The effect of immunosuppressive therapies on the endothelial host response in critically ill COVID-19 patients
Authors: Slim M. A. , Lim E. H. T. , van Vught L. A. , Boer A. M. Tuip-de , Rademaker E. , Mulier J. L. G. Haitsma , Engel J. J. ,   The Amsterdam UMC COVID-19 Biobank Study Group, van Agtmael M. , Algera A. G. , Appelman B. , Baarle F. , Beudel M. , Bogaard H. J. , Bomers M. , Bos L. D. , Botta M. , de Brabander J. , de Bree G. , de Bruin S. , Bugiani M. , Bulle E. , Buis D. T. P. , Chouchane O. , Cloherty A. , de Rotte M. C. F. J. , Dijkstra M. , Dongelmans D. A. , Dujardin R. W. G. , Elbers P. , Fleuren L. , Geerlings S. , Geijtenbeek T. , Girbes A. , Goorhuis B. , Grobusch M. P. , Hagens L. , Hamann J. , Harris V. , Hemke R. , Hermans S. M. , Heunks L. , Hollmann M. , Horn J. , Hovius J. W. , de Jong M. D. , Koning R. , Lim E. H. T. , van Mourik N. , Nellen J. , Nossent E. J. , Paulus F. , Peters E. , Piña-Fuentes D. A. I. , van der Poll T. , Preckel B. , Raasveld J. , Reijnders T. , Schinkel M. , Schultz M. J. , Schrauwen F. A. P. , Schuurman A. , Schuurmans J. , Sigaloff K. , Slim M. A. , Smeele P. , Smit M. , Stijnis C. S. , Stilma W. , Teunissen C. , Thoral P. , Tsonas A. M. , Tuinman P. R. , van der Valk M. , Veelo D. , Volleman C. , de Vries H. , Vught L. A. , van Vugt M. , Wouters D. , Zwinderman A. H. , Brouwer M. C. , Wiersinga W. J. , Vlaar A. P. J. , van de Beek D. ,   The Radboudumc Center for Infectious Diseases COVID-19 Study Group, Hijmans Anneke , van Cranenbroek Bram , Bleeker-Rovers Chantal , Jacobs Cor , Fasse Esther , van Rijssen Esther , Taks Esther , Weren Fieke , Nijman Gerine , Koenen Hans , Lemmers Heidi , Wertheim Heiman , Dijkstra Helga , van der Eng Hetty , Heesakkers Hidde , Kouijzer Ilse , Joosten Irma , Oever Jaap ten , Hoogerwerf Jacobien , Rahamat-Langendoen Janette , Gerretsen Jelle , Schouten Jeroen , Hopman Joost , van de Maat Josephine , Schraa Kiki , Buijsse Leonie , van Emst Liesbeth , Fransman Liz , Kolkman Manon , Klop-Riehl Margreet , Jaeger Martin , Waalders Nicole , Bruse Niklas , Rovers Noortje , Hemelaar Pleun , Debisarun Priya , de Mast Quirijn , van Crevel Reinout , Beunders Remi , Smeets Ruben , Moorlag Simone , van der Velde Sjef , Frenzel Tim , van Schaik Tirsa , Jansen Trees , Claassen Wout , Pickkers P. , van de Veerdonk F. L. , Vlaar A. P. J. , Derde L. P. G. , Juffermans N. P. 
Published: April 2024

While several effective therapies for critically ill patients with COVID-19 have been identified in large, well-conducted trials, the mechanisms underlying these therapies have not been investigated in depth. Our aim is to investigate the association between various immunosuppressive therapies (corticosteroids, tocilizumab and anakinra) and the change in endothelial host response over time in critically ill COVID-19 patients. We conducted a pre-specified multicenter post-hoc analysis in a Dutch cohort of COVID-19 patients admitted to the ICU between March 2020 and September 2021 due to hypoxemic respiratory failure. A panel of 18 immune response biomarkers in the complement, coagulation and endothelial function domains were measured using ELISA or Luminex. Biomarkers were measured on day 0–1, day 2–4 and day 6–8 after start of COVID-19 treatment. Patients were categorized into four treatment groups: no immunomodulatory treatment, corticosteroids, anakinra plus corticosteroids, or tocilizumab plus corticosteroids. The association between treatment group and the change in concentrations of biomarkers was estimated with linear mixed-effects models, using no immunomodulatory treatment as reference group. 109 patients with a median age of 62 years [IQR 54–70] of whom 72% (n = 78) was male, were included in this analysis. Both anakinra plus corticosteroids (n = 22) and tocilizumab plus corticosteroids (n = 38) were associated with an increase in angiopoietin-1 compared to no immune modulator (n = 23) (beta of 0.033 [0.002–0.064] and 0.041 [0.013–0.070] per day, respectively). These treatments, as well as corticosteroids alone (n = 26), were further associated with a decrease in the ratio of angiopoietin-2/angiopoietin-1 (beta of 0.071 [0.034–0.107], 0.060 [0.030–0.091] and 0.043 [0.001–0.085] per day, respectively). Anakinra plus corticosteroids and tocilizumab plus corticosteroids were associated with a decrease in concentrations of complement complex 5b-9 compared to no immunomodulatory treatment (0.038 [0.006–0.071] and 0.023 [0.000–0.047], respectively). Currently established treatments for critically ill COVID-19 patients are associated with a change in biomarkers of the angiopoietin and complement pathways, possibly indicating a role for stability of the endothelium. These results increase the understanding of the mechanisms of interventions and are possibly useful for stratification of patients with other inflammatory conditions which may potentially benefit from these treatments.