pathology and pathogenesis of chagas disease

Authors

J Antonio

Marin-Neto, MD,

PhD, FACC

Anis Rassi, Jr, MD,

PhD, FACC, FAHA,

FACP

Section Editors

William J McKenna,

MD

Peter F Weller, MD,

FACP

Deputy Editors

Susan B Yeon, MD,

JD, FACC

Elinor L Baron, MD,

DTMH

Pathology and pathogenesis of Chagas disease

Disclosures

Last literature review version 19.3: Fri Sep 30

00:00:00 GMT 2011 | This topic last updated: Wed

Jun 09 00:00:00 GMT 2010 (More)

INTRODUCTION — Chagas disease (also known as

American trypanosomiasis) is produced by the

hemoflagellate protozoan Trypanosoma cruzi [1]. Chagas

disease is transmitted via the bite of the reduviid bug, also

known as the triatomine insect or "kissing bug". In Latin

America, recent estimates indicate an infection prevalence

of 13 million and an annual incidence of 200,000 cases in

15 countries [2]. Formerly considered a rural disease,

Chagas disease is now ubiquitous because of changes in

the social patterns in most countries, mainly a result of

rural-urban migration [3]. Chagas disease also occurs in

nonendemic areas where it may be acquired by blood

transfusion, congenital transmission and organ

transplantation [2,4].

The major morbidity associated with this disease is

threefold: cardiac disease, megaesophagus, and

megacolon. Cardiac involvement is characterized by

myocarditis and ultimately a dilated cardiomyopathy that

becomes evident years after infection. The infection can

cause greater morbidity in individuals co-infected with HIV.

The pathology and pathogenesis of Chagas disease will be

reviewed here. Cardiac and gastrointestinal manifestations

and the epidemiology and control of the infection are

discussed separately. (See "Clinical manifestations and

diagnosis of Chagas heart disease" and "Treatment and

prognosis of Chagas heart disease" and "Evaluation and

management of gastrointestinal Chagas disease" and

"Epidemiology and control of Chagas disease".)

PATHOLOGY — Pathologic findings develop in two stages

— acute and chronic. The acute phase lasts for four to eight

weeks after the initial infection. Subsequently, parasitemia

falls to undetectable levels and any acute clinical

Pathology and pathogenesis of Chagas disease Find

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INTRODUCTION

PATHOLOGY

Acute phase

Chronic phase

PATHOGENESIS

Megaesophagus and megacolon

Chronic Chagas heart disease

- Neurogenic mechanisms

- Parasite-dependent inflammation

- Microvascular disturbances

- Immune-mediated cardiac

damage

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Epidemiology and control of Chagas

disease

Evaluation and management of

gastrointestinal Chagas disease

Treatment and prognosis of Chagas

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evidence of organ damage on routine clinical evaluation

[5].

Several animal models of experimental Chagas disease

have been used to reproduce various stages of the disease

[6-9]. Endomyocardial biopsy has also been employed in

subsets of the chagasic population, including patients with

the indeterminate form of the disease [10,11].

Acute phase — Most patients infected with T. cruzi are

asymptomatic during the acute stage of infection. In a

minority, acute infection may be associated with a

persistent local reaction, or either Chagoma (swelling and

local lymphadenopathy) or for bites involving the orbit,

Romaña's sign (unilateral edema, conjunctivitis and

lymphadenopathy). Other pathologic changes during the

acute phase consist of cardiac, liver, or spleen enlargement

[12-14]. All four cardiac chambers may become dilated,

and pericardial effusion is common. Macroscopic signs of

inflammation are also detected in the meninges and central

and peripheral nervous tissues.

Microscopic examination shows intense parasitism in

virtually every organic system, with prominent

inflammatory changes in the vicinity of ruptured infected

cells (pseudocystis) [6-8,13-15]. Myocarditis is intense and

diffuse, showing myocyte necrosis, interstitial edema,

vascular dilation, and mononuclear and polymorphonuclear

infiltration (picture 1). Involvement may extend to the

endocardium, resulting in thrombus formation. The

conduction system is also involved, as well as the

intramural and extracardiac neuronal ganglia.

In the esophagus and colon, parasitism and inflammation

involve the smooth muscle and the neurons of Auerbach's

plexus. In addition, vasculitis has been noted in animal

models of the disease (picture 2) [6].

Chronic phase — Approximately 50 percent of infected

individuals develop cardiac and/or digestive forms of the

disease. Necroscopic examination in humans and in

experimental models typically demonstrate cardiomegaly,

megaesophagus, and megacolon; less frequent

manifestations include dilatation of the upper

gastrointestinal tract, ureter and bronchi [6-8,13-17].

In patients who die after the clinical onset of heart failure,

there is dilatation and an increase in cardiac weight

(usually 350 to 800 g). Dilation is usually more conspicuous

in the right chambers, and signs of systemic congestion

(ascites, hepatomegaly) predominate over lung congestion


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Although systemic infarcts are more common (primarily

involving the kidneys, spleen, and brain), deaths related to

pulmonary embolism are more prevalent [18]. (See

"Clinical manifestations and diagnosis of Chagas heart

disease".)

The most characteristic cardiac anatomic lesion is the

ventricular apical aneurysm which, in one series, was noted

in 52 percent of 1078 autopsied chagasic patients [19].

Even in the absence of a discrete aneurysm or left

ventricular enlargement, patients with Chagas

cardiomyopathy may have a left ventricular apical

deformation that results in disruption of the optimal global

prolate-ellipsoid shape [20].

Chagasic aneurysms are strikingly thinned (picture 3)

because they do not show the fibrosis usually seen in

aneurysms due to myocardial infarction, and they rupture

only in exceptional cases [19,21]. The typical apical

aneurysm has also been described in experimental models

of Chagas disease [21]. There is no relation between the

frequency of apical aneurysm and age or heart weight, and

aneurysms have been reported in patients who died

suddenly with no apparent previous clinical manifestations

of disease [16].

Histologic examination using the classic hematoxylin-eosin

staining reveals mild chronic myocarditis, manifested by

scattered mononuclear cells infiltrates with the surrounding

myocytes undergoing various stages of degeneration and

necrosis [13,15]. These changes do not seem to be related

to direct parasitism of myocardial cells, since intact

parasites are rarely detected in humans or in experimental

models of Chagas disease, when the examination is

performed with hematoxylin-eosin staining. However,

immunohistochemical techniques targeting anti-T. cruzi

antibodies show topographic correlation between these

findings and inflammatory foci [22,23]. T. cruzi genomic

fragments have also been identified with polymerase chain

reaction (PCR) methods in the areas of myocarditis, and T.

cruzi antigens have been detected by modern serologic

techniques in patients with Chagas disease [23-27]. Focal

and diffuse fibrosis is prominent, involving both the

myocardium and the conduction system [28]. Preferential

involvement of the right bundle branch and the left anterior

fascicle of the left bundle by inflammatory and fibrotic

changes explain the frequent occurrence of right bundle

branch block and left anterior fascicular block.

Microvascular changes consist of decapillarization,

interstitial edema, intravascular platelet aggregation and

thickening of the vascular basement membrane.


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Marked autonomic neuronal depopulation and nerve

degeneration, mostly in the cardiac, esophageal and colon

tissues, is another typical feature of chronic Chagas disease

[13,16,29]. However, there is no correlation between the

intensity of neuronal destruction and dilation of the organ

or other microscopic indices of myocarditis in the chronic

phase [16].

PATHOGENESIS — Target organ damage during the acute

phase is closely related to both high grade parasitemia and

direct tissue parasitism, mainly in the gastrointestinal tract,

central nervous system, and heart. Lymphadenopathy,

hepatomegaly, and splenomegaly are markers of

widespread immunologic reaction, probably exacerbating

tissue damage.

Megaesophagus and megacolon — Although direct

involvement of smooth muscle may be a contributory

factor, chronic digestive organ involvement in the chronic

phase is thought to result from sequelae of the neuronal

depopulation that primarily occurs in the acute phase

(picture 4) [13,30].

Chronic Chagas heart disease — The pathogenesis of

chronic Chagas heart disease remains obscure. However,

numerous clinical studies strongly support the hypothesis

that as the acute phase parasitemia and the systemic

inflammatory reaction subside, a silent focal myocarditis

persists during the indeterminate phase, with cumulative

destruction of cardiac fibers and reparative fibrosis. During

this period, ventricular arrhythmias and sudden death may

rarely occur as consequences of the underlying focal

inflammatory process [31]. The same process is eventually

responsible for progressive myocardial mass loss and

cardiac dilation that set the stage for the appearance of

malignant ventricular dysrhythmia.

Four mechanisms may contribute to the pathogenesis of

chronic Chagas heart disease: neurogenic mechanisms;

parasite-dependent inflammation; microvascular disease;

and immune-mediated injury.

Neurogenic mechanisms — In addition to the

extensive neuronal depopulation demonstrated in the

pathologic studies described above, there is a conspicuous

impairment of autonomic cardiovascular control and

peripheral and central chemoreceptor function in chagasic

patients at various stages of the disease [32-34]. Also,

studies using heart rate variability and other autonomic

tests found that parasympathetic dysfunction was present

in the early phases of Chagas disease and preceded left


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at the ventricular level and the degree of left ventricular

dysfunction, suggesting that the sympathetic innervation

disturbance could contribute to the progression of

myocardial damage [37].

A recent review on the pathogenesis of chronic Chagas

heart disease concluded that the neurogenic theory for

Chagas cardiomyopathy met several apparently unsolvable

conceptual obstacles [38]. Thus, it is unlikely that

autonomic dysfunction constitutes an essential pathogenic

mechanism for chronic cardiomyopathy because no

clear-cut correlation exists between the autonomic

derangement and the extent of left ventricular dysfunction.

Furthermore, no studies have shown that autonomic

impairment per se is prognostically important for chronic

chagasic patients. Nevertheless, neurogenic disturbances

may be a contributory factor to the complications of the

chronic phase of Chagas disease by triggering malignant

arrhythmia and sudden death, disturbing the coronary

microcirculation control, and potentiating the mechanical

consequences of ventricular dyssynergy [38].

Parasite-dependent inflammation — As noted above,

chronic Chagas disease is characterized by sparse

inflammatory infiltrates, minimal parasitemia, and

low-grade tissue parasitism. However, T. cruzi-related

antigenic materials have been identified in inflammatory

foci in biopsy and necropsy specimens of chronic chagasic

patients [22,23]. Although a possible relation between the

severity of these findings and the clinical course of the

disease remains to be defined.

An active and continuous role for the parasite in the

development of Chagas chronic cardiomyopathy is

suggested by the following observations:

Experimental models in which the tissue parasite

burden correlates with the intensity of the inflammatory

process [39].

Parasite load reduction by trypanocidal treatment leads

to attenuation of the intensity of the cardiomyopathy

process [39,40] and enhancement of parasite burden

results in exacerbation of the cardiomyopathy course

[41-43].

T cruzi genetic material could not be detected in the

heart from seropositive autopsied patients who had died

without signs of cardiac involvement, but was consistently

found in heart specimens from patients with chronic

Chagas cardiomyopathy [25].


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disease [44].

Circulating T. cruzi DNA could be detected with PCR in

subjects with well-defined Chagas disease; 86 percent of

these patients presented with chronic cardiomyopathy [24].

Microvascular disturbances — Several coronary

microvascular abnormalities have been reported in animal

models [45] and in limited studies in humans [33,37]. It

has been suggested that these changes might participate in

amplification and perpetuation of myocardial damage

associated with the inflammatory process [45]. Also,

abnormal reactivity to vasodilator and vasoconstrictor

stimuli has been reported in the epicardial coronary arteries

of chagasic patients [46]. Thus, It is possible that such

derangements are involved in the genesis of ischemic-like

symptoms, electrocardiographic changes, and perfusion

defects described in chagasic patients with angiographically

normal coronary arteries [33].

Longitudinal changes in LV myocardial perfusion and wall

motion abnormalities were examined in 36 patients with

chronic Chagas cardiomyopathy followed for a mean of 5.6

[47]. Reversible perfusion defects detected upon baseline

radionuclide myocardial perfusion imaging (rMPI)

evaluation were topographically correlated with new resting

perfusion defects at rest upon later study, indicating the

development of new areas of fibrosis with disease

progression. LV ejection fraction (LVEF) fell significantly

from 55±11 percent at baseline to 50±13 percent at

follow-up. Increase in resting perfusion defect with time

correlated with reduction in LVEF.

Immune-mediated cardiac damage — Immune-

mediated cardiac injury, primarily by the mononuclear

infiltrating cells, is probably an important mechanism

responsible for the development of chronic Chagas heart

disease (picture 2) [31]. The following observations are

compatible with this hypothesis:

A dominant autoantigen, which has been called Cha,

has been identified; Cha appears to contain both T and B

cell cross-reactive epitopes which can react with

autoreactive T cells from mice infected with T. cruzi [48].

Transfer of T cells from infected mice initiated anti-Cha

antibody production in the recipients, and these previously

naive animals developed cardiac pathology similar to that

found in T. cruzi infected mice.

In an animal model, cardiomyocytes infected with T.


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RANTES (regulated on activation normally T-cell expressed

and secreted) called met-RANTES reduces T cell infiltration

without interfering with parasitism [50].

A similar phenomenon has been described in mice that are

deficient in chemokine receptor 5 (CCR5) [51]. T-cell

infiltration into the myocardium markedly declined, but

susceptibility to infection was unchanged.

Ultrastructural studies in animal models have

demonstrated lysis of nonparasitized myocardial cells by

immune effector cells [52].

Depletion of the CD4+ T lymphocyte subpopulation

causes abrogation of myocardial injury in the murine model

of chronic Chagas disease [53]. On the other hand,

myocardial damage can be induced in nonchagasic animals

by passive transfer of CD4+ T cells from T. cruzi-infected

mice.

Whereas CD4+ T cells may cause myocardial injury,

CD8+ T cells appear to be lenient regarding the presence of

T. cruzi, but may be protective in respect to inflammation.

Thus, although mice depleted of CD8+ T cells have

exaggerated parasitemia, they show almost no

inflammatory infiltrates in parasite-infected tissues

following exposure to T. cruzi [54].

Crossreactivity between antigens of T. cruzi and cardiac

myosin heavy chain has been demonstrated, suggesting a

role for molecular mimicry. In one report, for example,

antibodies to the cardiac myosin heavy chain from sera of

patients with Chagas disease crossreacted with the B13

protein of T. cruzi in 100 percent of patients with chronic

cardiomyopathy versus only 14 percent of those who were

asymptomatic [55]. In another study, infiltrating T cell

clones from chronic chagasic heart lesions were responsive

to both cardiac myosin heavy chain and the B13 protein but

not other T. cruzi antigens [56].

In vitro sensitization of human peripheral lymphocytes

with B13 protein peptides elicited cardiac myosin–

cross-reactive T cell clones [57].

Sera from chronic chagasic patients with complex

arrhythmias, primarily the IgG fraction, reduced the heart

rate and induced atrioventricular block of perfused rabbit

hearts [58]. In contrast, sera from chagasic patients

without complex arrhythmias and from nonchagasic

patients had no effect.


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genome of humans, rabbits, and chickens [59].

In summary, it seems a plausible hypothesis that the

relentless myocardial degeneration in the chronic phase of

Chagas disease may result, at least in part, from immune

reaction. However, this form of chronic immune injury

appears to require initial parasitic infection of the heart

[60]. As a result, the relative role of parasite related and

autoimmune responses remains to be determined [61]. The

hypothesis of autoimmune pathogenesis also leaves

unanswered the question of why many patients remain in

the indeterminate form of the disease throughout their life

span, while others develop the chronic manifestations.

Moreover, there is the paradox of reactivation of Chagas

infection when the immune system is depressed either

through disease processes like AIDS or by iatrogenic

interventions, suggesting that a form of immunological

control of the infection is actually present in chronic

chagasic patients [31,38].

On the basis of the available evidence, etiological treatment

with trypanocidal agents is considered to be mandatory

only for either the acute phase or reactivation of chronic

Chagas disease (eg, during immunosuppressive therapy

after organ transplantation) [31]. However, if the

hypothesis of direct T cruzi involvement in triggering

myocardial damage could be proven to constitute the main

pathogenetic mechanism of chronic Chagas heart disease,

trypanocidal treatment would be indicated for most

patients with indeterminate form and also possibly even

with overt cardiomyopathy. On clinical grounds, this

hypothesis is currently under test by the BENEFIT trial, a

large, randomized, double blind, placebo controlled study of

benznidazole in patients with chronic Chagas

cardiomyopathy [62].

Finally, it should be emphasized that it is the rather

complex pathophysiology of chronic Chagas

cardiomyopathy that is probably responsible for

unexpectedly disappointing results obtained when

therapeutic measures that are beneficial in other conditions

are used in patients with this disease [63].

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63.


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TOPIC OUTLINE

INTRODUCTION

PATHOLOGY

Acute phase

Chronic phase

PATHOGENESIS







damage

REFERENCES

GRAPHICSView All

PICTURES





RELATED TOPICS




disease




heart disease



13 de 13 10/01/2015 23:51

pathology and pathogenesis of chagas disease

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