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Dermatitis is the most common adverse event during treatment with benznidazole in chronic Chagas disease and is probably mediated by T cells. A set of molecules representative of the different type IV hypersensitivity reactions was evaluated in the circulation and skin biopsies of Trypanosoma cruzi-infected subjects presenting dermatitis during benznidazole administration. Through cytometric bead assays and enzyme-linked immunosorbent assay capture techniques, the serum levels of cytokines, chemokines, proapoptotic molecules, and mediators of the activation and migration of eosinophils and T cells were measured in subjects infected with Trypanosoma cruzi who exhibited skin adverse events ( n  = 22) and compared with those without adverse events ( n  = 37) during benznidazole therapy. Serum levels of interleukin- 5 (IL-5), soluble Fas cell surface death receptor ligand (FAS-L), and interferon γ-induced protein (IP-10) significantly increased at 7 to 30 days posttreatment with benznidazole and decreased thereafter in subjects with dermatitis but not in those without dermatitis. Circulating eotaxin levels were lower in subjects with dermatitis than in those without. Two patterns emerged in the skin biopsies: a T helper 1/T cytotoxic profile and a T helper 2/T cytotoxic profile with the presence of CD4 + and CD8 + T cells. Increased low-density lipoprotein (LDL), glutamic-oxaloacetic transaminase (GOT), uremia, and T cell activation emerged as risk factors for the development of dermatitis during benznidazole administration. These results support a delayed-type hypersensitivity reaction to benznidazole, involving CD4 + and CD8 + T cells and eosinophils, and a mixed cytokine profile. This study provides new insights for better management of adverse drug reactions to benznidazole. IMPORTANCE This study identified the risk factors for the development of adverse reactions to benznidazole and identified a set molecule to monitor the appearance of these reactions. This knowledge might improve the safety of benznidazole administration.

This review is a perspective on the history of Chagas disease, and it adopts a novel approach from literary studies, historical documents and the science and epidemiology of the nature of the disease. From this analysis, comes the review's working definition of the Contact Zone (CZ): "the space in which geographically and historically separated people come into contact with each other and establish long-lasting relationships, which usually involve coercive conditions, radical inequality and intolerable conflict." In the Patient-Physician CZ, we verified the triple transition phenomena: the American trypanosomiasis shifted from a rural, acute, and vectorial transmitted disease to an urban, chronic and non-vectorial disease. In the Academic CZ, we describe the original disagreements which denied the existence of the disease and the current controversies about pathogenic mechanisms and etiological treatment. From the News from Latin America, and in the Original CZ, we will review the evolution of different forms of transmission. As in any good story, research across broad disciplines is necessary to reveal historical perspectives, scientific approaches, and the epidemiology of the disease, which has a prequel of 9000 years and an open ending: thus, we explore across the Global CZ, with its multiple and unexpected actors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The extent of inflammation, fibrosis, and progression of chronic Chagas heart disease (cChHD) was associated with persistence of parasite DNA in cardiac lesions of necropsies or explants from Argentinean cChHD patients. A Trypanosoma cruzi-based polymerase chain reaction showed a positive result in 1) 15% of cardiac sections with less than 10 mononuclear inflammatory cells/high-power field (440x) (MNC/HPF), 89% with 10-19 MNC/HPF, and 100% with more than 20 MNC/HPF (P < 0.0001); 2) 33% with less than 10% fibrosis, 79% with 10-19% fibrosis, and 100% with more than 20% fibrosis (P < 0.01); 3) 25% of specimens from patients classified in Kuschnir groups 0 and I, 70% in group II and 90% in group III (P < .001); and 4) 45% and 90% of the specimens from cChHD patients without or with heart failure, respectively (P < 0.01). These findings stress the role of the parasite in pathogenesis and disease progression of cChHD.

It is still unclear to what extent myocarditis-associated, chronic Chagas' heart disease is due to persisting Trypanosoma cruzi. In the present study, we have analyzed tissue samples from the hearts of three patients with this disease. In situ hybridization provided little evidence for the presence of intact T. cruzi even at sites of strong inflammation. Nevertheless, micromanipulation techniques detected remnants of both T. cruzi kinetoplast DNA and nuclear DNA. Trypanosoma cruzi DNA was also detected in single macrophages dissected directly from frozen heart tissue sections. Thus, this analysis demonstrates that T. cruzi kinetoplast DNA and nuclear DNA are widely dispersed in the heart tissue, although in low amounts. Since we rarely detected intact T. cruzi parasites during the chronic phase of Chagas' heart disease, we can exclude heart tissue as a major parasite reservoir.