▪ Epidemiology

Management of a history of adverse reactions to drugs is challenging for both the physician and the patient. Almost all persons will have some sort of adverse drug reaction during their lifetime. Adverse drug reactions are responsible for one in twenty hospital admissions and occur in nearly a fifth of hospitalized patients.¹ Fifty-nine percent of drug-related hospitalizations are preventable.² Patients experiencing adverse drug reactions are more likely to stay in the hospital longer, 10.6 verses 6.8 days in one study, and their hospital costs are over US$5000 higher.³ Adverse drug reactions are responsible for 106 000 deaths per year.⁴ This makes them the fourth leading cause of death of hospitalized patients, and is even likely a very low estimate given underreporting and misdiagnosis of cause of death.⁵ This is even more of a tragedy as many of them are preventable and can be avoided through education and correction of systems errors. Any drug can cause an adverse drug reaction, but only a few drugs have been found to cause the majority of severe immune reactions. By becoming familiar with adverse drug reactions, physicians can protect the safety of their patients without unnecessarily withholding vital and recommended treatments.

▪ Risks

Certain medications have been implicated more frequently than others in allergic adverse drug reactions. There are particular risk factors that make an exposure to a drug more likely to lead to a clinically significant reaction (Table 11.1).⁶ The underlying chemical properties of a drug may make it more likely to become antigenic by reaction with host tissue, for instance by acting as a hapten and complexing with a native protein. Concurrent illness may lead to a drug reaction that would otherwise not occur. For example, almost all cases of Epstein–Barr virus infection treated with a course of amoxicillin lead to a characteristic drug rash.⁷ This rash does not recur on readministration of the medication when the patient is no longer experiencing their active, primary infection. The molecular weight of a drug is also an important factor. Low molecular weight drugs are likely not immunogenic on their own without haptenizing. This includes most medications. However, newer biologic agents such as monoclonal antibodies, are often complex protein structures with a high molecular weight and are capable of inducing an immune response on their own. The route of administration may make a patient more likely to have a drug reaction. The oral route and the subcutaneous routes are less risky in most cases, versus the IV route of the same medication. When a patient is receiving a repeated course of a medication they may also be more likely to react. The likely mechanism for this type of reaction involves sensitization through antigen presentation to the immune system during the first course (sensitization), followed by faster more severe response with a second dose due to immunologic memory. Patients may also be more likely to experience a drug reaction if they have had a prolonged course at a high dose of a particular drug therapy.

TABLE 11.1 Risk factors for drug reaction

Atopy significantly increases the risk of both having reactions and having more serious reactions. Female gender is associated with a one-third higher risk of cutaneous reaction verses male counterparts. Extremes of age, the very young and the elderly have fewer allergic drug reactions.⁶ The mechanisms that predispose an individual to adverse effects are related to the method by which a certain patient’s immune system responds to an antigen and determines what is “foreign,” and to what degree immunologic tolerance exists. Interestingly, HLA genetic polymorphisms are being identified in the population that may make one patient more likely to experience a reaction to a drug verses another patient. This exciting new field of pharmacogenetics may eventually make it economically and clinically feasible to prescreen patients by a laboratory test prior to treatment with medications in order to minimize adverse reactions.⁷

▪ Pseudoallergic reactions

These reactions often include symptoms that are indistinguishable clinically from true IgE-mediated allergic reactions, including hives and life-threatening collapse of the respiratory and circulatory systems. Medications commonly implicated in pseudoallergic reactions are listed in Box 11.1. These reactions are usually non-IgE-mediated mast cell or basophil mediator release.⁸ No previous period of sensitization to the medication is required. Pseudoallergic reactions are typical of drug reactions to opiates, colloids, some nonsteroidal medications, radiocontrast media, and some antibiotics. The treatment of a pseudoallergic reaction is the same as that for allergic and anaphylactic reactions (see below). In the case of opiates, especially when clinically necessary as in palliative care, the physician often may treat through the reaction with H₁ and H₂ blockers or steroids. More severe reactions are rarely seen, and tolerance seems to develop just as it does to other side effects and therapeutic effects of the narcotic. Not all narcotics or synthetic narcotics have a similar risk of inducing pseudoallergic reactions. Morphine and codeine are frequently involved while fentanyl is not.

There is a 1 in 50 incidence of having a pseudoallergic reaction to radiocontrast media. Even though the reactions to radiocontrast media are pseudoallergic reactions, they should be taken seriously as they may be severe and are fatal in up to 1 in 50 000 events. Patients that react to radiocontrast media have a high likelihood, up to 44%, of having a reaction again on a second exposure. Premedication with antihistamines such as diphenhydramine and corticosteroids starting 12–24 hours before the procedure combined with the use of newer, lower osmolar contrast agents may minimize the chance of subsequent reaction to 1%.^9,10 This risk is not zero, however, as evidenced by a report of anaphylaxis despite premedication, thus patients should be apprised of the risks with informed consent prior to procedures.¹¹ While more controversial, oral ephedrine and oral albuterol may also be considered as prophylaxis in these cases of reaction to radiocontrast media. The physician must recall that radiocontrast media is also used in myelograms, hystosalpingograms, and retrograde pyelograms. Atopic individuals, those with asthma, chronic obstructive pulmonary disease, unstable heart disease using beta blockers, and those with previous adverse events to contrast in the past, are considered at risk of adverse events when receiving radiocontrast.^12,13 In contrast to a popular myth, radiocontrast does not cross-react with seafood or iodine.

Administration of vancomycin may be accompanied by erythema, flushing, and allergic-like symptoms. Known as red man’s syndrome, this type of reaction does not reflect true allergy and can usually be managed by slowing the infusion rate and using premedication such as antihistamines.¹⁴ However, although very rare, IgE-mediated anaphylaxis to vancomycin may occur. Pseudoallergic reaction to iron dextran has also been reported, and for patients who require this medication, a successful graded challenge protocol has been described.¹⁵

▪ Idiosyncratic Reactions

Most reactions to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) fit into this category, although true IgE-mediated reactions to isolated agents do occur rarely.¹⁶ By non-IgE-mediated reactions, aspirin and NSAID reactions may manifest as urticaria, angioedema, wheezing, nasal congestion, or may trigger recurrence of urticaria and angioedema in a person with chronic idiopathic urticaria. The mechanism to explain why patients with aspirin allergy, nasal polyps often leading to sinusitis, and asthma, which make up Samter’s triad, is also unknown.¹⁷ In those patients with Samter’s triad, a decrease in prostaglandin E₂ (PGE₂) and an increase in leukotrienes may be found, implicating a mechanism of action based on the cyclooxygenase and lipoxygenase pathways following breakdown of arachidonic acid.¹⁸ Involvement of this pathway also explains cross-reactive drug reaction with high dose acetaminophen in a third of these individuals. There is no value in skin testing these patients, since the mechanism is not IgE-mediated. These patients may respond to antileukotriene medications such as montelukast and zafirlukast as well as the 5-lipoxygenase inhibitor, zileuton. These patients with aspirin sensitivity may respond to graded challenge to aspirin as described below. Graded challenge leads to improved quality of life, improved asthma, less need for polypectomy and sinus surgery, reduced symptom of congestion and decreased emergency room visits and hospitalizations. Graded challenge protocols or desensitizations are usually not effective in patients with aspirin-induced urticaria or angioedema.¹⁹

Another idiosyncratic reaction is angioedema to ACE inhibitors. Up to a quarter of patients on ACE inhibitors may develop a persistent cough that may last for weeks after the drug is discontinued. This is more common in females and more likely to occur early during therapy.²⁰ Angiotensin receptor blockers have not been associated with cough. Angioedema secondary to ACE inhibitors is much less common, but can be serious, with one-third of patients hospitalized as a result and one tenth requiring intensive care²¹ (Figure 11.1). Physicians must have a high degree of suspicion to diagnose this condition, as it may occur after a patient has been asymptomatically on the medication for months to years. Unlike in the case with cough, angioedema to angiotensin receptor blockers has been described.²²

Figure 11.1 Angioedema. This patient had lip swelling, thought to be idiopathic or associated with unknown food, until an astute physician reviewed the medication list and noted the presence of lisinopril. Discontinuation of the drug was associated with resolution of symptoms. The medication was not considered as she had tolerated it for several years.

▪ Immune Mediated

Many, although not all, type B reactions with an immune basis can be classified using the Gell and Coombs classification²³ (Table 11.2). Under this classification, reaction types are numbered I through IV based on the immune system components thought to be responsible. This may be confusing, as a single drug can lead to different reactions in different patients, or the same patient, each of which may fit a different Gell and Coombs type. Also, this classification is for discussion and the reactions rarely occur in isolation. For instance, penicillin has been associated with reactions in each classification. Furthermore, the mechanism for many drug reactions is unknown, and other reaction types such as “typical maculopapular drug rash”, do not fit neatly into the classification scheme. However, the Gell and Coombs classification is frequently utilized in the literature to categorize drug reactions on an immunologic basis. Therefore physicians should have an understanding of its classes as well as examples of each type.

TABLE 11.2 Gell and Coombs classification scheme

Type I reactions are mediated by IgE and are the reactions that physicians usually consider to be true drug “allergies.” Prior exposure and sensitization is necessary in order to develop IgE. It is thought that either the medication or one of its metabolites is presented by MHC class II complexes on antigen presenting cells. As many drugs have low molecular weights, they need to covalently bond to self proteins to be immunogenic, a process termed haptenizing.²⁴ If the antigen presenting cell containing the drug/hapten complex is a B cell, and is recognized by a MHC/antigen-specific T cell in the presence of the correct cytokine milieu, usually IL-4 and IL-13, the B cell will be activated, leading to IgE production. On second exposure to the drug, drug-specific IgE molecules on mast cells may become cross-linked, leading to degranulation of mast cells and then the typical symptoms consistent with an allergic reaction (Figure 11.2). An example of a type 1 reaction would be the development of urticaria and anaphylaxis immediately following infusion of IV ampicillin, in a patient that had received the medication on a previous hospitalization without difficulty. In addition to the early phase of type 1 reactions, which are mainly secondary to histamine release from mast cells and basophils, a late phase may occur 3–6 hours later. This late phase is secondary to the influx and activation of inflammatory cells, such as the eosinophil, and may cause worsening symptoms hours after the initial event. Type 1 reactions may be evaluated by skin testing under the guidance of an allergist and often can be treated by desensitization protocols if necessaary.

Figure 11.2 IgE-mediated drug reaction. (A) Drug (orange), often in its haptenized form, is processed by antigen presenting cells, in this case B cells (brown), in the context of MHC molecules (olive). T cells (blue) recognize the antigen in the context of self MHC complexes via the T-cell receptor (black). Accessory cytokines and other receptors are not included in this illustration, but are an important part of the B-cell and T-cell interaction. (B) Stimulated B cells produce drug specific antibody. (C) Mast cells (pink) have antibody on their cell surface. (D) It requires second exposure to medication, with subsequent crosslinking of antibody (IgE) on mast cells, to cause mast cell mediator release, which leads to downstream anaphylactic symptoms.

Type 2 reactions are caused by antibody-dependent, cell-mediated cytotoxicity. The antigens, in this case the drug or its metabolite, becomes associated with cells or extracellular matrix proteins. IgG antibodies form against the antigen, in a mechanism similar to, although not identical to, the mechanism described above for IgE antibody formation. These IgG antibodies bind the drug/cell or drug/matrix complex. Complement fixation occurs and effector cells such as phagocytes and natural killer recognize the reaction by binding the Fc portion of the IgG, and lead to cytotoxic events that destroy surrounding tissue. Symptoms depend on the tissue or cells involved. An example of this type of reaction would be immune-mediated, hemolytic anemia causing destruction of red blood cells after taking penicillin or a related compound. Quinidine and alpha-methyldopa have also been implicated in this type of reaction.^25,26 Thrombocytopenia is frequently caused by this mechanism as well.

Type 3 reactions are usually due to the formation of immune complexes, containing IgM or IgG plus complement and a soluble antigen. This reaction is most likely to occur in cases of slight antigen excess, often a few weeks after the last dose of the medication. These complexes deposit in specific bodily tissues and when complement fixation or effector cell mediator release occurs, the organs or tissues into which the complexes have lodged become damaged, as innocent bystanders. Examples of this type of reaction include the Arthus’ reaction and serum sickness. This class of drug reaction may become more clinically relevant as more monoclonal antibodies containing mouse and other species’ proteins are marketed.

Type 4 reactions are cellular immune mediated. They can be secondary to a T-helper 1 cell mediated reaction with production of interferon gamma and an inflammatory response. Often it is not the medication itself but rather the chemical properties of the vehicle in which it is applied that lead to the reaction. Parabins, formaldehyde, and thimerosol are frequently implicated components. An example of a type 4 Gell and Coombs reaction is the development of a contact dermatitis after using a topical steroid preparation on a regular basis. Patch testing to the pharmaceutical or its chemical components may confirm the diagnosis.

▪ Others

Still, many other reactions are not well described by the Gell and Coombs classification table. Following multiple drugs, especially antibiotics, patients develop a morbilliform rash (Figures 11.3, 11.4) or bullous lesions, days after the medication has been started. Organ damage through fibrosis and inflammation occurs with broad medication classes and risk cannot be predicted for an individual patient. The lungs are at particular risk for drug reactions, and depending on the offending medication, almost every pathologic type of lung disease may occur. Sulfonamides, NSAIDs, and others may cause an acute pneumonitis picture. Narcotic drug abusers may develop a noncardiac pulmonary edema. Churg–Strauss vasculitis has been associated with the withdrawal of leukotriene receptor antagonists secondary to the ability to withdraw corticosteroids in asthmatic patients on these medications.²⁷ Methicillin and sulfonamides are classic as causes of interstitial nephritis. Urine eosinophils and increased IgE may be found and may aid in diagnosis in these cases.²⁸ Kidney biopsy is likely not necessary and function often returns to normal after drug discontinuation. Sun-induced rash is described with various antibiotics and some diuretics, among other medications. The frequently used medication for Parkinson’s disease, carbidopa/levidopa, is associated with a hypersensitivity pneumonitis. This may be an important association to keep in mind for those in geriatric medicine or who care for elderly patients. A spectrum of diseases, from erythema multiforme to Stevens–Johnson syndrome to toxic epidermal necrolysis (TEN), occurs most commonly following sulfonamides but also with other drugs. Stevens–Johnson syndrome has less than 10% involvement of the mucous membranes, while TEN has >30% mucosal involvement.

Figure 11.3 Morbilliform rash 1. This patient has erythemetous papules and macules consistent with a morbilliform reaction, in this case to a cephalosporin.

(Courtesy of Dr Jeffrey Miller, Associate Professor of Dermatology, Penn State Milton S. Hershey Medical Center.)

Figure 11.4 Morbilliform rash 2. This is a close-up of the rash described in Figure 11.3. The location is the back.

(Courtesy of Dr Jeffrey Miller, Associate Professor of Dermatology, Penn State Milton S. Hershey Medical Center.)