Hypersensitivity reactions to systemic glucocorticoids

INTRODUCTION — Glucocorticoids are prescribed for their immunosuppressive, antiproliferative, anti-inflammatory, and antiallergenic effects and are integral to the management of numerous conditions, including malignancies, transplantation, autoimmune and allergic diseases, and asthma. They are also administered to prevent late-phase anaphylactic reactions. However, injected, infused, or orally administered systemic glucocorticoids have been associated with immediate hypersensitivity (allergic) reactions, including life-threatening anaphylaxis.

This topic will review the epidemiology, clinical manifestations, diagnosis, and management of hypersensitivity reactions to systemic glucocorticoids. Topical corticosteroids, usually in the form of skin preparations or inhaled glucocorticoids, can cause contact hypersensitivity, which is discussed separately. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects' and "Major side effects of inhaled glucocorticoids", section on 'Contact hypersensitivity'.)

EPIDEMIOLOGY — Hypersensitivity reactions to systemic glucocorticoids are rare, although the exact incidence is unknown. These reactions appear to occur in ≥0.1 percent of parenteral administrations, as demonstrated in the following studies:

●An early report in the 1950s described 6700 glucocorticoid injections given to 2256 patients [1]. There were 20 instances of urticaria (including reactions localized to the injection site) or bronchospasm (0.29 percent of injections and 0.89 percent of patients).

●In a prospective study involving 202 children with rheumatologic diseases, approximately 0.1 percent of 10,000 doses of glucocorticoids administered were thought to cause reactions that were possibly of an allergic nature [2]. Symptoms included pruritus, hives, and anaphylactic-like reactions. There was no statistical difference with respect to the ethnicity or underlying rheumatologic condition.

●Voluntary reporting of adverse drug reactions to the national Swiss Drug Monitoring Center uncovered 14 cases of suspected hypersensitivity reactions after parenteral glucocorticoid administration in approximately 5 million inhabitants over 18 years [3]. However, data based on voluntary reporting generally underestimates the true incidence of an adverse event.

Risk factors — Reliable data about whether patients with specific diseases are at greater risk of developing hypersensitivity reactions to parenteral glucocorticoids are lacking. Although some reports suggested that renal transplant or asthmatic patients (especially those who are aspirin-sensitive) may be at higher risk [4-8], this could be attributable to the frequent use of these medications and not to the disease itself [9]. In the author's series, five patients received the offending drug for asthma, four for rheumatologic conditions, three for poison ivy, two for orthopedic conditions, and one for the treatment of an allergic reaction on one occasion and asthma on another [10].

The manner in which patients become sensitized to glucocorticoids is not clear. Many of the patients in the author's study had not received extensive systemic (oral, intra-articular, or intravenous) glucocorticoid therapy before developing an allergic reaction [10]. In other studies, some patients had prior systemic exposure to the same or different glucocorticoids [11-13], while others did not [14]. The role of topical corticosteroid administration in sensitizing these patients has not been evaluated.

PATHOPHYSIOLOGY — The allergenic moiety in glucocorticoids that is responsible for immediate reactions has not been determined. It could be part of the native molecule or a metabolite that acts as a hapten and binds to serum proteins, creating an allergenic complex.

CLINICAL MANIFESTATIONS — Hypersensitivity (or allergic) reactions to drugs are mediated by cells of the immune system. Hypersensitivity reactions may be categorized based upon the time required for the first signs or symptoms to appear after an administered dose. Immediate reactions usually begin within one hour of administration, and delayed reactions begin after one hour [15]. This classification system is intended to distinguish immunoglobulin (Ig)E-mediated reactions, which are most often immediate, from other types. A minority of IgE-mediated reactions appear after one hour, particularly after oral administration of a drug or if the drug is taken with food, although this categorization system identifies the majority of IgE-mediated reactions. It is important to distinguish IgE-mediated reactions because they carry the risk of anaphylaxis if the patient is re-exposed. Immediate hypersensitivity reactions to glucocorticoids are the focus of this review.

Immediate reactions — Signs and symptoms of immediate hypersensitivity to glucocorticoids include pruritus, rash, hives, angioedema, sneezing, nausea/vomiting, dyspnea, throat tightness, wheezing/bronchospasm, hypotension, and anaphylactic shock [9-14,16-27]. Hypersensitivity reactions have been reported following intravenous, intramuscular, oral, intra-articular, epidural, and topical administration.

The largest available series on immediate hypersensitivity reactions to systemic corticosteroids consisted of 15 patients (with a total of 19 reactions) who were evaluated with allergy testing at the author's center. These individuals presented over a 12-year period, although each patient was studied within one year of the inciting reaction [10]. All reported various combinations of the signs and symptoms listed above, ranging in severity from pruritic rash (three patients) to anaphylaxis (five patients).

Delayed recognition — It is not uncommon for patients to have had more than one reaction before the possibility of allergy to glucocorticoids is considered. Recognition of these reactions is complicated by several factors:

●Patients typically receive glucocorticoids for conditions, such as status asthmaticus, anaphylaxis, or shock, which have signs and symptoms similar to those of allergic reactions. In such settings, it can be difficult to distinguish a progressively worsening medical condition from a superimposed allergic reaction to a glucocorticoid. Reactions to glucocorticoids can also be mistaken for biphasic anaphylaxis. (See "Biphasic and protracted anaphylaxis".)

●Glucocorticoids may be given together with other medications that are more commonly implicated in allergic reactions, such as antibiotics or opioids. Even H1 and H2 antihistamines can cause rare allergic reactions. (See 'Differential diagnosis' below.)

●Clinicians may not be aware that it is even possible to become allergic to glucocorticoids.

Causative drugs — The likelihood of a specific glucocorticoid causing hypersensitivity appears to be related to the frequency with which it is used. Some papers noted that the incidence of hydrocortisone and methylprednisolone allergy seemed higher than allergy to other glucocorticoids [9,27]. However, in the series by the author's group, approximately one-half of reactions were caused by oral prednisone and prednisolone, which are commonly used for outpatient therapy [10]. Reactions to hydrocortisone and methylprednisolone accounted for 5 and 21 percent, respectively. Twenty percent of patients had a clinical reaction to more than one glucocorticoid. In a review of the English medical literature from 2004 to 2014, 120 immediate hypersensitivity reactions to glucocorticoids were reported in 106 patients (ages 2 to 90: 55 males, 51 females) [28]. Of these patients, 63 percent had anaphylaxis, 27 percent had urticaria and/or angioedema, 6 percent had bronchospasm and dyspnea, and 6 percent had unspecified rash. Methylprednisolone was the glucocorticoid most often implicated in anaphylaxis (41 percent) followed by triamcinolone acetate (19 percent). Considering all types of reactions, methylprednisolone accounted for 41 percent, prednisolone for 20 percent, and triamcinolone for 14 percent.

Delayed reactions — Delayed reactions to systemic glucocorticoids include delayed urticarial reactions and maculopapular exanthema. These reactions are uncommon and have been attributed to a T cell-mediated response [29]. Delayed reactions to systemic glucocorticoids are not discussed further in this review.

CROSS-REACTIVITY — The patterns of cross-reactivity among different drugs are not defined, although several patients with allergic reactions to more than one systemically administered glucocorticoid have been described [9,10,27,30]. Therefore, without an allergy evaluation or challenge procedure, it is not possible to choose a "safe" alternative glucocorticoid empirically for a patient who has had an immediate reaction to a specific agent. Various studies have tried to analyze the literature or small series for patterns of cross-reactivity without firm conclusions [9,10,16,18,21,23,27,31]. Some papers suggested that hydrocortisone cross-reacts more with methylprednisolone than with a halogenated steroid, such as dexamethasone and betamethasone [21,27]. In the 15-patient series, no patterns of cross-reactivity were apparent based upon the clinical history of allergic reactions and/or the results of the skin testing [10].

In the case of contact hypersensitivity to topical corticosteroids, at least two theories for predicting cross-reactivity among drugs have been proposed [32,33]. However, it is not clear that these theories, which concern T cell cross-sensitivity, have any utility in predicting potentially antibody-mediated reactions when glucocorticoids are given systemically.

REFERRAL — Patients with signs or symptoms of an immediate reaction to a systemic glucocorticoid should be referred to an allergy specialist whenever possible and advised to avoid systemic use of all glucocorticoids until evaluated. It is impractical to recommend indefinite avoidance of systemic glucocorticoids because of the widespread use of these agents for so many different disorders. If referral is not possible, then the patient could receive a different agent from the one that caused the original reaction using a graded challenge procedure under close medical supervision. (See 'Graded drug challenge' below.)

DIAGNOSIS — The diagnosis of an immediate hypersensitivity reaction to a systemic glucocorticoid is based upon clinical history, physical examination (if the patient is evaluated during the reaction), and when possible, skin testing with the culprit drug and possible alternatives. In many cases, a challenge procedure is needed to identify an alternative glucocorticoid that the patient can safely take in the future.

Skin testing — Immediate-type skin testing is recommended in patients with reactions that are consistent with immediate hypersensitivity. (See 'Immediate reactions' above.)

Skin testing requires training and knowledge to perform and interpret safely and correctly and should be done by an allergy specialist whenever possible. Skin testing with glucocorticoids is useful, although it is not validated, and the sensitivity and specificity are not well-defined.

Skin prick testing using the prick-puncture technique is suggested initially. In the author's series, we performed skin prick testing using a full-strength solution [10]. Testing performed on three healthy volunteers was negative.

Positive (histamine) and negative (normal saline) controls should always be included. Preservative-free glucocorticoid solutions are recommended whenever possible.

If the results of skin prick testing are negative and if the glucocorticoid is available in an injectable form (preservative-free if possible), intradermal testing is then performed. For intradermal testing, we used dilutions of 1:1000, followed if negative by 1:100, followed if negative by 1:10, and finally a full-strength solution of the drug. Other studies have used a dilution up to 1:10 for intradermal testing, although the full-strength solution for some glucocorticoids, such as methylprednisolone and triamcinolone, was four times higher than the products we used [34]. A general discussion of the technique of allergy skin testing is reviewed in more detail elsewhere. (See "Overview of skin testing for IgE-mediated allergic disease".)

Suggested drug concentrations — Based on the two largest studies on glucocorticoid sensitivity, we recommend the following preparations of glucocorticoids for skin testing (concentrations specified are for skin prick testing and highest concentration of intradermal) [10,34]:

●Methylprednisolone succinate (4 to 10 mg/mL, preservative-free) (if skin prick or intradermal test is positive, different methylprednisolone formulations not containing succinate ester may be used for testing, such as methylprednisolone acetate, to evaluate for succinate ester hypersensitivity).

●Dexamethasone sodium phosphate (0.4 to 4 mg/mL, containing benzyl alcohol).

●Hydrocortisone sodium succinate (5 to 10 mg/mL, preservative-free) (if skin prick or intradermal is positive, a different hydrocortisone formulation not containing succinate ester may be used for testing, such as hydrocortisone acetate or hydrocortisone sodium phosphate, to evaluate for succinate ester hypersensitivity).

●Betamethasone (4 to 6 mg/mL, containing betamethasone sodium phosphate and betamethasone acetate, with edentate disodium and benzalkonium chloride). Testing may also be done with preparations containing only one type of ester, such as betamethasone acetate or betamethasone sodium phosphate when available.

●Triamcinolone acetonide (4 to 10 mg/mL, containing benzyl alcohol).

●Prednisone sodium phosphate (15 mg/5 mL) (no injectable solution available for intradermal testing).

●Prednisolone sodium phosphate (15 mg/5 mL) (no injectable solution available for intradermal testing).

Interpretation — Positive skin test results are useful in confirming reactivity to the culprit drug, and negative results are helpful in identifying an alternative agent that is then administered using a graded challenge.

Skin test results are considered positive when the wheal produced by prick or intradermal testing is at least 3 mm larger than that elicited by normal saline control. Because the rate of false-positive reactions has not been clearly determined, it is recommended that if a positive result is obtained, the test should be performed on a healthy individual as a control to exclude an irritant reaction.

Information about the sensitivity and specificity of prick testing and intradermal skin testing to glucocorticoids is limited. In the 15-patient series, the sensitivity of intradermal testing was 86 percent [10]. In a review of the literature from 1966 to 1997, intradermal testing was found to be positive in 76 percent of 25 patients tested, and a negative intradermal test correlated with clinical tolerance of the glucocorticoid in multiple patients [9,10]. In a review of the English language literature from 2004 to 2014, skin and/or intradermal testing was positive in 74 percent of reactions [28].

Other possible allergens in glucocorticoid preparations — Other possible allergens in glucocorticoid preparations include esters, preservatives, and excipients.

Succinate esters — To create soluble injectable preparations, hydrophobic glucocorticoids are attached by a chemical bond to esters, such as sodium succinate and sodium phosphate. There is some evidence to suggest that patients can be reactive to these esters, rather than to the glucocorticoid itself. In a case report, the evaluation of a 39-year-old woman who developed generalized urticaria after receiving hydrocortisone sodium succinate on two occasions was described. Her intradermal testing was positive to hydrocortisone sodium succinate and methylprednisolone hemisuccinate and negative to hydrocortisone acetate, hydrocortisone sodium phosphate, and methylprednisolone (without an ester). She tolerated a single-blinded, graded challenge to hydrocortisone sodium phosphate [35]. Another patient reacted to methylprednisolone succinate infusion and had a positive skin test to this formulation, as well as to prednisolone-21-sodium succinate, while prick tests with prednisolone without ester and betamethase-21-hydrogen phosphate were negative. Specific IgE antibodies specific to methylprednisolone succinate were also detected at 44.8 kU/L [16]. Skin and in vitro testing to methylprednisolone without an ester was not performed. Oral challenge with prednisolone without ester and intravenous challenge with betamethasone-21-dihydrogen phosphate were well-tolerated.

Preservatives and excipients — Glucocorticoid preparations may contain preservatives and excipients, such as lactose, carboxymethylcellulose, polyethylene glycol, or hexylene glycol. Allergic reactions to these components are possible.

●Lactose is an excipient in certain preparations of methylprednisolone, specifically methylprednisolone sodium succinate 40 mg/mL. In a series of seven children who developed anaphylaxis after receiving this medication intravenously, casein protein was detectable in the drug solution at 1.7 ppm [36]. All seven children were skin test-positive to the causative drug but were negative to four alternative glucocorticoid preparations, although no intradermal testing was performed. Four of the children were skin tested to a preparation of methylprednisolone that does not contain lactose (methylprednisolone 62.5 mg/mL) and were negative, although they were not challenged to confirm lack of reactivity due to parental refusal. The report suggested that milk allergy should be considered as a possible alternative explanation for allergic reactions to methylprednisolone sodium succinate 40 mg/mL in patients with milk allergy.

Another paper reported the case of two pediatric patients with severe cow's milk allergy who developed severe anaphylaxis after a methylprednisolone sodium succinate infusion (40 mg/mL) that was given in the emergency room for wheezing. Skin prick testing with the 40 mg/mL formulation was positive, while the test was negative with the 68.5 mg/mL formulation that does not contain lactose. Subsequent drug provocation with the formulation not containing lactose, which is otherwise identical to the one that was implicated in the reaction, was tolerated. By employing a highly sensitive enzyme-linked immunosorbent assay (ELISA) (limit of detection = 0.5 ppm), traces of milk proteins within the range of 2.0 to 3.5 ppm were detected in samples from all five batches tested of the implicated product (Solu-Medrol 40 mg/mL) [37].

●Several patients were reported to have an allergic reaction to carboxymethylcellulose and less frequently, macrogol (polyethylene glycol or PEG) [17,25,38-45]. Polyethylene glycols (PEG) and polysorbates are structurally related compounds, found in a variety of medical and nonmedical products, which contain polyether groups and range in molecular weights from 200 to 35,000 g/mol [45]. PEG is most commonly encountered in osmotic laxatives and colonoscopy prep solutions. Some injectable glucocorticoids also contain PEGs or polysorbates (methylprednisolone acetate [contains PEG 3350] and triamcinolone acetonide [contains polysorbate 80]), whereas others do not (methylprednisolone succinate, betamethasone, and dexamethasone contain neither PEG nor polysorbate 80) [45]. PEG 3500 and polysorbate 80 in injectable glucocorticoids have been implicated in rare allergic reactions [42,45-47].

●One patient was reported to develop angioedema of the tongue and eyelids and dyspnea after applying a topical mometasone furoate cream containing hexylene glycol. Skin and rub testing (ie, applying the component directly to the skin and rubbing it in) was positive to hexylene glycol, while skin prick testing to mometasone furoate was negative [48].

For skin testing, preservative-free glucocorticoid solutions are preferred whenever possible. If a preservative-free preparation is not available and/or if a patient had an allergic reaction after receiving a glucocorticoid preparation containing a preservative, then a positive result to the preservative-containing preparation should be followed by skin testing with a preparation of the preservative (prick-puncture and if negative, intradermal). Skin testing to the relevant preservatives could be done during the same testing session as the glucocorticoid skin testing or done subsequently if a positive result is obtained with a preservative-containing preparation.

In vitro testing — In vitro immunoassays for glucocorticoid-specific IgE are limited to research settings because they have only been described in few papers [13,14,16] and are not commercially available.

A positive basophil activation test was reported (ie, 71 percent of basophils expressing CD203c after exposure to in vitro methylprednisolone) in a patient with methylprednisolone-induced anaphylaxis, who also had a positive intradermal skin test to methylprednisolone [24]. Two healthy controls had a negative (2 percent) basophil activation test. In another study, the basophil activation test was negative in one patient and positive in another for prednisolone sodium hemisuccinate and hydrocortisone sodium succinate but not hydrocortisone. The test was negative in two healthy controls. Both patients developed immediate hypersensitivity reaction to succinate glucocorticoids [49]. This very limited data suggested that basophil activation tests may be useful as a tool for diagnosis of IgE-mediated reactions to glucocorticoids, although we do not use them. Basophil activation assays are considered investigational in the United States, and the technical difficulties of manipulating basophils are reviewed elsewhere. (See "Overview of in vitro allergy tests", section on 'Basophil tests'.)

Graded drug challenge — Graded drug challenge involves administering a medication to a patient in a graded manner under close observation. This is also called test dosing or drug provocation testing. Challenges are used when the sensitivity of allergy tests for evaluating reactions to certain drugs is limited [50]. In most cases, graded challenges are performed with a drug to which the patient has not reacted and is believed likely to tolerate.

We use graded challenges to confirm that a patient tolerates an alternative glucocorticoid (other than the one implicated in the reaction) to which skin testing was negative [10].

Graded challenge does not modify the allergic response to the drug or prevent recurrent reactions. Therefore:

●Patients who tolerate a drug upon graded challenge prove that they are not allergic to it.

●A challenge procedure in a patient with a suspected IgE-mediated drug allergy could potentially induce anaphylaxis and should be performed by an allergy expert when possible and in a setting equipped to manage possible reactions.

At the author's center, challenges are performed starting with 1/100^th of the therapeutic dose, followed if tolerated 30 minutes later by 1/10^th of the dose, followed 30 minutes later if tolerated by 9/10^th of the dose. Patients are then observed for two hours. In the 15-patient series, 90 percent of subjects who had a negative skin prick test and a negative intradermal test (when the formulation is available in injectable form for intradermal testing) tolerated the glucocorticoid when a challenge was performed [10].

Desensitization — Drug desensitization is a procedure which temporarily alters the clinical sensitivity to the medication and results in short-term tolerance, allowing the patient with immediate allergy to receive an uninterrupted course of the medication safely. Drug desensitization renders mast cells unresponsive to the drug in question, although the exact immunologic mechanism is not understood [51]. Drug desensitization is effective as long as the patient is receiving the drug, although the patient's sensitivity returns shortly after the drug is cleared from the body. Therefore, desensitization must be repeated every time the patient requires a course of the glucocorticoid. Desensitization is reviewed briefly here and in greater detail separately. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

Indications — Desensitization should be considered in patients who are strongly suspected to have an immediate, IgE-mediated reaction to a glucocorticoid, with or without a positive skin test result, and for whom there are no acceptable alternate medications. At the author's center, it is a common practice to perform drug desensitization rather than a challenge in patients with a positive skin test, even if the patient never received the drug in question. A successful desensitization to methylprednisolone sodium succinate has been reported [52].

Safety issues — Drug desensitization should only be performed by clinicians trained in the technique (usually allergy specialists) in a hospital setting (or outpatient setting under close observation) with intravenous access and necessary medications, personnel, and equipment to treat anaphylaxis. (See "Rapid drug desensitization for immediate hypersensitivity reactions", section on 'Safety'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of immediate hypersensitivity to systemic glucocorticoids includes worsening of the underlying disorder for which the therapy was given (eg, asthma, allergic reaction), biphasic anaphylaxis, and allergic reactions to concomitantly administered medications (eg, opioids, antibiotics). (See 'Delayed recognition' above.)

Allergy to antihistamines — Allergic reactions to both H1 and H2 antihistamines have been described in case reports, although this appears to be a rare phenomenon [53-56]. There is another rare disorder of antihistamine-aggravated chronic urticaria [57]. A case report described four such patients, three of whom gained control of the chronic urticaria with montelukast [58].

OTHER MANAGEMENT ISSUES

●We advise patients to obtain a medical identification bracelet, since clinicians may not be aware that patients can be allergic to glucocorticoids, and these drugs are often given in hectic emergency environments. Under such circumstances, the presence of a bracelet corroborates the patient's history.

●If a patient experienced anaphylaxis to a glucocorticoid in the past, we suggest that he/she has an epinephrine autoinjector available when receiving an alternative glucocorticoid in the future. At least one report described a patient who tolerated several courses of an alternative glucocorticoid but subsequently developed an allergic reaction to the tolerated drug [10].

●It is also advisable to avoid the specific drug in all forms, including topical or inhaled, although data about this are very limited.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

SUMMARY AND RECOMMENDATIONS

●Signs and symptoms of immediate hypersensitivity to systemic glucocorticoids include pruritus, rash, hives, angioedema, sneezing, nausea/vomiting, dyspnea, throat tightness, wheezing/bronchospasm, hypotension, and anaphylactic shock. Hypersensitivity reactions have been rarely reported following intravenous, intramuscular, intra-articular, and oral administration. (See 'Clinical manifestations' above.)

●Patients may be allergic to more than one systemically administered glucocorticoid. Patterns of cross-reactivity are not well-defined, and in the absence of an allergy evaluation or a challenge procedure, it is not possible to choose a safe alternative agent empirically. (See 'Cross-reactivity' above.)

●Patients with signs or symptoms of an immediate reaction to a systemic glucocorticoid should be referred to an allergy specialist whenever possible and advised to avoid systemic use of all glucocorticoids until evaluated. It is impractical to recommend indefinite avoidance of systemic glucocorticoids because of the widespread use of these agents for so many different disorders. If referral is not possible, then the issue can be deferred until systemic glucocorticoids are medically necessary, at which point the patient could receive a different agent from the one that caused the original reaction, using a graded challenge procedure under close medical supervision. (See 'Referral' above and 'Graded drug challenge' above.)

●The diagnosis of an immediate hypersensitivity reaction to a systemic glucocorticoid is based upon clinical history, physical examination (if the patient is evaluated during the reaction), and when possible, skin testing with the culprit drug and possible alternatives. In many cases, a challenge procedure is needed to identify an alternative glucocorticoid that the patient can safely take in the future. (See 'Diagnosis' above.)

●Skin testing with glucocorticoids is not validated, and the sensitivity and specificity are not well-defined. Despite these limitations, positive results are useful in confirming reactivity to the culprit drug, and in patients with a positive skin test to a specific agent, negative results to other glucocorticoids are helpful in identifying an alternative agent that is then administered using a graded challenge. (See 'Skin testing' above and 'Graded drug challenge' above.)

●Desensitization should be considered in patients who are strongly suspected to have an immediate, immunoglobulin (Ig)E-mediated reaction to a glucocorticoid, with or without a positive skin test result, and for whom there are no acceptable alternate medications. Drug desensitization should only be performed by clinicians trained in the technique (usually allergy specialists) in a hospital setting (or outpatient setting under close observation) with intravenous access and necessary medications, personnel, and equipment to treat anaphylaxis. Desensitization must be repeated each time the patient requires a course of that specific glucocorticoid. (See 'Desensitization' above.)