Cytokines as predictors of COVID-19 severity: evidence from a meta-analysis. Authors' reply

Authors’ reply

We are grateful to Szarpak et al¹ for their interest in our review article describing the role of immune deregulation in the adverse clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, especially since the results of their meta-analysis confirm the essential role of immune alterations for the development of critical coronavirus disease 2019 (COVID-19). They report significantly higher serum levels of tumor necrosis factor alpha (TNFα), interleukin (IL) 6, IL-2R, IL-4, IL-8, and IL-10 in patients with a more severe clinical course of COVID-19, and emphasize a predictive role of IL-6 and IL-10 cytokines for development of critical disease requiring intensive care support. Their results are also consistent with a recent meta-analysis from 24 clinical studies identifying dramatically elevated levels of IL-6 and IL-10 as the most important clinical predictors of an unfavorable COVID-19 outcome.²

Among proinflammatory cytokines and chemokines whose level is elevated in patients with COVID-19, one of the most important is IL-6. It plays a key role in mortality in cytokine release syndrome which may lead to acute respiratory distress syndrome, multiorgan failure, and death, and is also observed in other coronavirus infections, such as severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). However, it should be noted that a unique cytokine signature of COVID-19 clinical course is systemic elevation of IL-10.³ Remarkably, elevation of serum IL-10, similarly to IL-6, was found to be mostly significant in patients with COVID-19 admitted to an intensive care unit (ICU). Furthermore, highly upregulated IL-10 and IL-6 were strongly correlated with each other and with biomarkers of inflammation, such as C-reactive protein. Of note, it has also been reported that IL-10 is substantially elevated earlier than IL-6 during COVID-19 development.³

The mechanism of this unique SARS-CoV-2 ability to stimulate IL-10 is still unknown. Initially, it was believed that upregulation of IL-10, a cytokine with immunoregulatory properties, is a part of a negative feedback loop induced in response to the rapid accumulation of several proinflammatory cytokines. However, there is a growing body of evidence that the dramatic systemic increase of IL-10 in COVID-19 might instead be involved in pathogenesis of the severity of SARS-CoV-2 infection rather than immunoregulation and inhibition of the immune system. The above suggestion is consistent with the observation that IL-10 strongly correlates with disease severity and poor clinical outcomes,³ which points to the possibility that IL-10 might play a role in immune activation in COVID-19 patients. Furthermore, serum IL-10 level is associated with levels of other proinflammatory cytokines such as TNF-α, IL-2R, IL-8, IL-18, interferon γ, and granulocyte-macrophage colony-stimulating factor in patients with critical COVID-19.^1,3 The finding of a correlation between elevated levels of IL-10 and an increased population of exhausted CD8⁺TIM3⁺PD1⁺ lymphocytes in peripheral blood may indicate a role of IL-10 in overactivation of T cells during COVID-19 progression.⁴ A role of IL-10 in aggravated inflammation and organ destruction related to COVID-19 might be strengthened by the direct impact of IL-10 on relative expansion of the pathogenic cytotoxic CD8⁺ T cells despite a reduction in the total number of lymphocytes in peripheral blood in critically ill COVID-19 patients.⁵

A meta-analysis performed by Szarpak et al¹ demonstrating significantly higher levels of both pathogenic IL-6 and IL-10 cytokines in patients admitted to the ICU compared with non-ICU patients, together with elevated levels of other proinflammatory cytokines such as TNF-α, IL-2R, and IL-8 in patients who died from COVID-19 complications, seems to support the suggestion of a predictive role of serum cytokine levels for the critical outcome of COVID-19.