• M Fish, J Rynne, A Jennings, C Lam, A A Lamikanra, J Ratcliff, S Cellone-Trevelin, E Timms, J Jiriha, I Tosi, R Pramanik, P Simmonds, S Seth, J Williams, A C Gordon, J Knight, D J Smith, J Whalley, D Harrison, K Rowan, H Harvala, P Klenerman, L Estcourt, D K Menon, D Roberts, M Shankar-Hari, and REMAP-CAP Immunoglobulin Domain UK Investigators.
• Centre for Inflammation Research, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland, UK.
• Intensive Care Med. 2022 Nov 1; 48 (11): 152515381525-1538.

PurposeBenefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs .MethodsWe tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) .ResultsUnsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (- 1, 21) vs 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs 0 (- 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008).ConclusionsWe reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.

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