The current COVID-19 pandemic has been a significant adjustment for everyone. We understand that you may be getting questions from your patients regarding nutrition and the use of supplements for the prevention or treatment of COVID-19 that are frequently mentioned in the media. The College’s Integrative Medicine Committee has compiled information supported by research. We hope it will help you and your patients answer some of the questions surrounding this topic.
We provide an overview of the various agents that may have a role in the prevention or treatment of COVID-19 based on a review of the most current literature. It is important to note, however, that no clinical studies with vitamins and supplements have been completed in humans that are specific to COVID-19. Much of this information is based on the hypothesis that excessive inflammation, a depressed immune system and an activated cytokine storm contribute to the pathogenesis of COVID-19. Further research is needed to validate these conclusions.
Vitamin D

Along with classic vitamin D functions that involve regulation of bone metabolism and calcium phosphorus homeostasis, vitamin D also appears to have a role in immune functioning. Vitamin D acts through the vitamin D receptors (VDR) present on the majority of immune cells and through local conversion of vitamin D to its active form. Together, vitamin D and VDR have a suppressive effect on autoimmunity and anti-inflammatory effects on immune cells (1).

In 2017 Martineau, et. al. (2) reviewed data from 25 randomized controlled trials (11,321 subjects) and noted that vitamin D reduced the risk of acute respiratory infections among all patients, especially in those with deficient levels of vitamin D. On May 9, 2020 Dr. D’Avolio, et.al. (3) noted that 25-hydroxyvitamin D concentrations were lower in patients with positive PCR for SARS-COV-2(COVID-19) in a retrospective investigation of a cohort of 107 Swiss patients. In PCR COVID-19 positive patients, the 25(OH) D median level was 11.1ng/dl compared to 24.6ng/dl for the PCR negative group. It has been hypothesized that ultraviolet-B irradiance and vitamin D reduce the risk of viral infections (4). There are several factors for vitamin D deficiency, including age older than

50, working indoors, living in low radiance areas of the country, and darker skin (due to the increased presence of melanin, which has a protective effect against UV radiation exposure). Many people may have more than one risk factor. Special consideration should be taken with Black patients who may be at an increased risk for COVID-19 mortality, particularly when residing in low radiance areas of the country. Recent studies by Alex Backer (5,6) found that in Detroit, an area of low radiance, the percentage of deaths due to COVID-19 among Black patients was 193 % higher compared to the percentage of the Black population. In Florida, an area of high irradiance, the percentage of mortality among Black people was 7 % higher than the percentage of Black people in the population. Statistically, p<0.05 in this article (5,6).

Additionally, irradiation penetration of human skin and COVID-19 cases and mortality rates appear to be higher in lower UVB irradiance localities and on lower UVB irradiance days (6). Per the WHO and others, the SARS virus (a close genetic cousin to COVID-19) is sensitive to ultraviolet, infrared and visible light (8). It is important to consider irradiances and check for and treat vitamin D deficiency in your patients. The below table summarizes how vitamin D sufficiency/deficiency are defined based on serum levels.

Microsoft Word – Vitamins and COVID.ACAAI2020.docx

When vitamin D serum levels are lower than 30ng/dl, supplementation is encouraged. Per the Endocrine Society’s clinical practice guideline, a daily 1,000-4,000 IU supplement of vitamin D is recommended for anyone with chronic disease and a 25(OH)D concentration level below 30 ng/ml (9). Grant et. al. recommend that 10,000 IU/day of vitamin D3 be given for a few weeks to rapidly raise 25(OH)D levels followed by 5,000 IU/day to get the concentrations to 40-60 ng/ml(100-150 nmol/L in patients at risk for COVID-19 and or Influenza (10).

Every patient is different, and we suggest rechecking levels intermittently while giving supplementation.
Vitamin C

Vitamin C is a monosaccharide antioxidant that like flavonoids, inhibits NLRP3 inflammasome activation, which is involved in COVID-19 disease (11). As observed in clinical trials, vitamin C shortens the duration, frequency and severity of the common cold and also the incidence of pneumonia (12). Suggested daily doses vary from 500 mg to 3000 mg, and higher doses are suggested during acute infection (11). Non-COVID-19 related meta analyses data has demonstrated significant benefits of vitamin C in the treatment of sepsis and septic shock as noted by Kashiouris, M.G. et.al (13). Dr. Erol Adnan believes that high dose vitamin C behaves as an antioxidant on lung epithelial cells and a pro-oxidant for immune cells (14) though more data is needed to confirm. Pharmacologic doses of intravenous vitamin C for a short course of therapy may be of benefit in treating COVID 19 and has been used in hospitals. Clinical trials with COVID-19 are currently underway and should give us data on efficacy, dosages and side effects when used for this pandemic virus. Side effects from Vitamin C can include nausea, vomiting, heartburn, stomach cramps, and headache.
Vitamin E

Vitamin E has strong antioxidant properties and could have a role in the treatment COVID- 19 patients, but we do not have a dose recommendation based on current research. There is no need to check levels. Dietary sources include sunflower seeds, almonds, spinach, avocados, squash, kiwifruit, trout, shrimp, olive oil, and broccoli.

Zinc

Trace elements such as copper, manganese and zinc have immunomodulatory properties (15). Zinc has been shown to decrease the duration of common colds (16, 17, 18). This mineral has intrinsic antiviral activity in vitro against corona viruses through inhibition of SARS-COV RNA (18) and may prevent coronavirus entry into cells and decrease virulence (11, 20, 21). However, this has not been documented for COVID-19. Typical daily dosing is 15-30 mg daily with lozenges potentially preventing viral entry in the upper airway (11). Doses over the recommended daily allowance of 40mg/day may give a metallic taste in the mouth and nausea. High doses may lead to copper deficiency, and only short courses of therapy are recommended. The primary dietary sources of zinc are fish, dairy products, shellfish (especially oysters) and red meat (22). According to the World Health Organization, there are no approved guidelines on the use of zinc in COVID-19 (23). Elderberry extract

Elderberry extract may have some effect on upper respiratory infections and influenza, but further studies are needed (16). Improperly cooked berries can cause cyanide toxicity and the plant is poisonous when consumed. Elderberry can increase inflammatory cytokines including IL-B1 so it should be discontinued once a patient has begun to show symptoms of infection with COVID-19 or has a positive test (11).

Echinacea

Echinacea has been studied in clinical trials, but the results are not conclusive and no data is available for COVID-19 infection (11).
Natural antivirals

Studies have shown glycyrrhizin from licorice root has some antiviral effect against coronaviruses, but has not been studied as a treatment for COVID-19. Other antivirals include oregano, ginger, sage, basil, fennel, garlic, lemon balm, peppermint, rosemary, echinacea purpurea, sambucus, astragalus, ginseng, dandelion, thyme, hyssop, sandalwood and star anise. None of these have been tested for their activity against coronaviruses (24). Gene-Eden-VIR/Novirin is a patented herbal antiviral treatment containing five ingredients: quercetin, green tea, cinnamon, licorice and selenium. Clinical trials have shown it is effective against several viruses including betacoronaviruses and SARS-CoV. It

is currently being tested in COVID-19. Epigallocatechine gallate (EGCG) from green tea has been shown to have a wide range of antiviral activity (11, 25).
Quercetin

Quercetin and the active ingredients in green tea called catechins have been shown to have a variety of anti-inflammatory, antioxidant and anti-enzymatic effects (25). Though quercetin is considered safe, more research is needed to understand its anti-inflammatory and antiviral effects as a stand-alone agent (26). Vitamin C has been shown to improve quercetin absorption and enhance plasma quercetin levels. Quercetin is found in several plants including onions, blueberries, kale, cranberries, broccoli and green tea (11). Resveratrol

Resveratrol (polyphenol from grape seeds and red wine) has been shown to have some antiviral effect on coronaviruses (24, 27).
Curcumin

Curcumin found in turmeric root is a widely used ayurvedic drug due to its antioxidant, antiviral, anti-septic, analgesic, antimalarial and anti-inflammatory properties. Recent molecular docking studies show that curcumin bears good binding potency against COVID- 19 and could be considered as an antiviral drug candidate. Validation studies, both in vitro and in vivo are needed (28). Several other medicinal plants used in Indian traditional medicine are also being studied for their immune boosting, antiviral and anti-inflammatory properties as potential treatments to be used in addition to standard therapeutics for infectious diseases like COVID-19 (29). Molecular docking analysis has been looked at and many of them show in vitro activity against COVID-19 including Apigenin (found in parsley and celery) in addition to Curcumin (30).

Melatonin

Melatonin has been shown to inhibit NFkB and NLRP3 inflammasome activation (11, 31). NLRP3 inflammasome has been shown to have a close connection to acute lung injury and acute respiratory distress syndrome (32). Melatonin also reduces oxidative lung injury and inflammatory cell recruitment during viral infections (11, 33). Melatonin is not virucidal but has indirect antiviral actions due to its anti-inflammation, antioxidation and immune-enhancing features (34). In addition, melatonin is beneficial in improving sleep quality, which might help improve outcomes for COVID-19 patients. The benefit of melatonin in COVID-19 specifically has not been studied, but it does appear to have a high safety profile. Melatonin dosing ranges from 0.3 mg to 20 mg (11), but higher doses can be associated with side effects and are generally not needed (32).

Other

There are a few additional agents that may have health benefits, but have not been

specifically studied in relation to COVID-19:

  • Garlic (with the active compound allicin) has been shown to decrease the frequency of colds and the duration of symptoms. It’s been hypothesized that garlic components may act as antioxidants and be able to scavenge free radicals (35). However, overdose side effects are possible.
  • Oregano oil may have antimicrobial properties.
  • Olive leaf extract (with the calcium elenolate active compound) has been shown to reduce severity and duration of upper respiratory infections (36).
  • Honey (especially raw) has antioxidant and some antimicrobial properties and also acts as a demulcent.
  • Andrographis paniculata plant has been shown to possess strong anti-inflammatory activity and has the potential to be used in a variety of inflammatory conditions, including inhibition of allergic lung inflammation (37). Conclusion In the first months of the COVID-19 pandemic, it was thought to be primarily a respiratory illness. It was later discovered that there is an important vascular component. As more is learned about the causes, progression and recovery from the disease, it is expected that research will look at prevention and treatment as they affect various organ systems. Strengthening the immune system and searching for effective antiviral treatments will continue to be important, but these approaches must be used in combination with masks, social distancing and adherence to other public health recommendations as the medical and scientific community work toward a safe, effective vaccine and/or a cure. The College will continue to monitor research results pertaining to the causes, prevention and treatment of COVID-19. Acknowledgements

We’d like to thank the ACAAI Integrative Medicine Committee for their work in developing this article. A special thanks to Pinkus Goldberg, MD, Rajah Darwish, Payel Gupta, MD, Dipa Sheth, MD and Ellen Sher, MD for reviewing the available literature, identifying the best practices and developing content for this article.

References

1. Sassi, F., et al. (2018). “Vitamin D: Nutrient, Hormone, and Immunomodulator.” Nutrients 10(11) PMID: 30400332

2. Martineau Adrian R, Jollife David A, Richard HL et al (2017) “Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.” BMJ 356:i6583

3. D’Avolio, A.; Avataneo, V.; Manca, A.; Cusato, J.; De Nicolò, A.; Lucchini, R.; Keller, F.; Cantù, M. “25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2.” Nutrients 2020, 12, 1359.

4. Grant, WB. (2008). “Hypothesis–ultraviolet-B Irradiance and Vitamin D Reduce the Risk of Viral Infections and Thus Their Sequelae, Including Autoimmune Diseases and Some Cancers.” Photochem Photobiol. Mar-Apr 2008;84(2):356-65.

5. Bäcker, Alex, (April 8, 2020) “Why COVID-19 May Be Disproportionately Killing African Americans: Black Overrepresentation among COVID-19 Mortality Increases with Lower Irradiance, Where Ethnicity Is More Predictive of COVID-19 Infection and Mortality Than Median Income.” Available at SSRN: https://ssrn.com/abstract=3571699 or http://dx.doi.org/10.2139/ssrn.3571699

6. Bäcker, Alex, (April 2, 2020). “Follow the Sun: Slower COVID-19 Morbidity and Mortality Growth at Higher Irradiances” Available at SSRN: https://ssrn.com/abstract=3567587 or http://dx.doi.org/10.2139/ssrn.3567587

7. Webb, A.R. and O. Engelsen (2006). “Calculated Ultraviolet Exposure Levels for a Healthy Vitamin D Status.” Photochemistry and Photo biology1697-1703.

8. “WHO Technical Reports; Series NO 924.” 2004.

9. Holick, M.F.; Binkley, N.C.; Bischoff-Ferrari, H.A.; Gordon, C.M.; Hanley, D.A.; Heaney, R.P.; Murad, M.H.; Weaver, C.M.“2011”; “Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline.” J. Clin. Endocrinol. Metab. 96, 1911–1930.

10. Grant WB, Lahore H, McDonnell SL,Baggerly CA, French CB, Aliano JL, Bhattoa HP.. (2020 Apr 2) “Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths.” Nutrients. 12(4). pii: E988. doi: 10.3390/nu12040988.

11. Alschuler, Lisa, et al. (5 2020) “Integrative considerations during the COVID-19 pandemic” Science Direct Elservier; https://www.elsevier.com/locate

  1. Hemilä H. (November 2004), “Vitamin C Supplementation and Respiratory Infections: A Systematic Review”, Military Medicine,Volume 169, Issue 11, , Pages 920–925, https://doi.org/10.7205/MILMED.169.11.920
  2. Kashiouris, M.G.; L’Heureux, M.; Cable, C.A.; Fisher, B.J.; Leichtle, S.W.; Fowler, A.A. (2020) “The Emerging Role of Vitamin C as a Treatment for Sepsis.”Nutrients , 12, 292.
  3. Erol, Adnan. (26 Feb2020). “High-dose Intravenous Vitamin C Treatment for COVID-19.” OSF Preprints, Web. https://www.researchgate.net/publication/339511104
  4. Chaturvedi, U. C., et al. “Viral Infections and Trace Elements: A Complex Interaction.” Current Science, vol. 87, no. 11,2004, pp. 1536–1554. JSTOR,www.jstor.org/stable/24109032. Accessed 18 May 2020.
  5. Mosman, MS. (2020) “COVID-19: A Skeptical Look at Supplements with Immune- BoostingClaims.”Endurelite.com.5 2020.
  6. Hemilä H1. “Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage.” JRSM Open. 2017 May 2;8(5):2054270417694291. doi: 10.1177/2054270417694291. eCollection 2017 May.
  7. Patel, Kamal (2020). “Summary of Zinc.” Examine.
  8. Skalny AV, Rink L, Ajsuvakova OP, et al. “Zinc and respiratory tract infections: Perspectives for COVID-19” (Review) [published online ahead of print, 2020 Apr 14]. Int J Mol Med. 2020;10.3892/ijmm.2020.4575. doi:10.3892/ijmm.2020.4575
  9. Phillips JM, et al. “Neurovirulent murine coronavirus jhm.sd uses cellular zinc metalloproteases for virus entry and cell-cell fusion.” J Virol. 2017;91(8)
  10. Han Y-S, et al. “Papain-like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV): expression, purification, characterization, and inhibition.” Biochemistry. 2005;44(30):10349.
  11. Shittu MO, Afolami OI. “Improving the efficacy of Chloroquine and Hydroxychloroquine against SARS-CoV-2 may require Zinc additives – A better synergy for future COVID-19 clinical trials.” Infez Med. 2020;28(2):192-197.
  12. Eubanas, GS. “Should zinc be used in the treatment of COVID-19?” (Review) The Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc. 02/April/2020.
  13. Petric D. “Immune System and COVID-19.” academia.edu/42281347/.
  14. Polansky H, Lori G. “Coronavirus disease 2019 (COVID-19): first indication of efficacy of Gene-Eden-VIR/Novirin in SARS-CoV-2 infection” [published online ahead of print, 2020 Apr 10]. Int J Antimicrob Agents. 2020;105971. doi:10.1016/j.ijantimicag.2020.105971
  15. Chaabi, M. “Antiviral Effects of Quercetin and Related Compounds.” Naturopathic Currents. Special Edition, April 2020.
  16. Lin SC, Ho CT, Chuo WH et al. “Effective inhibition of MERS-CoV infection by resveratrol.” BMC. Infect Dis. 2017;17:144.
  1. Bhaliya, J, Shah V. “Identification of potent COVID-19 Main Protease (Mpro) inhibitors from Curcumin” analogues by Molecular Docking Analysis. www.IJARIIT.com, vol 6, issue 2
  2. Gangal N, Nagel V, Pawar Y, Dasgupta S. “Reconsidering Traditional Medicinal Plants to Combat COVID-19.” Reliance Industries Ltd, RCP, Ghansoli, Thane-400701. AIJR Preprints. Article ID 34, Version 1, 2020.
  3. Sampangi-Ramaiah M, Vishwaarma R, Shaanker U. “Molecular docking analysis of selected natural products from plants for inhibition of SARS-CoV-2 protease.” Current Science VOL. 118, NO 7, 10 April 2020.
  4. Hardeland R. “Melatonin and inflammation-story of a double-edged blade.” J Pineal Res. 2018;65(4):e12525.
  5. Breus, M. “Can Melatonin Help Protect Against Covid-19?” Sleep Doctor. April 14, 2020.
  6. Silvestri M, Rossi GA. “Melatonin: its possible role in the management of viral infections-a brief review.” Ital J Pediatr. 2013;39:61.
  7. Zhang R, Wang X, Ni L, et al. “COVID-19: Melatonin as a potential adjuvant treatment.” Life Sci. 2020;250:117583. doi:10.1016/j.lfs.2020.117583
  8. Fanelli SL, Castro GD, de Toranzo EG, Castro JA. “Mechanisms of the preventive properties of some garlic components in the carbon tetrachloride-promoted oxidative stress. Diallyl sulfide; diallyl disulfide; allyl mercaptan and allyl methyl sulfide.” Research Communications in Molecular Pathology and Pharmacology. 1998 Nov;102(2):163-174.
  9. Summerville et al. “The Effect of Olive Leaf Extract on Upper Respiratory Illness in High School Athletes: A Randomised Control Trial.” Nutrients. 2019 Feb; 11(2): 358.
  10. Abu-Ghefreh AA, Canatan H, Ezeamuzie CI. “In vitro and in vivo anti-inflammatory effects of andrographolide.” Int Immunopharmacol. 2009;9(3):313-318. doi:10.1016/j.intimp.2008.12.002