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The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity

Research output: Contribution to journalReview articlepeer-review

Marcin F Osuchowski, Martin S Winkler, Tomasz Skirecki, Sara Cajander, Manu Shankar-Hari, Gunnar Lachmann, Guillaume Monneret, Fabienne Venet, Michael Bauer, Frank M Brunkhorst, Sebastian Weis, Alberto Garcia-Salido, Matthijs Kox, Jean-Marc Cavaillon, Florian Uhle, Markus A Weigand, Stefanie B Flohé, W Joost Wiersinga, Raquel Almansa, Amanda de la Fuente & 14 more Ignacio Martin-Loeches, Christian Meisel, Thibaud Spinetti, Joerg C Schefold, Catia Cilloniz, Antoni Torres, Evangelos J Giamarellos-Bourboulis, Ricard Ferrer, Massimo Girardis, Andrea Cossarizza, Mihai G Netea, Tom van der Poll, Jesús F Bermejo-Martín, Ignacio Rubio

Original languageEnglish
Pages (from-to)622-642
Number of pages21
JournalThe Lancet Respiratory Medicine
Issue number6
Early online date6 May 2021
E-pub ahead of print6 May 2021
PublishedJun 2021

Bibliographical note

Funding Information: No funding was provided for this Series paper. TSk is supported by the Poland National Science Centre (UMO-2020/01/0/NZ6/00218). MS-H is funded by a UK National Institute for Health Research (NIHR) Clinician Scientist Award (CS-2016-16-011). GL is a participant of the Berlin Institute of Health (BIH) Charit? Clinician Scientist Programme, which receives grants from the Charit??Universit?tsmedizin Berlin and the Berlin Institute of Health. MB is supported by the Deutsche Forschungsgemeinschaft-funded Collaborative Research Centre PolyTarget (SFB 1278, Project ID 316213987). WJW is supported by the Netherlands Organisation for Scientific Research. AT and JFB-M acknowledge funding from CIBERES in the context of CIBERESUCICOVID (part of Instituto de Salud Carlos III). AC acknowledges funding from the Ministero della Salute, Bando Ricerca COVID-19 (2020?2021, grant number COVID-2020-12371808). The views expressed in this publication are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the Department of Health and Social Care. We thank Margit Leitner for technical help with figure design. Funding Information: MSW has received unrestricted funding from Sartorius. GL reports personal fees from Swedish Orphan Biovitrum. TSp and JCS disclose institutional funding (received by the University of Bern) from Orion Pharma, Abbott Nutrition International, B Braun Medical, CSEM, Edwards Lifesciences, Kenta Biotech, Maquet Critical Care, Omnicare Clinical Research, Nestlé, Pierre Fabre Pharma, Pfizer, Bard Medica, Abbott, Anandic Medical Systems, PanGas Healthcare, Bracco, Hamilton Medical, Fresenius Kabi, Getinge Group Maquet, Dräger, Teleflex Medical, GlaxoSmithKline, Merck Sharp and Dohme, Eli Lilly, Baxter, Astellas, AstraZeneca, CSL Behring, Novartis, Covidien, Nycomed, Phagenesis, and Hemotune. MGN reports grants from GlaxoSmithKline and ViiV Healthcare, and was a scientific founder of TTxD. All other authors declare no competing interests. Publisher Copyright: © 2021 Elsevier Ltd Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.

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