Propolis allergy (IV) Studies with further sensitizers from propolis and constituents common to propolis, poplar buds and balsam of Peru

26 different compounds have been investigated experimentally for their sensitizing capacity in guinea pigs. 19 of these occur in propolis as well as in poplar bud exudates, and 14 of them are also found in balsam of Peru. 4 caffeates and benzyl isoferulate were found to be strong sensitizers. 7 compounds were moderate, and 13 compounds showed only weak sensitizing potency. Methyl cinnamate was negative. Patch tests in 11 propolis-sensitive patients once more revealed 3-methyl-2-butenyl caffeate and phenylethyl caffeate as the major sensitizers. In addition to the 8 compounds already known to occur in propolis as well as in balsam of Peru, we detected 5 further substances that both materials have in common. Among these, benzyl isoferulate is considered a noteworthy sensitizer. Coniferyl benzoate, which was shown to be a moderate sensitizer, is present in fresh samples of balsam of Peru, while in propolis it has been detected only once so far. The flavonoid aglycones occurring in poplar bud exudates, and hence also in propolis, are weak sensitizers which play only a minor role in propolis hypersensitivity.     

Dermatitis from propolis

22 patients with dermatitis from propolis were studied. In all the 21 tested subjects the tests with propolis were positive, and in 19 they were also positive to balsam of Peru. The chromatograms of the balsam and propolis show marked similarity and 3 identical peaks could be recognised in both substances. Among the patients sensitive to balsam of Peru and propolis, 12 were tested with some common components; 3 were positive to cinnamyl cinnamate, 2 to vanillin and 1 to benzyl cinnamate. Chromatograms of the 3 propolis samples from the Warsaw region were very similar, but not identical. Some of the patients were tested with 35 essential oils and eugenol. Sensitivity to clove oil was common.     

Propolis allergy

As shown in the preceding paper, propolis or bee-glue is the cause of an increasing number of allergic reactions in persons using it in external preparations and cosmetics. Propolis and its main contact allergen, 1,1-dimethylallyl caffeic acid ester, designated LB-1, show strong sensitizing properties in patients as well as in guinea pig experiments. 9 patients have been patch tested with this compound, 8 of whom reacted strongly. Chemical separation of different propolis samples and poplar bud extracts reveal that LB-1 is always present. Poplar bud secretion is the bee's major source for propolis and hence the origin of LB-1. A warning is indicated, in agreement with several other authors, that propolis should not be used in topical products because of its strong sensitizing properties.     

The incidence of allergy to propolis in 605 consecutive patients patch tested in Prague

605 consecutive patients were patch tested with the standard CDRG test series and with a 10% alcoholic solution of propolis. Positive allergic reactions to propolis were observed in 25 patients (4.2%); thirteen of them exhibited a simultaneous positive patch test to balsam of Peru. In view of the relatively high incidence of allergic reactions and the appearance of pseudo-cross-sensitivity to another common allergen, balsam of Peru, propolis should not be used in topical medicaments or as a component of cosmetic preparations.     

Contact dermatitis from propolis

Two patients with contact dermatitis due to the natural product propolis (bee glue) are reported. They presented perioral eczema and stomatitis which were recalcitrant until propolis was considered as the cause. Patch tests with propolis preparations were positive in both patients, and, furthermore, in the second patient the lesions relapsed after provocation tests. European standard patch test including balsam of Peru were negative. The complexity of propolis, its supposed anti-inflammatory effect due to flavonoids, and the sensitizing agents originating mainly from the poplar trees are discussed together with the cross-sensitization to balsam of Peru. Contact dermatitis due to propolis should be considered in unexplained eczemas, mainly perioral but also in other areas, as propolis preparations are available also as ointments and cosmetic creams.     

Propolis-induced contact allergy

Six patients with contact dermatitis to propolis are reported (3 women, 3 men; mean age 57 years). All three men had eczema on their hands and had acquired their sensitization in the course of bee keeping. The women had been sensitized by propolis contained in ointments of various kinds. Upon patch testing all six patients reacted to propolis and four also to Peruvian balsam. While ten flavonoids were test-negative, a cinnamic acid ester (1.1-dimethylallyl-3',4'-dihydroxy cinnamic acid ester) isolated both from propolis and from poplar buds was positive in two out of three patients; this may be the major allergen.     

Sensitization to propolis in 1255 children undergoing patch testing

To investigate the frequency and the features of contact sensitization to propolis in children, we patch tested 1255 consecutive children suspected of allergic contact dermatitis with propolis 20% petrolatum over an 8-year period (1995-2002). Positive responses were observed in 5.9% of patch-tested subjects, with a significantly higher frequency in boys than in girls. The dermatitis was localized mainly on the face, hands and limbs. A significant linear increase in the annual frequency of propolis allergy was noted. Confirming literature data, a significant association with balsam of Peru sensitivity was present in children reacting to propolis, linked to the presence of common constituents in the 2 substances. In conclusion, based on our data, we suggest that propolis should not be used in topical products for children because of its high sensitization rate at the paediatric age.     

Contact dermatitis to estradiol benzoate

Three patients developed facial dermatitis after contact with preparations containing estradiol benzoate. Patch tests were positive to estradiol henzoate 0.1% in MEK but negative to other related estrogens including estradiol. All three patients also had positive tests to resorcinol monobenzoate and two out of three to balsam of Peru.
Most likely estradiol benzoate was the primary sensitizer.     

Perfume dermatitis in children sensitized to balsam of Peru in topical agents

Hjorth in his classic monogram "Eczematous Allergy to Balsams" emphasized that sensitization to balsam of Peru is most important since secondary allergens such as "fragrances" are ubiquitous. The application of a topical medication containing balsam of Peru to the skin of an infant, particularly in the occluded diaper area, seems a great way to sensitize the infant not only to balsam of Peru but also to our fragrant environment.     

Benzyl alcohol allergy

A 63 year old woman presented with a 3 year history of vulval lichen sclerosus et alrophicus and vulval dermatitis resistant to multiple topical therapies. She was patch test positive to 5% benzyl alcohol which is a widely used preservative in topical creams and a component in balsam of Peru.     

Double-blind placebo-controlled peroral challenges in patients with delayed-type allergy to balsam of Peru

Patch tests (PTs) with spices, such as clove, cinnamon, Jamaica pepper and vanillin sugar, and with balsam of Peru were made on 29 patients 0.8–2.9 years after an allergy to balsam of Peru had been detected. Positive reactions to balsam of Peru were seen in 17 patients, and to clove, Jamaica pepper or cinnamon in 5. Double-blind placebo-controlled peroral challenges (DBPCPCs) with balsam of Peru and spices (active substances) were performed on 22 patients. A substantial increase (30–280%) in the number of palmar vesicles after the DHPCPC with the active substances, but not with placebo, was seen in 8 patients, an increase with both the acme substances and placebo in 3. and with placebo but not the active substances in 1 patient. 4 of the 8 patients with positive DBPCPCs with the active substances were negative to balsam of Peru in the 2nd PT. No other objective symptoms were seen after the DBPCPCs. Balsam of Peru and the spices were retested 3 months after the DBPCPC. Both alleviation and aggravation of the PT reactions were seen. It is concluded that ingested flavoured foods might cause systemic contact reactions in some patients with allergy to balsam of Peru, but the benefits of a flavour-avoiding diet are questionable in all of them.     

Dermatitis from phenyl salicylate in safety spectacle frames

We report 3 cases of allergic contact dermatitis behind the ears from wearing the same brand of industrial safety spectacles. In each case, a positive patch test was obtained with scrapings of the plastic frame. In 2 cases further patch tests with constituents of the plastic were carried out; positive patch tests were obtained with phenyl salicylate. Phenyl salicylate is used as an ultraviolet inhibitor in some cellulose acetate butyrate and cellulose acetate propionate formulae. It has previously been reported as a contact sensitizer from its use as a sun screen in a lip salve. Positive patch test reactions were also obtained variously in these patients with balsam of Peru, resorcinol monobenzoate, and epoxy resin.     

Immediate reactions to patch tests with balsam of Peru

Closed patch tests with balsam of Peru gave rise to nine immediate reactions among 121 patients with different dermatoses and to 10 reactions among 57 patients with chronic urticaria. Among compounds of balsam of Peru, cinnamic aldehyde, cinnamic acid benzoic acid and benzaldehyde also gave the same reactions. The reactions could not passively be transferred with serum from patients. They were abolished by antihistamine given before testing, and by pretreatment with compound 48/80. Balsam of Peru and cinnamic aldehyde did not provoke new symptoms when given orally to patients.     

Delayed-type allergy to spices

9 common spices were tested epicutaneously in 338 dermatological patients, 118 of whom were allergic to balsam of Peru. Positive reactions to one or more spices were seen in 50 patients all of whom except 2 were allergic to balsam of Peru. The spices giving positive reactions most often were clove, Jamaica pepper and cinnamon (cassia). 2/3 of the patients allergic to balsam of Peru or spices were women, usually suffering from hand eczema. Peroral challenge with spices was carried out in 71 patients allergic to balsam of Peru. Pompholyx on the palms and other objective symptoms were encountered in 7 cases, 3 of whom showed no reactions to spices in epicutaneous tests.     

Propolis allergy

The incidence of propolis contact sensitivity was 1.2-3.3% among 7483 hospital patients during the period 1981-1987, while the prevalence among 1,558 healthy volunteers was 0.64%. A group of 26 patients with contact allergy to propolis was challenged with identified substances isolated from propolis. The mixture of 3-methyl-2-butenylester (3M2B) and 3-methyl-3-butenylester (3M3B) from caffeic acid caused a positive reaction in 7 patients, and in 5 of 9 patients there was a positive reaction to the mixture of 3M2B and 3M3B from diacetyl-caffeic acid. Among the 19 patients challenged with the flavonoid group, 3 had positive reactions, and individual derivatives of cinnamic acid caused positive reactions in 3 and 4 patients each. When five components taken from poplar buds were tested, the one that provoked the largest number of positive reactions was the methanol component (15 of 19 patients). The results show that propolis contact allergy is not caused by one main allergen, but by several allergens varying in chemical composition; the presence of these in propolis depends on the nature of the source plant and the place and time of collection by the bees.     

Current contact allergens

We present the patch test results of 2,623 patients treated at the Department of Dermatology, University of Heidelberg, from July, 1984 to June, 1986. One test at least was positive in 680 patients (25.9%). 257 allergens produced a total of 1,450 positive reactions. (average: 2.1 per patient). 9.7% of the allergens caused 64.4% of the positive reactions. The 5 most frequent allergens were nickel sulfate, balsam of Peru, formaldehyde, neomycin sulfate, and cobalt sulfate. Mixed fragrances and Kathon CG were among the 20 most frequent allergens though only tested during half of the study period. Glyceril monothioglycolate was the leading allergen with hairdressers. Other allergens clinically relevant were rubber gloves, bufexamac, bronopol, and propolis.     

Sensitization to olive oil (olea europeae)

Sensitization to olive oil is seldom reported in the literature. By use of epiculaneous tests a delayed type of hypersensitivity to pure freshly-prepared olive oil could be demonstrated in two patients. Patch tests with certain major constituents of olive oil; the methyl ester of linoleic acid, the glyceryl ester of palmitic acid, the glyceryl ester of stearic acid, glyceryl trioleate and glycerids of arachidic acid, appeared to be negative. In one patient a weak, reaction to balsam of Peru was found, ft is concluded that Sensitization to olive oil must be taken into consideration, especially when it is used as a vehicle in patch testing.     

Assessment of balsam of Peru patch tests

To find an ideal test technique for as low a dose of balsam of Peru (Myroxylon Pereirae) as possible, subjects testing positive to balsam of Peru are re-tested with a 25% concentration of balsam of Peru in petrolatum. Applications are with Finn Chambers for 6 different application times, and directly by foils for 96 h (4 days (D)). The goals are to confirm which subjects are positive and which are not, and, using that information, to see if it is possible to distinguish between these 2 groups, tested concomitantly at much lower serial dose levels, in terms of perfusion or by visual assessments. 5 different serial doses are applied with strips for 3-96 h (4D) and with foils for 96 h (4D). The Finn Chamber tests allow a distinction between visually positive and negative subjects supported by perfusion assessments. With the foils, a 24x lower serial dose level than with the 25% test substance is sufficient to distinguish between positive and negative subjects in terms of perfusion values. This approach requires readings up to 9 days. With this test, the visual approach yields only 3 of 10 positive subjects. This study demonstrates that a lower test dose is possible with perfusion assessments compared to visual ones.     

Oral challenge with balsam of Peru

A placebo-controlled, double-blind, oral challenge with balsam of Peru was carried out in 221 patients with various types of dermatitis. 210 patients completed the study, and 45 of them experienced a flare of their symptoms after challenge with balsam of Peru but not after placebo. 15 patients reacted to the placebo, and 5 reacted to both balsam and placebo. Specific reactivity to balsam of Peru was seen particularly in patients with positive patch tests to this compound and in some patch-test-negative patients with vesicular hand eczema, ano-genital and axillary eczema. Dietary restriction of the intake of balsams was followed by marked improvement or clearance of the dermatitis in approximately half of the patients who adhered to the diet for at least 1 month.     

The influence of shaving method on perfume allergy

Among men, the most frequent contact allergens are perfumes (fragrance mix and balsam of Peru). Considering that the main cause of nickel allergy is ear-piercing, shaving with a razor blade might be the cause of perfume contact allergy, by creating small wounds that increase the penetration of applied perfume substances derived from soaps, shaving foams and after-shave lotions. 19 males with contact allergy to fragrance mix and/or to balsam of Peru were interviewed about their shaving habits by letter. 17 responded (89%), of whom 12 (71%) had been using razor blades continuously for a period of at least 1 year. At our clinic, the frequency of razor blade usage was found to be 45% in patch tested men without perfume contact allergy. When comparing the frequencies of razor blade usage among patch tested men with and without perfume contact allergy, there was a statistically significant over-representation ( p = 0.047) among those with perfume allergy. The risk of perfume allergy when using razor blades was found to be 2.9 (odds ratio).