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Leprosy is a disease caused by Mycobacterium leprae (ML) with diverse clinical manifestations, which are strongly correlated with the host’s immune response. Skin lesions may be accompanied by peri...

Knowledge of the role of Tregs in the immunopathogenesis of the different clinical outcomes within the leprosy spectrum remains limited due to the lack of studies directly assessing their suppression capacity. We thus tested a protocol to expand Tregs from the peripheral blood of patients across the leprosy spectrum and analyzed their suppressive capacity in autologous TCD4+ responses. Results of these pilot assays show that Tregs can be expanded and exert suppressive capacity, but also that their rate of expansion and suppressive capacity are influenced by the patient’s clinical classification, suggesting that they possibly retain some in vivo characteristics.

Background Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae. It is a polymorphic disease with a wide range of cutaneous and neural manifestations. Ulcer is not a common feature in leprosy patients, except during reactional states, Lucio’s phenomenon (LP), or secondary to neuropathies. Cases presentation We report eight patients with multibacillary leprosy who presented specific skin ulcers as part of their main leprosy manifestation. Ulcers were mostly present on lower limbs (eight patients), followed by the upper limbs (three patients), and the abdomen (one patient). Mean time from onset of skin ulcers to diagnosis of leprosy was 17.4 months: all patients were either misdiagnosed or had delayed diagnosis, with seven of them presenting grade 2 disability by the time of the diagnosis. Reactional states, LP or neuropathy as potential causes of ulcers were ruled out. Biopsy of the ulcer was available in seven patients: histopathology showed mild to moderate lympho-histiocytic infiltrate with vacuolized histiocytes and intact isolated and grouped acid-fast bacilli. Eosinophils, vasculitis, vasculopathy or signs of chronic venous insufficiency were not observed. Skin lesions improved rapidly after multidrug therapy, without any concomitant specific treatment for ulcers. Conclusions This series of cases highlights the importance of recognizing ulcers as a specific cutaneous manifestation of leprosy, allowing diagnosis and treatment of the disease, and therefore avoiding development of disabilities and persistence of the transmission chain of M. leprae.

BACKGROUND Histoid leprosy (HL) is a rare form of lepromatous leprosy, characterized by hyperchromic indurated nodules above normal skin. Its main histopathological aspect is spindle cells. Because it may simulate other aspects, such as dermatofibroma and neurofibroma, histoid leprosy poses itself as a diagnostic challenge. METHODS This is a retrospective study with all patients having been selected from the leprosy clinic of the Hospital das Clinicas da Universidade de Sao Paulo from 2006 to 2016. RESULTS There were 12 patients in this study, eight in the histoid group and four in the lepromatous leprosy group. The prevalence of HL was 1.12% in all leprosy subjects. All individuals from HL group were "de novo" cases, and the histopathological analysis of skin lesions presented spindle cells generating a storiform pattern. Immunohistochemistry for CD68, vimentin, and anti-BCG were positive in all 12 cases. Factor XIIIa was visualized only in the papillary dermis, and S100 protein was negative in all biopsies. Smooth-muscle actin was present in 62.5% of the HL samples. CONCLUSION The prevalence of HL was similar to previous reports. However, all histoid patients were "de novo" cases, differing from published studies. Fusocellular macrophage transformation could be explained by the differences in cytoskeleton proteins expressed in histoid lesions in comparison to other leprosy variants, with emphasis on vimentin and smooth muscle actin.

Background Due to its chronic subclinical course and large spectrum of manifestations, leprosy often represents a diagnostic challenge. Even with proper anti-mycobacteria treatment, leprosy follow up remains challenging: almost half of leprosy patients may develop reaction episodes. Leprosy is an infrequent complication of solid organ transplant recipients. This case report illustrates the challenges in diagnosing and managing leprosy and its reactional states in a transplant recipient. Case presentation A 53-year-old man presented 34 months after a successful renal transplantation a borderline-tuberculoid leprosy with signs of mild type 1 upgrading reaction (T1R). Cutaneous manifestations were atypical, and diagnosis was only made when granulomatous neuritis was found in a cutaneous biopsy. He was successfully treated with the WHO recommended multidrug therapy (MDT: rifampicin, dapsone and clofazimine). However he developed a severe T1R immediately after completion of the MDT but no signs of allograft rejection. T1R results from flare-ups of the host T-helper-1 cell-mediated immune response against Mycobacterium leprae antigens in patients with immunologically unstable, borderline forms of leprosy and has been considered an inflammatory syndrome in many aspects similar to the immune reconstitution inflammatory syndromes (IRS). The T1R was successfully treated by increasing the prednisone dose without modifying the other immunosuppressive drugs used for preventing allograft rejection. Immunological study revealed that the patient had a profound depletion of both in situ and circulating regulatory T-cells and lack of expansion of the Tregs upon M. leprae stimulation compared to T1R leprosy patients without iatrogenic immunosuppression. Conclusions Our case report highlights that leprosy, especially in the transplant setting, requires a high degree of clinical suspicion and the contribution of histopathology. It also suggests that the development of upgrading inflammatory syndromes such as T1R can occur despite the sustained immunosuppressors regimen for preventing graft rejection. Our hypothesis is that the well-known deleterious effects of these immunosuppressors on pathogen-induced regulatory T-cells contributed to the immunedysregulation and development T1R. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2406-9) contains supplementary material, which is available to authorized users.

Background Erythroderma is characterized by erythema and scaling affecting more than 90% of the body surface area. Inflammatory, neoplastic and, more rarely, infectious diseases may culminate with erythroderma. Diagnosis of the underlying disorder is therefore crucial to institute the appropriate therapy. Leprosy is a chronic infectious disease that is endemic in Brazil. Here we present an unusual case of leprosy and reversal reaction causing erythroderma, and we discuss the underlying immunological mechanisms which could contribute to the generalized skin inflammation. Case presentation We report a case of a patient with reversal reaction (RR) in borderline borderline leprosy presenting with erythroderma and neural disabilities. Histopathology of the skin showed regular acanthosis and spongiosis in the epidermis and, in the dermis, compact epithelioid granulomas as well as grouped and isolated bacilli. This duality probably reflects the transition from an anergic/multibacillary state to a state of more effective immunity and bacillary control, typical of RR. Leprosy was successfully treated with WHO’s multidrug therapy, plus prednisone for controlling the RR; the erythroderma resolved in parallel with this treatment. Immunologic studies showed in situ predominance of IFNγ + over IL-4+ lymphocytes and of IL-17+ over Foxp3+ lymphocytes, suggesting an exacerbated Th-1/Th-17 immunoreactivity and poor Th-2 and regulatory T-cell responses. Circulating Tregs were also diminished. We hypothesize that the flare-up of anti-mycobacteria immunoreactivity that underlies RR may have triggered the intense inflammatory skin lesions that culminated with erythroderma. Conclusions This case report highlights the importance of thorough clinical examination of erythrodermic patients in search for its etiology and suggests that an intense and probably uncontrolled leprosy RR can culminate in the development of erythroderma. Electronic supplementary material The online version of this article (10.1186/s12895-017-0068-3) contains supplementary material, which is available to authorized users.

Leprosy is a contagious and chronic systemic granulomatous disease caused by the bacillus Mycobacterium leprae. To our knowledge, no case of leprosy in a childhood-onset systemic lupus erythematosus (c-SLE) patient has been reported. For a period of 31 years, 312 c-SLE patients were followed at the Pediatric Rheumatology Unit of our University Hospital. One of them (0.3%) had tuberculoid leprosy skin lesions during the disease course and is here reported. A 10-year-old boy from Northwest of Brazil was diagnosed with c-SLE based on malar rash, photosensitivity, oral ulcers, lymphopenia, proteinuria, positive antinuclear antibodies, anti-double-stranded DNA, anti-Sm and anti-Ro/SSA autoantibodies. He was treated with prednisone, hydroxychloroquine and intravenous cyclophosphamide, followed by mycophenolate mofetil. At 12-years-old, he presented asymmetric skin lesions characterized by erythematous plaques with elevated external borders and hypochromic center with sensory loss. Peripheral nerve involvement was not evidenced. No history of familial cases of leprosy was reported, although the region where the patient resides is considered to be endemic for leprosy. Skin biopsy revealed a well-defined tuberculoid form. A marked thickening of nerves was observed, often destroyed by granulomas, without evidence of Mycobacterium leprae bacilli. At that time, the SLEDAI-2K score was 4 and he had been receiving prednisone 15 mg/day, hydroxychloroquine 200 mg/day and mycophenolate mofetil 3 g/day. Paucibacillary treatment for leprosy with dapsone and rifampicine was also introduced. In conclusion, we have reported a rare case of leprosy in the course of c-SLE. Leprosy should always be considered in children and adolescents with lupus who present skin abnormalities, particularly with hypoesthesic or anesthesic cutaneous lesions.

T regulatory cells (Tregs) play an important role in the mechanism of host's failure to control pathogen dissemination in severe forms of different chronic granulomatous diseases, but their role in leprosy has not yet been elucidated; 28 newly diagnosed patients (16 patients with lepromatous leprosy and 12 patients with tuberculoid leprosy) and 6 healthy Mycobacterium leprae-exposed individuals (contacts) were studied. Tregs were quantified by flow cytometry (CD4+ CD25+ Foxp3+) in peripheral blood mononuclear cells stimulated in vitro with a M. leprae antigenic preparation and phytohemagglutinin as well as in skin lesions by immunohistochemistry. The lymphoproliferative (LPR), interleukin-10 (IL-10), and interferon-γ (IFN-γ) responses of the in vitro-stimulated peripheral blood mononuclear cells and the in situ expression of IL-10, transforming growth factor-β (TGF-β), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) were also determined. We show that M. leprae antigens induced significantly lower LPR but significantly higher Treg numbers in lepromatous than tuberculoid patients and contacts. Mitogen-induced LPR and Treg frequencies were not significantly different among the three groups. Tregs were also more frequent in situ in lepromatous patients, and this finding was paralleled by increased expression of the antiinflammatory molecules IL-10 and CTLA-4 but not TGF-β. In lepromatous patients, Tregs were intermingled with vacuolized hystiocyte infiltrates all over the lesion, whereas in tuberculoid patients, Tregs were rare. Our results suggest that Tregs are present in increased numbers, and they may have a pathogenic role in leprosy patients harboring uncontrolled bacillary multiplication but not in those individuals capable of limiting M. leprae growth.

Background Post-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis (VL), which may occur after or during treatment. It has been frequently reported from India and the Sudan, but its occurrence in South America has been rarely reported. It may mimic leprosy and its differentiation may be difficult, since both diseases may show hypo-pigmented macular lesions as clinical presentation and neural involvement in histopathological investigations. The co-infection of leprosy and VL has been reported in countries where both diseases are endemic. The authors report a co-infection case of leprosy and VL, which evolved into PKDL and discuss the clinical and the pathological aspects in the patient and review the literature on this disease. Case presentation We report an unusual case of a 53-year-old female patient from Alagoas, Brazil. She presented with leprosy and a necrotizing erythema nodosum, a type II leprosy reaction, about 3 month after finishing the treatment (MDT-MB) for leprosy. She was hospitalized and VL was diagnosed at that time and she was successfully treated with liposomal amphotericin B. After 6 months, she developed a few hypo-pigmented papules on her forehead. A granulomatous inflammatory infiltrate throughout the dermis was observed at histopathological examination of the skin biopsy. It consisted of epithelioid histiocytes, lymphocytes and plasma cells with the presence of amastigotes of Leishmania in macrophages (Leishman’s bodies). The diagnosis of post-kala-azar dermal leishmaniasis was established because at this time there was no hepatosplenomegaly and the bone marrow did not show Leishmania parasites thus excluding VL. About 2 years after the treatment of PKDL with liposomal amphotericin B the patient is still without PKDL lesions. Conclusion Post-kala-azar dermal leishmaniasis is a rare dermal complication of VL that mimics leprosy and should be considered particularly in countries where both diseases are endemic. A co-infection must be seriously considered, especially in patients who are non-responsive to treatment or develop persistent leprosy reactions as those encountered in the patient reported here.

Leprosy still is an important public health problem in several parts of the world including Brazil. Unlike the diseases caused by other mycobacteria, the incidence and clinical presentation of leprosy seems little affected in immunosuppressed patients. We report the first case, to our knowledge, of a liver transplant patient who developed multi-bacillary leprosy. The patient presented with papules and infiltrated plaques with loss of sensation suggestive of leprosy 3.5 years after living-related liver transplantation for autoimmune hepatitis. A skin biopsy showing non-caseating macrophagic granulomas, neuritis, and intact acid-fast bacilli on Fite-Faraco stain, confirmed the diagnosis of borderline lepromatous leprosy. The donor of the liver did not show any evidence of leprosy. During follow-up, the patient presented 2 episodes of upgrading leprosy type I reactions, 1 mild before leprosy treatment, and 1 moderate 3 months after receiving standard multi-drug treatment (rifampicin, clofazimine, and dapsone). These reactions were accompanied by increase in liver function tests, especially of canalicular enzymes. This reaction occurred despite the patient's triple immunosuppression regimen. The moderate reaction was successfully treated with further immunosuppression (prednisone, 0.5 mg/kg). Currently, the patient is asymptomatic, off leprosy medication, with routine liver transplant follow-up. The dilemmas in diagnosis and management of such a case are discussed and the literature on leprosy in transplant recipients is reviewed.

Lepromatous leprosy patients may develop necrotic lesions, usually in the context of Lucio phenomenon (LP) or severe erythema nodosum (EN). The clinical and histopathological characteristics of the necrotic manifestations of both entities may eventually be confounded. We describe a patient with lepromatous leprosy who developed, since the 4th month of her first pregnancy, recurrent necrotic lesions in lower limbs, which, at the postpartum, worsened and led to partial destruction of ears and nose. In addition, she referred painful nodes on upper limbs since 1 year before pregnancy and intermittent swelling and tenderness of the ankles, which together with a right tibial and ulnar neuritis led to the diagnosis of, erythema nodosum leprosum (ENL). The histopathology of a biopsy of the upper limb (ENL) revealed a dermal-hypodermal inflammation with vasculitis and vascular lumen narrowing, whereas biopsy of the lower limb (LP) revealed small vessels with fibrin thrombi on the superficial layer of the dermis without inflammatory infiltrate and no evidence of vasculitis. Thus, besides having several different clinical features, LP and ENL result from different pathogenetic mechanisms. The histopathological and clinical features distinguishing both entities are proposed. This distinction is important because decrease in bacillary load through multidrug therapy is the main target in LP, whereas in ENL, concomitant reduction of the reaction by means of thalidomide or high-dose steroids is recommended.

Two case reports of patients with human immunodeficiency virus type 1 (HIV-1) infection who developed leprosy are presented. Both developed type 1 leprosy reactions in the absence of antiretroviral therapy. Reactions have been described for a number of HIV-1- and Mycobacterium leprae- coinfected patients and have been considered to be part of an immune reconstitution inflammatory syndrome (IRIS) since the reactions were usually linked to the administration of highly active antiretroviral therapy. The reports of our two patients suggest that the type 1 reactions in patients with leprosy and HIV may not always be an IRIS manifestation but may be akin to the classical reactional state described for the natural course of leprosy infection, which occurs in leprosy patients due to the fluctuations of the antimycobacterial immune response, whether they are coinfected with HIV or not.

Background Leprosy is a chronic granulomatous infectious disease and is still endemic in many parts of the world. It causes disabilities which are the consequence of nerve damage. This damage is in most cases the result of immunological reactions. Objectives To investigate the differences between a type 1 leprosy (reversal) reaction and relapse on using histopathology. Methods The histopathological changes in 167 biopsies from 66 leprosy patients were studied. The patients were selected when their sequential biopsies demonstrated either different patterns or maintained the same pattern of granulomatous reaction over more than two years during or after the treatment of leprosy. Results In 57 of the patients studied, a reactivation was seen which coincided with a decrease in the bacteriological index (BI), suggesting that this reactivation (reversal reaction or type 1 leprosy reaction) coincides with an effective capacity for bacteriological clearance. In nine patients, an increase of the bacteriologic index (IB) or persistence of solid bacilli occurred during the reactivation, indicating proliferative activity, suggestive of a relapse. The histopathological aspects of the granulomas were similar in both groups. Conclusion Bacterioscopy provided the only means to differentiate a reversal reaction from a relapse in patients with granulomatous reactivation. The type 1 leprosy reaction may be considered as a part effective immune reconstitution (reversal, upgrading reaction) or as a mere hypersensitivity reaction (downgrading reaction) in a relapse., Author Summary Leprosy is a serious infectious disease whose treatment still poses some challenges. Patients are usually treated with a combination of antimicrobial drugs called multidrug therapy. Although this treatment is effective against Mycobacterium leprae, the bacillus that causes leprosy, patients may develop severe inflammatory reactions during treatment. These reactions may be either attributed to an improvement in the immunological reactivity of the patient along with the treatment, or to relapse of the disease due to the proliferation of remaining bacilli. In certain patients these two conditions may be difficult to differentiate. The present study addresses the histopathology picture of and the M. leprae bacilli in sequential biopsies taken from lesions of patients who presented such reactions aiming to improve the differentiation of the two conditions. This is important because these reactions are one of the major causes of the disabilities of the patients with leprosy, and should be treated early and appropriately. Our results show that the histopathology picture alone is not sufficient, and that bacilli's counting is necessary.

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:22:25Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:43:48Z : No. of bitstreams: 1 2-s2.0-34547105805.pdf: 52059 bytes, checksum: 18a402e4ce1ccc6c9d08c89fe7f06c51 (MD5) Made available in DSpace on 2014-05-27T11:22:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-03-01 Inst. of Hlth., Sec. of Sao Paulo (Instituto de Saude, Secretaria de Estado da Saude de Sao Paulo), São Paulo S. Paulo Center for Dermatology (Centro de Dermatologia, Secretaria de Estado da Saude de Sao Paulo), São Paulo Department of Dermatology Faculty of Medicine, Botucatu, São Paulo

In a retrospective study, five patients are reported who suffered from a Mycobacterium leprae/HIV co-infection and were treated for their HIV infection with HAART. In four patients, this revealed their leprosy and induced a type I leprosy reaction. Two patients who were lepromin negative at diagnosis were retested after about 1 year of anti-retroviral treatment, and found to be positive.

Leprosy is an important public health problem in Brazil. However, this disease is still poorly diagnosed in its early stages, leading to permanent disability and disfigurement. We examined eight patients with clinical and histological diagnosis of multibacillary leprosy who were being treated for other diseases for about three years without clinical hypothesis of leprosy. These cases illustrate the importance of medical education and public information about leprosy’s signs and symptoms for prompt recognition and treatment, which are necessary to prevent permanent Leprosy is an important public health problem in endemic areas. In spite of governmental strategies for reducing the leprosy burden and leprosy control, with declining incidence since 1991 due to new strategies for dealing with this disease, including multidrug therapy with reduced duration of treatment and the adoption of new cure criteria, more than 250,000 new cases were registered in 2007, including about 40,000 in Brazil and 140,000 in India [1,2]. Leprosy is a chronic disease caused by an intracellular bacillus, Mycobacterium leprae, which multiplies very slowly. The incubation period of this disease is about five years. It is transmitted via secretion droplets, from the nose and mouth, during close and frequent contacts with untreated patients, which are the most important transmission foci. Clinically, leprosy mainly affects the nerves and skin. The commonest skin lesions are erythematous, hypopigmented and infiltrated plaques, which have reduced sensibility. Damage to the nerves explains the sensory loss; if untreated, there can be progressive and permanent disabilities. Other clinical aspects of leprosy are reactions, which may be defined as acute phases within the usual chronic evolution of the disease; sometimes these define the moment of diagnosis [3-5]. Diagnosis is clinical and treatment is made at public health facilities [2]. Eight patients were evaluated at the Clinical Dermatology Division of the Hospital das Clinicas da Universidade de Sao Paulo, where diagnosis of multibacillary leprosy was made clinically and histologically. All eight patients had been initially misdiagnosed. We present these cases, followed by a discussion regarding various aspects of Hansen disease and the importance of early diagnosis for preventing complications and transmission (Table 1). Discussion