Introduction
Chagas disease is a systemic parasitic infection caused by the protozoan Trypanosoma cruzi, which persists as an important public health problem, mainly in Latin America where triatomine vectors are located in three overlapping cycles of transmission: domestic, peridomestic, and sylvatic. Due to human migration from endemic to developed countries, in recent years Chagas disease has become a recognized global problem. This topic reviews current literature on chagasic cardiomyopathy, its etiology, epidemiology, immunology, and diagnosis, along with etiologic and symptomatic treatment and prognosis.
Etiology
One-hundred years after the discovery of Trypanosoma cruzi (Family: Trypanosomatidae, Order: Kinetoplastida) by Carlos Chagas in Brazil, many aspects of its biology and host relationship remain unraveled. The substantial biological, biochemical, and genetic variability of this parasite, as well as the multiclonal T. cruzi infection character are some of the factors that have hampered its study. T. cruzi is considered to have a clonal structure with some overlapping events of genetic exchange occurring in the past that have brought about the six currently recognized Discrete Typing Units (DTUs) I to VI. Moreover, within each DTU biological and genetic polymorphism is present, especially in DTUs I and III. The scenario is even more complicated. Recent reports showed that multiple genotypes were obtained when isolates from a single wild mammalian reservoir host were cloned (Llewelyn et al., 2011). The authors proposed that this huge diversity is at least, partially driven by the survival in the host. Nonetheless, significant progress has been achieved with the unveiled T. cruzi genome and the following OMICS initiatives such as RNAomic and proteomic analyses, which seek to apply translational medicine to Chagas disease in the near future.
Life cycle
T. cruzi exhibits a complex life cycle involving four well-defined developmental stages that interplay into two hosts, the blood-sucking insect vector, and the mammalian host (humans and animals). After already-infected insects feed on the mammalian host, they eliminate in their feces the metacyclic trypomastigotes (parasite infective form), which penetrate the body through the bite-wound, any damaged tissue, or the mucosa from eyes, nose, or even the digestive tract and invade host cells like fibroblasts, macrophages, and epithelial cells at the inoculation site. In the cytoplasm, free-parasites are differentiated into amastigotes (Fig.1A), the intracellular stage, which after several replication rounds transforms back into trypomastigotes that rupture the host membrane cell, infecting new cells or disseminating into other organs via the bloodstream.
Fig. 1. (A) Intracellular amastigotes of T. cruzi-infecting Vero cells, (B) Trypomastigotes, and (C) Epimastigotes stained with Giemsa.
Upon feeding, insects take the bloodstream trypomastigotes (Fig. 1B), which once in their digestive tract differentiate into epimastigotes, the insect replication stage (Fig. 1C). After reaching the rectum, parasites transform into metacyclic trypomastigotes ready to infect a new mammalian host. From this cycle, it is obvious that the differential expression of parasite genes enable the parasite to accomplish the role played by each of its developmental stages. In this sense, several proteomic studies have been performed to identify molecules participating in cycle-vital processes (Ulrich et al., 2011).
Epidemiology and risk factors
Burden of Chagas disease
An estimated 10-million people are infected worldwide, mostly in Latin America where Chagas disease is endemic. More than 25-million people are at risk of contracting the disease. It is estimated that in 2008 Chagas disease killed >10,000 people. With a latency of 10-30 years, nearly 30% of infected patients develop life-threatening complications, mostly Chagas heart disease (CHD) (WHO, 2010). Direct and indirect costs of T. cruzi infection impose an overwhelming load on healthcare systems secondary to hospitalizations and medical and surgical treatments for CHD, gastrointestinal dysfunction, and meningoencephalitis in Latin America (Franco-Paredes et al., 2007). In 1995, the burden of Chagas disease in Latin America was estimated at US$8.156-billion, equivalent to 2.5% of the foreign debt of continental Latin America (Moncayo, 2003). More recent data demonstrate that, globally, Chagas disease is associated with 0.7-million disability-adjusted life years, constituting the sixth most important neglected tropical disease worldwide (Hotez et al., 2006).
Globalization of Chagas disease
Political and economic situations have stimulated the flow of migration from the 17 Latin American endemic countries to the developed ones (Schmunis & Yadon, 2010). Because of this and parasite transfer by blood contact, intrauterine transfer, laboratory accidents, and organ transplantation; CHD could potentially become a worldwide problem (WHO, 2010) and emerge as a public health issue in non-endemic countries (Field et al., 2010). Currently, in the United States it is estimated that from more than 22 million of immigrants from endemic countries there are approximately 300,000 infected individuals (Bern & Montgomery, 2009). In 15 European countries in 2005, excluding Spain, 2.9% of the 483,074 legal Latin American immigrants were estimated to be infected with T. cruzi. By 2008, Spain had received 1,678,711 immigrants from Latin American endemic countries; of these, 5.2% were potentially infected with T. cruzi and 17,390 may develop Chagas disease. Likewise, in an analysis of Chagas disease in Spain, most patients were from Bolivia (94.7%) and less from Brazil, Chile, Ecuador, Paraguay, and Honduras (Norman et al., 2010). Other countries outside Europe, where the rates of Latin American immigration are high and present an important prevalence of Chagas disease are Australia, Canada, and Japan (Schmunis & Yadon, 2010).
Chagas heart disease in endemic countries
Triatomines, the T. cruzi vectors, are spread from the south of the United States to the south of Argentina. The rarity of vector-borne transmission in the United States, compared with Latin America, is thought to be the result of better housing conditions and lower efficiency of North American vectors (Bern & Montgomery, 2009). In Latin America, there are more than 125 potential vectors of Chagas disease. However, species with higher vectorial capacity, with domestic habits and with the most geographical distribution belong to Triatoma, Rhodnius, and Panstrongylus genera. For these reasons, there are different targets in control programs of vectors depending on regions. Thus, the Mexico and Central America Initiative (created in 1998) is focused in the control Rhodnius prolixus, Triatoma dimidiata, Triatoma barberi, and Rhodnius pallescences; the Initiative of the Andean Countries (created in 1997) is aimed at controlling R. prolixus, T. dimidiata and Triatoma maculata; and finally, the Initiative of the Southern Cone (created in 1991) is aimed at controlling Triatoma infestans, Triatoma brasiliensis, Triatoma sordida, and Panstrongylus megistus (Guhl, 2009). The main risk factors for vector-borne transmission are related to previous exposure to poor housing conditions in Latin America (Fig. 3), such as: palm or straw roofs, dirt floors, adobe walls or walls with low quality or incomplete plastering, and the presence of animals inside the bedroom.
Fig. 2. Typical house in a Chagas disease endemic region, Departamento de Boyaca.
An important change has occurred in trends of Chagas disease in Latin America over recent decades. Such is recognized by several researchers, control policies of vector and blood of T. cruzi transmission have shown a positive effect in reducing the incidence of this disease. Thus, since the 1990s until now, an important success in the control of Chagas disease has been observed, especially in Southern Cone countries. So, in 1990, the distribution of Chagas disease in 21 countries was estimated, with more than 45,000 deaths per year and 30-million cases of human infection; while in 2006 the distribution of Chagas disease in 18 countries was estimated, with approximately 12,500 deaths per year and nearly 15-million cases of human infection (Dias et al., 2008). Success in controlling vector transmission in some countries has led to also to focus the attention to other forms of non-vector transmission. Thereby, controlling transmission by transfusion has improved and screening is now obligatory in most endemic countries. Congenital transmission has been detected as an important transmission form, mainly in Bolivia, but other endemic countries have only recently started to approach to this problem. Orally acquired human infection with T. cruzi has been known since the 1930s but has the interest in this transmision has increased as a result of the series of outbreaks that have occurred in the Amazon region, which have been associated with the preparation and consumption of some foods, especially in Brazil, Venezuela, and Colombia (Miles, 2010). The rural-to-urban migration movements that have occurred in Latin America since the 1970s and 1980s have changed the traditional epidemiological pattern of Chagas disease as a rural condition and transformed it into an urban infection that can be transmitted via non-vector manners (Moncayo & Silveira, 2009). Moreover, in some countries the vector infestation has occurred in urban areas where vectors have been introduced by passive transportation during migration process, for instance in Cochabamba, Bolivia (Medrano-Mercado et al., 2008), Arequipa, Peru (Bayer et al., 2009), and in Yucatan, Mexico (Guzman-Tapia et al., 2007). On the other hand, adults infected with T. cruzi from childhood form a transitional generation, experiencing the simultaneous impact of past infectious exposures and current cardiovascular risk factors, such as sedentary lifestyle, calorie-dense diets, hypertension, and diabetes. Other variables such as longer residence in an endemic province, residence in a rural area and poor housing conditions, male sex, and increased age have been found independent predictors of Chagas cardiomyopathy severity (Hidron et al., 2010).
Surveillance and health policy
In endemic countries, the tools to interrupt the domestic cycle of T. cruzi transmission, such as chemical control, housing improvement, and health education are the most useful methods to prevent Chagas disease (Moncayo & Silveira, 2009). Blood screening is vital to prevent infection through transfusion and organ transplantation and governments should implement policies to promote it (WHO, 2010). In addition, an infrastructure that assures detection and treatment of acute and chronic cases, as well as congenital infection should be developed. In non-endemic countries, screening programs in Latin American pregnant women are increasing and it has been proposed that in some non-endemic countries there is cost-effectiveness to develop it (Sicuri et al., 2011). Regarding strategies to reduce transmission by transfusion in non-endemic countries, there are two different approaches: one is the deferral of individuals at risk of Chagas disease and the second approach is to accept blood donations if specific laboratory assays are negative. This second approach is being introduced in countries where there is a substantial Latin American population, such as the United States, Spain, and France (Castro, 2009). Also, taking into account that knowledge about Chagas disease among doctors in non-endemic countries is very limited (Verani et al., 2010), strategies to improve awareness are very important in order to enhance treatment and follow up of cases.
Clinical presentation
Acute phase
The symptomatic acute phase could be present at any age but it is most common in children under 10 years of age. When the infection is acquired via vector, it takes four to eight weeks for symptoms to develop. In this phase there is an important inflammatory response in the site of contact with bug feces and T. cruzi may multiply locally (cutaneous chagoma when it is in the skin). The insect prefers the thinnest skin and that is why the best known sign is Romana’s sign which consists in a unilateral conjunctivitis with periorbital edema, eyelid edema and pre-auricular adenopathy (Biolo et al., 2010). In younger children (under 4 years of age) it is common to found the following symptoms: fever, malaise, muscle pain, anorexia, anemia, sweating, hepatosplenomegaly, heart failure from myocarditis, pericardial effusion, seizures, and somnolence secondary to meningoencephalitis, the more infrequent form of presentation (Gomez et al., 2007). The acute congenital disease should be considered by the medical care system staff in endemic areas; it could be asymptomatic or may be associated to prematurity, low weight, hepatomegaly, splenomegaly, jaundice, anemia, neonatal hepatitis, meningoencephalitis, sepsis, myocarditis, fever, and less frequently megaesophagus, megacolon, megabladder. Without treatment, mortality is 5-10%, the leading causes are encephalomyelitis and heart failure (Prata, 2001). Patients with HIV could reactivate the disease and have meningoencephalitis as a first manifestation (Carod-Artal, 2006). In patients with history of solid organ or bone marrow transplants, 30% reactivate Chagas disease, the acute manifestations could be myocarditis, panniculitis, subcutaneous parasite-containing nodules, and meningoencephalitis (Bern et al., 2007).
Chronic phase
Once the acute phase is resolved, it begins the chronic phase. This chronic phase could be asymptomatic lifelong or progressive heart and/or gastro esophageal disease. The chronic asymptomatic or indeterminate phase lasts 10 to 30 years. For some authors its definition means epidemiological contact, positive serologic tests, normal physical examination and normal radiological, electrocardiographic and echocardiography studies. Around 30% of these have progressive disease (Higuchi et al., 2003). When Chagas becomes symptomatic, depending on the geographic zone, the disease will have different signs and symptoms. In Central America and northern South America, the heart disease is the common manifestation, but in Brazil and Southern Cone countries it coexists with digestive syndromes (Miles et al., 2003). For the purpose of this review, we will focus on Chagasic cardiomyopathy. The earliest manifestations of heart disease are electrocardiographic abnormalities as the expression of the damage of the conduction system and the symptoms that the patients experience could be related to those abnormalities: atrioventricular block, sinus bradycardia, premature ventricular contractions, atrial fibrillation, and ventricular tachycardia. In 40% of patients with mild heart disease there could be non-sustained ventricular tachycardia, as well as in 90% of patients with heart failure. Sudden death occurs in 38% of patients with chronic disease with or without heart failure, meaning more severe heart disease. The principal cause of sudden death is the malignant ventricular arrhythmia followed by advanced atrioventricular block and cerebral emboli. Non-sustained ventricular tachycardia in Holter monitoring and in stress test, together with low ejection fraction, syncope and pre-syncope, sinus node dysfunction, history of recovery from cardiac arrest, and dyspnea NYHA class III or IV have been recognized of prognostic value in sudden death (Prata, 2001). Symptomatic heart failure occurs in some patients before there is any significant electrocardiography alteration. It could be right or left heart failure; it is very common for patients to have severe structural heart disease and not show symptoms of severe heart failure. It is also common to find severe congestive hepatic disease. Pulmonary and systemic emboli due to dilated chambers of apical aneurism are common clinical manifestations of chronic heart disease (Bern et al., 2007); they have been described in 40% of autopsies (Prata, 2001). A Brazilian study found four predictors of emboli complications: age > 48 years, primary changes in repolarization, apical aneurism, and ejection fraction < 50%, with a 4% annual incidence if all four factors where present (Sousa et al., 2008). Precordial pain is a frequent complaint of patients with Chagas disease. The incidence of this symptom is 15% but other authors report up to 30% (Marin-Neto et al., 2007). The causes of the symptom are not clear; some authors believe that this pain could be caused by microvascular disease.
Classification
A simple classification, published by the Brazilian Consensus on Chagas Diseases, includes functional capacity, electrocardiographic findings, function and size of left ventricle. This classification allowed defining four disease stages with the aim to orientate the patient’s therapy (Table 1).
|
Stage |
Electrocardiogram |
Echocardiography |
Heart failure |
|
A |
Altered |
Normal |
Absent |
|
B1 |
Altered |
Altered LVEF >45% |
Absent |
|
B2 |
Altered |
Altered LVEF <45% |
Absent |
|
C |
Altered |
Altered |
Compensated |
|
D |
Altered |
Altered |
Refractory |
LVEF: left ventricular ejection fraction
Table 1. Classification of cardiac compromise in Chagas chronic cardiomyopathy
Pathogenesis of cardiac disease during T. cruzi infection
Host genetic influence
Some works approach the influence of human genetics such as Histocompability Complex Molecules (HLA) or polymorphism in cytokine promoters and their contribution to Chagas disease. So far, association with HLA class II indicated that infected individuals with and without cardiomyopathy had a higher frequency of DRB1*01, DRB1*08, and DQB1*0501 (Fernandez et al., 1998), and the DRB1*01 DQB1*0501 haplotype was more frequent in patients with Chagasic cardiomyopathy (Colorado et al., 2000). Additionally, the HLA-DRB1*1503 allele was associated with genetic susceptibility to cardiac damage (Garcia Borras et al., 2009). All these studies were conducted with small cohorts and with different Latin American populations. Polymorphisms of cytokine promoters assess the potential pattern of cytokine hypo or hyper secretion in individuals. A study showed the association of transforming growth factor beta (TGFP1) (Calzada et al., 2009) and lymphotoxin a (LTa) with the risk Chagasic cardiomyopathy progression (Ramasawmy et al., 2007). Tumor necrosis factor (TNFa), a pro-inflammatory agent, is the cytokine with the strongest relationship to cardiac tissue damage in Chagas. There is an association between T. cruzi seropositive individuals and the polymorphism in TNF-238A. Indeed, TNFa secretion is higher in non-stimulated and stimulated cells from chronic Chagasic donors (Pissetti et al., 2011) and TNFa serum levels were associated with heart failure (Talvani et al., 2004). In T. cruzi experimentally infected rats, the cardiomyopathy ameliorates in animals treated with a TNFa blocking monoclonal antibody (Perez et al., 2009).
