In 2020, Signer et al. published in vitro data revealing a broad virucidal activity for Echinacea purpurea (hydroethanolic extract (65% v/v) of freshly harvested Echinacea purpurea (L.) Moench (95% aerial parts and 5% root) in pharmaceutical quality according to good manufacturing practices (GMP)) against a broad number of coronaviruses ranging from the typical common cold CoV-229E to highly pathogenic SARS-CoV-2 viruses ^[8][13]. The clinical relevance of the findings, however, remained uncertain, because direct contact of the pathogen with the extract was a prerequisite for full activity, although this was considered possible by sucking Echinacea purpurea tablets and/or gargling tincture in the pharynx.

In addition to direct virucidal and antiviral capacity, Echinacea extracts influence the immune system in a manner best described as adaptive immune modulation, rather than pure immune stimulation. Echinacea significantly reduced expression of inflammatory cytokines tumor necrosis factor TNF-α and interleukin IL-1-β by up to 24% compared to baseline, and increased levels of the anti-inflammatory cytokine IL-10. Additionally, there was an increase of up to 50% in the production of the immune-response modulating and antiviral interferon IFN-γ ^[9][10][14,15]. Further immunomodulatory mechanisms of Echinacea were shown to involve potent activation of the endocannabinoid system (ECS) by specific N-alkylamides via the cannabinoid receptor type 2 (CB2) ^[11][12][16,17]. Several of these bioactive N-alkylamides are structurally similar to endocannabinoids (e.g., anandamide), which influence the cytokine milieu in an anti-inflammatory manner at low nanomolar concentrations ^[13][18]. During COVID-19 progression, activation of the endocannabinoid system (ECS) could be an additional approach against systemic inflammation and the cytokine storm ^[14][19]. Echinacea purpurea could therefore reduce inflammatory processes through synergistic immunopharmacological targeting of CB receptors, mild inhibition of the fatty acid amide hydrolase (FAAH), or endocannabinoid transport ^[15][16][20,21].

Echinacea has a long tradition for the prevention and the acute treatment of respiratory tract infections, and recent investigations attributed antiviral, immune-modulatory and anti-inflammatory pharmacological actions to the medicinal plant ^{[9][15][17][18][19]}[14,20,30,31,32]. A wide series of respiratory viruses have been shown to be sensitive to lipophilic extracts of freshly harvested Echinacea purpurea and an obvious specificity towards enveloped pathogens could be verified ^[20][33]. The extract appears to block interaction of viral docking receptors (e.g., hemagglutinin on influenza) with structures on the target cell and is thus expected to prevent infection, although the detailed mechanism of action remains to be elucidated ^[18][31].

Antiviral effects on endemic coronaviruses causing typical cold symptoms (CoV-229E) and on highly pathogenic SARS-CoV-1 and MERS-CoV type have been studied in vitro for several years. Recently, these effects have also been confirmed for the newly occurring SARS-CoV-2 ^[8][21][13,34]. Signer et al. concluded a generally applicable principle of action against coronaviruses, but pointed out that clinical data are needed to confirm their in vitro findings.

Four-month supplementation with Echinacea in adults and children reduced the incidence of coronaviruses as part of its effect on enveloped virus infections and virus concentration in nasopharynx in the latter, respectively. Jawad did not measure virus concentrations (Ct-value), and this information was therefore lacking. Ogal employed a newer, more sensitive method for detection that was able to detect as few as 100 viral genome copies. ItWe is proposed that that Echinacea’s antiviral effects reduce virus replication, therefore reducing virus load below detection limits for standard PCR resulting in decreased incidence with Echinacea as observed in the Jawad study. This is consistent with the lower virus Ct-values observed in the Ogal study as even residual, subclinical viral concentrations could still be quantified.

Interestingly, prevention with Echinacea appeared to reduce the symptomatic development only in children rather than in adults. However, Jawad et al. did not sample continuously, but only upon symptomatic infection, and may have missed potential subclinical infections with verum for the above reasons, skewing evaluation at this level. In contrast, the low virus detection limit in Ogal et al. due to the use of RT-qPCR methods might have identified more milder/subclinical episodes which would have further reduced symptoms with Echinacea treatment in adults as observed for children. In this respect, incidence (detections) and symptomatology/Ct values must be considered as complementary parameters, both indicative for antiviral effects of Echinacea. Taking this into account, it can be concluded that preventive treatment with Echinacea provides beneficial effects to coronavirus infections in both, adults and children. In adults, infections could be prevented, whereas children demonstrated significantly reduced virus loads, symptom reduction, as well as shortened duration of illnesses. In both cases, preventive effects of Echinacea against coronaviruses could be ascertained in controlled clinical settings. All coronaviruses share structural similarities, including an enveloped membrane containing the genetic material, i.e., RNA and spike proteins for attachment to target cells. Echinacea broadly inhibits enveloped respiratory viruses at physiological concentrations in vitro and in vivo; however, the exact mode-of-action remains to be elucidated. Due to this broad range of activity, deactivation of all measured coronavirus types, such as alpha (CoV-229E) and beta strains (MERS-CoV, SARS-CoV-1, SARS-CoV-2) by Echinacea, can realistically be assumed, and the results of this study point towards the clinical relevance of in vitro findings. Though not always reaching statistical significance for the particular virus, the effects of Echinacea against coronaviruses are mirrored and overarched by the effects seen against membranous viruses. Notably, all cited studies applied the same Echinacea purpurea extract (Echinaforce^®) either as diluted tincture or as tablets, both of which were kept in the mouth for a while prior to swallowing. As already hypothesized by Signer et al., pharyngeal administration of the extract may be key to inactivating respiratory viruses at the main entry site prior to infection ^[8][13]. Furthermore, any viral attenuation in this region could prevent further dissemination of nasal infections to the lungs, as seen with severe progressions of COVID-19. Indeed, a recent meta-analysis found a significant prevention of pneumonia secondary to viral respiratory tract infections upon 2 to 4 months of Echinacea preventive use ^[22][40].

3. Conclusions

A specific extract of Echinacea purpurea (L.) Moench exhibits direct antiviral activity against a broad range of respiratory pathogens, including coronaviruses. This extract supports the tonic production of IFN-γ and beneficially modulates inflammatory cytokines like TNF-α. Two RCTs with phytopharmaceutical preparations of this extract demonstrate effective protection against enveloped viruses including coronaviruses in adults and children. Preliminary published clinical results on SARS-CoV-2 may yet further support the use of Echinacea also against this particular coronavirus.