{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T19:17:48Z","timestamp":1773343068022,"version":"3.50.1"},"reference-count":100,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:00:00Z","timestamp":1619395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Sepsis remains the leading cause of mortality in hospitalized patients, contributing to 1 in every 2\u20133 deaths. From a pathophysiological view, in the recent definition, sepsis has been defined as the result of a complex interaction between host response and the infecting organism, resulting in life-threatening organ dysfunction, depending on microcirculatory derangement, cellular hypoxia\/dysoxia driven by hypotension and, potentially, death. The high energy expenditure driven by a high metabolic state induced by the host response may rapidly lead to micronutrient depletion. This deficiency can result in alterations in normal energy homeostasis, free radical damage, and immune system derangement. In critically ill patients, micronutrients are still relegated to an ancillary role in the whole treatment, and always put in a second-line place or, frequently, neglected. Only some micronutrients have attracted the attention of a wider audience, and some trials, even large ones, have tested their use, with controversial results. The present review will address this topic, including the recent advancement in the study of vitamin D and protocols based on vitamin C and other micronutrients, to explore an update in the setting of sepsis, gain some new insights applicable to COVID-19 patients, and to contribute to a pathophysiological definition of the potential role of micronutrients that will be helpful in future dedicated trials.<\/jats:p>","DOI":"10.3390\/medicina57050419","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T22:21:57Z","timestamp":1619475717000},"page":"419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Micronutrients in Sepsis and COVID-19: A Narrative Review on What We Have Learned and What We Want to Know in Future Trials"],"prefix":"10.3390","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2473-6357","authenticated-orcid":false,"given":"Matteo","family":"Rossetti","sequence":"first","affiliation":[{"name":"Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8443-2414","authenticated-orcid":false,"given":"Gennaro","family":"Martucci","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90133 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4918-1749","authenticated-orcid":false,"given":"Christina","family":"Starchl","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbrugger Platz 15, 8036 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Amrein","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbrugger Platz 15, 8036 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jcrc.2004.10.005","article-title":"Epidemiology and economic evaluation of severe sepsis in France: Age, severity, infection site, and place of acquisition as determinants of workload and cost","volume":"20","author":"Adrie","year":"2005","journal-title":"J. Crit. Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.jcrc.2015.09.034","article-title":"Epidemiology of severe sepsis: 2008-2012","volume":"31","author":"Stoller","year":"2016","journal-title":"J. Crit. Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1097\/00003246-200107000-00002","article-title":"Epidemiology of severe sepsis in the Unites States: Analysis of incidence, outcome, and associated costs of care","volume":"29","author":"Angus","year":"2001","journal-title":"Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1097\/01.CCM.0000261890.41311.E9","article-title":"Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: A trend analysis from 1993 to 2003","volume":"35","author":"Dombrovskiy","year":"2007","journal-title":"Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"342","DOI":"10.15585\/mmwr.mm6513a2","article-title":"Varying estimates of sepsis mortality using death certificates and administrative codes\u2013Unites States, 1999\u20132014","volume":"65","author":"Epstein","year":"2016","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1017\/S0954422418000124","article-title":"A review of micronutrients in sepsis: The role of thiamine, l-carnitine, vitamin C, selenium and vitamin D","volume":"31","author":"Belsky","year":"2018","journal-title":"Nutr. Res. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1007\/s00134-017-4846-5","article-title":"The effect of high-dose cholecalciferol on bioavailable vitamin D levels in critically ill patients: A post hoc analysis of the VITdAL-ICU trial","volume":"43","author":"Martucci","year":"2017","journal-title":"Intensive Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1164\/ajrccm.164.8.2102098","article-title":"A global approach to energy metabolism in an experimental model of sepsis","volume":"164","author":"Sebert","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1007\/s00134-018-5107-y","article-title":"Vitamin therapy in critically ill patients: Focus on thiamine, vitamin C, and vitamin D","volume":"44","author":"Amrein","year":"2018","journal-title":"Intensive Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.3390\/nu5072502","article-title":"Vitamin D and immune function","volume":"5","author":"Prietl","year":"2013","journal-title":"Nutrients"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1016\/j.clnu.2020.10.027","article-title":"Vitamin D levels in liver transplantation recipients and early postoperative outcomes: Prospective observational DLiverX study","volume":"40","author":"Martucci","year":"2020","journal-title":"Clin. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1016\/j.jcot.2019.07.004","article-title":"Vitamin D for skeletal and non-skeletal health: What we should know","volume":"10","author":"Charoenngam","year":"2019","journal-title":"J. Clin. Orthop. Trauma"},{"key":"ref_13","first-page":"S57","article-title":"The vitamin D hormone and its nuclear receptor: Molecular actions and disease states","volume":"154","author":"Haussler","year":"1997","journal-title":"J. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1038\/s41430-020-0558-y","article-title":"Vitamin D deficiency 2.0: An update on the current status worldwide","volume":"74","author":"Amrein","year":"2020","journal-title":"Eur J Clin Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1210\/jc.2011-0385","article-title":"Evaluation, treatment, and prevention ofvitamin D deficiency: An Endocrine Society clinical practice guideline","volume":"96","author":"Holick","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1465-9921-12-31","article-title":"The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer","volume":"12","author":"Herr","year":"2011","journal-title":"Respir. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/BF01986584","article-title":"Protective effect of vitamin D3 analogues on endotoxin shock in mice","volume":"33","author":"Horiuchi","year":"1991","journal-title":"Agents Actions"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S0140-6736(79)91076-6","article-title":"1, 25-dihydroxycholecalciferol in the pathogenesis of the hypercalcaemia of sarcoidosis","volume":"1","author":"Papapoulos","year":"1979","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/978-3-540-71029-5_12","article-title":"Induction of tolerogenic dendritic cells by vitamin D receptor agonists","volume":"188","author":"Adorini","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_20","first-page":"387","article-title":"Ligation of TLR9 induced on human IL-10-secreting Tregs by 1alpha,25-dihydroxyvitamin D3 abrogates regulatory function","volume":"119","author":"Urry","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1210\/me.2013-1252","article-title":"Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice","volume":"28","author":"Andrukhova","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1186\/s13054-020-02925-3","article-title":"COVID-19 and ECMO: The interplay between coagulation and inflammation-a narrative review","volume":"24","author":"Kowalewski","year":"2020","journal-title":"Crit Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1159\/000330075","article-title":"1\u03b1,25-Dihydroxycholecalciferol Induces Nitric Oxide Production in Cultured Endothelial Cells","volume":"27","author":"Molinari","year":"2011","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1007\/s00383-019-04586-y","article-title":"Protective effects of vitamin D against injury in intestinal epithelium","volume":"35","author":"Lee","year":"2019","journal-title":"Pediatr. Surg. Int."},{"key":"ref_25","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_26","first-page":"965","article-title":"Current status in vitamin D and regulatory T cells-immunological implications","volume":"117","author":"Mocanu","year":"2013","journal-title":"Med. Surg. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7708","DOI":"10.1038\/s41598-018-26064-6","article-title":"Vitamin D levels correlate with lymphocyte subsets in elderly patients with age-related diseases","volume":"8","author":"Mao","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"315","DOI":"10.3851\/IMP3199","article-title":"Vitamin D supplementation decreases immune activation and exhaustion in HIV-1-infected youth","volume":"23","author":"Eckard","year":"2018","journal-title":"Antivir. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1097\/INF.0000000000000483","article-title":"High-dose vitamin D3 supplementation in children and young adults with HIV: A randomized, placebo-controlled trial","volume":"34","author":"Stallings","year":"2015","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1097\/CCM.0b013e31829eb7af","article-title":"Association of low serum 25-hydroxyvitamin D levels and sepsis in the critically ill","volume":"42","author":"Moromizato","year":"2014","journal-title":"Crit Care Med."},{"key":"ref_31","first-page":"1704S","article-title":"Immunosuppressive actions of 1,25-dihydroxyvitamin D3: Preferential inhibition of Th1 functions","volume":"125","author":"Lemire","year":"1995","journal-title":"J. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4974","DOI":"10.4049\/jimmunol.167.9.4974","article-title":"1\u03b1,25-Dihydroxyvitamin D3 Has a Direct Effect on Naive CD4+ T Cells to Enhance the Development of Th2 Cells","volume":"167","author":"Boonstra","year":"2001","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4624","DOI":"10.4049\/jimmunol.0801543","article-title":"Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response","volume":"182","author":"Tang","year":"2009","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"R\u00fcbsamen, D., Kunze, M.M., Buderus, V., Brau\u00df, T.F., Bajer, M.M., Br\u00fcne, B., and Schmid, T. (2014). Inflammatory conditions induce IRES-dependent translation of cyp24a1. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085314"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"220","DOI":"10.4161\/derm.3.4.15027","article-title":"Antimicrobial implications of vitamin D","volume":"3","author":"Youssef","year":"2011","journal-title":"Dermato-endocrinology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1093\/infdis\/jiq008","article-title":"1,25-dihydroxyvitamin D3 modulates cytokine production induced by Candida albicans: Impact of seasonal variation of immune responses","volume":"203","author":"Khoo","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1001\/archinternmed.2008.560","article-title":"Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey","volume":"169","author":"Ginde","year":"2009","journal-title":"Arch. Intern. Med."},{"key":"ref_38","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_39","doi-asserted-by":"crossref","first-page":"R47","DOI":"10.1186\/cc13790","article-title":"Vitamin D status and its association with season, hospital and sepsis mortality in critical illness","volume":"18","author":"Amrein","year":"2014","journal-title":"Crit. Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1007\/s00134-010-1875-8","article-title":"Incidence and risk factors of vitamin D deficiency in critically ill patients: Results from a prospective observational study","volume":"36","author":"Lucidarme","year":"2010","journal-title":"Intensive Care Med"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"R292","DOI":"10.1186\/cc10585","article-title":"Vitamin D deficiency is associated with mortality in the medical intensive care unit","volume":"15","author":"Venkatram","year":"2011","journal-title":"Crit Care"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/1479-5876-7-28","article-title":"Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis","volume":"7","author":"Jeng","year":"2009","journal-title":"J. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1016\/S0021-9258(17)34915-3","article-title":"Carnitine biosynthesis: \u03b2 hydroxylation of trimethyllysine by an \u03b1-keto glutarate dependent mitochondrial dioxygenase","volume":"253","author":"Hulse","year":"1978","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.freeradbiomed.2008.12.018","article-title":"Vitamin C function in the brain: Vital role of the ascorbate transporter (SVCT2)","volume":"46","author":"Harrison","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1111\/j.1476-5381.2009.00282.x","article-title":"Vitamin C: Update on physiology and pharmacology","volume":"157","author":"Mandl","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Carr, A., and Maggini, S. (2017). Vitamin C and immune function. Nutrients, 9.","DOI":"10.3390\/nu9111211"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies (2013). Scientific opinion on dietary reference values for vitamin C. EFSA J., 11, 3418.","DOI":"10.2903\/j.efsa.2013.3418"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1097\/CCM.0b013e3182120cb8","article-title":"Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury","volume":"39","author":"Fisher","year":"2011","journal-title":"Crit Care Med"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/micc.12047","article-title":"Ascorbate reduces mouse platelet aggregation and surface P-selectin expression in an ex vivo model of sepsis","volume":"20","author":"Secor","year":"2013","journal-title":"Microcirculation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13054-015-1131-2","article-title":"Ascorbate-dependent vasopressor synthesis: A rationale for vitamin C administration in severe sepsis and septic shock?","volume":"19","author":"Carr","year":"2015","journal-title":"Crit. Care"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1159\/000080525","article-title":"Functional expression of sodium-dependent vitamin C transporter 2 in human endothelial cells","volume":"41","author":"Seno","year":"2004","journal-title":"J. Vasc. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4103\/2279-042X.179569","article-title":"Effect of high-dose ascorbic acid on vasopressor requirement in septic shock","volume":"5","author":"Khalili","year":"2016","journal-title":"J. Res. Pharm. Pract."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1479-5876-12-32","article-title":"Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis","volume":"12","author":"Fowler","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2050312118807615","DOI":"10.1177\/2050312118807615","article-title":"Vitamin C supplementation in the critically ill: A systematic review and meta-analysis","volume":"6","author":"Zhang","year":"2018","journal-title":"SAGE Open Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1001\/jama.2019.11825","article-title":"Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients with Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial","volume":"322","author":"Fowler","year":"2019","journal-title":"JAMA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1097\/MCO.0b013e32834b8911","article-title":"Thiamine supplementation in the critically ill","volume":"14","author":"Manzanares","year":"2011","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1093\/ajcn\/23.6.764","article-title":"Thiamin metabolism in man","volume":"23","author":"Balaghi","year":"1970","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/chf.12037","article-title":"Thiamine supplementation for the treatment of heart failure: A review of the literature","volume":"19","author":"DiNicolantonio","year":"2013","journal-title":"Congest Heart Fail"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.jcrc.2010.03.003","article-title":"Thiamine deficiency in critically ill patients with sepsis","volume":"25","author":"Donnino","year":"2010","journal-title":"J. Crit. Care"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.jcrc.2013.12.004","article-title":"Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock","volume":"29","author":"Costa","year":"2014","journal-title":"J. Crit. Care"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1097\/00003246-199504000-00011","article-title":"Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction","volume":"23","author":"Goode","year":"1995","journal-title":"Crit. Care Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1476-9255-11-11","article-title":"The effect of thiamine deficiency on inflammation, oxidative stress and cellular migration in an experimental model of sepsis","volume":"11","author":"Gayer","year":"2014","journal-title":"J. Inflamm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1097\/CCM.0000000000001572","article-title":"Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: A pilot study","volume":"44","author":"Donnino","year":"2016","journal-title":"Crit. Care Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1513\/AnnalsATS.201608-656BC","article-title":"Thiamine as a renal protective agent in septic shock: A secondary analysis of a randomized, double-blind, placebo-controlled trial","volume":"14","author":"Moskowitz","year":"2017","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.chest.2016.11.036","article-title":"Hydrocortisone, vitamin C and thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study","volume":"151","author":"Marik","year":"2016","journal-title":"Chest"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1080\/07315724.2005.10719495","article-title":"Chronic zinc deficiency in mice disrupted T cell lymphopoiesis and erythropoiesis while B cell lymphopoiesis and myelopoiesis were maintained","volume":"24","author":"King","year":"2005","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_67","first-page":"396","article-title":"Induction of differentiation in human marrow T cell precursors by the synthetic serum thymic factor, FTS","volume":"40","author":"Incefy","year":"1980","journal-title":"Clin. Exp. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.1086\/315916","article-title":"Effects of zinc deficiency on Th1 and Th2 cytokine shifts","volume":"182","author":"Prasad","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6491","DOI":"10.4049\/jimmunol.181.9.6491","article-title":"Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes","volume":"181","author":"Haase","year":"2008","journal-title":"J. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/ni1373","article-title":"Toll-like receptor\u2013mediated regulation of zinc homeostasis influences dendritic cell function","volume":"7","author":"Kitamura","year":"2006","journal-title":"Nat. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1002\/eji.200939574","article-title":"Zinc signals promote IL-2-dependent proliferation of T cells","volume":"40","author":"Kaltenberg","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"E952","DOI":"10.1152\/ajpendo.1997.272.6.E952","article-title":"Effects of endotoxin on zinc metabolism in human volunteers","volume":"272","author":"Gaetke","year":"1997","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.3945\/ajcn.110.008417","article-title":"A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission123","volume":"93","author":"Besecker","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1093\/jn\/123.4.642","article-title":"Metallothionein expression in rat bone marrow is dependent on dietary zinc but not dependent on interleukin-1 or interleukin-6","volume":"123","author":"Huber","year":"1993","journal-title":"J. Nutr."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Aydemir, T.B., Chang, S.M., Guthrie, G.J., Maki, A.B., Ryu, M.S., Karabiyik, A., and Cousins, R.J. (2012). Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048679"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"G768","DOI":"10.1152\/ajpgi.00179.2015","article-title":"Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation","volume":"309","author":"Wessels","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/S0002-9440(10)63713-3","article-title":"Abrogation of nuclear factor-\u03baB activation is involved in zinc inhibition of lipopolysaccharide-induced tumor necrosis factor-\u03b1 production and liver injury","volume":"164","author":"Zhou","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1146\/annurev.nutr.24.012003.132454","article-title":"Reprogramming of the immune system during zinc deficiency","volume":"24","author":"Fraker","year":"2004","journal-title":"Annu. Rev. Nutr."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3945\/ajcn.2008.27300","article-title":"Dietary zinc restriction and repletion affects DNA integrity in healthy men","volume":"90","author":"Song","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jcrc.2010.06.002","article-title":"Prognostic value of serum zinc levels in critically ill patients","volume":"26","author":"Cander","year":"2011","journal-title":"J. Crit. Care"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Hoeger, J., Simon, T.-P., Beeker, T., Marx, G., Haase, H., and Schuerholz, T. (2017). Persistent low serum zinc is associated with recurrent sepsis in critically ill patients\u2014A pilot study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176069"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1136\/jcp.37.9.1050","article-title":"Albumin bound and alpha 2-macroglobulin bound zinc concentrations in the sera of healthy adults","volume":"37","author":"Foote","year":"1984","journal-title":"J. Clin. Pathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0014-5793(89)80476-4","article-title":"Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes","volume":"242","author":"Castell","year":"1989","journal-title":"FEBS Lett."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1001\/jama.2020.12839","article-title":"Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review","volume":"324","author":"Wiersinga","year":"2020","journal-title":"JAMA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathologicalfindings of COVID-19 associated with acute respiratory distress syndrome","volume":"8","author":"Xu","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"m1985","DOI":"10.1136\/bmj.m1985","article-title":"ISARIC4C investigators. Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: Prospective observational cohortstudy","volume":"369","author":"Docherty","year":"2020","journal-title":"BMJ"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1146\/annurev-pathol-011110-130158","article-title":"The acute respiratory distress syndrome: Pathogenesis and treatment","volume":"6","author":"Matthay","year":"2011","journal-title":"Annu. Rev. Pathol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"101295","DOI":"10.1016\/j.redox.2019.101295","article-title":"Vitamin Dreceptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: Role of renin-angiotensin system","volume":"26","author":"Cui","year":"2019","journal-title":"Redox Biol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Murai, I.H., Fernandes, A.L., Sales, L.P., Pinto, A.J., Goessler, K.F., Duran, C.S.C., Silva, C.B.R., Franco, A.S., Macedo, M.B., and Dalmolin, H.H.H. Effect of a single dose of vitamin D on hospital length of stay in patients with moderate to severe COVID-19. JAMA, 2021. Online ahead of print.","DOI":"10.1001\/jama.2020.26848"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1001\/jama.2020.24127","article-title":"Sorting out whether vitamin D deficiency raises COVID-19 risk","volume":"325","author":"Rubin","year":"2021","journal-title":"JAMA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e031083","DOI":"10.1136\/bmjopen-2019-031083","article-title":"Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: A study protocol of a multicentre, placebo-controlled double-blind phase III RCT (the VITDALIZE study)","volume":"9","author":"Amrein","year":"2019","journal-title":"BMJ Open"},{"key":"ref_92","first-page":"541","article-title":"Antiviral effects of ascorbic and dehydroascorbic acids in vitro","volume":"22","author":"Furuya","year":"1998","journal-title":"Int J Mol Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1097\/AJP.0b013e318193cf32","article-title":"Plasma vitamin C is lower in postherpetic neuralgia patients and administration of vitamin C reduces spontaneous pain but not brush-evoked pain","volume":"25","author":"Chen","year":"2009","journal-title":"Clin. J. Pain"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Hemil\u00e4, H., and Chalker, E. (2013). Vitamin C for preventing and treating the common cold. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD006665.pub3"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/0306-9877(84)90149-X","article-title":"Vitamin C in the treatment of acquired immune deficiency syndrome (AIDS)","volume":"14","author":"Cathcart","year":"1984","journal-title":"Med. Hypotheses"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1111\/jphp.12529","article-title":"Red ginseng and vitamin C increase immune cell activity and decrease lung inflammation induced by influenza A virus\/H1N1 infection","volume":"68","author":"Kim","year":"2016","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Colunga Biancatelli, R., Berrill, M., Catravas, J., and Marik, P. (2020). Quercetin and vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front. Immunol.","DOI":"10.3389\/fimmu.2020.01451"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Pons, S., Fodil, S., Azoulay, E., and Zafrani, L. (2020). The vascular endothe- lium: The cornerstone of organ dysfunction in severe SARS- CoV-2 infection. Crit. Care.","DOI":"10.1186\/s13054-020-03062-7"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13613-020-00792-3","article-title":"Pilot trial of high-dose vitamin C in critically ill COVID-19 patients","volume":"11","author":"Zhang","year":"2021","journal-title":"Ann. Intensive Care"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"R133","DOI":"10.1530\/EJE-20-0665","article-title":"Mechanisms in endocrinology: Vitamin D and COVID-19","volume":"183","author":"Bilezikian","year":"2020","journal-title":"Eur. J. Endocrinol."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/57\/5\/419\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:52:46Z","timestamp":1760161966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/57\/5\/419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,26]]},"references-count":100,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["medicina57050419"],"URL":"https:\/\/doi.org\/10.3390\/medicina57050419","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,26]]}}}