Glucocorticoids are widely used to treat acute respiratory distress syndrome (ARDS) despite their use being highly controversial based on randomized controlled trials and meta-analyses . As type I interferons (IFNs) are our first line of defense against severe viral respiratory infections, we explored whether glucocorticoids interfere with IFN signaling and whether their use associates with outcome of IFN beta treatment of ARDS.
Methods are described in the eSupplement. We performed a propensity-matched post hoc analysis using data from the recent randomized INTEREST trial comparing IFN beta-1a to placebo in ARDS patients . Seventy-eight out of 144 patients (54%) included in the IFN beta-1a treatment arm of the INTEREST trial received glucocorticoids during the 28-day study period, 56% (44/78) at randomization (D0), 27% (21/78) during the treatment (D1–6) and 17% (13/78) after the treatment (D7 onward). Day-28 mortality for patients receiving glucocorticoids with IFN beta-1a was 39.7% compared to 10.6% for patients receiving IFN beta-1a alone. The Kaplan–Meier curves of the IFN beta-1a treatment arm adjusted by ARDS severity and divided according to the overlapping (D0–D6) use of glucocorticoids with IFN beta-1a treatment demonstrate significantly increased mortality by glucocorticoid use (p = 0.0002, see supplement).
In the post hoc propensity-matched analysis of the IFN beta-1a arm (n = 144), baseline systemic glucocorticoid treatment was independently associated with D28 mortality (OR 5.4, 95% CI 2.1–13.9, p < 0.001) according to logistic regression. When the propensity-matched analysis was performed using an exact matching (a precision of 0.01 propensity units), there were 49 pairs of patients who received or did not receive glucocorticoids (n = 98). Among these patients, OR for increased mortality was 4.6 (95% CI 1.6–13.5) for those who had baseline systemic glucocorticoid treatment and 3.5 (95% CI 1–12) for those who initiated glucocorticoid treatment while receiving IFN beta-1a (Fig. 1a).
Based on the results of these analyses, we utilized human lung tissue and pulmonary endothelial cell cultures to investigate the effect of hydrocortisone on IFN nuclear signaling and the protein transcription of CD73, a molecule responsible for vascular integrity and leukocyte infiltration to sites of inflammation .
When IFN beta-1a was applied to the lung organ cultures, CD73 expression was upregulated. However, in the presence of hydrocortisone, CD73 upregulation was inhibited (Fig. 1b, c). IFN beta-1a signaling via its receptor leads to the formation of a heterotrimeric transcription complex ISGF3 containing STAT1-STAT2 and IRF9, which then enters the nucleus and binds to the IFN beta responsive elements of several genes or assembly on DNA . In pulmonary endothelial cell cultures, IFN beta-1a induced the translocation of IRF9 into the nucleus, which was reduced by hydrocortisone treatment (Fig. 1d, e). In addition, hydrocortisone treatment decreased IRF9 and STAT1 mRNA synthesis when measured by qPCR (Fig. 1f), which was also seen at the protein level in Fig. 1d.
We conclude that glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung. This provides the mechanistic basis for the harmful association of glucocorticoids in IFN beta-treated patients in the INTEREST trial. This study takes the earlier preclinical evidence that steroids block endogenous IFN signaling  to the critical care setting. Our findings give mechanistic support to the ICM recommendation not to use glucocorticoids at the early stages of severe COVID-19 or viral-induced ARDS in general and highly recommends not to use systemic glucocorticoids together with type I interferons because of the harmful effects of this combination.
After publication, the data and the novel reagent (anti-CD73 antibody) will be made available to others on reasonable requests to the corresponding author.
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We thank Riikka Sjöroos and Sari Mäki for expert technical assistance and the study group of the INTEREST trial for participating to the study at the trial sites. The work was funded by Academy of Finland, Faron Pharmaceuticals Ltd, European Union Seventh Framework Program (Grant Agreement No. 305853).
Conflicts of interest
JJ is an employee and shareholders of Faron Pharmaceuticals. MH and SJ own stocks of Faron Pharmaceuticals and SJ has a patent (US 7534423).
Ethics approval and consent to participate
All procedures performed in studies involving human participants in the original INTEREST trial (ClincalTrials.gov Identifier NCT02622724) were in accordance with the ethical standards of the institutional and/or national research committees and the Helsinki declaration.
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Jalkanen, J., Pettilä, V., Huttunen, T. et al. Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung. Intensive Care Med 46, 1937–1940 (2020). https://doi.org/10.1007/s00134-020-06086-3