What the Chagas? The Impact of Chagas Cardiomyopathy

This is going to be a very different post, in that, while the topic is still related to infectious disease, I’ll delve into other parts of medicine as I think they are relevant. Chagas disease, widely considered a neglected tropical disease, is caused by Trypanosoma cruzi and it is a zoonosis transmitted among domestic and wild animals and by humans via triatomine insects called reduviid bugs, also known as kissing bugs (1). This organism is endemic to several parts of Latin America, such as Mexico and Brazil, as well as Central America (2). The most important route of transmission is via vector, however other important routes include congenital infection, transfusion-related, and via oral route. In brief, the disease can be divided into three stages (1, 3, 4):

• Acute: typically seen in children, with only a small portion of patients presenting with symptoms, which are non-specific. Romana sign, which is local edema of the face, as well as lymphadenopathy and hepatosplenomegaly can be seen. On occasion, you can have acute myocarditis, but this is rare. Yep, nothing really to tip you off about the actual organism
• Indeterminate – here, there is serological evidence of disease (Positive IgG) but no evidence of organ dysfunction.
• Chronic – typically seen 10-20 years after initial infection and manifests in adulthood. By far, the most common organ affected is the heart, which is marked by a chronic progressive and fibrosing myocarditis as well as substitution of cardiomyocytes by fibrotic tissue. Mega-esophaus and megacolon can also be seen.

Here, I will focus mostly on the cardiac part as I find it more interesting. One of the best charts that highlights the clinical spectrum of this disease using these phases is the following (4):

As you can see, only a small percentage of people who are infected develop acute symptoms. During the indeterminate phase, patients remain asymptomatic or have subclinical disease. Even those who have some sort of cardiac dysfunction, they remain asymptomatic. Only 10-20% end up having overt heart failure and electrophysiological abnormalities. 

Life Cycle

I absolutely hate learning about life cycles, but it’s mandatory. 

This is a very complicated image, but it is the one you’ll most commonly find. I think it is easy to define some terms prior to proceeding. There are several forms of the parasite. “Mastigote” are flagellate organisms. The prefix “epi” means around while “a-” means “without.” So “amastigote” means without a flagella, while “epimastigote” means “flagella around.” Trypanomastigote is the one where the flagella is at the end of the parasite, and hence able to move around more efficiently. In the “kissing bug” the organism is in its epimastigote stage. The organism replicates in the midgut of the bug and then develops into the trypomastigote in the hindgut. The bug goes to a vertebrate, takes a blood meal, and poops the contents of its hindgut to make room for the blood. Usually, the bug takes a bite around mucosal surfaces (such as conjunctiva, hence the Romana sign). From here, the trypomastigote with its flagella, is able to circulate the bloodstream and enter any nucleated cell. Once inside the cell, it doesn’t need its flagella anymore and becomes an “amastigote.” Inside the cell, the parasite can replicate and transition into trypomastigotes. The cell bursts and the cycle continues. 

Diagnosis

I won’t delve too much into the data for diagnosis but mention a few important points. During the acute phase, diagnosis depends on the observation of parasites. This can be seen in wet preparations of anticoagulated blood and also in Giemsa-stained smears (3). Chronic T. cruzi infection is diagnosed by detecting IgG antibodies that bind specifically to parasite antigen. There are many assays out there but the sensitivities and specificities are not great, and false positives reactions can occur with leishmaniasis, malaria, syphilis, and other parasites. 

Due to this, recommendations are to get at least 2 tests done on two different assays (either a combination of either ELISA, indirect hemagglutination, chemiluminescence, and indirect immunofluorescence). 

Chagas Cardiomyopathy, Pathology, and Risk Factors

The pathophysiology behind chagas cardiomyopathy is thought to be dependent upon low grade parasitemia (1,2,) followed by immune-mediated myocardial injury (5). The parasite itself causes myonecrosis, with the following inflammatory response and bystander damage causing infiltration of several immune cell lines like leukocytes and eosinophils (4):

Mononuclear cell infiltration, edema, myocyte destruction, and fibrosis are seen in histopathology, with almost no parasites seen in chronic infection. Thus, while it is believed that there needs to be some low grade parasitemia for the immune system to continue to be active, most of the damage is done by the immune response. Another hypothesis here is autoimmunity, where parasite-induced damage to myocardiocytes is followed by molecular mimicry, allowing fibrosis to continue. 

The symptoms that highlight chagas cardiomyopathy include those typical of congestive heart  failure, though right sided heart failure predominates. Other symptoms include pedal edema, syncope, electro cardiac abnormalities (usually RBBB). The diagnosis depends on EKG and TTE findings along with 2 serological tests. Multiple classifications have been employed that use said findings, and these are used through Latin America (5, 6):

One of the interesting bits with regards to Chagas cardiomyopathy is these patients tend to have more EKG changes. In one instance, a review noted that EKG abnormalities increase with age, but the effect was more pronounced in those with Chagas (7). Right bundle branch block was more prevalent in Chagas cardiomyopathy with a review noting an OR 10.73 (95% CI 10.10 to 11.41). Another 10-year review also noted that EKG findings were more frequently found in those with Chagas compared to those without it (88% vs 78%, p <0.001, 8). First degree AVB (OR 3.77, 95% CI 2.09-6.81), RBBB (9.69, 95% CI 6.34 to 14.82), and atrial fibrillation (OR 3.43, 95% CI 1.87 to 6.32) were more common amongst patients with Chagas cardiomyopathy after adjusting for several variables, including age and gender. While the risk of death increases with each EKG abnormality, it should be noted the risk was higher for the Chagas cohort than the non-chagas cohort (8):

A Mexican cohort of 387 patients who were seropositive for Chagas disease found they were more likely to have RBBB compared to seronegative patients (26% vs 6.6%) as well as RBBB with left anterior fascicular block (22% vs 0.27%, 9). In another cohort of 814 patients evaluated in an outpatient clinic, QT dispersion and QTc max were both significantly associated with chagas-related mortality and higher risk of sudden death (10):

In other words, these EKG changes are not insignificant. Whether the EKG changes are due to cardiac induced parasitological damage or other etiologies related to comorbidities is difficult to say, however it should be noted that Chagas cardiomyopathy in and of itself seems to be a risk factor for cardiac events and mortality. One prospective Portuguese study (11) found that heart failure due to chagas had worse prognosis when compared to other etiologies (RR 3.29, 95% CI 1.89 to 3.73):

In a similar study of 287 patients with dilated cardiomyopathy from either Chagas or idiopathic etiology, functional class, LV EF, and chagas as the etiology where independent predictors of cardiac events (12):

In this same cohort, a higher percentage of patients with chagas were more likely to experience RBBB and left anterior fascicular block (50% vs 5%) when compared to idiopathic cardiomyopathy. Conversely, those with idiopathic etiologies tended to have LBBB in higher frequencies (51% vs 10%). While not statistically significant, more patients in the Chagas group had apical thrombus (14% vs 6%). 

Multiple studies have attempted to evaluate risk factors for mortality and progression of cardiac disease. A cohort of 104 patients ejection fraction, maximal oxygen consumption were associated with higher mortality (13). Further, higher NYHA class was associated with higher mortality, with FC II having a predictive survival of 97% at 1 and 3 years, dropping to 38% and 16% at years 1 and 3, respectively, for class IV:

A retrospective study of 424 patients with cardiac Chagas was used to develop a risk score for mortality (14). Six variables had prognostic significance after multivariate analysis, most of which are easily obtained in the outpatient setting:

The patients were divided into 3 groups: low risk (0 to 6 points), intermediate risk (7 to 11 points) and high risk group (12 to 20). 10 year mortality in the development cohort was 10% for low risk, 44% for the intermediate risk, and 84% for the high risk. 

Similar results were seen in the validation cohort of the same study. An attempt at externally validating the Rassi score did not find a statistical significance with mortality, though there was an increase in mortality risk with increasing scores (15). 

A meta-analysis of 12 studies (16) found that LV dysfunction was the most common independent predictor of death, however there were different measures used when evaluating the data, which included the presence of LV aneurysm or apical aneurysm, evidence of segmental or global LV wall motion abnormality, increased LV systolic or diastolic dimension, and reduced EF. Further, dyspnea, NYHA functional class III/IV, and cardiomegaly were also found to predict mortality. The authors proposed the following approach to risk-stratifying patients based on echocardiogram and radiographic data:

They also note those who had NSVT had higher mortality, which was significantly worse when LV dysfunction was found along with NSVT:

Another study took a look at 100 patients and evaluated EKG, holter monitor, and TTE data to evaluate predictors of mortality, using bootstrapping procedures, and create a different novel score to that of the Rassi score (22). They found the presence of Q waves, NSVT, prolonged QRS duration (defined as a VM-filtered QRS complex duration >150ms), intraventricular electrical transients, and 24-hr standard deviations of normal RR intervals <100 as being associated with increased mortality. While some of these variables are difficult to interpret, some of the more important ones included Q waves in the anterior-septal leads (HR 18, 95% CI 2 to 161), EF <50% (HR 3.4, 95% CI 1.7-4.1) and VT on 24-hr ambulatory EKG (HR 3.6, 95% CI 1.7 to 7.1). This score was non-inferior to the Rassi score, though it required other measurements of EKG data.

Other factors associated with higher mortality include hyponatremia (HR 2.05, 95% CI 1.25 to 3.38), digoxin use (HR 2.79, 95% CI 1.42-5.96) and inotropic support (HR 1.84, 95% CI 1 to 1.1) were associated with increased mortality as well, while beta-blocker usage (HR 0.33, 95% CI 0.22 to 0.5) was associated with lower mortality (17, 18). 

Similarly a cohort of 165 patients found, using multivariate analysis, that gender, >2 second pauses on Holter monitor, length of digoxin therapy, and increased cardiothoracic ratio on CXR were associated with progression of cardiomyopathy (19):

Univariate analysis also found that increasing age (HR 2.18 above 50), non-sustained VT (HR 1.47), and prescription of heart failure medications such as loop diuretics, aldactone, or ACEi to be associated with higher risk of progression, though here BB were not protective:

Similarly, another cohort found protective effect to beta-blocker while a deleterious effect for digoxin (20):

Another study (21) found that beta-blocker provided benefit in those who had chagas cardiomyopathy and systemic arterial hypertension, with 60 month mortality in the BB group being 61% compared to 24% in the non-BB group:

These data suggest that, by far, the risk factors for progression of Chagas cardiomyopathy mirror those of other causes of congestive heart failure. Indeed, BB seems to provide some mortality benefit and the same could be said for drugs that prevent further cardiac remodeling such as ACE inhibitors/ARBs. Whether sacubitril-valsartan provides similar benefits to this population, remains to be seen

Thrombosis

One of the most fascinating aspects of the disease is the higher rate of thrombosis, both pulmonary and intracardiac that are seen in cases of Chagas cardiomyopathy. Indeed, it has also been found that many patients are at a higher risk of stroke. One review (23) highlights the fact these patients tend to have a higher rate of mural thrombosis, with heavier hearts being found to have cardiac thrombosis. Further, they note that apical thrombosis were found in 37% of patients with chronic chagas cardiomyopathy in autopsy studies, compared to only 11.1% of healthy hearts (23). 

More contemporary data comes from a retrospective study of 75 ambulatory patients with Chagas cardiomyopathy (24). The authors found that 7% had an apical aneurysm, and 23% had an apical thrombus on TTE. TEE was able to identify an additional 4 patients who had a thrombus in the left atrial appendage. Notably, 19% of the patients in the cohort had a prior episode of CVA, which was found to be associated with the presence of an apical thrombus. Another prospective study compared 94 stroke patients with positive chagas serology with 150 stroke patients as controls (25). When comparing the etiology, patients with positive chagas serology were more likely to have a cardioembolic stroke compared to controls (56% vs 9.3%, p – 0.000). Further, the non-chagas patients tended to have small vessel strokes and atherosclerotic strokes (20% vs 8.5%, and 35% vs 9.6%). A logistic regression model found that apical aneurysm (OR 86, 95% CI 10.5 to 705), EKG arrhythmia (OR 5.6, 95% CI 2.7 to 11.8), cardiac insufficiency (OR 8.6, 95% CI 2.4 to 30.5), and female gender (OR 2.2, CI 1.1 to 4.6) were associated with higher risk of thrombosis.  

Interestingly, BNP has also been found to be a predictor of stroke in patients with Chagas cardiomyopathy. In a prospective cohort study that included 1398 patients, of which 524 had positive chagas serology, 10-year stroke mortality risk was higher in the infected population (26):

After adjusting for sex and age, the risk of stroke in the infected patients included age, BNP, and atrial fibrillation on EKG:

Notably, the combination of atrial fibrillation and BNP level (based on whether the value was on the lower or top quartile) allowed for better prediction of risk for stroke, after adjustment for conventional risk factors:

Whether patients without a cause to go on anticoagulation (i.e. they have atrial fibrillation with a CHADS-VASC score >2 OR have an intramural thrombus) should be on it is a question that I do not know the answer to. Though I think it serves to contextualize the risk these patients face once the disease reaches its chronic form.

Chagas Specific Therapy

Two drugs are typically used for therapy of T. cruzi, nifurtimox and benznidazole. While therapy with acute T. cruzi is recommended, the question as to whether patients with indeterminate or chronic symptomatic phases of the disease is still debated. A meta-analysis attempted to evaluate the utility of therapy on parasitological and immunological cure (27), however I’ll look at the impact on chronic Chagas. Given that persistent parasitemia is thought to be contributing to the pathophysiology, it should stand to reason there may be a benefit to therapy. One phase III RCT compared benznidazole in the early chronic phase of T. cruzi infection in 130 symptom-free children (28). At the end of follow up, 58% of patients in the experimental group were negative for antibodies compared to only 5% in the placebo group:

While there may be a clear benefit in terms of serology, progression into cardiomyopathy is the key here. One study “randomized” patients in a 1:1 fashion to receive 5mg/kg of benznidazole for 30 days or no therapy and evaluated them at the end of 15 years (every other patient were put in the treatment group, though they were not stratified29). Based on the percentage of change to a more severe Kuschnir group, fewer patients in the treated group progressed compared to those in the untreated group (4.2% vs 14.1%, HR 0.24, 95% CI 0.10 to 0.59). The effect was more pronounced in those who were group III, 10% in the treated group vs 40% in the untreated group. This also held true for EKG changes, with fewer seen in the treated group compared to the untreated group, as well as a lower change in the ejection fraction. 

Another retrospective cohort of 346 patients evaluated the effect of 5mg/kg of benznidazole for 60 days (30). Those who were treated had lower rate of heart deaths and deaths overall:

Logistic regression model found that treatment with benznidazole was associated with a lower rate of combined heart failure, stroke, and total mortality. It should be noted, however, this was not a randomized study and that those who were treated tended to be younger, had maintained a more normal EKG for a longer period of time, and were more likely to have left the endemic area. 

Another cohort of patients with positive serology and history of treatment (either received treatment or not) were followed for up to 2 years after enrollment (31). 1813 patients were followed, with treatment having an average duration of 90 days within the 493 patients who were treated. The vast majority (84%) started therapy within a year of their serological diagnosis. After matching, treatment was associated with lower rates of 2-year mortality, lower EKG abnormalities, and lower PCR positivity compared to no treatment:

One of the largest RCTs evaluated 2 doses of benznidazole (5mg/kg for 60 days or 300mg per day for 40-80 days) in a 1:1 fashion with placebo (32).  Patients were evaluated up until 5 years with primary outcome being first occurrence of death, resuscitated cardiac arrest, insertion of pacemaker or ICD, sustained VT, heart transplant, TIA, stroke, new heart failure, thromboembolic event. 2854 patients were randomized, with primary outcome occurring in 27.5% of the treatment group and 29.1% in the placebo group:

More patients experienced treatment interruption in the therapy group (24% vs 10%) due to rash, GI symptoms, and nervous system disorders. Despite these results, PCR conversion favored benznidazole across all subgroups. 

Finally, a retrospective observational study evaluated patients with indeterminate form of Chagas who were treated and those who were not treated with BZN in terms of risk of progression (33). 114 patients who were treated were compared with 114 who were not, matched for several variables. The incidence of progression from indeterminate form to cardiac form was 21% in the treated patients compared to 8% in the non,treated patients:

Further, BZN treatment was associated with a lower rate of composite cardiovascular events after adjustment, but not mortality. 

Overall, it seems that the cohort studies suggest some degree of benefit, however it is difficult to ascertain at what point in their illness patients receive therapy. For instance, would giving patients with indeterminate chagas therapy, prior to any EKG anomalies to reduce parasite load end up benefiting a cohort in the long-run? What about those who have some degree of reduced ejection fraction? It seems the above studies gave a spectrum to the point the data suggest some degree of benefit. Other drugs, such as azoles, have been evaluated for acute disease with one study evaluating fosravuconazole in combination with benznidazole (34) but how this translates into chronic disease remains to be seen.

For the cardiac manifestations of the disease such as volume overload and arrhythmias, standard therapy with beta-blockers, ACEi/ARBs, spironolactone, and ICD/antiarrhythmics as necessary are the standard of care here (35, 36). Heart transplantation also seems to significantly reduce mortality, though this will be seen in another post.

TL;DR

• T. cruzi is carried by the “kissing bug” and most of patients get infected via vector
• The acute form of the disease is seen in a small percentage of patients and the symptoms are very nonspecific
• A small percentage of patients go on to develop the chronic form of the disease, marked by positive serology with either cardiac or GI manifestations
• Pathophysiology of chronic cardiac chagas may be related to persistent parasitemia and immune dysregulation
• Cardiac chagas is diagnosed by serology (you need at least 2 different assays as serological tests can cross react with other infectious diseases) and EKG/TTE. There are several classifications out there.
• Risk factors for death include reduced EF, RBBB and QTc prolongation hyponatremia, and requirement of digoxin. Beta-blockade seems to have a protective effect
• Therapy with benznidazole may have protective effects in terms of progression into cardiac chagas

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