National Library of Medicine: IGM Full Record Screen

SOURCE: JAMA 1964 SEP 28;189:985-8
NLM CIT. ID: 64146909


From the Department of Dermatology, University Hospital, Philadelphia


Generalized pustular psoriasis, reportedly due to an exquisite hypersensitivity to salicylates of tree, shrub, and medical origin, was observed in a six-year-old child. In an effort to account for the explosive appearance of the eruption each April he spent in the eastern Pennsylvania mountains, sweet birch (Betula lenta pollen was incriminated as the exciting agent since the tree produces large quantities of methyl salicylate (sweet birch oil). The biochemistry of the pharmacopeia as well as of plant life reveal many sources of salicylate.

The sophistication of modern medicine leads us to look for more and more complex causes of disease. Molecular biology, genetic drift, and spin resonance become our concepts. And yet ....

The following case illustrates how the obvious and the simple can cause a strange rare disease -- pustular psoriasis.

Report of a Case

In 1961, this child's problem was reported as a rare example of generalized pustular psoriasis. The underling nature of the malady remained completely unknown, despite extensive study in the hospital. In view of the complete remission experienced, the patient was not seen again until April 23, 1964, when he was readmitted to the University Hospital with a second episode of pustular erythroderma completely duplicating that of 1961.

At the time of his admission, over 80% of the body of this six-year-old boy was covered with erythematous plaques on which were numerous pustules. He was extremely ill and weak and had a temperature of 104 F (400 C). The eruption had begun early in April as a pustular erythematous eruption of the trunk. Associated with a temperature of 105 F (40.6 C), aspirin, antibiotics, and systemic steroids failed to afford relief. On admission he was receiving daily doses of 8 mg of triamcinolone and 80 units of corticotropin (ACTH). A diagnosis of pustular psoriasis was again made.

Initially his complete blood count (CBC) showed a hemoglobin level of 13.9 gm per 100 cc white blood cell (WBC) count, 11,700; neutrophils, 55%; nonfilamented neutrophils, 30%; lymphocytes, 10%; monocytes, 4%; and basophils, 1%. Urinalysis was normal. Blood cultures were repeatedly negative. Chest film was normal. Staphylococcus aureus was cultured from the skin and was shown to be sensitive to penicillin.

Hospital treatment consisted of daily doses of betamethasone (Celestone), 1.2 mg; diphenydramine (Benadryl) hydrochloride, 100 mg; and trimeprazine tartrate (Temaril), 10 mg. Aspirin, 300 mg, was given whenever the temperature exceeded 101.4 F (38.5 C). Multivitamin capsules, one a day, were given. Hydrocortisone acetate cream was applied topically three times a day.

The pustular psoriasis continued its unremitting course and the lesions spread to involve the entire body. Myriads of new pustules appeared daily and the temperature remained at 103 to 104 F )39.4 to 40.0 C). Potassium penicillin G, 1.6 million units daily by mouth, and gamma globulin, 2 cc intramuscularly, every other day, were added to the therapeutic attack. At this point the patient's condition showed a gradual improvement. By the 21st hospital day, he was afebrile and new pustules had stopped appearing. However, his entire body was erythrodermic, and a Philadelphia heat wave on the 35th ay produced a new bout of fever. This was followed by a new crop of pustules and deterioration of the child's general condition. His blood count at this time showed: WBC's, 18,600; neutrophils, 7%; nonfilamented neutrophils, 39%; lymphocytes, 38%; monocytes, 9%; basophils, 2%; atypical lymphocytes, 3%; and metamyelocytes, 2%.

Complete review of all aspects of the problem at this point led to the conclusion that aspirin might be n part responsible for the syndrome. A basophil degranulation test for antibodies proved to be positive and all aspirin was at once interdicted. Repeated basophil tests confirmed this sensitivity.

In view of the deleterious effect of the environmental heat and humidity on this child who had lost all of his cutaneous thermal control and aware of the possibility of airborne allergens, arrangements were made to have or patient and his mother enter into a controlled-climate chamber. He remained here 24 hours a day at an absolutely constant environment of 76 F, 30% humidity, and 30.0 inches of barometric pressure. His progress during three weeks in the chamber was one of continual daily improvement. All medication was discontinued except for erythromycin to prevent secondary infection.

The clinical course after aspirin was eliminated was that of steady involution except for one 48-hour period following the inadvertent administration of a compound of aspirin and caffeine (Anacin) one night by the mother who was unaware of its aspirin content. Shortly after receiving a single tablet of this compound, he became "purple all over." This flare gradually faded during the following days.

At the time of discharge on the 63rd hospital day, the patient was essentially free from all lesions. His subsequent course has been satisfactory.


Once the critical factor of aspirin sensitivity reached us a whole host of pieces of the diagnostic puzzle fell into place. Inasmuch as aspirin sensitivity is truly salicylate sensitivity, a search was made for salicylate exposure.

Our patient had had only two major attacks, three years apart, but each beginning in early April. We quickly learned that these two attacks coincided with living in the mountains of eastern Pennsylvania The years he had been free from the disease he had been living in Ohio. The April onset suggested a tree pollen, and what pollen could be more suspect than that of the tree which makes methyl salicylate (also known as sweet birch oil). Inquiry revealed that stands of sweet birth (Betula lenta) are common in his home area and that clouds of the pollen descend from the catkins early in April.

Further questioning disclosed that our patient loved to hike in the woods and chew on birch leaves and twigs as well as the related teaberry (Gaultheria procumbens) leaves (another natural factory of methyl salicylate, ie, oil of teaberry). Teaberry gum and birth beer were additional facets of his adventures. As a woods boy he also ate forest berries and fruits in the Pennsylvania spring.

As we began to reconstruct the sequence, it seemed evident that our patient had become sensitive to salicylates, possibly by occasional oral administration of aspirin. In the spring of the year massive pollination of the hillsides of sweet birch had challenged him as an inhalant allergen. This coupled with leaf chewing and possible use of oil of wintergreen in candy, toothpaste, and lozenges triggered a minor cutaneous eruption of psoriasis associated with "drug" fever. For this latter sign aspirin was the immediate remedy. Once such a cycle had been initiated it was continued for weeks until we became aware of the dangers of this "most common drug in the world." Significantly his first hospitalization was shorter than the second, apparently due to the fact that aspirin was prescribed but once during his first stay.

Sundry accessory items of interest are the fact that the patient's mother cannot take aspirin without a marked flush reaction. Recently an aunt of the patient has developed psoriasis and arthropathy for which she ha been taking large doses of aspirin. Finally the parents recall a minor exacerbation sustained by the patient in August, 1963. At that time his rectum, penis, and fingernails showed a dermatitic change. They could recall the patient having chewed teaberry leaves during that time. Other minor flares of a psoriatic eruption such as he experienced at six and ten months may have been related to aspirin intake.

It was evident that our patient must avoid all salicylate-containing medication, foods, beverages, toothpastes, gum, lozenges, and candies. Brannen and Forbes have recently outlined the many drug hazards for the salicylate-sensitive individual. This includes aspirin under many names as well as components of mixtures. (Table 1). The oil of wintergreen odor will serve to detect danger n many flavored items but vigilance must run high. Brannen and Forbes specifically cite the following types of preparations as having salicylates: analgesics, antacids, antipyretics, cold remedies, cough preparations, diarrhea remedies, douches, keratolytics, mouthwashes, nasal decongestants, sedatives, and topical counterirritants. Failure to miss a singe area of salicylate exposure, eg, a powder for vaginal cleansing ( Massengill), dooms the patient to continuing difficulties.

Even more occult are the botanical sources of salicylates. It was in 1763 that Reverend Edward Stone first recorded the therapeutic benefits of chewing the bark of willow, Salix (and hence the name Salicylate). Collier has carefully portrayed the chemical genealogy of the salicylate family as it developed down through the years. In 1829, the active ingredient of the willow bark was found to be salicin, a compound of glucose and salicyl alcohol. This was later hydrolyzed and oxidized to central compound salicylic acid. In 1831, another plant, meadowsweet flower (Spiraca, hence later aspirin) proved to be a source of salicylaldehyde and in turn salicylic acid. A third major source proved to be oil of wintergreen (Gaultheria) wherefrom methyl salicylate was extracted. This could readily be hydrolyzed to salicylic acid. By 1852, chemists were able to synthesize salicylic acid ad efforts to trace the compound throughout the plant kingdom diminished. Nevertheless, oil of teaberry, sweet birch oil, and betula oil were found to be synonyms of oil of wintergreen by virtue of their high methyl salicylate content. Chemical search of the botanical factories revealed further that this compound was in the leaves of Chenopodium, Clycanthus and Camellia; the fruits of Ribes, Fragaria, Rubus, Prunus, Vitis, and in the flower oil of acacia and other legumes. As the methyl ester glycoside, salicylic acid was also found in the flowers of Viola, and the leaves of the genus Gaultheria.

The dramatic antipyretic, analgesic, and anti-inflammatory effects of salicylic acid made it the wonder drug of the 19th century, but its use was limited by the untoward gastrointestinal irritation it produced in many patients. Interestingly, one of these patients with rheumatism who could not tolerate salicylic acid had a chemist son, who in 1899 found a simple way to make the acetyl compound of salicylic acid and thereby improve patient acceptance of salicylates.

With a usage measured in astronomical figures, aspirin and its congeners has induced remarkably few hypersensitivity reactions. In the classic monograph on salicylates, Pearson has reviewed the problem of hypersensitivity to aspirin. He points out that aspirin may cause anaphylactic shock, asthma, rhinorrhea, angioneurotic edema, urticaria, and purpura. Indeed, aspirin is the only drug which commonly induces asthma. An associated finding in the aspirin sensitive asthmatics is the high incidence of nasal polyps. This reached 40% in one series. We cannot help but suspect that botanical inhalant allergens (birch pollen) containing salicylates are operative in the production of these allergic polyps.

Other surveys of drug intolerance have stressed aspirin hypersensitivity, recording, in addition to Pearson's list, morbilliform eruptions, flushing of the face, erythemia nodosum, erythema multiforme, anaphylactoid purpura, thrombocytopenic purpura, dysidrosis, herpes progenitalis, and a bullous eruption of the palms. Death may occur within minutes from either anaphylactic shock or asthmatic asphyxia. The absence of an appropriate test for aspirin sensitivity has blunted our awareness of the problem. However, with the introduction of the basophil degranulation test it has been possible to detect circulating antibodies to aspirin. Brannen and Forbes have made a comprehensive study of such salicylate sensitivity using the basophil test as a guide. They found 75 patients with a positive basophil test to aspirin and reported such diverse entities as lichen planus, dermatitis herpetiformis, pityriasis rosea, and parapsoriasis as being associated with salicylate allergy. Clearing was induced by rigid elimination of all salicylates.

Our personal experience has been with two patients who experienced anaphylactic shock following aspirin. Another had a dermatomyositis syndrome due to aspirin. Five others experienced urticaria. In each the basophil test was positive for circulating antibodies to aspirin as was found in the present patient.

Recently, Weiner, Rosenblatt and Howes have described a modified hemagglutination technique for the detection of salicylate antibodies. This apparently is very sensitive and should provide additional aid in the recognition of the salicylate sensitive individual.

The problem of prophylaxis is uppermost in the mind once the offending allergen is recognized. It is evident that our patient must avoid all medications containing salicylate in an form. Herb decoctions would be especially dangerous. He must furthermore avoid foods, beverages, and sweets with wintergreen flavoring. He must also avoid eating large quantities of the fruits which contain salicylates (Table 2), and indeed direct contact with plants such as the violet, wintergreen camellia, and calycanthus. Even birch firewood could pose a hazard. It is apparent that such injunctions are simple compared to the problem of avoiding the season snow of pollen from plants synthesizing salicylates. The only trees which produce methyl salicylate in levels to be readily detected by the nose are sweet birch, black birch and to a lesser extent yellow birth (B lutea). Wintergreen (teaberry) is the only shrub with this property. It has been pointed out that the pollen of wintergreen, Spiraca, and willows should not pose a problem wince it is small and restricted in number, inasmuch as pollination is achieved by bees. However, sweet birch pollen is light and fluffy appearing in early April in great amounts. We assume that it was this pollen which triggered our patient's seasonal attacks. (This view is supported by the spectrophotometric finding of salicylates in birch pollen.) To avoid the pollen hazard and thus a possible recurrence next April, the family has been advised to move to the west or have the patient spend Aprils in Ohio where the birch is not found.

It seems evident that aspirin, man's constant friend, may be an occasional foe. To th already lengthy list of allergic reactions it ma induce, we must add generalized pustular psoriasis and erythroderma. How often aspirin and its congeners may contribute to the development of psoriasis vulgaris and psoriatic erythroderma deserves further study.

It is becoming evident that simple elimination of aspirin and salicylates from the medicine cabinet is inadequate for the patient with salicylate hypersensitivity. One must also caution against a large number of berries and fruits and contact with plants. The hazard of nibbling on twigs and leaves is evident. Furthermore, the avoidance of birch pollen would seem mandatory. This would seem especially significant for the aspirin-sensitive asthmatic.

TABLE 2 - Sources of Salicylates

Drugs Flavoring Foods Suntan Lotions Plants* Miscellaneous
* 36 families listed in Gross and Greenberg, and Klein