Interstitial lung damage following COVID-19 hospitalisation: an interim analysis of the UKILD Post-COVID study

Introduction Shared characteristics between COVID-19 and pulmonary fibrosis, including symptoms, genetic architecture, and circulating biomarkers, suggests interstitial lung disease (ILD) development may be associated with SARS-CoV-2 infection. Methods The UKILD Post-COVID study planned interim analysis was designed to stratify risk groups and estimate the prevalence of Post-COVID Interstitial Lung Damage (ILDam) using the Post-HOSPitalisation COVID-19 (PHOSP-COVID) Study. Demographics, radiological patterns and missing data were assessed descriptively. Bayes binomial regression was used to estimate the risk ratio of persistent lung damage >10% involvement in linked, clinically indicated CT scans. Indexing thresholds of percent predicted DLco, chest X-ray findings and severity of admission were used to generate risk strata. Number of cases within strata were used to estimate the amount of suspected Post-COVID ILDam. Results A total 3702 people were included in the UKILD interim cohort, 2406 completed an early follow-up research visit within 240 days of discharge and 1296 had follow-up through routine clinical review. We linked the cohort to 87 clinically indicated CTs with visually scored radiological patterns (median 119 days from discharge; interquartile range 83 to 155, max 240), of which 74 people had ILDam. ILDam was associated with abnormal chest X-ray (RR 1.21 95%CrI 1.05; 1.40), percent predicted DLco<80% (RR 1.25 95%CrI 1.00; 1.56) and severe admission (RR 1.27 95%CrI 1.07; 1.55). A risk index based on these features suggested 6.9% of the interim cohort had moderate to very-high risk of Post-COVID ILDam. Comparable radiological patterns were observed in repeat scans >90 days in a subset of participants. Conclusion These interim data highlight that ILDam was not uncommon in clinically indicated thoracic CT up to 8 months following SARS-CoV-2 hospitalisation. Whether the ILDam will progress to ILD is currently unknown, however health services should radiologically and physiologically monitor individuals who have Post-COVID ILDam risk factors. ### Competing Interest Statement 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. All remaining authors declare no competing interests. ### Funding Statement Jointly funded by UK Research and Innovation and National Institute of Health Research (grant references: MR/V027859/1 and COV0319). Ethics Approval Ethics Ref: 20/YH/0225 The authors would like to acknowledge the support of the eDRIS Team (Public Health Scotland) for their involvement in obtaining approvals, provisioning and linking data and the use of the secure analytical platform within the National Safe Haven. This study would not be possible without all the participants who have given their time and support. We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the study at all of the 65 NHS trusts/Health boards and 25 research institutions across the UK, as well as all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland, and UK Health Security Agency, and support from the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C). We thank Kate Holmes at the NIHR Office for Clinical Research Infrastructure (NOCRI) for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well as Ivana Poparic and Peter Sargent at NOCRI for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimers Research UK, Asthma & Lung UK, British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, McPin Foundations, and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group and the Long Covid Support Group. JB acknowledges MRC Transition Fellowship (MR/T032529/1) and Manchester BRC funding. BG acknowledges UKRI-MRC Programme Grant and Confidence in Concept Grant, British Lung Foundation and the NIHR Leicester BRC funding. BGG acknowledges funding from Wellcome Trust grant 221680/Z/20/Z. NG is funded by an NIHR fellowship. PLM and RJA are funded by the Action for Pulmonary Fibrosis Mike Bray Fellowships. DGW is funded by an NIHR Advanced Fellowship. JP is supported by UKRI PC-ILD grant, Breathing Matters Charity, and UCLH/UCL funding from the Department of Health NIHR Biomedical Research Centres funding scheme. AART is funded by an Intermediate Clinical Fellowship from the British Heart Foundation (FS/18/13/33281). LVW is supported by GSK / Asthma + Lung UK Chair in Respiratory Research (C17-1). GJ acknowledges funding from a NIHR Research Professorship. IS fellowship is funded by the Rayne Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Study has received ethical approval from the Yorkshire and Humber - Leeds West Research Ethics Committee and approval from the Health Research Authority. Ethics Approval Ref: 20/YH/0225 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. 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. Yes Data were obtained through the PHOSP-COVID Study