Disclosure
Background: Chagas disease is a protozoosis caused by the flagellate protozoa Trypanosoma cruzi. The infection is usually transmitted via the feces of blood-sucking insect vectors (reduviid bugs). The infection is mostly found in small mammals (sylvatic cycle), and human disease results from the colonization of the human habitat by some vector species (domestic cycle). The Brazilian physician Carlos R.J. Chagas discovered American trypanosomiasis in 1909. The work of Chagas is unique and exceptional in the story of medicine because he discovered the parasite in the vector insect before describing all the epidemiological and clinical aspects of the infection.
The parasite
T cruzi belongs to the Kinetoplastida order and the Trypanosomatidae family. It is in a special section called Stercoraria because it is the only human trypanosome to be transmitted by the feces of its invertebrate vector, as opposed to other trypanosomes transmitted by saliva (Salivaria section), ie, the African trypanosomes responsible for the sleeping sickness and Trypanosoma rangeli, a nonpathogenic species from South America transmitted by Triatominae and also able to infect humans.
Four main evolutive forms can be identified during the T cruzi life cycle.
The population of T cruzi is not homogenous, but composed of various strains. Although T cruzi is a diploid organism in which some genetic exchanges can occasionally occur, its genetic diversity mainly results from the evolution of independent clones remaining stable in time and space, such as in bacteria.
A consensus has recently been reached to group most of the previously described clones of T cruzi in 2 principal groups called T cruzi I and T cruzi II. The genetic distance between both groups is sufficiently important to consider the groups as 2 different subspecies. Although both groups of T cruzi cause the human disease, T cruzi II is more frequently associated with the domestic cycle and T cruzi I is more frequently associated with the sylvatic cycle.
The vectors and the intravectorial life cycle of T cruzi
The insect vectors of Chagas disease belong to the Hemiptera order, Reduviidae family, and Triatominae subfamily (kissing bugs). Although all Triatominae species may be potential vectors of T cruzi and many are involved in its sylvatic transmission to mammals, only 7-8 species (1.5-3.5 cm in length) are associated with parasite transmission to humans (domestic cycle). Their adaptation to the human habitat (domestication phenomenon), which offers abundant food (eg, blood of humans, domestic animals, associated rodents) and resting places easy to colonize (eg, cracks and crevices in walls made of dried mud, ie, adobe, and thatched roofs), define the vectorial importance of such species.
The 3 most important vector species of the human Chagas disease are Triatoma infestans, Rhodnius prolixus, and Triatoma dimidiata.
T infestans is responsible for more than half the infections and is found in the countries at the south of the Amazonian basin. For further reading, see the Carlo Denegeri Foundation. This species is very anthropophilic and prolific and rapidly adapts to the rustic habitat of Latin America.
R prolixus is found in Central America and in the countries at the north of the Amazonian basin such as Venezuela and Colombia. For more information, see the Carlo Denegeri Foundation.
T dimidiata is mainly active from Mexico to the north of Peru, in Colombia and Ecuador, and all along of the Pacific coast.
The other domestic species occupy more restricted areas and have a minor role in the transmission to humans. The sylvatic species can also colonize human habitats and, therefore, represent a potential risk for transmission.
The adult and nymphal stages of Triatominae can be infected by T cruzi sucking blood from infected mammals. In the intestinal tract of insects, the absorbed trypomastigotes undergo transformations into spheromastigotes and epimastigotes that divide by binary fission. Some epimastigotes migrate to the terminal part of the intestine and the malpighian tubules. By binding to the rectal epithelium, they are transformed into metacyclic trypomastigotes. The metacyclogenesis of T cruzi involves cyclic adenosine monophosphate (cAMP) and various factors contained in urine and the digestive tract of the insect. The infective forms of the parasite are then discharged with the feces and urine at the end of the blood meal. The complete intravectorial life cycle of T cruzi is achieved in 2-4 weeks.
The vertebrate reservoir and the life cycle of T cruzi
Only mammals are susceptible to infection with T cruzi (approximately 150 species belonging to 7 orders in the sylvatic cycle). Birds, amphibians, and reptiles are naturally resistant to infection. In the domestic cycle, frequently infected mammals, besides humans, are dogs, cats, mice, rats, guinea pigs, and rabbits. Pigs, goats, cattle, and horses only manifest transitory parasitemia and do not play an important role in the transmission of infection. Although uninfected, chickens are an important source of blood meals for Triatominae.
When introduced into the mammal host, the metacyclic trypomastigote must invade a cell to achieve its life cycle. It may potentially infect all nucleated cells. Cell invasion involves various parasitic and host molecules and a bidirectional signalization. Calcium-dependent and transforming growth factor-beta–dependent signals are necessary for the invasion of nonphagocytic cells, inducing rearrangement of the actin microfilaments and the subsequent recruitment of lysosomes at the site of parasite entry. Invasion of phagocytic cells seems to preferentially use the cAMP signal.
After the fusion of the parasitophorous vacuole with lysosomes, the trypomastigote is within an acidic environment and its differentiation into an amastigote is immediately initiated. The membrane of the vacuole is then lysed by parasitic proteins, and the amastigote is released in the cytoplasm of the host cells.
After a latency time of 20-35 hours, amastigotes initiate a process of binary division that is repeated every 12-14 hours. When the cell is saturated with parasites, amastigotes begin their differentiation into trypomastigotes. The intense movements of trypomastigotes disrupt the cell, releasing free parasites that can invade other cells or can be sucked from blood by a vector, likewise completing the parasite life cycle.
The modes of transmission of human disease
Vectorial transmission (via the feces of Triatominae) is responsible for 80% of human infections. The entry of metacyclic trypomastigotes via the mucosal route (oral or ocular) is easy. Direct skin penetration seems more difficult, and generally, the parasite enters via the site of the bite or the microlesions associated with scratching.
Transfusion of infected blood (containing trypomastigotes) is responsible for 5-20% of the human cases of Chagas disease, mainly in urban centers.
The maternofetal (vertical or congenital) transmission of the parasite occurs in 2-10% of infected women who are pregnant. In contrast to toxoplasmosis, the vertical transmission of T cruzi may occur at each pregnancy, in both acute and chronic forms of the disease. The transmission of infection via breast milk is extremely rare.
Oral transmission relates to the ingestion of food contaminated by feces of infected Triatominae. This mode of transmission seems particularly frequent among the settlers of Amazonian areas. Pathophysiology: The parasite plays a fundamental role in the genesis and development of organ lesions by sequentially inducing an inflammatory response, cellular lesions, and fibrosis. Such pathological processes may occur in many organs but appear more frequently and more intensively in the heart, esophagus, and colon.
The inflammatory response results from the rupture of infected cells releasing trypomastigotes, potent proinflammatory parasitic molecules, and cellular debris. It is intense in the acute phase, during which multiple cycles of intracellular parasite multiplication occur (leading to high parasitemia), but it is less intense in the chronic phase, when infection is partially controlled by the immune response.
The cellular lesions mainly affect the myocytes (myocytolysis) and the nervous cells (leading to an autonomic denervation). They result from direct destruction due to intracellular parasitism, necrosis related to inflammation, and other cytotoxic mechanisms involving CD8 T cells and, less frequently, CD4 T cells. Such cells recognize T cruzi epitopes at the surface of infected cells, which contain amastigotes, and noninfected cells, which have processed parasite antigens.
The fibrosis appears slowly and gradually (healing process) and regresses in the same manner. The fibrosis associated with chronic chagasic myocardiopathy is more intense than the fibrosis associated with any other cardiopathy.
Contradictory results have been reported on the participation of autoimmunity in experimental infection, and its role in the pathogenesis of Chagas disease remains controversial. However, the existence of molecular homologies between parasite and host molecules is indisputable, such as between the epitope B13 of T cruzi and the heavy chain of cardiac myosin or between the ribosomal proteins of T cruzi and some human P proteins and an extracellular functional loop of the human beta1-adrenergic receptor. The antibodies from infected patients, by their pharmacological action in recognizing such human antigens, might contribute to worsening the cardiac dysfunction induced by the parasites.
The heart is frequently affected in chronic Chagas disease, with significant destruction of the conduction system, myocytes, and parasympathetic cardiac nerves. This and the appearance of arrhythmogenic electric foci in the inflammatory areas are at the origin of the arrhythmic syndrome. The hypertrophy of the remaining myocytes and the intense fibrosis replacing the destroyed myocytes predispose to cardiac dilatation and failure. The left ventricular wall becomes thinner, allowing the formation of an apical aneurysm, a feature of Chagas disease. Thrombi are often present in such aneurysms, easily explaining the common occurrence of systemic and pulmonary thromboembolism. For further reading, see the Carlo Denegeri Foundation.
At the digestive level, the lesions (parasympathetic intramural denervation) are dispersed irregularly and mainly affect the esophagus and the colon (more frequently, the sigmoid colon). The affected segment may have a normal macroscopic appearance with only functional peristaltic alteration, it may be dilated (megaesophagus or megacolon), or it may be both dilated and elongated (dolichomegaesophagus). A hypertony of the cardia is present at the onset of esophageal dysfunction. Volvulus of the sigmoid colon is a complication appearing in advanced cases and is associated with a high risk of necrosis. Frequency: Mortality/Morbidity: Chagas disease results in 45,000-50,000 deaths per year. Mortality is mainly due to chronic chagasic cardiomyopathy. Sudden death, usually due to ventricular fibrillation, is the principal cause of death in 60% of cases. Bradyarrhythmia, thromboembolic phenomena, and, rarely, a ruptured aneurysm, are other causes of sudden death. Congestive heart failure (25-30% of cases), cerebral or pulmonary embolism (10-15% of cases), and, less frequently, volvulus of the dilated sigmoid megacolon (see Image 3) and severe acute myocarditis or meningoencephalitis in newborns (congenital infection) or young children, are other causes of death. Acute myocarditis or meningoencephalitis is also frequently lethal in chagasic patients co-infected with HIV.
Race: Morbidity and mortality are higher in black persons than in persons of mixed race or white children younger than 2 years who are acutely infected. Chronic chagasic cardiomyopathy also seems more severe in black persons than in white persons, whereas no data are available for the digestive forms of Chagas disease.
Sex: No difference exists between males and females in the prevalence of the acute phase, whereas chronic chagasic cardiomyopathy occurs earlier and is more severe in males than in females. Chagasic esophagopathy is more frequent and severe in males than in females.
Age: Symptomatic acute phases mainly occur in newborns (congenital infection) or young children. Chagasic esophagopathy is observed more frequently in the second decade of life, and chronic chagasic cardiomyopathy and colopathy are generally detected later, in the third, fourth, or fifth decade of life.
History: Physical: Causes:
Achalasia
The Romaña sign must be differentiated from an inflammatory reaction due to conjunctival contact with feces of uninfected Triatominae, which persists only 3-7 days instead of 30-60 days. |
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Medical Care: The goals of medical care in those with Chagas disease are to eliminate the parasites (etiological treatment) and to correct the damage caused by the parasites. The only available drug with some activity against T cruzi that is tolerated in humans is benznidazole. An urgent need exists for new drugs that act against T cruzi.
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Consultations: According to the clinical condition of the patient, consult the following:
Diet:
Activity:
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Drug Category: Antiprotozoal nitroimidazoles -- Used to treat infections caused by protozoa.
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