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Download This PDF File International Journal of Radiology Online Submissions: http: //www.ghrnet.org/index./ijr/ Int. J. of Radiology 2021 June; 8(1): 270-325 doi: 10.17554/j.issn.2313-3406.2021.08.88 ISSN 2313-3406 EDITORIAL 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 Joseph Prandota1, MD, PhD 1 Wroclaw Medical University, Wroclaw, Poland. explain several pathomechanisms involved in these processes. Vascular endothelial cells are particularly susceptible to infection with Conflict-of-interest statement: The author(s) declare(s) that there the parasite, which is associated with oxidative stress and endothelial is no conflict of interest regarding the publication of this paper. dysfunction. T. gondii exerts significant pathophysiologic role in altering actin cytoskeleton of endothelial cells, dysregulating vascular Open-Access: This article is an open-access article which was wall barrier function and changing microvascular and macrovascular selected by an in-house editor and fully peer-reviewed by external wall morphology observed in patients with primary and secondary reviewers. It is distributed in accordance with the Creative Com- RP. Development of RP has been associated with administration mons Attribution Non Commercial (CC BY-NC 4.0) license, which of several drugs and biological agents, and may be linked with T. permits others to distribute, remix, adapt, build upon this work non- gondii infection because these medications also have antitoxoplasmic commercially, and license their derivative works on different terms, activity, and in some cases specific toxoplasmosis treatment alleviated provided the original work is properly cited and the use is non- underlying disease manifestations. Acute or chronic latent infections commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ with the pathogen may be responsible for the increased blood viscosity and cryoglobulinemia in RP. The parasite probably also Correspondence to: Joseph Prandota, MD, PhD, Wroclaw Medi- participates in the formation of large von Willebrand factor multimers cal University, Wroclaw, Poland. and development of acquired von Willebrand syndrome. Blood Email: [email protected] volume expander hydroxyethyl starch administration, as well as the ORCID No: 0000-0001-5248-5669 intravenous fundus fluorescein angiography probably induce RP specifically in the patients with latent T. gondii infection. Similarly, Received: May 23, 2021 low weight, involuntary weight loss, and anorexia nervosa associated Revised: May 30, 2021 with RP may be caused by latent infection with that microbe in such Accepted: June 1, 2021 individuals. Furthermore, these infections may also be responsible Published online: June 21, 2021 for the hearing disturbances reported in the workers with hand-arm vibration syndrome and RP. Moreover, it must be noted that the ABSTRACT health improvements in both primary and secondary RP observed after treatment with vitamin D may be, at least in part, associated with Almost 160 years ago dr Maurice Raynaud described a clinical entity its antitoxoplasmc activity. Finally, based on the available literature usually called Raynaud’s phenomenon (RP) manifesting as recurrent data it is suspected that SARS-CoV-2 reactivates latent T. gondii episodes of vasoconstriction involving peripheral small vessels of the infection in the vascular endothelial cells and this coinfection may be fingers and toes exposed to cold, estimated at 3-5% of the world’s responsible for worsening of clinical course and increased mortality population and associated with increased mortality. T. gondii is a in some patients during the 2020/2021 COVID-19 pandemic. widespread intracellular parasite able to attack and proliferate in virtually all nucleated cells, and infecting approximately 30-50% of Key words: Raynaud’s phenomenon; Toxoplasma gondii; the world’s human population. but quite rarely manifesting clinically pathophysiology; Pathomechanisms; Drugs; Interferons; Blood in immunocompetent individuals. The aim of this work was to present viscosity; Cryoglobulinemia; Acquired von Willebrand syndrome; literature data linking development of primary and secondary RP Hydroxyethyl starch; Fundus fluorescein angiography; Anorexia with acute or chronic latent T. gondii infection, describe associated nervosa; Hand-arm vibration syndrome; Hearing disturbances; diseases and/or clinical events, biochemical abnormalities, and Vitamin D; COVID-19 pandemic 270 Prandota J. Raynaud’s phenomenon and latent Toxoplasma gondi infection © 2021 The Author(s). Published by ACT Publishing Group Ltd. B. T. gondii infection All rights reserved. This intracellular pathogen believed to be a global threat[48-50] infects approximately 30-50% of the human population, and Prandota J. Solving the Old Puzzle 1862-2021: Pathophysiology and ophthalmoimmunologists suggested that even some six billion people Pathomechanisms of Raynaud’s Phenomenon. Key Role of Acute and are chronically infected with T. gondii[49,51]. IgG seroprevalence Chronic Latent T. gondii Infection in these Clinical Events and their against the parasite varied from 6.7% in Korea[52], 47-50% in France Potential Link with COVID-19 Pandemic. International Journal of and Germany[53,54], to 98% in some regions[55]. In the US, T. gondii Radiology 2021; 8(1): 270-325 Available from: URL: http://www. is responsible for approximately million infections each year, and ghrnet.org/index.php/ijr/article/view/ the overall antibody seroprevalence among individuals ≥ 6 yrs of age in 2011-2014 was 13.3%[56,57]. The global annual incidence of I. INTRODUCTION congenital toxoplasmosis was estimated to be 190 100 cases (95% CI: 179 300-206 300)[58], sometimes causing epidemics[59]. In general A. Raynaud’s phenomenon (RP) population toxoplasmosis was the second most common foodborne In 1862, Maurice Raynaud as a medical student in Paris described parasitic disease (10.3 million cases, 95% uncertainty intervals 7.40- a phenomenon of “local asphyxia and symmetrical gangrene of the 14.9 million)[60]. The frequency of T. gondii infection was found to extremities” in 20 women and 5 men, being a part of his doctoral [51,57,61] [1-5] increase significantly with age in persons aged 66-75 years . thesis . At present, RP is de fined as recurrent, reversible episodes Toxoplasmosis is an opportunistic disease and the intracellular of va soconstriction involving peripheral small vessels of the fingers parasite is highly pathogenic especially for immunocompromised and toes, and sometimes also nose, ears, lips, tongue, oral mucosa, [62-64] [6,7] individuals . In immunocompetent persons T. gondii infection is or nipples , and associated with ischemia of tricolor pattern believed to be asymptomatic[63,64], but an increasing body of literature (white to blue to red) when exposed to cold environment and/or [8,9] data strongly suggests that the pathogen is emerging as a neglected emotional stress . These abnormalities are manifested clinically global health threat[48,50,62]. The parasite is omnipresent, and exposure by transient attacks of distal swelling, pain, burning, numbness, and/ [10,11] to kittens and raw or uncooked foods are the main risk factors for T. or paresthesia . RP is divided into primary RP (PRP) (Raynaud’s [65] [12] gondii infection in the United States . Contamination of drinking disease; idiopathic RP) (80-90%) with a relatively mild course, water with the parasite oocysts contributes to their widespread and secondary RP (SRP) (Raynaud’s syndrome), which is quite often [66] associated with several autoimmune diseases, broad range of medical dissemination . In North America, Europe, and Africa, there are conditions, physical-, chemical-, and drug-related causes, and with three dominant lineages of T. gondii called type I (e.g. RH and GT1), development of vascular structure and function abnormalities[8-10,13-16]. type II (ME49), and type III (VEG), which differ in prevalence, A prevalence of RP is estimated at 3-5% of the general population virulence, migratory capacity within the host, and ability to convert [67,68] and may be higher in those living in cold climates geographic regions to the bradyzoite cyst phase . [17,18]. The highest median prevalence was found in the USA (7.8% in Several authors documented that T. gondii infection was associated women, 5.8% in men)[19], and the lowest worldwide prevalence was with weight loss, hypermetabolism, cachexia, and anorexia nervosa [69-71] reported in Japanese population (2.1% in women, 1.1% in men)[20]. , and low-grade immune-activation with elevation of circulating RP is frequently observed in the so called “healthy population”[21-23]. IL-6 has been observed in certain diseases states, as well as in several [72-77] This clinical entity was described in newborns, infants, older children, healthy elderly individuals . For example, anorexia nervosa was [78,79] and adolescents[24-32]. In young women (15-30 years old) with low reported in autistic women , and in children and adolescents [80] blood pressure RP is diagnosed earlier and more frequently[33,34]. Low with systemic lupus erythematosus (SLE) . On the other hand, the [73,81,82] body weight and unintended weight loss may be associated with parasite has also been linked with overweight and obesity . RP[35], while people with obesity were positively correlated only with Studies showed that
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