TREATMENT OF THE COMMON COLD WITH UNREFINED ECHINACEA. A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL
 
   

Treatment of the Common Cold with Unrefined Echinacea.
A Randomized, Double-blind, Placebo-controlled Trial

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:
  Frankp@chiro.org
 
   

FROM:  Annals of Internal Medicine 2002 (Dec 17);   137 (12):   939–946 ~ FULL TEXT

Bruce P. Barrett, MD, PhD; Roger L. Brown, PhD; Kristin Locken, BA;
Rob Maberry, BA; James A. Bobula, PhD; and Donn D’Alessio, MD

Department of Family Medicine,
University of Wisconsin-Madison,
777 South Mills,
Madison, WI 53715, USA


Why was this study done?

The common cold is a viral illness that is spread by contagion. While it is rarely fatal, it does account for a large amount of discomfort, suffering, and loss of productivity. This study was designed to help define the role of a herbal remedy containing Echinacea in the treatment of the common cold.

What This Study Found

Supplementing with Echinacea (six dosages on day one, followed by three dosages every day after) in 148 students with recent-onset colds was not effective at reducing duration or severity of illness.


BACKGROUND:   Echinacea preparations are widely used to treat the common cold.

OBJECTIVE:   To assess the efficacy of dried, encapsulated, whole-plant echinacea as early treatment for the common cold.

DESIGN:   Randomized, double-blind, placebo-controlled community-based trial.

SETTING:   University of Wisconsin-Madison, Madison, Wisconsin.

PARTICIPANTS:   148 registered students with common colds of recent onset.

INTERVENTION:   An encapsulated mixture of unrefined Echinacea purpurea herb (25%) and root (25%) and E. angustifolia root (50%) taken in 1-g doses six times on the first day of illness and three times on each subsequent day of illness for a maximum of 10 days.

MEASUREMENTS:   Severity and duration of self-reported symptoms of upper respiratory tract infection.

RESULTS:   No statistically significant differences were detected between the echinacea and placebo groups for any of the measured outcomes. Trajectories of severity over time were nearly identical in the two groups. Mean cold duration was 6.01 days in both groups as a whole, 5.75 days in the placebo group, and 6.27 days in the echinacea group (between-group difference, -0.52 day [95% CI, -1.09 to 0.22 days]). After controlling for severity and duration of symptoms before study entry, sex, date of enrollment, and use of nonprotocol medications, researchers found no statistically significant treatment effect (adjusted hazard ratio, 1.24 [CI, 0.86 to 1.78]). Multivariable regression models assessing severity scores over time failed to detect statistically significant differences between the echinacea and placebo groups.

CONCLUSION:   Compared with placebo, unrefined echinacea provided no detectable benefit or harm in these college students who had the common cold.



From the FULL TEXT Article:

Background

The common cold is one of the world’s most prevalent illnesses. Upper respiratory tract infection, characterized by rhinosinusitis, pharyngitis, or tracheobronchitis, is caused by a wide array of agents. While rhinovirus is most common, coronavirus, respiratory syncytial virus, adenovirus, parainfluenza, and influenza virus all play important roles [1–4]. Effects on health, well-being, and productivity are significant. Although patients with such complications as asthmatic bronchospasm, bacterial sinusitis, otitis media, streptococcal pharyngitis, or pneumonia might benefit from medical intervention, few if any treatments have proven effective for community-acquired colds [5–10].

Preparations made from plants of the genus Echinacea are widely used for the prevention and treatment of colds [11–13]. Various whole-plant preparations and extracts made from the flowers, leaves, stems, and roots of E. purpurea, E. angustifolia, and E. pallida are sold worldwide. Hundreds of scientific studies, mostly German, have detailed echinacea’s botanical, chemical, and pharmacologic characteristics and its clinical effects [14–19].

There is no clear consensus about whether echinacea can benefit human health. Randomized, controlled trials have focused on the prevention or treatment of colds. Five such trials of prevention (four of which have been published) reported that echinacea had little effect in reducing the incidence of natural colds [20–23]; Calabrese C. Personal communication). The findings of the highest-quality study [21] are consistent with a 10% to 15% reduction in relative risk. Results of an induced-cold trial have been reported as negative but are consistent with a benefit of 10% to 15% [24]. The 11 published treatment trials are somewhat more positive [25–35], and systematic reviews have been cautiously optimistic [13, 14, 18, 36, 37]. Reported benefits have ranged from a 40% to 50% reduction in severity [31] and duration [29] of symptoms in studies with major methodologic limitations to more modest reductions of 10% to 30% in the most recent studies [25, 27, 28]. All studies to date have had important limitations, including lack of objective validated outcome measures, lack of description and verification of random allocation and concealment procedures, limitations related to sample size and power, and limited generalizability.



METHODS

In spring 1999, we conducted a randomized, doubleblind, placebo-controlled community-based trial evaluating the efficacy of an encapsulated whole-plant echinacea preparation used as early treatment for the common cold. Participants with early cold symptoms were randomly assigned (with allocation concealed) to echinacea treatment or placebo and were followed with self-reported duration and severity measures for the duration of illness, up to 10 days. All participants provided informed consent before the study, and the University of Wisconsin Medical School human subjects committee approved the protocol.

Shaklee Tecnica (Pleasanton, California) provided the echinacea and placebo preparations. Each active capsule contained a dried mixture of E. angustifolia root (50% [123 mg]), E. purpurea root (25% [62 mg]), and E. purpurea herb (25% [62 mg]). Echinacea capsules also contained thyme (49 mg) and peppermint (31 mg) to disguise taste and flavor, as well as citric acid (3 mg) as a preservative.

The placebo capsules contained 333 mg of alfalfa. Each participant was given a bottle containing 132 capsules and was instructed to take four capsules per treatment dose six times during the first 24 hours of the study, and three times each day thereafter until symptoms resolved, for a maximum of 10 days. Each four-capsule dose totaled 1 g. Thus, the dose schedule was 6 g of echinacea on the first day and 3 g on each subsequent day.

Participants were recruited from 4 February 1999 until 20 May 1999 from the University of Wisconsin—Madison student population. Advertisements throughout the student community (posters, newspaper advertisements, and e-mail messages) asked respondents to call a cellular telephone held by a research assistant at the first sign of cold or flu-like symptoms. Callers were screened by telephone and were invited to meet with a research assistant if eligible, usually within a few hours of the initial call. At the enrollment interview, the research assistant described the study protocol, obtained informed consent, gathered baseline data, and provided instruction on the paper questionnaire and the Web-based survey instrument.

To be included in the study, participants were required to be at least 18 years of age, to answer “Yes” to the question “Do you believe that you are coming down with a cold?”, to report at least 2 of 15 listed cold symptoms (at least 1 of which had to be specific to the respiratory tract), and to be apparently able and willing to adhere to the study protocol. Participants were excluded if they reported having any listed symptom for more than 36 hours; were pregnant; were currently using antibiotics, antihistamines, or decongestants; had specified chronic diseases (autoimmune disease, chronic bronchitis, HIV infection, lupus, rheumatoid arthritis); or had a history of asthma or allergic rhinitis and corresponding symptoms (itchy eyes, sneezing, wheezing) at the time of enrollment.

Randomization was designed so that each participant would have a 50% chance of assignment to placebo or echinacea. The Investigational Drug Service of the University of Wisconsin Hospitals randomized and sequentially labeled 200 bottles containing echinacea or placebo, using a random-number generator (Microsoft Excel, Microsoft Corp., Redmond, Washington) and a balanced blocks-offour design. Each sequentially enrolled participant received the next sequentially numbered bottle of capsules. The placebo and echinacea capsules were indistinguishable to study personnel and to the participants. Allocation to echinacea or to placebo was concealed from participants and from the investigational team until all data had been collected, entered, and cleaned.

Primary outcomes were defined prospectively as severity and duration of self-reported symptoms. Duration was defined as the number of days from study enrollment to the last day before the participant answered “No” to the question, “Do you think that you are still sick today?” Symptom severity was measured daily on nine-point Likert scales. The 15 symptoms assessed were dry cough, productive cough, cough interfering with sleep, sore throat, scratchy throat, hoarseness, runny nose, plugged or stuffy nose, sneezing, headache, fever, sweats, muscle aches, feeling “run down,” and loss of appetite. Each reported symptom was rated on a nine-point Likert severity scale with the following label: 1 (very mild), 3 (mild), 5 (moderate), 7 (severe), and 9 (extreme). Global severity of illness (“How sick do you feel today?”) was assessed by using a similar nine-point scale.

For each day of the trial, participants were asked to fill out both a paper and an electronic version of the questionnaire. The electronic version was adapted to a Web page format (www.fammed.wisc.edu/samplecold). Blinded data were downloaded and inspected periodically throughout the trial. The parallel data collection system enabled us to verify the time and date of response, protecting against errors from retrospective assessments. It also protected against data entry error and missing data and allowed comparison of data reported in electronic and paper formats.

Participants were in contact with the enrolling research assistant by telephone and e-mail throughout the study. They returned for an exit interview upon study completion. Adherence was assessed by pill counts (from bottles returned at the end of the study) and by the daily questionnaire (which asked the participants whether they had taken their pills and how many pills they had taken). Adverse effects were monitored each day and at the exit interview.

Our study was designed to have 150 participants, providing at least 80% power to detect a benefit of 2 days’ duration or an average reduction of two points in severity. These prospective power calculations [38, 39] assumed variance similar to that observed in cold studies [9, 10] and benefits similar to those reported in previous echinacea trials [27–31]. The minimal clinically important benefit for the common cold has not been determined [40, 41]. However, research on other illnesses suggests that an average two-point reduction in severity on a nine-point scale or a 2-day reduction in duration would be clinically significant [42–46].

A symptom-dimension measurement model was constructed by using structural equation modeling techniques [47, 48, 51]. From the pool of 15 symptoms, 14 items fit neatly into four symptom dimensions. Loss of appetite was an infrequent symptom that contributed insignificantly and was therefore dropped. The four dimensions and their associated reliability coefficients, calculated by using the method of Dillon and Goldstein [48], were cough (0.794), throat (0.668), nasal (0.663), and fever and aches (0.753). Reliability coefficients estimate the proportion of variability that is attributable to participants’ symptoms rather than to measurement error [45, 49, 50].

Five covariates were investigated as possible confounders:

1)   duration of symptoms before study entry,

2)   severity of illness at enrollment,

3)   date of enrollment (seasonal or etiologic agent effect),

4)   use of nonprotocol medications, and

5)   sex.


      Statistical Analysis

We considered all available data in our analysis. Methods included simple inspection, frequency analysis, analysis of variance, and multivariable analysis. Confidence intervals were constructed for all outcomes. A simple sum of the 15 symptom scores was selected as an overall severity marker for use in regression models. Changes over time in the summed severity score were explored by using the general linear mixed model for repeated measures [51]. Individual symptom scores and dimensional severities were similarly explored by using mixed modeling approaches [52]. Bootstrap resampling was used to calculate means and confidence intervals for duration [53]. A Cox multivariable proportional hazards regression model [54] for cold duration was used to control for potential confounding. The lack of time trends in the Schoenfeld residuals supports the proportional hazards assumption [55]. The five potential confounders previously noted were included in all multivariable models. Statistical analyses were done by using SAS software (SAS Institute, Inc., Cary, North Carolina).

      Role of the Funding Sources

The U.S. Department of Health and Human Services and the National Institutes of Health provided funding to Dr. Barrett during the study. Shaklee Tecnica provided monetary support for project costs and provided the study materials, but had no role in the design, conduct, or reporting of the data or in the decision to submit the manuscript for publication.



RESULTS

Figure 1

Table

Of 148 enrolled participants, 142 (69 in the echinacea group and 73 in the placebo group) completed our protocol successfully (Figure 1). Characteristics of the study sample are shown in the Table. We did not record the number of eligible persons who called the research center but were unwilling to participate in the study; however, it was clear that most eligible callers were enrolled. The mean time from onset of the first recognized symptom to study enrollment was 27 hours.

A total of 853 person-days of illness were reported. Six participants withdrew, 2 in the placebo group (1 because of feeling too sick and 1 for undisclosed reasons) and 4 in the echinacea group (2 because of being too sick to follow the protocol, 1 because the capsules tasted bad and were diffi- cult to swallow, and 1 for undisclosed reasons). In the echinacea group, 27 participants reported taking nonprotocol medications compared with 25 participants in the placebo group. Of the 142 participants who completed the study, 10 (5 in each group) reported having had at least one symptom for more than 36 hours at enrollment. For these 10 persons, the duration from first symptom to enrollment was 36 to 40 hours (n  2), 45 to 48 hours (n  6), 72 hours (n  1), or 168 hours (n  1). Because these protocol violations were discovered after the trial ended, we chose to include data from these 10 persons in our results. For the six persons lost to follow-up, no postenrollment data were available.

After unblinding in July 1999, samples of the echinacea formulation were sent to three independent laboratories for analytic testing. Dr. Rudolph Bauer (Institut fuer Pharmazeutische Biologie, Heinrich-Heine-Universitaet Duesseldorf, Duesseldorf, Germany) analyzed our formulation and found that it contained 0.26% echinoside; 0.77% cichoric acid; and 0.82% alkamides, including 0.42% dodecatetraenoic acid isobutylamide by weight [15, 56, 57]. Industrial Labs (Denver, Colorado) analyzed our product using a standardized method developed by their methods validation program and reported that it contained 0.20% echinoside, 0.84% cichoric acid, 0.03% chlorogenic acid, and 0.33% cafeolytartaric acid. Dr. Joseph Rininger at Paracelsian, Inc. (Langmuir Laboratories, Ithaca, New York), used cell culture and simulated digestion methods with bioequivalent doses of our study product to demonstrate macrophage activation and elevated levels of tumor necrosis factor. The equivalent of our first-day dose increased the mean level (SD) of tumor necrosis factor from 189 23 ng/L to 3679 154 ng/L, while the equivalent of our subsequent daily dose increased the mean level to 2347 66 ng/L. Together, these three analyses demonstrate that our product contained substantial quantities of phytochemicals as active constituents [14, 15].

Pill counts and daily computerized monitoring demonstrated protocol adherence. An overall adherence rate of 92% was calculated by dividing the number of pills missing from the bottles by the number that should have been missing based on the protocol. On the Web-based questionnaires, nearly all of the participants reported taking their pills nearly every day during their participation in the trial.

Before the study, we conducted several informal tests of blinding. Study personnel, friends, and colleagues could not distinguish between placebo and echinacea capsules. At the exit interview, we asked participants, “Do you think you were taking echinacea or placebo?” Blinding was successful: Thirty-one of 63 persons taking echinacea and 33 of 72 persons taking placebo guessed correctly (P 0.2). Seven participants declined to guess.

Of the 853 person-days of illness, 546 (64%) were captured by both paper and electronic data systems. Two hundred eighty-seven person-days (34%) were captured by paper surveys alone, while 18 (2%) were accounted for solely by the computerized system. Only 2 person-days (0.2%) were not accounted for by either system. Therefore, for 142 participants documenting 853 days of illness, our data capture rate was 99.8%. In constructing the final data set, we used the computerized data whenever available because they were verified by time and date. We used data originally recorded on paper as needed.

Comparing data from the computerized and paper symptom surveys provided some evidence of instrument reliability. Responses to the question about global severity of illness were identical on 512 of the 546 days for which both instruments provided data (94% concordant, 6% discrepant). Of 34 discrepancies, 29 were off by one point on the nine-point Likert scale and 5 were off by two points. Comparing computer and paper responses to the 15 specific-symptom questions also yielded high levels of concordance. Of 8,190 answers, 7,777 (95%) were concordant and 413 (5%) were classified as data discrepancies. Of these, 293 were off by one point on the nine-point scale, 68 were off by two points, 27 were off by three points, 17 were off by four points, 7 were off by five points, and 1 was off by six points.

Figure 2

Figure 3

Figure 4

We did not detect a difference in cold duration between the echinacea and placebo groups. Among the 142 participants completing our protocol, durations ranged from 2 to 10 days, with a median of 6 days and a mean (SD) of 6.01 2.34 days (Figure 2). The mean duration was 5.75 days in the placebo group and 6.27 days in the echinacea group (difference, 0.52 day [95% CI, 1.09 to 0.22 days]). Therefore, 0.22 day is the largest potential echinacea-related benefit in duration that would be statistically compatible with our results. After adjustment for the five potential confounders, Cox multivariable regression found no statistically significant treatment effects on duration (adjusted hazard ratio, 1.24 [CI, 0.86 to 1.78]), with the trend toward longer duration in the echinacea group.

We did not detect any significant differences in symptom severity between the echinacea and placebo groups. Figures 3 and 4 depict daily mean severities and 95% CIs for the symptoms assessed. The group sizes decrease over time, following recovery from illness. A general linear mixed model of the unweighted summed severity score (controlling for the five potential confounders) did not reveal any statistically significant differences between the echinacea and placebo groups. Duration of symptoms before study entry, date of enrollment, and sex were not statistically significant. Although use of nonprotocol medications and severity of illness at enrollment had independent effects on subsequent severity, neither potential confounder could account for the lack of observed treatment effects.

Models of individual symptoms and of symptom dimensions (again controlling for the five confounders) similarly failed to demonstrate treatment effects. Although uncontrolled linear models of the cough dimension indicated slightly more rapid recoveries in the placebo group, these differences were not apparent in more complex models that better represented dimension severity over time. More severe illness in the placebo group on the first day of the trial, before treatment was initiated, appeared to explain the trends favoring placebo in the linear models. There were no statistically significant differences between echinacea and placebo in scaled responses to the global severity question, “How sick do you feel today?” Mean scores of responses to this question are shown in Figure 3.

In our analysis, we included all available data from the 142 persons who completed the study protocol. We collected no useful data for the six participants who were enrolled but were lost to follow-up. Regression results described earlier and mean values portrayed in Figures 2, 3, and 4 do not include data for these six participants and therefore do not represent an intention-to-treat analysis. However, to assess whether data from the six persons who withdrew could have affected our results, we performed an analysis that imputed symptom-recovery trajectories for each missing participant based on the average of 1000 randomly selected trajectories. This analysis yielded results very similar to those described earlier (data not shown).

Specific adverse effects were reported on the daily questionnaires 22 times by 15 participants who completed the study (9 times by 7 participants in the placebo group and 13 times by 8 participants in the echinacea group). In the echinacea group, sleeplessness, heartburn, nausea, stomachache, and upset stomach were each reported by one participant and bad taste was noted by three participants. In the placebo group, stomachache was noted by three participants and nausea, belching, thirst, and abdominal pain with diarrhea were each noted by one participant. Reported adverse effects were therefore not statistically different between the echinacea and placebo groups.



DISCUSSION

We consider the results of this trial to be negative. We did not detect the effect size for which the trial was powered (2 days’ duration and two points in average severity on a nine-point scale) or any potentially significant trends. All differences noted between the echinacea and placebo groups could be explained by natural variability in the underlying symptoms measured. Our results do not support a benefit of echinacea in the treatment of common cold symptoms. However, we do not believe that our trial should be the last word on echinacea. Our results contradict the current published evidence, and our trial had limitations. Previous trials have reported statistically signifi- cant symptomatic benefit with echinacea taken early in the course of an acute upper respiratory tract infection [27–29, 31–35]. These trials, especially those by Brinkeborn [28] and Henneicke-von Zepelin [27] and colleagues, are similar to our trial in quality but report positive results. In addition, published systematic reviews have concluded that there may be benefit to early echinacea treatment [13, 18, 36, 37]. There are several possible reasons for this discrepancy. The positive results of previous trials could be due to bias or chance, and the widespread belief in echinacea’s benefit could be entirely false.

However, our trial had several limitations that should temper confidence in its negative results. First, the specific echinacea preparation used in our trial, a dried, encapsulated mixture of unrefined E. angustifolia root and wholeplant E. purpurea, has not been tested previously and may be ineffective because of bioavailability or phytochemical constituents. Previous trials with positive results have used extracts rather than whole-plant products [25, 27–35], and some have combined echinacea with other plant species [27, 32–35]. Because phytochemical constituents vary among botanical species, growing conditions, plant part, and extraction method, it is possible that one preparation would provide benefit while another would not.

Second, the type of people included in our study, healthy undergraduate college students, may not gain much benefit from echinacea. Previous trials have tended to include older adults and have sometimes sought to include those with histories of frequent colds. There is a prevailing notion that echinacea provides greatest benefit to persons who are immunocompromised, a state often evidenced by frequent colds or other viral illnesses. We made no effort to seek out such persons.

Third, although our modest-size trial would have detected a large benefit, an effect size of 5% or 10% could easily have been missed among the natural variability of symptoms found in persons with community-acquired colds. From a health measurement perspective, it should be emphasized that our study was limited because we used self-reported symptoms as primary outcomes [44, 45, 58, 59]. Subjective self-assessments can introduce several potential biases.

To date, there are no validated instruments for assessing the common cold [10, 40, 41]. We have begun refining and validating our instrument [60], but although its face validity is strong, construct validity has not been demonstrated. It should also be noted that we monitored participants for a maximum of 10 days and therefore do not know the frequency of longer illnesses. Finally, five people in each of our study groups received echinacea after having symptoms for 36 hours, which may have masked a benefit of echinacea given earlier in cold presentation. Future research is necessary to provide more definitive evidence about whether echinacea is an effective treatment for the common cold.


Acknowledgments:

The authors acknowledge the Native American peoples who first brought echinacea to the attention of the world community. They thank the study participants and the research assistants who worked with them: Beth Amspaugh, Kira Conroy Williams, and Peter Jung; and Marijka Hambrecht, who very effectively managed the Webbased data collection tool. They thank Carlo Calabrese, John Frey, Jim Gern, Jack Gwaltney, Mike Fleming, Pat McBride, Mary Beth Plane, and Bill Scheckler for helpful comments. In addition, they thank Pam Manning, Chris Jensen, and Eric Zaltas at Shaklee Tecnica for their excellent work.


Grant Support:

By the U.S. Department of Health and Human Services (Institutional National Research Service Award T-32 HP 10010-09 from the Health Resources and Services Administration [Dr. Barrett]), National Center for Complementary and Alternative Medicine at the National Institutes of Health (K23 AT00051-01 [Dr. Barrett]), and Shaklee Tecnica.


Potential Financial Conflicts of Interest:

None disclosed.



References:

  1. Arruda E, Pitka¨ranta A, Witek TJ Jr, Doyle CA, Hayden FG.
    Frequency and natural history of rhinovirus infections in adults during autumn.
    J Clin Microbiol. 1997;35:2864-8

  2. Gwaltney JM Jr.
    Virology and immunology of the common cold.
    Rhinology. 1985;23:265-71

  3. Monto AS.
    Viral respiratory infections in the community: epidemiology, agents, and interventions.
    Am J Med. 1995;99:24S-27S

  4. Walker TA, Khurana S, Tilden SJ.
    Viral respiratory infections.
    Pediatr Clin North Am. 1994;41:1365-81

  5. Diagnosis and Treatment of Acute Bacterial Rhinosinusitis.
    Agency for Health Care Policy and Research. Report No. 9. 1999.
    http://hstat.nlm.nih.gov/hq/Hquest/db/13/screen/DocTitle/odas/1/s/59480
    on 21 October 2002.

  6. Fahey T, Stocks N, Thomas T.
    Quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults.
    BMJ. 1998;316:906-10

  7. Little PS, Williamson I.
    Are antibiotics appropriate for sore throats? Costs outweigh the benefits.
    BMJ. 1994;309:1010-1

  8. Mainous AG 3rd, Hueston WJ, Clark JR.
    Antibiotics and upper respiratory infection: do some folks think there is a cure for the common cold.
    J Fam Pract. 1996;42:357-61

  9. Smith MB, Feldman W.
    Over-the-counter cold medications. A critical review of clinical trials between 1950 and 1991.
    JAMA. 1993;269:2258-63

  10. Turner RB.
    The treatment of rhinovirus infections: progress and potential.
    Antiviral Res. 2001;49:1-14

  11. Flannery MA.
    From rudbeckia to echinacea: the emergence of the purple cone flower in modern therapeutics.
    Pharm Hist. 1999;41:52-9

  12. Giles JT, Palat CT 3rd, Chien SH, Chang ZG, Kennedy DT.
    Evaluation of echinacea for treatment of the common cold.
    Pharmacotherapy. 2000;20:690-7

  13. Melchart D, Linde K, Fischer P, Kaesmayr J.
    Echinacea for preventing and treating the common cold.
    Cochrane Database Syst Rev. 2000;(2):CD000530

  14. Barrett B.
    Medicinal properties of echinacea: a critical review.
    Phytomedicine. 2003;10 [In press].

  15. Bauer R.
    Chemistry, analysis and immunological investigations of Echinacea phytopharmaceuticals.
    In: Wagner H, ed.
    Immunomodulatory Agents from Plants.
    Boston: Birkhauser Verlag; 1999:41-88.

  16. Bone K.
    Echinacea: what makes it work?
    Alternative Medicine Review. 1997; 2:87-9.

  17. Foster S.
    Echinacea: The Purple Coneflowers.
    Austin, TX: American Botanical Council; 1996.

  18. Melchart D, Linde K.
    Clinical investigations of Echinacea phytopharmaceuticals.
    In: Wagner H, ed. Immunomodulatory Agents from Plants.
    Boston: Birkhauser Verlag; 1999:105-18.

  19. Parnham MJ.
    Benefit and risks of the squeezed sap of the purple coneflower (Echinacea purpurea) for long-term oral immunostimulant therapy.
    In: Wagner H, ed. Immunomodulatory Agents from Plants.
    Boston: Birkhauser Verlag; 1999:119-36.

  20. Grimm W, Mu¨ller HH.
    A randomized controlled trial of the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections.
    Am J Med. 1999;106:138-43

  21. Melchart D, Walther E, Linde K, Brandmaier R, Lersch C.
    Echinacea root extracts for the prevention of upper respiratory tract infections: a double-blind, placebo-controlled randomized trial.
    Arch Fam Med. 1998;7:541-5

  22. Schmidt U, Albrecht M, Schenk N.
    Pflankliches Immunstimulans senkt Ha¨ufigkeit grippaler Infekte.
    Natur und GanzheitsMedizin. 1990;3:277-81.

  23. Forth H, Beuscher N.
    [Effect on the frequency of banal cold infections by Esberitox].
    ZFA (Stuttgart). 1981;57:2272-5

  24. Turner RB, Riker DK, Gangemi JD.
    Ineffectiveness of echinacea for prevention of experimental rhinovirus colds.
    Antimicrob Agents Chemother. 2000; 44:1708-9

  25. Schulten B, Bulitta M, Ballering-Bru¨hl B, Ko¨ster U, Scha¨fer M.
    Efficacy of Echinacea purpurea in patients with a common cold. A placebo-controlled, randomised, double-blind clinical trial.
    Arzneimittelforschung. 2001;51:563-8

  26. Lindenmuth GF, Lindenmuth EB.
    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.
    J Altern Complement Med. 2000;6:327-34

  27. Henneicke-von Zepelin H, Hentschel C, Schnitker J, Kohnen R, Ko¨hler G, Wu¨stenberg P.
    Efficacy and safety of a fixed combination phytomedicine in the treatment of the common cold (acute viral respiratory tract infection): results of a randomised, double blind, placebo controlled, multicentre study.
    Curr Med Res Opin. 1999;15:214-27

  28. Brinkeborn RM, Shah DV, Degenring FH.
    Echinaforce and other Echinacea fresh plant preparations in the treatment of the common cold. A randomized, placebo controlled, double-blind clinical trial.
    Phytomedicine. 1999;6:1-6

  29. Hoheisel O, Sandberg M, Bertram S, Bulitta M, Scha¨fer M.
    Echinagard treatment shortens the course of the common cold: a double-blind, placebocontrolled clinical trial.
    European Journal of Clinical Research. 1997;9:261-8.

  30. Dorn M, Knick E, Lewith G.
    Placebo-controlled double-blind study of Echinacea pallida radix in upper respiratory tract infection.
    Complementary Therapy Medicine. 1997;5:40-2.

  31. Bra¨unig B, Dorn M, Knick E. Echinaceae purpureae radix: zur sta¨rkung der ko¨rpereigenen abwehr bei grippalen infekten.
    Zeitschrift fur Phytotherapie. 1992; 13:7-13.

  32. Reitz HD.
    Immunmodulatoren mit pflanzlichen Wirkstoffen: eine wissenschaftliche Studie am Beispiel Esberitox N.
    Notabene Medici. 1990;20:362-6.

  33. Dorn M.
    Milerung grippaler Effeckte durch ein pflanzliches Immunstimulans.
    Nutur und Ganzheitsmedizin. 1989;2:314-9.

  34. Vorberg G.
    Pflanzliches Immunstimulans verku¨rzt grippalen Infeckt. Doppelblindstudie belegt die Steigerung der unspezifischen Infektabwehr.
    A¨rztliche Forschung. 1989;36:3-8.

  35. Vorberg G, Schneider B. Bei
    Erka¨ltung unspezifische Immunabwehr stimulieran: Doppelblindstudie zeigt: Das bewa¨hrte Phytotherapeutikum Esberitox verku¨rzt die Symptommatik.
    A¨rztliche Praxis. 1984;36:97-8.

  36. Barrett B, Vohmann M, Calabrese C.
    Echinacea for upper respiratory infection.
    J Fam Pract. 1999;48:628-35

  37. Barrett B.
    Echinacea for upper respiratory infection: an assessment of randomized trials.
    Health Notes: Review of Complementary and Integrative Medicine. 2000;7:211-8.

  38. Friedman LM, Furberg CD, DeMets DL.
    Fundamentals of Clinical Trials. 3rd ed. New York:
    Springer-Verlag; 1998.

  39. Stokes ME, Davis CS, Koch GG.
    Categorical Data Analysis Using the SAS System.
    Cary, NC: SAS Institute; 1995.

  40. Gwaltney JM Jr, Buier RM, Rogers JL.
    The influence of signal variation, bias, noise and effect size on statistical significance in treatment studies of the common cold.
    Antiviral Res. 1996;29:287-95

  41. Rao SS, Hendley JO, Hayden FG, Gwaltney JM.
    Symptom expression in natural and experimental rhinovirus colds.
    Am J Rhinol. 1995;9:49-52.

  42. Fischer D, Stewart AL, Bloch DA, Lorig K, Laurent D, Holman H.
    Capturing the patient’s view of change as a clinical outcome measure.
    JAMA. 1999; 282:1157-62

  43. Jaeschke R, Singer J, Guyatt GH.
    Measurement of health status. Ascertaining the minimal clinically important difference.
    Control Clin Trials. 1989;10: 407-15

  44. Juniper EF, Guyatt GH, Jaeschke R.
    How to develop and validate a new health-related quality of life instrument.
    In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed.
    Philadelphia: Lippincott–Raven; 1996:49-56.

  45. McDowell I, Newell C.
    Measuring Health: A Guide to Rating Scales and Questionnaires. 2nd ed.
    New York: Oxford Univ Pr; 1996.

  46. Redelmeier DA, Guyatt GH, Goldstein RS.
    Assessing the minimal important difference in symptoms: a comparison of two techniques.
    J Clin Epidemiol. 1996;49:1215-9

  47. Joreskog KG, Sorbom D.
    LISREL 8 User’s Reference Guide.
    Chicago: Scientific Software International; 1993.

  48. Dillon WR, Goldstein M.
    Multivariate Analysis: Methods and Applications.
    New York: J Wiley; 1984.

  49. Brown RL.
    Using covariance modeling for estimating reliability on scale with ordered polytomous variables.
    Educational and Psychological Measurement. 1989;49:26-39.

  50. Wittenborn JR.
    Reliability, validity, and objectivity of symptom-rating scales.
    J Nerv Ment Dis. 1972;154:79-87

  51. Littell RC, Milliken GA, Wolfinger RD.
    SAS System for Mixed Models.
    Cary, NC: SAS Institute; 1996.

  52. Davis CS.
    Semi-parametric and non-parametric methods for the analysis of repeated measurements with applications to clinical trials.
    Stat Med. 1991;10: 1959-80

  53. Efron B.
    Bootstrap methods: another look at the jackknife.
    Annals of Statistics. 1983;7:1-26.

  54. Cox DR.
    Regression models and life tables.
    Journal of the Royal Statistical Society. 1972;34:187-220.

  55. Allison PD.
    Survival Analysis Using the SAS System: A Practical Guide.
    Cary, NC: SAS Institute; 1995:175-9.

  56. Bauer R.
    Standardization of Echinacea purpurea expressed juice with reference to cichoric acid and alkamides.
    Journal of Herbs, Spices & Medicinal Plants. 1999;6:51-62.

  57. Bauer R.
    Echinacea: biological effects and active principles.
    In: Lawson LD, Bauer R, eds. Phytomedicines of Europe:
    Chemistry and Biological Activity.
    Washington, DC: American Chemical Soc; 1998:140-57.

  58. Guyatt G, Walter S, Norman G. Measuring change over time: assessing the usefulness of evaluative instruments.
    J Chronic Dis. 1987;40:171-8

  59. Streiner DL, Norman GR.
    Health Measurement Scales: A Practical Guide to Their Development and Use.
    2nd ed. New York: Oxford Univ Pr; 1995.

  60. Barrett B, Locken K, Maberry R, Schwamman J, Brown R, Bobula J, et al.
    The Wisconsin Upper Respiratory Symptom Survey (WURSS): a new research instrument for assessing the common cold.
    J Fam Pract. 2002;51:265

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