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.

Glucocorticoids as a novel approach to the treatment of disabling side effects of sodium stibogluconate.

WHAT IS KNOWN AND OBJECTIVE: Intravenous sodium stibogluconate (SbV) is the mainstay of treatment for mucocutaneous leishmaniasis. Incidence of this disease is increasing in the UK, partly because of returning military personnel. SbV has a side effect profile that requires treatment interruption in up to 28% of patients. Side effects can be unpleasant and - in the case of QTc prolongation - dangerous. CASE SUMMARY: A volunteer medical worker returning from Guatemala was diagnosed with mucocutaneous leishmaniasis. Because of previous renal problems, NSAIDs were contraindicated. Severe side effects of myalgia and arthralgia would have necessitated a treatment interruption, but a trial of prednisolone gave excellent symptomatic relief. The patient's QTc, amylase and C-reactive protein also fell following initiation of steroid treatment. The SbV treatment course was completed successfully. WHAT IS NEW AND CONCLUSION: This is the first reported case of the dangerous and disabling side effects of SbV being treated very effectively with glucocorticoids. Of note is the normalization of the apparently sodium stibogluconate-induced prolongation of the QTc interval. Further investigation into this potential beneficial effect is warranted.

Pentamidine as secondary prophylaxis for visceral leishmaniasis in the immunocompromised host: report of four cases.

We report a retrospective and descriptive study of four immunocompromised patients (three with HIV-1 and one with idiopathic CD4+-lymphopenia) with relapsing visceral leishmaniasis seen at the Hospital for Tropical Diseases, London, in whom pentamidine was used as secondary prophylaxis to prevent relapse. Patients experienced between one and four relapses before commencing prophylaxis with subsequent relapse-free periods ranging from 5 to 98 months. Based on these observational data, we recommend large trials to investigate the efficacy of pentamidine over other agents in preventing relapse of VL in the immunocompromised patient.

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.

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.

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.

Leprosy: a 'common' and curable cause of peripheral neuropathy with skin lesions.

Leprosy (or Hansen's disease) is a curable chronic infectious disease caused by the acid-fast bacillus Mycobacterium leprae. While leprosy remains one of the most common causes of neuropathy worldwide, its rarity in the UK means that many doctors are unfamiliar with the typical clinical features. This is problematic because early recognition and treatment is vital in order to minimise disease-related complications such as nerve injury. We describe a 75-year-old man who presented with multiple mononeuropathy (mononeuritis multiplex, particularly affecting the ulnar nerves) and typical granulomatous skin lesions, in whom the diagnosis was made on the basis of skin biopsy. We highlight the clinical features, investigations and treatment of the patient, and provide information about the epidemiology and pathogenesis of leprosy.

Borderline tuberculoid leprosy: an immune reconstitution phenomenon in a human immunodeficiency virus-infected person.

Two months after starting highly active antiretroviral treatment (HAART), an individual with human immunodeficiency virus type 1 (HIV-1) infection and profound CD4+ T lymphocytopenia developed several erythematous plaques on his face, which were due to borderline tuberculoid leprosy with reversal reaction. The temporal association between the development of these lesions and changes in blood CD4+ lymphocyte count and plasma HIV-1 load observed during HAART strongly suggests that the presentation of leprosy resulted from immune reconstitution.

The diagnosis of leprosy is delayed in the United Kingdom.

Diagnostic delay in leprosy can have serious neurological consequences for the patient. We studied the presentation of leprosy patients, focusing on delays in diagnosis, in a retrospective case-note review of 28 patients referred to The Hospital for Tropical Diseases during 1995-1998. The median ages at onset of symptoms and at diagnosis were 25.1 years (range 9-77.7) and 30.1 years (range 9-78.3), respectively. The median time from symptom onset to diagnosis was 1.8 years (0.2-15.2). Prior to referral to a leprologist, patients had seen a dermatologist (20), neurologist (9), orthopaedic surgeon (5) and rheumatologist (2). Delay in diagnosis occurred in 82% of cases. Misdiagnoses as dermatological and neurological conditions were important causes of delay, and 68% of patients had nerve damage resulting in disability. Leprosy can be difficult to diagnose outside endemic areas. Increased awareness amongst general practitioners and hospital specialists would lead to more rapid diagnosis, thus minimizing damage and disability.

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.

Skin problems in returning travelers.

A new skin lesion in a returning traveler often poses a difficult diagnostic problem for the clinician whose knowledge of geographic medicine is limited. To reach a diagnosis the physician has to consider the location and style of travel, exposure to pathogens, length of stay, epidemiology, incubation period, and clinical presentation of dermatologic diseases in the countries visited. As with any dermatologic problem, the appearance of the presenting lesion should help to establish the differential diagnosis. This article is a guide to the diagnosis and investigation of skin lesions in returning travelers; it is not intended as a comprehensive review of tropical dermatology.

New World cutaneous leishmaniasis in returned travellers: treatment failures using intravenous sodium stibogluconate.

Treatment outcome was determined among a cohort of travellers who returned to the UK between February 2000 and February 2001 with New World cutaneous leishmaniasis caused by species of the Leishmania (Viannia) subgenus. Among 18 patients who completed treatment with 20 mg/kg/d of i.v. sodium stibogluconate (NaSb) for 20 d, early relapse of disease occurred in 2 patients with regional dissemination in 1 and mucocutaneous involvement in the other. Drug susceptibility testing in vitro of the clinical isolate from 1 of these patients confirmed tolerance to high concentrations of NaSb.

Steroids in leprosy type 1 (reversal) reactions: mechanisms of action and effectiveness.

Steroids are widely used for the treatment of leprosy reactions. The effectiveness of steroid treatment is variable, with only 60% of patients regaining nerve function. Sequential skin biopsy specimens, obtained from 15 patients with type 1 (reversal) reactions, have been studied to document the cytokine profile and cellularity of the lesions. All of the patients were placed on a standard course of steroids after the first biopsy. Subsequent biopsies were performed seven, 28 and 180 days later. The specimens were stained for interferon-gamma (IFN gamma), interleukin-12 (IL-12) and inducible nitric oxide synthase (iNOS). After the first biopsy, all patients were placed on a standard reducing course of steroids beginning at 30 mg daily. By day 7, treatment with prednisolone showed little effect on the cellularity and cytokine profiles. However, by day 28, significant decreases of IFN-gamma, IL-12 and iNOS were found for most patients. Some patients maintained cytokine production at day 28 and even at day 180. These data illustrate the strong Th1 profile of type 1 reactional lesions, the relatively slow response to therapy, and the continuing activity after treatment with steroids for 180 days. The variation of individual responses emphasizes their importance. Additional prospective studies will be required to determine whether patients with high intra-lesional levels of cytokine are at risk of recurrent reactions. The need for studies both of different glucocorticoids and of other non-steroidal immunosuppressants for the treatment of reactions is discussed.

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.

The pattern of leprosy-related neuropathy in the AMFES patients in Ethiopia: definitions, incidence, risk factors and outcome.

The ALERT MDT Field Evaluation Study (AMFES) began in 1988 and followed patients prospectively for up to 10 years after release from treatment (RFT). This paper presents the findings from this cohort with regard to neuropathy and nerve damage. Five hundred and ninety-four new cases of leprosy are included in the study, 300 multibacillary (MB) and 294 paucibacillary (PB) cases. Fifty-five percent of patients had some degree of impairment at diagnosis and a further 73 (12%) developed new nerve function impairment (NFI) after starting multiple drug therapy (MDT). The overall incidence rate for neuropathy was 39 episodes per 100 PYAR in the first year after diagnosis, gradually declining to 12 episodes per 100 PYAR in the sixth year. In those patients without impairment at diagnosis, the incidence rate of neuropathy was 25 episodes per 100 PYAR for MB cases and 11 per 100 PYAR for PB cases in the first year; in 33% of MB cases whose first episode of neuropathy occurred after diagnosis, that first episode took place after the first year, or after the normal period of treatment with MDT. Seventy-three patients with neuropathy developing after diagnosis are reported more fully: 34 (47%) had only one nerve involved and of these 25 (73%) had a single, acute episode of neuropathy. Nine (27%) had further episodes. Thirty-nine (53%) had more than one nerve involved and of these 16 (41%) had a single, acute episode, while 23 (59%) had further episodes. The terms 'chronic' and 'recurrent' neuropathy are defined and used to describe the pattern of neuropathy in those with repeated attacks. In patients with no impairment at the start of the study, treatment with steroids resulted in full recovery in 88% of nerves with acute neuropathy but only 51% of those with chronic or recurrent neuropathy. The median time to full recovery from acute neuropathy was approximately 6 months, but in a few cases recovery occurred gradually over 2-3 years. Severe neuropathy was less likely to be followed by a complete recovery than mild or moderate neuropathy. Forty-two percent of nerves with acute neuropathy that were not treated with steroids also fully recovered. In the group of patients who were thought to have old, permanent impairments at diagnosis, full recovery of nerve function occurred in 87/374 (23%) of the nerves involved. The overall outcome is illustrated by examining the average EHF score for groups of patients. Patients with no new neuropathy after diagnosis show a gradual improvement in their EHF score, while those with any episodes of neuropathy after diagnosis show a gradual deterioration after completion of MDT. Possible explanations for these findings are discussed. Risk factors for neuropathy, for chronic and recurrent neuropathy, and for a poor outcome 5 years after release from treatment, are examined. Impairment at diagnosis was the main risk factor for a poor outcome, accompanied by the occurrence of chronic/recurrent neuropathy or a reversal reaction.

Childhood leprosy in an urban clinic, Hyderabad, India: clinical presentation and the role of household contacts.

A retrospective case note study was done of children below the age of 14 years who attended Dhoolpet Leprosy Research Centre (DLRC) over the decade 1990-1999. The aim of the study was to describe the pattern of clinical presentation, the role of household or near neighbour contacts and the incidence of neuritis and reactions. In all, 3118 leprosy patients were registered during this period, of whom 306 were children [182 (60%) male]; 95 children had a single patch, 159 had five or fewer than five patches and 37 had multiple patches. The youngest case detected was 9 months old. The spectrum of leprosy in these children was: TT 62 (20.3%); BT 203 (66.3%); BB 3 (1%); BL 23 (7.5%); LL 5 (1.6%) and PNL 10 (3.3%). Twenty-nine cases (9.4%) were smear positive. Ninety-one children (29.7%) developed a reaction, 86 type I and five type II. A history of contact was present in 119 (38.8%) cases, family contact in 113 (95%) and other than family in six (5%). Classification of the contact was available in only 60 patients. Among the contacts of the index case, 21 (35%) suffered from PB leprosy and 39 (65%) from MB leprosy. All contacts were from the immediate family. This study shows that childhood leprosy cases continue to present in significant numbers to this outpatient clinic. There is a high level of family contact with leprosy in these cases, strengthening the strategy of screening children in leprosy-affected households. The high incidence of reactions and nerve damage in children emphasizes the importance of early detection and treatment.

Immunohistochemical detection of PGL-1, LAM, 30 kD and 65 kD antigens in leprosy infected paraffin preserved skin and nerve sections.

A panel of lipid, carbohydrate and protein antibodies were optimized for use in detecting M. leprae antigens in paraffin embedded material. Skin and nerve biopsies from 13 patients across the leprosy spectrum were studied. All antibodies detected antigen in tissues with a BI > 1. Phenolic-glycolipid was not detected in bacteriologically negative tissue but lipoarabinomanan (LAM) and protein antigens were detected. Staining with LAM was strongest and gave least background. The transfer of this immunohistochemical technique to paraffin embedded material will allow examination of tissue with better morphology and from clinics without access to tissue freezing facilities.

Clinical experience of clerks and dressers: a three-year study of Birmingham medical students.

A survey of the clinical experience of junior medical clerks and surgical dressers on their first clinical attachment in the Birmingham University Teaching Hospitals was organized by students over a three-year period. A typical clinical student had performed basic clinical procedures such as putting up a drip, doing an ECG, bladder catheterization and seen a wide range of other procedures. Most students felt involved in the work of the firm, had clerked routine admissions, and regularly attended the firm's emergency admission night. Consultants on most firms were felt to be concerned about student progress. Students attached to district general hospitals gained a wider range of clinical experience than those at established teaching hospitals. Student-run audit is a useful way of monitoring the clinical experience gained by medical students.