March 2021 Issue
COVID-19 and the Role of Micronutrients
By Jamie Santa Cruz
Today’s Dietitian
Vol. 23, No. 3, P. 30
Research suggests certain vitamins and minerals may play a preventive and therapeutic role in fighting the coronavirus.
National distribution of vaccines to protect against COVID-19 continues, and drug therapies geared toward mitigating the severity of the disease to reduce hospital stays and mortality rates have improved patient outcomes. However, for the past several months there’s been much discussion on whether nutrition strategies can play an important role in reducing the risk of contracting the disease and improving the prognosis of those who become infected and ill. In particular, various micronutrients can significantly impact the functioning of the immune system and aid the body in fighting off COVID-19. In this article, Today’s Dietitian evaluates several of the key micronutrients that may have beneficial effects against COVID-19.
Micronutrients and Immune Function
There are several ways in which the immune system combats viral pathogens. First, it builds up barriers to prevent pathogens from entering the body. Some of these barriers, such as the epithelial layers in the gastrointestinal tract or respiratory tract, are physical; others are biological or chemical (antimicrobial molecules and the low pH of the stomach are two examples of chemical barriers).1
Second, the immune system identifies and eliminates pathogens. Phagocytes such as macrophages and dendritic cells engulf invading viruses and digest them. T lymphocyte immune cells stimulate B lymphocyte cells to produce antibodies that bind to bacteria or viruses, neutralizing the pathogens. Natural killer cells eliminate cells in the body that have become infected with the invading pathogen. Natural killer cells and T lymphocytes also produce interferons, which inhibit the replication of viruses.1
Third, the immune system creates an immunological memory of the pathogen, allowing for rapid defense against that pathogen if the host encounters it again. The main ways the immune system cultivates this memory is through the production of antibodies and memory T and B lymphocytes.1
Micronutrients are essential in all of the above processes. They contribute to the maintenance of the body’s epithelial barriers, aid in the production of antimicrobial molecules, regulate the production of inflammatory cytokines that stimulate other parts of the immune system, assist in the maturation and proliferation of immune cells, inhibit the replication of viruses in the body, promote phagocytosis of infected cells, and stimulate the production of antibodies.
“Normal states of nutrition really help maintain a functioning immune system,” says Keiy Murofushi, MS, RD, director of food and nutrition services at Cedars-Sinai Medical Center in West Hollywood, California, and moderator of a presentation at the 2020 Food & Nutrition Conference & Expo™ on the role of nutrition in supporting the immune system in COVID-19. “[With] certain types of nutrients, when they are at low values, your risks for having more adverse reactions are higher. So a focus of a lot of the research is on making sure—particularly in older individuals, who are particularly vulnerable to COVID-19—that they are of normal nutrition status.”
Vitamin C
One of the chief components of the immune system is vitamin C—for several reasons. “Vitamin C [is] key for the integrity of the epithelial barrier, for the function of the leucocytes, the macrophages, and the lymphocytes,” says Cristina Palacios, PhD, an associate professor of dietetics and nutrition at Florida International University and participant in an expert panel that compiled nutrition recommendations for essential workers exposed to COVID-19 in Latin America. Vitamin C promotes phagocytosis, contributes to the function of natural killer cells, and promotes production of antibodies.1 It’s also a powerful antioxidant, which is important because phagocytic cells produce reactive oxygen species as part of their defense against infection.2 These reactive oxygen species can in turn damage immune cells, necessitating an adequate supply of antioxidants to neutralize the threat.
Although vitamin C supplementation doesn’t reduce the risk of common colds,3 a meta-analysis found that it lowers risk of pneumonia, especially in people with low dietary intake of vitamin C.4 Supplementation also decreases the severity and duration of upper respiratory infections,5,6 as well as the duration of mechanical ventilation and length of stay in the ICU (outside of the COVID-19 context).7,8
As for the relevance of vitamin C in COVID-19, preliminary observational studies suggest that critically ill patients with COVID-19 tend to have low vitamin C status, and one small trial from China found that vitamin C supplementation significantly decreased mortality in severely ill COVID-19 patients.9
There’s some evidence that vitamin C supplementation decreases mortality by helping to prevent immune overreactions and cytokine storms, which are a component of severe COVID-19 cases.10 A small trial found that administering vitamin C (in combination with methylene blue and N-acetyl cysteine) decreased blood levels of multiple inflammatory cytokines in four of the five COVID-19 patients treated.11 Similarly, another study also found that IV administration of vitamin C (1 g every eight hours for three days) likewise reduced inflammatory markers.12 IV treatment with vitamin C has shown beneficial effects on sepsis, septic shock, and sepsis-induced acute respiratory distress syndrome, all of which are associated with COVID-19.13-15
Vitamin C is readily available from food sources including citrus fruits, berries, leafy greens, and tomatoes. An important question, however, is whether individuals also should take vitamin C supplements in the context of COVID-19. Some researchers don’t see sufficient evidence to recommend supplementation,16 but others have described vitamin C supplements as one of the most promising therapies for COVID-19.2 Vitamin C typically is beneficial only up to about 200 mg/ day, but higher intake may be helpful in patients who are at high risk of infection or who already are infected, since infection lowers vitamin C levels.3
Vitamin D
Vitamin D helps maintain the integrity of epithelial barriers in the body. It also stimulates production of antimicrobial peptides in lung membranes; such peptides have been shown to decrease replication of the influenza A virus.13 In addition, vitamin D aids the production of macrophage immune cells and increases phagocytosis.1 Finally, vitamin D regulates T cell responses and helps control the cytokine storms generated by the innate immune system in reaction to infections such as COVID-19.13
Cross-sectional studies in the United Kingdom and the United States have found an inverse linear relationship between vitamin D levels and risk of respiratory tract infections.17-19 Interestingly, one systematic review and meta-analysis on the impact of vitamin D on the efficacy of influenza vaccinations found that vitamin D deficiencies were linked to reduced protection against certain strains of influenza.20 By contrast, sufficient vitamin D levels have been linked to a lower risk of acute respiratory infection in both adults and children.21
As for the value of supplementation, several different meta-analyses have found that supplementing with vitamin D decreases risk of respiratory tract infections.22 Two different pilot studies demonstrated that high-dose supplementation with vitamin D improved the condition of critically ill patients on a ventilator and shortened their hospital stays.23,24
In the context of COVID-19, a range of studies suggests that incidence and severity of the disease are linked with vitamin D status. A European study found that patients who tested positive for COVID-19 had lower levels of vitamin D than those who tested negative—though the difference was significant only in individuals over the age of 70.25 In a meta-analysis of 1,368 COVID-19 patients, low levels of vitamin D were linked to worse outcomes in the disease.26 One study demonstrated that the mortality rate for hospitalized COVID-19 patients who had severe vitamin D deficiency was substantially greater than the mortality rate for hospitalized COVID-19 patients who were vitamin D sufficient (50% vs 5%, respectively).27
Although an array of research suggests a link between vitamin D levels and COVID-19 incidence and severity, it’s important to note a major exception to the pattern: An analysis of more than 500,000 participants in the UK Biobank study found that lower vitamin D levels were indeed linked to higher risk of infection but that this association disappeared after adjusting for confounding variables.28
There’s debate about whether the evidence justifies vitamin D supplementation in individuals who aren’t deficient. However, it’s worth noting that vitamin D deficiency is widespread, especially in older adults.29,30 For people with vitamin D deficiency as well as those at high risk of contracting COVID-19, one group of researchers has recommended a supplement of 10,000 IU/day for several weeks, followed by additional supplementation at 5,000 IU/day to raise vitamin D concentrations above 40 to 60 ng/mL. High-dose supplements also may be useful as an intervention in patients who already have COVID-19.31
Vitamin E
Like vitamin C, vitamin E is a potent antioxidant, and it’s present in high concentrations in immune cells to help protect cells from oxidative damage.3 Vitamin E deficiency reduces lymphocyte proliferation, the activity of natural killer cells, phagocytosis, and the production of antibodies. By contrast, vitamin E supplementation has been shown across several studies to improve various markers of immune function.1
In clinical studies, higher levels of plasma vitamin E are linked to lower risk of infections in adults over age 60.32 Although the research isn’t uniform, multiple studies have found that vitamin E supplements improve immune function and help prevent serious respiratory infections in older adults.1 Therefore, there’s some thought that increasing vitamin E intake might be beneficial in the context of COVID-19, especially in older adults and those with heart complications.3,33 However, the evidence is limited, and there are no specific recommended dosages. For individuals wanting to increase their intake of vitamin E through diet, good sources include nuts, seeds, vegetable oils, leafy greens, and fortified cereals.3
Zinc
Zinc also plays a vital part in immune function.2 Murofushi says, “Zinc has a very important role in the development and function of the macrophages and the immunoglobulins that are responsible for responding [to infection].” In addition to promoting the development of immune cells, zinc inhibits the replication of RNA viruses, including the SARS-CoV virus.1 Zinc deficiency also hinders phagocytosis, the activity of natural killer cells, and the production of T lymphocytes. Deficiency also spurs the production of inflammatory cytokines.2
However, zinc supplementation can correct these negative, wide-ranging effects on the immune system.1 Moderate doses of zinc were shown to reduce overproduction of inflammatory cytokines in older adults with zinc deficiency.34 Supplementation to correct a deficiency also has been shown to reduce the risk of skin infections and diarrhea. Some studies—though not all—also show that supplementation decreases risk of respiratory infections.1 Several systematic reviews and meta-analyses suggest that supplementing with zinc reduces the duration of the common cold, lowers risk of pneumonia in children, and decreases mortality when given to adults who have severe pneumonia.35
Currently, there’s a dearth of clinical data on the preventive or therapeutic value of zinc in COVID-19. However, one recent case series of patients with the disease found that high-dose zinc salt supplements produced significant benefits.36 Given the ability of zinc to inhibit viral replication, reduce inflammation, and impact the course of respiratory infections, various researchers have suggested that improving zinc status may be a useful preventive and/or therapeutic measure for COVID-19.37 The current RDA for zinc is 8 to 11 mg per day, but it’s been suggested that a higher intake of 30 to 50 mg per day could help fight COVID-19 in those infected.3,38 This may be particularly true for older adults, as zinc deficiencies are much more prevalent in older adults but uncommon in the general population in North America.39
Recommendations for RDs
In light of the unfolding research on the role micronutrients may have in the prevention and treatment of COVID-19, dietitians can take the following practical steps:
• Educate patients about the importance of good nutrition in the context of COVID-19. “A diet rich in vegetables, fruits, whole grains, lean protein, and dairy will provide the nutrients needed to support the body’s natural defense systems,” says Whitney Linsenmeyer, PhD, RD, an assistant professor of nutrition at Saint Louis University and a spokesperson for the Academy of Nutrition and Dietetics. “Registered dietitians can continue to champion our message that sound nutrition is fundamental to overall health and well-being.”
• Evaluate the supplements patients take. People who want to boost their immune systems are prone to taking supplements without seeking the advice from a dietitian or clinician. “Right now, there are a lot of ads for supplements,” Murofushi says. “There may be some [individuals] taking two different types of protein shakes and juice blends, and so they’re actually getting megadoses of zinc or megadoses of vitamin C, and they don’t know that.”
• Recommend supplementation of specific micronutrients based on the patient’s micronutrient status, risk level, and current infection status.
All sources interviewed for this article agree that dietary intake of vitamins and minerals generally is preferable to supplements. “Food sources are ideal in that the nutrients tend to be more bioavailable,” Linsenmeyer says. Individuals have less risk of excessive intake of micronutrients compared with supplementation, and food provides a host of other benefits such as dietary fiber and phytochemicals. Linsenmeyer adds that in most cases “it’s possible to obtain these nutrients by choosing a wide variety of nutrient-dense foods.”
However, supplementation is recommended for individuals who have micronutrient deficiencies and can’t meet their needs through food. For anyone in this category, “supplementation [is] routinely recommended,” Linsenmeyer says.
For patients without nutrient deficiencies, the case for supplementation is murkier—and more controversial. “Often, there’s actually a negative outcome” from megadosing with various micronutrients, Murofushi says, so there’s a need to be careful.
Some experts believe the benefits of supplementation in the context of COVID-19 may outweigh the risks in certain cases, even for individuals without a deficiency. Specifically, Palacios recommends all individuals take a vitamin D supplement for the duration of the pandemic as a prophylactic measure, as vitamin D deficiency is prevalent in the United States. She usually recommends 1,000 to 2,000 IU per day but says specific dosages will depend on the patient. “Darker-skinned people may need more, obese people may need more, older people may need more. I would defer that amount to the dietitian.” Unlike with vitamin D, Palacios doesn’t recommend routine supplementation of zinc and vitamin C as a preventive measure for most people. Deficiencies in these micronutrients are rare, though she does recommend supplementation of both micronutrients to anyone at high risk of becoming infected with COVID-19, such as front-line health care workers. She recommends consuming a zinc supplement that’s less than 40 mg per day, thereby not exceeding the upper limits for zinc. Palacios says doses of vitamin C above the RDA don’t prevent respiratory infections in most individuals, but some evidence shows vitamin C supplements help prevent respiratory infections among those under extreme physical stress or those exposed to extreme temperatures.6 Because frontline workers could fall within these categories in the context of COVID-19, vitamin C supplementation might benefit them, according to Palacios. She recommends 1 g vitamin C twice per day.
While Palacios’s recommendations are prophylactic, there’s some evidence to suggest that vitamin C, vitamin D, and zinc supplementation may serve as valuable therapies for individuals with COVID-19.
Yet, Linsenmeyer stops short of supporting the case for therapeutic supplementation in people with COVID-19, arguing the evidence isn’t strong. According to Murofushi, many hospitals have developed protocols for supplementation for patients with COVID-19 to ensure adequate intake of micronutrients. These protocols, Murofushi says, exist in part because it isn’t always known whether the patient is deficient, and in part because the gastrointestinal symptoms and appetite suppression associated with COVID-19 can reduce intake of needed micronutrients.
Final Thoughts
Supplementation with vitamins D and C as well as zinc may be beneficial for specific individuals in the context of COVID-19, either as a prophylactic measure or as a therapeutic treatment for individuals with the virus. However, dietitians should proceed with caution when recommending supplements to patients, recognizing the limits of the available research and weighing the benefits against potential harms.
— Jamie Santa Cruz is a freelance health and medical writer based in Parker, Colorado.
References
1. Calder PC. Nutrition, immunity and COVID-19. BMJ Nutr Prev Health. 2020;3(1):74-92.
2. Junaid K, Ejaz H, Abdalla AE, et al. Effective immune functions of micronutrients against SARS-CoV-2. Nutrients. 2020;12(10):2992.
3. Zabetakis I, Lordan R, Norton C, Tsoupras A. COVID-19: the inflammation link and the role of nutrition in potential mitigation. Nutrients. 2020;12(5):1466.
4. Hemilä H, Louhiala P. Vitamin C for preventing and treating pneumonia. Cochrane Database Syst Rev. 2013;(8):CD005532.
5. Hemilä H. Vitamin C and infections. Nutrients. 2017;9(4):339.
6. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2013;(1):CD000980.
7. Hemilä H, Chalker E. Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis. J Intensive Care. 2020;8:15.
8. Hemilä H, Chalker E. Vitamin C can shorten the length of stay in the ICU: a meta-analysis. Nutrients. 2019;11(4):708.
9. Carr AC, Rowe S. The emerging role of vitamin C in the prevention and treatment of COVID-19. Nutrients. 2020;12(11):3286.
10. Zhang J, Rao X, Li Y, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann Intensive Care. 2021;11(1):5.
11. Alamdari DH, Moghaddam AB, Amini S, et al. Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial. Eur J Pharmacol. 2020;885:173494.
12. Hiedra R, Lo KB, Elbashabsheh M, et al. The use of IV vitamin C for patients with COVID-19: a case series. Expert Rev Anti Infect Ther. 2020;18(12):1259-1261.
13. Bae M, Kim H. Mini-review on the roles of vitamin C, vitamin D, and selenium in the immune system against COVID-19. Molecules. 2020;25(22):5346.
14. Fowler AA 3rd, 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;322(13):1261-1270.
15. Waqas Khan HM, Parikh N, Megala SM, Predeteanu GS. Unusual early recovery of a critical COVID-19 patient after administration of intravenous vitamin C. Am J Case Rep. 2020;21:e925521.
16. Fernández-Quintela A, Milton-Laskibar I, Trepiana J, et al. Key aspects in nutritional management of COVID-19 patients. J Clin Med. 2020;9(8):2589.
17. Berry DJ, Hesketh K, Power C, Hyppönen E. Vitamin D status has a linear association with seasonal infections and lung function in British adults. Br J Nutr. 2011;106(9):1433-1440.
18. Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the third National Health and Nutrition Examination Survey. Arch Intern Med. 2009;169(4):384-390.
19. Monlezun DJ, Bittner EA, Christopher KB, Camargo CA, Quraishi SA. Vitamin D status and acute respiratory infection: cross sectional results from the United States National Health and Nutrition Examination Survey, 2001-2006. Nutrients. 2015;7(3):1933-1944.
20. Lee MD, Lin CH, Lei WT, et al. Does vitamin D deficiency affect the immunogenic responses to influenza vaccination? A systematic review and meta-analysis. Nutrients. 2018;10(4):409.
21. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5(6):e11088.
22. Science M, Maguire JL, Russell ML, Smieja M, Walter SD, Loeb M. Low serum 25-hydroxyvitamin D level and risk of upper respiratory tract infection in children and adolescents. Clin Infect Dis. 2013;57(3):392-397.
23. Han JE, Jones JL, Tangpricha V, et al. High dose vitamin D administration in ventilated intensive care unit patients: a pilot double blind randomized controlled trial. J Clin Transl Endocrinol. 2016;4:59-65.
24. Smith EM, Jones JL, Han JE, et al. High-dose vitamin D3 administration is associated with increases in hemoglobin concentrations in mechanically ventilated critically ill adults: a pilot double-blind, randomized, placebo-controlled trial. JPEN J Parenter Enteral Nutr. 2018;42(1):87-94.
25. D'Avolio A, Avataneo V, Manca A, et al. 25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2. Nutrients. 2020;12(5):1359.
26. Munshi R, Hussein MH, Toraih EA, et al. Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. J Med Virol. 2021;93(2):733-740.
27. Carpagnano GE, Di Lecce V, Quaranta VN, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19 [published online August 9, 2020]. J Endocrinol Invest. doi: 10.1007/s40618-020-01370-x.
28. Hastie CE, Mackay DF, Ho F, et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes Metab Syndr. 2020;14(4):561-565.
29. Liu X, Baylin A, Levy PD. Vitamin D deficiency and insufficiency among US adults: prevalence, predictors and clinical implications. Br J Nutr. 2018;119(8):928-936.
30. Meehan M, Penckofer S. The role of vitamin D in the aging adult. J Aging Gerontol. 2014;2(2):60-71.
31. Grant WB, Lahore H, McDonnell SL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020;12(4):988.
32. Chavance M, Herbeth B, Fournier C, Janot C, Vernhes G. Vitamin status, immunity and infections in an elderly population. Eur J Clin Nutr. 1989;43(12):827-835.
33. Wang JZ, Zhang RY, Bai J. An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients. Int J Cardiol. 2020;312:137-138.
34. Kahmann L, Uciechowski P, Warmuth S, et al. Zinc supplementation in the elderly reduces spontaneous inflammatory cytokine release and restores T cell functions. Rejuvenation Res. 2008;11(1):227-237.
35. Hemilä H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage. JRSM Open. 2017;8:205427041769429.
36. Finzi E. Treatment of SARS-CoV-2 with high dose oral zinc salts: a report on four patients. Int J Infect Dis. 2020;99:307-309.
37. Skalny AV, Rink L, Ajsuvakova OP, et al. Zinc and respiratory tract infections: perspectives for COVID 19 (review). Int J Mol Med. 2020;46(1):17-26.
38. Celik C, Gencay A, Ocsoy I. Can food and food supplements be deployed in the fight against the COVID 19 pandemic? Biochim Biophys Acta Gen Subj. 2021;1865(2):129801.
39. Cabrera ÁJ. Zinc, aging, and immunosenescence: an overview. Pathobiol Aging Age Relat Dis. 2015;5:25592.