Solving the Old Puzzle 1862-2021: Pathophysiology and Pathomechanisms of Raynaud’s Phenomenon. Key Role of Acute and Chronic Latent T. gondii Infection in these Clinical Events and their Potential Link with COVID-19 Pandemic

Abstract

Almost 160 years ago dr Maurice Raynaud described a clinical entity usually called Raynaud’s phenomenon (RP) manifesting as recurrent episodes of vasoconstriction involving peripheral small vessels of the fingers and toes exposed to cold, estimated at 3-5% of the world’s population and associated with increased mortality. T. gondii is a widespread intracellular parasite able to attack and proliferate in virtually all nucleated cells, and infecting approximately 30-50% of the world’s human population. but quite rarely manifesting clinically in immunocompetent individuals. The aim of this work was to present literature data linking development of primary and secondary RP with acute or chronic latent T. gondii infection, describe associated diseases and/or clinical events, biochemical abnormalities, and explain several pathomechanisms involved in these processes. Vascular endothelial cells are particularly susceptible to infection with the parasite, which is associated with oxidative stress and endothelial dysfunction. T. gondii exerts significant pathophysiologic role in altering actin cytoskeleton of endothelial cells, dysregulating vascular wall barrier function and changing microvascular and macrovascular wall morphology observed in patients with primary and secondary RP. Development of RP has been associated with administration of several drugs and biological agents, and may be linked with T. gondii infection because these medications also have antitoxoplasmic activity, and in some cases specific toxoplasmosis treatment alleviated underlying disease manifestations. Acute or chronic latent infections with the pathogen may be responsible for the increased blood viscosity and cryoglobulinemia in RP. The parasite probably also participates in the formation of large von Willebrand factor multimers and development of acquired von Willebrand syndrome. Blood volume expander hydroxyethyl starch administration, as well as the intravenous fundus fluorescein angiography probably induce RP specifically in the patients with latent T. gondii infection. Similarly, low weight, involuntary weight loss, and anorexia nervosa associated with RP may be caused by latent infection with that microbe in such individuals. Furthermore, these infections may also be responsible for the hearing disturbances reported in the workers with hand-arm vibration syndrome and RP. Moreover, it must be noted that the health improvements in both primary and secondary RP observed after treatment with vitamin D may be, at least in part, associated with its antitoxoplasmc activity. Finally, based on the available literature data it is suspected that SARS-CoV-2 reactivates latent T. gondii infection in the vascular endothelial cells and this coinfection may be responsible for worsening of clinical course and increased mortality in some patients during the 2020/2021 COVID-19 pandemic.