While here in New Zealand we are now very fortunate that very low numbers of new Covid-19 cases are being reported, and the wearing of masks and social distancing practices are starting to seem like a distant memory to many people, much of the world is not so lucky. As our days lengthen and thoughts of a forthcoming summer break brighten our days, the virus continues to wreak havoc and cause huge stress and loss of life, in so many other countries.

Over the next few months those lucky enough to be living in New Zealand will hopefully be able to attend concerts, shows, sports events and festivals again, and these will help facilitate some kind of ‘return to normality’ from our spells in lockdown over autumn and winter. However, the coming summer may become a period of relative respite, because pressure will grow to further reopen our borders, and no public health or border protection system is invincible. Therefore as we prepare for or engage with gatherings involving larger numbers of people where the risk of community transmission is greater, ensuring a healthy immunity over the next few months and then as we move into autumn, remains important.

Evidence of efficacy is often a challenging subject to address with phytomedicines, due to the phytochemical diversity of whole plants and the many different extracts and products to evaluate.  Not to mention the difficulties in accessing funding to undertake clinical trials where large patient numbers and/or lengthy treatment interventions are often required to achieve adequate statistical power.

Pandemics have afflicted the human race throughout our entire history, and plant-based medicines have been a cornerstone of how we dealt with these, way before single active chemical interventions (drugs or vaccines) were conceived. The current Covid-19 pandemic is a reminder that drugs are often unable to protect us against everything that the natural world throws at us.

Significant evidence indicates that a dysregulated innate immune response contributes to the clinical presentation of patients with severe Covid-19 infections^(1,2).  

Covid-19 pathology

A meta-analysis of 21 studies, found that biomarkers of inflammation, cardiac and muscle injury, liver and kidney function and coagulation measures were significantly elevated in patients with both severe and fatal Covid-19. In particular, interleukins 6 (IL-6) and 10 (IL-10) and serum ferritin were strong discriminators for severe disease⁽²⁾.

These elevations in inflammatory cytokines have led to the view that an immunity-mediated “cytokine storm,” is primarily responsible for the toxicity and end-organ damage mediated by Covid-19 infections. The combined effect seems to be promotion of granulocyte infiltration into the lungs, resulting in acute lung injury & sometimes death due to primary respiratory failure. An abnormal immune mechanism and upregulationof genes involved in apoptosis, tissue injury & oxidative damage, can also damage organs such as the heart, kidney and liver, and lead to multiple organ exhaustion and shut down, or residual damage to these post infection recovery.

Attenuation of the peak immune response, either with corticosteroids such as dexamethasone or more specifically targeting of interleukin IL-6 or IL-1β to limit damage to other organs during the early immune response, may benefit some patients^(3,4). There are risks with such drug therapy however, as early immune hyperactivity may be a reflection of high viral burden and a much-needed protective antibody response, and our understanding of the how this clever coronavirus influences immune mechanisms at different infection stages in different patients, is still lacking.

Echinacea’s immunomodulatory effects:

In western herbal medicine, one of the most highly regarded phytomedicines from both a traditional as well as evidence-based perspective, is the well known Echinacea (Purple coneflower). Two species are generally used, Echinacea purpurea and Echinacea angustifolia.

A principle application claimed for Echinacea-based products over the last 50 years has been as a prophylactic or treatment for colds and influenza. Several clinical trials have shown beneficial effects of Echinacea in this context, although others have had less favourable outcomes, particularly where product quality or doses used have been suboptimal⁽⁵⁾. Few adverse events have been reported, and the risk of interactions is low⁽⁶⁾.  But what is the evidence that this phytomedicine can help us during the current global Covid-19 pandemic?

A number of natural products including Echinacea have shown in vitro effects against the SARS-CoV-2 coronavirus responsible for Covid-19^(7-9), although these are limited to date, and clinical studies are lacking.

Echinacea is frequently portrayed as an ‘immune stimulant’ herb in the popular media and therefore sometimes claimed to be contraindicated in situations where elements of the immune system are ‘overactivated’. This is a gross simplification of the effects of this phytomedicine, as its widespread traditional use for conditions that are largely inflammatory and autoimmune in nature has been largely overlooked, as have anti-inflammatory properties particularly for its constituent alkylamides and high alkylamide-containing products^(10-12).

Studies using different types of Echinacea purpurea on murine dendritic cells (immune cells in mice which play important roles in activating and initiating immune responses) found immunostimulatory, immunosuppressive, and/or anti-inflammatory actions can all be produced, with distinctively different outcomes depending on the plant part and extraction method used⁽¹³⁾. Furthermore, different actions appear to occur during uninfected and infected states, suggesting that there is much more to Echinacea than a simple immune stimulant action. These include its influences on cytokine secretion.

Key outcomes when Echinacea is taken by healthy volunteers seem to be increased numbers of circulating white blood cells, monocytes, neutrophils and natural killer (NK) cells, and thus enhancement of the non-specific (innate) immune system. This is thought to improve the body’s ability to maintain immunosurveillance against a variety of potential viral or bacterial pathogens or spontaneous-developing tumours.  Daily administration of Echinacea purpurea root prolonged the life spans of normal mice⁽¹⁴⁾, and Echinacea purpurea had a suppressive effect on spontaneously occurring leukaemia caused by a murine leukaemia virus⁽¹⁵⁾. It has also been reported to have beneficial effects on stress-induced immunosuppression in rodents, by increasing splenocyte proliferation and NK cell activity, while restoring and modulating T lymphocyte subsets and serum cytokine levels⁽¹⁶⁾. These essentially prophylactic effects were largely related to enhancement of immune systems.

Administration of Echinacea during an infection however, is likely to produce somewhat different outcomes, as is shown by various studies^(17-19).

Rhinovirus infection in a line of human bronchial epithelial cells was shown to induce or increase the secretion of at least 31 different inflammatory cytokines and chemokines, including the interleukins IL-1β, IL-3, IL-5, IL-6, IL-17, granulocyte-macrophage colony stimulating factor, interferon-gamma (IFN-ﻻ), and tumor necrosis factor (TNF-α).  Echinacea treatment of the infected cells over 48 hours however, reversed this stimulation of inflammatory cytokine and chemokine levels, either partially or completely⁽¹⁷⁾. 

Subsequent studies reported that Echinacea purpurea reduced rhinovirus induced secretion of interleukin-6 and interleukin-8 from human bronchial epithelial cells, regardless of whether it was added before or after virus infection⁽¹⁸⁾.

In contrast to the above effects on infected cells, when uninfected cells were treated with Echinacea, cytokine levels were mostly increased, particularly by a root-derived rather than fresh whole plant-derived preparation.

These investigations provide support for an immunomodulatory mode of action for Echinacea, whereby the immune system is enhanced when Echinacea is taken in the absence of infection, but excessive and possibly damaging inflammation during a viral infection may be reduced. This suggests not only a useful prophylactic effect of Echinacea against unwanted viruses, but also a potential usefulness during upper respiratory tract viral infections such as rhinovirus. While much more work needs to be done, these effects could extend also to other highly pathogenic viral infections in which excessive activation of elements of the immune response and a sudden and unregulated increase in the production of pro-inflammatory cytokines, may occur^(19,20).

An assessment of human trials involving Echinacea use for up to 4 months, failed to locate any evidence of cytokine storm⁽²¹⁾. Furthermore, those which measured changes in cytokine levels in response to Echinacea use, provide results which are largely consistent with a decrease in pro-inflammatory cytokines. While there is currently no research on the therapeutic effects of Echinacea in the management of cytokine storm, this evidence suggests further research is warranted.

Traditional and modern day use experience points to potential benefits and few if any contraindications of daily prophylactic use of Echinacea to further enhance our immunity to contracting infection, beyond advisable public health measures such as social distancing and good hygiene. Additionally, while much is unknown and more research is advocated, this highly regarded phytomedicine could also provide useful anti-inflammatory and immunomodulatory effects as part of the very challenging management of seriously ill patients, where a hyperinflammatory situation seems contributory to worse outcomes.

Secondary bacterial infections:

Secondary or co-existing bacterial infections are a common cause of pneumonia and death in patients with viral infections of the respiratory tract. Viral infections can express bacterial adhesion receptors, and the virus-induced inflammatory response can also disturb the integrity of the physical barrier to bacteria.  The use of prophylactic antibiotics in Covid-19 infected patients has therefore become relatively common. Recent reviews however, suggest the frequency of such secondary bacterial infections may be less than initially thought. These found bacterial co-infection was identified in only 3.5-7% of patients, and secondary bacterial infection in 14% of patients ^(22,23), While such infections are more common in seriously ill and elderly patients, and antibiotics should of course be used when indicated, not overusing them in an age of increasing antibiotic resistance, is also important. As such, evidence suggesting echinacea may prevent virus-induced bacterial adhesion to cell membranes⁽²⁴⁾, suggests another potential mechanism of action to improve host resistance against such unwanted secondary infections.

Dietary supplementation with Echinacea purpurea has been reported to improve the final body weight and immune response of non-infected chickens, and reduce the mortality of those infected with E. coli⁽²⁵⁾. 

A recent clinical trial involving 300 children in Eqypt with recurrent tonsillitis, reported fewer tonsillitis attacks and less severe symptoms when Echinacea was taken alongside the antibiotic azithromycin, three times daily for 10 consecutive days every month for 6 consecutive months⁽²⁶⁾. While the plant part(s) used and phytochemical analysis of the preparation involved was not disclosed in this report, these findings are supported also by the clinical experience of many western medical herbalists, who prescribe concomitant Echinacea in patients receiving antibiotic treatment. Usage of Echinacea as an adjunctive with antibiotics, clearly warrants further clinical trials.

Effects on Stress?

Another unexpected but potentially helpful application of some Echinacea preparations in a stress-invoking pandemic world, is to help alleviate anxiety. Anxiolytic effects have been reported previously for certain Echinacea extracts and products, but clinical evidence has been lacking. However, a recent double blind, placebo controlled trial in which volunteers prone to anxiety took a standardized Echinacea angustifolia root extract twice daily for 7 days, found a decrease of 11 in state anxiety scores after 7 days of Echinacea, compared to only 3 in the placebo group⁽²⁷⁾.

Echinacea products are being sought after in northern hemisphere countries as second or third waves of the Covid-19 pandemic continue to plague multiple nations.  While clinical studies are sadly lacking and are sorely needed, the many potentially relevant pharmacological properties shown by this highly regarded phytomedicine would seem to go a long way to justify its recent rise in popularity.

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Refs:

1. Henry BM et al, Clin Chem Lab Med 2020 Jun 25;58(7):1021-1028
2. Jamilloux Y et al, Autoimmun Rev. 2020 Jul;19(7):102567
3. Vardhana SA et al, J Exp Med. 2020 Jun 1; 217(6): e20200678.
4. Conti P J BiolRegulHomeost Agents. 2020 Mar 14;34(2)
5. Shah SA et al, Lancet Infect Dis. 2007 Jul;7(7):473-80.
6. Rasmussen PL, Recent studies on Echinacea and interactions with drug medication. Phytonews 34, July 2010. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
7. Signer J et al, Virol J. 2020 Sep 9;17(1):136.
8. Mani JS et al, Virus Res 2020; Jul 15:284:197989.
9. Khalifa I et al, J Food Biochem. 2020 Aug 11;e13432.
10. Clifford LJ et al, Phytomedicine 9(3), 249-254, April 2002.
11. Rasmussen PL, Evaluation of anti-inflammatory effects of Echinacea purpurea and Hypericum perforatum. Phytonews 14, Dec 2002. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
12. Lalone CA et al, J Agric Food Chem. 2010 Aug 11;58(15):8573-84
13. Benson JM et al, Food Chem Toxicol. 2010 May;48(5):1170-7.
14. Brouseau M, Miller SC, Biogerontology. 2005;6(3):157-63.
15. Hayashi I et al, Nihon Rinsho Meneki Gakkai Kaishi. 2001;24(1):10-20.
16. Park S et al, J Med Food 2018 Mar;21(3):261-268.
17. Sharma M et al, Phytother Res 2006; 200(2):147-152.
18. Sharma M et al, Antiviral Res. 2009 Aug;83(2):165-70.
19. Rasmussen PL, Effects of Echinacea on virus-induced respiratory cytokines. Phytonews 24, Feb 2006, June. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
20. Rasmussen PL, Phytotherapy in an Influenza Pandemic: Swine Flu. Phytonews 32, 2009, June. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
21. Aucoin M et al, Adv Integr Med 2020; Aug 1. Doi: 10.1016/j.aimed.2020.07.004
22. Langford BJ et al, Clin Microbiol Infect. 2020 Jul 22;S1198-743X(20)30423-7
23. Lansbury L et al, J Infect. 2020 Aug;81(2):266-275
24. Vimalanathan S et al, Virus Res. 2017; 2(233):51-59.
25. Hashem MA et al, Trop Anim Health Prod. 2020 Jul;52(4):1599-1607.
26. Osama G Abdel-Naby Awad, Am J Otolaryngol. Jul-Aug 2020;41(4):102344.
27. Haller J et al, Phytother Res. 2020 Mar;34(3):660-668.