Chagasic Cardiomyopathy (Chagas Heart Disease) Part 3

Laboratory tests

Conventional parasitological tests

These can be classified into direct and indirect tests. Direct methods, employed basically in the acute phase, include parasite microscope-observation in blood fresh preparation which permits to observe parasite movement. On the contrary, thin or thick blood smears stained with Giemsa led to a better morphological identification, which is of special importance in areas where Trypanosoma rangeli also circulates. Importantly, parasite concentration methods like blood centrifugation, Strout method, and microhematocrit increase the probability of trypomastigote detection. Because of their great time consumption, indirect parasitological methods are generally used to diagnose patients in the chronic phase. They refer to hemoculture and xenodiagnosis (Luquetti, 2007).

Serological tests

There is a broad spectrum of serological tests, whose final goal is to detect anti-T. cruzi antibodies, usually of the IgG isotype in the chronic phase or IgM in the acute phase. The tests most used, called conventional tests for serological Chagas disease diagnosis, are the indirect immunofluorescence test (IFAT), the enzyme-linked immunoabsorbent assay (ELISA), and the indirect haemaglutination test (IHA). Generally, the antigens used are parasite lysates or mixtures of parasite recombinant proteins. Due to the huge parasite polymorphisms (Rodriguez et al., 2002), it is recommended to use isolates circulating in the specific endemic area or mixture of them.The applied method must be carefully standardized and validated in inter-laboratory international and national tests. Most of the above-mentioned tests can detect the infection in more than 95% of sera. Nevertheless, false-positive reactions can occur in T. rangeli or Lesihmania-infected patients, as well as false-negative in the case of recently-infected chronic patients or immunosuppressed patients (Gil et al., 2007; Luquetti, 2007).

PCR

PCR tests, because of their power of detection and specificity, constitute a complementary diagnostic method for detecting T. cruzi in diverse biological samples. They are of especial interest with chronic patients because of their higher sensitivity compared with conventional parasitological tests. There are several PCR tests available for detecting T. cruzi. Their performance varies depending on aspects like type and number of the target amplification, lack of polymorphisms among the parasite DTU-annealing primer target, sample volume, treatment and conservation, DNA extraction method, type of DNA polymerase used, and thermo-cycling program, among variables (Schijman et al., 2011). Some PCR tests show disadvantages like the amplification of polymorphic fragments or of similar-size bands in both T. cruzi and T. rangeli infections, the deviation of the test towards T. cruzi in mixed infections with T. rangeli, and the possible integration of the parasite’s kDNA in the human genome (Gil et al., 2007; Pavia et al., 2003, 2007). Bearing all this in mind, the Molecular Parasitology Laboratory at Pontificia Universidad Javeriana designed and standardized the TcH2AF-R PCR, specific for T. cruzi (Pavia et al., 2003). This PCR amplifies the 16-255 nucleotides of the T. cruzi SIRE repetitive element and does not present amplification signal in T. rangeli. Assays on triatomine vectors experimentally and naturally infected with T. cruzi revealed that TcH2AF-R PCR allows identifying the parasite in all the infected specimens, with performance equal to that of S35/S36 PCR, considered among the most sensitive PCR tests for T. cruzi identification (Pavia et al., 2007). Likewise, in blood samples from Chagasic patients, it was observed that of 156 samples, 84 (53.8%) were positive with both TcH2AF-R and S35/S36 PCRs, while 89 (57%) were positive for indirect immunofluorescence (IIF) and enzymatic immunoassay (ELISA) (Gil et al., 2007). A study of the performance of the TcH2AF-R and S35-S36 primers in cardiac tissue of mice infected with T. cruzi I showed that by using both pairs of primers it is possible to detect the parasite in the acute and chronic stages of the infection, with performance above that of the micro-hematocrit and eliminate of the histopathological analysis (Barrera et al., 2008). Recently, by combining TcH2AF-R and S35/S36 PCRs, it was possible to follow up a Colombian heart transplant in a Chagasic patient, as well as the first Colombian congenital case (Pavia et al., 2009, 2011). Because of its higher sensitivity, a few real time PCR (qPCR) methods have been developed to monitor drug efficacy and Chagas disease reactivation in transplanted Chagasic patients. However, international studies to evaluate PCR methods for parasite DNA detection in blood samples as that launched by Shijman et al., (2011) are urgently needed.

Epidemiological context

Epidemiological data, such as that shown in Table 2, seek to determine if the patient could have been in contact with the parasite.

Table 2. Epidemiological data supporting risk of T. cruzi infection

Treatment

Symptomatic

In the absence of random clinical studies in patients with Chagas disease and heart failure, traditionally the recommendations have been extrapolated from the management guides for heart failure from other causes (Jessup et al., 2009). However, it should be noted that in the physiopathology of the Chagas disease there are clinical and therapeutic peculiarities with important implications. For example, high doses of diuretics are necessary in advanced stages of the disease due to predominance of the systemic congestion manifestations over signs of pulmonary congestion. In patients with Chagas cardiopathy, conduction disturbances are also frequent, which may be aggravated by the use of Digoxin, Amiodarone, and specially Beta-blockers (Marin-Neto et al., 2010). Cardiac re-synchronization is a treatment alternative for patients with heart failure, especially in the presence of left bundle branch block. However, its usefulness in patients with right bundle branch block common in Chagas disease has not been shown as patients with another type of pathology in the presence of this conduction alteration. Other palliative procedures like dynamic cardiomyoplasty and partial left ventriluculotomy are contraindicated because of unsatisfactory results. Heart transplant is an option indicated in patients selected in final stages of cardiac insufficiency. In these cases, it must be highlighted that the immunosuppressant therapy indicated to avoid transplant rejection may induce reactivation of the T. cruzi infection (Campos et al., 2008). Under certain circumstances, reducing the dosage of immunosuppression is recommended, as well as starting etiological treatment in cases of reactivation (Fiorelli et al., 2005). The potential benefit of transplanting stem cells in patients with Chagasic cardiopathy is under evaluation (Tura et al., 2007). Because of the high frequency of thrombus-embolic phenomena, anticoagulation is indicated in patients with atrial fibrillation, in the prior embolism, in the presence of aneurysms or thrombi, and in cases of heart failure in advanced stages even in the absence of random controlled studies that prove its efficacy. Some observational data suggest that Amiodarone can improve survival in patients with Chagas disease with risk of sudden death due to malignant arrhythmia (Garguichevich et al., 1995). For this reason, Amiodarone is usually recommended in patients with sustained ventricular tachycardia and in cases of unsustained ventricular tachycardia associated to ventricular systolic dysfunction (Leite et al., 2003). Patients with sustained ventricular tachycardia with hemodynamic instability and in cases of aborted sudden death, the implant of a cardio-defibrillator is recommended (Rassi et al., 2009). Radiofrequency ablation is an alternative in patients with ventricular tachycardia (D’Avila et al., 2002); however, its impact on survival and recurrence of the arrhythmia is yet to be established. The finding of severe bradyarrhythmias like those observed in the complete AV block and in the sinus dysfunction must be treated by implanting a definitive pacemaker as in other cardiac conditions (Epstein et al., 2008). The benefit of the pacemaker implant in patients with Chagasic cardiopathy is mainly based on reports of case series.

Etiological

The only medications currently used with Chagas disease due to ethical and efficiency reasons are Nifurtimox and Benznidazole (Bern et al., 2007). Based on the literature review, the recommendations of the antitrypanocidal therapy vary according to the phase and form of the Chagas disease, the patient’s age, and the severity of the disease. The pharmacological therapy is recommended in all acute and congenital cases, in infection by reactivation, in patients up to 18 years of age, and in children. For adults between 19 and 50 years of age and without advanced cardiopathy, the treatment can be offered (Bern et al., 2007). In individuals above 50 years of age, risk of toxicity from the drug may be higher than in young adults and the treatment is considered optional. Once the diagnosis has been confirmed through corresponding serological tests, patients must be evaluated with a clinical history and a careful physical exam. Additionally, in all cases, an electrocardiogram should be performed. With asymptomatic individuals without electrocardiographic alterations, the prognosis tends to be favorable and it is recommended that these patients be monitored every 12 to 24 months. Patients with electrocardiographic changes consistent with the disease’s cardiovascular compromise should be evaluated via thoracic X-ray and echocardiogram that permit defining the ventricular size and function, as well as other types of structural alterations and via 24-h electrocardiographic monitoring or Holter test to detect arrhythmias.

Prognosis

The prognosis of some diseases like Chagas has not been easy to establish because of the great differences in their clinical course among the affected countries. Results like the survey by Maguire et al., (1987) showed that from 20-59 years of age, the risk was strongly related to electrocardiography status. Indeed, patients with ventricular conduction defects have higher mortality rates than infected patients without electrocardiographic abnormalities. Also, it was observed that abnormal diastolic function is related to severe myocardial damage (Rocha et al., 2009). Another survey found that there are six prognostic factors of disease development: NYHA class III or IV, cardiomegaly on chest radiography, segmental or global wall motion abnormalities on echocardiography, non-sustained ventricular tachycardia on Holter monitoring, low QRS voltage on electrocardiography, and male sex (Rassi et al., 2006). Recent studies have found that there are four echocardiographic variables associated with the disease outcome: left ventricular ejection fraction, right ventricular function, E/E’ ratio, and left atrium volume (Rocha et al., 2009). Finally, the prognosis of the patient will rest on the good care and follow up of the caregivers. Chagas disease is no longer a disease of the poor; it is now a disease of any country with important socioeconomic impact.

Conclusions

Prediction markers for disease development, and progression, immunotherapy and vaccine strategies, new anti-T. cruzi drugs, and world-standardized PCR tests, are urgently required to improve early diagnosis and treatment of this worldwide health problem. Government, health organizations, and scientists all over the world need to come together to construct policies and strategies to prevent and control this silent but devastating disease in endemic and non endemic countries.