Drug Allergy

The World Health Organization defines an adverse drug reaction (ADR) as “a response to a drug which is noxious and unintended, and which occurs at doses usually used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.”

Classification

• Predictable or on-target reactions are usually dose-dependent or related to the known pharmacology of the drug.

• Unpredictable or off-target reactions are generally dose-independent and unrelated to the pharmacologic action of the drug. Unpredictable reactions can be further subdivided as follows:

  • drug intolerances: undesirable pharmacologic effects

  • drug allergies: immunologically mediated ADRs, which can be classified by the Gell and Coombs system (see table below)

  • pseudoallergic reactions (previously known as anaphylactoid reactions): due to the direct release of mast-cell and basophil mediators

(Source: Antibiotic Allergy. Lancet 2019.)

Gell and Coombs classification divides hypersensitivity reactions into the following four types:

(Adapted from: Immediate Hypersensitivity Reactions to Penicillin and Related Antibiotics. Clin Allergy 1988.)

Drug Allergic Reactions and Syndromes

(Source: Penicillin Allergy. New Engl J Med 2019.)

(Reprinted from Drug Allergy: An Updated Practice Parameter, Ann Allergy Asthma Immunol 2010. Copyright [2010], with permission from Elsevier.)

Evaluation

In patients with suspected drug allergies, a thorough history is essential and can help guide further evaluation, workup, and management. The following questions can help to elucidate the history of the drug reaction:

• What medication is implicated in the reaction, and what other medications were taken concomitantly?

• How long ago did the reaction occur? What was the timing of the reaction in terms of course of medication (e.g., after the first or second dose, after the medication had been completed)?

• Which organ systems were involved, and what were the signs and symptoms of the reaction?

• What was the indication for the medication? Were there other concurrent events that could explain the symptoms (such as the morbilliform rash seen when ampicillin is administered to patients with Epstein-Barr virus [EBV] infection)?

• How was the reaction treated?

• What was the severity of the reaction? Was it life-threatening?

• Was the patient been exposed to the medication (or a cross-reactive medication) in the past? Has s/he been exposed to the medication since then? Were they able to tolerate it?

  • Has the patient had similar symptoms in the absence of taking the medication?

  • Are medical records describing the original reaction available? Were any photographs previously taken of rashes or cutaneous manifestations?

(Source: Drug Allergy: A 2022 Practice Parameter Update. J Allergy Clin Immunol 2022)

Diagnosis

To confirm the diagnosis of drug allergy, discontinuation of the suspected culprit medication with resolution of the allergic reaction helps to support the hypothesis.

• Laboratory evaluation depends on clinical suspicion based on the history and physical examination but may include complete blood count (CBC) with differential (with particular attention to eosinophils), liver and kidney function tests (to examine for organ involvement), a tryptase level (in the case of suspected anaphylaxis), or autoantibodies (e.g., antihistone antibody in the case of suspected drug-induced lupus erythematosus).

• Skin-prick and intradermal testing are available to evaluate immediate IgE-mediated hypersensitivity reactions (type l) for a limited number of medications

  • Skin testing for penicillin with commercially available benzylpenicilloyl polylysine and penicillin G has been validated and can be used to evaluate patients identified with a penicillin allergy that is likely to be IgE-mediated based on history.

  • The negative predictive value of penicillin skin testing is about 95% using the major determinant benzylpenicillin polylysine. The negative predictive values for other nonpenicillin drug skin tests are variable.

  • As many as 80% to 90% of patients who report a penicillin allergy do not have a true type l immediate allergy.

  • Even among patients with IgE-mediated allergy to penicillin, 70% to 80% will lose their penicillin allergy over a period of 10 years, thought to be due to waning specific antibodies over time.

  • Penicillin allergy is associated with increased health care costs, longer hospital stays, and increased incidence of nosocomial infections.

• Patch testing and delayed intradermal testing may be useful in determining the culprit medication for some delayed (type IV) severe cutaneous ADRs when there are no alternative medications. Delayed intradermal testing carries a risk of recurrent ADR and therefore the potential risk outweighs the benefit for severe reactions (e.g., Stevens-Johnson syndrome-toxic epidermal necrolysis [SJS-TEN]).

• Skin biopsy may be helpful depending on the clinical situation, especially if the diagnosis is unclear. Several other modalities of evaluation for diagnostic testing are currently being studied, including drug patch testing and basophil stimulation testing.

• Deliberate rechallenge with the suspect medication carries risk and should be performed only after risk/benefit analysis. Graded drug challenge can be performed in conjunction with specialty expertise (allergy-immunology consultation). When the benefit of treatment with the drug is thought to outweigh the risk of introducing a potential allergen, the following two methods for reintroduction of the medication are available. The choice largely depends on the pretest probability that the patient is allergic to the medication.

  • Graded challenge or test dose procedure:

    • Where there is a low suspicion that the patient’s reaction was truly due to the medication, a graded challenge (test dose) is sometimes performed.

    • Although practice varies, a common test-dose protocol involves administration of one fourth of the oral dose (or one tenth of the IV dose) of the medication in question, monitoring for 30-60 minutes, and then administration of the full dose of the medication again, with monitoring for one hour afterward.

    • Again, testing should be performed in consultation with an allergy-immunology specialist and by someone trained and comfortable in identification and management of anaphylaxis, with appropriate resuscitation equipment available. The graded challenge does not modify the patient’s immunologic or nonimmunologic response to the drug.

  • Induction of drug tolerance or drug desensitization:

    • In contrast with graded challenge, induction of drug tolerance (also known as drug desensitization) allows the patient to take a medication temporarily in a safe manner but does not modify the patient’s underlying immune response to the drug.

    • Temporary induction of tolerance is performed in patients who are thought to have had severe IgE-mediated reaction to the medication in the recent past (usually within the year), have had a positive skin test within the last 5 years to the required medication, are too unstable to undergo graded challenge, or fail graded challenge but no suitable alternative medication is available.

    • Induction is performed with stepwise administration of the incriminated medication, beginning with a starting dose of approximately 1/10,000 of the normal dose and slowly escalating over a period of time with incrementally larger doses.

    • The most common desensitization protocols consist of 12 steps.

    • Because desensitization is a temporary procedure, the procedure must be performed again if the patient stops the medication for a period greater than 2 to 3 half-lives of the medication.

    • Given the risk of anaphylaxis with introducing a suspected allergen, desensitization should be performed in a hospital (usually an intensive care unit) with appropriate resuscitation equipment available and in consultation with an allergy-immunology specialist.

    • Induction of drug tolerance or graded challenge procedures should not be performed if the reaction history is concerning for a severe non-IgE-mediated reaction or other severe reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), SJS-TEN, hepatitis, or hemolytic anemia.

Cross-Reactivity Between Penicillin and Cephalosporins

Early studies evaluating the cross-reactivity between penicillin and cephalosporins were performed before 1980, when cephalosporins were contaminated with trace amounts of penicillin, and suggested a high rate of cross-reactivity between the agents. Since then, several studies have found that <2% of patients with skin-test-proven sensitivity to penicillin can be expected to react to cephalosporins.

Penicillin allergy is typically mediated by the beta-lactam ring, while cephalosporin allergy is due to hypersensitivity to side chains. The risk of cross-reactivity of penicillin with third- and fourth-generation cephalosporins is considered much lower than with first- or second-generation cephalosporins, and many patients with penicillin allergy can still safely receive cephalosporins. The risk of cross-reactivity is possibly higher with first- and second-generation cephalosporins and thus, if available, penicillin skin testing is recommended to evaluate for allergy to the beta-lactam portion.

(Adapted from Drug Allergy: An Updated Practice Parameter. Ann Allergy Asthma Immunol 2010. Copyright [2010], with permission from Elsevier.)

Antibiotic Prescribing in Patients with Penicillin Allergy

The following clinical guideline developed for inpatient providers uses the allergy history to determine which beta-lactam antibiotics can be administered to patients with a history of penicillin or cephalosporin allergy using a full dose, a test dose, or only with preceding penicillin skin testing. This guideline still emphasizes a higher risk of penicillin cross-reactivity with the first- and second- generation cephalosporins, but as stated above, this risk may have been due to contamination in early studies and many clinicians now feel all cephalosporins have any equally low risk of penicillin cross-reactivity. Patients with a history of IgE-mediated penicillin allergy have a <1% risk of cross-reactivity to carbapenems.

(Reprinted from Acute Care Beta-Lactam Allergy Pathways: Approaches and Outcomes. Ann Allergy Asthma Immunol 2019. Copyright [2019], with permission from Elsevier.)

(Reprinted from Addressing Inpatient Beta-Lactam Allergies: A Multihospital Implementation. J Allergy Clin Immunol Pract 2017. Copyright [2017], with permission from Elsevier.)