Fifty percent of Australians report using some form of complementary alternative medicines (CAM) apart from vitamins in any 12-month period, with similar patterns of use in British and North American subjects. Despite the common perception that “natural therapy” is safe, toxic and hypersensitivity reactions to complementary and alternative medicine have been described. Given that these products are rarely packaged in childproof containers, accidental exposure also occurs. Allergic reactions are most common in atopic subjects. This is not surprising when one considers that up to 20% of atopic subjects use CAM. Furthermore, these patients are more likely than others to become sensitized to cross-reactive allergens and some use (or are advised to use) products such as Echinacea for treatment of allergic disease.
When interpreting reports of immediate hypersensitivity to Asteraceae-derived CAM, it is helpful to bear in mind a number of important concepts: (1) exposure to Asteraceae is common; (2) sensitization is more common in subjects with preexistent allergic disease; (3) there is allergenic cross-reactivity between different Asteraceae, and between Asteraceae and some foods; and (4) patients sensitized by inhalation may experience allergic reactions when exposed by other routes. The implication is that unexpected adverse reactions may occur even with first ever known exposure.
Not all adverse reactions to Asteraceae, however, are IgE mediated. Some patients will experience delayed hypersensitivity. Others experience adverse effects where the mechanism is poorly defined. An important implication is that not all adverse reactions will be confined to atopies, but may extend to others with undefined risk factors.
Immediate Hypersensitivity Reactions
With over 20,000 species of Asteraceae distributed worldwide (absent only from the Antarctic mainland, exposure to inhaled or ingested members of this family is inevitable. Echinacea (or coneflower) is a flowering member of the Asteraceae (Compositae) family whose other members include Ambrosia (ragweed) species, Artemisia (mugwort, sagebrush, wormwood) species, Parthenium (feverfew), and cultivated plants including chrysanthemums, dahlias, sunflowers, marigolds, safflower, and daisies. Edible plants such as lettuce, safflower, chicory, and artichoke are also Asteraceae. Some members are used as CAM, including Echinacea, dandelion, chamomile, feverfew, milk thistle, and wormwood.
Sensitization to Asteraceae is common. Asteraceae-derived pollens are an important trigger for allergic rhinitis and asthma, including Ambrosia (ragweed) in North America, Parthenium (feverfew) in South America and India, Artemisia (mugwort) in Spain, and Chrysanthemum and sunflower in occupational and population settings.
Cross-reactivity between inhaled and ingested allergen is a risk factor for allergic reactions with exposure via other routes. Precedents include oral allergy syndrome in pollen-sensitive subjects and some allergic reactions to sunflower seeds and crustaceans. Sensitization to Asteraceae has also been associated with immediate hypersensitivity to CAM, such as royal jelly, Echinacea, bee pollen extracts, and chamomile, and some foods such as celery, honey, sunflower seeds, carrot, lettuce, watermelon, and nuts. An appreciation of the concept of cross-sensitization makes unexpected reactions to complementary and alternative medicine with first known exposure (such as to chamomile, Echinacea, royal jelly and pollen-derived products) perhaps not so surprising after all.
These observations are consistent with the hypersensitivity reactions to Echinacea in Australian subjects. Of 26 subjects with immediate hypersensitivity, 4 had anaphylaxis, 12 suffered acute asthma attacks, and 10 experienced urticaria/angioedema. Reactions were not always mild: four were hospitalized, four reacted after their first ever known exposure, and one patient suffered multiple progressive systemic allergic reactions. Echinacea was the sole implicated medication in 15 cases.
Consistent with atopy being an important risk factor, over half were known to be atopic. Furthermore, when 100 consecutive atopic patients were skin tested, 20 had positive reactions to Echinacea, yet only three had ever taken it previously. While this cohort had large positive reactions to grass pollens on skin testing, reactions to Ambrosia sp. were either negative or no greater than 2 mm. Given that exposure to ragweed, feverfew, or mugwort pollen in Australia is either sparse or nonexistent, this was not a surprising result. The implication was that sensitization to Echinacea must have developed indirectly, by exposure to flowering ornamental Asteraceae, cross-reactive foods, or plants growing in the wild associated with Australian bush dermatitis.
Contact Allergic Dermatitis
Asteraceae are a common cause of occupational contact allergic dermatitis (CAD). Echinacea, daisies, chrysanthemum, chamomile, tansy, dandelion, feverfew, and sunflowers have all been associated with symptoms in domestic and market gardeners and florists. Some topical CAM, cosmetics, shampoos, and massage oils containing plant extracts cause similar symptoms.
Contact with airborne plant-derived oleoresins can also cause dermatitis, a condition commonly known as Australian bush dermatitis, ragweed dermatitis, and weed dermatitis. Asteraceae are also responsible for some cases of persistent light eruption. The face, eyelids, sides of the neck, and “V” area of the neck are the main areas affected, with sharp delineation between unaffected areas protected by clothing. Cross-reactive, oil-soluble sesquiterpene lactones are the dominant (but not only) allergens responsible. Ingestion of lettuce has been associated with aggravation of dermatitis in one report. Affected patients are often advised to avoid contact with all Asteraceae.
Other Adverse Reactions
Delayed Asthmatic Reactions
We have personally assessed four patients who developed delayed asthmatic responses following ingestion of Echinacea, reproducible on rechallenge in all cases. Whether these observations were due to coincidence, related to why Echinacea was taken (e.g., infection), or due to non-IgE-mediated pro-inflammatory properties of Echinacea is uncertain.
Twelve cases of nonurticarial rashes (out of 51 reports involving Echinacea) were noted in Australian adverse drug reports, and at least one was reproducible with rechallenge. A single case report has implicated Echinacea as a cause of recurrent erythema nodosum.
Echinacea contains potentially hepatotoxic pyrrolizidine alkaloids. Hepatitis has been described in 7 of 51 Australian and in U.S. adverse drug reports involving Echinacea ().
Tansy oil contains ketone beta-thujone, a toxic compound associated with gastritis, seizures, cardiovascular side effects, and death. Its sale is banned in many countries. Overdoses with wild lettuce (sometimes used as a sedative) have been blamed for respiratory depression, coma, and death in cattle.
Other Reported Adverse Reactions
Transient burning or stinging of the tongue is commonly reported after taking Echinacea (). Parenteral administration can cause shivering, fever, and muscle weakness. Additional complaints including nausea and constipation, and abdominal pain, diarrhea, dysphagia, and skin rashes in German adverse drug reports 1989 through 1995. In the Australian Adverse Drug Reactions Advisory Committee (ADRAC) database, additional symptoms included fatigue, arthralgia, or myalgia (four cases each), headache or hypertension (two cases each), and one case each of dizziness, atrial fibrillation, vasculitis, acute renal failure, nausea, and epistaxis.
Mouth irritation, mouth ulcers, reduced taste, dry tongue, and gastric irritation have been reported in those using feverfew. Milk thistle has been associated with reproducible symptoms of sweating, colicky abdominal pain, diarrhea, vomiting, weakness, and vascular collapse requiring hospitalization in one case report (ADRAC, 1999).
Use In Pregnancy, Breast Feeding, And Children
Given the paucity of published studies, the potential risks and benefits of using complementary and alternative medicine during pregnancy or lactation are difficult to assess. Nevertheless, up to 12% and 55%, respectively, of pregnant Nigerian and South African women have taken native herbs during pregnancy. complementary and alternative medicine are also used by 12% to 15% of pregnant American women to relieve morning sickness or treat intercurrent illness, most commonly ginger, chamomile, Echinacea, or vitamins, a practice associated with congenital lead poisoning in a recent report. Around half of American midwives in one study used herbal products to induce labor. This has been associated with anaphylaxis and fetal death following administration of a chamomile enema. Up to 7% may use complementary and alternative medicine during lactation.
Despite a Commission E monograph statement that Echinacea is safe in pregnancy, this has only been formally examined in one underpowered study of 206 Canadian women, 54% of whom took Echinacea during the first trimester. While no significant increase in the type or incidence of malformations or pregnancy-related complications was found compared to case-matched controls, this small study had only the power to detect a major teratogen. The amount of alcohol present in some Echinacea preparations (estimated at around 1 ml per day) has not been associated with fetal malformations.
There are no published studies examining the safety of other Asteraceae-derived products during pregnancy, yet the properties of some suggest they should be avoided. For example, feverfew is documented to trigger abortions in cattle and stimulate uterine contractions in pregnant women. Chamomile is teratogenic in animal studies. Safflower, tansy, feverfew, calendula, chamomile, yarrow, milk thistle, and wormwood promote menstruation, stimulate uterine contraction, and act as an abortiflcant. Taken together with the potential for allergic reactions in susceptible individuals, the use of Asteraceae-containing complementary and alternative medicine during pregnancy seems imprudent. Similarly, there are few studies of their use in infants and children. Despite this, a recent South Australian survey showed that 87% of children admitted to Adelaide’s Women’s and Children’s Hospital had received at least one complementary and alternative medicine in the previous 12 months, and that 16% had received six or more preparations. Given the unsupervised use of complementary and alternative medicine by many patients and tendency to underreport adverse reactions to medication of all types, the absence of published evidence of toxicity in this or other groups should not be interpreted as evidence of safety.
The increasing popularity of complementary and alternative medicine and concurrent use of conventional medication makes it increasingly likely that otherwise rare adverse reactions or drug interactions will occur. Administration of complementary and alternative medicine is largely unsupervised. Doctors and patients may find it difficult to distinguish symptoms due to disease from those secondary to treatment. Many medical practitioners are ignorant of the potential toxicity of CAM. These factors, together with underreporting of use by patients, may contribute to underreporting of adverse events.
The safety of any product is a relative concept that 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. Atopic patients appear to be at particular risk of allergic reactions of variable severity to Asteraceae-derived CAM, even with first ever known exposure. Patients should be warned appropriately. Consideration should be given to attaching warning labels similar to those currently attached to aspirin and royal jelly packets in some countries.