disease of the skin and nerves, but cases of pure neural involvement are relatively less. We hereby present 10 cases of pure neural leprosy in which the diagnosis of leprosy was difficult with routine methods. MATERIALS AND METHODS: The study was conducted at the main referral center and satellite clinics of our organization. A retrospective analysis of patient records for the last four years was undertaken to identify patients presenting with predominantly neurological manifestations and uncommon presentations including those without skin lesions. The medical records of the patients were used as source of data. All the patients were subjected to a detailed clinical examination and bacteriological examination with slit-skin smears. Investigations like nerve biopsy, electromyography, and nerve conduction studies were done in patients with diagnostic difficulties. RESULTS: Patients presented with neurological symptoms like paresthesias (60%), diminished sensations (40%), nonhealing ulcers (30%), and blisters (20%). All except one had thickened nerves on clinical examination. Slit-skin smear was negative in all but one patient. Nerve biopsy confirmed the diagnosis of leprosy in seven cases. CONCLUSION: Pure neural leprosy is difficult to diagnose with routine methods. The diagnosis should be considered, especially by neurologists and dermatologists, who are more likely to see such patients with predominant neural manifestations. The diagnosis should be confirmed with nerve biopsy to prevent delay in therapy and associated complications.

BCG immunotherapy as an adjunct to chemotherapy in BL-lL patients--its effect on clinical regression, reaction severity, nerve function, lepromin conversion, bacterial/antigen clearance and 'persister' M. leprae.

BACKGROUND AND OBJECTIVE: Multidrug therapy in leprosy has failed to eliminate the problem of persister bacilli. Clearance of bacterial antigens is extremely slow which could predispose to continued nerve damage even after release from treatment. In the present study the immunomodulatory efficacy of BCG vaccine administered post-MDT in BL-LL leprosy patients was investigated in depth with a view to determining if augmenting chemotherapy with immunotherapy would help in faster clearance of M. leprae/antigens, bring down the level of persisters and minimise the occurrence/severity of reaction and nerve damage. METHODS: This is a placebo-controlled study in treated BL-LL patients. The patients are matched with respect to age, sex, bacteriological index and history of reaction, stratified and allocated to the two groups. One group (Gr A) received two doses of BCG-MOSCOW (3-33 x 10(5) cells) and the other (Gr B) normal saline (0.85%), injected intra-dermally at 3 month intervals. The Primary outcomes assessed at the end of 6 months were bacterial/antigen clearance, lepromin conversion, granuloma clearance and the occurrence of persisters. The secondary outcomes were clinical regression, occurrence and severity of reaction and changes in nerve functions. MATERIAL: A total of 107 BL-LL patients comprised of 49 in Gr A and 58 in Gr B; of which 36 and 42 respectively completed the study as per protocol, and are included in the final analysis. FINDINGS: The study findings show that both the primary and the secondary out comes were comparable in the two groups. Two doses of BCG administered post-MDT (Gr A) did not significantly alter the level of persisters or help in hastening the bacterial/antigen clearance, clinical regression of lesions and granuloma clearance. Lepromin conversion rates were also comparable. While the frequency of lepra reaction/neuritis following the intervention was comparable, the severity of reactions was significantly higher in Gr A. On the positive side neural functions assessed by nerve conduction studies showed that deterioration of motor nerve conduction was significantly lower in the BCG arm. Since all patients developing moderate to severe reactions, immediately received a course of corticosteroids, it is possible that timely use of it might have helped.

Clinical, bacteriological and histopathological study of 62 referral relapse cases between Jan 2004 and Dec 2009 at the Foundation for Medical Research, Mumbai.

UNLABELLED: Sixty two patients with relapsed leprosy seen between Jan 2004 and Dec 2009 were studied using clinical, bacteriological and histopathological parameters. The findings thus obtained were correlated to parameters such as trend and source of referral, clinical characteristics at diagnosis, treatment received, other events during or after RFT and duration between cessation of treatment and relapse. FINDINGS: Referrals per year have doubled since 2006. Most patients were referred by NGOs (58%), followed by Govt. hospitals (16%) and then by GPs (25%); 76% had received one of the WHO - MDT regimens including 16 treated with 24 months or more MB - MDT, 23 with 12 months MB - MDT and eight with 6 months PB - MDT. Of the remaining 14 cases, four had received DDS mono-therapy, seven had single dose of Rifampicin, Ofloxacin and Minocycline (ROM) and four Rifampicin and Ofloxacin (RO) daily for 28 days. The average incubation time of relapse, defined as duration between cessation of treatment and relapse was (SD) + 6-4 years. 59% of patients had positive slit skin smears on relapse. Relapse for the second time occurred in six BL cases including five from group 2 and one RO treated patient and 11/23 cases from group 2 conferred to BT-BB leprosy. Clinical features at diagnosis and on relapse were comparable in 47% of cases. CONCLUSION: All leprosy patients, regardless of their type and MDT regime, carry 'risk of relapse'. A shorter treatment duration reduces the incubation time to relapse. In group 2 (treated with 12 months MB-MDT regime) 11/23 were BT-BB cases and 5/23 (21%) were relapse for the second time, which further supports our earlier documented findings and maybe the efficacy of WHO-MDT regime is poor in a small subset of patients.

Estudio clínico, bacteriológico e histopatológico de 62 casos de recidivas entre Enero de 2004 y Diciembre de 2009 en la fundación para la investigación médica de Bombay / No disponible

Se evaluaron mediante parámetros clínicos, bacteriológicos e histopatológicos 62 casos de recidivas, entre enero de 2004 y diciembre de 2009. Los hallazgos se correlacionaron con otros parámetros como posible sesgos y las causas de la derivación, características clínicas en el momento del diagnóstico, tratamiento recibido, otros eventos durante y después del cese del tratamiento RFT y periodo entre alta del tratamiento y la recidiva. Hallazgos: Las derivaciones por año se han doblado desde2006. La mayoría de los pacientes llegaron a través de ONGs (58%), seguido de hospitales gubernamentales (16%) y después por médicos comunitarios (25%); el 76% o más recibieron MB-MDT, 23 con 12 mese MB-MDT y 8 con 6 meses PB-MDT. De entre los 14 restantes, cuatro recibieron DDS monoterapia, siete una sola dosis de rifampicina, ofloxacino y minociclina (ROM) y cuator rifampicina y ofloxacino (RO) diarios durante 28 días. El periodo medio de incubación de las recidivas, definido como intervalo entre el cese del tratamiento y la recidiva (SD) fue de + 6.4 años. El 50% de pacientes presentaban fortis cutáneo positivo. Seis casos BL incluyendo cinco del grupo 2 y uno tratado con RO, y 11/23 casos del grupo 2 (BT-BB) recidivaron una segunda vez. Las características clínicas en el momento del diagnóstico y de recidivas resultaron comparables en el 47% de los casos. Conclusión: Todos los pacientes, independientemente de un tipo de lepra o pauta MDT, conllevaron el “riesgo de recidivas”. Un tratamiento más corto reduce el intervalo de aparición de la recidiva. En el grupo 2 (tratados con 12 meses de MB-MDT), 11/23 eran casos BT-BB y 5/23 (21%) eran recidivas por segunda vez, en consonancia con nuestros hallazgos anteriores 14,23 y quizás la eficacia de la pauta OMS-MDT es pobre en un pequeño subgrupo de pacientes (AU)

No disponible

Neuropathic pain and psychological morbidity in patients with treated leprosy: a cross-sectional prevalence study in Mumbai.

BACKGROUND: Neuropathic pain has been little studied in leprosy. We assessed the prevalence and clinical characteristics of neuropathic pain and the validity of the Douleur Neuropathique 4 questionnaire as a screening tool for neuropathic pain in patients with treated leprosy. The association of neuropathic pain with psychological morbidity was also evaluated. METHODOLOGY/PRINCIPAL FINDINGS: Adult patients who had completed multi-drug therapy for leprosy were recruited from several Bombay Leprosy Project clinics. Clinical neurological examination, assessment of leprosy affected skin and nerves and pain evaluation were performed for all patients. Patients completed the Douleur Neuropathique 4 and the 12-item General Health Questionnaire to identify neuropathic pain and psychological morbidity. CONCLUSIONS/SIGNIFICANCE: One hundred and one patients were recruited, and 22 (21.8%) had neuropathic pain. The main sensory symptoms were numbness (86.4%), tingling (68.2%), hypoesthesia to touch (81.2%) and pinprick (72.7%). Neuropathic pain was associated with nerve enlargement and tenderness, painful skin lesions and with psychological morbidity. The Douleur Neuropathique 4 had a sensitivity of 100% and specificity of 92% in diagnosing neuropathic pain. The Douleur Neuropathique 4 is a simple tool for the screening of neuropathic pain in leprosy patients. Psychological morbidity was detected in 15% of the patients and 41% of the patients with neuropathic pain had psychological morbidity.

The effect of corticosteroids usage on bacterial killing, clearance and nerve damage in leprosy; part 3--Study of two comparable groups of 100 multibacillary (MB) patients each, treated with MDT + steroids vs. MDT alone, assessed at 6 months post-release from 12 months MDT.

OBJECTIVE: To investigate effects of therapeutic usage of corticosteroids on M. leprae killing and clearance, on clearance of granuloma and on nerve damage in multibacillary (MB) leprosy patients. DESIGN: From a cohort of 400 untreated MB patients, a comparable group of 100 each receiving MDT + steroids (group A) vs MDT alone (group B) were assessed at 18 months as compared to month zero with respect to clinical and granuloma regression, M. leprae killing and clearance, and nerve functions. Analysis was performed using SPSS version 10.0. The significance of association was tested using Chi square and Fisher's exact tests. RESULTS: Regression of lesions assessed clinically and by histopathology was seen in 52% and 53% patients in group A and 46% and 63% in B respectively (P not significant). Clearance of bacteria assessed by bacteriological index (BI) in slit skin smears (SSS) and extent and intensity of antigen using anti-BCG staining were also comparable in the two groups. Multiplication of M. leprae in the mouse foot pad (MFP) indicating the presence of viable bacilli was seen in 14% and 16% of SSS positive BL-LLs patients in groups A and B respectively (P not significant). The occurrence of viable M. leprae was higher among patients with repeat reaction (19%) than single (11%). Using clinical tests (nerve palpation, monofilament and voluntary muscle testing), the proportion of sensory and motor nerves showing improvement or deterioration were similar in the two groups. However using nerve conduction studies, the overall proportion of nerves showing deterioration (22%) was significantly higher than improvement (9%) (P < 0.001). CONCLUSIONS: Treatment with MDT + corticosteroids does not adversely affect the clearance of granuloma, M. leprae and/or its antigens and M. leprae killing. However the continued presence of viable bacteria in > 14% of BL-LLs patients indicate that 12 months of MDT may be insufficient for complete bacterial killing. In both groups nerve conduction studies indicated that deterioration of nerves was high suggesting, MDT + corticosteroids was not very efficacious in the prevention or reversal of nerve damage. A better immuno-modulatory drug or a modified corticosteroid regime is needed.

The effect of corticosteroid usage on the bacterial killing, clearance and nerve damage in leprosy: a prospective cohort study: part 1--study design and baseline findings of 400 untreated multibacillary patients.

OBJECTIVE: To investigate possible adverse effects of therapeutic usage of corticosteroids on the killing and clearance of M. leprae and the clearance of granuloma, in patients with multibacillary (MB) leprosy. DESIGN: A cohort of 400 untreated MB patients were sub-grouped into those to be treated with corticosteroids (prednisolone 40 mg daily tapered to 5 mg over 12 weeks) along with MB-MDT for reaction and/or neuritis or silent neuropathy (SN) of <6 months duration (group A), and those with no reaction and to be treated with MDT only (group B). Clinical, bacteriological, histopathological and neurological test findings at fixed time points were compared. Analysis was performed using SPSS version 10.0. The significance of association was tested using Chi-square test. In the current report, we describe the study design and baseline findings of 400 untreated MB patients, with special emphasis on differences between patients in groups A and B. RESULTS: At baseline, applying Ridley-Jopling classification, 39% patients were BT, 20% BB, 24% BL, 12% sub-polar LL and 5% pure neural (PN). Overall, 60% patients were slit skin smear (SSS) negative and 33% presented with disability either grades 1 or 2. Overall 140/400 (35%) patients presented with reaction and/or neuritis and 11/400 (3%) presented with SN of <6 months duration. Comparing groups A and B, the percentage of patients presenting with DG2 was significantly higher in group A (43%). By clinical tests, monofilaments (MF) and voluntary muscle testing (VMT), the percentage of patients and nerves showing functional impairment was also significantly higher in group A. However, in the more sensitive nerve conduction velocity (NCV) test, the percentage of patients that showed nerve abnormalities was closely comparable; 94% and 91% in groups A and B respectively while number of affected nerves was higher in group A. CONCLUSION: At baseline, as recorded by NCV, peripheral nerve function abnormality was observed in almost all the MB patients regardless of reaction; but among those presenting with reaction or neuritis, the nerve damage was more severe and extensive.