Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial

REMAP-CAP Immunoglobulin Domain UK Investigators, Matthew Fish, Jennifer Rynne, Aislinn Jennings, C Lam, A Lamikanra, J Ratcliff, S Cellone-Trevelin, E Timms, Jakob Jeriha, I Tosi, R Pramanik, P Simmonds, Sohan Seth, J Williams, A C Gordon, J Knight, D J Smith, J Whalley, D HarrisonK Rowan, H Harvala, P Klenerman, L Estcourt, D K Menon, D Roberts, Manu Shankar-Hari*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID19) 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. Methods: We tested this hypothesis in a sub-study 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).
Results: Unsupervised 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 were 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).
Conclusions: We report 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.
Original languageEnglish
Pages (from-to)1525-1538
Number of pages38
JournalIntensive Care Medicine
Volume48
Issue number11
Early online date14 Sept 2022
DOIs
Publication statusPublished - 1 Nov 2022

Keywords / Materials (for Non-textual outputs)

  • Precision medicine
  • sub-phenotypes
  • convalescent plasma

Fingerprint

Dive into the research topics of 'Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial'. Together they form a unique fingerprint.

Cite this