Vitamin C Supplementation for the Treatment of COVID-19: A Systematic Review and Meta-Analysis
Monika Olczak-Pruc, Damian Swieczkowski, Jerzy R Ladny, Michal Pruc, Raul Juarez-Vela, Zubaid Rafique, Frank W Peacock, Lukasz Szarpak
Nutrients, doi:10.3390/nu14194217
Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe respiratory syndrome coronavirus 2 (SARS-CoV-2), millions of people have died, and the medical system has faced significant difficulties. Our purpose was to perform a meta-analysis to estimate the effect of vitamin C on in-hospital mortality and the ICU or hospital length of stay for patients diagnosed with COVID-19. We conducted a systematic review with meta-analysis in the following databases: PubMed, Web of Science, Scopus and Cochrane Central Register of Controlled Trials. We included studies that evaluated the effect of vitamin C supplementation, compared with standard treatment in COVID-19 patients who are ≥18 y of age. Nineteen trials were included in the meta-analysis. In-hospital mortality with and without vitamin C supplementation was 24.1% vs. 33.9% (OR = 0.59; 95%CI: 0.37 to 0.95; p = 0.03), respectively. Sub-analysis showed that, in randomized clinical trials, in-hospital mortality varied and amounted to 23.9% vs. 35.8% (OR = 0.44; 95%CI: 0.25 to 0.76; p = 0.003), respectively. In the non-randomized trials, in-hospital mortality was 24.2% vs. 33.5% (OR = 0.72; 95%CI: 0.38 to 1.39; p = 0.33), respectively. The ICU length of stay was longer in patients treated with vitamin C vs. standard therapy, 11.1 (7.3) vs. 8.3 (4.7) days (MD = 1.91; 95%CI: 0.89 to 2.93; p < 0.001), respectively. Acute kidney injury in patients treated with and without vitamin C varied and amounted to 27.8% vs. 45.0% (OR = 0.56; 95%CI: 0.40 to 0.78; p < 0.001), respectively. There were no differences in the frequency of other adverse events among patients' treatment with and without vitamin C (all p > 0.05). The use of vitamin C reduces hospital mortality. The length of stay in the ICU is longer among patients treated with vitamin C. In terms of patient safety, vitamin C has an acceptable profile. Low doses of vitamin C are effective and safe. Despite some evidence of the usefulness of vitamin C in modifying the course of COVID-19, it is too early to modify guidelines and recommendations. Further studies, in particular randomized clinical trials, are necessary.
Conflicts of Interest: The authors declare no conflict of interest.
References
Al Sulaiman, Aljuhani, Saleh, Badreldin, Al Harthi et al., Ascorbic acid as an adjunctive therapy in critically ill patients with COVID-19: A propensity score matched study, Sci. Rep,
doi:10.1038/s41598-021-96703-yAo, Li, Yuan, Wang, Nasr et al., Intravenous vitamin C use and risk of severity and mortality in COVID-19: A systematic review and meta-analysis, Nutr. Clin. Pract,
doi:10.1002/ncp.10832Bae, Kim, Mini-Review on the Roles of Vitamin C, Vitamin D, and Selenium in the Immune System against COVID-19, Molecules,
doi:10.3390/molecules25225346Beigmohammadi, Bitarafan, Hoseindokht, Abdollahi, Amoozadeh et al., The effect of supplementation with vitamins A, B, C, D, and E on disease severity and inflammatory responses in patients with COVID-19: A randomized clinical trial, Trials,
doi:10.1186/s13063-021-05795-4Bhowmik, Barek, Aziz, Islam, Impact of high-dose vitamin C on the mortality, severity, and duration of hospital stay in COVID-19 patients: A meta-analysis, Health Sci. Rep,
doi:10.1002/hsr2.762Biancatelli, Berrill, Catravas, Marik, Quercetin, 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.2020.01451Borges, Gennari-Felipe, Dias, Hatanaka, Melatonin et al., Potential Adjuvant Treatment for COVID-19 Patients, Front. Nutr,
doi:10.3389/fnut.2021.821824Carr, Rowe, Factors Affecting Vitamin C Status and Prevalence of Deficiency: A Global Health Perspective, Nutrients,
doi:10.3390/nu12071963Cerullo, Negro, Parimbelli, Pecoraro, Perna et al., The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19, Front. Immunol,
doi:10.3389/fimmu.2020.574029Coppock, Violet, Vasquez, Belden, Foster et al., Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial, Life,
doi:10.3390/life12030453Corrao, Mallaci Bocchio, Lo Monaco, Natoli, Cavezzi et al., Does Evidence Exist to Blunt Inflammatory Response by Nutraceutical Supplementation during COVID-19 Pandemic? An Overview of Systematic Reviews of Vitamin D, Vitamin C, Melatonin, and Zinc, Nutrients,
doi:10.3390/nu13041261Darban, Malek, Memarian, Gohari, Kiani et al., Efficacy of High Dose Vitamin C, Melatonin and Zinc in Iranian Patients with Acute Respiratory Syndrome due to Coronavirus Infection: A Pilot Randomized Trial, J. Cell. Mol. Anesth
Fashner, Ericson, Werner, Treatment of the common cold in children and adults, Am. Fam. Physician
Ferrón-Celma, Mansilla, Hassan, Garcia-Navarro, Comino et al., Effect of vitamin C administration on neutrophil apoptosis in septic patients after abdominal surgery, J. Surg. Res,
doi:10.1016/j.jss.2008.04.024Firouzi, Pahlavani, Navashenaq, Clayton, Beigmohammadi et al., The effect of Vitamin C and Zn supplementation on the immune system and clinical outcomes in COVID-19 patients, Clin. Nutr. Open Sci
Gao, Xu, Wang, Lv, Ma et al., The efficiency and safety of high-dose vitamin C in patients with COVID-19: A retrospective cohort study, Aging,
doi:10.18632/aging.202557Gavriatopoulou, Ntanasis-Stathopoulos, Korompoki, Fotiou, Migkou et al., Emerging treatment strategies for COVID-19 infection, Clin. Exp. Med,
doi:10.1007/s10238-020-00671-yGavrielatou, Xourgia, Xixi, Mantelou, Ischaki et al., Effect of Vitamin C on Clinical Outcomes of Critically Ill Patients with COVID-19: An Observational Study and Subsequent Meta-Analysis, Front. Med,
doi:10.3389/fmed.2022.814587Gröber, Holick, The coronavirus disease (COVID-19)-A supportive approach with selected micronutrients, Int. J. Vitam. Nutr. Res,
doi:10.1024/0300-9831/a000693Hakamifard, Soltani, Maghsoudi, Rismanbaf, Aalinezhad et al., The effect of vitamin E and vitamin C in patients with COVID-19 pneumonia; a randomized controlled clinical trial, Immunopathol. Persa
Hess, Halalau, Dokter, Paydawy, Karabon et al., High-dose intravenous vitamin C decreases rates of mechanical ventilation and cardiac arrest in severe COVID-19, Intern. Emerg. Med,
doi:10.1007/s11739-022-02954-6Higgins, Thompson, Deeks, Altman, Measuring inconsistency in meta-analyses, BMJ
Hozo, Djulbegovic, Hozo, Estimating the mean and variance from the median, range, and the size of a sample, BMC Med. Res. Methodol,
doi:10.1186/1471-2288-5-13Kaźmierczak-Bara Ńska, Boguszewska, Adamus-Grabicka, Karwowski, Two Faces of Vitamin C-Antioxidative and Pro-Oxidative Agent, Nutrients,
doi:10.3390/nu12051501Kocot, Luchowska-Kocot, Kiełczykowska, Musik, Kurzepa, Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders?, Nutrients,
doi:10.3390/nu9070659Kumari, Dembra, Dembra, Bhawna, Gul et al., The Role of Vitamin C as Adjuvant Therapy in COVID-19, Cureus,
doi:10.7759/cureus.11779Lamontagne, Masse, Menard, Sprague, Pinto et al., Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit, N. Engl. J. Med,
doi:10.1056/NEJMoa2200644Li, Ching, Hipple, Lopez, Sahibzada et al., Use of Intravenous Vitamin C in Critically Ill Patients with COVID-19 Infection, J. Pharm. Pract,
doi:10.1177/08971900211015052Liugan, Carr, Vitamin C and neutrophil function: Findings from randomized controlled trials, Nutrients,
doi:10.3390/nu11092102Majidi, Rabbani, Gholami, Gholamalizadeh, Bourbour et al., The Effect of Vitamin C on Pathological Parameters and Survival Duration of Critically Ill Coronavirus Disease 2019 Patients: A Randomized Clinical Trial, Front. Immunol,
doi:10.3389/fimmu.2021.717816Manning, Mitchell, Appadurai, Shakya, Pierce et al., Vitamin C promotes maturation of T-cells, Antioxid. Redox Signal,
doi:10.1089/ars.2012.4988Mcguinness, Higgins, Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments, Res. Synth. Methods,
doi:10.1002/jrsm.1411Migliorini, Vaishya, Eschweiler, Oliva, Hildebrand et al., Vitamins C and D and COVID-19 Susceptibility, Severity and Progression: An Evidence Based Systematic Review, Medicina,
doi:10.3390/medicina58070941Miranda-Massari, Toro, Loh, Rodriguez, Borges et al., The Effects of Vitamin C on the Multiple Pathophysiological Stages of COVID-19, Life
Muralidar, Ambi, Sekaran, Krishnan, The emergence of COVID-19 as a global pandemic: Understanding the epidemiology, immune response and potential therapeutic targets of SARS-CoV-2, Biochimie,
doi:10.1016/j.biochi.2020.09.018Page, Mckenzie, Bossuyt, Boutron, Hoffmann et al., The PRISMA 2020 statement: An updated guideline for reporting systematic reviews, BMJ,
doi:10.1136/bmj.n71Pedrosa, Barros, Leite-Lais, Nutritional risk of vitamin D, vitamin C, zinc, and selenium deficiency on risk and clinical outcomes of COVID-19: A narrative review, Clin. Nutr. ESPEN,
doi:10.1016/j.clnesp.2021.11.003Pourkarim, Pourtaghi-Anvarian, Rezaee, Molnupiravir: A new candidate for COVID-19 treatment, Pharmacol. Res. Perspect,
doi:10.1002/prp2.909Rawat, Roy, Maitra, Gulati, Khanna et al., Vitamin C and COVID-19 treatment: A systematic review and meta-analysis of randomized controlled trials, Diabetes Metab. Syndr,
doi:10.1016/j.dsx.2021.102324Shahbaz, Fatima, Basharat, Bibi, Yu et al., Role of vitamin C in preventing of COVID-19 infection, progression and severity, AIMS Microbiol,
doi:10.3934/microbiol.2022010Shakoor, Feehan, Al Dhaheri, Ali, Platat et al., Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19?, Maturitas
Shilotri, Bhat, Effect of mega doses of vitamin C on bactericidal ativity of leukocytes, Am. J. Clin. Nutr
Siahkali, Zarezade, Koolaji, Seyed Alinaghi, Zendehdel et al., Safety and effectiveness of high-dose vitamin C in patients with COVID-19: A randomized open-label clinical trial, Eur. J. Med. Res
Sterne, Hernán, Reeves, Savović, Berkman et al., ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions, BMJ
Sterne, Savović, Page, Elbers, Blencowe et al., RoB 2: A revised tool for assessing risk of bias in randomised trials, BMJ,
doi:10.1136/bmj.l4898Suna, Melahat, Murat, Figen, Ayperi, Effect of high-dose intravenous vitamin C on prognosis in patients with SARS-CoV-2 pneumonia, Med. Clin,
doi:10.1016/j.medcli.2021.04.010Szarpak, Pruc, Gasecka, Jaguszewski, Michalski et al., Should we supplement zinc in COVID-19 patients? Evidence from a meta-analysis, Pol. Arch. Intern. Med,
doi:10.20452/pamw.16048Teafatiller, Agrawal, De Robles, Rahmatpanah, Subramanian et al., Vitamin C Enhances Antiviral Functions of Lung Epithelial Cells, Biomolecules,
doi:10.3390/biom11081148Tehrani, Yadegarynia, Abrishami, Moradi, Gharaei et al., An investigation into the Effects of Intravenous Vitamin C on Pulmonary CT Findings and Clinical Outcomes of Patients with COVID 19 Pneumonia A Randomized Clinical Trial, Urol. J
Thomas, Patel, Bittel, Wolski, Wang et al., Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients with SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2021.0369Vollbracht, Kraft, Feasibility of Vitamin C in the Treatment of Post Viral Fatigue with Focus on Long COVID, Based on a Systematic Review of IV Vitamin C on Fatigue, Nutrients,
doi:10.3390/nu13041154Vollbracht, Kraft, Oxidative Stress and Hyper-Inflammation as Major Drivers of Severe COVID-19 and Long COVID: Implications for the Benefit of High-Dose Intravenous Vitamin C, Front. Pharmacol,
doi:10.3389/fphar.2022.899198Zhang, Rao, Li, Zhu, Liu et al., Pilot trial of high-dose vitamin C in critically ill COVID-19 patients, Ann. Intensive Care,
doi:10.1186/s13613-020-00792-3Zhao, Liu, Liu, Peng, Huang et al., High Dose Intravenous Vitamin C for Preventing The Disease Aggravation of Moderate COVID-19 Pneumonia. A Retrospective Propensity Matched Before-After Study, Front. Pharmacol,
doi:10.3389/fphar.2021.638556Zheng, Chen, Jiang, Guo, Luo et al., No significant benefit of moderate-dose vitamin C on severe COVID-19 cases, Open Med,
doi:10.1515/med-2021-0361
