Robust, reproducible clinical patterns in hospitalised patients with COVID-19

ISARIC4C Investigators

Research output: Other contributionpeer-review


Severe COVID-19 is characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. The clinical associations of different patterns of symptoms can influence diagnostic and therapeutic decision-making: for example, significant differential therapeutic effects in sub-groups of patients with different severities of respiratory failure have already been reported for the only treatment so far shown to reduce mortality in COVID-19, dexamethasone. We obtained structured clinical data on 68914 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 33468 cases according to symptoms reported at recruitment. We validated our findings in a second group of 35446 cases recruited to ISARIC-4C, and in separate cohort of community cases. A core symptom set of fever, cough, and dyspnoea co-occurred with additional symptoms in three patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were common, and a subgroup of patients reported 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 clusters were highly consistent in replication analysis using a further 35446 individuals subsequently recruited to ISARIC-4C. Similar patterns were externally verified in 4445 patients from a study of self-reported symptoms of mild disease. The large scale of ISARIC-4C study enabled robust, granular discovery and replication of patient clusters. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four patterns are usefully distinct from the core symptom groups: 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. These observations deepen our understanding of COVID-19 and will influence clinical diagnosis, risk prediction, and future mechanistic and clinical studies.Competing Interest StatementAll authors have completed the ICMJE uniform disclosure form at and declare: during the conduct of the study; JW reports he is an employee of ZOE Global Ltd; TDS reports he has acted as a consultant for ZOE Global Ltd; PJMO reports personal fees from Consultancy, grants from MRC, grants from EU Grant, grants from NIHR Biomedical Research Centre, grants from MRC/GSK, grants from Wellcome Trust, grants from NIHR (HPRU), grants from NIHR Senior Investigator, personal fees from European Respiratory Society, grants from MRC Global Challenge Research Fund, outside the submitted work; and The role of President of the British Society for Immunology was an unpaid appointment but my travel and accommodation at some meetings is provided by the Society; AMD reports grants from Department of Health and Social Care, during the conduct of the study; grants from Wellcome Trust, outside the submitted work; JKB reports grants from DHSC National Institute of Health Research UK, grants from Medical Research Council UK, grants from Wellcome Trust, grants from Fiona Elizabeth Agnew Trust, grants from Intensive Care Society, grants from Chief Scientist Office, during the conduct of the study; MGS reports grants from DHSC National Institute of Health Research UK, grants from Medical Research Council UK, grants from Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool, during the conduct of the study; other from Integrum Scientific LLC, Greensboro, NC, USA, outside the submitted work; the remaining authors declare no competing interests; no financial relationships with any organisations that might h ve an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work. Clinical TrialISRCTN66726260.Clinical Protocolshttps://isaric4c.netFunding StatementThis work is supported by grants from: the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; grant MC_PC_19059), the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (NIHR award 200907), Wellcome Trust and Department for International Development (DID; 215091/Z/18/Z), and the Bill and Melinda Gates Foundation (OPP1209135), and Liverpool Experimental Cancer Medicine Centre for providing infrastructure support for this research (grant reference C18616/A25153). The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust, or PHE.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study was approved by the South Central - Oxford C Research Ethics Committee (13/SC/0149) and by the Scotland A Research Ethics Committee (20/SS/0028).All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesWe welcome applications for data and material access through our Independent Data and Material Access Committee (
Original languageEnglish
Publication statusPublished - 1 Oct 2020

Publication series

PublisherCold Spring Harbor Laboratory Press


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