Increased levels of plasma cytokines and correlations to organ failure and 30-day mortality in critically ill Covid-19 patients

Abstract

Background: The infection caused by SARS CoV-2 has been postulated to induce a cytokine storm syndrome that results in organ failure and even death in a considerable number of patients. However, the inflammatory response in Corona virus disease-19 (Covid-19) and its potential to cause collateral organ damage has not been fully elucidated to date. This study aims to characterize the acute cytokine response in a cohort of critically ill Covid-19 patients.

Method: 24 adults with PCR-confirmed Covid-19 were included at time of admission to intensive care a median of eleven days after initial symptoms. Eleven adult patients admitted for elective abdominal surgery with preoperative plasma samples served as controls. All patients were included after informed consent was obtained. 27 cytokines were quantified in plasma. The expression of inflammatory mediators was then related to routine inflammatory markers, SAPS3, SOFA score, organ failure and 30-day mortality.

Results: A general increase in cytokine expression was observed in all Covid-19 patients. A strong correlation between respiratory failure and IL-1ra, IL-4, IL-6, IL-8 and IP-10 expression was observed. Acute kidney injury development correlated well with increased levels of IL-1ra, IL-6, IL-8, IL-17a, IP-10 and MCP-1. Generally, the cohort demonstrated weaker correlations between cytokine expression and 30-day mortality out of which IL-8 showed the strongest signal in terms of mortality.

Conclusion: The present study found that respiratory failure, acute kidney injury and 30-day mortality in critically ill Covid-19 patients are associated with moderate increases of a broad range of inflammatory mediators at time of admission.

Keywords: Acute kidney injury; Biomarkers; COVID-19; Cytokine storm; Inflammation; Intensive care.

Fig. 1

A heatmap showing hierarchical clustering of individual patients according to the detectable plasma concentration of 24 out of 27 analyzed cytokines (A). The clustering of patients in the general heatmap is largely driven by the relatively high concentrations of IP-10 and RANTES (A). The cytokines were further separated into subgroups and shown in separate heatmaps; Th1-cytokines (B), Th2-cytokines (C), Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing Proteins (NLRP) associated cytokines (D) and chemokines (E). IL-12, IL-2, IFN γ and TNF α were categorized as Th1-cytokines. Th1 cytokines participate in cell mediated immunity, promotes inflammation and tissue damage . IL-10, IL-4, IL-13, IL-7 and IL-9 were categorized as Th2-cytokines (C). Th2-cytokine expression plays a role in humoral immunity and may act anti-inflammatory . NLPR-associated mediators (D) IL-1β, IL-6, IL-8 and IL-1ra take part in the innate immune response including promoting immune cell infiltration of infected tissues. Notably, these cytokines clustered the groups perfectly , . MIP-1a, eotaxin, MCP-1, MIP-1b, IP-10 and RANTES were grouped as chemokines . The color key of the calculated z-score represents a scale of −4 to 4 SD where the individual value departs from the group mean as shown in the figure.

Fig. 2

Plasma concentrations of IL-8 at admission to intensive care in Covid-19 patients is associated with 30-day mortality (A), respiratory failure presented as PaO₂/FiO₂ (B) and acute kidney injury (AKI) stratified by Kidney Disease: Improved Global Outcome (C). Plasma concentrations of IL-8 demonstrated the strongest correlation with 30-day mortality (r = 0.503, p = 0.002) among the 27 cytokines analyzed in our panel. Increased plasma expression of IL-8 in Covid-19 correlated well with both respiratory failure (r = −0.681) as well as AKI development (r = 0.728, p = 0.000). Data shown as logarithmically transformed plasma concentration preoperatively in controls (filled triangles) and at admission to intensive care in Covid-19 patients (filled circles).