Challenges in the chemotherapy of Chagas disease: Looking for possibilities related to the differences and similarities between the parasite and host

Almost 110 years after the first studies by Dr. Carlos Chagas describing an infectious disease that was named for him, Chagas disease remains a neglected illness and a death sentence for infected people in poor countries. This short review highlights the enormous need for new studies aimed at the development of novel and more specific drugs to treat chagasic patients. The primary tool for facing this challenge is deep knowledge about the similarities and differences between the parasite and its human host.     

Impact of a community-based bug-hunting campaign on Chagas disease control: a case study in the department of Jalapa,Guatemala

Chagas disease control requires an innovative approach to strengthen community participation in vector surveillance. This paper presents a case study of a community-based bug-hunting campaign in Guatemala. The campaign was implemented in 2007 in the following three stages: (i) a four week preparation stage to promote bug-hunting, (ii) a one week bug-hunting stage to capture and collect bugs and (iii) a 10 week follow-up stage to analyse the bugs and spray insecticide. A total of 2,845 bugs were reported, of which 7% were Triatominae vectors, such as Rhodnius prolixus and Triatoma dimidiata. The bug-hunting campaign detected a five-six-fold higher amount of vectors in one week than traditional community-based surveillance detects in one year. The bug-hunting campaign effectively detected vectors during a short period, provided information to update the vector infestation map and increased community and political awareness regarding Chagas disease. This approach could be recommended as an effective and feasible strategy to strengthen vector surveillance on a larger scale.     

Case-control study of factors associated with chronic Chagas heart disease in patients over 50 years of age

A case-control study on chronic Chagas heart disease (CCHD) was carried out between 1997 and 2005. Ninety patients over 50 years of age were examined for factors related to (CCHD). Fourty-six patients (51.1%) with Chagas heart disease (anomalous ECG) were assigned to the case group and 44 (48.9%) were included in the control group as carriers of undetermined forms of chronic disease. Social, demographic (age, gender, skin color, area of origin), epidemiological (permanence within an endemic zone, family history of Chagas heart disease or sudden death, physical strain, alcoholism, and smoking), and clinical (systemic hypertension) variables were analyzed. The data set was assessed through single-variable and multivariate analysis. The two factors independently associated with heart disease were age--presence of heart disease being three times higher in patients over 60 years of age (odds ratio, OR: 2.89; confidence interval of 95%: 1.09-7.61)--and family history of Chagas heart disease (OR: 2.833, CI 95%: 1.11-7.23). Systemic hypertension and gender did not prove to hold any association with heart disease, as neither did skin color, but this variable showed low statistical power due to reduced sample size.     

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 noble enigma: Chagas' nominations for the Nobel prize

Carlos Chagas, a Brazilian physician, discovered the American trypanosomiasis in 1909. Like other remarkable discoveries of those days, his work helped to articulate the insect-vector theory and other theoretical guidelines in tropical medicine. Unlike all other discoveries, all the stages of this work were accomplished in a few months and by a single man. Chagas' discovery was widely recognized at home and abroad. He was twice nominated for the Nobel Prize - in 1913 and in 1921-, but never received the award. Evidence suggests that the reasons for this failure are related to the violent opposition that Chagas faced in Brazil. The contentions towards Chagas were related to a rejection of the meritocratic procedures that gave him prominence, as well as to local petty politics.     

Chagas disease: control,elimination and eradication. Is it possible?

From an epidemiological point of view, Chagas disease and its reservoirs and vectors can present the following characteristics: (i) enzooty, maintained by wild animals and vectors, with broad occurrence from southern United States of America (USA) to southern Argentina and Chile (42ºN 49ºS), (ii) anthropozoonosis, when man invades the wild ecotope and becomes infected with Trypanosoma cruzi from wild animals or vectors or when the vectors and wild animals, especially marsupials, invade the human domicile and infect man, (iii) zoonosis-amphixenosis and exchanged infection between animals and humans by domestic vectors in endemic areas and (iv) zooanthroponosis, infection that is transmitted from man to animals, by means of domestic vectors, which is the rarest situation in areas endemic for Chagas disease. The characteristics of Chagas disease as an enzooty of wild animals and as an anthropozoonosis are seen most frequently in the Brazilian Amazon and in the Pan-Amazon region as a whole, where there are 33 species of six genera of wild animals: Marsupialia, Chiroptera, Rodentia, Edentata (Xenarthra), Carnivora and Primata and 27 species of triatomines, most of which infected with T. cruzi . These conditions place the resident populations of this area or its visitors - tourists, hunters, fishermen and especially the people whose livelihood involves plant extraction - at risk of being affected by Chagas disease. On the other hand, there has been an exponential increase in the acute cases of Chagas disease in that region through oral transmission of T. cruzi , causing outbreaks of the disease. In four seroepidemiological surveys that were carried out in areas of the microregion of the Negro River, state of Amazonas, in 1991, 1993, 1997 and 2010, we found large numbers of people who were serologically positive for T. cruzi infection. The majority of them and/or their relatives worked in piassava extraction and had come into contact with and were stung by wild triatomines in that area. Finally, a characteristic that is greatly in evidence currently is the migration of people with Chagas disease from endemic areas of Latin America to non-endemic countries. This has created a new dilemma for these countries: the risk of transmission through blood transfusion and the onus of controlling donors and treating migrants with the disease. As an enzooty of wild animals and vectors, and as an anthropozoonosis, Chagas disease cannot be eradicated, but it must be controlled by transmission elimination to man.     

Mode of Death on Chagas Heart Disease: Comparison with Other Etiologies. A Subanalysis of the REMADHE Prospective Trial

Background

Sudden death has been considered the main cause of death in patients with Chagas heart disease. Nevertheless, this information comes from a period before the introduction of drugs that changed the natural history of heart failure. We sought to study the mode of death of patients with heart failure caused by Chagas heart disease, comparing with non-Chagas cardiomyopathy.

Methods and results

We examined the REMADHE trial and grouped patients according to etiology (Chagas vs non-Chagas) and mode of death. The primary end-point was all-cause, heart failure and sudden death mortality; 342 patients were analyzed and 185 (54.1%) died. Death occurred in 56.4% Chagas patients and 53.7% non-Chagas patients. The cumulative incidence of all-cause mortality and heart failure mortality was significantly higher in Chagas patients compared to non-Chagas. There was no difference in the cumulative incidence of sudden death mortality between the two groups. In the Cox regression model, Chagas etiology (HR 2.76; CI 1.34–5.69; p = 0.006), LVEDD (left ventricular end diastolic diameter) (HR 1.07; CI 1.04–1.10; p<0.001), creatinine clearance (HR 0.98; CI 0.97–0.99; p = 0.006) and use of amiodarone (HR 3.05; CI 1.47–6.34; p = 0.003) were independently associated with heart failure mortality. LVEDD (HR 1.04; CI 1.01–1.07; p = 0.005) and use of beta-blocker (HR 0.52; CI 0.34–0.94; p = 0.014) were independently associated with sudden death mortality.

Conclusions

In severe Chagas heart disease, progressive heart failure is the most important mode of death. These data challenge the current understanding of Chagas heart disease and may have implications in the selection of treatment choices, considering the mode of death.

Trial Registration

ClinicalTrails.gov {"type":"clinical-trial","attrs":{"text":"NCT00505050","term_id":"NCT00505050"}}NCT00505050 (REMADHE)     

V.—Notes on some Eastern Forms ofSturnus vulgaris

T he late Prof. Sushkin, shortly before his death, was engaged on a revision of the races of Sturnus vulgaris , for which purpose he assembled all the examples available in Russia, a great many of them breeding birds, and others were loaned him from private collections in England. Altogether he examined and compared over 2000 specimens. The Professor certainly never finished, and possibly never even started to write out, his paper on this difficult group; but before his death he sent to me an outline of his results in the form of a private letter (18 July, 1927), which seems worth putting on record, especially as it will be some years before anyone gets together so large a series of eastern forms for examination.—E d .     

Etiological treatment during early chronic indeterminate Chagas disease incites an activated status on innate and adaptive immunity associated with a type 1-modulated cytokine pattern

Pro-inflammatory immune response is usually associated with Chagas disease pathogenesis, but is also relevant to treatment effectiveness. Cross-sectional studies have suggested that this activated state may persist for years after therapeutic intervention. However, short-term longitudinal investigation has suggested that the Benznidazole treatment (Bz-treatment) leads to decreased immunological activation. In order to elucidate this issue, we performed a longitudinal study to evaluate the immunological status following Bz-treatment during early indeterminate Chagas disease. Our results demonstrated that Bz-treatment led to higher activation status of circulating monocytes but was negatively associated with the number of IL-12(+)CD14(+) cells. Moreover, Bz-treatment triggered a high frequency of circulating CD3(-)CD16(+)CD56(-) NK cells, in addition to elevated activation status associated with a type 1-modulated cytokine pattern. Bz-treatment induced substantial T and B-cell activation status associated with an overall IL-10 modulated type 1 cytokine profile. In summary, these findings provide new information regarding immune activation status following the etiological treatment of Chagas disease. These results suggest that in addition to the increased number of activated leukocytes in the peripheral blood, Bz-treatment may also involve a qualitative change in their functional capacity that drives their activation state toward a modulated cytokine profile. These changes may account for the benefits of etiological treatment of Chagas disease.     

Effect of clinician information sessions on diagnostic testing for Chagas disease

BackgroundChagas disease is a potentially life-threatening neglected disease of poverty that is endemic in continental Latin America. Caused by Trypanosoma cruzi (T. cruzi), it is one of six parasitic diseases in the United States targeted by the Centers for Disease Control as a public health problem in need of action. An estimated 300,000 people are infected with T. cruzi in the United States (US). Although its morbidity, mortality and economic burden are high, awareness of Chagas disease is lacking among many healthcare providers in the US. The purpose of this analysis is to determine if the number of diagnostic tests performed at a community health center serving an at-risk population for Chagas disease increased after information sessions. A secondary aim was to determine if there was a difference by provider type, i.e., nurse practitioner vs. physician, or by specialty in the number of patients screened.Methodology/Principal findingsWe conducted a retrospective data analysis of the number of Chagas serology tests performed at a community health center before and after information sessions for clinicians. A time series analysis was conducted focusing on the Adult and Family Medicine Departments at East Boston Neighborhood Health Center (EBNHC). Across all departments there were 1,957 T. cruzi tests performed before the sessions vs. 2,623 after the sessions. Interrupted time series analysis across departments indicated that testing volume was stable over time prior to the sessions (pre-period slope = +4.1 per month; p = 0.12), followed by an immediate shift after the session (+51.6; p = 0.03), while testing volume remained stable over time after the session (post-period slope = -6.0 per month; p = 0.11).Conclusion/SignificanceIn this study, Chagas testing increased after information sessions. Clinicians who began testing their patients for Chagas disease after learning of the importance of this intervention added an extra, potentially time-consuming task to their already busy workdays without external incentives or recognition.     

Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole

Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX^®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruziquantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.     

Acute Chagas Disease: New Global Challenges for an Old Neglected Disease

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi, and although over 100 years have passed since the discovery of Chagas disease, it still presents an increasing problem for global public health. A plethora of information concerning the chronic phase of human Chagas disease, particularly the severe cardiac form, is available in the literature. However, information concerning events during the acute phase of the disease is scarce. In this review, we will discuss (1) the current status of acute Chagas disease cases globally, (2) the immunological findings related to the acute phase and their possible influence in disease outcome, and (3) reactivation of Chagas disease in immunocompromised individuals, a key point for transplantation and HIV infection management.     

Achievements and Challenges upon the Implementation of a Program for National Control of Congenital Chagas in Bolivia: Results 2004–2009

Bolivia is one of the most endemic countries for Chagas disease. Data of 2005 shows that incidence is around 1.09‰ inhabitants and seroprevalence in children under 15 ranged from 10% in urban areas to 40% in rural areas. In this article, we report results obtained during the implementation of the congenital Chagas program, one of the biggest casuistry in congenital Chagas disease, led by National Program of Chagas and Belgian cooperation from 2004 to 2009. The program strategy was based on serological results during pregnancy and on the follow up of children born from positive mothers until one year old; if positive, treatment was done with Benznidazole, 10 mg/Kg/day/30 days with one post treatment control 6 months later. Throughout the length of the program, a total of 318,479 pregnant women were screened and 23.31% were detected positive. 42,538 children born from positive mothers were analyzed at birth by micromethod, of which 1.43% read positive. 10,120 children returned for their second micromethod control of which 2.29% read positive, 7,650 children returned for the serological control, of which 3.32% turned out positive. From the 1,093 positive children, 70% completed the 30 day-treatment and 122 returned for post treatment control with 96% showing a negative result. It has been seen that maternal-fetal transmission rates vary between 2% and 4%, with an average of 2.6% (about half of previously reported studies that reached 5%). In this work, we show that it is possible to implement, with limited resources, a National Congenital Chagas Program and to integrate it into the Bolivian health system. Keys of success are population awareness, health personnel motivation, and political commitment at all levels.     

Serodiagnosis of chronic Chagas infection by using EIE-Recombinant-Chagas-Biomanguinhos kit

A kit based on an enzyme immunoassay, EIE-Recombinant-Chagas-Biomanguinhos, developed by the Oswaldo Cruz Foundation, was evaluated for the serodiagnosis of chronic Chagas disease. Evaluation was performed with 368 serum samples collected from individuals living in an endemic area for Chagas disease: 131 patients in the chronic phase with confirmed clinical, epidemiological, and serological diagnosis (indirect immunofluorescence, indirect hemagglutination or enzyme-linked immunosorbent assay) and 237 nonchagasic seronegative individuals were considered negative control. The EIE-Recombinant-Chagas-Biomanguinhos kit showed high sensitivity, 100% (CI 95%: 96.4-100%) and high specificity, 100% (CI 95%: 98-100%). The data obtained were in full agreement with clinical and conventional serology data. In addition, no cross-reaction was observed with sera from patients with cutaneous (n=14) and visceral (n=3) leishmaniasis. However, when these sera were tested by conventional serological assays for Chagas disease, cross-reactions were detected in 14.3% and 33.3% of the patients with cutaneous and visceral leishmaniasis, respectively. No cross-reactions were observed when sera from nonchagasic seronegative patients bearing other infectious disease (syphilis, n=8; HTLV, n=8; HCV, n=7 and HBV, n=12) were tested. In addition, sera of patients with inconclusive results for Chagas disease by conventional serology showed results in agreement with clinical evaluation, when tested by the kit. These results are relevant and indicate that the referred kit provides a safe immunodiagnosis of Chagas disease and could be used in blood bank screening.     

Chagas infection transmission control: situation of transfusional transmission in Brazil and other countries of Latin America

The transmission of the transfusion-associated Chagas disease is an important mechanism of its dissemination in several Latin American countries. The transmission risk depends on five factors: prevalence of infection in blood donors, degree of serological coverage, sensibility of used tests, safety of obtained results and infection risk. The Southern Cone Iniciative set off by the Pan-American Health Organization, in 1991, is contributing to the implementation of blood law in each endemic country, and to reduce the risk of transfusional transmission of this horrible disease. Despite the clear improvement of Brasilian hemotherapy after 1980 (with the creation of the Blood National Program - Pró-Sangue) and the significant reduction of the chagasic infection among its blood donors; socio-economic, politic and cultural unlevels, prevent it from reaching the necessary universality and security. In order to assure both, the Brazilian Ministry of Health decided to restructure its blood system. In May, 1998, a great program was launched, to reach a specific goal: Blood - 100% with quality safety in all its process until 2003. It was divided in 12 projects, intends to guarantee the quality and self sufficiency in blood and hemoderivates.     

Optimization and evaluation of the ARCHITECT Chagas assay and in-house ELISA for Chagas disease in clinical settings in Japan

Approximately 250,000 immigrants from Latin America live in Japan and it is estimated that 1500–3000 of them are potentially infected with Trypanosoma cruzi, the cause of Chagas disease. Therefore, the establishment of a standardized diagnostic method for Chagas disease in Japan is urgently needed. In this study, we optimized and evaluated the ARCHITECT Chagas assay and in-house ELISA for Chagas disease in clinical settings. In particular, we evaluated the performance of ARCHITECT Chagas as well as ELISA with whole-cell lysates and three recombinant proteins (TcF, TcBCDE, and CP1 + CP3) using 93 Chagas disease-positive serum samples and 108 Chagas disease-positive samples. The sensitivities of ARCHITECT Chagas, whole-cell lysate, TcF, TcBCDE, and CP1 + CP3 ELISA were respectively 100%, 100%, 98.9%, 98.9%, and 89.2% and the corresponding specificities were 100%, 99.1%, 99.1%, 100%, and 99.1%. False-positive results were obtained for whole-cell lysate, TcF, and CP1 ± CP3 ELISA. This is the first evidence that OD cut-off values optimized for in-house ELISA are similar in terms of sensitivity and specificity to those of the ARCHITECT Chagas test, supporting the use of these in-house assays as diagnostic tests for Chagas disease in the clinical setting in Japan.     

First report of Panstrongylus megistus sylvatic focus in municipality of Bambuí, state of Minas Gerais, Brazil

In 1943, the Center for the Study and Prophylaxis of Chagas Disease, Oswaldo Cruz Foundation, state of Minas Gerais (MG), was created in the municipality of Bambuí to carry out studies related to Chagas disease in the mid-western region of MG. Since that time, several investigations have been conducted to determine the natural habitat of triatomines, but Panstrongylus megistus colonies have never been found in this region. This paper records the first finding of a P. megistus sylvatic colony in 69 years of research. The characteristics of this ecotope and its implications for the epidemiology of Chagas disease are discussed.     

Chagas Disease,Migration and Community Settlement Patterns in Arequipa,Peru

Background

Chagas disease is one of the most important neglected tropical diseases in the Americas. Vectorborne transmission of Chagas disease has been historically rare in urban settings. However, in marginal communities near the city of Arequipa, Peru, urban transmission cycles have become established. We examined the history of migration and settlement patterns in these communities, and their connections to Chagas disease transmission.

Methodology/Principal Findings

This was a qualitative study that employed focus group discussions and in-depth interviews. Five focus groups and 50 in-depth interviews were carried out with 94 community members from three shantytowns and two traditional towns near Arequipa, Peru. Focus groups utilized participatory methodologies to explore the community''s mobility patterns and the historical and current presence of triatomine vectors. In-depth interviews based on event history calendars explored participants'' migration patterns and experience with Chagas disease and vectors. Focus group data were analyzed using participatory analysis methodologies, and interview data were coded and analyzed using a grounded theory approach. Entomologic data were provided by an ongoing vector control campaign. We found that migrants to shantytowns in Arequipa were unlikely to have brought triatomines to the city upon arrival. Frequent seasonal moves, however, took shantytown residents to valleys surrounding Arequipa where vectors are prevalent. In addition, the pattern of settlement of shantytowns and the practice of raising domestic animals by residents creates a favorable environment for vector proliferation and dispersal. Finally, we uncovered a phenomenon of population loss and replacement by low-income migrants in one traditional town, which created the human settlement pattern of a new shantytown within this traditional community.

Conclusions/Significance

The pattern of human migration is therefore an important underlying determinant of Chagas disease risk in and around Arequipa. Frequent seasonal migration by residents of peri-urban shantytowns provides a path of entry of vectors into these communities. Changing demographic dynamics of traditional towns are also leading to favorable conditions for Chagas disease transmission. Control programs must include surveillance for infestation in communities assumed to be free of vectors.