Covid-19

In December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), emerged in Wuhan, China, causing pneumonia and fatal respiratory illness now known as Covid-19. The virus has since spread worldwide.

Risk Factors

Covid-19 has a more severe course in older people and those with underlying health conditions.[1] Early in the pandemic, the Centers for Disease Control and Prevention reported that, among individuals hospitalized for Covid-19 infections as of March 30, 2020, 43% were aged 65 and over, 50% had hypertension, 48% had a body mass index (BMI) ≥ 30, 35% had chronic lung disease, 28% had diabetes mellitus, and 28% had cardiovascular disease.[2] As the pandemic spread to the US, obesity, diabetes, and hypertension were commonly reported among hospitalized Covid-19 patients.[3]

These health conditions contribute to racial disparities in Covid-19 morbidity and mortality. In the US, Black persons comprise 13% of the population, but accounted for one-third of hospitalizations early in the pandemic.[2] In subsequent reports, Covid-19 death rates have remained much higher among Black and Hispanic persons, compared with non-Hispanic White persons.[4] This disproportionate toll is caused, not by race or ethnicity per se, but by differences in socioeconomic factors (e.g., access to care) and in underlying health conditions. In a retrospective cohort study conducted by Ochsner Health in Louisiana, after adjusting for differences in sociodemographic and clinical characteristics on admission, Black race was not associated with higher in-hospital mortality than White race.[5] This finding suggests that measures taken to improve these chronic health conditions may have a secondary benefit in reducing the consequences of infection with Covid-19.

Excess body fat. Prior to the emergence of Covid-19, obesity was known to increase the risk of developing respiratory tract infections, including viral influenzas such as H1N1.[6] Among California adults who contracted H1N1 infection in 2009, half had a BMI ≥ 30.[7] Obesity also worsens the clinical course and increases mortality when influenza occurs.[8]

In the context of Covid-19, having a BMI ≥ 30 is an independent risk factor for the need for invasive mechanical ventilation in patients hospitalized with Covid-19.[9] Compared with hospitalized Covid-19 inpatients with BMI < 25, those with BMI ≥ 35 have 7.4-fold increased odds of requiring invasive mechanical ventilation.[10]

Among the possible explanations for the relationship between obesity and adverse outcomes in Covid-19 is the fact that excess body weight increases the risk for lung diseases in general (e.g., asthma and chronic obstructive pulmonary disease), as well as cardiometabolic diseases (e.g., hypertension, diabetes, and cardiovascular disease) that may reduce defenses and complicate survival. In addition, excess body weight may impair immune cell function and increase white blood cell counts.[3],[11] Individuals with a BMI ≥ 30 typically have a poorer immune response to influenza vaccines.[12] Epicardial adipose tissue has also been implicated as a contributor to the cardiopulmonary complications of Covid-19, including myocarditis, which is postulated to be mediated by upregulation of inflammatory cytokines such as IL-6.[13]

Hypertension. Patients with preexisting hypertension are at excess risk of developing severe and fatal Covid-19 infections.[3],[14] Hypertension damages the cardiovascular system, presumably making affected individuals more susceptible to virus-induced heart disease.

Diabetes. According to findings from a retrospective multicentered study of 7,337 Covid-19 cases in Hubei Province, China, individuals with type 2 diabetes were much more likely to succumb to the disease, compared with individuals who did not have diabetes (7.8% versus 2.7%). Among those with type 2 diabetes, those with poor glucose control (hemoglobin A1C averaging 8.1%) had an in-hospital death rate of 11.0%. Those with good glucose control (hemoglobin A1C averaging 7.3%) had an in-hospital death rate of 1.1% and were less likely to experience organ damage or require medical interventions.[15] Among 1,122 patients hospitalized with Covid-19 in 88 US hospitals, mortality rate was 28.8% among those with evidence of type 2 diabetes or uncontrolled hyperglycemia compared to 6.2% among those without diabetes or hyperglycemia.[16] Patients with diabetes are estimated to have a 50% greater likelihood of fatal Covid-19 than nondiabetic SARS-CoV-2-infected patients.[14]

Diagnosis

Covid-19 is clinically similar to other influenza-like illnesses and respiratory tract infections, apart from the near-pathognomonic features of anosmia and dysgeusia. Microbiological confirmation of SARS-CoV-2 infection is therefore recommended. Current diagnosis of Covid-19 rests on either molecular detection of SARS-CoV-2 nucleic acid using tests such as polymerase chain reaction (PCR) or detection of viral antigen (protein) using point-of-care tests or immunoassays of clinical specimens such as nasopharyngeal swabs, nasal or oral swabs, saliva, sputum, and endotracheal aspirates.[17]

Detection of antibodies to SARS-CoV-2 by serological immunoassays has limited utility in the setting of acute Covid-19 illness due to more prolonged time for test processing and high rates of false negatives during the first few days of illness. Thus, serology tests for SARS-CoV-2 antibodies should be used to neither confirm nor exclude Covid-19 illness in acutely sick individuals. Rather, serology contributes more to the overall surveillance strategy for SARS-CoV-2 at a population level. Due to the evolving nature of laboratory testing for Covid-19 illness, it is recommended that authoritative sources such as the US Centers for Disease Control and Prevention or the World Health Organization be consulted for the most up-to-date testing guidance.[18]

Treatment

Treatment guidelines for Covid-19 continue to evolve and are available from the National Institutes of Health (NIH).[19] The mainstays of nonpharmacologic interventions for mild Covid-19—like many viral illnesses—are supportive and include adequate hydration and rest. Pharmacologic interventions for mild Covid-19 illness are aimed at symptom management and may include over-the-counter analgesics and antipyretics for fever, headache, and myalgia; decongestants and antihistamines for sinusitis and rhinorrhea; and antitussives and expectorants for cough. In the vast majority of people with a mild Covid-19 illness, rapid resolution of symptoms is complete and without complications.

For outpatients with mild to moderate Covid-19 with comorbidities that place them at high risk of clinical deterioration, the NIH recommends treatment with an anti-SARS-CoV-2 monoclonal antibody combination such as bamlanivimab plus etesevimab or casirivimab plus imdevimab. Both combinations are authorized for emergency use by the Food and Drug Administration.[20]

For patients with moderate-to-severe Covid-19 illness requiring hospitalization and/or intensive care, interventions can be broadly categorized into positioning; supportive interventions to ensure hemodynamic stability and adequate renal perfusion; targeted pharmacologic treatments (e.g., antivirals); immune-based therapies (e.g., blood-derived products, antibodies, and immunomodulators); and adjunctive interventions. Positional interventions, such as awake pronation and head elevation for the more moderately to severely ill Covid-19 patient, aim to improve oxygenation by reducing the diaphragmatic force against which infiltrated lungs must inflate. Use of targeted drug treatments should be guided by best available evidence and national authoritative guidelines, such as those produced by the NIH.[19]

At present, the antiviral remdesivir is the only targeted pharmacologic treatment for Covid-19 approved and licensed by the Food and Drug Administration and is recommended for hospitalized adults requiring supplemental oxygen.[21] For those hospitalized and requiring supplemental oxygen and/or mechanical ventilation, the corticosteroid dexamethasone is recommended. The recommendation for use of corticosteroids in severe or critically ill Covid-19 patients is echoed by World Health Organization clinical practice guidelines.[22]

Tocilizumab, the recombinant anti-interleukin-6 receptor monoclonal antibody, should be added to dexamethasone (with or without remdesivir, depending on clinical status) for hospitalized Covid-19 patients experiencing rapid respiratory deterioration.

For hospitalized Covid-19 patients on high-flow oxygen or noninvasive ventilation who are progressing clinically or are demonstrating increased markers of inflammation, the NIH recommends using either baricitinib (the oral Janus kinase inhibitor) or tocilizumab, combined with dexamethasone alone or dexamethasone plus remdesivir.

At the time of this writing, with few exceptions, the NIH generally recommends against the use of convalescent plasma for treatment of Covid-19; the NIH also recommends against the use of other blood-derived products outside of clinical trials.[19]

For hospitalized adults or children, agents to prevent the formation of blood clots are recommended, but thrombolytic agents (which target existing clots) are not.[19]

Nutritional Considerations

In the Covid-19 pandemic, three important roles for nutrition have emerged:

First, nutritional factors are key for the prevention and amelioration of the underlying health conditions that increase Covid-19 morbidity and mortality, particularly obesity, diabetes, and hypertension. A low-fat plant-based diet significantly improves control in each of these conditions and is superior in safety and efficacy, compared with other therapeutic diets (see respective chapters).

Second, studies suggest that a plant-based diet may reduce the risk of developing severe Covid-19. A 2021 case-control study of health care workers in 6 countries revealed that those following plant-based diets had 73% lower odds of developing moderate-to-severe Covid-19 (OR, 0.27; 95% CI, 0.10-0.81), compared with those following other diets. In contrast, low-carbohydrate, high-protein diets were associated with 48% greater odds of moderate-to-severe Covid-19 (OR, 1.48; 95% CI, 0.89-2.49).[23]

Similarly, the smartphone-based COVID Symptom Study, including 592,571 participants of whom 31,815 developed Covid-19, found that dietary patterns that were highest in fruits, vegetables, and plant-based foods in general were associated with a 41% lower risk of severe Covid-19 (HR, 0.59; 95% CI, 0.47-0.74) and a 9% reduction of Covid-19 infection of any severity (HR, 0.91; 95% CI, 0.88-0.94), compared with diets lowest in these foods.[24]

Third, nutrition may influence the effectiveness of vaccination due to its effect on underlying conditions that modulate immune response. In a 2021 study, the ability of the Pfizer vaccine to stimulate an effective immune response was studied in 86 health care workers. Response to the vaccine was inversely associated with waist circumference (R = -0.324, P = 0.004). In other words, increased body weight was associated with poorer vaccine efficacy. Elevated plasma cholesterol levels, high blood pressure, and smoking also impaired the response to the vaccine.[25] Body weight, blood pressure, and cholesterol levels are highly responsive to dietary interventions.

Nutritional Issues under Investigation

Apart from the above considerations, many nutrients (e.g., dietary fat, vitamins C or D, selenium, zinc) and foods (e.g., fruits and vegetables in general, allium vegetables) have been investigated for their ability to influence lung function. However, their role in influencing the course of a SARS-CoV-2 infection is not yet well characterized. Key findings are described below.

Vitamin C

Vitamin C, or L-ascorbic acid, is a water-soluble vitamin found in fruits and vegetables, especially citrus fruits, peppers, broccoli, sweet potatoes, and strawberries.[26] Several studies have supported the beneficial effects of vitamin C on immune function.[27],[28],[29],[30] A deficiency may lead to immune impairments and a higher risk of infections. A study including 57 hospitalized elderly patients with acute respiratory infections showed a benefit of vitamin C supplements over placebo.

An early review of acute respiratory infections and vitamin C found benefits for reducing the duration and/or severity of symptoms. Three controlled studies each found at least an 80% reduction in the risk of developing pneumonia among those taking vitamin C. Preventive benefits of supplementation may be more likely in those with marginal deficiency or under physical stress.[31]

A 2013 review examined placebo-controlled trials of vitamin C for the common cold. Vitamin C supplementation did not reduce the incidence of colds (29 trials) except in individuals under extreme physical stress (5 trials). Regular use of vitamin C supplements did modestly reduce the duration of symptoms (31 trials).[32]

A recent randomized controlled trial of vitamin C infusion in 167 critically ill patients with sepsis-induced ARDS demonstrated a significant 28-day mortality benefit: 29.8% in the vitamin C arm vs. 46.3% in the placebo arm.[33]

In the setting of Covid-19, the NIH reports that at present there are insufficient data to recommend either for or against adjunctive or stand-alone vitamin C for treatment of mild, moderate, or severe SARS-CoV-2 infections.[34]

Severe vitamin C deficiency is frequently complicated by pneumonia, which is among the most common causes of mortality in the Covid-19 patient population.[35]

Vitamin D

The human body produces vitamin D when UVB solar radiation strikes the skin. Darker skin, winter season, use of sunscreen, older age, and indoor time all reduce endogenous production. Vitamin D is essential to many processes in the body including calcium homeostasis and bone health, regulation of cell growth and differentiation, and neuromuscular and immune function.[36]

Observational and supplementation trials have suggested that higher circulating 25-hydroxy vitamin D (25(OH)D) concentrations are associated with reduced risk of several infectious diseases, including influenza, dengue, hepatitis, herpesvirus, and pneumonia.[37],[38],[39],[40] A meta-analysis of 25 randomized controlled trials, including data from 10,933 participants, showed that vitamin D supplementation decreased the risk of respiratory infections by 12%. Among those with baseline vitamin D levels below 10 ng/mL (25 nmol/L), the reduction in risk was 70%.[41]

Regarding Covid-19 specifically, a recent review identified multiple lines of suggestive evidence for vitamin D’s role, including that the outbreak began in the northern hemisphere where it was winter, when 25(OH)D levels are lowest; cases in the southern hemisphere, where the pandemic struck in late summer, were relatively low; vitamin D deficiency can worsen acute respiratory distress syndrome; and case-fatality increases with age and chronic disease comorbidity, both of which are linked to lower 25(OH)D levels. Furthermore, several studies across geographies have demonstrated lower overall serum vitamin D levels in Covid-19 patients compared with healthy population controls. Mechanisms by which vitamin D may be protective include induction of antiviral peptides, and decreased production of pro-inflammatory cytokines that can injure the lungs and cause pneumonia.[42]

Observational data for use of vitamin D in Covid-19 have yielded ambiguous findings. In 185 Covid-19 patients diagnosed and treated in Heidelberg, Germany, whose vitamin D status was examined retrospectively, age-, sex-, and comorbidity-adjusted vitamin D deficiency (< 12 ng/mL [< 30 nM]) was highly correlated to both increased risk of invasive mechanical ventilation (> 6-fold risk) and death (> 14-fold risk).[43] However, in a prospective, multicenter observational study of long-term outcomes in 109 Covid-19 patients with persistent symptoms in Austria and Germany, low serum vitamin D levels either acutely or at 2-month follow-up were not correlated to more persistent symptoms, functional lung impairment, or more significant abnormalities on CT scan, leading the authors to conclude that while vitamin D deficiency is common among Covid-19 patients, it is unrelated to disease outcomes.[44] In a retrospective observational study matching SARS-CoV-2 test results to 25(OH)D levels from the prior year in more than 190,000 patients across the US, the authors conclude that "SARS-CoV-2 positivity is strongly and inversely associated with circulating 25(OH)D levels, a relationship that persists across latitudes, races/ethnicities, both sexes, and age ranges."[45] The overall SARS-CoV-2 positivity rate among 191,779 tested individuals was 9.3%; however, positivity varied according to vitamin D level. For those with vitamin D deficiency (< 20 ng/mL; n=39,190), positivity rate was 12.5%, while for those with adequate levels (30-34 ng/mL; n=27,870), positivity rate was 8.1%, and for those with levels ≥ 55 ng/mL (n=12.321), positivity rate was 5.9%.[45]

Prospective clinical trials of vitamin D as a therapeutic intervention for Covid-19 illness have also produced mixed results. In an open-label randomized clinical trial in Cordoba, Spain, 76 Covid-19 patients fulfilling hospital admission criteria were treated with standard of care with or without 25(OH)D supplementation. Only 1 patient in the 25(OH)D arm required ICU admission, and none died, compared with 50% ICU admission and 8% mortality in the arm without supplementation. Adjusted for the comorbidities hypertension and diabetes, odds of ICU admission with 25(OH)D treatment was 0.03.[46] However, in a randomized, double-blind placebo-controlled trial in Brazil, which enrolled over 200 hospitalized patients with Covid-19, significant differences between the vitamin D and placebo arms for the outcomes of length of stay, ICU admission, need for invasive mechanical ventilation, or death were not observed.[47]

Taken together, the present state of evidence prevents recommendation either for or against the use of vitamin D as an adjunctive or stand-alone therapy for Covid-19.[48],[49]

Zinc

Zinc is an essential mineral found in legumes, nuts/seeds, oats, and meat. It plays an important role in immune function, and deficiency has been shown to adversely affect the function of T and B lymphocytes.[50],[51] Excess zinc can also impair immunity.[52]

Elderly populations are especially susceptible to zinc deficiency. They are also at risk for immune deficiencies and for respiratory infections.[53] However, there is mixed evidence about the effectiveness of zinc supplementation on immune function in this population. One randomized controlled trial of zinc supplementation in elderly individuals found significantly reduced incidence of infections in the supplemented group.[54] In contrast, a separate controlled study of zinc supplementation showed that up to 30 mg of zinc per day led to no significant long-term effects on immune status in healthy older adults.[55]

Zinc can also affect viruses directly. In cell-based studies, high levels of zinc ions (Zn2+) together with compounds that promote uptake of zinc into cells were found to inhibit replication of a variety of RNA viruses, including the original severe acute respiratory syndrome coronavirus (SARS-CoV). In assays measuring the activity of the SARS-CoV replication and transcription complex, without which the virus cannot multiply, Zn2+ efficiently inhibited synthesis of viral RNA.[56] Whether zinc administration could benefit those with Covid-19 is under investigation.[57]

A review of 16 randomized, placebo-controlled trials of zinc supplementation for treatment of the common cold found a significant reduction in duration (by 1.03 days) but not severity of common cold symptoms. Data from 2 preventive trials indicated that those taking zinc prophylactically for 5 or more months had a 36% lower incidence rate ratio of developing a cold than those in the placebo group.[52]

The evidence base supporting the use of zinc supplementation as either a preventive or a therapeutic intervention in Covid-19 is particularly scant, and for this reason, the NIH treatment guidelines specifically recommend against its use as a preventive maneuver and cite the need for additional studies before a recommendation for or against its use as a therapeutic intervention can be made.[58] One retrospective observational analysis compared outcomes in hospitalized Covid-19 patients in New York who received zinc supplementation or not in addition to hydroxychloroquine and azithromycin treatment.[59] Of 932 enrollees, 44% received zinc, and 56% did not. Baseline differences potentially biasing data interpretation include higher total lymphocyte count and lower troponin and procalcitonin levels in those receiving zinc supplementation. Those who received zinc had lower mortality rates and higher likelihood of being discharged home, a finding that was most significant for patients being treated outside of an ICU setting[59]

Selenium

Selenium is an essential trace element that contributes to many biological processes including cellular protection against oxidative stresses as well as infection. Rich dietary sources of selenium include Brazil nuts, long-grain brown rice, oats, and baked beans; however, the most common sources of selenium in the American diet are bread, grains, meats including poultry and fish, and eggs.[60] Selenium has been repeatedly demonstrated to have antiviral effects.[61] The most compelling evidence of selenium’s potential role in mitigation of viral-induced pathogenesis stems from our understanding of Keshan disease, in which the cardiomyopathy associated with selenium deficiency is mediated by intercurrent coxsackievirus infection, which also explains its seasonal variation. Population-level selenium supplementation in endemic areas has drastically reduced the incidence of Keshan disease. Selenium supplementation has also been found to confer morbidity and mortality benefits in other viral diseases, including HIV.[62],[63]

In Covid-19, population-level studies have demonstrated an inverse relationship between selenium levels and mortality, with areas having the lowest dietary intakes and historic serum or hair concentrations suffering the greatest mortality rates.[64] Similarly, areas known for high dietary intake demonstrated the lowest regional Covid-19 mortality rates. These population-level data from China have been corroborated in a cross-sectional study of hospitalized Covid-19 patients in Germany, in which selenium status was assessed consecutively in serum samples. Forty-four percent of Covid-19 patient specimens were found to be selenium deficient compared with reference controls, and deficiency was over-represented among those Covid-19 patients who died: 65% in those who died vs. 39% in those who survived.[65] Several hypotheses have emerged to explain such findings, all of which require further prospective interrogation and accrual of high-quality data before a therapeutic role of selenium is considered in the Covid-19 patient population.

Orders

See Basic Diet Orders chapter.

What to Tell the Family

Use of masks, personal hygiene, physical distancing, and vaccination remain key steps for preventing viral spread. The role of nutrition, particularly a low-fat, plant-based diet, is important in improving control of underlying conditions (obesity, diabetes, and hypertension) that increase Covid-19 pathogenicity.

High-quality evidence to support specific foods or nutrients for treatment or prevention of Covid-19 is lacking; however, available data suggest that an overall dietary pattern that is plant-based and rich in vegetables, nuts, and legumes may reduce the risk of developing moderate-to-severe Covid-19.

References

  1. CDC COVID-19 Response Team. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 - United States, February 12-March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(13):382-386.  [PMID:32240123]
  2. Garg S, Kim L, Whitaker M, et al. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 - COVID-NET, 14 States, March 1-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458-464.  [PMID:32298251]
  3. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020;323(20):2052-2059.  [PMID:32320003]
  4. Health equity considerations and racial and ethnic minority groups. Centers for Disease Control and Prevention. Updated April 19, 2021. Accessed August 6, 2021. https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/race-eth...
  5. Price-Haywood EG, Burton J, Fort D, et al. Hospitalization and Mortality among Black Patients and White Patients with Covid-19. N Engl J Med. 2020;382(26):2534-2543.  [PMID:32459916]
  6. Mancuso P. Obesity and respiratory infections: does excess adiposity weigh down host defense? Pulm Pharmacol Ther. 2013;26(4):412-9.  [PMID:22634305]
  7. Louie JK, Acosta M, Samuel MC, et al. A novel risk factor for a novel virus: obesity and 2009 pandemic influenza A (H1N1). Clin Infect Dis. 2011;52(3):301-12.  [PMID:21208911]
  8. Huttunen R, Syrjänen J. Obesity and the risk and outcome of infection. Int J Obes (Lond). 2013;37(3):333-40.  [PMID:22546772]
  9. Kalligeros M, Shehadeh F, Mylona EK, et al. Association of Obesity with Disease Severity Among Patients with Coronavirus Disease 2019. Obesity (Silver Spring). 2020;28(7):1200-1204.  [PMID:32352637]
  10. Simonnet A, Chetboun M, Poissy J, et al. High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Requiring Invasive Mechanical Ventilation. Obesity (Silver Spring). 2020;28(7):1195-1199.  [PMID:32271993]
  11. Sung KT, Kuo R, Sun JY, et al. Associations between CT-determined visceral fat burden, hepatic steatosis, circulating white blood cell counts and neutrophil-to-lymphocyte ratio. PLoS One. 2018;13(11):e0207284.  [PMID:30458019]
  12. Sheridan PA, Paich HA, Handy J, et al. Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes (Lond). 2012;36(8):1072-7.  [PMID:22024641]
  13. Malavazos AE, Goldberger JJ, Iacobellis G. Does epicardial fat contribute to COVID-19 myocardial inflammation? Eur Heart J. 2020;41(24):2333.  [PMID:32464641]
  14. Flaherty GT, Hession P, Liew CH, et al. COVID-19 in adult patients with pre-existing chronic cardiac, respiratory and metabolic disease: a critical literature review with clinical recommendations. Trop Dis Travel Med Vaccines. 2020;6:16.  [PMID:32868984]
  15. Zhu L, She ZG, Cheng X, et al. Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 2020;31(6):1068-1077.e3.  [PMID:32369736]
  16. Bode B, Garrett V, Messler J, et al. Glycemic Characteristics and Clinical Outcomes of COVID-19 Patients Hospitalized in the United States. J Diabetes Sci Technol. 2020;14(4):813-821.  [PMID:32389027]
  17. Overview of testing for SARS-CoV-2 (COVID-19). Centers for Disease Control and Prevention. Accessed September 18, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html
  18. Diagnostic testing for SARS-CoV-2: interim guidance. World Health Organization. Updated September 11, 2020. Accessed September 18, 2020. https://www.who.int/publications/i/item/diagnostic-testing-for-sars-cov-2
  19. What’s new in the guidelines. IN: COVID-19 Treatment Guidelines. National Institutes of Health. Updated August 4, 2021. Accessed August 8, 2021. https://www.covid19treatmentguidelines.nih.gov/whats-new/
  20. National Institutes of Health. Outpatient Management of Acute COVID-19. IN: COVID-19 Treatment Guidelines. Updated May 24, 2021. https://www.covid19treatmentguidelines.nih.gov/management/outpatient-manag...
  21. Therapeutic management of hospitalized adults with COVID-19. IN: COVID-19 Treatment Guidelines. National Institutes of Health. Accessed August 5, 2021. https://www.covid19treatmentguidelines.nih.gov/management/clinical-managem...
  22. Corticosteroids for COVID-19. World Health Organization. Updated September 2, 2020. Accessed September 18, 2020. https://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020...
  23. Kim H, Rebholz CM, Hegde S, et al. Plant-based diets, pescatarian diets and COVID-19 severity: a population-based case-control study in six countries. BMJ Nutr Prev Health. 2021;4(1):257-266.  [PMID:34308134]
  24. Merino J, Joshi AD, Nguyen LH. Diet quality and risk and severity of COVID-19: a prospective cohort study. medRxiv. Preprint posted online June 25, 2021. doi: 10.1101/2021.06.24.21259283
  25. Watanabe M, Balena A, Tuccinardi D, et al. Central obesity, smoking habit, and hypertension are associated with lower antibody titres in response to COVID-19 mRNA vaccine. Diabetes Metab Res Rev. 2021.  [PMID:33955644]
  26. Vitamin C: fact sheet for health professionals. National Institutes of Health Office of Dietary Supplements. Accessed April 10, 2020. https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/
  27. Wintergerst ES, Maggini S, Hornig DH. Immune-enhancing role of vitamin C and zinc and effect on clinical conditions. Ann Nutr Metab. 2006;50(2):85-94.  [PMID:16373990]
  28. Maggini S, Wenzlaff S, Hornig D. Essential role of vitamin C and zinc in child immunity and health. J Int Med Res. 2010;38(2):386-414.  [PMID:20515554]
  29. Pohanka M, Pejchal J, Snopkova S, et al. Ascorbic acid: an old player with a broad impact on body physiology including oxidative stress suppression and immunomodulation: a review. Mini Rev Med Chem. 2012;12(1):35-43.  [PMID:22070691]
  30. Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. 2017;9(11).  [PMID:29099763]
  31. Hemilä H, Douglas RM. Vitamin C and acute respiratory infections. Int J Tuberc Lung Dis. 1999;3(9):756-61.  [PMID:10488881]
  32. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2013.  [PMID:23440782]
  33. Fowler AA, 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.  [PMID:31573637]
  34. Vitamin C. IN: COVID-19 Treatment Guidelines. National Institutes of Health. Updated April 21, 2021. Accessed June 23, 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/vitam...
  35. Carr AC. Micronutrient status of COVID-19 patients: a critical consideration. Crit Care. 2020;24(1):349.  [PMID:32546195]
  36. Vitamin D: fact sheet for health professionals. National Institutes of Health Office of Dietary Supplements. Accessed April 10, 2020. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
  37. 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).  [PMID:32252338]
  38. Hu YC, Wang WW, Jiang WY, et al. Low vitamin D levels are associated with high viral loads in patients with chronic hepatitis B: a systematic review and meta-analysis. BMC Gastroenterol. 2019;19(1):84.  [PMID:31185932]
  39. Öztekin A, Öztekin C. Vitamin D Levels in Patients with Recurrent Herpes Labialis. Viral Immunol. 2019;32(6):258-262.  [PMID:31145049]
  40. Chung C, Silwal P, Kim I, et al. Vitamin D-Cathelicidin Axis: at the Crossroads between Protective Immunity and Pathological Inflammation during Infection. Immune Netw. 2020;20(2):e12.  [PMID:32395364]
  41. Martineau AR, Jolliffe DA, Greenberg L, et al. Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technol Assess. 2019;23(2):1-44.  [PMID:30675873]
  42. Hunt C, Chakravorty NK, Annan G, et al. The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections. Int J Vitam Nutr Res. 1994;64(3):212-9.  [PMID:7814237]
  43. Radujkovic A, Hippchen T, Tiwari-Heckler S, et al. Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients. 2020;12(9).  [PMID:32927735]
  44. Pizzini A, Aichner M, Sahanic S, et al. Impact of Vitamin D Deficiency on COVID-19-A Prospective Analysis from the CovILD Registry. Nutrients. 2020;12(9).  [PMID:32932831]
  45. Kaufman HW, Niles JK, Kroll MH, et al. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One. 2020;15(9):e0239252.  [PMID:32941512]
  46. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, et al. "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study". J Steroid Biochem Mol Biol. 2020;203:105751.  [PMID:32871238]
  47. Murai IH, Fernandes AL, Sales LP, et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. JAMA. 2021;325(11):1053-1060.  [PMID:33595634]
  48. Leaf DE, Ginde AA. Vitamin D3 to Treat COVID-19: Different Disease, Same Answer. JAMA. 2021;325(11):1047-1048.  [PMID:33595641]
  49. Vitamin D. IN: COVID-19 Treatment Guidelines. National Institutes of Health. Updated April 21, 2021. Accessed June 23, 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/vitam...
  50. Maares M, Haase H. Zinc and immunity: An essential interrelation. Arch Biochem Biophys. 2016;611:58-65.  [PMID:27021581]
  51. Wessels I, Maywald M, Rink L. Zinc as a Gatekeeper of Immune Function. Nutrients. 2017;9(12).  [PMID:29186856]
  52. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2013.  [PMID:23775705]
  53. Soldati L, Di Renzo L, Jirillo E, et al. The influence of diet on anti-cancer immune responsiveness. J Transl Med. 2018;16(1):75.  [PMID:29558948]
  54. Prasad AS, Beck FW, Bao B, et al. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr. 2007;85(3):837-44.  [PMID:17344507]
  55. Hodkinson CF, Kelly M, Alexander HD, et al. Effect of zinc supplementation on the immune status of healthy older individuals aged 55-70 years: the ZENITH Study. J Gerontol A Biol Sci Med Sci. 2007;62(6):598-608.  [PMID:17595415]
  56. te Velthuis AJ, van den Worm SH, Sims AC, et al. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010;6(11):e1001176.  [PMID:21079686]
  57. World-first trial to test benefit of intravenous zinc in COVID-19 fight. The University of Melbourne. Accessed April 10, 2020. https://about.unimelb.edu.au/newsroom/news/2020/april/world-first-trial-to...
  58. Zinc. IN: COVID-19 Treatment Guidelines. National Institutes of Health. Updated April 21, 2021. Accessed June 23, 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/zinc/
  59. Carlucci P, Ahuja T, Petrilli CM, Rajagopalan H, Jones S, Rahimian J. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. medRxiv. Preprint posted online May 8, 2020. doi: 10.1099/jmm.0.001250
  60. Selenium: fact sheet for health professionals. National Institutes of Health Office of Dietary Supplements. Accessed September 19, 2020. https://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/#h3
  61. Guillin OM, Vindry C, Ohlmann T, et al. Selenium, Selenoproteins and Viral Infection. Nutrients. 2019;11(9).  [PMID:31487871]
  62. Steinbrenner H, Al-Quraishy S, Dkhil MA, et al. Dietary selenium in adjuvant therapy of viral and bacterial infections. Adv Nutr. 2015;6(1):73-82.  [PMID:25593145]
  63. Baum MK, Shor-Posner G, Lai S, et al. High risk of HIV-related mortality is associated with selenium deficiency. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;15(5):370-4.  [PMID:9342257]
  64. Zhang J, Taylor EW, Bennett K, et al. Association between regional selenium status and reported outcome of COVID-19 cases in China. Am J Clin Nutr. 2020;111(6):1297-1299.  [PMID:32342979]
  65. Moghaddam A, Heller RA, Sun Q, et al. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients. 2020;12(7).  [PMID:32708526]
Last updated: August 23, 2021