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Infection with Leishmania amazonensis and L. mexicana may lead to diffuse cutaneous leishmaniasis. The cure is exceptional, especially for the strange case of this lady. Case report: The patient acquired the disease in childhood and remained with lesions for over 30 years, albeit several treatments. She worsened after a pregnancy, developing disseminated lesions. Miltefosine with amphotericin B and pentamidine resulted in remission. Lesions reappeared after one year, accompanied by intra-nasal infiltration of the disease. The nasal spraying of a single ampoule of pentavalent antimoniate resulted in the sustained disappearance of the nasal symptoms and all the cutaneous lesions. After over eight years, she remains disease-free, albeit under renal replacement therapy. The high nasal mucosal antimonial concentration may explain the long-lasting cure via new MHC class I epitope-specific CD8+ cell clones against L. amazonensis present in the nasal mucosa.
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Abstract Diffuse cutaneous leishmaniasis is a rare universal disease associated with an inadequate host cell immune response, caused by different species: infantum, aethiopica, major, mexicana, and others, which presents the challenge of a poor therapeutic response. In Brazil, it is caused by L. amazonensis. A case confirmed by histopathology with an abundance of vacuolated macrophages full of amastigotes and lymphocyte scarcity, identified by RFLP-ITS1PCR and in vitro decrease and exhaustion of the host cell immune response to L. amazonensis antigen, was treated early (3 months after the onset) with Glucantime (2 months) and allopurinol (29 months) with clinical cure, after a follow-up for 30 months after treatment.
Assuntos
Humanos , Leishmania mexicana , Leishmaniose Tegumentar Difusa/tratamento farmacológico , Leishmaniose Cutânea/tratamento farmacológico , Antiprotozoários/uso terapêutico , Brasil , Antimoniato de MegluminaRESUMO
Diffuse cutaneous leishmaniasis is a rare universal disease associated with an inadequate host cell immune response, caused by different species: infantum, aethiopica, major, mexicana, and others, which presents the challenge of a poor therapeutic response. In Brazil, it is caused by L. amazonensis. A case confirmed by histopathology with an abundance of vacuolated macrophages full of amastigotes and lymphocyte scarcity, identified by RFLP-ITS1PCR and in vitro decrease and exhaustion of the host cell immune response to L. amazonensis antigen, was treated early (3 months after the onset) with Glucantime (2 months) and allopurinol (29 months) with clinical cure, after a follow-up for 30 months after treatment.
Assuntos
Antiprotozoários , Leishmania mexicana , Leishmaniose Cutânea , Leishmaniose Tegumentar Difusa , Antiprotozoários/uso terapêutico , Brasil , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Tegumentar Difusa/tratamento farmacológico , Antimoniato de MegluminaRESUMO
INTRODUCTION: Leishmaniasis is a disease predominantly prevalent in the tropics, considered as one of the primary neglected diseases, preferably affects individuals of low socioeconomic status. Although this condition is well described in children, disseminated cutaneous leishmaniasis is a rare form of increasing importance and multiple cases observed in the adult population; however, still little described in children. CASE: We present the case of a 12-year-old male, who has multiple ulcerative and nodular lesions distributed throughout the body, of â¼1 year of evolution that did not respond to antimicrobial treatment. After the diagnostic process, positive serological tests were found for leishmaniasis, with improvement in the picture after the use of sodium stibogluconate. DISCUSSION: Disseminated cutaneous leishmaniasis is a clinical form that is described with increasing frequency and should be recognized and treated appropriately, mainly in the pediatric population, avoiding complications and sequelae.
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Leishmaniose Cutânea , Adulto , Gluconato de Antimônio e Sódio/uso terapêutico , Criança , Humanos , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/epidemiologia , Masculino , Doenças Negligenciadas , Peru/epidemiologiaRESUMO
La leishmaniasis cutánea o mucocutánea presenta variedad de formas clínicas, siendo la más frecuente la úlcera moldurada. Una forma poco frecuente es la llamada leishmaniasis cutánea difusa caracterizada por presentar pápulas, tubérculos, nódulos, placas e infiltración. Inicialmente localizadas, pero con tendencia a la progresión, pudiendo llegar a ser diseminadas. Es una forma aún no comunicada en Paraguay. Presentamos el caso de una mujer adulta mayor, con placas y nódulos en ambos miembros inferiores, y cuyo frotis y anatomía patológica confirmaron el diagnóstico de leishmaniasis. Clínicamente clasificada como leishmaniasis cutánea difusa, la PCR y HRM demostraron ser producida por Leishmania (Viannia) brasiliensis.
Cutaneous or mucocutaneous leishmaniasis presents a variety of clinical forms, the most common being a molded ulcer. A rare form is the so-called diffuse cutaneous leishmaniasis characterized by presenting papules, tubers, nodules, plaques and infiltration; initially located but with a tendency to progression, and may become widespread. It is a form not reported in Paraguay. We present the case of an older adult woman, with plaques and nodules on both lower limbs, and whose smear and pathological anatomy confirmed the diagnosis of leishmaniasis. Clinically classified as diffuse cutaneous leishmaniasis, PCR and HRM were shown to be produced by Leishmania (Viannia) brasiliensis.
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Leishmania braziliensis , Leishmaniose Tegumentar Difusa , Leishmaniose Tegumentar Difusa/epidemiologiaRESUMO
l-Arginine metabolism through arginase 1 (Arg-1) and inducible nitric oxide synthase (NOS2) constitutes a fundamental axis for the resolution or progression of leishmaniasis. Infection with Leishmania mexicana can cause two distinct clinical manifestations: localized cutaneous leishmaniasis (LCL) and diffuse cutaneous leishmaniasis (DCL). In this work, we analyzed in an in vivo model the capacity of two L. mexicana isolates, one obtained from a patient with LCL and the other from a patient with DCL, to regulate the metabolism of l-arginine through Arg-1 and NOS2. Susceptible BALB/c mice were infected with L. mexicana isolates from both clinical manifestations, and the evolution of the infection as well as protein presence and activity of Arg-1 and NOS2 were evaluated. The lesions of mice infected with the DCL isolate were bigger, had higher parasite loads, and showed greater protein presence and enzymatic activity of Arg-1 than the lesions of mice infected with the LCL isolate. In contrast, NOS2 protein synthesis was poorly or not induced in the lesions of mice infected with the LCL or DCL isolate. The immunochemistry analysis of the lesions allowed the identification of highly parasitized macrophages positive for Arg-1, while no staining for NOS2 was found. In addition, we observed in lesions of patients with DCL macrophages with higher parasite loads and stronger Arg-1 staining than those in lesions of patients with LCL. Our results suggest that L. mexicana isolates obtained from patients with LCL or DCL exhibit different virulence or pathogenicity degrees and differentially regulate l-arginine metabolism through Arg-1.
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Arginase/metabolismo , Arginina/metabolismo , Interações Hospedeiro-Patógeno , Leishmania mexicana/fisiologia , Leishmaniose Tegumentar Difusa/metabolismo , Leishmaniose Tegumentar Difusa/parasitologia , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Leishmania mexicana/isolamento & purificação , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Fatores de TempoRESUMO
American cutaneous leishmaniasis (ACL) is a parasitic protozoan disease caused by different Leishmania species widely distributed throughout Latin America. Fifteen Leishmania species belonging to the subgenera Viannia, Leishmania and Mundinia are known to cause ACL. Seven of these species are found in Brazil, of which Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis have the highest potential to cause mucosal (ML) and anergic diffuse cutaneous leishmaniasis (DCL), respectively, the most severe forms of ACL. The clinical and immunopathological differences between these two clinical forms are reviewed here, taking into account their different physiopathogenic mechanisms of dissemination from cutaneous lesions to mucosal tissues in the case of ML and to almost all body surfaces in the case of anergic DCL. We also discuss some immunopathogenic mechanisms of species-specific Leishmania antigens (from the subgenera Viannia and Leishmania) that are most likely associated with the clinical and immunopathological differences between ML and anergic DCL. Those discussions emphasize the pivotal importance of some surface antigens of L. (V.) braziliensis and L. (L.) amazonensis, such as lipophosphoglycan, phosphatidylserine and CD200 (an immunoregulatory molecule that inhibits macrophage activation), that have been shown to exert strong influences on the clinical and immunopathological differences between ML and anergic DCL.
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Species of the genus Leishmania are the causal agents of leishmaniasis, a disease with diametrically different clinical manifestations that have been attributed to the species and host immune response. Some Leishmania species, including Leishmania mexicana, are capable of causing both localized cutaneous leishmaniasis (LCL) and diffuse cutaneous leishmaniasis (DCL). Therefore, it is possible that intraspecific differences may exist that contribute to the development of distinct clinical forms. Dendritic cells (DC) are important host cells of Leishmania spp. parasites, and cytokine production and phagocytosis upon infection with the parasite are significant for the outcome of the disease. In the present study we analyzed the production of IL-12, TNF-α, and IL-10 by DC infected with L. mexicana amastigotes isolated from a patient with LCL (amastigote = Lac) and from a patient with DCL (amastigote = Diact) by murine DC. Furthermore, we compared the frequency of phagocytosis of L. mexicana amastigotes of each isolate by fluorescence and optical microscopy and by flow cytometry. We show that the infection of DC with Diact amastigotes elicited the secretion of IL-10, TNF-α, and IL-12 by DC to a major extent as compared to the infection with Lac amastigotes. On the other hand, Lac and Diact amastigotes were similarly phagocytosed by DC, but interestingly there were more vacuoles in DC infected with Diact amastigotes. Our results suggest that isolates from a same species of Leishmania, such as L. mexicana, with different degrees of virulence according to the clinical manifestation they cause, differ in their capacity to elicit cytokine production and form vacuoles in DC.
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Células da Medula Óssea/fisiologia , Citocinas/biossíntese , Células Dendríticas/fisiologia , Leishmania mexicana/fisiologia , Fagocitose , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/parasitologia , Células Dendríticas/imunologia , Células Dendríticas/parasitologia , Ensaio de Imunoadsorção Enzimática , Fêmur/citologia , Citometria de Fluxo , Leishmania mexicana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia , Microscopia de Fluorescência , Tíbia/citologiaRESUMO
Leishmania panamensis is the most common species of Leishmania in Panama, and it is known to cause cutaneous leishmaniasis, disseminated cutaneous leishmaniasis, and mucocutaneous leishmaniasis; however, it not associated with diffuse cutaneous disease. In this study, we report the first case of diffuse cutaneous leishmaniasis caused by L panamensis.
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Introduction: Diffuse cutaneous leishmaniasis (DCL) is a rare disease form associated with Leishmania (L.) amazonensis in South America. It represents the "anergic" pole of American Tegumentary Leishmaniasis, and the explanation for its resistance to treatment remains elusive. We aimed to study some possible immunological mechanisms involved in the poor DCL treatment response by evaluating some cell surface molecules obtained from a patient with DCL by flow cytometry. Case presentation: A 65-year-old DCL patient who initially failed to respond to the standard treatment for the disease showed vacuolated macrophages filled with amastigotes in lesion biopsy, and L. (L.) amazonensis was identified through ITS1PCR amplification. The Leishmania skin test and indirect immunofluorescence analysis revealed negative results. Peripheral blood from the patient was collected after a few months of treatment, when the patient presented with no lesion. Peripheral blood mononuclear cells were analyzed ex vivo and in vitro after 48 h of stimulation with soluble L. (L.) amazonensis antigen (SLA). Cell death, surface molecules, and intracellular molecules, such as IFN-γ and granzyme B, were analyzed in the cells using flow cytometry. Analysis of the surface markers showed an increased expression of the inhibitory molecule programmed death ligand 1 (PD-L1) in the monocytes restimulated with SLA (approximately 65%), whereas the negative controls were 35% positive for PD-L1. Conversely, compared with the negative controls, we observed a decrease in CD4+IFN-γ+ T cells (8.32 versus 1.7%) and CD8+IFN-γ+ T cells (14% versus 1%). We also observed a relevant decrease in the granzyme B levels in the CD8+ T cells, from 31% in the negative controls to 5% after SLA restimulation. Conclusion: The dysfunctional activation of PD-L1 inhibitory pathway after Leishmania antigen stimulation and reduced levels of IFN-gamma and granzyme B-producing cells could be closely related to unresponssiveness to standard drug treatment of DCL patient.
Assuntos
Antígeno B7-H1/genética , Leishmaniose Tegumentar Difusa/imunologia , Linfócitos T/imunologia , Idoso , Antígenos de Protozoários/imunologia , Antígeno B7-H1/imunologia , Biópsia , Citocinas/imunologia , Citometria de Fluxo , Granzimas/imunologia , Humanos , Interferon gama/imunologia , Leishmania , Leishmaniose Cutânea , Leishmaniose Tegumentar Difusa/tratamento farmacológico , Macrófagos/parasitologia , Macrófagos/patologia , Masculino , Monócitos/efeitos dos fármacos , Monócitos/parasitologia , Pele/parasitologia , Pele/patologia , Linfócitos T/patologia , Falha de TratamentoRESUMO
Disseminated leishmaniasis (DL) is a poorly described disease that is frequently misdiagnosed as other clinical manifestations of cutaneous leishmaniasis (CL) such as diffuse CL or post-kala-azar dermal leishmaniasis. Twenty-seven cases of DL diagnosed between 1997 and 2015 are described. A higher prevalence was observed in men (mean age 32 years). The number of lesions per patient ranged from 12 to 294, distributed mainly in the upper extremities, face and trunk. The lesions were mostly plaques or nodules. Seven patients had nasal mucous damage, 74% of the patients were of mixed race, 92% lived in northwestern Colombia, and Leishmania (Viannia) panamensis was identified as the causative agent in 58% of cases. Eighteen patients recovered with pentavalent antimonial. The importance of distinguishing DL from those other clinical presentations is based on the fact that disseminated, diffuse and post-kala-azar CL are very different in etiology, clinical manifestations and response to treatment and prognosis.
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Nucleoside hydrolases of the Leishmania genus are vital enzymes for the replication of the DNA and conserved phylogenetic markers of the parasites. Leishmania donovani nucleoside hydrolase (NH36) induced a main CD4(+) T cell driven protective response against L. chagasi infection in mice which is directed against its C-terminal domain. In this study, we used the three recombinant domains of NH36: N-terminal domain (F1, amino acids 1-103), central domain (F2 aminoacids 104-198), and C-terminal domain (F3 amino acids 199-314) in combination with saponin and assayed their immunotherapeutic effect on Balb/c mice previously infected with L. amazonensis. We identified that the F1 and F3 peptides determined strong cross-immunotherapeutic effects, reducing the size of footpad lesions to 48 and 64%, and the parasite load in footpads to 82.6 and 81%, respectively. The F3 peptide induced the strongest anti-NH36 antibody response and intradermal response (IDR) against L. amazonenis and a high secretion of IFN-γ and TNF-α with reduced levels of IL-10. The F1 vaccine, induced similar increases of IgG2b antibodies and IFN-γ and TNF-α levels, but no IDR and no reduction of IL-10. The multiparameter flow cytometry analysis was used to assess the immune response after immunotherapy and disclosed that the degree of the immunotherapeutic effect is predicted by the frequencies of the CD4(+) and CD8(+) T cells producing IL-2 or TNF-α or both. Total frequencies and frequencies of double-cytokine CD4 T cell producers were enhanced by F1 and F3 vaccines. Collectively, our multifunctional analysis disclosed that immunotherapeutic protection improved as the CD4 responses progressed from 1+ to 2+, in the case of the F1 and F3 vaccines, and as the CD8 responses changed qualitatively from 1+ to 3+, mainly in the case of the F1 vaccine, providing new correlates of immunotherapeutic protection against cutaneous leishmaniasis in mice based on T-helper TH1 and CD8(+) mediated immune responses.
RESUMO
The nucleoside hydrolase (NH) of Leishmania donovani (NH36) is a phylogenetic marker of high homology among Leishmania parasites. In mice and dog vaccination, NH36 induces a CD4+ T cell-driven protective response against Leishmania chagasi infection directed against its C-terminal domain (F3). The C-terminal and N-terminal domain vaccines also decreased the footpad lesion caused by Leishmania amazonensis. We studied the basis of the crossed immune response using recombinant generated peptides covering the whole NH36 sequence and saponin for mice prophylaxis against L. amazonensis. The F1 (amino acids 1-103) and F3 peptide (amino acids 199-314) vaccines enhanced the IgG and IgG2a anti-NH36 antibodies to similar levels. The F3 vaccine induced the strongest DTH response, the highest proportions of NH36-specific CD4+ and CD8+ T cells after challenge and the highest expression of IFN-γ and TNF-α. The F1 vaccine, on the other hand, induced a weaker but significant DTH response and a mild enhancement of IFN-γ and TNF-α levels. The in vivo depletion with anti-CD4 or CD8 monoclonal antibodies disclosed that cross-protection against L. amazonensis infection was mediated by a CD4+ T cell response directed against the C-terminal domain (75% of reduction of the size of footpad lesion) followed by a CD8+ T cell response against the N-terminal domain of NH36 (57% of reduction of footpad lesions). Both vaccines were capable of inducing long-term cross-immunity. The amino acid sequence of NH36 showed 93% identity to the sequence of the NH A34480 of L. amazonensis, which also showed the presence of completely conserved predicted epitopes for CD4+ and CD8+ T cells in F1 domain, and of CD4+ epitopes differing by a single amino acid, in F1 and F3 domains. The identification of the C-terminal and N-terminal domains as the targets of the immune response to NH36 in the model of L. amazonensis infection represents a basis for the rationale development of a bivalent vaccine against leishmaniasis.
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We reviewed the records of 151 patients diagnosed with American cutaneous leishmaniasis (ACL) from 1993 to 2009 in the municipality of Japura, Paraná, Brazil. Gender, age, occupation, place of residence, location of lesions, type and number of lesions were analyzed. The prevalence rate of ACL was 11.5/10,000 hab, of which 84.7% were male, 58.3% lived in rural area and 49.0% were farmers. The most frequent age group was between 30 to 39 years (26.6%). Skin lesions occurred in 92.7% of the patients with predominance in the lower limbs (23.9%) and 49.1% of the records did not include the number of lesions location due to incomplete filling. A single ulceration was present in 44.4%. Japurá is an endemic area for ACL, requiring public actions and preventive education.
Foram revistos os registros de 151 pacientes diagnosticados com leishmaniose tegumentar americana (LTA) de 1993-2009 no município de Japurá, Paraná, Brasil. Sexo, idade, profissão, local de residência, localização das lesões, tipo e número de lesões foram analisadas. A taxa de prevalência de LTA foi 11,5/10.000 hab, dos quais 84,7% eram do sexo masculino, 58,3% viviam na área rural e 49,0% eram agricultores. A faixa etária mais freqüente foi entre 30 a 39 anos (26,6%). Lesões de pele ocorreram em 92,7% dos pacientes com predominância nos membros inferiores (23,9%) e 49,1% dos registros não incluem o número e localização de lesões devido ao preenchimento incompleto. Ulceração única estava presente em 44,4%. Japurá é uma área endêmica para LTA, exigindo ações públicas e educação preventiva.
Assuntos
Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Leishmaniose Cutânea/epidemiologia , Brasil/epidemiologia , Estudos Transversais , PrevalênciaRESUMO
La leishmaniasis es una zoonosis ocasionada por la trasmisión del protozoo leishmania a causa de la picadura de mosquitos flebótomos de la especie Lutzomya. Se presentan diversas manifestaciones clínicas dependiendo de la cepa infectante y de la respuesta inmune del hospedero, la más frecuente la Leismaniasis Cutánea Localizada. En ocasiones se presentan formas atípicas como la forma difusa, en la cual el número de ulceras es mayor de 10, afectando diversas regiones corporales, requiriendo consideraciones especiales en su diagnóstico y manejo. En el presente artículo reportamos dos casos de pacientes con Leishmaniasis Cutánea Difusa generados por la cepa L. panamensis procedentes de zonas endémicas de Santander, destacando la necesidad de implementar protocolos de búsqueda activa para este tipo de casos en las zonas endémicas de todo el país.
Leishmaniasis is a zoonosis produced by the transmission of the protozoan leishmania caused by the bite of sand-flies from the Lutzomya specie. Several clinical manifestations present themselves, depending on the infecting strain and the host's immune response; the most frequent variety is localised cutaneous leishmaniasis. Atypical forms sometimes develop, such as the diffuse variety, in which the number of ulcers is greater than 10, thereby affecting several body areas requiring special considerations in its diagnosis and management. This article reports two cases of patients from endemic areas of Santander suffering from diffuse cutaneous leishmaniasis produced by the L. panamensis strain. Protocols for the active search of this type of case in endemic areas throughout Colombia should be implemented.