The prevalence of COVID-19 and the resulting high fatality in the ICU are major problems. Finding an ideal therapeutic strategy for patients in the ICU has been a challenge under the current circumstances. Identifying biomarkers that are produced during the course of the disease would be helpful for guiding the treatment and supervising the response. Cytokine storm syndrome (CSS) or hyperinflammation has been recognized in the pathogenesis of COVID-19. Several studies have shown that different inflammatory cytokines are correlated to the severity of the disease and survival of patients [15,16]. This study provided evidence that the kinetic variation of IL-6, IL-8, and IL-10 was closely associated with the prognosis in patients with severe COVID-19, independent of other risk factors including demographics, comorbidities, and common laboratory markers.
It has been reported that IL-6 is a potent predictive biomarker in patients with COVID-19 [11,17-18]. IL-6, produced by multiple cell types including monocytes and macrophages, is shown to be involved in inflammation and immune response and plays a role in CSS or cytokine release syndrome (CRS). Blocking IL-6 has been a main focus in mitigating cytokine storm-related symptoms in patients with severe COVID-19. Nevertheless, regarding the clinical symptoms of COVID-19, including lung injury and the circulation of various cytokines, the cytokine profiles in patients with COVID-19 were distinct from those of typical cytokine storm including CRS, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome [19,20]. IL-6 antagonists, which have been approved for treating chimeric antigen receptor T cell-induced CRS, have demonstrated various effects on patients with COVID-19 in multiple studies . It is difficult to draw conclusions because of the variable participants and intervention criteria. As the most common adverse event, serious infections were additional concerns. Soners et al. found that tocilizumab is associated with an increased proportion of superinfections in mechanically ventilated patients with COVID-19 . It is of importance that who might benefit from these therapy regimes considering heterogeneity of patients with COVID-19. Rossotti et al. performed a retrospective, single-center analysis on 74 patients treated with tocilizumab and 148 matched controls . They found that a steep increase in IL-6 levels in patients indicated a poor clinical outcome. Similarly, Quartuccio et al. showed that out of 24 patients who received tocilizumab treatment, 6 patients died, and 24–48 h post-tocilizumab treatment, IL-6 serum levels were significantly higher in non-survivors than in survivors . Two studies found that low levels of IL-6 at baseline were associated with a response to sarilumab or tocilizumab treatment [25,26]. Together with our results, supervising the dynamic changes in serum IL-6 levels might offer an opportunity to define inclusion population, predict the prognosis, and adjust the treatment regime in clinical trials or off-label treatment with IL-6 antagonists.
We found that continuous elevated level of serum IL-8 in non-survivors compared to the survivors despite statistic difference was only observed in patients after two weeks’ hospitalization. IL-8 is normally secreted by multiple cells exposed to stimuli and is considered to be the primary molecules of acute inflammation. Increased neutrophils have been thought to correlated to the severity of patients with COVID-19 in the previous clinical observation . IL-8 has the effect on potent neutrophil chemotactic and promotion of angiogenesis, might result in deterioration of COVID-19. IL-6 signaling promotes IL-8 recruitment and enhances the inflammation cascade.
We found that the increase in serum levels of IL-10, which is normally considered an anti-inflammatory molecule, was correlated with the increase in levels of pro-inflammatory factors including IL-6 and was also a predictor of survival in the ICU patients regardless of other severity factors. SARS-CoV-2 invasion is a trigger that induces a broad range of immunological events. High levels of circulating pro-inflammatory cytokines can lead to tissue damage and multi-organ failure. As a result, a negative feedback loop might be activated to alleviate the response and promote the transition from immune hyperactivity into the resolution phase. Studies show that anti-inflammatory and pro-inflammatory reactions arise concomitantly in patients with sepsis [28,29]. A shortage of IL-10 is indicated by the sustained elevation of TNF, IL-12, and interferon gamma levels in infected mice . Therefore, the increased levels of circulating IL-10 in patients with severe COVID-19 suggested that an immune regulatory network was activated to limit the magnitude of the immune response and repair the damage. The combination of pro-inflammatory and anti-inflammatory mediators represents the immunological pathogenesis of SARS-CoV-2 infection. Ying et al. reported that IL-6, IL-7, IL-10, IL-18, granulocyte colony stimulating factor (G-CSF), macrophge colony stimulating factor (M-CSF), monocyte chemoattractant protein-1 (MCP-1), MCP-3, interferon gamma-induced protein 10 (IP-10), monokine induced by gamma (MIG), and macrophage inflammatory protein 1 alpha (MIP1α ) were associated with the severity of COVID-19 . In another study that enrolled patients with moderate and severe COVID-19, IL-6 and IL-10 were used as predictors for recognizing patients at high risk of deterioration .
Our study is the first to show that the dynamic variation of specific cytokine profiles is correlated with the outcome of patients with COVID-19 admitted in the ICU. Limitations of this single-center study involve the small sample size and missing laboratory parameters that may induce potential bias. We observed the survival of patients during their ICU stay; this might slightly differ from the final clinical outcome. Notwithstanding, our results signified that circulating cytokine biomarkers might prove useful for evaluating therapeutic response and optimizing the therapeutic strategies in patients with severe COVID-19.