Caracterización y evolución temporal de la mortalidad por zoonosis bajo declaración obligatoria, entre los años 1997 y 2018 / Characterization and temporal evolution of mortality due to zoonoses under mandatory declaration, between the years 1997 and 2018

INTRODUCCIÓN: Las zoonosis son enfermedades transmitidas desde un hospedador animal al ser humano o viceversa. En Chile, las zoonosis de Notificación Obligatoria (NO) son: brucelosis, carbunco, triquinosis, hidatidosis, leptospirosis, dengue, enfermedad de Chagas, hantavirosis y rabia. OBJETIVO: Evaluar la tendencia y caracterizar la mortalidad por zoonosis de NO en Chile entre 1997-2018. METODOLOGÍA: Estudio ecológico de la mortalidad por zoonosis de NO. Se utilizaron bases de mortalidad y población oficiales. Se describió la mortalidad relativa, general y específica, según variables sociodemográficas. Se calcularon tasas de mortalidad anuales brutas (TMb) y ajustadas (TMa, método directo). Se evaluó la tendencia temporal con modelos de regresión de Prais-Winsten. Resultados: Entre 1997 y 2018 la mortalidad por zoonosis de NO correspondió al 0,12% (2.359 muertes) de la mortalidad total, siendo las principales causas la enfermedad de Chagas (59,8%), hidatidosis (23,9%) y hantavirosis (13,8%). La TMa general disminuyó significativamente (B: -0,017; IC95%: -0,024; -0,009) al igual que hidatidosis (B: -0,011; IC95%: -0,013; -0,008), sólo hantavirosis mostró un aumento (no significativo). CONCLUSIÓN: La mortalidad por zoonosis de NO disminuyó durante el período estudiado; solo la hantavirosis mostró un aumento en su tendencia. Se sugiere enfocar estrategias para prevenir la transmisibilidad y mortalidad por hanta, así como mejorar el acceso a tratamiento para las otras zoonosis.

BACKGROUND: Zoonoses are diseases transmitted from an animal host to humans or vice versa. In Chile, the zoonoses of mandatory notification are brucellosis, anthrax, trichinosis, hydatidosis, leptospirosis, dengue, Chagas disease, hantavirosis and rabies. AIM: To assess the trend and characterize the mortality from zoonoses of mandatory notification in Chile between 1997-2018. METHODS: An official mortality and population data were used. Relative, general and specific mortality rates were described according to sociodemographic variables. Crude and adjusted annual mortality rates (direct method) were calculated. Temporal trend was evaluated with the Prais-Winsten regression model. RESULTS: Between 1997 and 2018, the mortality rate due to zoonosis of mandatory notification corresponded to 0.13% (2152 deaths) of the total mortality, being Chagas disease (59.2%), hydatidosis (24.6%) and hantavirosis (13.5%) the main causes. The general adjusted mortality rate decreased significantly (B: -0.017; IC95%: -0.024; -0.009) as did hydatidosis (B: -0.011; IC95%: -0.013; -0.008), and only hantavirosis showed an increase trend (not significant). CONCLUSION: Mortality due to zoonoses decreased during the period; only hantavirosis showed an increasing trend. It is suggested to focus on strategies to prevent contagion and mortality by hantavirosis, as well as to improve access to treatment for the other zoonoses.

Clinical profile and mortality in patients with T. cruzi/HIV co-infection from the multicenter data base of the "Network for healthcare and study of Trypanosoma cruzi/HIV co-infection and other immunosuppression conditions".

OBJECTIVE: Chagas disease (CD) globalization facilitated the co-infection with Human Immunodeficiency Virus (HIV) in endemic and non-endemic areas. Considering the underestimation of Trypanosoma cruzi (T. cruzi)-HIV co-infection and the risk of life-threatening Chagas Disease Reactivation (CDR), this study aimed to analyze the major co-infection clinical characteristics and its mortality rates. METHODS: This is a cross-sectional retrospective multicenter study of patients with CD confirmed by two serological or one parasitological tests, and HIV infection confirmed by immunoblot. CDR was diagnosed by direct microscopy with detection of trypomastigote forms in the blood or other biological fluids and/or amastigote forms in inflammatory lesions. RESULTS: Out of 241 patients with co-infection, 86.7% were from Brazil, 47.5% had <200 CD4+ T cells/µL and median viral load was 17,000 copies/µL. Sixty CDR cases were observed. Death was more frequent in patients with reactivation and was mainly caused by CDR. Other causes of death unrelated to CDR were the manifestation of opportunistic infections in those with Acquired Immunodeficiency Syndrome. The time between the co-infection diagnosis to death was shorter in patients with CDR. Lower CD4+ cells count at co-infection diagnosis was independently associated with reactivation. Similarly, lower CD4+ cells numbers at co-infection diagnosis and male sex were associated with higher lethality in CDR. Additionally, CD4+ cells were lower in meningoencephalitis than in myocarditis and milder forms. CONCLUSION: This study showed major features on T. cruzi-HIV co-infection and highlighted the prognostic role of CD4+ cells for reactivation and mortality. Since lethality was high in meningoencephalitis and all untreated patients died shortly after the diagnosis, early diagnosis, immediate antiparasitic treatment, patient follow-up and epidemiological surveillance are essentials in T. cruzi/HIV co-infection and CDR managements.

Levels and trends in Chagas disease-related mortality in Brazil, 2000-2019.

Chagas disease remains an important public health problem with high morbidity and mortality in several Latin American countries. This nationwide population-based ecological study analyzes the epidemiological characteristics and time trends of Chagas disease-related mortality in Brazil, 2000-2019. We included all deaths reported in Brazil in which Chagas disease was mentioned in the death certificate either as an underlying or associated cause of death (multiple causes of death). Crude and age-adjusted mortality rates (per 100,000 inhabitants) were calculated and time trends analysis was performed using joinpoint regression models. In the study period, a total of 22,663,092 deaths were recorded in Brazil. Chagas disease was identified in 122,291 deaths (0.54%), 94.788 (77.5%) as an underlying cause and 27,503 (22.5%) as an associated cause. Average annual age-adjusted mortality rate was 3.22 deaths/100,000 inhabitants (95% confidence interval [CI]: 3.14-3.30). Chronic Chagas disease with cardiac involvement was the predominant clinical presentation mentioned. The highest mortality rates were observed in males, age group ≥80 years, black race/skin color, schooling 1-3 years of study, and residents in the Central-West region. Age-adjusted mortality rates showed a significant declining trend at the national level in the period (Average Annual Percent Change: -3.1%; 95% CI: -3.3; -3.0), with different local patterns and a more pronounced reduction in important endemic areas in the past. The findings show that, despite a consistent decline in mortality rates in Brazil over the study period, Chagas disease remains an important and neglected cause of death in the country, showing a marked regional variation that has social and health care implications. In addition to the control measures for disease transmission, it is necessary to guarantee access, coverage, and quality of health care to Chagas disease patients, seeking to prevent the occurrence of severe forms and deaths from the disease.

Measurement of multiple cytokines for discrimination and risk stratification in patients with Chagas' disease and idiopathic dilated cardiomyopathy.

Chagas' disease (CD), caused by the hemoflagellate protozoan, Trypanosoma cruzi, is endemic in most countries of Latin America. Heart failure (HF) is often a late manifestation of chronic CD, and is associated with high morbidity and mortality. Inflammatory processes mediated by cytokines play a key role in the pathogenesis and progression of CD. Keeping in view the inflammatory nature of CD, this study investigated the possible role of 21 different inflammatory cytokines as biomarkers for prediction and prognosis of CD. The plasma concentration of these cytokines was measured in a group of patients with CD (n = 94), and then compared with those measured in patients with dilated cardiomyopathy (DCM) from idiopathic causes (n = 48), and with control subjects (n = 25). Monovariately, plasma levels of cytokines such as stem cell growth factor beta (SCGF beta), hepatocyte growth factor (HGF), monokine induced by interferon gamma (CXCL9), and macrophage inhibitory factor (MIF) were significantly increased in CD patients with advanced HF compared to control group. None of the cytokines could demonstrate any prognostic potency in CD patients, and only MIF and stromal derived factor-1 alpha (CXCL12) showed significance in predicting mortality and necessity for heart transplant in DCM patients. However, multivariate analysis prognosticated a large proportion of CD and DCM patients. In CD patients, HGF and Interleukin-12p40 (IL-12p40) together separated 81.9% of 3-year survivors from the deceased, while in DCM patients, CXCL12, stem cell factor (SCF), and CXCL9 together discriminated 77.1% of survivors from the deceased. The significant increase in plasma concentrations of cytokines such as HGF and CXCL9 in CD patients, and the ability of these cytokines to prognosticate a large proportion of CD and DCM patients multivariately, encourages further studies to clarify the diagnostic and prognostic potential of cytokines in such patients.

Factors related to the discontinuation and mortality rates of a cardiac rehabilitation programme in patients with Chagas disease: a 6-year experience in a Brazilian tertiary centre.

OBJECTIVES: To describe the clinical and sociodemographic characteristics of participants as well as discontinuation and mortality rates in a cardiac rehabilitation programme (CRP) tailored to Chagas disease (CD). METHODS: Participants underwent functional capacity, anthropometry and cardiac function evaluations before beginning a CRP. Univariate and multivariate Cox proportional hazards models were performed to investigate the associations between clinical and sociodemographic characteristics at baseline with discontinuation rates and deaths. RESULTS: Forty-two patients were enrolled in the CRP (61.9% men, mean age of 58.1 ± 11.8 years). During a median follow-up period of 10.8 months, 74% discontinued and 14% died while enrolled in CRP. 34% of the patients who discontinued CRP died during follow-up. White race (HR = 0.09; 95% CI 0.01-1.00), right ventricular systolic dysfunction (HR = 10.54; 95% CI 1.24-89.50) and oxygen pulse (HR = 0.69; 95% CI 0.48-0.99) were independently associated with death while enrolled in CRP. Married status (HR = 0.44; 95% CI 0.21-0.95) was independently associated with discontinuation rates from CRP. VO2 peak (HR = 0.85; 95% CI 0.74-0.98) and CRP discontinuation due to CD-related reasons (HR = 8.33; 95% CI 1.91-36.27) were the variables independently associated with death after discontinuation of CRP. CONCLUSION: In this population, sociodemographic aspects and severity of CD were important determinants of CRP discontinuation and mortality.

OBJECTIFS: Décrire les caractéristiques cliniques et sociodémographiques des participants ainsi que les taux d'abandon et de décès dans un programme de réadaptation cardiaque (PRC) adapté à la maladie de Chagas (MC). MÉTHODES: Les participants ont subi des évaluations de la capacité fonctionnelle, de l'anthropométrie et de la fonction cardiaque avant de commencer un PRC. Des modèles de risques proportionnels de Cox univariés et multivariés ont été appliqués pour étudier les associations entre les caractéristiques cliniques et sociodémographiques au départ avec les taux d'abandon et les décès. RÉSULTATS: 42 patients ont été enrôlés dans le PRC (61,9% d'hommes, âge moyen de 58,1 ± 11,8 ans). Au cours d'une période médiane de suivi de 10,8 mois, 74% ont abandonné et 14% sont décédés durant leur enrôlement au PRC. 34% des patients qui ont arrêté le PRC sont décédés au cours du suivi. La race blanche (HR = 0,09; IC95%: 0,01-1,00), le dysfonctionnement systolique ventriculaire droite (HR = 10,54; IC95%: 1,24-89,50) et le pouls d'oxygène (HR = 0,69; IC95%: 0,48-0,99) étaient indépendamment associés avec le décès lors de l'enrôlement au PRC. Le statut marié (HR = 0,44; IC95%: 0,21-0,95) était indépendamment associé aux taux d'abandon de la CRP. Le pic de VO2 (HR = 0,85; IC95%: 0,74-0,98) et l'arrêt du PRC pour des raisons liées à la MC (HR = 8,33; IC95%: 1,91 à 36,27) étaient les variables indépendamment associées au décès après l'arrêt du PRC. CONCLUSION: Dans cette population, les aspects sociodémographiques et la sévérité de la MC étaient des déterminants importants de l'arrêt du PRC et du décès.

Evaluation of the Autonomic Nervous System in Chronic Chagasic Cardiopathy: A Systematic Review of the Literature

Abstract Background The importance of regional sympathetic denervation in the pathophysiology and prognosis of Chagas disease has been recognized. Objective To conduct a review of studies that have assessed dysautonomia in chronic Chagas heart disease. Methods The search was performed on the Medline, Pubmed, Lilacs and SciELO databases. The inclusion criteria were: original articles published in full; studies on individuals with Chagas disease, that used diagnostic methods for chagasic cardiomyopathy, and had clear inclusion and exclusion criteria. Duplicate studies, studies including children (0 to 10 years old), studies involving animals, in vitro experiments, case reports, editorials, theses, and dissertations were excluded. Results A total of 281 articles were retrieved, and 10 met the inclusion criteria and were analyzed. There was great heterogeneity as to the technique for assessing dysautonomia, groups of patients studied and classification of Chagas disease. The methods used for studying the autonomic system was immunohistochemistry (n=1), Valsalva and tilt-test (n=1), scintigraphy (n=6) and Holter monitoring (n=2). The results indicated dysautonomia in the indeterminate, digestive and cardiac forms of Chagas disease, and sympathetic denervation in the indeterminate and cardiac forms of the disease. There was agreement between areas of denervation, hypoperfusion and fibrosis, but areas of denervation were larger than those of hypoperfusion. The frequency of denervation and its extension increased from the indeterminate to the cardiac form. There was an association between extension of denervation and previous history of malignant ventricular arrhythmia. Conclusions The evidence presented in this review supports that an early diagnosis of autonomic denervation in chronic Chagas' disease allows the identification of patients with an increased risk of sudden death. Int J Cardiovasc Sci. 2020; [online].ahead print, PP.0-0

Histopathological changes in the gastrointestinal tract and systemic alterations triggered by experimental oral infection with Trypanosoma cruzi.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in almost all countries of Latin America. In Brazil, oral infection is becoming the most important mechanism of transmission of the disease in several regions of the country. The gastrointestinal tract is the gateway for the parasite through this route of infection, however, little is known about the involvement of these organs related to oral route. In this sense, the present study evaluated the impact of oral infection on the digestive tract in mice infected by Berenice-78 (Be-78) T. cruzi strain, in comparison with the intraperitoneal route of infection. In this work, the intraperitoneal route group showed a peak of parasitemia similar to the oral route group, however the mortality rate among the orally infected animals was higher when compared to intraperitoneal route. By analyzing the frequency of blood cell populations, differences were mainly observed in CD4+ T lymphocytes, and not in CD8+, presenting an earlier reduction in the number of CD4+ T cells, which persisted for a longer period, in the animals of the oral group when compared with the intraperitoneal group. Animals infected by oral route presented a higher tissue parasitism and inflammatory infiltrate in stomach, duodenum and colon on the 28th day after infection. Therefore, these data suggest that oral infection has a different profile of parasitological and immune responses compared to intraperitoneal route, being the oral route more virulent and with greater tissue parasitism in organs of the gastrointestinal tract evaluated during the acute phase.

Risk of Chronic Cardiomyopathy Among Patients With the Acute Phase or Indeterminate Form of Chagas Disease: A Systematic Review and Meta-analysis.

Importance: Chagas cardiomyopathy is associated with substantial morbidity and mortality. Precise estimates of the risk of developing cardiomyopathy among patients with the acute or indeterminate chronic forms of Chagas disease are lacking. Objective: To estimate the risk of developing chronic cardiomyopathy in patients with acute and indeterminate chronic forms of Chagas disease. Data Sources: A systematic search in the Cochrane Library, Embase, Latin American and Caribbean Health Sciences Literature (LILACS), Medline, and Web of Science Core Collection databases was conducted from October 8 to October 24, 2018. Studies published between January 1, 1946, and October 24, 2018, that were written in the English, Spanish, and Portuguese languages were included. Search terms included Chagas disease; development of cardiomyopathy; latency duration; and determinants of the Chagas latency period. Study Selection: Longitudinal observational studies of participants diagnosed with the acute phase of Chagas infection or the indeterminate chronic form of Chagas disease who were followed up until the development of cardiomyopathy were included. Studies were excluded if they did not provide sufficient outcome data. Of 10 761 records initially screened, 32 studies met the criteria for analysis. Data Extraction and Synthesis: Critical appraisals of studies were performed using checklists from the Joanna Briggs Institute Reviewer's Manual, and data were collected from published studies. A random-effects meta-analysis was used to obtain pooled estimated annual rates. Data were analyzed from September 11 to December 4, 2019. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for the registration of the protocol, data collection and integrity, assessment of bias, and sensitivity analyses. Main Outcomes and Measures: Main outcomes were defined as the composite of the development of any new arrhythmias or changes in electrocardiogram results, dilated cardiomyopathy and segmental wall motion abnormalities in echocardiogram results, and mortality associated with Chagas disease. Results: A total of 5005 records were screened for eligibility. Of those, 298 full-text articles were reviewed, and 178 of those articles were considered for inclusion in the quantitative synthesis. After exclusions, 32 studies that included longitudinal observational outcomes were selected for the analysis; 23 of those studies comprised patients with the indeterminate chronic form of Chagas disease, and 9 of those studies comprised patients in the acute phase of Chagas infection. The analysis indicated that the pooled estimated annual rate of cardiomyopathy development was 1.9% (95% CI, 1.3%-3.0%; I2 = 98.0%; τ2 [ln scale] = 0.9992) in patients with indeterminate chronic Chagas disease and 4.6% (95% CI, 2.7%-7.9%; I2 = 86.6%; τ2 [ln scale] = 0.4946) in patients with acute Chagas infection. Conclusions and Relevance: Patients with the indeterminate chronic form of Chagas disease had a significant annual risk of developing cardiomyopathy. The annual risk was more than double among patients in the acute phase of Chagas infection.

Spatiotemporal trends of Chagas disease-related mortality in the Northeast of Brazil, 2007-2017.

Chagas disease (CD) is a neglected disease and endemic in Brazil. In the Brazilian Northeast Region, it affects millions of people. Therefore, it is necessary to identify the spatiotemporal trends of CD mortality in the Northeast of Brazil. This ecological study was designed, in which the unit of analysis was the municipality of the Brazilian northeast. The data source was the Information System of Mortality. It was calculated relative risk from socioeconomic characteristics. Mortality rates were smoothed by the Local Empirical Bayes method. Spatial dependency was analysed by the Global and Local Moran Index. Scan spatial statistics were also used. A total of 11 287 deaths by CD were notified in the study. An expressive parcel of this number was observed among 70-year-olds or more (n = 4381; 38.8%), no schooling (n = 4381; 38.8%), mixed-race (n = 4381; 62.3%), male (n = 6875; 60.9%). It was observed positive spatial autocorrelation, mostly in municipalities of the state of Bahia, Piauí (with high-high clusters), and Maranhão (with low-low clusters). The spatial scan statistics has presented a risk of mortality in 24 purely spatial clusters (P < 0.05). The study has identified the spatial pattern of CD mortality mostly in Bahia and Piauí, highlighting priority areas in planning and control strategies of the health services.

Spatial patterns and temporal tendency of mortality related to Chagas disease in an endemic area of northeastern Brazil.

OBJECTIVE: To analyse spatial patterns and the temporal tendency of mortality related to Chagas disease, in order to identify priority control areas in the state of Sergipe, Northeast Brazil. METHODS: We conducted an ecological and time-series study with spatial analysis techniques on deaths from Chagas disease in the state of Sergipe (1996-2016). We used data from the Mortality Information System (SIM). The temporal analysis was performed using a statistical technique capable of describing changes in the trend pattern for the period. Thematic maps were elaborated from point and polygonal analyses. RESULTS: There were 247 deaths related to Chagas disease, with a mean of 11.7 deaths/year, most of them male (64%), and aged 50-59 years (21%) and 60-69 years (26%). Two segments with increasing, non-constant and significant trends were identified: 1996-2005 (APC = 21.6%; P = 0.01) and 2005-2016 (APC = 4.4%; P = 0.01), with APPC = 11.8% (P = 0.01). A positive and significant spatial autocorrelation with areas of higher risk of death was found in the southern region of the state. CONCLUSIONS: The trend of mortality related to Chagas disease in the state of Sergipe was increasing during the period analysed, with a heterogeneous distribution of cases. A main risk area was identified in the southern region of the state.

OBJECTIF: Analyser les profils spatiaux et la tendance temporelle de la mortalité liée à la maladie de Chagas, afin d'identifier les domaines de priorité de lutte dans l'Etat de Sergipe, dans le nord-est du Brésil. MÉTHODES: Nous avons mené une étude écologique et de séries chronologiques avec des techniques d'analyse spatiale sur les décès dus à la maladie de Chagas dans l'état de Sergipe (1996-2016). Nous avons utilisé les données du système d'information sur la mortalité (SIM). L'analyse temporelle a été réalisée à l'aide d'une technique statistique capable de décrire les changements dans le profil de tendance pour la période. Des cartes thématiques ont été élaborées à partir d'analyses ponctuelles et polygonales. RÉSULTATS: Il y a eu 247 décès liés à la maladie de Chagas, avec une moyenne de 11,7 décès/an, pour la plupart de sexe masculin (64%), et âgés de 50 à 59 ans (21%) et de 60 à 69 ans (26%). Deux segments avec des tendances à la hausse, non constantes et significatives ont été identifiés: 1996-2005 (APC = 21,6%; p = 0,01) et 2005-2016 (APC = 4,4%; p = 0,01), avec APPC = 11,8% (p = 0,01). Une autocorrélation spatiale positive et significative avec des zones à haut risque de décès a été trouvée dans la région sud de l'Etat. CONCLUSIONS: La tendance de la mortalité liée à la maladie de Chagas dans l'état de Sergipe a augmenté au cours de la période analysée , avec une répartition hétérogène des cas. Une principale zone à risque a été identifiée dans la région sud de l'Etat.

Galectin-3 mediates survival and apoptosis pathways during Trypanosoma cruzi-host cell interplay.

Neglected tropical diseases, such as Chagas disease caused by the protozoa Trypanosoma cruzi, affect millions of people worldwide but lack effective treatments that are accessible to the entire population, especially patients with the debilitating chronic phase. The recognition of host cells, invasion and its intracellular replicative success are essential stages for progression of the parasite life cycle and the development of Chagas disease. It is predicted that programmed cell death pathways (apoptosis) would be activated in infected cells, either via autocrine secretion or mediated by cytotoxic immune cells. This process should play a key role in resolving infections by hindering the evolutionary success of the parasite. In this research, we performed assays to investigate the role of the lectin galectin-3 (Gal3) in parasite-host signaling pathways. Using cells with endogenous levels of Gal3 compared to Gal3-deficient cells (induced by RNA interference), we demonstrated that T. cruzi mediated the survival pathways and the subverted apoptosis through Gal3 promoting a pro-survival state in infected cells. Infected Gal3-depleted cells showed increased activation of caspase 3 and pro-apoptotic targets, such as poly (ADP-ribose) polymerase (PARP), and lower accumulation of anti-apoptotic proteins, such as c-IAP1, survivin and XIAP. During the early stages of infection, Gal3 translocates from the cytoplasm to the nucleus and must act in survival pathways. In a murine model of experimental infection, Gal3 knockout macrophages showed lower infectivity and viability. In vivo infection revealed a lower parasitemia and longer survival and an increased spleen cellularity in Gal3 knockout mice with consequences on the percentage of T lymphocytes (CD4+ CD11b+) and macrophages. In addition, cytokines such as IL-2, IL-4, IL-6 and TNF-α are increased in Gal3 knockout mice when compared to wild type genotype. These data demonstrate a Gal3-mediated complex interplay in the host cell, keeping infected cells alive long enough for infection and intracellular proliferation of new parasites. However, a continuous knowledge of these signaling pathways should contribute to a better understanding the mechanisms of cell death subversion that are promoted by protozoans in the pathophysiology of neglected diseases such as Chagas disease.

MicroRNA-155 Deficiency Exacerbates Trypanosoma cruzi Infection.

Chagas disease, caused by the intracellular protozoan parasite Trypanosoma cruzi, is a public health problem affecting 6 to 8 million people, mainly in Latin America. The role of microRNAs in the pathogenesis of Chagas disease has not been well described. Here, we investigate the role of microRNA-155 (miR-155), a proinflammatory host innate immune regulator responsible for T helper type 1 and type 17 (Th1 and Th17) development and macrophage responses during T. cruzi infection. For this, we compared the survival and parasite growth and distribution in miR-155-/- and wild-type (WT) C57BL/6 mice. The lack of miR-155 caused robust parasite infection and diminished survival of infected mice, while WT mice were resistant to infection. Immunological analysis of infected mice indicated that, in the absence of miR-155, there was decreased interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. In addition, we found that there was a significant reduction of CD8-positive (CD8+) T cells, natural killer (NK) cells, and NK-T cells and increased accumulation of neutrophils and inflammatory monocytes in miR-155-/- mice. Collectively, these data indicate that miR-155 is an important immune regulatory molecule critical for the control of T. cruzi infection.

Resolvin D1 Administration Is Beneficial in Trypanosoma cruzi Infection.

Chagas disease is a major public health issue, affecting ∼10 million people worldwide. Transmitted by a protozoan named Trypanosoma cruzi, this infection triggers a chronic inflammatory process that can lead to cardiomyopathy (Chagas disease). Resolvin D1 (RvD1) is a novel proresolution lipid mediator whose effects on inflammatory diseases dampens pathological inflammatory responses and can restore tissue homeostasis. Current therapies are not effective in altering the outcome of T. cruzi infection, and as RvD1 has been evaluated as a therapeutic agent in various inflammatory diseases, we examined if exogenous RvD1 could modulate the pathogenesis of Chagas disease in a murine model. CD-1 mice infected with the T. cruzi Brazil strain were treated with RvD1. Mice were administered 3 µg/kg of body weight RvD1 intraperitoneally on days 5, 10, and 15 to examine the effect of RvD1 on acute disease or administered the same dose on days 60, 65, and 70 to examine its effects on chronic infection. RvD1 therapy increased the survival rate and controlled parasite replication in mice with acute infection and reduced the levels of interferon gamma and transforming growth factor ß (TGF-ß) in mice with chronic infection. In addition, there was an increase in interleukin-10 levels with RvD1 therapy in both mice with acute infection and mice with chronic infection and a decrease in TGF-ß levels and collagen content in cardiac tissue. Together, these data indicate that RvD1 therapy can dampen the inflammatory response, promote the resolution of T. cruzi infection, and prevent cardiac fibrosis.

Discovery of Pyrrolo[2,3-b]pyridine (1,7-Dideazapurine) Nucleoside Analogues as Anti-Trypanosoma cruzi Agents.

Trypanosoma cruzi is the causative pathogen of Chagas disease and the main culprit for cardiac-related mortality in Latin-America triggered by an infective agent. Incapable of synthesizing purines de novo, this parasite depends on acquisition and processing of host-derived purines, making purine (nucleoside) analogues a potential source of antitrypanosomal agents. In this respect, hitherto 7-deazaadenosine (tubercidin) analogues attracted most attention. Here, we investigated analogues with an additional nitrogen (N1) removed. Structure-activity relationship investigation showed that C7 modification afforded analogues with potent antitrypanosomal activity. Halogens and small, linear carbon-based substituents were preferred. Compound 11 proved most potent in vitro, showed full suppression of parasitemia in a mouse model of acute infection, and elicited 100% animal survival after oral dosing at 25 mg/kg b.i.d. for 5 and 15 days. Cyclophosphamide-induced immunosuppression led to recrudescence. Washout experiments demonstrated a lack of complete clearance of infected cell cultures, potentially explaining the in vivo results.

Duration and determinants of Chagas latency: an etiology and risk systematic review protocol.

OBJECTIVE: The objective of this systematic review is to explore and discuss the latency duration among asymptomatic people with chronic Chagas disease. INTRODUCTION: Studies estimate the latency period of Chagas disease to be approximately 10-30 years. However, new findings may indicate that this latency period is shorter and depends on the presence of clinical factors. This systematic review protocol will explore the duration and factors affecting this latency period to inform treatment, with the potential of improving outcomes. INCLUSION CRITERIA: Eligible studies will include asymptomatic people with indeterminate Chagas disease confirmed through positive serologic testing and the absence of structural cardiomyopathy with no heart failure symptoms and normal electrocardiography results. Studies that involve a longitudinal observation period of participants will be considered. This period must start from the acute acquisition of the infection or an already established indeterminate form of the disease until the development of a primary or secondary cardiac outcome. METHODS: The following electronic databases will be searched: MEDLINE, Embase, Cochrane Library, Web of Science Core Collection and LILACS. The search will include the following concepts: Chagas disease, latency duration and determinants of the Chagas latency period. The languages will be restricted to English, Spanish and Portuguese. Two reviewers will review the selected studies for methodological quality using critical appraisal tools and conduct data extraction. Studies will, where possible, be pooled in a statistical meta-analysis. All data will be presented and synthesized through tables, summaries, figures and charts. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42019118019.

In Search of Congenital Chagas Disease in the Sierra Nevada de Santa Marta, Colombia.

Chagas disease remains a major impediment to sustainable socioeconomic development in Latin America. Transplacental transmission explains the persistence of transmission in urban areas, in non-endemic regions, and in areas with an established interrupted vectorial transmission. One of every five cases of congenital Chagas disease in the world occurs in Colombia and Venezuela. The massive migration of impoverished populations from neighboring Venezuela has worsened the situation creating a humanitarian crisis in Northeastern Colombia, including the Sierra Nevada de Santa Marta. The prevalence of Chagas infection among pregnant women in these areas is higher than the national average, and the public health resources are insufficient. This perspective discusses the associated increased morbidity and mortality of congenital Chagas in this region, where stigmatization contributes to the impression among health authorities and the general population that it affects indigenous communities only. The monitoring and control of congenital Chagas disease in the Sierra Nevada of Santa Marta is a public health necessity that demands urgent and effective interventions.

An oral dose of Fluralaner administered to dogs kills pyrethroid-resistant and susceptible Chagas disease vectors for at least four months.

New vector control tools that can fit into a broader integrated vector management strategy are notably lacking. We conducted a seven-month randomized trial to assess the efficacy of a single oral dose of Fluralaner (Bravecto®) administered to dogs on the blood-feeding success, engorgement levels and mortality of pyrethroid-resistant and -susceptible Triatoma infestans third- and fifth-instar nymphs. The trial included 10 Fluralaner-treated and 10 placebo-treated (control) outbred healthy dogs residing in rural houses of the Argentine Chaco. Most (92.7%) of the 3017 triatomines exposed were able to blood-feed. Generalized linear models showed that blood-feeding success was not significantly modified by Fluralaner treatment, time posttreatment and their interaction. However, pyrethroid-susceptible fifth instars blood-fed significantly more frequently than susceptible third instars, and no significant differences were observed between the latter and resistant fifth instars. Engorgement levels were not significantly modified by Fluralaner treatment, time posttreatment and their interaction. Nearly all the triatomines that blood-fed on treated dogs up to 60 days posttreatment (DPT) died within 24 h regardless of pyrethroid susceptibility status combined with bug stage. Cumulative bug mortality over 4 days postexposure remained high over 90-120 DPT (70-81% in susceptible third and fifth instars, and 47-49% in resistant fifth instars), and was virtually nil at 210 DPT. Triatomines that fed on control dogs suffered marginal mortality (0-4%) except at 4 and 30 DPT. Fluralaner and xenointoxication are eligible for Phase III efficacy trials alone or combined with other methods in the frame of an integrated vector management strategy in areas with or without pyrethroid resistance.

Autophagy plays a protective role against Trypanosoma cruzi infection in mice.

Autophagy is a catabolic pathway required for cellular and organism homeostasis. Autophagy participates in the innate and adaptive immune responses at different levels. Xenophagy is a class of selective autophagy that involves the elimination of intracellular pathogens. Trypanosoma cruzi is the causative agent of Chagas, a disease that affects 8 million individuals worldwide. Previously, our group has demonstrated that autophagy participates in the invasion of T. cruzi in non-phagocytic cells. In this work we have studied the involvement of autophagy in the development of T. cruzi infection in mice. Beclin-1 is a protein essential for autophagy, required for autophagosome biogenesis and maturation. We have performed an acute model of infection on the autophagic deficient Beclin-1 heterozygous knock-out mice (Bcln±) and compared to control Bcln+/+ animals. In addition, we have analyzed the infection process in both peritoneal cells and RAW macrophages. Our results have shown that the infection was more aggressive in the autophagy-deficient mice, which displayed higher numbers of parasitemia, heart´s parasitic nests and mortality rates. We have also found that peritoneal cells derived from Bcln± animals and RAW macrophages treated with autophagy inhibitors displayed higher levels of infection compared to controls. Interestingly, free cytosolic parasites recruited LC3 protein and other markers of xenophagy in control compared to autophagy-deficient cells. Taken together, these data suggest that autophagy plays a protective role against T. cruzi infection in mice, xenophagy being one of the processes activated as part of the repertoire of immune responses generated by the host.

Burden of Chagas disease in Brazil, 1990-2016: findings from the Global Burden of Disease Study 2016.

Chagas disease continues to be an important cause of morbidity, mortality and disability in several Latin American countries, including Brazil. Using findings from the Global Burden of Disease Study 2016 (GBD, 2016), we present years of life lost, years lived with disability, and disability-adjusted life years due to Chagas disease in Brazil, by sex, age group, and Brazilian states, from 1990 to 2016. Results are reported in absolute numbers and age-standardized rates (per 100,000 population) with 95% uncertainty intervals. In 2016, 141,640 disability-adjusted life years (95% uncertainty intervals: 129,065-155,941) due to Chagas disease were estimated in Brazil, with a relative reduction of 36.7% compared with 1990 (223,879 disability-adjusted life years (95% uncertainty intervals: 209,372-238,591)). Age-standardized disability-adjusted life year rates declined at the national level (-69.7%) and in all Brazilian states between 1990 and 2016, but with different regional patterns. The decrease in the disability-adjusted life year rates was driven primarily by a consistent reduction in the years of life lost rates, the main component of total disability-adjusted life years for Chagas disease. The highest fatal and non-fatal burden due to Chagas disease was observed among males, the elderly, and in those Brazilian states encompassing important endemic areas for vector transmission in the past. Despite the consistent reduction in its burden during the period, Chagas disease is still an important and neglected cause of health lost due to premature mortality and disability in Brazil. Efforts should be made to maintain the political interest and sustainability of surveillance and control actions for Chagas disease, prevent the risk of re-emergence of vector transmission in endemic areas, and provide health care to chronically infected individuals, including early diagnosis and treatment interventions.

Spatial analysis of dengue, cysticercosis and Chagas disease mortality in Ecuador, 2011-2016.

Background: Neglected tropical diseases (NTDs) continue to be an important cause of disability and mortality in the poorest tropical and subtropical areas. Methods: This is an ecological study. We included all death certificates with dengue, cysticercosis and Chagas disease in Ecuador from 2011 to 2016. The spatial autocorrelation was evaluated by GeoDa software through the Global Moran's I index and the formation of clusters by the local index of spatial association. Results: The Global Moran's I index for the study period shows a positive spatial autocorrelation for dengue, cysticercosis and Chagas disease (0.25, p=0.001; 0.07, p=0.04; 0.45, p=0.001, respectively). Conclusions: The clusters identified as higher risk in the country could be targeted by policymakers to adequately develop strategies to strengthen health promotion policies that break the cycle of these diseases.