Geospatial epidemiology of leprosy in northwest Bangladesh: a 20-year retrospective observational study.

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.

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.

Patients with skin smear positive leprosy in Bangladesh are the main risk factor for leprosy development: 21-year follow-up in the household contact study (COCOA).

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<0.001). Being a blood relative was not a risk factor, no gender differences in susceptibility were found. INTERPRETATION: We found a dominance of a single variable predicting risk for leprosy transmission-skin smear positive index cases. A small number of cases are maintaining transmission in the household setting. Focus should be performing contact examinations on these households and detecting new skin smear positive index cases. Conducting slit-skin smears on new cases is needed for predicting risk; such services need supporting. If skin smear positive cases are sustaining leprosy infection within the household setting, the administration of single-dose rifampicin (SDR) to household contacts as the sole intervention in Bangladesh will not be effective.

Effectiveness of single-dose rifampicin after BCG vaccination to prevent leprosy in close contacts of patients with newly diagnosed leprosy: A cluster randomized controlled trial.

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 14988 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 1year and 2 years after intake. The main outcome measure was the occurrence of leprosy. RESULTS: The incidence rate per 10000 person-years at risk was 44 in the SDR-arm and 31 in the SDR+arm at 1year; 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.

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.

Outcome of 6 months MBMDT in MB patients in Bangladesh- preliminary results.

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.

Clinical manifestations of leprosy after BCG vaccination: an observational study in Bangladesh.

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.

Development and validation of a severity scale for leprosy type 1 reactions.

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.

Effective treatment of erythema nodosum leprosum with thalidomide is associated with immune stimulation.

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.

Measuring impairment caused by leprosy: inter-tester reliability of the WHO disability grading system.

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).

Clinical outcomes in a randomized controlled study comparing azathioprine and prednisolone versus prednisolone alone in the treatment of severe leprosy type 1 reactions in Nepal.

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.

Predicción casos muy positivos entre pacientes de lepra MB con parámetros clínicos

Aunque se sabe que los casos frotis muy bacilíferos presentan un riesgo elevado de recidivas después de ser dadas de alta de la MDT, los programas de control en el campo sin facilidades para efectuar frotis no disponen de un método alternativo para poder detectarlos. Este estudio presentó una prevalencia significativa de este tipo de casos entre 2.374 casos multibacilares nuevos recientemente detectados por frotis cutáneos en Nepal y análisis retrospectivos de 555 casos nuevos recien detectados, BL y LL sin tratar, para identificar parámetros clínicos y de laboratorio asociados con un frotis cutáneo muy bacilíferos. Mientras que alguno de estos parámetros presentan gran sensibilidad en precedir "casos muy bacilíferos", ninguno presenta simultáneamente elevada sensibilidad y especificidad.

Interferon-Gamma responses to candidate leprosy skin-test reagents detect exposure to leprosy in an endemic population

New tools for the detection of leprosy exposure in a community will be necessary for the eradication of leprosy. Candidate leprosy skin-test antigens derived from the fractionation of the leprosy bacillus into cytoplasmic and cell-wall proteins free of immuno-inhibitory mycobacterial lipoglycans and carbohydrates were used in an overnight blood test to determine whether exposure to leprosy can be detected by the production of the cytokine interferon gamma (IFN-gamma). Strong IFN-gamma responses were detected in leprosy contacts to both skin-test antigens compared with control subjects from the same endemic communities. There was little response in patients with tuberculosis. Responses were greatest in contacts with recent leprosy exposure. The implications of these findings for the application of these reagents in a field trial as skin tests to detect exposure to leprosy are discussed in light of the strong association between overnight IFN-gamma to PPD and the tuberculin skin-test responses previously reported.

Contribution of type 1 reactions to sensory and motor function loss in borderline leprosy patients and the efficacy of treatment with prednisone

The changes in nerve function tests in 297 new leprosy patients over an average period of 30 months were measured. The impact of type 1 reactions (T1R) on sensory and voluntary muscle function was measured by standard tests. Sensory function was improved in patients with single episodes of cutaneous T1R, but not improved in patients with neural T1R or with multiple episodes of either kind of T1R. Patients over 40 years of age improved less than younger patients, and patients admitted for treatment of T1R improved more than those treated as outpatients. These data point to a need to find better regimens for the treatment of nerve damage in T1R.