In this retrospective study, we analyzed the laboratory data of 585 COVID-19 infected cases in our hospital, including 44 cases accompanied with different cancers and 541 cases without cancer. The severity grading on admission was equal between these two groups.
In terms of laboratory tests, lymphopenia11,12, as well as increased NLR were common feature and thought to be a critical factor associated with disease severity and mortality in COVID-1913,14. Our results confirmed lymphopenia and increased NLR in patients with poor outcome in-hospital in both tumor group and non-tumor group.
Studies demonstrated that most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-inflammatory cytokines, including IL-6 and IL-1β, IL-17, G- CSF, GM-CSF…, characterized as cytokine storm1,2,15,16 as well as C- reactive protein17. IL-6 is a call-to-arms for some components of the immune system, including macrophages. Macrophages fuel inflammation and can damage normal lung cells18. Elevated IL-6 could trigger cytokine release syndrome through cis signaling or trans signaling. After binding to IL-6 receptor, downstream JAKs (Janus kinases)-STAT3 (signal transducer and activator of transcription 3) signaling results in activation of either immune system cells (B and T cells, neutrophils, macrophages, and natural killer cells) which can contribute to cytokine release syndrome19; or endothelial cells, which then results in a systemic “cytokine storm” charactered by secretion of additional IL-6, vascular endothelial growth factor (VEGF) and reduced E-cadherin expression on endothelial cells20. The latter two enhance vascular permeability and leakage, which play an important role in pulmonary dysfunction in ARDS5. The severity of IL-6 elevation correlated with the need for mechanical ventilation and mortality21. Consistently with previous reports, our analysis showed increased IL-6 level in patients with progression and death in-hospital in both tumor group and non-tumor group. Univariable and multivariable logistic regression analysis confirmed that the increase of IL-6 was positively correlated with progression and poor outcome in non-cancer group. This relationship was not observed in cancer group, indicated that except for IL-6 or CRP, other factors
Interestingly, IL-6 has been proposed to play key role in pathogenesis and development of cancer. Tumor cells themselves and immune cells around tumor can release IL-6, and hence increase plasma levels of IL-622. Besides, another analysis revealed an increase in circulating levels of IL-17A in cancer patients, of which the primary role is to induce the production of proinflammatory cytokines, such as IL-6, from the stromal cells as well as tumor cells8.
In the other side, tumor patients are frequently combined with cachexia in various degrees according to tumor type and stage23. It has been shown elevated IL-6 levels correlated with weight loss and performance status as well as tumor burden22,24. A tumor-specific profile of cachexia-inducing factors analyze showed upregulated IL-6 level in pancreatic adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, stomach adenocarcinoma, colon adenocarcinoma, acute myeloid leukemia, breast carcinoma, hepatocellular carcinoma25. Logically, our data indicated IL-6 level in cancer group was nearly 3 times of that in non-cancer group. Meanwhile, the mortality in cancer group was identically 3 times of that in non-cancer group. Thus we lanced univariable and multivariable logistic regression analysis to determine whether this increased level of IL-6 could contribute to the higher mortality in patients with cancer. Tables 2 and 4 showed that cancer, as comorbidity, was not a significant factor that affected the progression and survival of COVID-19 patients, which was consistent with the previous meta-analysis7; nevertheless dramatically, IL-6, upregulated in cancer group, was confirmed as a marked indicator of poor survival in COVID-19 patients. In summary, despite that cancer itself could not directly play a role in the prognostic of COVID-19, it could conduce to a poorer outcome through release of IL-6.
Elevated serum C-reactive protein (CRP), a protein whose synthesis and release are regulated by IL-6, is also a biomarker of severe COVID-19 infection5,26. CRP ≥ 5 mg/dl was considered as an important evidence of severe inflammation. Elder patients with higher CRP had higher in-hospital mortality with a RR of 2 compared with lower CRP group27. Similarly in our results, CRP level was significantly higher in patients with progression and death in-hospital in both tumor group and non-tumor group. Univariable and multivariable logistic regression analysis confirmed that the IL-6 level was positively correlated with progression and poor outcome in non-cancer group. Furthermore, increased CRP concentrations have been reported in different cancer type28. As mentioned above, tumor cells have been shown to secrete IL-6, which in turn induced the production of CRP. Consequently, our data revealed the CRP level in cancer group was marked elevated related to non-cancer group, and this increase of CRP was positively correlated with progression and poor outcome in non-cancer group. Univariable and multivariable logistic regression analysis confirmed CRP, together with IL-6, was a significant factor that affected the mortality of COVID-19 patients.
It is worthy to mention that neither IL-6 nor CRP, or other indicator was proved to affect the progression and death within the cancer group, although some laboratory test showed significant difference between survivors and non-survivors in univariable logistic regression analysis. This signified the prognosis of COVID-19 patients with cancers might be affected by some other critical indicators that were not covered in our study. Guan et al. reported that in severe COVID-19 cases, IL-2R, TNF-α and IL-10 concentrations were significantly higher; while IFN-γ level, CD4 + T cells and CD8 + T cells were significantly lower21. Qin et al. observed lower level of helper T cells (CD3 + CD4+) and increased level of naïve helper T cells (CD3 + CD4 + CD45RA+) in severe group15. These infection-related biomarkers and inflammatory cytokines were closely associated development of cancer29,30. Further investigation on the effect of interaction between cancer and inflammation on the prognostic of COVID-19 patients should be performed.