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Type I interferons, especially IFN-beta, have been appointed as potential leading therapeutics to tackle severe COVID-19 and are currently being evaluated in REMAP-CAP and the WHO’s Solidarity Trial. As a most recent example, combination treatments with IFN-beta, lopinavir-ritonavir, and ribavirin showed that the arm containing IFN-beta was superior in eliminating the virus from the nasopharyngeal swabs in phase II clinical trial [1]. Recent papers on the matter unfortunately fall short of differentiating between subcutaneous (s.c.) and intravenous (i.v.) administration, which are completely different treatments concerning drug exposure and wanted effects in the lung endothelium, which is under attack in COVID-19 [2]. We wish to highlight the differences of these two treatment methods and also other crucial aspects of IFN-beta treatment for COVID-19 and acute respiratory distress syndrome (ARDS). A recent report concluded that the pharmacological effects of s.c. vs. i.v. IFN-beta-1a are the same, because they produce similar anti-viral responses [3]. Importantly, however, the pharmacokinetics of s.c. vs. i.v. IFN-beta are complete mirror images, “flip-flops” [4]. Maximum serum concentrations (Cmax) and total exposure through serum concentrations are significantly higher after i.v. than s.c. injections (p = 0.0001). Prior corner stone PK studies investigating s.c. vs. i.v. administration of IFN-beta-1a conclude that s.c. administration produces significantly lower drug concentrations and incomplete bioavailability compared to i.v. dosing. The bioavailability via the s.c. route is about one third of that obtained by i.v. injections [4]. For critically ill patients on vasopressors and with very limited peripheral microcirculation, the bioavailability of s.c. dosed IFN-beta becomes even more questionable. IFNbeta is cleared almost solely through its receptor (IFNAR). With s.c. dosing, IFN-beta is slowly taken up by the lymphatic system, from which it enters the blood during a number of hours with modest peak concentrations. In contrast, i.v. dosing achieves high serum concentration and efficiently reaches vast capillary beds of central organs, where it is taken up by its receptors without saturating the body and causing unwanted adverse events. This is an important aspect as endothelial dysfunction is connected to COVID-19 infection [2, 5]. Nonetheless, the purpose of i.v. administered IFN-beta for the treatment of COVID-19 and ARDS is to maximise bioavailability of the drug at the lung vasculature, as well as other vascular beds. This is hardly achieved with s.c. dosing in critically ill patients. IFN-beta increases CD73 in pulmonary capillaries. This is of utmost importance as CD73 is the key enzyme for vascular integrity under hypoxic conditions. The protective effect of IFN-beta on the lung is attributed to the clearance of pro-inflammatory ATP and prothrombotic ADP from circulation and converting them into highly anti-inflammatory adenosine via AMP step by CD73 [6]. It is well known that corticosteroids as immunosuppressors dampen our natural anti-viral responses, and the direct inhibitory effect of corticosteroids on IFN signalling has been reported [7]. Still corticosteroids are widely used to treat ARDS and severe viral respiratory infections even though several studies have shown that corticosteroid use is associated with harm in viral outbreaks such as H1N1 and MERS [8]. In fact, reports on using type I IFNs for the treatment of MERS reveal that the majority of these patients received systemic corticosteroids with IFN. For example, 60% of MERS patients received corticosteroids with type I IFN [9]. In the recent INTEREST study investigating the use of i.v. IFNbeta-1a for ARDS, the primary analyses did not show any benefit for IFN-beta over placebo [10]. However,

Interferon beta-1a for COVID-19: critical importance of the administration route