Serial measurement of cytokines strongly predict COVID-19 outcome

Abstract

Purpose Cytokines are major mediators of COVID-19 pathogenesis and several of them are already being regarded as predictive markers for the clinical course and outcome of COVID-19 cases. A major pitfall of many COVID-19 cytokine studies is the lack of a benchmark sampling timing. Since cytokines and their relative change during an infectious disease course is quite dynamic, we evaluated the predictive value of serially measured cytokines for COVID-19 cases. Methods In this single-center, prospective study, a broad spectrum of cytokines were determined by multiplex ELISA assay in samples collected at admission and at the third day of hospitalization. Appropriateness of cytokine levels in predicting mortality were assessed by receiver-operating characteristic (ROC) analyses for both sampling times in paralel to conventional biomarkers. Results At both sampling points, higher levels of IL-6, IL-7, IL-10, IL-15, IL-27 IP-10, MCP-1, and GCSF were found to be more predictive for mortality (p<0.05). Some of these cytokines, such as IL-6, IL-10, IL-7 and GCSF, had higher sensitivity and specificity in predicting mortality. AUC values of IL-6, IL-10, IL-7 and GCSF were 0.85 (0.65 to 0.92), 0.88 (0.73 to 0.96), 0.80 (0.63 to 0.91) and 0.86 (0.70 to 0.95), respectively at hospital admission. Compared to hospital admission, on the 3rd day of hospitalization serum levels of IL-6 and, IL-10 decreased significantly in the survivor group, unlike the non-survivor group (IL-6, p = 0.015, and IL-10, p = 0.016). Conclusion Our study results suggest that single-sample-based cytokine analyzes can be misleading and that cytokine levels measured serially at different sampling times provide a more precise and accurate estimate for the outcome of COVID-19 patients.

Role of Innate and Adaptive Cytokines in the Survival of COVID-19 Patients

“…The biological activity of IL-6 is antagonized by a combination of sIL-6R and sgp130, which are soluble IL-6 receptors [ 42 , 43 , 44 ]. In agreement with previous studies, we found that severe COVID-19 patients had elevated serum levels of IL-1α, IL-1β IL-6 and IL-18 [ 18 , 25 , 26 , 32 , 37 ]. Our data show that the levels of these IL-1α, IL-1β IL-6 and IL-18 cytokines are significantly lower in severe COVID-19 survivors than in non-survivors.…”

“…The relevance of the level of IL-6 as a biomarker of the prognosis of the disease has previously been demonstrated, and this has been identified as a target of immunotherapy [ 34 ]. Furthermore, the levels of other cytokines also appear to have relevant roles as prognostic markers of severe COVID-19 [ 18 , 25 , 26 , 27 , 35 , 36 , 37 , 38 , 39 ]. Cytokines are a complex network of molecules with different biologic activities promoting or suppressing immune-inflammatory responses and the lesioning or repair of tissues [ 12 , 13 , 14 ].…”

“…There are also cytokines directly involved in the regulation of the adaptive immune response. Finally, a group of soluble factors plays a relevant role in wound healing/tissue repair [ 18 , 19 ].…”

“…There are a huge number of studies on the effects of cytokines on the pathology of COVID-19 and their role is being widely discussed [ 18 , 20 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. In this study, we investigated the possible existence of a different pattern of variation in circulating levels of a wide number of soluble mediators of the immune-inflammatory response between patients with severe COVID-19 who survive or with a fatal outcome.…”

Association of interferon gamma inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1 alpha, interleukin-6, and rs12252 single nucleotide polymorphism of interferon-induced transmembrane protein-3 gene with the severity of COVID-19 infection

“…Ozger et al showed that there was a significant statistical difference (p = 0.015) between MCP-1 levels in non-survivor and survivors of COVID-19 disease. Higher serum level of MCP-1 among critically ill and non-survivor COVID-19 patients possibly results from an ongoing monocyte efflux from the circulation [23].…”