Serum concentration of extracellular cold-inducible RNA-binding protein is associated with respiratory failure in COVID-19

Felix Schagatay, Klara Diamant, Mats Lidén, Alicia Edin, Simon Athlin, Olof Hultgren, Clas Ahlm, Mattias N E Forsell, Johanna Savilampi, Johan Normark, Anna Lange, Sara Cajander, Felix Schagatay, Klara Diamant, Mats Lidén, Alicia Edin, Simon Athlin, Olof Hultgren, Clas Ahlm, Mattias N E Forsell, Johanna Savilampi, Johan Normark, Anna Lange, Sara Cajander

Abstract

Uncontrolled release of damage-associated molecular patterns (DAMPs) is suggested to be a major trigger for the dysregulated host immune response that leads to severe COVID-19. Cold-inducible RNA-binding protein (CIRP), is a newly identified DAMP that aggravates inflammation and tissue injury, and induces respiratory failure in sepsis. Whether CIRP contributes to the pathogenesis of respiratory failure in COVID-19 has not yet been explored.

Aim: To investigate if the concentration of extracellular CIRP (eCIRP) in serum associates with respiratory failure and lung involvement by chest computed tomography (CT) in COVID-19.

Methods: Herein we report a prospective observational study of patients with COVID-19 included at two University Hospitals in Sweden between April 2020 and May 2021. Serum from hospitalized patients in Örebro (N=97) were used to assess the association between eCIRP and the level of respiratory support and its correlation with pulmonary involvement on chest CT and inflammatory biomarkers. A cohort of hospitalized and non-hospitalized patients from Umeå (N=78) was used as an external validation cohort. The severity of disease was defined according to the highest degree of respiratory support; mild disease (no oxygen), non-severe hypoxemia (conventional oxygen or high-flow nasal oxygen, HFNO <50% FiO2), and severe hypoxemia (HFNO ≥50% FiO2, mechanical ventilation). Unadjusted and adjusted linear regression was used to evaluate peak eCIRP day 0-4 in respect to severity, age, sex, Charlson comorbidity score, symptom duration, and BMI.

Results: Peak eCIRP concentrations were higher in patients with severe hypoxemia and were independently associated with the degree of respiratory support in both cohorts (Örebro; p=0.01, Umeå; p<0.01). The degree of pulmonary involvement measured by CT correlated with eCIRP, rs=0.30, p<0.01 (n=97).

Conclusion: High serum levels of eCIRP are associated with acute respiratory failure in COVID-19. Experimental studies are needed to determine if treatments targeting eCIRP reduces the risk of acute respiratory failure in COVID-19.

Keywords: CIRP; COVID-19; DAMPs; eCIRP; inflammation; severity.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Schagatay, Diamant, Lidén, Edin, Athlin, Hultgren, Ahlm, Forsell, Savilampi, Normark, Lange and Cajander.

Figures

Figure 1
Figure 1
Peak concentrations of eCIRP in relation to COVID-19 severity in Örebro cohort. Box-plots representing the highest eCIRP concentrations on day 0-4 after enrollment, grouped by COVID-19 severity in Örebro cohort. Mild disease: No oxygen treatment. Non-severe hypoxemia: Conventional oxygen treatment or HFNC with FiO2

Figure 2

Peak concentration of eCIRP in…

Figure 2

Peak concentration of eCIRP in relation to COVID-19 severity in the Umeå cohort.…

Figure 2
Peak concentration of eCIRP in relation to COVID-19 severity in the Umeå cohort. Box-plots representing the highest eCIRP concentrations on day 0-4 after enrollment, grouped by COVID-19 severity in Umeå cohort. Mild disease: No oxygen treatment. Non-severe hypoxemia: Conventional oxygen treatment or HFNC with FiO2

Figure 3

Peak eCIRP concentrations in relation…

Figure 3

Peak eCIRP concentrations in relation to the extent of pulmonary infiltration on chest…

Figure 3
Peak eCIRP concentrations in relation to the extent of pulmonary infiltration on chest CT. Multivariate bubble-plot of eCIRP-values, Örebro Covid-19 Scale (ÖCoS), sex, and outcome. Peak concentrations of eCIRP measured 0-4 days after enrollment. Maximal parenchymal infiltration in percent visualized by chest CT during hospitalization, graded by ÖCoS. ÖCoS ranges from 1-5, corresponding to the percentage of lung parenchymal involvement, ÖCoS 1 75%. Orange dots: Women. Black dots: Men. Large dots: Non-survivors (both men and women). Small dots: Survivors (both men and women).
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References
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Figure 2
Figure 2
Peak concentration of eCIRP in relation to COVID-19 severity in the Umeå cohort. Box-plots representing the highest eCIRP concentrations on day 0-4 after enrollment, grouped by COVID-19 severity in Umeå cohort. Mild disease: No oxygen treatment. Non-severe hypoxemia: Conventional oxygen treatment or HFNC with FiO2

Figure 3

Peak eCIRP concentrations in relation…

Figure 3

Peak eCIRP concentrations in relation to the extent of pulmonary infiltration on chest…

Figure 3
Peak eCIRP concentrations in relation to the extent of pulmonary infiltration on chest CT. Multivariate bubble-plot of eCIRP-values, Örebro Covid-19 Scale (ÖCoS), sex, and outcome. Peak concentrations of eCIRP measured 0-4 days after enrollment. Maximal parenchymal infiltration in percent visualized by chest CT during hospitalization, graded by ÖCoS. ÖCoS ranges from 1-5, corresponding to the percentage of lung parenchymal involvement, ÖCoS 1 75%. Orange dots: Women. Black dots: Men. Large dots: Non-survivors (both men and women). Small dots: Survivors (both men and women).
Figure 3
Figure 3
Peak eCIRP concentrations in relation to the extent of pulmonary infiltration on chest CT. Multivariate bubble-plot of eCIRP-values, Örebro Covid-19 Scale (ÖCoS), sex, and outcome. Peak concentrations of eCIRP measured 0-4 days after enrollment. Maximal parenchymal infiltration in percent visualized by chest CT during hospitalization, graded by ÖCoS. ÖCoS ranges from 1-5, corresponding to the percentage of lung parenchymal involvement, ÖCoS 1 75%. Orange dots: Women. Black dots: Men. Large dots: Non-survivors (both men and women). Small dots: Survivors (both men and women).

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