Miguel Hernán Vicco

Assessment of Cross-reactive Host-pathogen Antibodies in Patients With Different Stages of Chronic Chagas Disease

INTRODUCTION AND OBJECTIVES Trypanosoma cruzi infection has been shown to induce humoral autoimmune responses against host antigens tissues. Particularly, antibodies cross-reacting with myocardial antigens may play a role in the development of the severe forms of chronic Chagas disease. The aim of this study was to determine the association between clinical stage of the disease and the presence of autoantibodies in patients with chronic Chagasic disease. METHODS We performed a cross-sectional study in T. cruzi-seropositive patients divided into 3 groups according to the classic classification of chronic Chagas heart of Storino et al. All participants underwent complete clinical examination and their sera were used to measure autoantibody levels. RESULTS All patients had detectable levels of anti-p2β and anti-B13 autoantibodies but none had anti-Na-K-ATPase antibodies. No association was observed between electrocardiographic conduction disturbances and autoantibody levels. Patients with chronic Chagas disease stage III had the highest levels of anti-B13 antibodies and a high risk of mortality score, showing a clear association between disease stage and this score. CONCLUSIONS Anti-B13 antibodies were significantly higher in chronic Chagas disease stage III patients, suggesting that these antibodies may be involved in disease progression and that they might be a useful marker of poor prognosis in terms of heart compromise. Our results also reveal an important correlation between the level of anti-B13 autoantibodies and symptomatic heart failure and/or dilated cardiomyopathy.

Efficacy of a trans-sialidase-ISCOMATRIX subunit vaccine candidate to protect against experimental Chagas disease.

Recombinant protein vaccines are safe but elicit low immunological responses. The new generation of adjuvants is currently reversing this situation. Here, a new antigen-adjuvant combination for protection against experimental Chagas disease was assessed. The antigen used in the formulation was a glycosylated mutant inactive trans-sialidase (mTS) that was previously proven to be highly protective against Trypanosoma cruzi infection; here, we show that it can be produced in large quantities and high quality using Pichia pastoris. The adjuvant used in the formulation was ISCOMATRIX (IMX), which was found to be effective and safe in human clinical trials of vaccines designed to control other intracellular infections. Fifteen days after the third immunization, mice immunized with mTS-IMX showed a TS-specific IgG response with titers >10(6) and high avidity, an increased IgG2a/IgG1 ratio, significant delayed-type hypersensitivity (DTH) reactivity, a balanced production of IFN-γ and IL-10 by splenocytes and a strong IFN-γ secretion by CD8(+) T lymphocytes. When these mice where challenged with 1000 trypomastigotes of T. cruzi, all mTS-IMX immunized mice survived, whereas mice immunized with mTS alone, IMX or PBS exhibited high mortality. Remarkably, during acute infection, when the parasitemia is highest in this infection model (day 21), mTS-IMX immunized mice had ∼50 times less parasitemia than non-immunized mice. At this moment and also in the chronic phase, 100 days after infection, tissue presented ∼4.5 times lower parasite load and associated inflammatory infiltrate and lesions. These results indicate that protection against Chagas disease can be achieved by a protein antigen-adjuvant mTS formulation that is compatible with human medicine. Therefore, the current formulation is a highly promising T. cruzi vaccine candidate to be tested in clinical trials.

β1-Selective Adrenoceptor Antagonists Increase Plasma Levels of Anti-p2β Antibodies and Decrease Cardiac Involvement in Chronic Progressive Chagas Heart Disease

BACKGROUND Studies indicate that antibodies cross-reacting with cardiac β1 adrenergic receptors are likely to play a role in the development of chronic Chagas heart disease (CCHD). In parallel, clinical trials have shown that β1 antagonist drugs exert beneficial effects in the prognosis of patients with CCHD. In a group of patients with CCHD undergoing therapy with β1-blockers, we have now evaluated the levels of anti-p2β antibodies and the severity of CCHD. METHODS We performed a cross-sectional study in Trypanosoma cruzi seropositive patients categorized according to a standard CCHD classification. All individuals were subjected to a complete clinical examination. RESULTS There was no association between CCHD stages, electrocardiographic conduction disturbances, and echocardiogram pathological signs with the levels of autoantibodies. However, when patients were analyzed according to selective cardio-β1-blocker therapy, those receiving treatment had higher levels of anti-p2β. Patients from CCHD stage III treated with combined therapy of cardio-β1-selective blockers, enalapril, and statins, presented decreased cardiac involvement and lower score of risk of mortality than individuals from the same group who were not treated. CONCLUSIONS Our results suggest that selective cardio-β1-blockers might modify the autoantibody anti-p2β levels, and that combined therapy in patients with stage III CCHD might be associated with lower cardiac involvement and risk score of mortality in patients with heart failure. Longitudinal studies will help to ascertain the proper role of β1-blockers in the immunopathological processes underlying chronic Chagas disease.

Chronic Chagas disease with cardiodigestive involvement and the TcVI infective form of Trypanosoma cruzi. A case report

We report a patient with megacolon associated with TcVI infective lineage form of Trypanosoma cruzi. Although this megacolon was considered idiopathic, Chagas disease was suspected and diagnosed because of the concomitant cardiovascular involvement. Based on this case, we discuss the suitability of Chagas diagnosis in patients with tract motility involvement.

Chagas disease, a risk factor for high blood pressure

Abstract Background. Chagas disease is a parasite infection caused by the protozoan Trypanosoma cruzi. Its most common complications is chronic Chagas heart disease but impairments of the systemic vasculature also has been observed. Although the different mechanisms that regulate blood pressure are disrupted, to our knowledge data on the association of hypertension and chronic Chagas disease are scarce. In this regard we evaluate whether Chagas disease constitutes a high blood pressure risk factor. Materials and methods. We recruited 200 individuals, half of them with positive serology for T. cruzi. They were subjected to a complete clinical examination. Results. The mean age of sampled individuals was 46.7 ± 12.3, and the mean of systolic and diastolic blood pressure were 124 ± 12 mmHg and 82 ± 10 mmHg, respectively. There were no between-group differences regarding age, sex distribution or body mass index. Chagas disease contributed significantly to high blood pressure (OR = 4, 95% CI 1.8323–7.0864, p = 0.0002). Conclusion. Our results reveal an important association between Chagas disease and high blood pressure, which should be contemplated by physicians in order to promote preventive cardiovascular actions in patients with Chagas disease.

In-hospital mortality risk factors in patients with ascites due to cirrhosis

INTRODUCTION ascites is one of the most common complications of cirrhosis associated with a high rate of mortality. Although several scores have been developed in order to assess the prognosis of the disease, they were designed for predicting liver transplantation requirements and mortality in the short term, but not while in hospital. The aim of this study was to weigh risk factors for in-hospital mortality in adult patients with ascites due to alcoholic cirrhosis. MATERIAL AND METHODS we performed a cross-sectional study in 180 adult patients with diagnosis of cirrhosis with portal hypertension associated with high alcohol intake. The diagnosis of cirrhosis was made by liver echography and portal hypertension was defined by clinical features plus serum-ascites albumin gradient. Sampled individuals were subjected to complete clinical examination. Child Pugh and the MELD scores were applied in all the patients. RESULTS nineteen patients died while in-hospital. Mortality was associated with increased levels of serum white blood cell, urea, creatinine, prolonged prothrombin time, aspartate aminotransferase and alanine aminotransferase. We conducted a multiple binary logistic to predict in-hospital mortality which yielded that serum urea, creatinine and prothrombin time made a significant contribution to prediction with an OR 14 (95% CI 12.8 - 16.7 p = 0.03), 2 (95% CI 0.5 - 3.47, p = 0.04), and 2 (95% CI 1.03 - 2.31, p = 0.01) linearly-related. CONCLUSIONS our results suggest that acute renal failure and prolonged prothrombin time are predictors of in-hospital mortality in patients with portal hypertension due to alcoholic cirrhosis.

Trans-sialidase-based vaccine candidate protects against Trypanosoma cruzi infection, not only inducing an effector immune response but also affecting cells with regulatory/suppressor phenotype

Prophylactic and/or therapeutic vaccines have an important potential to control Trypanosoma cruzi (T. cruzi)infection. The involvement of regulatory/suppressor immune cells after an immunization treatment and T. cruzi infection has never been addressed. Here we show that a new trans-sialidase-based immunogen (TSf) was able to confer protection, correlating not only with beneficial changes in effector immune parameters, but also influencing populations of cells related to immune control. Regarding the effector response, mice immunized with TSf showed a TS-specific antibody response, significant delayed-type hypersensitivity (DTH) reactivity and increased production of IFN-γ by CD8+ splenocytes. After a challenge with T. cruzi, TSf-immunized mice showed 90% survival and low parasitemia as compared with 40% survival and high parasitemia in PBS-immunized mice. In relation to the regulatory/suppressor arm of the immune system, after T. cruzi infection TSf-immunized mice showed an increase in spleen CD4+ Foxp3+ regulatory T cells (Treg) as compared to PBS-inoculated and infected mice. Moreover, although T. cruzi infection elicited a notable increase in myeloid derived suppressor cells (MDSC) in the spleen of PBS-inoculated mice, TSf-immunized mice showed a significantly lower increase of MDSC. Results presented herein highlight the need of studying the immune response as a whole when a vaccine candidate is rationally tested.Prophylactic and/or therapeutic vaccines have an important potential to control Trypanosoma cruzi (T. cruzi)infection. The involvement of regulatory/suppressor immune cells after an immunization treatment and T. cruzi infection has never been addressed. Here we show that a new trans-sialidase-based immunogen (TSf) was able to confer protection, correlating not only with beneficial changes in effector immune parameters, but also influencing populations of cells related to immune control.Regarding the effector response, mice immunized with TSf showed a TS-specific antibody response, significant delayed-type hypersensitivity (DTH) reactivity and increased production of IFN-γ by CD8+ splenocytes. After a challenge with T. cruzi, TSf-immunized mice showed 90% survival and low parasitemia as compared with 40% survival and high parasitemia in PBS-immunized mice.In relation to the regulatory/suppressor arm of the immune system, after T. cruzi infection TSf-immunized mice showed an increase in spleen CD4+ Foxp3+ regulatory T cells (Treg) as compared to PBS-inoculated and infected mice. Moreover, although T. cruzi infection elicited a notable increase in myeloid derived suppressor cells (MDSC) in the spleen of PBS-inoculated mice, TSf-immunized mice showed a significantly lower increase of MDSC.Results presented herein highlight the need of studying the immune response as a whole when a vaccine candidate is rationally tested.

Chronic Chagas disease: can prophylaxis and therapeutic vaccines crack this ‘hard nut’?

Fil: Bontempi, Ivan. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Tecnologia Inmunologica; Argentina

In-hospital mortality risk factors in community acquired pneumonia: evaluation of immunocompetent adult patients without comorbidities

OBJECTIVE several scores were developed in order to improve the determination of community acquired pneumonia (CAP) severity and its management, mainly CURB-65 and SACP score. However, none of them were evaluated for risk assessment of in-hospital mortality, particularly in individuals who were non-immunosuppressed and/or without any comorbidity. In this regard, the present study was carried out. METHODS we performed a cross-sectional study in 272 immunocompetent patients without comorbidities and with a diagnosis of CAP. Performance of CURB- 65 and SCAP scores in predicting in-hospital mortality was evaluated. Also, variables related to death were assessed. Furthermore, in order to design a model of in-hospital mortality prediction, sampled individuals were randomly divided in two groups. The association of the variables with mortality was weighed and, by multiple binary regression, a model was constructed in one of the subgroups. Then, it was validated in the other subgroup. RESULTS both scores yielded a fair strength of agreement, and CURB-65 showed a better performance in predicting in-hospital mortality. In our casuistry, age, white blood cell counts, serum urea and diastolic blood pressure were related to death. The model constructed with these variables showed a good performance in predicting in-hospital mortality; moreover, only one patient with fatal outcome was not correctly classified in the group where the model was constructed and in the group where it was validated. CONCLUSION our findings suggest that a simple model that uses only 4 variables, which are easily accessible and interpretable, can identify seriously ill patients with CAP.

Non-uremic calciphylaxis and Chagas disease

Fil: Vicco, Miguel Hernan. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquimica y Ciencias Biologicas. Laboratorio de Tecnologia Inmunologica; Argentina