Development and Validation of SCOPE Score: A Clinical Score to Predict Progression to Severe Respiratory Failure in Hospitalized Patients With COVID-19 Pneumonia (preprint)

Most patients infected with SARS-CoV-2 (COVID-19) experience mild, non-specific symptoms, but several develop severe symptoms associated with an excessive inflammatory response. Elevated plasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) provide early warning of progression to severe respiratory failure (SRF) or death, but access to suPAR testing may be limited. The Severe COvid Prediction Estimate (SCOPE) score, derived from C-reactive protein, D-dimer, interleukin-6, and ferritin circulating concentrations at hospitalization during the SAVE-MORE study, offers comparable predictive accuracy for progression to SRF or death within 14 days as suPAR ≥6 ng/ml (area under receiver operator characteristic curve, 0.81 for both). SCOPE score was validated against an independent dataset from the SAVE study. The SCOPE score is an alternative to suPAR for predicting progression to SRF or death within 14 days of hospital admission for pneumonia, and it can be used to guide treatment decisions.Funding: The study was funded in part by the Hellenic Institute for the Study of Sepsis and by Swedish Orphan Biovitrum. The Hellenic Institute for the Study of Sepsis is the Sponsor of the SAVE and SAVE-MORE studies.Declaration of Interests:E. J. Giamarellos-Bourboulis has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and XBiotech Inc; independent educational grants from Abbott CH, AxisShield, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Sobi and XBiotech Inc.; and funding from the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis). G. Poulakou has received independent educational grants from Pfizer, MSD, Angelini, and Biorad. H. Milionis reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. L. Dagna had received consultation honoraria from SOBI. M. Bassetti has received funds for research grants and/or advisor/consultant and/or speaker/chairman from Angelini, Astellas, Bayer, Biomerieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Roche, Shionogi and Nabriva. P. Panagopoulos has received honoraria from GILEAD Sciences, Janssen, and MSD. G. N. Dalekos is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis, Sobi, received research grants from Abbvie, Gilead and has served as PI in studies for Abbvie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals. M. G. Netea is supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. Hes is a scientific founder of TTxD and he has received independent educational grants from TTxD, GSK, Ono Pharma and ViiV HealthCare. The other authors do not have any competing interest to declare.Ethics Approval Statement: The SAVE protocol was approved by the National Ethics Committee of Greece (approval 38/20) and National Organization for Medicines approval (ISO 28/20). The SAVE-MORE protocol was approved by the National Ethics Committee of Greece (approval 161/20) and by the Ethics Committee of the National Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS, in Rome (1 February 2021).Trial Registration: The SAVE study was prospectively registered prior to enrolling the first patient (EudraCT number 2020-001466-11; ClinicalTrials.gov identifier NCT04357366). The SAVE-MORE study was prospectively registered (EudraCT no. 2020-005828-11; ClinicalTrials.gov identifier NCT04680949). Written informed consent was provided by all patients prior to enrollment.

Early Treatment of COVID-19 Pneumonia with Anakinra Guided by Urokinase Plasminogen Receptor (preprint)

Early recognition of risk and start of treatment may improve unfavorable outcome of COVID-19. In the SAVE-MORE double-blind randomized trial, 594 patients with pneumonia without respiratory dysfunction at risk as defined by plasma suPAR (soluble urokinase plasminogen activator receptor) ≥ 6 ng/ml were 1:2 randomized to subcutaneous placebo or 100 mg anakinra once daily for 10 days; 85.9% were co-administered dexamethasone. After 28 days, anakinra-treated patients were distributed to lower strata of the 11-point World Health Organization ordinal Clinical Progression Scale (WHO-CPS) (adjusted odds ratio-OR 0.36; 95%CI 0.26–0.50; P < 0.001); anakinra protected from severe disease or death (≥ 6 points of WHO-CPS) (OR: 0.46; P: 0.010). The median WHO-CPS decrease in the placebo and anakinra groups was 3 and 4 points (OR 0.40; P < 0.0001); the median decrease of SOFA score was 0 and 1 points (OR 0.63; P: 0.004). 28-day mortality decreased (hazard ratio: 0.45; P: 0.045) and hospital stay was shorter. (Sponsored by the Hellenic Institute for the Study of Sepsis ClinicalTrials.gov identifier, NCT04680949)

ACTIVATE-2: A DOUBLE-BLIND RANDOMIZED TRIAL OF BCG VACCINATION AGAINST COVID19 IN INDIVIDUALS AT RISK (preprint)

SUMMARY BCG vaccination induces heterologous protection against respiratory tract infections, and in children improves survival independently of tuberculosis prevention. The phase III ACTIVATE-2 study assessed whether BCG could also protect against COVID19 in the elderly. In this double-blind, randomized trial, elderly Greek patients were randomized (1:1) to receive either BCG revaccination or placebo at hospital discharge, followed by 6 months observation for incidence of COVID19 infection. BCG revaccination resulted in 68% risk reduction for total COVID19 clinical and microbiological diagnoses (OR 0.32, 95% CI 0.13-0.79). Five patients in the placebo group and one in the BCG-vaccinated group had severe COVID19 that necessitated hospitalization. 3 months after BCG vaccination 1.3% of placebo and 4.7% of BCG-vaccinated volunteers had anti-SARS-CoV-2 antibodies. These data argue that BCG revaccination is safe and protects the elderly against COVID19. BCG revaccination may represent a viable preventive measure against COVID19.

Early Anakinra Treatment for COVID-19 Guided by Urokinase Plasminogen Receptor (preprint)

BackgroundIn a previous open-label trial, early anakinra treatment guided by elevated soluble urokinase plasminogen activator receptor (suPAR) prevented progression of COVID-19 pneumonia into respiratory failure. MethodsIn the SAVE-MORE multicenter trial, 594 hospitalized patients with moderate and severe COVID-19 pneumonia and plasma suPAR 6 ng/ml or more and receiving standard-of-care were 1:2 randomized to subcutaneous treatment with placebo or 100 mg anakinra once daily for 10 days. The primary endpoint was the overall clinical status of the 11-point World Health Organization ordinal Clinical Progression Scale (WHO-CPS) at day 28. The changes of the WHO-CPS and of the sequential organ failure assessment (SOFA) score were the main secondary endpoints. ResultsAnakinra-treated patients were distributed to lower strata of WHO-CPS by day 28 (adjusted odds ratio-OR 0.36; 95%CI 0.26-0.50; P<0.001); anakinra protected from severe disease or death (6 or more points of WHO-CPS) (OR: 0.46; P: 0.010). The median absolute decrease of WHO-CPS in the placebo and anakinra groups from baseline was 3 and 4 points respectively at day 28 (OR 0.40; P<0.0001); and 2 and 3 points at day 14 (OR 0.63; P: 0.003); the absolute decrease of SOFA score was 0 and 1 points (OR 0.63; P: 0.004). 28-day mortality decreased (hazard ratio: 0.45; P: 0.045). Hospital stay was shorter. ConclusionsEarly start of anakinra treatment guided by suPAR provides 2.78 times better improvement of overall clinical status in moderate and severe COVID-19 pneumonia. (Sponsored by the Hellenic Institute for the Study of Sepsis ClinicalTrials.gov identifier, NCT04680949)