Cytokine Profiles in the Detection of Severe Lung Involvement in Hospitalized Patients With COVID-19: the IL-8 – IL-32 axis

Abstract

Coronavirus disease 2019 (COVID-19) is an infectious respiratory disorder caused by a new coronavirus called SARS-CoV-2. The pathophysiology of severe COVID-19 is associated with a “cytokine storm”, characterized by anomalous release of various pro-inflammatory cytokines which contribute to alveolar exudation and lung damage. Overproduction of the proinflammatory cytokines IL-1, IL-6, IL-8 and TNF-α and low of expression IFN-γ have been found in severe COVID-19 patients. The mechanism by which IL-32 exerts its signalling properties is unclear. IL-32 is a key modulator in the pathogenesis of various clinical conditions and is mostly induced by IL-8. IL-32 modulates important inflammatory pathways (including TNF-α, IL-6 and IL-1b), contributing to the pathogenesis of inflammatory diseases. A total of 64 COVID-19 patients, stratifying as mild moderate and severe patients and 27 healthy controls were consecutively enrolled in the study. Serum concentrations of biomarkers including IL-1β, IL-10, IFN-γ, TNF-α and IL-6 were quantified by bead-based multiplex analysis and Serum concentration of IL-8 and IL-32 were determined by enzyme-linked immunosorbent assay (ELISA) kits. Interestingly, among the blood parameters, neutrophil and lymphocyte counts were significantly lower in severe COVID-19 patients than in the other, on the contrary, CRP was significantly higher in severe patients than in other groups. The cytokines that best distinguished controls from COVID-19 patients were IL-8 and IL-32.The best model performance for severe group was obtained by the combination of IL-32, IL-6 and IFN-γ, and serum concentrations of CRP increased model performance, showing AUC=0.83. New insights into the cytokine storm in COVID-19 patients, highlighting specific cytokine signatures among patients with different severity of infection.

Predicting roles of IL-27 and IL-32 in determining the severity and outcome of COVID-19

“…These findings were in contrast with a study showing IL-32 concentration was significantly higher in healthy subjects than COVID-19 patients. 8 However, our data were consistent with reports revealing IL-32 level had an increase in patients with non-severe COVID-19 compared with those suffering from severe disease. 8 Furthermore, it is speculated that IL-32 along with other cytokines may contribute to the increased occurrence of atherosclerosis observed in COVID-19 patients.…”

“…8 However, our data were consistent with reports revealing IL-32 level had an increase in patients with non-severe COVID-19 compared with those suffering from severe disease. 8 Furthermore, it is speculated that IL-32 along with other cytokines may contribute to the increased occurrence of atherosclerosis observed in COVID-19 patients. 17 Other studies on influenza A virus infection, a disease with similar pathogenesis to COVID-19, have revealed that IL-32 production was triggered by influenza A virus in human peripheral blood mononuclear cells (PBMCs) from healthy volunteers and, in turn, reduced viral replication.…”

“…5 Until now, many cytokines and chemokines along with immune cells have been investigated to clarify their roles in COVID-19 pathogenesis and provide a targeted personalized approach for its management. 8,9 Severe COVID-19 patients show the increased levels of IL-1, IL-8, IL-6, and tumor necrosis factor-alpha (TNF-α), and a decreased expression of IFN-γ. 6,10,11 Interleukin-27 (IL-27), a member of the IL-12 cytokine family, is a heterodimeric cytokine composed of p28 and Epstein-Barr virus-induced 3 (EBI3).…”

“…6,7 It is reported that changes in immune cells and different cytokines along with clinical and biochemical indexes can be served as predicting factors for clarifying disease severity and survival for patients with COVID-19. 8 The reduced numbers of lymphocytes and elevated levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are the most frequent abnormalities associated with COVID-19 and contribute to acute lung injury. 5 Until now, many cytokines and chemokines along with immune cells have been investigated to clarify their roles in COVID-19 pathogenesis and provide a targeted personalized approach for its management.…”

“…15 Some reports have revealed that IL-32 plays a key role in pathogenesis of various inflammatory diseases through inducing important inflammatory pathways involved in the expressions of TNF-α, IL-6, and IL-1β. 5 Although a few studies have reported the levels of IL-27 and IL-32 in COVID-19, 8,16,17 impacts of these cytokines on the disease severity and mechanisms involved in their roles in the disease development have not yet been identified. Therefore, this study was focused on determining whether the levels of IL-27 and IL-32 are associated with the severity and progression of COVID-19.…”