Relationship between IL-6 and COVID-19: to be considered during treatment

The detection and control of pro-inflammatory response is crucial in the early stages of viral infection. Coronavirus disease 2019 (COVID-19) is an emerging viral disease of global concern and optimal treatment has yet to be determined. Unknown response of treatment of COVID-19 is important during patient monitoring. IL-6 is one of the key cytokines after activated macrophages. Therefore, control of systemic IL-6 levels in SARS-CoV-2 infected patients may be a parameter for COVID-19 disease. This review is focused on the induction of IL-6 after viral infections as a target molecule for monitoring cellular response.


Viral infection & IL-6
After viral infection, viral products also enhance the transcription or translation of IL-6 from cells such as fibroblast, mesenchymal, endothelial and many other cells. Therefore, the control of IL-6 synthesis and secretion may be important to inhibit its signal that affects cells. Suppression of IL-6 expression strategies can also be chosen to negatively regulate the IL-6 transcription [6,7]. The triggering of the IL-6 and the secretion of other cytokines after viral infection cause a fatal immune reaction to the hyperactivation of T cells. After cancer immunotherapy, the same cytokine storm is also observed because of T-cell activation and a boost in IL-6 secretion [8]. Therefore, pathological IL-6 secretion is thought to be the cause of the clinical symptoms after severe disease.

Laboratory findings of COVID-19
Based on hospitalized patient data, substantial differences in laboratory findings were found in both deceased and recovered COVID-19 patients. In two reports where COVID-19 cases in Wuhan were investigated, white blood cell and neutrophil counts were significantly increased in correlation with disease severity. Also, COVID-19 patients had persistent and more severe lymphocytopenia and thrombocytopenia. A study reported that elevated neutrophils and reduced lymphocytes were also correlated with COVID-19 disease severity and death [9,10]. It can be suggested that a cellular level of immune deficiency state was related with poor prognosis.
The pathophysiology of SARS-CoV-2 with unusually high pathogenicity has not been exactly understood. In intensive care unit patients, pulmonary and extrapulmonary organ damage such as sepsis, heart failure, acute cardiac injury, acute kidney injury, shock, acidosis, alkalosis, acute liver injury may develop [11]. Recent studies have demonstrated that increased amounts of pro B type natriuretic peptide (NT-proBNP), creatine kinase-MB (CK-MB), high-sensitivity troponin-I (Hs-TnI), CRP, D-dimer and prothrombin were associated with inflammationrelated cardiac problems. Additionally, these parameters were also reported as risk factors of systematic inflammation related cardiac injury and were also correlated with the risk of in-hospital death [10,[12][13][14]. Furthermore, acute cardiac injury and heart failure may not be major fatality risk factors of COVID-19, but they could be co-existing disease outcomes of the acute respiratory distress syndrome and respiratory failure regardless of previous cardiovascular disease history.
Common laboratory abnormalities in COVID-19 patients included impaired liver and kidney function test parameters. Most patients had high concentrations of alanine aminotransferase, aspartate aminotransferase, total bilirubin, lactate dehydrogenase, alkaline phosphatase and γ-glutamyl transpeptidase and they were markedly higher in deceased patients compared with recovered patients. On the other hand, hypoalbuminaemia was shown in COVID-19 patients. Concentrations of blood urea nitrogen, ferritin, potassium and triglycerides were significantly increased in all COVID-19 patients, but were higher in deceased patients than in recovered patients [9,12]. Interestingly, a study reported significantly lower levels of thyroid stimulating hormone and free triiodothyronine in deceased patients than in recovered COVID-19 patients in China [9].

Cytokines & COVID-19
Cytokine storm is an interesting point in COVID-19 patients. High levels of inflammatory cytokines were observed in COVID-19 patients with more severe disease and were associated with pulmonary inflammation, lung damage and multiple organ failure [15]. A previous study showed that increased levels of pro-inflammatory cytokines in serum such as IL1β, IL6, IL12, IFNγ, IP10 and MCP1 were related with pulmonary inflammation in SARS patients [16]. Additionally, Huang et al. reported high levels of IL1β, IFNγ, IP10 and MCP1 in intensive care unit COVID-19 patients, which is probably the reason for the activated T-helper-1 (Th1) cell response [12]. Moreover, Diao et al. found that the levels of TNF-α, IL-6 and IL-10 were correlated with the severity of COVID-19 [17]. IL-6 is an important cytokine whose production is related with various inflammatory diseases. Subjects with SARS-CoV-2 had high levels of IL-6 that were correlated with patient symptomatology including pulmonary inflammation and extensive lung damage [11]. Additionally, patients with SARS-CoV-2 infection had low levels of suppressor of cytokine signaling-3, which regulates and stimulates the negative feedback mechanism of IL-6 [18]. On the same line, another study reported that IL-6 levels were higher in severe COVID-19 patients and this may be used as one of the bases for predicting the transition from mild to severe infection [19]. In particular, Diao et al. showed that COVID-19 patients in intensive care had lower CD8 + T cell counts and their total CD4 + and CD8 + T cell counts were also negatively correlated with TNF-α and IL-6 concentrations [17]. In addition, recent studies showed that higher level of IL-6, CRP and also IL-10 were more significant rather than other cytokines in critical group of COVID-19 patients [20,21]. It can be suggested that immune dysregulation is a highly important point effects; therefore, further studies are needed to explain the IL-6 mediated cellular response during viral infections, especially COVID-19.

Conclusion
The important role of IL-6 in host defense should always be considered in clinical practice. During COVID-19 treatments, several algorithms are used for patients who have several clinical symptoms. However, the responses of the treatment for cytokine storm, especially IL-6 production, are still unknown. Elevated systemic IL-6 levels according to COVID-19 severity should be important for determination of higher risk of disease deterioration. Therefore, monitoring of the IL-6 or targeting treatment of the IL-6 for COVID-19 positive patients may be a new target for effective treatment.
Future perspective SARS-CoV-2 was recognized in Wuhan and causes severe respiratory illness in humans, called COVID-19. A large number of vaccines and drugs are under investigation against COVID-19. Some of the vaccines showed promising results. New vaccines will become possible to create an immunity against SARS-CoV-2 and will be available in the market in future months. Another important point is that COVID-19 causes pulmonary and extrapulmonary organ damage which is mainly related to cytokine storm. IL-6 is the key molecule of cytokine storm, therefore IL-6 may be a target for drug development.

Executive summary
• IL-6 is an important cytokine with pleiotropic functions such as metabolic regulation to inflammation, auto-immunity and acute-phase response. • COVID-19 patients had high levels of IL-6 that were associated with pulmonary inflammation and extensive lung damage. • COVID-19 infection has an aggressive inflammatory response with a large amount of pro-inflammatory cytokines, known as the 'cytokine storm'. • Acute increase in circulating levels of pro-inflammatory cytokines including IL-6, IL-1, TNF-α and interferon is the reason for the cytokine storm. • IL-6 may be a therapeutic target for inhibiting the cytokine storm and cytokine storm-associated organ damage.

Author contributions
HS Vatansever wrote the primary manuscript and scientifically checked the manuscript. E Becer contributed writing-specific section.