A. Symptoms and Signs
The development of symptoms and the nature of the reaction can suggest whether an immunologic process is responsible for symptoms. In previously sensitized individuals, immediate hypersensitivity is manifested by rapid development of urticaria, angioedema, or anaphylaxis. Delayed onset of urticaria accompanied by fever, arthralgias, and nephritis may indicate the development of an immune complex-mediated disorder. Drug fever and Stevens-Johnson syndrome probably act by immune hypersensitivity mechanisms. Some drugs are clearly more immunogenic than others, and this can be reflected in the incidence of drug hypersensitivity. A partial list of drugs frequently implicated in drug reactions includes ß-lactam antibiotics, sulfonamides, phenytoin, carbamazepine, allopurinol, muscle relaxants used for general anesthesia, nonsteroidal anti-inflammatory drugs, antisera, and antiarrhythmic agents.
Many drugs can be associated with recognizable known toxicities, drug interactions, or idiosyncratic reactions that are not immune-mediated. These must be distinguished from true hypersensitivity reactions because the prognosis and management differ. Some estimate that only 10% or less of adverse reactions to drugs are true hypersensitivity reactions. Patients with multidrug hypersensitivity are quite rare, and those reporting “allergies” to more than three distinct classes of drugs should be carefully evaluated since intolerance to many of these drug classes may not be immunologic.
B. Laboratory Findings
1. Allergy testing
Allergy skin testing is available for a limited number of drugs, since patients may react to the native drug as well as any metabolite that covalently binds to native protein and becomes immunoreactive. Skin testing is available for patients with suspected immediate hypersensitivity to penicillin or ß-lactam antibiotics. The degree of cross-reactivity between the cephalosporin antibiotics and penicillins is uncertain. The incidence of IgE-mediated hypersensitivity appears to be less than 5%. There appears to be no allergic cross-reactivity between the monobactam antibiotics (aztreonam) and penicillin or other ß-lactam antibiotics. A high degree of cross-reactivity exists between penicillin and the carbapenem, imipenem, so this drug should be given to the penicillin-allergic patient with the same degree of caution as if the patient were to receive penicillin.
If the likelihood of immunologic reaction is low - based on the history and the assessment of likely offending agents - and if no allergy testing is available, judicious test dose challenges may be considered in a monitored setting. If the likelihood of IgE-mediated reaction is significant, these challenges are risky and rapid drug desensitization is indicated.
2. Provocation tests
Occasionally, direct allergen challenge of the target organ or tissue under controlled conditions is required for definitive diagnosis. Such challenges may be bronchial, nasal, conjunctival, oral, or cutaneous. A positive test confirms that the test substance can cause the reaction, but it does not prove that an immunologic mechanism is responsible.
a. Bronchoprovocation testing
Natural provocation field testing can be done by having the patient make serial determinations of peak expiratory flow rate (PEFR) using a portable peak flowmeter during periods of natural exposure to a suspected airborne allergen. Bronchoprovocation is not necessary in the routine diagnosis of allergic asthma, but it may be helpful in some cases of occupational asthma. Bronchial provocation with exercise or with inhalation of methacholine, histamine, or cold air can document the presence of nonspecific bronchial hyperreactivity during the diagnostic workup for respiratory symptoms but does not detect allergic sensitivities.
b. Oral provocation
In most cases of suspected allergy to a food or drug, placebo-controlled oral challenge is the definitive test. To be considered a positive result, the reported clinical findings must be reproduced during provocation testing. A blinded provocation test may be preceded by an open challenge (no placebo control), which, if negative, negates the necessity for logistically difficult blinded challenge. Freeze-dried foods in large opaque capsules provide a sufficient dose of allergen for testing. This should not be done in patients with suspected food-induced anaphylaxis.
Acute rapid desensitization for IgE allergy to certain drugs - especially penicillin and insulin - has been successful in many cases. This is accomplished by a course of oral or parenteral doses starting with extremely low doses (dilutions of 1 X 10 -6 or 1 X 10 -5 units) and increasing to the full dose over a period of hours. IgE-mediated reactivity diminishes during the course of this desensitization, creating a temporary drug-specific refractory state. During the refractory period, skin histamine responsiveness is maintained, and mast cells may be activated by other stimuli but the patient may receive the desired drug with a very low risk of anaphylaxis. Acute rapid desensitization may work through cellular mechanisms different from those involved in standard injection immunotherapy, and the refractory period is maintained only throughout the course of uninterrupted therapy.
Marshall GD Jr et al: Determining allergic versus nonallergic drug reactions. Clin Allergy Immunol 2000;15:217.
Revision date: July 4, 2011
Last revised: by Sebastian Scheller, MD, ScD