These insects belong to the order Hemiptera, family Reduviidae, and subfamily Triatominae. They are widely distributed in tropical and subtropical regions on the American continent, from south of the United States down to the northern and central regions of Chile and Argentina. Sixteen genera and more than 130 species have been described, as reported by the World Health Organization (WHO) (2002: i–vi, 1–109). These hematophagous insects lay up to 200 eggs during their lives (around 24 months), and evolve through five nymphal stages (Nymphs 1, 2, 3, 4, and 5) from egg hatching until reaching the adult stage (Figure 3). Triatomine bugs are obligate blood feeders from birth. Once infected with T. cruzi from an infected animal or human being, the insect keeps the T. cruzi in its intestine for life.
For the greater than 100 proven vectors, and potentially vector species, the ecological conditions that influence the parasite transmission pattern vary widely. Some vectors are exclusively domiciliated, such as T. infestans and Triatoma rubrofasciata. The situations of the other species of triatomae are shown in Table 1.
The most important species of the triatomidae transmitting T. cruzi to human beings are: T. infestans, Triatoma brasiliensis, Triatoma pseudomaculata, Triatoma sordida, Panstrongylus megistus, Triatoma dimidiata, and Rhodnius prolixus. The geographical distribution of the area of risk transmission of T. cruzi is shown in Figure 4.
Transmission Routes And Biological Cycle
In endemic zones, T. cruzi is mainly transmitted through the Triatominae vector. Other frequent transmission routes are blood transfusions due to the existence of infected donors who are unaware of their infection status. Congenital transmissions take place during gestation although it also can occur rarely during delivery. In organ transplants, transmission occurs when a donor is infected with T. cruzi; transmission is facilitated by the immunosuppression to prevent rejection of the transplanted organ. Other nonvectorial transmission is accidental transmission, which occurs when manipulating lab material infected with T. cruzi, accidents suffered by surgeons or other health workers, as well as transmission risk of injecting drug users sharing needles. Oral transmission caused by contaminated food and drink has been reported in sporadic human microepidemics in Brazil (Shikanai-Yasuda et al., 1991).
Epidemiology
In the Americas, there are approximately 16 million patients with chronic CD. This is a zoonosis that constitutes the fourth largest tropical disease burden only after malaria, tuberculosis, and schistosomiasis, as reported by Moncayo (2003).
The vectors of T. cruzi are much more widely spread than human cases of infection. Triatominae distribution is not limited to the American continent, where the presence of vectors, either actual or potential, was delimited between latitude 40 north and latitude 45 south. Specimens have been found at altitudes of up to 3000 meters above sea level. Natural human transmission of the disease has been observed from south of the United States, where several cases have been reported, down to the province of Chubut, Argentina. Vectorborne transmission in different areas is related to insect feeding and defecation habits, insect genetics and population dynamics, and infectivity of parasites.
The limits of the areas where the disease occurs, or where its transmission is endemic, are determined by or dependent on natural – primarily economic – variables. In Carlos Chagas’ own words, ‘‘this sanitary problem offers practical difficulties, all of economic order. The problem is linked to development, work, agriculture prosperity, soil settlement’’ (Chagas, 1909). As a consequence, disease distribution is often focal, although there can be extensive geographic areas with risk of transmission in homes, especially in areas of widespread, low income and limited social services.
Since the 1950s and 1960s, studies have shown a close correlation between infestation with triatomine bugs, the prevalence of T. cruzi infection, and heart disease, which can be attributed to CD, as described by Rosenbaum and Cerisola (1961). Additionally, because of increasing migration, no region is exempt from the occurrence of local transmission caused by blood transfusion, congenital transmission, organ transplantation, or by the use of needles shared by injecting drug users.
Cardiomyopathy secondary to T. cruzi infection is the most common form of nonischemic cardiomyopathy worldwide. The most recent figures provided by the WHO indicate that 40 million persons are exposed to infection, approximately 200 000 new cases occur per year, 16 million persons are currently infected, 20 to 30% of infected individuals will eventually develop cardiomyopathy, and 21 000 persons will die each year from CD.
Transmission of T. cruzi by blood transfusion results in the presence of trypomastigotes, albeit in low numbers, in a large number of persons in the chronic stage of CD. Transmission is possible through transfusion of whole blood as well as through blood components, such as platelets, leukocytes, frozen plasma, and cryoprecipitates. In the Southern Cone countries, approximately 6 million persons donate blood every year. According to Schmunis et al. (1998), in countries participating in the Southern Cone Initiative, the risk of transmission via donation of blood products varied from 219 out of 10 000 in Bolivia, 49 out of 10 000 in Peru, and 2–24 out of 10 000 in other countries. Donor selection and quality assurance in diagnostic tests used for screening donors account for varying numbers of transfusion-associated cases (Cura and Segura, 1998).
Due to an increase in the number of serologically screened blood donors and deferral of infected donors, as well as in the number of homes treated with insecticides in Argentina, Brazil, Chile, Uruguay, and Paraguay, there has been a steady decrease in the prevalence of positive serology for T. cruzi in blood collected in blood banks. In these countries, there also has been a decline in the number of infected pregnant women when compared to historical data. In other endemic countries, the prevalence of T. cruzi in pregnant women varies from 5 to 40%, depending on the geographical area. Migrations of persons from rural areas to areas surrounding the cities, where triatomines are not found, have facilitated detection of congenital T. cruzi infection because transmission by vectors can be ruled out. Although presumptive diagnosis of congenital infection can be made on clinical and epidemiological grounds, a case can be confirmed as congenital only if: (1) the baby is born from a mother with T.cruzi infection, and (2) either parasites are identified at birth, or specific antibodies are detected at birth, and such antibodies persist after 6–10 months of life or otherwise can be shown to originate in the infant and not the mother (Blanco et al., 2000). When antibodies are detected in a child born in a nonendemic area of a seronegative mother, transfusion-associated transmission must be ruled out.
In the Southern Cone countries the transmission rate of congenital T. cruzi infection, that is, the number of congenital cases/mothers infected with T. cruzi, varies widely, ranging from 1 to 12%. These differences have been discussed at length and attributed to possible special characteristics of the infecting parasites; differences in the host’s immunological, genetic, or nutritional status; specific epidemiological situations; or the different methodologies used for detection of congenital cases. PCR (polymerase chain reaction) is an efficient tool for diagnosis of infection in a newborn from a T. cruzi-infected mother, as demonstrated in Paraguay by Russomando et al. (2005).
In most studies of the last 20 years, congenital infection in most cases was asymptomatic. However, the Bolivian report of Torrico et al. (2004) indicates that symptomatic cases accounted for about 50% of overall congenital cases, and infected infants have a mortality rate of 6%.
Immunity To T. Cruzi
At the beginning of the infection, trypomastigotes deposited on the injured skin or on the mucous membranes enter macrophages and stimulate a local inflammatory reaction, the inoculation chagoma and/or Roman˜ a’s sign. Both the inoculation chagoma and Roman˜ a’s sign are specific to CD in its acute stage, although they occur in less than 5%.
Parasites invade macrophages at the site of inoculation, replicate as amastigotes, transform to trypomastigotes, and are released into the bloodstream from where they invade cells in the liver, spleen, lymph nodes, and skeletal and cardiac muscle (Figure 5). Replication of amastigotes in the myocardium leads to acute myocarditis with lymphocyte-monocyte infiltration, mediated by T CD4+ and CD8+ cells and IL2 and IL4 cytokines. The chronic inflammatory reaction leads to muscular and neuronal destruction, and is maintained by the presence of T. cruzi or T. cruzi fragments. The inflammatory reaction, damage to the microcirculation, and fibrosis cause chronic myocardial dilation, congestive heart failure arrhythmias, dysperistalsis, megaesophagus, and megacolon. Prevalence of these two last clinical conditions is lower in Argentina and Uruguay than elsewhere in the Southern Cone, but neither occurs in infections acquired north of the Amazon.
The presence of two developmental stages of T. cruzi in mammalian hosts provides two anatomically and antigenically distinct targets of immune detection: the trypomastigotes in the bloodstream and the amastigotes in the cytoplasm of infected cells. Thus, it would be expected that immune control of T. cruzi might require a combination of different immune responses effective against these stages, and experimental data provide strong evidence for this. At a minimum, the generation of a substantial antibody response, and the activation of both CD4+ and CD8+ T cell compartments are needed to prevent death from an overwhelming acute parasitemia as demonstrated by Tarleton et al. (1996). Additionally, these same responses are probably required to maintain control of T. cruzi during the chronic phase of the infection. The evidence for the latter comes from experimental models and natural human infections in which targeted depletions of immune cells, immunosuppressive treatments, or infection-induced immunosuppression result in an exacerbation of a chronic infection.
Three factors are likewise associated with the development (or not) of severe disease: (1) parasite burden, (2) effectiveness of the host immune response in controlling parasites in specific tissues, and (3) effectiveness of the host immune response in controlling damage to tissues. Parasite burden is, in turn, largely dependent on how effective the host immune response is in killing parasites or limiting parasite replication. When immune control is inefficient, parasite load and also inflammation – and therefore the potential for tissue damage – increase.
In the past, many investigators believed that Chagas’ heart disease was the consequence of an autoimmune process. However, the results of immunosuppression on CD are contrary to what would be predicted if CD were an autoimmune disease; immunosuppression should reduce the disease severity, but paradoxically, inflammation increases despite immunosuppression. It is possible that the effects of induced immunodeficiency regarding the development of CD may represent an accelerated and intensified version of what happens in the minority of T. cruzi–infected patients who develop severe acute CD; when one effector arm of the immune response is blocked or even suboptimal in efficiency, a compensatory but less effective and therefore potentially more damaging immune response takes its place.
There are no data that can absolutely rule out autoimmunity as having a role in disease development and being a primary cause of pathology. One area of agreement reached in recent years is that parasite persistence is required for the damage to occur. Whatever its triggering mechanism, one goal seems clear: patients will benefit from a reduced parasite burden. It is clear that this cannot be achieved by targeting autoimmunity as the problem in CD. A reduction in parasite burden can be achieved not only through the discovery and implementation of better chemotherapeutics, but also with the use of immunologicals, including therapeutic vaccines, to enhance host immune control of the infection.
Chronic T. cruzi infection results in tissue-specific damage focused primarily in the gut and heart and associated with the persistence of parasites in these disease sites. Tissue-specific control of T. cruzi infection is evidenced by Postan et al. (1983), early in the acute infection stage and is even more obvious in the chronic stage, with persistence of parasites most commonly restricted to muscle and, to a lesser extent, the central nervous system (CNS). It is not at all clear what factors allow for parasite clearance from some tissues but not from others. Parasite strain-specific factors almost certainly contribute. But it is unlikely that tissue restriction is due solely to differential tropism of distinct strains as parasites are widely distributed in most if not all tissues and organs early in the infection, before the full development of B and T cell responses. More likely, the tissue-specific persistence of T. cruzi in the chronic infection is related to qualitative and quantitative aspects of the local immune responses in these tissues.
Better knowledge of the immune response to the parasite will provide a basis for diverse approaches to vaccine development including: identification of the target molecules as potential vaccine target candidates, a therapeutic vaccine for T. cruzi, and/or transmission blocking vaccine for T. cruzi.
Pathophysiology
Organ damage arising during the acute phase is closely related to high-grade parasitemia and parasite presence in target organs (i.e., gastrointestinal tract, CNS, and heart). As the parasitemia abates and the systemic inflammatory reaction subsides, silent, relentless focal myocarditis ensues during the indeterminate form of CD. In predisposed hosts, encompassing approximately 20–30% of the infected population, this chronic myocarditis evolves to cumulative destruction of cardiac fibers and marked reparative fibrosis.
Apart from the possible ancillary role of neuronal depopulation and microvascular derangements as mechanisms of myocarditis, evidence gathered from physiopathological studies in animal models and in humans is consistent with two prevailing hypotheses to explain the pathogenesis of chronic CD: (1) T. cruzi infection induces immune responses that are targeted at host tissues and are independent from the parasite persistence (the so-called autoimmune hypothesis), and (2) parasite persistence at specific sites in tissues of the infected host results in chronic inflammatory reactions (the parasite persistence hypothesis)