Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence

Abstract

Coronavirus disease 2019 (COVID-19), a pandemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, can affect almost all systems and organs of the human body, including those responsible for reproductive function in women. The multisystem inflammatory response in COVID-19 shows many analogies with mast cell activation syndrome (MCAS), and MCAS may be an important component in the course of COVID-19. Of note, the female sex hormones estradiol (E2) and progesterone (P4) significantly influence mast cell (MC) behavior. This review presents the importance of MCs and the mediators from their granules in the female reproductive system, including pregnancy, and discusses the mechanism of potential disorders related to MCAS. Then, the available data on COVID-19 in the context of hormonal disorders, the course of endometriosis, female fertility, and the course of pregnancy were compiled to verify intuitively predicted threats. Surprisingly, although COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in MCAS, the available clinical data do not provide grounds for treating this mechanism as significantly increasing the risk of abnormal female reproductive function, including pregnancy. Further studies in the context of post COVID-19 condition (long COVID), where inflammation and a procoagulative state resemble many aspects of MCAS, are needed.

Pathophysiology of Post-COVID syndromes: a new perspective

“…Importantly, our findings highlight MCs as potential therapeutic targets for patients with PCS, which could be targeted with agents that reduce MC‐derived mediators, engage inhibitory receptors, or attenuate inflammation [ 182 ]. Analogous to respiratory function, it cannot be excluded that the cytokine storm accompanying SARS-CoV-2 infection and MCAS during COVID-19 may indirectly affect female reproductive function, especially in more severe cases [ 183 ]. Neutralization of upstream histamine, a major mediator derived from MCs, inhibits the nuclear translocation of NF- κ B, thereby preventing the release of the proinflammatory cytokines interleukin (IL-1 β , TNF- α , IL-6, and IL-10).…”

“…Neutralization of upstream histamine, a major mediator derived from MCs, inhibits the nuclear translocation of NF- κ B, thereby preventing the release of the proinflammatory cytokines interleukin (IL-1 β , TNF- α , IL-6, and IL-10). Despite the fact that COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in MCAS, the available clinical data do not provide grounds for treating this mechanism as a significant threat to female reproductive functions, including pregnancy [ 183 ]. Understandably, severe COVID-19 reduces female fertility and has been associated with impaired fetal growth during pregnancy, an approximate twofold increased risk of stillbirth, threefold increased risk of preterm birth (likely influenced by iatrogenic deliveries) and prematurity-related worse perinatal outcomes [ 182 , 183 ].…”

“…Despite the fact that COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in MCAS, the available clinical data do not provide grounds for treating this mechanism as a significant threat to female reproductive functions, including pregnancy [ 183 ]. Understandably, severe COVID-19 reduces female fertility and has been associated with impaired fetal growth during pregnancy, an approximate twofold increased risk of stillbirth, threefold increased risk of preterm birth (likely influenced by iatrogenic deliveries) and prematurity-related worse perinatal outcomes [ 182 , 183 ]. It should be noted that the pathophysiological spectrum of MCAS is extremely broad and heterogeneous.…”

“…It is noteworthy that PCS with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state resembles many aspects of MCAS. For example, in both pathologies, NLRP3 inflammasome may be crucial in the consolidation of coagulation disorders.Further studies are needed to determine whether MCAS-related clotting disorders (e.g., microcoagulopathy) are subjected to long-term modulation by SARS-CoV-2 infection with possible consequences on female reproductive function [ 182 , 183 ].…”

Long COVID – eine neue Herausforderung in der Medizin: Fokus auf Schwangerschaft und Stillzeit

“…Fernerhin greift die COVID-Schutzimpfung, trotz anfänglicher Befürchtungen in der Bevölkerung, nicht in die Fertilität bei Frauen oder Männern ein und ist in dieser Hinsicht unbedenklich [ 42 ]. Vielmehr könnte es im Verlauf einer COVID-19-Erkrankung zu einer Schädigung der Reproduktionsorgane, durch eine NLRP3-Inflammasom-Hyperaktivierung und ein prokoagulatorisches Milieu ähnlich wie bei einem Mastzellaktivierungssyndrom, kommen [ 43 – 45 ].…”