Visceral leishmaniasis and immunocompromise as a risk factor for the development of visceral leishmaniasis: a changing pattern at the hospital for tropical diseases, london.

METHODS AND PRINCIPAL FINDINGS: A retrospective study of imported VL to the HTD, London including patients diagnosed and/or managed at the HTD between January 1995 and July 2013. We analyse patient demographics, risk factors for developing VL, diagnosis, investigation, management and outcome. Twenty-eight patients were treated for VL at the HTD over an 18 year period. The median age at VL diagnosis was 44 years (range 4-87 years) with a male to female ratio of 2:1. Most patients were British and acquired their infection in the Mediterranean basin. The median time from first symptom to diagnosis was six months with a range of 1-12 months and diagnosis included microscopic visualisation of leishmania amastigotes, positive serological tests (DAT and k39 antibody) or identification of leishmania DNA. Nineteen patients had some form of immunocompromise and this has increased proportionally compared to previously described data. Within the immunocompromised group, the ratio of those with autoimmune disease has increased. Immunocompromised patients had lower cure and higher relapse rates. CONCLUSIONS: The rise of VL in patients with immunocompromise secondary to autoimmune disease on immunomodulatory drugs presents new diagnostic and therapeutic challenges. VL should be a differential diagnosis in immunocompromised patients with pyrexia of unknown origin returning from travel in leishmania endemic areas.

Clinical and histological features of leprosy and human immunodeficiency virus co-infection in Brazil.

BACKGROUND: Both leprosy and human immunodeficiency virus (HIV) are infectious diseases, and are an important global health problem. Patients with leprosy who are co-infected with HIV seem to be at higher risk of developing leprosy reactions. AIM: To examine the histological features of leprosy in patients with HIV and leprosy co-infection, particularly to determine whether the typical leprosy histopathology is present in skin biopsies, and to assess the histological features of leprosy reactions in co-infected patients. METHODS: This was a matched cohort study with 11 co-infected patients and 31 HIV-negative patients with leprosy. A structured protocol for skin-biopsy evaluation was followed, focusing on inflammation of the skin and dermal nerves. RESULTS: Of the 11 HIV-positive patients, 7 (63%) had borderline tuberculoid (BT) leprosy and 5 (70%) of these 7 patients had developed a type 1 reaction. The lesions in these patients were immunologically active, with 100% of biopsies having evidence of compact granulomas, 90% evidence of oedema and 30% evidence of necrosis. CONCLUSIONS: In this study, patients co-infected with HIV and M. leprae had the typical histological lesions of leprosy. There was evidence of immune activation in patients who received combination antiretroviral therapy, and these patients had BT leprosy and leprosy-upgrading reactions.

Clinical and histological features of leprosy and human immunodeficiency virus co-infection in Brazil

BACKGROUND: Both leprosy and human immunodeficiency virus (HIV) are infectious diseases, and are an important global health problem. Patients with leprosy who are co-infected with HIV seem to be at higher risk of developing leprosy reactions. AIM: To examine the histological features of leprosy in patients with HIV and leprosy co-infection, particularly to determine whether the typical leprosy histopathology is present in skin biopsies, and to assess the histological features of leprosy reactions in co-infected patients. METHODS: This was a matched cohort study with 11 co-infected patients and 31 HIV-negative patients with leprosy. A structured protocol for skin-biopsy evaluation was followed, focusing on inflammation of the skin and dermal nerves. RESULTS: Of the 11 HIV-positive patients, 7 (63%) had borderline tuberculoid (BT) leprosy and 5 (70%) of these 7 patients had developed a type 1 reaction. The lesions in these patients were immunologically active, with 100% of biopsies having evidence of compact granulomas, 90% evidence of oedema and 30% evidence of necrosis. CONCLUSIONS: In this study, patients co-infected with HIV and M. leprae had the typical histological lesions of leprosy. There was evidence of immune activation in patients who received combination antiretroviral therapy, and these patients had BT leprosy and leprosy-upgrading reactions.

The effect of systemic corticosteroid therapy on the expression of toll-like receptor 2 and toll-like receptor 4 in the cutaneous lesions of leprosy Type 1 reactions.

BACKGROUND: Leprosy is complicated by immunological reactions which can occur before, during and after successful completion of multidrug therapy. Genetic studies have suggested that polymorphisms in toll-like receptors (TLRs) may affect the susceptibility of an individual with leprosy to developing Type 1 reactions. OBJECTIVES: To examine the gene and protein expression of TLRs in the cutaneous lesions of leprosy Type 1 reactions at the onset of reaction and during systemic corticosteroid therapy. METHODS: Patients who were being treated for leprosy type 1 reactions with corticosteroids as part of a randomized controlled trial of corticosteroid treatment had skin biopsies performed before, during and at the end of treatment. The gene and protein expression of TLR2 and TLR4 were measured. RESULTS: We have demonstrated that the gene hARP-P0 is a suitable control gene for TLR gene expression studies in this population. The gene and protein expression of TLR2 and TLR4 were both reduced significantly during corticosteroid treatment. CONCLUSIONS: This is the first study to examine the expression of TLR2 and TLR4 in vivo in individuals experiencing leprosy Type 1 reactions. The data support the possibility of an important role for TLR2 and TLR4 in the pathogenesis of this important complication of leprosy.

Towards understanding the pathology of erythema nodosum leprosum.

Erythema nodosum leprosum (ENL) is an immune-mediated complication of leprosy presenting with inflammatory skin nodules and involvement of multiple organ systems, often running a protracted course. Immune complex production and deposition as well as complement activation have long been regarded as the principal aetiology of ENL. However, new data show that cell-mediated immunity is also important. We have performed a critical analysis of studies on the pathology of ENL. Our main findings are as follows. ENL is characterised by an inflammatory infiltrate of neutrophils with vasculitis and/or panniculitis. There is deposition of immune complexes and complement together with Mycobacterium leprae antigens in the skin. Changes in serum levels of Igs indicate a transient, localised immune response. The major T-cell subtype in ENL is the CD4 cell, in contrast to lepromatous leprosy where CD8 cells predominate. The cytokines TNFalpha and IL-6 are consistently found whilst IL-4 is low or absent in ENL lesions, indicating a T(H)1 type response. Keratinocyte 1a and intercellular adhesion molecule-1 (ICAM-1) have been shown to be present in the epidermis in ENL, which is evidence of a cell-mediated immune response. Co-stimulatory molecules such as B7-1 have also been studied but further work is needed to draw strong conclusions. We also highlight potential areas for future research.

The histological diagnosis of leprosy type 1 reactions: identification of key variables and an analysis of the process of histological diagnosis.

BACKGROUND: Type 1 leprosy reactions (T1R) are a major inflammatory complication of leprosy affecting 30% of patients with borderline leprosy, but there has been no diagnostic evaluation of the histological diagnosis of this entity. METHODS: In a prospective study based in India, skin biopsies were taken from 99 patients with clinically diagnosed T1R and 52 non-reactional controls. These were assessed histologically by four histopathologists whose assessments were then compared. RESULTS: Reactions were under-diagnosed, with 32-62% of clinically diagnosed reactions being given a histological diagnosis. The pathologists showed good specificities (range 72% to 93%) but much poorer sensitivities (range 42% to 78%). The most commonly reported histological features of TIR were cell maturity, oedema and giant cells. Five key variables were identified that the pathologists used in diagnosing a reaction: intra-granuloma oedema, giant cell size, giant cell numbers, dermal oedema and HLA-DR expression. A predictive model for the diagnosis of T1R was developed using stepwise logistic regression analysis, with clinical diagnosis of reaction as an outcome, and then identification of the key variables that each pathologist used in making the diagnosis of T1R. 34-53% of the variation between pathologists could be accounted for. The four pathologists used a similar diagnostic model and for all of them their estimations of epithelioid cell granuloma oedema, dermal oedema, plasma cells and granuloma fraction were significant variables in the diagnosis of T1R. Each pathologist then added in variables that were specific to themselves. CONCLUSIONS: This study has identified T1R as being under-diagnosed in comparison with clinical assessments. Key variables for diagnosing T1R were established. This comparative masked study highlights the need for such studies in other inflammatory conditions.

Response to ciclosporin treatment in Ethiopian and Nepali patients with severe leprosy Type 1 reactions.

Leprosy type 1 reactions (T1R) are immune-mediated events with inflammation of peripheral nerves and skin. We report the clinical outcomes of a closely monitored open prospective trial in which eight Nepali and 33 Ethiopian patients with T1Rs were treated with an Indian generic formulation of ciclosporin (Cn; 5-7.5 mg/kg/day) for 12 weeks and followed up for 24 weeks after starting treatment. Outcomes were measured using a clinical severity score. Among the Nepalis, 75-100% improved in all acute clinical parameters; 67-100% patients maintained improvement, except for those with acute sensory nerve impairment among whom 67% relapsed after stopping treatment. The skin lesions of all Ethiopians on 5 mg/kg/day of Cn improved and 50-60% had peripheral nerve function improvement. Most Ethiopians needed a higher dose of Cn to improve nerve impairment and neuritis, and 50-78% of them developed worse clinical severity scores when Cn was stopped. Four Ethiopians and two Nepalis developed elevated serum creatinine levels on 7.5 mg/kg/day Cn, and three (9%) Ethiopians developed treatable hypertension. This suggests that Cn monotherapy is an effective treatment for severe T1R with few adverse effects. A dose of 5 mg/kg/day seems efficacious in Nepalis, but a higher dose may be required in Ethiopian patients.

The clinical and immunological features of leprosy.

Leprosy is a granulomatous disease affecting the skin and nerves caused by Mycobacterium leprae. It continues to be a significant public health problem. Multidrug therapy (MDT) cures the infection, but immunological reactions may occur and neuropathy may lead to disability and deformity. It is important that the manifestations of the condition are recognized as early as possible so that early nerve damage can be identified and treated rapidly.

New world mucosal and cutaneous leishmaniasis: an emerging health problem among British travellers.

BACKGROUND: Mucosal leishmaniasis (ML) is an important complication of new world cutaneous leishmaniasis (CL) caused by species of the Leishmania Viannia subgenus. Previous reports of ML among travellers to Latin America are few. AIMS: To determine the annual number of cases of CL due to L. Viannia species diagnosed at this institution and to correlate this with changing patterns of travel. Secondly, to document the clinical presentation, diagnosis, treatment and outcome of ML at this institution. DESIGN: Retrospective observational study. METHODS: Data were collected from a clinical database, laboratory records, patient case notes and an international passenger survey. RESULTS: Between 1995 and 2003, the annual number of cases of CL (total 79) steadily increased from 4 per year to 18 per year; the estimated number of travellers from the UK to Latin America increased 3.5-fold. Six cases of ML were diagnosed among British travellers in 1995 (1), 1997 (1) and 2002 (4). These infections were acquired in Bolivia (3), Colombia (2) and Belize (1). Nasopharyngeal symptoms developed 0-15 months after returning to the UK. Four patients had concurrent CL at diagnosis. Diagnosis of ML was delayed up to 6 months from the onset of symptoms. Mucosal biopsies from all 6 patients were PCR-positive for L. (Viannia) DNA; microscopy and culture were less sensitive. ML relapsed in one patient following treatment. DISCUSSION: Increasing travel to Latin America from the UK was associated with an increasing number of diagnoses of L. Viannia CL. ML is likely to emerge as a more frequently imported infection among such travellers. Familiarity with these diseases is important for prompt diagnosis and optimal management.

A case of post-partum borderline tuberculoid leprosy complicated by a median nerve abscess, peptic ulceration and rifampicin-induced haemolytic renal failure.

We report a case of borderline tuberculoid leprosy complicated by a median nerve abscess, acute renal failure secondary to rifampicin-induced haemolysis and duodenal ulceration secondary to steroid use. Rifampicin induced hameolysis is a rare and probably under-reported complication of leprosy multi-drug therapy. It should be considered when patients complain of flu-like symptoms after taking their monthly rifampicin.

Leprosy

Leprosy remains an important health problem wordlwide. The disease is caused by a chronic granulomatous infection of the skin and peripheral nerves with Mycobacterium leprae. The clinical range from tuberculoid to lepromatous leprosy is a result of variation in the cellular immune response to the mycobacterium. The resulting impaiment of nerve function causes the disabilities associated with leprosy. This review summarises recent advances in understanding of the biology of leprosy, clinical features of the disease, the current diagnostic criteria, and the new approaches to treatment of the infection and the immune-mediated complications. Supervised multi-drug therapy (MDT) for fixed durations is highly effective for all forms of the disease. The widespread implementation of MDT has been associated with a fall in the prevalence of the leprosy but as yet no reduction in the case-detection rate globally. Thus, leprosy control activities must be maintained for decades to interrupt transmission of infection

Expression of CC and CXC chemokines and chemokine receptors in human leprosy skin lesions.

We have investigated the expression of chemokines and their receptors in leprosy skin lesions using immunohistochemistry. Skin biopsies from 25 leprosy patients across the leprosy spectrum, 11 patients undergoing type I reversal reactions and four normal donors were immunostained by ABC peroxidase method using antibodies against CC and CXC chemokines and their receptors. Using an in situ hybridization technique we have also studied the expression of monocyte chemoattractant protein 1 (MCP-1), RANTES and interleukin (IL)-8 chemokines mRNA in leprosy skin lesions. Chemokines and receptor expression was detected in all leprosy skin biopsies. Expression of CC chemokines MCP-1 (P < 0.01) and RANTES (P < 0.01) were elevated significantly in borderline tuberculoid leprosy in reversal reaction compared to non-reactional borderline tuberculoid leprosy, but there was no difference in the expression of IL-8 chemokine. Surprisingly, there was no significant difference in the expression of CC (CCR2 and CCR5) and CXC (CXCR2) chemokine receptors across the leprosy spectrum. Similarly, there was no significant difference in the expression of mRNA for MCP-1, regulated upon activation normal T cell expressed and secreted (RANTES) and IL-8 chemokines. Here, the presence of a neutrophil chemoattractant IL-8 in leprosy lesions, which do not contain neutrophils, suggests strongly a role of IL-8 as a monocyte and lymphocyte recruiter in leprosy lesions. These results suggest that the chemokines and their receptors, which are known to chemoattract T lymphocytes and macrophages, are involved in assembling the cellular infiltrate found in lesions across the leprosy spectrum.

Expression of CC and CXC chemokines and chemokine receptors in human in human leprosy skin lesions

We have investigated the expression of chemokines and their receptors in leprosy skin lesions using immunohistochemistry. Skin biopsies from 25 leprosy patients across the leprosy spectrum, 11 patients undergoing type I reversal reactions and four normal donors were immunostained by ABC peroxidase method using antibodies against CC and CXC chemokines and their receptors. Using an in situ hybridization technique we have also studied the expression of monocyte chemoattractant protein 1 (MCP-1), RANTES and interleukin (IL)-8 chemokines mRNA in leprosy skin lesions. Chemokines and receptor expression was detected in all leprosy skin biopsies. Expression of CC chemokines MCP-1 (P < 0.01) and RANTES (P < 0.01) were elevated significantly in borderline tuberculoid leprosy in reversal reaction compared to non-reactional borderline tuberculoid leprosy, but there was no difference in the expression of IL-8 chemokine. Surprisingly, there was no significant difference in the expression of CC (CCR2 and CCR5) and CXC (CXCR2) chemokine receptors across the leprosy spectrum. Similarly, there was no significant difference in the expression of mRNA for MCP-1, regulated upon activation normal T cell expressed and secreted (RANTES) and IL-8 chemokines. Here, the presence of a neutrophil chemoattractant IL-8 in leprosy lesions, which do not contain neutrophils, suggests strongly a role of IL-8 as a monocyte and lymphocyte recruiter in leprosy lesions. These results suggest that the chemokines and their receptors, which are known to chemoattract T lymphocytes and macrophages, are involved in assembling the cellular infiltrate found in lesions across the leprosy spectrum.