The Unfinished Public Health Agenda of Chagas Disease in the Era of Globalization

Many neglected tropical diseases (NTDs) began millions of years ago as enzoonotic diseases of wild animals that subsequently infected humans, leading in many cases to anthropozoonoses [2]. Because of their impoverished circumstances, most humans infected with NTD agents have few choices but to face daily the intense selective pressures associated with high levels of exposure and transmission that often flourish in these impoverished settings [3]. In this dynamic and relentless evolutionary battle, animal reservoirs, vectors, microbes causing NTDs, and humans are constantly adapting through what it is known as the ‘‘Red Queen Effect’’ from Lewis Carroll’s Red Queen character [4,5]. Typically, the battlegrounds of these molecular and ecological clashes are located in the poorest regions of developing countries where they mostly affect the world’s most vulnerable populations [3]. In Latin America, Chagas disease (CD), caused by infection with Trypanosoma cruzi, is a prime example of this co-evolutionary process in which parasites and mammalian reservoirs (including humans) are engaged in a dynamic race of ecological adaptation and counter-adaptation [6]. In the search for improved sources of income, agriculture, livestock rearing, and other socioeconomic activities, human populations began migrating into the natural wild habitats where T. cruzi infection was enzootic [2]. Ultimately, poverty, poor housing and sub-standard living conditions, deforestation, and other ecological factors promoted an adaptation of triatomine vectors to both humans and domestic animals, with increased efficiencies of the wild, domestic, and peridomestic cycles of T. cruzi transmission (Figure 1) [2,7–8]. Once humans became infected and acted as a reservoir for the infection, other forms of transmission also evolved through blood transfusion, congenital transmission, and organ transplantation. In some settings, oral transmission through contaminated food is now considered an important mode of transmission [3,8]. We are about to celebrate the 100th anniversary of the discovery of T. cruzi and its link to CD. The cycle of transmission (vector, reservoir, and infectious agent) and the clinical manifestations of the disease were elegantly described by Carlos Chagas (1879–1934) during the first decade of the 20th century. Oswaldo Cruz, his mentor, had set the stage for these achievements by creating a research institution bearing his name in Brazil (Instituto Oswaldo Cruz – FIOCRUZ) [7,9–10]. For his multiple achievements, Carlos Chagas received several awards and international distinctions and became the Director of the Institute in 1917 (after Oswaldo Cruz’s death), holding this title until his own death in 1934. It was Salvador Mazza in Argentina who brought again Chagas’s achievements into the international scope by identifying cases of CD in the Argentine Chaco region [9]. In subsequent years, a few dedicated clinicians in Latin America expanded the initial clinical descriptions of the disease made by Carlos Chagas. During this period, the French parasitologist Emile Brumpt is often credited with developing important xenodiagnostic techniques [10]. Due to these landmark discoveries, it is now recognized that the natural history of CD has three clinical stages [2,3]. An initial acute stage representing the entry of the parasite and invasion of the bloodstream in which most patients are asymptomatic is followed by an indeterminate stage that is defined by the absence of symptoms and clinical findings in patients with a positive serology for T. cruzi. The indeterminate stage (also called early chronic) is followed by chronic complications in approximately 20%–30% of patients many years after the initial infection. Serious cardiac (e.g., cardiomyopathy) and gastrointestinal (e.g., megaesophagus and megacolon) morbidities are the most frequent manifestations of chronic CD and the main cause of disability and death [2]. During the early 1980s, the prevalence of CD was first reliably estimated and the full social and economic implications of this condition were revealed. It was determined that there were 18 million cases in 21 endemic countries with 100 million people at risk of infection [9]. In 1993, CD ranked as the most important tropical disease in Latin America in terms of burden of disease [9]. Subsequently, through political commitment and effective public health interventions, some progress was achieved in reducing the incidence and prevalence of CD, particularly in the southernmost countries of Latin America. The major approaches to control CD have included improved case management and vector control programs,