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Evidence-Based, Integrative Considerations with Respect to Immune Support & COVID-19

Evidence-Based, Integrative Considerations with Respect to Immune Support & COVID-19

CAVEAT: integrative medicine measures have thus far NOT been validated in any human trials with respect to COVID-19, so in no way, shape, or form is this article specifically recommending any natural medicine treatments for COVID-19.

I had the privilege of attending National University of Natural Medicine to become a naturopathic doctor (ND), and one of my favorite professors is the brilliant Dr. Heather Zwickey, PhD, who taught us immunology and currently serves as executive program chair at NUNM and as the principal investigator at the Helfgott Research Institute. As an infectious diseases expert, she did her post-doctoral research at Yale, and one of her life purposes is to prove the efficacy of natural medicine with regard to the immunological response.

Recently, in one of my ND Facebook groups, a colleague shared Dr. Zwickey’s thoughts regarding COVID-19, with her permission, sent to her via an email exchange. Dr. Zwickey’s thoughts were then passionately shared back and forth on Facebook and in multiple groups, and as a result her email has been blowing up.

Last week, Dr. Zwickey was featured on Dr. Tyna’s Moore’s “Pain Free & Strong Radio,” in an episode entitled, “Corona Virus with Dr. Heather Zwickey: The Facts from an Immunologist and Infectious Disease Specialist, and just before that, Dr. Zwickey was on the Natural Medicine Journal podcast, discussing “Important Clarifications Regarding COVID-19 and Natural Medicine.” I highly recommend that you take the time to listen to both of these podcasts.

Here’s what Dr. Zwickey shared with her naturopathic physician colleague, verbatim:

I’m hearing a lot of misinformation floating around, so I thought I’d talk about whether or not to use herbs to prevent COVID19. (Everything is referenced.)

 

Prevention: As NDs, you are all aware of how to prevent upper respiratory infections. You’re going to increase Defensins (vitamin D) so that any virus landing on the skin or in the mouth are killed on contact. (1,2)

 

For upper respiratory herbs, I like the combo of 5.   Astragalus (for lungs) is adaptogenic. It reduces inflammation, but can also drive Th1 if you’re exposed to an infection or have lung cancer. It’s also anti-viral. (3,4)

 

Goldenseal and Oregon grape root are directly toxic to viruses (research on flu) and bacteria (think of killing secondary pneumonia). It’s also adaptogenic. It drives Tregs, but can elicit a Th1 response in the right microenvironment. (5,6,7,8,9,10)

 

Echinacea works best at the beginning of an infection and is adaptogenic. Echinacea induces inflammatory cytokines at the beginning of infection and help with resolution post infection. There’s also a meta-analysis showing that it reduces upper-respiratory infections, especially in those susceptible to them. (11,12)

 

Elderberry is also adaptogenic – increasing cytokines in some situations and decreasing them in others. The reason I include it is that it’s anti-viral. There’s research showing it blocks viral uptake. Again, so much research on this that there’s a meta-analysis. (13)

 

I actually developed a supplement with this combo. It’s called Immune and you can find it here: http://www.zamialife.com – not that anyone needs to buy it. You can combine the herbs yourself. It’s just more expensive to buy 5 bottles of herbs.   If people get an infection and you need additional support, Fungi Perfecti has a product called Comprehensive Immune Support that can further increase a Th1 response. (14,15) (The Guggenheim article is about cancer but goes through many of the Th1 stimulating studies.)

 

Do these therapies increase cytokines? Yes. But NOT to the level of cytokine storm. You have to work hard to trigger a cytokine storm. I have not yet seen a situation where an herb can trigger a cytokine storm. We see cytokine storms with super-antigens like staph enterotoxin A, or TSST-1. And in fact, the scientific literature suggests that herbs (including Echinacea) actually decrease cytokine storms. (12,16)

 

So yes, wash hands, don’t touch your face, and sneeze/cough into your elbow. And if you want to use herbs, use what you already know. There is evidence.

 

  1. Pinheiro da Silva F, Machado MCC. Antimicrobial peptides: clinical relevance and therapeutic implications. Peptides. 2012;36(2):308-314. doi:10.1016/j.peptides.2012.05.014
  2. Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011;50(3):194-200. doi:10.1016/j.jcv.2010.12.006
  3. Li X, Qu L, Dong Y, et al. A Review of Recent Research Progress on the Astragalus Genus. Molecules. 2014;19(11):18850-18880. doi:10.3390/molecules191118850
  4. Hsieh H-L, Liu S-H, Chen Y-L, Huang C-Y, Wu S-J. Astragaloside IV suppresses inflammatory response via suppression of NF-κB, and MAPK signalling in human bronchial epithelial cells. Arch Physiol Biochem. February 2020:1-10. doi:10.1080/13813455.2020.1727525
  5. Yan Y-Q, Fu Y-J, Wu S, et al. Anti-influenza activity of berberine improves prognosis by reducing viral replication in mice. Phytother Res. 2018;32(12):2560-2567. doi:10.1002/ptr.6196
  6. Kim TS, Kang BY, Cho D, Kim SH. Induction of interleukin-12 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid, deviates CD4+ T cells from a Th2 to a Th1 response. Immunology. 2003;109(3):407-414. doi:10.1046/j.1365-2567.2003.01673.x
  7. Cecil CE, Davis JM, Cech NB, Laster SM. Inhibition of H1N1 influenza A virus growth and induction of inflammatory mediators by the isoquinoline alkaloid berberine and extracts of goldenseal (Hydrastis canadensis). Int Immunopharmacol. 2011;11(11):1706-1714. doi:10.1016/j.intimp.2011.06.002
  8. Javadi B, Sahebkar A. Natural products with anti-inflammatory and immunomodulatory activities against autoimmune myocarditis. Pharmacol Res. 2017;124:34-42. doi:10.1016/j.phrs.2017.07.022
  9. Jamshaid F, Dai J, Yang LX. New Development of Novel Berberine Derivatives against Bacteria. Mini Rev Med Chem. January 2020. doi:10.2174/1389557520666200103115124
  10. Qin X, Guo BT, Wan B, et al. Regulation of Th1 and Th17 cell differentiation and amelioration of experimental autoimmune encephalomyelitis by natural product compound berberine. J Immunol Baltim Md 1950. 2010;185(3):1855-1863. doi:10.4049/jimmunol.0903853
  11. Schapowal A, Klein P, Johnston SL. Echinacea reduces the risk of recurrent respiratory tract infections and complications: a meta-analysis of randomized controlled trials. Adv Ther. 2015;32(3):187-200. doi:10.1007/s12325-015-0194-4
  12. Vimalanathan S, Schoop R, Suter A, Hudson J. Prevention of influenza virus induced bacterial superinfection by standardized Echinacea purpurea, via regulation of surface receptor expression in human bronchial epithelial cells. Virus Res. 2017;233:51-59. doi:10.1016/j.virusres.2017.03.006
  13. Hawkins J, Baker C, Cherry L, Dunne E. Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials. Complement Ther Med. 2019;42:361-365. doi:10.1016/j.ctim.2018.12.004
  14. Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology. – PubMed – NCBI. https://www-ncbi-nlm-nih-gov.liboff.ohsu.edu/pubmed/26770080. Accessed March 2, 2020.
  15. Antiviral activities of various water and methanol soluble substances isolated from Ganoderma lucidum. – PubMed – NCBI. https://www-ncbi-nlm-nih-gov.liboff.ohsu.edu/pubmed/10624872. Accessed March 2, 2020.
  16. The cytokine storm of severe influenza and development of immunomodulatory therapy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711683/. Accessed March 2, 2020.

Here are some key take-aways and reminders:

  1. At this point (spring, 2020), there are no human trials testing natural medicines against COVID-19, nor are there any registered therapeutics approved by the FDA. (1)
  2. Viruses aren’t actually alive without the use of your cells. (2)
  3. The way that COVID-19 enters the type two pneumocyte is through its S spike protein, which binds to ACE2 receptors. (3) This differentiates it from the average flu, which binds to sialic acid receptors. (4) ACE2 is expressed, for example, in vascular endothelial cells and renal tubular epithelium, and even resides in the gastrointestinal tract and the central nervous system (CNS). (5)
  4. COVID-19 has a furin cleavage site, which allows it to gain entry easily even if a person’s pneumocytes don’t have a lot of ACE2 receptors. (6) By the way, ACE2 inhibitors appear to upregulate ACE2 receptors, though this has not been proven yet.
  5. There are three main reasons the flu is particularly problematic in the winter but this does not seem to matter with COVID-19:
    • Diminished vitamin D exposure and production in the winter (7)
    • Humans are often inside in the winter with recirculated air which increases viral spread
    • Respiratory droplets in the air last longer in cold weather (8)
  6. In the average immune response to a virus, you want a strong Th1 response, which stimulates CD8 and NK cells to kill any virally infected cells. (9,10) Then, you want your immune system to calm down, by stimulating T regulatory cells (T regs). Not having active T regs can be a problem. Hence, you want to have a healthy gut, as an optimized microbiome plays a role in the regulation of T regs early in disease. (11)
  7. Once COVID-19 enters the cell, it stimulates an inflammasome (NLRP3, in particular, with respect to COVID-19), which is the collection of proteins, receptors and mediators involved in inflammation, causing uncontrolled inflammation. (12)
  8. One reason COVID-19 is so deadly is that it causes bilateral pneumonia.
  9. Another reason COVID-19 is so deadly is that people are getting pneumonia in their lower lobes, where fluids pools and then the subsequent pulmonary edema is spiking mortality. (13)
  10. COVID-19 may impact surfactant levels in the lungs, but to what degree this is unknown. Surfactant is responsible for keeping the alveoli open as well as protecting us from secondary infections.
  11. The particular protein made in the cytokine storms that can be induced by COVID-19 is called interleukin-1 beta (IL-1 beta), which drives fever and can mediate fatigue. Coronavirus has two virulence factors, which make it especially deadly, and can lead to a cytokine storm. One of these virulence proteins can trigger the overproduction of interferon-1 beta (IF-1 beta), by basically not allowing the body to turn off the production of IL-1 beta. (14,15)
  12. Three cytokines get activated together, typically, in inflammation, in general: IL-1 beta, IL-6, and TNF-alpha. IL-1, when high, can turn on IL-6, and also it can turn on TNF-alpha. IL-6 is a very strong cytokine, and it is associated with the induction of anxiety, as well as catastrophizing. (16)
  13. According to Dr. Zwickey, some herbs known to lower IL-6 are lemon balm, passionflower, ashwhaghanda, as well as feverfew (17) I was unable to locate studies on lemon balm and passionflower with particular regard to lowering IL-6, but there is limited evidence that rosemarinic acid, which exists in lemon balm, can lower IL-6.
  14. Ibuprofen is problematic because it blocks COX-2 which is in the same pathway as the renin-angiotensin-aldosterone system, which the virus also targets. Acetaminophen (Tylenol) may decrease intracellular glutathione levels in the type II pneumocytes, which are the exact cells targeted by COVID-19. (18)
  15. Hydrotherapy, when increasing core body temperature, motivates the mobilization of immune support to other organs in the body. (19)
  16. The Th1 response responds to viruses and bacteria. But, in asthma, there is a Th2 response going on in the lung, which could potentially “hypothetically” keep the Th1 response under control. Pregnancy also drives a strong Th2 response, which could balance out a Th1 response from the virus. (20)
  17. Melatonin can shut down the inflammasome (NLRP3). (21)
  18. The envelope on the virus makes it easier to kill, because soap and water can destroy it. 70% isopropyl alcocol is better than 100%. It dries out the lipid in the membrane of the virus.
  19. COVID-19 is an RNA virus, like HIV, not a DNA virus, and hence the RNA in the virus itself is more difficult to kill despite the fact it’s lipid membranes are easier to disrupt.
  20. Ascorbic acid or Vitamin C has a ton of literature behind it with regard to respiratory infections and it may be particularly helpful when a person is infected. (22,23)
  21. There are a number of antiviral herbs that are known to be effective, but we don’t yet know if they work particularly on COVID-19.
  22. Vitamins A and D, for example, can support the immune system, and Vitamin C can reduce the specific inflammasome associated with this disease (NLRP3). Melatonin and ascorbic acid both reduce NLRP3. Melatonin levels are inversely correlated with risk, as they can decrease NF-kappa B. (Integrative Considerations during the COVID 3.18.20)

Listen to “EP 86: Corona Virus with Dr. Heather Zwickey: The Facts from an Immunologist and Infectious Disease Specialist” on Spreaker. Resources:

  1. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation and Treatment Coronavirus (COVID-19). In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.
  2. Koonin EV, Starokadomskyy P. Are viruses alive? The replicator paradigm sheds decisive light on an old but misguided question. Stud Hist Philos Biol Biomed Sci. 2016;59:125–134. doi:10.1016/j.shpsc.2016.02.016
  3. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367(6483):1260–1263. doi:10.1126/science.abb2507
  4. Kimble B, Nieto GR, Perez DR. Characterization of influenza virus sialic acid receptors in minor poultry species. Virol J. 2010;7:365. Published 2010 Dec 9. doi:10.1186/1743-422X-7-365
  5. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–637. doi:10.1002/path.1570
  6. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020;176:104742. doi:10.1016/j.antiviral.2020.104742
  7. Saraff V, Shaw N. Sunshine and vitamin D. Arch Dis Child. 2016;101(2):190–192. doi:10.1136/archdischild-2014-307214
  8. Lowen AC, Steel J. Roles of humidity and temperature in shaping influenza seasonality. J Virol. 2014;88(14):7692–7695. doi:10.1128/JVI.03544-13
  9. Cook KD, Waggoner SN, Whitmire JK. NK cells and their ability to modulate T cells during virus infections. Crit Rev Immunol. 2014;34(5):359–388. doi:10.1615/critrevimmunol.2014010604
  10. Pallmer K, Oxenius A. Recognition and Regulation of T Cells by NK Cells. Front Immunol. 2016;7:251. Published 2016 Jun 24. doi:10.3389/fimmu.2016.00251
  11. Pandiyan P, Bhaskaran N, Zou M, Schneider E, Jayaraman S, Huehn J. Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa. Front Immunol. 2019;10:426. Published 2019 Mar 8. doi:10.3389/fimmu.2019.00426
  12. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies [published online ahead of print, 2020 Mar 14]. J Biol Regul Homeost Agents. 2020;34(2):1. doi:10.23812/CONTI-E.
  13. Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer [published online ahead of print, 2020 Feb 28]. J Thorac Oncol. 2020;S1556-0864(20)30132-5. doi:10.1016/j.jtho.2020.02.010
  14. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies [published online ahead of print, 2020 Mar 14]. J Biol Regul Homeost Agents. 2020;34(2):1. doi:10.23812/CONTI-E.
  15. Roerink ME, van der Schaaf ME, Dinarello CA, Knoop H, van der Meer JW. Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflammation. 2017;14(1):16. Published 2017 Jan 21. doi:10.1186/s12974-017-0796-7
  16. Lazaridou A, Martel MO, Cahalan CM, et al. The impact of anxiety and catastrophizing on interleukin-6 responses to acute painful stress. J Pain Res. 2018;11:637–647. Published 2018 Mar 28. doi:10.2147/JPR.S147735
  17. Pareek A, Suthar M, Rathore GS, Bansal V. Feverfew (Tanacetum parthenium L.): A systematic review. Pharmacogn Rev. 2011;5(9):103–110. doi:10.4103/0973-7847.79105
  18. Dimova S, Hoet PH, Dinsdale D, Nemery B. Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro. Int J Biochem Cell Biol. 2005;37(8):1727–1737. doi:10.1016/j.biocel.2005.03.005
  19. Mooventhan A, Nivethitha L. Scientific evidence-based effects of hydrotherapy on various systems of the body. N Am J Med Sci. 2014;6(5):199–209. doi:10.4103/1947-2714.132935
  20. Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis. 1999;5(4):285–294. doi:10.1097/00054725-199911000-00009
  21. Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R. Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation. Int J Endocrinol. 2017;2017:1835195. doi:10.1155/2017/1835195
  22. Hemilä H, Douglas RM. Vitamin C and acute respiratory infections. Int J Tuberc Lung Dis. 1999;3(9):756–761.
  23. Vorilhon P, Arpajou B, Vaillant Roussel H, Merlin É, Pereira B, Cabaillot A. Efficacy of vitamin C for the prevention and treatment of upper respiratory tract infection. A meta-analysis in children. Eur J Clin Pharmacol. 2019;75(3):303–311. doi:10.1007/s00228-018-2601-7

 

Breaking Down Seattle Intensivist ER Doc’s COVID-19 One Pager – Part 2

Breaking Down Seattle Intensivist ER Doc’s COVID-19 One Pager – Part 2

This COVID-19 one pager, made up by a Seattle ICU/ER doc (Nick Mark, MD) and which reads like the ultimate cheat sheet for a one hundred question exam on the virus, has been circulating among some of my medical colleagues. As a naturopathic physician, I thought I’d take a moment to draft a multi-part blog post which breaks down everything in it, with some links to studies.

Here is part 2, as promised.

Epidemiology

  1. Attack Rate = 30-40% (China). Attack Rate (AR), a biostatistical concept in epidemiology, measures the frequency of morbidity, that is, the speed at which the infection spreads in at risk populations. We of course use this to predict the rate at which an infection will spread hypothetically, particularly in an epidemic such as the one we are in now. There is no way that resources can be adequately marshalled if projections are not possible. It can be determined by dividing the number of new cases in the at risk population by the total number at risk. An AR of 30-40% means that about 1/3 of the at risk population becomes infected. (1)
  2. R0 = 2-4. R0 or “R nought” is another epidemiological measurement: the number of cases that on average a person who is infected will cause over the duration of their infection. In other words, it’s a reproduction number. The R0 for measles ranges from 12 to 18, wherethe R0 for influenza is much lower at 2 to 3. With COVID-19, an R0 of 2 to 4 means that2 to 4 new cases will be reproduced by one infected person. (2)
  3. Case fatality rate (CFR) = 2.3% (China). CFR is pretty straight-forward. 2.3 out of every 100 cases will result in death. (3)
  4. Incubation time = 3-14 days (up to 15 days). It takes the virus 3 to 14 days to incubate. According to a March, 2020 report from The Annals of Internal Medicine, “estimates imply that, under conservative assumptions, 101 out of every 10,000 cases (99th percentile, 482) will develop symptoms after 14 days of active monitoring or quarantine.” (4)
  5. Viral shedding = median 20 days (max 37 days): The virus will shed, that is, release its progeny as it reproduces during host-cell infection. On average, COVID-19 infections will produce viral shedding for 20 days, but it can last as long as 5 weeks. Just to be clear, viral shedding can take place in a number of ways, such as from a single cell, from one part of the body to another part, and from body parts into the environment. (5, 6)
  6. Breakdown of disease severity.
    • 80% Non-severe (mild pneumonia)
    • 15% Severe (hypoxia, respiratory distress)
    • 5% Critical (respiratory failure)
    • 80% of those are infected will actually get mild pneumonia of the non-severe type but 15% will actually experience respiratory distress and low blood-oxygen saturation. 5 out of every 100 persons will experience respiratory failure, which can lead to death if not treated quickly. (7, 8)
  7. Disease clusters: SNFs, Conferences, other. An SNF is a step-down facility where people go to recover from surgeries or other conditions, where medically necessary services are available for in-patient rehabilitation. These are obviously high-risk places where disease clusters can preponderate, as are nursing home and other long-term care facilities.
  8. Strategies: contact tracing, screening, social distancing. Pretty self-explanatory. (9, 10)
  9. #FlattenTheCurve: same AUC but distributed over a longer time, ensuring that hospitals don’t exceed capacity. 

Diagnosis/ Presentation

  1. Symptoms:
    • 65-80% cough
    • 45% febrile on presentation (85% febrile during illness)
    • 20-40% dyspnea
    • 15% URI symptoms: Classic symptoms include cough, nasal discomfort or congestion, rhinitis, a sore throat, mucus buildup, a mild fever
    • 10% GI symptoms (11)

Resources:

  1. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak [published online ahead of print, 2020 Feb 26]. J Autoimmun. 2020;102433. doi:10.1016/j.jaut.2020.102433
  2. Velavan TP, Meyer CG. The COVID-19 epidemic. Trop Med Int Health. 2020;25(3):278–280. doi:10.1111/tmi.13383
  3. Porcheddu R, Serra C, Kelvin D, Kelvin N, Rubino S. Similarity in Case Fatality Rates (CFR) of COVID-19/SARS-COV-2 in Italy and China. J Infect Dev Ctries. 2020;14(2):125–128. Published 2020 Feb 29. doi:10.3855/jidc.12600
  4. Lauer SA, Grantz KH, Bi Q, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application [published online ahead of print, 2020 Mar 10]. Ann Intern Med. 2020;M20-0504. doi:10.7326/M20-0504
  5. Zhang W, Du RH, Li B, et al. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect. 2020;9(1):386–389. Published 2020 Feb 17. doi:10.1080/22221751.2020.1729071
  6. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore [published online ahead of print, 2020 Mar 3]. JAMA. 2020;e203204. doi:10.1001/jama.2020.3204
  7. Sun P, Lu X, Xu C, Sun W, Pan B. Understanding of COVID-19 based on current evidence [published online ahead of print, 2020 Feb 25]. J Med Virol. 2020;10.1002/jmv.25722. doi:10.1002/jmv.25722
  8. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients [published online ahead of print, 2020 Feb 27]. J Med Virol. 2020;10.1002/jmv.25728. doi:10.1002/jmv.25728
  9. Stein R. COVID-19 and Rationally Layered Social Distancing [published online ahead of print, 2020 Mar 14]. Int J Clin Pract. 2020;e13501. doi:10.1111/ijcp.13501
  10. Wilder-Smith A, Freedman DO. Isolation, quarantine, social distancing and community containment: pivotal role for old-style public health measures in the novel coronavirus (2019-nCoV) outbreak. J Travel Med. 2020;27(2):taaa020. doi:10.1093/jtm/taaa020
  11. Zu ZY, Jiang MD, Xu PP, et al. Coronavirus Disease 2019 (COVID-19): A Perspective from China [published online ahead of print, 2020 Feb 21]. Radiology. 2020;200490. doi:10.1148/radiol.2020200490
Breaking Down Seattle Intensivist ER Doc’s COVID-19 One Pager – Part 1

Breaking Down Seattle Intensivist ER Doc’s COVID-19 One Pager – Part 1

This COVID-19 one pager, made up by a Seattle ICU/ER doc (Nick Mark, MD) and which reads like the ultimate cheat sheet for a one hundred question exam on the virus, has been circulating among some of my medical colleagues. As a naturopathic physician, I thought I’d take a moment to draft a multi-part blog post which breaks down everything in it, with some links to studies. 

And whenever possible I’ll link to some studies in natural medicine which may be related to the topics at hand. However, it needs to be reiterated that there currently are no registered medical treatments for COVID-19, and of course that includes natural and naturopathic medicine.

You’ll note the square at the top of the page, which can be scanned for updates.

Nomenclature

  1. Infection: Coronavirus Disease 2019 a.k.a. COVID-19 (1)
  2. Virus: SARS-CoV-2, 2019 Novel Coronavirus (2,3)
  3. NOT “Wuhan Virus.” As this Atlantic article explains, the term Wuhan virus suggests COVID-19 to be nothing but a Chinese scourge, but this terminology is a “racist trope.”

Biology

  1. 30 kbp, +ssRNA, enveloped corona virus. A kbp is a measurement unit used in genetics (DNA or RNA) signifying length and equivalent to 1,000 base pairs (standing for kilo-base pair). +ssRNA means it’s single-stranded. The corona virus has an envelope or outer wrapping, which comes from the infected host cell’s plasma membrane, as it “buds off” and forms virus particles. An envelope can help a virus live longer and potentially make it more infectious. (4)
  2. Likely zoonotic infection; source/reservoir unclear (Bats? / Pangolins? → people). The infection is likely caused by pathogenic germs from animals but it is unclear, precisely, from what reservoir. In fact, China has banned the consumption of wild animals as a result of COVID-19. (5)
  3. Now spread primarily person to person; can be spread by asymptomatic carriers! Yep. In fact, 80% of carriers are asymptomatic, and it is presumed that they can spread it, but the potential false-positive rate is high. (6,7)
  4. Viral particles enter into lungs via droplets. As with flu and rhinovirus, viral transmission is believed to occur via droplets from coughing and sneezing, but aerosol transmission is also possible. I don’t believe this has been proven yet but it makes sense. (8,9)
  5. Viral S spike binds to ACE2 on type two pneumocytes. COVID-19 uses its spike protein (S) to bind to receptors in an enzyme present type two pneumocytes in the lungs called ACE2. In other words, ACE2 is how COVID-19 enters the cell! Pneumocytes are surface epithelial cells of the alveoli and type two are particularly responsible for producing and secreting surfactant, which is a molecule that helps lower pulmonary fluid surface tension, thereby contributing to lung elasticity. Hence,ifyour type two pneumocytes go off line, pulmonary fluid tension will rise and lung elasticity will go out the door. (10)
  6. Effect of ACE/ARB is unclear; not recommended to change medications at this time. By the way, medications such as ARBs (angiotensin receptor blockers) actually upregulate the expression of ACE2 by three to five times, and thereby could give COVID-19 more portals of entry. Animal studies have shown that renin-angiotensin (RAS) inhibitors could relieve symptoms of acute severe pneumonia and respiratory failure by reducing poor prognostic indicators of severe pneumonia, such as ACE. When COVIC-19 binds ACE2, ACE2 is exhausted, and then the RAS pathway is inhibited, exacerbating acute severe pneumonia. As of yet there are no studies demonstrating beneficial or adverse outcomes in the use of antihypertensive medications, ACE-inhibitors or ARBs, for COVID-19. (11)
  7. Other routes of infections (contact, enteric) possible but unclear if these are significant means of spread. As mentioned, the host may be bats (particularly, BatCoV RaTG13), but the transmission routes may vary, as they include direct transmission (cough, sneeze, droplet inhalation), contact transmission (oral, nasal, eye mucous membranes), saliva, and potentially fetal-oral. (12)

Resources:

  1. Sun P, Lu X, Xu C, Sun W, Pan B. Understanding of COVID-19 based on current evidence [published online ahead of print, 2020 Feb 25]. J Med Virol. 2020;10.1002/jmv.25722. doi:10.1002/jmv.25722
  2. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents. 2020;55(3):105924. doi:10.1016/j.ijantimicag.2020.105924
  3. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak [published online ahead of print, 2020 Feb 26]. J Autoimmun. 2020;102433. doi:10.1016/j.jaut.2020.102433
  4. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;1282:1–23. doi:10.1007/978-1-4939-2438-7_1
  5. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak [published online ahead of print, 2020 Feb 26]. J Autoimmun. 2020;102433. doi:10.1016/j.jaut.2020.102433
  6. Bai Y, Yao L, Wei T, et al. Presumed Asymptomatic Carrier Transmission of COVID-19 [published online ahead of print, 2020 Feb 21]. JAMA. 2020;e202565. doi:10.1001/jama.2020.2565
  7. Zhuang GH, Shen MW, Zeng LX, et al. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(4):485–488. doi:10.3760/cma.j.cn112338-20200221-00144
  8. Wu YC, Chen CS, Chan YJ. The outbreak of COVID-19: An overview. J Chin Med Assoc. 2020;83(3):217–220. doi:10.1097/JCMA.0000000000000270
  9. Cascella M, Rajnik M, Cuomo A, et al. Features, Evaluation and Treatment Coronavirus (COVID-19) [Updated 2020 Mar 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554776/
  10. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics [published online ahead of print, 2020 Mar 4]. Drug Dev Res. 2020;10.1002/ddr.21656. doi:10.1002/ddr.21656
  11. Sun ML, Yang JM, Sun YP, Su GH. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(0):E014. doi:10.3760/cma.j.issn.1001-0939.2020.0014
  12. Peng X, Xu X, Li Y, Cheng L, Zhou X, Ren B. Transmission routes of 2019-nCoV and controls in dental practice. Int J Oral Sci. 2020;12(1):9. Published 2020 Mar 3. doi:10.1038/s41368-020-0075-9
COVID-19 and Some Evidence-Based Natural Medicine for Viral Respiratory Infections

COVID-19 and Some Evidence-Based Natural Medicine for Viral Respiratory Infections

This article takes a quick moment to review COVID-19, and some potential evidenced-based treatments to prevent or treat viral respiratory infections. However, just to be clear, there are no registered evidence-based treatments yet specifically for COVID-19.

The First Outbreak of COVID-19 and CT Findings

The first outbreak of COVID-19 (which stands for Coronavirus Disease 2019) occurred in December 2019 in Wuhan, Hubei Providence, China. Most infected patients were diagnosed with pneumonia and characteristic CT scans, therefore, CT findings are recommended as major evidence to detect early infection and for disease assessment. (1)Corona Virus COVID-19 evidence natural medicine treatment

Clinical Presentation of COVID-19

Clinical manifestations are nonspecific: runny nose, sore throat, cough, fever, and in severe cases, difficulty breathing. (2)

Transmission of COVID-19

Person-to-person transmission is thought mainly to occur much like that of influenza, that is, via respiratory droplets.

Typical CT Findings

Typical CT findings include ground-glass opacities (GGOs) which are peripherally distributed, with patchy consolidations. And posterior or lower lobe lung involvement is more common. If these GGOs are present in greater numbers or higher density, then it is indicative of disease progression. (3) The preferred type of CT is thin-slice, which is a slice thickness of 0.625 to 1.25 mm with a higher resolution, as opposed to the standard 5 mm CT imaging of the mediastinum and gross lungs. (4)

COVID-19 Viral Genome

Covid-19 virus infection natural medicineInterestingly, the viral genome of the COVID-19 shares 88% sequence identity with two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses.

Vitamin C and Viral Respiratory Infections

Because COVID-19 is a viral infection with proclivity to infect the respiratory tract, it stands to reason that vitamin C may help to prevent it.

A 1999 prospective, controlled study, from The Journal of Manipulative and Physiological Therapeutics, found that high dose vitamin C decreased the reported cold and flu symptoms of virus-induced respiratory infections by 85%. The treatment group received 1000 mg of vitamin C hourly, for the first six hours, and then three times daily thereafter. (5)

A 2017 review article in the journal, Nutrients, concluded that vitamin C plays a role in preventing and shorting diverse infections. In fact, five controlled trials found that vitamin C had significant benefit in treating pneumonia. (6)

Chinese Medicine and COVID-19

A 2020 guideline, in line with WHO standards, from the journal, Military Medical Research, details some Chinese medicine herbal protocols that might be used specifically for COVID-19 induced pneumonia: (7)

  • Moxa
  • Clove, fineleaf schizonepeta herb, Perilla frutescens, atractylodes lancea, cinnamon, biond magnolia flower, asarum sieboldii, and Elettaria cardamomum
  • Prescription of Chinese herbs for feet bath: vulgaris, carthamus, dried ginger
  • Chinese herbs for prophylaxis: Astragalus mongholicus, roasted rhizoma atractylodis macrocephalae, saposhnikovia divaricata, Cyrtomium fortunei, honeysuckle, dried tangerine or orange peel, eupatorium, and licorice

A 2020 Journal of Integrative Medicine in vitro study found 26 Chinese herbs, including licorice and gingko, used to treat viral respiratory infection with anti-COVID-19 properties. (8)

Vitamin D and Immunomodulation During Respiratory Virus Infection

Multiple studies have found that vitamin D has immunomodulatory properties that can improve the response to respiratory viruses. (9) A 2014 randomized controlled trial investigated vitamin D related respiratory disease in preschoolers, making the case that low wintertime vitamin D levels correlate with viral respiratory infections and asthma exacerbations in children. (10) Hence, bolstering up on vitamin D could lower the chances of a respiratory infection, such as COVID-19.

Selenium and Viral Infection

It’s a well known fact that selenium deficiency weakens our defense versus infectious disease agents by reducing selenoprotein expression. (11) As a key part of antioxidant defense, selenium helps to control oxidative stress, which can occur during viral respiratory infections. (12)

Zinc and Lower Respiratory Tract Infections

Zinc is a vital nutrient key to the growth and function of all cells in the human body.  According to the WHO, the fifth leading cause of mortality and morbidity in developing nations is zinc deficiency, estimated to affect one-third of the world population and accounting for 16% of lower respiratory tract infections. (13)

Summary

In summary, evidence points to vitamins C and D, zinc and selenium supplementation, and the use of Chinese herbal medicine, as possible evidence-based options for COVID-19 prevention and treatment. But it is recommended that these options are implemented only under the guidance of a board certified naturopathic doctor, or other integrative medicine physician. Also, just to reiterate, this article is not recommending treatments specifically for COVID-19, as there are as of yet no officially registered treatments back by evidence based studies.

Resources

  1. Zu ZY, Jiang MD, Xu PP, et al. Coronavirus Disease 2019 (COVID-19): A Perspective from ChinaRadiology. 2020:200490. doi:10.1148/radiol.2020200490.
  2. Raoult D, Zumla A, Locatelli F, Ippolito G, Kroemer G. Coronavirus infections: Epidemiological, clinical and immunological features and hypothesesCell Stress. 2020;4(4):66-75. doi:10.15698/cst2020.04.216.
  3. She J, Jiang J, Ye L, Hu L, Bai C, Song Y. 2019 novel coronavirus of pneumonia in Wuhan, China: emerging attack and management strategiesClinical and Translational Medicine. 2020;9(1). doi:10.1186/s40169-020-00271-z.
  4. Zu ZY, Jiang MD, Xu PP, et al. Coronavirus Disease 2019 (COVID-19): A Perspective from ChinaRadiology. 2020:200490. doi:10.1148/radiol.2020200490.
  5. Gorton H, Jarvis K. The effectiveness of vitamin C in preventing and relieving the symptoms of virus-induced respiratory infectionsJournal of Manipulative and Physiological Therapeutics. 1999;22(8):530-533. doi:10.1016/s0161-4754(99)70005-9.
  6. Hemilä H. Vitamin C and Infections. Nutrients. 2017;9(4):339. doi:10.3390/nu9040339.
  7. Jin Y-H, Cai L, Cheng Z-S, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Military Medical Research. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003341/. Published February 6, 2020. 
  8. Zhang D-hai, Wu K-lun, Zhang X, Deng S-qiong, Peng B. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. Journal of Integrative Medicine. Published February 20, 2020. 
  9. Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. Published May 29, 2015. 
  10. Maguire JL, Birken CS, Loeb MB, et al. DO IT Trial: vitamin D Outcomes and Interventions in Toddlers – a TARGet Kids! randomized controlled trial. BMC pediatrics. Published February 8, 2014.
  11. Guillin OM, Vindry C, Ohlmann T, Chavatte L. Selenium, Selenoproteins and Viral Infection. Nutrients. Published September 4, 2019. 
  12. Steinbrenner H, Al-Quraishy S, Dkhil MA, Wunderlich F, Sies H. Dietary selenium in adjuvant therapy of viral and bacterial infections. Advances in nutrition (Bethesda, Md.). Published January 15, 2015. .
  13. Gammoh NZ, Rink L. Zinc in Infection and Inflammation. Nutrients. Published June 17, 2017.