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Concomitant Sensitization to Inhaled and Oral Presenting as Allergic Contact Stomatitis and Systemic Allergic

Francisco Vega, MD; Tania Ramos, MD; Paloma Las Heras, MD; Carlos Blanco, PhD

PRACTICE POINTS • When lesions develop in the oral cavity during treatment with inhaled copycorticosteroids, delayed contact should be considered in the differential diagnosis along with fungal . • Although it generally is not considered to be allergenic due to its poor intestinal absorption, oral nystatin may induce systemic allergic disorders. • All drugs involved in a presumed allergic reaction must be evaluated since concomitant sensitization to multiple drugs could be present. Patch and challenge testingnot should be conducted to diagnose allergic contact dermatitis and assess drug cross-reactivity. Do

Concomitant allergic reactions to multiple drugs he development of concomitant allergic are uncommon. We report the case of a 66-year-old reactions to multiple drugs is uncommon. woman who presented with concomitant sensitiza- Dermatitis induced by topical or inhaled T 1 tion to inhaled budesonide and oral nystatin pre- (eg, budesonide) is rare, and allergic senting as allergic contact stomatitis and systemic reactions associated with oral nystatin, a macro- allergic contact dermatitis.CUTIS It is notable that one of lide drug, also are unusual.2 We present the reactions was caused by oral nystatin, which the case of concomitant sensitization to inhaled generally is not considered to be allergenic due budesonide and oral nystatin presenting as allergic to its poor intestinal absorption. Diagnoses were contact stomatitis and systemic allergic contact confirmed on patch testing with histologic exami- dermatitis. Concomitant allergic reactions to these nation along with oral challenge testing. We also treatments are rare and may result in diagnostic chal- used challenge testing to rule out cross-reactivity lenges for the physician. among nystatin and other macrolide drugs, both and . Case Report Cutis. 2016;97:24-27. A 66-year-old woman presented to the Allergy Department for evaluation of painful erosions on the oral mucosa that had developed 72 hours after she started treatment with inhaled budesonide (400 mcg From the Department of Allergy, Instituto de Investigación Sanitaria every 12 hours) prescribed by her general practitioner Princesa, Hospital Universitario de la Princesa, Madrid, . for a nonproductive cough. Budesonide The authors report no conflict of interest. Correspondence: Francisco Vega, MD, Hospital Universitario de la was discontinued due to suspected oral Princesa, Diego de León St 62, Madrid 28006, Spain and treatment with oral nystatin (500,000 IU every ([email protected]). 8 hours) was started, but the erosions did not resolve.

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After 2 days of treatment with oral nystatin, the the poor intestinal absorption of nystatin, systemic patient presented with erythematous macules on the contact dermatitis to this drug has been previously abdomen and thighs as well as a larger erythematous described.3 Patch testing with macrolides proved and edematous lesion with papules and vesicles useful for diagnosis in our patient, and based on on the hypothenar eminence of the right hand. the results we concluded that polyethylene glycol Nystatin was discontinued and the lesions turned seemed to be the optimal vehicle for patch testing desquamative and healed spontaneously 7 days later. macrolide drugs versus water or petrolatum, as has The oral lesions resolved after 15 days with no fur- been previously suggested.4 ther treatment. When a diagnosis of drug allergy is established, Patch testing was conducted using a commer- it is important to rule out cross-reactivity with other cially standard series of contact , all of similar drugs by assessing if they produce the same reac- which showed negative results at 48 and 96 hours tion despite differences in chemical structure. Possible except for budesonide and , which led cross-reactivity of nystatin with other macrolides to the diagnosis of allergic contact stomatitis from (validated on patch testing) has been reported but the the inhaled budesonide. Patch testing with other tolerability was not evaluated.5 Our patient showed corticosteroids was negative. Challenge tests with good tolerability to other macrolide drugs, both anti- alternative corticosteroids (ie, oral methylpredniso- biotics and antifungals. Therefore, nystatin does not lone, parenteral , topical seem to cross-react with other structurally related drugs furoate, inhaled ) were negative. belonging to the macrolide group based on our results. In order to rule out involvement of oral nystatin, are more common than a single-blind, placebo-controlled oral challenge test those associated with macrolides, especially con- was performed. Eight hours after taking oral nystatin tact dermatitis.copy Nonhalogenated corticosteroids (500,000 IU), erythematous macules developed on (eg, , budesonide) are most frequently the patient’s abdomen along with an erythematous, associated with allergic reactions,6 and patch test- 3×4-cm lesion with papules on the hypothenar emi- ing remains the diagnostic method of choice for the nence of the right hand that was similar in appear- detectionnot of delayed to corticoste- ance to the original presentation. The lesion on roids. In , standard series include budesonide the hand was biopsied and histologic examination and pivalate, and in the revealed spongiosis, of the superficial dermis, they include hydrocortisone 17–butyrate, triamcino- perivascular lymphocytic infiltrates, and extravaDo- lone acetonide, and 17–propionate.6 sated erythrocytes with no vasculitis. Further patch testing subsequently was conducted with antifungal and macrolides in different vehicles (ie, petrolatum, water, polyethylene glycol), as well as with excipients of the oral nystatin formulation that had been tested (Figure). Patch testing was posi- tive with nystatin 10% in petrolatum and nystatin 30,000 IU and 90,000 IUCUTIS in polyethylene glycol. Testing also were conducted in 7 healthy volun- teers to rule out an irritant reaction and showed negative results. Finally, challenge tests conducted in our patient with another antifungal macrolide (parenteral ) and antibiotic mac- rolides (oral clarithromycin, , and azithromycin) were negative. Patch and challenge test results along with the his- tologic findings led to diagnosis of concomitant sys- temic allergic contact dermatitis from oral nystatin.

Comment Patch test results at 96 hours for nystatin 2% in Our patient presented with 2 unusual delayed hyper- petrolatum (patch 14), nystatin 10% in petrolatum (patch 15), nystatin 30,000 IU in polyethylene glycol sensitivity reactions that occurred in the same medi- (patch 16), nystatin 90,000 IU in polyethylene glycol cal episode: allergic contact stomatitis from inhaled (patch 17), cinnamic aldehyde 1% in petrolatum budesonide and systemic allergic contact dermatitis (patch 19), paraben mix 16% in petrolatum (patch 20), from oral nystatin. It is noteworthy that, despite petrolatum (patch 21), and polyethylene glycol (patch 22).

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Classification of Corticosteroids and Cross-reactivity8

Class Structure Members Comment Group A No substitutions on the , Tixocortol 21-pivalate is (Hydrocortisone D ring except short- , the class representative; type) chain ester on C21 hydrocortisone, hydrocortisone members cross-react with acetate, , group D2 methylprednisone acetate, methylprednisone hemisuccinate, , , Group B C16, C17-cis-ketal , budesonide, (Triamcinolone or -diol structure , and budesonide are the acetonide type) acetonide, , class representatives; , triamcinolone budesonide specifically acetonide, triamcinolone cross-reacts with group D2 diacetate Group C C16 methyl substitution Betamethasone, Betamethasone is the class (Betamethasone on the D ring; desoxymethasone, copyrepresentative type) substitution , valerate, butyl, , acetate, ,not Group D1 Methyl substitution on dipropionate, Clobetasol 17-propionate is (Betamethasone C16 with side-chain beclomethasoneDo dipropionate, the class representative dipropionate type) ester on C17 and betamethasone dipropionate, possible side chain betamethasone 17–valerate, on C17/C21; , halogen substitution butyrate, diacetate, , CUTIS halobetasol propionate, mometasone furoate Group D2 No methyl substitution , Hydrocortisone 17–butyrate ( or halogenation on , is the class representative; aceponate type) C16; long-chain ester hydrocortisone 17-aceponate, members cross-react with on C17; possible side hydrocortisone 17-butyrate, group A and budesonide chain on C21 methylprednisolone aceponate,

To assess cross-reactivity among topical corti- 4 empirical groups: group A, hydrocortisone type; costeroids, patch testing with other should group B, acetonide type; group C, betamethasone be performed. In 1989, Coopman et al7 established type; and group D, ester type. The investiga- a classification system for corticosteroids based tors hypothesized that allergic contact reactions on molecular structure, thus dividing them into occurred more frequently with corticosteroids

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belonging to the same group, while cross-reactions in the differential diagnosis along with oral candi- were uncommon between groups; however, cross- diasis when oropharyngeal symptoms appear during reactivity is known to occur among corticosteroids inhaled corticosteroid along with . belonging to different groups in standard clinical We recommend that all drugs involved in a presumed practice, which conflicts with this claim. allergic reaction must be systematically evaluated Due to distinctively different behaviors among because an unexpected concomitant sensitization to certain compounds in group D, Matura et al8 pro- multiple drugs could be present. posed subdividing the ester steroids into 2 groups: group D1, containing C16 methyl substitution and REFERENCES halogenation on the B ring, and group D2, comprising 1. English JS. Corticosteroid-induced contact dermatitis: a the labile ester steroids that lack both substitutions. pragmatic approach. Clin Exp Dermatol. 2000;25:261-264. A modified classification system including these 2. Martínez FV, Muñoz Pamplona MP, García EC, subdivided groups is presented in the Table.8 et al. Delayed hypersensitivity to oral nystatin. Contact In recent years, new corticosteroid drugs such as Dermatitis. 2007;57:200-201. , fluticasone propionate, and mometasone 3. Quirce S, Parra F, Lázaro M, et al. Generalized dermatitis furoate have been developed, but classification of these due to oral nystatin. Contact Dermatitis. 1991;25:197-198. agents has been difficult due to differences in their 4. de Groot AC, Conemans JM. Nystatin allergy: petrolatum chemical structure, although mometasone furoate is not the optimal vehicle for patch testing. Dermatol Clin. and fluticasone propionate have been included in 1990;8:153-155. group D1.9 Futhermore, the structural differences of 5. Barranco R, Tornero P, de Barrio M, et al. Type IV these new steroids may mean less cross-reactivity with hypersensitivity to oral nystatin. Contact Dermatitis. other steroids, which would facilitate their use in 2001;45:60. copy patients who are allergic to classic steroids. However, 6. Jacob SE, Steele T. Corticosteroid classes: a quick cross-reactivity between mometasone furoate and cor- reference guide including patch test substances and ticosteroids belonging to group B has already been cross-reactivity. J Am Acad Dermatol. 2006;54:723-727. described,10 which may restrict its use in patients who 7. not Coopman S, Degreef H, Dooms-Goossens A. are allergic to other corticosteroids. Identification of cross-reaction patterns in allergic The classification of corticosteroids can provide contact dermatitis from topical corticosteroids. Br J useful information about cross-reactivity, which may Dermatol. 1989;121:27-34. help physicians in choosing an alternative drugDo in 8. Matura M, Goossens A. Contact allergy to corticosteroids. patients with an allergy to topical corticosteroids, but Allergy. 2000;55:698-704. this advice about cross-reactivity does not seem to 9. Baeck M, Chamelle JA, Goossens A, et al. Corticosteroid apply to systemic allergic dermatitis or immediate-type cross-reactivity: clinical and molecular modeling tools. reactions to corticosteroids.11 Therefore, in these types Allergy. 2011;66:1367-1374. of reactions, an individualized evaluation of the sen- 10. Seyfarth F, Elsner P, Tittelbach J, et al. Contact allergy sitization profile is needed, performing wider studies to mometasone furoate with cross-reactivity to group B with alternative corticosteroids by skin tests with late corticosteroids. Contact Dermatitis. 2008;58:180-181. readings and challenge tests.CUTIS 11. Torres MJ, Canto G. Hypersensitivity reactions to It is important to emphasize that hypersensitiv- corticosteroids. Curr Opin Allergy Clin Immunol. ity to corticosteroids should always be considered 2010;10:273-279.

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