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Review
. 2014 Jul 31;8(7):e3010.
doi: 10.1371/journal.pntd.0003010. eCollection 2014.

Acute chagas disease: new global challenges for an old neglected disease

Daniela V Andrade  1 , Kenneth J Gollob  2 , Walderez O Dutra  3
Affiliations
Review

Acute chagas disease: new global challenges for an old neglected disease

Daniela V Andrade et al. PLoS Negl Trop Dis. .

Abstract

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi, and although over 100 years have passed since the discovery of Chagas disease, it still presents an increasing problem for global public health. A plethora of information concerning the chronic phase of human Chagas disease, particularly the severe cardiac form, is available in the literature. However, information concerning events during the acute phase of the disease is scarce. In this review, we will discuss (1) the current status of acute Chagas disease cases globally, (2) the immunological findings related to the acute phase and their possible influence in disease outcome, and (3) reactivation of Chagas disease in immunocompromised individuals, a key point for transplantation and HIV infection management.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Challenges in human Chagas disease: control, diagnosis, treatment, and clinical management.
Regardless of the route of infection, control of T. cruzi transmission is still a challenge, especially considering disease emergence and re-emergence, as discussed in this review. It is also critical to detect infection early on in order to provide immediate treatment to the patients. It is estimated that treatment efficacy is observed in at least of 80% of treated acute patients. Lack of detection of the acute phase or treatment failure lead to disease chronification. Given that approximately 30% of the patients in the chronic phase will develop severe, clinical forms of Chagas disease, which often lead to death, clinical management is critical. However, given that the mechanisms responsible for patient progression from the indeterminate to the symptomatic forms of Chagas disease are not completely understood, clinical management presents another important challenge. The search of prognostic markers of disease progression is a critical aspect for preventing pathology and introducing better clinical measures.
Figure 2
Figure 2. Acute cases of Chagas disease worldwide.
The embedded table shows specific information on the transmission routes and number of affected individuals per case, when available. Asterisks (*) in the map indicate acute Chagas disease cases reported in the last ten years. Most cases in South America were due to vector transmission, congenital, and reactivation cases. In Brazil, the greatest number of cases were due to oral contamination. In Europe and the US, most cases were due to congenital or reactivation –.
Figure 4
Figure 4. Immune response in the experimental murine model.
Following infection with T. cruzi, the parasites infect and replicate in many nucleated cells. Innate immunity cells such as macrophages, dendritic cells, and NK cells provide the first line of defence against infection with T. cruzi, preceding the onset of the specific immune response by T and B lymphocytes. Parasite antigens induce macrophages to synthesize IL-12, a powerful inducer of IFN-gamma by NK cells. This inflammatory cytokine, together with TNF-alpha, triggers activation of macrophages and the inflammatory process, controlling parasite replication. Macrophage-derived reactive nitrogen intermediates (RNI) are directly associated with control of parasite burden. Differentiation and expansion of CD4+ and CD8+ T cells with polarization towards IFN- gamma are elicited by IL-12 derived from dendritic cells and NK cells, triggering cytotoxic activity by CD8+ T cells and effector mechanisms in macrophages. Effector CD4+ T cells stimulate B cells into proliferation and subsequent antibody production, which can lyse the trypomastigote forms. The acute phase is also characterized by recruitment of T cells to the tissues, in which IFN-gamma plays a major role by inducing chemokine production. In early immune responses, the inflammatory environment is crucial for host resistance to infection, but it might also lead to genesis of tissue damage. These immunological events were described in experimental models, and although the translation to human studies has limitations, they have elucidated many important aspects of T. cruzi infection.
Figure 3
Figure 3. Clinical evolution of human Chagas disease.
During the acute phase of human Chagas disease, macrophage and NK cell activation occur, as well as antibody production by plasma cells. These events lead to control of the parasite levels, observed in the late stages of the acute phase and throughout the chronic phase. NK cells and macrophages produce cytokines that might activate other cells such as CD4+, CD8+, and other T cell subpopulations, although the participation of these cells during the acute phase is not clear. The dotted boxes around some cytokines indicate that the cells associated with them may be responsible for their production, however, there is yet to be a definitive study confirming this. The production of IL-10 and other anti-inflammatory molecules may influence control of the response, decreasing tissue damage and allowing for the disease to enter into the chronic phase. In other studies, there is much evidence supporting that the predominance of an inflammatory environment during the chronic phase is associated with symptomatic forms (cardiac and digestive), whereas the predominance of an anti-inflammatory environment is associated with the maintenance of the indeterminate form.
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Grants and funding

Authors would like to acknowledge CNPq, INCT, CAPES and FAPEMIG for continuing support of their work. WOD and KJG are CNPq fellows. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.