About 8% of individuals in the United States healthcare system report an allergy to penicillin and 1% have a noted cephalosporin allergy.38 Avoidance of penicillins in patients with self-reported allergy is a growing health concern. The use of alternative antibiotics in these patients is associated with increased medical costs and an increased frequency of infection with methicillin-resistant Staphylococcus aureus (MRSA) and Clostridioides difficile.39 Only 10% to 20% of patients reporting penicillin allergy are found to be allergic by skin testing.3,40 Patients with a history of immediate penicillin allergy who have a negative penicillin skin test result are unlikely to react on subsequent courses of penicillins.3,40
The most common reactions to penicillin include urticaria, pruritus, and angioedema. All four of the major types of allergic reactions have been reported with penicillin, as well as some reactions that do not fit into these categories. A wide variety of idiopathic reactions occur, such as maculopapular eruptions, eosinophilia, SJS, and exfoliative dermatitis. Cutaneous reactions can occur in up to 4.4% of treatment courses of penicillin41 and in up to 8% of those of aminopenicillins.42 The incidence of ampicillin rash is close to 100% in patients with viral infections such as infectious mononucleosis.43
Some aspects of the mechanism of penicillin immunogenicity have been determined. As a relatively small molecule (356 Da), benzylpenicillin must combine with macromolecules (presumably proteins) to elicit an immune response. Penicillin is rapidly hydrolyzed to a number of reactive metabolites that have the ability to covalently link to proteins. Of these metabolites, 95% is in the form of benzylpenicilloyl that binds covalently to the lysine residues of proteins such as albumin through an amide linkage involving the β-lactam ring (see Fig. e104-1). This penicilloyl–protein conjugate is referred to as the major antigenic determinant. The other penicillin metabolites such as penilloate and penicilloate bind in lesser quantities to proteins. These are referred to as minor antigenic determinants. The terms major and minor refer to the relative proportions of these conjugates that are formed and not to the clinical severity of the reactions generated. Immediate hypersensitivity reactions may be mediated by IgE for both minor and major determinants. In fact, the minor antigenic determinants are more likely to cause life-threatening anaphylactic reactions.
Formation of a benzylpenicilloyl hapten–protein complex.
In addition to the major and minor determinants, unique side-chain determinants may mediate allergy to some penicillins. Based on recent studies, the frequency of reactions to the β-lactam core of penicillin as determined via skin testing is decreasing while reactions to the R-group side chains of the penicillins are increasing in occurrence.44 Both the aminopenicillins and piperacillin may cause hypersensitivity reactions via unique side chains on their structures.45,46 Therefore, a patient may exhibit hypersensitivity to amoxicillin or piperacillin via a side chain determinant while exhibiting no reactivity to other penicillins. Reports of selective allergy to amoxicillin have become relatively common. The R-group side chain of amoxicillin is believed to be the primary epitope, but selective reactivity to clavulanic acid has been postulated and evaluated in those experiencing a reaction to amoxicillin clavulanate.47–49 Careful history taking is needed to identify patients with a high likelihood of side-chain–specific reactions. Skin testing with dilute concentrations of amoxicillin, ampicillin, and piperacillin has been used to aid in the determination of side-chain–specific reactions.50–52
Patients who are allergic to penicillins also may be sensitive to other β-lactams. The exact incidence of cross-reactivity between cephalosporins and penicillins is not known but is believed to be low.3,38,53 The risk was originally reported as 10% to 15% in the 1970s when cephalosporins were contaminated with trace amounts of penicillin. Current estimates of the cross-reactive risk between penicillin and the first- and second-generation cephalosporins are 5% to 7.5% and as low as 1% between penicillin and the third- and fourth-generation cephalosporins.3 One percent to 8% of patients with penicillin-specific IgE may develop an immediate-type hypersensitivity reaction to cephalosporins.54 In contrast, patients with reported penicillin allergy and negative skin test results are at no greater risk.3
Ideally, cephalosporins should be avoided in patients with a history of an immediate hypersensitivity reaction to penicillin, although most studies report low risk of an allergic response to a cephalosporin even in a person with a positive skin test result to penicillin. Based on the results of one meta-analysis, patients with penicillin allergy have the highest risk of cross-reactivity with the first-generation cephalosporins (odds ratio [OR] 4.79; 95% confidence interval [CI] 3.71-6.17).55 The odds of reacting to a second- and third-generation cephalosporin were 1.13 (95% CI 0.61-2.12) and 0.45 (95% CI 0.18-1.13), respectively.55 The higher rate of cross-reactivity between penicillin and the first-generation cephalosporins has been attributed to similarities in the R1 side chains of these agents.3,52 The R1 side chain is connected to the opened β-lactam ring, thereby influencing the antigenicity of these agents. When assessing the potential for cross-reactivity between penicillins and cephalosporins, clinicians should evaluate the similarities in the R1 side chains of the agents.52,55,56 β-lactam antibiotics with an R1 substitution chemically similar to that of penicillin G are cephalothin and cefoxitin. In the R1 position, amoxicillin is chemically similar to ampicillin, cefaclor, cephalexin, and cefadroxil. Cefotaxime, ceftizoxime, ceftriaxone, cefpodoxime, and cefepime have chemically similar substitutions in the R1 position that may influence the risk of cross-reactivity.56
Cephalosporins rarely induce immune responses mediated by the core β-lactam structure, but they are more likely to do so via unique R-group side-chain determinants.55 In a patient with a cephalosporin allergy, skin testing with the major and minor determinants of penicillin can be used to identify the likelihood of reactivity to the core β-lactam ring. The risk of cross-reactivity between cephalosporins is higher than that between the penicillins and cephalosporins. Cross-reactions may occur through identical R1 side chains. Of note, ceftazidime shares a common side chain with aztreonam.
The actual risk of a cross-reaction between the penicillins and the carbapenems appears to be much lower than originally described. The initial estimate of the cross-reactive risk was 47.4%, but current estimates range from 0.9% to 11%.53 The initial estimate was based on the results of skin testing with penicillin and nonstandardized carbapenem reagents. Several retrospective studies reporting variable rates of cross-reactivity relied on self-reported histories as confirmation of penicillin allergy. In four recently published prospective studies, both skin testing methods and carbapenem challenge dosing were used to assess cross-reactive risk. In one of these studies, only one of 112 patients with skin test–confirmed penicillin allergy had a positive skin test result for imipenem.57 Challenge dosing with imipenem to a final dose of 500 mg was subsequently performed in 110 patients with negative imipenem skin test results; none of the 110 patients had a reaction. Results of two additional prospective studies, one of which was performed in children ages 3 to 14 years, suggest a low risk of cross-reactivity between penicillin and meropenem.58,59 In both studies, only one patient with skin test positivity to penicillin had a positive skin test result for meropenem. Graded challenge dosing with meropenem was tolerated in 100% of the skin test–negative patients in both studies. In a recent study, 212 patients with skin test positively to a penicillin underwent skin testing with ertapenem, meropenem, and imipenem.60 None of the 212 patients had skin test positivity to a carbapenem. Graded challenge to a full therapeutic dose of each carbapenem was subsequently performed in 211 subjects.60 No patient exhibited a reaction during challenge dosing. Based on these results, the routine practice of avoiding carbapenem use in patients with a history of penicillin allergy should be reconsidered.
Of the monobactams, aztreonam only weakly cross-reacts with penicillin and can be administered safely to most patients who are penicillin allergic.3,53 In 211 patients with skin test positivity to a penicillin, graded challenge dosing to a full therapeutic dose of aztreonam was uneventful in all patients.60
Radiocontrast agents frequently cause reactions categorized as immediate (in 1 hour) or nonimmediate (less than or equal to 1-10 days) via both IgE-mediated and non-IgE-mediated mechanisms.61 The frequency and severity of these reactions are influenced by the type of radiocontrast agent (ionic vs nonionic), and patient-specific factors such as history of atopy, asthma, or prior reaction to a radiocontrast agent. Current reported estimates of the frequency of immediate reactions with ionic and nonionic agents are 1% to 3% and less than 0.5%, respectively.3,17 Delayed skin reactions, usually presenting as maculopapular exanthems, occur in 1% to 3% of patients over 5 to 7 days.61 Severe, immediate anaphylactic reactions occur in 0.01% to 0.04% of patients.61 In addition, radiocontrast agents may cause dose-dependent toxic reactions that can produce renal impairment, cardiovascular effects, and arrhythmias.62 The mechanism of reactions to radiocontrast agents is not clearly understood. Histamine release and mast cell triggering have been documented in severe immediate reactions, suggesting an IgE-mediated mechanism. The older, high-osmolar radiocontrast agents can activate mast cells, basophils, and the complement system directly (IgE-independent mechanism), resulting in the release of inflammatory mediators. The delayed-onset maculopapular rash appears to be T-cell mediated. The low-osmolar nonionic contrast agents appear to cause fewer acute reactions.
The risk of immediate reactions to radiocontrast media is greater in women and in patients with a history of atopy or asthma.61 Other recognized risk factors include a history of previous reaction, severe drug allergies, cardiac disease, and treatment with β-blockers.3,17 Despite a common misconception, seafood allergy or iodine allergy does not predispose to radiocontrast media reactions. Although not recommended in current guidelines, there is a trend toward skin testing of patients with prior immediate reactivity to a radiocontrast agent. Skin testing with a panel of different radiocontrast agents may aid in the identification of a product with low reactive risk.61 Although some regimens have been recommended to prevent the recurrence of immediate events in patients who have experienced reactions previously, the value of these preventive regimens has not been proven, and their use remains controversial.61,63 A commonly recommended regimen in high-risk patients is oral prednisone (50 mg) 13, 7, and 1 hours before exposure with 50 mg of diphenhydramine given orally or intramuscularly 1 hour before exposure to prevent immediate reactions.17 Ephedrine 25 mg orally has also been recommended 1 hour before the radiocontrast study as a component of the pretreatment regimen, but ephedrine should not be used if the patient has a history of unstable angina, hypertension, or arrhythmia.3,17 Other studies have examined the use of H1- and H2-antihistamines, clemastine, or cimetidine, respectively.3,17
Immediate reactions to gadolinium, a noniodinated contrast agent, have been reported at frequencies of 0.07% in adults and 0.04% in children.64 Most reactions have been mild, requiring either no medical management or treatment with antihistamines. Moderate and severe reactions have also been rarely reported. Pretreatment regimens similar to those used with iodinated contrast studies are usually effective, but they have been associated with breakthrough reactions, particularly in patients with a history of reactions to gadolinium or iodinated contrast agents.65
Insulin can produce an IgE-mediated reaction, an immune complex reaction and delayed T-cell mediated allergy. The reported prevalence of insulin allergy is 0.1% to 3% and the most common manifestation is an IgE-mediated local reaction at the injection site.66 Allergic reactions have been reported with beef and pork insulin and more rarely with the recombinant human insulin. Insulin’s antigenicity may be explained by alterations in protein unfolding during the manufacturing process.66 Reactions may also occur to additives in insulin such as zinc or protamine. Development of anti-insulin IgG antibodies occurs commonly after a few months of therapy, but these antibodies remain inactive in most patients.
Local reactions present most often as a wheal and flare at the injection site and may occur immediately after injection or up to 8 to 12 hours later. These reactions are generally mild, do not require treatment, and resolve with continued insulin administration. Before labeling the patient as allergic to insulin, consideration should be given to the patient’s insulin administration technique. Systemic antihistamines may be administered in patients who continue to have local reactions, and a different insulin source may be substituted. Systemic reactions to insulin (eg, urticaria or anaphylaxis) rarely occur. Skin testing with various products is recommended to identify the type of insulin least likely to cause a systemic reaction.66 In some patients, insulin desensitization may be indicated.66
Aspirin and Nonsteroidal Anti-inflammatory Drugs
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can produce eight general types of DHRs, four of which are related to COX inhibition.67,68 These DHRs can involve asthma and rhinitis, urticarial/angioedema, anaphylaxis, aseptic meningitis, or pneumonitis. The two most common aspirin sensitivity reactions are respiratory (asthma and rhinorrhea) and urticarial/angioedema in patients without chronic urticaria. About 9% to 20% of people with asthma are sensitive to aspirin and other NSAIDs.67,69
The rhinosinusitis/asthma syndrome typically develops in middle-aged patients who are nonatopic and have no history of aspirin intolerance. Women are 2.5 times more likely to develop aspirin-induced asthma than men.70 It usually progresses from rhinitis to sinusitis with nasal polyps and steroid-dependent asthma. It is uncommon in children and young adults. However, children with asthma may be aspirin sensitive. Aspirin-sensitive asthma appears to be an inherited disorder characterized by overexpression of LTC4 synthase in airways.71 In aspirin-sensitive people with asthma, administration of aspirin and NSAIDs may provoke severe and sometimes fatal asthmatic attacks. The mechanism of aspirin sensitivity is not completely understood.
One suspected mechanism of aspirin and NSAID sensitivity is COX-1 blockade, which may facilitate depletion of prostaglandin E2 (PGE2) and production of alternative arachidonic acid metabolites (eg, LTs).67 PGE2 prevents mast cell degranulation, while LTs cause bronchoconstriction and increased mucus production. Increased LT production may also explain the development of angioedema and urticaria, based on the observed correlation between the degree of COX-1 blockade and the risk of a sensitivity reaction. Therefore, agents such as acetaminophen, which minimally block COX-1, rarely cause reactions. This mechanism is also supported by the clinical observation that LT-modifying drugs can reduce the severity of aspirin-induced asthma and urticaria.67 It is also possible that aspirin and NSAIDs stimulate mast cells directly to release inflammatory mediators. Subjects with aspirin-induced asthma also have a marked increase in airway responsiveness to LTs. Aspirin and the COX-2–selective inhibitors celecoxib and rofecoxib do not appear to be cross-reactive.72,73
In patients with aspirin sensitivity (asthma or urticaria) in which aspirin is indicated for cardiovascular disease, oral graded challenge dosing and/or desensitization is recommended.74 A number of different protocols have been described, and the risk for anaphylaxis cannot be reliably predicted.67,70,74 Both graded challenge and desensitization should be performed with caution in a hospital setting with resuscitation equipment at hand. For patients with a history of cutaneous reactions to aspirin, a two-dose challenge of 40.5 mg (one-half of an 81-mg tablet) given 90 minutes apart with no pretreatment has shown promising results.74 If no reaction occurs after administration of the second dose, the patient may receive 81 mg of aspirin per day for cardioprotective therapy.74 For patients with aspirin-induced asthma, induction of drug tolerance (desensitization) is recommended. A number of aspirin desensitization protocols have been described, ranging from 2- to 4-day protocols for patients with a history of asthma to rapid (2-5 hours) protocols.3,74,75 If oral challenge is not successful and desensitization is not performed, patients with aspirin sensitivity must avoid aspirin and the nonselective NSAIDs as the major preventive measure.
Individual NSAIDs (eg, ibuprofen, sulindac), and rarely aspirin, can cause IgE-mediated allergy. These reactions occur on reexposure to the drug and may present as urticaria, bronchospasm, or anaphylaxis with or without hypotension. A careful and complete allergy history may suggest true allergy to an isolated NSAID. Such patients should be advised to avoid the specific NSAID and any structurally similar NSAIDs (eg, all propionic acid derivatives, all indole acetic acid derivatives) because of the risk of cross-reactivity. Patients with a history of reacting to a specific NSAID other than aspirin can safely receive aspirin.74
NSAIDs have been associated with pulmonary infiltrates and eosinophilia syndrome. Pulmonary infiltrates and eosinophilia syndrome is associated with fever, cough, dyspnea, infiltrates on chest radiography, and peripheral eosinophilia that develops 2 to 6 weeks after initiating treatment. Pulmonary infiltrates and eosinophilia syndrome occurs more frequently for naproxen compared with other NSAIDs and is noted to resolve rapidly after discontinuation of the offending agent.76
Sulfonamide drugs containing the sulfa (SO2NH2) moiety include antibiotics, thiazide and loop diuretics, oral hypoglycemics, COX-2 inhibitors, and carbonic anhydrase inhibitors. Other less commonly recognized sulfonamides include antivirals (amprenavir, fosamprenavir, and darunavir), probenecid, tamsulosin, triptans, and zonisamide. Allergic reactions have been reported in 4.8% of 20,226 patients who received a sulfonamide antibiotic and in 2% of patients who received a nonantibiotic sulfonamide.77 Although immediate IgE-mediated reactions such as anaphylaxis can occur, sulfonamides typically cause delayed cutaneous reactions, often beginning with fever and then followed by a rash (eg, maculopapular or morbilliform eruptions). Infrequently, a seemingly benign maculopapular rash may progress to a mucocutaneous syndrome (eg, SJS or TEN).4 Other reactions to sulfonamides may include hepatic, renal, or hematologic complications, which may be fatal.
Immune-mediated sulfonamide reactions depend on the production of reactive metabolites in the liver.78 Trimethoprim–sulfamethoxazole, considered the most highly reactive sulfonamide, contains an arylamine in the N4 position of its chemical structure, allowing for the drug’s metabolism to two highly reactive metabolites, a hydroxylamine and a nitroso-sulfonamide.78,79 Structural differences between the sulfonamides antibiotics and nonantibiotics may influence the metabolic conversion and resultant reactivity of these compounds. Slow acetylator phenotype may also increase the risk for these reactions. When assessing the potential for allergy to a sulfonamide, the clinician should consider the chemical structure of the agent. Attention should be given to the presence of an arylamine group in the N4 position and/or an N-containing ring attached to the N1 nitrogen of the sulfonamide group.79
Cross-reactivity between sulfonamide antibiotics and nonantibiotics appears to be minimal, with cross-reactivity characterized as “highly unlikely.”80 In one study, about 10% of patients with a history of allergy to an antibiotic sulfonamide subsequently reacted to a nonantibiotic sulfonamide (eg, acetazolamide, loop diuretic, sulfonylurea, and thiazide).77 This low rate of cross-reactivity has been attributed in part to differences in the chemical structures of the antibiotic and nonantibiotic sulfonamides. The occurrence of allergic reactions after receipt of nonantibiotic sulfonamides has also been attributed to a predisposition to allergic reactions in the affected individuals rather than cross-reactivity with sulfonamide antibiotics.77 In fact, in one study, cross-reactivity between sulfonamide antibiotics and penicillin was higher than that between the antibiotic and nonantibiotic sulfonamides.77
Trimethoprim–sulfamethoxazole is used frequently for preventive or active treatment of Pneumocystis jiroveci pneumonia in patients with AIDS or hematologic malignancies. Adverse reactions to trimethoprim–sulfamethoxazole occur much more frequently in HIV-positive patients.81,82 Adverse effects to trimethoprim–sulfamethoxazole occur in 50% to 80% of AIDS patients compared with 10% of other immunocompromised patients.82 Trimethoprim–sulfamethoxazole was associated with an adverse event rate of 26.3 per 100 person-years and a hypersensitivity event rate of 22 per 100 person-years. Although reactions may include angioedema, SJS, and thrombocytopenia, most reactions to trimethoprim–sulfamethoxazole in HIV-infected patients are delayed and present as a diffuse maculopapular rash with or without fever. The mechanism by which these allergic or allergic-like reactions occur in HIV-infected patients is unclear. It is unlikely that these reactions are IgG or IgE mediated.83 Proposed mechanisms include alterations in drug metabolism caused by glutathione deficiency, a direct toxic or immunologic effect of the sulfonamide metabolites on body tissues, and increased expression of major histocompatibility complex proteins with increased recognition of the drug antigen by CD4 and CD8 cells.83 The adverse event rate has been associated with higher CD4+ T-cell count greater than 20 cells/mm3 (0.020 × 109/L), CD4 to CD8 ratio less than 0.10, and treatment for fewer than 14 days.82
Pharmaceutical Excipients and Additives
Pharmaceutical products contain a number of “inert” additives (eg, dyes, fillers, buffers, and stabilizers) in addition to the therapeutic ingredients. These additives are not always inert and may cause adverse effects, including allergic reactions. Excipients that may cause allergic reactions include benzyl alcohol, carboxymethylcellulose, povidone, dyes, sodium benzoate, sulfites, and polyethoxylated surfactants.84
The azo dye tartrazine (FD&C Yellow No. 5) has been associated with acute bronchospasm, urticaria, rhinitis, and contact dermatitis.85,86 Although the immunologic mechanisms are unclear, about 10% of aspirin-sensitive people with asthma have shown intolerance to tartrazine.87 Doses as low as 0.85-mcg or as much as 25 mg tartrazine have provoked positive responses.87 Most recently, challenge dosing with 35 mg of tartrazine was not shown to provoke either respiratory or cutaneous reactions in a double-blind, placebo cross-over study of 26 atopic individuals.88
Sulfites (including sulfur dioxide, sodium sulfite, sodium and potassium bisulfite, and sodium and potassium metabisulfite) are used commonly as antioxidants in pharmaceutical products and some foods. Many cases of adverse reactions associated with ingestion of sulfites (usually in foods) have been reported to the US Food and Drug Administration (FDA),89 including wheezing, dyspnea, chest tightness, urticaria, angioedema, flushing, weakness, nausea, anaphylaxis, and death. IgE-mediated and nonimmunologic sulfite hypersensitivity has been demonstrated in children with a history of chronic asthma. Adverse reactions to sulfite-preserved injectables, such as propofol, gentamicin, metoclopramide, lidocaine, and doxycycline, have been reported. In contrast to reactions caused by foods, these reactions do not occur more frequently in steroid-dependent people with asthma and do not always coincide with a positive oral sulfite challenge.90 Blunted bronchodilation may be observed in individuals with asthma after inhalation of sulfite-containing nebulizer solutions. Although many nebulizer solutions contain sulfites, metered-dose inhalers do not. Many aqueous epinephrine products also contain sulfites. The FDA labeling states that in emergency situations when sulfite-free preparations are not available, sulfite-containing epinephrine should not be withheld from a sulfite-intolerant individual because small subcutaneous doses of sulfites usually are well tolerated. However, an increased risk of anaphylaxis exists after subcutaneous injection in rare patients with a positive oral challenge of 5 to 10 mg of sulfite.
Parabens (including methyl-, ethyl-, propyl-, and butylparaben) are used widely in pharmaceutical products as a biocidal agent. Most allergic reactions to parabens are observed after topical exposure.91 Delayed hypersensitivity contact dermatitis occurs more often in individuals with preexisting dermatitis.87 Immediate hypersensitivity after parenteral administration is rare. Although these agents are chemically related to benzoic acid and p-aminobenzoic acid, the evidence for cross-sensitivity is lacking.87
Cancer Chemotherapy Agents
Chemotherapy agents are implicated in hypersensitivity reactions in 5% to 15% of patients who receive them.92 Up to 65% of patients receiving L-asparaginase experience immediate hypersensitivity reactions such as urticaria and anaphylaxis.93
The combination regimen of paclitaxel (or docetaxel) and carboplatin is frequently responsible for producing hypersensitivity reactions. Each agent precipitates a distinct reaction, allowing for differentiation between causative factors. Hypersensitivity or allergy-like reactions have been observed with paclitaxel and docetaxel in as many as 34% of patients.4,94,95 The reaction typically occurs within minutes after initiation of the first or second dose, suggesting a non-IgE-mediated mechanism. Both the vehicles of the taxanes (polyoxyethylated castor oil for paclitaxel; polysorbate 80 for docetaxel) and the taxanes themselves have been implicated as the cause of the reactions. A cross-reactive risk of 90% between paclitaxel and docetaxel provides further evidence that the reaction is most likely attributed to the taxane moiety.96 Severe reactions are characterized by dyspnea, bronchospasm, urticaria, and hypo- or hypertension. Minor reactions include flushing and rashes. In patients receiving a 3-hour infusion, the incidence of severe reactions is reduced to 1.3%, and the incidence of minor reactions is 42%.97 To reduce the risk of hypersensitivity reaction, patients are routinely premedicated with corticosteroids and both H1- and H2-receptor antagonists. A protein-bound formulation of paclitaxel (Abraxane®) devoid of the castor oil vehicle is available, avoiding some but not all reactions.
Hypersensitivity to platinum-containing agents is delayed, developing after six or more courses of carboplatin, cisplatin, or oxaliplatin.98–101 The reaction rates differ depending on the platinum agent with reported frequencies of 5% to 20% with cisplatin, 9% to 27% with carboplatin, and 10% to 19% with oxaliplatin.102 Reactions typically develop shortly after completing the infusion or up to 3 days after therapy.98 Symptoms of severe reactions include tachycardia, dyspnea, facial swelling, rigors, and hypotension. Mild reactions include itching, erythema, and facial flushing. An association between reactivity and the duration of the platinum-free interval has been described for carboplatin.103 The risk of a severe reaction was 47% if the platinum-free interval was greater than 24 months versus only 6.5% with intervals less than 12 months.103 Management strategies include decreasing the rate of infusion and administration of corticosteroids and H1- and H2-receptor antagonists.101 Skin testing with carboplatin has been described.99,102 Desensitization to carboplatin99,100 and oxaliplatin104,105 has been shown to be well tolerated.
Many anticonvulsant drugs produce a variety of DHRs. Drugs such as phenytoin, phenobarbital, carbamazepine, and lamotrigine can cause an “anticonvulsant hypersensitivity syndrome” characterized by fever, rash, lymphadenopathy, and internal organ involvement. Eosinophilia is frequently present and many reactions meet the definition of DRESS. The onset usually occurs several weeks into therapy.34 In some cases, morbilliform rash develops into exfoliative dermatitis. The risk of cross-reactivity between the aromatic anticonvulsants (eg, carbamazepine, phenobarbital, and phenytoin) ranges from 40% to 80%.34 Oxcarbazepine, the 10-keto derivative of carbamazepine, has exhibited both in vitro and in vivo cross-reactivity with carbamazepine. A genetic marker for severe reactions to carbamazepine, phenytoin, and fosphenytoin is the presence of the HLA-B*1502 allele.33 This allele is found in 10% to 15% of patients from China, Thailand, Malaysia, Indonesia, the Philippines, and Taiwan. In a population of patients from Taiwan, Japan, and Malaysia, genetic variation in the CYP2C gene, notably CYP2C9*3, was associated with phenytoin-induced SCARs (OR 11; 95% CI 6.2-11.8, P < 0.0001).37 Concomitant use of valproate with lamotrigine significantly increases the risk of DHRs as a result of reduced lamotrigine metabolism, leading to a prolonged elimination half-life.106
ACE Inhibitors and Angiotensin-Receptor Blockers
ACE inhibitor-associated angioedema occurs in 0.2% to 1% of treated patients.107 It usually involves the face, tongue, lips, and pharynx but may also extend to the gastrointestinal tract. ACE is a nonspecific dipeptidase that not only inhibits the conversion of angiotensin I to angiotensin II but is involved in the inactivation of bradykinin, substance P and neurokinin A. High levels of bradykinin and substance P have been associated with vasodilation, increased vascular permeability and inflammation resulting in angioedema in susceptible patients. The prevalence of ACE inhibitor–induced angioedema is highest in women and African Americans.107 An added risk factor is the concomitant use of medications that inhibit bradykinin metabolism, such as the neprilysin inhibitor, sacubitril. Current labeling for the sacubitril/valsartan combination product provides a cautionary recommendation for a 36-hour washout period when converting from an ACE inhibitor.108
Angioedema secondary to angiotensin-receptor blockers (ARBs) has been reported; the weighted incidence was 0.11% in a meta-analysis of 35,000 patients treated with an ARB.109 The mechanism by which ARBs cause angioedema is poorly understood. As such, the risk of a “cross-reaction” between ACE inhibitors and ARBs is not clear. ARBs may cause repeat events through an independent mechanism or through a common pathway not yet determined. Based on a systematic review of 71 patients, the risk of subsequent angioedema after switching to an ARB was 9.4% for possible cases and 3.5% for confirmed cases.110 None of the events were fatal. Before switching to an ARB in a patient with history of ACE inhibitor–related angioedema, consideration must be given to the severity of the initial event (ie, isolated nondiffuse facial swelling vs diffuse angioedema with laryngeal inflammation, esophageal or intestinal involvement), the prior responsiveness to treatment for angioedema and the benefit:risk ratio of using the ARB in the patient.
The prevalence of allergy or DHRs to chlorhexidine is not known, but cases ranging from anaphylaxis to contact dermatitis have been increasingly reported over the past 10 years.111 Chlorhexidine is one of the most frequently used antiseptics. Having both bacteriostatic and bactericidal activity, chlorhexidine is used as a skin antiseptic prior to surgery, for urethral catheterization as a lubricant gel, and as a coating in central venous catheters.112 It can also be found as an ingredient in toothpaste, mouthwashes, and mouth rinses. Sensitization is most commonly associated with the application to mucous membranes.112 When applied to the skin as a hand-washing solution, low sensitization rates are attributed to poor transdermal absorption of chlorhexidine. Most allergic reactions are confined to the skin and manifest as urticaria with itching or contact dermatitis; however, anaphylaxis has been reported perioperatively after skin antisepsis, following insertion of a chlorhexidine-coated central venous catheter, and during toothbrushing. Both skin prick and intradermal testing have been used to identify high-risk patients prior to surgery. In a case series of six severe, immediate reactions to chlorhexidine that occurred during surgery, the onset of reactivity was within 10 to 20 minutes of chlorhexidine exposure.111 When assessed 6 weeks after surgery, 5 of the 6 patients had self-reported prior histories of reactivity to chlorhexidine and 4 of the 6 demonstrated reactivity to skin prick testing.111 The results of skin testing, the rapid onset and the increased intensity of reactivity observed on reexposure to chlorhexidine support an IgE-mediated mechanism. Based on the widespread use of this antiseptic, chlorhexidine should be considered as a potential cause of any unexplained allergy. Once recognized as reactive, patients must be educated to avoid subsequent exposures in both healthcare settings (eg, handwashing solutions and skin antiseptics) and in the private home (eg, personal hygiene products containing chlorhexidine).
Biologic agents (eg, monoclonal antibodies, fusion proteins, and recombinant proteins) are derived from living sources such as yeast, bacteria, animal cells, or mammalian cells.113 Unlike nonbiologic agents, these large proteins can serve as complete antigens. Examples include recombinant insulin, erythropoietin, interferon-β, human growth hormone, infliximab, cetuximab, rituximab, and omalizumab. Immunologic reactions to these agents range from minor infusion or injection-site reactions to anaphylaxis. Depending on the agent, reactions can occur on first or subsequent exposure, and the timing may be within 4 hours of drug administration or up to 14 days after an infusion.113
Factors influencing the antigenicity of biologic agents are patient-specific (eg, atopy, congenital protein deficiency), production-related (eg, presence of contaminants or stabilizing agents, degree of protein glycosylation, presence of nonhuman protein sequences, and storage temperature), and administration related (eg, route of administration, frequency of use, concurrent immunosuppressant use).113 Of the monoclonal antibodies, reactions are most frequently observed with the murine-derived agents (0% human) and chimeric agents (75% human) as opposed to the humanized (greater than 90% human) and human (100% human) agents. Some immune reactions to biologic agents result from the development of neutralizing antibodies that can prevent the protein from exerting its intended effect. Neutralizing antibodies have been shown to mediate reactions to interferon-β1b and β1a, infliximab, natalizumab, recombinant factor VIII, and recombinant factor IX.113 Anti-infliximab antibodies, which occur in up to 60% of treated patients, are associated with higher frequency of infusion reactions and decreased therapeutic effect.114 Concomitant administration of immunosuppressive agents such as prednisone or low-dose methotrexate has been shown to decrease the incidence of antibody formation to infliximab.113,114
Cetuximab, a human-murine IgG1 monoclonal antibody used in the treatment of metastatic colon cancer and locally or advanced head and neck cancer, presents a unique situation as an allergen.115 Cetuximab carries a black box warning regarding serious infusion reactions that occurred largely on first dose administration in 3% of patients in pre-marketing studies. Following the release of the drug, reactive rates as high as 20% were noted in specific regions of southern United States.116 These reactions also occurred with the first infusion, but many were severe enough to warrant total discontinuation of therapy. Further investigation of these regional cases revealed a common link: the presence of preexisting IgE antibodies against the oligosaccharide, galactose-α-1,3- galactose secondary to lone star tick bites.117 This oligosaccharide present in the tick is also found on the Fab portion of the heavy chain of cetuximab, resulting in IgE cross-reactions on first drug exposure. Galactose-α-1,3-galactose is also present in the serum of nonprimate mammals and may be responsible for delayed hypersensitivity reactions secondary to the ingestion of certain meats.117 Experience with cetuximab as an immunogen has raised awareness of potential drug-food-environmental cross-reactions.
Delayed onset anaphylaxis, ranging from minutes to days postinjection, has been reported with omalizumab, a humanized monoclonal antibody targeted against IgE for the treatment of moderate-to-severe asthma or chronic idiopathic urticaria.118,119 Omalizumab-treated patients require observation for 2 hours after the first three injections and for 30 minutes after subsequent injections.119 Patients are advised to carry an epinephrine autoinjector during and for 24 hours after drug administration.118,119 Risk factors for this adverse event have not been identified. Inclusion of polysorbate 80 as a stabilizing agent in the formulation and an alteration in the protein sequence via glycosylation may influence the immunogenicity of omalizumab.119
Management of allergic or DHRs to biologic agents varies based on the culprit agent and the severity and nature of the reaction. Immediate management with epinephrine and permanent discontinuation of the drug may be warranted (eg, omalizumab-induced anaphylaxis). Depending on the biologic agent, reactions may be managed by decreasing the infusion rate (if given intravenously) or lessened by pretreating with antihistamines or corticosteroids or administering concomitant steroid therapy. Desensitization protocols for infliximab,102,120 cetuximab,121 rituximab,102,120 and trastuzumab102,120 have also been described.