Systematic Review of the Serotonergic System in the Pathophysiology of Severe Dengue: The Theory of Thrombocytopenia and Vascular Extrava-sation

Background: Severe dengue is characterized by thrombocytopenia, hemorrhaging, and/or capillary extravasation and may be linked to a reduced plasma concentration of serotonin (5-hydroxytriptamine, or 5-HT). Objective: The aim of the current contribution was to conduct a systematic bibliographic review of reports on the role of the peripheral serotonergic system in the pathophysiology of severe dengue. Methods: A bibliographic review was carried out of in vivo/in vitro models, clinical trials, and case series studies from 2010-2019. The selective criteria were the use of treatments with seroto-nin reuptake inhibitors and/or agonists/antagonists of 5-HT receptors and their impact on inflam-mation, coagulation, and endothelium. Moreover, cross-sectional and cohort studies on the relationship between intraplatelet and plasma 5-HT levels in patients with dengue were also included. The risk of bias in the selected reports was examined with domain-based assessment utilizing Cochrane-type criteria. The main results are summarized in Tables and Figures. Results: Based on descriptions of the effect of serotonergic drugs on 5-HT levels and the findings of clinical trials of dengue treatment, most receptors of the peripheral serotonergic system, and especially 5-HT2A, seem to participate in regulating serum 5-HT during severe dengue. Therefore, the peripheral serotonergic system probably contributes to thrombocytopenia and capillary extrav-asation. Conclusion: Regarding dengue, 5-HT may be a key parameter for predicting severity, and an un-derstanding of 5-HT-related mechanisms could possibly facilitate the development of new thera-pies. These proposals require further research due to the limited number of publications on the role of serotonergic receptors at the peripheral level.