The prevalence of hypersensitivity reactions to corticosteroids is reported to be between 0.3 and 0.5 percent based on various studies, with only a small portion of these hypersensitivities resulting in anaphylaxis [2, 3]. These reactions have been reported in patients as young as 18 months. A patch testing study of 2000 patients demonstrated a female predominance, with a 3:1 female to male ratio of reactivity to steroids . The most common corticosteroids that cause anaphylactic reactions are hydrocortisone, prednisone, and methylprednisolone . It is unclear if this is due to the relatively increased administration of these drugs, or whether these particular corticosteroids truly have a higher propensity for inducing anaphylaxis. Many risk factors for hypersensitivity to corticosteroids have been identified, including allergies, asthma, eczema, NSAID hypersensitivity, organ transplant, and past high dose applications of corticosteroids .
To what degree the epidemiology and risk factors of hypersensitivity to corticosteroids are influenced by selection bias is unclear. This uncertainty of causation versus correlation is a recurring theme throughout the literature, given the limited research that has been performed on the subject. There is evidence that suggests selection bias is indeed a confounding factor, as demonstrated by the increased incidence of hypersensitivity in populations who frequently receive steroids, such as patients with multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus .
Surprisingly, cases have been reported in both patients with a prior history of exposure to corticosteroids and in patients without such a history . There have also been cases reported of sensitization occurring through a specific route of exposure, followed by a reaction to administration of a corticosteroid through a different route. For example, one case report demonstrated a hypersensitivity reaction following the administration of systemic corticosteroids in a patient whose only prior route of exposure had been through topical means. Another reported case described an anaphylactic reaction to intravenous methylprednisolone succinate following an isolated episode of sensitization through ocular administration [2, 9]. A diagram depicting sensitization is illustrated below in Fig. 1. Sensitization has been demonstrated through various different routes of administration, including nasal, aerosol, parenteral, oral, cutaneous, and even intra-articular . There have also been recorded cases of cross-reactivity between different types of corticosteroids. For example, a patient who is sensitized to prednisone may later develop a reaction in response to methylprednisolone .
The exact cause of sensitization to corticosteroids is unknown, although several hypotheses exist. One such hypothesis suggests that the structural component of corticosteroids responsible for the induction of allergic reactions may be the native molecule itself or a metabolite that acts as a hapten to form an allergic complex . This interaction is demonstrated below in Fig. 1. Thus, the interaction may be due to the small molecular weight of corticosteroids, which allows haptenization with a larger carrier protein. This combination of molecules may elicit a reaction, while the drug in its native form fails to produce such a response.
Figure 2: Demonstrates the mechanism resulting in immunogenic complexes through the formation of haptens.
Corticosteroids are also routinely conjugated to esters in order to increase their solubility for intravenous administration . While this increases the solubility of corticosteroids, it also produces another potential source for a hypersensitivity reaction. Succinate esters in particular appear to have a higher propensity to induce sensitization compared to conjugation with other esters . Of note, patients may tolerate a previously intolerable corticosteroid once it has been conjugated to an alternative ester [3, 10]. For instance, Angel-Pereira and colleagues demonstrated that a patient was unable to tolerate sodium-succinate hydrocortisone, but was able to tolerate sodium-phosphate hydrocortisone. In contrast, there are also reports of positive skin testing to corticosteroids uniquely in the absence of ester conjugation . Figure 3 shows the classification of corticosteroids based on their chemical conjugation. Identification of the agent responsible for induction of anaphylactic reaction may allow for avoidance of corticosteroids with identical conjugations, thus preventing a reaction.
Figure 3. Classification of corticosteroids based on chemical composition . May inform the choice of alternative corticosteroids available for administration during emergent situations in the setting of anaphylactic shock to prior corticosteroid use.
Alternatively, corticosteroids may also contain preservatives or excipients which may result in sensitization and subsequent hypersensitivity reaction . Some such examples include lactose, carboxymethylcellulose, polyethylene glycol, and hexylene glycol. Such preservatives serve to increase the shelf life of the drug, while excipients bind to the active drug to facilitate entry and metabolism systemically. Possible sensitization to these compounds amplifies the difficulty practitioners experience when attempting to identify the causative agent . This concept may be responsible for the surprisingly common false negative skin prick test results in some patients with a definitive history of anaphylaxis in response to corticosteroids .
Reactions may also be due to non-immunologic means. For example, reactions similar to those associated with acetylsalicylic acid have been observed. In such a case, steroid-induced inhibition of cyclooxygenase blocks prostaglandin production, resulting in increased leukotriene production and the presentation of an aspirin-like asthma clinical picture that resembles anaphylaxis. Furthermore, reactions may also be due to mimicry of anaphylaxis due to rapid infusion of large amounts of corticosteroids. In this scenario, α-adrenergic blockade and negative inotropy leads to cardiovascular collapse due to decreased cardiac output, resulting in clinical manifestations similar to those of anaphylaxis .
Classically, the diagnosis of corticosteroid induced anaphylaxis is based on the clinical history and physical exam . However, as allergy testing has evolved, additional methods have been developed to further support this diagnosis. An algorithm of a diagnostic approach in patients with suspected corticosteroid hypersensitivity is included below in Fig. 4. In patients with a suspected immediate-type hypersensitivity reaction, it is recommended to utilize skin prick testing with a preparation of 15 mg/5 mL. A negative result should prompt follow up with a drug challenge at increasing concentrations. In patients with a suspected delayed phase hypersensitivity reaction, evaluation should begin with patch testing. A negative result should then be followed up with an incremental drug challenge [1, 2]. Other methods of diagnostic confirmation include the serial measurement of mast cell tryptase, immunoCAP assays, skin patch testing, lymphocyte transformation testing, and basophil activation testing [2, 11].
Despite the varying degrees of success, it is important to understand the various tests available to confirm anaphylactic response to corticosteroids. The immunoCAP assay measures IgE specific antigen levels . Alternatively, lymphocyte transformation testing measures T-cell proliferation in response to an allergen with the goal of identifying delayed-phase allergic responses . Basophil activation testing uses flow cytometry to measure IgE function, quantifying the body's ability to stimulate the activation of basophils following exposure to an allergen . Given the rapidly evolving nature of allergy and immunology, any of these tests may see further improvement and subsequent prominence. Unfortunately, the current variant of these tests have an unacceptably high false negative rate . This inaccuracy demonstrates the need for improvement in testing quality, which appears inevitable given the rapid rate of evolution of allergy testing. Thus, methods to accurately identify the causative agent of anaphylactic response to corticosteroids is essential in order to facilitate avoidance or rapid desensitization of corticosteroids for times of future use.
The management of corticosteroid-induced anaphylaxis is similar to the management of any other type of anaphylactic reaction. The most important component of treatment is epinephrine injection or infusion . Epinephrine works as an agonist at both α-1 and β-2 adrenergic receptors, leading to vasoconstriction with a decrease in mucosal edema and enhanced bronchodilation respectively . This treatment addresses two of the most severe issues in anaphylaxis: hypotension and bronchoconstriction. However, one study suggests that out of 200 deaths associated with anaphylaxis, as many as two and a half percent were a direct consequence of epinephrine overdose . While this is important to recognize, the benefits of epinephrine use in the setting of anaphylaxis far outweigh the risks, making it the cornerstone of treatment.
Epinephrine administration in and of itself is insufficient in the treatment of anaphylaxis. Another critical component of treatment is early and aggressive volume resuscitation. Volume resuscitation addresses hypotension and can prevent vascular collapse. Vascular collapse can also be managed through altering body position. Supine or Trendelenburg positions are the preferred positions for patients in anaphylactic shock . One article hypothesized that a patient in anaphylactic shock who sits up or stands may have decreased venous return and subsequent vascular collapse due to the increased capacity of veins and capillaries in the lower body. Furthermore, in this scenario, any amount of epinephrine given will not effectively circulate and will therefore be rendered inert . Patients in anaphylaxis should also be maintained at a high oxygen saturation in case airway compromise occurs. In situations of refractory bradycardia, atropine or potent vasoconstrictors may be utilized .
Non-emergent management of anaphylaxis patients should include avoidance of the inciting agent if such an agent can be determined. However, corticosteroids may be necessary in certain circumstances. In these cases, we can manage the patient with rapid desensitization, though sensitivity returns almost immediately after desensitization ceases. One example of such a case is illustrated by the use of intravenous methylprednisolone hypersensitivity in a patient with multiple sclerosis. This corticosteroid is the first line treatment for a multiple sclerosis exacerbation. Due to the critical nature of the exacerbation, Angel-Pereira and colleagues successfully demonstrated rapid desensitization to the drug, and successfully treated the exacerbation .
Considering our case, we identified several limitations in evaluating our patient due to our setting. Given the nature of hospital medicine, we were unable to perform the majority of the preferred diagnostic testing. Additionally, patient follow up with the care team was non-existent. While we successfully managed the patient at the time of presentation, the opportunity to perform more testing may have elucidated the exact cause of our patients’ anaphylaxis. In context to the discussion, our case raised awareness about the existence of anaphylaxis induced by corticosteroids. Prior to evaluating this patient, our team was completely unaware of this possibility. In the future, we will remain diligent in our evaluation of such patients and ensure that they receive appropriate treatment and counseling on the topics of future testing and management.
The field would benefit tremendously from additional studies focused on the development of tests with a higher degree of accuracy in identification of the causative agent of sensitization to corticosteroids. These tests would allow us to differentiate whether the responsible component is the native molecule itself or some other structural component. Additionally, further studies on the cross-reactivity between different classes of corticosteroids would also enhance our understanding of this condition. By accruing more knowledge and data on the exact causes and diagnostic interventions, we could more efficiently identify and manage corticosteroid-induced anaphylaxis.