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. 2022;14(3):218-228.
doi: 10.1159/000519090. Epub 2021 Dec 1.

ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients

Eleni Karakike  1 , George N Dalekos  2 , Ioannis Koutsodimitropoulos  3 , Maria Saridaki  1 , Chryssa Pourzitaki  4 , Georgios Papathanakos  5 , Antigone Kotsaki  1 , Stamatios Chalvatzis  1 , Vasiliki Dimakopoulou  6 , Nikolaos Vechlidis  1 , Elisabeth Paramythiotou  7 , Christina Avgoustou  1 , Aikaterini Ioakeimidou  8 , Elli Kouriannidi  1 , Apostolos Komnos  9 , Evangelia Neou  9 , Nikoletta Rovina  10 , Eleni Stefanatou  3 , Haralampos Milionis  11 , George Nikolaidis  8 , Antonia Koutsoukou  10 , Georgia Damoraki  1 , George Dimopoulos  7 , Vassileios Zoumpos  1 , Jesper Eugen-Olsen  12 , Karolina Akinosoglou  6 , Nikolaos K Gatselis  2 , Vasilios Koulouras  5 , Eleni Gkeka  4 , Nikolaos Markou  3 , Mihai G Netea  13   14 , Evangelos J Giamarellos-Bourboulis  1
Affiliations

ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients

Eleni Karakike et al. J Innate Immun. 2022.

Abstract

Background: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19.

Methods: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints.

Results: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment.

Conclusion: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

Keywords: COVID-19; Interleukin 1 receptor antagonist protein; Macrophage activation; Monocytes; Respiratory distress syndrome; Tocilizumab.

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Conflict of interest statement

George N. Dalekos has acted as advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Novartis, Roche, Amgen, MSD, Janssen, Ipsen, Genkyotex, Sobi, and Pfizer; has received grant support from Bristol-Myers Squib, Gilead, Roche, Janssen, Abbvie, and Bayer; and was or is currently PI in national and international protocols sponsored by Abbvie, Bristol-Myers Squibb, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc., Tiziana Life Sciences, Bayer, Astellas, Ipsen, Pfizer, Amyndas Pharamaceuticals, CymaBay Therapeutics Inc., and Roche. E. Karakike has received funding from Horizon 2020 Marie Skłodowska-Curie Grant European Sepsis Academy (Grant No. 676129), outside of the submitted work. Haralampos Milionis reports receiving honoraria, consulting fees, and nonfinancial support from health-care companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. J. Eugen-Olsen is a cofounder, shareholder, and CSO of ViroGates A7S, Denmark, and is named inventor on patents on suPAR owned by Copenhagen University Hospital Hvidovre, Denmark. He is granted by the Horizon 2020 European Grant RISKinCOVID. M.G. Netea is a scientific founder of TTxD and received research grants from GSK and ViiV Healthcare. E.J. Giamarellos-Bourboulis has received honoraria from Abbott CH, Angelini Italy, InflaRx GmbH, MSD Greece, XBiotech Inc., Sobi AB, and B.R.A.H.M.S GmbH (Thermo Fisher Scientific); independent educational grants from AbbVie Inc., Abbott CH, Astellas Pharma Europe, AxisShield, bioMérieux Inc, Johnson & Johnson, Novartis, InflaRx GmbH, Sobi AB, XBiotech Inc (granted to the Hellenic Institute for the Study of Sepsis); and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon 2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis), and the Horizon 2020 RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not report any conflict of interest.

Figures

Fig. 1
Fig. 1
Study flow of patients in the ESCAPE trial. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ITT, intent-to-treat; LRTI, lower respiratory tract infection; MALS, macrophage activation-like syndrome; PLT, absolute platelet count; PMNs, absolute neutrophil count.
Fig. 2
Fig. 2
Change of biomarkers after immunomodulatory treatment for critical COVID-19 patients. Patients were treated with anakinra (n = 60) or tocilizumab (n = 42). Comparative values of day 1 before start of treatment and of day 8 are provided for the absolute lymphocyte count, serum CRP, and the ratio of partial oxygen pressure to the fraction of inspired oxygen (PaO2/FiO2). Comparative values of day 1 before start of treatment and of day 4 are provided for ferritin, IL-6, suPAR, absolute number of molecules of HLA-DR (mHLA-DR) and MFI of HLA-DR on circulating monocytes. The p values of the respective comparisons by the Wilcoxon paired test are provided. CRP, C-reactive protein; IL, interleukin; HLA, human leukocyte antigen; MFI, mean fluorescence intensity; suPAR, soluble urokinase plasminogen activator receptor.
Fig. 3
Fig. 3
Modulation of mononuclear cell function (a–e) Concentrations of TNFα, of interleukin (IL)-6, IL-17 and IFN γ in the supernatants of PBMCs of patients treated with anakinra and with tocilizumab; PBMCs were isolated before start of treatment (day 1) and on day 4 of treatment and they were stimulated with LPS of Escherichia coli O55:B5 and with HKCA. p values indicate the level of significance after comparisons between days 1 and 4 by the Wilcoxon test. f, g Correlation between IL-6 produced by PBMCs on day 4 after stimulation with HKCA and the WHO-CPS on day 28. The Spearman correlation co-efficient (rs) and the p values of significance are provided. CPS, clinical progression scale; HKCA, heat-killed Candida albicans; IL, interleukin; IFN, interferon; LPS, lipopolysaccharide; PBMCs, peripheral blood mononuclear cells; TNFα, tumor necrosis factor-alpha.
Fig. 4
Fig. 4
Exploratory study endpoints. a Comparative distribution of the scales of the WHO clinical progression scale by day 28 between anakinra-treated patients, tocilizumab-treated patients, and available comparators; the indicated comparisons are done by Pearson's χ2 test. b Time to hospital discharge of patients receiving treatment with anakinra and with tocilizumab. The p value of comparison by the log-rank test is provided.
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