Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of Coronaviridae, a family of enveloped, positive-sense, single-stranded ribonucleic acid (RNA) viruses which infect humans and other mammals
[5]. It is transmitted by air and primarily affects the respiratory system. Previous studies demonstrated that severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS) were both capable of inducing a cytokine storm
[6]. Hence, after the advent of SARS-CoV-2, cytokine storm was advocated as a key pathogenetic factor in COVID-19. Numerous studies have shown that COVID-19 patients have increased levels of numerous inflammatory cytokines, including IL-1β, IL-2, IL-6, IL-10, IFN-γ, TNF-α, IFN-γ-inducible protein 10 (IP-10), granulocyte macrophage-colony stimulating factor (GM-CSF), and monocyte chemoattractant protein-1 (MCP-1), and that these cytokines correlate with the disease severity
[7][8][9][10][11]. Many studies also demonstrated the presence of inflammatory infiltrates within various tissues in COVID-19 patients, both from bioptic and autoptic samples
[12][13][14]. In most cases, the disease consists of a self-limiting flu-like syndrome; however, in predisposed subjects, the infection of lung cells, in particular of type II pneumocytes, can cause the recall of a rich inflammatory cell infiltrate, consisting of neutrophils, macrophages, CD8+ and CD4+ T lymphocytes, and massive production of cytokines, leading to bilateral pneumonia, ARDS, and multi-organ damage
[15].
The inadequate immune response to the virus has been proposed as a possible mechanism in the development of cytokine storms during SARS-CoV-2 infection
[16][17]. As demonstrated by Blanco-Melo and colleagues, infected cells show an impaired capacity to produce interferons, key mediators for a properly host response against viral infections; at the same time, they produce high levels of neutrophil- and macrophage-recruitant chemokines
[18]. Additionally, different research groups have demonstrated that COVID-19 patients produce autoantibodies against several immuno-modulatory proteins and, in particular, the presence of anti-type I interferon antibodies is associated with severe disease and death
[19][20]. Therefore, in the first phase of infection, the innate immune system may not be able to efficiently clear the infected cells and, on the contrary, could favor the replication of the virus. Consistently with this hypothesis, Jiadi Lv et al. observed that SARS-CoV-2 survives and replicates inside macrophages
[21]. In a second phase, the immune system would recover the ability to effectively fight the virus, but since the latter has been able to replicate undisturbed, it would at that point produce an exaggerated reaction.