Chagas disease is a complex zoonosis. Its natural history involves the interaction of transmitting arthropods with wild, peridomestic, and domestic mammals, and it has a great diversity of transmission forms. In a vertebrate host, the disease evolution is evinced by various clinical manifestations [1,2].

The disease is caused by Trypanosoma cruzi, a flagellated protozoan that is naturally transmitted by hematophagous Hemiptera insects (triatomines). The parasite was discovered in 1909 by Dr. Carlos Chagas in Minas Gerais, Brazil. Dr. Chagas also described a large part of the biological cycle, linking the parasite to the transmitting triatomine (Panstrongylus megistus). He was able to isolate the parasite and replicated the infection in experimental animals. Dr. Chagas also mentioned that rural housing conditions, which to date have not changed significantly in endemic countries, are important for the spread of the vector. As a clinical entity, Chagas disease is linked to poverty [1].

Chagas disease is endemic in 21 countries within continental Latin America. It is distributed from the south of the United States, in Central America, the Southern Cone, Andean countries, and Amazonian countries. In the Americas, 30,000 new cases are reported every year, 12,000 deaths on average, and 8600 newborns are infected at gestation. In 2019, a prevalence rate of 933.76 per 100,000 population was recorded. Currently, about 70 million people in the Americas live in areas at risk for the infection [3]. Humans become infected with T. cruzi by several mechanisms. The most important one is natural transmission, involving an infected triatomine bug. This transmission form is very common in rural areas, where housing traits and the ecotope favor a colonization of the domestic niche by insects. The second transmission form, restricted to urban areas, is related to the transfusion of blood or its components. This transmission form depends on the migration of rural population to cities, as more than 70% of the population in some cities had immigrated from high-prevalence areas of the disease [4].

The primary vectors for Chagas Disease are Triatoma infestans in Argentina, Bolivia, Brazil, Chile, Paraguay, Uruguay, and Peru; Rhodnius prolixus in Colombia, Venezuela, and Central America; T. dimidiata in Ecuador and Central America; and R. pallescens in Panama [3]. In the Americas, natural infection is associated with risk factors such as housing construction material and other characteristics that favor the colonization of human dwellings in rural areas. For this reason, it is considered as a neglected tropical disease [4]. PAHO/WHO, working with the endemic countries, have launched several Subregional Disease Prevention and Control Initiatives. These include the improvement of housing to halt vectorial transmission in 17 countries, and screening of blood donors in the 21 endemic countries, in addition to eliminating some vector species such as R. prolixus in El Salvador, Costa Rica, and Mexico, and T. infestans in Brazil and Uruguay [3,5].

Due to the increase in population mobility worldwide, Chagas disease is considered a major health problem, which has reached countries where vector transmission does not exist, due to the immigration of seropositive cases from endemic geographic areas. This poses a risk of transmission through transfusions, organ and tissue transplants, and even maternal-fetal transmission in the USA, Canada, and some European and Western Pacific countries. It has been estimated that Spain is the main non-endemic country in the number of transmissions, followed by the USA and Italy [6].

Chagas disease has two clinical phases: an acute phase and a chronic one. Most cases of acute Chagas disease are asymptomatic; only 5–10% of infected subjects develop symptoms, including persistent fever, asthenia, adynamia, headache, and hepatosple-nomegaly, all of which are nonspecific. Among these symptomatic individuals, the most frequent pathognomonic signs are the Romaña sign, characterized by unilateral bi-palpebral edema, which is observed in 50% of cases, and the indurated cutaneous chagoma, found in 25% of cases. Both signs are often accompanied by regional adeno-megaly. In the remaining 25% of patients, there is no sign of portal entry, but some of the nonspecific symptoms mentioned above can be found [7]. The most frequent symptom is fever, which is present in up to 95% of cases, usually without specific characteristics. All other signs and symptoms, including asthenia, adynamia, headache, and hepatosple-nomegaly, are nonspecific [3,5]. While T. cruzi can infect any nucleated cell, some strains exhibit a marked tropism for myocardial cells, smooth muscle cells of the digestive system, or nervous tissue, among other cell types. Cardiac manifestations include primarily organ enlargement (cardiomegaly) [7].

The chronic phase is divided into a chronic asymptomatic phase and a symptomatic phase; the former evolves without demonstrated pathology and can last 10–20 years; however, cases have been reported in minors in Mexico where this period lasts 2–7 years before the chronic form with cardiovascular symptomatology can be detected [8]; this phase is clinically asymptomatic and exhibits very low parasitemia, so that the methods of choice for diagnosis are serological, and confirmation requires two positive tests with different principles [9].

After this phase, patients progress to the chronic symptomatic phase, with a proven symptomatology, in which they develop mainly cardiac lesions and, to a lesser extent, digestive lesions, mainly in the esophagus and colon, and in a few cases in the peripheral nervous system. Cardiac lesions cause alterations in myocardial contractility and the electrical impulse, mainly in the bundle of His, the particular right bundle branch block with left anterior fascicular hemiblock, ventricular extrasystoles, and atrioventricular block [3,7]. The lesions in this cardiomyopathy involve several cardiac tissues, mainly the myocardium, and in severe cases, the endocardium pericardium; this can cause pleural effusion, which may evolve into sudden death, which is more frequent in cases with dilated heart disease and severe heart failure [10]. Carlos Chagas described digestive disorders linked to the disease in 1916, although Kidder and Fletcher had already done so in 1857, when they called it mal d’engasgo, i.e., “disease causing dysphagia” [11]. Esophageal involvement usually consists of a megaesophagus with slow esophageal transit disorders, along with pain and difficulty in swallowing. In cases of colon involvement, a megacolon and constipation are typical [12,13]. Chagas heart disease is clinically classified according to symptoms, and electrocardio-graphic, echocardiographic, and radiological abnormalities, especially changes in left ventricular function. Some risk factors predisposing one to a progression to the chronic phase include electrocardiographic abnormalities, male sex, systolic blood pressure less than 120 mmHg, altered systolic function, left ventricular dilatation, and complex arrhythmias; risk scores have been proposed to stratify the risk of death, although their clinical value is still under study [14]. In a consensus, several authors note that the main predictors of poor prognosis in chronic Chagas disease are a deterioration of left ventricular function, falling into classes III (fatigue, palpitations, dyspnea, or anginal pain) and VI (cardiomegaly and non-sustained ventricular tachycardia) of the New York Heart Association (NYHA) classification of heart failure [15]. Other risk scores have been proposed. Rassi uses a combination of clinical symptoms, cabinet test results, and demographic data [16]. On the other hand, de Sousa use a four-factor score that includes the QT dispersion interval on ECG, syncope, premature ventricular contractions, and left ventricular function [17].

Benznidazole and nifurtimox are the only drugs with proven efficacy against Chagas disease. Both drugs have been approved internationally. Antiparasitic treatment of these cardiomyopathies is accompanied by the administration of antiarrhythmics and pace-maker placement. In the most severe cases, heart transplantation can be required [5,7].

2. Pathogenic Mechanisms of Immune Response Evasion in Chagas Disease