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BRIEF REPORTS
Possible Leukopenia Associated with Long-term
Use of Echinacea
David Eric Kemp, MD and Kathleen N. Franco, MD
Americans spend between $3.5 and $5 billion an-
nually on herbal treatments,
1
and nearly 50 million
individuals currently report use of botanical sup-
plements.
2
With so many herbal products on the
market, it is imperative that physicians thoroughly
question patients with regard to supplement use.
Physicians must understand the benefits and risks
associated with medicinal herbs and counsel pa-
tients as to their safety. Echinacea is one such
supplement that has gained popularity in recent
years. A member of the daisy family—Asteraceae
(Compositae)—Echinacea purpurea is believed to
have properties that protect against upper respira-
tory tract infections such as the common cold. In
1998, retail sales of the product worldwide totaled
$69,702,144, and in Germany more than 2 million
prescriptions for echinacea were filled each year.
3
Animal studies show echinacea affects the im-
mune system by increasing the number of circulat-
ing white blood cells,
4
promoting phagocytosis,
and stimulating the production of cytokines.
5
Echi-
nacea is also found to improve wound healing by
inhibiting tissue and bacterial hyaluronidase
6
; its
extracts could potentially inhibit replication of
some viruses directly.
7
According to German Commission E mono-
graphs, arguably the best compilation of clinical
information about herbs, chronic use (longer than 6
to 8 weeks’ duration) is generally discouraged be-
cause of reported cases of immune suppression.
1,8
For this reason echinacea is contraindicated in pa-
tients with acquired immunodeficiency syndrome
and other disorders in which immune suppression
would be detrimental. Because echinacea is an im-
mune stimulant when administered short term both
in vivo and in vitro, it is contraindicated in patients
with autoimmune disorders, multiple sclerosis, tu-
berculosis, and those on immunosuppressant ther-
apy.
4,8
We describe a case in which chronic use of
echinacea resulted in an asymptomatic leukopenia.
We believe this case might be the first in the En-
glish literature to confirm the German Commis-
sion E reports that chronic use indeed results in
immune suppression.
Case Report
A 51-year-old woman visited her physician for her
yearly physical examination.. She had no com-
plaints, and her only known medication allergy was
to sulfa drugs, which precipitated a rash. According
to the patient’s medical history, she was taking
bupropion (Wellbutrin SR) for depression; her hay
fever was not being treated with any over-the-
counter or prescription drugs. She appeared
healthy from all aspects with the exception that her
white cell count had decreased from 5,800/L the
preceding year to 3,300/L (normal range 4,000 –
11.0/L). The only change found was an increased
use of herbal remedies and vitamin supplements.
The patient’s only medication was a stable dose of
bupropion 300 mg/d that she had been taking for
18 months.
For the past 8 weeks she had been taking vita-
mins C, E, and B complex, along with echinacea,
ginkgo biloba, and calcium. She initially began tak-
ing echinacea when family members became ill
with upper respiratory tract infections. The patient
believed echinacea had prevented her from getting
a cold and thus continued to take 450-mg capsules
of the herb, three times daily for 2 months. This
dose is typically recommended by manufactures
and European physicians, but generally for only up
to 6 weeks or less.
Submitted, revised, 25 March, 2002.
From the Northeastern Ohio University College of Med-
icine (DEK), Rootstown, Ohio, and the Section of Consul-
tation Liaison, Department of Psychiatry and Psychology
(KNF), Cleveland Clinic Foundation, Cleveland. Address
reprint requests to Kathleen N. Franco, MD, P57, Depart-
ment of Psychiatry and Psychology, Cleveland Clinic Foun-
dation, 9500 Euclid Ave, Cleveland, OH 44195.
Possible Leukopenia and Echinacea 417
A hematologist recommended testing again after
the patient discontinued echinacea, ginkgo biloba,
and bupropion. The patient refused to discontinue
taking bupropion but agreed to stop echinacea and
gingko biloba. One month later her white cell
count had increased slightly to 3,700/L and main-
tained that level for 3 months. An anemia profile,
electrolyte count, thyroid-stimulating hormone
level, and a differential blood count were normal.
The patient’s next visit was 1 year later for a
routine examination. The patient had continued
taking bupropion at the same dose, but for the
previous 2 months had resumed taking echinacea at
450 mg three times daily. She also took the recom-
mended calcium and multivitamin but had not re-
sumed taking gingko biloba. Her white cell count
was 2,880/L and on repeated testing the same day
was 3,000/L. Other normal laboratory findings
included an anemia profile, urinalysis, electrolytes,
lipid profile, urine monoclonal protein analysis, to-
tal urine protein, thyroid-stimulating hormone,
acute phase reactants, serum monoclonal protein
analysis, antinuclear antibodies, rheumatoid factor,
hepatitis panel, urine electrophoresis, and serum
electrophoresis. Although the differential blood
count was interpreted as normal, neutrophil counts
were slightly less than normal while lymphocyte
and monocyte counts were slightly increased. Tests
for human immunodeficiency virus (HIV) infection
were negative. The patient agreed to stop taking
echinacea and to have a bone marrow aspiration if
her white cell count did not return to normal.
Two months after discontinuing echinacea, her
white cell count was 3,440/L and 7 months later
rose to 4,320/L. It remains within normal range,
and she has not resumed using echinacea.
Discussion
Although we cannot be absolutely certain that echi-
nacea caused the decrease in white cell count, it is
noteworthy that stopping this herbal remedy led to
gradual improvement. The patient described did
not have atopy, HIV, or an autoimmune disorder,
yet the possibility of a type IV allergic response
with a delay in observation of the reduced white cell
count after weeks of echinacea is also worth con-
sideration. Although we could find no journal arti-
cles, there is drug company literature that describes
leukopenia secondary to bupropion.
9
It is possible
that bupropion exacerbated the response to echi-
nacea, but when echinacea was discontinued and
bupropion continued, the white cell count in-
creased, lending less support to the role of bupro-
pion.
The dose ingested by this patient, 1,350 mg/d
for 8 weeks, is not large and, in fact, was lower than
many others. During a recent pharmacy visit, we
found bottles listing echinacea in various doses
ranging from 380 mg to 1,200 mg and schedules
from 3 to 6 times per day.* The totals ranged from
2,500 mg to 3,600 mg daily to “stimulate the body’s
own defenses.” Four of five bottles recommended 8
weeks regular use with a 2-week hiatus before re-
starting, whereas one bottle did not. Four of five
bottles recommended that persons with known au-
toimmune disorders not ingest echinacea, but one
did not. One brand also recommended against use
in persons with severe systemic illness, tuberculo-
sis, muscular sclerosis, or allergy to sunflowers.
Echinacea is a popular herbal remedy taken by
many to treat upper respiratory tract infections and
a variety of other disorders. In assessing the thera-
peutic merit of echinacea, we found a review of 5
trials enrolling 1,272 subjects that tested echinacea
in the prevention of upper respiratory tract infec-
tions. The incidence of upper respiratory tract in-
fections was lower in the treatment branches of all
5 studies, with 2 trial results being statistically sig-
nificant.
10
A systematic review of the Cochrane
database found a total of 26 trials that studied
echinacea, with 8 addressing its effect on respira-
tory tract infections. Six of 8 trials showed a ben-
eficial effect with use of the herbal supplement.
11
Because the reviews on its effectiveness are mixed,
larger studies with improved methods might clarify
its value.
In the meantime, many patients continue to take
this product, believing it is a natural and therefore
safe remedy. Even patients without known autoim-
mune disorder or allergies to plants in the daisy
family might be at risk for side effects. Echinacea is
categorized as “generally regarded as safe for con-
sumption” (GRAS) by the Food and Drug Admin-
istration (FDA) based on popular, widespread use
and no serious side effects. Recent reports, how-
*Nature’s Way Products, Inc, Springville, Utah (echina-
cea, 1200 mg); Nature’s Bounty, Inc, Bohemia, NY (echi-
nacea alone, 500 mg liquid; echinacea with goldenseal,
500 mg); CVS brand, Woonsocket, RI (echinacea, 380 mg:
1,140 mg).
418 JABFP September–October 2002 Vol. 15 No. 5
ever, name echinacea as a possible cause of ery-
thema nodosum,
12
life-threatening anaphylaxis,
13
and possible hepatotoxicity in combination with
other drugs metabolized by the liver such as ami-
odarone, ketoconazole, and methotrexate.
14
Al
-
though short-term use can be beneficial when a
cold begins, some formulations of echinacea alone
or with goldenseal, carry labels implying it can be
used chronically to fend off colds—a potentially
harmful recommendation. Because the Dietary
Supplement Health and Education Act of 1994
states that herbal remedies are dietary supplements,
they are not required to undergo premarket testing
for safety and efficacy and are not regulated for
quality by the FDA.
Physicians must remind patients that herb-drug
interactions do occur, and because of the lack of
standardization, variability in herb content and ef-
ficacy often exist among different manufacturers.
15
Physicians should offer advice based on available
knowledge while making recommendations in a
manner compatible with the patient’s personal be-
liefs and needs. One author has proposed a step-
by-step strategy that physicians can use to discuss
use or avoidance of alternative therapies, empha-
sizing patient safety, need for documentation in the
patient record, and importance of collective deci-
sion making.
16
Another author has proposed a set
of 12 guidelines physicians should follow when
advising patients about herbal therapies.
17
Physi
-
cians should ask patients about herbal use and
should include these agents when considering side
effects or drug interaction in the differential diag-
nosis for newly discovered signs such as leukopenia.
Only through continued documentation of unusual
findings with herbal consumption can physicians
safely and accurately counsel patients on the subject
of herbal therapy.
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Possible Leukopenia and Echinacea 419