Pathophysiology of Post-COVID syndromes: a new perspective

Abstract

Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as “long-COVID” or “Post-COVID syndrome” (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

Post-COVID Syndrome in Adults—An Overview

“…Proposed underlying mechanisms related to the development and manifestation of post-COVID syndrome can include (1) viral persistence upon initial infection of host cells by SARS-CoV-2, (2) cellular damage due persistent hyperinflammation, (3) immunologic aberrations caused by molecular mimicry, epitope spreading, bystander activation, or superantigen, and (4) hemostatic changes, predominantly characterized by coagulation abnormalities [ 23 , 24 , 25 , 26 , 27 , 28 ]. Some of these mechanisms and abnormal or misdirected drivers are displayed in Figure 1 and discussed in more detail below.…”

“…Several investigators have observed pulmonary and gastrointestinal SARS-CoV-2 reservoirs that can persist for up to four months [ 25 , 29 ]. Moreover, in a recent autopsy study on 44 patients, persistent SARS-CoV-2 RNA was detected outside the respiratory tract in multiple anatomic sites, including the brain, as late as 230 days following onset of COVID-19 symptoms [ 30 ].…”

Expression of SARS-CoV-2 receptor angiotensin-converting enzyme 2 by activating protein-1 in human mast cells

“…Additionally, tryptase released by mast cells causes vascular barrier failure, lung fibrosis, and airway inflammation and encourages the spread of SARS-CoV-2 infection [21] . MCAS caused by SARS-CoV-2 may elevate the incidence of developing severe acute COVID-19 and chronic post-COVID-19 diseases [9] . Afrin et al [14] reported that MCAS targeted therapy can lessen the severity of the disease as soon as the development of a COVID-19 disease is identified or suspected.…”

“…The COVID-19 postmortem lung biopsies in SARS-CoV-2 infections patients exhibit an enormously elevated number of mast cells, indicating that SARS-CoV-2 infection may have attracted mast cells to the alveolar septa [8] . Post-COVID syndrome may progress in association with the development of mast cell activation syndrome (MCAS) [9] .…”

Dantrolene and ryanodine receptors in COVID‐19: The daunting task and neglected warden

“…A large body literature gave evidence that SARS‐CoV‐2 through activation of toll‐like receptor 4 (TLR4) and nuclear factor κ B (NF‐κB) trigger release of pro‐inflammatory cytokines like TNF‐α 5,71,72 . TNF‐α stimulates opening of Ca 2+ channels in ER through activation of IP3R, which in turn increase cytosolic Ca 2+ by activation of membrane store operated Ca 2+ channels 73 .…”