A challenge for physicians is the optimal management of an abnormal hyper-inflammatory state with elevated pro- and inflammatory cytokines, which could drive ARDS and has been described in numerous hospitalized COVID-19 patients [7]. To the best of our knowledge, a similar disorder has been described in juvenile Still disease, revealed as a cytokine storm leading to macrophage activation syndrome (MAS), secondary haemophagocytic lymphohistiocytosis (sHLH), or cytokine release syndrome (CRS) [6,20]. These pathological entities are more commonly driven by viral infections, autoimmune disorders, malignancy (HLH and MAS), sepsis, and the administration of chimeric antigen receptor T cell therapy (CRS) [21,22]. It is characterized by sudden fever, respiratory and kidney failure, hypotensive shock, and diffuse coagulation disorders, while laboratory examinations reveal anemia, neutrophilia, thrombocytopenia, and marked lymphopenia [23,24]. Multi-organ failure presented in many cases, while four molecular cascades were responsible for its course—complement, kinin, clotting, and fibrinolysis systems. A similar phenomenon has been observed in patients with severe COVID-19 pneumonia with primary HLH as the potential underlying cause [20,25].

The assumed underlying mechanism is the rocket of secreted inflammatory cytokine levels in the bloodstream of the patients. The critical pathogenic cytokines appear to vary according to illness, with IL-1β having an orchestrating role in Still disease, IL-18 in MAS, and IL-6 in CRS [26]. As far as the severe COVID-19 disease is concerned, the widespread hypothesis is that, in the early phase, failure of perforin, natural killer cells (NK), and CD8+ cytotoxic T-cells leads to cell lysis, initiating apoptosis of virally infected cells while interferon-γ (IFN-γ) causes excessive macrophage activation [25,27]. Multiple studies have revealed that the toll-like receptors (TLRs) and activated inflammasomes (Caspases) first release the primarily inflammatory component of the disease, IL-1β [28,29]. Parallel delayed secretion of type Ⅰ and Ⅲ IFNs, including IFN α/ß, in the early phase of infection and excessive secretion of pro-inflammatory cytokines from mononuclear macrophages is described in the later stage [30]. The cells release modest levels of antiviral factors—IFNs—as well as high amounts of pro-inflammatory cytokines—IL-1, IL-6, and TNF—and particular chemokines—C-C pattern chemokine ligand (CCL)-2, CCL-3, and CCL-5 [31,32]. Linear association of disease severity course and the type of elevated cytokines has not been well established yet. Several studies suggest that higher levels of IL-1β, IL-1RA, IL-7, IL-8, IL-10, IFN-ɣ, MCP-1, MIP-1α, G-CSF, and TNF-α have been observed in severe infection with marginal statistical significance [27,33]. Airway and alveolar epithelial cell apoptosis was induced by IFN-αβ and IFN-γ, increasing the inflammatory cell infiltration. Apoptosis of endothelial and epithelial cells affects the pulmonary microvascular and alveolar epithelial cell barriers, causing vascular leakage, alveolar edema, and, eventually, hypoxia [7,25]. The studies mentioned above emphasize that a failure in initial type-Ⅰ and Ⅲ IFN responses to SARS-CoV-2 leads to an excessive late immune response and severe form of COVID-19. The pro-inflammatory feed-forward loop of cytokines on innate immune cells results in a cytokine storm, coagulopathy, and acute respiratory distress syndrome (ARDS) [34,35]. On the other hand, in contrast with the widespread hypothesis of failure of the immune system, two other studies presented an interesting and quite different concept of cytokine storm onset, differentiating it into two stages. In the first, a short-term immune-deficient state is considered, followed by a second overactive immune condition which tries to counterbalance the agitated entropy from temporary immune target failure, driving to a cytokine storm [7,36]. As such, further molecular research on patients presented with cytokine storm caused by COVID-19 is required to clarify the phenomenon (Figure 1).

Many researchers support the position that cytokine storm in COVID-19 is related to individual genetic predisposition and vulnerability. This theory was strengthened by the evidence of genetic vulnerability in patients marked by primary HLH or cytokine storm in Still disease [14]. Failure of perforin and the activation of NK and cytotoxic T lymphocytes have been demonstrated as the main components of these pathologic entities.

Several studies have reported associations between human genes and COVID-19. ABO blood groups have been assessed in susceptibility to SARS-CoV-2, revealing a higher risk of infection for blood group A than non-A and a lower risk of infection for blood group O compared to non-O [37]. It is assumed that the formation of neutralizing antibodies against protein-linked N-glycans or indirect effects such as the stability of the von Willebrand factor have a partial impact on differing susceptibility [38,39,40]. Although the O blood type group seems to have an advantage concerning the susceptibility to SARS-CoV-2, there was no association between the ABO blood group and the severity of COVID-19 disease or mortality rate according to a recent meta-analysis [41]. As discussed above, invasion of SARS-CoV-2 is dependent on ACE2 and the transmembrane serine protease (TMPRSS2) [42]. Polymorphisms on the gene of ACE2 have been associated with adverse cardiovascular and pulmonary conditions in severe COVID-19 patients due to alterations to angiotensinogen. Furthermore, the localization of the ACE2 gene on the X chromosome may contribute to the generally higher burden observed in males as compared to in females [42]. On the other hand, a recent study illustrated that several ACE2 variants including K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L, and D509Y have less affinity to bind SARS-CoV-2 [43]. Although large cohort studies have not been completed yet and these variants are rare in the general population, this observation could be a cornerstone in the management of the disease [43]. In different populations, no polymorphisms or mutations associated with S binding protein have been documented [43]. Another analysis suggested that polymorphisms including rs233574, rs2074192, and rs4646188 would change COVID-19 binding to ACE2 expressing a protective profile [44]. Of interest is the fact that three well-known polymorphisms of ACE2 (p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg), as well as two rare variants p.(Leu351Val) and p.(Pro389His) have been identified and associated with a better course of the disease [45]. TMPRSS2 enzyme activity is important for coronavirus spread and pathogenesis in the infected host. The polymorphism p.Val160Met (rs12329760) seems to be related to increased susceptibility to SARS-CoV-2 while the oncogenic role of TMPRSS2 may be linked to poor disease outcomes [46].

The apolipoprotein E (ApoE) e4e4 homozygous genotype has been observed to enhance the risk of severe COVID-19, regardless of prior dementia, cardiovascular illness, or type 2 [47,48,49]. ApoE e4 rules the macrophage pro-/anti-inflammatory phenotypes, and it is expressed in type II alveolar cells in the lungs where the ACE2, which SARS-CoV-2 employs for cell entrance, is abundantly co-expressed [48,49]. Association of major histocompatibility complex (MHC) class I genes (human leukocyte antigen [HLA] A, B, and C) and the susceptibility to SARS-CoV-2 have been observed. More specifically, assessing the binding affinity across HLA phenotypes and viral peptides, it is shown that harbors of HLA-B*46:01, HLA-A*11:01, -B*51:01, -C*14:02, HLA-DRB1*15:01, -DQB1*06:02, and -B*27:07 alleles are more vulnerable to SARS-CoV-2, and these mutations predispose patients to a worse disease course [50]. Loss-of-function variants of the X chromosomal Toll-Like Receptor 7 (TLR7) gene have been described in individuals. The primary pathophysiologic mechanism predisposing patients to severe COVID-19 disease is the impaired type I and II IFN response and the retarded immune system reaction [50]. A wide genetic analysis of blood samples of 332 COVID-19 patients in China revealed that the most significant gene loci related to disease severity were the Transmembrane protein 189 and Ubiquitin Conjugating Enzyme E2 V1 (TMEM189-UBE2V1) which play an orchestrating role in the IL-1 signaling pathway [51]. As far as the complement protein system is concerned, polymorphisms such as C3 FF, C3 FS, and C3 SS have been recognized as potentially deleterious for the susceptibility to SARS-CoV-2 and the course of the disease. These preliminary data should be confirmed by the large ongoing SOLID-C19 trial [52]. Finally, the Solute Carrier Family 6 Member 20 (SLC6A20), Leucine zipper transcription factor like 1 (LZTFL1), C-C chemokine receptor type 9 (CCR9), FYVE and Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1), C-X-C Motif Chemokine Receptor 6 (CXCR6), and X-C Motif Chemokine Receptor 1 (XCR1) are genes highly expressed in human lung cells, and polymorphisms have been related to the increased risk of respiratory failure and ARDS in severe COVID-19 cases [53,54] (Table 1).