Pathology of intracardiac nerves in experimental Chagas disease

Severe destruction of intrinsic cardiac nerves has been reported in experimental acute Chagas myocarditis, followed by extensive regeneration during the chronic phase of the infection. To further study this subject, the sympathetic and para-sympathetic intracardiac nerves of mice infected with a virulent Trypanosoma cruzi strain were analyzed, during acute and chronic infection, by means of histological, histochemical, morphometric and electron microscopic techniques. No evidences of destructive changes were apparent. Histochemical demonstration for acetylcholinesterase and catecholamines did not reveal differences in the amount and distribution of intracardiac nerves, in mice with acute and chronic Chagas myocarditis or in non-infected controls. Mild, probably reversible ultrastructural neural changes were occasionally present, especially during acute myocarditis. Intrinsic nerves appeared as the least involved cardiac structure during the course of experimental Chagas disease in mice.

Chagas disease: current epidemiological trends after the interruption of vectorial and transfusional transmission in the Southern Cone countries

Chagas disease, named after Carlos Chagas who first described it in 1909, exists only on the American Continent. It is caused by a parasite, Trypanosoma cruzi, transmitted to humans by blood-sucking triatomine bugs and by blood transfusion. Chagas disease has two successive phases, acute and chronic. The acute phase lasts 6 to 8 weeks. After several years of starting the chronic phase, 20% to 35% of the infected individuals, depending on the geographical area will develop irreversible lesions of the autonomous nervous system in the heart, esophagus, colon and the peripheral nervous system. Data on the prevalence and distribution of Chagas disease improved in quality during the 1980's as a result of the demographically representative cross-sectional studies carried out in countries where accurate information was not available. A group of experts met in Brasília in 1979 and devised standard protocols to carry out countrywide prevalence studies on human T. cruzi infection and triatomine house infestation. Thanks to a coordinated multi-country program in the Southern Cone countries the transmission of Chagas disease by vectors and by blood transfusion has been interrupted in Uruguay in1997, in Chile in 1999, and in 8 of the 12 endemic states of Brazil in 2000 and so the incidence of new infections by T. cruzi in the whole continent has decreased by 70%. Similar control multi-country initiatives have been launched in the Andean countries and in Central America and rapid progress has been recorded to ensure the interruption of the transmission of Chagas disease by 2005 as requested by a Resolution of the World Health Assembly approved in 1998. The cost-benefit analysis of the investments of the vector control program in Brazil indicate that there are savings of US$17 in medical care and disabilities for each dollar spent on prevention, showing that the program is a health investment with good return. Since the inception in 1979 of the Steering Committee on Chagas Disease of the Special Program for Research and Training in Tropical Diseases of the World Health Organization (TDR), the objective was set to promote and finance research aimed at the development of new methods and tools to control this disease. The well known research institutions in Latin America were the key elements of a world wide network of laboratories that received - on a competitive basis - financial support for projects in line with the priorities established. It is presented the time line of the different milestones that were answering successively and logically the outstanding scientific questions identified by the Scientific Working Group in 1978 and that influenced the development and industrial production of practical solutions for diagnosis of the infection and disease control.

Acute schistosomiasis outbreak in the metropolitan area of Belo Horizonte, Minas Gerais: alert about the risk of unnoticed transmission increased by growing rural tourism

The present article describes the occurrence of 17 cases of acute schistosomiasis in the metropolitan area of Belo Horizonte, state of Minas Gerais, Brazil. All individuals affected took a bath in a swimming pool of a holiday resort that was provided with water from a nearby brook. The apparently clean water and the absence of snails in the pool gave the wrong impression that there was no risk for infection. During a malacological survey at the site snails of the species Biomphalaria glabrata were found and tested positive for Schistosoma mansoni. All the patients live in the middle-class area of Barreiro, metropolitan area of Belo Horizonte and have medium grade school education. The difficulties in establishing the right diagnosis is expressed by the search for medical attention in 17 different medical facilities, the wide range of laboratory test and the inadequate treatment administration. A lack of knowledge about the disease was found in all groups studied. The booming rural tourism in endemic areas is identified as a probable risk factor for infection, especially for individuals of the non-immune middle and upper class parts of the society in urban centers. Special attention is given to a multidisciplinary approach to the complex issue of disease control and prevention.

Trypanosoma cruzi: genetic structure of populations and relevance of genetic variability to the pathogenesis of chagas disease

Chagas disease, caused by the protozoan Trypanosoma cruzi, has a variable clinical course, ranging from symptomless infection to severe chronic disease with cardiovascular or gastrointestinal involvement or, occasionally, overwhelming acute episodes. The factors influencing this clinical variability have not been elucidated, but it is likely that the genetic variability of both the host and the parasite are of importance. In this work we review the the genetic structure of T. cruzi populations and analyze the importance of genetic variation of the parasite in the pathogenesis of the disease under the light of the histotropic-clonal model.

Update on Chagas disease in Venezuela: a review

The present article reviews the status of Chagas disease in Venezuela based on the detection of Trypanosoma cruzi infections both in referred patients with clinical presumptive diagnosis (1988-2002) and in individuals sampled from rural localities representative of the different geographical regions of the country (1995-2002). In the former group from 306 individuals examined, 174 (56.8%) were seropositive to T. cruzi; 73 (42%) in the acute phase with 52 (71%) showing blood circulating parasites, and from these 38% were children under 10 years old. The other 101 (58%) showed chronic infection at different degrees of cardiac complication. In addition, serologic examination of 3835 individuals from rural areas revealed 11.7% seroprevalence. From these, 8.5% (38/448) were children aged from 0 to 10 years old. These figures suggest that Chagas disease may be re-emerging in Venezuela judging for the active transmission detected during the last decade. The success of the Venezuelan anti-chagasic campaign during the last 40 years is evaluated in the frame of the present results. The epidemiological situation is discussed and recommendation to consider Chagas disease as a national priority is given.

Ticks, ivermectin, and experimental Chagas disease

Following an infestation of dogticks in kennels housing dogs used for long-term studies of the pathogenesis of Chagas disease, we examined the effect of ivermectin treatment on the dogs, ticks, trypanosome parasites, and also on triatomine vectors of Chagas disease. Ivermectin treatment was highly effective in eliminating the ticks, but showed no apparent effect on the dogs nor on their trypanosome infection. Triatominae fed on the dogs soon after ivermectin treatment showed high mortality, but this effect quickly declined for bugs fed at successive intervals after treatment. In conclusion, although ivermectin treatment may have a transient effect on peridomestic populations of Triatominae, it is not the treatment of choice for this situation. The study also showed that although the dogticks could become infected with Trypanosoma cruzi, this only occurred when feeding on dogs in the acute phase of infection, and there was no evidence of subsequent parasite development in the ticks.

Activated peripheral lymphocytes with increased expression of cell adhesion molecules and cytotoxic markers are associated with dengue fever disease

The immune mechanisms involved in dengue fever and dengue hemorrhagic/dengue shock syndrome are not well understood. The ex vivo activation status of immune cells during the dengue disease in patients was examined. CD4and CD8 T cells were reduced during the acute phase. Interestingly, CD8 T cells co-expressing activation marker HLA-DR, Q, P, and cytolytic granule protein-Tia-1 were significantly higher in dengue patients than in controls. Detection of adhesion molecules indicated that in dengue patients the majority of T cells (CD4 and CD8) express the activation/memory phenotype, characterized as CD44HIGH and lack the expression of the naïve cell marker, CD62L LOW. Also, the levels of T cells co-expressing ICAM-1 (CD54), VLA-4, and LFA-1 (CD11a) were significantly increased. CD8 T lymphocytes expressed predominantly low levels of anti-apoptotic molecule Bcl-2 in the acute phase, possibly leading to the exhibition of a phenotype of activated/effector cells. Circulating levels of IL-18, TGF-b1 and sICAM-1 were significantly elevated in dengue patients. Early activation events occur during acute dengue infection which might contribute to viral clearance. Differences in expression of adhesion molecules among CD4 and CD8 T cells might underlie the selective extravasation of these subsets from blood circulation into lymphoid organs and/or tissues. In addition, activated CD8 T cells would be more susceptible to apoptosis as shown by the alteration in Bcl-2 expression. Cytokines such as IL-18, TGF-b1, and sICAM-1 may be contributing by either stimulating or suppressing the adaptative immune response, during dengue infection, thereby perhaps establishing a relationship with disease severity.

Evolution and pathology in Chagas disease: a review

Trypanosoma cruzi acute infections often go unperceived, but one third of chronically infected individuals die of Chagas disease, showing diverse manifestations affecting the heart, intestines, and nervous systems. A common denominator of pathology in Chagas disease is the minimal rejection unit, whereby parasite-free target host cells are destroyed by immune system mononuclear effectors cells infiltrates. Another key feature stemming from T. cruzi infection is the integration of kDNA minicircles into the vertebrate host genome; horizontal transfer of the parasite DNA can undergo vertical transmission to the progeny of mammals and birds. kDNA integration-induced mutations can enter multiple loci in diverse chromosomes, generating new genes, pseudo genes and knock-outs, and resulting in genomic shuffling and remodeling over time. As a result of the juxtaposition of kDNA insertions with host open reading frames, novel chimeric products may be generated. Germ line transmission of kDNA-mutations determined the appearance of lesions in birds that are indistinguishable from those seen in Chagas disease patients. The production of tissue lesions showing typical minimal rejection units in birds' refractory to T. cruzi infection is consistent with the hypothesis that autoimmunity, likely triggered by integration-induced phenotypic alterations, plays a major role in the pathogenesis of Chagas disease.

Chagas disease in the Amazon Region

The risk that Chagas disease becomes established as a major endemic threat in Amazonia (the world's largest tropical biome, today inhabited by over 30 million people) relates to a complex set of interacting biological and social determinants. These include intense immigration from endemic areas (possibly introducing parasites and vectors), extensive landscape transformation with uncontrolled deforestation, and the great diversity of wild Trypanosoma cruzi reservoir hosts and vectors (25 species in nine genera), which maintain intense sylvatic transmission cycles. Invasion of houses by adventitious vectors (with infection rates > 60%) is common, and focal adaptation of native triatomines to artificial structures has been reported. Both acute (~ 500) and chronic cases of autochthonous human Chagas disease have been documented beyond doubt in the region. Continuous, low-intensity transmission seems to occur throughout the Amazon, and generates a hypoendemic pattern with seropositivity rates of ~ 1-3%. Discrete foci also exist in which transmission is more intense (e.g., in localized outbreaks probably linked to oral transmission) and prevalence rates higher. Early detection-treatment of acute cases is crucial for avoiding further dispersion of endemic transmission of Chagas disease in Amazonia, and will require the involvement of malaria control and primary health care systems. Comprehensive eco-epidemiological research, including prevalence surveys or the characterization of transmission dynamics in different ecological settings, is still needed. The International Initiative for Chagas Disesae Surveillance and Prevention in the Amazon provides the framework for building up the political and scientific cooperation networks required to confront the challenge of preventing Chagas disease in Amazonia.

Chagas disease: what is known and what is needed - A background article

Chagas disease began millions of years ago as an enzootic disease of wild animals and started to be transmitted to man accidentally in the form of an anthropozoonosis when man invaded wild ecotopes. Endemic Chagas disease became established as a zoonosis over the last 200-300 years through forest clearance for agriculture and livestock rearing and adaptation of triatomines to domestic environments and to man and domestic animals as a food source. It is estimated that 15 to 16 million people are infected with Trypanosoma cruzi in Latin America and 75 to 90 million people are exposed to infection. When T. cruzi is transmitted to man through the feces of triatomines, at bite sites or in mucosa, through blood transfusion or orally through contaminated food, it invades the bloodstream and lymphatic system and becomes established in the muscle and cardiac tissue, the digestive system and phagocytic cells. This causes inflammatory lesions and immune responses, particularly mediated by CD4+, CD8+, interleukin-2 (IL) and IL-4, with cell and neuron destruction and fibrosis, and leads to blockage of the cardiac conduction system, arrhythmia, cardiac insufficiency, aperistalsis, and dilatation of hollow viscera, particularly the esophagus and colon. T. cruzi may also be transmitted from mother to child across the placenta and through the birth canal, thus causing abortion, prematurity, and organic lesions in the fetus. In immunosuppressed individuals, T. cruzi infection may become reactivated such that it spreads as a severe disease causing diffuse myocarditis and lesions of the central nervous system. Chagas disease is characterized by an acute phase with or without symptoms, and with entry point signs (inoculation chagoma or Romaña's sign), fever, adenomegaly, hepatosplenomegaly, and evident parasitemia, and an indeterminate chronic phase (asymptomatic, with normal results from electrocardiogram and x-ray of the heart, esophagus, and colon) or with a cardiac, digestive or cardiac-digestive form. There is great regional variation in the morbidity due to Chagas disease, and severe cardiac or digestive forms may occur in 10 to 50% of the cases, or the indeterminate form in the other asymptomatic cases, but with positive serology. Several acute cases have been reported from Amazon region most of them by T. cruzi I, Z3, and a hybrid ZI/Z3. We conclude this article presenting the ten top Chagas disease needs for the near future.

Urban transmission of Chagas disease in Cochabamba, Bolivia

Chagas disease is a major public health problem in Bolivia. In the city of Cochabamba, 58% of the population lives in peripheral urban districts ("popular zones") where the infection prevalence is extremely high. From 1995 to 1999, we studied the demographics of Chagas infections in children from five to 13 years old (n = 2218) from the South zone (SZ) and North zone (NZ) districts, which differ in social, environmental, and agricultural conditions. Information gathered from these districts demonstrates qualitative and quantitative evidence for the active transmission of Trypanosoma cruzi in urban Cochabamba. Seropositivity was high in both zones (25% in SZ and 19% in NZ). We observed a high risk of infection in children from five to nine years old in SZ, but in NZ, a higher risk occurred in children aged 10-13, with odds ratio for infection three times higher in NZ than in SZ. This difference was not due to triatomine density, since more than 1,000 Triatoma infestans were captured in both zones, but was possibly secondary to the vector infection rate (79% in SZ and 37% in NZ). Electrocardiogram abnormalities were found to be prevalent in children and pre-adolescents (SZ = 40%, NZ = 17%), indicating that under continuous exposure to infection and re-infection, a severe form of the disease may develop early in life. This work demonstrates that T. cruzi infection should also be considered an urban health problem and is not restricted to the rural areas and small villages of Bolivia.

Cytokine profile associated with chronic and acute human schistosomiasis mansoni

The production and regulation of interleukin (IL) IL-13, IL-4 and interferon-gamma (IFN-³) was evaluated in 43 schistosomiasis patients with different clinical forms. Whole-blood cultures cytokine production in response to soluble egg antigen (SEA), soluble worm adult preparation (SWAP), mitogens, neutralizing antibodies or recombinant IL-13 were measured by ELISA. After SWAP stimulation, chronic patients, particularly hepatointestinals, produced higher levels of IL-4 in comparison with acute patients, suggesting the presence of a type 2 cytokine profile in these patients. Following SEA and SWAP stimulation, hepatosplenic (HS) patients showed increased levels of IFN-³ when compared with acute patients, indicating that HS disease in humans is associated with a type 1 cytokine response. The mechanisms of immune regulation are apparently different between the clinical stages of the disease, some of which are antigen-specific.

Delay in maturation of the submandibular gland in Chagas disease correlates with lower DNA synthesis

It has been demonstrated that the acute phase of Trypanosoma cruzi infection promotes several changes in the oral glands. The present study examined whether T. cruzi modulates the expression of host cell apoptotic or mitotic pathway genes. Rats were infected with T. cruzi then sacrificed after 18, 32, 64 or 97 days, after which the submandibular glands were analyzed by immunohistochemistry. Immunohistochemical analyses using an anti-bromodeoxyuridine antibody showed that, during acute T. cruzi infection, DNA synthesizing cells in rat submandibular glands were lower than in non-infected animals (p < 0.05). However, after 64 days of infection (chronic phase), the number of immunolabeled cells are similar in both groups. However, immunohistochemical analysis of Fas and Bcl-2 expression did not find any difference between infected and non-infected animals in both the acute and chronic stages. These findings suggest that the delay in ductal maturation observed at the acute phase of Chagas disease is correlated with lower expression of DNA synthesis genes, but not apoptotic genes.

Acute acquired toxoplasmosis: clinical-laboratorial aspects and ophthalmologic evaluation in a cohort of immunocompetent patients

Most cases of acute acquired toxoplasmosis (AAT) are oligosymptomatic and self-limited. Therefore, these infections rarely indicate treatment. Prospective studies of AAT patients are rare in the medical literature. The frequency of systemic manifestations has not been sufficiently studied. In order to search for risks factors for systemic and ocular involvement, 37 patients were submitted to a diagnostic investigative protocol. The most frequent findings were lymph node enlargement (94.6%), asthenia (86.5%), headache (70.3%), fever (67.6%) and weight loss (62.2%). Hepatomegaly and/or splenomegaly were present in 21.6% of cases (8/37). Liver transaminases were elevated in 11 patients (29.7%) and lactic dehydrogenase in 17 patients (45.9%). Anaemia was found in four patients (10.8%), leucopoenia in six patients (16.2%), lymphocytosis in 14 patients (37.8%) and thrombocytopenia in one patient (2.7%). Fundoscopic examination revealed retinochoroiditis in four patients (10.8%). No statistical association was found between any one morbidity and retinochoroiditis. Nevertheless, a significant association was found between the presence of more than eight morbidity features at evaluation and long-lasting disease. An ideal diagnostic protocol for AAT would include evidence of systemic involvement. Such a protocol could be used when planning treatment.

Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemiology, surveillance and health policy

Chagas disease, named after Carlos Chagas, who first described it in 1909, exists only on the American Continent. It is caused by a parasite, Trypanosoma cruzi, which is transmitted to humans by blood-sucking triatomine bugs and via blood transfusion. Chagas disease has two successive phases: acute and chronic. The acute phase lasts six-eight weeks. Several years after entering the chronic phase, 20-35% of infected individuals, depending on the geographical area, will develop irreversible lesions of the autonomous nervous system in the heart, oesophagus and colon, and of the peripheral nervous system. Data on the prevalence and distribution of Chagas disease improved in quality during the 1980s as a result of the demographically representative cross-sectional studies in countries where accurate information was not previously available. A group of experts met in Brasilia in 1979 and devised standard protocols to carry out countrywide prevalence studies on human T. cruzi infection and triatomine house infestation. Thanks to a coordinated multi-country programme in the Southern Cone countries, the transmission of Chagas disease by vectors and via blood transfusion was interrupted in Uruguay in 1997, in Chile in 1999 and in Brazil in 2006; thus, the incidence of new infections by T. cruzi across the South American continent has decreased by 70%. Similar multi-country initiatives have been launched in the Andean countries and in Central America and rapid progress has been reported towards the goal of interrupting the transmission of Chagas disease, as requested by a 1998 Resolution of the World Health Assembly. The cost-benefit analysis of investment in the vector control programme in Brazil indicates that there are savings of US$17 in medical care and disabilities for each dollar spent on prevention, showing that the programme is a health investment with very high return. Many well-known research institutions in Latin America were key elements of a worldwide network of laboratories that carried out basic and applied research supporting the planning and evaluation of national Chagas disease control programmes. The present article reviews the current epidemiological trends for Chagas disease in Latin America and the future challenges in terms of epidemiology, surveillance and health policy.