Echinacea for Preventing and Treating the Common Cold

Transcription

1 Mini Review 633 Echinacea for Preventing and Treating the Common Cold Author Karin Woelkart 1, Klaus Linde 2, Rudolf Bauer 1 Affiliation 1 Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl-Franzens University, Graz, Austria 2 Centre for Complementary Medicine Research, Technical University of Munich, Munich, Germany Key words " Echinacea " Asteraceae " common cold meta-analysis " Abstract Echinacea preparations are widely used for common cold. Many consumers and healthcare professionals are not aware that products available under the term Echinacea may differ in their composition, due to the use of different species, plant parts, extraction methods and addition of other components. In 2005, a Cochrane review has been published to provide objective evidence whether the various Echinacea preparations are more effective than no treatment, more effective than placebo or similarly effective to other treatments in the prevention and the treatment of the common cold. In contrast to other reviews, the specific criteria for pooling of data from different trials have been predefined to assure a meaningful meta-analysis. In the meantime two further meta-analyses have been published. In the present mini-review, these latest meta-analyses are evaluated and discussed. received October 9, 2007 revised November 15, 2007 accepted November 20, 2007 Bibliography DOI /s Planta Med 2008; 74: Georg Thieme Verlag KG Stuttgart New York Published online January 10, 2008 ISSN Correspondence Univ.-Prof. Dr. Rudolf Bauer Institute of Pharmaceutical Sciences Pharmacognosy Karl-Franzens University Graz Universitätsplatz Graz Austria Tel.: Fax: rudolf.bauer@uni-graz.at Introduction Acute upper respiratory infection (URI), especially the common cold, is the second most common diagnosis in physician's offices and the most common discharge diagnosis in emergency departments [1]. According to a Cochrane review, the evidence on the benefits of antibiotics in the treatment of URIs does not warrant their use [2], since most URIs are viral infections. Therefore, common cold is often treated with over-thecounter medicines, often involving phytotherapeutics. Echinacea is one of the most extensively used plants for the prevention and treatment of URIs and currently in the US market the second top-selling herbal product [3]. The products contain one or more species of Echinacea (E. angustifolia, E. purpurea and E. pallida), and may contain extracts of roots, or aerial parts, or both. These preparations contain quite a different profile of constituents with various amounts and hence are not therapeutically comparable [4]. Recently, several meta-analyses have been published which evaluated the available evidence from clinical trials in a rather different manner. The concept and the outcome of these reviews shall be discussed and recommendations shall be developed for future clinical studies with Echinacea. Evaluation of Recent Reviews In one meta-analysis, all performed clinical trials were pooled regardless of the product tested or the trial approach used [5], the second included only trials with experimentally induced infections [6] while the third used a lot of predefined criteria for pooling [7] ( " Table 1). The Cochrane meta-analysis identified the problems inherent in assessing the efficacy of Echinacea preparations using this pooling technique, namely lack of comparability of all available preparations, study designs and outcome measures used. Furthermore, a crucial factor in the investigation of a cold remedy is the timely initiation of treatment. In various clinical Echinacea studies, the start of medication varied from the time of occurrence of first symptoms to several hours afterwards, therefore it is not surprising that the outcomes differ considerably and result in a critical divergence [6], [8], [9]. Thus, the developed experimental induction system allows previously uncontrollable variables, such as time to initiation of treatment, virus type and dose, and immune competence of volunteers, to be standardized [9]. It provides a homogeneous study design and was found to be suitable for performing meta-analysis. If such criteria like, e. g., pooling of only experimentally induced studies, pooling the

2 634 Mini Review Table 1 Summary of the evaluated meta-analyses Meta-analyses Objectives Echinacea species (Products tested) Number of studies Outcome measures Cochrane review [7] Prevention trials with a (total severity and duration measures) (outcome of number of participants who developed the full picture of a cold) (sum of symptoms score as an outcome measure; after 2 to 4 days) E. angustifolia (roots); [30 % alcoholic] E. angustifolia (part not specified) 2 No significant differences 6 A statistically significant effect over placebo was found for the pressed juice of E. purpurea and for the standardised E. purpurea 40 % alcoholic preparation. In the four other trials no differences between Echinacea and placebo were found. 2 In one trial the number of participants who developed the full picture of a cold was significantly lower in the Echinacea group. In the other trial the difference just missed statistical significance. 5 Significant differences were detected for the high dose of E. purpurea root extract and for the standardised E. purpurea preparation. (sum of symptoms score as an outcome measure; after 5 to 10 days) E. purpurea herb (95 %) and root (5 %); E. purpurea root [alcoholic extracts] 7 StandardizedE. purpurea preparation and the high dose of E. purpurea root extract showed statistically significant differences. An extract from the root of E. purpurea,aswell as for the less and more concentrated extracts from 95 % E. purpurea herb and 5 % E. purpurea root. (nasal symptoms after 2 to 4 days as a outcome measure) 5 Significant differences over placebo were found for the standardied E. purpurea preparation and the high dose of E. purpurea root extract. Woelkart K et al. Echinacea for Preventing Planta Med 2008; 74:

3 Mini Review 635 Meta-analyses Objectives Echinacea species (Products tested) Number of studies Outcome measures (nasal symptoms after 5 to 10 days as a outcome measure) 7 Significant differences were again found for the standardised E. purpurea preparation and the high dose of E. purpurea root extract and for the more concentrated extract from 95 % E. purpurea herb and 5 % E. purpurea root. E. purpurea herb (95 %) and root (5 %); E. purpurea root [alcoholic extracts] Shah et al. [5] (calculation regarding duration of colds) Treatment trials with no treatment comparison nother treatment comparison Effect of Echinacea on the incidence and duration of the common cold (prevention and treatment) E. pallida roots 2 AtrialofE. pallida root extract reported a highly significant results whereas a trial on a mixture of 50 % E. angustifolia root, 25 % E. purpurea root and 25 % E. purpurea herb found no difference compared to placebo. 2 One trial showed a trend in favour of the tested Echinacea preparation, the other trial found no difference 1 Controlwassignificantlybetter than Echinacea E. angustifolia (roots) [60%,20%alcoholicandaCO 2 extract] 14 Echinacea decreased the odds of developing the common cold by 58 % (p < 0.001) and the duration of a cold by 1.4 days (p = 0.01) E. purpurea and E. angustifolia (aerial parts); E. purpurea (roots) [tea bags] E. angustifolia (roots); [30 % alcoholic] E. pallida (roots) E. purpurea (aerial parts) and E. angustifolia (roots), propolis, vitamin C Schoop et al. [6] Prevention of induced experimental rhinovirus infection E. angustifolia (roots) [60 %, 20 % alcoholic and a CO 2 extract] 3 Odds of experiencing a clinical cold was 55 % higher with placebo than with Echinacea (OR, 1.55; P < 0.043)

4 636 Mini Review same control strategy (placebo, no treatment, treatment with another intervention), pooling trials with treatment given for the same purpose (prevention or treatment) or pooling trials using the same preparation and in similar dosage, were not predefined, as is the case in the recently published trial by Shah et al. [5], it is evident why a discrepancy of results emerges. Compared to the Cochrane review [7], the findings and conclusions in the Shah study [5] are much more positive. The most likely reason for that is that Shah et al. combined trials regardless of the product tested and included trials in which an Echinacea preparation is combined with another herbal product. Different Echinacea preparations used In previous studies, often the quality of the herb or even its species or dosage was not specified, thus making the findings not precise and not reproducible. In 16 randomised controlled trials summarised in the Cochrane database, only eight (50 %) reported the exact characterisation of the herbal remedy being used [7]. In the three experimental infection studies pooled by Schoop and colleagues only one (33 %) has been included without content details of the tested Echinacea product [6]. In the 14 randomised clinical trials included in the meta-analysis by Shah et al., five (36 %) reported the chemical profiling of the herbal product used [5]. That means the newly published meta-analysis pooled results for all Echinacea preparations although the original publication did not adequately describe the preparations tested. This lack of information needs to be taken into account when research on Echinacea is evaluated. Besides the lack of quality analysis, the great heterogeneity of preparations tested in clinical trials makes general statements and conclusions difficult. Most of the preparations used in those trials were pressed juices (stabilised with alcohol), alcoholic tinctures, or tablets made from dried extracts. That is why future clinical trials should take care of a proper characterisation of the products and should comply with the guidelines for reporting clinical trials of herbal medicine [10]. Different trial approaches and outcome measurements used Three different study approaches: prevention trials, self-treatment and treatment trials have been applied to test Echinacea preparations. The majority of studies investigated whether Echinacea preparations taken after onset of cold symptoms shorten the duration of the common cold or decrease the severity of symptoms, compared with placebo. All prevention trials used similar primary outcomes, like the number of participants experiencing at least one cold episode, the number of participants experiencing more than one cold episode, severity scores, and cold duration in days. Among the self-treatment and treatment trials, methods for outcome measurements and the results actually presented varied substantially. This problem is due to the lack of well-developed and validated outcome measures in common cold research. Therefore, it would be desirable if available recommendations for outcome measures like WURSS (Wisconsin Upper Respiratory Symptom Survey), an evaluative illness-specific quality of life instrument, designed to assess the negative impact of the common cold, [11], [12] were commonly used. Quality of Studies The majority of trials included in all the described meta-analyses were of reasonable to good quality according to the Jadad criteria [13]. The median Jadad score in the recent Cochrane study reviewing 16 controlled clinical trials was 3.5 (range 0 to 5) and the median value for the Internal Validity Scale was 4.25 (range 0 to 6). The Cochrane review concluded that preparations, both alcoholic extracts and pressed juice, that are based primarily on the aerial parts of Echinacea purpurea might have beneficial effects on cold symptoms in adults if treatment is started early [7]. The meta-analysis by Shah et al. included two sets of studies: nine studies investigating whether Echinacea compounds prevent colds and seven studies investigating whether they shorten their duration. One minor, but potentially misleading error is made in the data of the study by Barrett et al. [14]. While the descriptive overview table of the Shah et al. study correctly displays that patients receiving Echinacea had longer cold episodes than patients in the placebo groups, the Forest plot (meta-analytic display) shows a non-significant superiority of the tested Echinacea product [15]. Nevertheless, even after correction, it can be stated that there is a significant improvement of common cold after taking Echinacea. In detail, Echinacea decreased the odds of developing the common cold by 58 % and the duration of a cold by 1.4 days [5]. The meta-analyses of three preventative trials using an experimental virus challenge model showed that all demonstrated at least a trend in favour of Echinacea. This may indicate that most available prevention trials did simply not include sufficient numbers of participants. After pooling of 3 induced rhinovirus prevention studies, the odds of experiencing a clinical cold were 55 % higher with placebo than with Echinacea [6]. Conclusions As with most medications for the treatment of the common cold, the clinical data on Echinacea so far are not conclusive. There is a clear indication that preparations from the aerial parts and roots of Echinacea purpurea may be effective. However, more studies with precisely standardised products (pressed juices and tinctures) are necessary in various clinical settings, also for prevention. So far in preventative trials, only a trend in inhibition of the development and severity of colds could be demonstrated. Preparations from Echinacea angustifolia and E. pallida roots need further controlled clinical trials, in order to provide a better evidence for clinical efficacy. In addition to studies with laboratory-measured biomarkers, also more studies on patient-oriented quality-of-life measures are needed [16]. The Jackson scale assesses eight symptoms, sneezing, nasal obstruction, nasal discharge, sore throat, cough, headache, chilliness and malaise, using a three- or four-point response range, but does not evaluate functional or quality-of-life items [17]. Therefore, the Wisconsin Upper Respiratory Symptom Survey (WURSS) was developed as an evaluative illness-specific quality-of-life outcomes instrument, to measure change over time in domains most important to cold sufferers [11], [12]. That means WURSS scores correlate better with general health-related quality-of-life. A recently published study using data from an induced rhinovirus (RV)-cold Echinacea trial clearly demonstrated a relation between questionnaire and laboratory parameters [12]. Both the Jackson and Woelkart K et al. Echinacea for Preventing Planta Med 2008; 74:

5 Mini Review 637 the WURSS scales correlate significantly with laboratory-assessed measures. The results and information presented here should be a motivation to conduct larger prevention trials in the future. The WURSS-21 score, a short form of WURSS-44, which also includes functional and quality-of life domains, should be used as outcome measurement instrument, in regard to the estimated 74 participants needed to detect the minimal important difference in a two-armed clinical trial compared with 92 for the WURSS- 44 (32 items assessing symptoms, 10 functional items and 2 global assessment items) and 124 participants for the Jackson score. References 1 Woodwell DA, Cherry DK. National ambulatory medical care survey: 2002 summary. Adv Data 2004; 346: Arroll B, Kenealy T. Antibiotics for the common cold and acute purulent rhinitis (Cochrane Review). The Cochrane Library, (1). Chichester: Wiley; Blumenthal M. Herb sales down 6 percent in mainstream market. Herbal Gram 2005; 66: 63 4 Bauer R. Chemistry, analysis and immunological investigations of Echinacea phytopharmaceuticals In: Wagner H, editor. Immunomodulatory agents from plants. Basel, Boston, Berlin: Birkhäuser Verlag; 1999: Shah SA, Sander S, White CM, Rinaldi M, Coleman CI. Evaluation of Echinacea for the prevention and treatment of the common cold: a metaanalysis. Lancet Infect Dis 2007; 7: Schoop R, Klein P, Suter A, Johnston SL. Echinacea in the prevention of induced rhinovirus colds: a meta-analysis. Clin Ther 2006; 28: Linde K, Barrett B, Wölkart K, Bauer R, Melchart D. Echinacea for preventing and treating the common cold. The Cochrane Database of Systematic Reviews;;;Issue 1: Melchart D, Linde K, Worku F, Bauer R, Wagner H. Immunmodulation with Echinacea A systematic review of controlled clinical trials. Phytomedicine 1994; 1: Gwaltney JM Jr, Hendley JO, Patrie JT. Symptom severity patterns in experimental common colds and their usefulness in timing onset of illness in natural colds. Clin Infect Dis 2003; 36: Gagnier JJ, Boon H, Rochon P, Moher D, Barnes J, Bombardier C. CON- SORT Group. Recommendations for reporting randomized controlled trials of herbal interventions: Explanation and elaboration. J Clin Epidemiol 2006; 59: 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: Barrett B, Brown R, Voland R, Maberry R, Turner R. Relations among questionnaire and laboratory measures of rhinovirus infection. Eur Respir J 2006; 28: Jadad AR, Moore RA, Carrol D, Jenkinson C, Reynolds DJM, Gavaghan DJ et al. Assessing the quality of reports of randomized trials: is blinding necessary? Control Clin Trials 1996; 17: Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, D'Alessio D. Treatment of the common cold with unrefined Echinacea. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002; 137: Linde K. Do Echinacea products prevent and shorten the common cold? Focus Complement Altern Ther,;in press 16 Gillespie EL, Coleman CI. The effect of Echinacea on upper respiratory infection symptom severity and quality of life. Conn Med 2006; 70: Jackson GG, Dowling HF, Muldoon RL. Present concepts of the common cold. Am J Public Health 1962; 52: 940 5