A recent short review article contained a subtitle: “Long COVID: A frequent syndrome with unclear pathogenesis” (Yavropoulou et al. 2022). This is indeed a short and crisp assessment of our sad situation with the understanding of the molecular and cellular mechanisms of long COVID. The little we know so far about the pathogenesis is summarized in Fig. 4. Namely, we know from the early research on the mechanisms of acute COVID-19 that the initial cellular targets are the epithelial cells lining the nose, bronchi and alveolar sacs in the lung. These cells represent the entry point of the SARC-Co-2 in the organism, but surprisingly, despite being the original targets, the virus entry was followed only by mild inflammation, contrary to the clinical presentation of initial SARS and MERS that were associated with severe pneumonia and bronchitis.

  Pathogenesis - the little we know so far...

On the other hand, severe COVD-19 patients suffered from a rapidly developing lung edema, i.e., accumulation of fluid in the alveolar spaces that are normally filled only with air, since the venous blood is oxygenated there before returning to the heart for distribution of oxygenated blood to our organs. Such a rapidly developing pulmonary edema could come only from increased vascular permeabilities, i.e., from arterioles, capillaries and venules surrounding the alveolar sacs, as illustrated in Fig. 4. Mechanistically, increased vascular permeability is usually triggered by a sudden release of histamine from nearby mast cells or of vascular endothelial growth actor (VEGF) which is usually stored/bound to heparin in the adjacent loose connective tissue. Not too many people know that the initial name of VEGF was VPF (vascular permeability factor) which on a molar basis is more potent than histamine to cause vascular leakage (Dvorak et al. 1995). VPF/VEGF receptors, flt-1 and kdr, are overexpressed by endothelial cells that line the microvessels that supply alveoli, and because of these pathogenic elements, numerous clinical reports showed the beneficial effects of bevacizumab, an anti-VPF/VEGF in treating patients with severe forms of COVID-19, and new clinical trials are still ongoing (Pang et al. 2021; Sahebnasagh et al. 2021).

Figures 4 and 5 also illustrate the transition of vascular-based elements into the development of long COVID, like the cytokine storm, fibrin clots on the damaged capillary endothelial cells that attract platelets, over which fibrin fibres to form thrombus. The additional pathogenic factor in long COVID is that this microthrombi may get dislodged and form microemboli distributed all over the body, creating ischemic microinfarcts in several organs, especially in the brain that may lead to impairment in brain functions that patients may experience in the form of ‘brain fog’. Furthermore, recently SARS-Co-2 aggregates have been identified in organs other than the lungs, e.g., in brain, kidney, muscle, peripheral nerves, adrenal cortex (Weixel 2022). Thus, mechanistically, “COVID-19 is, in the end, an endothelial disease” (Libby and Luscher 2020), as some of us were proposing from the very beginning of this pandemic, in part because of the similar, critical role of vascular factors in the cellular and molecular pathogenesis of gastrointestinal (GI) ulceration (Szabo 2020, 2021).

The mechanistic role for VPF/VEGF and anti-VEGF (bevacizumab) in the pathogenesis and treatment of COVID-19