Cop?rigltt 0 Mlcnksgaard 1 9 9 9

CONTACT DERMATITIS ISSN 0105-1873

A study of the - sensitization rate to sesquiterpene lactone mix in Singapore

EILEEN TAN, YLSG HIAN LEOW. SEE KET NG AND CHEE LEOK GOH National Skin Centre. 1 Mandalay Road, Singapore 308205

We report a study of the sensitization rate to sesquiterpene lactone (SL) mix at the National Skin Centre. Singapore. This is a retrospective review of 1256 patients who were patch tested to SL mix (0.1%) from January 1995 to December 1997. 18 out of 1256 patients (1.43%) reacted positively to SL mix. Their ages ranged from 13 to 58 years (average 33.8 years). There were 15 Chinese, 2 Indian and 1 Malay patients. There was a female preponderance, with a female: male ratio of 3.5: 1. The most common clinical presentation were dermatitis of the hands (8; 44%), face (5 ; 28%), and generalized involvement ( 5 : IS%,). After extensive evaluation, only 2 patients had a positive patch test reaction that was of current clinical relevance. 13 patients had concomitant sensitization to other allergens. The 3 commonest concomitant allergens were nickel, balsam of Peru and fra- grance mix. In our series, SL allergy is observed to be more common in females and the mean age is laver compared to the classical Compositae dermatitis. The sensitization rate is comparable to other studies, although the clinical relevance is only 1 I'%.

K q . ~ w d , s ; allergic contact dermatitis; contact allergy; plants; Compositae: sesquiterpene lactone mix; plant extracts; herbal remedies; medicaments; occupational. 0 Munksgaard, 1999.

Accepted for publication 5 d4orch 1999

Sesquiterpene lactones (SLs) are a large, diverse group of compounds found in the Compositae family of plants. They are capable of causing al- lergic contact dermatitis, with an incidence vary- ing from country to country (1, 2). The present study from January 1995 to December 1997 was made to analyse the sensitization rate to sesquiter- pene lactone in Singapore.

Materials and Methods

The commercial preparation of 0.1% sesquiterpene lactone (SL) mix in petrolatum (Hermal, Reinbek, West Germany) was included in the European standard patch test series at our centre from Jan- uary 1995. A total of 1256 patients were patch tested from January 1995 to December 1997. All patients were patch tested t o the European stan- dard series. The testing agents were applied to Finn Chambers (Epitest Ltd., Helsinki, Finland) which were fixed to the upper back with Scanpor tape, then secured by 3M tape. The patches were removed after 2 days (D) and the test sites were examined for evidence of reaction at D 3. Positive reactions were graded from + to +++. as rec- ommended by the International Contact Derma- titis Research Group ( 3 ) .

Res u I ts

1256 patients were patch tested to the European standard series at our specialist contact clinic from January 1995 to December 1997. The patients were referred from general practitioners to the National Skin Centre. They were initially screened at the general dermatology clinic and they were then re- ferred to the contact clinic for suspected allergic or irritant contact dermatitis. However, none of the referrals bore a clinical suspicion of sesquiterpene lactone allergy.

18 out of 1256 patients (1.43%) had a positive patch test reaction t o SL mix in the standard series (Table 1). 14 were female and 4 male. Their ages ranged from 13 to 58 years. There were 15 Chinese, 2 Indian and 1 Malay patients. After extensive evaluation, there was no direct clinical correlation in 16 of the patients with a positive PT reaction. The other 2 are described below.

Case no. 1

A 37-year-old Chinese physician-cum-chiropractor for more than 10 years. He was exposed to various herbs, oils and ointments in his working environ- ment. He had first presented with a photodistribut-

SESOUITERPENE LACTONE SENSITIZATION 81

Tuhle 1. Cases of allergy to SL mix from 1995-1997

No (years) Sex Race Occupation atopy involvement Source of sensitization Age Existing Site of

1 37 M Chinese Chinese physician cum chiropractor - generalized possibly occupational 2 58 F Chinese teacher + face unknown 3 43 M Chinese factory operator - hands unknown 4 19 F Chinese student + generalized unknown 5 18 F Chinese student + generalized unknown 6 37 M Chinese teacher + generalized. unknown 7 33 F Chinese psychotherapist - face unknown 8 38 F Chinese despatch worker - hands unknown

unknown 9 31 F Chinese clerk - face 10 24 F Chinese hawker - hands unknown 11 55 M Chinese hawker - hands unknown 12 49 F Indian school cleaner - hands unknown 13 36 F Chinese housewife - hands unknown 14 13 F Chinese student - hands topical herbal medicament 15 24 F Chinese clerk + hands unknown 16 31 F Chinese housewife - generalized unknown 17 23 F Malay engineer - face unknown 18 40 F Indian housewife - face unknown

ed dermatitis 5 years ago, but it had later become generalized. All investigations, including full blood count, electrolytes, liver function, serudurine por- phyrins and ANA, were within normal limits. A skin biopsy was reported as chronic dermatitis. Phototesting showed a markedly reduced minimal erythema dose (MED) (10 J/cm2) to UVA. Patch testing showed a positive reaction to SL mix, nut- meg oil, turpentine oil, oil mixtures and vinyl gloves. He declined a photopatch test. After much evaluation, a final diagnosis of chronic actinic der- matitis was made because of the clinical features in association with the reduction in the MED to UVA. A delayed hypersensitivity reaction to SL was suggested as a possible contributory factor. He was started on potent topical corticosteroid but with minimal improvement of the dermatitis. Other treatment options like PUVA and azathio- prine were considered, but the patient declined them.

Case no. 2

A 13-year-old girl who presented with acute der- matitis of both hands and forearms. She recalled applying a topical herbal medicament (contents unknown) to the wrist for a week preceding the dermatitis. Patch testing was positive to the herbal medicament and to SL mix. We postulated that the herbal medicament might contain Compositae ex- tracts.

13 patients (10 female, 3 male) had concomitant allergens detected in the standard series. The com- monest of these were nickel (9), balsam of Peru ( 5 ) and fragrance mix (4). The others included oil mixtures, neomycin, flavine, colophony, thimerosal and vinyl gloves (Table 2).

Discussion

Plants belonging to the Compositae family have long been recognised as an important cause of al- lergic contact dermatitis. They are commonly found in gardens, as house plants and widely dis- tributed in nature. Some of the Compositae that are found in tropical countries such as Malaysia and China include chrysanthemun, dandelion and lettuce. In Singapore, the majority of the Composi- tae plants are imported in the form of medic- aments, fresh flowers and vegetables.

In 1970 and 1971, Mitchell et al. (4, 5 ) isolated and identified SLs as the allergen responsible for al- lergic contact dermatitis from Compositae. The current commercial SL mix is a mixture of 3 lacton- es in equimolar quantities, namely alantolactone, dehydrocostus lactone and costunolide. In recent studies, several authors (6, 7 ) have highlighted the importance of testing the response of SL-mix-nega-

Tuble 2. Patients with concomitant allergens Patient Concomitant allergens nohex

1 IM

21F 31M 4/F 5/F 9/F

1 O/F 1 IIM 12lF 13lF 15/F 16/F 17/F

nutmeg oil 10% +, turpentine oil 10% +, vinyl glove, oil mixture 10% + nickel sulfate 5% + +, balsam of Peru + nickel sulfate 5% ++, flavine + nickel sulfate 5% ++, neomycin 20% +. thimerosal + nickel sulfate 5% + +, balsam of Peru + nickel sulfate 5% ++, thimerosal + nickel sulfate 5% + +, positive prick test to prawns, squid fragrance mix +, colophony 20% + +, balsam of Peru + nickel sulfate 5% + +, balsam of Peru + nickel sulfate 5% + + fragrance mix + +, balsam of Peru + nickel sulfate 5% + +, fragrance mix + fragrance mix + +

tive patients to additional Compositae extracts, when there is a clinical suspicion of SL allergy.

The risk of sensitization after exposure to SL- containing plants seems highly individualized; little is known about the risk of sensitization after ex- posure (4) . Generally, the incidence of SL allergy is thought to be relati\,ely low ( I , 2). In various studies, the reported sensitization rates fall be- tween 1.4-1.8Y0 on routine patch testing (1. 2. 6. 8). Our local series seemed to echo this obser- vation, as only 18 out of 1356 patients (sensitiza- tion rate of 1.43%) were reported as positive to SL mix, only 2 ( 11%) of which reactions were deemed clinically relevant.

Compositae dermatitis was originally described mainly in men over 40 years of age with a history of outdoor exposure; women and children seemed rarely to be affected (9). In our study, there was a female preponderance, with a female-to-male ratio of 3.5: 1. Our patients tended to be younger. their average age being 33.8 years and the majority fall- ing between 20-35 years. The average age of the female cohort was 31 years (the youngest being 13 years) and that of the male 43 years. Our study seemed to suggest an increase prevalence of SL al- lergy in younger women. This may be explained by women having a higher risk of exposure to differ- ent skin care products, perfumes and medicaments.

Compositae dermatitis has variable clinical pres- entations ( 8 ) and recurrent summertime flares are typical (10). In our series. the most common clin- ical presentations were dermatitis of the hands ( 8 ; 44'%1, 5 female and 2 male). face ( 5 ; 28'%, all were female) and generalized involvement ( 5 ; 28%: 3 fe- male and 2 male). 5 patients had existing atopy. This selected group had variable clinical presen- tations and patch testing revealed sensitization to multiple allergens. In 8 patients (6 female and 2 male; patient nos. 1, 3. 6. 7. 9, 16, 17 and 18). a history of sun aggravation suggested photosensit- ivity. These patients presented with face and/or generalized dermatitis. They underwent cutaneous phototesting but only 1 male patient (patient no. I ) had an abnormal test result.

Current clinical relevance could be postulated in only 2 out of the 18 patients. None of the patients had direct occupational exposure in horticulture or floristry. In addition. 15 patients denied re- creational exposure to plants or plant extracts. On further questioning, however, all patients had been exposed to some form of herbal product pre- viously (orally and/or topically). Examples include chrysanthemun. elecampane, etc. It is common and culturally acceptable to seek traditional heal- ing i n Singapore and we believe that our patients may have been sensitized inadvertently by increas- ingly popular "natural" remedies. However, the

importance of this mode of sensitization remains largely unknown.

In our series, the 3 commonest concomitant allergens were nickel (9). balsam of Peru ( 5 ) and fragrance mix (4). The rest included oil mixtures, neomycin, flavine, colophony, thimerosal and vinyl gloves. Concomitant sensitization to other aller- gens is not uncommon in SL-sensitized individuals. Cross-reactions to balsam of Peru and fragrance mix have been explained by the presence of SL- related contents (1 1) . Cross-reactions to anti- genically distant diterpenes, such as colophony, and monoterpenes, such as turpentine, have also been previously reported (1 2).

In patient no. 1, the diagnosis of chronic actinic dermatitis was made by the clinical features in as- sociation with a reduction in the MED to UVA. He was exposed to various herbs, oils and ointments in his working environment and was probably occu- pationally sensitized. He stopped working for 8 months and avoided the allergens, but there was only minimal improvement in his dermatitis. His clinical presentation seemed to suggest a possible link between SL allergy and chronic actinic derma- titis or a persistent reactor state (8,9, 13).

Patient no. 14 is an example of an individual who most likely developed allergic contact derma- titis from SL-containing topical herbal medication. However, we recognize that further chemical analy- sis of contents is necessary to substantiate our hypothesis.

Conclusion

We conclude that the rate of sensitization to SL mix (1.43%) is relatively low, though comparable to European series. The limitation remains that our review was retrospective and some valuable in- formation. especially with regard to exposure his- tory and contactants, may have been lost. When- ever possible, a detailed search is necessary to as- certain the clinical relevance, such that avoidance of the allergens can be emphasized.

In summary, the diagnosis of SL allergy is not al- ways straightforward in view of its variable clinical features. Therefore, we consider that SL mix should remain in the standard patch test series as a screen- ing tool for possible Compositae allergy. Although 16 out of the 18 patients had no current clinical cor- relation, they may have been sensitized unknow- ingly through increasingly popular proprietary preparations containing Compositae extracts.

References 1 , Ducombs G. Benezra C, Talaga P, Andcrson K E, Burrows

D. Camarasa J G, Dooms Goossens A. Patch testing with

SESQUITERPENE LACTONE SENSITIZATION 83

sesquiterpene lactone mix: A marker for contact allergy to Compositae and other sesquiterpene lactone containing plants. A multi-center study of the EECDRG. Contact Der- matitis 1990: 22: 249-252.

2. Roed-Petersen J, Hjorth N. Compositae sensitivity among patients with contact dermatitis. Contact Dermatitis 1976; 2: 271-281.

3. Wilkinson D S, Fregert S, Magnusson B, et al. Terminology of contact dermatitis. Acta Dermato-venereologica 1970; 50: 287-292.

4. Mitchell J C, Fritig B, Singh B, Towers G H N. Allergic contact dermatitis from Frullania and Compositae. The rBle of sesquiterpene lactones. J Invest Dermatol 1970; 54: 233-239.

5 . Mitchell J C, Geissman T A, Dupuis G, et al. Allergic con- tact dermatitis caused by Artemisia and Chrysanthemum species. The rBle of sesquiterpene lactones. J Invest Derma-

6. Paulsen E, Andersen K E, Hausen B M. Compositae der- matitis in a Danish dermatology department in one year (I). Results of routine patch testing with the sesquiterpene lactone mix supplemented with aimed patch testing with extracts and sesquiterpene lactones of Compositae plants. Contact Dermatitis 1993; 29: 6-10,

7. Goulden V, Wilkinson S M. Patch testing for Compositae allergy. Br J Dermatol 1998; 138: 1018-1021.

to1 1971; 56: 98-101.

8. Ross J S, Du Peloux Menage H, Hawk J L M, White I R. Sesquiterpene lactone contact sensitivity: clinical patterns of Compositae dermatitis and relationship to chronic ac- tinic dermatitis. Contact Dermatitis 1993: 29: 8 4 8 7 .

9. Arlette J, Mitchell J C. Compositae dermatitis. Contact Dermatitis 1981; 7: 129-136.

10. Paulsen E. Compositae dermatitis: a survey. Contact Der- matitis 1992; 26: 76-886.

11. Mitchell J C, Epstein W L. Contact hypersensitivity to a perfume material, Costus Absolute. The role of sesquiter- pene lactones. Arch Dermatol 1974; 110: 871-73.

12. Storrs F J, Mitchell J C, Rasmussen J E. Contact sensitivity to liverwort and the compositae family of plants. Cutis

13. Frain-Bell W, Johnson B E. Contact allergic sensitivity to plants and the photosensitivity dermatitis and actinic reti- culoid syndrome. Br J Dermatol 1979; 101: 503-512.

1976; 18: 681-686.

Address: Eileen Tan National Skin Centre I Mandalay Road Singapore 30820.5