Chagas Disease Diagnostic Applications

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a lifelong and debilitating illness of major significance throughout Latin America and an emergent threat to global public health. Being a neglected disease, the vast majority of Chagasic patients have limited access to proper diagnosis and treatment, and there is only a marginal investment into R&D for drug and vaccine development. In this context, identification of novel biomarkers able to transcend the current limits of diagnostic methods surfaces as a main priority in Chagas disease applied research. The expectation is that these novel biomarkers will provide reliable, reproducible and accurate results irrespective of the genetic background, infecting parasite strain, stage of disease, and clinical-associated features of Chagasic populations. In addition, they should be able to address other still unmet diagnostic needs, including early detection of congenital T. cruzi transmission, rapid assessment of treatment efficiency or failure, indication/prediction of disease progression and direct parasite typification in clinical samples. The lack of access of poor and neglected populations to essential diagnostics also stresses the necessity of developing new methods operational in point-of-care settings. In summary, emergent diagnostic tests integrating these novel and tailored tools should provide a significant impact on the effectiveness of current intervention schemes and on the clinical management of Chagasic patients. In this chapter, we discuss the present knowledge and possible future steps in Chagas disease diagnostic applications, as well as the opportunity provided by recent advances in high-throughput methods for biomarker discovery.

Introduction

Chagas disease or American Trypanosomiasis, caused by the parasitic protozoan Trypanosoma cruzi (Kinetoplastida, Trypanosomatidae), is a life-long, neglected tropical disease and leading cause of cardiomyopathy in endemic areas (Rassi et al., 2010). With 8–10 million people already infected and up to 120 million individuals at risk of infection, Chagas disease constitutes the most important parasitic disease in Latin America and one of the most common globally (Stanaway and Roth, 2015). Its exact burden is, however, difficult to assess due to several factors including the widespread geographic distribution of T. cruzi vectorborne transmission, the decades-long lag between infection and appearance of symptoms, certain pitfalls of current diagnostic methods, biased prevalence data and incomplete recognition of Chagas disease-attributable symptoms (Stanaway and Roth, 2015). The most recent estimates indicate that Chagas disease is responsible for ∼550,000 disability-adjusted life years (DALYs), a measure that captures both premature mortality (∼12,000 deaths per year) and nonfatal health losses (Stanaway and Roth, 2015). Despite this enormous toll, only two trypanocydal drugs, benznidazole and nifurtimox, are currently available for chemotherapy. Both are nitroheterocyclic, oral compounds that require prolonged administration, may display severe adverse effects, cannot be used to treat pregnant women due to their uncertain teratogenic risks and, most importantly, show high efficacy solely if administered at the onset of infection (Carlier and Truyens, 2015, Rassi et al., 2010, Viotti et al., 2006). The prospects for the development of an effective vaccine for prophylactic and/or therapeutic purposes, on the other hand, are still clouded by substantial scientific and socioeconomic challenges (Beaumier et al., 2016, Bustamante and Tarleton, 2015).

T. cruzi transmission primarily occurs when humans are exposed to the contaminated feces of infected, haematophagous triatomine vectors. Large-scale intervention schemes launched in different regions of Latin America in the 1990s have successfully shrunk the geographic limits and prevalence of vectorborne parasite transmission and led to an overall ∼40% reduction of disease prevalence (Schofield et al., 2006). However, different ecological and demographic issues converged in the last decades to shift the epidemiological landscape for this disease. For instance, recent outbreaks of acute cases in certain regions from Brazil and Venezuela were not strictly vectorborne but rather due to accidental ingestion of T. cruzi-tainted food and fluids (Alarcon de Noya et al., 2010, Segovia et al., 2013). This ‘foodborne’ transmission mode likely constitutes an ancient epidemiological trait, very important to the zoonotic spreading of the parasite (Gurtler and Cardinal, 2015), and appears to be associated with increased virulence and a higher case-fatality rate in humans (Alarcon de Noya et al., 2010, Segovia et al., 2013). In addition, migratory trends of infected populations from rural areas to urban centres and/or to nonendemic regions along with changes in the ecogeographical distribution of vector populations have led to the gradual urbanization and globalization of Chagas disease, which is now recognized as an emerging worldwide threat to public health (Eisenstein, 2016). Indeed, the risk of acquiring Chagas disease through infected blood transfusion and organ transplantation is becoming a major problem even in areas of nonendemicity, such as the United States, Australia and Europe (Requena-Mendez et al., 2015, Schmunis and Yadon, 2010). Moreover, the congenital route of infection, which constitutes the main transmission mode of T. cruzi in nonendemic areas, is now estimated to be responsible for 22% of new annual infections in endemic countries with active programs for home vector infestations control (Carlier and Truyens, 2015).

In this scenario, a strong and global partnership aimed to coordinate actions to control parasite transmission is urgently needed. In particular, we need to redouble our efforts to control home vector infestation, to screen blood supplies and to identify and subsequently treat T. cruzi-infected people who are still in the early stages of the disease to avoid sequelae, morbidity and economic losses. As a major step towards these goals, we ought to develop novel biomarkers able to overcome the limitations of current diagnostic applications. In this chapter, we critically appraise what has so far been achieved in this area. We also discuss possible ways to proceed to address major and still unmet diagnostic demands and the opportunity provided by recent advances in high-throughput methods (i.e., peptide synthesis technology, genomics and proteomics) in Chagas disease biomarker discovery.