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.

The new EASL guidelines for the management of chronic hepatitis B infection adapted for Swiss physicians.

Since the arrival of several new antivirals and due to the growing molecular and clinical knowledge of hepatitis B virus (HBV) infection, therapy of hepatitis B has become complex. Clinical guidelines aim at streamlining medical attitudes: in this respect, the European Association for the Study of the Liver (EASL) recently issued clinical practice guidelines for the management of chronic hepatitis B. Guidelines made by international experts need however to be adapted to local health care systems. Here, we summarise the EASL guidelines with some minor modifications in order to be compatible with the particular Swiss situation, while discussing in more detail some aspects. Chronic hepatitis B is a complex disease with several phases where host and viral factors interact: the features of this continuous interplay need to be evaluated when choosing the most appropriate treatment. The EASL guidelines recommend, as first-line agents, using the most potent antivirals available with the optimal resistance profile, in order to abate HBV DNA as rapidly and as sustainably as possible. Once therapy has been started, the infection evolves and resistant viral strains may emerge. Rescue therapy needs to be started early with more potent agents lacking cross-resistance.

Predominance of Trypanosoma rangeli infection in children from a Chagas disease endemic area in the west-shore of the Panama canal

A total of 206 serum samples from children (3-14 years old) living in the Amador County (La Chorrera District, Province of Panama) were screened by indirect immunofluorescence antibody test (IFAT) for the presence of antibodies against Trypanosoma cruzi. Positive sera were confirmed by recombinant enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. The presence of blood trypanosomes was investigated by hemoculture and subsequently identify by a duplex polymerase chain reaction (PCR) followed by dot blot hybridization. The results indicated a prevalence of 9.7% for trypanosome infections, a seroprevalence of 2.9% against T. cruzi and a predominance of T. rangeli infection (6.8%). The immunological and clinical implications of these findings are discussed.

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.

TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-α blockade

In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-α) is important for resistance to acute Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi infection, plasma TNF-α levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-α, especially signaling through the receptor TNFR1/p55, to the pathophysiology of T. cruzi infection was evaluated with a focus on the development of myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of TNFR1/p55+ and TNF-α+ splenocytes. Although TNFR1-/- mice exhibited reduced myocarditis in the absence of parasite burden, they succumbed to acute infection. Similar to C57BL/6 mice, Benznidazole-treated TNFR1-/- mice survived acute infection. In TNFR1-/- mice, reduced CD8-enriched myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-TNF-α treatment reduced the frequency of CD8+CCR5+ circulating cells and myocarditis, though parasite load was unaltered in infected C3H/HeJ mice. TNFR1-/- and anti-TNF-α-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-α treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/TNFR1 signaling promotes CD8-enriched myocarditis formation and heart tissue damage, implicating the TNF/TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited cardiomyopathy.

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.

Genetic variability in the 5' UTR and NS5A regions of hepatitis C virus RNA isolated from non-responding and responding patients with chronic HCV genotype 1 infection

Sequence variation among different hepatitis C virus (HCV) isolates has adaptive significance and reflects the modes and intensities of selection mechanisms operating on the virus. In this work, we sought to investigate using classical population genetics parameters, the genetic variability of HCV genotype 1 using the 5' UTR and NS5A regions from treatment non-responding and responding groups of patients. Both regions showed low genetic varia-bility and the 5' UTR showed neutral deviation. No differences were observed in the nonsynonymous/synonymous nucleotide substitution ratio among groups for NS5A. The analysis of molecular variance test of the 5' UTR region showed an 11.94% variation among groups. Phylogenetic analysis showed no correlation between sequence variations and therapeutic responses.

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.

Epidemiology, control and surveillance of Chagas disease: 100 years after its discovery

Chagas disease originated millions of years ago as an enzootic infection of wild animals and began to be transmitted to humans as an anthropozoonosis when man invaded wild ecotopes. While evidence of human infection has been found in mummies up to 9,000 years old, endemic Chagas disease became established as a zoonosis only in the last 200-300 years, as triatomines adapted to domestic environments. It is estimated that 15-16 million people are infected with Trypanosoma cruzi in Latin America, and 75-90 million are exposed to infection. Control of Chagas disease must be undertaken by interrupting its transmission by vectors and blood transfusions, improving housing and areas surrounding dwellings, providing sanitation education for exposed populations and treating acute and recently infected chronic cases. These measures should be complemented by surveillance and primary, secondary and tertiary care.

Usefulness of PCR-based assays to assess drug efficacy in Chagas disease chemotherapy: value and limitations

One major goal of research on Chagas disease is the development of effective chemotherapy to eliminate the infection from individuals who have not yet developed cardiac and/or digestive disease manifestations. Cure evaluation is the more complex aspect of its treatment, often leading to diverse and controversial results. The absence of reliable methods or a diagnostic gold standard to assess etiologic treatment efficacy still constitutes a major challenge. In an effort to develop more sensitive tools, polymerase chain reaction (PCR)-based assays were introduced to detect low amounts of Trypanosoma cruzi DNA in blood samples from chagasic patients, thus improving the diagnosis and follow-up evaluation after chemotherapy. In this article, I review the main problems concerning drug efficacy and criteria used for cure estimation in treated chagasic patients, and the work conducted by different groups on developing PCR methodologies to monitor treatment outcome of congenital infections as well as recent and late chronic T. cruzi infections.

Innate immunity and regulatory T-cells in human Chagas disease: what must be understood?

There is a general consensus that during chronic Trypanosoma cruzi infection, the host immune system induces complex processes to ensure the control of parasite growth while preserving the potential to mount and maintain a life-long controlled humoral and cellular immune response against the invading pathogen. This review summarises evidence in an attempt to elucidate "what must be understood" to further clarify the role of innate immunity in the development/maintenance of clinical Chagas disease and the impact of etiological treatment on host immunity, highlighting the contributions of the innate immunity and regulatory T (Treg) cells. Recently, increasing focus on innate immunity suggest that chronic T. cruzi infection may cause morbidity when innate effector functions, or the down-regulation of adaptive regulatory mechanisms are lacking. In this context, stable asymptomatic host-parasite interactions seem to be influenced by the effector/regulatory balance with the participation of macrophages, natural killer (NK) and CD8+ T cells in parallel with the establishment of regulatory mechanisms mediated by NKT and Treg cells. Moreover, a balanced innate immune activation state, apart from Treg cells, may play a role in controlling the adverse events triggered by the massive antigen release induced by trypanosomicidal agents during Chagas disease etiological treatment.

Soluble inflammatory markers as predictors of virological response in patients with chronic hepatitis C virus infection treated with interferon-α plus ribavirin

The host immune response plays an important role in viral clearance in patients who are chronically infected with hepatitis C virus (HCV) and are treated with interferon and ribavirin. Activation of the immune system involves the release of pro and anti-inflammatory molecules that can be measured in plasma samples. The present study aimed to evaluate the association between pretreatment plasma levels of chemokines and soluble tumor necrosis factor receptors (sTNF-R) and the virological response in treated patients with chronic hepatitis C infection. Forty-one chronically-infected HCV patients that were being treated with interferon-α (IFN-α) plus ribavirin were included in the study. Socio-demographic, clinical and laboratory data were collected and pretreatment plasma levels of chemokine CCL2, CCL3, CCL11, CCL24, chemokine CXCL9, CXCL10, sTNF-R1 and sTNF-R2 were measured. The virological response was assessed at treatment week 12, at the end of treatment and 24 weeks after treatment. Pretreatment CXCL10 levels were significantly higher in patients without an early virological response (EVR) or sustained virological response (SVR) compared to responders [512.9 pg/mL vs. 179.1 pg/mL (p = 0.011) and 289.9 pg/mL vs. 142.7 pg/mL (p = 0.045), respectively]. The accuracy of CXCL10 as a predictor of the absence of EVR and SVR was 0.79 [confidence interval (CI) 95%: 0.59-0.99] and 0.69 (CI 95%: 0.51-0.87), respectively. Pretreatment plasma levels of the other soluble inflammatory markers evaluated were not associated with a treatment response. Pretreatment CXCL10 levels were predictive of both EVR and SVR to IFN-α and ribavirin and may be useful in the evaluation of candidates for therapy.

Cardiomyocyte dysfunction during the chronic phase of Chagas disease

Chagas disease, which is caused by the parasite Trypanosoma cruzi, is an important cause of heart failure. We investigated modifications in the cellular electrophysiological and calcium-handling characteristics of an infected mouse heart during the chronic phase of the disease. The patch-clamp technique was used to record action potentials (APs) and L-type Ca2+ and transient outward K+ currents. [Ca2+]i changes were determined using confocal microscopy. Infected ventricular cells showed prolonged APs, reduced transient outward K+ and L-type Ca2+ currents and reduced Ca2+ release from the sarcoplasmic reticulum. Thus, the chronic phase of Chagas disease is characterised by cardiomyocyte dysfunction, which could lead to heart failure.

A serological, parasitological and clinical evaluation of untreated Chagas disease patients and those treated with benznidazole before and thirteen years after intervention

The etiological treatment of Chagas disease is recommended for all patients with acute or recent chronic infection, but controversies remain regarding the benefit of chemotherapy and interpretations of the parasitological cure after etiological treatment. This study compares the laboratory and clinical evaluations of Chagas disease patients who were diagnosed 13 years earlier. Fifty-eight Chagas disease patients (29 treated with benznidazole and 29 untreated) were matched at the time of treatment based on several variables. Conventional serology revealed the absence of seroconversion in all patients. However, lower serological titres were verified in the treated group, primarily among patients who had the indeterminate form of the disease. Haemoculture performed 13 years after the intervention was positive for 6.9% and 27.6% of the treated and untreated patients, respectively. Polymerase chain reaction tests were positive for 44.8% and 13.8% of the treated and untreated patients, respectively. Patients who presented with the indeterminate form of the disease at the beginning of the study exhibited less clinical progression (17.4%) compared with the untreated group (56.5%). Therefore, this global analysis revealed that etiological treatment with benznidazole may benefit patients with respect to the clinical progression of Chagas disease and the prognosis, particularly when administered to patients with the indeterminate form of the disease.