Lower levels of leptin are associated with severity parameters in visceral leishmaniasis patients.

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, and if untreated may be fatal. It affects important organs of the immune system and is characterized by a specific immunosuppression, along with intense cellular activation and cytokine storm. Moreover, VL is now recognized as a systemic inflammatory response syndrome (SIRS), in which multiple cytokines and other pro-inflammatory molecules are released. The action of these inflammatory mediators may be considered risk factors for poor prognosis and death. Leptin, a hormone derived from adipose tissue, has been described with several immunoregulatory functions in vitro and in vivo Leishmania infection models, particularly for enhancing the macrophage microbicidal mechanisms. Considering that evaluation of immunologic parameters that may be associated with this clinical scenario may help to decrease VL lethality, we evaluated whether leptin is associated with VL pathogenesis. Thirty-one patients were recruited in the active phase of VL, of which 22 were followed up until one month after therapy (1mpt). Except for creatinine levels, all clinical parameters were altered in active VL patients, especially leucocyte counts and albumin and hemoglobin levels. Also, elevated levels of lipopolysaccharide (LPS), immunoglobulins (Ig)G1 and G3 anti-Leishmania and interleukins (IL)-6 and -10 were higher than in healthy individuals. In contrast, active VL patients presented diminished serum leptin levels and positive correlation with leukocytes counts and hemoglobin and albumin levels. After 1mpt, VL patients showed a significant increase in leptin levels, reaching values similar to healthy volunteers. As expected, only LPS levels remained elevated after 1mpt. These findings suggest that leptin levels are affected in Leishmania infection and the correlation with important parameters associated with the prognosis of VL points to the involvement of this molecule in VL immunopathogenesis. Additional studies are needed to evaluate the possibility of leptin as a prognostic marker of VL.

Avaliação das concentrações séricas de leptina, lipopolissacarídeo, imunoglobulinas 1 e 3 como fatores associados a gravidade na leishmaniose visceral / Assessment of serum concentrations of leptin, lipopolysaccharide, immunoglobulins 1 and 3 as factors associated with severity in visceral leishmaniasis

A Leishmaniose Visceral (LV) é a forma clínica mais grave das leishmanioses, devido às frequentes complicações e potencial de evolução para a morte, quando não tratada. Apresenta ampla distribuição geográfica, prevalecendo em condições de pobreza, o que contribui para manutenção do quadro de desigualdade social. O propósito desta tese foi i) Descrever as características sociodemográficas de indivíduos com LV atendidos no Hospital São José de Doenças Infecciosas (HSJ); ii) Avaliar as características clínicas e laboratoriais dos indivíduos com LV não coinfectados pelo HIV; iii) Avaliar se os níveis séricos das interleucinas (IL) 6 e 10 estão aumentados em indivíduos com LV, nas fases ativa e pós tratamento; iv) Correlacionar as concentrações séricas de leptina e lipopolissacarídeo com indicadores hematológicos e bioquímicos utilizados como parâmetros de gravidade em indivíduos com LV e v) Observar se as subclasses de imunoglobulinas IgG1 e IgG3 podem ser preditivas de prognóstico de evolução clínica na LV. No período de maio de 2015 a agosto de 2016, foram selecionados 64 casos, 53 (83%) eram do sexo masculino e 11 (17%) do feminino. A idade média foi de 43 anos, tendo participantes de 7 a 85 anos, internados ou em atendimento ambulatorial. O tempo médio para o diagnóstico de LV foi de 65 dias. Os indivíduos foram entrevistados e tiveram suas amostras sanguíneas colhidas para avaliação de parâmetros hematológicos e bioquímicos, em períodos definidos como fase ativa e um mês pós-tratamento (1mpt). Desta população, foram identificados 31 indivíduos não coinfectados, de 18 a 60 anos e que, por apresentarem algum parâmetro de gravidade, foram internados para tratamento. Para a realização das quantificações séricas de leptina, subclasses de IgG1 e IgG3 e IL-6 e IL-10, foram utilizados ensaio imunoenzimático (ELISA) e para a quantificação de lipopolissacarídeo (LPS), o ensaio do Lisado de Amebócitos do Limulus (LAL). Doadores de sangue sem LV e sem HIV (N=10) constituíram o grupo controle. Em relação aos biomarcadores, os níveis elevados de LPS e de IL-6 e IL-10 na fase ativa da LV e diminuídas no pós-tratamento corroboram com a hipótese de que a translocação bacteriana ocorre na LV e deve ser um fator adicional a contribuir na ativação celular. Foram encontradas correlações significativas (p<0,05) entre a leptina e as contagens de leucócitos, dosagens de hemoglobina e albumina e o LPS teve correlação com as contagens de leucócitos, demonstrando que estes biomarcadores estão associados aos parâmetros de gravidade laboratoriais. O maior decréscimo dos níveis de IgG3, após um mês de tratamento, sugere que este critério laboratorial pode ser utilizado para avaliar a evolução clínica na LV.

Visceral Leishmaniasis (VL) is the most severe clinical form of leishmaniasis, due to the frequent complications and the potential for evolution to death, when left untreated. It has a wide geographical distribution, prevailing in conditions of poverty, which contributes to maintaining the situation of social inequality. The purpose of this thesis was i) To describe the sociodemographic characteristics of individuals with VL treated at Hospital São José de Infectious Diseases (HSJ); ii) Assess the clinical and laboratory characteristics of individuals with VL not co-infected with HIV; iii) Assess whether serum levels of interleukins (IL) 6 and 10 are increased in individuals with VL, in the active and post-treatment phases; iv) Correlate serum leptin and lipopolysaccharide concentrations with hematological and biochemical indicators used as severity parameters in individuals with VL and v) Observe whether the subclasses of immunoglobulins IgG1 and IgG3 can be predictive of the prognosis of clinical evolution in VL. From May 2015 to August 2016, 64 cases were selected, 53 (83%) were male and 11 (17%) female. The average age was 43 years, with participants from 7 to 85 years old, hospitalized or in outpatient care. The mean time to diagnosis of VL was 65 days. The individuals were interviewed and had their blood samples collected for evaluation of hematological and biochemical parameters, in periods defined as the active phase and one month after treatment (1mpt). Of this population, 31 non-coinfected individuals, aged 18 to 60 years, were identified and, for presenting some severity parameter, were admitted for treatment. To perform serum leptin quantifications, subclasses of IgG1 and IgG3 and IL-6 and IL-10, immunoenzymatic assays (ELISA) were used and for the quantification of lipopolysaccharide (LPS), the Limulus Amebocyte Lysate (LAL) assay ). Blood donors without VL and without HIV (N = 10) constituted the control group. Regarding biomarkers, high levels of LPS and IL-6 and IL-10 in the active phase of VL and decreased in post-treatment corroborate the hypothesis that bacterial translocation occurs in VL and should be an additional contributing factor in cell activation. Significant correlations (p <0.05) were found between leptin and leukocyte counts, hemoglobin and albumin measurements and LPS correlated with leukocyte counts, demonstrating that these biomarkers are associated with laboratory severity parameters. The greatest decrease in IgG3 levels, after one month of treatment, suggests that this laboratory criterion can be used to assess the clinical evolution in VL.