Rana Misiak, MD
Epidemiology of Drug-Induced Allergic Reactions
An adverse drug reaction (ADR) is any noxious, unintended, or undesired effect of a drug that occurs at doses used for prevention, diagnosis, or treatment, as defined by the World Health Organization. 1 Adverse drug reactions include drug-induced allergic reactions. One study which analyzed data collected by the Boston Collaborative Drug Surveillance Program from June 1975 to 1982, found that antibiotics account for most drug-induced cutaneous allergic reactions, including amoxicillin, trimethoprim-sulfamethoxazole, ampicillin, cephalosporins, erythromycin, and penicillin G. 2
Classification of Drug-Induced Allergic Reactions
ADRs may be classified into type A and type B reactions (Table 1). Type A reactions account for approximately 80% of ADRs, and are predictable, common, and related to the pharmacologic actions of the drug. 3 This type of reaction includes overdose (e.g., acetaminophen causing hepatic failure), side effects (e.g., nausea and headache with methylxanthines), secondary or indirect effects (e.g., GI bacterial overgrowth with antibiotics), and drug interactions (e.g., erythromycin increasing digoxin serum levels). 4
Type B reactions are unpredictable, uncommon, and usually not related to the pharmacologic actions of the drug. 3 This type of reaction includes drug intolerance, idiosyncratic reactions, and allergic or hypersensitivity reactions. A drug intolerance is a pharmacologically predictable side effect or toxicity that occurs at a low or subtherapeutic dose, such as tinnitus after a single aspirin. 4 Idiosyncratic reactions are qualitatively distinct from known pharmacologic toxicity profiles. These may result from a defined genetic defect, in the case of primaquine in a patient with G6PD deficiency, or may result from an obscure mechanism, such as with radiocontrast media reactions. 4 Allergic or hypersensitivity reactions are immune mediated. This type of reaction may be further classified according to the Coombs and Gell classification, as described in Table 2.
Pathogenesis of Drug-Induced Allergic Reactions
Risk factors for drug allergy include the molecular weight of the drug and other chemical properties. 5 In order for a drug to induce an immune response, it must be an effective immunogen. Some drugs, such as peptide hormones, are able to accomplish this intrinsically. 6 Others must bind covalently to high-molecular weight proteins and undergo bioactivation (usually via cytochrome P 450 enzymes in the liver) to a reactive form. 6
When evaluating a patient who reports a drug allergy, a detailed history can provide valuable information. As Salkind, et. al 7 described, the following questions should be addressed:
Depending on the clinical scenario, helpful tests may include a chest x-ray, electrocardiogram, compete blood count with differential, sedimentation rate, nuclear and cytoplasmic autoantibody tests, and specific immunologic tests. However, none of these tests are specific for identifying a particular drug as being culpable. In order to detect IgE-mediated drug reactions caused by penicillin, the most useful test is the immediate hypersensitivity skin test. 5 To make the diagnosis of contact dermatitis caused by topically applied drugs, patch testing has been the preferred technique. 5
Penicillin and Other ß-Lactam Drugs
Patients commonly report allergies to penicillin and other ß-lactam drugs. Although anaphylaxis to penicillin is rare, penicillin is the most common cause of drug-induced anaphylaxis. 8 , 9 Penicillins contain an unstable ß-lactam ring that can open and form amide linkages with lysine on adjacent proteins, resulting in benzyl penicilloyl, or the major penicillin determinant. 10 Penicilloyl polylysine (PPL) consists of the penicilloyl determinant coupled to a polylysine carrier, and is currently the only penicillin skin test reagent commercially available. 6 Penicillin also forms minor determinants that are capable of inducing IgE mediated reactions.
Rarely do patients with a positive history but negative skin tests to both PPL and minor determinants have an IgE-mediated reaction with readministration of penicillin. 11 , 12 , 13 , 14 Skin testing with PPL alone, though, can miss up to 25% of positive skin test reactions. 13 If only one minor determinant is used (in addition to PPL), 5-10% of positive skin test reactions will be missed. 13 , 15 Please see Table 3. For penicillin allergic patients who require such a drug for treatment, desensitization may be performed. This involves the administration of incremental doses of a drug over a period of hours to days, which induces a state of drug tolerance. 6
Other beta lactam antibiotics include carbapenems and monobactams. Carbapenems, such as imipenem, have a high degree of cross-reactivity with penicillin, and therefore should not be administered to patients with penicillin allergy or used with extreme caution. 16 Monobactams, such as aztreonam, on the other hand, rarely cause clinical reactions in penicillin sensitive patients. 5
Cephalosporins share a ß-lactam ring with penicillins, therefore the clinically relevant question arises: Can a cephalosporin be safely administered to a patient with a penicillin allergy? One study that analyzed published data of administering a cephalosporin to penicillin-allergic patients, found that the reaction rate was 4.4% (or 6 out of 135) for patients with positive skin tests, and 1.3% (or 2 out of 351) for patients with negative skin tests. 17 Other studies have shown that the risk of reaction to cephalosporins is minimal. 18 , 19 First generation cephalosporins are thought to have a greater risk than second or third generation cephalosporins for cross-reactivity with penicillin. 5 Therefore, the entire clinical picture, including the type of reaction in question and available medication alternatives, should be carefully evaluated.
Sulfonamide antibiotics have a different chemical structure than other sulfonamide-containing medications (thiazide diuretics, sulfonylureas, furosemide, and celecoxib) due to an aromatic amine. 6 Cutaneous reactions to sulfonamide antibiotics occur in 50-60% of patients with AIDS and approximately 2-4% of healthy people. 6 The immunogenic sulfonamide hapten is formed via P 450 oxidation in the liver. 20 There is no commercially available skin test for sulfonamide antibiotics. Skin testing with the native drug may produce false negative responses due to an absence of antigenic determinants. 6 However, a positive skin test (which is absent in a healthy control) may signify drug-specific IgE antibodies. 6
A severe hypersensitivity syndrome (HSS) which includes fever, rash, and lymphadenopathy may result from phenytoin, phenobarbital, and carbamazepine. The rash may range from a benign morbilliform eruption to a frank exfoliative dermatitis, and may occur weeks into therapy. 6 The mechanism involves cytochrome P 450 oxidation to a reactive arene oxide metabolite that acts via direct cellular necrosis or haptenation of protein carrier. 21
IgE-mediated reactions to local anesthetics are rare, but pseudoallergic symptoms may occur in patients, particularly with dental procedures. 4 Symptoms may include vasovagal syncope, paresthesias, and lightheadedness (especially with "caines"). Anxiety toward the upcoming procedure may contribute to anticipatory recurrences. The diagnosis and management of such cases includes skin testing, followed by subcutaneous dose challenges.
Many responses attributed to radiocontrast media are due to the hypertonicity of the infusion, which is believed to augment histamine release from basophils and mast cells, rather than to its iodine content. 4 The use of non-ionic, nearly isotonic, media is associated with fewer pseudoallergic reactions. 22 Pretreatment with prednisone (at 1 mg/kg administered at 1, 7, and 13 hours prior to the procedure) and diphenhydramine (1 mg/kg administered at 1 hour prior) can reduce these reactions by 5-10 fold. 23 , 24 Risk factors for anaphylactoid reactions include atopy and severe cardiovascular disease. 24 , 25
Aspirin (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used medications. Adverse reactions include hepatitis, erythema multiforme, anemia, interstitial nephritis, toxic epidermal necrolysis, and the Stevens Johnson syndrome. Currently, there is no in vitro test to identify patients with ASA/NSAID-induced asthma/rhinitis, urticaria, angioedema, or anaphylaxis. Therefore, a definitive diagnosis is made by oral provocative challenge testing. Reactions can include severe bronchospastic reactions, especially in an irritated tracheobronchial tree. Therefore, corticosteroids (inhaled, oral, and intranasal), theophylline, and long-acting bronchodilators should be continued at the time of oral challenges.
The classic triad of asthma, rhinitis/nasal polyps, and ASA sensitivity was described by Samter. In patients with ASA-exacerbated respiratory disease, or AERD, the clinical symptoms resemble an immediate hypersensitivity reaction with bronchospasm and naso-ocular reaction. The time course, however, is 20min-3 hrs after ASA/NSAID ingestion (later onset than for Type 1 Hypersensitivity). The mechanism is not IgE-mediated; instead it is thought to be related to COX inhibition in respiratory cells and subsequently driven by leukotriene release. Patients with AERD can respond to structurally distinct NSAIDs on first exposure.
In patients without underlying disease, single drug-induced urticaria/angioedema or anaphylaxis is likely IgE mediated. These patients often react to only one NSAID or ASA, and can consider undergoing a challenge with other structurally different NSAIDs.
One classification scheme is summarized in Table 4 describing the allergic and pseudoallergic reactions to ASA and NSAIDs.
Management of ADRs
The treatment of anaphylaxis is described elsewhere and will therefore not be discussed here. For mild reactions, withdrawal may be the only intervention necessary. Glucocorticosteroids may speed recovery from immune complex and cytotoxic drug reactions. 5
For medications where skin testing reagents are available, skin testing should be performed . Skin testing, if negative, should be repeated in approximately 6 weeks, especially after anaphylactic events . If skin testing is positive and no suitable alternative is available, desensitization may be used in sensitive individuals.
For medications without skin testing reagents, if an alternative drug exists, then avoidance of the suspected agent may be employed. If the previous event in question was suggestive of an IgE-mediated reaction and was not life-threatening, a graded challenge can be considered. If, however, the previous event in question was suggestive of a severe IgE-mediated reaction, then desensitization in a controlled setting or employing an alternative agent should be considered.
2 Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions: a report from the Boston Collaborative Drug Surveillance Program on 15,238 consecutive inpatients, 1975-1982. JAMA 1986; 256:3358-63.
8 Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of anaphylaxis. J Allergy Clin Immunol 1998; 101(6 Pt 2):S465-528.
12 Green G, Rosenblum R, Sweet L. Evaluation of penicillin hypersensitivity: value of clinical history and skin testing with penicilloyl-polylysine and penicillin G. A cooperative prospective study of the Penicillin Study Group of the American Academy of Allergy. J Allergy Clin Immunol 1977;60:339-45.
14 Sogn D, Evans RE, Shepherd G, Casale T, Condemi J, Greenberger P, et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med 1992;152:1025-32.
19 Novalbos A, Sastre J, Cuesta J, De Las Heras M, Lluch-Bernal M, Bombin C, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy 2001; 31:438-43.