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Background Leprosy is known to be unevenly distributed between and within countries. High risk areas or ‘hotspots’ are potential targets for preventive interventions, but the underlying epidemiologic mechanisms that enable hotspots to emerge, are not yet fully understood. In this study, we identified and characterized leprosy hotspots in Bangladesh, a country with one of the highest leprosy endemicity levels globally. Methods We used data from four high-endemic districts in northwest Bangladesh including 20 623 registered cases between January 2000 and April 2019 (among ~ 7 million population). Incidences per union (smallest administrative unit) were calculated using geospatial population density estimates. A geospatial Poisson model was used to detect incidence hotspots over three (overlapping) 10-year timeframes: 2000–2009, 2005–2014 and 2010–2019. Ordinal regression models were used to assess whether patient characteristics were significantly different for cases outside hotspots, as compared to cases within weak (i.e., relative risk (RR) of one to two), medium (i.e., RR of two to three), and strong (i.e., RR higher than three) hotspots. Results New case detection rates dropped from 44/100 000 in 2000 to 10/100 000 in 2019. Statistically significant hotspots were identified during all timeframes and were often located at areas with high population densities. The RR for leprosy was up to 12 times higher for inhabitants of hotspots than for people living outside hotspots. Within strong hotspots (1930 cases among less than 1% of the population), significantly more child cases (i.e., below 15 years of age) were detected, indicating recent transmission. Cases in hotspots were not significantly more likely to be detected actively. Conclusions Leprosy showed a heterogeneous distribution with clear hotspots in northwest Bangladesh throughout a 20-year period of decreasing incidence. Findings confirm that leprosy hotspots represent areas of higher transmission activity and are not solely the result of active case finding strategies.

Objective: To assess the effectiveness of single-dose rifampicin (SDR) after bacillus Calmette–Guérin (BCG) vaccination in preventing leprosy in contacts. Methods: This was a single-centre, cluster-randomized controlled trial at a leprosy control programme in northwest Bangladesh. Participants were the 14 988 contacts of 1552 new leprosy patients who were randomized into the SDR − arm (n = 7379) and the SDR + arm (n = 7609). In the intervention group, BCG vaccination was followed by SDR 8–12 weeks later. In the control group, BCG vaccination only was given. Follow-up was performed at 1 year and 2 years after intake. The main outcome measure was the occurrence of leprosy. Results: The incidence rate per 10 000 person-years at risk was 44 in the SDR − arm and 31 in the SDR + arm at 1 year; the incidence rate was 34 in the SDR − arm and 41 in the SDR + arm at 2 years. There was a statistically non-significant (p = 0.148; 42%) reduction for paucibacillary (PB) leprosy in the SDR+ arm at 1 year. Of all new cases, 33.6% appeared within 8–12 weeks after BCG vaccination. Conclusions: In the first year, SDR after BCG vaccination reduced the incidence of PB leprosy among contacts by 42%. This was a statistically non-significant reduction due to the limited number of cases after SDR was administered. To what extent SDR suppresses excess leprosy cases after BCG vaccination is difficult to establish because many cases appeared before the SDR intervention. Trial registration: Netherlands Trial Register: NTR3087. Keywords: Leprosy, Bacillus Calmette–Guérin vaccine, Rifampicin, Household contacts, Chemoprophylaxis, Immunoprophylaxis

Additional file 1: Figure S1. Trends over time of the number of new leprosy cases registered, where indicated whether or not GPS coordinates could be collected. Figure S2. Estimated annual population size per district. Figure S3. Estimated population density per union per 5-year time frame. Table S2. Demographic, disease and location characteristics of leprosy cases overall, and cases for which GPS coordinate were collected retrospectively in northwest Bangladesh, detected between January 2000 and April 2019. Figure S4. Mean population size (panels A, B, C), cumulative case counts (panels D, E, F) and unsmoothed cumulative incidence levels (panels G, H, I) and hotspots detected with spatial scan statistics with identification numbers (panels J, K, L) in northwest Bangladesh between January 2000 and April 2019. Table S3. Leprosy hotspots in northwest Bangladesh between January 2000 and April 2019, detected with spatial scan statistics ( https://www.satscan.org/ ). The location identification numbers of hotspots are shown in Figure S3 (panels J to L). The area locations are shown in Figure 3. Table S4. Demographic, disease and location characteristics of leprosy cases in northwest Bangladesh, detected from January 2000 to April 2019.

People with leprosy-related disability in north west Bangladesh were surveyed for diabetes. According to patient reports,97 (27.1/1000) already knew they suffered from diabetes mellitus. Amongst 3573 subjects who underwent a random blood sugar test, anyone with random blood sugar level above 11.0 mmol/l was referred for confirmation of diabetes and advice (111). Unexpectedly, we also found that 30.1% asymptomatic people without a previous diagnosis of diabetes had random blood sugar in the “impaired glucose tolerance” range (i.e. 7.8- 11.0 mmol/l). These people were asked to have a second blood test for fasting blood sugar level, and if this was high (above 7.0 mmol/l) they were advised to have a review with a doctor, preferably at the local diabetic clinic. A sample of people (5%) with Blood sugar levels in the normal range were also invited to have a second test for fasting blood sugar; amongst them only 2 had elevated fasting blood sugar levels (>7.0). Thus another 14 were referred with high fasting blood sugar levels. Of those125 people (considered to be Diabetes suspects) newly-detected with hyperglycaemia, 121 attended a suitable service provider for confirmation/exclusion of diabetes, within 1month of their abnormal blood test. Of them 47 (37.6%) were diagnosed with diabetes. However, 4 people did not take action as advised, and 2 died before attending clinic. Taking into account new diagnoses and old, we estimate a minimum prevalence of 40.3/1,000 amongst leprosy-disabled people in NW Bangladesh. These findings indicate the advisability of routine screening for diabetes amongst people affected by leprosy during routine clinic reviews, and that the ability and motivation to manage their own self-care of people with leprosy related disability and diabetes should be assessed. Appropriate follow up and advice for those with blood sugar in impaired glucose tolerance (IGT) range needs consideration, to minimise their future risk.Bangladesh J Medicine Jan 2017; 28(1) : 13-23

Background: Diabetes and leprosy are chronic conditions for which patients need to practise self-care. Little is known about how patients manage such comorbidities in Bangladesh.Methods: Leprosy disabled people in north-west Bangladesh were surveyed for diabetes. Random blood glucose levels were measured. Data on disability levels and body mass index were collected and diabetic subjects were interviewed about self-care for their disease.Results: Of the 3573 people with leprosy-related disability surveyed, 97(2.7%) were previously diagnosed with diabetes. They were variously receiving treatment and advice from specialist clinic services or other sources; 65% were on regular medication and only 16% were attending clinic for review more frequently than once in 3 months. Other patients were not receiving regular treatment or medical attention for their diabetes. A random blood glucose done by finger prick test showed 51/97 had levels >11.0 mmol/l and 20/97 had levels >18.0 mmol/l. Their self-reported compliance with medical advice was low. Amongst leprosy-disabled people, not previously known to be diabetic, with random blood glucose >11.0 mmol/l, referred for further assessment. Another 47 cases were confirmed to have diabetes making total prevalence about 4% in this population.Conclusions: The survey results suggest that routine screening for diabetes amongst people affected by leprosy should be considered and that special attention needs to be directed to the ability and motivation of people with leprosy related disability to manage their own diabetes self-care.Birdem Med J 2016; 6(2): 100-106

IntroductionErythema 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 analysisMaPs 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 disseminationResults 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.

Introduction Duration of leprosy treatment remains long and difficult to complete in resource poor areas. Studies suggest that shortening duration of therapy for MB patients to 6 months may be possible. Methods New MB patients in 2005 in two NGO projects in Bangladesh were treated with 6 months WHO MB MDT and the rate of relapse and fall in BI on slit skin smear during follow up to date were compared with a control group treated for 12 months the previous year. Results 1612 patients were enrolled in the trial, and the average duration of follow up was over 7 years after diagnosis. During 11,425 PYAR of follow-up, no relapses were detected, by bacteriological or clinical criteria, in the 918 patients in the 6 months MB MDT group, nor in the 694 patients in the control group. Rate of decline of BI in those who were smear positive was not significantly different between groups. Conclusion The data does not suggest that shortening duration of treatment from 2 months to 6 months MDT for MB leprosy patients leads to increased rates of relapse.

Background Leprosy transmission is ongoing; globally and within Bangladesh. Household contacts of leprosy cases are at increased risk of leprosy development. Identification of household contacts at highest risk would optimize this process. Methods The temporal pattern of new case presentation amongst household contacts was documented in the COCOA (Contact Cohort Analysis) study. The COCOA study actively examined household contacts of confirmed leprosy index cases identified in 1995, and 2000–2014, to provide evidence for timings of contact examination policies. Data was available on 9527 index cases and 38303 household contacts. 666 household contacts were diagnosed with leprosy throughout the follow-up (maximum follow-up of 21 years). Risk factors for leprosy development within the data analysed, were identified using Cox proportional hazard regression. Findings The dominant risk factor for household contacts developing leprosy was having a highly skin smear positive index case in the household. As the grading of initial slit skin smear of the index case increased from negative to high positive (4–6), the hazard of their associated household contacts developing leprosy increases by 3.14 times (p, Author summary The number of newly detected leprosy cases worldwide has remained stable over the last ten years. Household contacts of leprosy cases are at increased risk of leprosy development. Household contact examinations and case detection are critical aspects of control. Specific risk factors (recognizable by field staff) for leprosy development need to be identified to aid these control efforts. Targeted household examinations could increase early case detection: this is important because untreated leprosy cases are sustaining transmission. This is the largest, most comprehensive study of development of leprosy in household contacts conducted recently with a maximum follow-up of 21 years. We found a single dominant risk factor for the development of leprosy in the household setting, namely slit skin smear positivity in the index case. This is important for leprosy control because household contact examinations can be focused on contacts at highest risk. Implementation would be simple as the risk factor is identified by leprosy staff in the field. Prioritising households known to be at highest risk of leprosy development would allow efficient allocation of resources. Our results cast doubt on the success of administering the recommended prophylactic intervention for contacts; the use of this intervention needs to be re-evaluated.

Duration of leprosy treatment remains long and difficult to complete in resource poor areas. Studies suggest that shortening duration of therapy for MB patients to 6 months may be possible.New MB patients in 2005 in two NGO projects in Bangladesh were treated with 6 months WHO MB MDT and the rate of relapse and fall in BI on slit skin smear during follow up to date were compared with a control group treated for 12 months the previous year.1612 patients were enrolled in the trial, and the average duration of follow up was over 7 years after diagnosis. During 11,425 PYAR of follow-up, no relapses were detected, by bacteriological or clinical criteria, in the 918 patients in the 6 months MB MDT group, nor in the 694 patients in the control group. Rate of decline of BI in those who were smear positive was not significantly different between groups.The data does not suggest that shortening duration of treatment from 2 months to 6 months MDT for MB leprosy patients leads to increased rates of relapse.

Background: Although BCG is used as a vaccine against tuberculosis, it also protects against leprosy. Previous evaluation over 18 years of an intervention of two doses BCG for 3536 household contacts of leprosy patients showed that 28 (23%) out of 122 contacts diagnosed with leprosy, developed symptoms 2-10 months after vaccination. This study describes contacts of leprosy patients in Bangladesh who developed leprosy within 12 weeks after receiving a single BCG dose. Methods: A cluster RCT in Bangladesh aims to study the effectiveness of the BCG vaccine versus BCG in combination with single dose rifampicin (SDR) given 2 to 3 months after BCG, in the prevention of leprosy among contacts of newly diagnosed leprosy patients. During the first 1,5 years of this ongoing trial we identified contacts who developed leprosy within the first 12 weeks after receiving BCG vaccination, the timeframe before SDR is given. Results: We identified 21 contacts who developed leprosy within 12 weeks after BCG vaccination among 5196 vaccinated contacts (0.40%). All 21 cases presented with paucibacillary (.PB) leprosy, including children and adults. About half of these cases had previously received BCG vaccination as indicated by the presence of a BCG scar; 43% presented with signs of nerve function impairment and/or Type 1 (reversal) reaction, and 56% of the index patients had multibacillary (MB) leprosy. Conclusion: An unexpectedly high proportion of healthy contacts of leprosy patients presented with PB leprosy within 12 weeks after receiving BCG vaccination, possibly as a result of boosted cell-mediated immunity by homologues of Mycobacterium leprae antigens in BCG. Various immunological mechanisms could underlie this phenomenon, including an immune reconstitution inflammatory syndrome (IRIS). Further studies are required to determine whether BCG vaccination merely altered the incubation period or actually changed the course of the infection from self-limiting, subclinical infection to manifest disease. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

© Lepra. Erythema nodosum leprosum (ENL) is a multisystem reaction which affects some people with multibacillary (MB) leprosy, but more specifically those with BL or LL type leprosy. The symptoms of ENL can lead to long term physical, social and economic losses, although very little is known about the effect ofENLon quality of life. Methods: A cross-sectional study was conducted in northwest Bangladesh. A Bengali version of the RAND 36-Item Health Survey 1·0 (SF-36) was administered to people under treatment for ENL (n = 29) and controls affected by MB leprosy (n = 46) matched for: sex, treatment status, age, Disability grade at diagnosis, education level and housing type. Chi Square and Wilcoxon RST were used to analyse the data using the R statistical package. Results: Patients with ENL had significantly (P < ·001) worse Health Related Quality of life (HRQoL) scores on all eight SF-36 health concepts: physical functioning, pain, role limitations due to physical and emotional limitations, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Cohen's d indicated a large effect (d = ·96 to 1·67). The results are compared with results of other published works which examined similar populations Conclusion: HRQoL is significantly impaired in Bangladeshi people suffering from ENL compared with people with MB leprosy and no ENL. ENL affects all areas of a person's HRQoL measured by the SF-36. Health care providers need to spend time addressing other aspects of a person's life and not just the physical symptoms.

This paper reports the results of a study on the inter-tester reliability of the WHO disability grading system. The WHO disability grading system is the most frequently used method of grading impairment in leprosy patients. With this method, a grade of 0-2 is assigned to each of six individual body sites (both eyes, hands and feet). The maximum grade of any of these sites is used as an overall indicator of the person's impairment status. To date, the WHO disability grading scale has not been subjected to reliability testing. The reliability of the grading system depends on the operational definitions of the grades, the way the tester interprets these definitions and the skill of the tester. It is therefore important that the definitions are unambiguous and leave as little room as possible for multiple interpretations. Three testers with varying degrees of experience did paired assessments on a total of 150 leprosy patients in the Leprosy Mission Hospital Purulia, India, using recently published operational definitions of the WHO disability grades. For every patient, they determined the maximum grade (minimum 0, maximum 2), and calculated the impairment sum-score (EHF score), adding up the six grades for eyes, hands and feet (minimum 0, maximum 12). The weighted Kappa statistic (Kw) was used as the coefficient of inter-tester reliability. A kappa of 0 represents agreement no better than chance, and 1.0 complete (chance-corrected) agreement. Kw values of > or = 0.80 are considered very good and adequate for monitoring and research. Weighted Kappa analysis yielded a reliability coefficient of 0.89 (95%CI 0.84-0.94) for the maximum grade and a Kw of 0.97 (95%CI 0.96-0.98) for the EHF score. We concluded that, when using standard operational definitions, the WHO disability grading system can be used reliably in the hands of both experienced and inexperienced testers, provided adequate training has been given. Reliability should be evaluated further in a field setting, when used by primary health care workers. It is recommended that the 'WHO disability grading' be renamed 'WHO impairment grading', using the terminology as defined by the International Classification of Functioning, Disability and Health (ICF).

Objectives To develop a valid and reliable quantitative measure of leprosy Type 1 reactions. Methods A scale was developed from previous scales which had not been validated. The face and content validity were assessed following consultation with recognised experts in the field. The construct validity was determined by applying the scale to patients in Bangladesh and Brazil who had been diagnosed with leprosy Type 1 reaction. An expert categorized each patient's reaction as mild or moderate or severe. Another worker applied the scale. This was done independently. In a subsequent stage of the study the agreement between two observers was assessed. Results The scale had good internal consistency demonstrated by a Cronbach's alpha >0.8. Removal of three items from the original scale resulted in better discrimination between disease severity categories. Cut off points for Type 1 reaction severities were determined using Receiver Operating Characteristic curves. A mild Type 1 reaction is characterized using the final scale by a score of 4 or less. A moderate reaction is a score of between 4.5 and 8.5. A severe reaction is a score of 9 or more. Conclusions We have developed a valid and reliable tool for quantifying leprosy Type 1 reaction severity and believe this will be a useful tool in research of this condition, in observational and intervention studies, and in the comparison of clinical and laboratory parameters., Author Summary Leprosy is caused by a bacterium and is curable with a combination of antibiotics known as multi-drug therapy which patients take for six or 12 months. However, a significant proportion of leprosy patients experience inflammation in their skin and/or nerves which may occur even after successful completion of multi-drug therapy. These episodes of inflammation are called leprosy Type 1 reactions. Type 1 reactions are an important complication of leprosy because they may result in nerve damage which leads to disability and deformity. Type 1 reactions require treatment with immunosuppressive agents such as corticosteroids. The severity of Type 1 reactions varies with time, treatment and between individuals. We have developed a clinical severity scale to measure the severity of Type 1 reactions. The scale has three sections. The first measures the involvement of the skin using the number of affected skin lesions, the degree of inflammation of those lesions and the presence of swelling of the hands, feet or face. The second section is a measurement of the sensory function of the nerves supplying the eyes, hands and feet by assessing a patient's ability to feel graded nylon fibres. The third section uses a standard measure of muscle power to assess motor function of the nerves of the face, hands and feet. The clinical severity scale we have developed will facilitate the study of Type 1 reactions and enable direct comparison between different studies. This will improve the management of this disabling complication of leprosy.

The immunomodulatory drug thalidomide is the treatment of choice for erythema nodosum leprosum (ENL), an inflammatory cutaneous and systemic complication of multibacillary leprosy. To elucidate the mechanism of action of thalidomide in this syndrome, we prospectively investigated 20 patients with ENL who were treated with thalidomide for 21 days. All patients responded to treatment, with the majority of them having complete resolution of cutaneous lesions within 7 days. This response was associated with a marked but transient increase in ex vivo mitogen-induced expression of interleukin (IL)-2 and interferon- gamma by CD4(+) and CD8(+) T cells that was observed on treatment day 7, but these returned to pretreatment levels by day 21. Plasma tumor necrosis factor- alpha levels were not high at baseline, and they increased modestly during treatment. Plasma levels of IL-12 increased steadily during thalidomide treatment. Hence, the therapeutic effect of thalidomide in ENL appears to be associated with transient immune stimulation, which suggests that the drug may promote an active immunoregulatory response.

The ILEP nerve function impairment and reaction research programme (INFIR 2) was a group of clinical trials conducted to identify second-line treatments for severe leprosy type 1 reactions (T1R). This paper presents the clinical results of one of these trials in which azathioprine was used in combination with short-course prednisolone to ascertain if the combination was effective in controlling the symptoms and signs of reaction. Forty patients were alternately assigned to a 12-week treatment with either AP (12 weeks azathioprine at 3mg/kg/d plus 8 week reducing course prednisolone starting at 40mg/d) or P (12-week reducing course prednisolone starting at 40mg/d). Evaluation included serial quantitative clinical assessments. The overall frequency of side effects was similar in both groups. Results show that there was no difference in clinical outcome in the AP and P groups and a similar number of patients in each group required extra prednisolone for worsening clinical features. We conclude that a 12-week course of azathioprine at 3mg/kg/day plus an 8 week reducing course of prednisolone starting at 40mg/d is as effective as a 12 week reducing course of prednisolone starting at 40mg/d and that the combination therapy is well-tolerated in severe leprosy T1R patients.

Introduction: There is a lack of evidence on which to base decisions about the ideal duration of surveillance for household contacts of newly diagnosed leprosy cases. Methods: We reviewed 9538 households of leprosy cases diagnosed in Bangladesh over 21 years, to establish the temporal pattern of new case detection during routine surveillance periods, which were two years for Paucibacillary (PB) cases and five years for Multibacillary (MB) cases. Results: In both MB and PB households we found the highest new case detection rates at the first examination, completed within a few weeks of diagnosis of the index case. These new cases were effectively co-prevalent with the index case. In subsequent years, the new case detection rate fell markedly. However, at each time point we found the new case detection rate to be higher amongst the household contacts of MB index cases as compared with contacts of PB index cases. Discussion: We conclude that an initial contact examination completed at the earliest opportunity after the index diagnosis is a high priority for every PB and MB household. When first seen, those individual contacts found to be healthy should be warned about their continuing risk of developing leprosy. Where resources allow, health workers should prioritise annual re-assessments of contacts of MB index cases.