Abstract: Open access Original research Emma A Hurst,1,2 Richard J Mellanby,1 Ian Handel,1 David M Griffith ‍ ‍,3 Adriano G Rossi,4 Timothy S Walsh,4,5 Manu Shankar-­Hari,6,7 Jake Dunning,8 Natalie Z Homer,2 Scott G Denham,2 Kerri Devine,2 Paul A Holloway,9 Shona C Moore,10 Ryan S Thwaites,11 Romit J Samanta,12 Charlotte Summers ‍ ‍,12 Hayley E Hardwick,10 Wilna Oosthuyzen,13 Lance Turtle,10,14 Malcolm G Semple,10,15 Peter J M Openshaw,11 J Kenneth Baillie,5,13 Clark D Russell ‍ ‍,4,13 ISARIC4C Investigators To cite: Hurst EA, Mellanby RJ, Handel I, et al. Vitamin D insufficiency in COVID-­19 and influenza A, and critical illness survivors: a cross-­ sectional study. BMJ Open 2021;11:e055435. doi:10.1136/ bmjopen-2021-055435 ►► Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (http://​dx.​doi.o​ rg/​10.​1136/​ bmjopen-​2021-​055435). Received 13 July 2021 Accepted 30 September 2021 © Author(s) (or their employer(s)) 2021. Re-­use permitted under CC BY. Published by BMJ. For numbered affiliations see end of article. Correspondence to Dr Clark D Russell; ​clark.​russell@e​ d.​ac.​uk ABSTRACT Objectives The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-­hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-­19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors. Design Cross-­sectional study. Setting and participants Plasma was obtained from 295 hospitalised people with COVID-­19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009–2010 H1N1 pandemic) and 139 survivors of non-­selected critical illness (prior to the COVID-­19 pandemic). Total 25(OH)D was measured by liquid chromatography-­tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-­19 samples. Outcome measures Receipt of invasive mechanical ventilation (IMV) and in-­hospital mortality. Results Vitamin D insufficiency (total 25(OH)D 25– 50 nmol/L) and deficiency (<25 nmol/L) were prevalent in COVID-­19 (29.3% and 44.4%, respectively), influenza A (47.3% and 37.6%) and critical illness survivors (30.2% and 56.8%). In COVID-­19 and influenza A, total 25(OH) D measured early in illness was lower in patients who received IMV (19.6 vs 31.9 nmol/L (p<0.0001) and 22.9 vs 31.1 nmol/L (p=0.0009), respectively). In COVID-­19, biologically active free 25(OH)D correlated with total 25(OH)D and was lower in patients who received IMV, but was not associated with selected circulating inflammatory mediators. Conclusions Vitamin D deficiency/insufficiency was present in majority of hospitalised patients with COVID-­19 or influenza A and correlated with severity and persisted in critical illness survivors at concentrations expected to disrupt bone metabolism. These findings support early supplementation trials to determine if insufficiency is Strengths and limitations of this study ►► Liquid chromatography-­tandem mass spectrometry was used to quantify 25-­hydroxy vitamin D (25(OH) D) in plasma samples from well-­characterised..