Safety and effectiveness of high-dose vitamin C in patients with COVID-19: a randomized open-label clinical trial

The coronavirus disease 2019 (COVID-19) pandemic which started at late 2019 and spread the world outrageously is caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a member of the coronaviridae family. By January 2021, more than two million lives have been sacrificed by this disease, even more deaths are expected unless proper management does not take into place soon, in terms of prevention, transmission control, and treatment. Ascorbic acid or ascorbate (vitamin C) is an essential water-soluble nutrient that functions as a key antioxidant and is involved in the synthesis of collagen and neurotransmitters, and affects wound healing, energy metabolism, nervous system function, and immune cell health [1‐3]. The serum level of this vitamin has been correlated with its effect on the endothelial function [4], cellular immune function [5], anti-oxidative capacity, neutrophil function [6], and even for treatment of cancer and pancreatitis [7, 8]. Intravenous (IV) administration increases the plasma ascorbate concentrations more than oral supplementation (30 mM vs. 0.2 mM, respectively) [9, 10].

The evidence behind theoretical possible effect of vitamin C against COVID-19 is promising [11]. In a clinical study of the role of ascorbic acid against Epstein–Barr virus (EBV) infection showed the EBV IgG and IgM antibody levels reduced during IV vitamin C therapy [12]. Also in a case report of enterovirus/rhinovirus-induced acute respiratory distress syndrome (ARDS) in 2017, infusion of high-dose IV vitamin C (HDIVC) was associated with rapid resolution of lung injury [13]. The impact of vitamin C administration on alleviating lung injury has also been investigated and supported in other studies [14]. There are other studies expressing the positive effect of IV vitamin C in patients with severe sepsis [15‐17]. A meta-analysis also reported the impact of vitamin C on decreasing the duration of intensive care unit (ICU) admission and mechanical ventilation care in patients with ARDS [18‐20].

Given the positive effect of IV vitamin C for viral-induced ARDS and its role for enhancing the function of immune system, we aimed to investigate the correlation of the HDIVC administration with improvement of 2019-nCoV-induced ARDS. There is lack of data and clinical trials that studied this correlation recently.

Until the time of this study, no definite treatment option has been suggested and cleared for COVID-19. While this pandemic is still responsible for death of above two million people and infection of many more, search for better treatment options should never be delayed [22, 23]. Vitamin C is an essential water-soluble nutrient that has important roles in our body, especially in immune cell functions [1, 2, 4]. Studies report that vitamin C can be effective in treatment of bacterial and viral infection [24‐26]. These studies showed vitamin C weakly inhibits the multiplication of viruses such as influenza type A, Herpes simplex virus type 1 (HSV-1) and poliovirus type 1. A clinical study showed the effect of IV vitamin C therapy on reduction of IgG and IgM antibody levels in EBV infection [12]. There is also a report of a case of enterovirus/rhinovirus-induced ARDS where the infusion of HDIVC was associated with rapid resolution of lung injury [13].

Some studies showed that serum vitamin C levels may plummet in some patients especially in the critically ill during the course of infection [27, 28]; and vitamin C deficiency may contribute to organ injury and immune dysfunction which leads to the assumption that high doses of vitamin C might improve clinical outcomes of critically ill patients [27]. There is also some evidence that shows vitamin C may reduce patients’ susceptibility to lower respiratory tract infections such as pneumonia and it may have a protective role in lung infections, but further studies need to evaluate the efficacy of treatment with vitamin C in severe viral respiratory tract infections [27‐31].

Meta-analyses demonstrated that the use of intravenous vitamin C as a therapy for sepsis and ARDS has benefits such as a lower rate of vasopressor requirements, shorter duration of both mechanical ventilation and admission in the ICUs; along with a shorter hospital admission in critically ill patients [19, 32‐34]. Lin et al. found that administration of more than 50 mg/kg daily vitamin C had a significant effect in reduction of mortality rate in patients with severe sepsis. They concluded that a better survival rate correlated with administration of high doses of vitamin C [35]. Fowler et al. reported in their randomized, double-blind, placebo-controlled, multicenter trial that high doses of vitamin C did not significantly improve organ dysfunction scores in patients with severe sepsis or ARDS but in three secondary outcomes, use of vitamin C was associated with a significantly lower risk of mortality on the 28th day after diagnosis of the infection (29.8% vs. 46.3%), a higher number of ventilator-free days (13.1 vs. 10.6 days) and a higher number of ICU-free days (10.7 vs. 7.7 days) [36].

All these findings emphasize possible beneficial effects of vitamin C as a treatment for COVID-19. Here, we conducted a randomized clinical trial with 60 patients in two groups. Thirty patients were treated with 1.5 g of IV vitamin C, every 6 h for 5 days in addition to the main treatment regimen (case group), whereas the other 30 patients were treated only with the standard regimen. Demographic characteristics, underlying diseases, and clinical and laboratory findings were not significantly different between the two groups. Fever and myalgia were significantly more frequent in the control group but, other clinical findings were not notably different. SpO₂ was improved in all patients. There is a similar report of SpO₂ improvement associated with treatment with HDIVC (doses range from 2 to 10 g per day in 8–10-h IV infusions) in 50 moderate-to-severe COVID-19 patients. They also reported that all patients were cured and discharged [37]. However, the absence of a control group weakened the conclusions based on this report.

In the present study, there was no significant difference in oxygen SpO₂ levels between the two groups at discharge, but the median of SpO₂ levels were significantly higher in the case group on the 3rd day of admission. The mean body temperature significantly decreased during the admission in both groups and there was no significant difference between two groups regarding the core body temperature at discharge but, on the 3rd day of treatment, the mean of patients’ body temperature was significantly lower in the case group. Length of stay in the hospital had a median of 8.5 days and it was unexpectedly higher in the case group (8.5 vs. 6.5, p = 0.028). Other outcomes including number of deaths, number of intubations and duration of ICU admission were not significantly different between two groups. We did not find any side effects in the patients. Other studies also reported good tolerance of HDIVC in their trials [38].

There are not enough data and clinical trials that have evaluated the correlation between HDIVC treatment in COVID-19 patients with ARDS and improvement of their status, but there are several ongoing studies that aim to investigate the impact of high-dose vitamin C on COVID-19 patients (details of ongoing studies are presented in Table 2). Investigators in these studies will assess primary outcomes such as 50% reduction in symptoms score in 28 days, incidence of adverse effects (including severe adverse reactions), time to clinical improvement (TTIC), TTIC of National Early Warning Score 2 (NEWS2), number of hospital admission days, the rate of decline in lung infection rate, in-hospital mortality rates and number of ventilator-free days. The findings of these studies will be valuable and we hope to see promising results in their studies.

It is worthy to note that some studies have used higher doses of vitamin C in their patients [39, 40]. The highest dose was used in the work of Zhang et al. who have used 24 g daily in the form of 12 g of vitamin C/50 ml every 12 h for 7 days at a rate of 12 ml/h. Although they did not find superior results in terms of improving invasive mechanical ventilation-free days in 28 days (IMVFD28), but have found improving PaO2/FiO2 and hence benefiting oxygenation for critically ill patients [39]. Marik et al. also suggested MATH + protocol for COVID-19 patients, including methylprednisolone, ascorbic acid, thiamine, heparin, and supplemental oxygen. They suggest using vitamin C 3 g IV q 6 hourly for at least 7 days or until transferred out of ICU [40]. There are also other large randomized controlled trials (RCTs) using different doses of vitamin C. The largest RCT is the Lessening Organ Dysfunction with Vitamin C-COVID (LOVIT-COVID) trial in Canada assessing efficacy of 50 mg/kg every 6 h vitamin C, i.e., equivalent to 15 g/day for a 75 kg person (NCT04401150). Another large study is underway in Italy recruiting 500 patients in whom use of 10 g vitamin C is being tested. [NCT04323514] Although the results of these trials will also help our understanding of the preferred dose of vitamin C in COVID-19 patients, the available results point to the fact that higher doses can also be safe and effective (compared to the six g daily dose used in this study).

Another important topic is the length of vitamin C administration. Some studies suggest better outcome by administering vitamin C for longer duration, i.e., for at least 7 days [40]. However, a recent meta-analysis and systematic review of 17 studies reporting the effect of vitamin C supplementation in COVID-19 concluded that the best duration for administering vitamin C is over 3–4 days, with lower efficacy if used less than 3 days or more than 5 days [41].

Despite practicing proper randomization, certain factors were different between two groups (higher rate of myalgia and mean body temperature in control group), which can be overcome by having a larger patient population. Although by clinical judgment, one can assume that myalgia does not have much role in the prognosis of patients and given its subjectivity, it is of lower significance compared to other important prognostic factors. Also for body temperature, in this study more emphasis was put on the progression of patient symptoms. By viewing the results at different days of hospitalization, one can see that at discharge, both groups had values below the threshold of considering as fever. Although there was a difference between groups (36.76 vs. 36.85), still this value is not considered in the threshold of fever.

Our study has its own limitations, which can be covered in the future studies. The open-label design of the study and relatively small patient population are the main limitations. Further randomized double-blind clinical trials with more patient population can be beneficial.

In this study, we found that there were improvements in peripheral oxygen saturation and body temperature in both groups during the time of admission, but we did not find significantly better outcomes in the group who were treated with high-dose vitamin C in addition to the main treatment regimen at discharge.