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Possible leukopenia associated with long-term use of echinacea

Authors:
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.
References
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4. Bauer VR, Jurcic K, Puhlmann J, Wagner H. Immu-
nologic in vivo and in vitro studies on echinacea
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5. Luettig B, Steinmuller C, Gifford GE, Wagner H,
Lohmann-Marthes ML. Macrophage activation by
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Possible Leukopenia and Echinacea 419
... V literaturi ni zaslediti posebnih opozoril glede varnosti jemanja pripravkov ameriškega slamnika. Omenja se primer asimptomatske levkopenije v povezavi z daljšim jemanjem ameriškega slamnika (Kemp & Franco 2002). Ker je ameriški slamnik imunostimulant, ga ne priporočamo pri bolnikih z avtoimunskimi boleznimi, multiplo sklerozo, tuberkulozo in tistih, ki so na terapiji z imunosupresivi. ...
... Ker je ameriški slamnik imunostimulant, ga ne priporočamo pri bolnikih z avtoimunskimi boleznimi, multiplo sklerozo, tuberkulozo in tistih, ki so na terapiji z imunosupresivi. Kronična uporaba pripravkov ameriškega slamnika, ki traja 8 tednov ali dlje, ni priporočljiva zaradi možnih imunosupresivnih učinkov (Kemp & Franco 2002, Kreft & Razinger 2014. Kemijska sestava ekstraktov ameriškega slamnika je precej podobna med posameznimi vrstami z manjšimi variacijami v količini aktivnih substanc. ...
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IzvlečekPripravki ameriškega slamnika (Echinacea purpurea) se zaradi svojih imunostimulativnih učinkov zelo pogosto uporabljajo predvsem pri prehladih in gripi. Uporaba in popularnost teh pripravkov je v zadnjih letih zelo narasla, kar dokazujejo tudi vedno večja ponudba na trgu. Številne raziskave so bile narejene na področju gojenja, kvantifikaciji aktivnih učinkovin, učinkovitosti in varnosti. Ugotavljali smo, kakšna je gostota listnih rež na zgornji in spodnji strani listov ter merili dolžino listnih rež na spodnji strani listov ameriškega slamnika pri 213 vzorcih. Vzorci so se razlikovali po načinu gojenja rastlin. Gostote in dolžine rež smo merili z mikroskopiranjem odtisov epiderme, ki smo jih naredili s prozornim lakom. Preverili smo vpliv velikosti lista in vpliv pozicije na listu, kjer smo izvajali meritve. Ugotovili smo, da se gostote in dolžine listnih rež med lokacijami po širini lista značilno razlikujejo. Zato smo v nadaljevanju poskusa merili reže na določenem mestu na sredini med osrednjo žilo in listnim robom. Najbolj izrazit in signifikanten vpliv na lastnosti listnih rež ima sezona žetve. Pri jesenski žetvi v primerjavi s poletno je bila gostota rež zgornje strani listov 66 % večja (p<0,001), dolžina rež spodnje strani pa 11 % večja (p<0,001). Pri proučevanju vplivov agronomskih dejavnikov (namakanje, starost rastlin, lokacija njive) nismo našli signifikantnih vplivov na lastnosti listnih rež. Opazili smo tudi signifikantno negativno korelacijo med gostoto in dolžino rež ter pozitivno korelacijo med gostoto rež spodnje in zgornje strani lista. Večje rastline so imele daljše listne reže in manjšo gostoto listnih rež v primerjavi z manjšimi rastlinami. Ta vpliv je bil statistično signifikanten, vendar majhen. Rastline z večjim odstotkom suhe mase v požeti biomasi (manjša vsebnost vode) so imele večjo gostoto rež in manjšo dolžino listnih rež, vendar so povezave signifikantne le pri poletni žetvi. Med koncentracijami cikorne in kaftarne kisline in gostoto ter dolžino listnih rež ni signifikantnih korelacij. Ključne besede: listne reže, Echinacea purpurea, ameriški slamnik AbstractHerbal preparations from Echinacea purpurea (purple coneflower) are often used in common cold and flu because of their immune stimulatory effects. The popularity of these products has grown considerably in recent years, and there is increasing market supply. Numerous studies have been made investigating the cultivation, quantification of active ingredients, safety and efficacy of Echinacea purpurea. In this study we determined the density of the leaf stomata on the lower and upper sides of the leaves and the length of the leaf stomata on the lower side of leafs in 213 samples of E. purpurea plants, which differed in the cultivation parameters. Density and length were measured with the microscopic examination of the imprint of the epidermis, which we made with clear nail varnish. We checked the effect of the size of the leaf and the influence of the measuring position on the leaf. We found that the densities and the length of the stomata were significantly different across the width of the leaf. Therefore, we carried out measurements at a constant position in the middle between the central vein and the leaf edge. The most pronounced parameter influencing the stomata properties was season of harvesting. In the autumn harvest compared to summer, the density of the stomata of the upper side was 66% higher (p <0.001) and the stomata length on the lower side was 11% higher (p <0.001). We did not find significant effects of any of the studied agronomical parameters (irrigation, age of plants and location of plantation) on the properties of leaf stomata. We also observed a significant negative correlation between the stomata density and stomata length and a positive correlation between the stomata density of the lower on the upper side of the leaf. We observed that larger plants had longer stomata and lower stomata density compared to smaller plants. This effect was statistically significant but small. Plants with a higher percentage of dry mass in harvested biomass (lower water content) had a higher stomata density and smaller stomata lengths, but the correlation was significant only in summer harvest. There are no significant correlations between chicoric and caftaric acids concentrations and the stomata density or length. Key words: leaf stomata, Echinacea purpurea, purple coneflower
... Two months after discontinuing taking Echinacea, her white cell count was 3440/µL and 7 months later arose to 4320/µL. Due to the fact, that the authors could not find another reason for the leucopenia, they assumed a relationship to the intake of Echinacea [60]. Although it is known that the concomitant ingested product, bupropion (Wellbutrin SR ® ), releases changes in hematology. ...
... The published data on leucopenia have to be considered as not relevant for the safety of Echinacea due to reports concerning the occurrence of changes in hematology, like anemia and pancytopenia after a concomitant ingestion of bupropion (product information Wellbutrin, PDR, USA). Moreover, the patient showed also low respectively borderline levels of the white cell counts without Echinacea [60]. A specific risk in children is not documented and adverse events are very rare, with no causality. ...
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... ), leucopenia(Kemp and Franco 2002), eosinophilia(Maskatia and Baker 2010), Sjögren syndrome(Logan and Ahmed 2003), erythema nodosum(Lee Soon and Crawford 2001), exanthema(Lee and Werth 2004), anaphylaxis and other allergic reactions(Mullin 1998;Mullins and Robert 2002). ...
... In a case report, leukopenia was reported with a combination of psychotropic medications including bupropion but it was associated with lamotrigine due to temporal features of the symptoms (11). In a brief report, leukopenia was reported with a combination of echinacea and bupropion (12) and it was associated with Echinacea, but it was discussed that bupropion might exacerbate the leukopenic effect of echinacea. Previous case presentations reported a variety of hematologic side effects such as eosinophilia and leukocytosis with bupropion and there was only one case presentation (9) that reported leukopenia without neutropenia with bupropion. ...
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... Accordingly, along with labeled drugs for this complication, several complementary therapies have been proposed, and Echinacea is one of the most well-known ones. Despite some claims about the proven effect of Echinacea compounds in human bone marrow stimulation and increasing leucocyte production in the context of chemoradiation in few studies [25], Echinacea-induced leucopenia has been reported, as well [26]. In an open prospective trial by Melchart et al. [27] on 15 high-staged gastric cancer patients under chemotherapy, administration of polysaccharide extracts was only associated with a nonsignificant preventive effect on leucopenia. ...
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In this study, acidic arabinogalactan, a highly purified polysaccharide from plant cell cultures of Echinacea purpurea, with a molecular weight of 75, 000, was effective in activating macrophages to cytotoxicity against tumor cells and micro-organisms (Leishmania enriettii). Furthermore, this polysaccharide induced macrophages to produce tumor necrosis factor (TNF-α), interleukin-1 (IL-1), and interferon-β2. Arabinogalactan did not activate. B cells and did not induce T cells to produce interleukin-2, interferon-β2, or interferon-γ, but it did induce a slight increase in T-cell proliferation. When injected ip, this agent stimulated macrophages, a finding that may have therapeutic implications in the defense against tumors and infectious diseases. [J Natl Cancer Inst 81: 669–675, 1989]
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Ethanolic extracts of Echinacea purpurea, E. pallida and E. angustifolia roots were examined for immunological activity in the carbon clearance test with mice and in the granulocyte test. In the in vivo experiment all extracts, administered orally, were found to enhance phagocytosis significantly. These results correlate with the stimulation of phagocytosis in the in vitro granulocyte test. The lipophilic fractions of the extracts appeared to be more active than the polar fractions. All extracts were analyzed by HPLC in order to correlate the chemical constituents with the immunological activities.
Article
Alternative medical therapies, such as chiropractic, acupuncture, homeopathy, and herbal remedies, are in great public demand. Some managed care organizations now offer these therapies as an "expanded benefit." Because the safety and efficacy of these practices remain largely unknown, advising patients who use or seek alternative treatments presents a professional challenge. A step-by-step strategy is proposed whereby conventionally trained medical providers and their patients can proactively discuss the use or avoidance of alternative therapies. This strategy involves a formal discussion of patients' preferences and expectations, the maintenance of symptom diaries, and follow-up visits to monitor for potentially harmful situations. In the absence of professional medical and legal guidelines, the proposed management plan emphasizes patient safety, the need for documentation in the patient record, and the importance of shared decision making.
Article
This article describes and discusses five placebo-controlled randomized studies investigating the immunomodulatory activity of preparations containing extracts of Echinacea in healthy volunteers. A total of 134 (18 female and 116 male) healthy volunteers between 18 and 40 years of age were studied. Two studies tested intravenous homeopathic complex preparations containing Echinacea angustifolia D1 (study 1) and D4 (study 5). Two studies (2 and 3a) tested oral alcoholic extracts of roots of E. purpurea, one study an extract of E. pallida roots (study 3b), and one study an extract of E. purpurea herb (study 4). Test and placebo preparations were applied for four (study 5) or five (studies 1-4) consecutive days. The primary outcome measure for immunomodulatory activity was the relative phagocytic activity of polymorphonuclear neutrophil granulocytes (PNG), measured in studies 1 and 2 with a microscopic method and in studies 3, 4, and 5 with two different cytometric methods. The secondary outcome measure was the number of leukocytes in peripheral venous blood. Safety was assessed by a screening program of blood and other objective parameters as well as by documentation of all subjective side effects. In studies 1 and 2 the phagocytic activity of PNG was significantly enhanced compared with placebo [maximal stimulation 22.7% (95% confidence interval 17.5-27.9%) and 54.0% (8.4-99.6%), respectively], while in the other studies no significant effects were observed. Analysis of intragroup differences revealed significant changes in phagocytic activity during the observation periods in five test and three control groups. Leukocyte number was not influenced significantly in any study. Side effects due to the test preparations could not be detected. Our studies provide evidence for immunomodulatory activity of the homeopathic combination tested in study 1 and the E. purpureae radix extract tested in study 2. The negative results of the other three studies are difficult to interpret due to the different methods for measuring phagocytosis, the relevant changes in phagocytic activity within most placebo and treatment groups during the observation period, and the small sample sizes. Future studies should be performed on patients rather than healthy volunteers and use standardized or chemically defined monopreparations of Echinacea.
Article
Herbal medicinals are being used by an increasing number of patients who typically do not advise their clinicians of concomitant use. Known or potential drug-herb interactions exist and should be screened for. If used beyond 8 weeks, Echinacea could cause hepatotoxicity and therefore should not be used with other known hepatoxic drugs, such as anabolic steroids, amiodarone, methotrexate, and ketoconazole. However, Echinacea lacks the 1,2 saturated necrine ring associated with hepatoxicity of pyrrolizidine alkaloids. Nonsteroidal anti-inflammatory drugs may negate the usefulness of feverfew in the treatment of migraine headaches. Feverfew, garlic, Ginkgo, ginger, and ginseng may alter bleeding time and should not be used concomitantly with warfarin sodium. Additionally, ginseng may cause headache, tremulousness, and manic episodes in patients treated with phenelzine sulfate. Ginseng should also not be used with estrogens or corticosteroids because of possible additive effects. Since the mechanism of action of St John wort is uncertain, concomitant use with monoamine oxidase inhibitors and selective serotonin reuptake inhibitors is ill advised. Valerian should not be used concomitantly with barbiturates because excessive sedation may occur. Kyushin, licorice, plantain, uzara root, hawthorn, and ginseng may interfere with either digoxin pharmacodynamically or with digoxin monitoring. Evening primrose oil and borage should not be used with anticonvulsants because they may lower the seizure threshold. Shankapulshpi, an Ayurvedic preparation, may decrease phenytoin levels as well as diminish drug efficacy. Kava when used with alprazolam has resulted in coma. Immunostimulants (eg, Echinacea and zinc) should not be given with immunosuppressants (eg, corticosteroids and cyclosporine). Tannic acids present in some herbs (eg, St John wort and saw palmetto) may inhibit the absorption of iron. Kelp as a source of iodine may interfere with thyroid replacement therapies. Licorice can offset the pharmacological effect of spironolactone. Numerous herbs (eg, karela and ginseng) may affect blood glucose levels and should not be used in patients with diabetes mellitus.