key: cord-0839149-oyf23gu5
authors: Aucoin, Monique; Cooley, Kieran; Saunders, Paul Richard; Carè, Jenny; Anheyer, Dennis; Medina, Daen N.; Cardozo, Valentina; Remy, Daniella; Hannan, Nicole; Garber, Anna
title: The effect of Echinacea spp. on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review
date: 2020-08-01
journal: Adv Integr Med
DOI: 10.1016/j.aimed.2020.07.004
sha: d179adef5b8b2c84baa05a6d0e14a12f9e11c27c
doc_id: 839149
cord_uid: oyf23gu5

Brief overview Current evidence suggests that Echinacea supplementation may decrease the duration and severity of acute respiratory tract infections; however, no studies using Echinacea in the prevention or treatment of conditions similar to COVID-19 have been identified. Few adverse events were reported, suggesting that this herbal therapy is reasonably safe. Because Echinacea can increase immune function, there is a concern that it could worsen over-activation of the immune system in cytokine storm; however, clinical trials show that Echinacea decreases levels of immune molecules involved in cytokine storm. Verdict Echinacea supplementation may assist with the symptoms of acute respiratory infections (ARI) and the common cold, particularly when administered at the first sign of infection; however, no studies using Echinacea in the prevention or treatment of conditions similar to COVID-19 have been identified. Previous studies have reported that Echinacea may decrease the severity and/or duration of ARI when taken at the onset of symptoms. The studies reporting benefit used E. purpurea or a combination of E. purpurea and E. angustifolia containing standardized amounts of active constituents.Few adverse events from the use of Echinacea were reported, suggesting that this herbal therapy is reasonably safe. No human trials could be located reporting evidence of cytokine storm when Echinacea was used for up to 4 months.When assessing all human trials which reported changes in cytokine levels in response to Echinacea supplementation, the results were largely consistent with a decrease in the pro-inflammatory cytokines that play a role in the progression of cytokine storm and Acute Respiratory Distress Syndrome (ARDS), factors that play a significant role in the death of COVID-19 patients. While there is currently no research on the therapeutic effects of Echinacea in the management of cytokine storm, this evidence suggests that further research is warranted.

Few adverse events from the use of Echinacea were reported, suggesting that this herbal therapy is reasonably safe. No human trials could be located reporting evidence of cytokine storm when Echinacea was used for up to 4 months.

When assessing all human trials which reported changes in cytokine levels in response to Echinacea supplementation, the results were largely consistent with a decrease in the pro-inflammatory cytokines that play a role in the progression of cytokine storm and Acute Respiratory Distress Syndrome (ARDS), factors that play a significant role in the death of COVID-19 patients. While there is currently no research on the therapeutic effects of Echinacea in the management of cytokine storm, this evidence suggests that further research is warranted.

Echinacea species are native to North America and have been used by indigenous peoples for a range of illnesses. As an herbal medicine, Echinacea has been the subject of significant research over the past century, particularly with respect to its role in the treatment and prevention of respiratory illnesses. It is one of the most popular natural health products purchased worldwide, with the majority of commercially available products containing E. purpurea and/or E. angustifolia (1) . Many naturopathic doctors recommend Echinacea supplements for immune support. A wide range of reports have described its immuno-modulatory properties including macrophage activation and effects on cytokine expression. Because significant effects on cytokine levels have been observed in response to Echinacea use, there is a theoretical concern about its contribution to cytokine storm (also known as cytokine release syndrome) (1) . Cytokine storm is a poorly understood phenomenon involving excessive, rapid release of pro-inflammatory cytokines (2) . In COVID-19, cytokine storm can lead to ARDS which carries a 40% mortality rate (3) . Cytokines associated with cytokine storm include pro-inflammatory interleukin (IL)-6, IL-8, IL-1B, IL-12 and tumor necrosis factor (TNF)α, while other cytokines, such as IL-10, have established anti-inflammatory effects and a role in downregulating excessive immune activity (2) . In OR randomized controlled trial.pt. OR multicenter study.pt. OR clinical trial.pt. OR exp Clinical Trials as topic/ OR (clinical adj trial$).tw. OR ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. OR PLACEBOS/ OR placebo$.tw. OR randomly allocated.tw. OR allocated adj2 random$).tw.) NOT (letter/ OR historical article/)) AND (Echinacea or Echinacea angustifolia or Echinacea purpurea or Echinace or coneflower) AND ("avian influenza (H5N1)"/ or "influenza A (H1N1)"/ or Influenza A virus/ or influenza C/ or exp influenza/ or highly pathogenic avian influenza/ or Influenza B virus/ or highly pathogenic avian influenza virus/ or avian influenza virus/ or seasonal influenza/ or "Influenza A virus (H1N1)"/ or OR historical article/)) AND (Echinacea or Echinacea angustifolia or Echinacea purpurea or Echinace or coneflower) AND (Cytokine$ or cytokine storm or cytokine release syndrome or chemokine$ or interferon$ or interleukin$ or tumour necrosis factor$ or colony-stimulating factor$) Screening Titles and abstract screening and full text screening were completed by one reviewer and checked for accuracy by a second reviewer. Similarly, data extraction was completed by a single reviewer and checked for accuracy by a second reviewer. Any discrepancies were resolved by consensus.

The risk of bias (RoB) of study findings was assessed using the revised Cochrane RoB tool for randomised trials (RoB 2) https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-version-of-rob-2?authuser=0.

The protocol was registered with PROSPERO: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=186339

The search identified 382 results, including 85 duplicates. 297 citations were screened. After title and abstract reviews, 37 citations remained and 260 citations were excluded, as these did not meet the inclusion and exclusion criteria. The full-text of the remaining 37 articles were assessed for eligibility and 23 were excluded (wrong study design n=20, duplicate n=1, not accessible n=1, wrong outcome n=1).

Three additional studies were identified through a bibliography search. A total of 17 studies underwent data extraction (Table 1) .

Ten studies were conducted in the World Health Organization (WHO) region of the Americas, with five in the European region, one in the Western Pacific region and one in the South-East Asia region.

J o u r n a l P r e -p r o o f All 17 studies were double-blind, placebo-controlled, randomized clinical trials. One study had additional arms using open-label Echinacea and no treatment (4) and several studies had multiple arms comparing different Echinacea species, commercial formulas or doses (5) (6) (7) (8) . Studies were designed to assess for the prevention or treatment of ARI, primarily, the common cold. Six studies assessed the impact on prevention: four in normal daily life (duration 6 to 16 weeks), one in response to a strenuous exercise challenge (duration 4 weeks) (9) and one in response to long-distance air travel (duration 4 weeks) (10) .

Two studies assessed the impact of Echinacea 7 days before and 5 to 7 days after a viral challenge (8, 11) . Nine studies assessed the use of Echinacea for 5 to 14 days in the treatment of a new onset respiratory tract infection, one in patients with chronic obstructive pulmonary disease (COPD) who were administered antibiotics concurrently and the remaining were conducted in healthy adults (5) . In all 17 studies, participants were located in the community (i.e. not in-patient settings).

In total, the 17 studies included 3363 participants with a mean sample size of 224 participants (SD=229, range: 32 to 755).

Eleven studies used intervention formulas containing E. purpurea, two used E. angustifolia, four used a combination of E. purpurea and E. angustifolia, and one used E. pallidae radix.

Echinacea dose and method of extraction across all of the included studies were quite variable. Studies used different parts of the herb, including root, whole plant and aerial parts, as well as different methods of preparation. Echinacea interventions were delivered in the form of pressed juice, hydroalcohol extracts, capsules of dry herb and infusions. The lowest dose used was 100 mg of herb (12) while other studies used as much as 10.2g per day in capsules on the first day of treatment (4) . Five studies reported using formulas that were standardized to include a specific amount of active constituent (6, (12) (13) (14) .

The studies assessed for ARI, viral respiratory infections or the common cold. The two studies that used a viral challenge administered rhinovirus 39 and monitored for the common cold (8, 11) .

The Cochrane Risk of Bias 2.0 assessment tool was used to evaluate the included studies. Of the six studies assessing prevention, four were rated low risk of bias (7, 10, 13, 15) while two were rated high risk (9, 16) . Among the two studies testing prevention and treatment in response to a viral challenge, one was rated high risk of bias (11) and one low risk of bias (8) . Among the nine studies assessing treatment of new onset infections, four were rated low (4, 14, 17, 18) , four rated high (5, 6, 19, 20) and one was rated as having some concerns (12) . Reasons for a high risk of bias included per-protocol J o u r n a l P r e -p r o o f analysis (6, 16) , lack of description of dropouts (9) , incomplete reporting of data (5, 19) , and lack of baseline data comparing the treatment groups (20) . One study terminated the study before recruiting the sample size needed to detect significance based on a power calculation completed midway through the study (11) . These judgments should be taken into consideration when interpreting the findings of this review.

The search identified 100 results, including 26 duplicates. 74 citations were screened. After title and abstract reviews, 18 citations remained and 56 citations were excluded as these did not meet the inclusion and exclusion criteria. The full-text of the remaining 18 articles were assessed for eligibility and six were excluded (protocol only n=1, incorrect outcome n=2, duplicate data from included publication n=1, unable to locate full text n=1). A total of 12 studies underwent data extraction ( Table 2) .

Of these, five included healthy participants who consumed oral doses of Echinacea before blood levels of cytokines were measured (21) (22) (23) (24) (25) . Three studies included participants with respiratory tract infections (4, 5, 8) and four included healthy participants whose ex vivo blood samples were stimulated and immune response observed (26) (27) (28) (29) . The studies assessed cytokines including TNFα (n=9), IL-1B, IL-2, IL-3 IL-6, IL-8, IL-10, IL-12 and Interferon (IFN)α2.

The six studies that administered Echinacea to healthy participants for two to four months and assessed prevention of naturally acquired upper respiratory tract infections (URIs), measured the frequency and/or duration of infections (7, 9, 10, 13, 15, 16) . Five of these studies assessed infection frequency and of these, two reported a statistically significant reduction (10, 13) . Three studies assessed duration of illness and of these, one reported a statistically significant decrease (9) .

In the two studies that provided Echinacea supplementation before and after study-administered viral challenge, one reported no difference in infection frequency or severity compared to placebo (8) .

The nine studies assessing the use of Echinacea at the onset of a URTI measured infection duration and symptom severity (4-6, 12, 14, 17-20) . All studies assessed for impact on symptom severity and five reported statistically significant reductions in symptom severity (4, 6, 14, 19, 20) . A sixth study, that included participants with COPD experiencing an acute exacerbation of respiratory symptoms, found a reduction in severity in response to supplementation with Echinacea in combination with zinc, selenium and ascorbic acid but not for Echinacea alone (5) . Seven of the studies using Echinacea at URTI symptom J o u r n a l P r e -p r o o f onset assessed the duration of symptoms and five reported a statistically significant reduction in duration compared to participants receiving placebo (4, 14, (18) (19) (20) .

With respect to risk of bias, of the ten studies that reported a positive outcome, five were rated as high risk of bias (5, 6, 9, 19, 20) and five were rated as low risk of bias (4, 10, 13, 14, 18) .

Among the 13 studies that reported intervention dose with an equivalent dose of dry herb (or a liquid extraction and extraction strength), the mean dose was calculated. In cases where a range or variable doses were given, the highest doses was selected. The mean dose used in studies reporting benefit was 7.3 grams per day (SD 6.4) and the mean dose used in studies that failed to detect benefit was 1.7 grams per day (SD 2.1). The studies reporting benefit used E. purpurea (n=6) or a combination of E. purpurea and E. angustifolia (n=3) or E. pallidae radix (n=1). Of the five studies using extracts with a standardized level of active constituents, four reported benefit. These active constituents included dodecatetraenoic acid, isobutylamide, alkylamides, cichoric acid and soluble -1,2-D-fructofuranosides (6, 10, (12) (13) (14) . Table 3 While seven studies did not report adverse events, the remainder reported few adverse effects, in most cases similar to the control group. One reported a serious reaction involving generalized erythema which resolved with anti-histamine treatment (5) and mild adverse events of which insomnia was the most common. Another reported primarily gastro-intestinal side effects (8) and another reported one case of anxiety and nervousness and a recurrence of bilateral arthritis symptoms which the patient had previously experienced (22) .

Echinacea supplementation may assist with the symptoms of ARI and the common cold, particularly when administered at the first sign of infection; however, no studies have been identified which use Echinacea in the prevention or treatment of conditions similar to COVID-19. When taken at the onset of symptoms, Echinacea may decrease the severity or duration of ARI.

Because the vast majority of studies involved participants who were free from serious or chronic illness, and without known issues related to immune function, it is not possible to infer what the role of Echinacea spp. could be in those at highest risk of COVID-19.

With respect to the impact of Echinacea on cytokine levels, the majority of evidence suggests a decrease in levels of pro-inflammatory cytokines associated with cytokine storm. While the potential for Echinacea to provide a clinical therapeutic benefit is speculative, animal studies using pharmaceuticals that decrease production of IL-1α, IL-6 and TNFα cytokines have increased survival of mice infected with severe influenza (2) 

No side effects were reported by any of the subjects Table 1 J o u r n a l P r e -p r o o f

Potential usage of immune modulating supplements of the Echinacea genus for COVID-19 infection

Into the eye of the cytokine storm

The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

Echinacea for Treating the Common Cold

Echinacea purpurea along with zinc, selenium and vitamin C to alleviate exacerbations of chronic obstructive pulmonary disease: results from a randomized controlled trial

A proprietary extract from the echinacea plant (Echinacea purpurea) enhances systemic immune response during a common cold

Echinacea root extracts for the prevention of upper respiratory tract infections: a double-blind, placebo-controlled randomized trial

An Evaluation of Echinacea angustifolia in Experimental Rhinovirus Infections

Echinacea Purpurea and Mucosal Immunity

Randomised, Double Blind, Placebo-Controlled Trial of Echinacea Supplementation in Air Travellers

Echinacea purpurea for Prevention of Experimental Rhinovirus Colds

Echinacea purpurea therapy for the treatment of the common cold: a randomized, double-blind, placebo-controlled clinical trial

Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial

Efficacy of a standardized echinacea preparation (EchinilinTM) for the treatment of the common cold: a randomized, double-blind, placebo-controlled trial

A randomized controlled trial of the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections * * Access the

Effects of echinacea on the frequency of upper respiratory tract symptoms: a randomized, double-blind, placebo-controlled trial

Treatment of the Common Cold with Unrefined Echinacea

Efficacy of Echinacea purpurea in Patients with a Common Cold

Placebo-controlled, double-blind study of Echinaceae pallidae radix in upper respiratory tract infections

The Efficacy of Echinacea Compound Herbal Tea Preparation on the Severity and Duration of Upper Respiratory and Flu Symptoms: A Randomized, Double-Blind Placebo-Controlled Study

Pharmacokinetics and immunomodulatory effect of lipophilic Echinacea extract formulated in softgel capsules

Immunological activity of larch arabinogalactan and Echinacea: a preliminary, randomized, double-blind, placebo-controlled trial

The effect of 4 wk of oral echinacea supplementation on serum erythropoietin and indices of erythropoietic status

Regulation of human immune gene expression as influenced by a commercial blended Echinacea product: preliminary studies

Pharmacokinetics and immunomodulatory effects of phytotherapeutic lozenges (bonbons) with Echinacea purpurea extract

Immunomodulation mediated by a herbal syrup containing a standardized Echinacea root extract: A pilot study in healthy human subjects on cytokine gene expression

Effects of Echinaforce® treatment on ex vivostimulated blood cells

Bioavailability and pharmacokinetics of Echinacea purpurea preparations and their interaction with the immune system

Oral administration of freshly expressed juice of Echinacea purpurea herbs fail to stimulate the nonspecific immune response in healthy young men: results of a double-blind, placebo-controlled crossover study

J o u r n a l P r e -p r o o f (21)