Residual Lung Abnormality Following COVID-19 Hospitalisation is Characterised by Epithelial Injury

Background: Long term respiratory symptoms are reported following recovery of acute COVID-19 infection and residual lung abnormalities (RLA) on follow-up thoracic computed tomography (CT) after COVID-19 hospitalisation have been observed. It is unknown whether RLA are associated with epithelial lung injury. Methods: Plasma was sampled from the Post HOSPitalisation-COVID cohort at five months post-hospitalisation. Epithelial injury biomarkers Krebs von den Lungen-6 (KL-6), matrix metalloproteinase 7 (MMP-7), surfactant protein-D (SP-D) and surfactant protein-A (SP-A) were assayed. In those without follow-up CT, RLA at-risk was defined by percent predicted DLCO <80% and/or abnormal chest X-ray, otherwise they were considered low-risk. Follow-up CT RLA was defined as combined involvement of ground glass opacity and reticulation ≥10%. Findings: A total of 957 people were included, 846 people with no CT (at-risk n=103; 12.2%), 111 people with follow-up CT (RLA ≥10% n=85; 76.6%). All epithelial injury biomarkers were significantly elevated in people at-risk of RLA compared with low-risk. KL-6 and MMP-7 were significantly higher in people with ≥10% RLA than those with <10%, SP-D and SP-A did not reach significance. SP-D and SP-A were associated with percent involvement of reticulation (3.22%, 95%CI 1.19 to 5.24; 3.03%, 95%CI 0.76 to 5.30, respectively). Interpretation: RLA after acute COVID-19 infection were consistent with elevated epithelial injury biomarkers and pro-fibrotic signalling. Future studies should address the temporal association between fibrotic biomarkers and resolution or progression of radiological involvement. Funding: PHOSP-COVID is jointly funded by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19 (grant references: MR/V027859/1 and COV0319). Declaration of Interest: JJ reports fees from Boehringer Ingelheim, F. Hoffmann-La Roche, GlaxoSmithKline, NHSX, Takeda and patent: UK patent application number 2113765.8 all unrelated to the submitted work. PMG reports honoraria from Boehringer Ingelheim, Roche, AstraZeneca, Cipla, Brainomix. JCP reports grants from LifeArc, NIHR, Breathing Matters, consulting fees from Carrick Therapeutics, AstraZeneca and honoraria from The Limbic. RAE reports speaker fees from Boehringer Ingelheim and membership positions on European Respiratory Society and American Thoracic Society committees. PM reports consulting fees from EUSA pharma and SOBI, and honoraria from SOBI, UCB, Lilly, and Abbvie. MGS reports grants from NIHR, MRC, board positions on Pfizer External Data Monitoring Committee and Integrum Scientific LLC Infectious Disease Scientific Advisory Board, member positions of HMG UK SAGE and MHG UK NERVTAG, stocks in Integrum Scientific LLC and MedEx Solutions Ltd, gifts from Chiesi Farmaceutici S.p.A. AART reports grants and travel support from Janssen-Cilag Ltd. CEB reports consultancy fees paid to institution from GSK, AstraZeneca, Sanofi, Boehringer Ingelheim, Chiesi, Novartis, Roche, Genentech, Mologic, 4DPharma, TEVA. LVW reports recent and current research funding from GSK and Orion, and consultancy from Galapagos. RGJ reports honoraria from Chiesi, Roche, PatientMPower, AstraZeneca, GSK, Boehringer Ingelheim, and consulting fees from Bristol Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, Pliant, Chiesi. AM, AS, MP and SY are employees of Sysmex. All remaining authors declare no competing interests. Ethical Approval: The study cohort included participants of the PHOSP–COVID study, a prospective longitudinal cohort study of adults discharged from National Health Service hospitals across the United Kingdom after admission for confirmed or clinically diagnosed COVID-19, previously described in detail (Ethics Approval Ref: 20/YH/0225).