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Requests for reprints should be addressed to Wolfram Grimm, MD, Department of Medicine, Philipps-University Marburg, Baldingerstraße, 35033 Marburg, Germany
Affiliations
Department of Medicine, Institute of Medical Biometry and Epidemiology, Philipps-University of Marburg, Marburg, Germany
Purpose: Fluid extracts of Echinacea purpurea are widely used for the prevention and treatment of colds and respiratory infections, although the clinical efficacy of this agent has not been proven.
Patients and Methods: A total of 109 patients with a history of more than 3 colds or respiratory infections in the preceding year were randomly assigned to receive 4 mL fluid extract of Echinacea purpurea or 4 mL placebo-juice twice a day in a double-blind manner. (One patient withdrew his consent before taking the first dose of the allocated medication; thus, only 108 patients were included for analysis.) The incidence and severity of colds and respiratory infections were determined during 8 weeks of follow-up, based on patient reported symptoms together with findings on physical exam. The severity of each infection was graded by the investigators. Relative risks (RR) and 95% confidence intervals (CI) were estimated.
Results: During the 8-week treatment period, 35 (65%) of 54 patients in the Echinacea group and 40 (74%) of 54 patients in the placebo group had at least one cold or respiratory infection [RR = 0.88; 95% CI (0.60, 1.22)]. The average number of colds and respiratory infections per patient was 0.78 in the Echinacea group, and 0.93 in the placebo group [difference = 0.15; 95% CI (−0.12, 0.41), P = 0.33]. Median duration of colds and respiratory infections was 4.5 days in the Echinacea group and 6.5 days in the placebo group (95% CI: −1, +3 days; P = 0.45). There were no significant differences between treatment groups in the number of infections in each category of severity. Side effects were observed in 11 patients (20%) of the Echinacea group and in seven patients (13%) of the placebo group (P = 0.44).
Conclusion: Treatment with fluid extract of Echinacea purpurea did not significantly decrease the incidence, duration or severity of colds and respiratory infections compared to placebo.
The genus Echinacea (purple coneflower) is represented by nine species found in the United States and in south central Canada (
). Echinacea species have been described as the most important plants used by the Native Americans for treatment of many diseases, including colds, tonsillitis, toothaches, bowel pain, snake bites, rabies, seizures, wound infections, septic conditions (
). In 1996, German pharmacists listed more than 500 different Echinacea-containing products and phytopharmaceuticals (plant-based medicines), including a variety of homeopathic preparations. In 1993 about 45 million German marks were spent for 2.5 million prescriptions of the three most common forms of Echinacea (
). Fluid extracts of Echinacea purpurea are currently most often used as immunostimulating agents for the treatment and prevention of various infectious disorders, including colds and infections of the upper and lower respiratory system (
Stimulation of the immune response in outpatients with hepatocellular carcinomas by low doses of cyclophosphamide (LDCY), Echinacea purpurea extracts (Echinacin) and thymostimulin.
Nonspecific immunostimulation with low doses of cyclophosphamide, thymostimulin, and Echinacea purpura extracts (Echinacin) in patients with far advanced colorectal cancers preliminary results.
Application of purified polysaccharides from cell cultures of the plant Echinacea purpurea to mice mediates protection against systemic infections with Listeria monocytogenes and Candida albicans.
In vitro effects of Echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or aquired immunodeficiency syndrome patients.
). During the past five decades, more than 200 papers have been published on the chemistry, pharmacology, and clinical use of Echinacea purpurea, and to a lesser extent Echinacea angustifolia and Echinacea pallida(
Application of purified polysaccharides from cell cultures of the plant Echinacea pur-purea to test subjects mediates activation of the phagocyte system.
Effects of non-specific immunostimulants (Echinacin, isoprinosine and thymus factors) on the infection and antigen expression in herpesvirus-6 exposed human lymphoid cells.
Echinacea-containing preparations need to be classified by the plant species used, as well as by the processed part of the plant (root, upper parts, or whole plant), the mode of processing and the mode of application (local vs systemic, oral vs injectable forms). Pharmacologic effects, mainly directed toward the nonspecific cellular immune system, have been found in vitro and in vivo for the expressed juice of the upper parts of Echinacea purpurea and for alcoholic extracts of the roots of Echinacea pallida, angustifolia. and purpurea. Several constituents are believed to be immunologically active, including polysaccharides, glycoproteins, caffeic acid derivates (cichoric acid), and alkamides (
). Intravenous application of polysaccharides from cell cultures of Echinacea purpurea induced acute phase reactions and activation of phagocytes in humans (
Application of purified polysaccharides from cell cultures of the plant Echinacea pur-purea to test subjects mediates activation of the phagocyte system.
Application of purified polysaccharides from cell cultures of the plant Echinacea pur-purea to test subjects mediates activation of the phagocyte system.
). These polysaccharides may also enhance the resistance of immunosuppressed mice against systemic infections with Candida albicans and Listeria monocytogenes(
However, the clinical efficacy of various preparations of Echinacea has not been proven in randomized controlled trials. This placebo-controlled double-blind study was designed to determine the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections.
Methods
Subjects
Patients were recruited at a large general practice in Dettelbach, Germany, between December 1990 and May 1991. Patients were eligible for study entry if they reported more than three respiratory airway infections or common colds in the preceding year, were at least 12 years old, and had given written informed consent for study participation. For patients younger than 18 years old, the parents gave written informed consent.
General exclusion criteria were acute infections of any kind within 1 week of recruitment; pregnancy or nursing; use of immunostimulating drugs within 4 weeks before study entry; known allergy against coneflowers; severe underlying disease or immunosuppression; inability to give informed consent; or unreliability for follow-up as judged by the investigator.
According to the study protocol, we planned to enroll approximately 120 patients to be able to follow at least 100 patients until study completion, based on an estimated drop-out rate of 15%. (The size of the study population was defined arbitrarily based on the estimated feasibility of patient recruitment and patient follow-up in this general practice.)
Therapy assignment and masking
All study patients were assigned to an 8-week treatment period with either placebo juice 4 mL twice a day or fluid extract of Echinacea purpurea (verum) 4 mL twice a day according to a computer-generated randomization list in a double-blind fashion. The randomization list was generated using a random number generator in the Department of Biometry of Madaus AG, Cologne, Germany. Study medication was packed in a box with five brown bottles of verum or placebo. Each bottle contained 100 mL of verum or placebo juice labeled as “100 mL Liquidum EC31J0, for use in a clinical trial.” In addition, the five bottles within each box were labeled 1 to 5. Both verum and placebo juice were provided by Madaus AG. According to the manufacturer, verum and placebo were indistinguishable as to appearance, color, or flavor. The verum was identical to commercially available Echinacin-Liquidum made from fresh expressed juice of whole flowering plants of Echinacea purpurea harvested without its roots; it contains 22% alcohol (
). The placebo juice also consisted of an alcohol/water solution with artificial color, without any Echinacea extracts. The dose of verum and placebo as well as the treatment duration of 8 weeks was chosen according to the recommendation of the draft monograph “Echinaceae purpureae herba” (
In case of severe side effects, the investigators had the opportunity to unblind the medication for a given patient by opening a sealed emergency envelope stored in the practice. None of the patients enrolled in this study were unblinded until the trial was completed, and all emergency envelopes were returned sealed to the company.
Baseline examination and follow-up
Medical history, physical exam, and hematologic examinations were performed at baseline, after 4 weeks and at the final visit 8 weeks after enrollment. After written informed consent was obtained, each study patient received the assigned box with five bottles of study medication. Patients were instructed to start with the first dose of 4 mL of study medication from bottle 1 on the day of randomization. Each patient received a form with the dates for the 4- and 8-week follow-up visits, as well as instructions to see the investigator in the general practice at any time if he or she noticed any of the following signs and symptoms: burning or tearing eyes, ear pain, loss of hearing with pressure in the ear, stuffed nose, runny nose, sore throat, difficulty swallowing, hoarseness, coughing, sputum, headache, joint pain, myalgia, fever, rigors, sweating, and general weakness or tiredness.
Efficacy evaluations
The primary efficacy parameters were the incidence and severity of colds and respiratory infections during the 8-week treatment period according to a blinded investigator’s assessment during the regular or unscheduled patient visits described above. Presence and severity of colds and respiratory infections were determined by one of the two investigators in the general practice based on patient’s symptoms together with the findings on physical exam. When a patient presented with symptoms and clinical findings that were considered by the investigator to result from a cold or a respiratory infection, further follow-up visits were scheduled at 2- to 3-day intervals to determine the duration and severity of the infection. Laboratory tests, including chest radiographs, were not used routinely to confirm the presence of an infection. The severity of each cold or respiratory infection was graded by the investigators as mild (grade 1), moderate (grade 2), or severe (grade 3). A cold or respiratory infection was defined as grade 1 if there was only slight patient discomfort without interruption of work or school attendance. Grade 2 was defined as moderate patient discomfort with interruption of work or school attendance. Grade 3 was considered to be present if the patient had to stay in bed most of the day. In addition, all side effects reported by the patients or observed by the investigators were recorded. To assess the adequacy of blinding, each patient was asked by one of the blinded investigators at the end of follow-up whether he or she would like to continue to take the study medication for prophylaxis of colds and respiratory infections.
Statistical analysis
All values were presented as mean ± SD unless otherwise specified. Baseline demographic categorical variables (gender, predisposing conditions, influenza vaccination, cigarette smoking, alcohol intake, regular sport activities) were compared using Fisher’s exact test. Continuous demographic variables (age, body mass index) were compared using the Mann-Whitney U test. The primary efficacy parameters of the incidence and severity of colds and respiratory infections, as well as the secondary efficacy parameters of duration of colds and respiratory infections, were compared using the Mann-Whitney U test as prespecified in the study protocol. Adjustment for multiple testing was performed with the Hochberg procedure (
). According to the protocol, 95% confidence intervals (CI) for the differences in the total number and duration of colds and respiratory infections were estimated with the nonparametric Mann-Whitney U statistic using the Hodges-Lehmann methods (
). The 95% confidence interval for the mean difference in the number of colds and respiratory infections was calculated using the assumption of a normal distribution. Finally, the incidence of adverse effects during follow-up was compared using Fisher’s exact test. Relative risks (RR) and 95% confidence intervals (CI) were calculated. Statistical significance was set at P < 0.05 (two-sided).
Results
A total of 109 patients with a history of more than three colds or respiratory infections in the preceding year were enrolled in the study (Figure 1). Since one patient withdrew his consent before taking the first dose of the allocated medication, only 108 patients (54 in each group) were included in the analysis. Their baseline characteristics are shown in Table 1.
Figure 1Enrollment, randomization, and follow-up of patients.
Incidence, duration, and severity of respiratory system infections
There were no significant differences in the incidence, duration, or severity of colds and respiratory infection in the two groups (Table 2). During the 8-week treatment period, 35 (65%) of 54 patients in the Echinacea group and in 40 (74%) of 54 patients in the placebo group had at least one cold or respiratory infection [RR = 0.88; 95% CI (0.60, 1.22)]. The mean number of colds and respiratory infections per patient was 0.78 in the Echinacea group and 0.93 in the placebo group [difference = 0.15; 95% CI for the difference (−0.12, 0.41), P = 0.33]. The median duration of colds and respiratory infections was 4.5 days (range, 0 to 50 days) in the Echinacea group and 6.5 days (range 0 to 24 days) in the placebo group [95% CI for the difference (−1, 3), P = 0.45]. There were no significant differences between treatment groups in the number of infections in each category of severity (P = 0.15).
Table 2Incidence and Severity of Respiratory System Infections in 108 Study Patients
Outcome
Echinacea Group (n = 54)
Placebo Group (n = 54)
P Value
Median duration of treatment (days)
57
57
25th percentile
56
57
75th percentile
58
58
Median duration of colds and respiratory infections during the treatment period (days)
4.5
6.5
0.45
25th percentile
0
0
75th percentile
12
10
Total number of colds and respiratory infections in each group
42
50
0.33
Patients without infection
19 (35%)
14 (26%)
0.40
Patients with 1 infection
28 (52%)
32 (59%)
0.56
Patients with 2 infections
7 (13%)
6 (11%)
1.00
Patients with 3 infections
0 (0%)
2 (4%)
0.50
Specific diagnosis of colds and respiratory infections
Adverse events were observed in 11 (20%) patients in the Echinacea group compared with 7 (13%) patients in the placebo group (P = 0.44). The majority of adverse events were mild and transient and did not require discontinuation of the allocated treatment. There were four drop-outs (7%) in the Echinacea group after a median follow-up of 22 days (range 3 to 32 days) and three drop-outs (6%) in the placebo group after a median follow-up of 29 days (range, 8 to 29 days). Reasons for withdrawal in the Echinacea group were nausea (n = 1), constipation (n = 1), “awful taste” of the study medication (n = 1), and patient’s choice without specific reason (n = 1). Reasons for withdrawal before trial completion in the placebo group were side effects (sweating and paresthesia after intake, n = 1), “awful taste” of the study medication (n = 1), and patient’s choice without any specific reason (n = 1). Table 3.
Table 3Adverse Effects during Follow-up
Side Effect
Echinacea Group (n = 54)
Placebo Group (n = 54)
P Value
Any
11 (20%)
7 (13%)
0.44
Central nervous system symptoms (tiredness, somnolence, dizziness, headache, tendency to aggressiveness)
4 (7%)
0 (0%)
Gastrointestinal symptoms (nausea or heartburn after intake, mild epigastric pain, constipation)
At the end of follow-up, 27 (50%) of 54 patients in the Echinacea group stated that they would like to continue to take the allocated medicine compared to 23 (43%) of 54 patients in the placebo group (P = 0.54).
Discussion
This randomized blinded trial investigated the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections during 8 weeks of follow-up in 108 selected patients with a history of more than three colds or respiratory infections in the preceding year. We found that treatment with fluid extract of Echinacea purpurea did not significantly decrease the incidence or severity of colds and respiratory infections compared to placebo juice.
Several other studies have tested the efficacy of various preparations of Echinacea extracts for the treatment of colds and respiratory infections in adults (
). The majority of these studies were retrospective and uncontrolled and frequently tested preparations that contained plant extracts besides Echinacea (
). We are not aware of any other randomized controlled trial that has investigated the prophylactic use of Echinacea purpurea extracts in patients with a history of frequent colds and respiratory infections. Two previously reported placebo-controlled trials, evaluated the therapeutic utility of Echinacea preparations in patients with colds and upper respiratory infections (
) investigated the efficacy of two different doses (450 mg/day and 900 mg/day) of expressed juice of Echinacea purpurea roots compared to placebo juice in 180 patients with colds and upper respiratory infections. Both verum juice and placebo juice in that study contained 50% to 55% alcohol. Primary efficacy parameters included a sum score of symptoms and clinical findings, as assessed by the investigators after 3 to 4 days and again after 8 to 10 days of follow-up. The major finding of that study was that the higher dose of Echinacea purpurea root extract significantly improved the sum score of patient’s symptoms and clinical findings at both times, whereas the lower dose of Echinacea was not superior to placebo juice.
The second placebo-controlled trial, performed by the same investigators, compared the efficacy of an ethanolic extract of Echinacea pallida roots (900 mg/day) and placebo juice on symptoms and infection duration in 160 patients with colds and upper respiratory infections (
). All patients in this study were treated and followed for 8 to 10 days. Colds and upper respiratory infections were categorized by the investigators as viral infections or bacterial infections. The authors observed a shorter mean infection duration of 9.8 days in the Echinacea group compared to 13.0 days in the placebo group for bacterial infections and 9.1 days in the Echinacea group compared to 12.9 days in the placebo group for viral infections (reported P value <0.0001).
The explanation for the difference in outcomes between the two previous trials and our study is unclear. Unfortunately, the previous trials did not report details concerning the process of randomization, the efficacy of patient’s and physician’s blinding, and the drop-out rate (
), we observed similar incidences of mild and reversible side effects in the Echinacea and placebo groups. We did not observe any life-threatening side effects.
One limitation of our study is that the size of the study sample was not sufficiently large to detect small to moderate differences in the incidence and severity of colds and respiratory infections between the Echinacea and the placebo groups. Another limitation is that no systematic investigation was performed before the study to prove that placebo and verum juice were indistinguishable. The observation that similar numbers of patients in both the Echinacea and the placebo group wanted to continue to take the allocated medicine after the end of follow-up suggests that blinding was successful. This observation also supports the hypothesis that a substantial placebo effect was present. Finally, both Echinacea juice and placebo juice contained about 20% alcohol, which may have had an unknown effect on symptoms.
Despite a large body of information concerning the use of Echinacea, the clinical efficacy of various preparations of Echinacea has not been proven in rigorous randomized blinded trials. We found that during 8 weeks of follow-up, treatment with fluid extract of Echinacea purpurea did not decrease the incidence or severity of colds and respiratory infections as compared to placebo. Although side effects were usually mild and transient in our study, life-threatening allergic reactions have been observed in rare cases even after oral administration of Echinacea extracts (
Höffler D, für die Arzneimittelkommission der deutschen Ärzteschaft. Aus der 59. Sitzung des Ausschusses “unerwünschte Arzneimittelnebenwirkungen.” Arzneiverordnung in der Praxis 1996;3:7–8.
). Therefore, the drug commission of the German physicians recommend against the use of Echinacea extracts as immunostimulating agents until their clinical efficacy is demonstrated in appropriate designed trials (
Höffler D, für die Arzneimittelkommission der deutschen Ärzteschaft. Aus der 59. Sitzung des Ausschusses “unerwünschte Arzneimittelnebenwirkungen.” Arzneiverordnung in der Praxis 1996;3:7–8.
Stimulation of the immune response in outpatients with hepatocellular carcinomas by low doses of cyclophosphamide (LDCY), Echinacea purpurea extracts (Echinacin) and thymostimulin.
Nonspecific immunostimulation with low doses of cyclophosphamide, thymostimulin, and Echinacea purpura extracts (Echinacin) in patients with far advanced colorectal cancers.
Application of purified polysaccharides from cell cultures of the plant Echinacea purpurea to mice mediates protection against systemic infections with Listeria monocytogenes and Candida albicans.
In vitro effects of Echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or aquired immunodeficiency syndrome patients.
Application of purified polysaccharides from cell cultures of the plant Echinacea pur-purea to test subjects mediates activation of the phagocyte system.
Effects of non-specific immunostimulants (Echinacin, isoprinosine and thymus factors) on the infection and antigen expression in herpesvirus-6 exposed human lymphoid cells.
Höffler D, für die Arzneimittelkommission der deutschen Ärzteschaft. Aus der 59. Sitzung des Ausschusses “unerwünschte Arzneimittelnebenwirkungen.” Arzneiverordnung in der Praxis 1996;3:7–8.
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