CD is classified evolutionary into two phases: an initial acute phase, followed by a chronic phase. Each phase has distinct clinical characteristics, diagnostic parameters, and treatment [72, 73, 74, 75, 76]. The acute phase is characterized by intense parasitism related with nonspecific symptoms, including fever, eyelid edema (denominated Chagoma), edema, and myocarditis. In general, the progression of disease can take years to reach the chronic phase, which presents four clinical forms: indeterminate (without clinical manifestations), cardiac, digestive, and mixed (association of cardiac and digestive) [77, 78, 79, 80, 81].
4.1. Chronic Chagas cardiomyopathy (CCC)
Chronic Chagas cardiomyopathy (CCC) is associated with high rates of morbidity and mortality, and it is categorized into stages of cardiac impairment (A, B, C, and D) according to the manifestations, electrocardiograph, radiological alterations, and changes in ventricular function [72, 74, 75, 82, 83]. Approximately 20–40% of patients with the indeterminate form will develop CCC. Several mechanisms contribute to this including the persistence of the parasite and autoimmunity. Moreover, factors such as dysautonomia (neurogenic mechanisms) and microvascular dysfunctions may potentiate and amplify this damage [74, 75, 77, 79, 80, 81, 84].
The cardiac form of Chagas can occur with or without ventricular failure [25, 82, 84]. Although the most common is the coexistence of arrhythmic manifestations with the congestive form, some patients have only arrhythmias and intraventricular and atrioventricular conductions compromising with normal ventricular function. Management of CCC treatment is based on the following clinical manifestations such as heart failure, cardiac arrhythmia, and thromboembolism [25, 79, 84].
Although, Chagas disease represents an important cause of heart failure (HF), limited studies have established the use of these drugs in Chagas patients. The treatment of CCC aims to reduce symptoms, delay the evolution of ventricular dysfunction, and prolong survival. In the asymptomatic or mild stages of HF, it is intended to delay the evolution of the disease. In the advanced stages, the objective is to improve the quality of life and the survival of patients. The efficacy and tolerability of these drugs in patients with CCC is extrapolated from the results obtained for other etiologies. Therefore, the CCC treatment is suggested to be performed in accordance with the general guidelines for HF treatment and should consist of the combination of three therapeutic classes: angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), diuretics, and adrenergic beta blockers (BB) [40, 72, 82].
Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) have an essential role in adverse cardiac remodeling and ventricular dysfunction progression of HF [40, 72, 82]. In experimental studies reported in the literature, captopril and enalapril demonstrated to diminish myocarditis and fibrosis of CCC [85, 86, 87, 88]. These drugs should be administrated initially in low doses. In spite, some physicians report that CCC does not tolerate high doses of ACEI, according to the degree of tolerability; the dose can be progressively increased [25, 78, 81]. ACEI is recommended to patients with a left ventricular ejection fraction (LVEF) <45% [82, 83]. Regarding ARB, spironolactone and eplerenone have been evaluated in studies and data have shown that these drugs are effective in improving the quality of life and reduction of symptoms associated with CCC [89, 90, 91] and this class is considered as the treatment of choice for Chagas patients with LVEF <45%, or patients with LVEF<35% and New York Heart Association (NYHA) Class III/IV [82, 83]. In addition, in cases that are contraindicated to ACEI and ARB (hyperkalemia and progressive renal failure), the combination of hydralazine and isosorbide dinitrate should be prescribed [25, 73, 79, 83].
Beta-adrenergic blockers (carvedilol, bisoprolol, or metoprolol) are suggested in association with ACEI and ARB due to autonomous nervous system involvement in CCC and the production of antibodies against β-1 adrenergic and M-2 muscarinic receptors [25, 73, 79, 83]. Limited reports address the efficacy of this therapeutic class to treat Chagas patients with ventricular dysfunction [86, 92, 93, 94, 95, 96]. Beta blockers have been avoided because of the presence of frequent bradycardia; therefore these drugs are not indicated for patients with bradycardia ≤50 bpm or AV conduction disorders (PR > 280 ms) [25, 73, 79, 83].
Moreover, digoxin and diuretics are considered a pharmacological option in CCC, justifying the use of digoxin for patients with symptomatic LVEF ≤45%, principally in the presence of atrial fibrillation when the ventricular frequency is increased and diuretics to improve congestive symptoms and signs. For advanced HF stages, the combination of thiazides with loop diuretics has been proven to be more effective [25, 72, 73, 79, 83].
The annual incidence of thromboembolism in Chagas patients is between 1 and 2%, affecting mainly patients with HF. Occasionally, this aggravation is the first manifestation of the CD. Cardiac emboli can reach both the pulmonary and systemic circulation, with the cerebral territory being the most clinically evident [40, 79, 82]. The treatment of thromboembolism is performed based on the established recommendations, alternating according to the extension and compromised organ. For this, a score derived from a prospective cohort study with 1043 patients was recently available to evaluate the risk and to implement preventing thromboembolisms in CCC. Through risk-benefit analysis, warfarin is indicated for patients with 4–5 point. In the case of 3 points, acetylsalicylic acid (AAS) or warfarin could be used. For 2 points, it is suggested to use AAS or no prophylaxis, and 0–1 points do not need prophylaxis [79, 81, 97].
Patients with CCC usually present ventricular arrhythmia. The most frequent ventricular arrhythmias in Chagas patients are ventricular ectopies, isolated or repetitive. The presence of these arrhythmias in asymptomatic patients with preserved ventricular function does not require antiarrhythmic treatment, whereas in symptomatic cases, the antiarrhythmic treatment can be individualized. The goal of pharmacological treatment of arrhythmias is the control of symptoms. Amiodarone is widely used, despite the high incidence of adverse events. At the usual doses of 200–400 mg/day, it can be associated with alternative agents recommended for cardiopathies of other etiologies, such as propafenone, sotalol, and beta blockers, to reduce severe arrhythmic events. However, drugs belonging to class I (sodium-channel blockers) should be avoided, principally in patients with ventricular dysfunction due to proarrhythmic effects, whereas propafenone is contraindicated in patients with left ventricular dysfunction [77, 79, 83, 98]. Bradyarrhythmia is related with sinus node dysfunction or atrioventricular blocks. For the treatment of symptomatic bradyarrhythmias in CCC, a permanent pacemaker implant is usually performed .
4.2. Digestive form of CD
The digestive manifestations of the CD correspond to the functional alterations observed in the esophagus and intestine, which result in the formation of mega-esophagus or megacolon, respectively. These deformations are related with the involvement of the enteric nervous system, especially the Auerbachs plexus. Degenerative phenomena in this region are caused by the presence of inflammatory processes associated with autoimmune responses. Therefore, both megacolon and mega-esophagus results in alterations in motility, and consequently, in slow transit and difficulty to empty, followed by increased organ caliber [99, 100, 101, 102].
Mega-esophagus is classified into four groups with the objective of situating the different radiological aspects within the evolutionary spectrum of the affection. In addition, the classification of the mega-esophagus is important for the choice of treatment [99, 100, 101, 103].
The symptoms commonly reported in mega-esophagus are: dysphagia, regurgitation and esophageal pain. Treatment of mega-esophagus included clinical, pharmacological measures, dilatation and surgical procedure to aid in the transit of foods and liquids. The choice of treatment to be applied depends on the following factors: patient agreement, relevance of symptoms, degree of classification, nutritional status, clinical condition, comorbidities, age and available hospital infrastructure [40, 103, 104].
Clinical and pharmacological treatment is indicated for patients in group I, or patients at high risk of being treated with other forms of treatment, or in cases refusing invasive treatment. Patients must frequently drink water during the meals, eat slowly, and give preference to food in a pasty consistency. Hot and cold foods and drink and eating prior to bedtime are not recommended because food may be retained in the esophagus, causing pain or nocturnal regurgitation during sleep. The pharmacological treatment is based on substances that aim to relax the esophageal sphincter; however, the beneficial effect of these drugs is restricted to the period of action, being only a symptomatic treatment. The nitric derivatives (isosorbitol dinitrate) and the calcium channel blockers (nifedipine) are recommended [40, 101, 104, 105].
Alternative treatment is forced dilation of the distal segment of the esophagus and esophagic junction using a pneumatic or hydrostatic balloon or surgery. Surgery is performed for patients classified in group II (according to the intensity of the symptoms), III, and IV, and for patients without adequate response to clinical treatment. Another alternative is the injection of botulinum toxin, which acts to inhibit acetylcholine release [40, 101, 105].
The most frequent symptoms in megacolon consist of intestinal constipations, abdominal distension discomfort, occlusive phenomena associated with fecaloma, and sigmoid volvulus [106, 107]. Megacolon treatment may be clinical or surgical and varies according to patient agreement, level of complications, nutritional status, clinical condition, presence of comorbidity, and age . If the clinical treatment indicates an alteration in the diet, use of laxatives, such as lubrificant laxatives (mineral oils) and emollient laxatives, and intestinal washes with water and glycerin may be used .