Prospective validation of the 4C prognostic models for adults hospitalised with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol

Stephen R Knight; Rishi K Gupta; Antonia Ho; Riinu Pius; Iain Buchan; Gail Carson; Thomas M Drake; Jake Dunning; Cameron J Fairfield; Carrol Gamble; Christopher A Green; Sophie Halpin; Hayley E Hardwick; Karl A Holden; Peter W Horby; Clare Jackson; Kenneth A Mclean; Laura Merson; Jonathan S Nguyen-Van-Tam; Lisa Norman; Piero L Olliaro; Mark G Pritchard; Clark D Russell; Catherine A Shaw; Aziz Sheikh; Tom Solomon; Cathie Sudlow; Olivia V Swann; Lance C W Turtle; Peter J M Openshaw; J Kenneth Baillie; Annemarie Docherty; Malcolm G Semple; Mahdad Noursadeghi; Ewen M Harrison; ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C) Investigators; ISARIC4C investigators

doi:10.1136/thoraxjnl-2021-217629

Prospective validation of the 4C prognostic models for adults hospitalised with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol

Thorax. 2022 Jun;77(6):606-615. doi: 10.1136/thoraxjnl-2021-217629. Epub 2021 Nov 22.

Authors

Stephen R Knight¹, Rishi K Gupta², Antonia Ho³, Riinu Pius¹, Iain Buchan^{4

5}, Gail Carson⁶, Thomas M Drake¹, Jake Dunning^{7

8}, Cameron J Fairfield¹, Carrol Gamble⁹, Christopher A Green¹⁰, Sophie Halpin⁹, Hayley E Hardwick¹¹, Karl A Holden¹¹, Peter W Horby⁶, Clare Jackson⁹, Kenneth A Mclean¹, Laura Merson⁶, Jonathan S Nguyen-Van-Tam¹², Lisa Norman¹, Piero L Olliaro¹³, Mark G Pritchard¹³, Clark D Russell¹⁴, Catherine A Shaw¹, Aziz Sheikh¹⁵, Tom Solomon¹¹, Cathie Sudlow¹⁶, Olivia V Swann¹⁷, Lance C W Turtle^{18

19}, Peter J M Openshaw²⁰, J Kenneth Baillie²¹, Annemarie Docherty¹, Malcolm G Semple^{11

22}, Mahdad Noursadeghi²³, Ewen M Harrison²⁴; ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C) Investigators; ISARIC4C investigators

Collaborators

J Kenneth Baillie, Malcolm G Semple, Peter Jm Openshaw, Gail Carson, Beatrice Alex, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Graham S Cooke, Annemarie B Docherty, Jake Dunning, Ana da Silva Filipe, Tom Fletcher, Christopher A Green, Ewen M Harrison, Julian A Hiscox, Antonia YingWai Ho, Peter W Horby, Samreen Ijaz, Saye Khoo, Paul Klenerman, Andrew Law, Wei Shen Lim, J Mentzer Alexander, Laura Merson, Alison M Meynert, Mahdad Noursadeghi, Shona C Moore, Massimo Palmarini, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Clark D Russell, Vanessa Sancho-Shimizu, Janet T Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Richard S Tedder, Emma C Thomson, Ryan S Thwaites, Lance Cw Turtle, Maria Zambon, Hayley Hardwick, Chloe Donohue, Jane Ewins, Wilna Oosthuyzen, Fiona Griffiths, Lisa Norman, Riinu Pius, Tom M Drake, Cameron J Fairfield, Stephen R Knight, Kenneth A Mclean, Derek Murphy, Catherine A Shaw, Jo Dalton, Michelle Girvan, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Gary Leeming, Andrew Law, Ross Hendry, William Greenhalf, Victoria Shaw, Sarah McDonald, Katie A Ahmed, Jane A Armstrong, Milton Ashworth, Innocent G Asiimwe, Siddharth Bakshi, Samantha L Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Benjamin Wa Catterall, Jordan J Clark, Emily A Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lewis Ws Fisher, Terry Foster, Isabel Garcia-Dorival, Willliam Greenhalf, Philip Gunning, Catherine Hartley, Antonia Ho, Rebecca L Jensen, Christopher B Jones, Trevor R Jones, Shadia Khandaker, Katharine King, Robyn T Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, L Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A Livoti, Maria Mancini, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S Miah, Joanna Middleton, Joyce Mitchell, Shona C Moore, Ellen G Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, P Matthew Ridley, Debby Sales, Victoria E Shaw, Rebecca K Shears, Benjamin Small, Krishanthi S Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J Eunice Zhang, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Ana Alegria, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Nicola Best, Pieter Bothma, David Brealey, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, David Chadwick, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Samir Dervisevic, Phil Donnison, Sam Douthwaite, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Cariad Evans, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Sanjeev Garg, Atul Garg, Jo Godden, Arthur Goldsmith, Clive Graham, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B Hawcutt, Maria Hobrok, Luke Hodgson, Anita Holme, Anil Hormis, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Susan Larkin, Tamas Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Mariyam Mirfenderesky, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig Morris, Katherine Mortimore, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Megan Nagel, Thapas Nagarajan, Mark Nelson, Igor Otahal, Mark Pais, Selva Panchatsharam, Hassan Paraiso, Brij Patel, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Brendan Ryan, Taranprit Saluja, Aarti Shah, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jeremy Sizer, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamas Szakmany, Kate Tatham, Jo Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Andrew Ustianowski, Nick Vallotton, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Sarah Wilson, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G Wooton, Andrew Workman, Bryan Yates, Peter Young

Affiliations

¹ Centre for Medical Informatics, The University of Edinburgh, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK.
² University College London Institute for Global Health, London, UK.
³ Medical Research Council University of Glasgow Centre for Virus Research, Glasgow, UK.
⁴ Manchester Academic Health Science Centre, Manchester, UK.
⁵ Department of Public Health and Policy, University of Liverpool, Liverpool, UK.
⁶ Nuffield Department of Clinical Medicine, ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
⁷ Public Health England National Infection Service, Salisbury, UK.
⁸ National Heart and Lung Institute, Imperial College London, London, UK.
⁹ Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK.
¹⁰ Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
¹¹ NIHR Health Protection Research Unit, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
¹² Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
¹³ Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
¹⁴ Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
¹⁵ Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
¹⁶ Health Data Research UK, London, UK.
¹⁷ Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.
¹⁸ Clinical Infection, Microbiology and Immunology, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK.
¹⁹ Liverpool University Hospitals Foundation Trust, Member of Liverpool Health Partners, Liverpool, UK.
²⁰ Respiratory Department, Imperial College, London, UK.
²¹ Genetics and Genomics, Roslin Institute, University of Edinburgh, Edinburgh, UK.
²² Respiratory Medicine, Alder Hey Children's Hospital, University of Liverpool, Liverpool, UK.
²³ Division of Infection and Immunity, University College London, London, UK.
²⁴ Centre for Medical Informatics, The University of Edinburgh, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK ewen.harrison@ed.ac.uk.

Abstract

Purpose: To prospectively validate two risk scores to predict mortality (4C Mortality) and in-hospital deterioration (4C Deterioration) among adults hospitalised with COVID-19.

Methods: Prospective observational cohort study of adults (age ≥18 years) with confirmed or highly suspected COVID-19 recruited into the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study in 306 hospitals across England, Scotland and Wales. Patients were recruited between 27 August 2020 and 17 February 2021, with at least 4 weeks follow-up before final data extraction. The main outcome measures were discrimination and calibration of models for in-hospital deterioration (defined as any requirement of ventilatory support or critical care, or death) and mortality, incorporating predefined subgroups.

Results: 76 588 participants were included, of whom 27 352 (37.4%) deteriorated and 12 581 (17.4%) died. Both the 4C Mortality (0.78 (0.77 to 0.78)) and 4C Deterioration scores (pooled C-statistic 0.76 (95% CI 0.75 to 0.77)) demonstrated consistent discrimination across all nine National Health Service regions, with similar performance metrics to the original validation cohorts. Calibration remained stable (4C Mortality: pooled slope 1.09, pooled calibration-in-the-large 0.12; 4C Deterioration: 1.00, -0.04), with no need for temporal recalibration during the second UK pandemic wave of hospital admissions.

Conclusion: Both 4C risk stratification models demonstrate consistent performance to predict clinical deterioration and mortality in a large prospective second wave validation cohort of UK patients. Despite recent advances in the treatment and management of adults hospitalised with COVID-19, both scores can continue to inform clinical decision making.

Trial registration number: ISRCTN66726260.

Keywords: COVID-19.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
COVID-19* / therapy
Hospital Mortality
Humans
Observational Studies as Topic
Prognosis
SARS-CoV-2
State Medicine
World Health Organization

Associated data

ISRCTN/ISRCTN66726260.

Abstract

Publication types

MeSH terms

Associated data

Grants and funding