Drug allergy is defined as an immunological response to a pharmaceutical and/or formulation (excipient) agent in a sensitized person.1 It is a type of adverse drug reaction and can present with variable clinical manifestations.
Mechanism of Drug Allergy
Various immunological mechanisms have been postulated for drug allergy (Table 1). These have been stratified based on classification by Gell and Coombs.1 Type I reactions are immediate-type reactions that are mediated by drug-specific immunoglobulin (Ig) E antibodies. Type I reactions can result in urticaria, angioedema, and even anaphylaxis in severe cases. Type II reactions are cytotoxic reactions mediated by drug-specific IgG or IgM antibodies. Type III reactions are immune complex-mediated reactions, and type IV or delayed-type hypersensitivity reactions are cell mediated.1 The classic reaction in type IV category is contact dermatitis in which symptoms are usually limited to the skin and can appear a few hours to 10 days after contact with the allergen. Other examples of type IV reactions include maculopapular exanthems and acute generalized exanthematous pustulosis.2
Immunological Classification of Drug Allergy
Drug allergy can affect multiple organ systems (Table 2). Cutaneous manifestations tend to be the most common; however, other organ systems, including gastrointestinal, pulmonary, hematologic, and renal, can also be involved.3 Skin involvement can vary from urticaria, angioedema, and exanthems to pustular or blistering lesions. Presence of urticaria and angioedema indicate an IgE-mediated etiology, whereas generalized exanthems are usually suggestive of delayed hypersensitivity. Thus, characterization of these cutaneous lesions can help in identifying the etiology and provide information for further evaluation. The most severe manifestations of skin involvement include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and both of these are associated with high morbidity and mortality. Patients may present with fever, oral and ocular involvement, and epidermal detachment.3 The drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a multiorgan inflammatory response that can also be life-threatening. Symptoms can develop 2 to 8 weeks after initiation of therapy and may worsen after the offending drug is discontinued. Symptoms may persist for weeks or even months.4
Drug-Induced Allergic Reactions and Syndromes
A thorough history should be obtained while evaluating patients with suspected drug allergies. History taking in such patients should focus on obtaining information regarding:
Name of the offending drug
Onset and duration of symptoms
Clinical manifestations and involvement of various organ systems
Concurrent infections—symptoms of the underlying infection may resemble drug allergy and the medication may be mistakenly blamed (eg, penicillin therapy for scarlet fever)
Concurrent medications—opiates and nonsteroidal anti-inflammatory drugs (NSAIDs) frequently cause urticaria
Previous exposure to the offending drug that was well tolerated—risk of allergic sensitization
Past history of similar symptoms in the absence of drug treatment—patients diagnosed with chronic urticaria tend to develop hives even in the absence of the offending drug
Exposure to the same or similar drug since the reaction
Time since the initial reaction—allergy to some drugs (eg, penicillin) tends to resolve over time
Physical examination should focus on all systems that could be involved in patients with drug allergy. Cutaneous involvement is the most common and can be variable. Generalized exanthems (maculopapular lesions) tend to be the most common.1 Other lesions include urticarial/angioedema, fixed drug eruptions, pustules, and target lesions/erythema multiforme. Patients should be monitored for any mucosal involvement (oral and genitourinary) and epidermal detachment as seen in patients with SJS and TEN. Eye involvement, lymphadenopathy, hepatosplenomegaly, and joint involvement (swelling/tenderness) should be evaluated.
Routine laboratory testing has a limited role in evaluation of a patient with a suspected drug allergy. Because multiple organs may be involved, laboratory tests including complete blood count, liver enzymes, and kidney functions should be obtained. Complete blood count may show eosinophilia, but it is not diagnostic of a drug-induced allergic reaction.3
Type I or immediate-hypersensitivity reactions are mediated by drug-specific IgE antibodies. These can be demonstrated by in vivo (skin test) or in vitro (laboratory) assays. Currently, standardized and reliable skin test reagents are available only for the penicillins.1 Diagnostic testing is presently not available for most other medications. Specific IgE in vitro assays are available, but they are not adequately validated and hence not reliable.3 A radioallergosorbent test detects specific IgE antibodies and is based on radioimmunoassay. Another test is based on fluorescence enzyme-labeled assays and is a more sensitive test compared to the radioallergosorbent test. A third type of test uses enzyme-amplified chemiluminescent assay for detection of antibody or antigen.
A patch test for drugs can be helpful in evaluation of certain type IV or cell-mediated cutaneous drug reactions such as contact dermatitis, maculopapular exanthems, and fixed drug eruptions.5
The basophil activation test (BAT) is an in vitro assay that has been evaluated in patients with possible IgE-mediated drug allergies.6 Basophils are stimulated with an allergen (drug), which results in upregulation of specific markers in the basophils. These markers are then detected using specific antibodies in the laboratory. BAT has been used to evaluate IgE-mediated allergy to certain medications including beta-lactam antibiotics, NSAIDs, and muscle relaxants. However, only limited data are available presently regarding its efficacy.6
A skin biopsy may be helpful in some patients with severe or persistent reactions, although there are no definite diagnostic criteria of drug-induced reactions.7
Drug Allergic Reactions to Specific Agents
Beta-Lactam Antibiotics: Penicillins
Penicillin is the most common cause of drug allergy. About 10% of patients report penicillin allergy.3 However, penicillin-specific IgE antibodies tend to fade over time, so 90% of these patients are able to tolerate penicillins eventually.8 Patients are also often misdiagnosed as being allergic to penicillin because clinical manifestations of an underlying sickness may mimic allergic reaction to a drug. As a result, more expensive and broad-spectrum antibiotics are used, which can lead to development of drug-resistant bacteria, which results in higher health care costs.9
Penicillin tends to spontaneously metabolize and generate reactive intermediates that can bind to self-proteins and generate an immune response. These include the major antigenic determinant (penicilloyl moiety) and the minor antigenic determinants among which penicilloate and penilloate are the most important for inducing allergic responses.8
A penicillin skin test should be done using validated reagents if symptoms are consistent with IgE-mediated reactions.8 This should preferably be done when patients are doing well. The negative predictive value of the test is approximately 100% using both minor and major determinants for IgE-mediated reactions.1,3,8 A negative skin test response should always be followed by oral challenge with penicillin. A very small proportion of patients (1%–3%) with negative skin test responses developed mild reactions on being challenged with the drug.8 In the case of positive skin test, penicillin can be administered only after desensitization or induction of tolerance.
A history of reaction to penicillin is a poor predictor of who will have a positive response to a penicillin skin test. If a penicillin skin test is not available, the clinical decision should be based on reaction history. Patients with vague reactions or reactions more than 10 years ago are less likely to be allergic and penicillin can be administered through a graded challenge. In contrast, patients who have a history of anaphylaxis to penicillin should undergo desensitization.10
Patients who are allergic to the core beta-lactam group of penicillins tend to cross-react to all penicillin drugs. However, a small group of patients react selectively to particular penicillin compounds (eg, amoxicillin) and are able to tolerate other penicillin. This is due to allergy to the R-group side chain, which varies among different penicillins.11
In the past, cephalosporin preparations frequently contained minute quantities of penicillin. This resulted in frequent reactions when patients with penicillin allergy were administered cephalosporins. However, there is no penicillin contamination in the cephalosporin preparations available presently. When possible, penicillin skin testing should be performed prior to cephalosporin administration in patients with a history of penicillin allergy. Patients with reported penicillin allergy and a positive penicillin skin test are at a higher risk of reaction to cephalosporins (6%) compared to patients with a negative skin test (0.7%).12
Patients who are allergic to amoxicillin should avoid cephalosporins, which have identical R-group side chains (cefadroxil), due to high cross-reactivity.13 Similarly, ampicillin and certain cephalosporins (cephalexin, cefaclor) also have an identical R-group side chain, so they should be avoided in patients with ampicillin allergy or those patients should receive them only after induction of drug tolerance.13
Sulfonamide antibiotics (tri-methoprim/sulfamethoxazole [TMP-SMX]) are a common cause of drug reactions, seen in up to 4% patients exposed to these medications.14 Delayed maculopapular/morbilliform eruptions are the most common manifestations.14 Sulfonamides are the also most common cause of SJS and TEN.15 They usually do not cause IgE-mediated reaction. Sulfonamide antibiotics differ structurally from non-antibiotic sulfonamides (ie, sulfasalazine, furosemide). Thus, there is no cross-reactivity between the antibiotic and non-antibiotic sulfonamides, so non-antibiotic sulfonamides can be safely given to patients who are allergic to sulfonamide antibiotics.16
People infected with HIV tend to develop generalized skin rash when they are exposed to sulfonamide antibiotics. This may be due to allergic sensitization related to their frequent use in people infected with HIV. Between 40% and 80% of HIV-infected patients develop rash with TMP-SMX, in contrast to 3% to 5% people not infected with HIV.14 The rash is usually maculopapular and itchy and tends to develop during the second week of treatment. TMP-SMX tends to be the treatment of choice for various HIV-associated infections, specifically infection with Pneumocystis jiroveci. In such patients, TMP-SMX can be safely administered using desensitization or drug tolerance procedures.17
Reactions to NSAIDs can vary from IgE-mediated reactions (urticaria, angioedema, anaphylaxis) to non–IgE-mediated reactions (aspirin exacerbated respiratory disease [AERD], pneumonitis). Anaphylaxis to NSAIDs is usually drug-specific and other NSAIDs are well tolerated.18 Patients with AERD exhibit cross-reactivity to other NSAIDs.18
Local anesthetics are broadly classified into two groups: benzoate esters (benzocaine) and amides (lidocaine). Although the benzoate esters exhibit cross-reactivity among each other, the amides do not. Local anesthetics usually do not cause IgE-mediated reactions.19 Most adverse reactions are related to anxiety associated with the injection or psychogenic response. Also, unintentional intravenous injection of the local anesthetic can result in overdose or toxic reaction.20 Occasionally, patients may be allergic to preservatives in local anesthetics.21 In these situations a preservative-free local anesthetic should be used.
Angiotensin-Converting Enzyme Inhibitor: Cough and Angioedema
Angiotensin-converting enzyme inhibitor (ACEI) use is commonly associated with adverse effects such as cough and angioedema. ACEI-associated cough can affect 5% to 35% patients.22 It is seen more commonly in women and nonsmokers. Onset of cough can be early, within hours of the first dose, or may be delayed for weeks or months. It usually resolves in 1 to 4 weeks upon stopping the medication.22
ACEI-induced angioedema tends to affect the head and neck region, especially the lips and tongue. It is a common cause of ED visit for angioedema in adults, accounting for up to one-third of these patients.23 Onset of symptoms can vary from a few hours to 10 years after starting treatment, with a mean of 1.8 years.24 Angioedema in these patients is mediated by bradykinin, thus there is no associated urticaria and pruritis.25 These patients tend to tolerate angiotensin II receptor blockers well.
Adverse effects related to the use of radio-contrast media (RCM) are usually non IgE-mediated (anaphylactoid). Most of the effects are due to direct effects of RCM on mast cells and basophils. This results in release of the mediators, which can cause anaphylactoid reactions. These occur in about 1% to 3% of patients who receive ionic radiocontrast media and <0.5% of patients who receive nonionic agents.26 Ionic contrast media usually have higher osmolality and are thus associated with more side effects.27 Adverse reactions are more common in female patients, patients who have asthma or cardiovascular conditions, and those using beta-blockers.28
Patients with an allergy to seafood can safely receive iodinated RCM, as adverse reactions to RCM are unrelated to the iodine content of seafood.29
Occasionally patients may develop skin eruptions, which are T-cell mediated reactions, 1 week after the use of RCM.
Patients infected with HIV are prone to develop drug-induced allergic reactions.30 TMP-SMX tends to be a common cause of drug reactions in these patients. Other antiretroviral drugs are also commonly involved. Patients with certain human leukocyte antigen (HLA) alleles are at a higher risk. Abacavir, which is a nucleoside reverse transcriptase inhibitor, can cause hypersensitivity reactions manifesting as fever, rash, gastrointestinal involvement, and respiratory involvement. HLA-B*5701 is associated with an increased risk for these reactions.31 Genetic screening prior to starting therapy has decreased the rate of abacavir-associated reactions.
The most common adverse effect associated with the use of corticosteroids is allergic contact dermatitis due to topical steroid preparations. Immediate hypersensitivity reactions to corticosteroids are rare. Most case reports mention intravenous methylprednisone and hydrocortisone as the culprit drug;32,33 patients can usually tolerate other corticosteroids. Preservatives and diluents are believed to be responsible for these reactions in some cases.33 Thus, skin testing should be done for the corticosteroid in question as well as for the preservative/diluent. Some of these reactions may be anaphylactoid in nature and a skin test would be negative in such cases.
Adverse reactions to cancer chemotherapeutic agents can vary from mild skin eruptions to anaphylaxis.34 Platinum compounds (cisplatin and carboplatin) can cause immediate hypersensitivity reactions, usually after repeated exposures, whereas taxanes, such as paclitaxel, can cause anaphylactoid reactions with the first dose. These reactions can be prevented in more than 90% of cases with pretreatment by using antihistamines and corticosteroids.35 These drugs can, however, be safely administered using desensitization or induction of drug tolerance procedures.36
Biologic modifiers include cytokines, monoclonal antibodies, and interferons. These are immune modulatory agents and are used in treatment of various inflammatory conditions and tumors.
Interferons are associated with adverse reactions such as flu-like symptoms, depression, headache, and autoimmune reactions.37 IgE-mediated reactions may vary from urticaria to anaphylaxis.
Anti-tumor necrosis factor alpha agents such as infliximab and adalimumab are used for treatment of different inflammatory conditions such rheumatoid arthritis and Crohn's disease. Their use is associated with variable adverse reactions including urticaria, life-threatening anaphylaxis, and serum sickness.38 Guillain-Barre syndrome and other demyelinating syndromes have also been reported.39
Omalizumab has been approved for the treatment of asthma. It is a monoclonal antibody to human IgE. Occasionally, patients may develop anaphylaxis. Reactions usually occur within 2 hours of the injection and are more commonly seen with the first three doses.40
Intravenous gamma globulin can cause infusion reactions manifesting with fever, chills, headache, anxiety, myalgias, and occasionally hypotension. These reactions may occur 6 to 24 hours after an infusion.41
Complementary medicines include herbal medicines, essential oils, bee pollen, vitamins, and minerals. These products are usually considered safe and natural; however, allergic reactions have been reported with some products such as bee pollen and echinacea (an herb).42,43 Some homeopathic products have been reported to cause systemic contact dermatitis in patients allergic to nickel.44 Thus, a history should always be obtained from patients regarding the use of any herbal products or supplements, including vitamins.
Management of Drug Allergy
Avoidance of the culprit drug is most important. All cross-reacting drugs should also be avoided. A “medic alert” bracelet can warn the treating physicians, who can then avoid the use of culprit drugs. It is important to make patients aware of their drug allergies, and their medical records should always be updated to include their drug allergy profile. Patients should also be provided with an epinephrine injector to be used in case of anaphylaxis. Sometimes, a particular drug may be life-saving or essential for optimal treatment of certain clinical conditions such as syphilis in pregnancy. In such cases, temporary drug tolerance can be achieved via desensitization.45 The drug can then be safely administered. A graded drug challenge can be done if the history is not suggestive of a drug allergy. In case of severe non–IgE-mediated reactions (ie, SJS, TEN, DRESS), induction of drug tolerance procedures is contraindicated.
In acute settings, the offending drug should be immediately stopped. In type 1 reactions, an epinephrine injector should be administered along with other emergency resuscitative measures. In the case of non–IgE-immediate reactions, treatment should be initiated with corticosteroids and antihistamines; however, in patients with advanced stages of SJS and TEN, corticosteroids are contraindicated. These patients should be managed in burn units instead. Intravenous immunoglobulin has also been shown to be helpful in some cases of SJS/TEN.46