Ten months of temporal variation in the clinical journey of hospitalised patients with COVID-19: an observational cohort

Abstract
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Abstract

Background: There is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high density unit (HDU). On the other hand, limited resources at times of high demand may lead to rationing. Nevertheless, these variables may be used as static proxies for disease severity, as outcome measures for trials, and to inform planning and logistics.

Methods: We investigate these time trends in an extremely large international cohort of 142,540 patients hospitalised with COVID-19. Investigated are: time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, hospital case fatality ratio (hCFR) and total length of hospital stay.

Results: Time from onset to admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December 2020. ICU/HDU admission was more frequent from June to August. The hCFR was lowest from June to August. Raw numbers for overall hospital stay showed little variation, but there is clear decline in time to discharge for ICU/HDU survivors.

Conclusions: Our results establish that variables of these kinds have limitations when used as outcome measures in a rapidly-evolving situation.

Funding: This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z] and the Bill and Melinda Gates Foundation [OPP1209135]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability

The data that underpin this analysis are highly detailed clinical data on individuals hosptialised with COVID-19. Due to the sensitive nature of these data and the associated privacy concerns, they are available via a governed data access mechanism following review of a data access committee. Data can be requested via the IDDO COVID-19 Data Sharing Platform (www.iddo.org/covid-19). The Data Access Application, Terms of Access and details of the Data Access Committee are available on the website. Briefly, the requirements for access are a request from a qualified researcher working with a legal entity who have a health and/or research remit; a scientifically valid reason for data access which adheres to appropriate ethical principles. The full terms are at https://www.iddo.org/document/covid-19-data-access-guidelinesA small subset of sites who contributed data to this analysis have not agreed to pooled data sharing as above. In the case of requiring access to these data, please contact the corresponding author in the first instance who will look to facilitate access.We have provided the R code used to process data and run the regression analysis at https://github.com/ISARICDataPlatform/InpatientJourneyDataProcessing. Source data for all figures has also been provided.

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ISARIC Clinical Characterisation Group

Competing interests
Allavena, C. declares personal fees from ViiVHealthcare, MSD, Janssen and Gilead, all outside the submitted work. Andréjak, C. declares personal fees for lecture from Astra Zeneca, outside the submitted work. Cheng, M. declares grants from McGill Interdisciplinary Initiative in Infection and Immunity, grants from Canadian Institutes of Health Research, during the conduct of the study; personal fees from GEn1E Lifesciences (as a member of the scientific advisory board), personal fees from nplex biosciences (as a member of the scientific advisory board), outside the submitted work. He is the co-founder of Kanvas Biosciences and owns equity in the company. In addition, M. Cheng reports a patent Methods for detecting tissue damage, graft versus host disease, and infections using cell-free DNA profiling pending, and a patent Methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA pending. Cholley, B. declares personal fees (for lectures and participation to advisory boards) from Edwards, Amomed, Nordic Pharma, and Orion Pharma. Cruz-Bermúdez, J.L. declares personal fees from Elsevier for advice, outside the submitted work. Cummings, M. and O'Donnell, M. participated as investigators for clinical trials evaluating the efficacy and safety of remdesivir (sponsored by Gilead Sciences) and convalescent plasma (sponsored by Amazon) in hospitalized patients with COVID-19. Support for this work is paid to Columbia University. Dalton, H. declares personal fees for medical director of Innovative ECMO Conceots and honorarium from Abiomed/BREETHE Oxi-1 and Instrumentation Labs. Dyrhol-Riise, AM. declares grants from Gilead outside this work. Deplanque, D. declares personal fees from Biocodex, Bristol-Myers Squibb and Pfizer (advisory boards). Dudman, S. reports grants from Research Council of Norway grant no 312780. Durante-Mangoni, E. declares funding via his Institution from MSD, Pfizer, and personal fees or participation in advisory boards or participation to the speaker's bureau of Roche, Pfizer, MSD, Angelini, Correvio, Nordic Pharma, Bio-Merieux, Abbvie, Sanofi-Aventis, Medtronic, Tyrx and DiaSorin. Grasselli, G. declares personal fees from Getinge, Biotest, Draeger Medical, Fisher & Paykel, MSD and unrestricted research grant from MSD and Fisher & Paykel, all outside the submitted work. Guerguerian, AM. participated as site investigator for the Hospital For Sick Children, Toronto, Canada as a site through SPRINT-SARI Study via the Canadian Critical Care Trials Group sponsored in part by the Canadian Institutes of Health Research. Ho, A. declares grant funding from Medical Research Council UK, Scottish Funding Council - Grand Challenges Research Fund, and the Wellcome Trust, outside this submitted work. Holter, J. C. reports grants from Research Council of Norway grant no 312780, and from Vivaldi Invest A/S owned by Jon Stephenson von Tetzchner, during the conduct of the study. Kimmoun, A. declares personal fees (payment for lectures) from Baxter, Aguettant, Aspen. Kumar, D. declares grants and personal fees from Roche, GSK and Merck; and personal fees from Pfizer and Sanofi. Kutsogiannis, D.J. declares personal fees for a lecture from Tabuk Pharmaceuticals and the Saudi Critical Care Society. Kutsyna, G. declares the study consulting fee for clinical trial ClinicalTrials.gov Identifier: NCT04762628. Laffey, J. reports that he has received fees for consultancy from GlaxoSmithKline and from Baxter Therapeutics for work outside the scope of this work. Lairez, O. declares grant funding from Pfizer; conference fees from Amicus, GE Healthcare, Novartis, Sanofi-Genzyme, and Takeda-Shire; and consultancy fees from Alnylam, Amicus, Pfizer, Takeda-Shire. Lee, J. reports grants from European Commission PREPARE grant agreement No 602525, European Commission RECOVER Grant Agreement No 101003589 and European Commission ECRAID-Plan Grant Agreement 825715 supporting the conduct, coordination and management of the work. Lee, T.C. declares research salary support from les Fonds de recherche du Québec - Santé. Lefèvre, B. declares travel/accommodation/meeting expenses from Mylan and Gilead, all outside the submitted work. Lemaignen, A. declares personal fees (payment for lectures) from MSD and Gilead; and travel/accommodation/meeting expenses from Pfizer. Lescure, F.X. declares personal fees (payment for lectures) from Gilead, MSD; and travel/accommodation/meeting expenses from Astellas, Eumedica, MSD. Liu, K. reports personal fees from MERA and receives a salary from TXP Medical completely outside the submitted work. Martin-Loeches I. declares consulting fees for Gilead outside of the submitted work. Martín-Quiros, A. declares consulting fees for Gilead. Mentré F, declares consulting fees from IPSEN, Servier and Da Volterra, and reports research grants to her group from Sanofi, Roche, Servier and Da Voleterra, all outside the submitted work. Murthy, S declares receiving salary support from the Health Research Foundation and Innovative Medicines Canada Chair in Pandemic Preparedness Research. Nichol, A. declares a grant from the Health Research Board of Ireland to support data collection in Ireland (CTN-2014-012). Openshaw, P. has served on scientific advisory boards for Janssen/J&J, Oxford Immunotech Ltd, GSK, Nestle and Pfizer (fees to Imperial College). He is Imperial College lead investigator on EMINENT, a consortium funded by the MRC and GSK. He is a member of the RSV Consortium in Europe (RESCEU) and Inno4Vac, Innovative Medicines Initiatives (IMI) from the European Union. Peltan, I.D. declares grant support from the National Institutes of Health and, outside the submitted work, grant support from Centers for Disease Control and Prevention, and Jannsen and payments to his institution for trials by Regeneron and Asahi Kasei Pharma on which he served as an investigator. Pesenti, A. declares personal fees from Maquet, Novalung/Xenios, Baxter, and Boehringer Ingelheim. Poissy, J. declares personal fees from Gilead for lectures, outside the submitting work. Povoa, P. declares personal fees (for lectures and advisory boards) from MSD, Technophage, Sanofi, and Gilead. Póvoas, D. declares consulting fees (for lectures and/or participation in advisory boards) from Roche and Viiv Healthcare; and travel/accommodation/meeting expenses from Abbvie, Gilead Sciences, Janssen Cilag, Merck Sharp & Dohme and ViiV Healthcare. Rewa, O. declares consulting fees from Baxter Inc. Rossanese, A. declares consulting fees (for lectures and/or participation to advisory boards) from Emergent BioSolutions and Sanofi Pasteur, but all outside of the frame of the submitted work. Săndulescu, O. has been an investigator in COVID-19 clinical trials by Algernon Pharmaceuticals, Atea Pharmaceuticals, Regeneron Pharmaceuticals, Diffusion Pharmaceuticals, and Celltrion, Inc., outside the scope of the submitted work. Semple, M.G. reports grants from DHSC National Institute of Health Research UK, from the Medical Research Council UK, and from the Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool, supporting the conduct of the study; other interest in Integrum Scientific LLC, Greensboro, NC, USA, outside the submitted work. Serpa Neto, A. declares personal lecture fees from Drager outside the submitted work. Shrapnel, S. participated as an investigator for an observational study analysing ICU patients with COVID-19 (for the Critical Care Consortium including ECMOCARD) funded by The Prince Charles Hospital Foundation during the conduct of this study. S. Shrapnel reports in kind support from the Australian Research Council Centre of Excellence for Engineered Quantum Systems (CE170100009). Streinu-Cercel, Adrian has been an investigator in COVID-19 clinical trials by Algernon Pharmaceuticals, Atea Pharmaceuticals, Regeneron Pharmaceuticals, Diffusion Pharmaceuticals, and Celltrion, Inc., outside the scope of the submitted work. Streinu-Cercel, Anca has been an investigator in COVID-19 clinical trials by Algernon Pharmaceuticals, Atea Pharmaceuticals, Regeneron Pharmaceuticals, Diffusion Pharmaceuticals, and Celltrion, Inc., outside the scope of the submitted work. Summers, C. reports that she has received fees for consultancy for Abbvie relating to COVID-19 therapeutics. She was also the UK Chief Investigator of a GlaxoSmithKline plc sponsored study of a therapy for COVID, and is a member of the UK COVID Therapeutic Advisory Panel (UK-CTAP). Outside the scope of this work, Dr Summers' institution receives research grants from the Wellcome Trust, UKRI/MRC, National Institute for Health Research (NIHR), GlaxoSmithKline and AstraZeneca to support research in her laboratory. Tedder, R. reports grants from MRC/UKRI during the conduct of the study. In addition, R. Tedder has a patent United Kingdom Patent Application No. 2014047.1 "SARS-CoV-2 antibody detection assay" issued. Timsit, J.F. declares personal fees from Merck, Pfizer, Gilead, Beckton dickinson, Medimune, Bayer pharma, and reports research grants to his research unit from Pfizerpers, Merck, Thermofisher. Troost, J. declares personal fees from General Electric and Procter and Gamble. Turtle, L. reports fees from Eisai for delivering a lecture related to COVID-19 and cancer, paid to the University of Liverpool. Ullrich, R. reports grant funding to his institution from Apeptico, APEIRON, Biotest, Bayer, CCORE and Philips, as well as personal fees from Biotest. He holds European patent EP15189777.4 "Blood purification device" and equity in CCORE Technology GesmbH, a medical device research and development company. Visseaux, B. declares personal fees from BioMérieux, Qiagen and Gilead and research grants from Qiagen, all outside the submitted work.
Matthew D Hall

Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

For correspondence
matthew.hall@bdi.ox.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2671-3864
Joaquín Baruch

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Gail Carson

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Barbara Wanjiru Citarella

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Andrew Dagens

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Emmanuelle Dankwa

Department of Statistics, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Christl A Donnelly

Department of Statistics, University of Oxford, Oxford, United Kingdom

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The authors declare that no competing interests exist.
Jake Dunning

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Martina Escher

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Christiana Kartsonaki

Department of Statistics, University of Oxford, Oxford, United Kingdom

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The authors declare that no competing interests exist.
Laura Merson

Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4168-1960
Mark Pritchard

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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The authors declare that no competing interests exist.
Jia Wei

Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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Peter W Horby

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

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The authors declare that no competing interests exist.
Amanda Rojek

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Piero Luigi Olliaro

ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.

Funding

UK FCDO and Wellcome Trust (215091/Z/18/Z)

Joaquín Baruch
Jake Dunning
Martina Escher
Jia Wei
Peter W Horby
Piero Luigi Olliaro

Bill and Melinda Gates Foundation (OPP1209135)

Joaquín Baruch
Jake Dunning
Martina Escher
Jia Wei
Peter W Horby
Piero Luigi Olliaro

University of Oxford's COVID-19 Research Response Fund (0009146)

Laura Merson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study was approved by the World Health Organization Ethics Review Committee (RPC571 and RPC572). Local ethics approval was obtained for each participating country and site according to local requirements. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.