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Introduction Chagas disease affects 6 - 7 million people, mainly in the Americas, and benznidazole is one of the two therapeutic options available. Trypanocide treatment aims to eliminate the parasite from the body to prevent the establishment or progression of visceral damage, mainly cardiac and/or digestive. Remarkably, it helps interrupt vertical transmission when administered to women of childbearing age. Areas covered we discuss the basic and scarce data regarding chemical, pharmacokinetic and pharmacodynamic structure. We also collect the most important data from previous phase II and III studies, as well as studies currently underway and upcoming. We reflect on the main indications for treatment and its challenges, such as the profile of adverse effects in adults, the pharmaceutical formulations, the search for reliable biomarkers, as well as regulatory aspects and access barriers. Alternative strategies such as shorter regimens, lower doses, and fixed doses are currently being evaluated to improve access and the safety profile of this treatment. Expert opinion benznidazole is likely to continue to be the drug of choice for Chagas disease in the coming years. However, it would probably be with a different treatment scheme.

Chagas disease, caused by the protozoa parasite

Different diagnostic tests were evaluated in a cluster of six European travellers with acute schistosomiasis (AS) acquired in Mozambique. Adult worm and soluble egg antibodies, circulating anodic antigen (CAA) and DNA detection allowed early confirmation of AS. CAA permitted monitoring treatment response and Sm1-7 polymerase chain reaction allowed identification of Schistosoma mansoni complex.

Malaria and Chagas disease, caused by Plasmodium spp. and Trypanosoma cruzi parasites, remain important global health problems. Available treatments for those diseases present several limitations, such as lack of efficacy, toxic side effects, and drug resistance. Thus, new drugs are urgently needed. The discovery of new drugs may be benefited by considering the significant biological differences between hosts and parasites. One of the most striking differences is found in the purine metabolism, because most of the parasites are incapable of de novo purine biosynthesis. Herein, we have analyzed the in vitro anti-P. falciparum and anti-T. cruzi activity of a collection of 81 purine derivatives and pyrimidine analogs. We firstly used a primary screening at three fixed concentrations (100, 10, and 1 µM) and progressed those compounds that kept the growth of the parasites < 30% at 100 µM to dose–response assays. Then, we performed two different cytotoxicity assays on Vero cells and human HepG2 cells. Finally, compounds specifically active against T. cruzi were tested against intracellular amastigote forms. Purines 33 (IC50 = 19.19 µM) and 76 (IC50 = 18.27 µM) were the most potent against P. falciparum. On the other hand, 6D (IC50 = 3.78 µM) and 34 (IC50 = 4.24 µM) were identified as hit purines against T. cruzi amastigotes. Moreover, an in silico docking study revealed that P. falciparum and T. cruzi hypoxanthine guanine phosphoribosyltransferase enzymes could be the potential targets of those compounds. Our study identified two novel, purine-based chemotypes that could be further optimized to generate potent and diversified anti-parasitic drugs against both parasites., SAF2016-76080-R (Spanish Ministry of Economy (AEI/FEDER, UE)), PID2019-110810RB-I00 (Spanish Ministry of Science and Innovation), Generalitat of Catalonia Universities and Research Department, Spain (AGAUR; 2017SGR00924), Carlos III Health Institute (ISCIII), RICET Network for Cooperative Research in Tropical Diseases (ISCIII; RD12/0018/0010), Generalitat of Catalonia Department of Health (PERIS 2016–2010 SLT008/18/00132), Spanish Ministry of Education, Culture, and Sports (FPU grant ref. 14/00818), Spanish Ministry of Science, Innovation, and Universities through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), CERCA Program

Background: Pre-exposure prophylaxis (PrEP) is a promising strategy to break COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment and post-exposure prophylaxis, it is not evaluated for COVID-19 PrEP yet. The aim of this study was to evaluate efficacy and safety of PrEP with hydroxychloroquine against placebo in healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period.Methods: We conducted a double-blind placebo-controlled randomized clinical trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers screened, we included 269 participants with no active or past SARS-CoV-2 infection (determined by a negative nasopharyngeal SARS-CoV-2 PCR and a negative serology against SARS-CoV-2). Participants allocated in the intervention arm (PrEP) received 400mg of hydroxychloroquine daily the first four consecutive days and subsequently, 400mg weekly during the study period. Participants in the control group followed the same treatment schedule with placebo tablets. Results: 52.8% (142/269) of participants were in the hydroxychloroquine arm and 47.2% (127/269) in the placebo arm. Both groups showed similar proportion of participants experiencing at least one adverse event (AE) (p=0.548). No serious AEs were reported. Almost all AEs (96.4%, 106/110) were mild. Only mild gastrointestinal symptoms were significantly higher in the hydroxychloroquine arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), p=0.041). Given the national epidemic incidence decay, only one participant in each group was COVID-19 diagnosed. Consequently, our study design deemed underpowered to evaluate any benefit regarding PrEP efficacy.Conclusions: First month follow-up analysis displayed that PrEP with hydroxychloroquine at low doses is safe.Trial registration: This trial was registered at clinicaltrials.gov (NCT04331834) on April 2nd 2020. https://clinicaltrials.gov/ct2/show/NCT04331834?term=NCT04331834&draw=2&rank=1

Chagas disease, caused by the parasite Trypanosoma cruzi, affects over six million people worldwide, mainly in Latin American countries. Currently available drugs have variable efficacy in the chronic phase and significant side effects, so there is an urgent need for safer chemotherapeutic treatments. Natural products provide privileged structures that could serve as templates for the synthesis of new drugs. Among them, Amaryllidaceae plants have proved to be a potential natural source of therapeutical agents due to their rich diversity in alkaloids.To identify alkaloids with anti-T. cruzi activity from Habranthus brachyandrus (Baker) Sealy (Amaryllidaceae, subfamily Amaryllidoideae) collected in Argentina.An H. brachyandrus alkaloid extract was tested against T. cruzi, and its cytotoxicity profile was evaluated against two mammalian cell lines to ascertain its selectivity against the parasite and potential liver toxicity. It was also assessed by a stage-specific anti-amastigote assay and analysed by GC/MS to determine its alkaloid profile. The isolated alkaloids were also tested using the aforementioned assays.The extract showed high and specific activity against T. cruzi. The alkaloids lycoramine, galanthindole, 8-O-demethylmaritidine, 8-O-demethylhomolycorine, nerinine, trisphaeridine, deoxytazettine, and tazettamide were identified by means of GC-MS. In addition, hippeastidine (also named aulicine), tazzetine, ismine, and 3-epimacronine were isolated. The alkaloid ismine was specifically active against the parasite and had low toxicity against HepG2 cells, but did not show anti-amastigote activity.The extract had specific anti-T. cruzi activity and the isolated alkaloid ismine was partially responsible of it. These results encourage further exploration of H. brachyandrus alkaloids in search of novel starting points for Chagas disease drug development.Copyright © 2022. Published by Elsevier GmbH.

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC50 = 0.27 &mu, mol L&minus, 1) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages.

Background Pre-exposure prophylaxis (PrEP) is a promising strategy to break COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment and post-exposure prophylaxis, it is not evaluated for COVID-19 PrEP yet. The aim of this study was to evaluate the efficacy and safety of PrEP with hydroxychloroquine against placebo in healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period. Methods We conducted a double-blind placebo-controlled randomized clinical trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers screened, we included 269 participants with no active or past SARS-CoV-2 infection (determined by a negative nasopharyngeal SARS-CoV-2 PCR and a negative serology against SARS-CoV-2). Participants allocated in the intervention arm (PrEP) received 400 mg of hydroxychloroquine daily for the first four consecutive days and subsequently, 400 mg weekly during the study period. Participants in the control group followed the same treatment schedule with placebo tablets. Results 52.8% (142/269) of participants were in the hydroxychloroquine arm and 47.2% (127/269) in the placebo arm. Given the national epidemic incidence decay, only one participant in each group was diagnosed with COVID-19. The trial was stopped due to futility and our study design was deemed underpowered to evaluate any benefit regarding PrEP efficacy. Both groups showed a similar proportion of participants experiencing at least one adverse event (AE) (p=0.548). No serious AEs were reported. Almost all AEs (96.4%, 106/110) were mild. Only mild gastrointestinal symptoms were significantly higher in the hydroxychloroquine arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), p=0.041). Conclusions Although the efficacy of PrEP with hydroxychloroquine for preventing COVID-19 could not be evaluated, our study showed that PrEP with hydroxychloroquine at low doses is safe. Trial registration ClinicalTrials.govNCT04331834. Registered on April 2, 2020.

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC50 = 0.27 μmol L−1) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages.

Chagas disease (CD) and tuberculosis (TB) are important health problems in Bolivia. Current treatments for both infections require a long period of time, and adverse drug reactions (ADRs) are frequent. This study aims to strengthen the Bolivian pharmacovigilance system, focusing on CD and TB. A situation analysis of pharmacovigilance in the Department of Cochabamba was performed. The use of a new local case report form (CRF) was implemented, together with the CRF established by the Unidad de Medicamentos y Tecnologia en Salud (UNIMED), in several healthcare centers. Training and follow-up on drug safety monitoring and ADR reporting was provided to all health professionals involved in CD and TB treatment. A comparative analysis of the reported ADRs using the CRF provided by UNIMED, the new CRF proposal, and medical records, was also performed. Our results showed that out of all patients starting treatment for CD, 37.9% suffered ADRs according to the medical records, and 25.3% of them were classified as moderate/severe (MS). Only 47.4% of MS ADRs were reported to UNIMED. Regarding TB treatment, 9.9% of all patients suffered ADRs, 44% of them were classified as MS, and 75% of MS ADRs were reported to UNIMED. These findings show that the reinforcement of the Bolivian pharmacovigilance system is an ambitious project that should involve a long-term perspective and the engagement of national health workers and other stakeholders at all levels. Continuity and perseverance are essential to achieve a solid ADR reporting system, improving patient safety, drug efficacy and adherence to treatment. Chagas disease and tuberculosis are important public health problems in Bolivia, where the prevalence and incidence of these diseases are high compared to other Latin American countries. Treatment for both infections requires a long period of time, and adverse drug reactions (ADRs) are frequent. One of the main challenges in the management of Chagas disease and tuberculosis is poor adherence to treatment. In this context, strengthening the Bolivian pharmacovigilance system is proposed as a key issue to reinforce therapeutic strategies. Several interventions were carried out in fifteen health centers of the Department of Cochabamba and included a situation analysis of pharmacovigilance, the implementation of a new local case report form, specific training on drug safety monitoring and reporting, and follow-up visits. ADRs were also analyzed. Overall, our findings suggest that the Bolivian pharmacovigilance system still presents some challenges that should be addressed in the coming years in order to achieve a strong, integrated and consolidated ADR reporting system, which will be essential for avoiding patient abandonment and achieving therapeutic success.

Chagas disease treatment relies on the lengthy administration of benznidazole and/or nifurtimox, which have frequent toxicity associated. The disease, caused by the parasiteWe provide an updated view of the path to achieve the aforementioned goal. From state-of-the-artIn addition to the necessary research on new drugs and much awaited biomarkers of treatment efficacy, a key step will be to generalize access to diagnosis and treatment and maximize efforts to impede transmission.

Chagas disease is emerging in countries to which it is not endemic. Biomarkers for earlier therapeutic response assessment in patients with chronic Chagas disease are needed. We profiled plasma-derived extracellular vesicles from a heart transplant patient with chronic Chagas disease and showed the potential of this approach for discovering such biomarkers. Barcelona Institute for Global Health (ISGlobal) receives support from the Spanish Ministry of Science, Innovation and Universities through the Centro de Excelencia Severo Ochoa 2019–2023 Program (CEX2018-000806-S). ISGlobal and Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP) are members of the Centres de Recerca de Catalunya (CERCA Program), Generalitat de Catalunya. Work in the laboratory of C.F.B. is funded by Fundació La Marató de TV3 (reference 566/U/2018) and Fundación Mundo Sano. This project was co-financed by the European Union through the European Regional Development Fund with the support of Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya. N.C., M.G., J.G., and M.J.P. receive funds from the Redes temáticas de investigación cooperativa en salud (RETICS), Spanish Tropical Diseases Network “RD12/0018/0010” and from the Agencia de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya; grant “2017 SGR 00924.” M.G., C.B., J.G., M.J.P., and I.C.A. belong to the Ibero-American Nuevas Herramientas para el Diagnóstico y la Evaluación del Paciente con Enfermedad de Chagas network. I.C.A. is partially supported by grants no. 2G12MD007592 and 5U54MD007592 from the National Institute on Minority Health and Health Disparities of the US National Institutes of Health. We are grateful to the Biomolecule Analysis Core Facility at University of Texas at El Paso, Border Biomedical Research Center, funded by National Institute on Minority Health and Health Disparities grants 2G12MD007592 and 5U54MD007592. M.T.M. received a PhD fellowship from the Science Without Borders Program, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil. Sí

Background Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected disease that affects ~7 million people worldwide. Development of new drugs to treat the infection remains a priority since those currently available have frequent side effects and limited efficacy at the chronic stage. Natural products provide a pool of diversity structures to lead the chemical synthesis of novel molecules for this purpose. Herein we analyzed the anti-T. cruzi activity of nine alkaloids derived from plants of the family Amaryllidaceae. Methods The activity of each alkaloid was assessed by means of an anti-T. cruzi phenotypic assay. We further evaluated the compounds that inhibited parasite growth on two distinct cytotoxicity assays to discard those that were toxic to host cells and assure parasite selectivity. Results We identified a single compound (hippeastrine) that was selectively active against the parasite yielding selectivity indexes of 12.7 and 35.2 against Vero and HepG2 cells, respectively. Moreover, it showed specific activity against the amastigote stage (IC50 = 3.31 μM). Conclusions Results reported here suggest that natural products are an interesting source of new compounds for the development of drugs against Chagas disease.

Chagas disease is caused by infection with the parasite Trypanosoma cruzi, which might lead to a chronic disease state and drive to irreversible damage to the heart and/or digestive tract tissues. Endemic in 21 countries in the Americas, it is the neglected disease with a highest burden in the region. Current estimates point at ~6 million people infected, of which ~30% will progress onto the symptomatic tissue disruptive stage. There is no vaccine but there are two anti-parasitic drugs available: benznidazole and nifurtimox. However, their efficacy is variable at the chronic symptomatic stage and both have frequent adverse effects. Since there are no prognosis markers, drugs should be administered to all T. cruzi-infected individuals in the indeterminate and early symptomatic stages. Nowadays, there are no tests-of-cure either, which greatly undermines patients' follow-up and the search of safer and more efficacious drugs. Therefore, the identification and validation of biomarkers of disease progression and/or treatment response on which to develop tests of prognosis and/or cure is a major research priority. Both parasite- and host-derived markers have been investigated. In the present manuscript we present an updated outlook of the latter.

The most severe clinical symptomatology of Chagas disease affects ~30% of those chronically infected with the Trypanosoma cruzi parasite. The pathogenic mechanisms that lead to life-threatening heart and gut tissue disruptions occur "silently" for a longtime in a majority of cases. As a result, despite there are several serological and molecular methods available to diagnose the infection in its acute and chronic stages, diagnosis is often achieved only after the onset of clinical symptoms in the chronic phase of the disease. Furthermore, although there are two drugs to treat it, the assessment of their performance is impractical with current parasite-derived diagnostics, and therapeutic efficacy cannot be acknowledged in a timely manner.In this chapter we present two procedures to measure host-derived molecules as surrogates of therapeutic response against chronic T. cruzi infection. Their outputs relate to the generation and activity of thrombin, a major component of the blood coagulation cascade. This is due to the fact that a hypercoagulability state has been described to occur in chronic Chagas disease patients and revert after treatment with benznidazole.

Introduction: Chagas disease, caused by infection with the parasite Trypanosoma cruzi, represents a huge public health problem in the Americas, where millions of people are affected. Despite the availability of two drugs against the infection (benznidazole and nifurtimox), multiple factors impede their effective usage: (1) gaps in patient and healthcare provider awareness; (2) lack of access to diagnosis; (3) drug toxicity and absence of treatment algorithms to address adverse effects; (4) failures in drug supply and distribution; and (5) inconsistent drug efficacy against the symptomatic chronic stage. Areas covered: We review new approaches and technologies to enhance access to diagnosis and treatment to reduce the disease burden. We also provide an updated picture of recently published and ongoing anti-T. cruzi drug clinical trials. Although there has been progress improving the research and development (R&D) landscape, it is unclear whether any new treatments will emerge soon. Literature search methodologies included multiple queries to public databases and the use of own-built libraries. Expert opinion: Besides R&D, there is a major need to continue awareness and advocacy efforts by patient associations, local and national governments, and international agencies. Overall, health systems strengthening is essential to ensure vector control commitments, as well as patient access to diagnosis and treatment. Fil: Alonso Padilla, Julio. Universidad de Barcelona; España Fil: Cortés Serra, Nuria. Universidad de Barcelona; España Fil: Pinazo, María Jesús. Universidad de Barcelona; España Fil: Bottazzi, María Elena. Texas Children's Hospital Houston; Estados Unidos. Baylor University; Estados Unidos. Baylor College Of Medicine; Estados Unidos Fil: Abril, Marcelo. Fundación Mundo Sano; Argentina Fil: Barreira, Fabiana. No especifíca; Fil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina Fil: Hotez, Peter Jay. Texas Children's Hospital Houston; Estados Unidos. Baylor College Of Medicine; Estados Unidos. Baylor University; Estados Unidos Fil: Gascón, Joaquim. Universidad de Barcelona; España

The most severe clinical symptomatology of Chagas disease affects ~30% of those chronically infected with the Trypanosoma cruzi parasite. The pathogenic mechanisms that lead to life-threatening heart and gut tissue disruptions occur "silently" for a longtime in a majority of cases. As a result, despite there are several serological and molecular methods available to diagnose the infection in its acute and chronic stages, diagnosis is often achieved only after the onset of clinical symptoms in the chronic phase of the disease. Furthermore, although there are two drugs to treat it, the assessment of their performance is impractical with current parasite-derived diagnostics, and therapeutic efficacy cannot be acknowledged in a timely manner.In this chapter we present two procedures to measure host-derived molecules as surrogates of therapeutic response against chronic T. cruzi infection. Their outputs relate to the generation and activity of thrombin, a major component of the blood coagulation cascade. This is due to the fact that a hypercoagulability state has been described to occur in chronic Chagas disease patients and revert after treatment with benznidazole.

IntroductionChagas disease (CD) and Tuberculosis (TB) are important health problems in Bolivia. Current treatments for both infections require a long period of time, and unwanted drug-related adverse events (ADRs) are frequent.PurposeThis study aims to strengthen the Bolivian Pharmacovigilance system, focusing on CD and TB.MethodsA situational diagnosis of Pharmacovigilance in the Department of Cochabamba was performed. The use of a new Local Case Report Form (CRF) was implemented, together with the CRF established by the Unidad de Medicamentos y Tecnología en Salud (UNIMED), in several health care centers. Training and follow-up on drug safety monitoring and ADR reporting was provided to all health professionals involved in CD and TB treatment. A comparative analysis of the reported ADRs using the CRF provided by UNIMED, the new CRF proposal, and medical records, was performed.ResultsOut of the total patients starting treatment for CD, 35,35% suffered ADR according to the information collected in the medical records, and 25% of them were classified as moderate/severe (MS) types. Only 51,43% of MS ADRs were reported to UNIMED. Regarding TB treatment, 9,89% of the total patients suffered ADR, 44% of them were classified as MS, and 75% of MS ADRs were reported to UNIMED.ConclusionsThe reinforcement of the Bolivian Pharmacovigilance system is an ambitious project that should take a long-term perspective and the engagement of national health workers and other stake holders at all levels. Continuity and perseverance are essential to achieve a solid ADR reporting system, improving patient safety, drug efficacy and adherence to treatment.

Chagas disease has the highest prevalence of any parasitic disease in the Americas, affecting 6-7 million people. Conventional diagnosis requires a well-equipped laboratory with experienced personnel. The development of new diagnostic tools that are easy to use and adapted to the reality of affected populations and health systems is still a significant challenge. The main objective of this study was to measure Trypanosoma cruzi infection status using saliva samples of infected subjects. Blood and saliva samples from 20 T. cruzi-seropositive individuals and 10 controls were tested for T. cruzi infection using two different commercial serological tests. We have shown that detection of T. cruzi infection is possible using saliva samples, supporting the potential use of saliva to diagnose Chagas disease in humans. This method could provide a simple, low-cost but effective tool for the diagnosis of T. cruzi infection. Its noninvasive nature makes it particularly well suited for endemic areas.

Background: Chagas disease (CD) is endemic in Latin America and particularly common in Bolivia, but there is little information on the characteristics of chronic digestive involvement. Objectives: To determine the prevalence and characterize digestive manifestations in chronic CD patients in Cochabamba, Bolivia. Methods: Eighty-five T. cruzi-seropositive individuals with or without digestive symptoms (G1 group), and fifteen T. cruzi-seronegative patients with similar digestive symptoms to those seen in CD (G2 group) were included in the study. All patients underwent a detailed history including past medical history, epidemiological information, hygiene and dietary habits, a complete physical examination, two serological tests for T. cruzi, video endoscopy, barium swallow, and barium enema. Findings: We observed digestive manifestations in T. cruzi seropositive and seronegative patients. Colonic manifestations were detected in both groups, highlighting the relevance of other confounder factors in the region. Constipation was present in 52.9% of G1 patients, 62.4% presented two or more upper digestive tract symptoms, and 5.9% of them presented esophageal manifestations. Helicobacter pylori infection was detected in 58.8% of G1 patients, and all patients presented gastritis on endoscopy. Conclusions: Prevalence of digestive involvement in CD patients is higher than expected. However, digestive symptoms are not always caused by T. cruzi infection and require differential diagnoses.

Dear Editor, We appreciate the comments on our recent review article about strategies to enhance access to diagnosis and treatment for Chagas disease patients [1,2]. We also appreciate the opportunity to respond to them, and expand the discussion on this crucial topic given that it is estimated that no more than 1% of the infected population by Trypanosoma cruzi (of ~7 million people) ultimately get access to treatment [3]. The letter comments mainly refer to two of the sections of the review article: diagnostics to detect the infection (section 2), and treatment opportunities and possibilities (section 7).