APPENDIX 9
Acute Chagas’ Disease
In 1909 Carlos Chagas diagnosed a child named Rita as having an acute attack of parasitemia caused by T. cruzi, and accurately described its symptoms:
Among the chief clinical symptoms of this child, whose fever had come on some eight or ten days before examination, were the following: axillary temperature 40°C (105°F) spleen enlarged and to be felt under the edge of the ribs; liver also enlarged; groups of peripheral lymph nodes swollen etc. Most noticeable was a generalized infiltration, more pronounced in the face, and which did not show the characteristics of renal oedema but rather of myxoedema. This last symptom, which I later found to be one of the most characteristic of the acute form of the disease, already then revealed some functional alternation of the thyroid gland, perhaps affected by the pathogenic action of the parasite (Chagas 1922).
Rita died three days later. The pathology of acute Chagas’ disease varies from a mild to a virulent infection. Some symptoms of acute Chagas’ are related to inflammation, which is one of the body’s defenses against T. cruzi and tissue damage, facilitating repair of the damage. Inflammation often includes fever, general malaise, and swelling and soreness of the lymph nodes and spleen, which contain large numbers of macrophages and T and B lymphocytes activated to combat antigens peculiar to T. cruzi. Inflammation’s redness and warmth result from the increased amount of blood in the area. Swelling results from more proteins and fluids escaping into the tissue (Schmidt and Roberts 1989:27).
Definite symptoms of acute Chagas’ are the ophthalmo-ganglial complex (Romafia’s sign) and chagoma of cutaneous inoculation, which occurs near the bite site in 90 percent of the people recently infected (WHO 1991; see Figure 4). However, Borda (1981) claims lesser percentages of from 1 to 3 percent. Romafia’s sign is not frequently found in Bolivia; if found, it is usually confused with an eye irritation. Appearing suddenly, Romafia’s sign is the swelling of the upper and lower eyelids in one eye. An infection occurs through the skin of the eyelid, developing into inflammation around the eye with edema and inflammation of the local lymph nodes. The swollen eyelids are firm to the touch, purple, and not painful. There can be an inflammation of the conjunctiva or the mucous membrane that lines the eyelids (Katz, Despommier, and Gwadz 1989:174). Moderate swelling extends to the same side of the face, which, if touched, is found to be hard. This swelling gradually disappears after a month. The duration and durability of Romafia’s sign set it apart from the swelling of other minor eye irritations.
Chagomas also appear at the infected bite sites of other parts of the body, especially on uncovered areashands, forearms, feet, calves, and legs. Nodule-like protrusions, chagomas are cutaneous tumors beneath the skin, resulting from the hardening of skin and subcutaneous cells. Chagomas are painful, firm, feverish, and abnormally red, which is due to capillary congestion in inflammations. When chagomas slowly disappear after a month, they leave a depigmentation, like a burn wound.
Acute infections also alter the cardiovascular system, with tachycardia (without correspondence to the intensity of fever), cardiac enlargement, hypotension, and heart failure (Andrade 1994, Köberle 1968:80). Heart alterations vary from slight to severe, as registered by electrocardiogram, but disappear after the acute phase (Borda 1981). Seventy percent of acute cases show no electrocardiographic or radiological abnormalities due to acute myocarditis of different stages (Laranja et al. 1956, WHO 1991:3). The remaining 30 percent indicate such electrocardiographic irregularities as sinus tachycardia, low QRS voltage, prolonged P-R interval, and primary T-wave changes. Chest x-rays can reveal cardiomegaly of varying degrees of severity.
About 2-3 percent of the acute cases with myocarditis die. Infants under two years constitute the greater number in this group. Also common to children of this age group is meningoencephalitis, another severe complication of the acute stage. Patients suffer convulsions, with or without fever, and lose consciousness to varying degrees (WHO 1991:3). The death rate for acute Chagas’ with meningoencephalitis can be as high as 50 percent (WHO 1991).
For the remaining cases, the symptoms subside spontaneously within one to two months, without clinical symptoms in the short or medium term. Sometimes the frequency of tachycardia is extremely high and continues to increase after the remission of the temperature during the recovery process (Köberle 1968:80).
For those who survive the acute phase or who do not experience it, death from subsequent acute phases is frequently prevented by the presence of the parasite and the complement immune system. This is referred to as partial immunity, and it is important to consider in attempts to destroy the parasite during initial attacks within the acute stagewhich may not be a good idea if the patient is to be subjected to new infections and subsequent violent acute phases. However, even with partial immunity over time, there is molecular mimicry between T. cruzi and the host’s nervous tissue (Avila 1994), rendering Chagas’ an autoimmune disease in that its antibodies destroy nerve cells. As one bonus, research concerning Chagas’ disease adds to the scientific understanding of autoimmune diseases.
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 autoant
ibodies (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.)
Detecting Acute Stages
In endemic areas of Chagas’ disease it is important to detect acute and even asymptomatic infections in children so that specific therapy can be started immediately. Serologic profiles of eighty-six chagasic children and fifty-six healthy children from a highly endemic area in Cochabamba, Bolivia, indicate that alpha-2-macroglobulin (A2M) and C-reactive protein (CRP) were significantly increased in acute chagasic children (MedranoMercado et al. 1996). Because parasites are commonly present in blood and tissues during the acute phase, it is possible that the high levels of A2M may act as inhibitors of a high level of proteinases, derived from the parasites, from host cell damage, or from both. These results open a route to discern different stages in the acute infection by examination of sera and using humoral criteria:
1) an early acute stage, with an increase only in specific anti-T. cruzi immunoglobulin M (IgM) levels (group 1);
2) an intermediate acute stage having high specific IgM levels and/or high immunoglobulin G (IgG) levels and/or high anti-galactose (anti-Gal) levels and increased A2M and/or CRP levels;
3) a late acute stage, with low IgM levels but high A2M, CRP, anti-Gal, and specific IgG levels.
The detection of high immunoglobulin G alone is indicative of the chronic/indeterminate stage of C
hagas’ disease (Medrano-Mercado et al. 1996).
In Bolivia, however, serological methods involve many problems, including difficulties in sample collection and storage until the time of screening; difficulties in the standardization of the diagnostic methods commonly used, such as the indirect hemagglutination test, the indirect immunofluorescence test, ELISA, or complement fixation; and the absence of a clear correlation of the results of tests performed in different laboratories (Pless et al. 1992). The procedures and techniques to quantify five relevant proteins are easy to perform and to automate for large-scale screening, in contrast to other immunologic techniques that are used for serodiagnosis of Chagas’ disease. They would consititute a tool in detecting acute Chagas’ disease, especially in endemic rural areas.
APPENDIX 10
Chronic Heart Disease
Symptoms of chronic Chagas’ disease are insidious and progressive (see Figure 8). After recovering from acute phases, many people, perhaps the majority, remain asymptomatic for the rest of their lives, while others remain in good health for many years before developing symptoms and signs of the chronic stage of disease. The chronic phase is characterized by widespread damage to the organ(s) and the multiform chagasic syndrome, with its digestive (aperistalsis, megaesophagus, megacolon), respiratory (megatrachea, bronchiectasis), urinary (megaloureter), cardiac (denervation), and neurological (myelopathy, encephalopathy) components (Köberle 1968, Iosa 1994).
Cardiac abnormalities range from types of rhythm disturbances to various forms of heart block, including right- and left-bundle branch block, hemiblocks and atrioventricular blocks (see Andrade 1994, Iosa 1994). Some tested patients show a normal electrocardiogram (ECG) reading, particularly in the early stages, but stress testing may reveal ECG abnormalities such as heart block or arrhythmias which might not be seen in resting ECGs. Sometimes available in urban centers, echocardiography may also be useful in evaluating cardiac chamber size and left-ventricular function and in following the progression of the disease.
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