suPAR-guided Anakinra Treatment for Validation of the Risk and Management of Respiratory Failure by COVID-19 (SAVE)

The major hurdle of Coronavirus disease 2019 (COVID-19) is the early recognition of the
patients at high risk for the development of severe respiratory failure (SRF). If this can be
achieved early, then appropriate immunomodulatory treatment may be administered to prevent
development of SRF. This scenario is extremely visionary since it prevents the development of
the major fatal consequence of COVID-19 but also alleviates the heavy medical and financial
burden of Intensive Care Unit (ICU) admission.

Current evidence suggests that SARS-CoV-2 activates endothelial function which leads to
over-production of D-dimers. Urokinase plasminogen activator receptor (uPAR) is anchored to
the cell membranes of the lung endothelial cells. As result of the activation of kallikrein,
uPAR is cleaved and enters the systemic circulation as the soluble counterpart suPAR.
Preliminary unpublished data from 57 Greek patients hospitalized after March 1st, 2020 in
Greek hospitals due to pneumonia by confirmed SARS-CoV-2 infection showed that those with
suPAR admission levels ≥ 6 ng/ml had greater risk for the development of SRF within 14 days
than patients with suPAR less than 6ng/ml. The sensitivity of suPAR to detect these patients
was 85.9% and the positive predictive value 85.9%. It needs to be underlined that all 21
Greek patients with suPAR≥ 6ng/ml were under treatment with hydroxychloroquine and
azithromycin. These data were confirmed in 15 patients hospitalized for pneumonia by
SARS-CoV-2 in Rush Medical Center at Chicago.

This prognostic ability of suPAR for unfavourable outcome is not presented for the first
time; in the TRIAGE III trial that was conducted among 4,420 admissions in the emergency
department in Denmark the interquartile range of suPAR was between 2.6 and 4.7 ng/ml in
30-day survivors and between 6.7 and 11.8 ng/ml in 30-day non-survivors. Previous data from
the Hellenic Sepsis Study Group on 1,914 patients clearly shows a high prognostic utility of
admission suPAR for 28-day mortality.

It is obvious that suPAR can early identify the start of such a type of inflammatory process
in the lung parenchyma that has will soon be intensified. A recent publication has shown that
this is due to the early release of interleukin-1α (IL-1α) from lung epithelial cells that
are infected by the virus. This IL-1α acts as a promoting factor that stimulates the
production of IL-1β and of a further cytokine storm from alveolar macrophages.

Anakinra is the only marketed product that inhibits both IL-1β and IL-1α and hence it is able
to block an inflammatory response early on and to prevent the downstream inflammatory
cascade. suPAR can be used as the biomarker tool to indicate patients with COVID-19 pneumonia
in risk of SRF and for whom early start of anakinra may prevent development of SRF.

Anakinra is a safe drug that has been licensed for chronic subcutaneous administration in
rheumatoid arthritis, refractory gout and chronic auto-inflammatory disorders. The safety
profile was further proven when it was administered in two randomized clinical trials where
more than 1,500 critically ill patients with severe sepsis were intravenously treated.