Pathology of the Acute Phase

The pathology of the acute phase begins with an increase of trypomastigotes circulating in the blood (George Stewart, interview 2/21/92). During this phase, trypomastigotes can be detected in blood samples, whereas in later phases very few circulate and either serodiagnosis for antibodies or xenodiagnosis for circulating parasites is needed to test for infection.

Trypomastigotes spread through lymphatics, with resulting lymphadenopathy. Initially, trypomastigotes actively penetrate host cells, but they may also enter through phagocytosis by host macrophages, reproducing as amastigote forms (Schmidt and Roberts 1989:65). The trypomastigotes lose their undulating membrane and flagellum inside the host cell and begin reproducing by means of binary fissioneventually producing so many amastigotes that the host cell is ruptured and killed. Amastigotes form into cystlike pockets, called pseudocysts, within the muscle cells. Some amastigotes evolve into trypomastigotes and find their way into the bloodstream, where they are picked up by vinchucas to be passed on to another host. All cells are susceptible, but parasites show great affinity for fixed macrophages of the spleen and liver and muscle cells (especially the myocardium). Myocardial fibrosis (myocarditis) is the most serious clinical consequence.

The pathology of the acute phase is the least understood because the phase is very short and not everyone infected passes through it. As parasitologist George Stewart (interview 4/15/92) explains it: cellular response on the part of macrophages encapsulating trypomastigotes at the site of the bite results in inflammatory responses that set off the acute phase. The invasion by macrophages results in a cascade of events. One such event alters the immune system. During the acute phase there are dramatic alterations in macrophage and lymphocyte cell populations, along with T‑cell and B‑cell responses. Macrophages are antigen‑presenting cells (APCs) that consume the antigen, partially digest it, and display its epitope and class‑II protein on their surfaces. T‑cells recognize the antigen’s epitope found on antigen‑presenting macrophages and activate B‑cells to produce plasma cells that secrete antibodies specific to the antigen. Throughout the acute infection period, parasites can be detected in most tissues, including trypomastigote forms in fairly large numbers. The sites of the growth are characterized by inflammatory cellular infiltrates. Wherever the parasite is growingin lymph nodes and locally in the skinmacrophages, T‑cells, and B‑cells massively invade these cells. This invasion does not continue into the chronic phase.

This pan‑lymphocyte proliferation is accompanied by severe immunodepression‑the immune system becomes exhausted and specific antibodies against the parasite are inadequately produced. Very few antibodies are produced against the parasite, because there is massive polyclonal non‑specific B‑cell stimulation. Suppression is achieved by polyclonal B‑cell activation early in the infection; many subtypes of B‑cells are stimulated to divide and to produce nonspecific IgG and autoantibodies (Schmidt and Roberts 1989, Kobayakawa et al. 1979).

The result is a random, nonspecific impact on the parasites. It acts more like a bombing in a blitzkrieg than targeting bombs with radar and aiming at a specific site. Suppression of the immune system is indicated to some degree by the fact that all this activity is ineffectual. Experimentally, chagasic antigens have been injected into the host during the acute phase of the disease, resulting in the nonresponse of antibodies to these antigens and further indicating the parasite’s ability to alter the immune system.

Experiments with mice indicate that if scientists destroy T‑helper cells by injecting mice with T‑helper cell antibodies, polyclonal B‑cell activation will be stopped. This implies that such activation is T‑helper‑cell mediated and that trypomastigotes alter the T‑cells; so it is not simply mitogenic stimulation of B‑cells. As mentioned, acutely infected patients respond with a massive proliferation of B‑ and T‑cells, but the T‑cells don’t live up to their reputation and are deficient in their cytotoxic influence. Causing this are suppressor T‑cells that are highly active during the acute phase and figure in the immunosuppression, but the major players are the macrophage subpopulations. When the trypomastigotes initially enter the body, antigens are consumed by macrophages that partially digest the antigen. The macrophages initiate cytokene communication that leads to enormous proliferation of T‑helper cells and B‑cells and that probably stimulates suppressor T‑cell activity. T‑suppressor cells interact with T‑helper cells by dampening the immune response and by lessening the effect of cytotoxic cells, which have an effect opposite those of T‑helper cells (Schmidt and Roberts 1989).

Researchers at IBBA in La Paz, Bolivia, also have been studying the pathogenesis of acute Chagas’ disease among high‑altitude patients (Carrasco and Antezana 1991). They provide an alternative explanation: after the parasite penetrates the blood in the acute phase, it produces septicemia with hematogenous metastasis, which refers to the presence of T. cruzi in the blood and its entrance into other parts of the body, especially the muscles, through the blood. Trypomastigotes are guided to cells. As to what guides them, Carrasco and Antezana provide one explanation. Trypomastigotes need carbohydrates to survive, and it is possible that they have a product in their metabolism that searches the blood, acting like a “trigger” and informing trypomastigotes of cells rich in glycogen, such as muscles. After trypomastigotes leave the blood by perforating the walls of the capillaries, they penetrate the plasmatic membrane of cells. Inside cells, metacyclic trypomastigotes lose their tails and evolve into small, round, and tailless shapes called amastigotes. Amastigotes develop into trypomastigotes in these cystic cavities.

Maturation of trypomastigotes is uniform, but not all leave the cyst to become active at the same time. Maturity of the nascent trypanosomes requires adequate biochemical conditions. Mature trypanosomes return to the blood, where they circulate throughout the body searching out other cells to continue their cycle or to be picked up by vinchucas (Carrasco and Antezana 1991).

Other trypomastigotes remain in the cysts and self‑destruct, leaving behind an array of toxic materials, dead parasitic material, pseudocysts, and destroyed cells that produce inflammations and tumors underneath the skin, such as chagoma and Romaña’s sign. According to Carrasco and Antezana (1991), the inflammatory process is self‑limiting and does not attack other organs. Other researchers, however, referred to in Carrasco and Antezana, indicate effects upon the central nervous system. Viana in 1911 described an alteration of ganglion cells and their disintegration corresponding to the velocity of broken pseudocysts within the central nervous system of acute patients (Brénière et al. 1983). Monckeberg mentioned in 1924 severe lesions of nerves and ganglions in the hearts of dogs experimentally infected with T cruzi. Degenerative and inflammatory lesions coexisted during the rupture of the pseudocysts, with degenerative lesions apparently appearing first. Köberle in 1957 and 1959 suggested the presence of a neurotoxin, that would be released after the destruction of trypomastigotes and that would act locally or at short distances (Pereira Barreto 1985, Köberle 1970). The fact that approximately 80 percent of the ganglion cells could be destroyed in the acute phase constitutes the fundamental revelation of Köberle’s neurogenesis theory (Köberle 1970). However, first Andrade in 1958 and later Dominguez and Suarez in 1963 did not find a similar correlation in their experiments (Carrasco and Antezana 1991).

According to neurotoxic theory, it is the trypomastigotes that remain in the pseudocysts and self‑destruct that produce the toxic materials within the tumors and cause the inflammations. T. cruzi alters cell permeability and thus dramatically increases calcium levels that are toxic to human cells. The parasite needs high levels of calcium for its own cytoplasm, but extra calcium alters cell metabolism and could explain some of the cellular necrosis (George Stewart, interview 2/4/94).

A more scientifically acceptable theory holds that damages during acute phases are due to an overreaction, as well as ineffective reaction, of the autoimmune system (see Brener 1994). Pathogenesis during the acute phase is the result of a cascade of events involving the immune system in which panlymphocyte proliferation is accompanied by a severe immunodepression: the immune system becomes exhausted and specific antibodies against the parasite are inadequately produced. The fact that the human immune system is implicated within the pathogenesis indicates, as in AIDS, the deficiencies of the human body’s defenses against viruses and parasites and the need for more research into the complexities of the immune system and how it sometimes becomes our own worst enemy. Simplistic theories of antigens and antibodies have been replaced by complex synergetic interactions of events and cascades of events between complex parasitic and human immune systems.

When symptoms of Chagas’ disease appear among patients in endemic areas, health workers should test for acute Chagas’. At this stage, parasitological examinations are more easily performed because T. cruzi are circulating in the blood and can be observed in drops of blood examined under the microscope. Antibodies are also in high number, assisting in the detection through use of ELISA immunosorbent assay. Xenodiagnosis is often necessary during indeterminate and chronic stages of the disease because parasites circulating in the blood are fewer in number. As discussed, in contrast to other means of testing such as through extraction of blood in a syringe, xenodiagnosis uses sterile vinchucas to feed in the armpit of the patient for thirty or more minutes, providing the bugs with time to ingest T. cruzi and blood. It is often difficult to catch T. cruzi in the bloodstream because its natural habitat is intracellular. Xenodiagnosis can also determine the zymodeme and population size of T. cruzi, which is important for treating latent and chronic stages. (See Appendix 12.)