Vitamin C for COVID-19 Treatment: Have We Got Enough Evidence?
Siti Rohaiza Ahmad- PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Gadong, Brunei
Introduction
COVID-19, an infectious disease caused by SARS-CoV-2, was discovered at the end of 2019. COVID-19 virus invades the lungs, causing pneumonia. Fever, shortness of breath, and taste loss are common symptoms of COVID-19. About 2–3% of the COVID-19 cases lead to death. Over the past year, scientists and healthcare professionals learned more about the virus. Until today, the battle to find the most suitable treatment strategies for COVID-19 is still ongoing. One of the main areas of debate is nutrition strategies for the cure and prevention of COVID-19.
Vitamin C is a water-soluble nutrient that is essential to humans. Vitamin C intake of about 200 mg per day is recommended to reduce the risk of chronic diseases (1). Consume five servings of fresh vegetables and fruits every day or take a 200 mg vitamin C supplement to acquire 200 mg of vitamin C per day. This recommendation, however, may vary depending on the population.
Since many people believe vitamin C is non-toxic and beneficial to health, it is frequently consumed in large quantities (2). The Tolerable Upper Intake Level (UL) for vitamin C varies according to age group (2). The UL for adults aged 19 and up is 2,000 mg/day of vitamin C. The UL for children aged 1–3 years is 400 mg of vitamin C per day. The UL for those aged 4–6 years is 650 mg/day of vitamin C. The UL for adolescent (14–18 years old) is 1,200 mg/day of vitamin C. However, the UL is not intended to apply to people who are receiving vitamin C under medical supervision.
Acute respiratory distress syndrome, acute cardiac problems, multiple organ dysfunction syndrome, septic shock, and death are possible sequelae in more severe cases of COVID-19 (3). The cytokine storm, in which viral replication produces a massive release of cytokines and other immune-related stimuli, resulting in hyper-inflammation, is thought to cause these problems (4–6). The most common cytokine elevated in critically ill COVID-19 patients was Interleukin-6 (IL-6) (4). A preliminary report suggested that the need for mechanical ventilation is connected to elevated Interleukins 6 (IL-6) levels and that mildly raised IL-6 levels are sufficient to identify COVID-19 individuals at high risk of respiratory failure (7). On the other hand, severe COVID-19 was previously reported to have a larger degree of T-cell proliferation, activation, and cytotoxicity in the late stages of illness (8). As a result, in critically ill COVID-19 patients, suppression of cytokine storms and immune function attacks (hyper-inflammation) may be the appropriate treatment strategy.
Vitamin C is one of the nutrients of interest in COVID-19 cure and prevention. Vitamin C may have a number of immune-modulatory mechanisms that can help to mitigate or reduce COVID-19 pathophysiology (4, 5, 9–11). Vitamin C may act as an antioxidant (9–11). Vitamin C supplementation is thought to help reduce oxidative damage and thus prevent worsening internal vascular endothelial injury (4). It has been proposed that vitamin C also can protect against cytokine attack during SARS-CoV-2 infections (4, 5, 9–11) (Tumor Necrosis Factor). TNF-α and other pro-inflammatory cytokines are reduced by vitamin C, whereas anti-inflammatory cytokines are increased Interleukins 10 (IL-10) (9). In humans, vitamin C treatment reduces IL-6 and inhibits in vivo IL-6 release in the endothelium induced by endothelin-1 (ET-1) (4). ET-1 is a potent vasoconstrictor peptide that has also been linked to pneumonia and other lungs diseases. As a result of vitamin C's ability to modulate various immune-modulatory responses, vitamin C was identified as a potential COVID-19 treatment regime. This article aims to report the latest findings on potential applications of vitamin C as a prevention and treatment for COVID-19.
As Daily Supplements–Prevention Measures
Vitamin C therapy has antiviral effects (9, 12). It is long known that vitamin C is used to combat the common cold (13). According to the famous 1970s Linus Pauling's theory, vitamin C intake help to reduce susceptibility to respiratory tract infections. The theory has remained controversial over the years; however, the sales of vitamin C have increased substantially in the US market (13). A balanced diet can fulfill the daily needs of vitamin C, boosting the immune system and thus reducing susceptibility to respiratory infections (14). However, not much data supported the intake of oral vitamin C supplements to increase immunity (13). Several studies have shown that oral vitamin C supplementations since COVID-19 have increased (15, 16). However, dietary supplements in those studies against COVID-19 were not evidence-based. Most of the respondents were influenced by healthcare professionals, social media, family and friends. Speakman et al. (17) stated that the currently available evidence of vitamin C supplementations' effectiveness was generally small sample sizes and varying doses. Another researcher also corroborated that evidence to justify vitamin C supplements is still lacking and needs further investigation (18).
As Treatment for Critically Ill Patients
The Vitamin C regime is used to treat critically ill patients with COVID-19. Table 1 shows some recent studies or reports on vitamin C treatment for COVID-19 critically ill patients. An observational and subsequent meta-analysis study among 1,807 patients by Gavrielatou et al. (19) reported that critically ill patients with COVID-19 prescribed vitamin C were not associated with a lower mortality rate. Only six observational studies and five RCTs were included in the meta-analysis. Another latest systematic review and meta-analysis by Ao et al. (20), also reported that short-term intravenous vitamin C treatment did not reduce the risk of severity and mortality in patients with COVID-19. The small number of high-quality studies included in the meta-analysis was one of the limitations highlighted by the researchers. Furthermore, the definition of COVID-19 severity varies between studies. There was also insufficient information about the timing and duration of the therapy in those studies. Similarly, another published work by Kwak et al. (21) showed that there is currently a lack of evidence supporting the therapeutic use of intravenous vitamin C. By which the mortality rate of hospitalized patients was not significantly different between patients treated with intravenous vitamin C and those who did not receive it.
Table 1. Shows some of the recent studies or reports on vitamin C treatment for COVID-19 critically ill patients.
On the other hand, Shakoor et al. (9) reported that vitamin C supplementations showed positive improvements during COVID-19 infections. On this note, however, no clinical trials looking at the associations of diet and COVID-19 have been reported. On the other hand, some clinical trials are already ongoing to establish the possible link of several nutrients for treatment among COVID-19 patients (9).
In conclusion, due to much-conflicting evidence, this calls for more robust investigations on the impact of vitamin C supplementation therapy on the immune response of patients with COVID-19. Furthermore, many reported studies are pilot stage and lack RCTs (22–25). Hemilla et al. (26), suggested that methodologically sound trials with larger patient populations are required to investigate vitamin C's treatment effects against COVID-19. It was also observed that the duration of intravenous vitamin C treatment varies in the research cited above. Therefore, it is highly debated whether vitamin C poses beneficial therapeutic effects on treating respiratory infections and very sick patients with COVID-19.
As Treatment-Drug Combinations
Interestingly, several recent studies reported how vitamin C could be used in combinations with other drugs or medications in the COVID-19 treatment regime (Supplementary Table S1–as Supplementary File). A recent report by Sahoo et al. (27) attempted to study the combinations of various anti-HIV viral drugs with vitamin C to combat the COVID-19 virus via a computational bioinformatic tool study. The computational investigation showed that the combination of 'darunavir with L-ascorbyl-2,6-dibutyrate or ascorbic acid-2-sulfate' strongly impedes the SARS-CoV-2-main protease as a potential COVID-19 treatment option. This study showed that vitamin C could be potentially used in the COVID-19 treatment regime. However, more trials (in vivo or in vitro studies) are required to confirm these findings. Another report by Ang et al. (28) showed that the combination of Traditional Chinese medicine with high-dose vitamin C regime showed a faster recovery period, reduced symptoms, improved chest condition and loss of taste improvement. However, only 60 COVID-19 patients were enrolled in this particular study, which thus requires a more robust investigation. Another survey by Tan et al. (29), combined vitamin C administration with another drug, diammonium glycyrrhizinate, prevented the worsening symptoms among COVID-19 patients. In conclusion, to confirm the efficacy of these drugs, however, a large and prospective cohort of patients is required.
Discussions
Vitamin C is an effective antioxidant with antiviral effects, making it a promising choice for combating SARS-CoV-2 infections. Vitamin C may have a number of immune-modulatory mechanisms that can help to mitigate COVID-19 pathophysiology The applications of vitamin C in terms of COVID-19 cure and prevention include vitamin C supplementations, intravenous vitamin C administration for critically ill patients and the study of combined effects with other antiviral drugs.
The currently available evidence of vitamin C supplementations' effectiveness was generally small sample sizes and varying doses. More studies are required to confirm the effectiveness of dietary vitamin C supplementations against COVID-19.
Apart from that, based on the currently available findings, robust data on the effectiveness of intravenous vitamin C for the treatment of COVID-19 patients is still lacking. The studies condition or criteria also varied greatly. For example, the definition of COVID-19 severity varies between studies. There was also insufficient information about the timing and duration of the therapy in those studies. The vitamin C doses used in the studies also varied. Therefore, studies all over the globe lack standardization and needs to be synchronized. Many of the reported studies on intravenous vitamin C for critically ill patients were found to be at a pilot stage. There is also a lack of RCTs and some are believed to be on the way. Therefore, this calls for more studies to be conducted.
Several recent studies reported how vitamin C could be used in combinations with other drugs or medications in the COVID-19 treatment regime. Many of these studies are still in their early stages and however, pose some promising results. Therefore, in order to confirm the efficacy of these drugs, however, a large and prospective cohort of patients is required.
In conclusion, more research on the effectiveness of vitamin C in COVID-19 prevention and treatment is needed, particularly RCTs and large cohort studies.
Author Contributions
SA solely wrote the article.
Conflict of Interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnut.2022.892561/full#supplementary-material
References
1. Gröber U, Holick MF. The coronavirus disease (COVID-19)-a supportive approach with selected micronutrients. Int J Vitam Nutr Res. (2022) 92:13–34. doi: 10.1024/0300-9831/a000693
2. Abobaker A, Alzwi A, Alraied AHA. Overview of the possible role of vitamin C in management of COVID-19. Pharmacol Rep. (2020) 72:1517–28. doi: 10.1007/s43440-020-00176-1
3. Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda H, La Frano MR, et al. Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: considerations during the COVID-19 crisis. Nutrients. (2020) 12:1562. doi: 10.3390/nu12061562
4. Feyaerts AF, Luyten W. Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19? Nutrition. (2020) 79–80:110948. doi: 10.1016/j.nut.2020.110948
5. Liu F, Zhu Y, Zhang J, Li Y, Peng Z. Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomized controlled trial. BMJ Open. (2020) 10:e039519. doi: 10.1136/bmjopen-2020-039519
6. Lu L, Zhang H, Dauphars DJ, He YW. A potential role of interleukin 10 in COVID-19 pathogenesis. Trends Immunol. (2021) 42:3–5. doi: 10.1016/j.it.2020.10.012
7. Herold T, Jurinovic V, Arnreich C, Hellmuth JC, von Bergwelt-Baildon M, Klein M. Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients. medRxiv. (2020). doi: 10.1101/2020.04.01.20047381
8. Kang CK, Han GC, Kim M, Kim G, Shin HM, Song KH, et al. Aberrant hyperactivation of cytotoxic T-cell as a potential determinant of COVID-19 severity. Int J Infect Dis. (2020) 97:313–21. doi: 10.1016/j.ijid.2020.05.106
9. Shakoor H, Feehan J, Al Dhaheri AS, Ali HI, Platat C, Ismail LC, et al. Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: could they help against COVID-19?. Maturitas. (2021) 143:1–9. doi: 10.1016/j.maturitas.2020.08.003
10. Milani GP, Macchi M, Guz-Mark A. Vitamin C in the treatment of COVID-19. Nutrients. (2021) 13:1172. doi: 10.3390/nu13041172
11. Yaseen MO, Jamshaid H, Saif A, Hussain T. Immunomodulatory role and potential utility of various nutrients and dietary components in SARS-CoV-2 infection. Int J Vitam Nutr Res. (2022) 92:35–48. doi: 10.1024/0300-9831/a000715
12. Bae M, Kim H. Mini-review on the roles of vitamin C, vitamin D, and selenium in the immune system against COVID-19. Molecules. (2020) 25:5346. doi: 10.3390/molecules25225346
13. Cerullo G, Negro M, Parimbelli M, Pecoraro M, Perna S, Liguori G, 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. (2020) 11:574029. doi: 10.3389/fimmu.2020.574029
14. Granger M, Eck P. Dietary Vitamin C in human health. New Research and Developments of Water-Soluble Vitamins. (2018) 281–310. doi: 10.1016/bs.afnr.2017.11.006
15. Radwan H, Hasan H, Jaafar Z, Abbas N, Saif ER, Al Kitbi M, et al. Diets and dietary supplements used during the COVID-19 pandemic in the United Arab Emirates: a cross-sectional survey. Saudi Pharm J. (2022) 421–32. doi: 10.1016/j.jsps.2022.01.019
16. Mukattash TL, Alkhalidy H, Alzu'bi B, Abu-Farha R, Itani R, Karout S, et al. Dietary supplements intake during the second wave of COVID-19 pandemic: a multinational Middle Eastern study. Eur J Integr Med. (2022) 49:102102. doi: 10.1016/j.eujim.2022.102102
17. Speakman LL, Michienzi SM, Badowski ME. Vitamins, supplements and COVID-19: a review of currently available evidence. Drugs Context. (2021) 10:2021-6-2. doi: 10.7573/dic.2021-6-2
18. Adams KK, Baker WL, Sobieraj DM. Myth busters: dietary supplements and COVID-19. Ann Pharmacother. (2020) 54:820–6. doi: 10.1177/1060028020928052
19. Gavrielatou E, Xourgia E, Xixi NA, Mantelou AG, Ischaki E, Kanavou A, 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. (2022) 9:814587. doi: 10.3389/fmed.2022.814587
20. Ao G, Li J, Yuan Y, Wang Y, Nasr B, Bao M, et al. Intravenous vitamin C use and risk of severity and mortality in COVID-19: a systematic review and meta-analysis. Nutr Clin Pract. (2022). doi: 10.1002/ncp.10832
21. Kwak SG, Choo YJ, Chang MC. The effectiveness of high-dose intravenous vitamin C for patients with coronavirus disease 2019: a systematic review and meta-analysis. Complement Ther Med. (2022) 64:102797. doi: 10.1016/j.ctim.2021.102797
22. Zhang J, Rao X, Li Y, Zhu Y, Liu F, Guo G, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann Intensive Care. (2021) 11:5. doi: 10.1186/s13613-020-00792-3
23. Huang L, Wang L, Tan J, Liu H, Ni Y. High-dose vitamin C intravenous infusion in the treatment of patients with COVID-19: a protocol for systematic review and meta-analysis. Medicine. (2021) 100:e25876. doi: 10.1097/MD.0000000000025876
24. Borges L, Gennari-Felipe M, Dias BB, Hatanaka E. Melatonin, zinc, and vitamin C: potential adjuvant treatment for COVID-19 patients. Front Nutr. (2022) 8:821824. doi: 10.3389/fnut.2021.821824
25. Moscatelli F, Sessa F, Valenzano A, Polito R, Monda V, Cibelli G, et al. COVID-19: role of nutrition and supplementation. Nutrients. (2021) 13:976. doi: 10.3390/nu13030976
26. Hemilä H, Carr A, Chalker E. Vitamin C may increase the recovery rate of outpatient cases of SARS-CoV-2 infection by 70%: reanalysis of the COVID A to Z randomized clinical trial. Front Immunol. (2021) 12:674681. doi: 10.3389/fimmu.2021.674681
27. Sahoo A, Swain SS, Paital B, Panda M. Combinatorial approach of vitamin C derivative and anti-HIV drug-darunavir against SARS-CoV-2. Front Biosci. (2022) 27:10. doi: 10.31083/j.fbl2701010
28. Ang X, Wang Y, Liu Y, Shang L, Cheng Z, Fang L, et al. Traditional Chinese medicine together with high-dose vitamin C improves the therapeutic effect of western medicine against COVID-19. Am J Transl Res. (2022) 14:501–10. Available online at: www.ajtr.org/ISSN:1943-8141/AJTR0140606
Keywords: vitamin C, COVID-19, supplementations, intravenous, treatment
Citation: Ahmad SR (2022) Vitamin C for COVID-19 Treatment: Have We Got Enough Evidence? Front. Nutr. 9:892561. doi: 10.3389/fnut.2022.892561
Received: 09 March 2022; Accepted: 29 April 2022;
Published: 19 May 2022.
Edited by:
Caterina Conte, Università Telematica San Raffaele, ItalyReviewed by:
Mohammad Safiqul Islam, Noakhali Science and Technology University, BangladeshJie Zhao, The University of Hong Kong, Hong Kong SAR, China
Amal Akour, The University of Jordan, Jordan
Copyright © 2022 Ahmad. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Siti Rohaiza Ahmad, rohaiza.ahmad@ubd.edu.bn