Distinct clinical symptom patterns in patients hospitalised with COVID-19 in an analysis of 59,011 patients in the ISARIC-4C study
Authors: Millar Jonathan E. , Neyton Lucile , Seth Sohan , Dunning Jake , Merson Laura , Murthy Srinivas , Russell Clark D. , Keating Sean , Swets Maaike , Sudre Carole H. , Spector Timothy D. , Ourselin Sebastien , Steves Claire J. , Wolf Jonathan , Docherty Annemarie B. , Harrison Ewen M. , Openshaw Peter J. M. , Semple Malcolm G. , Baillie J. Kenneth ,   ISARIC-4C ,   Consortium Lead Investigator, Baillie J. Kenneth ,   Chief Investigator, Semple Malcolm G. ,   Co-Lead Investigator, Openshaw Peter J. M. ,   ISARIC Clinical Coordinator, Carson Gail ,   Co-Investigators, Alex Beatrice , Bach Benjamin , Barclay Wendy S. , Bogaert Debby , Chand Meera , Cooke Graham S. , Docherty Annemarie B. , Dunning Jake , da Silva Filipe Anna , Fletcher Tom , Green Christopher A. , Harrison Ewen M. , Hiscox Julian A. , Ho Antonia YW , Horby Peter W. , Ijaz Samreen , Khoo Saye , Klenerman Paul , Law Andrew , Lim Wei Shen , Mentzer Alexander J. , Merson Laura , Meynert Alison M. , Noursadeghi Mahdad , Moore Shona C. , Palmarini Massimo , Paxton William A. , Pollakis Georgios , Price Nicholas , Rambaut Andrew , Robertson David L. , Russell Clark D. , Sancho-Shimizu Vanessa , Scott Janet T. , Sigfrid Louise , Solomon Tom , Sriskandan Shiranee , Stuart David , Summers Charlotte , Tedder Richard S. , Thomson Emma C. , Thwaites Ryan S. , Turtle Lance C. W. , Zambon Maria ,   Project Managers, Hardwick Hayley , Donohue Chloe , Ewins Jane , Oosthuyzen Wilna , Griffiths Fiona ,   Data Analysts, Norman Lisa , Pius Riinu , Drake Tom M. , Fairfield Cameron J. , Knight Stephen , Mclean Kenneth A. , Murphy Derek , Shaw Catherine A. ,   Data and Information System Manager, Dalton Jo , Girvan Michelle , Saviciute Egle , Roberts Stephanie , Harrison Janet , Marsh Laura , Connor Marie ,   Data integration and presentation, Leeming Gary , Hendry Ross ,   Material Management, Greenhalf William , Shaw Victoria , McDonald Sarah ,   Local Principal Investigators, Adeniji Kayode , Agranoff Daniel , Agwuh Ken , Ail Dhiraj , Alegria Ana , Angus Brian , Ashish Abdul , Atkinson Dougal , Bari Shahedal , Barlow Gavin , Barnass Stella , Barrett Nicholas , Bassford Christopher , Baxter David , Beadsworth Michael , Bernatoniene Jolanta , Berridge John , Best Nicola , Bothma Pieter , Brealey David , Brittain-Long Robin , Bulteel Naomi , Burden Tom , Burtenshaw Andrew , Caruth Vikki , Chadwick David , Chambler Duncan , Chee Nigel , Child Jenny , Chukkambotla Srikanth , Clark Tom , Collini Paul , Cooke Graham , Cosgrove Catherine , Cupitt Jason , Cutino-Moguel Maria-Teresa , Dark Paul , Dawson Chris , Dervisevic Samir , Donnison Phil , Douthwaite Sam , DuRand Ingrid , Dushianthan Ahilanadan , Dyer Tristan , Evans Cariad , Eziefula Chi , Fegan Chrisopher , Finn Adam , Fullerton Duncan , Garg Sanjeev , Garg Atul , Godden Jo , Goldsmith Arthur , Graham Clive , Hardy Elaine , Hartshorn Stuart , Harvey Daniel , Havalda Peter , Hawcutt Daniel B. , Hobrok Maria , Hodgson Luke , Holme Anita , Hormis Anil , Jacobs Michael , Jain Susan , Jennings Paul , Kaliappan Agilan , Kasipandian Vidya , Kegg Stephen , Kelsey Michael , Kendall Jason , Kerrison Caroline , Kerslake Ian , Koch Oliver , Koduri Gouri , Koshy George , Laha Shondipon , Larkin Susan , Leiner Tamas , Lillie Patrick , Limb James , Linnett Vanessa , Little Jeff , MacMahon Michael , MacNaughton Emily , Mankregod Ravish , Masson Huw , Matovu Elijah , McCullough Katherine , McEwen Ruth , Meda Manjula , Mills Gary , Minton Jane , Mirfenderesky Mariyam , Mohandas Kavya , Mok Quen , Moon James , Moore Elinoor , Morgan Patrick , Morris Craig , Mortimore Katherine , Moses Samuel , Mpenge Mbiye , Mulla Rohinton , Murphy Michael , Nagel Megan , Nagarajan Thapas , Nelson Mark , Otahal Igor , Pais Mark , Panchatsharam Selva , Paraiso Hassan , Patel Brij , Pepperell Justin , Peters Mark , Phull Mandeep , Pintus Stefania , Pooni Jagtur Singh , Post Frank , Price David , Prout Rachel , Rae Nikolas , Reschreiter Henrik , Reynolds Tim , Richardson Neil , Roberts Mark , Roberts Devender , Rose Alistair , Rousseau Guy , Ryan Brendan , Saluja Taranprit , Shah Aarti , Shanmuga Prad , Sharma Anil , Shawcross Anna , Sizer Jeremy , Smith Richard , Snelson Catherine , Spittle Nick , Staines Nikki , Stambach Tom , Stewart Richard , Subudhi Pradeep , Szakmany Tamas , Tatham Kate , Thomas Jo , Thompson Chris , Thompson Robert , Tridente Ascanio , Tupper-Carey Darell , Twagira Mary , Ustianowski Andrew , Vallotton Nick , Vincent-Smith Lisa , Visuvanathan Shico , Vuylsteke Alan , Waddy Sam , Wake Rachel , Walden Andrew , Welters Ingeborg , Whitehouse Tony , Whittaker Paul , Whittington Ashley , Wijesinghe Meme , Williams Martin , Wilson Lawrence , Wilson Sarah , Winchester Stephen , Wiselka Martin , Wolverson Adam , Wooton Daniel G. , Workman Andrew , Yates Bryan , Young Peter 
Published: April 2022

COVID-19 is clinically characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied clustering techniques to a large prospective cohort of hospitalised patients with COVID-19 to identify clinically meaningful sub-phenotypes. We obtained structured clinical data on 59,011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25,477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33,534 cases recruited to ISARIC-4C, and in 4,445 cases recruited to a separate study of community cases. Unsupervised clustering identified distinct sub-phenotypes. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were also identified, alongside a sub-phenotype of patients reporting few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom sub-phenotypes were highly consistent in replication analysis within the ISARIC-4C study. Similar patterns were externally verified in patients from a study of self-reported symptoms of mild disease. The large scale of the ISARIC-4C study enabled robust, granular discovery and replication. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four sub-phenotypes are usefully distinct from the core symptom group: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms.