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

the 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

the REMAP-CAP Immunoglobulin Domain UK Investigators

Peter Gorer Department of Immunobiology

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1525-1538
Number of pages	14
Journal	Intensive Care Medicine
Volume	48
Issue number	11
DOIs	https://doi.org/10.1007/s00134-022-06869-w
Publication status	Published - Nov 2022

Keywords

Convalescent plasma
Precision medicine
Subphenotypes

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10.1007/s00134-022-06869-w

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@article{f1c9402331e54a33b86251e5f8db8074,

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

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",

author = "{the REMAP-CAP Immunoglobulin Domain UK Investigators} and M. Fish and J. Rynne and A. Jennings and C. Lam and Lamikanra, {A. A.} and J. Ratcliff and S. Cellone-Trevelin and E. Timms and J. Jiriha and I. Tosi and R. Pramanik and P. Simmonds and S. Seth and J. Williams and Gordon, {A. C.} and J. Knight and Smith, {D. J.} and J. Whalley and D. Harrison and K. Rowan and H. Harvala and P. Klenerman and L. Estcourt and Menon, {D. K.} and D. Roberts and M. Shankar-Hari",

note = "Funding Information: We are grateful to the NIHR Clinical Research Network (UK) for their support in participant recruitment. We are grateful to the UK Blood Services (NHS Blood and Transplant, Northern Ireland Blood Transfusion Service, Scottish National Blood Transfusion Service and Welsh Blood Service) for the supply of convalescent plasma in the UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care. This research was supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London and/or the NIHR Clinical Research Facility. Funding Information: This study was supported by National Institute for Health (UKRIDHSC COVID-19 Rapid Response Rolling Call, “The use of convalescent plasma to treat hospitalized and critically ill patients with COVID-19 disease”, Grant Reference Number COV19-RECPLAS). MF was supported by a National Institute of Academic Anesthesia BJA/RCoA fellowship (WKRO-2018–0047). JR was supported by the Marshall Scholarship and Clarendon Fund. ACG was funded by an NIHR Research Professorship (RP-2015-–06-18). DKM was supported by the NIHR through the Cambridge NIHR BRC and the Addenbrooke{\textquoteright}s Charitable Trust. MS-H is funded by a clinician scientist fellowship 2016-16-011 from the National Institute for Health Research. The REMAP-CAP has four regional nonprofit sponsors: Monash University, Melbourne, Australia (Australasian sponsor); Utrecht Medical Center, Utrecht, the Netherlands (European sponsor); St Michael{\textquoteright}s Hospital, Toronto, Ontario, Canada (Canadian sponsor); and the Global Coalition for Adaptive Research, San Francisco, California (US sponsor). REMAP-CAP was additionally funded by FP7-health-2013-innovation-1 (#602,525) from the European Union Platform for European Preparedness Against Reemerging Epidemics grant, the Rapid European COVID-19 Emergency Research response (RECOVER) consortium by the European Union{\textquoteright}s Horizon 2020 research and innovation programme (#101,003,589), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, Collection of UK plasma was funded by the DHSC through core funding under COVID-19 and EU SoHo Grants. The funders/sponsors had no role in the design and conduct of the trial; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health and Social Care. Funding Information: We are grateful to the NIHR Clinical Research Network (UK) for their support in participant recruitment. We are grateful to the UK Blood Services (NHS Blood and Transplant, Northern Ireland Blood Transfusion Service, Scottish National Blood Transfusion Service and Welsh Blood Service) for the supply of convalescent plasma in the UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care. This research was supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London and/or the NIHR Clinical Research Facility. Funding Information: LE reported receiving grants from the National Institute for Health Research and European Union Horizon 2020. ACG reported receiving grants from the National Institute for Health Research and receiving personal fees from 30 Respiratory, GlaxoSmithKline, and Bristol Myers Squibb. DKM reports consultancy agreements, educational support, or research collaborations with NeuroTrauma Sciences LLC, GlaxoSmithKline Ltd, Calico Ltd, Lantmannen AB, Cortirio Ltd, and Gryphon Inc., all outside the research in this manuscript. MSH reports receiving grant from the Chief Scientists Office, Scotland, for time-critical precision medicine in adult critically ill patients (TRAITS Programme) and highlights industry support for TRAITS research programme ( https://www.ed.ac.uk/inflammation-research/clinical-trials/traits-ci-trial ). Publisher Copyright: {\textcopyright} 2022, Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2022",

month = nov,

doi = "10.1007/s00134-022-06869-w",

language = "English",

volume = "48",

pages = "1525--1538",

journal = "Intensive Care Medicine",

issn = "0342-4642",

publisher = "Springer Verlag",

number = "11",

}

TY - JOUR

T1 - Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults

T2 - secondary analyses of a randomized clinical trial

AU - the REMAP-CAP Immunoglobulin Domain UK Investigators

AU - Fish, M.

AU - Rynne, J.

AU - Jennings, A.

AU - Lam, C.

AU - Lamikanra, A. A.

AU - Ratcliff, J.

AU - Cellone-Trevelin, S.

AU - Timms, E.

AU - Jiriha, J.

AU - Tosi, I.

AU - Pramanik, R.

AU - Simmonds, P.

AU - Seth, S.

AU - Williams, J.

AU - Gordon, A. C.

AU - Knight, J.

AU - Smith, D. J.

AU - Whalley, J.

AU - Harrison, D.

AU - Rowan, K.

AU - Harvala, H.

AU - Klenerman, P.

AU - Estcourt, L.

AU - Menon, D. K.

AU - Roberts, D.

AU - Shankar-Hari, M.

N1 - Funding Information: We are grateful to the NIHR Clinical Research Network (UK) for their support in participant recruitment. We are grateful to the UK Blood Services (NHS Blood and Transplant, Northern Ireland Blood Transfusion Service, Scottish National Blood Transfusion Service and Welsh Blood Service) for the supply of convalescent plasma in the UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care. This research was supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. Funding Information: This study was supported by National Institute for Health (UKRIDHSC COVID-19 Rapid Response Rolling Call, “The use of convalescent plasma to treat hospitalized and critically ill patients with COVID-19 disease”, Grant Reference Number COV19-RECPLAS). MF was supported by a National Institute of Academic Anesthesia BJA/RCoA fellowship (WKRO-2018–0047). JR was supported by the Marshall Scholarship and Clarendon Fund. ACG was funded by an NIHR Research Professorship (RP-2015-–06-18). DKM was supported by the NIHR through the Cambridge NIHR BRC and the Addenbrooke’s Charitable Trust. MS-H is funded by a clinician scientist fellowship 2016-16-011 from the National Institute for Health Research. The REMAP-CAP has four regional nonprofit sponsors: Monash University, Melbourne, Australia (Australasian sponsor); Utrecht Medical Center, Utrecht, the Netherlands (European sponsor); St Michael’s Hospital, Toronto, Ontario, Canada (Canadian sponsor); and the Global Coalition for Adaptive Research, San Francisco, California (US sponsor). REMAP-CAP was additionally funded by FP7-health-2013-innovation-1 (#602,525) from the European Union Platform for European Preparedness Against Reemerging Epidemics grant, the Rapid European COVID-19 Emergency Research response (RECOVER) consortium by the European Union’s Horizon 2020 research and innovation programme (#101,003,589), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, Collection of UK plasma was funded by the DHSC through core funding under COVID-19 and EU SoHo Grants. The funders/sponsors had no role in the design and conduct of the trial; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health and Social Care. Funding Information: We are grateful to the NIHR Clinical Research Network (UK) for their support in participant recruitment. We are grateful to the UK Blood Services (NHS Blood and Transplant, Northern Ireland Blood Transfusion Service, Scottish National Blood Transfusion Service and Welsh Blood Service) for the supply of convalescent plasma in the UK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care. This research was supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. Funding Information: LE reported receiving grants from the National Institute for Health Research and European Union Horizon 2020. ACG reported receiving grants from the National Institute for Health Research and receiving personal fees from 30 Respiratory, GlaxoSmithKline, and Bristol Myers Squibb. DKM reports consultancy agreements, educational support, or research collaborations with NeuroTrauma Sciences LLC, GlaxoSmithKline Ltd, Calico Ltd, Lantmannen AB, Cortirio Ltd, and Gryphon Inc., all outside the research in this manuscript. MSH reports receiving grant from the Chief Scientists Office, Scotland, for time-critical precision medicine in adult critically ill patients (TRAITS Programme) and highlights industry support for TRAITS research programme ( https://www.ed.ac.uk/inflammation-research/clinical-trials/traits-ci-trial ). Publisher Copyright: © 2022, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2022/11

Y1 - 2022/11

N2 - 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.

AB - 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.

KW - Convalescent plasma

KW - Precision medicine

KW - Subphenotypes

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DO - 10.1007/s00134-022-06869-w

M3 - Article

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JO - Intensive Care Medicine

JF - Intensive Care Medicine

IS - 11

ER -

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

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