**3. Cytokine storm and inflammatory pathways associated with Covid-19**

In Covid-19, clinical deterioration and a high risk of death may be associated with the cytokine storm that develops as a result of the inflammatory response stimulated [14]. Blood levels of various cytokines such as monocyte chemoattractant protein 1 (MCP1), and interferon-alpha (IFN-α), IL-1ß, interferon-gamma (IFN-γ), induced protein 10 (IP10) increased in Covid-19 patients. Also, it has been determined that IL-10, IL-7, IL-2, macrophage inflammatory protein 1-α, IP10, granulocyte colony-stimulating factor (G-CSF), MCP1, and TNF-α levels are quite high in severe Covid-19 patients [47]. It was determined that those who had the severe Covid-19 disease and died had very high IL-6 levels [48]. This shows the importance of cytokines in the severe course of Covid-19. In a study, cytokine storm was divided into two stages [49]. The first stage is an immunodeficiency state. The secondary stage is an overactive immune state that appears to be a clinical manifestation of a cytokine storm [50]. Experimental studies have determined that the effect of coronavirus on cytokines stimulates the delayed secretion of type I and III IFNs including IFN-α/ß in the early stage and the excessive secretion of pro-inflammatory cytokines from mononuclear macrophages in the next stage [51]. It has been shown that impaired type 1 IFN responses and hyperinflammatory responses involving IL-6 and TNF-α occur with the low level of IFN activity and down-regulation of IFN-induced genes [52]. Based on this information, it is understood why COPD accompanies severe Covid-19. Failure of the immune response

in the initial period of infection causes general hyper-inflammation of the lung leading to acute lung injury and COPD. In some studies, it has been determined that there is a genetic predisposition that makes some patients more sensitive to cytokine storms in Covid-19 disease [53–57].
