DRUG & FOOD ALLERGY

General Considerations
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
-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.
Four foods account for 90% of food allergy in adults: peanuts, tree nuts, fish, and shellfish. Food hypersensitivity must be distinguished from food intolerance, which is more common and more variable in terms of underlying mechanism. An example of food intolerance would be lactose intolerance, which is due to an enzyme deficiency rather than an IgE-mediated hypersensitivity.
Clinical Findings
SYMPTOMS AND SIGNS
The development of symptoms and the nature of the adverse drug reaction can suggest whether an immunologic process is responsible for symptoms. Factors to consider include type of symptoms, history of previous drug exposure, time of onset after starting the drug, presence of other systemic involvement, coexisting illness, and concurrent drug use. 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. In genetically slow acetylators and in AIDS patients with depleted hepatic glutathione levels, drugs such as sulfamethoxazole are not rapidly excreted during drug metabolism. This altered drug metabolism favors the generation of haptenated immunoreactive metabolites as well as drug reactions, such as delayed morbilliform eruptions. Other types of immune-mediated dermatologic drug reactions include lupus-like syndromes caused by procainamide, isoniazid, phenytoin, or hydralazine. Drugs that have been associated with the development of systemic or cutaneous vasculitis include leukotriene receptor antagonists, allopurinol, phenytoin, thiazides, nonsteroidal anti-inflammatory drugs, furosemide, cimetidine, gold, hydralazine, and many antibiotics (eg, penicillin, sulfonamides, quinolones, and tetracycline). Cutaneous vasculitides are usually associated with fixed lesions, with histologically-proven immune-complex involvement.
Food hypersensitivity is manifest by symptoms consistent with IgE-mediated immediate hypersensitivity/anaphylaxis but commonly is also accompanied by abdominal pain, nausea, vomiting, or diarrhea. More rarely, atopic dermatitis may be the sole clinical expression of food allergy. The onset of allergic food reactions is rapid, usually within minutes to a couple of hours of ingestion, and the reaction is usually quite reproducible. Oral allergy syndrome is a self-limited form of fruit and vegetable hypersensitivity, where symptoms are confined to the oropharynx. Due to cross-reactivity between certain fruit and vegetable allergens and certain seasonal pollens, ingestion of these foods causes a contact allergy with pruritus of lips, tongue, and palate typically without other symptoms or signs of systemic anaphylaxis. The most common cross-reacting foods and pollens are apples and carrots, which cross-react with birch pollen; melons and bananas, which cross-react with ragweed pollen. Many of these antigens involved in oral allergy syndrome are heat labile and denature during cooking. Immunologic cross-reactivity appears to also underlie the association of latex allergy and hypersensitivity to avocado, banana, chestnut, kiwi, and papaya. Unlike the oral allergy syndrome, however, systemic anaphylaxis upon ingestion of these foods may develop in 35–50% of patients who are allergic to latex (so called latex-fruit syndrome).
LABORATORY FINDINGS
Allergy testing
Allergy skin testing is only available for a limited number of drugs (penicillin, insulin, streptokinase, chymopapain, heterologous serum), 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
-lactam antibiotics (see Infectious Diseases: Common Problems & Antimicrobial Therapy). 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
-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.
The gold standard for allergy food testing is skin-prick testing with actual food items, but due to the inconvenience and potential risk for systemic reactions, this form of testing is usually preceded by IgE RAST testing or skin prick testing with commercially available extracts or both. Food allergy testing must be interpreted within the context of the clinical picture, since false-positive tests can occur.
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.
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- or drug-induced anaphylaxis.
Treatment
For IgE-mediated drug hypersensitivity, acute rapid desensitization may allow administration of a drug if there is no suitable alternative treatment regimen. This procedure carries a significant risk and should be undertaken in an intensively monitored setting. 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.
Various slow desensitization protocols have been developed for patients suffering from late-appearing morbilliform eruptions (eg, AIDS patients with sulfamethoxazole-induced dermatitis). These eruptions are not IgE-mediated, and the slow reintroduction of drug allows for less haptenation during sulfonamide metabolism with generation of less immunoreactive drug metabolites. This form of desensitization is distinct from rapid desensitization of IgE-mediated drug allergy. Desensitization for non–IgE-mediated drug reactions has been successful for aspirin, nonsteroidal anti-inflammatory drugs, and allopurinol.
Any history or finding consistent with toxic epidermal necrolysis or Stevens-Johnson syndrome would be an absolute contraindication for drug readministration.
For any proven food hypersensitivity, strict avoidance is the only rational recommendation. Patients should also be provided with an epinephrine autoinjector (Epi-pen) if indicated.

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