Review

Chagas disease

Clinical and epidemiological aspects of Chagas disease

Aluzio Prata

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. During the past decades, after urban migrations, Chagas disease became frequent in cities and a health problem in non-endemic countries, where it can be transmitted vertically and by blood transfusion or organ transplantation. Microepidemics of acute Chagas disease have been reported, probably due to oral transmission. Heart involvement is the major feature of the disease because of its characteristics, frequency, and consequences, and is also the source of most controversies. The indeterminate clinical form, despite its good prognosis on at least a medium-term basis (510 years), has acquired increasing importance due to the controversial meaning of the abnormality of some tests and the myocardial focal lesions found in many patients. Simultaneous evaluation of the parasympathetic and of the sympathetic system in the heart has been done by spectral analysis of heart rate. The physiopathological and clinical significance of denervation in Chagas disease is still incompletely understood. There are major divergences of opinion on specific treatment during the chronic phase because of the doubts about cure rates. Changes of Chagas disease prevalence in many countries have been certified by the Pan American Health Organization, and are ascribed to large-scale vectorcontrol programmes with modern pyrethroid insecticides and to improvement in lifestyle.
Lancet Infectious Diseases 2000; 1: 92100

Figure 1. Acute chagasic myocarditis. Inflammatory infiltrate, and intense oedema separating the cardiac fibres, several of them containing amastigote forms of T cruzi (magnification x10).

is not so frequently seen in the southern cone countries (Argentina, Brazil, Chile, Paraguay, and Uruguay) but is almost the only form found in human infections north of the Amazon region. T cruzi II seems primitively associated with rodents and with Triatoma infestans. Both T cruzi I and T cruzi II are associated with cardiac lesions in human infections (figure 1), but it seems that only T cruzi II is also associated with digestive tract lesions. Of the more than 100 recognised triatomine species, only about ten are widespread colonisers of human dwellings. Some have become completely adapted to dwellings and are highly anthropophilic, such as T infestans in the southern cone countries (responsible for 85% of cases) and Rhodnius prolixus2 in many countries in Central America.
Transmission

General considerations
Infection with Trypanosoma cruzi is an enzootic disease extending from the USA to the south of South America (sylvatic cycle), which can lead to human infection when the insect vectorstriatomine bugsadapt to human dwellings (domestic cycle). This adaptation occurs in different manners and at different times.
The parasite and vectors

There are various strains of Trypanosoma cruzi, which differ in terms of epidemiology, pathogeny, response to treatment, biochemistry, or immunogeny. The absence of a common nomenclature has impaired a correlation with the complex clinical and epidemiological manifestations of the disease. The tendency is to assign to all isolated strains to two major T cruzi groups, defined as I and II.1 T cruzi I is extremely widespread within the sylvatic cycle, highly associated with opossums, and may represent the original form of T cruzi. It
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Manan accidental host for T cruzi is infected at night through the contact with the faeces of blood-sucking triatomines. Often, the bugs defaecate on the host while feeding, and the infected faecal droplets may be inadvertently passed to the mucosa of eye, nose, or mouth. Parasite transmission through intact skin probably does not occur. The probability of human infection through contact with an infected triatomine is about one in a thousand.3
AP is full professor and head of Tropical Medicine Departament of the Faculdade de Medicina do Tringulo Mineiro, Uberaba, MG, Brazil Correspondence: Professor Aluzio Prata, Tropical Medicine Department of the Faculdade de Medicina do Tringulo Mineiro, PO Box 118, Postal code 38001-970, Uberaba, MG, Brazil. Tel +55 34 3318 5254; fax +55 34 3318 5279; email a_prata@mednet.com.br THE LANCET Infectious Diseases Vol 1 September 2001

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Chagas disease

Review
Panel 2. Control initiatives
1 Southern Cone Initiative (started 1991/92): Argentina, Brazil, Bolivia, Chile, Paraguay, Uruguay, and southern Peru (from 1996/97). Uruguay, Chile, and most of central and southern Brazil are now certified (by PAHO) as free of transmission, and there is currently a proposal to certify similarly eight provinces of Argentina. Central American Initiative (started 1997/98): Guatemala, Honduras, Nicaragua, El Salvador, Panama. No control programme currently in Costa Rica or Belize, but preliminary survey work is beginning. Andean Pact Initiative (started 1997/98): Venezuela, Colombia, Ecuador; survey work underway, control activities being restarted in Venezuela and planned for Colombia and Ecuador. North Peru beginning survey work and preliminary control trials. Mexican Initiative (2000/01): survey work beginning, but very incomplete coverage at present. Countries with no current control or surveillance activities: USA, Guyana, Suriname, French Guiana.

Panel 1. Epidemiological profile of chagasic patients

Mean age: 38 years Origin: rural Living: at the periphery of towns Cultural level: low Work activity: manual jobs Reason for seeking medical care: positive serology, an abnormal electrocardiogram or symptoms. Another mechanism of transmission, responsible for approximately 10% of cases, is transfusion of whole blood or blood derivatives, except for lyophilised products. The risk of acquiring the infection after receiving a transfusion of blood from an infected donor is about 20%.4 This is the major route of transmission in urban zones. The third most important route of transmission is the congenital one, with approximately 500018 000 cases per year. The likelihood of congenital transmission in children of chagasic mothers ranges from less than 1% to 10%. This type of transmission may also occur outside endemic areas. Microepidemics of acute Chagas disease, probably due to oral transmission through contaminated food such as meat, sugar cane juice, or aai (Euterpe oleracea) fruit juice, have been described, especially in the Amazon Region. Also in the Amazon Region, piasava (Leopoldinia piaaba) pickers have been reported to be attacked by triatomines during the daytime, this unusual mechanism of transmission probably being the primitive one.5 Other sporadic mechanisms of transmission include accidental contamination during laboratory work (including the conjunctival route through aerosol formed during centrifugation and accidental finger-prick with contaminated syringes), and organ transplantation (kidney, heart, bone marrow, and others).
Geographic distribution

4 5

autonomic nervous system in central Brazil, and of anectasic oesophagopathy in Argentina8 and rare occurrence in the north of the Amazon river; frequency of heart disease in Brazilian states evaluated by a national electrocardiographic survey; response to aetiologic treatment, with higher cure rates in Argentina, Chile, and in the Brazilian Rio Grande do Sul State; and congenital transmission, which is lower in Brazil than in Bolivia, Chile, and some parts of Argentina.
Medical and social importance

Detected in Andean mummies dating back to 4000 BC,6 Chagas disease started to expand at the end of the 19th century and reached a peak in the first half of the 20th century. Chagas disease attacks people living in remote rural areas, or with poor sanitation, that lack diagnostic facilities and good health records or statistics (panel 1). For this reason, sufficient epidemiological information about its magnitude or even about its existence has not always been available. The prevalence, morbidity, and geographic distribution of the a disease were determined only when and where the diagnostic importance of serological reactions and electrocardiography were recognised, and in many countries almost a century was needed for this to occur. With migration, many infected individuals moved from the rural zone to cities7 and to other countries. A few hundred thousand chagasic individuals are estimated to live today in the USA, Europe, and Asia.
Geographic differences

The WHO calculates that in the 1980s, before the setting up of successful control programmes, there were 1618 million people infected with T cruzi in the Americas (see www.who.int/health-topics/chagas.htm), reaching about 20% of the population in countries such as Bolivia. In Brazil, the 1975 national serologic survey revealed a 42% rate of infected people in the rural zone. The incidence for America as a whole has been calculated to be about 300 000 new cases per year in the absence of control interventions. Morbidity in the 1980s has been estimated as 1 200 000 patients with heart disease, 10% of them with severe disease, and at least 200 000 with megaoesophagus and/or megacolon. There is a significant under-registration of Chagas disease as a cause of death. In Brazil, in 1980 the mortality due to Chagas disease was 51 per 100 000 inhabitants. The World Bank estimates that 23 000 deaths due to Chagas disease occur every year, and that in Latin America, only acute respiratory infections, diarrhoeal disease, and AIDS produce a greater socioeconomic burden than Chagas disease.
Control

There are sharp geographic differences mostly attributable to the parasite strain, especially in terms of: frequency of megaoesophagus, megacolon, and denervation of the
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Over the past decades there have been changes to some of the above data, especially due to large-scale vector-control programmes with modern pyrethroid insecticides (panel 2), added to considerable migration to cities and improvements in the lifestyle of the population. The control
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Review

Chagas disease

Figure 2. Six patients with acute Chagas disease (Romaa sign).

programmes have exposed the vulnerability of triatomines, which are highly sensitive to insecticides, especially pyrethroids, reproduce slowly (one to two generations per year), and have low genetic variability with a consequent low ability to resist insecticides.9 The expenses involved in control programmes are compensatory, with very significant benefits in terms of reduced costs and high rates of economic return. Political decisions led to the creation of governmental programmes, first in the south of the continent, and then in Andean and Central American countries.10 A concomitant improvement in the quality of transfused blood occurred, also due to the fear of HIV infection. As a result, among about 18 million military conscripts in Argentina, for example, the prevalence of positive serology decreased from 58% in 1981 to 19% in 1993.11 In Brazil, the prevalence of positive serology in the school population (714 years) decreased to 014% during the past decade.12
Present situation

conjunctivitis, unilateral palpebral oedema, and preauricular satellite adenopathy (Romaa sign) (figure 2). Manifestations of generalised infection occur concomitantly, with fever, tachycardia not related to the degree of hyperthermia, lymphadenopathy, mild splenomegaly, and oedema, at times of elastic consistency. White cell counts commonly show lymphocytosis. The involvement of the heart is similar to that occurring with other types of myocarditis (figure 1). The electrocardiogram frequently shows low QRS voltage, prolonged PR and/or QT intervals, and primary T-wave changes in addition to sinus tachycardia. Ventricular extrasystoles, auricular fibrillation, or advanced grade right-branch block are rare and indicate a poor prognosis. The parasite is disseminated and can be seen relatively easily by direct blood examination. However, in the vast majority of patients the acute phase of the disease goes unperceived by not being recognised or due to the scarcity or absence of clinical manifestations (immune response depression promoted by the parasites, to facilitate their invasion and reproduction). The acute congenital phase may be symptomless or may be associated with hepatosplenomegaly, jaundice, skin haemorrhages, and neurological signs, especially in premature newborn infants. The acute phase usually occurs in children. Without treatment, about 510% of symptomatic patients die during this phase due to encephalomyelitis or severe cardiac failure, and rarely due to sudden death.

Chronic disease manifestations

After 24 months the acute clinical manifestations disappear and the parasites are seldom detected in peripheral blood. The disease enters the chronic phase, generally starting with a long period of clinical latency called indeterminate form, which lasts 1030 years or throughout life. After this period many infected patients present manifestations related to the involvement of certain organs such as heart, oesophagus, colon, and nervous system, characterising other clinical forms.
Indeterminate form

Chagas disease continues to be a priority health problem for several reasons, including: the need to keep control over areas where the transmitters have peridomiciliary (ie, near to rural human dwellings) and wild habitats, such as in the northern part of South America where many acute cases are reappearing;13 the difficulty in obtaining priority for the support of control actions where the disease has been eradicated; the identification of wild triatomines with the potential to become domiciliary;14 and the medical and social costs of care for infected people in the absence of efficient and well-tolerated drugs for specific treatment. Epidemiological data suggest that the frequency of clinical progression in cardiopathy may decline with interruption of vector-born transmission.

Acute disease manifestation

T cruzi may mark its point of entry into the human body by inflammation, and when this occurs in the eye there may be
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In cross-sectional studies conducted in endemic areas, about half the chagasic population have the intermediate form of the disease. The individuals feel nothing, have no reduction in the cell immune response, and electrocardiogram and radiologic examination of the heart, oesophagus, and colon are normal. They are unaware of their disease, which is demonstrated by positive serology and by the detection of the parasite by xenodiagnosis or blood culture, or by PCR. Apparently this clinical form should be of no particular interest but, paradoxically, it has acquired increasing importance from a practical and scientific viewpoint.
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Chagas disease

Review

Recognition of the indeterminate form has delimited a group of patients with low morbidity, capable of performing any type of activity, and with an excellent prognosis, at least on a medium-term basis (510 years). These patients can be submitted to several examinations, sometimes for research purposes, such as evaluation of heart disease (ergometry, dynamic electrocardiography, vetocardiography, echocardiography, radioisotope techniques, haemodynamic, electrophysiological study and the evaluation of autonomic cardiac control, and even an endomyocardial biopsy) and of the digestive form, especially oesophagopathy (radiologic examination and manometric techniques). A variable proportion of patients presents abnormality in some of these tests, often of low intensity and frequently isolated, which can occasionally be found also in healthy individuals. Thus, the prognostic importance of these findings has not been determined. Nevertheless, some investigators believe that these patients should be considered to have early heart or oesophageal disease. About 60% of the endomyocardial biopsies from patients with the indeterminate form reveal focal lesions. It has been debated whether these lesions represent sequelae of the acute phase, a parasitehost state of equilibrium, or are cumulative, progressing to diffuse myocardial involvement with time, including widespread fibrosis. The importance of the parasite itself or of its products in focal lesions,15 and also in more severe lesions, has been recently emphasised. The importance of the parasite in the genesis of the lesions is not always related to the degree of parasitaemia as shown by xenodiagnosis, blood culture, or, more recently, by PCR. By contrast with what occurs with reactivations related to immunodepression, a higher parasitaemia does not affect the course of the disease.
Cardiac involvement

Figure 3. Chronic chagasic myocarditis. Inflammatory infiltrate and intense fibrosis of the myocardium (magnification x200).

block of non-advanced degree, first-degree A-V block, premature ventricular beats and low voltage QRS, not associated with echocardiogram changes in the left ventricle. These patients usually are 2050 years old and are symptom-free or show mild symptoms. About 2030% of the total chagasic population in endemic areas has symptomless heart disease and these patients may live for many years. Heart disease worsens in some of them, with increasing arrhythmias or heart failure (panel 4).
Severe heart disease

Heart involvement is the major aspect of Chagas disease because of its characteristics (panel 3), frequency, and consequences, and is also the source of most controversies.
Mild heart disease

Electrocardiograms obtained in longitudinal studies in endemic areas have shown that about 2% of patients with the indeterminate form progress to the cardiac form every year. The early changes are discrete and nonspecific, such as primary ST-T changes, right bundle branch

Panel 3. Clinical features suggestive of Chagas heart disease

Passive liver congestion as the initial manifestation, rarity of orthopnoea and paroxysmal nocturnal dyspnoea or acute pulmonary oedema, easy restoration of circulatory equilibrium during the first episodes of decompensation, slow evolution with a long survival except when decompensation occurs in young people, unfolding of the second sound in the pulmonary focus, at times precordial pain, thromboembolic phenomena, association with megaoesophagus or megacolon, palpitations, lipothymia, syncope, and sudden death.
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The electrocardiographic changes most suggestive of the disease are atrioventricular blocks, intraventricular blocks (right bundle branch block and block of the anterosuperior division of the left branch), sinus bradycardia (with premature ventricular contractions or primary and diffuse alterations of ventricular repolarisation), and premature ventricular contractions (five or more per minute). Particularly interesting is the rarity of complete left branch block of advanced degree, by contrast with what occurs in idiopathic dilated cardiomyopathy. The frequency of electrocardiographic alterations is biased by patient selection. It is obviously higher for hospital patients than for patients from endemic areas. The WHO has standardised the reading of electrocardiograms for comparative studies.16 There is good agreement between the electrocardiographic findings and the distribution of lesions of the excito-conductor system of the human heart, and also between clinical deterioration, extent of myocardial damage, and the presence and complexity of arrhythmias (figure 3). One of the characteristics of chronic Chagas heart disease is the high frequency of arrhythmias. Particularly outstanding for their prevalence and clinical implications are premature ventricular beats including periods of ventricular tachycardia and bradycardia secondary to sinus node disease and atrioventricular blocks. Episodes of unsustained ventricular tachycardia are observed in 40% of patients with mild abnormality of ventricular wall contraction and in 90% of patients with heart failure, higher values than observed in other cardiomyopathies.17
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Thromboembolism

Chagas disease

The thromboembolism of Chagas disease, detected in 44% of necropsies, is correlated with cardiomegaly and with systemic congestion. Thrombosis is more common in the right auricle and in the apex of the left ventricle, and thromboemboli are found mainly in the lungs, kidneys, spleen, and brain. The significance and relevance of the thrombi are not well understood.
Precordial pains

Figure 4. Chronic Chagas heart disease. Lesion of the left vortex. Note the circumscribed thinning of the vortex region.

Left ventricle aneurysms

Myocardial involvement evaluated by echocardiography in an endemic area18 showed mainly segmental alterations in 30% of chagasic patients, with 45% of them having normal ventricular function. The most peculiar finding in Chagas disease, although also observed in other types of heart disease, is the thinning and deficit preferentially localised on the apex of the left ventricle (apical lesion), with or without thrombus. It differs from arteriosclerotic aneurism (post-infarction) by not being formed of scar tissue (figure 4). In the endemic area,18 this lesion occurs in 19% of chagasic patients and becomes visible by the age of 20. Its frequency is directly related to the severity of the cardiomyopathy (55% in the severe form). In 95% of cases it is accompanied with electrocardiographic changes (ventricular extrasystoles, right branch block, and left anterosuperior divisional block). Many theories have been advanced to explain the ventricular aneurysms. A recent one proposes a disorder of perfusion due to sympathetic dysfunction.19
Sudden death

Precordial pains appear in about 15% of patients with Chagas heart disease. Their characteristics vary and they are usually intermittent, occurring in different manners. They may be of oesophageal origin or may be related to functional disorders of the coronary circulation, depending on vasodilatory dysfunction of the endothelium22 or perhaps at the microvascular level.23 They often represent a difficult diagnostic problem.
Involvement of the digestive tract

Sudden death is a characteristic of chronic Chagas disease occurring in about 38% of patients with or without congestive heart failure (panel 5). It mainly occurs in males aged 1360 years, more frequently between 38 and 46. In unexpected sudden death, one third of all patients have no previous symptoms such as dizziness, effort dyspnoea, or syncope. In about 90% of cases death is instantaneous, not foreseen by the patient, or occurs in a matter of seconds. The final event usually is ventricular fibrillation and rarely bradyarrhythmia (figure 5).

In an endemic area, 1520% of chagasic patients develop alterations of motility, secretion, and absorption in the digestive tract, especially the oesophagus and colon. Changes in motility first arise with slow transit and difficulty in emptying, followed by increased calibre of the organ and increased difficulty in emptying characterising the presence of megaoesophagus (grade I to IV) or megacolon (figure 6). In a longitudinal study in an endemic area,24 every year 033% of the patients with the indeterminate form progress to oesophagopathy associated or not with dysphagia. Oesophageal involvement is progressive in some patients and not in others and evolves independently of cardiac involvement. However, about half the patients with oesophagopathy have electrocardiographic alterations compatible with those of Chagas heart disease. In the megaoesophagus and megacolon there is always some degree of destruction of the autonomic nervous system, which is presumed to precede the changes in motility. There may be severe denervation in the presence of a normal oesophageal calibre. There are lesions in the muscle layers but it is not known whether they are primary or secondary.

Panel 5. Major predictors of sudden death in Chagas heart disease

Ventricular dysfunction, unsustained ventricular tachycardia during Holter monitoring, especially accompanied by ventricular dysfunction, sustained ventricular tachycardia, recovery from cardiac arrest, severe bradyarrhythmia (sinus node dysfunction, advanced A-V blocks) and syncope.20 Sustained ventricular tachycardia seems to result from a macro-re-entry circuit usually located on the low-lateral wall of the left ventricle and not on the apex, probably related to fibrosis,21 which is reproduced in 85% of patients during ventricular stimulation.

Panel 4. Factors possibly associated with the progression of cardiopathy in Chagas disease
Disease duration, male sex, intense physical activity, parasite strain, exposure to reinfection, genetic background, black colour, age, severity of acute infection, nutritional status, alcoholism, and other concomitant diseases.
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neurovegetative origin has not always been duly confirmed. Changes in the neurovegetative system are not exteriorised into manifestations that will correspond to demonstrable clinical forms. Dysfunction of the neurovegetative system is assumed to be related to the contractile strength of the myocardium, to focal necroses, apical aneurism, haemodynamic changes, arrhythmias, and sudden death. Due to their strict anatomical relation with the conduction system, correlations with rhythm disorders Figure 5. Dynamic electrocadiogram (Holter) in a case of sudden death. Beginning of arrhythmia (a), are predictable, although they torsade de pointes (after 9 s) (b), ventricular fibrillation (after 4 s) (c), electric asystole are not more frequent where the after 16 s (d). lesions of the nervous plexuses are more intense in the acute phase In oesophagopathy there may be dysphagia, oesophageal and in the digestive form. The physiopathological and pain, regurgitation, pyrosis, hiccups, cough, parotid clinical significance of denervation in Chagas disease is still hypertrophy, and weight loss. Dysphagia is the most incompletely understood.27 important symptom and starts slowly, promoted by the cold or warm temperature of the food. The patient must Peripheral nervous system frequently drink water during the meals. Dysphagia does not In the peripheral nervous system there is a well individualised always depend on alteration of the terminal oesophagus. neuritis. Some patients, including those with the Oesophageal pain often appears with deglutition as a indeterminate form, present sensorimotor polyneuritis consequence of spasmodic contraction of a hypersensitive characterised by hypaesthesia and paraesthesia, but mainly by oesophagus. Regurgitation manifests soon after a few a reduction or abolition of osteo-tendinous reflexes. Electromyography shows destruction of motor neurons and swallows when the ectasia is small. Non-ectasic colonopathy is demonstrated by of peripheral sensory nerve fibres. manometry and by the response to a cholinergic substance (methacholine). The symptoms arise only when the Central nervous system megacolon becomes installed, generally in the form of Involvement of the central nervous system in Chagas obstipation. Meteorism, dyskinesia, and abdominal pain disease has been well established in acute phase may occur. The complications are faecaloma, volvuli, ulcers, meningoencephalitis and in immunodepression. In the chronic phase, there are reports of isolated cases of and peritonitis. clear psychic changes, pointed out by Jorg,28 which are insufficient to reach a consensus that will permit Involvement of the nervous system the acceptance of a defined clinical form. The frequency Neurovegetative In no infectious disease is the involvement of the of that electrophysiological alterations29 suggests autonomic nervous system as important as it is in Chagas the nervous form of Chagas disease remains an open disease. This is demonstrated by the presence of lesions, question. denervation, and functional disorders. Denervation of the parasympathetic system has been better documented and is much more intense than denervation of the sympathetic system. Simultaneous evaluation of both systems in the heart has been performed by spectral analysis of heart rate. Destruction mainly occurs in peripheral neurons25 and is more frequently observed in the acute phase, probably continuing during the chronic phase. During the latter, it is more evident in the cardiac and digestive forms than in the indeterminate form. Also, muscarinic cholinergic and beta-adrenergic antibodies are more frequently detected in the cardiac and digestive clinical forms.26 Many welldocumented alterations of homoeostatic equilibrium, manifesting as functional metabolic disorders, have been demonstrated in chagasic patients, being related Figure 6. Chagasic oesophagopathy. Anectasic (a), to disorders of carbohydrate, lipid, and water-salt mild megaoesophagus (b), moderate megaoesophagus (c), metabolism and of hormonal regulation, although their dolichomegaoesophagus (d).
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Disease reactivation

Chagas disease

Substances or conditions that provoke immunodepression may reactivate Chagas disease, with parasite proliferation, necrotic or tumoural lesions in the brain (75%), and intensification of myocarditis (44%). This has frequently occurred with HIV co-infection and peripheral blood CD4 cells under 200/L, and in organ transplantation.
HIV co-infection

Panel 6. Role of general clinicians or infectious disease physicians in the management of chagasic patients
Chagasic patients are usually seen by general clinicians in endemic areas and by infectious disease physicians in nonendemic areas to: Confirm the aetiological diagnosis Define the clinical form Determine the extent of lesions Consider the prognosis Decide on specific and symptomatic treatment Determine the type of physical activity Decide the need for specialist help Give compulsory notification (acute phase)

In AIDS, reactivation may occur in patients with the indeterminate, cardiac, or digestive form, with a marked increase in parasitaemia, with no IgM antibodies and with no increase in IgG titres. There is acute myocarditis, exacerbation of cardiopathy, and congestive heart failure. The clinical picture includes systemic manifestations, outstanding among them fever and symptoms related to meningoencephalitis (figure 7). The major neurologic changes reflect intracranial hypertension, meningitis, and involvement of the cranial nerve roots and are paresis, plegia, progressive loss of consciousness, headache, and convulsions. A normal number of cells or pleocytosis may be present in cerebrospinal fluid, with a predominance of lymphocytes and increased protein levels. T cruzi may be detected by direct examination of cerebrospinal fluid or blood. Computed tomography or magnetic resonance reveals single or multiple necrotising lesions with haemorrhages, which may retain the contrast dye throughout the lesion or in a ring shape, usually in the subcortical white matter of the brain hemispheres and occasionally at other sites such as the cerebellum and brain stem. The main differential diagnosis has been with toxoplasmosis. It should be kept in mind that the lesions of Chagas disease are located more in the white matter than in the grey matter and do not appear in the basal nuclei, with haemorrhage being diffuse and more intense. Other possible differential diagnoses are abscesses, mycoses, mycobacteria, metastases, lymphoma, and progressive multifocal leukoencephalopathy.
Transplant

myocarditis, skin lesions, and negative IgM. The parasites are frequently detected in skin lesions or in cardiac biopsies. During the first 3 months after renal transplantation, reactivation occurs in about 20% of patients,30 as revealed by fever and by the presence of T cruzi by direct examination of peripheral blood or skin lesions containing the parasite. When there is no reactivation, serology may become negative in about 40% of patients from the second or third month after transplantation onwards.

Management
Specific treatment

After a heart transplant, parasitaemia occurs in chagasic patients as revealed by direct examination of peripheral blood in 3080% of cases, and is difficult to differentiate from rejection and reactivation, which is accompanied with fever,

Chagas disease is not cured spontaneously and specific treatment is a controversial matter (panels 6 and 7). Patients may be treated orally, with nifurtimox or, preferentially, with benznidazole. In some cases side effects require suspension of the treatment. The most important are hypersensitivity (rash, fever, generalised oedema, lymphadenopathy, and joint and muscle pain), bone marrow depression (neutropenia, thrombocytopenic purpura) and peripheral polyneuropathy. These side effects are highly dose-dependent. The daily dose for benznidazole is 57 mg/kg body weight and 810 mg for nifurtimox, during 30, or better yet, 60 days. Benznidazole is currently available from Hoffman La Roche, and nifurtimox from Bayer. Neither drug is available in every country or is well tolerated. These drugs are not applied in programmes of disease control. They are believed to reverse fibrotic lesions in animals, but not in human beings. There is agreement about drug use under the following circumstances. Firstly, in the prophylaxis of accidental contamination. Since the procedure of treating

Panel 7. Routine examination of symptom-free chagasic patients

Anamnesis Physical examination Conventional electrocardiogram Chest radiography Radiologic examination of the oesophagus Radiologic examination of the intestine Follow-up once a year
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Figure 7. Necrohaemorrhagic lesions in focal necrotising chagasic meningoencephalitis in a patient with AIDS.

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Search strategy and selection criteria
The bibliographic search was done in the Medline/PubMed database and in many articles in the authors files. Works published in the last 3 years, mainly in English, are preferably cited in the references. However, most of the consulted articles were written in Portuguese or Spanish. A great deal of information on longitudinal studies in endemic areas, and prognosis, is found in some partly published theses.

immediately those exposed to contagion and to continue treatment for at least 10 days was adopted, no new cases have been recorded in that group. Secondly, during the acute phase of the disease. There is improvement of symptoms and the parasites disappear from peripheral blood after the 5th day of treatment. Later the serology becomes negative (3080%). Treatment applied some time (we do not know how long) after the acute phase may also produce good results. This is why treatment of children has been suggested, who also better tolerate the medication. In the reactivation of infection in immunosuppressed subjects, treatment may improve the clinical picture, turn parasitaemia negative, cause regression of meningoencephalic lesions, and attenuate myocarditis. For secondary prophylaxis in AIDS co-infection, continuous treatment with 5 mg/kg of benznidazole three times a week is indicated. There is no agreement about primary prophylaxis. There is also disagreement about specific treatment during the chronic phase because of doubts about cure rates (less than 10% for some authors), often due to the use of different cure criteria.3134 During the chronic phase, specific treatment reduces parasitaemia, as evaluated by xenodiagnosis, blood culture, and PCR, although parasites may be detected in the myocardium.35 The titres of T cruzi antibodies may decrease but this does not necessarily indicate a cure since in some patients long-term follow-up shows evolution of the disease. The disease does not progress when parasitaemia and standard serology (haemagglutination, immunofluorescence, and ELISA) are negative. Fourth-generation azole derivatives (14C alpha demethylase esterol inhibitors) are currently being evaluated for treatment.36
Symptomatic treatment

coronary chemical ablation and catheter ablation42 have been attempted in some patients. Finally, heart transplantation, despite reactivation and the possibility of neoplasia43 and rejection,44 has demonstrated equal benefits compared with other cardiopathies, suggesting that, at least in Central and South America, the presence of Chagas disease either in the recipient or the donor should not represent a contraindication for organ transplantation. In the presence of megaoesophagus, dilation of the oesophagogastric junction may be done with a balloon. Surgery is indicated in other cases, with cardiotomy being the most frequent procedure. Isorbide dinitrate (5 mg sublingually) may reduce oesophageal meal retention. Injections of botulin toxin into the oesophagus have been used.45 Faecaloma are removed after being fragmented. Atonic segments of the megacolon may be removed (some hospitals in endemic areas have rooms destined only to colon emptying).
Acknowledgments

Heart failure should be managed according to the principles that rule the treatment of this syndromeie, sodium restriction and the use of diuretics and digitalis. With respect to angiotensin converting enzyme inhibitors, on the basis of what occurs with other types of heart disease, some investigators recommend their use even for symptom-free patients with mild ventricular dysfunction. Beta-blockers, which are useful in other types of heart disease,37 have been avoided because of bradyarrhythmia and atrio-ventricular conduction dysfunction. Because of the high incidence of thromboembolism in Chagas heart disease, anticoagulants are recommended for patients with atrial fibrillation, previous embolic episodes and apical aneurysm, although their efficacy has not been confirmed.17 Pacemakers are implanted in patients with severe bradyarrhythmias. In sustained and unsustained ventricular tachycardia, amiodarone is recommended, especially in the presence of ventricular dysfunction.20,38 For patients with recurrent sustained ventricular tachycardia and haemodynamic instability, or survivors of a cardiac arrest, the implantation of an automatic cardioverter-defibrillator is proposed. Other methods such as aneurysmectomy, cardiomyoplasty and left ventriculectomy,39,40 surgical ablation,41 transTHE LANCET Infectious Diseases Vol 1 September 2001

The author thanks Edison Reis Lopes for figures 1, 3, 4, and 7, and Sylvio Pontes Prata for figure 5.
References

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