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BRIEF REPORTS
Possible Leukopenia Associated with Long-termUse of Echinacea David Eric Kemp, MD and Kathleen N. Franco, MD Americans spend between $3.5 and $5 billion an- mune stimulant when administered short term both nually on herbal treatments,1 and nearly 50 million in vivo and in vitro, it is contraindicated in patients individuals currently report use of botanical sup- with autoimmune disorders, multiple sclerosis, tu- plements.2 With so many herbal products on the berculosis, and those on immunosuppressant ther- market, it is imperative that physicians thoroughly question patients with regard to supplement use.
We describe a case in which chronic use of Physicians must understand the benefits and risks echinacea resulted in an asymptomatic leukopenia.
associated with medicinal herbs and counsel pa- We believe this case might be the first in the En- tients as to their safety. Echinacea is one such glish literature to confirm the German Commis- supplement that has gained popularity in recent sion E reports that chronic use indeed results in years. A member of the daisy family—Asteraceae (Compositae)—Echinacea purpurea is believed tohave properties that protect against upper respira-tory tract infections such as the common cold. In Case Report
1998, retail sales of the product worldwide totaled A 51-year-old woman visited her physician for her $69,702,144, and in Germany more than 2 million yearly physical examination. She had no com- prescriptions for echinacea were filled each year.3 plaints, and her only known medication allergy was Animal studies show echinacea affects the im- to sulfa drugs, which precipitated a rash. According mune system by increasing the number of circulat- to the patient’s medical history, she was taking ing white blood cells,4 promoting phagocytosis, bupropion (Wellbutrin SR) for depression; her hay and stimulating the production of cytokines.5 Echi- fever was not being treated with any over-the- nacea is also found to improve wound healing by counter or prescription drugs. She appeared inhibiting tissue and bacterial hyaluronidase6; its healthy from all aspects with the exception that her extracts could potentially inhibit replication of 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 graphs, arguably the best compilation of clinical use of herbal remedies and vitamin supplements.
information about herbs, chronic use (longer than 6 The patient’s only medication was a stable dose of to 8 weeks’ duration) is generally discouraged be- bupropion 300 mg/d that she had been taking for cause of reported cases of immune suppression.1,8 For this reason echinacea is contraindicated in pa- For the past 8 weeks she had been taking vita- tients with acquired immunodeficiency syndrome mins C, E, and B complex, along with echinacea, and other disorders in which immune suppression ginkgo biloba, and calcium. She initially began tak- would be detrimental. Because echinacea is an im- ing echinacea when family members became illwith upper respiratory tract infections. The patientbelieved echinacea had prevented her from getting Submitted, revised, 25 March, 2002.
From the Northeastern Ohio University College of Med- a cold and thus continued to take 450-mg capsules icine (DEK), Rootstown, Ohio, and the Section of Consul- of the herb, three times daily for 2 months. This tation Liaison, Department of Psychiatry and Psychology(KNF), Cleveland Clinic Foundation, Cleveland. Address dose is typically recommended by manufactures reprint requests to Kathleen N. Franco, MD, P57, Depart- and European physicians, but generally for only up ment of Psychiatry and Psychology, Cleveland Clinic Foun-dation, 9500 Euclid Ave, Cleveland, OH 44195.
A hematologist recommended testing again after nacea, but when echinacea was discontinued and the patient discontinued echinacea, ginkgo biloba, bupropion continued, the white cell count in- and bupropion. The patient refused to discontinue creased, lending less support to the role of bupro- taking bupropion but agreed to stop echinacea and gingko biloba. One month later her white cell The dose ingested by this patient, 1,350 mg/d count had increased slightly to 3,700/␮L and main- for 8 weeks, is not large and, in fact, was lower than tained that level for 3 months. An anemia profile, many others. During a recent pharmacy visit, we electrolyte count, thyroid-stimulating hormone found bottles listing echinacea in various doses level, and a differential blood count were normal.
ranging from 380 mg to 1,200 mg and schedules The patient’s next visit was 1 year later for a from 3 to 6 times per day.* The totals ranged from routine examination. The patient had continued 2,500 mg to 3,600 mg daily to “stimulate the body’s taking bupropion at the same dose, but for the own defenses.” Four of five bottles recommended 8 previous 2 months had resumed taking echinacea at weeks regular use with a 2-week hiatus before re- 450 mg three times daily. She also tookthe recom- starting, whereas one bottle did not. Four of five mended calcium and multivitamin but had not re- bottles recommended that persons with known au- sumed taking gingko biloba. Her white cell count toimmune disorders not ingest echinacea, but one was 2,880/␮L and on repeated testing the same day did not. One brand also recommended against use was 3,000/␮L. Other normal laboratory findings in persons with severe systemic illness, tuberculo- included an anemia profile, urinalysis, electrolytes, sis, muscular sclerosis, or allergy to sunflowers.
lipid profile, urine monoclonal protein analysis, to- Echinacea is a popular herbal remedy taken by tal urine protein, thyroid-stimulating hormone, many to treat upper respiratory tract infections and acute phase reactants, serum monoclonal protein a variety of other disorders. In assessing the thera- analysis, antinuclear antibodies, rheumatoid factor, peutic merit of echinacea, we found a review of 5 hepatitis panel, urine electrophoresis, and serum trials enrolling 1,272 subjects that tested echinacea electrophoresis. Although the differential blood in the prevention of upper respiratory tract infec- count was interpreted as normal, neutrophil counts tions. The incidence of upper respiratory tract in- were slightly less than normal while lymphocyte fections was lower in the treatment branches of all and monocyte counts were slightly increased. Tests 5 studies, with 2 trial results being statistically sig- for human immunodeficiency virus (HIV) infection nificant.10 A systematic review of the Cochrane were negative. The patient agreed to stop taking database found a total of 26 trials that studied echinacea and to have a bone marrow aspiration if echinacea, with 8 addressing its effect on respira- her white cell count did not return to normal.
tory tract infections. Six of 8 trials showed a ben- Two months after discontinuing echinacea, her eficial effect with use of the herbal supplement.11 white cell count was 3,440/␮L and 7 months later Because the reviews on its effectiveness are mixed, rose to 4,320/␮L. It remains within normal range, larger studies with improved methods might clarify and she has not resumed using echinacea.
In the meantime, many patients continue to take this product, believing it is a natural and therefore Discussion
safe remedy. Even patients without known autoim- Although we cannot be absolutely certain that echi- mune disorder or allergies to plants in the daisy nacea caused the decrease in white cell count, it is family might be at riskfor side effects. Echinacea is noteworthy that stopping this herbal remedy led to categorized as “generally regarded as safe for con- gradual improvement. The patient described did sumption” (GRAS) by the Food and Drug Admin- not have atopy, HIV, or an autoimmune disorder, istration (FDA) based on popular, widespread use yet the possibility of a type IV allergic response and no serious side effects. Recent reports, how- with a delay in observation of the reduced white cellcount after weeks of echinacea is also worth con-sideration. Although we could find no journal arti- *Nature’s Way Products, Inc, Springville, Utah (echina- cles, there is drug company literature that describes cea, 1200 mg); Nature’s Bounty, Inc, Bohemia, NY (echi- leukopenia secondary to bupropion.9 It is possible nacea alone, 500 mg liquid; echinacea with goldenseal,500 mg); CVS brand, Woonsocket, RI (echinacea, 380 mg: that bupropion exacerbated the response to echi- 418 JABFP September–October 2002 Vol. 15 No. 5
ever, name echinacea as a possible cause of ery- 3. Cirigliano MD. Clinical use of echinacea. UpTo- thema nodosum,12 life-threatening anaphylaxis,13 Date online 9.2. Available at www.uptodate.com. Ac- and possible hepatotoxicity in combination with other drugs metabolized by the liver such as ami- 4. Bauer VR, Jurcic K, Puhlmann J, Wagner H. Immu- nologic in vivo and in vitro studies on echinacea odarone, ketoconazole, and methotrexate.14 Al- extracts. Arzneimittelforschung 1998;38:276 – 61? though short-term use can be beneficial when a 5. Luettig B, Steinmuller C, Gifford GE, Wagner H, cold begins, some formulations of echinacea alone Lohmann-Marthes ML. Macrophage activation by or with goldenseal, carry labels implying it can be the polysaccharide arabinogalactan isolated from used chronically to fend off colds—a potentially plant cell cultures of Echinacea purpurea. J Nat Can- harmful recommendation. Because the Dietary Supplement Health and Education Act of 1994 6. Leung AY, Foster S. Encyclopedia of common nat- ural ingredients used in food, drugs, and cosmetics.
states that herbal remedies are dietary supplements, they are not required to undergo premarket testing 7. Turner RB, Riker DK, Gangemi JD. Ineffectiveness for safety and efficacy and are not regulated for of echinacea for prevention of experimental rhinovi- rus colds. Antimicrob Agents Chemother 2000;44: Physicians must remind patients that herb-drug interactions do occur, and because of the lackof 8. Blumenthal M, Gruenwald J, Hall T, Riggins C, standardization, variability in herb content and ef- Rister R. German Commission E monographs: me-dicinal plants for human use. Austin, Tex: American ficacy often exist among different manufacturers.15 Physicians should offer advice based on available 9. Wellbutrin SR (bupropion hydrochloride) sustained- knowledge while making recommendations in a release tablets prescribing information. Research manner compatible with the patient’s personal be- Triangle Park, NC: Glaxo Wellcome, 2000.
liefs and needs. One author has proposed a step- 10. Melchart D, Linde K, Worku R, et al. Results of five by-step strategy that physicians can use to discuss randomized studies on the immunomodulatory ac- use or avoidance of alternative therapies, empha- tivity of preparations of Echinacea. J Alter Comple-ment Med 1995;l:145– 60.
sizing patient safety, need for documentation in the 11. Goroll AH, May LA, Mulley AG Jr, editors. Primary patient record, and importance of collective deci- care medicine, office evaluation and management of sion making.16 Another author has proposed a set the adult patient. 4th ed. Philadelphia: Lippincott, of 12 guidelines physicians should follow when advising patients about herbal therapies.17 Physi- 12. Soon SL, Crawford RJ. Recurrent erythema nodo- cians should askpatients about herbal use and sum associated with Echinacea herbal therapy. J Am should include these agents when considering side effects or drug interaction in the differential diag- 13. Mullins RJ. Echinacea-associated anaphylaxis. Med J nosis for newly discovered signs such as leukopenia.
14. Miller LG. Herbal medicinals: selected clinical con- Only through continued documentation of unusual siderations focusing on known or potential drug- findings with herbal consumption can physicians herb interactions. Arch Intern Med 1998;158: safely and accurately counsel patients on the subject 15. Ernst E. Harmless herbs? A review of the recent literature. Am J Med 1998;104:170 – 8.
References
16. Eisenberg DM. Advising patients who seekalterna- 1. Ernst E, Pittler MH. Herbal medicine. Med Clin tive medical therapies. Ann Intern Med 1997;127: 2. Hellmich N. Popularity of herbs sprouts from pub- 17. Cirigliano M, Sun A. Advising patients about herbal licity. USA Today July 13, 1998, D04.

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