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REVIEW
Echinacea Reduces the Risk of Recurrent Respiratory
Tract Infections and Complications: A Meta-Analysis
of Randomized Controlled Trials
Andreas Schapowal •Peter Klein •Sebastian L. Johnston
To view enhanced content go to www.advancesintherapy.com
Received: February 4, 2015 / Published online: March 18, 2015
ÓSpringer Healthcare 2015
ABSTRACT
Introduction: Respiratory tract infections are
common, and these infections occur frequently
in children, susceptible adults, and older
persons. The risk for recurrences and
complications relates not only to the presence
of viruses but also to immune function.
Therefore, modulation of the immune system
and antiviral interventions such as echinacea
might reduce the risk of recurrences and
possibly the development of complications.
Methods: MEDLINE, EMBASE, CAplus, BIOSIS,
CABA, AGRICOLA, TOXCENTER, SCISEARCH,
NAHL, and NAPRALERT were searched for
clinical trials that studied recurrent respiratory
infections and complications on treatment with
echinacea extracts in a generally healthy
population. Two independent reviewers
selected randomized, placebo-controlled
studies of high methodological quality and a
Jadad score of C4. Relative risks (RRs) with 95%
confidence intervals (CIs) were calculated
according to a fixed effect model.
Results: Six clinical studies with a total of 2458
participants were included in the meta-analysis.
Use of echinacea extracts was associated with
reduced risk of recurrent respiratory infections
(RR 0.649, 95% CI 0.545–0.774; P\0.0001).
Ethanolic extracts from echinacea appeared to
provide superior effects over pressed juices, and
increased dosing during acute episodes further
enhanced these effects. Three independent
studies found that in individuals with higher
susceptibility, stress or a state of immunological
weakness, echinacea halved the risk of recurrent
respiratory infections (RR 0.501, 95% CI
0.380–0.661; P\0.0001). Similar preventive
effects were observed with virologically
Electronic supplementary material The online
version of this article (doi:10.1007/s12325-015-0194-4)
contains supplementary material, which is available to
authorized users.
A. Schapowal (&)
Allergy Clinic, Landquart, Switzerland
e-mail: andreas@schapowal.ch
P. Klein
d.s.h. Statistical Services Gmbh, Rohrbach, Germany
S. L. Johnston
Airway Disease Infection Section, National Heart
and Lung Institute, Imperial College London,
London, UK
S. L. Johnston
MRC & Asthma UK Centre in Allergic Mechanisms
of Asthma, Imperial College London, London, UK
Adv Ther (2015) 32:187–200
DOI 10.1007/s12325-015-0194-4
confirmed recurrent infections (RR 0.420, 95%
CI 0.222–0.796; P=0.005). Complications
including pneumonia, otitis media/externa,
and tonsillitis/pharyngitis were also less
frequent with echinacea treatment (RR 0.503,
95% CI 0.384–0.658; P\0.0001).
Conclusion: Evidence indicates that echinacea
potently lowers the risk of recurrent respiratory
infections and complications thereof. Immune
modulatory, antiviral, and anti-inflammatory
effects might contribute to the observed clinical
benefits, which appear strongest in susceptible
individuals.
Keywords: Complications; Echinacea; Meta-
analysis; Recurrences; Respiratory tract
infections
INTRODUCTION
Respiratory tract infections (RTIs) are common
and demonstrate a high propensity to recur.
Adults and children experience up to 5 and 12
infections, respectively, for a total of up to 4–11
recurrent infections within a single cold season
[1].
These infections can be debilitating and
immune depleting, with physical damage of
the airway epithelium that can increase risk of
further infection [2–6]. Infections are associated
with reduced salivary immunoglobulin (Ig) A
and interferon-gamma (IFN-c) secretion, which
otherwise would provide immunity against
recurrences [7,8]. Without intervention,
infections tend to recur and in turn increase
the risk for complications [9].
Therapeutic options for acute infections are
scarce and no therapies have shown benefit in
reducing recurrences to justify continuation of
prophylactic after acute treatment. Echinacea
extracts could present an interesting solution
here. Traditionally, these extracts have been
used to support the immune system, and newer
studies indicate immunomodulatory effects via
interaction with endocannabinoid receptors
(CB2R). In particular, tumor necrosis factor-
alpha (TNF-a) was down-regulated in contrast to
an increased production of IFN-cor
macrophage chemotactic protein-1 (MCP-1)
during treatment with echinacea [10,11].
Direct antiviral and anti-inflammatory effects
further add to the pharmacodynamic profile of
echinacea, suggesting its potential for treating
recurrent infections and complication
prevention [12].
In 2007, Shah and colleagues [13] performed
a meta-analysis of the incidence and duration of
common colds in randomized placebo-
controlled clinical studies investigating
echinacea containing products for treatment
and/or prophylaxis, and reported a significant
benefit for echinacea in reducing common cold
rates [odds ratio (OR) 0.42; P\0.001]. They also
reported a reduced infection duration of
1.4 days (P\0.01). We previously reported
significant benefit with 7–14 days pre-
treatment plus 5 days post-inoculation
treatment with echinacea in prevention of
rhinovirus-induced colds, studying exclusively
experimentally induced infections, and
identified a 55% higher likelihood for clinical
colds with placebo (P\0.05) [14]. Only the
early acute phase was observed and recurrent
infections or complications resulting therefrom
were not studied. Likewise, a very recent update
on Cochrane review found a risk ratio (RR) of
0.83 [95% confidence interval (CI) 0.75–0.92;
P\0.001] when evaluating participants with at
least one cold episode, i.e., the occurrence of
first infections. This analysis also regarded
studies on artificially induced infections as
well as unpublished reports without restriction
for methodological quality [15].
188 Adv Ther (2015) 32:187–200
The aim of this meta-analysis, therefore, was
to evaluate studies reporting the risk of
recurrent RTIs and of complications following
a treatment period with echinacea.
METHODS
Two reviewers (AS, PK) independently
conducted a systematic literature research of
MEDLINE, EMBASE, CAplus, BIOSIS, CABA,
AGRICOLA, TOXCENTER, SCISEARCH, NAHL,
and NAPRALERT and the search terms
echinacea,black Sampson,coneflower, and Roter
Sonnenhut with no restriction for year or
publication status. Articles were further
evaluated for human subjects treated with
echinacea under randomized, placebo-
controlled conditions and information
concerning recurrent RTIs [16–21]. Some
studies explicitly stated the number of
recurrent infections [17,18,21] while others
gave the total number of episodes and the
number of first infections and/or the number of
participants with C1 episode [16,19,21]. In the
latter case, the number of recurrent RTIs was
deduced by subtracting the number of first
episodes from the total number of infections.
When different echinacea preparations were
applied in parallel within a single study, we
pooled the data from the echinacea arms [19].
All studies included generally healthy
volunteers without underlying health
conditions or allergies to plants of the
composite family. The analysis in this article is
based on previously conducted studies and does
not involve any new studies of human or
animal subjects performed by any of the
authors.
In a next step, articles were assessed for
suitability for analysis using quality of reporting
of meta-analyses criteria [22]. The quality of the
included studies was assessed by Jadad score
considering randomization procedure and
blinding efficacy as well as traceability of study
subjects during the trial [23]. Only high-quality
studies with a total Jadad Score of C4 were
selected for analysis to control the risk of bias.
Included studies were evaluated and assessed by
AS, PK, and SJ. In case of disagreement,
consensus was sought and resolved. This study
was conducted according to recommendations
from the PRISMA group for reporting of meta-
analyses [24].
The primary outcome was recurrent
infection risk, e.g., the total of second, third,
fourth, and fifth episodes under echinacea or
placebo continuous treatment for 2–4 months
[17–21] or in one study, during a surveillance
period (4 months) of repetitive acute
treatments, each over 10 days [16]. In
addition, the number of participants
experiencing recurrent infections (with [1
infection per investigation period) was
displayed as a confirmatory variable. This
analysis integrated data on RTIs and
complications that followed a treatment
period with echinacea.
A formal meta-analysis was conducted by
pooling results from eligible studies. The ratios
of recurrent infection and complication
incidences under echinacea or placebo were
compared to the ratios of the underlying
populations and 95% CIs were calculated for
the RRs. Results from the particular studies were
combined using the calculated weighted means
of the log-RRs [25]. Because of the rather small
number of included studies, a fixed-effects
model was used at first to calculate overall
estimators and tests for difference, assuming
that the characteristics of patients contributing
data were the same as those in the total
population. Results were compared to
calculations using a random-effects model
Adv Ther (2015) 32:187–200 189
referring to a more conservative approach,
which allows for a greater influence of
variability in treatment difference estimates.
Quantitative heterogeneity of effect differences
between trials was estimated using a chi square
test as proposed by Hedges and Olkin [26] and
was considered significant if P\0.1.
Complications developing under placebo
and echinacea were deduced by cumulating
the total reports on conjunctivitis, sinusitis,
otitis media/externa, tonsillitis, pharyngitis,
bronchitis, and pneumonia from every clinical
study. RRs were deduced as described above.
The associated intake of antibiotics was
estimated from days under treatment with this
therapeutic class.
Finally, safety was assessed by calculating
total numbers of adverse events reported during
the observation period as well as study subjects
experiencing adverse events. The occurrence of
severe adverse events was separately expressed.
The validated program MetaSub version 1.3.4
(IDV, Gauting/Munich, Germany) was used in
this analysis.
RESULTS
Of 949 hits for search term ‘‘echinacea,’’ 681
non-clinical studies and 167 non-human
studies were excluded based on title inspection
(Fig. 1). Abstracts of the remaining 101 articles
were scanned and 89 excluded because they did
not include RTIs as indications, studied
pharmacodynamic effects, lacked appropriate
placebo control, or had inappropriate
endpoints. Twelve clinical trials qualified for
further investigation. One clinical trial by Berg
and colleagues [27] was rejected because of low
methodological quality (Jadad score =3).
Similarly, clinical trials by Turner et al. [28,
29] and Sperber et al. [30] were excluded
because they investigated experimentally
induced infections in which the post-
treatment period was not surveyed.
Scho
¨neberger’s report [31] and the analysis by
Weber et al. [32] were used supportively for
discussion of pharmacodynamics but were not
included in the primary meta-analysis because
they relied on subgroups of original papers [16,
17]. Finally, data from the six clinical trials were
extracted for meta-analysis [16–21]. Melchart
et al. [19] tested two echinacea preparations
(Echinacea angustifolia and Echinacea purpurea).
In our analysis, we pooled the incidence of
recurrent infections and safety data from the
two arms for comparison to placebo.
Principally, the two reviewers (AS and PK)
agreed on the selections with the exception of
the Berg study, which finally was rejected
because of inappropriate blinding and sample-
size calculations [27]. Our methodology was
very similar to that of the Shah meta-analysis
[12], but here we followed a more restrictive
approach and excluded the studies by Turner
Fig. 1 Description of included and excluded studies. RTI
respiratory tract infection
190 Adv Ther (2015) 32:187–200
et al. [28,29], Sperber et al. [30], Berg et al. [27],
and Hoheisel et al. [33] because of the above-
mentioned reasons but included the newer
trials by Jawad et al. [21] and qualitatively
discussed Heinen-Kammerer et al. [34].
Table 1summarizes the clinical studies that
were of appropriate methodological quality
(Jadad score C4) and for which data regarding
recurrent infections and complications were
available. The studies varied in echinacea
preparations and doses administered. Four
studies employed ethanol/glycerol extractions
from E. purpurea/E. angustifolia (500–4000 mg
extract/day), and two used pressed juices from
E. purpurea (6200–10,000 mg/day). Extracts
present a rather lipophilic spectrum of active
substances (e.g., alkylamides, polyacetylenes)
while pressed juices contain many hydrophilic
arabinogalactans and polysaccharides [35].
Supplementary treatments were not permitted
except in the trials by Cohen et al. [20] and
Schmidt et al. [18] (Table 1). In all clinical
studies, cold symptoms were self-reported
during the observation period by the treated
subject prior to RTI confirmation by a physician
or study staff. Jawad et al. [21] was the largest
clinical study with 757 subjects. In that study,
RTIs were identified based on definition by
Jackson and colleagues [36]. All six studies
defined RTIs based on symptoms, but Jawad
et al. [21] also reported virally confirmed RTIs,
providing a specific case definition, which was
separately analyzed.
As Table 2demonstrates, effect sizes of
individual studies on recurrent RTI varied
(RRs), but all trials reported lower incidence
for recurrent infections in echinacea-treated
versus placebo-treated groups. Only studies by
Cohen et al. [20] and Jawad et al. [21] yielded
significant benefits, with an average RR of 0.498
(95% CI 0.386–0.642; P\0.0001). Pooling all
included clinical studies still yielded an overall
RR of 0.649 (95% CI 0.545–0.774) on the level
of P\0.0001 (Table 2; Fig. 2). The largest two
clinical studies by Jawad et al. [21] and Schmidt
et al. [18], both testing echinacea alcoholic
extracts, showed effects that were similar to the
overall calculated RR, i.e., RR =0.663 and
0.734, respectively. Heterogeneity between
study results was indicated with I
2
=72%
(P=0.0069). Because all single results were
positive, the reason for heterogeneity was
quantitative rather than qualitative. In a more
conservative approach employing the random-
effects model, the results (overall RR of 0.640,
95% CI 0.451–0.910; P=0.0129) were
consistent with the fixed-effects model for
which data are presented (Table 2).
We next examined numbers of participants
experiencing at least one recurrent RTI. For this
analysis, we retrieved data from the four studies
for which such data were available [17,19,21,
32]. Table 2shows that the protective effect for
echinacea (RR 0.769, 95% CI 0.598–0.990;
P=0.041) approximates the estimates from
the overall incidences of RTIs. This analysis
included patient-related data from Melchart
et al. [19], which showed a slightly different
picture for E. angustifolia than for E. purpurea,
but the weight effect of the difference was small
on the overall analysis because of low sample
size.
Despite the robustness of the results, we
decided to perform subgroup analyses to
investigate the sensitivity of our analyses. As
noted in the Methods, the tested echinacea
preparations varied. The test preparations were
therefore grouped into lipophilic extracts
(which included the studies performed by
Jawad et al. [21], Cohen et al. [20], and
Schmidt et al. [18]) and those using the
pressed juices [16,17]. RR for prevention of
recurrent infections with echinacea alcoholic
extracts was 0.542 (95% CI 0.432–0.679;
Adv Ther (2015) 32:187–200 191
Table 1 Description of included studies and assessment of methodological quality according to Jadad scoring
Study Echinacea
species
Extraction
method
Supplement Duration
of treatment/
observation
Daily dose/
amount
of echinacea
Patient number Cold definition Jadad
score
Schmidt et al. [18] EA Ethanolic
extract
Eupatorium/baptisia 2 months 1 912 ml/1440 mg
a
609 Patient reported,
confirmed by
physician
4
Grimm et al. [17]/
Schoeneberger [31]
EP Pressed juice None 2 months 2 94 ml/6200 mg
b
108/66 with weak immune
response
Patient reported,
confirmed by
physician
5
Melchart et al. [19],
three-arm study
EP Ethanolic
extract
None 3 months 2 950 drops/1800 mg
c
99 (90 placebo) Patient reported,
confirmed by
physician
4
EA Ethanolic
extract
None 2 950 drops/1800 mg
c
100 (90 placebo)
Cohen et al. [20]EP?EA Glycerol
extract
Propolis ?vitamin C 3 months 2–4 95–7.5 ml/
500–1500 mg
328 Patient reported,
confirmed by
physician
4
Taylor et al. [16]/
Weber et al. [32]
EP Pressed juice None 10 days/
4 months
7.5–10 ml/
7500–10,000 mg
407/401 Study staff confirmed 5
Jawad et al. [21] EP Ethanolic
extract
None 4 months 2.7–4.5 ml/
2400–4000 mg
717 Patient reported,
confirmed by
Jackson method
5
717 Virally-confirmed
infections
EA Echinacea angustifolia,EP Echinacea purpurea
a
With 120 mg/ml EA extract
b
Product contains 22% ethanol for stabilization
c
At 20 drops/ml and d=0.9 g/ml
192 Adv Ther (2015) 32:187–200
Table 2 Incidence of recurrent infections and number of participants experiencing recurring infections for the individual studies
Study NIncidence of recurrent infections Ratio of incidences Number of subjects with recurrent
infections (>1 infection)
Ratio of patients with
recurrent infections
Echinacea Placebo Echinacea Placebo RR (95% CI) Pvalue Echinacea Placebo RR (95% CI) Pvalue
Schmidt et al. [18] 303 306 32 44 0.734 (0.453–1.190)
P=0.182
N/a N/a –
Grimm et al. [17]/
Schoenberger [31]
54 54 14 18 0.778 (0.352–1.720)
P=0.480
7 8 0.875
(0.296–2.582)
P=0.796
Melchart et al. [19],
three-arm study
99 (EP) 90 – – – 4 6 0.829
(0.297–2.312)
P=0.712
100 (EA) – – – 7
Cohen et al. [20] 160 168 53 158 0.352 (0.241–0.515)
P\0.0001
N/a N/a N/a
Taylor et al. [16]/
Weber et al. [32]
200/197 207/204 137/- 163/- 0.870 (0.645–1.173)
P=0.229
-/110 -/142 0.802 (0.584–1.101)
P=0.082
Jawad et al. [21] 355 362 65 100 0.663 (0.469–0.936)
P=0.009
28 43 0.664 (0.404–1.093)
P=0.090
Overall (fixed effect) 1271 1187 301 483 0.649 (0.545–0.774)
P\0.0001
156 199 0.769 (0.598–0.990)
P=0.041
Heterogeneity Chi
2
14.129
P0.0069
I
2
72%
Heterogeneity Chi
2
0.477
P0.924
I
2
0%
Random effects RR (95% CI) 0.640 (0.451–0.910)
P0.0129
Random effects RR (95% CI) 0.769
(0.598–0.990)
P0.041
CI confidence interval, N/a not available, RR relative risk
Adv Ther (2015) 32:187–200 193
P\0.0001) while for pressed juices, the RR was
0.858 (95% CI 0.649–1.135; missing statistical
significance in the latter with P=0.283).
These analyses employed a patient-reported
and symptomatic assessment of RTIs, but Jawad
et al. [21] provided data on virally confirmed
infections, using an objective measure. In the
echinacea group, 54 nasal secretions from 355
subjects tested positive for respiratory viruses in
comparison to 74 infections from 362 placebo
recipients. Of those, 14 and 34 samples,
respectively represented recurring viral
infections in the echinacea and placebo
groups, which corresponds to an RR of 0.420
(95% CI 0.222–0.796; P=0.005).
The literature discusses several factors
leading to increased susceptibility to RTIs.
Patient subgroups with risk factors including
exposure to stress (perceived stress score, PSS-
10), being an active smoker, poor sleep, with
presumed immune weakness due to low T4/T8
ratio \1.5, and a history of [2 colds/year were
separately analyzed in two clinical trials [21,
31]. The risk for contracting recurrent RTI in
these groups was lower with a RR of 0.501 (95%
CI 0.380–0.661; P\0.0001) than for the total
population. Overall estimates must be
considered with caution, however, because
effects from the different groups are based on
two clinical trials, not the six independent
studies (Fig. 3).
Complications including conjunctivitis,
sinusitis, otitis media/externa, tonsillitis/
pharyngitis, bronchitis, and pneumonia were
reported in three studies [17,20,21]. As
Table 3shows, the overall complication
incidence was effectively reduced by 50%
with echinacea (RR 0.503, 95% CI
0.384–0.658; P\0.0001). The reduction of
pneumonia was most prominent at a 64.9%
decrease (P\0.0001). Similar reductions were
observed for otitis media/externa and
tonsillitis/pharyngitis (P\0.0001 and
P=0.021, respectively). Complication
reduction finally was associated with a
decreased need for antibiotics, which was
noted in two placebo-controlled studies and
in one study comparing echinacea with
Fig. 2 Effect of echinacea on recurrent RTIs as demonstrated by RR. Error bars indicate the 95% confidence intervals. LCL
lower confidence limit, RR relative risk, RTI respiratory tract infection, UCL upper confidence limit
194 Adv Ther (2015) 32:187–200
standard treatment. Cohen et al. [20] reported
a total of 1084 days with antibiotic use in the
placebo group (n=168) compared to 541 days
in the echinacea group (n=160),
corresponding to a 50% reduction [20].
Unpublished results cited in Jawad et al. [21]
were 7 days with antibiotic treatment under
echinacea and 33 days for placebo (personal
communication).
Safety profile data were available either as
total adverse events or as number of subjects
experiencing one or more adverse events and
from a total of 1440 echinacea-treated subjects
and 1326 subjects receiving placebo. Overall,
491 adverse events occurred with echinacea in
comparison to 474 with placebo. Most affected
the gastrointestinal tract and were mild and
transient; only two severe adverse events
(stridor) occurred with echinacea and one
(glandular fever, requiring hospitalization) in
the placebo group (Table 4). No differences in
laboratory biochemical and hematological
parameters were identified in 4 months with
echinacea prevention. Finally, personal
assessments of tolerability were mostly
assessed as ‘‘good’’ or ‘‘very good’’ [21].
DISCUSSION
RTIs belong to the most frequent illnesses
worldwide. With an average of 2.5 episodes
per year, we experience approximately 200
infections in our life, lasting for 4–5 years in
total [37]. Recurrences therefore are a
significant medicinal issue, especially in
susceptible populations [1]. Depending on an
individual’s immunological condition, these
infections can produce serious complications,
morbidity, and even mortality. In view of the
high risk for recurrences and complications, an
effective management of RTI’s might benefit
from going beyond treatment of acute
symptoms of infection in order to prevent
the consequences of infections, which finally
are a main reason for prescription of
antibiotics [37].
Fig. 3 The RR of recurring infections between echinacea
and placebo in subgroups with increased susceptibility to
RTIs. LCL lower confidence limit, PSS perceived stress
score, RR relative risk, RTI respiratory tract infection, UCL
upper confidence limit
Adv Ther (2015) 32:187–200 195
The study aim was to review the existing
literature and estimate in a meta-analysis
echinacea’s preventive effect on recurrent
respiratory infection and complications. Data
on recurrent infections were available from six
clinical trials and a total of 2458 participants,
who received a variety of echinacea extracts for
up to 4 months [16–21]. Despite heterogeneity
of treatment and dosage ranges, in all studies,
the risk for recurrent infections was reduced
with echinacea compared to placebo. The
overall number of recurrent infections
correlated well with the number of
participants experiencing recurrent episodes as
well as with the number of virologically
confirmed recurrent infections.
The heterogeneous treatment modes could
be considered as a potential weakness of this
analysis. On the other hand, the variation in
effects might serve to optimize therapy. The
studies by Cohen et al. [20] and Jawad et al.
[21] provided a statistically significant effect
when analyzed individually and prevented
approximately 50% of recurrences. Both
applied alcoholic extracts prepared from
echinacea herb and roots continuously over 3
and 4 months and doubled the dose of
echinacea during acute treatment, reflecting
an already proposed ‘‘mixed’’ therapeutic
intervention combining preventive and acute
treatment [38]. One study looked specifically at
recurrent infections during repeated acute
therapies [16]. Although the overall benefit
was lower than for the combined acute and
prevention approach, even short-term therapy
with echinacea appeared to support
immunological processes with beneficial effect
on recurrent infections. We hypothesize, that
increased dosing upon treatment of an initial
‘‘trigger’’ infection (in addition to basic
prevention) could reduce inflammatory tissue
damage (airway reactiveness), which otherwise
would lead to further infections and
complications.
Several pharmacological properties of
echinacea could be responsible for the
observed effects. The support of particular
immune functions potentially increases
resistance to viral infections [10,11]. Two
studies tested the preventive benefits in a
subgroup with reported risk factors to
infection like stress, poor sleep, and infection
susceptibility [18,21]. In all subgroups, superior
effects were observed compared to the overall
study population, further indicating possible
immune supportive influence. In addition,
antiviral effects are attributed to echinacea
[12], which have been observed in vitro as well
as in a clinical study by Jawad et al. [21].
Considering the heterogeneity of investigated
extracts, the observed preventive benefits are
likely to be a combination of pharmacodynamic
effects that contribute to overall outcomes to
various extents.
Table 3 Cumulated number of complications including
conjunctivitis, sinusitis, otitis media/externa, tonsillitis,
pharyngitis, bronchitis, and pneumonia
Complication Echinacea
(N5569)
Placebo
(N5584)
Relative risk
(95% confidence
interval)
Pvalue
Conjunctivitis 2 3 0.684 (0.114–4.110)
P=0.676
Sinusitis 4 5 0.821 (0.219–3.073)
P=0.768
Otitis media/
externa
31 74 0.430 (0.278–0.664)
P\0.0001
Tonsillitis/
pharyngitis
37 61 0.623 (0.407–0.952)
P=0.021
Bronchitis 10 17 0.604 (0.274–1.330)
P=0.201
Pneumonia 13 38 0.351 (0.185–0.666)
P\0.0001
Total 97 198 0.503 (0.384–0.658)
P\0.0001
196 Adv Ther (2015) 32:187–200
Only one study [21] provided a detailed
chemical analysis of the tested product, which
makes overall recommendations for
standardization on the basis of marker
substances difficult. On the level of
manufacturing procedureslipophilicextracts
appeared to outperform hydrophilic pressed
juices, but definite conclusions are limited
due to the low number of referenced studies.
It would be highly desirable that future
research focusses on chemically standardized
extracts.
A very recent Cochrane review compared
echinacea with placebo in the prevention of
first infections (participants with at least one
cold episode) [15]. Nine prevention trials were
evaluated, including artificial inoculation
studies [28–30]. Most of these studies did not
report recurrences as well as complications
following the analyzed first infection. Results
were not significant on the single study level
but an exploratory meta-analysis pooling all
trials yielded a reduced risk of experiencing first
cold infections (RR 0.83, 95% CI 0.75–0.92;
P\0.001). Despite heterogeneity of tested
preparations, the result was highly consistent
across included studies. Whereas the effect on
first infections was considered small by the
authors, our data indicate an increased benefit
upon long-term echinacea prevention (2–4
months) on recurrent infections (RR =0.649)
as well as complications (RR =0.503).
This meta-analysis investigated for the first
time the potential reduction in recurrent RTIs
and complications by comparing echinacea
with placebo treatment. The identified effects
might be an underestimation of the overall
benefit because the placebo effect in cold
studies is substantial [39]. One non-controlled,
open study estimated the gross benefit of
echinacea prevention for recurrent infections
[34]. A total of 213 patients with an initial
infection were treated with standard therapy
including analgesics, expectorants, and
conventional cough, rhinitis, and sinusitis
therapies. Another 782 patients received
echinacea in addition to this standard therapy.
Throughout the 3-month surveillance period,
15.1% (88/584) of echinacea recipients
developed recurrent infections in comparison
to 34.9% (53/152) in the reference group
(P=0.001). Overall, the risk for recurrent
Table 4 Number of AEs, patients experiencing AEs and SAEs as per safety collectives of the respective studies
Study NNumber of AEs Patients with AEs Number of SAEs
Echinacea Placebo Echinacea Placebo Echinacea Placebo Echinacea Placebo
Schmidt et al. [18] 322 324 12 10 12 10 0 0
Grimm et al. [17] 55 54 N/a N/a 11 7 0 0
Melchart et al. [19] (EP) 103 96 13 12 10 11 0 0
Melchart et al. [19] (EA) 103 21 18 0
Cohen et al. [20] 215 215 N/a N/a 9 7 0 0
Taylor et al. [16] 263 261 152 146 N/a N/a 2 0
Jawad et al. [21] 379 376 293 306 177 172 0 1
Overall 1440 1326 491 474 237 207 2 1
AEs adverse events, EA Echinacea angustifolia,EP Echinacea purpurea,N/a not available, SAEs serious adverse events
Adv Ther (2015) 32:187–200 197
episodes was 2.3 times higher in the absence of
echinacea. With echinacea supplementation the
frequency of prescription of antibiotics and anti-
infectives was reduced from 14.3% to 4.4% [34].
In parallel with the recurrent RTIs,
complications were significantly reduced from
an overall number of 197 events in the placebo
group to 97 in the echinacea group, a
magnitude similar to the recurrence effects.
Safety is critical, especially in therapies
applied over a long period of time. In this
regard, echinacea demonstrated a very positive
picture. The vast majority of reported events
were mild and transient and not significantly
different between echinacea and placebo
groups. Laboratory values remained stable, and
the overall assessment by patients was (very)
good in general.
CONCLUSIONS
Echinacea presents an effective option for the
longer term management of recurrent RTIs and
related complications. Differences in efficacy
may exist, possibly explained by differences in
preparation methods. People with presumed
lower immune function and a consequently
high susceptibility might benefit most. In
parallel with the reduced risk for infections,
complications like pneumonia, otitis, or
tonsillitis are prevented, as well as the
associated need for antibiotic therapy. Finally,
the good safety profile allows for long-term
prevention with echinacea.
ACKNOWLEDGMENTS
No funding or sponsorship was received for this
study or publication of this article. All named
authors meet the International Committee of
Medical Journal Editors (ICMJE) criteria for
authorship for this manuscript, take
responsibility for the integrity of the work as a
whole, and have given final approval for the
version to be published.
Conflict of interest. Andreas Schapowal and
Peter Klein have no conflict of interest to
declare. Sebastian Johnston received consulting
fees from Bioforce, for review of this work; grants
and personal fees from Centocor; grants and
personal fees from Sanofi Pasteur; grants and
personal fees from GSK; grants and personal fees
from Chiesi; grants and personal fees from
Boehringer Ingelheim; personal fees from
Gru
¨nenthal; grants and personal fees from
Novartis; grants, personal fees and
shareholding from Synairgen, personal fees
from Bioforce, outside the submitted work; In
addition, Dr. Johnston has a patent Blair ED,
Killington RA, Rowlands DJ, Clarke NJ, Johnston
SL. Transgenic animal models of HRV with
human ICAM-1 sequences. UK patent
application No. 02 167 29.4, 18 July 2002 and
International patent application No. PCT/
EP2003/007939, 17 July 2003 licensed, a patent
Wark PA, Johnston SL, Holgate ST, Davies DE.
Anti-virus therapy for respiratory diseases. UK
patent application No. GB 0405634.7, 12 March
2004 licensed, a patent Wark PA, Johnston SL,
Holgate ST, Davies DE. Interferon-Beta for Anti-
Virus Therapy for Respiratory Diseases.
International Patent Application No. PCT/
GB05/50031, 12 March 2004 licensed, a patent
Wark PA, Johnston SL, Holgate ST, Davies DE.
The use of Interferon Lambda for the treatment
and prevention of virally induced exacerbation
in asthma and chronic pulmonary obstructive
disease. UK patent application No. 0518425.4, 9
September 2005 licensed, a patent Wark PA,
Johnston SL, Holgate ST, Davies DE. Anti-Virus
Therapy for Respiratory Diseases. US Patent
Application—11/517,763, Patent No.7569216,
198 Adv Ther (2015) 32:187–200
National Phase of PCT/GB2005/050031, 04
August 2009 licensed, a patent Wark PA,
Johnston SL, Holgate ST, Davies DE. Interferon-
beta for Anti-Virus Therapy for Respiratory
Diseases. European Patent Number 1734987, 5
May 2010 licensed, a patent Wark PA, Johnston
SL, Holgate ST, Davies DE. Anti-Virus Therapy
for Respiratory Diseases (IFNb therapy) Hong
Kong Patent Number 1097181, 31 August 2010
licensed, a patent Wark PA, Johnston SL,
Holgate ST, Davies DE. Anti-Virus Therapy for
Respiratory Diseases (IFNb therapy). Japanese
Patent Number 4807526, 26 August 2011
licensed, a patent Wark PA, Johnston SL,
Holgate ST, Davies DE. Interferon-beta for Anti-
Virus Therapy for Respiratory Diseases. New
Hong Kong—Divisional Patent Application No.
11100187.0, 10 January 2011 licensed, and a
patent Burdin N, Almond J, Lecouturieir, V,
Girerd-Chambaz Y, Guy, B, Bartlett N, Walton R,
McLean G, Glanville N, Johnston SL. Induction
of cross-reactive cellular response against
rhinovirus antigens European Patent Number
13305152, 4 April 2013 pending.
Compliance with ethics guidelines. The
analysis in this article is based on previously
conducted studies and does not involve any
new studies of human or animal subjects
performed by any of the authors.
REFERENCES
1. Johnston SL. Cromolyns: treatment for the
common cold? Clin Exp Allergy. 1996;26:989–94.
2. Levandowski RA, Ou DW, Jackson GG. Acute-phase
decrease of T lymphocyte subsets in rhinovirus
infection. J Infect Dis. 1986;153:743–8.
3. Aherne W, Bird T, Court SDM, Gardner PS,
McQuillin J. Pathological changes in virus
infections of the lower respiratory tract in
children. J Clin Pathol. 1970;23:7–18.
4. Elkhatieb A, Hipskind G, Woerner D, Hayden FG.
Middle ear abnormalities during natural rhinovirus
colds in adults. J Infect Dis. 1993;168:618–21.
5. Chidekel AS, Rosen CL, Bazzy AR. Rhinovirus
infection associated with serious lower respiratory
illness in patients with bronchopulmonary
dysplasia. Pediatr Infect Dis J. 1997;16:43–7.
6. Collins PL, Graham BS. Viral and host factors in
human respiratory syncytial virus pathogenesis.
J Virol. 2008;82:2040–55.
7. Pene F, Merlat A, Vabret A, et al. Coronavirus 229E-
related pneumonia in immunocompromised
patients. Clin Infect Dis. 2003;37:929–32.
8. Message SD, Johnston SL. Host defense function of
the airway epithelium in health and disease:
clinical background. J Leukoc Biol. 2004;75:5–17.
9. Fox JP, Cooney MK, Hall CE. The Seattle virus
watch. V. Epidemiologic observations of rhinovirus
infections, 1965–1969, in families with young
children. Am J Epidemiol. 1975;101:122–43.
10. GertschJ,SchoopR,KuenzleU,SuterA.Echinacea
alkylamides modulate TNF-alpha gene expression via
cannabinoid receptor CB2 and multiple signal
transduction pathways. FEBS Lett. 2004;577(3):563–9.
11. Ritchie MR, Gertsch J, Klein P, Schoop R. Effects of
Echinaforce(R) treatment on ex vivo-stimulated
blood cells. Phytomedicine. 2011;18:826–31.
12. Pleschka S, Stein M, Schoop R, Hudson JB. 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). Virol J. 2009;6:197.
13. Shah SA, Sander S, White CM, Rinaldi M, Coleman
CI. Evaluation of echinacea for the prevention and
treatment of the common cold: a meta-analysis.
Lancet Infect Dis. 2007;7:473–80.
14. Schoop R, Klein P, Suter A, Johnston SL. Echinacea
in the prevention of induced rhinovirus colds: a
meta-analysis. Clin Ther. 2006;28:174–83.
15. Karsch-Vo
¨lk M, Barrett B, Kiefer D, Bauer R,
Ardjomand-Woelkart K, Linde K. Echinacea for
preventing and treating the common cold.
Cochrane Database Syst Rev. 2014;2:CD000530.
16. Taylor JA, Weber W, Standish L, et al. Efficacy and
safety of echinacea in treating upper respiratory
tract infections in children: a randomized
controlled trial. JAMA. 2003;290:2824–30.
17. Grimm W, Muller HH. A randomized controlled
trial of the effect of fluid extract of Echinacea
Adv Ther (2015) 32:187–200 199
purpurea on the incidence and severity of colds and
respiratory infections. Am J Med. 1999;106:138–43.
18. Schmidt U, Albrecht M, Schenk N. Pflanzliches
Immunstimulans senkt Ha
¨ufigkeit grippaler
Infekte. Natur- und Ganzheitsmedizin.
1990;3:277–81.
19. 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.
20. Cohen HA, Varsano I, Kahan E, Sarrell EM, Uziel Y.
Effectiveness of an herbal preparation containing
echinacea, propolis, and vitamin C in preventing
respiratory tract infections in children: a
randomized, double-blind, placebo-controlled,
multicenter study. Arch Pediatr Adolesc Med.
2004;158:217–21.
21. Jawad M, Schoop R, Suter A, Klein P, Eccles R. Safety
and efficacy profile of Echinacea purpurea to prevent
common cold episodes: a randomized, double-
blind, placebo-controlled trial. Evid Based
Complement Alternat Med. 2012;2012:841315.
22. Moher D, Cook DJ, Jadad AR, et al. Assessing the
quality of reports of randomised trials: implications
for the conduct of meta-analyses. Health Technol
Assess. 1999;3:1–98.
23. Jadad AR, Moore RA, Carroll D, et al. Assessing the
quality of reports of randomized clinical trials: is
blinding necessary? Control Clin Trials.
1996;17:1–12.
24. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA
Group. Preferred reporting items for systematic
reviews and meta-analysis: the PRISMA statement.
PLoS Med. 2009;6:e1000097.
25. Whitehead A. Meta-analysis of controlled clinical
trials. Chichester: Wiley Ltd.; 2002. p. 352.
26. Hedges LV, Olkin I. Statistical methods for meta-
analysis. London: Academic Press; 1985. p. 369.
27. Berg A, Northoff H, Konig D, et al. Influence of
echinacin (ED31) treatment on the exercise-
induced immune response in athletes. J Clin Res.
1998;1:367–80.
28. Turner RB, Bauer R, Woelkart K, Hulsey TC,
Gangemi JD. An evaluation of Echinacea
angustifolia in experimental rhinovirus infections.
N Engl J Med. 2005;353:341–8.
29. Turner RB, Riker DK, Gangemi JD. Ineffectiveness of
echinacea for prevention of experimental
rhinovirus colds. Antimicrob Agents Chemother.
2000;44:1708–9.
30. Sperber SJ, Shah LP, Gilbert RD, Ritchey TW, Monto
A. Echinacea purpurea for prevention of
experimental rhinovirus colds. Clin Infect Dis.
2004;38:1367–71.
31. Schoeneberger C. The influence of the immuno
stimulating effects of pressed juice from Echinacea
purpurea on the course and severity of cold
infections. Forum Immunologie. 1992;8:18–22.
32. Weber W, Taylor JA, Stoep AV, Weiss NS, Standish
LJ, Calabrese C. Echinacea purpurea for prevention of
upper respiratory tract infections in children.
J Altern Complement Med. 2005;11:1021–6.
33. Hoheisel O, Sandberg M, Bertram S, Bulitta M,
Schafer M. Echinaguard treatment shortens the
course of the common cold: a double-blind,
placebo-controlled clinical trial. Eur J Clin Res.
1997;9:261–8.
34. Heinen-Kammerer T, Holtmannspo
¨tter C, Schnabel
S, Motzkat K, Kiencke P, Rychlik R.
Nutzenbewertung der Therapie chronisch
rezidivierender Atemwegsinfekte mit Echinacin.
Gesundheitswesen. 2005;67:296–301.
35. Bauer R. In: Bauer R, Wagner H, editors. Echinacea:
Handbuch fu
¨rA
¨rzte, Apotheker und andere
Naturwissenschaftler. Stuttgart: Wissenschaftliche
Verlagsgesellschaft; 1990. p. 9–21.
36. Jackson GG, Dowling HF, Spiesman IG, Boand AV.
Transmission of the common cold to volunteers
under controlled conditions. I. The common cold
as a clinical entity. AMA Arch Intern Med.
1958;101:267–78.
37. Fendrick AM, Monto AS, Nightengale B, Sarnes M.
The economic burden of non-influenza-related viral
respiratory tract infection in the United States. Arch
Intern Med. 2003;163:487–94.
38. European Scientific Cooperative on Phytotherapy
(ESCOP). Echinacea purpurea herba/radix. In:
ESCOP Monographs, 2nd edition, Suppl. New
York, NY, USA: Thieme, 2009. pp. 91–109.
39. Barrett B, Brown R, Rakel D, et al. Placebo effects
and the common cold: a randomized controlled
trial. Ann Fam Med. 2011;9:312–22.
200 Adv Ther (2015) 32:187–200