Integrative Considerations during the COVID-19 pandemic - March 19, 2020

The Integrative Medicine faculty from the University of Arizona has spent the last several days drafting a set of recommendations in response to the COVID-19 pandemic, which we would like to share with our community.

There is a high level of interest in integrative strategies to augment public health measures to prevent COVID-19 infection and associated pneumonia. Unfortunately, no integrative measures have been validated in human trials. Notwithstanding, this is an opportune time to be proactive. Using available in-vitro evidence, an understanding of the virulence of COVID-19, as well as data from similar, but different, viruses, we offer the following strategies to consider.

Again, it should be stressed that these are supplemental considerations to the current recommendations that emphasize regular hand washing, social distancing, stopping non-essential travel, and getting tested if you develop symptoms.

The pathogenicity of COVID-19 is complex and it is important to understand the role of inflammation in this disease. The virulence and pathogenicity (including acute respiratory distress syndrome) associated with SARS corona viruses develops as the result of viral activation of cytoplasmic NLRP3 inflammasome. This inflammasome within activated (upregulated NFkB) macrophages and Th1 immune cells releases proinflammatory cytokines, namely IL-1B and IL18, which dictate the pathogenic inflammation responsible for the virulence and symptoms of COVID-19.[1] Understanding this component of COVID-19 infection provides a mechanistic underpinning to several of the following.

RISK REDUCTION

• Adequate sleep: Shorter sleep duration increases the risk of infectious illness. One study found that less than 5 hours of sleep (monitored over 7 consecutive days) increased the risk of developing rhinovirus associated cold by 350% (odds ratio [OR] = 4.50, 95% confidence interval [CI], 1.08-18.69) when compared to individuals who slept at least 7 hours per night.[2] Important to COVID-19, sleep deprivation increases CXCL9 levels. CXCL9 is a monokine, induced by interferon, and which increases lymphocytic infiltration,[3] and which is implicated in NLRP3 inflammasome activation.[4] Adequate sleep also ensures the secretion of melatonin, a molecule which may play a role in reducing coronavirus virulence (see Melatonin below).

• Stress management: Psychological stress disrupts immune regulation and is specifically associated with increased pro-inflammatory cytokines such as IL-65 . Acute stress in mice increases IL-1B via NLRP3 inflammasome activation.[6] Various mindfulness techniques such as meditation, breathing exercises, guided imagery, etc. reduce stress, reduce activated NFkB, may reduce CRP and do not appear to increase inflammatory cytokines.[7]

• Zinc: Coronavirus appear to be susceptible to the viral inhibitory actions of zinc. Zinc may prevent coronavirus entry into cells [8] and appears to reduce coronavirus virulence.[9] Typical daily dosing of zinc is 15mg – 30mg daily with lozenges potentially providing direct protective effects in the upper respiratory tract.

• Vegetables and Fruits +/- isolated Flavonoids: Many flavonoids have been found, in vitro, to reduce NLRP3 inflammasome signaling, and consequently NFkB, TNF-a, IL-6, IL- 1B and IL-18 expression.[10] Some of the specific flavonoids which have been shown to have this effect, and which can be found in the diet and/or dietary supplements include:

  • baicalin[11] and wogonoside[12] from Scutellaria baicalensis (Chinese skullcap)

  • liquiritigenin[13] from Glycyrrhiza glabra (licorice)

  • dihydroquercetin[14] and quercetin[15] found in onions and apples

  • myricetin[16] found in tomatoes, oranges, nuts, berries, tea and red wine

  • apigenin[17] (found in Matricaria recutita (Chamomile), parsley and celery.

At least 5 – 7 servings of vegetables and 2-3 servings of fruit daily provide a repository of flavonoids and are considered a cornerstone of an anti-inflammatory diet. Also see “foods-to-boost-the-immune-system”.

• Vitamin C: Like flavonoids, ascorbic acid inhibits NLRP3 inflammasome activation.[18] Clinical trials have found that vitamin C shortens the frequency, duration and severity of the common cold and the incidence of pneumonia.[19] Typical daily dosing of vitamin C ranges from 500mg to 3000mg daily with even higher doses utilized during times of acute infection.

• Melatonin: Melatonin has been shown to inhibit NFkB activation and NLRP3 inflammasome activation.[20] In fact, the age-related decline in melatonin production is one proposed mechanism to explain why children do not appear to have severe symptoms and older adults do. Melatonin also reduces oxidative lung injury and inflammatory cell recruitment during viral infections.[21] Typical dosing of melatonin varies widely from 0.3mg to 20mg (the latter used in the oncological setting).

• Sambucus nigra (Elderberry): There is preclinical evidence that elderberry inhibits replication and viral attachment of Human coronavirus NL63 (HCoV-NL63)[22], different than COVID-19, but a member of the coronavirus family. Sambucus appears most effective in the prevention or early stage of corona virus infections.[23] Of note, Sambucus significantly increases inflammatory cytokines, including IL-B124 so should be discontinued with symptoms of infection (or positive test). An evidence-based systematic review of elderberry conducted by the Natural Standard Research Collaboration concluded that there is level B evidence to support the use of elderberry for influenza[25] which may or may not be applicable to COVID-19 prevention. Typical dosing of 2:1 elderberry extract is 10mL -60mL daily for adults and 5mL-30mL daily for children.

• Vitamin D: In certain conditions, vitamin D has been found to decrease NLRP3 inflamasome activation[26] and vitamin D receptor activation reduces IL-1b secretion.[27] However, 1,25(OH)vitamin D has also been found to increase IL-1b levels,[28,29] and should, therefore, be used with caution and perhaps discontinued with symptoms of infection.

DURING SYMPTOMS OF INFECTION OR POSITIVE TEST FOR COVID-19

To Avoid:

Given the integral role of inflammatory cytokines (namely IL-1B and IL-18) in the pathogenicity of COVID-19, as well as the impossibility of predicting which individuals are susceptible to the “cytokine storm”, technically called secondary hemophagocytic lymphohistiocytosis, or sHLH, it appears to be prudent to avoid high and regular use of immunostimulatory agents which increase these cytokines. Again, in the absence of human clinical data, caution is warranted with the following immune activating agents due to preclinical evidence of increased IL-1B and/or IL-18 production in infected immune cells:

  • Sambucus nigra (Elderberry)[30]

  • Polysaccharide extracts from medicinal mushrooms[31,32]

  • Echinacea angustifolia and E. purpurea[33,34]

  • Larch arabinogalactan[35]

  • Vitamin D[36,37]

Likely Safe:

Other commonly used natural immunostimulatory and antiviral agents including the following do not appear to increase IL-1B or IL-18 as a part of their immunomodulatory actions. Several of these, in fact, reduce these cytokines and may restore immune homeostasis. These are, therefore, likely safe to use both prior to, and during, COVID-19 infection. Whether these agents mitigate the symptoms or virulence of COVID-19 is unknown and therefore the benefit of these agents during COVID-19 infection is unknown.

  • Allium sativum (garlic)[38]

  • Quercetin[39]

  • Astragalus membranaceus[40,41]

  • Full mycelium mushroom extracts[42,43]

  • Mentha piperita (peppermint)[44]

  • Andrographis paniculata[45]

  • Zinc[46]

  • Vitamin A[47](see note with below references)

  • Vitamin C[49]

The information and understanding of COVID-19 continues to change rapidly. It is important to reiterate that there are no clinically evidence-based integrative prevention or treatment strategies for COVID-19 infection.

Reviewed by:

Fabio Almeida MD ABNM, ABOM, ABoIMe
Director Center for Integrative Healing & Wellness
Fellow of the University of Arizona Integrative Medicine Program, Andrew Weil Center for Integrative Medicine

Lise Alschuler ND
Professor of Clinical Medicine
University of Arizona College of Medicine Assistant Director, Fellowship in Integrative Medicine, Andrew Weil Center for Integrative Medicine (Primary Author)

Ann Marie Chiasson MD
Associate Professor of Clinical Medicine
University of Arizona College of Medicine Director, Fellowship in Integrative Medicine Andrew Weil Center for Integrative Medicine

Robert Crocker MD
Assistant Professor of Medicine
University of Arizona College of Medicine Director, Strategic and Clinical Planning and Implementation, Andrew Weil Center for Integrative Medicine

Randy Horwitz MD PhD FACP
Professor of Medicine,
University of Arizona College of Medicine Medical Director, Andrew Weil Center for Integrative Medicine

Victoria Maizes MD
Professor of Clinical Medicine, Family Medicine and Public Health
University of Arizona Andrew Weil Endowed Chair in Integrative Medicine Executive Director, Andrew Weil Center for Integrative Medicine

Paul Stamets
Mycologist

Andrew Weil MD
Professor of Medicine and Public Health,
University of Arizona Endowed Chair in Integrative Rheumatology, University of Arizona Founder, Andrew Weil Center for Integrative Medicine

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36. Verway M, et al. Vitamin D Induces interleukin-1β Expression: Paracrine Macrophage Epithelial Signaling Controls M. Tuberculosis Infection. PLoS Pathog. 2013;9(6):e1003407.
37. Tulk SE, et al. Vitamin D₃ Metabolites Enhance the NLRP3-dependent Secretion of IL-1β From Human THP-1 Monocytic Cells. J Cell Biochem. 2015;116(5):711.
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42. Ulbricht C, et al. An Evidence-Based Systematic Review of Elderberry and Elderflower (Sambucus Nigra) by the Natural Standard Research Collaboration. J Diet Suppl. 2014;11(1):80.
43. Benson KF, The mycelium of the Trametes versicolor (Turkey tail) mushroom and its fermented substrate each show potent and complementary immune activating properties in vitro. MC Complementary and Alternative Medicine. 2019;19:342.
44. Li Y, et al. In Vitro Antiviral, Anti-Inflammatory, and Antioxidant Activities of the Ethanol Extract of Mentha piperita L. Food Sci Biotechnol. 2017;26(6):1675.
45. Chandrasekaran CV, et al. In Vitro Comparative Evaluation of Non-Leaves and Leaves Extracts of Andrographis Paniculata on Modulation of Inflammatory Mediators. Antiinflamm Antiallergy Agents Med Chem. 2012;11(2):191.
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47. Farhangi MA, et al. Vitamin A Supplementation and Serum Th1- And Th2-associated Cytokine Response in Women. J Am Coll Nutr. 2013;32(4):280. This study found that 25,000iu daily for 4 months in 84 women resulted in lower serum IL-1b and IL-1b/IL-4 ratios in obese women. Oral vitamin A can causes hypervitaminosis A especially at doses greater than 25,000 IU daily for more than 6 years or 100,000iu daily for more than 6 months.[48] Monitoring liver function tests for hepatotoxicity during vitamin A dosing of any duration, even at lower doses, is advised given variable individual sensitivity.
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49. Choe J-Y, et al. Quercetin and Ascorbic Acid Suppress Fructose-Induced NLRP3 Inflammasome Activation by Blocking Intracellular Shuttling of TXNIP in Human Macrophage Cell Lines. Inflammation. 2017;40(3):980.

 
 
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