The term “cytokine storm syndrome” describes a clinical syndrome that can occur in patients with severe COVID-19 disease, being characterized by a fulminant and often fatal hyper-cytokinemia leading to multi-organ failure [
3,
4]. The term was originally employed to describe the impressive activation of the immune system in the context of graft-versus-host disease [
5]. Similar conditions were also described in other pathologic conditions, both infectious (i.e., avian H5N1 influenza virus infection [
6] and SARS-Cov-1 infection) and non-infectious (i.e., leukemia patients receiving engineered T cell therapy). The widespread use of the term “cytokine storm” is probably due to its immediate meaning, which actually recalls the role of the immune system in producing an uncontrolled inflammatory response that is detrimental to host cells. Nevertheless, there is still no consensus regarding the exact definition of “cytokine storm”. In the case of COVID-19 disease, the cytokine storm could be the pathogenic process leading to ARDS, which characterizes the most severe cases [
7,
8]. ARDS is a devastating event, with an estimated mortality of approximately 40%, defined as lung edema (not explained by cardiac failure or fluid overload) and acute onset of bilateral infiltrates, which result in severe hypoxemia [
9,
10]. The exact physio-pathologic mechanisms underlying COVID-19 related cytokine storm are not fully understood; however, data from recent in vitro and in vivo studies and evidence coming from other coronaviruses (such as SARS and MERS) suggest an inflammatory vicious cycle that derives both from the direct cytotoxic effect of the virus on target cells and from the activation of immune cells. [
11]. SARS-Cov-2, similarly to SARS-CoV and MERS-CoV viruses, uses the angiotensin-converting enzyme-related carboxypeptidase (ACE-2) receptor to infect target cells [
12]. In addition to furin pre-cleavage, the cellular serine protease TMPRSS2 is also required to properly process the SARS- CoV-2 spike protein and facilitate host cell entry. When SARS-CoV-2 infects ACE-2-expressing cells, such as pneumocytes, the active replication and release of the virus can cause abrupt cell damage. This process is called pyroptosis, an abrupt inflammatory form of programmed cell death that leads to the subsequent release of intracellular molecules, including ATP, nucleic acids and damage-associated molecular patterns (PAMPs). These mediators are recognized by nearby endothelial and epithelial cells and alveolar macrophages, triggering the production of pro-inflammatory cytokines, in particular IL-1 β. Using a variety of pattern- recognition receptors (PRRs), alveolar epithelial cells and alveolar macrophages detect the released PAMPs, such as viral RNA, and damage- associated molecular patterns (DAMPs), including ATP, DNA and protein oligomers. A wave of local inflammation ensues, involving increased secretion of the pro-inflammatory cytokines and chemokines (i.e., IL-6, IFNγ, MCP1 and CXCL-10) into the blood of affected patients. The secretion of such cytokines and chemokines attracts immune cells, notably monocytes and T lymphocytes, but not neutrophils, from the blood into the infected site. Pulmonary recruitment of immune cells from the blood and the infiltration of lymphocytes into the airways may explain the lymphopenia and increased neutrophil/lymphocyte ratio seen in around 80% of patients with SARS- CoV-2 infection. The ACE-2 is also present in many immune cells, such as macrophages, dendritic cells and monocytes [
13,
14]. The direct SARS-Cov-2 infection of these cell subtypes results in their activation and secretion of inflammatory cytokines, such as interleukin-6 (IL-6) [
15]. IL-6 is crucially involved in acute inflammation due to its role in regulating the acute phase response [
16]. It is produced by almost all stromal cells and by B lymphocytes, T lymphocytes, macrophages, monocytes, dendritic cells, mast cells and other non-lymphocytic cells, such as fibroblasts, endothelial cells, keratinocytes, glomerular mesangial cells and tumor cells [
17]. While in most cases, the infection is followed by an efficient defensive immunological response, in some patients the response is dysfunctional, causing a flood cytokines and chemokines in the serum and resulting in severe lung and even systemic damage. In this scenario, IL-6 exerts potent pro-inflammatory activities through binding to both its membrane receptor (mIL6-R) on immune cells and to a soluble receptor (sIL-6R). The activation of mIL6-R leads to pleiotropic effects on both the innate and acquired immune system. IL-6 binding to sIL-6R also forms a dimeric complex that can bind to the surface of any cell, including lung endothelial cells, resulting in the massive secretion of chemotactic molecules such as vascular endothelial growth (VEGF), monocyte chemoattractant protein–1 (MCP-1), CXCL8 and additional IL-6. This phenomenon attracts more immune cells in the infection site, causing an exponential escalation of the inflammatory process, commonly referred to as “cytokine storm”. Moreover, reduced E-cadherin expression and increased secretion of VEGF increase vascular permeability and leakage, which further contribute to the pathogenesis of ARDS [
18]. In spite of the many cytokines, such as IL-1β [
19‐
23], IL-10 [
7,
19‐
21,
24], TNF-α: [
1,
19,
22,
23,
25‐
27] and IFNγ [
19,
21,
26,
27], and chemokines, such as CXCL8: [
7,
19,
21‐
23,
25,
28‐
31], CXCL9: [
20,
22,
31,
32], CCL5 [
24,
25,
30,
33,
34], CCL2 [
1,
19,
22‐
25,
32,
35], CCL20: [
24,
36], CCL3: [
1,
19,
22‐
24,
35,
36] and CCL4 [
19,
22,
35,
36] involved in the dysfunctional immunologic response in COVID-19 disease (which are summarized in Table
1), the cytokine IL-6 [
20‐
22,
27‐
29,
33,
36‐
45] and the chemokine CXCL10 [
1,
20,
22‐
25,
27,
28,
31,
32,
35,
46,
47] have clearly emerged as recurrent markers of disease severity and poor outcome [
38,
41,
42,
48].
Table 1
Summary of the cytokines and chemokines involved in COVID-19 pathogenesis
Cytokines |
IL-1β | Increased in COVID-19 patients compared with controls [ 19]. Increased in patients with severe disease when compared with those with mild disease [ 20], increased in the acute phase of multisystem inflammatory syndrome in children (MIS-C) [ 21], increased release in broncholaveolar lavage fluid [ 22], overexpressed mRNA by lung macrophages [ 22, 23] |
IL-6 | Increased in patients with severe disease when compared with those with mild disease [ 29, 37‐ 39, 106]. Elevated in late stages of sever COVID-19 [ 33]. Correlated with disease severity [ 28, 41], predictor of mortality [ 42‐ 44], higher in patients requiring ICU admission [ 41], correlated with RNAemia [ 101], increased release in broncholaveolar lavage fluid [ 22], overexpressed mRNA by lung macrophages [ 22] and pneumocytes [ 27], increased in the acute phase of multisystem inflammatory syndrome in children (MIS-C) [ 21, 36] |
IL-10 | Increased in patients with severe disease when compared with those with mild disease [ 7, 20, 24], Increased in COVID-19 patients compared with controls [ 19], increased in the acute phase of multisystem inflammatory syndrome in children (MIS-C) [ 21] |
TNF-alfa | Increased in COVID-19 patients compared with controls [ 19]. Increased in patients with severe disease when compared with those with mild disease [ 1, 25]. Up-regulation of the tumor necrosis factor-driven inflammatory response in PBMCs from COVID-19 patients [ 26], overexpressed mRNA by lung macrophages [ 22, 23] and pneumocytes [ 27] |
IFNγ | Increased in COVID-19 patients compared with controls [ 19], Up-regulation of the IFNγ-driven inflammatory response in PBMCs from COVID-19 patients [ 26], increased in the acute phase of multisystem inflammatory syndrome in children (MIS-C) [ 21]. Lack of IFN response by lung macrophages [ 27] |
Chemokines |
CXCL10 (IP10) | Increased in COVID-19 patients when compared with controls [ 32], Increased in patients with severe disease when compared with those with mild disease [ 1, 20, 24, 25, 46, 47], Correlated with disease severity [ 28], increased release in broncholaveolar lavage fluid [ 35], overexpressed mRNA by lung macrophages [ 22, 23] and pnemocytes [ 27], predictor of mortality [ 24], overexpression in nasal swabs of COVID-19 patients [ 31] |
CXCL8 (IL-8) | Correlated with disease severity [ 7, 25, 28, 29], Increased in COVID-19 patients compared with controls [ 19], increased release in broncholaveolar lavage fluid [ 22], overexpressed mRNA by lung macrophages [ 23], increased in the acute phase of multisystem inflammatory syndrome in children (MIS-C) [ 21, 30], overexpression in nasal swabs of COVID-19 patients [ 31] |
CXCL9 (MIG) | Increased in COVID-19 patients when compared with controls [ 32], Increased in patients with severe disease when compared with those with mild disease [ 20], overexpressed mRNA by lung macrophages [ 22], overexpression in nasal swabs of COVID-19 patients [ 31] |
CCL5 (RANTES) | Increased in patients with severe disease when compared with those with mild disease [ 24, 25], predictor clinical outcome [ 33], increased in children with COVID-19 as compared with adults [ 30, 34] |
CCL2 (MCP-1) | Increased in COVID-19 patients when compared with controls [ 32], increased in patients with severe disease when compared with those with mild disease [ 1, 24, 25], increased release in broncholaveolar lavage fluid [ 35], increased in COVID-19 patients compared with controls [ 19], overexpressed mRNA by lung macrophages [ 22, 23] |
CCL20 (MIP3 α) | Increased in patients with severe disease when compared with those with mild disease [ 24], increased in the acute phase of multisystem inflammatory syndrome in children (MIS-C) [ 36] |
CCL3 (MIP1α) | Increased in patients with severe disease when compared with those with mild disease [ 1, 24] increased release in broncholaveolar lavage fluid [ 35], increased in COVID-19 patients compared with controls [ 19], overexpressed mRNA by lung macrophages [ 22, 23], increased in the acute phase of multisystem inflammatory syndrome in children (MIS-C) [ 36] |
CCL4 (MIP1β) | increased release in broncholaveolar lavage fluid [ 35], Increased in COVID-19 patients compared with controls [ 19], overexpressed mRNA by lung macrophages [ 22], increased in the acute phase of multisystem inflammatory syndrome in children (MIS-C) [ 36] |