Visceral Leishmaniasis in Traveler to Guyana Caused by Leishmania siamensis, London, UK.

The parasite Leishmania siamensis is a zoonotic agent of leishmaniasis; infection in animals has been documented in Europe and the United States. Reported authochthonous human infections have been limited to Thailand. We report a case of human visceral Leishmania siamensis infection acquired in Guyana, suggesting colonization in South America.

A comparison of the change in clinical severity scale score and a retrospective physician assessment of neurological outcome in individuals with leprosy associated nerve function impairment after treatment with corticosteroids.

OBJECTIVES: To determine whether the measured change in score of a validated clinical severity scale reflected physician assessed improvement in individuals who had received corticosteroid therapy for leprosy associated nerve damage. DESIGN: Patients with nerve function impairment who participated in a randomised controlled trial of corticosteroids were classified into two groups using a retrospectively determined physician assessment of improvement. One group consisted of patients who had recovered or improved the other of patients who were unchanged or had deteriorated. The change in the clinical severity scale scores of these two groups was compared. RESULTS: The change in the clinical severity scale scores of the 34 eligible individuals in the two groups were significantly different (P = 0.003). Individuals in the group who recovered or improved had a greater change in severity score than those whose nerve function was unchanged or deteriorated. CONCLUSION: The scale for measuring the severity of leprosy Type 1 reactions (T1Rs) and/or nerve function impairment reflects the clinical improvement of individuals with leprosy associated nerve damage.

Regulatory T cells in erythema nodosum leprosum maintain anti-inflammatory function.

BACKGROUND: The numbers of circulating regulatory T cells (Tregs) are increased in lepromatous leprosy (LL) but reduced in erythema nodosum leprosum (ENL), the inflammatory complication of LL. It is unclear whether the suppressive function of Tregs is intact in both these conditions. METHODS: A longitudinal study recruited participants at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before and after 24 weeks of prednisolone treatment for ENL and multidrug therapy (MDT) for participants with LL. We evaluated the suppressive function of Tregs in the peripheral blood mononuclear cells (PBMCs) of participants with LL and ENL by analysis of TNFα, IFNγ and IL-10 responses to Mycobacterium leprae (M. leprae) stimulation before and after depletion of CD25+ cells. RESULTS: 30 LL participants with ENL and 30 LL participants without ENL were recruited. The depletion of CD25+ cells from PBMCs was associated with enhanced TNFα and IFNγ responses to M. leprae stimulation before and after 24 weeks treatment of LL with MDT and of ENL with prednisolone. The addition of autologous CD25+ cells to CD25+ depleted PBMCs abolished these responses. In both non-reactional LL and ENL groups mitogen (PHA)-induced TNFα and IFNγ responses were not affected by depletion of CD25+ cells either before or after treatment. Depleting CD25+ cells did not affect the IL-10 response to M. leprae before and after 24 weeks of MDT in participants with LL. However, depletion of CD25+ cells was associated with an enhanced IL-10 response on stimulation with M. leprae in untreated participants with ENL and reduced IL-10 responses in treated individuals with ENL. The enhanced IL-10 in untreated ENL and the reduced IL-10 response in prednisolone treated individuals with ENL was abolished by addition of autologous CD25+ cells. CONCLUSION: The findings support the hypothesis that the impaired cell-mediated immune response in individuals with LL is M. leprae antigen specific and the unresponsiveness can be reversed by depleting CD25+ cells. Our results suggest that the suppressive function of Tregs in ENL is intact despite ENL being associated with reduced numbers of Tregs. The lack of difference in IL-10 response in control PBMCs and CD25+ depleted PBMCs in individuals with LL and the increased IL-10 response following the depletion of CD25+ cells in individuals with untreated ENL suggest that the mechanism of immune regulation by Tregs in leprosy appears independent of IL-10 or that other cells may be responsible for IL-10 production in leprosy. The present findings highlight mechanisms of T cell regulation in LL and ENL and provide insights into the control of peripheral immune tolerance, identifying Tregs as a potential therapeutic target.

What is the evidence that the putative Mycobacterium lepromatosis species causes diffuse lepromatous leprosy?

Han et al. have made a retrospective isolation of DNA from two patients with fatal Lucio's phenomenon. This DNA does have some molecular differences to M. leprae and may constitute a variant of M. leprae. However the experiments and data needed to confirm that this is a new leprosy-causing species have not yet been done. We have outlined the work that does need to be done. For the moment the assertion that 'M. lepromatosis' is a new leprosy-causing species is not proven.

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.

Leprosy and HIV, where are we at?

The impact of leprosy and HIV co-infection is an evolving picture. Surprisingly the outcomes that were feared, of more lepromatous disease has not materialised. But with the roll-out of antiretroviral therapy, the emergence of leprosy as Immune Reconstitution Inflammatory Syndrome is re-focusing attention on the characteristics of this important co-infection.

Impacts of the diagnosis of leprosy and of visible impairments amongst people affected by leprosy in Cebu, the Philippines.

PURPOSE: To quantify the impact of the diagnosis of leprosy and of visible impairments in people affected by leprosy. SUBJECTS AND METHODS: Three interview-based questionnaires designed to measure activity limitation, participation restriction, and general self-efficacy were used to collect data from three Groups. Group 1: leprosy affected people with visible impairment, Group 2: newly diagnosed leprosy patients with no visible impairment, Group 3: patients with other skin diseases symptomatic for more than 1 month. RESULTS: One hundred and eight subjects were recruited. The subjects with visible impairments (Group 1) had higher levels of participation restriction than those with skin disease (P0.012), and participation restriction was similar between subjects in Groups 2 and 3 (P0-305). The people in Group 1 (35 subjects) also reported significantly more activity limitation compared to the people in either Group 2 (35 subjects) or Group 3 (38 subjects) (P 0-001, respectively). The subjects in Group 2 had no significant activity limitation compared with those in Group 3 (P0.338). A multivariate analysis showed that severe visible impairment was a risk factor for activity limitation (odds ratio 5.68, 95% CI: 1.09-297, P0.039) and a low level of self-efficacy (Odds ratio 6.38, 95% CI: 1.06-38.3, P0-043) among people affected by leprosy. CONCLUSION: Visible impairments affected the activities and attitudes of people affected by leprosy. However, others without visible impairment, had activity limitations, participation restrictions and levels of general self-efficacy that were similar to patients with other skin diseases. Prevention of visible impairments should be considered a key intervention for stigma reduction.

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.

Interventions for erythema nodosum leprosum.

BACKGROUND: Erythema nodosum leprosum (ENL) is a serious immunological complication of leprosy, causing inflammation of skin, nerves, other organs, and general malaise. Many different therapies exist for ENL, but it is unclear if they work or which therapy is optimal. OBJECTIVES: To assess the effects of interventions for erythema nodosum leprosum. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 1, 2009), MEDLINE (from 2003), EMBASE (from 2005), LILACS and AMED (from inception), CINAHL (from 1981), and databases of ongoing trials, all in March 2009. We checked reference lists of articles and contacted the American Leprosy Missions in Brazil to locate studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions for ENL in people with leprosy. DATA COLLECTION AND ANALYSIS: Two authors performed study selection, assessed trial quality, and extracted data. MAIN RESULTS: We included 13 studies with a total of 445 participants. The quality of the trials was generally poor and no results could be pooled due to the treatments being so heterogeneous. Treatment with thalidomide showed a significant remission of skin lesions compared to acetylsalicylic acid (aspirin) (RR 2.43; 95% CI 1.28 to 4.59) (1 trial, 92 participants). Clofazimine treatment was superior to prednisolone (more treatment successes; RR 3.67; 95% CI 1.36 to 9.91) (1 trial, 24 participants), and thalidomide (fewer recurrences; RR 0.08; 95% CI 0.01 to 0.56) (1 trial, 72 participants). We did not find any significant benefit for intravenous betamethasone compared to dextrose (1 trial, 10 participants), pentoxifylline compared to thalidomide (1 trial, 44 participants), indomethacin compared to prednisolone, aspirin or chloroquine treatments (2 trials, 80 participants), or levamisole compared to placebo (1 trial, 12 participants). Mild to moderate adverse events were significantly lower in participants taking 100 mg thalidomide compared to 300 mg thalidomide daily (RR 0.46; 95% CI 0.23 to 0.93). Significantly more minor adverse events were reported in participants taking clofazimine compared with prednisolone (RR 1.92; 95% CI 1.10 to 3.35). None of the studies assessed quality of life or economic outcomes. AUTHORS' CONCLUSIONS: There is some evidence of benefit for thalidomide and clofazimine, but generally we did not find clear evidence of benefit for interventions in the management of ENL. However, this does not mean they do not work, because the studies were small and poorly reported. Larger studies using clearly defined participants, outcome measures, and internationally recognised scales are urgently required.

Interventions for erythema nodosum leprosum. A Cochrane review.

INTRODUCTION: Treatment for erythema nodosum leprosum (ENL), an immunological complication of leprosy, is diverse. We undertook a systematic review as it was not clear which treatments were most beneficial. METHODS: We did a systematic search to identify randomised controlled trials (RCTs) comparing treatment with placebo, no treatment or another therapy. Two authors assessed quality and checked data. RESULTS: We included 13 studies involving 445 participants. These trials assessed: betamethasone, thalidomide, pentoxifylline, clofazimine, indomethacin and levamisole. The quality of the trials was generally poor and no results could be pooled due to the treatments being so heterogeneous. Treatment with thalidomide showed a significant benefit compared to aspirin (RR 2.43; 95% CI 1.28 to 4.59). Clofazimine treatment was superior to prednisolone (more treatment successes; RR 3.67; 95% CI 136 to 9.91) and thalidomide (fewer recurrences; RR 0.08; 95% CI 0.01, 0-56). Minor adverse events were significantly lower in participants on a low dose thalidomide regimen compared to a high dose thalidomide regimen (RR 0.46; 95% CI 0.23 to 0.93). Significantly more minor adverse events were reported in participants taking clofazimine compared with prednisolone (RR 1.92; 95% CI 1.10 to 3.35). None of the studies assessed quality of life or economic outcomes. CONCLUSION: There is some evidence of benefit for thalidomide and clofazimine, but generally we did not find clear benefits for interventions in the management of ENL. This does not mean they do not work because the studies were small and poorly reported. Larger studies using clear definitions and internationally recognised scales are urgently required.

Chronic aspects of leprosy-neglected but important.

The chronic aspects of leprosy are discussed here. They are a consequence of the peripheral nerve damage that affects many patients during their lifetime with leprosy. The peripheral nerve damage leaves people unable to feel and with weakness in their hands and feet. They are at risk of damaging their hands and feet, causing the disabilities and deformities that characterise late leprosy. More than 200 000 new leprosy patients are diagnosed globally each year. Better data are needed from cohort studies to estimate the number of patients developing nerve damage and modelling studies are needed to estimate the number of patients who develop disabilities. For some of them, this will be a lifelong disability. Nerve damage is caused by inflammation in leprosy-affected nerves. Patients with nerve damage of <6-mo duration need treatment with steroids. About 66% of multibacillary patients will develop nerve damage. Plastic graded monofilaments can be used to detect nerve damage in leprosy and diabetic clinics. Assessing nerve damage and treating patients with steroids in leprosy programmes needs to be strengthened. The World Health Organization has a successful programme for supplying antibiotics for treating leprosy infection to national leprosy programmes. They should take responsibility for providing steroids to national programmes since this is a core part of the treatment for >66% of multibacillary patients. Patients need to be asked about neuropathic pain symptoms and treated if necessary. Treated leprosy patients are at risk of developing ulcers in their feet. Treatment and prevention needs to be improved through health education, providing protective footwear and patient empowerment.

Leprosy type 1 (reversal) reactions and their management.

The type of leprosy that affects an individual depends on the immune response mounted against the organism. This leads to a spectrum of disease which may be complicated by immunological phenomena called reactions. Antimicrobial chemotherapy is effective in treating the Mycobacterium leprae infection but up to 30% of individuals with borderline disease experience Type 1 reactions (T1Rs). T1Rs are immunologically mediated episodes, localised in skin and nerves, which are a major cause of nerve function impairment. Nerve function impairment may result in disability and deformity. We review the frequency and features of Type 1 reactions. The data from the limited number of randomised controlled trials of treatment are discussed. These four randomised controlled trials were all conducted in south Asia. The accepted treatment of T1Rs is with oral corticosteroids but there is no consensus about the dose or duration of treatment due to the lack of data. One randomised controlled trial showed that patients treated with a 5 month course of prednisolone (total dose 2.31 g) were less likely to need additional prednisolone than those treated with a 3 month course of prednisolone (total dose 2.94 g). This study did not use nerve function as an outcome measure. The improvement in nerve function impairment with steroid treatment is highly variable, with 33-73% of nerves recovering fully. Optimal steroid regimes and alternative treatments need to be identified if the disability associated with leprosy is to be minimised. Search strategy Papers for this review were identified by repeated searches of the Cochrane Clinical Trials Register, PubMed and LILACS with various combinations of the following search terms 'leprosy', 'lepra', 'reaction', 'steroids', 'corticosteroids', 'reversal', 'Type 1', 'Hansen*'. Searches were complete to the end of November 2008.

Diagnosis and impact of neuropathic pain in leprosy patients in Nepal after completion of multidrug therapy.

OBJECTIVES: Neuropathic pain (NP) can occur as a chronic complication of leprosy neuropathy. NP epidemiology and its impact on patients have not been well documented. This study investigates NP prevalence and impact in the years after patients are declared "released from treatment" (RFT) following multidrug therapy (MDT) completion. METHODS: In this cross-sectional study, 85 RFT patients were recruited within leprosy referral services in Nepal. The Douleur Neuropathique 4 Questionnaire (DN4) was used to screen for NP. Pain severity, impacts on patients' daily activities and mental health were measured by using the Brief Pain Inventory (BPI), Screening of Activity Limitation and Safety Awareness (SALSA), and General Health Questionnaire-12 (GHQ-12) respectively. RESULTS: 96% surveyed had been treated for multibacillary leprosy. 44 (52%) complained of pain of which 30 (68%) were diagnosed with NP. NP was not associated with age, gender, or presence of skin lesions or nerve symptoms at leprosy diagnosis. 70% of patients with NP had either history of or ongoing reactions and 47% had grade 2 disability. Nerve tenderness (p = 0.023) and current reactions (p = 0.018) were significant risk factors for NP. Patients with NP suffered significantly higher intensity pain (p = 0.023) and daily life interference (p = 0.003) and were more likely to have moderate to extreme daily activity limitations (p = 0.005). 13 (43%) exhibited psychological distress, and medications only reduced moderate degree (50-60%) of pain. CONCLUSIONS: In our study, 35% of RFT patients had ongoing NP. Risk factors include nerve tenderness and reaction. They suffer from more daily life interference and psychological distress. Leprosy patient care should include recognition and management of NP.

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

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

Cutaneous leishmaniasis.

Cutaneous leishmaniasis is a widespread tropical infection caused by numerous different species of Leishmania protozoa that are transmitted by sandflies. Its clinical presentations are extremely diverse and dependent on a variety of parasite and host factors that are poorly understood. Diagnosis should aim to identify the exact species involved, but this requires laboratory investigations that are not widely available. No single ideal treatment has been identified, and those available are limited by variable success rates and toxicity. Clinical guidelines are needed to make better use of the investigations and treatments that do exist. Prevention is currently limited to bite prevention measures.