*4.2. Cytokine Storm Syndrome (CSS)*

In the severe COVID-19 phase, the pathophysiological response is a cytokine-mediated systemic hyperinflammation, called cytokine storm syndrome (CSS) or cytokine release syndrome (CRS). CSS is a life-threatening emergency associated with high mortality. It was first described in renal allograft recipients [28], receiving the anti-T-cell antibody muromonab-CD3 (OKT3), an immunosuppressive drug [28]. These patients developed systemic reactions that closely resembled the symptoms induced by the injection of pure recombinant cytokines [28], which was related to a massive release of highly biologically active mediators [28]. In CSS, laboratory results demonstrate pancytopenia (anemia, leukocytopenia, thrombocytopenia), coagulation disorders, elevated serum creatinine, liver enzymes, C-reactive protein (CRP) and hyperferritinemia.

The presence of hyperferritinemia seems to play a relevant pathophysiological role in CSS. In autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and the anti-phospholipid syndrome, it is a well-known feature [29]. H-ferritin has been shown to suppress myeloid cells, and also affects lymphoid cells by suppressing the proliferation of T-cells and impair the maturation of B-cells [30]. Moreover, ferritin may favor the loss of tolerance and the onset of autoimmunity [30]. Ferritin can be also a pro-inflammatory signaling molecule [29]. Hyperferritinemia has been associated with different CSS-related conditions such as macrophage activation syndrome (MAS) and septic shock [29].

CSS is clinically characterized by persistent fever, lymphadenopathy, hepatosplenomegaly, central nervous system (CNS) abnormalities with multiple organ failure (MOF), disseminated intravascular coagulation (DIC), renal and/or cardial insufficiency, and shock.

In COVID-19, the CSS spectrum of respiratory symptoms is wide, and can be mild (cough, mild dyspnea) to severe (severe dyspnea, with progression to Acute Respiratory Distress Syndrome (ARDS) or Acute Lung Injury (ALI), with a fulminant post-ARDS pulmonary fibrosis. The pulmonary complications in CSS has an aerogenic and a vascular route. The first is by aerogenic SARS-CoV-2 transmission which leads to SARS-CoV-2 reaching the ACE-2 receptors in the alveolar epithelial cells. This results in the downregulation of ACE-2 expression and increasing the angiotensin level, leading to increased pulmonary capillary permeability and pulmonary edema [31]. The second is by the blood circulation, where SARS-CoV-2 reaches the lung again, interacting with the ACE-2 receptors on the surface of alveolar capillary endothelial cells, where it attacks the capillary endothelium. The resultant

immune responses further aggravate lung injury by the CSS [31]. These cytokines include interleukin (IL)-1β, IL-1Rα, IL-2, IL-10, fibroblast growth factor (FGF), granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), interferon-γ-inducible protein (IP10), monocyte chemo attractant protein (MCP1), macrophage inflammatory protein 1 alpha (MIP1A), platelet derived growth factor (PDGF), tumor necrosis factor (TNFα) and vascular endothelial growth factor (VEGF) [32]. Moreover, in severe COVID-19, there is a reduction of natural killer (NK) cells, CD4+ and CD8+ T-lymphocytes and IFN-γ expression in CD4+ T-lymphocytes. In this phase, SARS-CoV-2 infection leads to a reduction and functional exhaustion of T cells [33] and by the above described mechanisms, SARS-CoV-2 is hijacking our immune defense systems.

These inflammatory factors may be among the leading causes in the rapid worsening of COVID-19. Similar to SARS-CoV and MERS-CoV, in SARS-CoV-2 increased amounts of proinflammatory cytokines in serum were associated with pulmonary inflammation and extensive lung damage [34]. Moreover, compared to patients with less severe disease, patients requiring ICU admission had higher serum cytokine concentrations than those that did not require ICU admission, suggesting that the cytokine storm was associated with disease severity [34]. However, regarding the role of cytokine storm in COVID-19, it still is not clear which cytokine(s) plays a critical role in the initiation of severe COVID-19 [35].

Another major unanswered question is why most COVID-19 patients with CSS are elderly patients, and CSS is extremely rare in young COVID-19 patients. One explanation might be that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, including IL-6, IL-8, TNF-α, IL-13, IFN-γ, as well as acute phase proteins. This chronic mild inflammation in aging, so-called "inflamm-aging" [36], results in an increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection [36].
