- Citado por Google
- Similares en SciELO
- Similares en Google
versión impresa ISSN 0037-8682
Rev. Soc. Bras. Med. Trop. vol.45 no.3 Uberaba maryo/jun. 2012
REVIEW ARTICLE ARTIGO DE REVISÃO
Doença de Chagas. O que é conhecido e o que deve ser melhorado: uma visão sistêmica
José Rodrigues Coura; José Borges-Pereira
Laboratório de Doenças Parasitárias, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ
This study consists of a broad review on what is known and what should be improved regarding knowledge of Chagas disease, not only through analysis on the main studies published on the topics discussed, but to a large extent based on experience of this subject, acquired over the past 50 years (1961-2011). Among the subjects covered, we highlight the pathogenesis and evolution of infection by Trypanosoma cruzi, drugs in use and new strategies for treating Chagas disease; the serological tests for the diagnosis and the controls of cure the infection; the regional variations in prevalence, morbidity and response to treatment of the disease; the importance of metacyclogenesis of T. cruzi in different species of triatomines and its capacity to transmit Chagas infection; the risks of adaptation of wild triatomines to human dwellings; the morbidity and need for a surveillance and control program for Chagas disease in the Amazon region and the need to prioritize initiatives for controlling Chagas disease in Latin America and Mexico and in non-endemic countries, which is today a major international dilemma. Finally, we raise the need for to create a new initiative for controlling Chagas disease in the Gran Chaco, which involves parts of Argentina, Bolivia and Paraguay.
Keywords: Chagas disesase. Evolutive patterns. Trypanosoma cruzi vector interactions. New strategies for treatment. Surveillance and control.
Neste trabalho, fazemos uma ampla revisão sobre o que sabemos e o que deve ser melhorado no conhecimento da doença de Chagas, não somente através da análise dos principais trabalhos publicados sobre os tópicos discutidos, mas em grande parte com base na experiência sobre o assunto, que adquirimos nos últimos 50 anos (1961-2011). Entre os assuntos abordados, destacamos a patogenia e evolução da infecção pelo Trypanosoma cruzi, drogas em uso e novas estratégias para o tratamento da doença de Chagas; os testes sorológicos para o diagnóstico e o controle de cura da infecção; as variações regionais da prevalência, morbidade e resposta ao tratamento da doença; a importância da metaciclogênese do T. cruzi em diferentes espécies de triatomíneos e sua capacidade de transmissão da infecção chagásica; os riscos de adaptação dos triatomíneos silvestres ao domicílio humano; a morbidade e a necessidade de um programa de vigilância e controle da doença de Chagas na região Amazônica e a necessidade de priorização das Iniciativas de controle da Doença de Chagas na América Latina e México e nos países não endêmicos, hoje um grande dilema internacional. Finalmente, levantamos a necessidade da criação de uma nova iniciativa de controle da doença de Chagas no Gran Chaco, que envolve parte da Argentina, Bolívia e Paraguai.
Palavras-chaves: Doença de Chagas. Padrão evolutivo. Interação Trypanosoma cruzi-vetores. Novas estratégias para o tratamento. Vigilância e controle.
A few years ago, we wrote a review article with the title Chagas disease: what is known and what is needed1. In that article, we discussed the natural history, the origin and distribution of the disease, the determining factors for infection and the pathogenesis of the disease, which we know little about, the phases and clinical forms, and the disease in the Amazon region, where knowledge is also scarce. Finally, we listed the following ten main problems relating to knowledge of Chagas disease that needed to be addressed: A) to explain the pathogenesis and evolutionary pattern of the disease; B) to develop a drug that is efficient for treating the acute and chronic phases; C) to improve the tests for diagnosing the infection, which at that time consisted of Trypanosoma cruzi I, II, Z3 and Z1/Z3 hybrids, which are today consensually known as TcI to TcVI2; D) to standardize the serological techniques for the diagnosis and for Chagas infection cure control; E) to compare the morbidity of Chagas disease induced in different regions by the various types of T. cruzi; F) to study the metacyclogenesis of different strains and clones of T. cruzi among different vector species; G) to analyze the risk of wild triatomines adapting to human dwellings; H) to evaluate the morbidity of Chagas disease in the Amazon region; I) to establish a surveillance and control program for Chagas disease in the Amazon region; J) to prioritize disease control programs in Latin America and Mexico, through stimulating the initiatives created by the Pan-American Health Organization.
The objective of this new review was to emphasize what should be improved regarding knowledge of Chagas disease, evaluate some of the progress achieved over the last five years and suggest measures that are necessary for research, technological development and surveillance and control of Chagas disease in Latin America and Mexico and in non-endemic countries. On the other hand, the aim was to raise new issues in relation to the pathogenesis of the disease, regional differences, diagnosis, treatment and perspectives for surveillance and control of the disease.
PATHOGENESIS AND EVOLUTION OF INFECTION BY TRYPANOSOMA CRUZI
Since American trypanosomiasis was discovered, numerous studies have been conducted on the pathogenesis of the disease and the evolution of human infection by T. cruzi in its acute and chronic phases and the respective clinical3-6. Over the past 100 years since the study by Gaspar Vianna7 on the pathology of the Illness of Carlos Chagas, numerous other studies on this theme have been carried out. However, the only finding that remains incontestable is that, as described by that author: Trypanosoma cruzi penetrates in the host's cells and multiplies in amastigote form to create pseudocysts that break and give rise to an inflammatory reaction that scars as a fibrosis. Through the rupture of the pseudocysts new forms of trypomastigotes are released, which circulate in the organism and invade new cells, repeating the cycle and consequently producing new lesions. The second possible mechanism for the pathogenesis of Chagas disease, which is more complex and controversial, is autoimmunity8,9. However, Tarleton10 questioned the autoimmunity mechanism, emphasizing the role of parasite persistence in the pathogenesis of Chagas disease. Teixeira et al.11 reported in their text: Questions related to the mechanism by which tissue lesions are formed in the course of T. cruzi infection have long been a matter of contentious debate. Although numerous reviews have proposed a plethora of brilliant hypotheses, the origin of the pathological lesions of Chagas disease remain open to investigation.
On the other hand Higushi12 state that sensitivity of TCD4+ and TCD8+ lymphocytes by T. cruzi, with development of anti-myocardial cells, associated with migration and activation of macrophages and the release of platelet aggregation factors, there by respectively inducing chronic Chagas myocarditis and myocardial ischemic lesions, may explain the findings encountered in cases of chronic myocardiophaty, but in agreement with Tarleton10 the pathogenesis of chronic myocarditis in Chagas disease is directly related with the presence of T. cruzi). According to Köberle hipothesis13 megaesopgagus, megacolon and cardiac conduction disturbances in Chagas disease are consequence of the desnervation of the parasympathetic autonomous system. Prata14, Teixeira et al.11 and other considerer that the neuron destruction in the heart, esophagus, colon and other hollow viscera may be explained both by direct inflammatory phenomena and by imumunological mechanism that results in the cardiopathy, megaesophagus, megacolon and other visceral alargements seen in Chagas disease.
What is still unknown in the pathogenesis of Chagas disease: A) why some patients infected with T. cruzi develop heart disease, others present megaesophagus or megacolon, others remain in an indeterminate form and yet others develop a mixed form with both heart disease and megas; B) why some patients present mild heart disease and do not evolve to a severe heart condition, while others do and even die of heart failure or sudden death. Likewise, why some develop an associated form, such as megaesophagus and megacolon, while 80 to 90% do not develop any mega; C) why T. cruzi does not attack organs like the lungs and kidneys, where it circulates all the time during the acute and chronic phase; D) why there is no megaesophagus and megacolon in the countries with endemic Chagas disease that are located north of the Equator; E) how the regional differences in Chagas disease morbidity can be explained.
Andrade15,16 and Andrade & Magalhães17 grouped T. cruzi into three groups or biodemes (Types I, II and III) according to its biological characteristics, tissue tropism, morphology, virulence and pathogenicity for mice. Type I: macrophage tropism during the initial phase of the infection, with high virulence, maximum parasitemia of 7 to 12 days and 100% mortality of mice within 12 days of infection, with predominance of the thin forms of T. cruzi; Type II: myotropism with predominance in the myocardium during the acute phase, predominance of wide forms, but with a percentage of thin forms, with maximum parasitemia and mouse mortality in 12 to 20 days; Type III: myotropism for skeletal muscle, with predominance of wide forms, maximum parasitemia in 25 to 30 days and low mortality among mice.
Despite the great importance of this classification, it does not explain the variations of human Chagas disease. Macedo & Pena18 correlated the genetic variations of T. cruzi and their implications for the pathogenesis of Chagas disease, according to the clonal histotropic receptors for different strains and clones of the parasite. However, this very logical and attractive theory has not been fully proven in practice. Greater severity in the acute phase, especially among children, observed by Dias19 in Bambuí, State of Minas Gerais, Brazil, coincided with a greater percentage of severe chronic forms. Similarly, the reinfections in the chronic phase observed by Macedo20 favored development and evolution of forms of greater severity among patients who remained in endemic areas with great infection pressure from T. cruzi. In a study on disease evolution that we carried out in Rio de Janeiro on 510 patients from several states in Brazil21, we observed that 52.1% had heart disease, 39% had the indeterminate form and 14.3% had megaesophagus and megacolon, with 5.4% presenting an association between megas and heart disease. The states with highest frequency of patients with heart disease were Goiás (66.6%), Bahia (65.5%), Minas Gerais (55.7%) and Pernambuco (50.9%).
DRUGS IN USE AND NEW STRATEGIES FOR TREATING CHAGAS DISEASE
The current recommendations for chemotherapy treatment of Chagas disease in Brazil are based on decisions made by specialists who were brought together by the Ministry of Health in 1997, with subsequently revalidation by experts coordinated by the Pan-American Health Organization in 197822,23, i.e. about 13-14 years ago. These recommendations suggested that acute cases of Chagas disease acquired through vector, oral or congenital transmission, or through laboratory accidents or any other transmission route should be immediately treated with one of the drugs that are currently available: nifurtimox and benznidazole. It was also recommended that children up to the age of 12 years should be treated, as well as cases of recent infection in adults over known periods within the last 10 to 12 years. Coura24 reviewed those recommendations and suggested that combinations of drugs, such as benznidazole + nifurtimox, and benznidazole or nifurtimox + antifungals that inhibit ergosterol in double or triple associations should be used, as is done with drugs for treating tuberculosis, leprosy and human immunodeficiency virus/acquired mmunodeficiency syndrome (HIV/AIDS). More recently, on the basis on the pathogenesis of the disease and its evolution, Coura & Borges-Pereira25 recommended that the treatment should be broadened to chronic cases at initial evolutionary stages, such as stage II of the New York Heart Association26 and up to stage III, at the discretion of the attending doctor and with the patient's agreement.
Since 1912, numerous drugs have been used experimentally and in clinical trials for treating Chagas disease23-25,27. However, only when Packachanian28,29 demonstrated experimentally that nitrofurans were promising for treating T. cruzi infection and Brener30 proved that nitrofurazone acted to cure chronically infected mice, with treatment for 53 days, did clinical treatment of Chagas disease began with some efficiency. Ferreira and Ferreira et al.31-33 demonstrated good results among children treated with nitrofurazone. Coura et al.34 managed to cure 3/10 chronic cases of the disease among adults treated for 60 days with a nitrofurazone dose of 10mg/kg/day, but with major side effects, especially polyneuropathy.
Currently, only two drugs are in use for treating Chagas disease: nifurtimox at a dose of 7.5 to 10mg/kg/day and benznidazole at a dose of 5 to 7.5mg/kg/day for 60 days. Several authors cited by Coura & Castro, Coura and Coura & Borges Pereira23-25 also conducted studies with nifurtimox and/or benznidazole in acute and chronic phase of Chagas disease. In a controlled study, was demonstrated that benznidazole was more efficient than nifurtimox for suppressing parasitemia in cases of chronic infection35. On the other hand, in a multicenter study, was demonstrated that treatment with benznidazole had the same suppressive action on parasitemia over 30 or 60 days of treatment36. Nifurtimox is a nitrofuran with a mechanism of action that (in a simplified manner) involves production of nitro-anion radiation, which in the presence of oxygen impedes the capacity of T. cruzi to detoxify the free radicals that act on it37. On the other hand, benznidazole acts by binding its metabolites to the nuclear deoxyribonucleic acid (DNA) of the parasite, and to its lipids and proteins38,39. Several clinical studies have been conducted and hundreds of patients have been treated with nifurtimox or benznidazole, with variations in the results between the studies and the regions where they were carried out. The average cure rate among acute and recent cases is 80%, while it is less than 20% among chronic cases23-25. A pilot study, the Benefit project - Benznidazole Evaluation for Interruping Trypanosomiasis - an international, multicenter, double-bind, placebo-controlled trial of tripanocidal chronic Chagas heart disease is in course40,41.
Several other drugs have been shown to be effective in vitro against T. cruzi. Among these are allopurinol, an antiuricemic hypoxanthine that is used to treat gout, and antifungals that inhibit ergosterol, such as ketoconazole, itraconazole and fluconazole42-46. These have not been shown to be effective in vivo, including during the acute phase of the disease. More recently, posaconazole, another azolic derivate, was shown to be very promising and is now at the clinical trial phase44.
What we do not know regarding the treatment of Chagas disease: A) why acute and recent cases of T. cruzi infection are more frequently cured than the chronic cases; B) why patients in a certain geographical area respond better to treatment than in other areas; C) why the serological parameters of chronic cases of Chagas disease do not become negative immediately after the cure has been achieve, but take years to become negative; D) why has there never been an attempt to use associations of drugs for treating Chagas disease, as is done in cases of tuberculosis, leprosy and HIV/AIDS, which came under control after using combinations of drugs. It is known that certain strains and clones of T. cruzi are resistant to treatment, as is the case of the Colombian strain. Cross-resistance to nifurtimox and benznidazole has also been observed.
In the areas where Chagas infection is more easily and frequently cured, this is probably achieved through greater sensitivity of the strains of T. cruzi and lower frequency of resistance to chemotherapy. Andrade et al.47,48 and Portella & Andrade49 showed that the dendritic cells of animals that had been experimentally treated remained impregnated with T. cruzi antigens, thus stimulating the presence of antibodies. This would explain the positive serological tests even after achieving parasitological cure.
SEROLOGICAL TESTS FOR DIAGNOSIS AND CURE VERIFICATION
The conventional serological tests for diagnosing Chagas disease and verifying its cure are indirect hemagglutination (IHA), indirect immunofluorescence (IIF), the immunoenzymatic test or enzyme-linked immunoabsorbent assay (ELISA). Other tests, such as Western blot, complement-mediated trypomastigote lysis and recombinant proteins are less used, mainly because of their high cost or the greater complexity of performing them. An extensive recent review by Luquetti and Schmunis50, on diagnosis of Trypanosoma cruzi, analysed carrefuly all serological tests for diagnosis and cure evaluation of Chagas infection. In this Review they states that the antibodies demand different timing to disappear according to the phase of the disease, and the type of T. cruzi. The acute phase and cronically infected with less than 10 years the antibodies desapear between 2 and 10 years51. In those countries where T. cruzi I predominates the antibody responses evanish by 16 in children52.
Despite the high specificity and ease of implementation of indirect hemagglutination, its sensitivity presents great variability, according to the origin of its production53. Thus, a second confirmatory test is required, especially when the titers range between 1/40 and 1/80. Indirect immunofluorescence, which was initially developed by Fife & Muschell54 for serological tests on T. cruzi infection and was adapted for blood collected on filter paper by Sousa & Camargo55, is a good test regarding its sensitivity. However, as well as the subjectivity of readings, it frequently presents cross-reactions with other diseases, especially with titers of 1/40 to 1/80. Nonetheless, according to Luquetti et al.56 it is an excellent test for diagnosing T. cruzi infection when the titers are greater than or equal to 1/320. The ELISA test developed by Voller et al.57 included adaptation for blood collected on filter paper, and it presents sensitivity similar to that of IIF, with the advantage of the possibility of automated reading. This avoids subjectivity and making it possible to apply the test to readings on a great number of samples, as is done in blood banks.
The Western blot test, and particularly the TESA blot using the excretion and secretion antigen of T. cruzi, as developed by Umezawa et al.58, is an excellent confirmatory test that is used especially in research laboratories, since its high cost makes its use in routine diagnosis prohibitive. On the other hand, although complement-mediated trypomastigote lysis, which was developed by Krettli & Brener59, is a good test for cure verification, its technique is difficult to reproduce in diagnostic laboratories. Some tests with recombinant proteins present high sensitivity and specificity, particularly the mixture of CRA and FRA (Biomanguinhos), and the recombinant Wiener ELISA has been applied with good results, but some kits may present false positive reactions, especially when adapted for quick tests, in the same way as synthetic peptides.
The great requirement today is for a quick test with high sensitivity, specificity and stability for fieldwork and blood bank emergencies, in different geographical areas where different strains and clones of T. cruzi (TcI to TcVI) circulate. The tests available, such as Stat-Pack® and Imbios®, present great variation in their sensitivity and specificity according to the geographical area, such as Central America, Bolivia and the Amazon region, and they must always be accompanied by a second confirmatory test60. Therefore, it is extremely important and necessary to develop a quick test with high sensivity and specificity.
MORBIDITY DIFFERENCES IN CHAGAS DISEASE ACCORDING TO GEOGRAPHICAL AREA
The regional variations in Chagas disease morbidity were very well evaluated by 32 specialists from nine countries in the Americas (Argentina, Bolivia, Brazil, Chile, Costa Rica, Paraguay, Peru, USA and Venezuela) during a meeting on Geographical Differences of Chagas disease in Brasília on August 4 to 5, 1975, coordinated by Prata61. Although the determining factors for these variations are not exactly known, they could be related to: A) virulence and pathogenesis of the strains and clones of T. cruzi circulating in the area (TcI to TcVI) and their biodemes15-17; B) qualities of the vector: anthropophily, capacity for metacyclogenesis to infecting forms of T. cruzi, time of evacuation (after or during the meal), number of infecting forms eliminated during excretion62; C) initial inoculum of infecting forms of T. cruzi and the number of reinfections19,20; D) initial and late host immune response, escape mechanisms for T. cruzi and its adherence to clonal histotropic receptors1,11,18; E) other factors that have still not been determined, such as adaptation of wild strains of T. cruzi to man, individual genetic factors and others that have not yet been characterized.
In the meeting on the geographical differences of Chagas disease, Professor Aluízio Prata, in his objective style, formulated 52 questions for the participants to answer, of which 48 were answered. These questions were in relation to: epidemiology (12), clinical characteristics (13), anatomopathological characteristics (11), chemotherapy and prevention (12) and not answered (4). The responses showed that there were striking differences in the prevalence and morbidity of Chagas disease, with regard to both heart disease and megas, with greater severity of the disease in countries south of the Equator. To the north, heart disease seemed to be less severe, there were practically no megas and the response to treatment had been seen to be better. Naturally, there were intraregional variations regarding epidemiological, clinical and anatomopathological factors and in relation to the response to treatment, which have also been observed more recently. On the other hand, there were also variations from one area to another within the same country, as in Brazil.
The evolutionary pattern of Chagas disease is still not completely defined because the morbidity and mortality varies considerably from one area to another. In the study that we carried out in Rio de Janeiro on 510 patients from several states in Brazil21, 39% were in the indeterminate clinical form, 52.1% in the heart disease form and 14.3% had megaesophagus and/or megacolon. An association between heart disease and megas was observed in 5.4% and between megaesophagus and megacolon in 10.9%. The highest heart morbidity was observed among patients in Goiás, Bahia, Minas Gerais and Pernambuco, while the lowest was among patients in Rio de Janeiro and Paraíba.
Over the past 38 years (1973-2011), several cross-sectional and longitudinal case-control studies have been conducted to evaluate the morbidity of Chagas disease in Brazil by our group over different periods and in different geographical areas of the State of Minas Gerais (Iguatama and Pains in the northwest of the state, Virgem da Lapa and Berilo in the Jequitinhonha valley)63-67; in the Caatinga (scrublands) of Piauí68; in the Sertão (semi-arid backcountry) of Paraíba69-70; and in areas of the Rio Verde region, Mato Grosso do Sul and the microregion of the middle and upper Negro River, State of Amazonas71-78, Borges-Pereira et al.79-88. Figure 1 shows the locations of the various field areas that have been or are being studied. There is a great variation of morbidity from one area to other89-91.
From 1999 onwards, we started to classify the areas into two categories: A) areas of high morbidity; and B) areas of low morbidity92.
Areas of high morbidity
Evolutionary (follow-up) studies were carried out in Iguatama (Area 1) and Pains (Area 2) in the northwest of Minas Gerais for 25 years (1973-1998) among 264 pairs of individuals (initially) of the same age and gender; in Virgem da Lapa (Area 3), among 1,109 pairs of individuals (initially), between 1976 and 2011; and in Berilo (Area 4) in the Jequitinhonha valley, in the north of Minas Gerais, among 100 pairs of individuals (initially). All the pairs of individuals who were investigated in the endemic areas underwent the same types of anamnesis, clinical examinations, electrocardiograms (ECG) with the 12 classical derivations with long D2 and chest X-rays, emphasizing cardiac and digestive signs and symptoms. Two cross-sectional studies with the same parameters were also carried out in the district of Oeiras (Area 5), in the State of Piauí, northeastern Brazil, separated by an interval of 20 years (1976-1996) among 109 pairs of individuals (initially).
The first cross-sectional study conducted in Iguatama (Area 1) and Pains (Area 2), Virgem da Lapa (Area 3), Berilo (Area 4) and Oeiras (Area 5) showed that the serological prevalence of Chagas infection (from indirect immunofluorescence) was 17.1% for Iguatama, 10.4% for Pains, 12.9% for Virgem da Lapa, 12.7% for Berilo and 12.1% for Oeiras. Heart morbidity evaluated by means of the gradient of electrocardiographic alterations among seropositive and seronegative individuals was, respectively, 23.4% in Iguatama, 18.4% in Pains, 19% in Virgem da Lapa, 22.5% in Berilo and 18.2% in Oeiras. In the evolutionary study, Chagas disease was progressive, by an average of 2.5 to 3% patient/year. Mortality was 5 times higher among Chagas patients and the lethality rate was approximately 2% patient/year, varying naturally with the initial severity of the heart disease92. Figures 2A, B and C shows the gradient of the clinical and electrocardiographic manifestations and the mortality among cases of Chagas disease and their controls, in Virgem da Lapa (Area 3).
Areas of low morbidity
A cross-sectional study carried out in 8 municipalities in the Sertão of Paraíba (Area 6) and in 12 municipalities in the Rio Verde region, Mato Grosso do Sul (Area 7), involving respectively 5,137 and 14,700 people, showed that the serological prevalence of Chagas infection in Paraíba was 9.5%, while it was only 1.8% in Mato Grosso do Sul. Heart morbidity, as evaluated according to the electrocardiographic gradient among seropositive and seronegative individuals, was 12.8% among 305 pairs of individuals studied in Paraíba and 15% among 70 pairs of autochthonous individuals in Mato Grosso do Sul. Chagas disease was progressive, at the rate of 1.3% patient/year in Paraíba, although the lethality due to the disease was very low (less than 0.4% patient/year). Mortality and lethality were not evaluated in Mato Grosso do Sul.
In three cross-sectional studies carried out in the municipality of Barcelos (Area 8), in the Negro River microregion, State of Amazonas, respectively in 1991, 1993 and 199776, screening serological tests on 2,254 serum samples showed a variation in positivity from 12.5% to 13.7%. However, only 2.8 to 5% were confirmed as positive by means of IIF, ELISA and Western blot (TESA-blot), with a high percentage of cross-reactions. In a recent serological study (2010-2011), IIF on filter paper revealed positivity of 4.5% among 4,880 serum samples from this area. A study on 38 pairs of serologically positive and negative individuals carried out recently by Brum-Soares et al.93 showed that the electrocardiograph gradient was 15.3% greater among the seropositive individuals, while the echocardiogram was altered among 36.8% of the seropositive individuals and among 18.4% of the seronegative individuals, with an echocardiograph gradient of 13.2%. Taking into considering the small number of patients, it was not possible to safely evaluate the real morbidity of Chagas disease. However, typical and fatal cases of chronic Chagas heart disease have been described in this area94,95.
Finally, we draw attention to the great regional and personal variation of morbidity among Chagas disease cases. Knowledge of these variations needs to be improved at both national and international level. Another challenge is the indeterminate form of Chagas disease defined since Chagas5 and validated by the Brazilian Society of Tropical Medicine89 as asymptomatic human infection by T. cruzi without ECG and Rx abnormality in the heart, esophagus or colon25. Even though some abnormalities may appear in the ECG and in the echocardiogram. The indeterminate form of Chagas disease clearly represents a benign condition with a long-term prognosis90.
METACYCLOGENESIS OF TRYPANOSOMA CRUZI IN DIFFERENT SPECIES OF TRIATOMINES AND DIFFERENCES IN INFECTION ACCORDING TO THE PARASITE STRAIN
Metacyclogenesis of T. cruzi in different species of triatomines is of great importance in the transmission of Chagasic infection. Some species such as T. pseudomaculata can transform T. cruzi into infective metacyclic species in little more than 10% of the cases. Thus, this species of triatomine is considered to be a vector of poor efficiency. Other species such as T. infestans, R. prolixus and P. megistus can transform 60 to 70% of the strains of T. cruzi into forms that are infective to humans and other vertebrates. This is a very important characteristic in the transmission dynamics and, thus, in the quality of the vector.
Trypanosoma cruzi in the digestive tract of triatomines goes through several transformations from ingested trypomastigotes, to spheromastigotes and epimastigotes, until reaching the infective metacyclic trypanosomes. These are then eliminated through the feces and urine of the vectors96,97. This process involves a series of biochemical and immunological mechanisms, in which the enzymes, hemolysins, agglutinins and other antimicrobacterial agents have still not been properly investigated98. According to these authors, better understanding of the basic mechanisms of parasite-vector interactions will bring new perspectives for controlling some parasitic diseases.
In an experimental study by Perlowagora-Szunlewicz et al.99 on the interactions of nine vector species (R. prolixus, R. megistus, T. infestans, T. braziliensis, T. sordida, T. pseudomaculata, T. rubrovaria and T. dimidiata) that were fed on guinea pigs infected with seven different strains of Trypanosoma cruzi (Berenice, Y, FL, CL, São Felipe, Colombiana and Gávea), the following mean triatomine infection rates were demonstrated 30, 60, 90 and 120 days after infection. As can be seen, there was great variation in the triatomine infection rates according to the species and strain of the infecting T. cruzi (Table 1).
The mean positivity rate among the various species of triatomines ranged from 9.8% (T. dimidiata) to 91.4% (T. pseudomaculata), with mean positivity of 67.3%. T. pseudomaculata (91.4%) Triatoma sordida (89.7%), R. neglectus (89.7%), P. megistus (87.9%) and T. rubrovaria (80.8%) were above the mean, while T. dimidiata (9.8%), T. infestans (45.4%), R. prolixus (46%) and T. braziliensis (65.4%) were below it. The authors concluded that the domesticated species of triatomines (T. dimidiata and T. infestans) were less infected than the wild species, which is true, but they considered that P. megistus, T. sordida and T. pseudomaculata were wild species. In reality, these are not exclusively wild species, but can also be peridomestic and domestic. Among the species studied, R. neglectus and T. rubrovaria can be considered to be wild. On the other hand, the best transmitters are not always the vectors that were most infected experimentally, because of metacyclogenesis of T. cruzi in the digestive tract. This was the case of T. pseudomaculata, which was the species most infected in this experiment, but it converts little more than 10% of the ingested T. cruzi into the infecting form. In the cited study, it was demonstrated that this species may be best for xenodiagnosis, but not as a vector for T. cruzi.
RISKS OF WILD TRIATOMINE ADAPTATION TO HUMAN DWELLINGS
Primitive trypanosomes were monogenetic parasites of non-blood sucking insects that were probably predators. When these insects acquired the habit of sucking blood millions of years ago, they underwent morphological and functional adaptations such that they developed an undulating membrane and flagellum to circulate in the blood of vertebrates, which is the most likely hypothesis for their evolution100. Triatomines have been known since the 14th century, but were only described in 1773 by DeGeer, who described Cimex rubrofasciata (Triatoma rubrofasciata), originally from India101. Since then, more than 130 species of 19 genera of the Triatominae subfamily have been described, of which the vast majority are wild triatomines.
The domestication process among wild triatomines is still not completely known. The evolution from predators to blood suckers was associated with a series of morphological, behavioral and demographic modifications relating to three key factors: a) exploitation of vertebrate blood as a food source; b) adaptation to the host's environment; c) progressive dependence on the host as a means of dispersion through passive transportation102. This process involves genetic specialization and simplification. The sensory system of triatomines has become progressively simplified with the stability of the domestic habitat103. On the other hand, reduction of the size of the insects and sexual dimorphism may have occurred104. The high gnetic variability of wild T. infestans favours the hipothesis that the Andean were the centre of dispersal of this specie through South America and it adaptation to human dwellings105.
Wild triatomines approach human peridomestic and domestic areas primarily due to feeding needs, due to deforestation and the distance from their natural sources, which are wild mammals, or when the numbers of these animals become reduced in the natural habitats106,107. Sometimes, wild triatomines are attracted by domestic lights or they penetrate the home due to its proximity to palm trees, which occurs frequently in the Amazon region1,78. Thus, people may become infected accidently or there may even be epidemic outbreaks due to food contamination and oral transmission108,109.
The adaptation of wild triatomines to human homes is perhaps the most polemical and uncertain issue among all the knowledge on Chagas disease. It is certainly one of the most important matters, since even if we can control the few domesticated species of triatomines, there will always be the risk of reinvasion of homes by another hundred wild species.
MORBIDITY OF CHAGAS DISEASE IN THE AMAZON REGION
Since Carlos Chagas110 confirmed as T. cruzi trypanosomes isolated from the monkey Saimiri sciureus, from Pará, Chagas disease has been considered to be an enzootic disease of wild animals in the Amazon region. Deane111-115, Deane & Jansen116 and Deane & Damasceno117 and several other authors confirmed this concept, describing the presence of T. cruzi among 33 species of six orders of wild animals (Marsupialia, Chiroptera, Rodentia, Edentada or Xenarthra, Carnivora and Primata). Floch & Tasqué118 and Floch & Cormain119 reported the first cases of humans with acute Chagas disease in French Guiana (Amazon region), and Shaw et al.120 described the four first acute cases of the disease that occurred in an outbreak in Belém in Pará, Brazil, probably through oral transmission. Since then, more than 60 outbreaks of the acute disease have been described in this region, especially in Pará, Amapá and Amazonas108,109,121. Between 1969 and 2008, the Surveillance Department of the Brazilian Ministry of Health notified 761 cases of Chagas disease in the Brazilian Amazon region, and 75% of these (568 cases) were between 2002 and 200893.
Over the last 20 years (1991-2011), we have developed seroepidemiological surveys and clinical, radiological and electrocardiographic studies among populations that were seropositive for Chagas infection, in the middle and upper regions of the Negro River, in the State of Amazonas72-74,76-78. Several typical and fatal chronic cases of Chagas disease were described94,95, involving more than 7,000 screening serological reactions and more than 300 confirmatory serological reactions. In three preliminary seroepidemiological surveys conducted in 1991, 1993 and 1997, we carried out 2,254 screening serological reactions using IIF on blood collected on filter paper and found that the mean positivity rate was 13%76, although only 2.5% to 5% were confirmed by means of serum IIF, ELISA and trypomastigote excreted-secreted antigens (TESA)-blot. More recently, we carried out 4,880 screening serological reactions using IIF on blood samples on filter paper and found a positivity rate of 4.5% for Chagas infection. These cases are now undergoing confirmatory serological reactions.
In a recent seroepidemiological study93 carried out among 152 individuals living in the municipality of Barcelos, of whom several had already been evaluated previously, serological reactions by means of immunofluorescence, conventional and recombinant ELISA and TESA-blot were used. Thirty-eight (25%) individuals were considered positive i.e. with at least two positive reactions from different mechanisms, 31 (20.4%) were uncertain with only one positive reaction, and 83 (54.6%) were negative, with the four reactions negative. Positive serological reactions were 10.4 times more frequent among piaçaba (Attalea funifera) gatherers, and thus Chagas infection was characterized as a professional disease. A total of 86.7% of the seropositive individuals recognized Rhodnius as the local vector, while only 34.2% of the seronegative individuals recognized it as such. The 38 seropositive individuals were matched by age and gender with other, seronegative individuals and underwent clinical, electrocardiograph and echocardiograph examinations. Twenty-nine of these pairs underwent chest radiography with contrasted esophagus. The most evident clinical manifestations were palpitations in 31.6% of the seropositive group and 21.8% of the seronegative group and chest pain in, respectively, 28.9% and 15.8% of the seropositive and seronegative groups. The electrocardiogram was altered in 36.8% of the seropositive group and 21.5% of the seronegative group (gradient of 15.3%) and the echocardiogram was altered in 31.6% of the seropositive individuals and 18.4% of the seronegative individuals (gradient of 13.2%). The cardiothoracic rate was greater than 0.5 in four (13.8%) seropositive patients and three (10.3%) seronegative individuals, while the esophagus radiography did not show alterations in either of the groups. It can be concluded that heart morbidity in this area is low and esophagus morbidity is absent, and that it is necessary to increase the number of studied cases for better evaluation of the morbidity of the disease in this area.
Need to establish a surveillance and control program for Chagas disease in the Amazon region
In September of 2004 a meeting was held by the Pan-American Health Organization with the objective of organizing an Initiative for Surveillance and Control of Chagas Disease in Amazon Countries, which was called AMCHA (Amazonas Chagas). Representatives of the governments of the nine countries of the Amazon region and more than 90 researchers from the different countries, including the president of the Brazilian National Research Council (CNPq), participated in this meeting. At the end of the meeting, the following objectives were established: a) To assess the risks of Chagas disease becoming endemic in the Amazon region; b) To define the research needed for surveillance and prevention of the disease in the region; c) To propose surveillance and control measures for the disease in the region; d) To establish a proposal for an international cooperation system among the nine Amazon countries for an integrated surveillance and control system. Three other meetings were held, respectively in Cayenne, French Guiana, in 2005; in Quito, Ecuador, in 2006; and in Caracas, Venezuela, in 2008. However, despite recognition of the risks of the disease becoming endemic in the region, the need to increase knowledge through research on Chagas disease in the region and several proposals for surveillance and prevention, very little has been done up to the present date.
Most cases in the Brazilian Amazon region occur through outbreaks caused by oral transmission108, while vector transmission occurs mainly among plant product extractive workers, particularly in relation to piaçaba93. The perspectives for control over the disease in this region are as follows: a) the Surveillance Department of the Ministry of Health has established a surveillance system in the Brazilian Amazon region through compulsory notification of the disease; b) Courses have been conducted to train the malaria microscopists and capacitate the public laboratory networks (LACENs) of the nine Brazilian states in the Amazon region, with support from Doctors Without Borders between 2006 and 2008; c) A manual was prepared for these microscopists and technicians of the public laboratories122. Consequently, 100 to 150 new acute cases of Chagas disease are being notified in the Amazon region every year. However, from our perspective, this represents less than 10% of the occurrence of cases, given that most these individuals do not seek the healthcare services because they do not know of the disease, or because of the distance from medical care centers, among other factors.
We also suggest that training should be provided for elementary school teachers and community health agents to work as knowledge multipliers about the disease and its vectors, so as to widen the surveillance and control network for Chagas disease in the Brazilian Amazon region. Teachers have access to children, who are naturally curious and, through familiarity, can locate vectors in the peridomestic and domestic areas. On the other hand, when community health agents are well informed, not only can they recognize the vectors and the disease, but also they can send the insects collected and the suspected patients to the regional health centers, in order to identify the specimens and provide possible treatment for the patients.
PRIORITIZATION OF CONTROL INITIATIVES FOR CHAGAS DISEASE IN LATIN AMERICA AND MEXICO AND IN NON-ENDEMIC COUNTRIES
The control initiatives for Chagas disease in endemic countries, created respectively for the Southern Cone in 1991, Andean Countries in 1997, Central America and Mexico in 1998 and the Amazon region in 2004, received a large boost early on, especially in the Southern Cone, where Uruguay, Chile and Brazil eliminated T. infestans and Paraguay and Argentina have been working towards this objective. In South America, the biggest current problems are located in Bolivia and in the Gran Chaco, belonging to Argentina, Bolivia and Paraguay, where the prevalence of Chagas infection is very high in some communities. Several countries in Central America are working towards the aim of eliminating R. prolixus. We see these as countries where control measures should be stimulated. Moreover, in Bolivia and Mexico, the problem is significant but the control measures are limited. On the other hand, the Andean countries and the Amazon Initiative need a greater boost.
Several meetings have been held in different countries to discuss the subject. In 2009, a meeting was held in Uberaba, State of Minas Gerais, Brazil123. At this meeting, the outcomes from several initiatives were weighed up, with a focus on the following challenges: I) stimulation to reestablish the political priority of controlling Chagas disease; II) reinforcement of the international coordination and evaluation of national programs through the initiatives; III) effective definition and implementation of quality standards for all the preventive actions, giving priority to vector control, blood banks, treatment of acute cases and care for chronic patients. In 2011, another meeting was held in Bogotá, Colombia and another meeting is scheduled to be held in Rio de Janeiro, during the 18th International Congress of Tropical Medicine and Malaria on September 23-27, 2012.
Finally, it is important to highlight the problem of Chagas disease in non-endemic countries, especially in Europe and in the United States124 125. Regarding the new initiatives, we suggest that in 2012 international congress, there should be discussion about the need to create a specific control initiative for Chagas disease in the Gran Chaco.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Project 471716/2009-0 and Fundação Oswaldo Cruz (FIOCRUZ).
1. Coura JR. Chagas disease: what is known and what is needed - A background article. Mem Inst Oswaldo Cruz 2007; 102:113-122. [ Links ]
2. Zingales B, Andrade SA, Briones MRS, Campbell DA, Chiari E, Fernandes O, et al. A new concensus for Trypanosoma cruzi intraespecific nomenclature: second revision meeting recommends TcI to TcVI. Mem Inst Oswaldo Cruz 2009; 104:1051-1054. [ Links ]
3. Chagas C. Nova tripanozomiase humana. Estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruzi n. gen. n. sp., ajente etiolójico de uma nova entidade mórbida do homem. Mem Inst Oswaldo Cruz 1909; 1:159-218. [ Links ]
4. Chagas C. Tripanosomiase americana. Forma aguda da moléstia. Mem Inst Oswaldo Cruz 1916a; 8:37-60. [ Links ]
5. Chagas C. Processos patojenicos da Tripanozomiase Americana. Mem Inst Oswaldo Cruz 1916b, 8:5-36. [ Links ]
6. Chagas C, Villela E. Forma cardíaca da Trypanosomiase Americana. Mem Inst Oswaldo Cruz 1922; 14:5-61. [ Links ]
7. Vianna G. Contribuição para o estudo da anatomia patológica da "Moléstia de Carlos Chagas". Mem Inst Oswaldo Cruz 1911; 3:276-293. [ Links ]
8. Santos-Buch CA, Teixeira ARL. The immunology of experimental Chagas disease. III. Rejection of allogeneic heart cells in vitro. J Exp Med 1974; 140:38-53. [ Links ]
9. Teixeira ARL. Autoimmune mechanism in Chagas' disease. In: American Trypanosomiasis Research. Pan Am Health Org Sci Publ 1975; 318:98-108. [ Links ]
10. Tarleton RL. Chagas disease: a role for autoimmunity? Trends Parasitol 2003; 19: 447-451. [ Links ]
11. Teixeira ARL, Nascimento RJ, Sturm NR. Evolution and pathology in Chagas disease - A Review. Mem Inst Oswaldo Cruz 2006; 101: 463-491. [ Links ]
12. Higuchi ML. Human Chronic Chagas Cardiopathy: Participation of Parasite Antigens, subsets of Lymphocytes, Cytokines and Microvascular Abnormalities. Mem Inst Oswaldo Cruz 1999; 94 (Suppl I): 263-267. [ Links ]
13. Köberle F. Patologia y anatomia patológica de la enfermedad de Chagas. Bol Ofi Sanit Panam 1961; 51: 404-428. [ Links ]
14. Prata A. Clinical and epidemiological aspects of Chagas disease. Lancet Infect Dis 2001; 1:92-100. [ Links ]
15. Andrade SG. Caracterização de cepas de Trypanosoma cruzi isolados no Recôncavo Bahiano. Rev Pat Trop 1974; 3:65-121. [ Links ]
16. Andrade SG. Tentative for grouping different Trypanosoma cruzi strains in some types. Rev Inst Med Trop São Paulo 1976; 18: 140-141. [ Links ]
17. Andrade SG, Magalhães JB. Biodemes and Zimodemes of Trypanosoma cruzi strains: correlations with clinical data and experimental pathology. Rev Soc Bras Med Trop 1997; 30: 27-35. [ Links ]
18. Macedo AM, Pena SDJ. Genetic variability of Trypanosoma cruzi implications for the pathogenic of Chagas disease. Parasitol Today 1998; 14: 119-124. [ Links ]
19. Dias JCP. Doença de Chagas em Bambuí, Minas Gerais, Brasil. Estudo clínico-epidemiológico a partir da fase aguda entre 1940 e 1982. [Doctors Thesis]. [Belo Horizonte]: Universidade Federal de Minas Gerais 1982; 376 p. [ Links ]
20. Macedo VO. Influência da exposição à reinfecção na evolução da doença de Chagas (Estudo evolutivo de cinco anos). Rev Pat Trop 1976; 5:33-116. [ Links ]
21. Coura JR, Anunziato N, Willcox HPF. Morbidade da doença de Chagas. I Estudo de casos procedentes de vários estados do Brasil, observados no Rio de Janeiro. Mem Inst Oswaldo Cruz 1983; 78:363-372. [ Links ]
22. Luquetti AO. Etiological treatment for Chagas disease. The National Health Foundation of Brazil. Parasitol Today 1977; 127-128. [ Links ]
23. Coura JR, Castro SL. A critical review on Chagas disease Chemotherapy. Mem Inst Oswaldo Cruz 2002; 97: 3-24. [ Links ]
24. Coura JR. Present Situation and new Strategies for Chagas disease Chemotherapy - a proposal. Mem Inst Oswaldo Cruz 2009; 104: 549-554. [ Links ]
25. Coura JR, Borges-Pereira J. Chronic phase of Chagas disease: why should it be treated? A comprehensive Review. Mem Inst Oswaldo Cruz 2011; 106:641-645. [ Links ]
26. New York Heart Association. Nomenclature and criteria for diagnonis of diseases of the heart and great vessels. 7th edition. Boston: Little and Brown Company; 1973. [ Links ]
27. Coura JR, Silva JR. Aspectos atuais do tratamento da doença de Chagas. Arq Bras Med 1961; 51:283-290. [ Links ]
28. Packchanian A. Chemotherapy of experimental Chagas disease with nitrofuran compounds. J Parasitol 1952; 38:30-40. [ Links ]
29. Packchanian A. Chemotherapy of experimental Chagas disease with nitrofuran compounds. Antibiot Chemother 1957; 7:12-23. [ Links ]
30. Brener Z. Atividade terapêutica do 5-nitrofuraldeido-semicarbazona (nitrofurazona) em esquema de duração prolongada na infecção experimental pelo Trypanosoma cruzi. Rev Inst Med Trop de São Paulo 1961; 3:43-49. [ Links ]
31. Ferreira HO. Forma aguda da doença de Chagas tratada pela nitrofurazona. Rev Inst Med Trop de São Paulo 1961; 3: 287-289. [ Links ]
32. Ferreira HO. Fase aguda da doença de Chagas. O Hospital 1962; 61:307-311. [ Links ]
33. Ferreira HO, Prata A, Rassi A. Administração prolongada da nitrofurazona no tratamento da doença de Chagas aguda. O Hospital 1963; 63:1391-1396. [ Links ]
34. Coura JR, Ferreira LF, Silva JR. Experiência com nitrofurazona na fase crônica da doença de Chagas. O Hospital 1962; 62: 957-964. [ Links ]
35. Coura JR, Abreu LL, Willcox HPF, Petana W. Comparrative controled study on the use of benznidazole, nifurtimox and placebo in the chronic form of Chagas disease in a field area with interrupted transmission. I - Preliminar evaluation. Rev Soc Bras Med Trop 1997; 30:139-144. [ Links ]
36. Coura JR, Brindeiro PJ, Ferreira I. Benznidazole in the treatment of Chagas disease. Current Chemother Proc 10th Int Cong Chemother 1978; 1:161-162. [ Links ]
37. Campo R, Moreno SNJ. Free radical metabolism antiparasit agent. Fed Proceed 1986; 45: 2471-2476. [ Links ]
38. Polack A, Richle R. Mode of action of 2-nitro-imidazole derivative benznidazole. Ann Trop Med Parasitol 1978; 72:228-232. [ Links ]
39. Dias-de-Toranzo EG, Castro JA, Franke-de-Cazzulo BM, Cazzulo JJ. Interaction of benznidazole reative metabolism with nuclear and kinoplastic DNA, protein and lipids from. Trypanosoma cruzi. Experientia 1988; 44: 880-881. [ Links ]
40. Marin-Neto JA, Rassi Jr A, Morillo CA, Avezum A, Connolli SJ, Sosa-Estani S, et al. BENEFIT Investigators rationale and design of a radonmized placebo-controlled trial of etiologic treatment in Chagas cardiomyopathty. The Benznidazole Evaluation for Interrpting Trypanosomiasis (BENEFIT). Am Heart J 2008; 156: 37-43. [ Links ]
41. Marin-Neto JA, Rassi Jr A, Avezum Jr A, Mattos AC, Rassi A. The BENEFIT trial: testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease. Mem Inst Oswaldo Cruz 2009; 104 (supl I): 319-324. [ Links ]
42. Urbina JA, Poyares G, Molina J, Sanoja C, Liendo A, Lazardi K, et al. Cure of short and long-term experimental Chagas disease using DO870. Science 1996; 273: 969-971. [ Links ]
43. Urbina JA, Lira R, Visbal G, Bartroli J. In vitro antiproliferative effects and mechanism of action of the new triazole derivate UR - 9825 against the protozoan Trypanosoma (Schizotrypanum) cruzi. Antimiocrob Agents Chemother 2000; 44: 2498-2502. [ Links ]
44. Molina J, Martins-Filho O, Brener Z, Romanha AJ, Loebenberg D, Urbina JA. Activicties of the triazole SCH 56592 (pozoconazole) against drug-resistance strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine host. Antimicrob Agents Chemother 2000; 44:150-155. [ Links ]
45. Molina J, Urbina J, Gref R, Brener Z, Rodriguez-Junior JM. Cure of experimental Chagas disease by the bis-triazole DO870 incorporated into "Stealth" polyethyleneglycol-polylactide nanospheres. J Antimicrob Chemother 2001; 47:101-104. [ Links ]
46. Campo R. Recent developments in the chemotherapy of Chagas disease. Curr Pharm Design 2001; 7:1157-1164. [ Links ]
47. Andrade SG, Freitas LAR, Peyrol S, Pimentel AR, Sardigursky M. Experimental chemotherapy of Trypanosoma cruzi infection persistence of parasite antigens and positive serology in parasitologically cured mice. Bull WHO 1991; 69:191-199. [ Links ]
48. Andrade SG, Pimentel AR, Souza MM, Andrade ZA. Interstitial dendritic cells of the heart harbor Trypanosoma cruzi antigens in experimentally infected dogs: importance for the pathogenesis of chagasic myocarditis. Am J Trop Med Hyg 2000; 63: 64-70. [ Links ]
49. Portella RS, Andrade SG. Trypanosoma cruzi parasite antigens sequestred in heart interstitial dentritic cells are related to persisting myocarditis in benznidazole treated mice. Mem Inst Oswaldo Cruz 2009; 104:1023-1030. [ Links ]
50. Luquetti AO, Scmunis GA. Diagnosis of Trypanosoma cruzi infection. In: Telleria J, Tibayrenc M, editors. American tripanosomiasis (Chagas disease) one hundred years of research. E-book. Amsterdam: Elsevier 2010; p. 743-792. [ Links ]
51. Rassi A, Luquetti AO. Specific treatment for Trypanosoma cruzi infection (Chagas disease). In: Tyler KM, Miles MA, editor. American Trypanosomiasis. Kluwer Academic Publishers, Boston 2003: 117-125. [ Links ]
52. Yun O, Lima MA, Ellman I, Chambi W, Castilho S, Flevaud L, et al. Feasibility, drug safety, and efectiveness of etiological treatment programs for Chagas disease in Honduras, Guatemala and Bolivia: 10 years experience of Médecin Sans Frontières. PLoS Negl Trop Dis 3; e 488. [ Links ]
53. Saez-Alquezar A, Luquetti AO, Borges-Pereira J, Furtado EM, Gadelha MFS, Garcia Zapata MT, et al. Estudo multicêntrico: avaliação do desempenho de conjuntos diagnósticos de hemaglutinação indireta, disponíveis no Brasil para o diagnóstico sorológico da infecção pelo Trypanosoma cruzi. Rev Patol Trop 1977; 267:334-374. [ Links ]
54. Fife EH, Muschel LH. Fluorescent Antibody Technic for Serodiagnosis of Trypanosoma cruzi infection. Proc Soc Exp Biolog Med 1959; 101: 540-543. [ Links ]
55. Souza SL, Camargo ME. The use of filter paper blood smear in a pratical fluorescent test for American Trypanosomiasis serodiagnosis. Rev Inst Med Trop São Paulo 1966; 8:255-258. [ Links ]
56. Luquetti AO, Tavares SBN, Oliveira RA, Siriano LR, Costa DG, Oliveira EC, et al. Sorologia como critério de cura em pacientes tratados com benzonidazol. Títulos obtidos por imunofluorescência indireta. Rev Soc Bras Med Trop 2008; 41(Supl III): 242-243. [ Links ]
57. Voller A, Draper C, Bidwell DE, Barlett A. A microplate enzyme-linked immune absorbent assay (ELISA) for Chagas disease. Lancet 1975; 1: 426-429. [ Links ]
58. Umezawa ES, Nascimento MS, Kesper Junior N, Coura JR, Borges-Pereira J, Junqueira ACV, et al. Immunoblot assay using excreted-secreted antigens of Trypanosoma cruzi in serodiagnosis of congenital, acute and chronic Chagas disease. J Clin Microbiol 1996; 34:2143-2147. [ Links ]
59. Krettli AU, Brener Z. Resistance against Trypanosoma cruzi Associated to Anti-living trypomastigote antibodies. J Immunol 1982; 128:2009-2012. [ Links ]
60. Luquetti AO, Ponce C, Ponce E, Esfandiari J, Schijman A, Revolvollo S, et al. Chagas disease diagnosis: a multicentric evaluation of Chagas Stat-Pak, a rapid immunochromatographic assay with recombinant proteins of Trypanosoma cruzi. Diagnostic Microbiol and Infec Dis 2003; 46:265-271. [ Links ]
61. Prata A. Reunião sobre Diferenças Geográficas na Doença de Chagas. Brasília: Escopo Editora; 1975. [ Links ]
62. Coura JR. Determinantes epidemiológicos da doença de Chagas: a infecção, a doença e sua morbi-mortalidade. Mem Inst Oswaldo Cruz 1988; 83 (supl I):392-402. [ Links ]
63. Abreu LL. Doença de Chagas. Estudo da Morbidade no município de Pains, Minas Gerais. [Masters Dissertation]. [Rio de Janeiro]: Universidade Federal do Rio do Janeiro; 1977. 87 p. [ Links ]
64. Dubois LEG. Morbidade da doença de Chagas. Estudo Seccional em uma área endêmica. [Masters Thesis]. [Rio de Janeiro]: Universidade Federal do Rio de Janeiro; 1997. 82 p. [ Links ]
65. Borges-Pereira J. Morbidade da doença de Chagas. Estudo Seccional e longitudinal de uma área endêmica, Virgem da Lapa, MG. [Masters Dissertation]. [Rio de Janeiro]: Instituto Oswaldo Cruz; 1983. 132 p. [ Links ]
66. Borges-Pereira J. Doença de Chagas Humana. Estudo da Infecção Crônica, Morbidade e Mortalidade em Virgem da Lapa, MG, Brasil. (1976-1996). [Doctors Thesis]. [Rio de Janeiro]: Instituto Oswaldo Cruz; 1997. 197 p. [ Links ]
67. Araújo RM. Morbidade da doença de Chagas no município de Berilo, Minas Gerais, Brasil. Estudo seccional e evolutivo de 10 anos (1987-1997). [Doctors Theis]. [Rio de Janeiro]: Instituto Oswaldo Cruz; 1998. 153 p. [ Links ]
68. Correia-Lima FG. Doença de Chagas no município de Oeiras, Piauí. Estudo seccional nas localidades de Colonia e Oitis. [Masters Thesis]. [Rio de Janeiro]: Universidade Federal do Rio de Janeiro; 1976. 67 p. [ Links ]
69. Arruda Junior ER. Estudos sobre a doença de Chagas nos municípios de Aguiar e Boqueirão dos Cochos, Vale do Piancó, Estado da Paraíba. [Masters Thesis]. [Rio de Janeiro]: Universidade Federal do Rio de Janeiro; 1981. 80 p. [ Links ]
70. Coura JR, Abreu LL, Dubois LEG, Correia-Lima FG, Arruda-Junior ER, Willcox HPF, et al. Morbidade da doença de Chagas. II. Estudos seccionais em quatro áreas de campo no Brasil. Mem Inst Oswaldo Cruz 1984; 79:
101-124. [ Links ]
71. Coura JR, Abreu LL, Borges-Pereira, Willcox HPF. Morbidade da doença de Chagas. IV. Estudo longitudinal de dez anos em Pains e Iguatama, Minas Gerais, Brasil. Mem Inst Oswaldo Cruz 1985; 80:73-80. [ Links ]
72. Coura JR, Junqueira ACV, Giordano CM, Fumatsu IR. Chagas disease in the Brazilian Amazon. I - A short review. Rev Inst Med Trop São Paulo 1994a; 36:363-368. [ Links ]
73. Coura JR, Arboleda-Naranjo M, Willcox HPF. Chagas disease in the Brazilian Amazon. II - A serological survey. Rev Inst Med Trop São Paulo 1995a; 37:103-107. [ Links ]
74. Coura JR, Willcox HPF, Arboleda-Naranjo M, Fernandes O, Paiva DD. Chagas disease in the Brazilian Amazon. III. A cross-sectional study. Rev Inst Med Trop São Paulo 1995b; 37:415-420. [ Links ]
75. Coura JR, Borges-Pereira J, Alves-Filho FI, Castro JAF, Cunha RV, Costa W, et al. Morbidade da doença de Chagas em áreas do Sertão da Paraíba e da Caatinga do Piauí. Rev Soc Bras Med Trop 1996; 29:197-205. [ Links ]
76. Coura JR, Junqueira ACV, Boia MN, Fernandes O. Chagas disease: from bush to huts and houses. Is it the case of the Brazilian Amazon? Mem Inst Oswaldo Cruz 1999a; 94 (supl 1): 379-384 [ Links ]
77. Coura JR, Junqueira ACV, Boia MN, Fernandes O, Bonfante C, Campos JE, et al. Chagas disease in the Brazilian Amazon. IV - A new cross-sectional study. Rev Inst Med Trop São Paulo 2002a; 44:159-165. [ Links ]
78. Coura JR, Junqueira ACV, Fernandes O, Valente SAS, Miles MA. Emerging Chagas disease in Amazonian Brazil. Trends in Parasitol 2002b; 18:171-176. [ Links ]
79. Borges-Pereira J, Willcox HPF, Coura JR. Morbidade da doença de Chagas. III - Estudo longitudinal de seis anos em Virgem da Lapa, MG, Brasil. Mem Inst Oswaldo Cruz 1985; 80:63-71. [ Links ]
80. Borges-Pereira J, Coura JR. Morbidade da Doença de Chagas. Estudo seccional em uma área endêmica, Virgem da Lapa, Minas Gerais. Rev Soc Bras Med Trop 1986; 19: 139-148. [ Links ]
81. Borges-Pereira J, Coura JR. Morbidade da doença de Chagas em populações urbanas do Sertão da Paraíba. Rev Soc Bras Med Trop 1987; 20:101-107. [ Links ]
82. Borges-Pereira J, Cunha RV, Willcox HPF, Coura JR. Evolução da cardiopatia chagásica no Sertão do Estado da Paraíba, Brasil, no período de 4,5 anos. Rev Soc Bras Med Trop 1990; 23:141-147. [ Links ]
83. Borges-Pereira, Willcox HPF, Coura JR. Evolução da cardiopatia chagásica crônica I - Influência da Parasitemia. Rev Soc Bras Med Trop 1992; 25:101-108. [ Links ]
84. Borges-Pereira J, Xavier SS, Pirmez C, Coura JR. Doença de Chagas em Virgem da Lapa, Minas Gerais, Brasil. IV - Aspectos clínicos e epidemiológicos do aneurisma ventricular esquerdo. Rev Soc Bras Med Trop 1998; 31:457-463. [ Links ]
85. Borges-Pereira J, Zauza PL, Galhardo MCG, Nogueira JS, Pereira G, Cunha RV. Doença de Chagas na população urbana do Distrito Sanitário do Rio Verde, Mato Grosso do Sul, Brasil. Rev Soc Bras Med Trop 2001; 34:399-405. [ Links ]
86. Borges-Pereira J, Castro JAF, Campos JHF, Nogueira JS, Zauza PL, Marques P, et al. Estudo da infecção e morbidade da doença de Chagas no município de João Costa - Parque Nacional Serra da Capivara, Piauí, Brasil. Rev Soc Bras Med Trop 2002; 5:315-322. [ Links ]
87. Borges-Pereira J, Castro JAF, Silva AR, Zauza PL, Bulhões TP, Gonçalves MER, et al. Soroprevalência da infecção chagásica no Estado do Piauí 2002. Rev Soc Bras Med Trop 2006; 39:530-539. [ Links ]
88. Borges-Pereira J, Xavier SS, Castro JAF, Zauza PL, Coura JR. Prevalência do aneurisma do ventrículo esquerdo em pacientes chagásicos crônicos de duas Áreas do Estado do Piauí. Rev Soc Bras Med Trop 2007; 40:521-526. [ Links ]
89. Anonimous. Consenso Brasileiro em Doença de Chagas. Rev Soc Bras Med Trop 2005; 38:(Supl III):1-29. [ Links ]
90. Ianni BM, Arteaga E, Frim CC, Barretto ACP, Mady C. Chagas Heart Disease: Evolutive Evaluation of Electrocardiographic and Echocardiographic Parameters in Parameters in Patient with the Indeterminate Form. Arq Bras Cardiol 2001; 77: 59-62. [ Links ]
91. Borges-Pereira J, Sarquis O, Zauza PL, Britto C, Lima MM. Epidemiologia da doença de Chagas em quatro localidades rurais de Jaguarauana, Estado do Ceará. Rev Soc Bras Med Trop 2008; 41:345-351. [ Links ]
92. Coura JR, Borges-Pereira J, Araujo RM. Morbidity and Regional variation in Chagas disease in Brazil. Mem Inst Oswaldo Cruz 1999b; 94 (supl II); 26-27. [ Links ]
93. Brum-Soares L, Xavier SS, Sousa AS, Borges-Pereira J, Ferreira JMBB, Costa IR, et al. Morbidade da doença de Chagas em pacientes autóctones da microrregião do Rio Negro, Estado do Amazonas. Rev Soc Bras Med Trop 2010; 43:170-177. [ Links ]
94. Albajar PV, Laredo SV, Terrazas MB, Coura JR. Miocardiopatia dilatada em pacientes com infecção chagásica crônica. Relato de dois casos fatais autóctones do Rio Negro, Estado do Amazonas. Rev Soc Bras Med Trop 2003; 36: 401-407. [ Links ]
95. Xavier SS, Sousa AS, Junqueira ACV, Boia MN, Coura JR. Cardiopatia chagásica crônica no Rio Negro, Estado do Amazonas. Relato de três novos casos autóctones, comprovados por exames sorológicos, clínicos, radiográficos de tórax, eletro e ecocardiográfico. Rev Soc Bras Med Trop 2006; 39:211-216. [ Links ]
96. Alvarenga NJ. Evolução do Trypanosoma cruzi no trato intestinal do Triatoma infestans. [Maters Thesis]. [Belo Horizonte]: Universidade Federal de Minas Gerais; 1974. [ Links ]
97. Alvarenga NJ, Brofen E. Metaciclogênese do Trypanosoma cruzi como parâmetro de interação do parasita com o triatomíneo vetor. Rev Soc Bras Med Trop 1997; 30:247-250. [ Links ]
98. Garcia ES, Genta FA, Azambuja P, Schaub GA. Interactions between intestinal compounds of triatomines and Trypanosoma cruzi. Trends in Parasitol 2010; 20:499-505. [ Links ]
99. Perlowagora-Szunlewicz A, Muller CA, Moreira CJC. Studies in search of a suitable experimental insect model for xenodiagnosis of host with Chagas disease. III - On the observation of vector species and parasitic strain in the reaction of bugs to infection by Trypanosoma cruzi. Rev Saude Publica 1998; 24:390-400. [ Links ]
100. Hoare CA. The Trypanosomes of Mammals. Blackwell Sci Pub Oxford and Edinburgh; 1972. [ Links ]
101. Lent H, Wygodzinsky P. Revision of the Triatomines (Hemiptera, Reduviidae) and their significance as vectors of Chagas disease. Bull Amer Museum of Natural History 1979; 63:125-520. [ Links ]
102. Schofield CJ, Diotaiuti L, Dujardin PJ. The Process of Domestication in Triatominae. Mem Inst Oswaldo Cruz 1999; 94 (supl I):375-378. [ Links ]
103. Catalá S. Antenal sensila of Triatominae (Hemipter, Reduviidae): a comparative study over five genera. Intern J Insect Morphol and Embriol 1997; 26:67-73. [ Links ]
104. Dujardin JP. Population genetics and natural history of domestication in Triatominae. Mem Inst Oswaldo Cruz 1998; 93 (supl II):34-36. [ Links ]
105. Noireau F. Wild Triatoma infestans, a potential threat that needs to be monitored. Mem Inst Oswaldo Cruz 2009; (supl I):60-64. [ Links ]
106. Coura JR, Barrett TV, Arboleda MN. Ataque de populações humansa por triatomíneos silvestres no Amazonas: uma nova forma de transmissão da infecção chagásica? Rev Soc Bras Med Trop 1994; 27:251-253. [ Links ]
107. Valente VC, Valente SAS, Noireau F, Carrasco HU, Milles MA. Chagas disease in the Amazon Basin: association of Panstrongylus geniculatus (Hemitera: Reduviidae) with domestic pigs. J Med Entomol 1998; 35:99-103. [ Links ]
108. Pinto AYN, Valente SAS, Valente VC, Ferreira-Junior AG, Coura JR. Fase aguda da doença de Chagas na Amazônia brasileira. Estudo de 233 casos do Pará, Amapá e Maranhão observados entre 1988 a 2005. Rev Soc Bras Med Trop 2008; 42:602-614. [ Links ]
109. Valente SAS, Valente VC, Pinto AYN, Cesar MUR, Santos MP, Miranda COS, et al. Trans Roy Soc Trop Med Hyg 2009; 103:291-297. [ Links ]
110. Chagas C. Infection naturelle dês singes du Pará (Chrysotrix sciureus) par Trypanosoma cruzi. Comp Rend Séanc Soc Biol Ses Fin 1924; 90:873-876. [ Links ]
111. Deane LM. Novo hospedeiro de tripanosomos dos tipos T. cruzi e T. rangeli encontrados no Estado do Pará: o marsupial Metachirops opossum opossum. Rev Bras Malariol D Trop 1958; 10:531-541. [ Links ]
112. Deane LM. Sobre um tripanosoma do tipo T. cruzi encontrado em rato silvestre no Estado do Pará. Rev Bras Malariol D Trop 1960; 12:87-102. [ Links ]
113. Deane LM. Tripanosomatideos de mamíferos na região amazônica. I - Alguns flagelados encontrados no sangue de mamíferos silvestres do Estado do Pará. Rev Inst Med Trop São Paulo 1961; 3:15-28. [ Links ]
114. Deane LM. Tripanosomideos da região Amazônica. III - Hemoscopia e xenodiagnóstico de animais silvestres dos arredores de Belém, Pará. Rev Inst Med Trop São Paulo 1964; 6:225-232. [ Links ]
115. Deane LM. Tripanosomídeos de mamíferos da região Amazônica. IV - Hemoscopia e xenodiagnóstico de animais silvestres na estrada Belém-Brasília. Rev Inst Med Trop São Paulo 1967; 9:143-148. [ Links ]
116. Deane LM, Jansen G. Encontro do Schizotrypanum cruzi (Chagas 1909) em marsupiais da Marmosa cinerea Demarest. Brasil Med 1939; 53:263-266. [ Links ]
117. Deane LM, Damasceno RG. Tripanosomideos de mamíferos da Região Amazônica. II. Tripanossomos de macacos da zona do Salgado, Estado do Pará. Rev Inst Med Trop São Paulo 1961; 3:61-70. [ Links ]
118. Floch H, Tasqué P. Um cas de maladie de Chagas em Guyane Française. Bull Soc Path Exot 1941; 40:36-37. [ Links ]
119. Floch H, Comain R. Deux nouveanx cas de maladie de Chagas em Guyane Française. Bull Soc Path Exot 1948; 47:22-25. [ Links ]
120. Shaw J, Lainson R, Fraiha Neto H. Considerações sobre a epidemiologia dos primeiros casos autóctones da doença de Chagas em Belém, Pará, Brasil. Rev Saude Publica 1969; 3:153-157. [ Links ]
121. Valente SAS, Valente VC, Fraiha Neto H. Considerations on the epidemiology and transmission of Chagas disease in the Brazilian Amazon. Mem Inst Oswaldo Cruz 1999; 94 (Supl 1):395-398. [ Links ]
122. Junqueira ACV, Gonçalves TCM, Moreira CJC. Curso de Capacitação dos Microscopistas de Malária e dos Laboratórios da Rede Pública na detecção do Trypanosoma cruzi. Organização Panamericana da Saúde; 2009. [ Links ]
123. Coura JR, Abad-Franch F, Aguilera X, Dias JCP, Gil E, Junqueira ACV, et al. The Initiatives for the control of Chagas disease in the Americas and in non-endemic countries: overview and perspectives. Rev Soc Bras Med Trop 2009; 42 (supl II):106-110. [ Links ]
124. Vilarde-Rodrigues M, Avaria-Saavedra A, Gomez-i-Prat J, Jackson Y, Oliveira-Junior WA, Camps-Carmona B, et al. Needs of comprehensive health care for Trypanosoma cruzi infected immigrants in Europe. Rev Soc Bras Med Trop 2009; 42 (supl II):110-114. [ Links ]
125. Coura JR, Albajar-Viñas P. Chagas disease: a new worldwide challenge. Nature outlook 2010; XXX (supl):56-57. [ Links ]
Dr. José Rodrigues Coura.
Lab. Doenças Parasitárias/IOC/FIOCRUZ.
Av. Brasil 4365, Manguinhos,
21040-360 Rio de Janeiro, RJ, Brasil
Phone: 55 21 2562-1204; 55 21 9966-3738
Received in 10/02/2012
Accepted in 12/05/2012