Full text of DOI:10.1016/S1081-1206(10)63591-0

Adverse reactions associated with echinacea:
the Australian experience
Raymond J. Mullins, PhD, FRACP, FRCPA* and Robert Heddle, PhD, FRACP, FRCPA†
Background: Fifty percent of Australians use complementary and alternative med-
icines (other than vitamins) in any 12-month period, of which echinacea-containing
products are increasingly popular. Recent reports have highlighted the risk of allergic
reactions to complementary medicines in atopic patients.
Objective: To determine the characteristics of adverse reactions linked to use of
the popular herbal remedy echinacea.
reactions to herbal remedies such as
royal jelly in asthmatic patients,8–10
and more recently, echinacea.11,12
Echinacea (or coneflower) is a flow-
ering member of the Asteraceae (Com-
positae) family whose other members
include Ambrosia (ragweed) species,
Artemisia (mugwort, sagebrush) spe-
cies, as well as chrysanthemums, dahl-
ias, sunflowers, marigolds, and dai-
sies.13 The plant is native to the United
States. Large-scale cultivation com-
bined with increasing popularity and
community awareness in Australia
and the United States has led to
widespread use.14
Methods: Five privately referred patients were evaluated by the authors in their
office practice via skin prick testing (SPT) on the volar aspect of the forearm and
radioallergosorbent test after adverse reactions to echinacea. As there was little
published information on adverse reactions to echinacea, reports to the Australian
Adverse Drug Reactions Advisory Committee were reviewed. Those suggestive of
possible allergic reactions were evaluated in greater detail by anonymously survey-
ing the healthcare professionals who had reported the cases and from one unreported
case. Serum was collected for further analysis where possible.
Results: Five cases of adverse reactions to echinacea were personally evaluated
by the authors. Two patients suffered anaphylaxis and a third had an acute asthma
attack 10 minutes after their first ever dose of echinacea. The fourth patient suffered
recurrent episodes of mild asthma each time echinacea was ingested, and the fifth
developed a maculopapular rash within 2 days of ingestion which recurred when
rechallenged. Three of the patients had positive SPT results. Three reported repeated
spontaneous “challenges” and symptoms after further ingestion of echinacea. Fifty-
one Australian adverse drug reports implicating echinacea were also reviewed.
There were 26 cases suggestive of possible immunoglobulin E-mediated hypersen-
sitivity (4 anaphylaxis, 12 acute asthma, 10 urticaria/angioedema). Of these 26
patients, age ranged from 2 to 58 years, 78% were female and Ͼ50% were known
to be atopic. Four were hospitalized, 4 reacted after their first known exposure, and
1 patient suffered multiple progressive systemic reactions. Twenty percent of 100
atopic subjects who had never taken echinacea also had positive SPT results to this
substance when tested by one of the authors in his office practice.
Extracts of Echinacea angustifolia
(and its close relative Echinacea pur-
purea) were originally used by Native
Americans as antiseptics and for the
treatment of wounds and infection.15
This is reflected it its contemporary
use to enhance resistance against infec-
tion, although some practitioners have
advised its use for treatment of other
conditions including allergy.16 Extracts
of the flower, root, or whole plant are
available as capsules, tablets, liquid, or
in a dried form for infusion.
Plant-derived polysaccharides are
thought to be responsible for many of
echinacea’s in vitro immunomodula-
tory properties. Minor constituents
such as inulin, alkaloids, and caffeic
acid esters seem to be bioactive as
well. Echinacea is not in itself viricidal
or bactericidal. Rather, activation of
natural killer cells and macrophages,
inhibition of hyaluronidase, increased
production of cytokines (interleukin 1,
tumor necrosis factor), and oxygen
free radicals, and anti-inflammatory
effects are thought to be responsible
for its purported properties.17–21 De-
spite evidence of in vitro immuno-
modulatory activity, the results of hu-
man studies are either conflicting or
Conclusion: Some atopic subjects have positive SPT results to echinacea in the
absence of known exposure. Atopic subjects are also overrepresented in those
experiencing reactions to echinacea. The possibility that cross-reactivity between
echinacea and other environmental allergens may trigger allergic reactions in
“echinacea-na¨ıve” subjects is supported by the Australian data. Given its wide-
spread (and largely unsupervised) community use, even rare adverse events become
inevitable. Atopic patients should be cautioned appropriately.
Ann Allergy Asthma Immunol 2002;88:42–51.
INTRODUCTION
Despite the common perception that
“natural therapy” is safe, toxic and hy-
persensitivity reactions to comple-
mentary and alternative medicine
(CAM) have been described.1– 4
Atopic individuals seem to be at par-
ticular risk of allergic reactions.5,6
This is of particular concern, given
that atopic patients are increasingly
using these medicines for treatment
of their allergies.7 Recent reports
have highlighted the risk of allergic
* John James Medical Centre, Deakin, Australia.
† Department of Immunology, Allergy and Ar-
thritis, Flinders Medical Centre, Bedford Park,
Adelaide, Australia.
Received for publication August 14, 2001.
Accepted for publication in revised form Sep-
tember 10, 2001.
42
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

RESULTS
open to interpretation, largely related
to trial size and design.22–27
rhinitis, atopic dermatitis, drug allergy,
anaphylaxis, and angioedema.
Case Reports
The Australian Adverse Drug Reac-
tions Advisory Committee (ADRAC)
maintains a database of voluntary re-
ports of suspected adverse drug reac-
tions which is a public document.
Anonymous reports involving CAM
were obtained from ADRAC and re-
viewed. Reactions involving echinacea
were examined in greater detail. Cases
were considered to be possibly consis-
tent with IgE-mediated hypersensitiv-
ity if one or more reactions (urticaria,
angioedema, bronchospasm, anaphy-
laxis) was reported.
Case 1. A 37-year-old female was re-
ferred for investigation of anaphylaxis
METHODS
after ingesting echinacea.11
Within 5
Adverse reactions to echinacea were
observed by the authors in five patients
referred for evaluation by their general
practitioner. Skin prick testing (SPT)
was performed in the authors’ practice
using commercially available glycerin-
ated allergen extracts and histamine
acid phosphate 10 mg/mL as the posi-
tive control, as previously described11
(Bayer Australia, Sydney, Australia)
and using a commercially available
glycerinated extract of echinacea pur-
chased by RJM. This extract had been
shown to contain echinacea (Dr.
Patrick Purcell, Therapeutic Goods
Administration [TGA], Australian
Commonwealth Department of Health,
personal communication, 1998). SPT
was performed on the volar aspect of
the forearm using metal lancets (Miles
Allergy Products/Hollister Stier, Spo-
kane WA), puncturing the skin at an
angle of 45° to 60° to the skin surface.
Allergen extracts were spaced no
closer than 2 cm apart. Wheal size was
recorded after 15 to 20 minutes.28 SPT
results were defined as positive with a
mean wheal diameter of 2 mm or more
than the negative control.
Blood was drawn from some pa-
tients for radioallergosorbent testing
(RAST) for echinacea-reactive immu-
noglobulin (Ig)E, which was per-
formed as previously described29 by
the Kolling Institute for Medical Re-
search, Sydney. Results were com-
pared with 3 negative control assayed
in parallel. Radio-iodine uptake greater
than 3 times the mean of negative con-
trol sera (NCS) was considered to rep-
resent a positive result. Results were
reported by the clinical laboratory as
follows: 1 ϩ (3 to 5 ϫ NCS value), 2
ϩ (5.1 to 10 ϫ NCS), 3 ϩ (10.1 to
20 ϫ NCS), or 4 ϩ (Ͼ20 ϫ NCS). An
additional 24 stored sera were assayed
by the same clinical laboratory, de-
rived from samples sent for clinical
testing in patients with asthma, allergic
minutes of ingestion of echinacea, she
experienced burning throat, chest
tightness, urticaria, and diarrhea, and
required admission to hospital for
treatment. She had ingested echinacea
from the same bottle 2 weeks earlier
uneventfully. She was known to be
atopic and suffered from allergic rhi-
nitis, oral allergy syndrome (OAS)
with banana ingestion, and occasional
wheeze. SPT was performed using
commercially available glycerinated
allergen extracts as previously de-
scribed 11(Bayer Australia). SPT with
the aqueous echinacea solution in-
gested gave a 3-mm flare alone,
whereas a glycerinated extract from
the same manufacturer (which she had
also ingested in the past) resulted in a
3-mm wheal and 5-mm surrounding
flare. Similar results were obtained
with intradermal testing of the same
extracts diluted in sterile saline, with
demonstrable wheals at concentrations
of 1/100 and 1/10,000, respectively.
Details of further investigation are
shown in Table 1.
Case 2. A 19-year-old female suf-
fered an acute asthma attack and se-
verely itchy and watery eyes and runny
nose within 10 minutes of her first ever
exposure to echinacea-containing tea
at 8 AM. Symptoms resolved gradually
over several hours. She had intercur-
rent problems of seasonal allergic rhi-
nitis, nasal polyposis, and sinusitis
without asthma. No other food or med-
ication had been ingested for Ͼ12
hours. SPT with the same brand of
aqueous echinacea solution from case
1 (which had been shown to contain
echinacea) a week later resulted in a
3-mm wheal (Table 1).
Additional data were obtained from
the reporting doctors and pharmacists
via anonymous surveys distributed by
the TGA of the Australian Common-
wealth Department of Health. Each re-
porter was questioned about demo-
graphic characteristics, intercurrent
atopic disease, the time between inges-
tion and the reaction, whether the pa-
tient had taken it before, the use of
other medication, their opinion as to
causality, general comments about the
reaction, and missing data from the
report forms. Serum was collected
from patients for further analysis
where possible. Other international
government drug agencies were also
contacted for information regarding
adverse reports involving echinacea.
A retrospective private office-based
chart review was undertaken by RJM
of 600 consecutively referred (predom-
inantly atopic) patients seen in consul-
tation in the years 1995 to 1997 (200
files per year) to determine the fre-
quency of use of herbal products, in-
cluding echinacea. A more detailed
prospective survey of CAM use by 200
consecutively referred atopic patients
was undertaken by one of the authors
in March and April, 2000. Data were
obtained from a routine preconsulta-
tion questionnaire completed by each
patient, which included questions on
use of prescribed medication, CAM,
and echinacea. SPT of 100 of these
subjects with glycerinated echinacea
extract was also performed by RJM in
his office practice.
Case 3. Within 20 minutes of inges-
tion of an echinacea-containing tablet,
a 31-year-old health professional suf-
fered generalized urticaria, facial and
upper airway angioedema, difficulty
swallowing, bronchospasm, dizziness,
and disorientation. Symptoms resolved
VOLUME 88, JANUARY, 2002
43

Table 1. Results of Investigation of Adverse Reactions Associated with Echinacea
Investigations
Case 1
Case 2
Case 3
Case 4
Case 5
Not
available
–
Echinacea RAST (%
iodine uptake)
Uptake/control uptake
Echinacea RAST score*
SPT Echinacea
SPT Ambrosia sp
SPT Lolium perenne
SPT Phalaris canariensis
SPT Plantago sp
SPT C. dactylon
SPT D. pteronyssinus
SPT D. farinae
SPT F. domesticus
SPT C. familiaris
4.4%
1.6%
1.4%
0.7%
14.7
2ϩ
5.3
1ϩ
4.7
1ϩ
2.4
Negative
2 mm
0 mm
8 mm
6 mm
8 mm
2 mm
0 mm
0 mm
2 mm
0 mm
–
3 mm
2 mm
10 mm
8 mm
8 mm
12 mm
10 mm
8 mm
5 mm
0 mm
2 mm
0 mm
7 mm
10 mm
0 mm
6 mm
1 mm
3 mm
4 mm
0 mm
0 mm
2 mm
8 mm
7 mm
1 mm
4 mm
8 mm
5 mm
9 mm
2 mm
0 mm
0 mm
0 mm
–
0 mm
0 mm
0 mm
0 mm
0 mm
0 mm
* Skin prick test results are tabulated as weal size in mm. RAST results were scored by the reporting laboratory, with positive results defined as
% radio-iodine uptake at least 2.5 above the mean of 3 negative control sera assayed in parallel. The ratio of test/control sera is also described.
gradually over several hours. During 3
of the preceding 4 days, she had taken
the same echinacea tablets and had ex-
perienced headache and mild facial an-
gioedema within 20 minutes of each
administration but no reaction on the
echinacea-free day. The patient was
known to be allergic to latex and had a
long history of perennial allergic rhi-
nitis with seasonal exacerbation. She
complained that sulfite-containing dried
fruit would trigger urticaria, flushing,
mild wheeze, and nasal obstruction. On
one occasion she had experienced an ep-
isode of exercise-related anaphylaxis.
Further investigation implicated previ-
ous ingestion of rye or mushroom (4 to 5
mm SPT to both) or nonsteroidal anti-
inflammatory agents. No further epi-
sodes have occurred with avoidance of
these substances. The patient, a trained
observer, could not recall exposure to
these agents or latex on the days in ques-
tion and considered the relationship of
reactivity to echinacea ingestion to be
consistent and, in high probability, caus-
ative. SPT with the same aqueous echi-
nacea solution from case 1, 1 year later,
was negative (Table 1).
tion of these tablets. He had intercur-
rent problems of allergic rhinitis.
There was no known food or drug al-
lergy, and he had taken no other med-
ication during this period. Symptoms
resolved within a few days of stopping
echinacea. SPT with the same aqueous
echinacea solution from case 1, 6
months later, was negative (Table 1).
Case 5. A 48-year-old female expe-
rienced a maculopapular rash over
thighs and abdomen within 2 days of
ingestion of echinacea tablets which
had been taken to prevent infection.
The rash resolved within 1 week with
use of topical steroids. A week later,
she recommenced echinacea from the
same bottle and redeveloped a similar
but more severe and generalized pru-
ritic rash within 48 hours. It settled
gradually over a period of 6 weeks and
required a course of oral steroids to
assist resolution. She had intercurrent
problems of nonallergic (vasomotor)
rhinitis and took no regular medica-
tion. SPT with the same aqueous echi-
nacea solution from case 1, 5 months
later, was negative (Table 1).
same period.11 When a more detailed
prospective survey was undertaken in
March and April of 2000, 44% of pa-
tients were currently using a regular
vitamin/mineral supplement and 24%
were using CAM (excluding vitamins/
minerals) other than echinacea. Of
these, 73% had heard of echinacea and
had some idea of its purported proper-
ties, 38% had used echinacea some
time in their lives, and 15% had used
echinacea in the previous 3 months.
Australian Reports of Adverse
Reactions to CAM
When interpreting Australian and in-
ternational adverse drug reports, it is
important to bear in mind that 1) the
data represent voluntary reports of ad-
verse events; 2) the reports may be
incomplete; 3) the number of reports
may not be indicative of the preva-
lence of adverse reactions; 4) associ-
ation of a medication with an adverse
outcome is not in itself proof that the
medication in question caused the re-
action; and 5) the reported event may
have another explanation.
Between January 1979 and March
10, 2000, 483 reports involving CAM
were reported to ADRAC. In two-
thirds of cases, the CAM was the sole
medication taken and was held respon-
sible for the reaction. The majority of
reports of hypersensitivity reactions
were linked to ingestion of royal jelly
or echinacea. Forty-one of the 51 re-
Use of CAM by Australian Atopic
Patients
Case 4. A 56-year-old male reported
the new onset of documented asthma
coincident with the ingestion of echi-
nacea tablets for treatment of an inter-
current upper respiratory tract infec-
tion. On three separate occasions, he
developed severe difficulty breathing
and coughing within 2 hours of inges-
A retrospective chart review from pa-
tients seen by RJM in consultation
1995 to 97 demonstrated that CAM use
(including vitamin) had risen from 7.5
to 25%, and that echinacea use had
risen from zero to 3 to 5% over the
44
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

ports associated with echinacea impli-
cated this substance as the sole sus-
pected trigger. Twenty-six of these
were considered by the authors to be
consistent with IgE-mediated hyper-
sensitivity, in that one or more reac-
tions of urticaria, angioedema, exacer-
bation of asthma, or anaphylaxis was
described (Table 2).
mediate hypersensitivity, non-urticar-
ial rash (12 cases) and hepatitis (7
cases) were the most common com-
plaints. Other symptoms included fa-
tigue, arthralgia or myalgia (4 in-
stances each), headache or increased
blood pressure (2 instances each), and
1 case each of dizziness, atrial fibrilla-
tion, vasculitis, acute renal failure,
nausea, or epistaxis.
Twenty-six cases were identified as
suggestive of IgE-mediated reactions.
Most were young female adults (medi-
an age 32 years, 80% female), of
which the youngest (2 years old) suf-
fered from facial and periorbital
edema. Four patients required hospital-
ization for treatment of their allergic
reaction. One subject (case 3 described
previously) had three mild systemic re-
actions before anaphylaxis occurred.
At least six different brands involv-
ing at least three different formulations
(tea, tablets, and liquid) were impli-
cated. It was only possible to verify
the presence of echinacea in one of
these products with analysis using
high-pressure liquid chromatography
in the first11 of the index cases
(Dr. Patrick Purcell, TGA, personal
communication).
Australian Reports of Adverse
Reactions to Echinacea
Fifty-one adverse reaction reports in-
volving echinacea were submitted to
ADRAC from 7 of the 8 Australian
states and territories. Reports were
scattered throughout the year without a
discernible seasonal distribution. Of
reports that were not suggestive of im-
Replies were received from 20 of 27
potential reporters, and 4 of these
helped to exclude an allergic cause (1
case each of Henoch-Scho¨nlein pur-
pura, and subacute spongiotic dermati-
Table 2. Adverse Reactions Associated with CAM* in Australia
Cardiac
arrest
Allergic
reaction
Sole
suspected
Medication
Death
Anaphylaxis
Bronchospasm
Rhinitis
Urticaria
Angioedema
Bee pollen
Walnut
Oil
1
1
1
1
1
Celery
1
Seed
Extract
Cranberry
Echinacea†
Feverfew ϩ
Willow
1
14
1
1
13
1
4
12
1
6
Bark
Garlic
Ginger
Ginseng§
Glucosamine
HCl
1
1
1
2
1
2
0
3
0
0
1
Herbal laxative
Horseradish‡
Hypericum
Phytoestrogen
compound
Propolis
Royal jelly
Valerian
1
1
1
0
1
2
1
1
1
1
2
1
1
2
3
2
1
5
21
2
3
2
1
1
18
5
6
7
2
1
7
1
1
Other
unidentified
medication
4
15
TOTAL
5
3
12
41
31
21
3
* Data updated March 10, 2000.
† More than one symptom occurred in some cases.
‡ Echinacea also implicated.
§ Royal jelly also implicated in this reaction.
Between January 1979 and March 2000, 483 reports involving CAM were recorded in Australia, of which some were considered by the authors
to be consistent with IgE-mediated reactions, defined as the presence of one or more of urticaria, angioedema, bronchospasm, or anaphylaxis.
VOLUME 88, JANUARY, 2002
45

tis with eosinophilia, photosensitive
rash, and scalp itch).
RAST of 11 of 16 randomly selected
stored sera from patients with allergic
rhinitis, asthma, and atopic dermatitis
demonstrated similar results (Table 4).
Serum was available in only two addi-
tional “survey” cases for RAST. This
resulted in 1.0% radio-iodine uptake in
one case of anaphylaxis and 0.9% in
one case of acute asthma with serum
collected 2 years after the event. These
were scored as borderline positive and
negative, respectively, in that particu-
lar assay.
Reasons given are to enhance well-
being rather than to treat illness.31,32
Nevertheless, these preparations are
increasingly used to treat allergic dis-
ease as well.7 Similar patterns of use
have been noted in British and North
American subjects.33,34 Further, many
Australian and British doctors either
use CAM in their own practice or refer
patients to practitioners who do.35,36
This popularity is reflected in the
amount of money spent on CAM. In
Australia, for example, this is more
than the amount out of pocket spent on
conventional medicine, estimated at
Ͼ$900 million per year (approximate-
ly A$45 per person per year31). Expen-
diture in the United States is even
higher, with an estimated doubling of
expenditure from US$14 billion to $28
billion in the years 1990 to 1997 (ap-
proximately US$ 100 per person per
year33,37,38).
Unfortunately, “natural” does not al-
ways equal safe. Some CAM interact
with conventional medicines or are in-
trinsically toxic.38,39 Because they are
rarely packaged in childproof contain-
ers,4 younger patients are at risk of
accidental exposure. This is consistent
with an estimated 400,000 reported
cases of “poisoning” inquiries to
American Poison Control Centers in
1996 associated with CAM.3
More than 50% of the reports were
from patients with known asthma, al-
lergic rhinoconjunctivitis, or atopic
dermatitis. Atopic disease was re-
ported in 3 of 4 cases of anaphylaxis (1
unknown), 7 of 10 cases of broncho-
spasm (3 unknown), but only 1 of 12
cases of urticaria/angioedema (5 nona-
topic, 6 unknown). Of the 4 subjects
reacting within 1 hour of their first
ever dose, 2 were known to be atopic
and 2 were not (Fig 1). Three subjects
reacted after their second ever dose (1
atopic, 2 unknown). No deaths were
recorded. Symptoms appeared within 6
hours of ingestion in 62% of patients,
within 12 hours in 75%, and within 24
hours in 94% of cases (information
available for 16 of 26 subjects).
In the 24 of the 26 cases for which
information was available, causality
was indicated in the ADRAC data as
certain (2 reports), probable (10 re-
ports), or possible (12 reports). When
asked their opinion as to the cause of
the adverse reaction as part of this sur-
vey, all 17 respondents to the survey
blamed echinacea. Echinacea was the
sole medication being taken in at least
15 cases (4 unknown). The remaining
7 cases involved a total of 11 medica-
tions (Table 3).
Reports to International Government
Agencies of Adverse Reactions to
Echinacea
A number of countries collect volun-
tary reports of adverse reactions to
CAM. Information regarding reports
associated with echinacea was pro-
vided by the Committee on Safety of
Medicines (UK), the Special Nutrition-
als Adverse Event Monitoring System
of the Food and Drug Administration
(USA),30 the Adverse Drug Reactions
Monitoring Program (Canada), and the
Center for Adverse Reactions Monitor-
ing (New Zealand). Reports were con-
sidered by the authors to be consistent
with IgE-mediated hypersensitivity if
one or more reactions of urticaria, an-
gioedema, exacerbation of asthma, or
anaphylaxis was described These data
are summarized in Table 5.
Hypersensitivity reactions have also
been reported to CAM other than echi-
nacea. Examples include royal jelly,
pollen-containing preparations, cham-
omile, and other plant-derived com-
Allergic Reactions to Echinacea:
DISCUSSION
Allergy Testing of Australian Cases
Because there are few references to
allergic reactions to echinacea in the
literature, potential sensitivity to this
plant was evaluated by adding in SPT
for echinacea into the routine panel of
allergens tested for in consecutive pa-
tients referred for evaluation of asthma
or allergic rhinitis.11 SPT of 100 atopic
patients demonstrated reactivity to the
same aqueous or glycerinated extracts
of echinacea (defined as a wheal size at
least 2 mm greater than the negative
control) in 20% of patients; only three
had ever ingested echinacea. Almost
all subjects had strong reactivity to grass
pollens on SPT (Ͼ90%). By contrast,
SPT wheals to Ambrosia sp. were either
negative or no greater than 2 mm.
Fifty percent of Australians report us-
ing some form of CAM (apart from
vitamins) in any 12-month period.
Figure 1. Onset of symptoms as a function of atopy. The onset of adverse reactions associated with
echinacea is shown according to atopic status: atopic (black bars), nonatopic (shaded bars), and status
unknown (white bars).
46
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

pounds.8–10,41–44 This is not surprising
when one takes into account the wide-
spread use of CAM in the community
and the propensity of atopic subjects to
develop cross-reactive allergic re-
sponses to a variety of botanically or
structurally related compounds.45
Cross-reactivity may, in fact, be the
explanation for the observation that
four Australian subjects reacted to
their first ever dose of echinacea, and
one medically trained subject had sev-
eral mild systemic reactions culminat-
ing in anaphylaxis (case 3). This is
consistent with the presence of positive
RAST and skin tests to echinacea in
many of the personally observed cases,
as well as 20% of asymptomatic atopic
subjects, most of whom never ingested
the plant.11
Table 3. Other Medications Used by Australian Patients with Possible Allergic Reactions to
Echinacea
Symptoms
Case
Medication
Indication
Mild asthma
associated with
echinacea
1
2
Inhaled beclomethasone,
albuterol
Roxithromycin,
Severe asthma
Urticaria
Upper respiratory tract
infection
dihydrocodeine,
dexchlorpheniramine/
pseudoephedrine
Horse radish and garlic,
allopurinol, enalapril
3
Hypertension, gout,
upper respiratory tract
infection
Angioedema
4
5
6
7
Ethinyloestradiol,
levonorgestrel
Intranasal
beclomethasone
Topical betamethasone
valerate
Contraception
Anaphylaxis
Severe asthma
Urticaria
Allergic rhinitis
Atopic dermatitis
Enhance well-being
Vitamin preparations
Anaphylaxis
There are many precedents for clin-
ical cross-sensitization between in-
gested and inhaled allergens. For ex-
ample, pollen-containing CAM have
triggered anaphylaxis42,43 and others
(eg, royal jelly) contain pollen-derived
allergens.10,46 Patients who are allergic
to ragweed and mugwort pollen, for
example, may be clinically sensitive to
watermelon, banana, honey, and royal
jelly.10,47,48 Sensitization via the respi-
ratory route has even been postulated
to explain some allergic reactions to
food, including sunflower seeds and
crustaceans.49,50 OAS is common
among grass, weed, and tree pollen-
sensitive subjects, and anaphylaxis has
been described under some circum-
stances.51 Indeed, in a personal series
of 430 patients evaluated for ana-
phylaxis, 78 of 262 of food-related
episodes were triggered by the combi-
nation of exercise and ingestion of
semi- or uncooked fruit and vegetables
in patients with OAS (RJM, unpub-
lished observations, 2000).
Of the 26 reports considered to be consistent with IgE-mediated hypersensitivity, Echinacea
was the sole medication ingested in 15 cases, whereas 7 patients were taking other medication
and no information was available in the remaining 4 cases.
marigolds, and daisies, or via cross-
reactive foods such as those described
above. Flowering Asteraceae (Com-
positae) are not only popular ornamen-
tal plants, but exposure to plants grow-
ing in the wild is common in arid areas
of Australia, where it is a common
cause of “Australian bush dermati-
tis.”52 However, allergens have been
identified that are common to Aster-
aceae (Compositae) and pollinating
grasses.53 It is uncertain, however,
whether the high frequency of grass
sensitivity in patients with positive
skin tests to echinacea11 supports
cross-reactivity is simply a marker of
atopy, or reflects contamination of
echinacea products with grass pollen-
derived allergen.
of patients who suffered from acute
asthma attacks or anaphylaxis were
atopic. The reliability of the data is
enhanced by having had direct contact
with the majority of the reporters for
additional information and the direct
evaluation of five of these by consul-
tant physicians in clinical immunology
and allergy.
Similar reports of adverse reactions
to echinacea have been recorded in
several international databases. Al-
though caution must be used when in-
terpreting voluntary reports of adverse
drug reactions, a relationship between
a medication and an adverse reaction is
more likely when: 1) only one medi-
cation is implicated; 2) the reactions
can not be easily explained by an un-
derlying medical condition; 3) the on-
set of symptoms occurs soon after in-
gestion of the drug; 4) the reaction is
consistent with a known property of
the preparation; 5) one can identify a
particular population at risk by means
of age, sex, or underlying disease; and
6) there is a mechanism for confirming
the relationship by specific testing or
rechallenge. None of the patients seen
by the authors in consultation were
The Australian data provide the best
evidence to date of an uncommon po-
tential for serious allergic reactions to
echinacea in atopic patients, similar to
that reported previously in association
with allergic reactions to royal jel-
ly.8–10 Echinacea accounts for Ͼ10%
of adverse reports involving CAM in
Australia, with Ͼ50% exhibiting con-
sistent-seeming IgE-mediated hyper-
sensitivity. Atopic patients seem to be
at particular risk. More than two-thirds
Despite its recent appearance in
nurseries as an ornamental plant, expo-
sure to echinacea pollen (and to Aster-
aceae [Compositae] weed pollen such
as ragweed) is extremely limited in
Australia. The implication is that for
sensitization to occur, it must do so
indirectly by exposure to more com-
mon members of that family, such as
chrysanthemums, dahlias, sunflowers,
VOLUME 88, JANUARY, 2002
47

Table 4. Echinacea RAST in Atopic Control Subjects
Echinacea RAST
(% iodine uptake)
RAST
grade
Echinacea RAST
(test/control ratio)
History
Other positive RAST
Asthma
10.6
9.4
3ϩ
3ϩ
17.7
15.7
House dust mite
House dust mite, cat,
royal jelly
House dust mite
House dust mite
House dust mite, cat,
cockroach
Asthma, anaphylaxis
to royal jelly (fatal)
Asthma
Asthma
Allergic rhinitis
4.7
4.2
2.5
1ϩ
1ϩ
1ϩ
7.8
7.0
4.2
Allergic rhinitis
Allergic rhinitis
Allergic rhinitis
Allergic rhinitis
3.4
5.3
3.6
1.3
1ϩ
2ϩ
1ϩ
–
5.7
8.8
6.0
2.2
House dust mite, cat,
grass
House dust mite, cat,
grass
House dust mite, mold,
grass
House dust mite, weeds,
grass
Allergic rhinitis
Allergic rhinitis
Allergic rhinitis
Allergic rhinitis
Atopic dermatitis
Atopic dermatitis
1.6
1.0
1.7
0.5
23.9
4.1
–
–
–
–
4ϩ
2ϩ
2.7
0.2
2.8
0.8
39.8
6.8
House dust mite, grass
House dust mite
Ryegrass
Grass
House dust mite
House dust mite, cat,
grass, weeds, mold
House dust mite
Cephalosporins
Cephalosporins
Cephalosporins
Scopolamine
Nuts
Atopic dermatitis
Drug reaction
Drug reaction
Drug reaction
Drug reaction
Anaphylaxis
Anaphylaxis
Anaphylaxis
Angioedema
Normal sera
Cord serum
2.2
19.6
19.2
12.4
1.6
24.0
2.6
1.6
1ϩ
4ϩ
4ϩ
4ϩ
–
4ϩ
1ϩ
–
3.7
32.7
32.0
20.7
2.7
40.0
4.3
2.7
Nuts
Chinese herbal remedy
Grass, mold
–
1.2
0.6
0.3
–
–
–
2.0
1.0
0.5
–
Stored sera were assayed for echinacea-binding IgE. RAST results were scored by the reporting laboratory, with positive results defined as %
radio-iodine uptake at least 2.5 standard deviations greater than the mean of 3 negative control sera assayed in parallel. The ratio of test/control
sera is also described. Additional clinical information is listed, where known.
willing to undergo deliberate challenge
with echinacea.
angiotensin-converting enzyme in-
hibitors,54 and acute bronchospasm
or urticaria could have been triggered
by infection for which echinacea
was taken.55,56
Although non-IgE–mediated mech-
anisms have been proposed to explain
some “allergic syndromes” related to
medication,57,58 more than two-thirds
of patients suffering from serious
symptoms of asthma or anaphylaxis
were atopic. A role for allergy is sup-
ported by evidence of positive SPT
results or RAST to echinacea in 4 of
the 5 patients seen personally (2 of 4
positive to both; 2 of 4 positive to
RAST or skin tests) and the onset of
symptoms within 1 hour in at least 6
of the 16 patients for whom informa-
tion was available. Although these
patients declined specific rechallenge,
at least three reported repeated“chal-
lenges” and symptoms after ingestion
of echinacea.
The increasing popularity of echi-
nacea is consistent with the high
level of community awareness and
use of echinacea by atopic patients in
this study; the estimated 200 million
doses consumed in Australia per year
(equivalent to 10 doses per person
per year)14 and the 68% increase in
echinacea’s herbal medicine market
At least six different brands involv-
ing at least three different formulations
(tea, tablets, and liquid) were impli-
cated in Australian reports. This sug-
gests that echinacea itself (rather than a
contaminant or excipient) was respon-
sible for the reaction. Echinacea was
the sole implicated trigger in at least 15
of 26 patients. In the remaining 7 pa-
tients taking other medications, the re-
action reported might be explained by
either medication or underlying dis-
ease process in only the first 3 cases
(Table 3). For example, angioedema
is a potential complication of use of
48
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

Table 5. International Reports of Adverse Reactions Associated with Echinacea
Committee on
Adverse Drug
Reactions
Monitoring
Programme
(Canada)
Centre for
Adverse
Reactions
Monitoring
(New Zealand)
Food and
Safety of
Drug
Medicines
Administration
Yellow card
(U.S.A.)
Scheme (U.K.)
Total reports
Number of cases
consistent with
IgE-mediated
hypersensitivity*
Date of update
Anaphylaxis
Exacerbation of
asthma
52
6
9
3
12
2†
2
1
Oct 20, 1998
March 28, 2000
1
April 3, 2000
1
April 8, 2000
Non-urticarial
rash
2
1
Urticaria
Angioedema
2
2
2
1
1
1
* Reports were classified by the authors.
† More than one symptom described.
Adverse drug reports involving echinacea were obtained from several international drug agencies and classified by the authors as being consistent
with IgE-mediated hypersensitivity if one or more of urticaria, angioedema, exacerbation of bronchospasm, or anaphylaxis were described.
health professions. Med J Aust 1997;
166:538–541.
2. Vickers A, Zollman C. ABC of com-
plementary medicine: herbal medicine.
BMJ 1999;319:1050–1053.
3. Portyansky E. Alternative medicine.
Drug Topics 1998;142:44–50.
4. Anderson LA. Concern regarding
herbal toxicities: case reports and
counselling tips. Ann Pharmacother
1996;30:79–80.
5. van Asperen PP, Kemp AS, Mellis
CM. A prospective study of the clini-
cal manifestations of atopic disease in
infancy. Acta Paediatr Scand 1984;73:
80–85.
6. Adkinson NF Jr. Risk factors for drug
allergy. J Allergy Clin Immunol 1984;
74:567–572.
7. Bielory L, Lupoli K. Herbal interven-
tions in asthma and allergy. J Asthma
1999;36:1–65.
8. Leung R, Thien FC, Baldo B, Czarny
D. Royal jelly-induced asthma and
anaphylaxis: clinical characteristics
and immunological correlations. J Al-
lergy Clin Immunol 1995;96:
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share in the United States between
1995 and 1996.38
of Medical Research, Royal North
Shore Hospital, Sydney) in performing
in vitro assays is gratefully acknowl-
edged. Case 1 was presented in ab-
stract form at the Australasian Society
for Clinical Immunology and Allergy
meeting in Adelaide in December 1996
and subsequently published in The
Medical Journal of Australia.11 The re-
maining data were presented in part at
the American Academy of Allergy,
Asthma and Immunology meeting in
San Diego in March 2000 and pub-
lished in abstract form in the Journal
of Allergy and Clinical Immunology
2000, 105:S340—S341. Reports of
adverse reactions associated with echi-
nacea were kindly supplied by the Ad-
verse Drug Reactions Advisory Com-
mittee, Australia (Dr. P. Purcell), the
Center for Adverse Reactions Monitor-
ing, New Zealand (Dr. M. Tatley), the
Medicines Control Agency, UK (Dr. S.
Davis), the Adverse Drug Reaction
Monitoring Program, Canada (P.
Springuel), and the Food and Drug Ad-
ministration, USA.
The safety of any product is a rela-
tive concept which takes into account
the potential for toxicity in the entire
population as a whole, as well as those
at particular risk by virtue of age, sex,
organ dysfunction, or atopy. As has
been observed with royal jelly,8,10
atopic patients seem to be at particular
risk of developing potentially life-
threatening allergic reactions to echi-
nacea. It is conceivable that relatively
minor reactions such as transient rashes
or aggravation of underlying asthma
may go unnoticed and unreported.
CONCLUSION
It is na¨ıve to assume that natural
products are always safe. Indeed,
given the popularity of echinacea,
even rare adverse events become in-
evitable when a large proportion of
the population uses it mostly unsu-
pervised. Because these reactions
may occur with even their first ever
known exposure, atopic patients
should be cautioned appropriately.
9. Leung R, Ho A, Chan J, et al. Royal
jelly consumption and hypersensitivity
in the community. Clin Exp Allergy
1997;27:333–336.
10. Lombardi C, Senna GE, Gatti B, et al.
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jelly and their relationship with sensi-
ACKNOWLEDGMENTS
The assistance of Dr. Brian Baldo and
Ms. Gail Knowland (Kolling Institute
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