Does Evidence Exist to Blunt Inflammatory Response by Nutraceutical Supplementation during COVID-19 Pandemic? An Overview of Systematic Reviews of Vitamin D, Vitamin C, Melatonin, and Zinc.
More than one year has passed since the first cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus were reported in Wuhan (China), rapidly evolving into a global pandemic. This infectious disease has become a major public health challenge in the world. Unfortunately, to date, no specific antivirals have been proven to be effective against COVID-19, and although a few vaccines are available, the mortality rate is not decreasing but is still increasing. One therapeutic strategy has been focused on infection prevention and control measures. In this regard, the use of nutraceutical supports may play a role against some aspect of the infection, particularly the inflammatory state and the immune system function of patients, thus representing a strategy to control the worst outcomes of this pandemic. For this reason, we performed an overview including meta-analyses and systematic reviews to assess the association among melatonin, vitamin C, vitamin D, zinc supplementation and inflammatory markers using three databases, namely, MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews. According to the evidence available, an intake of 50,000 IU/month of vitamin D showed efficacy in CRP. An amount of 1 to 2 g per day of vitamin C demonstrated efficacy both in CRP and endothelial function, and a dosage of melatonin ranging from 5 to 25 mg /day showed good evidence of efficacy in CRP, TNF and IL6. A dose of 50 mg/day of elemental zinc supplementation showed positive results in CRP. Based on the data reported in this review, the public health system could consider whether it is possible to supplement the current limited preventive measures through targeted nutraceutical large-scale administration.
COVID-19: Up to 82% critically ill patients had low Vitamin C values.
Nutrition journal. 2021;(1):66
There are limited proven therapeutic options for the prevention and treatment of COVID-19. We underwent an observational study with the aim of measure plasma vitamin C levels in a population of critically ill COVID-19 adult patients who met ARDS criteria according to the Berlin definition. This epidemiological study brings to light that up to 82% had low Vitamin C values. Notwithstanding the limitation that this is a single-center study, it nevertheless shows an important issue. Given the potential role of vitamin C in sepsis and ARDS, there is gathering interest of whether supplementation could be beneficial in COVID-19.
Ascorbic acid as an adjunctive therapy in critically ill patients with COVID-19: a propensity score matched study.
Scientific reports. 2021;(1):17648
Ascorbic acid represents an appealing option for clinicians to utilize in the context of the global COVID-19 pandemic due to its proposed clinical efficacy, relative safety, and low cost. The aim of this study was to evaluate the efficacy and safety of using ascorbic acid in supplemental doses as adjunctive therapy for patients critically ill with COVID-19. This was a two-center, non-interventional, retrospective cohort study. All critically ill adult patients admitted to ICU with a confirmed COVID-19 diagnosis between March 1st and December 31st, 2020, were included in the final analysis. The study was conducted at two large governmental tertiary hospitals in Saudi Arabia. The purpose was to investigate the clinical outcomes of low-dose ascorbic acid as adjunctive therapy in COVID-19 after propensity score matching using baseline severity scores, systematic use of corticosteroids, and study centers. A number of 739 patients were included in this study, among whom 296 patients were included after propensity score matching. There was no association between the administration of ascorbic acid and in-hospital mortality or the 30-day mortality [OR (95% CI) 0.77 (0.47, 1.23), p value = 0.27 and OR (95% CI) 0.73 (0.43, 1.20), p value = 0.21, respectively]. Using ascorbic acid was associated with a lower incidence of thrombosis compared with the non-ascorbic-acid group [6.1% vs. 13% respectively; OR (95% CI) 0.42 (0.184, 0.937), p value = 0.03]. Low dose of ascorbic acid as an adjunctive therapy in COVID-19 critically ill patients was not associated with mortality benefits, but it was associated with a lower incidence of thrombosis. Further studies are required to confirm these findings.
High-dose vitamin C ameliorates cardiac injury in COVID-19 pandemic: a retrospective cohort study.
BACKGROUND Cardiac injury is common and associated with poor clinical outcomes in COVID-19. Data are lacking whether high-dose intravenous vitamin C (HIVC) could help to ameliorate myocardial injury in the pandemic. METHODS The retrospective cohort study included consecutive severe and critically ill COVID-19 patients with cardiac injury receiving symptomatic supportive treatments alone or together with HIVC. Troponin I and inflammatory markers were collected at admission and day 21 during hospitalization from the electronic medical records. RESULTS The patients (n = 113) were categorized into the ameliorated cardiac injury (ACI) group (n = 70) and the non-ameliorated cardiac injury (NACI) group (n = 43). Overall, fifty-one (45.1%) patients were administered with HIVC, the percentages of patients with HIVC were higher in the ACI group than those in the NACI group. Logistic regression analysis revealed that HIVC was independently associated with the improvement of myocardial injury. Further analysis showed that inflammatory markers levels significantly decreased at day 21 during hospitalization in patients with HIVC therapy compared to those administered with symptomatic supportive treatments alone. Meanwhile, similar results were also observed regarding changes in inflammatory markers levels from baseline to day 21 during hospitalization in the patients treated with HIVC. CONCLUSIONS HIVC can ameliorate cardiac injury through alleviating hyperinflammation in severe and critically ill patients with COVID-19.
Vitamin C in Critically Ill Patients: An Updated Systematic Review and Meta-Analysis.
BACKGROUND Vitamin C is a water-soluble antioxidant vitamin. Oxidative stress and its markers, along with inflammatory markers, are high during critical illness. Due to conflicting results of the published literature regarding the efficacy of vitamin C in critically ill patients, and especially the concerns for nephrotoxicity raised by some case reports, this meta-analysis was carried out to appraise the evidence and affirmation regarding the role of vitamin C in critically ill patients. METHODS We searched the database thoroughly to collect relevant studies that assessed intravenous vitamin C use in critically ill patients published until 25 February 2021. We included randomized controlled trials and observational studies with 20 or more critically ill patients who have received intravenous ascorbic acid (vitamin C). After screening 18,312 studies from different databases, 53 were included in our narrative synthesis, and 48 were included in the meta-analysis. We used the Covidence software for screening of the retrieved literature. Review Manager (RevMan) 5.4 was used for the pooling of data and Odds Ratios (OR) and Mean difference (MD) as measures of effects with a 95% confidence interval to assess for explanatory variables. RESULTS Pooling data from 33 studies for overall hospital mortality outcomes using a random-effect model showed a 19% reduction in odds of mortality among the vitamin C group (OR, 0.81; 95% CI, 0.66-0.98). Length of hospital stay (LOS), mortality at 28/30 days, ICU mortality, new-onset AKI and Renal Replacement Therapy (RRT) for AKI did not differ significantly across the two groups. Analysis of data from 30 studies reporting ICU stay disclosed 0.76 fewer ICU days in the vitamin C group than the placebo/standard of care (SOC) group (95% CI, -1.34 to -0.19). This significance for shortening ICU stay persisted even when considering RCTs only in the analysis (MD, -0.70; 95% CI, -1.39 to -0.02). CONCLUSION Treatment of critically ill patients with intravenous vitamin C was relatively safe with no significant difference in adverse renal events and decreased in-hospital mortality. The use of vitamin C showed a significant reduction in the length of ICU stays in critically ill patients.
Vitamin C and COVID-19 treatment: A systematic review and meta-analysis of randomized controlled trials.
Diabetes & metabolic syndrome. 2021;(6):102324
BACKGROUND AND AIMS Vitamin C has been used as an anti-oxidant in various diseases including viral illnesses like coronavirus disease (COVID-19). METHODS Meta-analysis of randomized controlled trials (RCT) investigating the role of vitamin C supplementation in COVID-19 was carried out. RESULTS Total 6 RCTs including n = 572 patients were included. Vitamin C treatment didn't reduce mortality (RR 0.73, 95% CI 0.42 to 1.27; I2 = 0%; P = 0.27), ICU length of stay [SMD 0.29, 95% CI -0.05 to 0.63; I2 = 0%; P = 0.09), hospital length of stay (SMD -0.23, 95% CI -1.04 to 0.58; I2 = 92%; P = 0.57) and need for invasive mechanical ventilation (Risk Ratio 0.93, 95% CI 0.61 to 1.44; I2 = 0%; P = 0.76). Further sub-group analysis based on severity of illness (severe vs. non-severe), route of administration (IV vs. oral) and dose (high vs. low) failed to show any observable benefits. CONCLUSION No significant benefit noted with vitamin C administration in COVID-19. Well-designed RCTs with standardized control group needed on this aspect.
'Colouring' wipes phenomenon: a peculiar skin pigmentation induced by ascorbic acid observed during lockdown.
Clinical and experimental dermatology. 2021;(6):1075-1078
During the SARS-CoV-2 (COVID-19) pandemic, an unusual outbreak of yellow-brown pigmentation on the skin of children was reported. Because of the restrictions on movement promulgated during the lockdown, most consultancies were performed using teledermatology. Data concerning personal care products and application of topical substances were collected, which revealed use of the same brand of wipes for all patients. A liquid chromatography-mass spectrometry analysis was performed to compare the components of the wipes before and after the observation of the pigmentation, in order to detect the responsible substance. This analysis revealed a level about 10-fold higher than normal of ascorbic acid and its oxidation products (dehydroascorbic acid and L-threonic acid) in the wipes associated with the pigmentation. These 'colouring wipes' represent a peculiar but harmless phenomenon that highlights the importance of careful questioning about personal care products used by patients.
Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial.
BMJ open. 2020;(7):e039519
INTRODUCTION The rapid worldwide spread of COVID-19 has caused a global health crisis. To date, symptomatic supportive care has been the most common treatment. It has been reported that the mechanism of COVID-19 is related to cytokine storms and subsequent immunogenic damage, especially damage to the endothelium and alveolar membrane. Vitamin C (VC), also known as L-ascorbic acid, has been shown to have antimicrobial and immunomodulatory properties. A high dose of intravenous VC (HIVC) was proven to block several key components of cytokine storms, and HIVC showed safety and varying degrees of efficacy in clinical trials conducted on patients with bacterial-induced sepsis and acute respiratory distress syndrome (ARDS). Therefore, we hypothesise that HIVC could be added to the treatment of ARDS and multiorgan dysfunction related to COVID-19. METHODS AND ANALYSIS The investigators designed a multicentre prospective randomised placebo-controlled trial that is planned to recruit 308 adults diagnosed with COVID-19 and transferred into the intensive care unit. Participants will randomly receive HIVC diluted in sterile water or placebo for 7 days once enrolled. Patients with a history of VC allergy, end-stage pulmonary disease, advanced malignancy or glucose-6-phosphate dehydrogenase deficiency will be excluded. The primary outcome is ventilation-free days within 28 observational days. This is one of the first clinical trials applying HIVC to treat COVID-19, and it will provide credible efficacy and safety data. We predict that HIVC could suppress cytokine storms caused by COVID-19, help improve pulmonary function and reduce the risk of ARDS of COVID-19. ETHICS AND DISSEMINATION The study protocol was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (identifiers: Clinical Ethical Approval No. 2020001). Findings of the trial will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER NCT04264533.
Mini-Review on the Roles of Vitamin C, Vitamin D, and Selenium in the Immune System against COVID-19.
Molecules (Basel, Switzerland). 2020;(22)
Low levels of micronutrients have been associated with adverse clinical outcomes during viral infections. Therefore, to maximize the nutritional defense against infections, a daily allowance of vitamins and trace elements for malnourished patients at risk of or diagnosed with coronavirus disease 2019 (COVID-19) may be beneficial. Recent studies on COVID-19 patients have shown that vitamin D and selenium deficiencies are evident in patients with acute respiratory tract infections. Vitamin D improves the physical barrier against viruses and stimulates the production of antimicrobial peptides. It may prevent cytokine storms by decreasing the production of inflammatory cytokines. Selenium enhances the function of cytotoxic effector cells. Furthermore, selenium is important for maintaining T cell maturation and functions, as well as for T cell-dependent antibody production. Vitamin C is considered an antiviral agent as it increases immunity. Administration of vitamin C increased the survival rate of COVID-19 patients by attenuating excessive activation of the immune response. Vitamin C increases antiviral cytokines and free radical formation, decreasing viral yield. It also attenuates excessive inflammatory responses and hyperactivation of immune cells. In this mini-review, the roles of vitamin C, vitamin D, and selenium in the immune system are discussed in relation to COVID-19.
Vitamin C for COVID-19: A living systematic review.
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.