Evaluating the Efficacy of Adjunctive Therapies Used to Treat COVID-19: The Role of Vitamin C and Zinc

Multiple OTC products have been proposed to treat coronavirus 2019 (COVID-19), but their true role remains unclear. Vitamin C and zinc are among the adjuvant treatments being evaluated for patients with COVID-19 due to their various immune-enhancing properties and possible antiviral effects.

Vitamin C

Vitamin C, at doses higher than usually seen in outpatient care, has been shown to improve mortality in sepsis and to have positive clinical results in patients suffering from viral infections.^1,2 The exact mechanism of vitamin C’s beneficial effects is unclear; however, it is known that vitamin C is a potent antioxidant with immunomodulatory properties and significantly concentrates in important immune cells.¹

It supports the function and proliferation of lymphocyte cells and enhances phagocytic capacity and oxidative killing by neutrophils. Its additional antioxidant properties make it extremely beneficial to clearing harmful reactive oxygen species (ROS) used by immune cells to deactivate viruses, but also cause inflammation and harm to human cells.¹ ROS are especially critical in patients with respiratory disease as they cause damage to the lungs.¹ This could contribute to the inflammatory storm that affects patients with severe COVID-19. Having a powerful antioxidant to clear the ROS may be helpful in symptomatic COVID-19 patients.

Studies have shown possible clinical benefits in patients with other viruses, including herpes zoster, varicella zoster, and influenza through an unclear antiviral mechanism.¹ It is proposed this may occur with coronaviruses as well.

For example, studies have indicated that vitamin C helps to prevent the common cold, caused by another coronavirus, in patients whose bodies had undergone physical stress. Vitamin C also reduced the duration and severity of cold symptoms in supplementation trials.³ Additionally, vitamin C has shown some benefit in sepsis patients and, though still under investigation, may prove to be helpful in severe COVID-19 patients.²

A study conducted in 2019 of sepsis patients with acute respiratory distress syndrome (ARDS) (n = 167) demonstrated a lower 28-day mortality rate and increased number of ICU-free and hospital-free days in patients randomized to intravenous (IV) vitamin C (50 mg/kg every 6 hours) compared with placebo.⁴ As ARDS is a major complication in severe COVID-19, it is possible that vitamin C may prove beneficial. These were secondary outcomes though and consistent results in studies in which they are evaluated as primary outcomes are needed to confirm the findings.

One precaution noted from previous vitamin C trials is that it can alter the results from typical point-of-care glucose testing, causing blood glucose levels to be erroneously high, which in turn may result in too highs dose of insulin.⁵ One solution for this problem could be to monitor serum blood glucose levels rather than point-of-care levels in hospitalized patients receiving high dose vitamin C. Other possible adverse effects of note include hypernatremia, oxalate nephropathy, and hemolysis in G6PD deficiency patients, but these were rare.⁵

Several studies are underway to evaluate the effects of vitamin C in the treatment of COVID-19. One phase 2 study is evaluating how high dose IV vitamin C (12 g infused over 4 hours every 12 hours for 7 days) treatment affects severe COVID-19 associated pneumonia.⁶ A phase 3 trial in Canada is studying the effects of vitamin C (50 mg/kg IV every 6 hours for 4 days) on organ dysfunction and mortality in COVID-19.⁷ The results for both of these studies are set to be available this fall and will provide more evidence to determine what, if any, role vitamin C has in the treatment of COVID-19.

Zinc

Zinc is naturally found in the body and is the second-most abundant trace element.⁸ It has been taken OTC for years to relieve symptoms of viruses such as the common cold or influenza. Unlike vitamin C, zinc’s antiviral mechanism is more established. It inhibits RNA-dependent RNA polymerase necessary for viral replication, including viruses such as influenza and COVID-19.⁸

In COVID-19, zinc appears to work synergistically with hydroxychloroquine (HCQ) and chloroquine, whose mechanism increase the uptake of zinc into host cells.⁹ This allows more zinc to reach the infected host cells to exert its inhibiting action upon viral polymerase.

A retrospective analysis conducted at the NYU Langone Health hospitals across New York City evaluated the addition of zinc to HCQ plus azithromycin (n=411) compared with HCQ plus azithromycin alone (n=521).¹⁰ The addition of zinc sulfate (220 mg capsule containing 50 mg elemental zinc twice daily for five days) was associated with a decrease in mortality or transition to hospice (OR 0.449, 95% CI 0.271-0.744, p=0.002) and increased frequency of being discharged home (OR 1.53, 95% CI 1.12-2.09, p=0.008) among patients who did not require ICU level of care.¹⁰

This association was not significant in severe patients who were treated in the ICU.¹⁰ The study did not evaluate zinc monotherapy or in addition to each drug alone. With current uncertainty of HCQ’s role in COVID-19, whether zinc without HCQ is helpful is unclear, but studies underway should provide such data in the coming year.

Conclusion

Although further studies are needed to establish a firm recommendation regarding the use of vitamin C and zinc in the treatment of COVID-19 positive patients, their past success in other viruses and sepsis, ease of access, relatively low price, and strong safety profiles makes them attractive choices as adjuvant therapies.

The data available are primarily limited to hospitalized patients. Whether they will be beneficial in outpatients with less severe disease also remains to be determined. As with so many other aspects of COVID-19, it is important for pharmacists to be aware of the ongoing studies and adapt accordingly as more robust information becomes available.

References

• Colunga Biancatelli RML, Berrill M, Marik PE. The antiviral properties of vitamin C. Expert Rev Anti Infect Ther. 2020 Feb;18(2):99-101. doi: 10.1080/14787210.2020.1706483. Epub 2019 Dec 23.
• Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid. Nutrients. 2018 Nov 14;10(11):1762. doi: 10.3390/nu10111762.
• Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD000980. doi:10.1002/14651858.CD000980.pub4.
• Fowler AA III, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019 Oct 1;322(13):1261-1270. doi:10.1001/jama.2019.11825. Erratum in: JAMA. 2020 Jan 28;323(4):379.
• Yanase F, Fujii T, Naorungroj T, et al. Harm of IV High-Dose Vitamin C Therapy in Adult Patients: A Scoping Review. Crit Care Med. 2020 May 13. doi: 10.1097/CCM.0000000000004396. Epub ahead of print.
• Wu R, Wang L, Kuo HD, et al. An Update on Current Therapeutic Drugs Treating COVID-19. Curr Pharmacol Rep. 2020 May 11:1-15. doi: 10.1007/s40495-020-00216-7. Epub ahead of print.
• ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). IdentifierNCT04401150, Lessening Organ Dysfunction With VITamin C - COVID-19 (LOVIT-COVID); 2020 May 26 [cited 2020 Jun 15]; [about 3 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT04401150
• Shittu MO, Afolami OI. Improving the efficacy of Chloroquine and Hydroxychloroquine against SARS-CoV-2 may require Zinc additives - A better synergy for future COVID-19 clinical trials. Infez Med. 2020 Ahead of print Jun 1;28(2):192-197.
• Xue J, Moyer A, Peng B, et al. Chloroquine is a zinc ionophore. PLOS One. 2014 Oct 1;9(10):e109180. doi: 10.1371/journal.pone.0109180.
• Carlucci P, Ahuja T, Petrilli CM, et al. 2020. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. medRxiv doi: 10.1101/2020.05.02.20080036. [cited 2020 Jun 15]. Available from: https://www.medrxiv.org/content/10.1101/2020.05.02.20080036v1