Chiappini, Elena

De Martino, Maurizio

Galli, Luisa

Montagnani, C

Mori, F

Novembre, Elio Massimo

Pantano, S

Rossi, Me

English

Florence Research

International Journal of Immunopathology and Pharmacology2015, Vol. 28(3) 411 –414© The Author(s) 2015Reprints and permissions: sagepub.co.uk/journalsPermissions.navDOI: 10.1177/0394632015589518iji.sagepub.comIntroductionThe antimalarial artemisin (Chinese: qinghaosu; belonging to the traditional Chinese medicine) is the active principle extract of the plant qinghao [Artemisia annua Linnnaeus (L.)]. This plant belongs to the family of Asterbaceae composed of more than 23,000 species. Artemisia vulgaris L (mugwort or common wormwood) is one of sev-eral species in the genus Artemisia and it is found mainly in Europe. Artemisia vulgaris L is very similar to Artemisia annua L.1Antimalarial properties of this weed plant were discovered in China in 1972.Because artemisin itself has physical properties, such as poor bioavailability, that limit its effective-ness, semi-synthetic derivates of artemisin have been developed. Two of these are artesunate (water soluble) and artemether (lipid soluble). The water soluble is used orally and by injection and the lipid soluble is used intramuscularly. In particular, artesunate is a highly efficacious and relatively safe antimalarial agent. Consequently, artesunate is the most widely used of these antimalarials worldwide.2Skin prick test results to artesunate in children sensitized to Artemisia vulgaris LF Mori,1 S Pantano,2,3 ME Rossi,1 C Montagnani,3 E Chiappini,3,4  E Novembre,1,3 L Galli3,4 and M de Martino3 AbstractArtemisia vulgaris L and Artemisia annua L (Chinese: qinghao) are similar plants of the Asterbaceae family. Artesunate, a semi-synthetic derivate of artemisin which is the active principle extract of the plant qinghao, has antimalarial properties. Some cases of severe allergic reactions to artesunate have been described.The purpose of this study was to evaluate the association between positive skin tests to Artemisia vulgaris L allergen and a preparation of injectable artesunate.A total of 531 children were skin prick tested with inhalants (including Artemisia vulgaris L), foods, and artesunate.Among the 59 patients positive to Artemisia vulgaris L only one child was also positive to artesunate. No child was positive to artesunate in those negative to Artemisia vulgaris L.We conclude that Artemisia vulgaris L sensitization is not associated with sensitization to artesunate; consequently, skin test to artesunate should not be carried out before using the drug considering the rare allergic reactions.KeywordsArtemisia vulgaris L, artesunate, children, skin prick testsDate Received 16 September 2014; accepted 8 May 20151 Allergy Unit, Anna Meyer Children’s University Hospital, Florence, Italy2 Department of Pediatrics, St Salvatore Hospital, University of Aquila, Italy3 Department of Health Sciences, University of Florence, Anna Meyer Children’s University Hospital, Florence, Italy4 Infectious Diseases Unit, Anna Meyer Children’s University Hospital, Florence, ItalyCorresponding author:Maurizio de Martino, Anna Meyer Children’s University Hospital, Department of Health Sciences, University of Florence, Viale Pieraccini, 24 50139, Florence, Italy. Email: maurizio.demartino@unifi.it589518 IJI0010.1177/0394632015589518International Journal of Immunopathology and PharmacologyMori et al.research-article2015Letter to the editor412 International Journal of Immunopathology and Pharmacology 28(3) According to a prospective study on 3500 patients, artesunate and artemether are both remark-ably well tolerated.3 Severe allergic reactions have been rarely reported with artesunate use.4Severe allergic reactions to oral artesunate have been reported4 as well as anaphylaxis to parenteral artesunate. Both events are extremely uncommon in spite of its widespread use. Literature search reveals only two case reports of anaphylaxis to intravenous artesunate.5,6 It is poorly known whether allergic reactions to artesunate depend on cross-reactions to Artemisia vulgaris L and consequently whether sub-jects allergic to Artemisia vulgaris L are at higher risk of allergic reactions to artesunate. This hypoth-esis is biologically plausible since Artemisia annua L and Artemisia vulgaris L belong to the same genus. In the present study we evaluated in a pediatric pop-ulation the association between positive skin tests to Artemisia vulgaris L allergens and a preparation of injectable artesunate.Materials and methodsFrom September 2012 to February 2013, 530 chil-dren (mean age, 99 months; age range, 7–211 months; male to female ratio = 1.62) referred to the Allergy Unit of the Anna Meyer Children’s University Hospital, were consecutively evaluated for suspected allergy to foods or inhalants.In particular, 29% children had history of asthma, 20.7% children suffered from conjunctivi-tis and rhinitis, 13.6% children had rhinitis, 9.7% children had atopic dermatitis, and 10.6% children had history of reactions to foods.Skin tests were performed and read after 10 min by the same investigator in order to avoid variability linked to the operator. We tested all children with common inhalants and foods (pol-lens, mites, molds, cat and dog epithelia, milk, albumen, soy, wheat, cod fish, peanut, latex; com-mercial extracts, at 0.1 mg/mL concentration Alk Abellò, Milan, Italy). The pollens tested were grass, olive, Cupressus arizonica, Betula pendula (birch), Artemisia vulgaris (mugworth), Carpinus betulus, and Parietaria mix (pellittory). Patients suspected to be allergic to nuts (i.e. almond, hazelnut, walnut) were tested with the culprit nut by using the prick-to-prick method. Skin prick tests were performed on the volar surface of the forearm by using a standard 1-mm tip lancet, according to the recommendations of the European Academy of Allergy and Clinical Immunology group.7Positive controls for prick and prick-to-prick tests were performed with histamine (Alk-Abellò, Milan, Italy: 10 mg/mL concentration). Normal saline was used as a negative control of prick and prick-to-prick tests.The skin prick test results were considered posi-tive if the difference between the mean diameter of the wheal and the negative control was at least of 3 mm. Children had been off antihistamines or oral corticosteroids 10 days before skin testing.Moreover, all children underwent skin prick test with artesunate (intravenous formulation), Guilin Pharmaceutical Co, Ltd., PR China) at 60 mg/mL concentration. Such a concentration was obtained by adding sodium bicarbonate at 5% to the vial. Given the fact that no previous studies had been published on skin prick tests to artesunate we decided to test the full strength concentration.8ResultsThree hundred and sixty-three (68.5%) out of 530 patients were skin test positive to one or more allergens (Table 1). Six patients were negative to inhalants but they were sensitized to food (two to milk, one to egg, one to almond, one to hazelnut, and one to walnut).Among the 59 patients positive to Artemisia vulgaris L only one (1.7%) child was also positive to artesunate with a wheal diameter of 3 mm. On the other hand none was positive to artesunate in the group of children negative to Artemisia vul-garis L.The child, sensitized to both Artemisia vulgaris L and artesunate, had a history of seasonal rhinitis and conjunctivitis, plus angioedema with almond and he was positive to almost all inhalants.In the group of 59 patients (48 boys, 11 girls) sensitized to Artemisia vulgaris L, six children were monosensitized to such a pollen.Moreover about half (27 children; 45.8%) of the 59 patients positive to Artemisia vulgaris L suf-fered from both seasonal rhinitis and conjunctivitis and 21 (35.6%) children had asthma.Three out of 59 patients had an Artemisia vul-garis L wheal diameter >8 mm, in particular the only patient with a double positivity to both Artemisia vulgaris L and artesunate had an Artemisia vulgaris L wheal diameter of 8 mm.Mori et al. 413DiscussionThis is the first pediatric study about possible in vivo cross-reactivity between Artemisia vulgaris L and artesunate. According to our results there is no a correlation between the skin prick test to Artemiasia vulgaris L and the risk of being artesu-nate sensitized.We studied the sensitization to artesunate in chil-dren sensitized to inhalants and in particular in the group of those sensitized to Artemisia vulgaris L. Fifty-nine out of 363 patients sensitized to inhalants were positive to Artemisia vulgaris but only one child had a double positivity to Artemisia vulgaris and artesunate, showing that our results were not affected by the fact that the study was carried out not in a random group of children, but in a group with an increased chance of a positive skin test.According to the experience of Leonardi and co-workers,9 17,000 patients have been treated with artemisin derivatives but allergic reactions occurred in only six cases (out of them two children). The incidence of allergic reactions to artemisin deriva-tives was one out of 2833 treated patients. Such a low incidence of allergic reaction is in agreement with a recent paper showing the antiallergic prop-erties of artesunate in mouse model.10 In the publi-cation by Leonardi and co-workers, all six patients had urticaria and in two cases, who also developed an anaphylactic reaction, epinephrine was required due to the severity of the reactions. Both patients had previously been prescribed artesunate.9 In par-ticular, the two children, who were treated with artemisin derivatives plus mefloquine, had urti-caria, but it was not possible to prove a state of hypersensitivity because urticaria did not recur when using the drugs a second time.3 The authors had not investigated the role of a possible Artemisia species sensitization. Anyway, artemisin deriva-tives should not be used to treat uncomplicated Plasmodium falciparum malaria if there is a previ-ous history of allergic reactions after their use, or if an urticarial rash develops during treatment.Dube et al.5 and Mohapatra et al.6 published case reports of anaphylaxis to intravenous artesunate administered to adults. Recently, adverse drug reactions to artesunate have been related to genetic polymorphisms of CYP 2A 6 as well as gender influence.11The sensitization to Artemisia vulgaris L cannot predict the occurrence of allergy to artesunate, never mind the severity of possible reactions with the use of intravenous artesunate. Given the scarcity of reports on allergy to artesunate (fewer than 10 cases published in literature while more than 200 million treatment courses administered every year), we think that the presence of a positivity to artesunate should not be checked when intravenous adminis-tration with this drug is required, even considering that such an investigation is safe and very poorly Table 1. Inhalants and artesunate skin tests results.Allergen Positive children (n [%]) in the overall dataset (n = 530)Positive children (n [%]) among allergic children (n = 363)Dermatophagoides pteronyssinus 252 (47.5%) 252 (69.4%)Dermatophagoides farinae 251 (47.5%) 251 (69.4%)Grass pollen 232 (43.8%) 232 (63.9%)Dog epithelium 157 (29.6%) 157 (43.2%)Olive pollen 130 (24.5%) 130 (35.8%)Cupressus arizonica pollen 127 (24%) 127 (35%)Cat epithelium 122 (23%) 122 (33.6%)Carpinus betulus pollen 71 (13.4%) 71 (19.6%)Betula pendula pollen 69 (13%) 69 (19%)Alternaria alternata 62 (11.7%) 62 (17.1%)Artemisia vulgaris pollen 59 (11%) 59 (16.2%)Parietaria mix 52 (9.8%) 52 (14.3%)Horse epithelium 28 (5.3%) 28 (7.7%)Rabbit epithelium 19 (3.6%) 19 (5.2%)Cladosporium herbarum 8 (1.5%) 8 (2.2%)Latex 3 (0.6%) 3 (0.8%)Artesunate 1 (0.2%) 1 (0.3%)Negative patients 167 (31.5%)  414 International Journal of Immunopathology and Pharmacology 28(3) time-consuming. In the current literature, all patients who described having had a severe reaction to artesunate had not been previously investigated from an allergy point of view. However, since in high-endemic countries the World Health Organization12 recommends artemisin-based com-bination treatments (ACTs) as the first-line therapy of uncomplicated malaria and intravenous artesu-nate for the treatment of severe malaria, limiting the use of a life-saving drug because of very rare possi-ble occurrences of severe allergic reactions may be unreasonable. Therefore, careful reports of severe adverse events when administering intravenous artesunate may be more reasonably encouraged. In low-endemic countries, considering that parenteral artesunate is not currently available as manufactured under Good Manufacturing Practices and conse-quently is not registered by regulatory agencies, intravenous artesunate can only be administered in severe malaria with a very high parasitemia by expert physicians to reduce mortality in severe imported malaria cases.13 In this setting, in our opin-ion, only in the rare subjects with a skin test positive to artesunate and a history of artemisin reaction, the intravenous use of such a drug should be carefully evaluated.AcknowledgementsThe authors thank Dr Giancarlo la Marca at Biochemistry and Pharmacology Labs, Anna Meyer Children’s University Hospital, Florence, Italy for drug samples preparation.Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.FundingThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.References 1. Funk VA, Susanna A, Stuessy TF, et al. (2009) Classification of compositae. In: Funk VA, Susanna, Stuessy TF, et al. (eds) Systematics, Evolution, and Biogeography of Compositae. Vienna: International Association for Plant Taxonomy (IAPT). 2. Price RN (2000) Artemisinin drugs: Novel antimalar-ial agents. Expert Opinion on Investigational Drugs 9: 1815–1827. 3. Price R, van Vugt M, Phaipun L, et al. (1999) Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. American Journal of Tropical Medicine and Hygiene 60: 547–555. 4. Rosenthal PJ (2008) Artesunate for the treatment of severe falciparum malaria. New England Journal of Medicine 358: 1829–1836. 5. Dube SK, Panda PS, Agrawal GR, et al. (2012) Anaphylaxis to artesunate? Indian Journal of Critical Care Medicine 16: 55–57. 6. Mohapatra MK, Srinivas D, Kar AK, et al. (2009) Anaphylactic reaction to intravenous artesunate. Journal of the Association of Physicians of India 57: 183–184. 7. Dreborg S (1989) Skin tests used in the diagnosis of type I allergy testing: Position paper. Allergy 44 (Suppl. 10): 22–31. 8. Brockow K, Garvey LH, Aberer W, et al.; ENDA/EAACI Drug Allergy Interest Group (2013) Skin test concentrations for systemically administered drugs – an ENDA/EAACI Drug Allergy Interest Group posi-tion paper. Allergy 68: 702–712. 9. Leonardi E, Gilvary G, White NJ, et al. (2001) Severe allergic reactions to oral artesunate: A report of two cases. Transcripts of the Royal Society of Tropical Medicine and Hygiene 95: 182–183. 10. Cheng C, Ng DS, Chan TK, et al. (2013) Anti-allergic action of anti-malarial drug artesunate in experimen-tal mast cell-mediated anaphylactic models. Allergy 68: 195–203. 11. Yusof W and Hua GS (2012) Gene, ethnic and gen-der influences predisposition of adverse drug reac-tions to artesunate among Malaysians. Toxicology Mechanisms and Methods 22: 184–192. 12. World Health Organization (2010) Guidelines for the treatment of malaria. 2nd edn. Geneva: World Health Organization. 13. Bartoloni A, Tomasoni L, Bartalesi F, et al. (2010) Combined intravenous treatment with artesunate and quinine for severe malaria in Italy. American Journal of Tropical Medicine and Hygiene 83: 274–276.

Skin prick test results to artesunate in children sensitized to Artemisia vulgaris L.

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Skin prick test results to artesunate in children sensitized to Artemisia vulgaris L.

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