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Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19

Lookup NU author(s): Dr Luke Milross, Bethany Hunter, Dr David McDonald, George Merces, Dr Amanda Thomson, Professor Catharien Hilkens, Kasim Jiwa, Dr Joaquim Majo, Dr Christopher DuncanORCiD, Professor Andrew FilbyORCiD, Professor Andrew FisherORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 The Author(s)Background: Lung damage in severe COVID-19 is highly heterogeneous however studies with dedicated spatial distinction of discrete temporal phases of diffuse alveolar damage (DAD) and alternate lung injury patterns are lacking. Existing studies have also not accounted for progressive airspace obliteration in cellularity estimates. We used an imaging mass cytometry (IMC) analysis with an airspace correction step to more accurately identify the cellular immune response that underpins the heterogeneity of severe COVID-19 lung disease. Methods: Lung tissue was obtained at post-mortem from severe COVID-19 deaths. Pathologist-selected regions of interest (ROIs) were chosen by light microscopy representing the patho-evolutionary spectrum of DAD and alternate disease phenotypes were selected for comparison. Architecturally normal SARS-CoV-2-positive lung tissue and tissue from SARS-CoV-2-negative donors served as controls. ROIs were stained for 40 cellular protein markers and ablated using IMC before segmented cells were classified. Cell populations corrected by ROI airspace and their spatial relationships were compared across lung injury patterns. Findings: Forty patients (32M:8F, age: 22–98), 345 ROIs and >900k single cells were analysed. DAD progression was marked by airspace obliteration and significant increases in mononuclear phagocytes (MnPs), T and B lymphocytes and significant decreases in alveolar epithelial and endothelial cells. Neutrophil populations proved stable overall although several interferon-responding subsets demonstrated expansion. Spatial analysis revealed immune cell interactions occur prior to microscopically appreciable tissue injury. Interpretation: The immunopathogenesis of severe DAD in COVID-19 lung disease is characterised by sustained increases in MnPs and lymphocytes with key interactions occurring even prior to lung injury is established. Funding: UK Research and Innovation/ Medical Research Council through the UK Coronavirus Immunology Consortium, Barbour Foundation, General Sir John Monash Foundation, Newcastle University, JGW Patterson Foundation, Wellcome Trust.

Publication metadata

Author(s): Milross L, Hunter B, McDonald D, Merces G, Thomson A, Hilkens CMU, Wills J, Rees P, Jiwa K, Cooper N, Majo J, Ashwin H, Duncan CJA, Kaye PM, Bayraktar OA, Filby A, Fisher AJ

Publication type: Article

Publication status: Published

Journal: eBioMedicine

Year: 2024

Volume: 99

Print publication date: 01/01/2024

Online publication date: 23/12/2023

Acceptance date: 14/12/2023

Date deposited: 08/01/2024

ISSN (electronic): 2352-3964

Publisher: Elsevier B.V.


DOI: 10.1016/j.ebiom.2023.104945


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