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

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; REMAP-CAP Immunoglobulin Domain UK Investigators

doi:10.1007/s00134-022-06869-w

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 Nov;48(11):1525-1538. doi: 10.1007/s00134-022-06869-w. Epub 2022 Sep 14.

Authors

M Fish^{1

2}, J Rynne¹, A Jennings^{1

2}, C Lam³, A A Lamikanra⁴, J Ratcliff⁵, S Cellone-Trevelin⁶, E Timms², J Jiriha⁷, I Tosi⁸, R Pramanik⁹, P Simmonds⁵, S Seth¹⁰, J Williams¹¹, A C Gordon¹², J Knight¹³, D J Smith¹³, J Whalley¹³, D Harrison¹⁴, K Rowan¹⁴, H Harvala¹⁵, P Klenerman⁵, L Estcourt¹⁶, D K Menon¹⁷, D Roberts¹⁶, M Shankar-Hari^{18

19

20}; REMAP-CAP Immunoglobulin Domain UK Investigators

Affiliations

¹ Centre for Inflammation Research, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland, UK.
² Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK.
³ Critical Care Unit, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK.
⁴ Blood Research Laboratory, NHS Blood and Transplant, Headley Way, Oxford, UK.
⁵ Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.
⁶ Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, James Black Centre, London, UK.
⁷ Center for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, London, UK.
⁸ St John's Institute of Dermatology, King's College London, London, UK.
⁹ NIHR Guy's and St Thomas' Biomedical Research Centre, Guys Hospital, 9Th Floor Tower Wing, London, UK.
¹⁰ School of Informatics, University of Edinburgh, 10 Crichton Street, Edinburgh, UK.
¹¹ Centre for Gene Therapy and Regenerative Medicine, King's College London, Guy's Hospital, London, UK.
¹² Division of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, London, UK.
¹³ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁴ Intensive Care National Audit & Research Centre (ICNARC), Napier House, 24 High Holborn, London, UK.
¹⁵ Microbiology Services, NHS Blood and Transplant, Charcot Road, Colindale, UK.
¹⁶ Radcliffe Department of Medicine and BRC Hematology Theme, University of Oxford, Oxford, UK.
¹⁷ University Division of Anesthesia, Addenbrooke's Hospital Cambridge, Cambridge, UK.
¹⁸ Centre for Inflammation Research, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland, UK. manu.shankar-hari@ed.ac.uk.
¹⁹ Intensive Care Unit, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, Scotland, UK. manu.shankar-hari@ed.ac.uk.
²⁰ Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. manu.shankar-hari@ed.ac.uk.

Abstract

Purpose: Benefit 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 .

Methods: We 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) .

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 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).

Conclusions: We 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.

Keywords: Convalescent plasma; Precision medicine; Subphenotypes.

Publication types

Randomized Controlled Trial

MeSH terms

Adult
Biomarkers
COVID-19 Serotherapy
COVID-19* / therapy
Critical Illness / therapy
Cytokines
Humans
Treatment Outcome

Substances

Biomarkers
Cytokines

Grants and funding

COV19-RECPLAS/National Institute for Health Research