1. 1
    Current Diagnosis

    • Detailed history should include past medical history; current diagnosis; previous and current medication use, including over-the- counter drugs and herbals; duration of the medication use; any similar reactions in the past.

    • Physical examination should include vitals, temperature, and skin examination for rash.

    • Laboratory testing should be conducted based on symptoms that may include complete blood count (CBC) with differential, including eosinophils, sedimentation rate, liver enzymes, international normalized ratio (INR), diagnostic skin biopsy, or testing.

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    Current Therapy

    • For life-threatening anaphylaxis reaction, start basic life support using pneumonic ACB (airway, compression, breathing) and give epinephrine immediately.

    • Discontinue the offending drug if medically possible. Try drug substitution if warranted.

    •   An alternative option is to reduce the dose or frequency of the drug.

    • Start symptomatic treatment based on the type of reaction and the offending medication.

    • Some reactions may respond to treatment with antihistamines, H2 blockers, or steroids.

  3. 3

    Drug hypersensitivity reactions are one of the many different types of adverse drug reactions (ADRs). ADRs are common, yet the more severe reactions have been estimated to cause 3% to 6% of hospital admissions. More than 100,000 deaths annually are caused by serious ADRs, making these reactions one of the leading causes of death in the United States. Early detection of all ADRs can potentially improve patient outcomes and lower health care costs.

  4. 4

    An ADR is a broad term that refers to any predictable or unpredictable reaction to a medication. A predictable (type A) reaction is dose dependent and is related to the known pharmacologic properties of the drug. Predictable reactions account for about 80% of all ADRs. An example of a type A reaction is gastritis that results from taking nonsteroidal antiinflammatory drugs (NSAIDs). The remaining 20% of ADRs are caused by unpredictable (type B) reactions. Type B reactions occur in susceptible individuals. These are hypersensitivity reactions that are different from the pharmacologic actions of the drug; they are results of interactions between the drug and the individual human immune system. Type B reactions can be further divided into drug intolerance, drug idiosyncrasy, drug allergy (immunologically medicated), and pseudoallergic reactions (anaphylactoid reactions). This chapter will focus on these type B drug hypersensitivity reactions.

  5. 5

    Several mechanisms may play a role in the underlying etiology of immunologic drug reactions. The Gell and Coombs classification system was the original system to describe four predominant immune mechanisms. These four reaction types are listed as type I reactions (IgE medicated), type II reactions (cytotoxic), type III reactions (immune complex), and type IV reactions (delayed, cell mediated).

    Table 1 provides a detailed description of this classification. Type I and IV reactions are more common than type II and III reactions. Most drugs cause one type of reaction, while certain drugs, such as penicillin, can induce all four types of reactions.

    Table 1

    Classification of Drug Hypersensitivity Reactions

    The Gell and Coombs classification has recently been revised to reflect the functional heterogeneity of T cells. Under the new system, type IV reactions are further subclassified into four categories: IVa (macrophage activation), IVb (eosinophils), IVc (CD4+ or CD8+ T cells), and IVd (neutrophils). Nevertheless, many common hypersensitivity reactions cannot be classified in this system because of the lack of knowledge of their immune mechanism or a mixed mechanism.

    A new concept of drug interaction with immune receptors has recently been developed by Pichler and colleagues. It is called the p-i concept (pharmacologic interaction with immune receptors). In this concept, a drug binds noncovalently to a T-cell receptor and stimulates an immune response, which can cause inflammatory reactions of different types. The stimulation of the T cell is enhanced by the additional interaction with the major histocompatibility complex molecule. This is direct stimulation of memory and effector T cells, and no sensitization is required. The skin has a high concentration of effector memory T cells, which can be rapidly stimulated by antigen penetration. The skin also possesses a dense network of dendritic cells that act as antigen-presenting cells and increase hypersensitivity reactions. As a result, clinical symptoms by p-i drugs may appear more rapidly. Some severe reactions—such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), the drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, or hypersensitivity syndrome—are thought to be p-i related. Examples are abacavir (Ziagen) hypersensitivity syndrome and SJS/TEN from carbamazepine (Tegretol).


  6. 6
    Risk Factors for Hypersensitivity Drug Reactions

    The chemical structure and molecular weight of the drug may help predict the type of hypersensitivity reaction. Larger drugs with greater structural complexity are more likely to be immunogenic.

    However, drugs with small molecular weight (< 1000 Da) can elicit hypersensitivity reactions by coupling with carrier proteins to form hapten-carrier complexes. Other drug-related factors include the dose, route of administration, duration of treatment, repetitive exposure to the drug, and concurrent illness. Topical and intravenous drug administrations are more likely to cause hypersensitivity reactions than are oral medications.

    Patient risk factors include age, female gender, infection with human immunodeficiency virus, atopy, specific genetic polymorphisms, previous drug hypersensitivity reactions, and inherent predisposition to react to multiple unrelated drugs.


  7. 7
    Clinical Manifestations

    Drug hypersensitivity reactions can manifest in a great variety of clinical symptoms and diseases. While some reactions are mild and often unnoticed, others, such as anaphylaxis, can be severe and even fatal. Dermatologic symptoms are the most common physical manifestation of allergic drug reactions. Drug hypersensitivity reactions can also affect various internal organs, causing diseases such as hepatitis, nephritis, and pneumonitis. The noncutaneous physical findings are generally nonspecific and may not be helpful and even delay the diagnosis and management decisions.

    Dermatologic Symptoms

    The most common allergic drug reactions affect the skin and can cause a variety of different exanthems. The most common skin reaction is the classic “drug rash,” which is a morbilliform eruption originating on the trunk. Other dermatologic symptoms include urticaria, angioedema, acne, bullous eruptions, fixed drug eruptions, erythema multiforme, lupus erythematosus, photosensitivity, psoriasis, purpura, vasculitis, and pruritus. The most severe form of cutaneous drug reactions are SJS, TEN, and DRESS syndrome.

    Stevens-Johnson Syndrome

    SJS is a systemic disorder that has cutaneous manifestations. SJS was previously thought to be synonymous with erythema multiforme major. There are now criteria that separate the two disorders. In contrast to erythema multiforme, the target lesions associated with SJS have only two rings. The inner ring may have urticaria, pustules, or necrotic lesions surrounded by macular erythema. It is a T-cell- mediated toxic reaction to the basement membrane of the epidermal cells. There is massive and widespread apoptosis, for which there are several associated cytokines. The recent theories suggest that there are two pathways, one that consists of granule-medicated exocytosis (perforin and granzyme B), and one that consists of Fas-Fas ligand interaction associated apoptosis for the keratinocytes. More recent data suggest that granulysin, which is a cationic cytolytic protein released by T lymphocytes, may play a role as well.

    Interestingly, HLA genotype may predispose patients to SJS or TEN. Those patients with the HLA-B1502 found among the Han Chinese population may be associated with increased risk of developing SJS/TEN and use of carbamazepine.

    SJS and TEN are on the same continuum. The definition of epidermal detachment and desquamation of epidermal cells is less than 10% of the body surface area for SJS and more than 30% for TEN. There is an overlapping diagnosis of SJS/TEN for the 10% to 30% category. To help differentiate from other ADRs, there is often a prodromal period in which a patient may have a cough and a fever.

    The lesions may occur up to 4 weeks after exposure to the drug. In addition, the lesions may be limited to the trunk; however, they more commonly involve the palmar surface of the hands and the dorsum of the feet as well as the mucous membranes.

    The most common drug classes associated with SJS and TENs are sulfonamides, cephalosporins, imidazole agents, and oxicam derivatives. Drugs such as carbamazepine, phenytoin (Dilantin), valproic acid (Depakote), lamotrigine (Lamictal), allopurinol (Zyloprim), nevirapine (Viramune), peramivir (Rapivab), and quinolones have been reported to cause SJS/TEN. In a retrospective chart review of 64 patients who had a diagnosis of SJS/TEN, Miliszewski et al. identified allopurinol as the single most common offending agent (20% of cases). According to the US Food and Drug Administration (FDA) Safety Alerts in 2013, acetaminophen has been associated with SJS, TEN, and acute generalized exanthematous pustulosis (AGEP). The evidence supporting causality primarily comes from a small number of cases reported in the medical literature.

    The treatment is immediate cessation of the culprit drug and symptomatic treatment. Glucocorticoids are controversial and depend on the course and extent of the disease.

    Toxic Epidermal Necrolysis

    As previously stated, TEN is the cell-mediated disorder that involves more than 30% of the body surface. This is the more severe form of the ADR: the mortality rates may be as high as 50%, mostly from sepsis.

    Patients are usually admitted to the burn unit for electrolyte and infection management. Glucocorticoids are contraindicated. There have been mixed results using IV immunoglobulin (IVIG)1 in these patients. The IVIG is believed to inhibit the Fas-Fas ligand, which is the underlying mechanism for the basement membrane separation.

    Drug Rash with Eosinophilia and Systemic Symptoms

    DRESS syndrome or drug-induced hypersensitivity syndrome (DIHS) is a rare, life-threatening drug-induced reaction with a mortality rate of 10%. Therefore, it is important to recognize the signs and symptoms early to initiate treatment. Most patients will have fever, lymphadenopathy (75%), eosinophilia, and an erythematous morbilliform rash on the face and body in addition to liver and multiorgan damage. The symptoms can occur 2 to 6 weeks after the drug administration. There are many drugs that can cause DRESS syndrome such as allopurinol, sulfonamides, and psychotropic medications. Based on literature review, DRESS syndrome is increasingly being recognized by psychiatrists. Carbamazepine is the most frequently reported etiology; however, DRESS syndrome is also seen with lamotrigine, phenytoin, valproate, and phenobarbital. The treatment is drug withdrawal, systemic corticosteroids, topical treatment for lesions, and supportive care often in the ICU or burn unit.

    Acute Generalized Exanthematous Pustulosis

    AGEP is a rare ADR that presents as a fever and small nonfollicular pustules on a widespread erythematous background. AGEP may closely mimic pustular psoriasis clinically. The presence of acanthuses and papillomatosis and a personal or family history of psoriasis favor a diagnosis of pustular psoriasis. Exposure to medication, especially antibiotics with a short latency from the initiation of the drug, favors AGEP. The eruption usually occurs within 24 hours of the initiation of the drug, and healing occurs quickly after the discontinuation of the drug. Lesions heal within 2 weeks of discontinuation without scarring. The exact mechanism of drug-specific T lymphocytes is unknown, yet IL-3 and IL-8 may be the trigger for neutrophil- activating cytokines in the skin.

    Acute Interstitial Nephritis

    Acute interstitial nephritis (AIN) is an important cause of acute kidney injury (AKI). Over two-thirds of AIN cases are caused by drug hypersensitivity reactions. Drugs most commonly associated with AIN include antibiotics (particularly β-lactam, fluoroquinolones, and rifampicin), NSAIDs, proton pump inhibitors, phenytoin, allopurinol, and 5-aminosalicylates.

    The clinical presentation of drug-induced AIN is highly variable and depends on the class of drug involved. Patients with AIN may be asymptomatic with elevation in creatinine or blood urea nitrogen or abnormal urinary sediment. When present, symptoms are nonspecific. The “classic” triad of fever, rash, and eosinophilia is present in less than 5% to 10% of patients. Each individual component of the triad also occurs at various rates.

    A diagnosis of AIN should be considered in any patients with unexplained AKI, clinical manifestations of a hypersensitivity reaction, and a history of exposure to any drug associated with AIN. A definitive diagnosis of AIN is established by kidney biopsy. AIN is characterized by interstitial inflammation, tubulitis, edema, and, in some cases, eventual interstitial fibrosis. The precise disease mechanism is unclear, but the presence of T lymphocytes in the inflammatory infiltrate suggests a type IV hypersensitivity response.

    Early recognition is crucial as patients can ultimately develop chronic kidney disease. The mainstay of therapy is timely discontinuation of the causative agent. If AIN persists, corticosteroids may be used to improve kidney function. However, available data on corticosteroids are inconclusive, and randomized controlled trials are needed to confirm the benefits of corticosteroids in the treatment of AIN.

  8. 8

    As the history is essential for determining if a patient is experiencing a drug hypersensitivity reaction, it is important to review all medications and the timeline of exposure. This includes any over-the- counter medications, herbal supplements, or occasional-use medications. Occasional-use medications may include NSAIDs, acetaminophen, cold medications, and so forth. It is important to establish a temporal relationship to the onset of the medication and the initiation of the symptoms. Oftentimes, the medication may have been discontinued before the appearance of the first symptom, so a review of medications from several weeks before the symptoms is also important. In addition, as the host immune response plays a role in some of the IgE-mediated reactions, it is important to review any immunocompromising chronic or acute illnesses or states that the patient may have or is currently experiencing. This includes HIV, chronic obstructive pulmonary disease (COPD), asthma, chemotherapy, and pregnancy. For some ADRs, HLA type may be important. A patient’s known genetic predisposition needs to be taken into account as well. A thorough history will also need to include any organ system or symptom that may be related to the suspected ADR.

    A physical examination should augment and help to establish the working diagnosis of the type of ADR and the potentially offending drug. This should include vital signs of temperature, respiratory, and hydration status. The skin examination is important, as are appropriate evaluation and documentation of the type of lesion or lesions present. An examination of the oral mucosa and the conjunctiva of the eye should be done. Any lymphadenopathy, petechiae, or pallor should be noted.

    Laboratory testing may be obtained to confirm or rule out a diagnosis. This may include a chest x-ray, CBC with differential, possible skin biopsy, liver function testing, creatinine, and electrolyte testing. A sedimentation rate and CRP testing may also be useful.

    While additional autoimmune or antibody testing may be done, caution is suggested. There may not be a high yield on these tests and they can be quite costly for patients.

  9. 9


    Anaphylaxis can be a fatal drug hypersensitivity reaction because of its rapid onset. It is often underrecognized and undertreated because it can mimic other conditions and is variable in its presentation.

    However, respiratory compromise and cardiovascular collapse are of greatest concern, because they are the most common cause of death. Urticaria and angioedema are the most common manifestations, but may be delayed or absent. The more quickly anaphylaxis occurs after exposure to the offending agent, the more likely the reaction is to be severe and potentially life threatening.

    Most anaphylaxis episodes are IgE-mediated reactions resulting in a sudden mast cell and basophil degranulation. This sudden release of mediators affects the cutaneous, pulmonary, cardiac, GI, vascular, and neurologic systems. Medications are a common trigger of anaphylaxis in adults. Most cases of IgE-mediated drug anaphylaxis in the United States are due to penicillins and cephalosporins. Antibiotics are also the most common cause of perioperative anaphylaxis because skin eruptions may be missed in patients who are draped during surgery.

    Some anaphylaxis reactions involve other immunologic mechanisms. Administration of blood products (e.g., IVIG, animal antiserum) can cause an anaphylactoid reaction due, at least in part, to complement activation. Activation of the complement cascade can cause mast cell/basophil degranulation. Anaphylaxis episodes can also occur independently of any immunologic mechanism. Certain drugs, such as opioids, dextrans, and protamine, can cause a direct release of histamine and other mediators from mast cells and basophils. Finally, there are acute systemic reactions without any obvious triggers or mechanisms (idiopathic anaphylaxis).

    Anaphylaxis is a clinical diagnosis with a short window of treatment time available. Therefore, laboratory testing is limited and may not be of much value. Initially, the patient will describe flushing, pruritus, and a sense of impending doom. Some patients will have dyspnea, dizziness, syncope, and/or GI symptoms of diarrhea and abdominal cramping. Most patients will have cutaneous symptoms of flushing, urticaria, or angioedema. Some patients will progress to respiratory or cardiovascular complications.

    The goal of therapy should be early recognition and treatment with epinephrine to prevent a progression to life-threatening respiratory and/or cardiovascular failure. The immediate intervention should include stopping the offending drug if possible, epinephrine injection, basic life support, high-flow oxygen, cardiac monitoring, and IV access. Epinephrine is the drug of choice for anaphylaxis. The therapeutic actions of epinephrine include α-1-adrenergic vasoconstrictor effects (decreases mucosal edema, thereby relieving upper airway obstruction, and increases blood pressure to prevent shock), β-1-adrenergic effects (increases rate and force of cardiac contractions), and β-2 effects (increases bronchodilation and decreases the release of mediators of inflammation from mast cells/basophils).

    Delayed epinephrine administration has been associated with fatalities. Intramuscular epinephrine in the thigh results in high- plasma concentrations and is preferred in the setting of anaphylaxis. The recommended dose of epinephrine is 0.3 mg (1 mg/mL) IM every 5 minutes. Typically, only one or two additional doses are needed.

    Patients in shock should receive epinephrine by slow IV infusion at 2 to 10 mcg/min with the rate titrated according to response and the presence of continuous hemodynamic monitoring. Patients taking beta-blockers may be resistant to treatment with epinephrine. In this case, glucagon1 1 to 5 mg IV over 5 minutes should be administered because its cardiac effects are not mediated through beta-receptors.

    Adjunctive therapies for the treatment of anaphylaxis include antihistamines and corticosteroids. Consider an inhaled beta-agonist if wheezing. Diphenhydramine (Benadryl), an H1 antihistamine, may be given intravenously at the dose of 25 to 50 mg. If an H2 blocker is considered, give ranitidine (Zantac)1 50 mg/20 mL as an IV infusion over 5 minutes. Use of both diphenhydramine and ranitidine is superior to diphenhydramine alone. Corticosteroids are used to prevent a potential late-phase reaction that may occur in up to 23% of adults with anaphylaxis. There is no proven best dose or route of steroid therapy. The most common dosage is prednisone 20 to 60 mg daily for 3 to 5 days.


    Angioedema is characterized by a deep dermal, subcutaneous, and/or mucosal swelling. Many patients present with both urticaria and angioedema. Angioedema can progress rapidly from a mild swelling of the oral mucosal to a life-threatening laryngeal edema. With this rapid sequence of events, the most important part of treatment is obtaining and maintaining a patent airway. Epinephrine 0.3 mg IM every 10 minutes should be administered to patients who present with anaphylaxis, respiratory distress, or severe laryngeal edema. Once the airway is patent, the patient should be treated with H1 antihistamines, H2 blockers, and steroids. The milder cases may be treated similarly to other allergic reactions. H1 antihistamines such as diphenhydramine and hydroxyzine (Atarax) are effective in relieving pruritus but can cause significant sedation. Therefore, second- generation H1 antihistamines (loratadine [Claritin],1 cetirizine [Zyrtec],1 desloratadine [Clarinex],1 fexofenadine [Allegra]1) are often chosen for outpatient therapy. Doxepin (Sinequan),1 a tricyclic antidepressant with potent H1 and H2 blocker activities, can be used as an alternative to H1 antihistamines. However, it should not be used as first-line treatment for acute urticaria and angioedema due to its significant side effects of severe sedation, dry mouth, and weight gain. Corticosteroids are used in patients who are not responsive to antihistamines. For most patients, a short course of oral prednisone is adequate.

    In drug-induced angioedema, the offending drug should be stopped and avoided. Further trial of the medication is not recommended, as the patient will respond more quickly and with more severe symptoms upon reintroduction. The patient should be counseled, and epinephrine 0.3 mg in an auto-injectable device (EpiPen) may be prescribed in case of recurrence in the future.

  10. 10
    Specific Drugs

    Almost all drugs can cause a drug hypersensitivity reaction. However, certain drugs are more frequently associated with specific types of reactions. Some of the more commonly used drugs are discussed here in more detail.


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    Penicillin allergy is the most well-known drug allergy and also the most costly ADR. Although most drugs usually have type I and type IV reactions, penicillin may cause all four types of allergic drug reactions. The rate of penicillin-induced anaphylaxis after intravenous administration is approximately 1 to 2 per 10,000 treated patients.

    Only about 10% of patients who report a penicillin drug allergy actually have a true immunologic response. The other 90% are actually able to tolerate penicillin or a cephalosporin. Because of this overreporting, there are several patient safety concerns. These include the antibiotic coverage of an organism not being optimal and an increase in drug resistance, which results in higher health care costs.

    Therefore, it is important to evaluate a patient for true penicillin allergy.

    Penicillin skin testing is the best method for diagnosing an IgE- mediated penicillin allergy. A commercially available product, PrePen, contains benzylpenicilloyl polylysine (PPL), which is a major antigenic determinant of penicillin. Minor determinants are metabolic derivatives of penicillin that may also produce an immune response. The current recommendations for penicillin skin testing are to administer both the major determinant (PPL) and the minor determinants (penicillin G). These two tests identify approximately 90% to 97% of the currently allergic patients. Patients with a history of penicillin allergy but negative skin testing to PPL and the minor determinants rarely experience allergic reactions on reexposure. If they should occur, the reactions are mild and self-limiting.

    In general, patients who report symptoms consistent with an immediate or type I reaction or are skin-test positive to penicillin should not receive penicillin. Desensitization should be considered if penicillin is the treatment of choice for an infection and no acceptable nonpenicillin alternatives are available. Patients should be desensitized in a hospital setting. Desensitization involves administering incremental doses of oral penicillin every 15 minutes for a total of 4 to 12 hours, after which time the first dose of penicillin is given. An example of a penicillin desensitization protocol is available in the Morbidity and Mortality Weekly Report at https://www.cdc.gov/std/tg2015/pen-allergy.htm.

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    Penicillin and Cephalosporin Cross- Reactivity

    The rate of cross-reactivity between penicillin and cephalosporins has been historically cited to be as high as 10%. Recent data suggest that the rate may be much lower. The degree of cross-reactivity is highest between penicillins and first-generation cephalosporins, which have identical R-group side chains. In this case amoxicillin would be cross- reactive with cefadroxil (Duricef) and cefprozil (Cefzil), while ampicillin would be with cefaclor and cephalexin. Because of the differences in the chemical structures, second- and third-generation cephalosporins (cefdinir [Omnicef], cefuroxime [Ceftin], cefpodoxime [Vantin], and ceftriaxone [Rocephin]) are unlikely to be associated with cross-reactivity with penicillin. According to the latest guidelines for acute otitis media from the American Academy of Pediatrics and American Academy of Family Physicians, alternative initial antibiotics in patients with penicillin allergy include cefdinir, cefuroxime, cefpodoxime, or ceftriaxone.

    Patients with penicillin allergy who have a negative skin-test result to penicillin (major and minor determinants) may safely receive cephalosporins. Cephalosporin treatment of patients with penicillin allergy who did not have a severe or recent penicillin reaction history shows a reaction rate of 0.1%. Use cephalosporin with caution in patients who report an immediate or accelerated penicillin allergy or those with a positive skin test to penicillin.

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    Sulfonamides (Sulfa Drugs)

    Beside penicillins, sulfonamide antibiotics are the second most common cause of drug-induced allergic reactions. They commonly cause a delayed maculopapular/morbilliform eruption. Acute urticarial reactions (IgE mediated) to sulfamethoxazole (SMX) or trimethoprim (TMP) are relatively infrequent; the incidence of skin rash resulting from SMX-TMP (Bactrim) in healthy subjects is estimated to be 3%. Sulfonamides are also the most common cause of SJS and TEN.

    Patients with HIV have the greatest risk of sulfonamide-induced allergic reactions. The typical reaction to SMX-TMP in patients with HIV is a generalized maculopapular eruption that occurs during the second week of treatment and is usually accompanied by pruritus and fever. Because SMX-TMP is the drug of choice for a number of HIV- associated infections such as Pneumocystis carinii pneumonia and spontaneous bacterial peritonitis, several methods of desensitization have been devised to administer SMX-TMP to patients with HIV with a history of allergic reaction to the drug.

    There are three classes of sulfonamides based on chemical structure: sulfonylarylamines (including sulfa antibiotics), nonsulfonylarylamines, and sulfonamide-moiety-containing drugs. A sulfonylarylamine has a sulfonamide moiety directly attached to a benzene ring with an amine (–NH2) moiety at the N4 position. A nonsulfonylarylamine also has a sulfonamide moiety attached to a benzene ring, but it does not have an amine group at the N4 position. A sulfonamide-moiety-containing drug has a sulfonamide group that is not connected to a benzene ring. Table 2 presents a list of sulfonamide-containing drugs based on their chemical structure.

    Table 2

    Classification of Sulfonamides Based on Chemical Structure

    The N4 amine is critical for the development of delayed reactions to sulfa antibiotics. Given the important chemical differences between drugs containing sulfa antibiotics and sulfa in nonantibiotics, the risk of cross-reactivity is extremely unlikely. A retrospective cohort study by Strom and colleagues showed that approximately 90% of patients with sulfa antibiotic allergy did not have a reaction to a sulfonamide nonantibiotic. Patients with allergic reactions to sulfa antibiotics are also more likely to experience allergic reactions to the other types of sulfonamides, but this is not because of cross-sensitivity. There is no reliable skin test to rule out or confirm sulfa allergy. Some experts recommend avoiding all classes of sulfonamides in patients with serious reactions such as SJS, TEN, and/or anaphylaxis to any one sulfonamide.

    Most diuretics are sulfonamide derivatives. The only diuretics that are not in this group are the potassium-sparing diuretics (triamterene [Dyrenium], spironolactone [Aldactone], amiloride [Midamor]) and ethacrynic acid (Edecrin). Dapsone is a sulfone that is chemically unrelated to sulfonamides. It should also be noted that sulfates, sulfur, and sulfites are chemically unrelated to sulfonamides and do not cross-react.


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    Angiotensin-Converting Enzyme Inhibitors

    Angiotensin-converting enzyme inhibitors (ACEIs) have two major adverse effects: cough and angioedema. The cough is typically dry and nonproductive. The incidence of ACEI-induced cough has been reported to be 5% to 35%. Cough occurs more commonly in women, African-Americans, and Asians. The onset of cough ranges from within hours of the first dose to months after the initiation of therapy. The diagnosis is confirmed by the resolution of cough, usually within 1 to 4 weeks after discontinuation of the ACEI; however, the cough can linger for up to 3 months. The cause for ACEI-induced cough is unclear but might be related to bradykinin, substance P, or another mechanism. Angiotensin II receptor blockers (ARBs) are not associated with an increased incidence of cough and can be used as an alternative to ACEIs. As the cough may persist for several months after stopping the ACEI, starting the ARB is not a contraindication at this time, yet the cough may persist through the initiation of the new drug.

    The incidence of angioedema with ACEIs is approximately 0.1% to 0.7%. With the widespread use of ACEIs, angioedema has become a growing problem. ACEI-induced angioedema is more common in patients who are over age 65, black, or female. Angioedema frequently involves swelling of the face or upper airway and can be life threatening or fatal. It can occur within days, months, or even years after the start of treatment. However, nearly 60% of cases occur within the first week of therapy. ACEIs cause angioedema by direct interference with the degradation of bradykinin, thereby increasing bradykinin levels and leading to increased vascular permeability, inflammation, and activation of nociceptors. Bradykinin is also a prominent mediator in hereditary angioedema. Therefore, ACEIs are contraindicated in patients with hereditary angioedema.

    ARBs directly inhibit the angiotensin receptor and do not interfere with bradykinin degradation. Theoretically, they can be relatively safe alternatives for patients with a previous history of ACEI-associated angioedema. However, some reports of ARB-induced angioedema have recently been published. The mechanism of how ARBs cause angioedema is unclear. A metaanalysis suggests that for patients who developed angioedema when taking an ACEI, the risk of persistent angioedema when subsequently switched to an ARB is less than 10%. Therefore, ARBs may be an alternative only for patients with a high therapeutic need for angiotensin inhibition. ARB treatment should be started with observation. Patients should be educated on the signs of angioedema and provided with proper emergency instructions on how to proceed if angioedema should occur.

    The direct renin inhibitor aliskiren (Tekturna) does not alter local or circulating bradykinin and is thought to be an alternative in patients with ACEI- and ARB-related angioedema. However, cases of angioedema have been reported with aliskiren. As with ARBs, renin inhibitors should be used with caution in patients who previously experienced angioedema to ACEIs.

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    Aspirin and NSAIDs

    Aspirin (ASA) and NSAIDs can cause several types of hypersensitivity reactions. The four most common types of reactions are based on the drug pathways. Aspirin-exacerbated respiratory disease (AERD) is a serious reaction induced by ASA and NSAIDs in patients with asthma and chronic rhinosinusitis. AERD does not fit precisely into a specific type of ADR and is often referred to as a type of pseudoallergic reaction. AERD affects up to 20% of adults with asthma. It is more common in women. The usual age of onset is around 30 years. The pathophysiology of AERD is related to aberrant arachidonic acid metabolism. Patients with AERD also have increased respiratory tract expression of cysteinyl leukotriene 1 receptor and heightened responsiveness to inhaled leukotriene E4. Administration of aspirin or an NSAID to these patients leads to inhibition of cyclooxygenase 1 (COX-1), resulting in a decrease in prostaglandin E2 levels. Prostaglandin E2 normally inhibits 5-lipooxygenase. As a result of decreased prostaglandin E2 levels, arachidonic acid is preferentially metabolized in the 5-lipooxygenase pathway, leading to increased production of cysteinyl leukotrienes.

    Patients with AERD typically have both rhinoconjunctivitis and bronchospasm within minutes of ingestion of a dose of ASA or NSAID. The bronchospasm can be severe and result in respiratory failure, which may require intubation and mechanical ventilation. Management of patients with AERD involves treatment of the patient’s asthma and chronic rhinosinusitis and avoidance of aspirin and NSAIDs. Desensitization is available in cases when the patient has a specific therapeutic need for regular ASA or NSAID therapy.

    Selective COX-2 inhibitors very rarely cause reactions in patients with AERD and can be taken safely.

    The second type of ASA and NSAID hypersensitivity reaction is an exacerbation of urticaria or angioedema in patients with chronic idiopathic urticaria. Approximately 20% to 40% of patients with chronic urticaria may have this drug-induced reaction. The mechanism of this reaction is related to COX-1 inhibition. The exacerbating effects are usually dose dependent. All drugs that inhibit COX-1 cross-react to cause this reaction. Selective COX-2 inhibitors are generally considered safe to take in patients with chronic idiopathic urticaria.

    The third type of hypersensitivity reaction is an anaphylactic or immediate urticarial reaction or angioedema appearing soon after the intake of a specific NSAID. Other NSAIDs from other groups or even an NSAID from the same group with a slightly different chemical structure is tolerated by the patient. An IgE-mediated mechanism is implicated only in some instances. The diagnosis is made mainly by exclusion. Further research is needed in this topic.

    The fourth type of hypersensitivity reaction is urticaria or angioedema caused by ASA or any NSAID that inhibits COX-1 in patients without chronic urticaria. These reactions may be either drug specific or cross-reactive to other NSAIDs. Rarely, patients may have combined respiratory and cutaneous reactions that cannot be classified into one of the four reaction types described.


    Corticosteroids are the most frequently used drugs for the treatment of allergic conditions, yet they can also induce hypersensitivity reactions. Most hypersensitivity reactions to steroids can be classified into type I (immediate, IgE-mediated) and type IV (delayed, cell- mediated) mechanisms. Type I reactions are characterized by the presence of urticaria and anaphylaxis. Type IV reactions can be presented as maculopapular exanthema and delayed urticaria.

    Allergic contact dermatitis (type IV reaction) caused by topical administration of steroids is the most common type of allergic reaction induced by this class of drugs, occurring at the rate of 3% to 6%. Usually this is seen as a failure to improve or a worsening of an existing dermatitis that is being treated with topical steroid. Keep in mind that the reaction can also be due to other constituents of the creams, such as neomycin or cetostearyl alcohol. The diagnosis can be done using patch testing, which detects more than 90% of allergic patients. The topical steroids most frequently involved are nonfluorinated, such as hydrocortisone and budesonide.

    Inhaled and intranasal steroids can induce both local and systemic reactions. Local reactions include contact dermatitis, pruritus, nasal congestion, erythema, and dry cough and are quite often irritant in nature. Systemic reactions include eczematous lesions, particularly on the face, exanthema, and urticaria. The most frequently involved steroid is budesonide. The actual mechanism of this reaction is not clear, but it may be a T-cell-mediated reaction.

    Hypersensitivity reactions to systemically administered steroids seldom occur. Most of the data come from case reports. Both immediate and delayed reactions have been described, ranging from urticaria to sudden cardiovascular collapse and death. Most immediate reactions are caused by intravenous methylprednisolone and hydrocortisone. In a few cases, the reactions can be induced by salts, such as succinate, or rarely by certain diluents such as carboxymethylcellulose or metabisulfite. Nonimmediate reactions are mainly mild, such as delayed urticaria or maculopapular exanthema. The drug involved most often is betamethasone.

    Cross-reactivity between steroids is difficult to assess. Based on corticosteroid patch test results and their chemical structure, Coopman and colleagues divided the steroids into four groups: A (hydrocortisone type), B (triamcinolone acetonide type), C (betamethasone type), and D (hydrocortisone-17-butyrate type).

    Group D can be subdivided into D1 and D2 depending on the presence or absence of a C16 methyl substitution and/or halogenations on the C9 of the B ring. Table 3 provides the listing of the four groups. High cross-reactivity exists between corticosteroids in each group as well as between group D2 and groups A and B, with group D1 exhibiting quite low cross-reactivity with the other groups.

    Table 3

    Coopman Classification of Cross-Reactivity in Corticosteroids

    Group Type                                        Drugs
    A Hydrocortisone Hydrocortisone  (acetate,  succinate, phosphate)
    Methylprednisolone (acetate, succinate, phosphate) Prednisolone,  prednisolone acetate

    Tixocortol pivalate*

    B Triamcinolone acetonide Amcinonide (Cyclocort)

    Budesonide (Pulmicort, Rhinocort, Entocort) Desonide  (Desonate, DesOwen)


    Fluocinolone acetonide (Synalar) Fluocinolone

    Halcinonide (Halog) Triamcinolone

    Triamcinolone  acetonide (Kenalog)

    C Betamethasone Betamethasone (Celestone) Desoxymethasone Dexamethasone Paramethasone* Fluocortolone*
    D1 Hydrocortisone-17-butyrate Beclomethasone dipropionate (QVAR) Betamethasone valerate Betamethasone dipropionate Clobethasone  17-butyrate*

    Clobetasol  17-propyonate (Clobex)

    D2 Hydrocortisone-17-butyrate Fluticasone (Flonase) Mometasone Prednicarbate  (Dermatop)

    Hydrocortisone 17-butyrate (Locoid) Hydrocortisone 17-propionate* Methylprednisolone  aceponate*

    From Torres and Canto (2010).

    *  Not available in the United States.

    Local Anesthetics

    The most common immunologic reaction to local anesthetic is allergic contact dermatitis (type IV). IgE-mediated reactions (type I) to local anesthetics are very rare. Most adverse reactions are due to nonallergic factors such as vasovagal response, anxiety, dysrhythmias, and toxic reactions resulting from inadvertent IV epinephrine effects.

    Any patient who presents with a history of an allergic reaction to local anesthetics should be carefully evaluated. Skin testing and graded challenge can be performed in patients who present with a history suggestive of a possible IgE-mediated allergic reaction to these drugs. A local anesthetic that does not contain epinephrine or other additives, such as parabens or sulfites, is preferred in this situation.

    It is necessary to identify the type of local anesthetics to be used.

    Local anesthetics are classified as esters or amides based on their chemical structure. Drugs in the esters group include benzocaine (Americaine, Dermoplast, Lanacane, Hurricaine), chloroprocaine, cocaine, procaine (Novocaine), proparacaine (Alcaine, Opthaine), and tetracaine (Tetcaine). Most allergic reactions reported in the literature have been caused by agents in the esters group, which are derivatives of para-aminobenzoic acid (PABA), a known allergen. Cross-reactivity occurs among members of the ester group, but the esters do not cross- react with the amides. Agents in the amides group include bupivacaine (Marcaine), lidocaine, mepivacaine (Polocaine), prilocaine (Citanest), and ropivacaine (Naropin). Amide local anesthetics generally do not cross-react with other amides or with the esters.


  16. 16
    Radiocontrast Media

    There are two types of radiocontrast media (RCM): ionic high osmolality and nonionic low osmolality. Both of these agents contain iodine. The nonionic RCMs are much more widely used today than the ionic agents.

    Allergic reactions to RCM are common and can range from mild to life threatening. Anaphylactoid reactions and severe life-threatening reactions occur in 1% to 3% and 0.22% of patients who receive ionic RCM, respectively. Less than 0.5% and 0.04% of patients who receive nonionic agents have anaphylactoid reactions and severe reactions, respectively. The fatality rate is approximately 1 to 2 per 100,000 procedures, and it is similar for both ionic and nonionic agents. RCM reactions are typically not mediated by IgE antibodies. RCM acts directly on mast cells and basophils, resulting in the release of histamine and other systemic mediators, which cause the anaphylactoid reactions. Patients at greater risk for more serious anaphylactoid reactions include females; those with asthma, heart disease, and a history of previous anaphylactoid reaction to RCM; and those taking beta-blockers. People who have seafood allergy are not at increased risk for reactions to RCM compared to the general population. The pathogenesis of anaphylactoid reactions is also not related to iodine.

    Management of patients with previous RCM reactions include the use of a nonionic, low-osmolarity agent and a pretreatment regimen. One common regimen consists of prednisone (50 mg PO at 13, 7, and 1 hour before the procedure), diphenhydramine (50 mg at 1 hour before the procedure), and a histamine H2-receptor antagonist (1 hour before the procedure). This will significantly reduce the risk for anaphylactoid reaction with reexposure to RCM.

    Delayed reactions to RCM occur 1 hour to 1 week after RCM administration. Approximately 2% of patients have delayed reactions to RCM. These reactions are generally mild, self-limited cutaneous eruptions. The mechanism is usually T-cell mediated. Rarely, more serious and life-threatening delayed reactions such as SJS, TEN, and DRESS syndrome have been reported.


  17. 17

    Chlorhexidine gluconate is an antiseptic agent. It is commonly available in OTC products as a skin and wound disinfectant (e.g., Betasept, Hibiclens). Hypersensitivity reactions to chlorhexidine include contact dermatitis, pruritus, urticaria, dyspnea, and anaphylaxis. Prescription chlorhexidine gluconate mouthwashes and oral chips used for gum disease contain a warning about the rare but serious allergic reactions in their labels. According to a recent FDA Drug Safety Communication, the number of reports of serious allergic reactions to chlorhexidine-containing products has increased over the last several years. As a result, an anaphylaxis warning is now added to the OTC product labels under Drug Facts.

    Several case reports have suggested that some patients with prior exposure to chlorhexidine and patients with chlorhexidine-induced contact dermatitis may be susceptible to anaphylaxis caused by chlorhexidine sensitization. Since chlorhexidine is the standard skin disinfectant used before surgery or invasive procedures, the exposure to the agent becomes more widespread. Even though severe anaphylaxis to chlorhexidine has been estimated to be rare, the actual rate may be higher than reported. Such reports remind clinicians to be vigilant about chlorhexidine as a hidden allergen, especially in surgical patients.

  18. 18
    Herbal Supplements

    There is a perception that herbal supplements are “natural” and therefore safe. In fact, severe allergic reactions including asthma and anaphylaxis have been well documented in patients using bee pollen products and echinacea. Echinacea is an herb belonging to a group of flowering plants known as Asteraceae. Asteraceae-derived pollens are an important cause of hay fever and asthma. Asteraceae may cause contact allergic dermatitis. Cross-reactivity exists between members of the Asteraceae family, such as ragweed, dandelion, daisy, chamomile, echinacea, feverfew, and milk thistle.

    A lack of quality control has been a major concern in the herbal supplement industry. Chinese herbal products may be adulterated with synthetic medications not listed on the label. Contaminated supplements may be a potential risk for systemic contact dermatitis in nickel- and mercury-allergic patients. Because of the widespread use of herbal supplements and the underreporting of adverse events to herbs, all patients should be questioned about the use of herbal supplements when being evaluated for hypersensitivity reactions.

  19. 19

    Drug hypersensitivity reactions are common; fortunately, severe and often fatal reactions are not. It is important for the clinician to have a working knowledge of common drug-induced hypersensitive reactions as well as the ability to identify and document common dermatologic findings. With that background knowledge, a thorough history and physical examination should enable the clinician to diagnose the majority of these types of reactions. A timely and appropriate management plan can then be implemented. As always, it is important to educate patients regarding their drug hypersensitivity history and the potential for future reactions.

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    American Academy of Pediatrics. Clinical practice guideline.

    The diagnosis and management of acute otitis media.

    Pediatrics. 2013;131:e964–e969.

    Bommersbach T.J., Lapid M.I., Leung J.G., et al. Management of psychotropic drug-induced DRESS syndrome: A systematic review. Mayo Clin Proc. 2016;91(6):787–801.

    CDC. Sexually transmitted disease treatment guidelines 2015.

    MMWR. 2015;64(3):149–151.

    Fernando S.L. Acute generalized exanthematous pustulosis.

    Australas J Dermatol. 2012;53:87–92.

    Harr T., French L. Toxic epidermal necrolysis and Stevens- Johnson syndrome. Orphanet J Rare Dis. 2010;5:39. Available at http://www.ojrd.com/content/5/1/39 (accessed March 6, 2014).

    Haymore B.R., Yoon J., Mikita C.P., et al. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: A meta-analysis. Ann Allergy Asthma Immunol.


    Husain Z., Reddy B.Y., Schwartz R.A. DRESS syndrome, part I. Clinical perspectives. J Am Acad Dermatol. 2013;68:693.e1– 693.e14.

    Inomata N. Recent advances in drug-induced angioedema.

    Allergol Int. 2012;61:545–557.

    Joint Task Force on Practice Parameters, AAAAI, ACAAI. Drug allergy: An updated practice parameter. Ann Allergy Asthma Immunol. 2010;105:259–273.

    Khan D.A., Solensky R. Drug allergy. J Allergy Clin Immunol.


    Lieberman P., Nicklas R.A., Opperheimer J., et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. 2010;126:477–480.

    Miliszewski M.A., Kirchhof M.G., Sikora S., et al. Stevens-

    Johnson syndrome and toxic epidermal necrolysis: An analysis of triggers and implications for improving prevention. Am J Med. 2016;129(11):1221–1225.

    Moka E., Argyra E., Siafaka I., Vadalouca A. Chlorhexidine: Hypersensitivity and anaphylactic reactions in the perioperative setting. J Anaesthesiol Clin Pharmacol.


    Murata J., Abe R. Soluble Fas ligand: Is it a critical mediator of toxic epidermal necrolysis and Stevens-Johnson syndrome? J Invest Dermatol. 2007;127:744–745.

    Perazella M.A., Markowitz G.S. Drug-induced acute interstitial nephritis. Nat Rev Nephrol. 2010;6(8):461–470.

    Philips J.F., Yates A.B., Deshazo R.D. Approach to patients with suspected hypersensitivity to local anesthetics. Am J Med Sci. 2007;334:190–196.

    Pichler W.J. Consequences of drug binding to immune receptors: Immune stimulation following pharmacological interaction with immune receptors (T-cell receptor for antigen or human leukocyte antigen) with altered peptide-human leukocyte antigen or peptide. Dermatol Sin. 2013;31:181–190.

    Ponka D. Approach to managing patients with sulfa allergy. Use of antibiotic and nonantibiotic sulfonamides. Can Fam Physician. 2006;52:1434–1438.

    Sharma P., Nagarajan V. Can an ARB be given to patients who have had angioedema on an ACE inhibitor? Cleve Clin J Med. 2013;80:755–757.

    Torres M.J., Canto G. Hypersensitivity reactions to corticosteroids. Curr Opin Allergy Clin Immunol. 2010;10:273– 279.

    1 Not FDA approved for this indication.

    1 Not FDA approved for this indication.

    1  Not FDA approved for this  indication.

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