Pittsburgh Poison Center, Children's Hospital of Pittsburgh, and Schools of Pharmacy and Medicine University of Pittsburgh; Hunt Institute for Botanical Documentation, Carnegie Mellon University; Keck Center for Computational Biology, University of Pittsburgh.

American mistletoe has a lurid history filled with myth, legend, and powerful magic, much of which was perpetuated by European settlers who revered European mistletoe and associated the same myths with native American mistletoe. The genus Phoradendron consists of approximately 200 species. It is parasitic on other woody plants and is found in the east from New Jersey to Florida, and as far north as southern Ohio and southern Indiana; it is very prevalent in Texas, and some species are common from California to Oregon. The flowers occur from October through December and ripen into clusters of whitish translucent berries which are popular adornments during the Christmas holiday season.

Although little has been published regarding American mistletoe, there is an abundance of historical literature which describes the mystical, magical and medicinal properties of European mistletoe, Viscum album. To the Gauls and Druids, oak trees and everything associated with them were sacred. Since mistletoe was parasitic on the oaks, it too assumed great importance as a panacea of all ills and bodily misfortunes. Pliny and Galen recommended it for the treatment of cancer, an indication that is still being investigated. Viscum has been associated with fatalities, and the toxicity identified with the medicinal and mythical applications has made American mistletoe guilty by association of having the same profile of toxicity.

Both the lay public and medical professionals have a healthy respect for mistletoe. In general, it is considered to be extremely toxic. To determine if American mistletoe is befitting of its reputation, the outcomes of 1,754 mistletoe exposures were examined.

METHODS

All mistletoe exposures reported to the American Association of Poison Control Centers (AAPCC) national data collection system for the period of 1985 to 1992 were extracted from an electronic file of all plant exposures in the AAPCC database over the same period of time and analyzed using a relational database. The data were graciously provided to the investigators as a data grant by the AAPCC. The AAPCC database represents exposures reported on a standardized patient documentation/data entry form that is used by participating centers and tabulated on an annual basis. The contributing centers are a combination of AAPCC-certified regional poison information centers and noncertified centers. Only data that meet specific quality control parameters are included in the database.

The following data fields were extracted as a subset from the larger mistletoe data set: patient age, reason for the exposure, initial

symptom assessment, management site, decontamination therapy, patient outcome, and geographic region of the exposure. Patient outcome was further subdivided to enable comparison with the type of gastrointestinal (GI) decontamination and outcome. The age field was queried to identify the subset of accidental exposures.

The outcome parameters are those defined by the AAPCC Toxic Exposure Surveillance System:

No effect--The patient developed no symptoms as a result of the exposure.

Minor effect--The patient exhibited some symptoms as a result of the exposure, but they were minimally bothersome to the patient.

Moderate effect--The patient exhibited symptoms as a result of the exposure which were more pronounced, more prolonged, or more of a systemic nature than minor symptoms. The symptoms were not life-threatening.

Major effect--The patient exhibited some symptoms as a result of the exposure. The symptoms were life-threatening or resulted in significant residual disability or disfigurement.

Unknown nontoxic--The final patient outcome was unknown, but the case was deemed to be a nontoxic exposure.

Unknown potentially toxic--The final patient outcome was unknown and it was deemed as a potentially toxic exposure.

Unrelated effect--The effects were unrelated to the exposure.

RESULTS

The extraction of mistletoe exposures from the human plant exposure database of 734,786 cases yielded 1,754 mistletoe exposures. Pediatric exposures accounted for 92.1% of the exposures, adults 6.3%, and in the remainder the age was unknown. Ingestion was the route of exposure in 95.9% of cases, dermal 2.7%, ocular 0.7%, inhalation 0.3% and other routes constituted the remainder.

Accidental exposure was the reason in 95.4% of the cases and 4.1% were intentional in nature. Among the 72 intentional exposures, 61.1% were classified as abuse or misuse of mistletoe, 11.1% used mistletoe for suicidal purposes, and in 27.8% of the exposures the specific intentional reason was unknown. There were no fatalities. The outcomes of all accidental exposures by age are listed in Table 1 .

When the initial assessment of the patient was known, 94.7% were asymptomatic, 4.9% had symptoms consistent with the exposure, and in the remaining 0.4% that were symptomatic, their symptoms were either unrelated or it was unknown if the symptoms were related to the exposure.

In patients who were initially asymptomatic and received absolutely no therapy (n = 486), 86.8% were categorized into the no effect or unknown nontoxic outcome groups, 1.9% had minor effects, and only 1 patient experienced a moderate effect outcome (Table 2) . The initially asymptomatic patients who received some form of GI decontamination (emesis, lavage, activated charcoal, or dilution; n = 1,011) experienced outcomes similar to the no-therapy group--92.5% had either no effect or an unknown nontoxic outcome, 2.6% had a minor effect, and one patient had a moderate effect outcome (Table 2) . The outcomes of all asymptomatic patients who were treated with some form of GI decontamination are listed in Table 2 .

In the 4.9% of patients who were initially symptomatic (n = 86), 34.9% (n = 30) received no type of therapeutic intervention. Unknown nontoxic effects or no effect occurred in 13.3%, minor effect outcomes were experienced by 33.3%, and 6.7% had a moderate effect outcome. The initially symptomatic subset that received some form of GI decontamination (n = 43) failed to develop any effects or had an unknown nontoxic exposure in 20.9% of cases, 62.8% had a minor effect, and 9.3% had a moderate effect. Table 3 lists the entire profile for the initially symptomatic subset of patients.

When the route of exposure was by ingestion and the patient was followed up to confirm a final outcome (n = 1,090), 90.3% were asymptomatic, 8.6% experienced minor effects, 0.9% had moderate effects, and 0.2% were categorized as major effects. In cases where final follow-up beyond the initial call to the poison center was not completed (n = 608), 69.4% were documented as unknown nontoxic exposure, 21.5% were unknown potentially toxic exposure, and 9.1% had symptoms that were not related to the exposure.

Some form of gastric decontamination therapy, excluding dilution, was used in 47.7% of the patients. The outcomes of all patients who were treated with syrup of ipecac-induced

TABLE 1 -- Accidental Mistletoe Exposures: Outcome by Age

Outcome	<1 Year	1-5 Years	6-12 Years	13-17 Years	Adults
No Effect	63.3%	58.3%	42.5%	32%	25.8%
Minor Effect	5.5%	4.7%	7.1%	18%	13.8%
Moderate Effect	0.5%	0.7%	0%	0%	1.2%
Major Effect	0%	0%	0%	0%	0%
Unknown Nontoxic	23.1%	24.9%	32.8%	34%	33.3%
Unknown   Potential Toxic	8.1%	8.1%	8.8%	14%	12.3%
Unrelated Effect	3.3%	3.3%	8.8%	2%	13.6%
Sample Size	830	575	113	50	81

In 79.4% of the exposures, the patient was managed without referral to a health care facility. Poison information centers referred 13.3% of the patients for treatment, 5.3% of patients were self-referred without prior consultation with a poison information center, and in 2% of the cases the treatment site was unknown. The final dispositions of patients referred by poison information centers and self-referred are listed in Table 5 .

There was seasonal clustering of the exposures; 87% occurred during the months of November, December, and January (Figure 3) . A majority, 51.9%, of the cases occurred in five states. The remaining states had fewer than 2.6% of the exposures and the location of the exposure was unavailable in 18% of the incidents.

DISCUSSION

This report on the outcome of 1,754 exposures to American mistletoe is the largest compilation of such cases. Prior to this report a total of 424 exposures was described in the published literature. Hall and colleagues ^[2] collected data on 14 Phoradendron exposures. Eleven of the patients ingested berries and three ingested leaves. Five of the patients had syrup of ipecac-induced emesis, nine were observed at home, and all remained asymptomatic. In the same publication, 1984 data from the American Association of Poison Control Centers on 141 Phoradendron exposures were tabulated. ^[2] Initially, 86% of the patients were asymptomatic and none of those patients progressed to the symptomatic state. Only 5% were symptomatic, and the initial assessment was unknown in 9%. Poison centers referred 30.5% of the patients to health care facilities, and 7.1% of patients were self-referred. There were no fatalities in this series.

Additionally, 177 cases described as mistletoe from the

TABLE 3 -- Initially Symptomatic Mistletoe Exposures: Outcome by Therapy

Outcome	No Therapy	GI Decontamination	Ipecac Syrup	Gastric Lavage	Activated Charcoal	Dilution Other
No Effect	3.5%	11.6%	12.5%	0%	6.2%	17.6%
Minor Effect	34.5%	62.8%	62.5%	0%	56.3%	58.8%
Moderate Effect	6.9%	9.4%	12.5%	50%	18.8%	6.0%
Major Effect	0%	2.3%	12.5%	50%	6.2%	0%
Unknown Nontoxic	10.3%	11.6%	0%	0%	0%	17.6%
Unknown Potential Toxic	31.0%	2.3%	0%	0%	6.2%	0%
Unrelated Effect	13.8	0%	0%	0%	0%	0%
Sample Size	29	43	8	2	16	17

Food and Drug Administration Poison Control Center Case Reporting Systems were briefly cited. ^[2] Only 14.7% of the cases developed any signs or symptoms and no fatalities were documented. The conclusion of this report is that the ingestion of one to three berries or one or two leaves of Phoradendron species is unlikely to result in any significant toxicity.

Spiller et al ^[3] described 92 American mistletoe exposures reported to three poison information centers. The median age was 2 years, and only 12% of the patients were symptomatic from their exposure. GI decontamination was performed in 57.6% of patients, but it was deemed not to influence patient outcome. The amount ingested was quantified and ingestions of up to 20 berries and five leaves occurred. When the amount ingested was known and five or more berries were consumed, all patients remained asymptomatic. Three of 11 patients who ingested one to five leaves developed GI symptoms and one patient who consumed five leaves was asymptomatic. One child experienced a seizure but it could not be confirmed whether there was an alternative etiology for the event. The conclusion was that symptoms are uncommon, even with large ingestions.

Despite its morbid reputation, American mistletoe exposures have not been responsible for any fatalities in the 2,178 cases reported in the literature and this investigation (Table 6) . Although both Phoradendron spp and Viscum spp have similar peptide toxins, several reasons may account for the relatively low order of toxicity that is apparent with Phoradendron exposures. The volumes of literature that describe Viscum album and its associated toxicity along with the common name, "mistletoe," which both Viscum and Phoradendron share, has probably bestowed an unjustifiable reputation for toxicity on Phoradendron. The literature on Viscum is so extensive (including the reports of fatalities) regarding its alleged medicinal and mystical qualities that this has led to excessive use in herbal preparations such as

In this series, 90.3% of the exposure victims remained asymptomatic when the final outcome was known. However, in cases that are deemed to be nontoxic exposures, the poison information specialist has the prerogative of not conducting a follow-up call to confirm the final outcome. If the unknown nontoxic cases are included, 93% of the exposures had a nontoxic outcome. Including minor effects with the no effect and the unknown nontoxic categories, 99.2% of patients who ingested mistletoe had a no-morbidity outcome.

Another factor that contributes to the low morbidity associated with American mistletoe exposures is the accidental nature of the cases. Only 4.1% of the exposures were intentional, and it should be considered that these exposures may have involved the ingestion of larger quantities.

A limitation of poison center databases is the inability to confirm the exposure. Neither laboratory confirmation nor botanical identification occurs with any frequency, and the capability of assessing this is not an option. Therefore, some of the no-effect exposures may have been the result of no exposure to American mistletoe. It is unlikely that this factor significantly influenced the outcomes, but it must be considered because it cannot be ruled out.

Spiller et al ^[3] indicated that GI decontamination treatment did not influence patient outcome. When the outcome was

TABLE 5 -- Mistletoe Exposures: Disposition of Poison Center Referral Versus Self-Referral

Disposition	Poison Center Referral	Self-Referral
Treated/released	64.2%	76.8%
Admitted	2.2%	12.5%
Psych admission	0%	0.9%
Lost to follow-up	17.9%	9.8%
Refused referral	15.7%	0%
Sample size	229	112

Figure 3. Mistletoe exposure frequency by month.

Evaluation in a health care facility occurred in 18.6% of patients compared to 37.6% in the 1984 AAPCC data. Based on the previously published data and the data from this series, such a high referral rate cannot be justified. It is difficult to control self-referrals which accounted for 28.5% of the referrals. However, poison center-initiated referrals were responsible for 72.5% of the health care facility visits, which suggests the lack of clear direction in the management of these cases because of the paucity of literature on Phoradendron exposures. It is hoped that this compilation of exposures, in conjunction with the other published series, will communicate to health care providers that American mistletoe exposures are not associated with noteworthy morbidity and no mortality. Furthermore, observation may be adequate management in accidental exposures that do not involve herbal, folklore, or medicinal use of American mistletoe.

It is possible that Viscum album may have been involved in some of these exposures because of the gross similarities of the two species. However, Viscum album is not indigenous to the United States and is only cultivated in isolated

TABLE 6 -- Comparison of American Mistletoe Case Series

	Current Series	Spiller et al	Hall et al	Hall et al, 1984 AAPCC	Hall et al, FDA
Asymptomatic	90.3%	88.0%	100%	86%	85.3%
Symptomatic	9.7%	12.0%	0%	5%	14.7%
Sample size	1090	92	14	141	177
Fatalities	0	0	0	0	0

CONCLUSIONS

American mistletoe ( Phoradendron spp) does not live up to its ill-fated reputation as being "the kiss of death." The majority of patients did not experience morbidity, and there were no fatalities among 1,754 exposures. Although it was not possible to quantify ingestions, it is apparent that accidental exposures, especially by children, are associated with little or no toxicity and observation of the child should suffice as treatment. Most of the patients who were initially asymptomatic remained free of symptoms, and GI decontamination did not appear to influence the outcome of patients. Unless the patient has symptoms or circumstances that justify referral to a health care facility, observation without referral is adequate intervention.

REFERENCES