The role of nutrition in supporting immune system function has been well recognized. Inadequate levels of certain nutrients can lead to a decreased resistance to infections and thus, an increase in disease burden (1).

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There are specific nutrients that play key roles in maintaining the integrity and function of the immune system, namely vitamin D, vitamin C, and zinc. Indeed, a growing number of studies are being published showing the importance of these nutrients to prevent, treat and reduce the severity of acute respiratory infections, including COVID-19. There are many ongoing clinical trials and in this article, we review the scientific evidence up to date about the associations between these nutrients and COVID-19.

 

Vitamin D

Several studies before the COVID-19 outbreak had already shown that vitamin D decreases acute respiratory infections (e.g. (2)). This, together with other observational evidence - including the fact that the outbreak occurred in winter (when vitamin D levels are lowest), that the number of cases in the Southern Hemisphere near the end of summer is low, and that fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower vitamin D levels (3) – have led many researchers last year to discuss the role of vitamin D in reducing the risk of COVID-19 (e.g. (4)). This discussion was based on several observational studies. For example, a study showed that 82.2% of 216 hospitalized COVID-19 cases have vitamin D deficiency (5).

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Another study analyzed vitamin D data and its relationship with morbidity and mortality in 20 European countries (6). They observed that the lower the mean levels of vitamin D, the higher the number of COVID-19 cases and mortality per 1 million people in those countries. They further noted that vitamin D levels are severely low in the elderly populations of Spain, Italy, and Switzerland, which happened to also be the most vulnerable group to COVID-19.

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Several other studies have also suggested that vitamin D deficiency may increase the severity of COVID-19, namely upper respiratory tract infections and thrombotic episodes (e.g.(7))

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In another observational study published in Scientific Reports, 91 asymptomatic COVID-19 patients and 63 severely ill COVID-19 patients requiring intensive care were included (8). They found that the prevalence of vitamin D deficiency was 3 times higher in the severely ill group (97% vs 33%), inflammatory markers (IL-6, ferritin, TNFα) were higher in vitamin D deficient patients, and the fatality rate was 7 times higher in vitamin D deficient patients (21% vs 3%). Given these remarkable results, the authors recommended a “mass administration of vitamin D supplements to population at risk for COVID-19” (8).

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In a prospective pilot study, 76 hospitalized patients with COVID-19 were included (9). All 76 patients received standard therapy, but 50 of these patients received also vitamin D3. They found that of the 50 patients treated with vitamin D3, 1 required intensive care, no one died and all were discharged without complications. However, of the 26 patients not treated with vitamin D3, 13 required intensive care and 2 died. These are quite impressive results.

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Not only does vitamin D deficiency seems to increase the severity of the disease and improve the course of the disease, but it also seems to increase the chances of being diagnosed with COVID-19. A large study including over 190,000 people observed that the COVID-19 positivity rate was strongly and inversely associated with vitamin D levels (10). This relationship persisted across latitudes, races/ethnicities, both sexes, and age ranges.

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The mechanisms through which vitamin D confers its protective effect include inducing cathelicidins and defensins that can lower viral replication rates, reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs (leading to pneumonia), and increasing concentrations of anti-inflammatory cytokines (3).

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Based on all these remarkable findings, scientists are recommending vitamin D supplementation, especially in populations at risk (3).

 

Vitamin C

Vitamin C has antioxidant, anti-inflammatory, and immunomodulating effects and several studies have shown it plays an important role as an adjunctive therapy in the critical care of COVID-19 patients.

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It has been argued that while the average requirement of 90 mg/day for men and 80mg/day for women may be sufficient to prevent scurvy, it may be inadequate when a person is undergoing a viral infection and physiological stress. Indeed, plasma vitamin C levels decline rapidly under conditions of physiological stress such as infection and may result in vitamin C deficiency in hospitalized patients  (11, 12). Low vitamin C levels and elevated oxidative stress are common in critically ill hospitalized patients with respiratory infections, pneumonia, and sepsis (13). This is thought to be due to increased metabolic consumption of vitamin C (14). 

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People with vitamin C deficiency may have a higher susceptibility to severe respiratory infections, such as pneumonia. A prospective study of 19,357 men and women followed over 20 years found that people in the top quartiles of baseline plasma vitamin C concentrations had a 30% lower risk of pneumonia (15). Indeed, the evidence to date indicates that oral vitamin C (2–8 g/day) may reduce the incidence as well as the duration and severity of respiratory infections, and intravenous vitamin C (6–24 g/day) could reduce mortality, intensive care, and hospital stays, and time on mechanical ventilation for severe respiratory infections, as reviewed recently in (14). Similar findings were observed in critically ill patients with sepsis. A randomized controlled trial in 167 patients with sepsis-related acute respiratory distress syndrome indicated that administration of 15 g/day of intravenous vitamin C for 4 days decreased mortality in these patients (16). Given that pneumonia and sepsis could be complications of severe COVID-19, these results are highly relevant for COVID-19 as well.

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Studies have related the severity of COVID-19 infection with low levels of vitamin C (17). There are currently many randomized controlled trials registered globally that are assessing intravenous vitamin C in COVID-19 patients. However, there are already some preliminary data and case reports.

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In a randomized controlled trial carried out in Wuhan, China, 54 ventilated COVID-19 patients were treated with a placebo (sterile water) or intravenous vitamin C at a dose of 24 g/day for 7 days (18). They found that blood oxygenation and inflammatory markers improved, and the mortality rate after 28 days was reduced in severely ill patients (18% versus 50%). No adverse events were found.

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A pilot study of 21 critically ill COVID-19 patients found low serum levels of vitamin C, and the mean vitamin C level for the survivors was double the levels for the non-survivors (29 vs 15 µmol/L) (19).

A case study reported a dramatic and fast recovery of a critical COVID-19 patient after intravenous vitamin C injection (11g/day) (20).

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A group of emergency medicine experts, the Frontline COVID-19 Critical Care Expert Group (FLCCC), developed a protocol called MATH+, which includes the combined use of 6 g/day intravenous vitamin C, steroids, and anticoagulants. They reported that with this protocol mortality was 5% in two intensive care units in the US, which were the lowest in their counties (21).

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The action of vitamin C seems to be through the increased antiviral cytokines and free radical formation, which decreases viral yield, and also attenuation of excessive inflammatory responses and hyperactivation of immune cells (22).

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There is also evidence that vitamin C and the bioflavonoid quercetin co-administration exerts a synergistic antiviral action due to antiviral and immunomodulatory properties, and the capacity of vitamin C to recycle quercetin, increasing its efficacy (23).

 

Zinc

Another nutrient that plays a very important role in our immune system's ability to fight off viral infections is zinc. Zinc is a trace element with immunoregulatory, antioxidant, anti-inflammatory, and anti-viral properties. Zinc's primary antiviral action is to impair viral replication inside the cell (24).

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Zinc gluconate, zinc acetate, and zinc sulphate have been shown to reduce the severity and duration of viral infections such as the common cold (25-27).

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Since zinc cannot easily cross the cell membranes, it is important to be taken with a zinc ionophore (a zinc transport molecule) such as quercetin and epigallocatechin-gallate (EGCG) (24). Indeed, it has been shown that increasing the intracellular zinc concentration with zinc-ionophores can efficiently impair the replication of many RNA viruses, including poliovirus, influenza virus, and SARS-coronavirus (24). 

 

In a prospective study, fasting zinc levels in 47 COVID-19 patients at the time of hospitalization was measured and compared with those of 45 healthy controls (28). COVID-19 patients showed significantly lower zinc levels when compared to healthy controls (74.5 μg/dl vs 105.8 μg/dl). Among the COVID-19 patients, 27 had zinc deficiency. These patients had higher rates of complications, acute respiratory distress syndrome, corticosteroid therapy, prolonged hospital stay, and increased mortality.

 

In a retrospective observational study including 249 COVID-19 patients, a correlation between serum zinc levels and COVID-19 outcome was observed (29). Serum zinc levels lower than 50 µg/dl at admission correlated with worse clinical presentation, longer time to reach stability, and higher mortality, and low zinc levels favored viral expansion in infected cells.

 

Conclusions

Current data clearly shows interesting and important correlations between low vitamin D, vitamin C, and zinc and a poor COVID-19 outcome. While larger studies are still warranted, there are already promising results from pilot studies regarding the amelioration of COVID-19 with high dose supplementation of these nutrients.

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References

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15.    Myint PK, Wilson AM, Clark AB, Luben RN, Wareham NJ, Khaw KT. Plasma vitamin C concentrations and risk of incident respiratory diseases and mortality in the European Prospective Investigation into Cancer-Norfolk population-based cohort study. European journal of clinical nutrition. 2019;73(11):1492-500.

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16.    Fowler AA, 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, 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;322(13):1261-70.

 

17.    Patterson T, Isales CM, Fulzele S. Low level of vitamin C and dysregulation of vitamin C transporter might be involved in the severity of COVID-19 infection. Aging and disease. 2021;12(1):14-26.

 

18.    Zhang J, Rao X, Li Y, Zhu Y, Liu F, Guo G, et al. High-dose vitamin C infusion for the treatment of critically ill COVID-19. preprint. 2021.

 

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20.    Waqas Khan HM, Parikh N, Megala SM, Predeteanu GS. Unusual Early Recovery of a Critical COVID-19 Patient After Administration of Intravenous Vitamin C. The American journal of case reports. 2020;21:e925521.

 

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27.    Kurugol Z, Akilli M, Bayram N, Koturoglu G. The prophylactic and therapeutic effectiveness of zinc sulphate on common cold in children. Acta paediatrica. 2006;95(10):1175-81.

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29.    Vogel-González M, Talló-Parra M, Herrera-Fernández V, Pérez-Vilaró G, Chillón M, Nogués X, et al. Low zinc levels at clinical admission associates with poor outcomes in COVID-19. preprint. 2020.