Clinical Manifestations Of Chagas Disease Research Articles

New insights into Trypanosoma cruzi genetic diversity, and its influence on parasite biology and clinical outcomes.

Chagas disease, caused by Trypanosoma cruzi, remains a serious public health problem worldwide. The parasite was subdivided into six distinct genetic groups, called "discrete typing units" (DTUs), from TcI to TcVI. Several studies have indicated that the heterogeneity of T. cruzi species directly affects the diversity of clinical manifestations of Chagas disease, control, diagnosis performance, and susceptibility to treatment. Thus, this review aims to describe how T. cruzi genetic diversity influences the biology of the parasite and/or clinical parameters in humans. Regarding the geographic dispersion of T. cruzi, evident differences were observed in the distribution of DTUs in distinct areas. For example, TcII is the main DTU detected in Brazilian patients from the central and southeastern regions, where there are also registers of TcVI as a secondary T. cruzi DTU. An important aspect observed in previous studies is that the genetic variability of T. cruzi can impact parasite infectivity, reproduction, and differentiation in the vectors. It has been proposed that T. cruzi DTU influences the host immune response and affects disease progression. Genetic aspects of the parasite play an important role in determining which host tissues will be infected, thus heavily influencing Chagas disease's pathogenesis. Several teams have investigated the correlation between T. cruzi DTU and the reactivation of Chagas disease. In agreement with these data, it is reasonable to suppose that the immunological condition of the patient, whether or not associated with the reactivation of the T. cruzi infection and the parasite strain, may have an important role in the pathogenesis of Chagas disease. In this context, understanding the genetics of T. cruzi and its biological and clinical implications will provide new knowledge that may contribute to additional strategies in the diagnosis and clinical outcome follow-up of patients with Chagas disease, in addition to the reactivation of immunocompromised patients infected with T. cruzi.

A Review on the Immunological Response against Trypanosoma cruzi

Chagas disease is a chronic systemic infection transmitted by Trypanosoma cruzi. Its life cycle consists of different stages in vector insects and host mammals. Trypanosoma cruzi strains cause different clinical manifestations of Chagas disease alongside geographic differences in morbidity and mortality. Natural killer cells provide the cytokine interferon-gamma in the initial phases of T. cruzi infection. Phagocytes secrete cytokines that promote inflammation and activation of other cells involved in defence. Dendritic cells, monocytes and macrophages modulate the adaptive immune response, and B lymphocytes activate an effective humoral immune response to T. cruzi. This review focuses on the main immune mechanisms acting during T. cruzi infection, on the strategies activated by the pathogen against the host cells, on the processes involved in inflammasome and virulence factors and on the new strategies for preventing, controlling and treating this disease.

Polymorphism in the catalytic subunit of the PI3Kγ gene is associated with Trypanosoma cruzi-induced chronic chagasic cardiomyopathy.

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. During the chronic phase of disease, while most infected people do not present symptoms, characterizing the asymptomatic form, some patients develop the cardiac form or chronic chagasic cardiomyopathy, which is considered the most severe manifestation of this disease. Considering that the activation of the PI3Kγ signaling pathway is essential for an efficient immune response against T. cruzi infection, we evaluated the PIK3CG C>T (rs1129293) polymorphism in exon 3 of this gene, which encodes the catalytic subunit of PI3Kγ. The PIK3CG CT and TT genotypes were found to be associated with an increased risk of developing the cardiac form of the disease rather than the asymptomatic or digestive forms. In conclusion, the presence of the T allele at single or double doses may differentiate the cardiac from other clinical manifestations of Chagas disease. This finding should help in further studies to evaluate the mechanisms underlying the differential association of PIK3CG in Chagas disease.

Factors associated with quality of life in patients with Chagas disease: SaMi-Trop project.

Chagas disease (CD) is a neglected tropical disease and its main consequence is chronic chagasic cardiomyopathy (CCC). The clinical manifestations of CD can cause functional limitation and impact on the perception of quality of life (QoL). We evaluated the QoL profile of patients with CD living in remote regions, and their association with socio-demographic, behavioral, and clinical characteristics.A cross-sectional study, using the baseline of a cohort study (SaMi-Trop) was conducted in the state of Minas Gerais, Brazil, an endemic region for CD. The cohort is composed of 1959 patients with CD. The patients were interviewed, and blood collection and electrocardiogram (ECG) were performed. The WHOQOL-BREF scale was used to assess QoL. Descriptive statistics were performed and, for the QoL scale, measures of central tendency and dispersion were calculated. Inflated beta regression models constructed using the gamlss framework were used, and fitted using R software. A significance level of 5% for all analyzes was adopted.QoL was evaluated in 625 participants. The Environment (57.66) and Social Relationships (73.17) domains presented the lowest and highest QoL score respectively. There was no statistically significant difference between QoL domains in the presence of CCC. In the multivariate analysis, the factors associated with a lower QoL were in the Physical domain age increase (OR: 0.95, CI: 0.91–0.99) and using an angiotensin converting enzyme inhibitor (OR 0.89; CI: 0.80–0.99); in the Social Relations domain a history of acute myocardial infarction (OR: 0.75; CI: 0.61–0.92); and in the Environment domain age increase (OR 0.94, CI 0.91–0.97). The factor associated with higher QoL was the use of angiotensin receptor blockers (OR: 1.15; CI 1.04–1.26).The findings of this study reinforce the importance of QoL indicators for planning care and clinical management of patients from remote regions with CD.Trial registrationNCT02646943.

Geographic distribution of Trypanosoma cruzi genotypes detected in chronic infected people from Argentina. Association with climatic variables and clinical manifestations of Chagas disease

Chronic Chagas disease affects large number of people in Latin America where it remains one of the biggest public health problems. Trypanosoma cruzi is genetically divided into seven discrete typing units (DTUs), TcI-TcVI and Tcbat, and exhibits differential distribution across vectors, host and transmission cycles. Clinical manifestations (cardiac, digestive and / or neurological) vary according to the geographical region; and the DTUs more frequently found in any of the chronic form of the disease, indeterminate or clinical, are TcI, TcII, TcV and TcVI. However, why they have a particular geographical distribution and how they affect the development of Chagas disease is still unknown. In this study, we assessed the geographic distribution of T. cruzi genotypes detected in chronic infected people from 57 localities of endemic regions of Argentina and analyzed their association with climatic variables. The prevalent DTUs detected in the whole population were TcV (47.4%) and TcVI (66.0%). TcI and TcII were identified in 5.2% each. All DTUs were detected in single and mixed infections (78.4% and 21.6%, respectively). TcV was found in infected people from localities with significantly higher average annual temperature, seasonal temperature and annual temperature range than those infected with TcVI. When we evaluated the association of DTUs with clinical manifestations of Chagas disease, the probability of finding TcVI in subjects with chronic Chagas cardiomyopathy (CCC) was higher than other DTUs, but without reaching statistical significance. Moreover, the probability of finding TcV in those who have not developed the disease after 20 years of infection was significantly higher than in CCC, either if it was present as unique DTU (reciprocal OR=4.95 95%CI: 1.42 to 17.27) (p=0.0117) or if it was also part of mixed infections (reciprocal OR=3.375; 95%CI: 1.227 to 9.276) (p=0.0264). There was no difference in the distribution of TcI between asymptomatic people and those with clinical manifestations, while TcII appeared more frequently in CCC cases, but without statiscal significance.

Prevention and Control of Chagas Disease – An Overview

Chagas disease is the main cause of heart failure and sudden death in the Western Hemisphere. The literature of the last decades reported on the changing epidemiological profiles of Chagas disease, which now threats the human population in the cities. The exodus of the Latin America people to the Northern Hemisphere explains the growing concern in countries where the transmission of Trypanosoma cruzi was accidental or transferred from a mother to her offspring. Herein, we present the evidence of the possible acquisition of the T. cruzi infection by sex. The staggering demonstration of the transmission of the T. cruzi infections from males and females to naive mates by intercourse introduces substantial changes in the surveillance of the Chagas disease. Notably, the sexual transmission of the T. cruzi introduces changes in the concepts of medical care, prevention and control; specifically, the risk for the vertical transfer of the parasiteinduced kDNA mutations, underpinning the genetically driven autoimmunity, inheritance, and pathogenesis associated with multifaceted clinical manifestations of Chagas disease with high ratios of morbidity and mortality. In this regard, the endemics require much paradigm research with new approaches and innovation technologies, aiming at its control. For example, the recent knowledge anticipates useful measures for preventing the potential forthcoming pandemic Chagas parasites. A long-lasting multicenter research program is needed for creative, drug discovery for curtailment of Chagas disease. Meanwhile, the prevention shall rely on the education, information, and communication program for health.

Genetic Susceptibility to Cardiac and Digestive Clinical Forms of Chronic Chagas Disease: Involvement of the CCR5 59029 A/G Polymorphism.

The clinical manifestations of chronic Chagas disease include the cardiac form of the disease and the digestive form. Not all the factors that act in the variable clinical course of this disease are known. This study investigated whether the CCR5Δ32 (rs333) and CCR5 59029 A/G (promoter region—rs1799987) polymorphisms of the CCR5 gene are associated with different clinical forms of chronic Chagas disease and with the severity of left ventricular systolic dysfunction in patients with chronic Chagas heart disease (CCHD). The antibodies anti-T. cruzi were identified by ELISA. PCR and PCR-RFLP were used to identify the CCR5Δ32 and CCR5 59029 A/G polymorphisms. The chi-square test was used to compare variables between groups. There was a higher frequency of the AA genotype in patients with CCHD compared with patients with the digestive form of the disease and the control group. The results also showed a high frequency of the AG genotype in patients with the digestive form of the disease compared to the other groups. The results of this study show that the CCR5Δ32 polymorphism does not seem to influence the different clinical manifestations of Chagas disease but there is involvement of the CCR5 59029 A/G polymorphism in susceptibility to the different forms of chronic Chagas disease. Besides, these polymorphisms do not influence left ventricular systolic dysfunction in patients with CCHD.

Opportunities for Improved Chagas Disease Vector Control Based on Knowledge, Attitudes and Practices of Communities in the Yucatan Peninsula, Mexico

BackgroundChagas disease is a vector-borne parasitic disease of major public health importance. Current prevention efforts are based on triatomine vector control to reduce transmission to humans. Success of vector control interventions depends on their acceptability and value to affected communities. We aimed to identify opportunities for and barriers to improved vector control strategies in the Yucatan peninsula, Mexico.Methodology/principal findingsWe employed a sequence of qualitative and quantitative research methods to investigate knowledge, attitudes and practices surrounding Chagas disease, triatomines and vector control in three rural communities. Our combined data show that community members are well aware of triatomines and are knowledgeable about their habits. However, most have a limited understanding of the transmission dynamics and clinical manifestations of Chagas disease. While triatomine control is not a priority for community members, they frequently use domestic insecticide products including insecticide spray, mosquito coils and plug-in repellents. Families spend about $32 US per year on these products. Alternative methods such as yard cleaning and window screens are perceived as desirable and potentially more effective. Screens are nonetheless described as unaffordable, in spite of a cost comparable to the average annual spending on insecticide products.Conclusion/SignificanceFurther education campaigns and possibly financing schemes may lead families to redirect their current vector control spending from insecticide products to window screens. Also, synergism with mosquito control efforts should be further explored to motivate community involvement and ensure sustainability of Chagas disease vector control.

Lack of association betweenIL-6−174G/C gene polymorphism and Chagas disease

The aim of this study was to investigate the role of the IL-6-174G/C gene polymorphism in susceptibility/resistance to Trypanosoma cruzi infection in two independent cohorts from Colombia and Peru. We determined the IL-6-174G/C genotypes in a sample of 399 seronegative individuals and 317 serologically positive patients from Colombia and Peru. All individuals are from regions where T. cruzi infection is endemic. No statistically significant differences in the frequency of IL-6-174G/C gene polymorphism between chagasic patients and controls or between asymptomatic and individuals with cardiomyopathy were observed. Our results do not support an evidence for a major role contribution of this IL-6 gene polymorphism in the susceptibility to or clinical manifestations of Chagas disease in these studied cohorts.

Mixed infection of Trypanosoma cruzi I and II in a Colombian cardiomyopathic patient

The Trypanosoma cruzi taxon is composed of 2 major lineages, T cruzi I and T cruzi II. The clinical symptoms of Chagas disease are highly variable, and their geographic distribution is correlated with the distribution of the parasite lineages. In Colombia and northern South America, T cruzi I lineage is associated with chagasic cardiomyopathy. Alternatively, in the countries south cone of South America, there is a predominance of T cruzi II, which is associated with cardiomyopathy and digestive diseases. We report for the first time a mixed infection consisting of both T cruzi I and T cruzi II detected in the esophagus and in the heart, respectively, of a cardiomyopathic patient from an endemic area in Santander, Colombia. This finding has epidemiological relevance related to the association of T cruzi II with the clinical manifestations of Chagas disease and its frequency in Colombia and countries in northern South America.

KDNA gene signatures of Trypanosoma cruzi in blood and oesophageal mucosa from chronic chagasic patients

Trypanosoma cruzi presents a high degree of intraspecific variability, with possible implications for the pathogenesis of Chagas disease. The aim of this study was to evaluate T. cruzi kDNA minicircle gene signatures using the low-stringency single-specific-primer PCR technique in both peripheral blood and oesophageal mucosa from chronic chagasic patients, with or without megaesophagus, alone or in combination with cardiopathy and megacolon. It was not possible to identify a uniform pattern of shared bands between blood and oesophageal mucosa samples from individuals with the same clinical form or mixed forms, suggesting multiple T. cruzi infections with differential tissue tropism. Thus, the results indicate that there is an intense intraspecific variability in the hypervariable regions of T. cruzi kDNA, which has so far made it impossible to correlate the genetic profile of this structure with the clinical manifestations of Chagas disease.

Chagas Disease in Ancient Hunter-Gatherer Population, Brazil

Chagas Disease in Ancient Hunter-Gatherer Population, Brazil

Caracterización biológica y genética de dos clones pertenecientes a los grupos I y II de Trypanosoma cruzi de Colombia

Genetic differences between T. cruzi I and T. cruzi ll may determine differences in their tissue tropism in the vertebrate host and may also be responsible for the differences in clinical manifestations of Chagas disease. Two Colombian clones of the T. cruzi groups I and II were characterized biologically and genetically in a murine model. Strains Cas15 and AF1 belonging to the T. cruzi groups I and II were cloned in semisolid medium. A clone of each strain and a mix of both were used to infect mice; the mice were subsequently sacrificed at selected post-infection intervals. In order to identify the parasite presence in blood and organs, two methods were used (a) microhematocrit and (b) polymerase chain reaction with primers for satellite DNA and the intergenic region of miniexon. The T. cruzi I clone was more infectious, with a preferential tropism observed in heart, rectum and skeletal muscle, whereas clone T. cruzi II exhibited a preferential tropism for spleen and liver. During the infection with the clone mixture a predominance of the T. cruzi I clone over clone II in blood as well as in organs was observed. The results corroborate that the genetic differences between the T. cruzi groups correlate with their tissue tropism, and can play an essential role in explaining the clinical manifestations of Chagas disease observed in Colombia.

Clinical evolution and morbi-mortality in Chagas disease.

The knowledge firstly achieved by CarlosChagas and his colleagues of the Instituto OswaldoCruz, increased with all those acquired to date, al-low us to outline the general scheme (modifiedfrom Dias & Coura 1997) of American trypanoso-miasis natural history (Figure).The knowledge of this natural history makesmore comprehensible the clinical evolution of thedisease, as it will be demonstrated by the reportersof the subject.The Chagas Disease Control Campaign, to-gether with other conditions, has contributed in adecisive way for the significant reduction of thenumber of new cases of the disease. Nevertheless,millions of chagasic individuals still live in ourcountry as well as in other ones of Latin America(Moncayo 1993, Schmunis 1997, Dias & Coura1997). Only this would be enough to justify theconcern with morbidity and mortality due to Ameri-can trypanosomiasis.In addition, the current data about morbidity(analyzed either by the number of individuals whoacquire the disease or by the number of cases inwhich trypanosomiasis has arisen), as well as thecoefficients or rates of mortality allow the under-standing of the severe medicosocial problems con-tinuously generated by the endemic.In the other hand, the prophylatic and thera-peutic measures can explain the significant reduc-tion of morbility and mortality rates in Chagas dis-ease (CD) acute phase in the last years, as it maybe confirmed by comparing Chagas references(1910, 1916) and Chagas and Villela (1922) withthose of Dias (1955), Ferreira (1986) and Dias andCoura (1997).In order to analyse the morbity and mortality inchronical CD, two facts must be initially remem-bered: first, in the chronic phase of American trypa-nosomiasis, the main lesions are situated in the heartand digestive tract; second, the digestive form ofthe disease was characterized only in the 50s(Rezende 1956). This last fact may explain the lackof references on digestive manifestations inchronical CD in the first half of century (Chagas1910, Chagas & Villela 1922), what reflects on com-parative analyses, specially regarding morbidity.In conclusion, it is clear since the beginning ofthe studies on CD that cardiac alterations are themain responsible for morbidity and mortality.Longitudinal studies as those carried out ini-tially in Bambui, State of Minas Gerais, Brazil, fol-lowed by other more recent ones as those ofMacedo (1973) and Dias (1982), allow us to con-clude that only half of the individuals infected withT. cruzi show, in the course of their lives, clinicalmanifestations of CD; among those, only about50% die as a direct or indirect result of the infec-tious course. Mortality is generally high amongchagasic individuals who develop chronic cardi-opathy, mainly when cardiac failure and/or severearrythmias occur. Grossly, it means that 25% ofthe chagasic individuals (which correspond to350,000 people in Brazil) are bound to die becauseof CD. The death official registry service in Brazilindicates that the mortality due to disease is about6,000 deaths/year, prone to decrease in the last de-cade. In Latin America, Moncayo (1993) evalu-ates that 45,000 yearly deaths are due to CD.In the micro-regions of major endemicity, thedeath rate due to CD among adult individuals mayreach 200 per 100,000 inhabitants or more. Theserates are surely underdimensioned since that a sig-nificative number of deaths due to chronicalchagasic cardiopathy are registered as either dueto non defined causes or lack of medical care ordue to other cardiopathies.Data from the World Bank in 1993 show theenormous social burden as a consequence of CD.This burden is significantly greater than that pro-duced by other tropical diseases prevalent in theAmericas. Malaria, schistosomiasis, leishmaniasis,filariasis, oncocercosis and leprosy produce all to-