{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:33:15Z","timestamp":1790947995618,"version":"4.1.0"},"reference-count":119,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T00:00:00Z","timestamp":1607299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>There are limited proven therapies for COVID-19. Vitamin C\u2019s antioxidant, anti-inflammatory and immunomodulating effects make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19. This literature review focuses on vitamin C deficiency in respiratory infections, including COVID-19, and the mechanisms of action in infectious disease, including support of the stress response, its role in preventing and treating colds and pneumonia, and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2\u20138 g\/day) may reduce the incidence and duration of respiratory infections and intravenous vitamin C (6\u201324 g\/day) has been shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical ventilation for severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in respiratory infections, it may be worthwhile testing patients\u2019 vitamin C status and treating them accordingly with intravenous administration within ICUs and oral administration in hospitalised persons with COVID-19.<\/jats:p>","DOI":"10.3390\/nu12123760","type":"journal-article","created":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T12:24:39Z","timestamp":1607343879000},"page":"3760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":129,"title":["Vitamin C\u2014An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19"],"prefix":"10.3390","volume":"12","author":[{"given":"Patrick","family":"Holford","sequence":"first","affiliation":[{"name":"Institute for Optimum Nutrition, Ambassador House, Richmond TW9 1SQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5890-2977","authenticated-orcid":false,"given":"Anitra C.","family":"Carr","sequence":"additional","affiliation":[{"name":"Nutrition in Medicine Research Group, Department of Pathology &amp; Biomedical Science, University of Otago, Christchurch 8140, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Jovic","sequence":"additional","affiliation":[{"name":"Reconstructive Surgery &amp; Regenerative Medicine Research Group, Institute of Life Sciences, Swansea University Medical School, Swansea University, Swansea SA2 8PY, UK"},{"name":"Welsh Centre for Burns &amp; Plastic Surgery, Morriston Hospital, Swansea SA6 6NL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R.","family":"Ali","sequence":"additional","affiliation":[{"name":"Reconstructive Surgery &amp; Regenerative Medicine Research Group, Institute of Life Sciences, Swansea University Medical School, Swansea University, Swansea SA2 8PY, UK"},{"name":"Welsh Centre for Burns &amp; Plastic Surgery, Morriston Hospital, Swansea SA6 6NL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain S.","family":"Whitaker","sequence":"additional","affiliation":[{"name":"Reconstructive Surgery &amp; Regenerative Medicine Research Group, Institute of Life Sciences, Swansea University Medical School, Swansea University, Swansea SA2 8PY, UK"},{"name":"Welsh Centre for Burns &amp; Plastic Surgery, Morriston Hospital, Swansea SA6 6NL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E.","family":"Marik","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA 23507, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. David","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"371","DOI":"10.2174\/138920211796429736","article-title":"The genetics of vitamin C loss in vertebrates","volume":"12","author":"Drouin","year":"2011","journal-title":"Curr. Genomics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S1095-6433(03)00084-9","article-title":"Micronutrient intakes of wild primates: Are humans different?","volume":"136","author":"Milton","year":"2003","journal-title":"Comp. Biochem. Physiol. A Mol. Integr. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/S0899-9007(99)00078-7","article-title":"Nutritional characteristics of wild primate foods: Do the diets of our closest living relatives have lessons for us?","volume":"15","author":"Milton","year":"1999","journal-title":"Nutrition"},{"key":"ref_4","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_5","unstructured":"Bates, B., Collins, D., Cox, L., Nicholson, S., Page, P., Roberts, C., Steer, T., and Swan, G. (2019). National Diet and Nutrition Survey Years 1 to 9 of the Rolling Programme (2008\/2009\u20132016\/2017): Time Trend and Income Analyses, Public Health England."},{"key":"ref_6","unstructured":"Berger, M.M., Bischoff-Ferrari, H.A., Zimmermann, M., Herter, I., Spieldenner, J., and Eggersdorfer, M. (2020). White Paper on Nutritional Status in Supporting a Well-Functioning Immune System for Optimal Health with a Recommendation for Switzerland, SGE."},{"key":"ref_7","unstructured":"Linus Pauling Institute, and Micronutrient Information Center (2020, October 20). Micronutrients for Older Adults Oregon State University, Available online: https:\/\/lpi.oregonstate.edu\/mic\/life-stages\/older-adults."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1073\/pnas.93.8.3704","article-title":"Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance","volume":"93","author":"Levine","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9842","DOI":"10.1073\/pnas.171318198","article-title":"A new recommended dietary allowance of vitamin C for healthy young women","volume":"98","author":"Levine","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"533","DOI":"10.7326\/0003-4819-140-7-200404060-00010","article-title":"Vitamin C pharmacokinetics: Implications for oral and intravenous use","volume":"140","author":"Padayatty","year":"2004","journal-title":"Ann. Intern. Med."},{"key":"ref_11","first-page":"1368","article-title":"Vitamin-C pharmacokinetics in critically ill patients: A randomized trial of four intravenous regimens","volume":"153","author":"Zandvliet","year":"2018","journal-title":"Chest"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/003693307301800102","article-title":"Changes in leucocyte ascorbic acid during the common cold","volume":"18","author":"Hume","year":"1973","journal-title":"Scott. Med. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.nut.2009.08.015","article-title":"Metabolic origin of hypovitaminosis C in acutely hospitalized patients","volume":"26","author":"Eintracht","year":"2010","journal-title":"Nutrition"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/S0002-9343(01)00893-2","article-title":"Vitamin C deficiency in elderly hospitalized patients","volume":"111","author":"Teixeira","year":"2001","journal-title":"Am. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.ejim.2003.08.006","article-title":"Hypovitaminosis C in hospitalized patients","volume":"14","author":"Fain","year":"2003","journal-title":"Eur. J. Intern. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1080\/07315724.2008.10719721","article-title":"Vitamin C deficiency in a university teaching hospital","volume":"27","author":"Gan","year":"2008","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.pathol.2018.07.004","article-title":"Vitamin C deficiency in an Australian cohort of metropolitan surgical patients","volume":"50","author":"Ravindran","year":"2018","journal-title":"Pathology"},{"key":"ref_18","first-page":"212","article-title":"The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections","volume":"64","author":"Hunt","year":"1994","journal-title":"Int. J. Vitam. Nutr. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1017\/S0007114599001063","article-title":"Micronutrients: Highlights and research challenges from the 1994-5 National Diet and Nutrition Survey of people aged 65 years and over","volume":"82","author":"Bates","year":"1999","journal-title":"Br. J. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1177\/014107680710001109","article-title":"Vitamin C may affect lung infections","volume":"100","author":"Louhiala","year":"2007","journal-title":"J. R. Soc. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1038\/s41430-019-0393-1","article-title":"Plasma vitamin C concentrations and risk of incident respiratory diseases and mortality in the European Prospective Investigation into Cancer-Norfolk population-based cohort study","volume":"73","author":"Myint","year":"2019","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hemil\u00e4, H., and Louhiala, P. (2013). Vitamin C for preventing and treating pneumonia. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD006665.pub3"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e000724","DOI":"10.1136\/bmjresp-2020-000724","article-title":"SARS-CoV-2 organising pneumonia: \u2018Has there been a widespread failure to identify and treat this prevalent condition in COVID-19?\u2019","volume":"7","author":"Kory","year":"2020","journal-title":"BMJ Open Respir. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Carr, A.C., Spencer, E., Dixon, L., and Chambers, S.T. (2020). Patients with community acquired pneumonia exhibit depleted vitamin C status and elevated oxidative stress. Nutrients, 12.","DOI":"10.20944\/preprints202004.0243.v1"},{"key":"ref_25","first-page":"263","article-title":"Ascorbic acid in blood serum of patients with pulmonary tuberculosis and pneumonia","volume":"8","author":"Bakaev","year":"2004","journal-title":"Int. J. Tuberc. Lung. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"581","DOI":"10.3181\/00379727-88-21659","article-title":"Dehydroascorbic acid level in blood of patients suffering from various infectious diseases","volume":"88","author":"Chakrabarti","year":"1955","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_27","first-page":"17","article-title":"Ascorbic acid in the complex therapy of acute pneumonia","volume":"9","author":"Mochalkin","year":"1970","journal-title":"Voen. Med. Zhurnal"},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1186\/s13054-017-1891-y","article-title":"Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes","volume":"21","author":"Carr","year":"2017","journal-title":"Crit. Care"},{"key":"ref_30","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_31","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1111\/j.1472-8206.2008.00573.x","article-title":"Plasma antioxidant status in septic critically ill patients: A decrease over time","volume":"22","author":"Doise","year":"2008","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1080\/10715760290032557","article-title":"Decreased plasma and cerebrospinal fluid ascorbate levels in patients with septic encephalopathy","volume":"36","author":"Voigt","year":"2002","journal-title":"Free Radic. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1093\/ajcn\/63.5.760","article-title":"Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients","volume":"63","author":"Schorah","year":"1996","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Arvinte, C., Singh, M., and Marik, P.E. (2020). Serum levels of vitamin C and vitamin D in a cohort of critically ill COVID-19 patients of a north American community hospital intensive care unit in May 2020: A pilot study. Med. Drug Discov.","DOI":"10.1016\/j.medidd.2020.100064"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1186\/s13054-020-03249-y","article-title":"Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome","volume":"24","author":"Roca","year":"2020","journal-title":"Crit. Care"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chen, Q., and Vissers, M. (2020). Vitamin C in pneumonia and sepsis. Vitamin C: New Biochemical and Functional Insights, CRC Press\/Taylor & Francis.","DOI":"10.1201\/9780429442025"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13054-018-1950-z","article-title":"Doctor-your septic patients have scurvy!","volume":"22","author":"Marik","year":"2018","journal-title":"Crit. Care"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.21037\/jtd.2019.12.64","article-title":"Vitamin C: An essential \u201cstress hormone\u201d during sepsis","volume":"12","author":"Marik","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.pharmthera.2018.04.007","article-title":"Vitamin C for the treatment of sepsis: The scientific rationale","volume":"189","author":"Marik","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1080\/14787210.2020.1706483","article-title":"The antiviral properties of vitamin C","volume":"18","author":"Berrill","year":"2020","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_41","first-page":"370","article-title":"Vitamin C and immunity: An assessment of the evidence","volume":"32","author":"Thomas","year":"1978","journal-title":"Clin. Exp. Immunol."},{"key":"ref_42","first-page":"280","article-title":"The effect of ascorbic acid on production of human interferon and the antiviral activity in vitro","volume":"84","author":"Dahl","year":"1976","journal-title":"Acta Pathol. Microbiol. Scand. B"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/j.1753-4887.2007.tb00298.x","article-title":"Update: Effects of antioxidant and non-antioxidant vitamin supplementation on immune function","volume":"65","author":"Webb","year":"2007","journal-title":"Nutr. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Paoletti, R., Sies, H., Bug, J., Grossi, E., and Poli, A. (1998). Vitamin C and infectious diseases. Vitamin C, Springer.","DOI":"10.1007\/978-88-470-2244-7"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Carr, A.C., and Maggini, S. (2017). Vitamin C and immune function. Nutrients, 9.","DOI":"10.3390\/nu9111211"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13816","DOI":"10.1073\/pnas.94.25.13816","article-title":"Ascorbate recycling in human neutrophils: Induction by bacteria","volume":"94","author":"Wang","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10128","DOI":"10.1074\/jbc.M210686200","article-title":"Recycling of vitamin C by a bystander effect","volume":"278","author":"Nualart","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/biof.134","article-title":"Ascorbic acid prevents oxidant-induced increases in endothelial permeability","volume":"37","author":"May","year":"2011","journal-title":"Biofactors"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1089\/ars.2013.5205","article-title":"Role of vitamin C in the function of the vascular endothelium","volume":"19","author":"May","year":"2013","journal-title":"Antioxid. Redox Signal"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1096\/fasebj.10.7.8635688","article-title":"Antioxidant and redox regulation of gene transcription","volume":"10","author":"Sen","year":"1996","journal-title":"FASEB J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"426740","DOI":"10.1155\/2014\/426740","article-title":"Vitamin C mitigates oxidative stress and tumor necrosis factor-alpha in severe community-acquired pneumonia and LPS-induced macrophages","volume":"2014","author":"Chen","year":"2014","journal-title":"Mediators Inflamm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1007\/s10753-019-01020-2","article-title":"The protection potential of antioxidant vitamins against acute respiratory distress syndrome: A rat trial","volume":"42","author":"Erol","year":"2019","journal-title":"Inflammation"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.cell.2020.04.026","article-title":"Imbalanced host response to SARS-CoV-2 drives development of COVID-19","volume":"181","author":"Liu","year":"2020","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"70","DOI":"10.4110\/in.2013.13.2.70","article-title":"Vitamin C is an essential factor on the anti-viral immune responses through the production of interferon-a\/b at the initial stage of influenza A virus (H3N2) infection","volume":"13","author":"Kim","year":"2013","journal-title":"Immune Netw."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Hemil\u00e4, H. (2017). Vitamin C and infections. Nutrients, 9.","DOI":"10.3390\/nu9040339"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/BF01317848","article-title":"The effect of ascorbic acid on infection chick-embryo ciliated tracheal organ cultures by coronavirus","volume":"56","author":"Atherton","year":"1978","journal-title":"Arch. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1080\/03079459208418879","article-title":"Ascorbic acid and infectious bronchitis infections in broilers","volume":"21","author":"Davelaar","year":"1992","journal-title":"Avian Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"110024","DOI":"10.1016\/j.mehy.2020.110024","article-title":"COVID-19 as a viral functional ACE2 deficiency disorder with ACE2 related multi-organ disease","volume":"144","author":"Gan","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ni, W., Yang, X., Yang, D., Bao, J., Li, R., Xiao, Y., Hou, C., Wang, H., Liu, J., and Yang, D. (2020). Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit. Care, 24.","DOI":"10.1186\/s13054-020-03120-0"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Ma, S., Sun, S., Li, J., Fan, Y., Qu, J., Sun, L., Wang, S., Zhang, Y., Yang, S., and Liu, Z. (2020). Single-cell transcriptomic atlas of primate cardiopulmonary aging. Cell Res.","DOI":"10.1038\/s41422-020-00412-6"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kumar, V., and Jena, M. (2020). In silico virtual screening-based study of nutraceuticals predicts the therapeutic potentials of folic acid and its derivatives against COVID-19. Res. Square.","DOI":"10.21203\/rs.3.rs-31775\/v1"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.it.2012.09.004","article-title":"The inflammatory response in sepsis","volume":"34","author":"Bosmann","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2119\/molmed.2010.00138","article-title":"Contribution of neutrophils to acute lung injury","volume":"17","author":"Grommes","year":"2011","journal-title":"Mol. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1126\/science.1092385","article-title":"Neutrophil extracellular traps kill bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.3390\/nu5083131","article-title":"Vitamin C: A novel regulator of neutrophil extracellular trap formation","volume":"5","author":"Mohammed","year":"2013","journal-title":"Nutrients"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"L20","DOI":"10.1152\/ajplung.00300.2011","article-title":"Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid","volume":"303","author":"Fisher","year":"2012","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1749-6632.1975.tb29271.x","article-title":"Distribution of ascorbic acid, metabolites and analogues in man and animals","volume":"258","author":"Hornig","year":"1975","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/ajcn\/86.1.145","article-title":"Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone","volume":"86","author":"Padayatty","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_69","first-page":"1079","article-title":"Vitamin C infusion treatment enhances cortisol production of the adrenal via the pituitary ACTH route","volume":"8","author":"Kodama","year":"1994","journal-title":"In Vivo"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.chest.2017.07.014","article-title":"Hydrocortisone and ascorbic acid synergistically prevent and repair lipopolysaccharide-induced pulmonary endothelial barrier dysfunction","volume":"152","author":"Barabutis","year":"2017","journal-title":"Chest"},{"key":"ref_71","unstructured":"Recovery Collaborative Group, Horby, P., Lim, W.S., Emberson, J.R., Mafham, M., Bell, J.L., Linsell, L., Staplin, N., Brightling, C., and Ustianowski, A. (2020). Dexamethasone in hospitalized patients with Covid-19-preliminary report. N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1073\/pnas.68.11.2678","article-title":"The significance of the evidence about ascorbic acid and the common cold","volume":"68","author":"Pauling","year":"1971","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Pauling, L. (1970). Vitamin C the Common Cold and Flu, Freeman.","DOI":"10.1001\/jama.1971.03180280086025"},{"key":"ref_74","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_75","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/BF02850271","article-title":"Preventing the common cold with a vitamin C supplement: A double-blind, placebo-controlled survey","volume":"19","author":"Josling","year":"2002","journal-title":"Adv. Ther."},{"key":"ref_76","first-page":"101","article-title":"Massive doses of vitamin C and the virus diseases","volume":"113","author":"Klenner","year":"1951","journal-title":"South Med. Surg."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1001\/jama.1979.03290350028016","article-title":"Vitamin C prophylaxis in marine recruits","volume":"241","author":"Pitt","year":"1979","journal-title":"JAMA"},{"key":"ref_78","first-page":"2413","article-title":"Colored precipitation reaction of the urine according to Kimbarowski (FARK) as an index of the effect of ascorbic acid during treatment of viral influenza","volume":"22","author":"Kimbarowski","year":"1967","journal-title":"Dtsch Gesundheitsw."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S0022172400012596","article-title":"The administration of vitamin C in a large institution and its effect on general health and resistance to infection","volume":"42","author":"Glazebrook","year":"1942","journal-title":"J. Hyg."},{"key":"ref_80","first-page":"77","article-title":"Early adjuvant intravenous vitamin C treatment in septic shock may resolve the vasopressor dependence","volume":"5","author":"Ahmed","year":"2017","journal-title":"Int. J. Microbiol. Adv. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4103\/2279-042X.179569","article-title":"Effect of high-dose ascorbic acid on vasopressor\u2019s requirement in septic shock","volume":"5","author":"Zabet","year":"2016","journal-title":"J. Res. Pharm. Pract."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Zhang, J., Rao, X., Li, Y., Zhu, Y., Liu, F., Guo, G., Luo, G., Meng, Z., De Backer, D., and Xiang, H. (2020). High-dose vitamin C infusion for the treatment of critically ill COVID-19. Res. Square.","DOI":"10.21203\/rs.3.rs-52778\/v1"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Zhang, M., and Jativa, D.F. (2018). Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. SAGE Open Med., 6.","DOI":"10.1177\/2050312118807615"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Hemila, H., and Chalker, E. (2019). Vitamin C can shorten the length of stay in the ICU: A meta-analysis. Nutrients, 11.","DOI":"10.3390\/nu11040708"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40560-020-0432-y","article-title":"Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: A meta-regression analysis","volume":"8","author":"Hemila","year":"2020","journal-title":"J. Intensive Care"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/S0022-4804(02)00083-5","article-title":"Ascorbic acid dynamics in the seriously ill and injured","volume":"109","author":"Long","year":"2003","journal-title":"J. Surg. Res."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Kashiouris, M.G., L\u2019Heureux, M., Cable, C.A., Fisher, B.J., Leichtle, S.W., and Fowler, A.A. (2020). The emerging role of vitamin C as a treatment for sepsis. Nutrients, 12.","DOI":"10.3390\/nu12020292"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Marik, P.E., Kory, P., Varon, J., Iglesias, J., and Meduri, G.U. (2020). MATH+ protocol for the treatment of SARS-CoV-2 infection: The scientific rationale. Expert Rev. Anti Infect. Ther., 1\u20137.","DOI":"10.1080\/14787210.2020.1808462"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Hemil\u00e4, H., and Chalker, E. (2020). Reanalysis of the effect of vitamin C on mortality in the CITRIS-ALI trial: Important findings dismissed in the trial report. Front. Med.","DOI":"10.3389\/fmed.2020.590853"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1001\/jama.2019.21987","article-title":"Vitamin C for sepsis and acute respiratory failure\u2014Reply","volume":"323","author":"Fowler","year":"2020","journal-title":"JAMA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1001\/jama.2019.22176","article-title":"Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients with Septic Shock: The VITAMINS Randomized Clinical Trial","volume":"323","author":"Fujii","year":"2020","journal-title":"JAMA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1001\/jama.2020.5844","article-title":"Vitamin C, hydrocortisone, and thiamine for septic shock","volume":"323","author":"Long","year":"2020","journal-title":"JAMA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13054-020-02853-2","article-title":"Is the VITAMINS RCT indicating potential redundancy between corticosteroids and vitamin C?","volume":"24","author":"Carr","year":"2020","journal-title":"Crit. Care"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Carr, A.C., and Rowe, S. (2020). Factors affecting vitamin C status and prevalence of deficiency: A global health perspective. Nutrients, 12.","DOI":"10.3390\/nu12071963"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Patterson, G., Isales, C.M., and Fulzele, S. (2020). Low level of vitamin C and dysregulation of vitamin C transporter might be involved in the severity of COVID-19 Infection. Aging Dis., 12.","DOI":"10.14336\/AD.2020.0918"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0003-9861(02)00678-1","article-title":"Age-related decline of sodium-dependent ascorbic acid transport in isolated rat hepatocytes","volume":"410","author":"Michels","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"G241","DOI":"10.1152\/ajpgi.00071.2018","article-title":"Tumor Necrosis Factor alpha (TNF-alpha) reduces intestinal vitamin C uptake: A role for NF-kB-mediated signaling","volume":"315","author":"Subramanian","year":"2018","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.bbamem.2017.10.010","article-title":"Inhibition of intestinal ascorbic acid uptake by lipopolysaccharide is mediated via transcriptional mechanisms","volume":"1860","author":"Subramanian","year":"2018","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_99","unstructured":"(2020, September 26). Domain-Specific Appendix: VITAMIN, C. REMAP-CAP: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia 2020. Available online: https:\/\/static1.squarespace.com\/static\/5cde3c7d9a69340001d79ffe\/t\/5f1bba732cda7f10310643fe\/1595652735252\/REMAP-CAP+Vitamin+C+Domain+Specific+Appendix+V2+-+08+June+2020_WM.pdf."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1136\/emermed-2020-210199","article-title":"Development and implementation of a COVID-19 near real-time traffic light system in an acute hospital setting","volume":"37","author":"Vizcaychipi","year":"2020","journal-title":"Emerg. Med. J."},{"key":"ref_101","unstructured":"ICNARC Report on COVID-19 in Critical Care: Chelsea and Westminster Hospital Intensive Care Unit (2020, June 12). London. Available online: https:\/\/www.patrickholford.com\/uploads\/2020\/chelwesticnarcreportjune.pdf."},{"key":"ref_102","unstructured":"(2020, June 26). ICNARC Report on COVID-19 in Critical Care. London. Available online: https:\/\/www.patrickholford.com\/uploads\/2020\/nationwideicnarcreportjune.pdf."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1093\/pubmed\/fdn076","article-title":"Estimated prevalence and predictors of vitamin C deficiency within UK\u2019s low-income population","volume":"30","author":"Mosdol","year":"2008","journal-title":"J. Public Health"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1080\/14787210.2020.1794819","article-title":"The use of IV vitamin C for patients with COVID-19: A case series","volume":"18","author":"Hiedra","year":"2020","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_105","first-page":"e925521","article-title":"Unusual early recovery of a critical COVID-19 patient after administration of intravenous vitamin C","volume":"21","author":"Parikh","year":"2020","journal-title":"Am. J. Case Rep."},{"key":"ref_106","unstructured":"(2020, October 10). Vitamin C: Fact Sheet for Health Professionals USA: National Institutes of Health, Available online: https:\/\/ods.od.nih.gov\/factsheets\/VitaminC-HealthProfessional\/."},{"key":"ref_107","unstructured":"Scientific Committee on Food Scientific Panel on Dietetic Products Nutrition and Allergies (2006). Tolerable Upper Intake Levels for Vitamins and Minerals, EFSA."},{"key":"ref_108","unstructured":"Phoenix Labs (2020, November 23). Ascorbic Acid Injection 500mg\/5ml Clonee, Ireland 2014. Available online: https:\/\/www.medicines.org.uk\/emc\/product\/1520\/smpc#gref."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s13054-019-2397-6","article-title":"Is intravenous vitamin C contraindicated in patients with G6PD deficiency?","volume":"23","author":"Marik","year":"2019","journal-title":"Crit. Care"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1024\/0300-9831.69.2.67","article-title":"High-dose vitamin C: A risk for persons with high iron stores?","volume":"69","author":"Gerster","year":"1999","journal-title":"Int. J. Vitam. Nutr. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1016\/0306-9877(81)90126-2","article-title":"Vitamin C, titrating to bowel tolerance, anascorbemia, and acute induced scurvy","volume":"7","author":"Cathcart","year":"1981","journal-title":"Med. Hypotheses"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Padayatty, S.J., Sun, A.Y., Chen, Q., Espey, M.G., Drisko, J., and Levine, M. (2010). Vitamin C: Intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011414"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1515\/CCLM.1998.027","article-title":"The effect of ascorbic acid ingestion on the biochemical and physicochemical risk factors associated with calcium oxalate kidney stone formation","volume":"36","author":"Auer","year":"1998","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1681\/ASN.V104840","article-title":"Intake of vitamins B6 and C and the risk of kidney stones in women","volume":"10","author":"Curhan","year":"1999","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_115","first-page":"115","article-title":"Ascorbic acid supplements and kidney stones incidence among men and women: A systematic review and meta-analysis","volume":"16","author":"Jiang","year":"2018","journal-title":"Urol. J."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.metabol.2008.09.023","article-title":"Oxalic acid excretion after intravenous ascorbic acid administration","volume":"58","author":"Robitaille","year":"2009","journal-title":"Metabolism"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e000085","DOI":"10.1136\/bmjnph-2020-000085","article-title":"Nutrition, immunity and COVID-19","volume":"3","author":"Calder","year":"2020","journal-title":"BMJ Nutr. Prev. Health"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Jovic, T.H., Ali, S.R., Ibrahim, N., Jessop, Z.M., Tarassoli, S.P., Dobbs, T.D., Holford, P., Thornton, C.A., and Whitaker, I.S. (2020). Could vitamins help in the fight against COVID-19?. Nutrients, 12.","DOI":"10.3390\/nu12092550"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Calder, P.C., Carr, A.C., Gombart, A.F., and Eggersdorfer, M. (2020). Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. 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