{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T06:05:09Z","timestamp":1771049109646,"version":"3.50.1"},"reference-count":112,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"scientific research program","award":["P3-0124"],"award-info":[{"award-number":["P3-0124"]}]},{"name":"scientific research program","award":["J3-1756"],"award-info":[{"award-number":["J3-1756"]}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Vitamin D deficiency is common in hospitalized COVID-19 patients and is associated with increased severity. However, single-biomarker approaches provide insufficient prognostic precision. We developed an integrative inflammatory-metabolic risk index combining vitamin D status, systemic inflammation, and coagulation activation. This is a prospective cohort study of 512 hospitalized COVID-19 patients (September 2022\u2013December 2023) with serum 25(OH)D3 measurement at admission. The primary analysis (N = 301) included patients with complete data for VDIBS-Core components (CRP, ferritin, D-dimer, LDH). The Vitamin D Inflammatory Burden Score-Core (VDIBS-Core; range 0\u20137) integrated the following: (1) vitamin D tier (deficient &lt; 30 nmol\/L: 3 points; insufficient 30\u201350: 2; non-optimal 50\u201375: 1; sufficient &gt; 75: 0), (2) inflammation score (CRP \u2265 100, ferritin \u2265 1000 each +1 point; 0\u20132 total), and (3) coagulation score (D-dimer \u2265 1000, LDH \u2265 3\u20136 or \u2265 6 each +0\u20132 points; 0\u20132 total). The IL-6 measurement (N = 48, 9.4%) was explored separately as VDIBS-Plus in the secondary analysis. The outcomes were severe COVID-19 (defined as the worst severity classification during hospitalization per WHO criteria), ICU admission, and mortality. The mean vitamin D was 63.4 \u00b1 33.2 nmol\/L (68.1% deficient). Among N = 301 with complete VDIBS-Core data, severe disease occurred in 221 (73.4%), ICU admission in 15 (5.0%), and mortality in 8 (2.7%). VDIBS-Core risk stratification showed the following: low-risk (VDIBS 0\u20132, n = 178) 8.4% severe; moderate-risk (VDIBS 3\u20135, n = 245) 45.7% severe; and high-risk (VDIBS 6\u20137, n = 89) 78.6% severe; \u03c72 = 142.3, p &lt; 0.001. VDIBS-Core predicted severe disease with AUC 0.78 (95% CI 0.74\u20130.82), with excellent calibration (Hosmer\u2013Lemeshow p = 0.40). When compared to complex multivariate models incorporating all seven individual biomarkers, VDIBS-Core demonstrated equivalent discrimination (AUC 0.82, \u0394 = 0.04, p = 0.08, not statistically significant) with superior clinical simplicity. Bootstrap internal validation confirmed modest optimism (optimism-corrected AUC 0.76). An incremental value analysis demonstrated that the vitamin D component contributes a significant additional predictive value compared to inflammation\/coagulation biomarkers alone (LR test p = 0.004). VDIBS-Core provides bedside-implementable risk stratification using three simple components measurable in &lt;5 min, integrating vitamin D-dependent immune regulation with systemic inflammation and coagulation activation. This composite approach offers a practical tool for treatment intensity escalation and monitoring frequency assignment in hospitalized COVID-19 patients. External validation in geographically diverse cohorts is required before widespread clinical implementation.<\/jats:p>","DOI":"10.3390\/ijms27041770","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:05:46Z","timestamp":1770897946000},"page":"1770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Vitamin D-Inflammatory-Coagulation Biomarker Index Predicts COVID-19 Severity: Development and Validation of the Vitamin D Inflammatory Burden Score (VDIBS)"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1839-2415","authenticated-orcid":false,"given":"Jo\u0161ko","family":"Osredkar","sequence":"first","affiliation":[{"name":"Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, Zalo\u0161ka c 2, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana, A\u0161ker\u010deva 7, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4447-3435","authenticated-orcid":false,"given":"Uro\u0161","family":"Godnov","sequence":"additional","affiliation":[{"name":"Natural Science and Information Technologies, Faculty of Mathematics, University of Primorska, Gljagolja\u0161ka ulica 8, 6000 Koper, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darko","family":"Siuka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, University Medical Centre Ljubljana, Zalo\u0161ka c 2, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/joim.13646","article-title":"Effective Prognostic and Clinical Risk Stratification in COVID-19 Using Multimodality Biomarkers","volume":"294","author":"Liu","year":"2023","journal-title":"J. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"124","DOI":"10.18433\/jpps32518","article-title":"Association Between Vitamin D Levels and Inflammatory Markers in COVID-19 Patients: A Meta-Analysis of Observational Studies","volume":"25","author":"Hopefl","year":"2022","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3434","DOI":"10.1038\/s41467-020-17292-4","article-title":"Marked T Cell Activation, Senescence, Exhaustion and Skewing towards TH17 in Patients with COVID-19 Pneumonia","volume":"11","author":"Meschiari","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Polidoro, R.B., Hagan, R.S., De Santis Santiago, R., and Schmidt, N.W. (2020). Overview: Systemic Inflammatory Response Derived From Lung Injury Caused by SARS-CoV-2 Infection Explains Severe Outcomes in COVID-19. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01626"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"144","DOI":"10.14336\/AD.2021.0704","article-title":"Coagulation Disorders and Thrombosis in COVID-19 Patients and a Possible Mechanism Involving Endothelial Cells: A Review","volume":"13","author":"Chen","year":"2022","journal-title":"Aging Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"254","DOI":"10.12688\/f1000research.131730.2","article-title":"The Effect of Vitamin D Levels on the Course of COVID-19 in Hospitalized Patients\u2013a 1-Year Prospective Cohort Study","volume":"12","author":"Siuka","year":"2024","journal-title":"F1000Research"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Grant, W.B., Lahore, H., McDonnell, S.L., Baggerly, C.A., French, C.B., Aliano, J.L., and Bhattoa, H.P. (2020). Evidence That Vitamin D Supplementation Could Reduce the Risk of Influenza and COVID-19 Infections and Deaths. Nutrients, 12.","DOI":"10.20944\/preprints202003.0235.v2"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1007\/s40520-020-01570-8","article-title":"The Role of Vitamin D in the Prevention of Coronavirus Disease 2019 Infection and Mortality","volume":"32","author":"Ilie","year":"2020","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"D\u2019Avolio, A., Avataneo, V., Manca, A., Cusato, J., De Nicol\u00f2, A., Lucchini, R., Keller, F., and Cant\u00f9, M. (2020). 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2. Nutrients, 12.","DOI":"10.3390\/nu12051359"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1111\/j.1365-2265.2011.04261.x","article-title":"An Update on Vitamin D and Human Immunity","volume":"76","author":"Hewison","year":"2012","journal-title":"Clin. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.3390\/nu7043011","article-title":"Vitamin D and 1,25(OH)2D Regulation of T Cells","volume":"7","author":"Cantorna","year":"2015","journal-title":"Nutrients"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1126\/science.1123933","article-title":"Toll-like Receptor Triggering of a Vitamin D\u2013Mediated Human Antimicrobial Response","volume":"311","author":"Liu","year":"2006","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1096\/fj.04-3284com","article-title":"Human Cathelicidin Antimicrobial Peptide (CAMP) Gene Is a Direct Target of the Vitamin D Receptor and Is Strongly up-Regulated in Myeloid Differentiation","volume":"19","author":"Gombart","year":"2005","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ragab, D., Eldin, H.S., Taeimah, M., Khattab, R., and Salem, R. (2020). The COVID-19 Cytokine Storm; What We Know so Far. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01446"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0140-6736(20)30628-0","article-title":"COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.immuni.2020.05.002","article-title":"Immunology of COVID-19: Current State of the Science","volume":"52","author":"Vabret","year":"2020","journal-title":"Immunity"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1753466620937175","DOI":"10.1177\/1753466620937175","article-title":"C-Reactive Protein, Procalcitonin, D-Dimer, and Ferritin in Severe Coronavirus Disease 2019: A Meta-Analysis","volume":"14","author":"Huang","year":"2020","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1136\/bmj.39335.541782.AD","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for reporting observational studies","volume":"335","author":"Altman","year":"2007","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"i6583","DOI":"10.1136\/bmj.i6583","article-title":"Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data","volume":"356","author":"Martineau","year":"2017","journal-title":"BMJ"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.3945\/ajcn.2009.29094","article-title":"Randomized Trial of Vitamin D Supplementation to Prevent Seasonal Influenza A in Schoolchildren","volume":"91","author":"Urashima","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e561","DOI":"10.1542\/peds.2011-3029","article-title":"Randomized Trial of Vitamin D Supplementation and Risk of Acute Respiratory Infection in Mongolia","volume":"130","author":"Camargo","year":"2012","journal-title":"Pediatrics"},{"key":"ref_22","unstructured":"Mercier, N., de Brito Montredon, M.F., Kalfin, R., Monteiro, J.G.d.C., Yeghiazaryan, N.L., and Kone, M. (2021). Vitamin D: From Innate Immunity to Immunotolerance. Front. Immunol., 12."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3310\/hta23020","article-title":"Vitamin D supplementation to prevent acute respiratory infections: Individual participant data meta-analysis","volume":"23","author":"Martineau","year":"2019","journal-title":"Health Technol. Assess."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hosseini, B., El Abd, A., and Ducharme, F.M. (2022). Effects of Vitamin D Supplementation on COVID-19 Related Outcomes: A Systematic Review and Meta-Analysis. Nutrients, 14.","DOI":"10.3390\/nu14102134"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.clnu.2024.09.030","article-title":"Metabolic Phenotypes and Vitamin D Response in the Critically Ill: A Metabolomic Cohort Study","volume":"43","author":"Kobayashi","year":"2024","journal-title":"Clin. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1007\/s40618-021-01566-9","article-title":"Retrospective Analysis of Vitamin D Status on Inflammatory Markers and Course of the Disease in Patients with COVID-19 Infection","volume":"44","author":"Cander","year":"2021","journal-title":"J. Endocrinol. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/S0895-4356(96)00236-3","article-title":"A Simulation Study of the Number of Events per Variable in Logistic Regression Analysis","volume":"49","author":"Peduzzi","year":"1996","journal-title":"J. Clin. Epidemiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/sim.5941","article-title":"Graphical Assessment of Internal and External Calibration of Logistic Regression Models by Using Loess Smoothers","volume":"33","author":"Austin","year":"2014","journal-title":"Stat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1175\/1520-0493(1950)078<0001:VOFEIT>2.0.CO;2","article-title":"Verification of Forecasts Expressed in Terms of Probability","volume":"78","author":"Brier","year":"1950","journal-title":"Mon. Weather Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/(SICI)1097-0258(19960229)15:4<361::AID-SIM168>3.0.CO;2-4","article-title":"Multivariable Prognostic Models: Issues in Developing Models, Evaluating Assumptions and Adequacy, and Measuring and Reducing Errors","volume":"15","author":"Harrell","year":"1996","journal-title":"Stat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1177\/0272989X06295361","article-title":"Decision Curve Analysis: A Novel Method for Evaluating Prediction Models","volume":"26","author":"Vickers","year":"2006","journal-title":"Med. Decis. Mak."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Steyerberg, E.W., Moons, K.G.M., Van Der Windt, D.A., Hayden, J.A., Perel, P., Schroter, S., Riley, R.D., Hemingway, H., Altman, D.G., and for the PROGRESS Group (2013). Prognosis Research Strategy (PROGRESS) 3: Prognostic Model Research. PLoS Med., 10.","DOI":"10.1371\/journal.pmed.1001381"},{"key":"ref_33","first-page":"947","article-title":"Towards Better Clinical Prediction Models: Seven Steps for Improved Calibration","volume":"44","author":"Steyerberg","year":"2014","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the Areas under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/sim.2929","article-title":"Evaluating the Added Predictive Ability of a New Marker: From Area under the ROC Curve to Reclassification and Beyond","volume":"27","author":"Pencina","year":"2008","journal-title":"Stat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Austin, P.C., and Steyerberg, E.W. (2012). Interpreting the Concordance Statistic of a Logistic Regression Model: Relation to the Wilcoxon\u2013Mann\u2013Whitney Test. BMC Med. Res. Methodol., 12.","DOI":"10.1186\/1471-2288-12-82"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1046\/j.1525-1497.2002.10750.x","article-title":"Simplifying Likelihood Ratios","volume":"17","author":"McGee","year":"2002","journal-title":"J. Gen. Intern. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1161\/HYPERTENSIONAHA.110.160929","article-title":"25-Hydroxyvitamin D Deficiency Is Associated with Inflammation-Linked Vascular Endothelial Dysfunction in Middle-Aged and Older Adults","volume":"57","author":"Jablonski","year":"2010","journal-title":"Hypertension"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Rubin, D.B. (1987). Multiple Imputation for Nonresponse in Surveys, John Wiley & Sons.","DOI":"10.1002\/9780470316696"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1080\/01621459.1988.10478722","article-title":"A Test of Missing Completely at Random for Multivariate Data with Missing Values","volume":"83","author":"Little","year":"1988","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"van der Ploeg, T., Austin, P.C., and Steyerberg, E.W. (2014). Modern Modelling Techniques Are Data Hungry: A Simulation Study for Predicting Dichotomous Endpoints. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-137"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.jclinepi.2014.06.018","article-title":"A New Framework to Enhance the Interpretation of External Validation Studies of Clinical Prediction Models","volume":"68","author":"Debray","year":"2015","journal-title":"J. Clin. Epidemiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"105751","DOI":"10.1016\/j.jsbmb.2020.105751","article-title":"Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study","volume":"203","author":"Bouillon","year":"2020","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1001\/jama.2020.26848","article-title":"Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients with Moderate to Severe COVID-19: A Randomized Clinical Trial","volume":"325","author":"Murai","year":"2021","journal-title":"JAMA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"100291","DOI":"10.1016\/j.xcrm.2021.100291","article-title":"Comparative Immune Profiling of Acute Respiratory Distress Syndrome Patients with or without SARS-CoV-2 Infection","volume":"2","author":"Roussel","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_46","unstructured":"World Health Organization (2021). Clinical Management of COVID-19: Living Guideline, World Health Organization."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Recovery Collaborative Group (2021). Dexamethasone in Hospitalized Patients with COVID-19. N. Engl. J. Med., 384, 693\u2013704.","DOI":"10.1056\/NEJMoa2021436"},{"key":"ref_48","first-page":"1581","article-title":"Vitamin D Supplements Don\u2019t Reduce COVID-19 Risk","volume":"328","author":"Slomski","year":"2022","journal-title":"JAMA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1097\/TIN.0000000000000284","article-title":"Immunomodulatory Effects of Vitamin D and Prevention of Respiratory Tract Infections and COVID-19","volume":"37","author":"Shoemaker","year":"2022","journal-title":"Top. Clin. Nutr."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Pludowski, P., Takacs, I., Boyanov, M., Belaya, Z., Diaconu, C.C., Mokhort, T., Zherdova, N., Rasa, I., Payer, J., and Pilz, S. (2022). Clinical Practice in the Prevention, Diagnosis and Treatment of Vitamin D Deficiency: A Central and Eastern European Expert Consensus Statement. Nutrients, 14.","DOI":"10.3390\/nu14071483"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"T\u00f3th, B.E., Tak\u00e1cs, I., K\u00e1d\u00e1r, K., Mirani, S., Vecserny\u00e9s, M., and Lakatos, P. (2024). Safety and Efficacy of Loading Doses of Vitamin D: Recommendations for Effective Repletion. Pharmaceuticals, 17.","DOI":"10.3390\/ph17121620"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1093\/pubmed\/fdae007","article-title":"Therapeutic High-Dose Vitamin D for Vitamin D-Deficient Severe COVID-19 Disease: Randomized, Double-Blind, Placebo-Controlled Study (SHADE-S)","volume":"46","author":"Singh","year":"2024","journal-title":"J. Public Health"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"S\u00eerbu, A.C., Sabin, O., Boc\u0219an, I.C., Vesa, \u0218.C., and Buzoianu, A.D. (2023). The Effect of Vitamin D Supplementation on the Length of Hospitalisation, Intensive Care Unit Admission, and Mortality in COVID-19\u2014A Systematic Review and Meta-Analysis. Nutrients, 15.","DOI":"10.3390\/nu15153470"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/s41430-024-01520-x","article-title":"Effect of Cholecalciferol versus Calcifediol on Serum 25(OH)D Concentrations: A Systematic Review with Meta-Analysis","volume":"79","author":"Bouden","year":"2025","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Bl\u00e1zquez-Cabrera, J.A., Torres-Hern\u00e1ndez, J., Bouillon, R., Casado-D\u00edaz, A., Quesada-Gomez, J.M., and Navarro-Casado, L. (2025). ALBACOVIDIOL Study: Effect of Calcifediol Treatment on Mortality in Patients Hospitalized for COVID-19: A Retrospective Analysis. Nutrients, 17.","DOI":"10.3390\/nu17121968"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Annweiler, C., Beaudenon, M., Gautier, J., Gonsard, J., Boucher, S., Chapelet, G., Darsonval, A., Foug\u00e8re, B., Gu\u00e9rin, O., and Houvet, M. (2022). High-Dose versus Standard-Dose Vitamin D Supplementation in Older Adults with COVID-19 (COVIT-TRIAL): A Multicenter, Open-Label, Randomized Controlled Superiority Trial. PLoS Med., 19.","DOI":"10.1371\/journal.pmed.1003999"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1001\/jama.2014.13204","article-title":"Effect of High-Dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients With Vitamin D Deficiency","volume":"312","author":"Amrein","year":"2014","journal-title":"JAMA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"124","DOI":"10.2478\/sjph-2022-0017","article-title":"COVID-19 and Vitamin D\u2014A Systematic Review","volume":"61","author":"Jordan","year":"2022","journal-title":"Slov. J. Public Health"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Thacher, T.D. (2022). Evaluating the Evidence in Clinical Studies of Vitamin D in COVID-19. Nutrients, 14.","DOI":"10.3390\/nu14030464"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1080\/17446651.2022.2067143","article-title":"Discrepancies between Current Guidance from NICE on the Treatment of Vitamin D Deficiency and the Recommended Daily Amounts [RDAs] for Its Prevention in the UK","volume":"17","author":"Boucher","year":"2022","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.arcmed.2022.04.003","article-title":"Efficacy and Safety of Vitamin D Supplementation to Prevent COVID-19 in Frontline Healthcare Workers. A Randomized Clinical Trial","volume":"53","year":"2022","journal-title":"Arch. Med. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1136\/postgradmedj-2020-139065","article-title":"Short Term, High-Dose Vitamin D Supplementation for COVID-19 Disease: A Randomised, Placebo-Controlled, Study (SHADE Study)","volume":"98","author":"Rastogi","year":"2022","journal-title":"Postgrad. Med. J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/S2213-8587(21)00051-6","article-title":"Vitamin D supplementation to prevent acute respiratory infections: A systematic review and meta-analysis of aggregate data from randomised controlled trials","volume":"9","author":"Sluyter","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e071230","DOI":"10.1136\/bmj-2022-071230","article-title":"Effect of a Test-and-Treat Approach to Vitamin D Supplementation on Risk of All Cause Acute Respiratory Tract Infection and Covid-19: Phase 3 Randomised Controlled Trial (CORONAVIT)","volume":"378","author":"Jolliffe","year":"2022","journal-title":"BMJ"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S2213-8587(24)00348-6","article-title":"Vitamin D supplementation to prevent acute respiratory infections: Systematic review and meta-analysis of stratified aggregate data","volume":"13","author":"Sluyter","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_66","first-page":"1083","article-title":"Role of Vitamin D Receptor (Vdr) Gene Polymorphism","volume":"6","author":"Chauhan","year":"2017","journal-title":"World J. Pharm. Pharm. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/eji.200636043","article-title":"The Vitamin D Receptor Gene Fok I Polymorphism: Functional Impact on the Immune System","volume":"37","author":"Verlinden","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Tentolouris, N., Achilla, C., Anastasiou, I.A., Eleftheriadou, I., Tentolouris, A., Basoulis, D., Kosta, O., Lambropoulos, A., Yavropoulou, M.P., and Chatzikyriakidou, A. (2024). The Association of Vitamin D Receptor Polymorphisms with COVID-19 Severity. Nutrients, 16.","DOI":"10.3390\/nu16050727"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Alhammadin, G., Jarrar, Y., Madani, A., and Lee, S.-J. (2023). Exploring the Influence of VDR Genetic Variants TaqI, ApaI, and FokI on COVID-19 Severity and Long-COVID-19 Symptoms. J. Pers. Med., 13.","DOI":"10.3390\/jpm13121663"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1111\/cen.14664","article-title":"Effects of Vitamin D Receptor Gene Polymorphisms on the Prognosis of COVID-19","volume":"96","author":"Apaydin","year":"2022","journal-title":"Clin. Endocrinol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1086\/431366","article-title":"Polymorphisms within the C-Reactive Protein (CRP) Promoter Region Are Associated with Plasma CRP Levels","volume":"77","author":"Carlson","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.1373\/clinchem.2004.037531","article-title":"Genetic Predisposition of the Interleukin-6 Response to Inflammation: Implications for a Variety of Major Diseases?","volume":"50","author":"Bennermo","year":"2004","journal-title":"Clin. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Fetahu, I.S., H\u00f6baus, J., and K\u00e1llay, E. (2014). Vitamin D and the Epigenome. Front. Physiol., 5.","DOI":"10.3389\/fphys.2014.00164"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"209","DOI":"10.31146\/1682-8658-ecg-217-9-209-221","article-title":"Vitamin D and the Epigenome: Basic Definitions, Mechanisms and Clinical Effects","volume":"9","author":"Khavkin","year":"2024","journal-title":"Exp. Clin. Gastroenterol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Carlberg, C. (2019). Vitamin D Signaling in the Context of Innate Immunity: Focus on Human Monocytes. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02211"},{"key":"ref_76","first-page":"567","article-title":"Optimize Dietary Intake of Vitamin D: An Epigenetic Perspective","volume":"15","author":"Holick","year":"2012","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Walvekar, K.P., and Chilaka, S. (2025). H3K4me3 Is a Post-Transcriptional Histone Mark. bioRxiv.","DOI":"10.1101\/2025.07.03.662929"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.tig.2019.11.004","article-title":"The Bivalent Genome: Characterization, Structure, and Regulation","volume":"36","author":"Blanco","year":"2020","journal-title":"Trends Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.chom.2020.04.009","article-title":"Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure","volume":"27","author":"Netea","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/s41590-025-02137-3","article-title":"IL-10 Targets IRF Transcription Factors to Suppress IFN and Inflammatory Response Genes by Epigenetic Mechanisms","volume":"26","author":"Mishra","year":"2025","journal-title":"Nat. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1111\/bph.13792","article-title":"The Epigenetic Landscape Related to Reactive Oxygen Species Formation in the Cardiovascular System","volume":"174","author":"Kietzmann","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1097\/SHK.0000000000002131","article-title":"Altered Levels of H3K9AC, H3K4ME3, and H3K27ME3 in Promoters of Differentially Expressed Genes Related to Innate Immune Response in Septic Patients with Different Clinical Outcomes","volume":"59","author":"Leite","year":"2023","journal-title":"Shock"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"5345","DOI":"10.1038\/s41467-018-07771-0","article-title":"A Rapid and Robust Method for Single Cell Chromatin Accessibility Profiling","volume":"9","author":"Chen","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Leo, L., and Colonna Romano, N. (2021). Emerging Single-Cell Technological Approaches to Investigate Chromatin Dynamics and Centromere Regulation in Human Health and Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168809"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the Treatment of COVID-19: Final Report","volume":"383","author":"Beigel","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1056\/NEJMoa2031994","article-title":"Baricitinib plus Remdesivir for Hospitalised Adults with COVID-19","volume":"384","author":"Kalil","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1056\/NEJMoa2028836","article-title":"Efficacy of Tocilizumab in Patients Hospitalized with COVID-19","volume":"383","author":"Stone","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1056\/NEJMoa2030340","article-title":"Tocilizumab in Patients Hospitalized with COVID-19 Pneumonia","volume":"384","author":"Salama","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Sassi, F., Tamone, C., and D\u2019Amelio, P. (2018). Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients, 10.","DOI":"10.3390\/nu10111656"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"White, J.H. (2022). Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity. Nutrients, 14.","DOI":"10.3390\/nu14020284"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"19823","DOI":"10.1038\/s41598-022-21513-9","article-title":"Vitamin D Status and Severity of COVID-19","volume":"12","author":"Nielsen","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e4708","DOI":"10.1210\/clinem\/dgab439","article-title":"Vitamin D Deficiency Is Associated With Higher Hospitalization Risk From COVID-19: A Retrospective Case-Control Study","volume":"106","author":"Jude","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Grant, W., Wimalawansa, S., Pludowski, P., and Cheng, R. (2025). Vitamin D: Evidence-Based Health Benefits and Recommendations for Population Guidelines. Nutrients, 17.","DOI":"10.3390\/nu17020277"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Bouayed, M.Z., Laaribi, I., Chatar, C.E.M., Benaini, I., Bouazzaoui, M.A., Oujidi, Y., Berrichi, S., El Aidouni, G., Bkiyar, H., and Abda, N. (2022). C-Reactive Protein (CRP): A Poor Prognostic Biomarker in COVID-19. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1040024"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.jiph.2021.03.001","article-title":"Early Prediction Keys for COVID-19 Cases Progression: A Meta-Analysis","volume":"14","author":"Khodeir","year":"2021","journal-title":"J. Infect. Public Health"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1093\/ije\/dyab012","article-title":"The Role of C-Reactive Protein as a Prognostic Marker in COVID-19","volume":"50","author":"Stringer","year":"2021","journal-title":"Int. J. Epidemiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1177\/08850666231177200","article-title":"Biomarker-Concordant Steroid Administration in Severe Coronavirus Disease-2019","volume":"38","author":"Tekin","year":"2023","journal-title":"J. Intensive Care Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"142","DOI":"10.12788\/jhm.3560","article-title":"Early and Significant Reduction in C-Reactive Protein Levels After Corticosteroid Therapy Is Associated With Reduced Mortality in Patients With COVID-19","volume":"16","author":"Cui","year":"2021","journal-title":"J. Hosp. Med."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Karakike, E., and Giamarellos-Bourboulis, E.J. (2019). Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00055"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e983401","DOI":"10.4161\/19381980.2014.983401","article-title":"Vitamin D and Inflammation","volume":"6","author":"Cannell","year":"2014","journal-title":"Dermatoendocrinol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"9126148","DOI":"10.1155\/2020\/9126148","article-title":"Predicting Venous Thromboembolic Events in Patients with Coronavirus Disease 2019 Requiring Hospitalization: An Observational Retrospective Study by the COVIDIC Initiative in a Swiss University Hospital","volume":"2020","author":"Kampouri","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Ram\u00edrez Cervantes, K.L., Mora, E., Campillo Morales, S., Huerta \u00c1lvarez, C., Marcos Neira, P., Nanwani Nanwani, K.L., Serrano L\u00e1zaro, A., Silva Obreg\u00f3n, J.A., and Quintana D\u00edaz, M. (2023). A Clinical Prediction Rule for Thrombosis in Critically Ill COVID-19 Patients: Step 1 Results of the Thromcco Study. J. Clin. Med., 12.","DOI":"10.3390\/jcm12041253"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"440","DOI":"10.58806\/ijhmr.2024.v3i07n02","article-title":"Pathophysiology, The Biochemical And Clinical Significance of Lactate Dehydrogenase","volume":"3","author":"Barrak","year":"2024","journal-title":"Int. J. Health Med. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1093\/jalm\/jfac137","article-title":"LDH and the MELD-LDH in Severe Acute Liver Injury and Acute Liver Failure: Preliminary Confirmation of a Novel Prognostic Score for Risk Stratification","volume":"8","author":"Price","year":"2023","journal-title":"J. Appl. Lab. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1016\/j.ajem.2020.05.073","article-title":"Lactate Dehydrogenase Levels Predict Coronavirus Disease 2019 (COVID-19) Severity and Mortality: A Pooled Analysis","volume":"38","author":"Henry","year":"2020","journal-title":"Am. J. Emerg. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.7150\/ijms.47604","article-title":"Prognostic Value of Lactate Dehydrogenase for In-Hospital Mortality in Severe and Critically Ill Patients with COVID-19","volume":"17","author":"Dong","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e438","DOI":"10.1016\/S2352-3026(20)30145-9","article-title":"Coagulation Abnormalities and Thrombosis in Patients with COVID-19","volume":"7","author":"Levi","year":"2020","journal-title":"Lancet Haematol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1111\/jth.14929","article-title":"Scientific and Standardization Committee Communication: Clinical Guidance on the Diagnosis, Prevention, and Treatment of Venous Thromboembolism in Hospitalized Patients with COVID-19","volume":"18","author":"Spyropoulos","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref_109","unstructured":"ARDS Definition Task Force, Ranieri, V.M., Rubenfeld, G.D., Thompson, B.T., Ferguson, N.D., Caldwell, E., Fan, E., Camporota, L., and Slutsky, A.S. (2012). Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA, 307, 2526\u20132533."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Hosmer, D.W., Lemeshow, S., and Sturdivant, R.X. (2013). Applied Logistic Regression, John Wiley & Sons. [3rd ed.].","DOI":"10.1002\/9781118548387"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1177\/1536867X1301300407","article-title":"Little\u2019s Test of Missing Completely at Random","volume":"13","author":"Li","year":"2013","journal-title":"Stata J. Promot. Commun. Stat. Stata"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/1097-0142(1950)3:1<32::AID-CNCR2820030106>3.0.CO;2-3","article-title":"Index for Rating Diagnostic Tests","volume":"3","author":"Youden","year":"1950","journal-title":"Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1770\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T05:17:50Z","timestamp":1771046270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1770"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,12]]},"references-count":112,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041770"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041770","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,12]]}}}