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Abstract
Background Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS.
Methods Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality.
Results Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality.
Conclusions Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS.
- ARDS
- Cytokine Biology
- Critical Care
Data availability statement
Data are available upon reasonable request.
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Data availability statement
Data are available upon reasonable request.
Footnotes
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PM and RJS contributed equally.
Correction notice This article has been corrected since it was published Online First. An author affiliation was listed incorrectly.
Contributors Conceived and designed study: PM, RJS, CMOK and DFMA. Analysed data from the ROSE cohort: KW. Drafted manuscript: PM, RJS, RCC, DFMA and CMOK. Data collection, analysis and interpretation: PM, RJS, KW, RCC, TM, PGMA, AJB, JC, MS-H, AR, CSC, MAM, CS, RCC, DFMA and CMOK. Revision of the manuscript and approved the final version: PM, RJS, KW, RCC, TM, PGMA, AJB, JC, MS-H, AR, CSC, MAM, CS, RCC, DFMA and CMOK. CMOK is the guarantor of the paper.
Funding UK Efficacy and Mechanism Evaluation Programme.
Competing interests PM and RJS are/were clinical training fellows within the Experimental Medicine Initiative to Explore New Therapies (EMINENT) network and receive project funding unrelated to this article from the Medical Research Council and GlaxoSmithKline. PM also receives co-funding by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. RJS receives co-funding by the Cambridge NIHR Biomedical Research Centre. PM reports consultancy fees from SOBI, UCB, Lilly, AbbVie, Boehringer and EUSA Pharma outside the submitted work. KW reports grants from National Institutes of Health, during the conduct of the study. TM reports PhD studentship funding from the Department for the Economy Northern Ireland. RCC reports grants from the Royal Society and the Academy of Medical Sciences during the conduct of the study; personal fees from BioAge Labs, personal fees from ImmVention Therapeutix, outside the submitted work; In addition, RCC has a patent US 10,538,487 licensed to Inflazome Ltd, a patent PCT/IB2017/053059 licensed to Inflazome Ltd and a patent PCT/EP2017/053498 licensed to Inflazome Ltd. AJB reports received funding from the Northern Ireland Health and Social Care Research and Development office for research outside of the submitted work. MS-H reports grants and other from National Institute for Health Research, during the conduct of the study. MS-H is supported by the NIHR Clinician Scientist Award (CS-2016-16-011). AR reports other from Merck, outside the submitted work. CSC reports grants from NIH R35-HL140026, during the conduct of the study; grants and personal fees from Roche/Genentech, grants and personal fees from Bayer, personal fees from Quark Pharmaceuticals, personal fees from Gen1e Life Sciences, personal fees from Vasomune, grants from Quantum Leap Healthcare Collaborative, outside the submitted work. MAM reports grants from Roche Genentec, personal fees from Novartis, personal fees from Johnson and Johnson, personal fees from Gilead Pharmaceuticals, personal fees from Pliant Therapeutics, outside the submitted work. CS is the Director of the EMINENT research training scheme supporting RJS and PM, and reports research funding to her institution from the Wellcome Trust, the Medical Research Council, the NIHR, GlaxoSmithKline, AstraZeneca and the Cambridge NIHR Biomedical Research Centre, all unrelated to this work. CS also reports personal fees for consultancy from Roche, GlaxoSmithKline and AbbVie. RCC reports grants from UKRI-MRC, NIHR-UCLH BRC and GSK, outside the submitted work. DFMA chairs the NIHR and Medical Research Council funding committee for COVID-19 for therapeutics and vaccines. DFMA reports personal fees from consultancy for ARDS for GlaxoSmithKline, Boehringer Ingelheim, and Bayer; in addition, his institution has received funds from grants from the UK NIHR, Wellcome Trust, Innovate UK and others, all unrelated to this Correspondence. DFMA also has a patent issued to his institution for a treatment for ARDS. DFMA is a Director of Research for the Intensive Care Society and NIHR Efficacy and Mechanism Evaluation Programme Director. CMOK reports grant funding from the Wellcome Trust, MRC, Innovate UK and NIHSC R&D for unrelated work. CMOK reports fees for consultancy from Insmed and for reviews from the California Institute of Regenerative Medicine (CIRM) unrelated to this work. CMOK’s spouse has received consultancy fees from BI, Bayer and GSK unrelated to this work. All other authors declare no competing interests. The views expressed in this manuscript are those of the authors and not necessarily those of the Medical Research Council (MRC), National Health Service, NIHR or Department of Health and Social Care. This study was supported by the UK EME Programme, an MRC and NIHR partnership (08/99/08 and 16/33/01). The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland, the National Institute for Social Care and Health Research in Wales, and the Health and Social Care (HSC) Research and Development Division, Public Health Agency for Northern Ireland. TM is supported by a PhD studentship from the Department for the Economy Northern Ireland. RCC is supported by an Academy of Medical Sciences Springboard Award (SBF005\1104), a Royal Society Research Grant (RGS\R1\201127), and institutional funding from the Wellcome-Wolfson Institute for Experimental Medicine and Queen’s University Belfast.
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