CPE Monthly: Nutrition’s Role in Managing COVID-19
By Danielle VenHuizen, RDN
Today’s Dietitian
Vol. 25 No. 4 P. 40

CPE Level 2

Take this course and earn 2 CEUs on our Continuing Education Learning Library

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), more commonly known as COVID-19, has significantly impacted people all over the world. According to the CDC, as of early 2022, more than 960,000 deaths have been recorded in the United States and over 6 million globally.1,2 When COVID-19 was first established as a pandemic by the World Health Organization in 2020, little was known about its serious impacts and factors that hindered or hastened its spread.3

Due to these unknowns, prevention has been a key strategy. Reductions in gatherings, social distancing, masking, handwashing, and vaccines have been the first lines of defense.4 Fortunately, now much more is known about COVID-19 and the risks. Recent statistics show that while approximately 80% of those infected will have a mild course of the disease, 13.8% will have severe effects and 6.1% will be become critically ill.5 Given the high rates of severe disease, especially in older populations, along with the knowledge of asymptomatic spread, prevention remains a top priority.

Recent evidence suggests that nutrition status may play a protective role both in preventing COVID-19 infection and as a supportive role in treatment.2,6 For clinicians, this area may be of unique interest for patient education given that vaccines aren’t 100% protective and severe disease and even death still can occur.7

Current public health messaging regarding diet-related measures that may help prevent disease or reduce the severity is unclear. This information is of particular importance for clients who are older, immune compromised, or at greater risk of COVID-19 complications and fear vaccination isn’t enough to protect them from severe illness. There’s evidence to suggest, however, that there are dietary approaches this cohort can use to reduce the likelihood of infection or help ward off severe disease.

This continuing education course examines dietary nutrients and their potential immune-supportive role in preventing severe COVID-19 outcomes and how RDs can educate clients on evidence-based diet patterns.

Current Knowledge of COVID-19 and Risk Factors
At this point in the pandemic, much more is known about COVID-19 transmission and the factors that increase the risk of severe disease. It appears outcomes tend to worsen for older adults, those with preexisting conditions, and/or individuals experiencing nutrient deficiency.8

Statistics show that people older than 70 are in the highest risk category for hospitalization and death from COVID-19.8 This is likely because of the gradual reduction in function of the immune system in advanced age, but also due to additional strains on the immune system from the increase of comorbid conditions, greater inflammatory levels, and higher likelihood of malnutrition in elderly patients.9-11

Preexisting conditions, including obesity, diabetes, hypertension, COPD, chronic kidney disease, and cancer, appear to increase the likelihood that a person will be hospitalized or die from COVID-19.12-14 One common characteristic among these conditions is an increase in inflammatory markers that tends to exacerbate the immune response to COVID-19.

The CDC gathered data of hospitalized patients from more than 800 hospitals between March 2020 and March 2021 and found that more than 94% had a preexisting condition, with high cholesterol, hypertension, and obesity the most common.15 A retrospective cohort study conducted in a New York hospital with mostly Black patients found that 98% of those hospitalized had at least one comorbidity.16

In addition, the evidence seems to suggest that malnutrition increases a person’s susceptibility to becoming infected as well as contributes to more severe forms of the disease. Protein-energy malnutrition in particular is known as a leading cause of immune deficiency. Chronic conditions increase metabolic demands on the body, which further increase malnutrition, especially in the elderly.17

A recent prevalence study by Azar and colleagues showed that more than 42% of those admitted to a nonintensive medical care unit were malnourished, and 18.4% of those were severely malnourished. Of those that came from the ICU, 66.7% were malnourished.18 While age and comorbid conditions are unmitigable risk factors, diet may be an area where health practitioners can intervene and support the immune response. There’s evidence that addressing nutrition status may enhance immune function and play a role alongside vaccines in preparing the body to fight a COVID-19 infection.

Micronutrients and Potential Immune-Supportive Roles
There’s ongoing research regarding particular micronutrients and their potentially beneficial role in reducing severe COVID-19 outcomes. Iron, vitamin C, vitamin D, zinc, and omega-3s are some of the more well studied. Polyphenols also are being evaluated, and the Mediterranean diet (MDiet) is an area garnering more interest and research.11,17,19 These nutrients and dietary patterns may play a supportive role in COVID-19 infections.

Adequate iron status plays an important role in several factors related to COVID-19. Hemoglobin, which transports oxygen throughout the body, is dependent upon iron. Reduced iron levels could impact peripheral tissues that have increased oxygen demands during infection.20 Immune cells use iron in a series of critical reactions that help kill off invading microbes. When iron deficiency is present before infection, the immune system’s ability to respond and attack is weakened. 21 In fact, there’s evidence that iron deficiency before vaccinations in general may decrease the antibody response and reduce their efficacy.21,22

During an active infection, the amount of iron released into the bloodstream decreases and the amount of iron converted to its storage form, ferritin, increases. This process reduces the availability of iron to the invading pathogen and hampers its ability to proliferate. While designed to be a short-term response, the long-term consequence of this process is anemia of chronic disease characterized by elevated ferritin levels and low levels of circulating iron.21

The RDA for iron is 8 mg/day for men of all ages and postmenopausal women. It’s 18 mg/day for premenopausal women. The tolerable upper limit is set at 45 mg/day.23

Recent evidence hints at the role iron dysregulation may play in COVID-19 infections. A recent meta-analysis pooled results from studies examining biomarkers of iron metabolism among COVID-19 patients. It found that hemoglobin levels decreased with age and the number of comorbid conditions, and that ferritin levels were elevated in most patients. They were unable to associate low hemoglobin with severity of disease but did associate higher ferritin levels (>300) with increased rates of hospitalization.20 A retrospective cohort study conducted in Wuhan, China, reviewed medical records of hospitalized COVID-19 patients. The findings showed a correlation between low serum iron levels and elevated ferritin with disease severity.24

For clinicians, these findings highlight the importance of addressing iron status. Adequate iron intake and absorption before infection appear to be important for an appropriate immune response. Iron also may be critical for the body to produce an antibody response postvaccination.22 Preexisting conditions and malnutrition, which are known risk factors for severe COVID-19, are states in which there’s a higher likelihood of iron deficiency or anemia of chronic disease. Assessing iron status in individuals before infection, especially in those at higher risk of severe disease, is warranted.

Supplementation to normalize iron levels should be encouraged, but only in the case of documented deficiency, and certainly shouldn’t be initiated during active infection without doctors’ orders.25 Any signs or concerns of iron deficiency should be referred to a physician for proper diagnosis before recommending supplementation or diet changes that would significantly increase iron intake.

Vitamin C
It’s well documented that vitamin C plays a crucial role in fighting infections. Leukocytes, cells of the immune system that fight infection, accumulate vitamin C at concentrations 50 to 100 times higher than in plasma.5 Clinical trials have linked vitamin C intake with reduced duration and severity of conditions including pneumonia, sepsis, lower respiratory tract infections, and the common cold. It’s theorized that vitamin C also could be of clinical usefulness in COVID-19 infections, especially in reducing severe lung injury.26,27

Despite the relative abundance and availability of food in the Western world, epidemiologic studies have shown that between 50% to 75% of Americans don’t meet the RDA of 90 mg/day of vitamin C.11 Some researchers suggest that intake should be even higher, recommending upward of 200 mg/day as a preferred target for immune health.27,28 It has been shown that in vitamin C–deficient hospitalized patients, it can take gram doses of the vitamin to
restore adequate levels.11

While it’s known that patients in the ICU typically have low serum levels of vitamin C, evidence is lacking for COVID-19 patients.28 Small studies do suggest that the majority of hospitalized COVID-19 patients have inadequate vitamin C levels.27 In fact, in one study in Barcelona, Spain, looking at 18 patients that had progressed to acute respiratory distress syndrome, 17 had undetectable levels of vitamin C.28

Few studies are available on the efficacy of vitamin C therapy in the treatment of COVID-19 patients, but there are several underway. A recent meta-analysis of six randomized controlled trials found no benefit for vitamin C therapy administered either orally or by IV on reducing disease severity.29 While not an official study, a hospital in China reported on treating 50 moderate-to-severe COVID-19 patients with high-dose IV vitamin C therapy and found shorter hospital stays and no deaths among those patients.30

Assessing vitamin C status for those at high risk of severe COVID-19 is prudent to help improve serum levels before an infection. Increased intake of foods rich in vitamin C could be considered as well as supplements, which appear to be safe with few side effects.31 At this point, high-dose vitamin C therapy doesn’t seem warranted and should be considered only in a hospital setting under physician supervision.

Vitamin D
The role of vitamin D has been well studied in immune function. Vitamin D receptors are found in immune cells throughout the body. Vitamin D helps ward off infection by regulating tight junctions, which prevent entry of pathogens into cells, increasing the release of antimicrobial peptides, and stimulating the production of anti-inflammatory cytokines, while reducing the production of those that are inflammatory.26,32

The RDA for vitamin D intake is set at 600 IU/day for most adults. This increases to 800 IU/day for adults over 70. However, doses used to correct deficiencies and those used in studies often are much higher. The upper limit is set at 1,000 IU/day, but toxicity is rare at levels up to 10,000 IU/day.33

Studies have shown that vitamin D can reduce the risk of severe respiratory infections. A meta-analysis of more than 25 studies found that individuals receiving daily or weekly vitamin D supplementation had greater protection from acute respiratory tract infections.34 Another meta-analysis found low levels of vitamin D were linked with higher risk of pneumonia.35 The National Health and Nutrition Survey reported an inverse correlation between vitamin D levels and the risk of severe respiratory infections.36

Results on the impact of vitamin D on seasonal influenza have been much more mixed. Some studies show modest benefit in reducing the severity and duration of influenza, some show no change, and one reported longer duration of illness in the treatment arm.37,38

These associations hint at the potential protective role adequate vitamin D intake may play in COVID-19 disease severity, especially for reducing the incidence of severe lung injury. In fact, death rates from COVID-19 are higher in latitudes that receive less sunlight and have higher rates of vitamin D deficiency, suggesting that deficiency impairs the immune response.32

The individual studies evaluating COVID-19 and vitamin D status are inconclusive. A cross-sectional study conducted in China comparing 355 hospitalized COVID-19 patients against controls found lower serum vitamin D levels were correlated with COVID-19 and increased the risk of severe outcomes.39 A retrospective study in Indonesia also found promising results. It examined 780 hospitalized cases of COVID-19 and reported that low vitamin D status coupled with other risk factors, including older age and preexisting conditions, was clearly associated with higher mortality rates.40 This study was widely cited by subsequent studies and reported in various news outlets and across social media platforms as proof vitamin D was protective against COVID-19. Notably, the article appears to have since been removed due to an inability to locate the authors and the methods used to gather the confidential patient information they claim to report.41

Meta-analyses on vitamin D related to COVID-19 also show conflicting results. One such review that looked at three studies involving 532 hospitalized COVID-19 patients found that vitamin D supplementation lowered ICU admission rates. However, death rates appeared to be unaffected when compared with placebo.42

Another meta-analysis including five studies didn’t see a reduction in ICU admission rates or mortality with vitamin D supplementation during active infection.43 A third meta-analysis reviewing 10 case-control studies found an inverse correlation with vitamin D status and incidence of COVID-19 but couldn’t establish a clear link with severe disease and mortality.44 A recent meta-analysis looking at 31 peer reviewed observational studies found a trend between low vitamin D status and worse outcomes in COVID-19, but these correlations weren’t statistically significant.45 Yet, another meta-analysis reviewing 23 studies and 11,901 participants concluded that most hospitalized COVID-19 patients are vitamin D deficient and the odds of becoming infected with COVID-19 are 3.3 times higher in those who are deficient.46

The limitations in these meta-analyses primarily relate to the study designs in that none of them were large scale, randomized controlled trials. Many of these studies were observational, had small sample sizes, and used varied supplement doses and timing in supplementation.

Interestingly, a retrospective study conducted in Israel by Dror and colleagues was published in February 2022. It investigated preinfection vitamin D status and severity of disease outcomes. They reported that patients with a documented vitamin D deficiency before infection were 14 times more likely to be classified as having severe disease than those with adequate levels preinfection.47 While not a double-blinded controlled trial, it does provide some interesting information as to preinfection vitamin D deficiency and potential impact on COVID-19 severity. A review study in 2021 had similar findings, showing that preinfection vitamin D status appeared to be linked to risk of mortality from COVID-19.48

While studies on vitamin D continue to emerge, higher quality studies, especially double-blinded, randomized controlled trials, are much needed. Evidence seems to suggest that sufficient vitamin D status preinfection may reduce the risk of becoming infected, but there’s less clear evidence on how it impacts disease severity, hospitalization rates, and overall mortality in COVID-19 patients. Correcting a vitamin D deficiency would be an appropriate recommendation, but high-dose supplementation should be considered only under a physician’s supervision and care. There are currently several large, randomized controlled trials underway to evaluate this topic more closely.

It’s well documented that zinc plays a crucial role in immune health. Zinc is a cofactor in hundreds of reactions related to the production of immune-related proteins and in reactions related to antioxidant function.40 Zinc supports the production of proinflammatory cytokines to fight disease and protects against oxidative damage from the inflammatory process.49 Zinc also can downregulate the ACE-2 enzyme, the main entry point of COVID-19.50 In addition, it’s known to have potent antibacterial properties. Its role in viral infections, especially related to COVID-19, is less clear.17

It’s estimated that somewhere between 17% and 20% of the global population is zinc deficient, with higher rates of deficiency among the elderly and those with chronic diseases.17 The RDA for zinc in adults is 11 mg/day for men and 8 mg/day for women. The upper limit is set at 40 mg/day for all adults.51

Evidence has emerged since the 1970s suggesting zinc may help reduce the incidence and duration of viral infections.52 Several studies have concluded that zinc supplementation decreases duration of the common cold and may decrease the severity of symptoms.53-55 Low zinc status also is correlated with incidence of pneumonia.56,57 These potential benefits have heightened the interest in the use of zinc to prevent severe COVID-19 outcomes.

Research studies to date have been limited and conflicting, but many are ongoing and more data are expected soon. In a recent clinical trial, patients with COVID-19 were randomized to receive 10 days of high-dose zinc supplementation, vitamin C supplementation, both micronutrients together, or standard care. None of the treatment arms were shown to have any impact on the duration of symptoms.58

In another study by Gordon and colleagues, 112 outpatient clients were randomized to receive 10 mg, 25 mg, or 50 mg of zinc daily. Participants were monitored by phone every two to three weeks for five months. At every level, zinc supplementation was correlated with a reduced risk of developing symptomatic COVID-19 over controls, even after controlling for comorbidities, age, BMI, and vitamin D status.50

More high-quality studies are needed to understand the role of zinc related to COVID-19 outcomes. The available data are conflicting and the sample sizes are small. Recommending widespread zinc supplementation without further data should be recommended with caution. While zinc deficiency is far more common than toxicity, high doses of zinc long term can interfere with absorption of other nutrients, particularly iron and copper.59 There’s even evidence that long-term use of high-dose zinc can impair immune function.60 Dietary intake should be recommended to meet RDA recommendations and correct for any deficiencies, especially in those most vulnerable to suboptimal zinc status. Doses exceeding the upper limit should be avoided unless prescribed by a physician.

Omega-3 Fatty Acids
It has been established that omega-3 fatty acids exert potent anti-inflammatory effects and support immune regulation.3,61 Alpha-linolenic acid (ALA), EPA, and DHA are incorporated into cell membranes and enhance the activity of T cells. They also suppress cytokine production and increase the production of anti-inflammatory leukocytes.17 Omega-3s also have been shown to inhibit viral replication.5

Omega-3 deficiency is thought to be common in the United States and most Western countries with the shift toward diets higher in processed foods.62 The recommended intake of omega-3 (as ALA) is 1.1 g/day for adult females and 1.6 g/day for males.63

Due to these anti-inflammatory properties, there’s interest in understanding whether omega-3 intake might have an effect on COVID-19 outcomes. A double-blinded randomized controlled trial on 128 hospitalized COVID-19 patients was conducted in 2021. One group was supplemented with an omega-3 fortified formula and compared with controls. They reported that the supplement group had an increased rate of survival at one month than those in the control group.64

A Chilean study sought to examine omega-3 status, measured as the percentage by weight of omega-3 fatty acids in red blood cell membranes, and the impact on severe disease in COVID-19. Of the 74 hospitalized patients studied, there was a clear inverse relationship between omega-3 status and risk of severe disease. Patients with the highest omega-3 status had the lowest risk of progressing to mechanical ventilation and death, even when adjusted for comorbidities, age, BMI, and tobacco use.65

Current studies are promising, but more randomized controlled trials are needed to better understand the link to COVID-19 and whether diet and/or supplementation may not only help before infection but also during treatment. It would be reasonable at this point to encourage dietary intake of omega-3 rich foods for general immune support, especially before infection. Supplementation for those not willing or able to consume omega-3 rich foods also can be suggested. Up to 5 g/day is considered safe.63,66

Significant research has been focused on the role of plant-based antioxidants and their impact on inflammation. Compounds such as curcumin, resveratrol, quercetin, and polyphenols in tea all have research demonstrating anti-inflammatory benefits. Evidence also is starting to emerge for a potentially protective role in COVID-19.

A review of six randomized, placebo-controlled trials looked at the use of curcumin during COVID-19 infection. All of the studies reported less severe and shorter duration of symptoms. Four of the studies evaluated mortality and found reduced risk of death. The authors concluded that while more studies are needed, especially to determine timing of administration and appropriate dosage, the use of curcumin both during and post COVID-19 infection should be considered.67

In a recent study, resveratrol, which has documented antiviral and anti-inflammatory properties, was shown to inhibit viral replication of COVID-19 in-vitro.68 One difficulty with resveratrol is the poor bioavailability in-vivo, so additional research is needed on route of administration and dosage and whether food sources could offer sufficient therapeutic benefit.

Quercetin also has demonstrated potent anti-inflammatory effects, notably in the blood vessels and lungs. A prospective, randomized cohort study evaluating 429 hospitalized COVID-19 patients found that those supplemented with a mixture of quercetin, vitamin C, and bromelain had improved lung function over controls.69 Another study evaluated 152 outpatient clients with symptomatic COVID-19 infection and administered 400 mg quercetin daily to the treatment group. Researchers found reduced incidence of hospitalization, reduced length of stay for those admitted, lower rate of ICU admissions, and reduced mortality over controls. The authors concluded that quercetin should be considered as a treatment strategy and warrants further investigation.70

Green tea polyphenols are widely known to exert anti-inflammatory benefits and may be protective against cancer, diabetes, CVD, and influenza.71 Preliminary data show that epigallocatechin-3-gallate and theaflavin, two polyphenols in green tea, inhibit viral replication of COVID-19 in-vitro.72 This doesn’t suggest that green tea can impact COVID-19 infections in-vivo, but it does indicate the need for more studies.

Mediterranean Diet
The MDiet has continued to garner interest over the years due to its significant benefits in a variety of disease states. It has been shown to be beneficial for those with type 2 diabetes, CVD, neurodegenerative diseases, and cancer. It also improves overall mortality regardless of disease.73,74

Interest is growing to determine whether the MDiet may be protective against COVID-19, especially given the research on its abundant micronutrients and polyphenols that already show strong evidence for immune support. There’s evidence that countries with the least adherence to MDiet principles, particularly the United States and the United Kingdom, are showing the highest rates of COVID-19–related deaths per million.75

An observational case-control study in Lebanon used an online survey to gather information related to diet and health status of 399 participants who previously had COVID-19 or never had been infected. They couldn’t find any clear associations between diet quality and disease severity, but they noted a decrease in likelihood of infection with higher adherence to the MDiet.76

Another study employed the use of surveys with Spanish university graduates and examined their dietary patterns and risk of COVID-19 infection. They found that students with higher adherence to MDiet principles were less likely to become infected.77 A third study used e-mail surveys and queried 900 Italian health care professionals regarding diet and COVID-19 status and severity of previous disease. They, too, found that lower adherence to the MDiet correlated with a higher incidence of infection. They noted that disease severity was directly correlated with age and the intake of saturated fats.78

While none of these studies are the large-scale, randomized controlled trials needed to better understand these diet connections, they’re a start in moving the discussion forward and demonstrate preliminary links that warrant further investigation. More results are forthcoming. For example, a study using data from the COVID Symptom Study shows that the MDiet, and particularly plant-based foods, is associated with lower risk and severity of COVID-19.79

Given that the MDiet encourages consumption of foods that contain the nutrients previously discussed, is high in anti-inflammatory polyphenols, and is known to protect against or ameliorate several disease states linked to severe COVID-19 outcomes, it seems wise at this time to encourage clients concerned about their COVID-19 risk to consume a diet more in line with MDiet principles.

Putting It Into Practice
COVID-19 continues to be a major health threat, especially for more vulnerable populations. It’s evident that deficiencies in one or more nutrients can negatively impact immune function and lessen defenses against COVID-19. It’s important to address nutrient status before infection, especially for the elderly and those with chronic diseases where deficiencies and malnutrition are more common.

Use of the MDiet in patient education appears to be the best dietary strategy for those at risk of severe COVID-19 infection. Emphasis should be placed on food sources for the nutrients highlighted in this course. However, in some cases, supplementation may be warranted. Intake shouldn’t exceed the RDA except when recommended by a physician. Intakes above recommended values for some nutrients can reduce the absorption of others or induce toxicity. Higher-supplement doses may be required in the cases of vitamin D and iron deficiencies, but these should be evaluated through labwork before initiating a supplement regimen. The role of polyphenols also shouldn’t be overlooked, but it’s advised to encourage a diet rich in those food sources.

While vaccines and other preventative measures remain the first lines of defense against COVID-19, diet may play a critical role in reducing the incidence of severe disease. RDs are well equipped to provide this level of detailed, patient-centered education.

— Danielle VenHuizen, RDN, is a Seattle-based dietitian and owner of Food/Sense Nutrition.

Learning Objectives
After completing this continuing education course, nutrition professionals should be better able to:
1. Counsel clients on the micronutrients and polyphenols that may play a role in protecting against severe COVID-19 infection.
2. Distinguish common nutrient deficiencies and groups at highest risk.
3. Educate patients on best diet practices that support immune health.

1. From the CDC data gathered in 2020 and 2021, researchers found that over what percentage of patients hospitalized with COVID-19 had a preexisting condition?
a. 45%
b. 57%
c. 82%
d. 94%

2. Per the CDC data, of those hospitalized with COVID-19, the most common preexisting conditions were:
a. High cholesterol, hypertension, and obesity
b. Chronic kidney disease, heart disease, and autoimmune diseases
c. Cancer (of any type), diabetes, and metabolic syndrome
d. Elevated fasting blood glucose, high triglycerides, and anemia

3. According to the prevalence study by Azar and colleagues, over what percentage of patients receiving hospital care were malnourished?
a. 42%
b. 45%
c. 62%
d. 28%

4. During chronic infection, how does the body regulate iron?
a. By decreasing iron stored as ferritin and increasing circulating iron in the blood stream
b. By increasing circulating iron and increasing iron stored as ferritin
c. By decreasing circulating iron and increasing iron stored as ferritin
d. By increasing iron absorbed from dietary sources and increasing circulating iron

5. What is one of the reasons to recommend a Mediterranean diet to patients who are concerned about their risk of COVID-19?
a. To increase immune-supportive nutrients found in many of the plant foods included in this diet
b. To increase immune-supportive nutrients found in the healthful fats included in this diet
c. To improve blood glucose regulation
d. To promote the environmental benefits of eating more plant foods

6. In the study on zinc supplementation by Gordon and colleagues, what dose was more effective for reducing the risk of symptomatic COVID-19 infection?
a. 10 mg zinc
b. 25 mg zinc
c. 50 mg zinc
d. All treatment doses were effective

7. The most recent study on vitamin D related to COVID-19 by Dror and colleagues showed which result?
a. Vitamin D supplementation for hospitalized patients improved time of recovery.
b. Adequate vitamin D status before infection reduced the risk of developing severe disease.
c. Adequate vitamin D status before infection decreased the risk of mild infection.
d. Vitamin D supplementation during active infection reduced severity of symptoms.

8. What are the areas that should be assessed when working with a client potentially at risk of severe COVID-19 infection?
a. Hemoglobin A1c and C-reactive protein levels
b. Iron, ferritin, and vitamin D levels
c. Thyroid function
d. Folate and B12 levels

9. For suspected nutrient deficiencies in patients at risk of severe COVID-19 infection, which of the following should an RD recommend?
a. Start high-dose vitamin supplements for suspected areas of deficiency
b. Meet the RDA for nutrients of concern with dietary sources
c. Recommend a B complex vitamin supplement
d. Start high dose iron but refer to a physician for other supplement recommendations

10. Current studies on the use of curcumin during COVID-19 infection seem to suggest that its use may do which of the following?
a. Reduce duration and severity of symptoms
b. Reduce the incidence of hospitalization and admittance to the ICU
c. Have no effect on risk of severe disease
d. Worsen severity of symptoms in older adults

1. COVID data tracker. Centers for Disease Control and Prevention website. https://covid.cdc.gov/covid-data-tracker. Updated March 16, 2022. Accessed March 16, 2022.

2. WHO coronavirus (COVID-19) dashboard. World Health Organization website. https://covid19.who.int/. Updated March 16, 2022. Accessed March 16, 2022.

3. Morais AHA, Aquino JS, da Silva-Maia JK, Vale SHL, Maciel BLL, Passos TS. Nutritional status, diet and viral respiratory infections: perspectives for severe acute respiratory syndrome coronavirus 2. Br J Nutr. 2021;125(8):851-862.

4. Pradhan D, Biswasroy P, Kumar Naik P, Ghosh G, Rath G. A review of current interventions for COVID-19 prevention. Arch Med Res. 2020;51(5):363-374.

5. Shakoor H, Feehan J, Al Dhaheri AS, et al. Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: could they help against COVID-19? Maturitas. 2021;143:1-9.

6. Butler MJ, Barrientos RM. The impact of nutrition on COVID-19 susceptibility and long-term consequences. Brain Behav Immun. 2020;87:53-54.

7. Liu Q, Qin C, Liu M, Liu J. Effectiveness and safety of SARS-CoV-2 vaccine in real world studies: a systemic review and meta-analysis. Infect Dis Poverty. 2021;10(1):132.

8. Gao Y, Ding M, Dong X, et al. Risk factors for severe and critically ill COVID-19 patients: a review. Allergy. 2021;76(2):428-455.

9. Chen Y, Klein SL, Garibaldi BT, et al. Aging in COVID-19: vulnerability, immunity and intervention. Ageing Res Rev. 2021;65:101205.

10. Norman K, Haß U, Pirlich M. Malnutrition in older adults—recent advances and remaining challenges. Nutrients. 2021;13(8):2764.

11. Gröber U, Holick MF. The coronavirus disease (COVID-19)—a supportive approach with selected micronutrients. Int J Vitam Nutr Res. 2022;92(1):13-34.

12. Singh A, Gillies C, Singh R, et al. Prevalence of co-morbidities and their association with mortality in patients with COVID-19: a systematic review and meta-analysis. Diabetes Obes Metab. 2002;22(10):1915-1924.

13. Azar WS, Njeim R, Fares AH et al. COVD-19 and diabetes mellitus: how one pandemic worsens the other. Rev Endocr Metab Disord. 2020;21(4):451-463.

14. Fedele D, De Francesco A, Riso S, Collo A. Obesity, malnutrition, and trace element deficiency in the coronavirus disease (COVD 19) pandemic: an overview. Nutrition. 2021;81:111016.

15. Kompaniyets L, Pennington A, Goodman A, et al. Underlying medical conditions and severe illness among 540,667 adults hospitalized with COVID-19, March 2020–March 2021. Prev Chronic Dis. 2021;18:E66.

16. Gupta R, Agrawal R, Bukhari Z, et al. Higher comorbidities and early death in hospitalized African-American patients with COVID-19. BMC Infect Dis. 2021;21(1):78.

17. James P, Ali Z, Armitage A, et al. The role of nutrition in COVID-19 susceptibility and severity of disease: a systematic review. J Nutr. 2021;151(7):1854-1878.

18. Bedock D, Bel Lassen P, Mathian A, et al. Prevalence and severity of malnutrition in hospitalized COVID-19 patients. Clin Nutr ESPEN. 2020;40:214-219.

19. Richardson D, Lovegrove J. Nutritional status of micronutrients as a possible and modifiable risk factor for COVID-19: a UK perspective. Br J Nutr. 2021;125(6):678-684. 

20. Taneri PE, Gómez-Ochoa SA, Llanaj E, et al. Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis. Eur J Epidemiol. 2020;35(8):763-773.

21. Cronin SJF, Woolf CJ, Weiss G, Penninger JM. The role of iron regulation in immunometabolism and immune-related disease. Front Mol Biosci. 2019;6:116.

22. Drakesmith H, Pasricha S, Cabantchik I, et al. Vaccine efficacy and iron deficiency: an intertwined pair? Lancet Haematol. 2021;8(9):E666-E669.

23. Iron fact sheet. National Institutes of Health Office of Dietary Supplements website. https://ods.od.nih.gov/factsheets/Iron. Updated March 30, 2021. Accessed February 3, 2022.

24. Lv Y, Chen L, Liang X, et al. Association between iron status and the risk of adverse outcomes in COVID-19. Clin Nutr. 2021;40(5):3462-3469.

25. Habib HM, Ibrahim S, Zaim A, Ibrahim WH. The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators. Biomed Pharmacother. 2021;136:111228.

26. Skrajnowska D, Brumer M, Kankowska S, Matysek M, Miazio N, Bobrowska-Korczak B. Covid 19: diet composition and health. Nutrients. 2021;13(9):2980.

27. Holford P, Carr AC, Jovic TH, Ali SR, et al. Vitamin C—an adjunctive therapy for respiratory infection, sepsis, and COVID-19. Nutrients. 2020;12(12):3760.

28. Hemilä H, de Man AME. Vitamin C and COVID-19. Front Med (Lausanne). 2021;7:559811.

29. Rawat D, Roy A, Mairta S, Gulati A, Khanna P, Baidya DK. Vitamin C and COVID-19 treatment: a systematic review and meta-analysis of randomized control trials. Diabetes Metab Syndr. 2021;15(6):102324.

30. Uddin MS, Millat MS, Baral PK, et al. The protective role of vitamin C in the management of COVID-19: a review. J Egypt Public Health Assoc. 2021;96(1):33.

31. Vitamin C fact sheet. National Institutes of Health Office of Dietary Supplements website. https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/. Update March 26, 2021. Accessed February 5, 2022.

32. 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.

33. Vitamin D fact sheet. National Institutes of Health Office of Dietary Supplements website. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/. Updated August 17, 2021. Accessed February 5, 2022.

34. Martineau AR, Joliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infection: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.

35. Zhou YF, Luo BA, Qin LL. The association between vitamin D deficiency and community-acquired pneumonia: a meta-analysis of observational studies. Medicine (Baltimore). 2019;98(38):e17252.

36. Monlezun DJ, Bittner EA, Christopher KB, et al. 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.

37. Gruber-Bzura BM. Vitamin D and influenza—prevention or therapy? Int J Mol Sci. 2018;19(8):2419.

38. 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.

39. Luo X, Liao Q, Shen Y, Li H, Cheng L. Vitamin D deficiency is associated with COVID-19 incidence and disease severity in Chinese people. J Nutr. 2021;151(1):98-103.

40. Iddir M, Brito A, Dingeo G, et al. Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: considerations during the COVID-19 crisis. Nutrients. 2020;12(6):1562.

41. Henrina J, Lim M, Pranata R. COVID-19 and misinformation: how an infodemic fuelled the prominence of vitamin D. Br J Nutr. 2021;125(3):359-360.

42. Shah K, Saxena D, Mavalankar D. Vitamin D supplementation, COVID-19 and disease severity: a meta-analysis. QJM. 2021;114(3):175-181.

43. Rawat D, Roy A, Maitra S, Shankar V, Khanna P, Baidya DK. Vitamin D supplementation and COVID-19 treatment: a systematic review and meta-analysis. Diabetes Metab Syndr. 2021;15(4):102189.

44. Liu N, Sun J, Wang X, Zhang T, Zhao M, Li H. Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis. Int J Infect Dis. 2021;104:58-64.

45. Bassatne A, Basbous M, Chakhtoura M, Zein OE, Rahme M, Fuleihan GE. The link between COVID-19 and vitamin D (VIVID): a systematic review and meta-analysis. Metabolism. 2021;119:154753.

46. Ghasemian R, Shamshirian A, Heydari K, et al. The role of vitamin D in the age of COVID-19: a systematic review and meta-analysis. Int J Clin Pract. 2021;75(11):e14675. 

47. Dror A, Morozov N, Daoud A, et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. Plos One. 2022;17(2):e0263069.

48. Borsche L, Glauner B, von Mendel J. COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/mL 25(OH)D3: results of a systematic review and meta-analysis. Nutrients. 2021;13(10):3596. 

49. Junaid K, Ejaz H, Abdalla AE, et al. Effective immune functions of micronutrients against SARS-CoV-2. Nutrients. 2020;12(10):2992.

50. Gordon AM, Hardigan PC. A case-control study for the effectiveness of oral zinc in the prevention and mitigation of COVID-19. Front Med (Lausanne). 2021;8:756707.

51. Zinc fact sheet. National Institutes of Health Office of Dietary Supplements website. https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/. Updated December 7, 2021. Accessed February 4, 2022.

52. Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The role of zinc in antiviral immunity. Adv Nutr. 2019;10(4):696-710.

53. Hulisz D. Efficacy of zinc against common cold viruses: an overview. J Am Pharm Assoc. 2004;44(5):594-603.

54. Science M, Johnstone J, Roth DE, Guyatt G, Loeb M. Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. CMAJ. 2012;184(10):E551-E561.

55. Wang MX, Win SS, Pang J. Zinc supplementation reduces common cold duration among healthy adults: a systematic review of randomized controlled trials with micronutrients supplementation. Am J Trop Med Hyg. 2020;103(1):86-99.

56. Haase H, Mocchegiani E, Rink L. Correlation between zinc status and immune function in the elderly. Biogerontology. 2006;7(5-6):421-428.

57. 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.

58. Thomas S, Patel D, Bittel B, et al. Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: the COVID a to z randomized clinical trial. JAMA Netw Open. 2021;4(2):e210369.

59. de Oliveira KdJF, Donangelo CM, de Oliveira AV Jr, da Silveira CLP, Koury JC. Effect of zinc supplementation on the antioxidant, copper, and iron status of physically active adolescents. Cell Biochem Funct. 2009;27(3):162-166.

60. Pal A, Squitti R, Picozza M, et al. Zinc and COVID-19: basis of current clinical trials. Biol Trace Elem Res. 2021;199(8):2882-2892.

61. Hathaway D, Pandav K, Patel M, et al. Omega 3 fatty acids and COVID-19: a comprehensive review. Infect Chemother. 2020;52(4):478-495.

62. Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood). 2008;233(6):674-688.

63. Omega-3 fatty acids. National Institutes of Health Office of Dietary Supplements website. https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/. Updated August 4, 2021. Accessed February 5, 2022.

64. Doaei S, Gholami S, Rastgoo S, et al. The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial. J Transl Med. 2021;19(1):128. 

65. Zapata BR, Müller JM, Vásquez JE, et al. Omega-3 index and clinical outcomes of severe COVID-19: preliminary results of a cross-sectional study. Int J Environ Res Public Health. 2021;18(15):7722.

66. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99(6A):35C-43C.

67. Vahedian-Azimi A, Abbasifard M, Rahimi-Bashar F, et al. Effectiveness of curcumin on outcomes of hospitalized COVID-19 patients: a systematic review of clinical trials. Nutrients. 2022;14(2):256. 

68. McCreary MR, Schnell PM, Rhoda DA. Randomized double-blind placebo-controlled proof-of-concept trial of resveratrol for outpatient treatment of mild coronavirus disease (COVID-19). Sci Rep. 2022;12(1):10978.

69. Önal H, Arslan B, Üçüncü Ergun N, et al. Treatment of COVID-19 patients with quercetin: a prospective, single center, randomized, controlled trial. Turk J Biol. 2021;45(4):518-529.

70. Di Pierro F, Derosa G, Maffioli P, et al. Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: a prospective, randomized, controlled, and open-label study. Int J Gen Med. 2021;14:2359-2366. 

71. Khan N, Mukhtar H. Tea polyphenols in promotion of human health. Nutrients. 2018;11(1):39. 

72. Jang M, Park Y, Cha Y, et al. Tea polyphenols EGCG and theaflavin inhibit the activity of SARS-CoV-2 3CL-protease in vitro. Evid Based Complement Alternat Med. 2020;2020:5630838. 

73. Davis C, Bryan J, Hodgson J, Murphy K. Definition of the Mediterranean diet; a literature review. Nutrients. 2015;7(11):9139-9153.

74. Dinu M, Pagliai G, Casini A, Sofi F. Mediterranean diet and multiple health outcomes: an umbrella review of meta-analyses of observational studies and randomised trials. Eur J Clin Nutr. 2018;72(1):30-43.

75. Greene MW, Roberts AP, Frugé AD. Negative association between Mediterranean diet adherence and COVID-19 cases and related deaths in Spain and 23 OECD countries: an ecological study. Front Nutr. 2021;8:591964.

76. El Khoury CN, Julien SG. Inverse association between the Mediterranean diet and COVID-19 risk in Lebanon: a case-control study. Front Nutr. 2021;8:707359.

77. Perez-Araluce R, Martinez-Gonzalez MA, Fernández-Lázaro CI, Bes-Rastrollo M, Gea A, Carlos S. Mediterranean diet and the risk of COVID-19 in the 'Seguimiento Universidad de Navarra' cohort [published online April 15, 2021]. Clin Nutr. doi: 10.1016/j.clnu.2021.04.001.

78. Ponzo V, Pellegrini M, D'Eusebio C, et al. Mediterranean diet and SARS-COV-2 infection: is there any association? A proof-of-concept study. Nutrients. 2021;13(5):1721.

79. Merino J, Joshi AD, Nguyen LH, et al. Diet quality and risk and severity of COVID-19: a prospective cohort study. Gut. 2021;70(11):2096-2104.