The role of interleukin 17-mediated immune response in Chagas disease:High level is correlated with better left ventricular function

Interleukin 17A (IL-17A) has been associated with protective rather than pathogenic response in Chagas disease (ChD). However, it is not established whether or not IL-17A-mediated immune response is correlated with patient's left ventricular (LV) function in ChD. To address this question we have gathered cardiac functional parameters from ChD patients and analysed the possible relationship between their plasma IL-17A levels and LV function. Plasma IL-17A levels were measured by BD Cytometric Bead Array (CBA) in 240 patients with positive specific serology for Trypanosoma cruzi (T. cruzi) grouped as indeterminate (IND) and Chagas cardiomyopathy (CARD) forms. The levels of IL-17A in ChD patients were compared with 32 healthy individuals, mean age of 39 years, 50% male, that were also included as a control group (non-infected [NI]). The overall mean age of ChD patients was 46 years and 52% were male. The IND group included 95 asymptomatic patients, with ages ranging from 27 to 69 years (mean of 43 years), and 42.1% of them were male. The CARD group included 145 patients, which 58.6% were male, with ages ranging from 23 to 67 years (mean of 49). The IND group presented substantially higher levels of IL-17A, median of 26.16 (3.66-48.33) as compared to both the CARD group, median of 13.89 (3.87-34.54) (P <0.0001), and the NI group, median of 10.78 (6.23-22.26) (P <0.0001). The data analysis demonstrated that the IND group comprises a significantly greater proportion (P <0.001) of high IL-17A producers (52.6%, 50 of 95 subjects) than do the other groups. A significant direct correlation was verified between IL-17A levels and cardiac function expressed by LV ejection fraction (LVEF), LV diastolic diameter (LVDd), and body surface area (BSA)-indexed LVDd as well as ratio of the early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/e') in both groups. We demonstrated that plasma IL-17A levels has an accurate sensitivity and specificity to predict heart failure in serology-positive patients and might be a useful parameter to distinguish patients with or without cardiac impairment. This study indicates a consistent relationship between high expression of IL-17A and better LV in human chronic ChD. Our data raise the possibility that IL-17A plays an important immunomodulatory role in the chronic phase of ChD and might be involved in protection against myocardial damage

Citocinas plasmáticas como biomarcadores de morbidade cardíaca na doença de Chagas

Exportado OPUSMade available in DSpace on 2019-08-13T10:24:35Z (GMT). No. of bitstreams: 1 disserta__o_giovane_rodrigo_de_sousa.pdf: 3317504 bytes, checksum: 9f7a7bf69981fcdbed283c4ca9861868 (MD5) Previous issue date: 18Este estudo foi desenvolvido para determinar se a expressão de marcadores imunolológicos em pacientes com diferentes formas da doença de Chagas associa-se a fatores determinantes de morbidade cardíaca nessa doença. Pacientes infectados por Trypanosoma cruzi, com idade variando entre 23 e 69 anos (média de 45,6 ± 11,25) foram agrupados como forma indeterminada (IND) e com cardiomiopatia (CARD). O grupo IND incluiu 82 pacientes assintomáticos, com idade entre 24 e 66 anos (média de 39,6 ± 10.3), sem alterações significantes ao eletrocardiograma, radiografia do tórax e ao ecocardiograma. O grupo CARD incluiu 94 pacientes, com idade entre 23 e 69 anos (média de 48 ± 12,52) com cardiomiopatia dilatada, caracterizada por achados ecocardiográficos de dilatação do ventrículo esquerdo com comprometimento da função ventricular sistólica. Constituíram o grupo-controle (NI) 24 indivíduos saudáveis, com testes sorológicos negativos para infecção pelo T. cruzi, provenientes de área não endêmica. Os resultados demonstraram que pacientes IND expressam elevados níveis de interleucina (IL)-10, comparados com indivíduos dos outros grupos. Todavia, a expressão de citocinas inflamatórias, como interferon (IFN)-, fator de necrose tumoral (TNF)-, IL-6 e IL-1, provou ser mais elevada no grupo CARD. Análise de correlação evidenciou que a alta expressão de IL-10 associa-se à melhor função cardíaca, determinada pela fração de ejeção do ventrículo esquerdo e diâmetro diastólico ventricular esquerdo. Os achados corroboram com o papel da IL-10 na proteção contra o dano cardíaco. Em conjunto, os resultadosindicam que o bom equilíbrio entre as citocinas inflamatórias e reguladoras representa elemento-chave no estabelecimento de formas distintas da doença de Chagas. Além disso, este estudo ajudou a lançar luz sobre a complexa rede de citocinas subjacente à imunopatogênese da cardiopatia chagásica crônica.The present study was designed to determine if the expression of immunological markers in patients with different forms of Chagas disease is associated with determining factors of cardiac morbidity in this disease. Patients infected with Trypanosoma cruzi were grouped as indeterminate form (IND) and cardiac (CARD) patients ranging from 23 to 69 years of age (mean of 45.6 ± 11.25). The IND group included 82 asymptomatic individuals, ranging from 24 to 66 years of age (mean of 39.6 ± 10.3), with no significant alterations in electrocardiography, chest X-ray, and echocardiogram. The CARD group included 94 patients ranging from 23 to 69 years of age (mean of 48 ± 12.52) presenting with dilated cardiomyopathy, characterized by the echocardiographic finding of a dilated left ventricle with impaired ventricular systolic function. Healthy individuals, ranging from 29 to 55 years of age (mean of 42.6 ± 8.8), from a non-endemic area for Chagas disease and showing negative serological tests for the infection were included as a control group (NI). Data analysis demonstrated that IND patients have a higher intensity of interleukin (IL)-10 expression when compared with individuals in the other groups. By contrast, the forms of inflammatory cytokine expression, such as interferon (IFN)-, tumor necrosis factor (TNF)-, IL-6, and IL-1, proved to be the highest in the CARD group. Correlated analysis showed that high IL-10 expression was associated with better cardiac function, as determined by left ventricular ejection fraction and left ventricular diastolic diameter values. The findings support the protective role of IL-10 against cardiac damage in human Chagas disease. Altogether, the results indicate that a fine balance between regulatory and inflammatory cytokines represents a key element in the establishment of distinct forms of chronic Chagas disease. Furthermore, this study helped to shed light on the complex cytokine network underlying the immunopathogenesis of chronic chagasic cardiopathy

Expressão de citocinas e quimiocinas e sua associação com a imunopatogenia da cardiopatia chagásica crônica

Exportado OPUSMade available in DSpace on 2019-08-13T07:06:05Z (GMT). No. of bitstreams: 1 ppgcs_infectmedtropical_tese_giovane_sousa_versao_correta_21set2016.pdf: 3496962 bytes, checksum: 4d9a85225189f8bdf5773a6f0e327c35 (MD5) Previous issue date: 1Citocinas e quimiocinas possuem um papel importante na modulação da resposta imune. Entretanto, desconhece-se a existência, ou não, de um padrão estável de expressão de citocinas e quimiocinas na doença de Chagas e se este constituiria uma característica individual do paciente ou de grupo de pacientes com grau semelhante de morbidade. Este estudo foi planejado para identificar um conjunto de biomarcadores associados com a morbidade e investigar o perfil de expressão de citocinas e quimiocinas no curso médio da infecção crônica pelo Trypanosoma cruzi (T. cruzi). O estudo pode ser considerado uma das mais amplas análises envolvendo amostra significativa de pacientes com forma indeterminada (IND, n=93) e cardiomiopatia dilatada (CARD, n=141). Indivíduos saudáveis (n=32) foram incluídos como grupo controle (não infectados [NI}). A média de idade dos pacientes foi de 46.83±9.97 (23 a 69 anos) e 119 (51%) eram do sexo masculino. O grupo IND apresentou níveis substancialmente mais elevados de IL-17, quando comparado ao grupo NI e CARD. Além disso, verificou-se correlação significativa entre altos níveis de IL-17 e melhor função ventricular esquerda. Análise exploratória de rede de citocinas e quimiocinas no grupo CARD evidenciou correlações positivas e significativas entre IFN- CXCL10 e CXCL9 CXCL10, assim como correlações fortes e inversas envolvendo IL-10 com CXCL9 e TNF-. No entanto, no grupo IND, observou-se uma rede com fortes conexões ao longo dos eixos IL-10 IL-17, e IL-10 IFN-comparado aos outros grupos. Análises adicionais mostraram que níveis elevados de IFN-, TNF-, CXCL9, e CXCL-10 associados a níveis reduzidos de IL-10 e IL-17 associam-se com maior morbidade cardíaca na doença de Chagas. O ensaio de algoritmo de aprendizado de máquina indicou IFN-, TNF-, IL-10, e IL-17 como fortes candidatos à biomarcadores imunológicos na doença de Chagas. Nenhum padrão de expressão de IL-10 e IFN- foi observado no grupo IND. Por outro lado, estas citocinas exibiram perfil estável no grupo CARD. As evidências deste estudo revelam a existência de um perfil estável de expressão de citocinas e quimiocinas ao longo infecção crônica pelo T. cruzi e sua associação com a morbidade na doença de Chagas.Cytokines and chemokines play an important role in modulating immune response; however, their pattern of expression in short, medium, and long-terms throughout the chronic phase of Chagas disease (ChD) have never been elucidated. This study was designed to identify a composite set of biomarkers associated with morbidity and to investigate the pattern of cytokine and chemokine expression in ChD. It is one of the largest analyses involving large set of samples from a cohort of patients grouped as indeterminate form (IND, n=93) and Chagas cardiomyopathy (CARD, n=141). Healthy individuals (n=32) were also included as a control group (non-infected [NI]). Mean age of ChD patients was 46.83±9.97 years (range, 23-69 years), and 119 (51%) were male. The IND group presented substantially higher levels of IL-17 compared to the CARD group and the NI group. Moreover, a significant correlation was verified between lower levels of IL-17 and cardiac morbidity. Exploratory analysis of cytokine and chemokine networks in the CARD group revealed significant positive correlations amongst IFN- CXCL10 and CXCL9 CXCL10 as well as negative strong axes connecting IL-10 with CXCL9 and TNF-. By contrast, in the IND group was remarkable the presence of an overall multifaceted network with stronger connections between IL-10 and IL-17, and IL-10 and IFN- axes along when compared to the other groups. Additional analyses showed that higher levels of IFN-, TNF-, CXCL9, and CXCL-10 together with lower levels of IL-10 are also associated with worse left ventricular function in ChD. The machine learning algorithms assays pointed out IFN-, TNF-, IL-10, and IL-17 as putative immunological biomarkers in ChD. No pattern could be observed when evaluating the IL-10 and IFN- expression in the IND group. On the other hand, these cytokines proved to be stable in the CARD group. All together, this study revealed a stable pattern of cytokine and chemokine expression troughout the chronic infection with T. cruzi and also their association with morbidity in ChD

Combined parasitological and molecular-based diagnostic tools improve the detection of Trypanosoma cruzi in single peripheral blood samples from patients with Chagas disease

Abstract INTRODUCTION In order to detect Trypanosoma cruzi and determine the genetic profiles of the parasite during the chronic phase of Chagas disease (ChD), parasitological and molecular diagnostic methods were used to assess the blood of 91 patients without specific prior treatment. METHODS Blood samples were collected from 68 patients with cardiac ChD and 23 patients with an indeterminate form of ChD, followed by evaluation using blood culture and polymerase chain reaction. T . cruzi isolates were genotyped using three different genetic markers. RESULTS: Blood culture was positive in 54.9% of all patients, among which 60.3% had the cardiac form of ChD, and 39.1% the indeterminate form of ChD. There were no significant differences in blood culture positivity among patients with cardiac and indeterminate forms. Additionally, patient age and clinical forms did not influence blood culture results. Polymerase chain reaction (PCR) was positive in 98.9% of patients, although comparisons between blood culture and PCR results showed that the two techniques did not agree. Forty-two T . cruzi stocks were isolated, and TcII was detected in 95.2% of isolates. Additionally, one isolate corresponded to TcIII or TcIV, and another corresponded to TcV or TcVI. CONCLUSIONS Blood culture and PCR were both effective for identifying T. cruzi using a single blood sample, and their association did not improve parasite detection. However, we were not able to establish an association between the clinical form of ChD and the genetic profile of the parasite

Health-related quality of life in patients with Chagas disease: a review of the evidence

Chagas disease (ChD), a neglected tropical disease caused by infection with the parasite Trypanosoma cruzi (T. cruzi), remains a serious public health issue in Latin America and is an emerging disease in several non-endemic countries, where knowledge of the condition and experience with its clinical management are limited. Regionally, the disease is the major cause of disability secondary to tropical diseases in young adults. Health-related quality of life (HRQoL) impairment is common in patients with ChD, especially in those with Chagas dilated cardiomyopathy, the most severe manifestation of the disease, which frequently leads to heart failure. The aim of this review was to conduct a literature search for studies that have evaluated the determining factors of HRQoL in ChD patients. We included cross-sectional, case-control, cohort, and experimental studies, as well as clinical trials that evaluated the HRQoL in ChD patients aged 18 to 60 years and are presenting an explicit description of statistical analysis. Using a combination of keywords based on Descriptors in Health Sciences (DeCS) and Medical Subject Headings (MeSH) for searches in PubMed and the Scientific Electronic Library Online (SciELO), 148 studies were found. After exclusions, 12 studies were selected for analysis. Three main findings were extracted from these studies: 1) cardiac involvement is associated with a worse HRQoL in ChD patients; 2) HRQoL is associated with the patients' functional capacity; and 3) simple and inexpensive therapeutic measures are effective for improving HRQoL in ChD patients. Hence, ChD patients' functional capacity, the effectiveness of non-surgical conservative treatment, and cardiac involvement are important determining factors for the HRQoL in ChD patients

Inspiratory muscle weakness in patients with Chagas heart disease: Echocardiographic and functional predictors

Background: Patients with Chagas heart disease (CHD) usually present progressive fatigue and dyspnea. The inspiratory muscle weakness (IMW) may be a marker of exercise intolerance during disease progression. However, the factors related to IMW in CHD patients still remain unknown. Methods: Forty-eight CHD patients aged 56.4 (53.3–59.5) years were selected and underwent respiratory muscle strength, echocardiography, Cardiopulmonary Exercise Testing and International Physical Activity Questionnaire (IPAQ). The sample was stratified according to the percentage (%) of maximum inspiratory pressure (MIP) achieved in preserved muscle strength (MIP > 70%) or IMW (MIP ≤ 70%). Chi-square and Poisson regression analysis was performed to verify the predictors of IMW. Results: The %MIP predicted correlated with left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd) and minute ventilation-carbon dioxide production slope (VE/VCO2 slope). Significant differences in the IPAQ scores (p = 0.036), LVEF (p = 0.020) and VE/VCO2 slope (p = 0.008) were found between groups with preserved inspiratory muscle strength and with IMW. In multivariate analysis, sedentary patients and those with reduced LVEF and impaired VE/VCO2 slope had 6.3, 5.5 and 1.2-fold increased risk for IMW, respectively. Conclusion: The sedentary lifestyle, reduced LVEF and impaired VE/VCO2 slope showed to be independent predictors of IMW, probably by the association between these variables and the presence of inflammation in CHD patients. The detection of IMW may be helpful in identifying patients at high risk based on echocardiographic and functional aspects without much operating costs

Exercise-induced ventricular arrhythmias and vagal dysfunction in Chagas disease patients with no apparent cardiac involvement

INTRODUCTION : Exercise-induced ventricular arrhythmia (EIVA) and autonomic imbalance are considered as early markers of heart disease in Chagas disease (ChD) patients. The objective of the present study was to verify the differences in the occurrence of EIVA and autonomic maneuver indexes between healthy individuals and ChD patients with no apparent cardiac involvement. METHODS : A total of 75 ChD patients with no apparent cardiac involvement, aged 44.7 (8.5) years, and 38 healthy individuals, aged 44.0 (9.2) years, were evaluated using echocardiography, symptom-limited treadmill exercise testing and autonomic function tests. RESULTS : The occurrence of EIVA was higher in the chagasic group (48%) than in the control group (23.7%) during both the effort and the recovery phases. Frequent ventricular contractions occurred only in the patient group. Additionally, the respiratory sinus arrhythmia index was significantly lower in the chagasic individuals compared with the control group. CONCLUSIONS : ChD patients with no apparent cardiac involvement had a higher frequency of EIVA as well as more vagal dysfunction by respiratory sinus arrhythmia. These results suggest that even when asymptomatic, ChD patients possess important arrhythmogenic substrates and subclinical disease

Low levels of vasoactive intestinal peptide are associated with Chagas disease cardiomyopathy.

The interconnection between immune and neuroendocrine systems influences regulation of inflammatory responses. The possible relevance that this integrative response may have during the course of Chagas disease remains poorly characterized. In this context, our study was designed to determine the expression of vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties, in blood from the indeterminate and cardiac polarized forms of Chagas disease. Moreover, we determined whether the differential expression of VIP is associated with the development of cardiomyopathy in individuals infected with Trypanosoma cruzi. Finally, we analyzed gene polymorphisms of VIP receptors, VPAC1 and VPAC2, and performed correlation analysis of these polymorphisms with the different clinical forms of Chagas disease. Our results demonstrated that low plasma levels of VIP were associated with the cardiac morbidity in Chagas disease. Accordingly, correlation analysis showed that low plasma levels of VIP were associated with worse cardiac function, as determined by left ventricular ejection fraction and left ventricular diastolic diameter values. Polymorphism analysis showed a significant association between VPAC1 and the indeterminate form of Chagas disease development. Our data indicate that VIP expression and its receptors’ polymorphism may be important in determining susceptibility to progression from mild to severe forms of Chagas disease