With hundreds of thousands of new cases being reported every day, over a year after its onset, the coronavirus disease 2019 (COVID-19) pandemic is still making its presence felt worldwide. Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pandemic is estimated to be about ten-fold bigger than the number of reported infections.
It has proved difficult to contain the spread of SARS-CoV-2 because of the asymptomatic nature of a large percentage of infections, the high transmissibility of the virus, and its spread by direct contact, especially indoors.
A new study in the Journal of dietary supplements shows that nutritional supplements, including several vitamins and the mineral zinc, may be useful in preventing the infection or reducing its severity if caught.
Vaccination appears to be the only safe and effective route to achieve durable and global immunity and end the pandemic. Other short-term preventive methods include behavioral changes and non-pharmaceutical interventions, including mask-wearing in public, social distancing and hand washing.
Secondary prevention includes effective therapies that could disrupt the progression of the infection. Treatment options are limited, with remdesivir being among the few drugs to receive early approval for emergency use in COVID-19. Dexamethasone, tocilizumab, and hydroxychloroquine are among other drugs used on empirical grounds, with varying degrees of effectiveness.
The odds of severe COVID-19 are higher in people with risk factors such as cardiovascular disease, obesity, diabetes mellitus and lung disease, besides advancing age. The mechanism of severity operating to produce heightened risk in these conditions ranges from exaggerated inflammation to airway damage.
The association of severe COVID-19 with inflammatory conditions and weakened or altered immunity suggests that these are intrinsic to the clinical course.
Since dietary and nutritional measures are linked to marked changes in immunity, many have explored the effects of macro- and micronutrients in erecting a defense against this virus. Moreover, nutritional approaches are safe and possibly effective by their positive impact on immunity.
Old age is associated with immunosenescence as well as frailty, which in turn is linked to nutritional deficiencies of calcium, vitamin C, vitamin D, folate and zinc. Vitamin B3 deficiency could also be key to immune decline, since it is a precursor of nicotinamide adenine dinucleotide (NAD), a fundamental metabolic mediator.
Some researchers have therefore explored the possible advantages of using nutritional supplements, especially vitamin C, vitamin D, zinc, and B3 vitamins, as part of primary and secondary COVID-19 prevention.
Viral infections lead to cell damage and death through various mechanisms: hijacking the cellular energy metabolism pathways; suppressing cellular synthesis of biomolecules; competing for ribosomes; and competing for transcription factors. As the cell detects this process, it reacts with innate immune responses, which leads to more powerful and specific adaptive immunity eventually.
The work of Linus Pauling indicated the potential for vitamin C to reduce the severity of the common cold, as well as its duration. This has been confirmed by a meta-analysis of almost 30 studies. Moreover, vitamin C may also reduce or prevent other infections, including those caused by bacteria, viruses and protozoa, being a potent immunomodulator.
However, the benefits of vitamin C may be obvious only in those who are vitamin C deficient, and in children, and those with infections that cause metabolic complications resulting in a lowering of vitamin C levels.
Vitamin C is a very safe molecule. Its antioxidant activity is particularly effective in light of the high inflammatory and oxidative markers in COVID-19, especially hsCRP, and the cytokine storm, which is another marker of oxidative stress.
In one study of patients in an intensive care unit (ICU), and patients on mechanical ventilation because of acute inflammatory lung disease associated with oxidant damage, the use of vitamin C reduced the duration spent in the ICU and the outcome in ventilated patients.
One Chinese study showed that boluses of vitamin C given by intravenous infusion to COVID-19 patients, with repeated boluses if the condition was critical, improved the oxygenation status. All patients under treatment were discharged to home. Controlled trials of vitamin C therapy in patients hospitalized with severe COVID-19 are underway.
Vitamin D also has a vital role in immunity, as its active form interacts with the vitamin D receptor (VDR) on the nucleus of immune cells. It stimulates the generation of antimicrobial peptides, such as cathelicidins and defensins, broad-spectrum agents against a range of pathogens, thus bolstering innate immune responses.
On the other hand, it modulates the adaptive immune response, including inflammatory cytokine release. This could tone down cytokine levels in COVID-19, and thus prevent the cytokine storm that underlies severe COVID-19 presentations. It also helps maintain epithelial integrity via tight junctions, gap junctions and adherens junctions, reducing the odds that pathogens can pass through to the underlying tissues.
Vitamin D deficiency is thought to be a risk factor for COVID-19 among older people, Black individuals, those with a higher body mass index and smokers. Other immune disorders, including autoimmune conditions like rheumatoid arthritis, multiple sclerosis (MS), and inflammatory bowel disease, are found to be associated with low vitamin D levels.
Again, vitamin D deficiency is more common at regions farther to the north of the globe, where solar radiation is relatively less intense. MS sets in earlier in such regions, while type I diabetes and inflammatory bowel disease are more common. Moreover, the type of MS called relapsing-remitting MS is partially improved with supplemental vitamin D.
The case fatality rate in the 1918 influenza pandemic dropped as sunlight increased (specifically, ultraviolet B radiation). Other studies show that the number of cases of infectious diseases like the flu or septic shock varies with the season.
Recent studies indicate that in vitamin D-deficient people, vitamin D supplementation may help reduce the risk of respiratory infections. With COVID-19, the risk of being diagnosed with this condition was 1.8 times higher with vitamin D deficiency relative to adequate vitamin D status. The risk of hospitalization may also be higher in the former group.
Vitamin D reduces angiotensin-converting enzyme 2 (ACE2) levels. This molecule acts as an entry receptor for SARS-CoV-2, and at higher levels, it may increase vulnerability to more severe manifestations.
The first outbreak of the pandemic occurred, as did its spread, during the winter when vitamin D levels were likely to be reduced. During the first wave, the higher toll taken on dark-skinned people in the developed world could be due to their lower vitamin D levels. If so, the disparity would be expected to be less obvious as summer set in, and this has indeed occurred.
Vitamin D deficiency is also a risk factor for acute respiratory distress syndrome (ARDS), a common fatal complication of critical COVID-19.
Based on these findings, vitamin D intake has been advised in COVID-19 patients to push the serum concentrations above 40–60 ng/mL. Trials are ongoing to investigate the role of vitamin D.
Zinc is commonly present in every tissue and metallo-enzyme in the body but is deficient in about a third of human beings worldwide. Insufficient zinc intake has been linked to many health conditions, including skin disorders and cognitive issues. Immune function is also impaired. Phytate and fiber in the diet can reduce zinc absorption, putting those on a strictly vegetarian diet at a higher risk of zinc deficiency. This is also found in several chronic disease conditions.
Zinc is involved in innate and adaptive immune responses, from immune cell development onwards, through mucosal integrity. Supplementation with zinc has been found to reduce respiratory infections in children, and to cut short colds by a day.
Studies are ongoing to test the effects of zinc supplementation in COVID-19.
Vitamin B3 is a complex of three vitamins, namely, nicotinamide riboside (NR), nicotinamide (NAM), and nicotinic acid (NA), which are precursors of NAD+, a central catalyst of metabolism. NAD depletion is associated with poor immunity since cellular immune responses consume NAD.
Two components of the cell response to coronavirus infection include SIRT and PARP molecules, both of which compete for NAD. Reduced SIRT activation due to hyperactivation of PARPs leads to hyperinflammation, and a cytokine storm, with added oxidative stress due to viral activation.
The presence of highly reactive oxygen species (ROS) leads to further oxidative damage to DNA and cell membranes, with further PARP activation for repair processes to proceed. Type I interferons are triggered by some viruses, activating CD38, which further consumes NAD and also promotes further inflammation.
Vitamin B3 deficiency causes pellagra, and its supplementation could help avoid age-related frailty. Coronaviruses encode enzymes that oppose PARP pathway activation, thus preventing NAD depletion
Lymphocytopenia is a unique clinical feature of COVID-19 infection, unlike the rise that occurs in the lymphocyte count with other viral infections. One reason could be the high PARP activation levels during the innate immune response that depletes NAD and further modulates the adaptive immune response. Indeed, PARP upregulation with coronavirus infection has been confirmed in a recent paper.
Supplementation with B3 may thus boost both innate and adaptive immunity in COVID-19. NR appears to be the most suited for this purpose, with better pharmacological properties and a safety profile to match.
One recent trial showed that a combined nutritional supplement including NR with standard care shortened the recovery period in COVID-19 by a third, and larger studies are warranted with these findings.
What are the implications?
“Vitamins B3, C and D and Zinc have been shown to impact the initial innate immune response and/or modulate subsequent downstream processes related to viral infection.”
These early preclinical and clinical study findings form a solid grounding for further exploring the potential benefit of supplementation on COVID-19 incidence and severity.
Some important caveats apply. First, supplements are not regulated by the Food and Drug Administration (FDA) in the U.S. with the same rigor as prescription drugs. They require only that the agency be satisfied with the safety of New Dietary Ingredients (NDI, those ingredients brought to market after October, 1994).
Thus, quality and safety challenges may exist, and all claims made by the manufacturer may not be true. Their over-the-counter status may pose a problem if too much is ingested with some supplements. And thirdly, some conditions or sensitivities may rule out supplement use in some cases, as with those that thin the blood or interact with prescription drugs.
Another set of issues unique to COVID-19 is the difficulty of obtaining data from ambulatory patients due to the mandatory quarantine, which leaves home visits by the investigators as the only way out. Secondly, funding for nutritional approaches can be very costly, while this avenue is not a high priority.
Data support the model that essential nutrients may aid cellular defense and repair mechanisms and thus promote recovery and/or control of symptoms in late-stage disease, such approaches may be just as beneficial as pharmaceutical products.”