Echinacea-based Infusion Noninferior to Oseltamivir in Early Influenza Treatment
By Erica Benedicto, PA-C, MPH
Founder, Shiny Healthy People and Whole Health Collective, Austin, TX
Ms. Benedicto reports no financial relationships relevant to this field of study.
SYNOPSIS: Echinacea Hotdrink was found to be as effective as oseltamivir as early treatment intervention of clinically diagnosed and lab-confirmed influenza virus infections and had fewer adverse effects.
SOURCE: Raus K, et al. Effect of an echinacea-based hot drink versus oseltamivir in influenza treatment: A randomized, double-blind, double-dummy, multicenter, noninferiority clinical trial. Curr Ther Res Clin Exp 2015;77:66-72. doi: 10.1016/j.curtheres.2015.04.001.
SUMMARY POINTS
- Both clinically diagnosed and virologically confirmed influenza patients participated in a randomized, double-blind, double-dummy, multicenter, noninferiority clinical trial in the Czech Republic.
- Echinaforce Hotdrink was found to be noninferior compared to oseltamivir for early intervential treatment of influenza virus.
- Incidence of complications was lower with Echinaforce Hotdrink and fewer participants experienced adverse events, mostly nausea and vomiting.
Influenza virus infections make up the vast majority of acute visits to physicians’ offices during the autumn and winter months. With 25-50 million cases of influenza each year resulting in about 150,000 hospitalizations and 30,000-40,000 deaths in the United States, according to the World Health Organization, options for early treatment and intervention are important. Antiviral treatments that are safe, effective, and easy to recommend during high flu season are an essential part of the clinical toolbox. Influenza vaccines are standard, but they may not be available to certain populations or in a timely manner, as experienced with the 2009 H1N1-type pandemic strain of swine origin.1 As a result, the quest for a complementary approach for this common but challenging acute condition continues.
This study examined the effect of an Echinacea purpurea-based infusion vs oseltamivir as early interventional treatment for influenza-positive patients. Neuraminidase inhibitors are recommended within 48 hours of onset of influenza symptoms by the Centers for Disease Control and Prevention (CDC) and are recognized as the gold standard. Both oseltamivir and zanamivir have been shown to reduce severity and duration of symptoms, but early intervention is critical. Adverse effects include nausea, diarrhea, vomiting, and skin, renal, and psychiatric events. A plant-based alternative with similar efficacy, safety, less side effects, and easier accessibility would be an important option to prevent complications of influenza.
The purpose of the study was to determine noninferiority of treatment of influenza virus with Echinaforce Hotdrink (EH) when compared to the neuraminidase inhibitor oseltamivir. The noninferiority study design likely was chosen given the known benefits of neuraminidase inhibitors in suspected influenza infections; it would be unethical to withhold such treatments from this study population in the creation of a true placebo group.
After obtaining informed consent, 473 patients from multiple primary care clinics throughout the Prague area of the Czech Republic were diagnosed with influenza virus clinically and via nasal swab, and randomized for treatment for 10 days. Most patients were adults, with a mean age of 37 years, and nine children ages 12 to 17 years were included in the study. The treatment and placebo groups were comparable in regard to age, body weight, height, body mass index, and sex distribution.
Patients who had < 48 hours of symptoms were tested using a diagnostic test from mid-turbinate nasal samples. Samples were placed in a tube containing a transport medium and shipped for influenza detection using reverse transcription-PCR. Forty-one patients tested positive for one type of influenza: type A, non-typeable influenza A, influenza B, or coinfection with A and B. Participants were asked to record symptoms over the 10 days of treatment and blood work was taken at the beginning and end of study. Those meeting the inclusion criteria for clinical diagnosis of influenza had at least one respiratory symptom, one constitutional symptom, fever > 37.8° C, and symptoms present for ≤ 48 hours. Exclusion criteria were outlined in the material and methods section. Once randomized, the codes were placed in a sealed envelope and kept closed unless an emergency arose.
The formulation of 240 mg of EH was made from the leaves, flowers, and roots of E. purpurea, with an additional 276.5 mg of Sambucus fructus succus recentis (elderberry). The echinacea placebo was given the same colorants and flavors as the EH with the same excipients as the echinacea. Both were placed in 200 mL dark brown glass bottles.
Oseltamivir and its placebo were made equally indistinguishable by over-encapsulating the original oseltamivir capsules. Identical placebo capsules were manufactured. All capsules were made by Corden Pharma GmbH and placed in matching bottles with 10 capsules each. All participants took a liquid form of a substance, either echinacea infusion or placebo, from the indistinguishable glass bottles for 10 days. Simultaneously, the entire population took capsules (oseltamivir or placebo) twice daily for 10 days, qualifying it as a double-dummy study. For the first 5 days, those in oseltamivir group took active capsules twice daily followed by 5 days of placebo. Of the participants, only 16.2% in the EH group and 18.2% in the oseltamivir group guessed which therapy they received, achieving successful blinding of study.
In the end, 203 and 217 patients were included in per-protocol group for analysis of efficacy. More than 90% of the patients in both groups took at least 80% of the assigned treatment. (See Table 1.)
Table 1: Treatment Groups in Echinacea Trial |
|
|
EH/Echinacea Placebo |
Oseltamivir/Oseltamivir placebo |
|
n = 237 |
n = 236 |
|
34 lost to protocol |
19 lost to protocol |
|
203 used in analysis of efficacy |
217 used in analysis of efficacy |
The primary endpoint of the study occurred when the majority of patients had mild or no symptoms after day 1, 5, and 10. Recovery was defined as the first day where symptoms of cough, nasal obstruction, sore throat, fatigue, headache, myalgia, and fever were absent or mild in the evening. At each time point, a similar number of participants had recovered in both groups, as seen in Table 2.
Table 2: Percent of Research Subjects Achieving Primary Endpoint in Echinacea vs Oseltamivir Groups |
||
|
Mild or No Symptoms (Primary Endpoint) |
Echinacea Infusion |
Oseltamivir |
|
Day 1 |
1.5% |
4.1% |
|
Day 5 |
50.2% |
48.8% |
|
Day 10 |
90.1% |
84.8% |
Overall, the study showed noninferiority (95% confidence interval, 0.487-0.5265 by generalized Wilcoxon test). Secondary variables included return to daily activities and sleep disruption among other influenza-associated symptoms. Standard noninferiority methods were used in the statistical analysis.
Recovery from upper respiratory infection symptoms was comparable in the two treatment groups: day 1, 1.5% vs 4.1%; day 5, 50.2% vs 48.8%; and day 10, 90.1% vs 84.8% with EH infusion vs oseltamivir, respectively. Medical complications (i.e., pneumonia, bronchitis, sinusitis, etc.) occurred in both groups with statistically similar rates: EH vs oseltamivir (2.46% vs 6.45%, P = 0.076). Adverse effects were also reported by both groups, 11.4% in EH and 13.9% (no P value offered) of those in oseltamivir. Of note, nausea and vomiting occurred five times more frequently in the oseltamivir group than the echinacea group.
COMMENTARY
There has been ample research on echinacea for early treatment of cold viruses and upper respiratory tract infections. Most of the studies are considered methodologically weak for a variety of reasons. One of the main reasons lies in the variety of sources, species, and preparations available. There is also the issue with lack of regulation, standardization, and testing. One review showed weak evidence that some studies show minimal benefit of echinacea in treatment, perhaps even prevention, of colds.3
This study was double-blind and double-dummy, which minimizes bias. However, in this case, the research was paid for by A. Vogel Bioforce AG, the manufacturer of the EH product, causing concern for a possible conflict of interest in the research results presented here.
All treatments involved in this study, echinacea (and the other herbal medicine in this formulation, elderberry) and oseltamivir, have mechanisms of action that can explain their antiviral effects. Echinacea’s mechanism of action immunologically involves production of interferon, TNF, and interleukin-1, in addition to macrophage proliferation and phagocytosis.4 Oseltamivir inhibits the neuraminidase enzyme. This enzyme causes the virus to be released from infected cells and helps move it through the respiratory tract.5 Elderberry has multiple mechanisms of action and it works as an antiviral to inhibit replication of the influenza type A and B as well as herpes simplex virus-1 by using coating to render the virus nonfunctional.8
One criticism of this study is that only 41 out of 473 (8%) subjects tested positive for one of the strains of influenza. The CDC states that positive influenza testing is not necessary to make a decision on using antivirals, leaving treatment and prophylaxis decisions to be based on clinical presentation and high influenza activity in the community. Nonetheless, the study would have been more convincing if a greater percentage had been virologically confirmed.
Clinicians and patients in both Europe and North America use E. purpurea for its immunological properties. According to this study, the use of EH in early interventional treatment of influenza is approximately equal in therapeutic effects to oseltamivir with a significance level α = 0.05 (2-sided). Noninferiority studies show that the new intervention is not inferior to the previous one or that the new treatment is equivalent to standard treatment.7 In addition to being noninferior, the adverse effects were less severe and less common with EH.
The challenge is trying to make concrete clinical recommendations from this study's results. For instance, for some patients influenza is self-limiting and they will not need either intervention based on the natural course of the disease. In addition, the exact formulation studied in this trial is not available in the United States, but a similar product or products could be used if matched to the dosing described in the materials and methods section.
In the greater context, well-researched herbal alternatives to pharmaceuticals are essential for clinicians. In this case, EH might indeed be an option for suspected influenza or upper respiratory tract infections. It goes without saying that clinicians should continue to encourage supportive care for people who have suspected influenza and such advice might include recommending rest and hydration.
Oseltamivir may need to remain the gold standard for the treatment of suspected influenza until stronger, unbiased evidence for the use of echinacea surfaces. In addition, a reliable source of the particular E. purpurea–elderberry combination will need to be available in the United States to begin to use these research results clinically. Until then, clinicians can start to become familiar with some of the comparable third-party certified products available in the United States should particular patient circumstances or requests dictate a botanical option.
REFERENCES
- Pleschka S, et al. Anti-viral properties and mode of action of standardized Echinacea purpurea extract against highly pathogenic avian Influenza virus (H5N1, H7N7) and swine-origin H1N1 (S-OIV). Virology J 2009;6:197.
- Lau L, et al. Viral shedding and clinical illness in naturally acquired influenza virus infections. J Infect Dis 2010;201:1509-1516.
- Karsch-Volk M, et al. Echinacea for preventing and treating the common cold (Review). Cochrane Database Syst Rev 2014;2:CD000530.
- Sigma-Aldrich. Echinacea. 2010; Available at: http://www.sigmaaldrich.com/life-science/nutrition-research/learning-center/plant-profiler/echinacea.html. Accessed Dec. 3, 2015.
- UPMC Center for Health Security. Overview of Oseltamivir Phosphate and Key Points. Available at: http://www.upmc-cbn.org/report_archive/2005/cbnTOPICS_081105.html. Accessed Nov. 14, 2015.
- Centers for Disease Control and Prevention. Guidance for Clinicians on the Use of RT-PCR and Other Molecular Assays for Diagnosis of Influenza Virus Infection. Available at: http://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm. Accessed Nov. 14, 2015.
- MedicineNet.com. Definition of Non-inferiority clinical trial. Available at: http://www.medicinenet.com/script/main/art.asp?articlekey=39072. Accessed Nov. 14, 2015.
- Sigma-Aldrich. Elder (Sambucus Nigra). Available at: http://www.sigmaaldrich.com/life-science/nutrition-research/learning-center/plant-profiler/sambucus-nigra.html. Accessed Nov. 14, 2015.
Echinacea Hotdrink was found to be as effective as oseltamivir as early treatment intervention of clinically diagnosed and lab-confirmed influenza virus infections and had fewer adverse effects.
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