Bruce Barrett, MD, PhD Monica Vohmann, MD Carlo Calabrese, ND, MPH Madison, Wisconsin, and Seattle, Washington Submitted, revised, February 25, 1999. From the Department of Family Medicine, University of Wisconsin-Madison (B.B., M.V.) and Bastyr University, Seattle (C.C.). Requests for reprints should be addressed to Bruce Barrett, MD, PhD, Department of Family Medicine, University of Wisconsin-Madison, 777 S Mills, Madison, WI 53715. E-mail: bbarrett@fammed.wisc.edu.
References
Echinacea extracts are thought to have immunomodulating pharmacologic activity. Most notably, macrophage activation and enhanced phagocytosis have been reported in a number of studies.36-42 Serum levels of properdin, a member of the complement system, increase after Echinacea administration.43 Increased levels of tumor necrosis factor alpha, interleukins 1, 6, and 10, and of several other cytokines have also been variously reported.44,45 Leukocytosis (especially granulocytes and macrophages) has been variably observed in tissue culture and live animal experiments.43 Echinacea extracts given to mice before an injection with Candida and Listeria species have improved survival rates.46,47 Anti-inflammatory effects have also been reported,48-50 as have antibacterial, antiviral, and antiparasitical activities.43,51 Echinacea’s pharmacologic effects appear to result from a combination of active ingredients rather than from a single agent. Various chemical constituents, including alkamides, caffeic acid derivatives (cicchoric acid), flavonoids, glycoproteins, isobutylamides, polyenes, and polysaccharides, have been identified and implicated as active constituents.52,53 These phytochemicals occur at variable levels among the flowers, leaves, stems, and roots of the 3 medicinal species, E purpurea, E angustifolia, and E pallida.
Methods
The goal of our search strategy was to locate, retrieve, and review the original reports of all blinded randomized trials of Echinacea for the prevention or treatment of acute URI. Throughout 1997 and 1998, we used MEDLINE and other bibliographic reference services to find relevant articles. Searches using variants of the key word “echinacea” were repeated on multiple occasions, covering all years available. More than 100 articles, books, and book chapters were reviewed for content and further references. Herbal medicine experts in the United States and Germany were contacted and questioned concerning their knowledge of published and unpublished controlled trials. All relevant original reports of randomized controlled trials (RCTs) were requested and reviewed in detail. Several of the RCTs we reviewed were not cited in MEDLINE. Retrieval of a few of the older German studies required personal contact with physicians and researchers in Germany, as medical libraries in the United States were unable to locate the studies. Seven of the RCTs were reviewed in the original German by a family physician fluent in the language. Review considerations included randomization, blinding, power, validity and clinical relevance of outcome measurements, inclusion and exclusion criteria, indistinguishability of treatment and placebo, and appropriateness of conclusions for the data presented. Because of dissimilarities in products, methods, and outcome measurements, meta-analysis was not a viable option.
Results
Following the search strategy outlined above, reports of 13 blinded randomized studies were obtained and reviewed Table 1. We found no meta-analyses of Echinacea trials. However, Melchart and colleagues54 reviewed 26 prospective trials (18 randomized, 11 double-blind) testing Echinacea for a variety of indications. Some 30 of 34 reported outcomes in treatment groups were claimed to be superior to controls by the original authors. However, Melchart and coworkers concluded that only 22 of the 34 outcomes were reasonably demonstrated. Further, only 8 of the 26 trials earned 50% or better on the researchers’ quality point-scoring system. Of the 12 URI trials, (6 prevention, 6 treatment), 9 were double-blinded,55-63 but only 5 of these earned more than 50 quality points.55-57,60,63 We reviewed all 9 randomized blinded URI trials identified by Melchart and coworkers, as well as 4 trials conducted subsequently.64-66 Of the 13 trials we reviewed, 9 were treatment trials, and 4 were prevention trials. All studies were randomized and double-blinded. Eight of 9 treatment trials reported benefit. The study reporting no treatment benefit remains unpublished.64 Two of the prevention trials reported marginal benefit.58,60 A third was reported in 1992 to show benefit61—subgroup analyses found statistical significance—but was later reported as largely negative.65 The authors of the fourth study (which we judged to be of the highest quality) found no statistically significant benefit, but noted that a 15% reduction in URI incidence attributable to Echinacea was consistent with their findings.66
Treatment Trials
The most recently reported Echinacea treatment trial was published by Brinkeborn and colleagues66 in 1998. Approximately 119 participants were treated for 8 days with 3 doses of 2 tablets each of Echinaforce, a dried ethanolic extract of E purpurea (95% herb, 5% root). Ten symptoms and the “overall clinical picture” were assessed on a severity scale of 0 to 3 with a physician visit at the beginning of an acute URI (day 1 or 2 of symptoms) and again at day 8. An intention-to-treat analysis showed statistically significant benefit, with an indexed score dropping from 9.0 to 4.1 in the treatment group compared with 8.8 to 5.3 in the placebo group (P = .045). A per-protocol analysis of 87 of the participants yielded highly significant results (P = .007). Construction of the index was not described, and inclusion criteria, exclusion criteria, and verification of randomization and blinding were not properly reported.
