Marc A. Riedel
Drug reactions encompass all adverse events related to drug administration, regardless of etiology.1 While adverse drug reactions are common, only a small portion of these represent drug hypersensitivity, defined as an immunologically-mediated response to a drug agent in a sensitized patient. In turn, only a subset of drug hypersensitivity reactions represent a true drug allergy, which refers specifically to a reaction mediated by IgE.2 These distinctions are important for optimal patient management, risk assessment, and education of patients regarding specific drug reactions.
Drug reactions can be classified into immunologic and nonimmunologic etiologies.3 The majority (75–80%) of adverse drug reactions are due to predictable, nonimmunologic effects. Drug reactions due to overdose, toxicity, pharmacologic side effects, indirect side effects (ie, oral thrush with antibiotics), or drug–drug interactions are included in this category. The remaining 20% to 25% of adverse drug events are due to unpredictable effects, which may or may not be immune mediated. These unpredictable reactions are usually dose independent and unrelated to the drug’s pharmacologic action. Immune-mediated reactions constituting true drug hypersensitivity account for 5% to 10% of all drug reactions. Other causes of unpredictable reactions include drug-direct mast cell stimulation (sometimes termed pseudoallergic).
Adverse drug reactions are a major cause of morbidity and mortality, with antibiotics and NSAID agents being the most common offending drugs. Drug exposure in the setting of concomitant inflammation from infection, autoimmunity, or other systemic conditions may lead to increased immunological reactivity to drug antigens. Individuals with chronic medical conditions are often administered multiple therapeutic medications and therefore may have more adverse drug effects due to increased drug exposure. Variability in drug metabolism due to differences in drug acetylation or haptenation rates is an important factor for drug hypersensitivity. Although atopic patients do not have a higher rate of sensitization to drugs, they are at increased risk for serious allergic reactions.
A number of drug-related characteristics are important factors for drug hypersensitivity. Drugs with greater structural complexity (eg, proteins such as heterologous antisera, streptokinase, insulin, and monoclonal antibodies) are more likely to be immunogenic. In addition, drugs must have a sufficient molecular weight (> 1000 daltons) to be immunogenic in their native state. Most drugs have a smaller molecular weight but become immunogenic by coupling with carrier proteins, such as albumin, to form simple chemical (hapten) carrier complexes.4 Topical, intramuscular, and intravenous administration pose a higher risk of hypersensitivity reactions than does the oral route of administration.
CLINICAL FEATURES AND DIAGNOSIS
Drug hypersensitivity reactions should be considered in the differential diagnosis of patients with allergic symptoms of anaphylaxis, urticaria, and asthma, but also with serum sickness-like symptoms, skin rash, fever, pulmonary infiltrates with eosinophilia, hepatitis, acute interstitial nephritis, and lupuslike syndromes. Efforts should be made to differentiate between immunological drug hypersensitivity and other adverse drug reactions. Generally speaking, immune-mediated drug hypersensitivity reactions pose a predictable, more serious health risk with reexposure to a drug, whereas nonimmune drug reactions tend to be less severe and less reproducible. An initial history should include recording of all prescription and nonprescription drugs taken within the past month, including dates of administration and dosage. The temporal relationship between drug intake and the onset of clinical symptoms is important when considering the specific immune-mediated processes that lead to drug hypersensitivity. Patients should be queried regarding previous drug exposure and drug reaction history. Identification of coexisting conditions is important in order to assess possible alternative causative explanations for perceived drug-induced symptoms (ie, viral exanthems).
Drug hypersensitivity reactions commonly manifest with dermatologic symptoms, frequently as morbilliform rashes or exanthems. Skin manifestations of drug hypersensitivities are discussed in more detail in Chapter 362. Typically, an erythematous, maculopapular rash appears within 2 weeks of drug initiation and originates on the trunk, with eventual spread to the limbs. Pruritus and low-grade fever may accompany the drug eruption. Urticaria is often a manifestation of an allergic, type I IgE-mediated hypersensitivity reaction, though urticaria may occur with type III or pseudoallergic reactions as well. Severe immunologic cutaneous reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis represent bullous skin diseases that require prompt recognition due to their association with significant morbidity and mortality. Eczematous rashes are most commonly associated with topical medications and usually represent contact dermatitis (type IV hypersensitivity) to a drug exposure.
On physical examination, a prudent first step is to evaluate for signs and symptoms of systemic hypersensitivity reactions, as these constitute the most severe life-threatening form of an adverse drug reaction. Urticaria, laryngeal or upper airway edema, wheezing, and hypotension may be warning signs of IgE-mediated reactions with impending cardiovascular collapse. Blistering or peeling skin lesions, diffuse erythroderma, or mucocutaneous lesions suggest toxic epidermal necrolysis or Stevens-Johnson syndrome (see Chapter 352).6,7 The physical exam should document the presence of fever, mucous membrane lesions, lymphadenopathy, joint tenderness and swelling, or an abnormal result of a pulmonary exam, as these signs may suggest serious adverse drug reactions such as seen with the anticonvulsant hypersensitivity syndrome.8 A detailed skin examination is essential because this is the single organ most frequently and prominently affected by adverse drug reactions. Distinctions should be made between the various types of skin lesions, because this may provide substantial clues as to the mechanism of the drug reaction.
An important challenge in evaluating adverse drug reactions is the paucity of available laboratory testing.10,11 Suspected type I hypersensitivity reactions require the presence of antigen-specific IgE. Skin testing is a particularly useful diagnostic procedure in these select instances. Skin testing is standardized for penicillin and well described for local anesthetics and muscle relaxant agents. It may also be informative when testing high-molecular-weight protein substances such as insulin, vaccines, streptokinase, polyclonal or monoclonal antibodies, and latex. Positive skin testing confirms the presence of antigen-specific IgE and is supportive of a type-I hypersensitivity reaction in the appropriate clinical setting. Negative skin testing is helpful only for penicillin skin testing because the test specificity has been adequately established. With other drug agents, a negative skin test does not effectively rule out the presence of specific IgE. In vitro testing for IgE is available for a limited number of drugs in the form of radioallergosorbent testing. Drug-specific IgE antibody tests (in vitro or in vivo) are not diagnostic of other types of immune-mediated drug hypersensitivity, including cytotoxic, immune complex, or cell-mediated drug hypersensitivity reactions. Laboratory tests measuring mast cell activation may be helpful to confirm drug-induced anaphylaxis if they are conducted within 4 to 6 hours of onset of the suspected allergic reaction.
Due to the frequent lack of drug-specific testing, the diagnosis of drug hypersensitivity is often based on clinical judgment. Whenever possible, it is important to distinguish between immune-mediated hypersensitivity reactions and other predictable adverse drug reactions. Classifying all adverse drug reactions as “allergies” is a disservice to both the patient and clinician in terms of providing effective medical therapy, particularly for individuals with complex medical issues or a history of multiple adverse drug reactions. It is important to observe the consequences of stopping or substituting suspect medications.
With rare exceptions, symptoms should resolve within 2 weeks if the diagnosis of drug hypersensitivity is correct. In cases where there is no suitable alternative for a drug that has previously caused an IgE-mediated hypersensitivity reaction, a drug desensitization procedure may be required, supervised by an experienced allergist.
Besides avoidance of the offending drug, specific therapy for drug hypersensitivity reactions is largely supportive and symptomatic. Systemic corticosteroids may speed recovery in severe cases of drug hypersensitivity. Topical corticosteroids and oral antihistamines may improve dermatologic symptoms. When discontinuing a drug due to hypersensitivity, the patient should be provided with a list of substitute medications for future use, as well as potential cross-reactive medications that should be avoided. The use of medical alert bracelets is recommended for patients with a history of serious drug hypersensitivity reactions.
SPECIFIC ADVERSE DRUG REACTION
Penicillin is the most commonly reported medication allergy and warrants special mention. Although at least 80% of patients with a self-reported penicillin allergy are able to tolerate treatment, true allergic reactions can be severe, and penicillin remains a leading cause of fatal drug reactions.11 Patients who have a clinical history suggestive of an IgE-mediated allergic reaction to penicillin should undergo penicillin allergy skin testing prior to drug administration. Penicillin skin testing should be performed with both the major and minor determinants to achieve a sensitivity of 97% to 99%. Varying degrees of cross-reactivity have been documented between penicillins and structurally related compounds containing a β-lactam ring. Imipenem use should generally be avoided in penicillin-allergic patients due to data suggesting a high rate of cross-reactivity with penicillin. Aztreonam cross-reactivity is extremely rare in penicillin-allergic patients, but significant cross-reactivity occurs with ceftazidime. The rate of cross-reaction between penicillin and second- or third-generation cephalosporins has been found to be 5% or less, but is greater for first-generation cephalosporins. Accordingly, caution is advised when administering cephalosporin therapy to patients with a history of penicillin allergy. A more conservative approach includes skin testing prior to cephalosporin therapy, particularly for patients with a history of serious allergic reactions to penicillin. IgE-mediated penicillin allergy may be lost over time with successful avoidance.
ANTICONVULSANT HYPERSENSITIVITY SYNDROME
Anticonvulsant hypersensitivity syndrome, also known as drug rash with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (DIHS) is a rare, multisystem disorder that is most often associated with administration of aromatic anti-seizure medications.8,12 The most commonly involved agents include carbamazepine, phenytoin, lamotrigine and phenobarbital. Symptoms of erythroderma, fever and lymphadenopathy are observed in over half of affected patients. Leukocytosis, eosinophilia and elevated liver enzymes are characteristic findings. Initial management of affected patients begins with early recognition of symptoms, cessation of the drug, immediate of the associated anticonvulsant agent and supportive therapy including intravenous fluids if required and ocular care. Systemic corticosteroids are usually required. Intravenous immunoglobulins are often used but their efficacy is unproven. Cross-sensitivity to other aromatic anticonvulsant drugs is reported in over half of affected patients such that they should avoid further use of aromatic anticonvulsant drugs. Family members of patients with anticonvulsant hypersensitivity syndrome are at higher risk for the disorder if they require anticonvulsant treatment. Safe anticonvulsant drugs for these patients include valproic acid and benzodiazepines.13