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Objective
This living systematic review aims to provide a timely, rigorous, and continuously updated summary of the available evidence on the role of vitamin C in treating patients with COVID-19.

Data sources
We conducted searches in PubMed/MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature, and in a centralized repository in L·OVE (Living OVerview of Evidence). In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it comprises and has been customized to group all COVID-19 evidence in one place. All the searches covered the period until April 29, 2020 (one day before submission).

Study selection and methods
We adapted an already published standard protocol for multiple parallel systematic reviews. We searched for randomized trials evaluating the effect, in patients with COVID-19, of vitamin C versus placebo or no treatment. Anticipating the lack of randomized trials directly addressing this question, we also searched for trials evaluating MERS-CoV and SARS-CoV, and non-randomized studies in COVID-19. Two reviewers independently screened each study for eligibility. A living, web-based version of this review will be openly available during the COVID-19 pandemic, and we will resubmit it to the journal whenever there are substantial updates.

Results
We screened 95 records, but no study was considered eligible. We identified 20 ongoing studies, including 13 randomized trials evaluating vitamin C in COVID-19.

Conclusions
We did not find any studies that met our inclusion criteria, and hence there is no evidence to support or refute the use of vitamin C in the treatment of patients with COVID-19. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers soon.

PROSPERO Registration number:
CRD42020181216

Authors: Eduard Baladia[1], Ana Beatriz Pizarro[2], Luis Ortiz-Muñoz[3], Gabriel Rada[3,4,5], COVID-19 L·OVE Working Group []

Affiliation:
[1] Red de Nutrición Basada en la Evidencia, Academia Española de Nutrición y Dietética, Pamplona, España
[2] Departamento de Epidemiología Clínica y Bioestadística, Pontificia Universidad Javeriana, Bogotá, Colombia
[3] UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile
[4] Fundación Epistemonikos, Santiago, Chile
[5] Internal Medicine Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: e.baladia@academianutricion.org

Author address:
[1] C/ Consell de Cent 314, pral B 08007
Barcelona, España

Citation: Baladia E, Pizarro AB, Ortiz-Muñoz L, Rada G, COVID-19 L·OVE Working Group. Vitamin C for COVID-19: A living systematic review . Medwave 2020;20(6):e7978 doi: 10.5867/medwave.2020.06.7978

Submission date: 2/5/2020

Acceptance date: 9/6/2020

Publication date: 28/7/2020

Origin: Not commissioned.

Type of review: Externally peer-reviewed by four reviewers, double-blind.

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1. World Health Organization. Director-General’s remarks at the media briefing on 2019-nCoV on February 11 2020. World Health Organization; 2020 [Accessed on April 8, 2020 ]. [Internet] | Link |
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5. Tavakoli A, Vahdat K, Keshavarz M. Novel Coronavirus Disease 2019 (COVID-19): An Emerging Infectious Disease in the 21st Century. Iran South Med J 2020, 22(6): 432-450. | CrossRef |
6. Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020 Jun;92(6):577-583. | CrossRef | PubMed |
7. Global Covid-19 Case Fatality Rates. UK: Centre for Evidence-Based Evidence. [Accessed on April 8, 2020 ]. [Internet] | Link |
8. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020 Mar-Apr;34:101623. | CrossRef | PubMed |
9. Heikkinen T, Järvinen A. The common cold. The Lancet. 2003 Jan 4;361 (9351): 51-9. | CrossRef |
10. Hemilä H. Vitamin C intake and susceptibility to the common cold. Br J Nutr. 1997 Jan;77(1):59-72. | CrossRef | PubMed |
11. Gómez E, Quidel S, Bravo-Soto G, Ortigoza Á. Does vitamin C prevent the common cold?. Medwave. 2018 Aug 6;18(4):e7235. | CrossRef | PubMed |
12. Hemilä H, Chalker E. Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis. Nutrients. 2019 Mar 27;11(4):708. | CrossRef | PubMed |
13. Carr AC. A new clinical trial to test high-dose vitamin C in patients with COVID-19. Version 2. Crit Care. 2020 Apr 7;24(1):133. | CrossRef | PubMed |
14. Zabetakis I, Lordan R, Norton C, Tsoupras A. COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation. Nutrients. 2020 May 19;12(5):1466. | CrossRef | PubMed |
15. Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?. Med Drug Discov. 2020 Mar;5:100028. | CrossRef | PubMed |
16. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009 Oct;62(10):1006-12. | CrossRef | PubMed |
17. Rada G, Verdugo-Paiva F, Ávila C, Morel-Marambio M, Bravo-Jeria R, Pesce F, et al. Evidence synthesis relevant to COVID-19: a protocol for multiple systematic reviews and overviews of systematic reviews. Medwave. 2020 Apr 1;20(3):e7868. | CrossRef | PubMed |
18. Baladía E, Pizarro A, Rada G. Vitamin C for COVID-19: A living systematic review protocol. medRxiv. 2020.04.28.20083360 | CrossRef |
19. Github repository [Accessed 2020 April 12]. [Internet] | Link |
20. Epistemonikos Database Methods. Santiago: Epistemonikos Foundation [Accessed 2020 April 12]. [Internet] | Link |
21. Methods for the special L·OVE of Coronavirus infection. Santiago: Epistemonikos Foundation [Accessed 2020 April 12]. [Internet] | Link |
22. Schünemann HJ, Cuello C, Akl EA, Mustafa RA, Meerpohl JJ, Thayer K, et al. GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence. J Clin Epidemiol. 2019 Jul;111:105-114. | CrossRef | PubMed |
23. Jin X, Pang B, Zhang J, Liu Q, Yang Z, Feng J, et al. Core Outcome Set for Clinical Trials on Coronavirus Disease 2019 (COS-COVID). Engineering (Beijing). 2020 Mar 18. | CrossRef | PubMed |
24. COVID-19 Core Outcomes. [Accessed 2020 April 12]. [Internet] | Link |
25. Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013 Feb;66(2):158-72. | CrossRef | PubMed |
26. Collaboratron [Software]. Santiago: Epistemonikos Foundation, 2017.
27. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. | CrossRef | PubMed |
28. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016 Oct 12;355:i4919. | CrossRef | PubMed |
29. Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, et al. GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles-continuous outcomes. J Clin Epidemiol. 2013 Feb;66(2):173-83. | CrossRef | PubMed |
30. Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013 Feb;66(2):158-72. | CrossRef | PubMed |
31. Review Manager (RevMan) [Software]. Version 5.3.5 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
32. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr 26;336(7650):924-6. | CrossRef | PubMed |
33. Borah R, Brown AW, Capers PL, Kaiser KA. Analysis of the time and workers needed to conduct systematic reviews of medical interventions using data from the PROSPERO registry. BMJ Open. 2017 Feb 27;7(2):e012545. | CrossRef | PubMed |
34. Shojania KG, Sampson M, Ansari MT, Ji J, Doucette S, Moher D. How quickly do systematic reviews go out of date? A survival analysis. Ann Intern Med. 2007 Aug 21;147(4):224-33. | CrossRef | PubMed |
35. Coronavirus and the risks of ‘speed science’ Reuters; 2020 [Accessed 2020 April 12]. [Internet] | Link |
36. Kelly SE, Moher D, Clifford TJ. Quality of conduct and reporting in rapid reviews: an exploration of compliance with PRISMA and AMSTAR guidelines. Syst Rev. 2016 May 10;5:79. | CrossRef | PubMed |
37. Elliott JH, Synnot A, Turner T, Simmonds M, Akl EA, McDonald S, et al. Living systematic review: 1. Introduction-the why, what, when, and how. J Clin Epidemiol. 2017 Nov;91:23-30. | CrossRef | PubMed |
38. Akl EA, Haddaway NR, Rada G, Lotfi T. Future of Evidence Ecosystem Series: Evidence synthesis 2.0: when systematic, scoping, rapid, living, and overviews of reviews come together. J Clin Epidemiol. 2020 Jul;123:162-165. | CrossRef | PubMed |
39. Neumann I, Schünemann HJ. Guideline groups should make recommendations even if the evidence is considered insufficient. CMAJ. 2020 Jan 13;192(2):E23-E24. | CrossRef | PubMed |
40. Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. | CrossRef | PubMed |

World Health Organization. Director-General’s remarks at the media briefing on 2019-nCoV on February 11 2020. World Health Organization; 2020 [Accessed on April 8, 2020 ]. [Internet] | Link |

Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - The latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis. 2020 Feb;91:264-266. | CrossRef | PubMed |

Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020 May;20(5):533-534. | CrossRef | PubMed |

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. | CrossRef | PubMed |

Tavakoli A, Vahdat K, Keshavarz M. Novel Coronavirus Disease 2019 (COVID-19): An Emerging Infectious Disease in the 21st Century. Iran South Med J 2020, 22(6): 432-450. | CrossRef |

Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020 Jun;92(6):577-583. | CrossRef | PubMed |

Global Covid-19 Case Fatality Rates. UK: Centre for Evidence-Based Evidence. [Accessed on April 8, 2020 ]. [Internet] | Link |

Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020 Mar-Apr;34:101623. | CrossRef | PubMed |

Heikkinen T, Järvinen A. The common cold. The Lancet. 2003 Jan 4;361 (9351): 51-9. | CrossRef |

Hemilä H. Vitamin C intake and susceptibility to the common cold. Br J Nutr. 1997 Jan;77(1):59-72. | CrossRef | PubMed |

Gómez E, Quidel S, Bravo-Soto G, Ortigoza Á. Does vitamin C prevent the common cold?. Medwave. 2018 Aug 6;18(4):e7235. | CrossRef | PubMed |

Hemilä H, Chalker E. Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis. Nutrients. 2019 Mar 27;11(4):708. | CrossRef | PubMed |

Carr AC. A new clinical trial to test high-dose vitamin C in patients with COVID-19. Version 2. Crit Care. 2020 Apr 7;24(1):133. | CrossRef | PubMed |

Zabetakis I, Lordan R, Norton C, Tsoupras A. COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation. Nutrients. 2020 May 19;12(5):1466. | CrossRef | PubMed |

Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?. Med Drug Discov. 2020 Mar;5:100028. | CrossRef | PubMed |

Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009 Oct;62(10):1006-12. | CrossRef | PubMed |

Rada G, Verdugo-Paiva F, Ávila C, Morel-Marambio M, Bravo-Jeria R, Pesce F, et al. Evidence synthesis relevant to COVID-19: a protocol for multiple systematic reviews and overviews of systematic reviews. Medwave. 2020 Apr 1;20(3):e7868. | CrossRef | PubMed |

Baladía E, Pizarro A, Rada G. Vitamin C for COVID-19: A living systematic review protocol. medRxiv. 2020.04.28.20083360 | CrossRef |

Github repository [Accessed 2020 April 12]. [Internet] | Link |

Epistemonikos Database Methods. Santiago: Epistemonikos Foundation [Accessed 2020 April 12]. [Internet] | Link |

Methods for the special L·OVE of Coronavirus infection. Santiago: Epistemonikos Foundation [Accessed 2020 April 12]. [Internet] | Link |

Schünemann HJ, Cuello C, Akl EA, Mustafa RA, Meerpohl JJ, Thayer K, et al. GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence. J Clin Epidemiol. 2019 Jul;111:105-114. | CrossRef | PubMed |

Jin X, Pang B, Zhang J, Liu Q, Yang Z, Feng J, et al. Core Outcome Set for Clinical Trials on Coronavirus Disease 2019 (COS-COVID). Engineering (Beijing). 2020 Mar 18. | CrossRef | PubMed |

COVID-19 Core Outcomes. [Accessed 2020 April 12]. [Internet] | Link |

Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013 Feb;66(2):158-72. | CrossRef | PubMed |

Collaboratron [Software]. Santiago: Epistemonikos Foundation, 2017.

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. | CrossRef | PubMed |

Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016 Oct 12;355:i4919. | CrossRef | PubMed |

Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, et al. GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles-continuous outcomes. J Clin Epidemiol. 2013 Feb;66(2):173-83. | CrossRef | PubMed |

Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013 Feb;66(2):158-72. | CrossRef | PubMed |

Review Manager (RevMan) [Software]. Version 5.3.5 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr 26;336(7650):924-6. | CrossRef | PubMed |

Borah R, Brown AW, Capers PL, Kaiser KA. Analysis of the time and workers needed to conduct systematic reviews of medical interventions using data from the PROSPERO registry. BMJ Open. 2017 Feb 27;7(2):e012545. | CrossRef | PubMed |

Shojania KG, Sampson M, Ansari MT, Ji J, Doucette S, Moher D. How quickly do systematic reviews go out of date? A survival analysis. Ann Intern Med. 2007 Aug 21;147(4):224-33. | CrossRef | PubMed |

Coronavirus and the risks of ‘speed science’ Reuters; 2020 [Accessed 2020 April 12]. [Internet] | Link |

Kelly SE, Moher D, Clifford TJ. Quality of conduct and reporting in rapid reviews: an exploration of compliance with PRISMA and AMSTAR guidelines. Syst Rev. 2016 May 10;5:79. | CrossRef | PubMed |

Elliott JH, Synnot A, Turner T, Simmonds M, Akl EA, McDonald S, et al. Living systematic review: 1. Introduction-the why, what, when, and how. J Clin Epidemiol. 2017 Nov;91:23-30. | CrossRef | PubMed |

Akl EA, Haddaway NR, Rada G, Lotfi T. Future of Evidence Ecosystem Series: Evidence synthesis 2.0: when systematic, scoping, rapid, living, and overviews of reviews come together. J Clin Epidemiol. 2020 Jul;123:162-165. | CrossRef | PubMed |

Neumann I, Schünemann HJ. Guideline groups should make recommendations even if the evidence is considered insufficient. CMAJ. 2020 Jan 13;192(2):E23-E24. | CrossRef | PubMed |

Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. | CrossRef | PubMed |