J. Russell May and Philip H. Smith
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Describe the potential incidence of allergic and pseudoallergic reactions and why it is difficult to obtain accurate numbers.
2. Describe the Gell and Coombs categories of reactions.
3. Identify the classes of drugs most commonly associated with allergic and pseudoallergic reactions.
4. Recommend specific treatment for a patient experiencing anaphylaxis.
5. Recommend an approach to drug selection in patients with multiple drug allergies.
6. Describe drug desensitization procedures for selected drugs.
KEY CONCEPTS
Allergic and pseudoallergic reactions represent 24% of reported adverse drug reactions, are costly, and cause considerable morbidity and mortality.
Drug allergy is an adverse immune response to a stimulus; such responses are traditionally placed in the Gell and Coombs categories: type I (immediate hypersensitivity), type II (complement-mediated antibody reactions), type III (immune complex reactions), and type IV (cellular or delayed-type hypersensitivity). However, drug exposures may stimulate several or all of these types of reactions. To complicate the picture further, drug reactions do not always fit the categories.
Reactions that clinically resemble allergic reactions but lack an immune basis have been referred to as “pseudoallergic.” They include almost the entire range of immediate hypersensitivity clinical patterns and range in significance from the alarming but trivial anxiety or vasovagal reactions caused by local dental anesthetics to the potentially fatal reactions to ionic radiocontrast media.
Penicillins and cephalosporins both have a β-lactam ring joined to an S-containing ring structure (penicillins: a thiazolidine ring, cephalosporins: a dihydrothiazine ring). Because of this structural difference, the extent of cross-allergenicity appears to be relatively low. Cross-allergenicity is less likely with newer generation cephalosporins compared to the first generation agents.
Reactions to sulfonamide antibiotics, ranging from mild (most common) to life-threatening (rare), occur in 2% to 4% of healthy patients, with rates as high as 60% in patients with AIDS.
IgE-mediated urticarial/angioedema reactions and anaphylaxis are associated with aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Urticaria is the most common form of IgE-mediated reaction. However, most reactions are the result of metabolic idiosyncracies, such as aspirin-induced respiratory disease which may produce severe and even fatal bronchospasm. This class is second, only to β-lactams, in causing anaphylaxis.
Radiocontrast media may cause serious immediate pseudoallergic reactions such as urticaria/angioedema, bronchospasm, shock, and death. These reactions have been reduced with the introduction of nonionic, lower osmolality products.
Opiates (morphine, meperidine, codeine, hydrocodone, and others) stimulate mast cell release directly, resulting in pruritis and urticaria with occasional mild wheezing. Though these reactions are not allergic, many patients state that they are “allergic” to one or more of the opiates. Pretreatment with an antihistamine may reduce these reactions. These pseudoallergic reactions are rarely, if ever, life threatening.
Drug desensitization is a potentially life-threatening procedure, and requires continuous monitoring in a hospital setting, with suitable access to emergency treatment and intubation. It should only be undertaken under the direction of a physician with suitable training and experience and only when a suitable alternative is not available. In such hands, desensitization may present less risk than treatment failure with a less effective alternative medication.
INTRODUCTION
Allergic and pseudoallergic drug reactions are reported together. They are rarely confirmed by testing, making statistical analysis imprecise, with both over-reporting and under-reporting. But there is no doubt they are costly and cause considerable morbidity and mortality. Allergic reactions may represent as many as 24% of reported adverse drug reactions.1 Between 10% and 20% of hospitalized patients incur drug reactions (7% in the general population), with about one-third possibly due to hypersensitivity; however, most of these reactions are not reported, especially in pediatrics.1–3 Patients experiencing an allergic drug reaction in the hospital result in increased costs of $275 to $600 million annually.4 This financial burden can occur due to several reasons including increased indirect cost of: (a) time and lost labor, (b) the use of costlier alternative medications, and (c) treatment failures. Outpatient rates are not well studied and much harder to collect. Relying on a patient’s history without an attempt to verify the relationships between drugs taken and symptoms experienced results in confusion. Health care professionals and patients use the term “drug allergy” in such a general way that it is not medically useful and, further, perpetuates a level of fear and concern in the public and in medical practice that is inappropriate and costly. This same confusion and anxiety sometimes leads medical personnel to ignore or forget “drug allergy” with potentially catastrophic results. Clearly, an understanding of how allergic and pseudoallergic reactions occur and how they might be managed or prevented is important to health care professionals and their patients.
PATHOPHYSIOLOGY
Drug allergies are immune responses resulting from different mechanisms of immunologic recognition and activation, and reactions are produced by multiple physiologic pathways. This produces a confusing spectrum of clinical pictures and complex pathophysiologic mechanisms. Allergy is an adverse immune response to a stimulus and is traditionally placed in the Gell and Coombs categories: type I (immediate hypersensitivity), type II (complement-mediated antibody reactions), type III (immune complex reactions), and type IV (cellular or delayed-type hypersensitivity). Drug exposures often stimulate several or all of these types of reactions, and clinical symptoms do not always fit neatly into the categories.
The immune system uses many tools such as blood vessel dilation or constriction, causing fluid to flood an infected area, or even producing special cells to kill bacteria or the infected cells in which they harbor. The pattern of these responses is either inborn (the innate immune response) or learned from previous infections and injuries (the adaptive immune response). Most drug reactions involve the adaptive response and certainly, in the sense that they cause more harm than good, are “mistakes.”
T cells control these “learned” responses and decide which “tools” to use in the reaction. Sometimes they choose several different “tools” at once, and multiple reactions ensue, as when a person becomes sensitized to penicillin and has not only anaphylaxis but hemolytic anemia and serum sickness, as well. There are different types of T cells, and they communicate either directly with other cells or by chemical messages, called “cytokines.” The pattern of cytokines released is one way T cells have of determining which kind of response will occur. They are broadly called Th1 and Th2 responses, with Th1 mostly responding to infections and Th2 sometimes producing allergy or asthma.
Immunologic drug reactions generally represent T-cell activation. The type of T cell activated determines the type of reaction to the drug. Th1 cytokines (largely interferon-γ) produce many more chronic (and at times serious) skin reactions and destruction of cells (as in hemolytic anemia or thrombocytopenia). Sometimes these responses can damage tissues, such as the kidney (interstitial nephritis). Th2 cytokines tend to cause the antibodies produced to be switched to the immune globulin E (IgE) or allergic antibody class, which can result in hives or anaphylaxis. Other classes of antibodies are often made, and these can produce serum sickness or indirect destruction of cells (thrombocytopenia). T-cell receptors respond to one peptide only, which makes each activation response exclusive to the original stimulus (drug) or to chemical structures with very close resemblance.
Antigens
Antigen-presenting cells recognize complex, three-dimensional protein molecules of at least 1,000 Daltons (Da) in size. Most drugs are much smaller than this, and cannot be recognized on their own. Only proteins such as insulin or exogenous sera are identified and their peptides presented directly to T cells.
Drugs that are chemically reactive may bond covalently to body proteins, altering them and forming large enough molecules for antigen-presenting cells to recognize. This process is called haptenation, and the smaller reactive molecule, a hapten. Some other drugs are inert until they are partially metabolized (prohaptens), and their breakdown products bind native proteins to serve as antigens. Metabolic variations in some patients may produce more active haptens, or prevent these fragments from being detoxified, causing them to accumulate and make binding proteins more likely.
Gell and Coombs
Type I reactions occur when the drug or its bound hapten incites an IgE antibody response. IgE binds to high-affinity receptors on mast cells and basophils. When the original antigen cross-links cell-bound IgE, the effector cell releases enormous amounts of preformed mediators, producing the well-known symptoms of immediate hypersensitivity: urticaria, rhinitis, bronchoconstriction, and anaphylaxis.
Type II reactions are produced by IgG (or IgM) antibody. The drug or hapten that elicited the antibody response binds to target cells. When antibody binds the drug, complement activation destroys the cell. Blood dyscrasias like thrombocytopenia or hemolytic anemia are the most common examples of type II reactions.
Type III or immune complex reactions also involve IgG antibody production. In this case, when the concentration of the sensitizing drug or hapten is in slight excess to the antibody, the two combine in the serum, producing lattices of antigen–antibody complexes. These are deposited, particularly in vessel walls. They activate complement, causing vasculitis. The classic forms of type III reaction are serum sickness (usually including arthralgias, fever, malaise, and urticaria that develop 7 to 14 days after exposure to the causative antigen) and the localized Arthus reaction, a local inflammatory response due to deposition of immune complexes in tissues.
Type IV reactions are mediated by T cells themselves. “Delayed-type hypersensitivity” reactions from positive tuberculin tests to contact dermatitis are typical type IV reactions, but understanding T-cell function allows us to further define this category as shown in Table 54–1.5,6
Pseudoallergic Drug Reactions
Reactions that clinically resemble allergic reactions but lack an immune basis have been referred to as “pseudoallergic.” They include almost the entire range of immediate hypersensitivity clinical patterns. Pseudoallergic reactions range in significance from the alarming but trivial anxiety or vasovagal reactions caused by local dental anesthetics to sometimes fatal reactions to ionic radiocontrast media. However, cytotoxic reactions, serum sickness, and severe dermatologic reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) are immunologic processes that are not likely to be mimicked by nonimmune processes seen with pseudoallergic reactions.
Pseudoallergic reactions are important in patient counseling and management considerations. The reactions represent common biological functions (direct histamine release by vancomycin, opiates), whereas immunologic (allergic) reactions are based on the structure of the drug. Even a mild drug allergy may carry significant potential for anaphylaxis on readministration. In contrast, pseudoallergic reactions tend to remain constant whether mild or severe and are dose-related.
Pseudoallergic reactions, then, are reactions where the tools of the immune system are used in exactly the same way, but without the “learning” response by T cells and generally without the much greater danger that true immunologic sensitization implies. Pseudoallergic reactions may be thought of as a subtype of idiopathic reactions, rather than an activation of the patient’s immune system. The pathophysiology of pseudoallergic reactions is generally unknown, but indicators of immune activation are not seen when they occur.
PROBLEMATIC DRUG CLASSES AND TREATMENT OPTIONS
The first priority is to avoid doing serious harm by administering a drug that the patient cannot tolerate. We can generally establish the likelihood of a relationship between the suspected drug and the observed reaction and, also, whether it is likely to be an immune or idiopathic reaction by examining the time-course and specific signs and symptoms as precisely and objectively as possible. Reevaluating the patient’s physical findings and laboratory values (taking into account pre-existing diseases) allows further clarification of the need to change treatments and to add therapy for the reaction itself.
Table 54–1 Reaction Classification, Clinical Symptoms, and Potential Causative Drugs
Clinical Presentation and Diagnosis of Allergic and Pseudoallergic Drug Reactions
The clinical presentation of a patient experiencing an allergic reaction varies greatly. The primary reactions are described below:
• Anaphylaxis: Anaphylaxis is an acute life-threatening allergic reaction. Signs and symptoms involve the skin (e.g., pruritis, urticaria), respiratory tract (e.g., dyspnea, wheezing), gastrointestinal tract (e.g., nausea, cramping), and cardiovascular system (e.g., hypotension, tachycardia). Onset is usually within 30 minutes, but can be as long as 2 hours. Treatment must begin immediately. Anaphylaxis may recur 6 to 8 hours after exposure so patients experiencing anaphylaxis should be observed for at least 12 hours.
• Cytotoxic reactions: These reactions usually take the form of hemolytic anemia, thrombocytopenia, granulocytopenia, or agranulocytosis.
• Immune complex reactions: These reactions usually involve a serum sickness-like syndrome (e.g., arthralgias, fever, malaise, and urticaria) that usually develops 7 to 14 days after exposure to the causative antigen.
• Dermatologic reactions: Rashes may range from mild to life-threatening
• Urticaria: These are itchy, raised, swollen areas on the skin. Also known as hives.
• Maculopapular rash: A rash that contains both macules and papules. A macule is a flat discolored area of the skin, and a papule is a small raised bump. A maculopapular rash is usually a large area that is red, and has small, bumps.
• Erythema multiforme: A rash characterized by papular (small raised bump) or vesicular lesions (blisters), and reddening or discoloration of the skin often in concentric zones about the lesion.
• Stevens-Johnson syndrome: A severe expression of erythema multiforme (also known as erythema multiforme major). It typically involves the skin and the mucous membranes with the potential for severe morbidity and even death.
• Toxic epidermal necrolysis: A life-threatening skin disorder characterized by blistering and peeling of the top layer of skin.
Reviewing the original indications for the treatment that caused the reaction is important. For example, in many respiratory illnesses, a prescribed antibiotic may be unnecessary. If the disease persists and indications for some treatment are established, alternatives must be sought, either by adjusting dose or administration rate, finding effective and unrelated alternative medication, or desensitizing the patient to the original drug.
When adverse drug reactions occur, the health care provider should carefully describe all aspects of the reaction and assess the potential for it to reoccur. Many patients have frightening associations of the term “allergy” with severe and unpredictable anaphylaxis. It is difficult to undo fears created by injudiciously labeling a patient as allergic in the medical record. Labeling a person “allergic” may hamper future medical care, as patients may refuse treatment or fail to adhere to medication regimens. If the original reaction is clearly documented, health care providers can appropriately counsel patients about any true dangers.
Anaphylaxis is a true medical emergency and must be treated promptly. Otherwise, managing allergic reactions begins with stopping the offending agent. Understanding the allergic reaction and potential for cross-allergenicitybetween similar drugs will assist in selecting an alternative medication. Desensitization is a management option if the patient truly needs the medication and alternative drugs are not available. While any drug may cause an allergic or pseudoallergic reaction, several drugs and drug classes are strongly associated with such reactions (Table 54–2). These classes will be discussed individually.
β-Lactam Antibiotics
Hypersensitivity reactions with β-lactam antibiotics, especially penicillin, may encompass any of the Type I through IV Gell-Coombs classifications. The most common reactions are maculopapular and urticarial eruptions.7 While rare (lesser than 0.05%), anaphylaxis to penicillins cause the greatest concern, as they are responsible for the majority of all drug-induced anaphylaxis deaths in patients, accounting for 75% of all anaphylaxis cases in the United States.5,8 The treatment of anaphylaxis is given in Table 54–3.9
Table 54–2 Problematic Drug Classes
β-Lactam antibiotics
Sulfonamide antibiotics
Aspirin and nonsteroidal anti-inflammatory drugs
Radiocontrast media
Opiates
Chemotherapy
Insulin
Anticonvulsants
Table 54–3 Pharmacologic Management of Anaphylactic Reactions
Immediate Intervention
Epinephrine 1:1,000 (1 mg/mL)
• Adults: Give 0.2–0.5 mg intramuscular (IM) or subcutaneous (SC); repeat every 5 minutes as needed
• Pediatrics: 0.01 mg/kg (maximum 0.3 mg) IM or SC, repeat every 5 minutes as needed
Subsequent Interventions
Normal Saline Infusion
• Adults: 1–2 L at a rate of 5–10 mL/kg in the first 5 minutes, followed by slow infusion
• Pediatrics: up to 30 mL/kg in the first hour
Epinephrine Infusion
If patient is NOT responding to epinephrine injections and volume resuscitation:
• Adults: epinephrine infusion (1 mg in 250 mL dextrose 5% in water [D5W]): 1–4 mcg/min, titrating based on clinical response or side effects
• Pediatrics: epinephrine 1:10,000 (0.1 mg/mL): 0.01 mg/kg (up to 0.3 mg) over several minutes
Other Considerations after Epinephrine and Fluids
Diphenhydramine
• Adults: 25–50 mg intravenous (IV) or IM
• Pediatrics: 1–1.25 mg/kg (maximum of 300 mg/24 hour)
Ranitidine
• Adults: 50 mg in D5W 20 mL IV over 5 minutes
• Pediatrics: 1 mg/kg (up to 50 mg) in D5W 20 mL IV over 5 minutes
Inhaled β-agonist (bronchospasm resistant to epinephrine) 2–5 mg in 3 mL of normal saline, nebulized, repeat as needed
Dopamine (hypotension refractory to fluids and epinephrine) 2–20 mcg/kg/min titrated to maintain systolic blood pressure greater than 90 mm Hg
Hydrocortisone (severe or prolonged anaphylaxis)
• Adults: 250 mg IV (prednisone 20 mg can be given orally in mild cases)
• Pediatrics: 2.5–10 mg/kg/24 hours
From Ref. 9.
Patient Encounter 1
A 44-year-old male is admitted to the hospital for treatment of a cellulitis. He states that he has no known allergies. He is prescribed IV nafcillin for his infection. During the first infusion, he notices that his ears are itching and he calls for a nurse. Upon the nurse’s arrival, the patient appears nervous and is having difficulty breathing.
What type allergic reaction is the patient most likely having?
What is the first action this nurse should take?
Outline the medical treatment for this reaction and how fast should it be started?
The health care professional is faced with a difficult task when approaching a patient who claims a history of penicillin allergy. While as many as 12% of hospital patients state they have an allergy to penicillin, about 90% will have negative skins tests.10 Table 54–4 shows the traditional protocol for penicillin skin testing.11 This test only evaluates IgE-mediated reactions. A patient with a history of other serious reactions such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis should not receive penicillins and should not be tested.
Penicillins and cephalosporins both have a β-lactam ring joined to an S-containing ring structure (penicillins: a thiazolidine ring, cephalosporins: a dihydrothiazine ring). The extent of cross-allergenicity appears to be relatively low, with an estimate of around 4%.12 Cross-allergenicity is less likely with newer generation cephalosporins compared to the first generation agents. Anaphylactic reactions to cephalosporins are rare, with a predicted range of 0.0001% to 0.1%. Minor skin reactions including urticaria, exanthem, and pruritis are the most common allergic reactions with cephalosporins, showing severe reactions less often than with penicillins.13
Table 54–4 Procedure for Performing Penicillin Skin Testing
B. Intradermal Skin Testing
For other β-lactam agents, the recommendations are fairly straightforward.9 Carbapenems should be considered cross-reactive with penicillins. Monobactams (e.g., aztreonam) do not cross react with any β-lactam drugs except ceftazidime because they share an identical R-group side chain.
Sulfonamide Antibiotics
Sulfonamides are compounds that contain a sulfonamide moiety (i.e., SO2NH2). This group includes sulfonamide antibiotics, furosemide, thiazide diuretics, sulfonylureas, and celecoxib. The sulfonamide antibiotics contain an aromatic amine at the N4 position and a substituted ring at the N1 position. Because of this different chemical structure, cross-allergenicity with the other sulfonamides may not occur. Predisposition to allergic reactions is a more likely reason than cross-reactivity between these differing molecules.14 The sulfonamide antibiotics are significant because they account for the largest percentage of antibiotic-induced toxic epidermal necrolysis and Stevens-Johnson syndrome cases.15
Reactions to sulfonamide antibiotics, ranging from mild (most common) to life-threatening (rare), occur in 2% to 4% of healthy patients, with rates as high as 60% in patients with AIDS.7 Anaphylaxis or anaphylactoidreactions almost always occur within 30 minutes but may be up to 90 minutes after exposure, most commonly after parenteral administration. Isolated angioedema or urticaria can occur within minutes to days. Serum sickness occurs within 1 to 2 weeks. Fixed drug eruptions (lesions) occur within a half-hour to 8 hours. These lesions resolve within 2 to 3 weeks after drug removal. The more severe conditions of Stevens-Johnson syndrome and toxic epidermal necrolysis tend to occur 1 to 2 weeks after initiation of therapy. Because trimethoprim-sulfamethoxazole is the drug of choice for patients infected with Pneumocystis carinii, desensitization may be necessary. A history of Stevens-Johnson syndrome or toxic epidermal necrolysis is an absolute contraindication for the desensitization procedure.
Patients With Multiple Antibiotic Allergies
Dealing with patients who claim to have multiple antibiotic allergies can be challenging. Combining knowledge of cross-allergenicity with a careful assessment of patient history may be helpful in designing an antimicrobial regimen. Table 54–5 outlines a series of questions that can be useful in developing an effective treatment plan.16 If available and indicated, skin testing may be useful to complete the puzzle. Often with careful assessment, an antibiotic of choice may be used when the patient’s initial history would have ruled it out. Based on data gathered, the patient’s record should reflect: antibiotics safe to use if needed; antibiotics to be avoided; and antibiotics that can be used only after desensitization. While this table was designed with antibiotics in mind, it can be modified for any multiple allergy situations.
Table 54–5 Multiple Antibiotic Allergies: Obtaining Background Information
For each antibiotic to which the patient claims to be allergic, gather the following information:
What type of infection was being treated?
Have you ever received the drug without experiencing a reaction?
How many times have you received the drug and experienced a reaction?
What was the drug dose and route of administration with the last reaction?
How many doses did you take before the onset of the last reaction?
How many doses did you take after the last reaction?
Can you describe the adverse reaction?
What was the duration of the reaction?
What treatment was given for the reaction?
Was there any permanent damage?
For each antibiotic that the patient has received and does not claim allergy, gather the following information:
What was the last type of infection being treated?
What was the drug dose and route of administration?
Have you received this drug more than once without reactions?
Other information to be gathered:
Have you had adverse reactions to any other drugs? If so, give dates and describe the reaction
Document any risk factors for allergic reactions such as chronic urticaria, liver or kidney disease, HIV (human immunodeficienc virus), or any other immune deficiencies
From Ref. 15.
Aspirin and Nonsteroidal Anti-inflammatory Drugs
Aspirin and the nonsteroidal anti-inflammatory drugs (NSAIDs) can induce allergic and pseudoallergic reactions. Because these drugs are so widely used, with much over-the-counter use, the health care professional must have a basic understanding of the types of reactions that can occur and how to prevent them. Three types of reactions occur: bronchospasm with rhinoconjunctivitis, urticaria/angioedema, and anaphylaxis. Remember that patients with gastric discomfort or bruising from these agents may describe themselves as being allergic, however these are not allergic or pseudoallergic reactions.
Two specific conditions: aspirin-exacerbated respiratory disease (AERD) and chronic idiopathic urticaria, are important because they are commonly seen. AERD may include asthma, rhinitis with nasal polyps, and aspirin sensitivity.17 Upon exposure to aspirin or a NSAID, patients with AERD experience rhinorrhea, nasal congestion, conjunctivitis, laryngospasm, and asthma. Chronic idiopathic urticaria may also be seen with aspirin or NSAID-induced pseudoallergic reactions.18 Patients with a history of chronic idiopathic urticaria are likely to see a flare of urticaria if aspirin or a cyclooxygenase (COX)-1 inhibiting NSAID is given. Cross-reactions between aspirin and older COX-1 inhibiting NSAIDs exist in patients with AERD and chronic idiopathic urticaria. Even though product warning labels for COX-2 inhibitors state that these agents should not be used in these two conditions, there are no reports of cross-reactivity in AERD and only rare reports in patients with chronic idiopathic urticaria.19
IgE-mediated urticarial/angioedema reactions and anaphylaxis are associated with aspirin and NSAIDs. Urticaria is the most common form of IgE-mediated reaction. However, most reactions are the result of metabolic idiosyncracies, such as aspirin-induced respiratory disease which may produce severe and even fatal bronchospasm. This class is second only to β-lactams in causing anaphylaxis. Most reactions in this class are due to a complex metabolic pattern which causes increasingly recurrent and severe nasal polyps and often refractory asthma. The metabolic problem is constant, once it emerges, accounting for the persistence and difficulty of these clinical problems, but is also capable of causing severe, sometimes fatal acute reactions to aspirin or many if not all the other NSAIDs as well. Rare reports of non-cross-reactive severe reactions suggest possible specific IgE-mediated reactions to individual NSAIDs, and there are some occurrences of urticaria related to NSAIDs as well. Because aspirin therapy is highly beneficial in primary and secondary prevention in coronary artery disease (CAD), aspirin desensitization should be considered in patients who have had reactions to aspirin. Desensitization is contraindicated in patients who have experienced aspirin-induced anaphylactoid reaction, hypotension, tachypnea, or altered consciousness. Alternate agents must be used. A comprehensive approach to aspirin-sensitive patients with CAD has been described.20
Radiocontrast Media
Radiocontrast media may cause serious, immediate pseudoallergic reactions such as urticaria/angioedema, bronchospasm, shock, and death. These reactions have been reduced with the introduction of nonionic, lower osmolality products. Because a small percentage of patients who have reacted previously to radiocontrast media will react if reexposed, several steps (listed below) should be taken to prevent reactions in these patients. These steps should also be followed in patients with high risk factors: asthmatic patients, patients on β-blockers, and patients with cardiovascular disease.5
• Determine if the study is essential
• Be sure the patient understands the risks
• Ensure adequate hydration
• Use nonionic, lower osmolar agents
• Pretreat with prednisone 50 mg orally 13, 7, and 1 hour(s) before the procedure and diphenhydramine 50 mg orally 1 hour before the procedure
Delayed reactions with these agents occur in 1% to 3% of patients.21 Although reactions are occasionally severe, most are mild and manifest as maculopapular rashes, fixed eruptions, erythema multiforme, and urticarial eruptions.
Opiates
Opiates (morphine, meperidine, codeine, hydrocodone, and others) stimulate mast cell release directly, resulting in pruritis and urticaria with occasional mild wheezing. Though these reactions are not allergic, many patients state that they are “allergic” to one or more of the opiates. Pretreatment with an antihistamine may reduce these reactions. These pseudoallergic reactions are rarely, if ever, life threatening.5 Avoiding other mast cell degranulating medications while patients require opiates also reduces the chances of frightening and uncomfortable reactions. Patients may state they are allergic if they have experienced gastrointestinal upset, a common side effect to opiates, with previous exposures. Obtaining a thorough history from the patient will prove useful. If a more serious reaction has occurred, a non-narcotic analgesic should be selected.
Chemotherapy
Hypersensitivity reactions have occurred with all chemotherapy agents. Reactions are most common with the taxanes, platinum compounds, asparaginases, and epipodo-phyllotoxins.7 Reactions range from mild (flushing and rashes) to severe (dyspnea, bronchospasm, urticaria, and hypotension). IgE-mediated type I reactions are the most common. To reduce the risk, patients are routinely premedicated with corticosteroids and H1 and H2 receptor antagonists. The platinum compounds have produced anemia, probably via a cytotoxic immunologic mechanism.
Insulin
Insulin is one of a very few medications which is itself a whole protein, and can induce IgE sensitivity directly. This can result in anaphylaxis. Adverse reactions to insulin also include erythema, pruritis, and indurations,22 which are usually transient and may be injection site-related. For the sensitivity reactions, treatment options include dexamethasone or desensitization. If the reaction is injection site-related, a change in delivery system (i.e., insulin pump or inhaled insulin) may be helpful.
Anticonvulsants
A life-threatening syndrome can occur following a few weeks of therapy with anticonvulsants, such as phenytoin, phenobarbital, and carbamazepine. Symptoms include fever, a maculopapular rash, generalized lymphadenopathy and varying degrees of internal organ dysfunction. The rash may be mild at first but can progress to exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. The causative agent should be withdrawn immediately. Valproic acid, gabapentin, and lamotrigine may be acceptable alternatives for seizure control.5
Drug Desensitization
Drug desensitization may be undertaken for some drugs in the absence of useful alternative medications. The risk of severe systemic reactions and anaphylaxis associated with desensitization must be compared to the risk of not treating the patient. Thorough evaluation should establish that the drug probably caused the reaction by an allergic mechanism. Because of the dangers involved with drug desensitization, an expert review of the patient’s indication for the drug should be conducted. Consider the possibility that the patient does not really need the drug.
Patient Encounter 2
A 55-year-old female is admitted to the hospital with an intra-abdominal infection. During the patient interview, she states that she is allergic to aspirin, codeine, sulfa drugs, penicillin, levofloxacin, and vancomycin. The reactions are described as follows:
Aspirin: Easy bruising
Codeine: Upset stomach and itching after one dose
Sulfa drugs: Mild rash occurred 2 hours after taking a double strength trimethoprim-sulfamethoxazole tablet prescribed for a urinary tract infection
Penicillin: Rash, itching, and shortness of breath
Levofloxacin: Upset stomach
Vancomycin: Burning sensation when the drug was infused
Based on the patient’s descriptions, which of the reactions represent an allergic or pseudoallergic reaction?
Which medications would you want to avoid based on this history?
What further questions would be useful to ask before developing a care plan?
If narcotic analgesics are required to treat this patient, what medication may be helpful as a pretreatment?
Desensitization is a potentially life-threatening procedure, and requires continuous monitoring in a hospital setting, with suitable access to emergency treatment and intubation if required. It should only be undertaken under the direction of a physician with suitable training and experience. In such hands, desensitization may present less risk than treatment failure with a less effective alternative medication.
The possibility of readministering a suspected drug may be safely tested by gradual dose escalation in some cases, and there are certainly many more patients who are harmed by inappropriately withholding medications than there are those who suffer significant harm from testing and desensitization.23
Only type I IgE-mediated allergy may be treated by classical desensitization. Desensitization may occur within hours to several weeks, unlike specific immunotherapy injections for inhalant allergy (i.e., “allergy shots” which may take months of therapy before a patient realizes any benefit and years to complete). The mechanism of drug desensitization is poorly understood, but produces temporary drug-specific tolerance of the offending drug. Any interruption of therapy of 24 hours or more requires full repeat desensitization, and abrupt significant increases of dosage have been reported to break through the tolerance with some drugs.
The process probably involves either: (a) cross-linking small subthreshold numbers of bound IgE molecules gradually depleting mast cells of their mediators, or (b) binding of the IgE by monomers or hapten-protein entities which cannot cross-link the antibody. The low doses used at the beginning of all protocols would provide small amounts of antigen, favoring these mechanisms. Both drug-specific IgE and IgG serum concentrations increase after successful desensitization, but skin test positivity generally decreases.24
Oral and intravenous protocols are available for most drugs in this category, with the oral route producing somewhat milder reactions, but the intravenous route providing more precision in dosing. Intravenous administration can also be used in unresponsive patients where the oral route is not feasible. Protocols generally begin at about 1% of the therapeutic dose and increase in intervals defined by the patient s reaction and the distribution and metabolism of the drug itself. Half-log10 dose increases (about threefold) are often tolerated.
Penicillin desensitization is the most common drug desensitization protocol, and is required for penicillin-allergic patients when penicillin is clearly the only treatment option, for example when syphilis is present in pregnancy. Protocols have been adapted to most antibiotics. Tables 54–6 and 54–7 describe procedures for intravenous and oral penicillin desensitization.25
Table 54–6 Protocol for Oral Penicillin Desensitization
Aspirin desensitization is useful in diseases where low-level antiplatelet action is needed and in the care of patients with aspirin sensitivity and intractable nasal polyps. Lysine aspirin availability in Europe allows desensitization by inhalation at greatly reduced risk. New procedures utilizing ketorolac as a nasal topical application may allow similar reduction of risk in the United States.26 As with all desensitizations, constant daily administration must be maintained once the desired dose is reached. Table 54–8 summarizes several similar aspirin desensitization protocols.27 Table 54–9 depicts a 2-day alternative protocol.28
All desensitization procedures are expected to produce mild symptoms in the patient at some point, and the patient must be made to understand this before doses are started. Mild sensitivity to the drug still remains, and large dose increases as well as missing doses should be avoided. Late complications, such as urticaria, may occur with Type I desensitization, and serum sickness or hemolytic anemia may also occur with high-dose therapy in allergic, desensitized patients.
Table 54–7 Parenteral Penicillin Desensitization Protocol
Table 54–8 Oral Aspirin Desensitization Protocols
Some regimens are designed for outpatient administration over much longer time periods and have been used, for example with allopurinol dermal reactions. Such late-onset morbiliform reactions, sometimes overlapping with erythema multiforme minor, are difficult to evaluate as it is often unclear to what extent the patients were at risk for recurrent reaction.
Severe life-threatening reactions not mediated by IgE, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, are absolute contraindications to testing, desensitization attempts, and readministration.
Table 54–9 Oral Aspirin Desensitization Protocol
Patient Encounter 3
A 50-year-old male is visiting the clinic for a routine checkup. Pertinent findings are below:
PMH: Hypertension diagnosed 5 years ago, currently controlled; seasonal allergic rhinitis
FH: Father died of myocardial infarction at age 59; grandfather died of a stroke at age 62
SH: Smokes less than one pack a day; drinks one glass of red wine daily
Meds: Hydrochlorothiazide 25 mg orally once daily; atenolol 50 mg once daily; fluticasone nasal spray, one spray in each nostril daily during allergy season; loratadine 10 mg daily during allergy season
Allergies: History of an anaphylactoid reaction after taking aspirin one year ago for headache
Development of a Care Plan
Based on the patient’s history, is he a candidate for daily aspirin therapy?
If so, is the patient a candidate for aspirin desensitization? Why or why not?
OUTCOME EVALUATION
To successfully treat a patient with a drug allergy or pseudoallergy, several goals must be accomplished:
• If a reaction occurs, it must be identified and managed quickly.
• The patient should be educated about the reaction.
• True drug contraindications should be avoided if at all possible.
• Patients should receive the medications they need or a suitable alternative. If this is not possible due to an allergy, desensitization should be considered.
• Patients should always be monitored for adverse drug reactions.
CONCLUSION
Allergic and pseudoallergic reactions may be mild or life threatening. Efforts to manage these reactions or change the patient’s treatment due to the reactions may increase costs and prevent best therapeutic outcomes. The health care professional should carefully explore all available information to accurately assess potential risks from drugs after an apparent reaction to guide both avoidance and alternative treatments. The health care professional should partner with the patient to document reactions so the patient can avoid drugs that present dangers to them if possible and receive the best drug choices when needed.
Patient Care and Monitoring
1. Before administering any medication, take a thorough drug history to establish any past allergic or adverse reactions experienced by the patient.
2. For any reaction, use questions given in Table 54–5 to establish the nature of the reaction and the likelihood it was caused by the suspected drug. For nonantibiotics, the first question regarding infection type is not needed.
3. Document the reaction, in detail, in the patient’s medical record.
4. Recommend an alternative choice if the prescribed drug is contraindicated, and develop a plan to assess safety and effectiveness.
5. Consult with a physician trained in desensitization if the patient has a true allergy and no acceptable alternative medication is available.
6. Educate the patient about the allergy or pseudoallergy so they are able to work with health care providers to avoid the reaction in the future.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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