**2. Research in context**

Chagas disease (CD) is caused by infection with the protozoa *Trypanosoma cruzi* and affects 6–7 million people, leading to 12,000 deaths annually in more than 21 countries, mainly in Latin America, where Brazil, Bolivia, and Argentina are the most affected nations [6]. CD is considered by the WHO as a neglected tropical disease, due to several factors such as (i) the global disinterest of the pharmaceutical industry related to the low-profit perspective in the development of new drugs and vaccines for a vulnerable population that is affected by the CD; (ii) related to social determinants of the affected population, including poverty, malnutrition, poor housing/sanitation, and low education levels [7]. As a consequence of the low investment in drug development for CD, only first-generation drugs dated from the seventies are currently in use for trypanocidal treatment—benznidazole (BZN) and nifurtimox (Nif). Nevertheless, it is estimated that only 1% of the infected persons are etiologically treated, due to the second dimension of negligence that is related to the negligence of public health policies to identify, diagnose, treat, and monitor chronically affected CD people.

To enhance the visibility to the real dimension of CD, WHO instituted a *World Chagas disease Day* in 2020 (https://www.who.int/campaigns/world-chagasdisease-day). The real dimension of CD worldwide is still only estimated, based on data that is more than 10 years old. In Brazil, national guidelines for therapeutics and clinical protocols (PCDT-Chagas) were adopted only in 2018 [8]. Treatment is recommended to prevent or reduce CD progression in both the acute and early chronic phases by using BZN or Nif [6]. About 20–30% of the infected persons will develop chronic complications related to cardiovascular and digestive systems, and CCC is the most relevant infectious heart condition in Latin America [6, 9, 10]. We recently reviewed the complex physiopathology of CCC and the possible interactions where Se could act to reduce oxidative damage that is caused by multiple determinants [11, 12]. **Figure 1** shows the main strategies that we could mobilize to face the complex physiopathogenesis of CD, which involves anti-parasite drugs (AP), modulators of inflammation (MI), immune stimulators (IS), regulators of pathology (RP), and the combination of different therapeutic strategies (CT).

The idea of using Se as a complementary treatment rises from its role in 25 human selenoproteins, some of them acting as antioxidants and others in endocrine and immune pathways [13, 14]. Therefore, the effect of Se therapy in CD development needed proof of concept related to experimental infection and in patients. Our group and other researchers are adding evidence in this direction.

*The Saga of Selenium Treatment Investigation in Chagas Disease Cardiopathy: Translational… DOI: http://dx.doi.org/10.5772/intechopen.103772*

#### **Figure 1.**

*Five different therapeutic strategies that may be applied for Chagas disease treatment in the complexity of its multifactorial causality. Anti-parasite (AP) drugs such as benznidazole and nifurtimox, as well as others that are currently been studied, may reduce the parasite load in the early acute phase and in chronic infection when the parasite still evading the immune system. Infection in the hosts/patients triggers both local and systemic inflammation and a strong specific immune response. An adequate balance of these two mechanisms regulates the control of parasite growth and the regulation of physiopathology. Different strategies are under study in basic research for intervention in these four arms—Modulators of inflammation (MI), as cytokines, chemokines and their antagonists, immune stimulators (IS) as adjuvants, vaccines, and antioxidants, such as Se, regulators of pathology (RP) as neuro-humoral blockers, anti-fibrotic and anti-arrhythmic agents, prevention of thromboembolic events, cell therapy and others. The combination of different therapeutic strategies (CT) should help to face this complexity. However, the translation from basic to clinical studies and to patient access is still far.*

However, combined therapies are scarcely being tested in basic science [15, 16], and its translation to humans must also be investigated, mainly related to more clinical trials, as we performed for Se [5], opening more new doors than solving questions. As shown in **Figure 1**, the strategies of using combined trypanocidal chemotherapy and other agents to mitigate inflammatory disbalance, in which cytokine networks assume pathological roles, as well as increased fibrinogenic and neurodegenerative mechanisms, became co-protagonists in CD physiopathology [9, 10, 17].
