[en] [en] BACKGROUND: Convalescent plasma (CP) reduced the mortality in COVID-19 induced ARDS (C-ARDS) patients treated in the CONFIDENT trial. As patients are immunologically heterogeneous, we hypothesized that clusters may differ in their treatment responses to CP.
METHODS: We measured 20 cytokines, chemokines and cell adhesion markers using a multiplex technique at the time of inclusion in the CONFIDENT trial in patients of centers having accepted to participate in this secondary study. We performed descriptive statistics, unsupervised hierarchical cluster analysis, and examined the association between the clusters and CP effect on day-28 mortality.
RESULTS: Of the 475 patients included in CONFIDENT, 391 (82%) were sampled, and 196/391 (50.1%) had been assigned to CP. We identified four sub-phenotypes representing 89 (22.8%), 178 (45.5%), 38 (9.7%), and 86 (22.0%) patients. The most contributing biomarkers in the principal component analysis were IL-1β, IL-12p70, IL-6, IFN-α, IL-17A, IFN-γ, IL-13, TFN-α, total IgG, and CXCL10. Sub-phenotype-1 displayed a lower immune response, sub-phenotype-2 a higher adaptive response, sub-phenotype-3 the highest innate antiviral, pro and anti-inflammatory response, and adhesion molecule activation, and sub-phenotype-4 a higher pro and anti-inflammatory response, migration protein and adhesion molecule activation. Sub-phenotype-2 and sub-phenotype-4 had higher severity at the time of inclusion. The effect of CP treatment on mortality appeared higher than standard care in each sub-phenotype, without heterogeneity between sub-phenotypes (p = 0.97).
CONCLUSION: In patients with C-ARDS, we identified 4 sub-phenotypes based on their immune response. These sub-phenotypes were associated with different clinical profiles. The response to CP was similar across the 4 sub-phenotypes.
TRIAL REGISTRATION: Ethics Committee of the University Hospital of Liège CE 2020/239.
CLINICALTRIALS: gov NCT04558476. Registered 2020-09-11, https://www.
CLINICALTRIALS: gov/study/NCT04558476 .
Disciplines :
Anesthesia & intensive care
Author, co-author :
Misset, Benoît ; Université de Liège - ULiège > Département des sciences cliniques > Soins intensifs
Diep, Anh Nguyet ; Université de Liège - ULiège > Santé publique : de la Biostatistique à la Promotion de la Santé
BERTRAND, Axelle ; Centre Hospitalier Universitaire de Liège - CHU > > Service des soins intensifs
Piagnerelli, Michael; Department of Intensive Care Medicine, Marie-Curie University Hospital, Université Libre de Bruxelles, Charleroi, Belgium
Hoste, Eric; Department of Intensive Care Medicine, University Hospital, Ghent, Belgium
Michaux, Isabelle; Department of Intensive Care, Université Catholique de Louvain, CHU UCL Namur, Yvoir, Belgium
De Waele, Elisabeth; Department of Clinical Nutrition, Vrije Universiteit Brussel Brussels University Hospital, Jette, Belgium
Dumoulin, Alexander; Department of Intensive Care Medicine, Delta General Hospital, Roeselare, Belgium
Jorens, Philippe G; Department of Intensive Care Medicine, Antwerp University Hospital, University of Antwerp, LEMP, Edegem, Belgium
van der Hauwaert, Emmanuel; Department of Intensive Care Medicine, Imelda General Hospital, Bonheiden, Belgium
Vallot, Frédéric ; Université de Liège - ULiège > Département des sciences cliniques > Médecine interne générale ; Department of Intensive Care Medicine, Wallonie Picarde General Hospital, Tournai, Belgium
Swinnen, Walter; Department of Intensive Care Medicine, Sint Blasius General Hospital, Dendermonde, Belgium
De Schryver, Nicolas; Department of Intensive Care Medicine, Saint-Pierre Medical Clinic, Ottignies, Belgium
de Mey, Nathalie; Department of Intensive Care Medicine, OLV General Hospital, Aalst, Belgium
LAYIOS, Nathalie ; Centre Hospitalier Universitaire de Liège - CHU > > Service des soins intensifs
Mesland, Jean-Baptiste; Department of Intensive Care Medicine, Saint-Luc University Hospital, Brussels, Belgium
Robinet, Sébastien ; Université de Liège - ULiège > Département des sciences cliniques
Cavalier, Etienne ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Donneau, Anne-Françoise ; Université de Liège - ULiège > Département des sciences de la santé publique
Moutschen, Michel ; Université de Liège - ULiège > GIGA > GIGA I3 - Immunology & Infectious Diseases
Laterre, Pierre-François; Department of Intensive Care Medicine, Mons-Hainaut Regional Hospital, Mons, Belgium
E. Tan J. Song A.M. Deane M.P. Plummer Global impact of coronavirus disease 2019 infection requiring admission to the ICU Chest 2021 159 524 536 10.1016/j.chest.2020.10.014 33069725
M. Griffiths S. Meade C. Summers D.F. McAuley A. Proudfoot M.M. Baladia et al. RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic Thorax 2022 77 129 135 10.1136/thoraxjnl-2021-216904 34045363
Axfors C, Janiaud P, Schmitt AM, Van’t Hooft J, Smith ER, Haber NA, et al. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials. BMC Infect Dis. 2021;21:1170.
Iannizzi C, Chai KL, Piechotta V, Valk SJ, Kimber C, Monsef I, et al. Convalescent plasma for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2023;5:CD013600.
Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, et al. Effect of convalescent plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2021;326:1690–702.
M. Fish J. Rynne A. Jennings C. Lam A.A. Lamikanra J. Ratcliff et al. Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial Intensive Care Med 2022 48 1525 1538 10.1007/s00134-022-06869-w 36102943 9472738
M. Kox N.J.B. Waalders E.J. Kooistra J. Gerretsen P. Pickkers Cytokine levels in critically Ill patients with COVID-19 and other conditions JAMA 2020 324 1565 1567 10.1001/jama.2020.17052 32880615 7489366
Brabander J de, Boers LS, Kullberg RFJ, Zhang S, Nossent EJ, Heunks LMA, et al. Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality. Thorax. 2023 [cited 2023 Jul 18]; Available from: https://thorax.bmj.com/content/early/2023/05/04/thorax-2023-219989
L. Bakkerus P. Pickkers Personalized medicine in COVID-19 Intensive Care Med 2022 48 1607 1610 10.1007/s00134-022-06908-6 36210384 9548417
B. Misset M. Piagnerelli E. Hoste N. Dardenne D. Grimaldi I. Michaux et al. Convalescent plasma for Covid-19–induced ARDS in mechanically ventilated patients N Engl J Med 2023 389 1590 1600 10.1056/NEJMoa2209502 37889107 10755833
A.G. Laing A. Lorenc I.D.M.D. Barrio A.M.L. DasFishMonin et al. A dynamic COVID-19 immune signature includes associations with poor prognosis Nat Med 2020 26 1623 1635 10.1038/s41591-020-1038-6 32807934
D.M. Del Valle S. Kim-Schulze H.-H. Huang N.D. Beckmann S. Nirenberg B. Wang et al. An inflammatory cytokine signature predicts COVID-19 severity and survival Nat Med 2020 26 1636 1643 10.1038/s41591-020-1051-9 32839624 7869028
C. Lucas P. Wong J. Klein T.B.R. Castro J. Silva M. Sundaram et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19 Nature 2020 584 463 469 10.1038/s41586-020-2588-y 32717743 7477538
B. Sposito A. Broggi L. Pandolfi S. Crotta N. Clementi R. Ferrarese et al. The interferon landscape along the respiratory tract impacts the severity of COVID-19 Cell 2021 184 4953 4968.e16 10.1016/j.cell.2021.08.016 34492226 8373821
Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, Liew F, Russell CD, Moore SC, et al. Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19. Sci Immunol. 2021;6:eabg9873.
WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA. 2021;326:499–518.
M. Merad J.C. Martin Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages Nat Rev Immunol 2020 20 355 362 10.1038/s41577-020-0331-4 32376901 7201395
P. Brodin Immune determinants of COVID-19 disease presentation and severity Nat Med 2021 27 28 33 10.1038/s41591-020-01202-8 33442016
B. Guidet D.W. de Lange A. Boumendil S. Leaver X. Watson C. Boulanger et al. The contribution of frailty, cognition, activity of daily life and comorbidities on outcome in acutely admitted patients over 80 years in European ICUs: the VIP2 study Intensive Care Med 2020 46 57 69 10.1007/s00134-019-05853-1 31784798
WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020;20:e192–7.
ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307:2526–33.
A. Padoan C. Cosma F. Bonfante F.D. Rocca F. Barbaro C. Santarossa et al. SARS-CoV-2 neutralizing antibodies after one or two doses of Comirnaty (BNT162b2, BioNTech/Pfizer): Kinetics and comparison with chemiluminescent assays Clin Chim Acta Int J Clin Chem 2021 523 446 453 10.1016/j.cca.2021.10.028
B. Shakoory J.A. Carcillo W.W. Chatham R.L. Amdur H. Zhao C.A. Dinarello et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial Crit Care Med 2016 44 275 281 10.1097/CCM.0000000000001402 26584195 5378312
D.C. Angus T. van der Poll Severe sepsis and septic shock N Engl J Med 2013 369 840 851 10.1056/NEJMra1208623 23984731
R.L. Thorndike Who belongs in the family? Psychometrika 1953 18 267 276 10.1007/BF02289263
M.T. Keegan O. Gajic B. Afessa Severity of illness scoring systems in the intensive care unit Crit Care Med 2011 39 163 169 10.1097/CCM.0b013e3181f96f81 20838329
M. Parlato J.-M. Cavaillon Host response biomarkers in the diagnosis of sepsis: a general overview Methods Mol Biol Clifton NJ 2015 1237 149 211 10.1007/978-1-4939-1776-1_15
T. van der Poll M. Shankar-Hari W.J. Wiersinga The immunology of sepsis Immunity 2021 54 2450 2464 10.1016/j.immuni.2021.10.012 34758337
D.C. Fajgenbaum C.H. June Cytokine Storm N Engl J Med 2020 383 2255 2273 10.1056/NEJMra2026131 33264547 7727315
J.-M. Cavaillon D. Annane Compartmentalization of the inflammatory response in sepsis and SIRS J Endotoxin Res 2006 12 151 170 16719987
M. Parlato F. Philippart A. Rouquette V. Moucadel V. Puchois S. Blein et al. Circulating biomarkers may be unable to detect infection at the early phase of sepsis in ICU patients: the CAPTAIN prospective multicenter cohort study Intensive Care Med 2018 44 1061 1070 10.1007/s00134-018-5228-3 29959455
Carroll TD, Wong T, Morris MK, Di Germanio C, Ma Z-M, Stone M, et al. Administration of vaccine-boosted COVID-19 convalescent plasma to SARS-CoV-2 infected hamsters decreases virus replication in lungs and hastens resolution of the infection despite transiently enhancing disease and lung pathology. BioRxiv Prepr Serv Biol. 2023;55:3458.
