The rapid deterioration of severely affected COVID patients may be attributable to an over-reacting immune system. This response may evolve from multiple pathways, including, but not limited to, NF-κB signaling, the JAK/STAT pathway, the NLRP3 pathway, and granulocyte macrophage-colony stimulating factor (GM-CSF) activation pathways [13,15]. While SARS-CoV-2 virus infects epithelial cells, the above immune pathways are activated, and several pro-inflammatory cytokines are released, including interleukin 1β, (IL-1β), IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, TNF-α, and interferons (INFs) [3,9,13]. Elevated cytokine levels result in the recruitment of immune cells such as macrophages, T cells, and neutrophils to the infected area. Meanwhile, released serum cytokines such as interleukin-6 (IL-6), lead to increased synthesis of prototypic acute phase reactants, such as C-reactive protein (CRP), from the liver and into the bloodstream. Eventually, all of these dysregulated immune responses elicit various sequelae, such as the destabilization of endothelial cell-to-cell interactions, the destruction of the capillary and vascular barrier, tissue damage, and multiple organ failure, which may eventually result in the death of the infected individual [3,16].

The relationship between interleukin-6 and COVID-19 severity has been investigated by many studies [17,18,19]. Interleukin-6 (IL-6), a cytokine secreted by stimulated monocytes and macrophages, mediates a broad range of biological reactions [20]. Plasma IL-6 increases only 1 h after bodily insult and peaks after about 3–6 h [21,22]. Measurably increased IL-6 levels have been noted following trauma, stress, and infection [20]. A multifunctional cytokine that transmits cell signals and regulates immune cells, IL-6 has a strong proinflammatory effect associated with multiple biological functions and plays an important role in inflammation, tumor growth, and hematological diseases [23,24]. IL-6 triggers multiple immune responses by forming a positive feedback loop that eventually results in a cytokine storm, and elevated serum IL-6 may indicate disease severity and prognosis. Among COVID-19 patients admitted to the hospital, IL-6 was higher in the non-survival group than in the survival group [25,26]. Many studies have recognized IL-6 as a pivotal marker for implying the prognosis and severity of various diseases [27,28,29,30]. In addition, serum IL-6 may be useful for monitoring treatment response and evaluating the efficacy of medications such as tocilizumab, an IL-6 receptor blockade used for treating severe COVID-19 infections [19,31].

As serum cytokines such as IL-6 and TNF-α are released, they further stimulate several downstream immune pathways, increasing the production of acute-phase reactants such as C-reactive protein (CRP) and procalcitonin (PCT). CRP is a non-specific acute-phase protein induced by IL-6 in the liver and a sensitive biomarker of inflammation, infection, and tissue damage [38].

CRP level is usually low in the bloodstream. Following acute inflammatory reactions, serum CRP increases significantly within 12–24 h, with a 20–72 h plateau and a subsequent return to baseline levels in 3–7 days [39,40,41]. As most CRP components are synthesized in the liver, liver failure would hinder the production of CRP [42]. COVID-19 patients with higher serum CRP are prone to evolve to severe disease states [43]. Among these COVID-19 patients, higher circulating CRP is associated with a higher rate of adverse events, such as venous thromboembolism events, acute kidney injury, and higher in-hospital mortality [44].

Procalcitonin (PCT), the precursor of calcitonin, is a glycoprotein consisting of a 116-amino acid, which is typically synthesized and released by thyroid parafollicular C cell [45,46]. Procalcitonin increases within four hours of response to infection or acute injury as an acute inflammatory marker, peaks at 6 h with a plateau at 8–24 h, and a return to baseline levels in 2–3 days [41]. Increased serum PCT level is associated with a high risk of bacterial infections and sepsis rather than viral infections, and PCT has previously been used to distinguish between bacterial and viral infections [47]. However, elevated PCT levels are correlated with the severity of SARS-CoV-2 infection [48,49,50]. Compared to moderate COVID-19 patients with abnormal image findings and clinical symptoms only, severe cases demonstrated a four to eight times higher procalcitonin level during severe or critical SARS-CoV-2 infection, respectively [50]. PCT levels appear to be useful as a disease severity predictor and may further imply concomitant bacterial infections. Co-infection rates were higher during severe SARS-CoV-2 infection and were accompanied by raised PCT levels [50]. For this reason, gradually increasing serum PCT levels may indicate a poorer prognosis.

Ferritin, an acute-phase protein, may interfere with iron metabolism [51]. Iron parameters, such as ferritin and transferrin, are not yet considered standard biomarkers for monitoring COVID-19 disease progression because the relationship between iron metabolism and COVID-19 remains unclear [52]. Some studies have claimed that elevated ferritin is a risk factor for COVID-19 severity [53,54,55].