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

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

Intensive care medicine. 2022;:1-14
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PICO Summary

Population

Critically ill COVID-19 patients enrolled in the REMAP-CAP trial (n= 1,239).

Intervention

High-titer convalescent plasma.

Comparison

Usual care.

Outcome

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)). Organ support free days at 21 days (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.
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.
Study details
Language : eng
Credits : Bibliographic data from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine