Abstract
Background: Chagas disease (CD), caused by Trypanosoma cruzi, affects 6-7 million people worldwide annually, primarily in Central and South America, and >300,000 people in the United States. CD consists of acute and chronic stages. Hallmarks of acute CD include fever, myalgia, diaphoresis, hepatosplenomegaly, and myocarditis. Symptoms of chronic CD include pathologic involvement of the heart, esophagus, and colon. Myocardial involvement is identifiable by electrocardiogram and cardiac magnetic resonance imaging showing inflammation and left ventricular wall functional abnormalities.
Case Reports: We present two cases of CD identified in a single hospital in the Southeastern United States. Case 1 presents a patient with symptoms of anginal chest pain and associated shortness of breath with myocardial involvement suggestive of ischemic infarction but normal coronary arteries. Case 2 describes a patient with no physical symptoms and echocardiogram with ejection fraction of 50% with posterolateral and anterolateral wall hypokinesis but normal coronary arteries.
Conclusion: With a growing number of immigrants from Central and South America in the United States, it is imperative for clinicians to include CD as part of the differential diagnosis for patients presenting with heart disease who have a history of exposure to T. cruzi endemic areas.
INTRODUCTION
Discovered in 1909 by Carlos Chagas, Chagas disease (CD) is caused by the parasite Trypanosoma cruzi. The disease is estimated to affect 6-7 million people worldwide annually. Although CD occurs mainly in Latin America, it has been increasingly detected in the United States, Canada, Europe, and the Western Pacific countries in the past decades with >300,000 cases in the United States alone. CD is associated with the highest mortality and morbidity caused by a parasite in the Western Hemisphere. Up to 30% of chronically infected people develop cardiac alterations, and up to 10% develop digestive, neurologic, or mixed alterations.1 In 2012, 21 million Latin Americans resided in the United States, representing more than half of the foreign-born population.2 From 2000 to 2010, the representation of Latin Americans in the state of Louisiana's population increased from 2.4% to 4.2%.3 Therefore, the importance of addressing the concerns of immigrants with chronic CD has become paramount. We report two cases of patients with CD who presented to our hospital.
CASE 1
A 60-year-old Hispanic male, a native of Guatemala who had recently immigrated and had lived previously under a thatched roof, presented with symptoms suggestive of anginal chest pain and associated shortness of breath. He had an elevated blood pressure of 170/103 mmHg with a soft systolic murmur at the apex with radiation to the axilla. Significant laboratory data included brain natriuretic peptide (BNP) of 385 pg/mL and a peak troponin I level of 0.07 ng/mL. His transthoracic echocardiogram demonstrated an ejection fraction of 35% with mild mid inferolateral hypokinesis. Left ventricular internal diastolic dimension measured 5.9 cm, and a normal septal wall thickness was noted. Coronary angiography showed no coronary artery stenosis. During his hospitalization, the patient demonstrated various conduction abnormalities, including a left anterior fascicular block with nonspecific ST segment and T-wave abnormalities (Figure 1). Telemetry monitoring revealed a transient episode of idioventricular rhythm (Figure 2). Chagas antibody titers were positive for immunoglobulin (Ig) G, confirming CD as an etiology of the patient's nonischemic cardiomyopathy.
CASE 2
A 62-year-old female, a native of Honduras who grew up under a thatched roof and had lived in New Orleans for >20 years, presented with atypical chest pain lasting >2 weeks with no exertional component. Her blood pressure was 124/68 mmHg with no pertinent positive findings. Laboratory evaluation showed a troponin I level of 1.8 ng/mL, creatine kinase (CK) of 265 U/L, an MB fraction >20% of total CK, and BNP of 71 pg/mL. Chest x-ray was unremarkable, but echocardiogram revealed an ejection fraction of 50% with posterolateral and anterolateral wall hypokinesis. Her coronary angiogram was normal. A Chagas titer showed reactive IgG antibodies to T. cruzi with nonreactive IgM.
TRANSMISSION OF CD
T. cruzi uses an insect vector of the Reduviidae family and Triatominae subfamily, most commonly Triatoma infestans, Rhodnius prolixus, and Triatoma dimidiata. Triatomines are typically found in poorly constructed housing in rural areas, particularly in houses with cracked mud walls and thatched roofs. Triatomines emerge at night and feed on, defecate on, and inoculate humans.4 T. cruzi, a protozoan parasite, causes CD by releasing trypanosomes in the insect vector's feces at the bite wound on the host skin or mucosal membrane, thus leading to trypanosomiasis. Transmission of CD can also occur via blood transfusion, placental transport, organ transplantation, and laboratory accidents.
STAGES OF CD
CD consists of acute and chronic stages. The initial acute stage of infection with T. cruzi lasts 4-8 weeks with self-limiting febrile illness.5,6 Many patients are asymptomatic and do not experience Chagas-like symptoms.4 In those with symptoms, symptoms occur approximately 1 week after infection with the parasite; the interval may be longer if the infection is the result of a blood transfusion. A triatomine bite produces a local skin erythema and edema called chagoma.6 Severe symptoms of the acute phase include fever, myalgia, diaphoresis, hepatosplenomegaly, and myocarditis. If the portal of entry is the mucous membrane of the eye, local swelling occurs called the Romaña sign.4 The electrocardiogram (ECG) could show sinus tachycardia, first-degree atrioventricular block, low QRS voltage, or primary T-wave changes. Mortality at the acute stage is 5%-10%.6 Manifestations of acute disease resolve in 90% of infected patients even without trypanocidal drug treatment.6
The chronic phase of CD appears 10-30 years after the initial infection and lasts a lifetime.6 Sixty to seventy percent of CD patients have the indeterminate form of chronic CD, defined as positivity for antibodies for T. cruzi in the serum; normal 12-lead electrocardiogram; and normal radiographic imaging of the chest, esophagus, and colon.5,6 The remaining 30%-40% of CD patients develop a determinate form of chronic CD that consists of principally cardiodigestive manifestions.4,6 The digestive form is primarily seen in southern South America and consists of megaesophagus and megacolon.4 Cardiac manifestations can present as congestive heart failure, arrhythmias, or thromboembolic events. Common ECG abnormalities include right bundle branch block, left anterior fascicular block, ventricular premature beats, ST-T changes, abnormal Q waves, and low voltage of QRS. The presence of right bundle branch block suggests Chagas cardiomyopathy (CC).7
The most common cause of death in patients with CD is sudden cardiac death, accounting for 55%-65% of deaths.8 Heart failure (30%) and thromboembolic events (15%) are other CD-related causes of death.8
DIAGNOSIS OF CD
The evaluation of a patient with the potential diagnosis of CD should start with a medical history that includes questioning for potential T. cruzi exposure in endemic areas, living infrastructure, and previous blood transfusions, focusing on symptoms suggestive of cardiac arrhythmias, early congestive heart failure, and gastrointestinal tract disease.5 Then, patients should receive a thorough physical examination and a resting 12-lead ECG with a 30-second lead II rhythm strip, an echocardiogram, and possibly magnetic resonance imaging (MRI) if echocardiogram is abnormal.5
Signs and symptoms suggesting a diagnosis of Chagas myocarditis (CM) include syncope, ventricular dysfunction, ventricular tachycardia on resting ECG, severe sinus node dysfunction, and high-degree atrioventricular block.5 Chest pain is another concerning symptom requiring evaluation for ischemia and, if ischemia is absent, evaluation for a noncardiac etiology, particularly esophagitis.5
Diagnosis of CD is confirmed through various tests depending on the stage of disease. In the acute phase, direct microscopy of the trypomastigotes through examination of fresh blood or buffy coat is used.6,7 Testing for the presence of antibodies for IgG is performed during the chronic phase of the disease by conventional serology, enzyme-linked immunosorbent assay, indirect hemagglutination test, indirect immunofluorescence testing, or indirect parasitologic methods.9 Detection of antigens requires two of these methods to confirm diagnosis. Polymerase chain reaction is not helpful in routine diagnosis.6 Cardiac scintigraphy can help detect perfusion defects that reflect microvascular ischemia or fibrosis.5
Imaging studies including ECG and MRI indicate the presence and severity of myocardial involvement. During the acute phase of CD, pericardial effusions and segmental left ventricular wall motion abnormalities can be seen. Left ventricular systolic function is usually normal in the acute phase. In the intermediate stage of CD, ECG findings are also usually normal.
Tissue Doppler imaging has shown that patients with the indeterminate form of chronic CD and normal echocardiograms have increased isovolumetric relaxation time and deceleration time of mitral flow compared to non-CD patients.10 Cardiac MRI is used to evaluate wall motion abnormalities, particularly in the right ventricle. Apical left ventricular aneurysms are visible in the cardiac MRIs of approximately half of symptomatic patients.7 In addition, measurement of BNP can provide clues to the extent of myocardial involvement. Talvani et al have shown that BNP levels >60 pg/mL have a 91.7% sensitivity and 82.8% specificity for detecting left ventricular dysfunction associated with CC.11
PATHOLOGY OF CD
The pathogenesis of the disease involves more than isolated parasitic cellular damage. At the microcirculatory level, CD is characterized by vasodilation and vasoconstriction. Murine models show microcirculatory derangements with thrombi in coronary arteries leading to ischemia.12 Chagasic hearts show focal distribution of cell necrosis followed by reparative interstitial fibrosis. Histologic examination shows destruction of myocardial cells, diffuse fibrosis, monocellular cell infiltration, and scarring of the conduction system.6 The histologic findings help explain some of the aforementioned ECG abnormalities.
In the acute phase of the disease process, significant parasitic burden in the myocardium results in intense and diffuse myocarditis.13 Trypomastigotes invade endothelial cells, vascular smooth muscle cells, and the interstitial areas of the vasculature and myocardium of the cardiac myocytes.7 Examination of nonparasitized myocardiocytes also demonstrates isolated necrosis, suggesting an autoimmune process.13
Chronic CD is a progressive disease. In the chronic phase, T.cruzi genetic material is still present in the hearts of patients.12 Although clinically silent, myocarditis is present in chronic patients as suggested by experimental models.12 Chronic CD is also characterized by an exacerbated helper T-cell type 1 immune response producing more interferon (IFN)-γ and less interleukin-10, suggesting that IFN-γ has a role in CC.12 Parasite persistence can be lowered by trypanocidal treatment.12
An autoimmune relationship seems to exist in CC, as evidenced by the fact that sera from patients with CD contain autoantibodies specific for various autoantigens.10 In addition, in patients with chronic CD, studies have shown cross-reactivity between human and T. cruzi proteins, particularly the human cardiac myosin heavy chain and T. cruzi protein B13.12 The immunohistopathology of CD is still an area of uncertainty.
TREATMENT OF CD
The Rassi score is a well-validated tool for predicting total mortality.14 Risk factors include Class III or IV heart failure (5 points), cardiomegaly (5 points), segmental or global motion abnormality (3 points), nonsustained ventricular tachycardia (3 points), low QRS voltage (2 points), and male sex (2 points). High risk (12-20 points) indicates a 5-year mortality of 63% and 10-year mortality of 84%, while low risk (0-6 points) indicates a 5-year mortality of 2% and a 10-year mortality of 10%.6
CC is a chronically progressive disease. Clinical left ventricular systolic dysfunction should be treated as systolic heart failure of any etiology with angiotensin-converting enzyme inhibitors, beta blockers, aldosterone receptor antagonists, possibly hydralazine/nitrate, and diuretics as needed.15 However, a metaanalysis of two randomized clinical studies assessing the effect of carvedilol for treating symptomatic heart failure in patients with CC, irrespective of left ventricular ejection fraction stage, showed a lack of evidence for the effects of carvedilol.16
Because of the high prevalence of sudden cardiac death in patients with CD, evidence supports the use of implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden death.8,15 In addition, amiodarone may prove to be an effective adjunct to prevent sudden death in high-risk subjects who already have ICDs.15 Amiodarone's effectiveness is being further investigated in an upcoming clinical trial.15
An infectious disease physician should evaluate and treat patients with suspected CD. Strong evidence (grade A recommendation according to the Infectious Diseases Society of America [IDSA]) supports administering antitrypanosomal drugs to treat acute T. cruzi infection, early congenital T. cruzi infection, reactivated T. cruzi infection in an immunosuppressed individual, and chronic T. cruzi infection in children <18 years.5 Although no definitive studies confirm the cure rate with treatment, a 70% cure rate has been suggested in the acute phase, and a <10% cure rate has been suggested in the chronic stage.5,7 The Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial aims to determine whether continued use of benznidazole and nifurtimox is an effective treatment for chronic CD.17
DISCUSSION
As represented in our cases, CD has a wide variety of symptomatic presentations, so including CD in all differential diagnoses for patients from endemic areas with suspected cardiac involvement is critical. Case 1 is an example of typical CM with segmental wall motion abnormalities, conduction abnormalities noted on ECG, and left ventricular systolic dysfunction but no ischemia. Case 2 represents an earlier stage of chronic CD, again with evidence of myocardial involvement but with only a mildly reduced left ventricular ejection fraction. Because of the nature of the signs and symptoms in both cases, serologic antigen tests were indicated. In both of these cases, myocarditis was demonstrated by abnormal cardiac enzymes confirming myocyte damage with resulting wall motion abnormalities.
Based on the previously mentioned IDSA recommendations for CD noted in Bern et al, both of these patients did not appear to have an absolute indication for antitrypanosomal drugs.5 The likely diagnosis of CD in both of these patients is doubly important, not only for the diagnosis itself but also for the consideration of ICDs if cases similar to ours arise in the future.
We had a possible third patient with identifiable coronary artery disease who initially tested positive for T. cruzi in screening but was declared negative for CD after repeat testing.
Since 1991, the estimated global prevalence of CD has actually decreased from 18 million to 6-7 million.18 However, with the increasing immigration of Latin Americans to the United States and the Latin American population having doubled in Louisiana, the prevalence of CD is increasing significantly in Louisiana and the Southeastern United States.2,4 The Centers for Disease Control and Prevention (CDC) and the Bern and Montgomery study estimate that the prevalence of chronic CD in the United States is now >300,000.19,20 The CDC considers CD one of the five most neglected parasite infections.19 Ninety percent of acute cases are asymptomatic, and the triggering of the chronic phase of CD is also asymptomatic. Consequently, most patients with CD are unaware that they have CD.
More concerning is that healthcare providers seem to have a knowledge gap with regard to CD as a potential diagnosis; 29%-60% of physicians surveyed by Stimpert and Montgomery had never considered the risk for CD in their patient population.21 Many of the diagnostic tests currently available have low sensitivity, making clinical suspicion and diagnostic persistence essential to accurately diagnosing CD.22 Other important infectious causes to consider include viral etiologies such as coxsackie B virus; other neglected tropical diseases such as leishmaniasis, trachoma, and dengue; and other bacterial organisms that can cause cardiomyopathy such as Borrelia burgdorferi.23,24
CONCLUSION
CC may exist in the presence of more common causes of cardiomyopathy such as coronary artery disease and hypertension, but identifying the multifactorial etiology of the disease process is critical to offer optimal therapy. The patient in Case 1 presented with hypertension, suggesting that the diagnosis could have been hypertensive cardiomyopathy with systolic dysfunction. However, the identification of CC indicated the need for a very different therapeutic approach. Consequently, it is important to keep CD as part of the differential diagnosis in patients presenting with cardiac disease with a history of exposure to T. cruzi endemic areas.
This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care and Medical Knowledge.
ACKNOWLEDGMENTS
The authors have no financial or proprietary interest in the subject matter of this article.
- © Academic Division of Ochsner Clinic Foundation