Immediate hypersensitivity reactions to corticosteroids

Ann Allergy Asthma Immunol xxx (2015) 1e5

Contents lists available at ScienceDirect

Review Article

Immediate hypersensitivity reactions to corticosteroids Adesh Patel, MD; and Sami L. Bahna, MD, DrPH Allergy & Immunology Section, Louisiana State University Health, Shreveport, Louisiana

A R T I C L E

I N F O

Article history: Received for publication May 28, 2015. Received in revised form June 19, 2015. Accepted for publication June 24, 2015.

A B S T R A C T

Objective: To review the literature on immediate hypersensitivity reactions to corticosteroids and classify them according to manifestations, routes of exposure, causative preparations, diagnostic tests, and management. Data Sources: PubMed search for English-language publications from January 1, 2004 through December 31, 2014 using search terms corticosteroid, glucocorticoid, or steroid combined with hypersensitivity, allergy, or anaphylaxis. Study Selection: Only reports of immediate hypersensitivity reactions that occurred sooner than 24 hours after administration of a corticosteroid were included. Excluded were reports on patients with delayed reactions, including contact dermatitis. Results: Forty-eight articles fulfilled the criteria, reporting 120 reactions in 106 patients 2 to 90 years of age (55 male and 51 female). The most commonly reported manifestation was anaphylaxis in 60.8% (73 of 120) followed by urticaria and/or angioedema in 26.7%. Exposure to corticosteroid was through any route, with intravenous being the most common (44.2%, 53 of 120), followed by oral in 25.8% and intra-articular in 11.7%. Methylprednisolone was the most commonly implicated (40.8%) followed by prednisolone (20.0%). Some reacted to more than 1 preparation. Pharmacologically-inactive ingredients were implicated in 28.3%. Diagnosis was based primarily on medical history and in most cases was confirmed by challenge testing. Skin tests were positive in 74.1%. The vast majority of patients tolerated at least 1 alternative preparation, and very rarely desensitization was required. Conclusion: Corticosteroids seem to be rare causes of immediate hypersensitivity reactions but possibly are misdiagnosed or under-reported relative to their worldwide use. Physicians should be cognizant of this entity and identify safe alternative preparations. Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction Corticosteroids (CSs) are among the most widely used medications worldwide. They are considered frequent therapy for many allergic disorders and other inflammatory conditions. Because they are considered antiallergic medications, they are very rarely suspected of causing hypersensitivity. Methods The English-language literature during an 11-year period (January 1, 2004 through December 31, 2014) was reviewed for reported immediate-type hypersensitivity reactions caused by CSs. The search was conducted using the PubMed database. Search terms steroid OR corticosteroid AND hypersensitivity OR immediate OR allergy OR anaphylaxis were used and limited to English and humans. Included were patients who developed reactions Reprints: Sami L. Bahna, MD, DrPH, Allergy & Immunology Section, Louisiana State University Health, 1501 Kings Highway, Shreveport, LA 71130-3932; E-mail: [email protected]. Disclosures: Authors have nothing to disclose.

immediately after a known CS administration. Patients were excluded if they developed delayed (
24-hour) reactions. In the 48 articles evaluated, 120 reactions were described that occurred after systemic or topical administration of CSs (Table 1). Results Immediate-type Reactions to CS The prevalence of immediate-type hypersensitivity reactions to CS has been estimated as 0.1% to 0.3%, which is rare relative to their extensive use worldwide.1 In contrast, delayed-type reactions, mostly allergic contact dermatitis to topical CSs, has an estimated prevalence of up to 5%.2 The present review disclosed 120 immediate-type reactions in 106 patients who were 2 to 90 years of age, with an almost equal sex distribution (55 male and 51 female). Most patients tolerated at least 1 other CS preparation when challenged. The most commonly reported manifestation was anaphylaxis in more than half the reactions (60.8%) followed by urticaria and/or angioedema (26.7%), but this is probably a reflection of the reaction’s severity that prompted reporting.

http://dx.doi.org/10.1016/j.anai.2015.06.022 1081-1206/Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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A. Patel and S.L. Bahna / Ann Allergy Asthma Immunol xxx (2015) 1e5

Table 1 Manifestations of corticosteroid immediate hypersensitivity reactions according to route of administration reported in the English-language literature from January 2004 through December 2014 Route of administration

Manifestation (reported frequency)

Intravenous

Anaphylaxis (33), urticaria/angioedema (11), bronchospasm/dyspnea (5), rash (4) Anaphylaxis (5), urticaria/angioedema (1) Anaphylaxis (14) Urticaria/angioedema (15), anaphylaxis (11), rash (3), bronchospasm/dyspnea (1), flushing (1) Anaphylaxis (2), urticaria/angioedema (1) Anaphylaxis (2), urticaria/angioedema (1) Anaphylaxis (1) Anaphylaxis (1) Rash (1) Anaphylaxis (4), urticaria/angioedema (3)

Intramuscular Intraarticular Oral Intralesional Topical Epidural Inhalation Iontophoresis Unknown Total

Reactions, n

Positive STa reactions, n (%)

Patients, n

53

48

41/51 (80.4)

6 14 31

6 14 27

6/6 (100.0) 13/14 (92.9) 11/26 (42.3)

3 3 1 1 1 7 120

3 3 1 1 1 7 111b

1/2 2/3 1/1 1/1 1/1 6/7

(50.0) (66.7) (100.0) (100.0) (100.0) (85.7)

83

Abbreviation: ST, skin testing. a Positive skin test to the implicated preparation by skin prick or intradermal testing. b The total is 5 more than the number of patients (106) because 1 had reactions by 3 different routes and 3 had reactions by 2 different routes.

Systemic anaphylaxis Seventy-three systemic anaphylaxis reactions to CS were reported in 67 (63.2%) of the 106 patients (median age 26 years, range 2e90 years). The adjusted frequency per 1-year age interval was highest (2.22) in the 2- to 10-year-old group (20 patients) and lowest (0.43) in the 51- to 90-year-old group (17 patients). There was preponderance of male patients (38, 59.4%). The CS most implicated in systemic anaphylaxis was methylprednisolone (30 of 73, 41.1%) followed by triamcinolone acetate (14 of 73, 19.2%; Table 2). The intravenous (IV) route was the most common, being responsible for 45.2% (33 of 73) of the systemic anaphylaxis reactions, followed by the intra-articular route (19.2%, 14 of 73). Interestingly, all reported reactions that followed intra-articular administration were systemic anaphylaxis. Such figures primarily reflect reporting rather than incidence. Of all systemic anaphylaxis reactions, 86.3% (63 of 73) followed IV, intra-articular, oral, and intramuscular administrations. The remaining 13.7% (10 of 73) followed other routes or the route was not specified. One patient had reactions to the same CS preparation by 3 different routes (oral, epicutaneous, and intramuscular).3 No cases of fatal anaphylaxis were encountered in the Englishlanguage literature search from 2004 through 2014. However, in a 1999 review by Kamm and Hagmeyer,4 12 cases of fatal anaphylaxis to systemic CSs were reported during a 32-year period (1966e1997).

Urticaria and/or angioedema Urticaria and/or angioedema was the second most frequent manifestation, occurring 32 times in 29 (27.4%) of 106 patients (age range 2e78 years). Unlike anaphylaxis, most patients who developed urticaria and/or angioedema were female (18 of 29, 62.1%). Like anaphylaxis, the CS most implicated was methylprednisolone (13 of 32, 40.6%) followed by prednisolone (7 of 32, 21.9%; Table 2). The oral route was the most common, being responsible for 46.9% (15 of 32) of the reactions, followed by the IV route (34.4%, 11 of 32). Pharmacologically-inactive ingredients were responsible for 15.6% (5 of 32). Bronchospasm and/or dyspnea Bronchospasm and/or dyspnea was reported in only 6 (5.7%) of the total 106 patients (age range 8e64 years, median 26 years). Three were male patients and the sex was not specified for the other 3. However, this manifestation might be underdiagnosed because CSs are rarely considered a cause of bronchospasm in patients with asthma. All 6 reactions occurred after IV administration (3 to methylprednisolone and 3 to prednisolone). In 1 case, the culprit was the pharmacologically-inactive ingredient succinate ester. Unspecified rash Rash to CS was reported 8 times in 6 (5.7%) of the 106 patients (age range 3 to 53 years, median 10 years; Table 2). The mechanism of these rashes was not elucidated and it is unclear whether an IgEmediated process was responsible because skin testing was positive

Table 2 Corticosteroid preparations causing various manifestations reported in 106 patients in the English-language literature from January 2004 through December 2014 Corticosteroid (frequency)

M:F

Age (y), range (median)

Anaphylaxis

Methylprednisolone (30), triamcinolone (14), prednisolone (11), hydrocortisone (6), betamethasone (6), prednisone (3), dexamethasone (1), mometasone (1), fluticasone/ salmeterol (1) Methylprednisolone (13), prednisolone (7), hydrocortisone (5), triamcinolone (3), dexamethasone (2), prednisone (2) Methylprednisolone (3), prednisolone (3) Methylprednisolone (3), dexamethasone (2), hydrocortisone (1), prednisolone (1), prednisone (1) Prednisolone

38:26

2e90 (26)

73

67

60/71 (84.5)

8:18

2e78 (29)

32

29

16/27 (59.3)

3:0 4:2

8e64 3e53

6 8

6 6

3/5 (60.0) 4/8 (50.0)

0:1 53:47b

87 2e90

1 120

Urticaria and/or angioedema Bronchospasm and/or dyspnea Rash Flushing Total

Reactions, n

Patients, n

Positive STa reactions, n (%)

Manifestation

1 109c

Abbreviations: F, female; M, male; ST, skin testing. a Positive skin test to the implicated preparation by skin prick or intradermal testing. b Age was not specified in 4 female and 2 male patients, of whom 2 had anaphylaxis, 1 had anaphylaxis and urticaria, and 3 had bronchospasm. c Three patients had more than 1 manifestation on separate occasions.

0/1 (0.0) 83

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Reactions to Pharmacologically-Inactive Ingredients in CS This review showed that inactive ingredients also can be the culprit rather than the CS molecule, such as succinate esters, carboxymethylcellulose (CMC), polyethylene glycol (PEG; macrogol), and lactose (Table 3). These ingredients were responsible for 28.3% (34 of 120) of all CS hypersensitivity reactions; succinate ester was the most common cause (12 of 34, 35.3%) followed by lactose (10 of 34, 29.4%). Inactive ingredients caused 37.0% (27 of 73) of anaphylaxis reactions.

Figure 1. Total hypersensitivity reactions to various corticosteroid preparations as reported in the English-language literature from January 1, 2004 through December 31, 2014. *Mometasone and fluticasone plus salmeterol.

in only 4 of 8 reactions.5,6 The CS most implicated was methylprednisolone (3 of 8, 37.5%) followed by prednisolone (2 of 8, 25.0%). Route of Administration and Specific Preparations Immediate hypersensitivity reactions to CS occurred through almost any route of exposure. Intravenous was the most common, occurring in 44.2% (53 of 120) of the reactions, followed by oral in 25.8% (31 of 120) and intra-articular (Table 1). However, this, at least in part, reflects the reporting. Regarding specific preparations, methylprednisolone was the most common, being implicated in 40.8% (49 of 120), followed by prednisolone in 20.0% (24 of 120), and the least were dexamethasone and prednisone (Fig 1). Risk Factors for CS Immediate Hypersensitivity Reactions Asthma, hypersensitivity to nonsteroidal drugs, and renal transplantation could be associated with an increased risk for CS hypersensitivity.4 This might be due to the increased use of CSs in these patients. In this review, the reported indication for CS administration was asthma in 28.3% (30 of 106) of patients (including 1 with aspirin-exasperated respiratory disease) and renal transplantation in 2 patients, but the actual numbers might be larger. Prior sensitization to CS does not seem to be a prerequisite; reactions occurred in patients without previous CS exposure or a history of atopy.7 Cross-reactivity among CSs Although cross-reactivity has been demonstrated among topical CSs causing allergic contact dermatitis, this has not been necessarily the case in immediate hypersensitivity reactions.8 Challenge testing has shown that patients often tolerate other CS members from the same chemical group.8e11 Graded challenge is recommended to ensure tolerance of the alternative preparation. Mechanism of CS Immediate Hypersensitivity Unlike penicillin or antibacterial sulfonamides, a specific moiety in CS has not been identified as a major culprit. Hence, a unified pathogenetic mechanism for CS immediate hypersensitivity has not been established, and multiple mechanisms are likely. Some patients had positive skin test reactions, specific serum IgE, or basophil histamine release test, indicating an IgE-mediated mechanism.1,10e12 When such test results are negative, a noneIgE-mediated mechanism has been proposed, such as a “pseudoallergic” type reaction similar to nonsteroidal anti-inflammatory drug reactions.13

Succinate and phosphate esters Owing to the hydrophobic nature of CSs, to create a soluble injectable preparation, they are attached to esters such as sodium succinate or sodium phosphate.14 In this review, the succinate ester was implicated in 10% (12 of 120) of all hypersensitivity reactions, including 7 with anaphylaxis and 3 with urticaria. The IV preparation of methylprednisolone succinate was responsible for 7 (58.3%) of the 12 reactions. Several reports have shown that skin testing in CS-sensitive patients can be positive to esterified CS but negative to the same CS without the succinate ester (eTable 1). Also, patients can tolerate the same offending CS preparation if nonsuccinylated.7,15e17 The exact mechanism has not been elucidated. Skin testing and challenge with succinic acid and non-CS reagents containing succinate salts did not cause reactions.17,18 It has been proposed that CSs act only as haptens owing to their low molecular weight and the addition of succinate esters creates an antigenic complex, suggesting that the combination rather than the ester alone is responsible for the reaction.9 In contrast, this review did not find a similar role for the phosphate ester. Only 4 immediate hypersensitivity reactions to betamethasone sodium phosphate were noted.19e22 However, the researchers did not challenge the patients with the same CS without the phosphate ester. Carboxymethylcellulose Carboxymethylcellulose is derivative of cellulose that is used in the pharmaceutical and food industries as an emulsifying and thickening agent. It is used in injectable CS preparations to maintain their solubility. CMC was implicated in 7 anaphylaxis reactions to a triamcinolone acetate preparation: 4 after intra-articular administration, 1 after intralesional administration, and the route was not specified in 2 instances (eTable 1). Skin test (prick or intradermal) reactions were positive in 6 of the 7 patients. The seventh patient did not undergo intradermal testing. None of these patients were subjected to parenteral challenge with the same CS without CMC. One study performed oral challenges with CMC in 3 patients who developed hypersensitivity to parental administration. These challenges did not cause any reaction, which might indicate a role for the route of exposure.23 Polyethylene glycol Polyethylene glycol is frequently used as a surfactant, solvent, or dispersing agent in foods, cosmetics, and medications. Polyethylene glycols were implicated as the cause for immediate hypersensitivity reactions in 5 cases. One patient with a CS reaction developed acute angioedema to an oral challenge with PEG.24 Another patient developed anaphylaxis to intradermal testing with PEG.25 It would be prudent to avoid PEG-containing medications in patients sensitive to PEG through any route. Lactose Lactose, commonly derived from bovine milk, is commonly used as an excipient in pharmaceuticals, including CSs for asthma treatment (Table 4). Commercial lactose can be contaminated with minute quantities of milk proteins, but synthetic or pharmaceutical

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Table 3 Pharmacologically-inactive ingredients implicated in immediate hypersensitivity reactions to corticosteroids in 34 cases Positive STa reactions, n (%)

Ester/excipient implicated

Corticosteroid preparation (frequency)

Manifestations (frequency)

Reactions, n

Patients, n

Succinate ester

Methylprednisolone (7), hydrocortisone (3), prednisolone (2) Methylprednisolone (10) Triamcinolone (7) Methylprednisolone (2), betamethasone (2), mometasone (1)

Anaphylaxis (7), urticaria/angioedema (4), dyspnea (1) Anaphylaxis (8), urticaria/angioedema (2) Anaphylaxis (7) Anaphylaxis (5)

12

12

9/11 (81.8)

10 7 5

10 7 5

10/10 (100.0) 6/7 (85.7) 4/5 (80.0)

Lactose CMC Polyethylene glycols

Abbreviations: CMC, carboxymethylcellulose; ST, skin testing. a Positive skin test reaction to the implicated preparation by skin prick or intradermal testing.

grade lactose is unlikely to contain milk protein. In this review, lactose was reported as the culprit in 10 patients who had adverse reactions to CS. All 10 patients were children (3e15 years) and all had cow’s milk allergy. Nine patients reacted to IV “Sol-Medrol 40 mg/mL” (methylprednisolone sodium succinate), which contains lactose. Two patients were challenged with another methylprednisolone sodium succinate IV preparation (“Sol-Medrol 125 mg”), which does not contain lactose, and no reaction occurred. Analysis of “Sol-Medrol 40 mg” demonstrated that a 1-mL vial contained 112.5 ng of the major milk allergen b-lactoglobulin.26 The remaining patient, who previously tolerated inhaled fluticasone and salmeterol powder (Advair Diskus, GlaxoSmithKline, Brentford, United Kingdom), developed anaphylaxis to a different batch of the same medication that was found to contained lactose.27 Therefore, in patients with severe cow’s milk allergy, special attention should be paid to ensure the prescribed medication does not contain lactose. Diagnosis Being a common therapy for allergic reactions, CSs are rarely suspected of causing immediate hypersensitivity reactions. Therefore, awareness about the problem is of utmost importance. There is no specific standardized test for diagnosis of immediate hypersensitivity reactions to CS. Skillful history taking can be of great value and could be supplemented with skin testing or certain in vitro tests. From this literature review, skin test reactions were positive in most patients tested, whereas in vitro testing was of limited value. A definitive confirmation requires a graded challenge if the risk is not high. Skin testing Skin testing is the most commonly used diagnostic procedure in allergy practice. In general, skin prick testing (SPT) should be done first using the preparation’s full strength. If the SPT result is negative, then intradermal testing (IDT) is done usually at 1:1,000, although some investigators used 1:100 and, if negative, used 1:10.6,17 In this review, skin testing was performed in 112 reactions of the total 120. The SPT was positive in 39.3% (44 of 112), and when it was negative or not performed, then the IDT was positive in 57.4%

(39 of 68). Therefore, SPT and/or IDT were positive in 74.1% (83 of 112) of reactions. Skin testing seems to have high specificity because it was negative in almost all healthy control subjects tested and was positive in most patients with CS allergy. Caution must be exercised when performing IDT because some cases could develop reactions, including anaphylaxis.26 In vitro testing Assays for in vitro testing for CS hypersensitivity are primarily research tools and are not commercially available. Testing for specific IgE to CS was tried by some investigators and the reaction was positive in only 3 of 6 patients tested.3,10,28 The basophil activation test consists of quantifying changes in the expression of basophil activation markers CD63 and CD203c. This test has been suggested to be helpful in evaluating some drugs such as b-lactams.29 However, it is not validated for CS. In this review, the test result was noted to be positive in 7 of 10 tested.10e12,18,30,31 Drug challenge Unless the medical history is very obvious, a graded challenge is required to confirm the offending preparation and to identify safe alternatives. The starting dose and the cumulative dose should be individualized. The test should be done under supervision, preferably in a single-blinded, placebo-controlled fashion to exclude any potential bias by the patient. In a series by Rachid et al,6 10 patients were subjected to challenge with alternative preparations that produced a negative skin test reaction, and 9 tolerated at least 1 preparation. Management Although immediate hypersensitivity reactions to CS are rare, the clinician must be astute in recognizing these reactions after administration of any CS. Whenever a CS is among the suspect agents for an acute reaction, symptomatic treatment should not include any CS until an alternative safe preparation is identified. Because CSs are frequently used and sometimes urgently, it is important to identify at least 1 preparation safe for the patient. Skin testing with multiple preparations should be followed by challenge tests of those that produced a negative result and preferably that do

Table 4 Lactose-containing asthma medications Preparation

Manufacturer

Active ingredients

Lactose contenta

Advair Diskus Asmanex Twisthaler Breo Ellipta Flovent Diskus Pulmicort Flexhaler Serevent Diskus Foradil Aerolizer Solu-Medrol Injectable

GlaxoSmithKline Merck GlaxoSmithKline GlaxoSmithKline AstraZeneca GlaxoSmithKline Merck Pfizer

Fluticasone þ salmeterol Mometasone Fluticasone þ vilanterol Fluticasone Budesonide Salmeterol Formoterol Methylprednisolone succinate 40 mg

12.5 mg/blister Small amounts 24.7 mg/blister 12.5 mg/blister Small amounts 12.5 mg/blister 25 mg/capsule 25 mg/vial

a

According to the manufacturer’s package insert at the time of preparing this review.

A. Patel and S.L. Bahna / Ann Allergy Asthma Immunol xxx (2015) 1e5

not contain excipients. Special attention should be paid to ingredients that previously caused a reaction. In this literature review, most patients tolerated an alternative CS preparation by challenge testing. In the rare cases in which a safe alternative cannot be identified, when CS is needed, desensitization could be performed. Lee-Wong et al32 reported on a patient who had diffuse urticaria after an unknown intra-articular CS; the SPT was positive to 3 CS preparations tested. The patient was successfully desensitized to hydrocortisone over 4.5 hours using an 18-step protocol without any premedication. The starting dose was 0.001 mg and was gradually increased every 15 minutes until a cumulative dose of 256 mg was achieved. Because slight pruritus and erythema developed after the third dose, 50 mg of diphenhydramine was administered and the procedure was continued without any reaction. Another patient with multiple sclerosis who developed diffuse urticaria after the first administration of IV methylprednisolone succinate was successfully desensitized using a 12-step protocol.17 The starting dose was 0.20 mg, which was gradually increased every 15 minutes until reaching a cumulative dose of 1,000 mg. The procedure was uneventful and without any premedication. Conclusion Immediate hypersensitivity reactions to CS seem to be rare relative to their worldwide use. This literature review of the past 11 years found reports on 106 patients who developed 120 reactions, 60.8% of which were anaphylaxis. Some patients had more than 1 manifestation on separate occasions and some reacted to more than 1 CS preparation. The problem is possibly underdiagnosed or under-reported, particularly because CSs are common therapy for hypersensitivity disorders. Physicians should be cognizant of this entity and identify safe alternative preparations through screening by skin testing followed by graded challenge. In the rare cases in which an alternative cannot be identified, desensitization by an experienced allergy specialist can be pursued. Supplementary Data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.anai.2015.06.022. References [1] De Sousa NG, Santa-Marta C, Morais-Almeida M. Systemic corticosteroid hypersensitivity in children. J Investig Allergol Clin Immunol. 2010;20: 529e532. [2] Baker A, Empson M, The R, Fitzharris P. Skin testing for immediate hypersensitivity to corticosteroids: a case series and literature review. Clin Exp Allergy. 2014;45:669e676. [3] Erdmann SM, Abuzahra F, Merk HF, Schroeder A, Baron JM. Anaphylaxis induced by glucocorticoids. J Am Board Fam Pract. 2005;18:143e146. [4] Kamm GL, Hagmeyer KO. Allergic-type reactions to corticosteroids. Ann Pharmacother. 1999;33:451e460. [5] Nahum A, Garty BZ, Marcus N, Shoenfeld T, Levy Y. Severe hypersensitivity reactions to corticosteroids in children. Pediatr Emerg Care. 2009;25:339e341. [6] Rachid R, Leslie D, Schneider L, Twarog F. Hypersensitivity to systemic corticosteroids: an infrequent but potentially life-threatening condition. J Allergy Clin Immunol. 2011;127:524e528. [7] Koutsostathis N, Vovolis V. Severe immunoglobulin Eemediated anaphylaxis to intravenous methylprednisolone succinate in a patient who tolerated oral methylprednisolone. J Investig Allergol Clin Immunol. 2009;19:330e332.

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[8] Coopman S, Degreef H, Dooms-Goossens A. Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids. Br J Dermatol. 1989;121:27e34. [9] Venturini M, Lobera T, del Pozo MD, González I, Blasco A. Immediate hypersensitivity to corticosteroids. J Investig Allergol Clin Immunol. 2006;16: 51e56. [10] Aranda A, Mayorga C, Ariza A, et al. IgE-mediated hypersensitivity reactions to methylprednisolone. Allergy. 2010;65:1376e1380. [11] Said B, Leray V, Nicolas JF, Rozieres A, Berard F. Methylprednisolone-induced anaphylaxis: diagnosis by skin test and basophil activation test. Allergy. 2010; 65:531e532. [12] Lehmann S, Ott H. Glucocorticoid hypersensitivity as a rare but potentially fatal side effect of paediatric asthma treatment: a case report. J Med Case Rep. 2008;2:186. [13] Dajani BM, Sliman NA, Shubair KS, Hamzeh YS. Bronchospasm caused by intravenous hydrocortisone sodium succinate (Solu-Cortef) in aspirinsensitive asthmatics. J Allergy Clin Immunol. 1981;68:201e204. [14] Anderson BD, Condradi RA, Knuth KE. Strategies in the design of solutionstable, water-soluble prodrugs: I: a physical-organic approach to promoiety selection for 21 esters of corticosteroids. J Pharm Sci. 1985;7:365e374. [15] Caimmi S, Caimmi D, Bousquet PJ, Demoly P. Succinate as opposed to glucocorticoid itself allergy. Allergy. 2008;63:1641e1643. [16] Gelincik A, Yazici H, Emre T, Yakar F, Buyukozturk S. An alternative approach to a renal transplant patient who experienced an immediate type systemic reaction due to methylprednisolone sodium succinate. J Investig Allergol Clin Immunol. 2009;19:162e163. [17] Angel-Pereira D, Berges-Gimeno MP, Madrigal-Burgaleta R, Ureña-Tavera MA, Zamora-Verduga M, Alvarez-Cuesta E. Successful rapid desensitization to methylprednisolone sodium hemisuccinate: a case report. J Allergy Clin Immunol Pract. 2014;2:346e348. [18] Walker AI, Räwer HC, Sieber W, Przybilla B. Immediate-type hypersensitivity to succinylated corticosteroids. Int Arch Allergy Immunol. 2011;155:86e92. [19] Dewachter P, Mouton-Faivre C. Anaphylaxis to macrogol 4000 after a parenteral corticoid injection. Allergy. 2005;60:705e706. [20] Ehret GB, Deluze C, Dayer P, Desmeules JA. Systemic allergic reaction and diffuse bone pain after exposure to a preparation of betamethasone. Eur J Intern Med. 2005;16:612e614. [21] Hama K, Nakahata K, Iranami H, Hatano Y. Immediate allergic reaction to betamethasone during anesthesia. Anesth Analg. 2006;102:1904e1905. [22] Ventura MT, Sanapo F, Calogiuri GF, Satriano F. Anaphylaxis induced by intramuscular betamethasone disodium phosphate: reflections on a clinical case. Int J Immunopathol Pharmacol. 2007;20:387e391. [23] Bigliardi PL, Izakovic J, Weber JM, Bircher AJ. Anaphylaxis to the carbohydrate carboxymethylcellulose in parenteral corticosteroid preparations. Dermatology. 2003;207:100e103. [24] Sohy C, Vandenplas O, Sibille Y. Usefulness of oral macrogol challenge in anaphylaxis after intra-articular injection of corticosteroid preparation. Allergy. 2008;63:478e479. [25] Borderé A, Stockman A, Boone B, et al. A case of anaphylaxis caused by macrogol 3350 after injection of a corticosteroid. Contact Dermatitis. 2012;67: 376e378. [26] Eda A, Sugai K, Shioya H, et al. Acute allergic reaction due to milk proteins contaminating lactose added to corticosteroid for injection. Allergol Int. 2009; 58:137e139. [27] Nowak-Wegrzyn A, Shapiro GG, Beyer K, Bardina L, Sampson HA. Contamination of dry powder inhalers for asthma with milk proteins containing lactose. J Allergy Clin Immunol. 2004;113:558e560. [28] Sousa NG, Faria E, Carrapatoso I, Almeida E, Geraldes L, Chieira C. Deflazacort: a possible alternative in corticosteroid allergy. J Investig Allergol Clin Immunol. 2010;20:449e451. [29] De Weck AL, Sanz ML, Gamboa PM, et al. Diagnosis of immediate-type b-lactam allergy in vitro by flow-cytometric basophil activation test and sulfidoleukotriene production: a multicenter study. J Investig Allergol Clin Immunol. 2009;19:91e109. [30] Nucera E, Lombardo C, Aruanno A, et al. ‘Empty sella syndrome’: a case of a patient with sodium succinate hydrocortisone allergy. Eur J Endocrinol. 2011; 164:139e140. [31] Atanaskovi c-Markovi c M, Gavrovi c-Jankulovi c M, Jankovi c S, et al. Immediate allergic reaction to methylprednisolone with tolerance of other corticosteroids. Srp Arh Celok Lek. 2012;140:233e235. [32] Lee-Wong M, McClelland S, Chong K, Fernandez-Perez ER. A case of hydrocortisone desensitization in a patient with radiocontrast-induced anaphylactoid reaction and corticosteroid allergy. Allergy Asthma Proc. 2006;27: 265e268.

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eTable 1 Cases of immediate hypersensitivity reactions to corticosteroids reported in the English-language literature from January 1, 2004 to December 31, 2014 Study

Year

Sex

Age (y)

Implicated steroid(s)

Route

Reaction by history

SPT

IDT

Ester or excipient implicated in reaction

Calogiuri et al1 Nowak-Wegrzyn et al2 Saito et al3 Currie et al4 Dewachter et al5 Ehret et al6 Erdmann et al7

2004 2004 2004 2005 2005 2005 2005

F M M F M F F

9 8 22 39 45 42 23

De Souza et al8 Hama et al9 Sheth et al10 Venturini et al11

2006 2006 2006 2006

Compalati et al12 Deruaz et al13 Laing et al14 Rodrigues-Alves et al15

2007 2007 2007 2007

Ventura et al16 Caimmi et al17

2007 2008

Escobosa et al18 Lehmann and Ott19 Sohy et al20 Eda et al21

2008 2008 2008 2009

Field et al22 Gelincik et al23 Koutsostathis et al24 Nahum et al25

2009 2009 2009 2009

Steiner et al26

2009

Aranda et al27

2010

Said et al28 de Sousa et al29

2010 2010

Sousa et al30

2010

M F M M F F M F M F F F M F F F F F M M F M F F M M M F M M M M M M F F F F M M M M M 4F, 2Ma

28 58 64 54 47 69 38 63 72 76 39 21 24 78 28 30 39 57 20 18 32 2 44 8 3 23 26 26 7 5 8 67 54 32 46 65 22 18 9 10 8 4 2 NR NR NR NR

HC Fluticasone þ salmeterol MP HC BM BM 1. PDSN 2. PDSN 3. PDSN TA BM MP TA TA TA TA MP MP MP MP MP TA PDSN HC MP MP BM MP MP MP PDSN MP MP MP TA MP MP MP MP MP TA TA MP MP MP MP MP PDSN PDSN BM BM PDSN MP PDSN HC 1. MP 2. PDSN MP PDSN Mometasone TA MP HC 1. MP 2. DM PDSN PDSN MP MP PD 1. PDSN 2. PD TA 1. PD

IM Inhaled IV IV IA IA Oral Topical IM IL IV IV NR NR NR NR NR NR NR IV IV IL Oral IV IV IV IM IV IV IV IV IA IV IV IA IV IV IV IV IV IA IA Oral Oral Oral Oral IV IV Oral Oral Oral Oral IV IV IV IV IV IV IV Topical IA Oral IM IV IV Oral Oral IV IV Oral Oral Oral IM Oral

Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Bronchospasm Urticaria and/or angioedema Urticaria Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Urticaria Angioedema Urticaria Anaphylaxis Urticaria Urticaria Urticaria, angioedema Anaphylaxis Anaphylaxis Angioedema Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Urticaria Urticaria Anaphylaxis Dyspnea Anaphylaxis Anaphylaxis Rash Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Urticaria Urticaria Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Urticaria/angioedema Bronchospasm Bronchospasm Anaphylaxis Urticaria Anaphylaxis Anaphylaxis Bronchospasm Anaphylaxis Anaphylaxis Urticaria Urticaria Anaphylaxis Anaphylaxis Urticaria Dyspnea Anaphylaxis Rash Urticaria Anaphylaxis Anaphylaxis Anaphylaxis Rash

þ þ NP NP þ  þ þ þ NP NP NP   þ þ þ þ   þ      þ þ  NP þ þ þ þ   þ þ þ  þ þ þ   þ þ þ þ   NP   þ      þ NP þ NP NP   NP NP    NP 

NP NP þ NP þ þ NP NP NP NP þ NP  þ NP NP NP NP þ þ þ NP þ þ þ þ þ NP þ  NP NP NP NP þ þ þ NP NP NP NP NP NP  þ NP þ  NP þ þ NP þ þ NP þ NP þ  NP þ NP þ þ þ NP NP þ þ NP NP NP þ þ

NR Lactose NR Succinate ester Macrogol 4000 NR NR NR NR NR NR NR NR NR CMC CMC NR NR Succinate ester NR NR CMC NR NR NR NR NR Succinate ester Succinate ester NR NR Macrogol 4000 Lactose Lactose CMC Succinate ester Succinate ester NR NR NR CMC CMC NR NR NR NR NR NR NR NR NR NR NR NR NR NR

Spoerl et al31 Al Hadithy et al32 Jang et al33 Nucera et al34 Rachid et al35

2010 2011 2011 2011 2011

M F F F F

NR NR 30 74 52 45 10

M M M M F M

5 8 4 3 24 9

M M

20 10

NR NR Hexylene glycol CMC NR Succinate ester None None NR NR NR NR NR NR NR NR NR (continued on next page)

A. Patel and S.L. Bahna / Ann Allergy Asthma Immunol xxx (2015) 1e5

5.e2

eTable 1 (continued ) Study

Year

Savvatianos et al36

2011

Walker et al37

2011

Atanaskovi c-Markovi c et al Borderé et al39 Leberge et al40 Moran et al41 Calogiuri et al42 Ventura et al43 Angel-Pereira et al44 Baker et al45

b

38

2012 2012 2012 2012 2013 2013 2014 2014

46

Fie et al Levy et al47

2014 2014

Kim et al48

2014

Sex

Age (y)

M F

10 2

F M F M M M M

3 11 15 10 9 7 26

M

70

M F F M F F M M M M F M F M F

12 54 51 36 76 22 46 34 67 52 51 37 90 53 65

M F

2 24

F

53

F F F F F M F M M

34 87 57 6.5 3 15 5 6 10

Implicated steroid(s)

Route

Reaction by history

SPT

IDT

Ester or excipient implicated in reaction

2. DM PD 1. PDSN 2. DM 3. HC PDSN MP DM PD MP MP 1. PDSN 2. MP 1. PDSN 2. HC MP MP TA MP HC HC MP MP TA TA TA TA TA MP 1. PDSN 2. HC PDSN 1. PDSN 2. HC 1. MP 2. HC 3. DM PDSN PDSN PDSN MP MP MP MP MP MP

Oral Oral Oral Oral Oral Oral IV Iontophoresis Oral IV IV IV IV IV IV IV IA IL Epidural IM IV IV IV IA IA IA IA IA IA Oral Topical Oral Oral IV IV IV Oral Oral Oral IV IV IV IV IV IV Oral

Urticaria Urticaria Urticaria and/or angioedema Urticaria Urticaria Angioedema Urticaria Rash Rash Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Urticaria Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Urticaria Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Urticaria Anaphylaxis Urticaria and/or angioedema Urticaria and/or angioedema Rash Rash Rash Angioedema Flushing Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis Anaphylaxis

NP  NP NP NP  NP NP  þ þ þ þ    þ  þ      þ  þ             þ þ þ þ þ þ 

 NP NP NP NP NP þ þ NP NP NP NP NP þ  þ NP þ NP þ  þ  þ NP þ NP þ  þ þ         NP NP NP NP NP NP þ

NR NR NR NR NR NR NR NR NR Lactose Lactose Succinate ester Succinate ester Succinate ester Succinate ester NR Macrogol 3350 NR Macrogol 3350 NR NR NR Succinate ester NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR Lactose Lactose Lactose Lactose Lactose NR

Abbreviations: BM, betamethasone; CMC, carboxymethylcellulose; DM, dexamethasone; F, female; HC, hydrocortisone; IA, intra-articular; IDT, intradermal test with implicated corticosteroid; IL, intralesional; IM, intramuscular; IV, intravenous; M, male; MP, methylprednisolone; NP, not performed; NR, not reported; PD, prednisone; PDSN, prednisolone; SPT, skin prick test with implicated corticosteroid; TA, triamcinolone. a Age was not specified for these 4 female and 2 male patients.

5.e3

A. Patel and S.L. Bahna / Ann Allergy Asthma Immunol xxx (2015) 1e5

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