DIAGNOSTIC TESTING FOR DRUG HYPERSENSITIVITY

Adverse drug reactions are important and frequent complications of medication therapy. Estimates are that 5% to 15% of patients develop adverse reactions to medication during treatment. 19,32 As many as 30% of hospitalized patients experience at least one adverse drug reaction. 10,32 Approximately 3% of all acute care medical admissions and 0.3% of all hospital admissions are attributed to adverse medication reactions. 19 Fatal drug reactions occur in 0.1% of medical in-patients and 0.01% of surgical in-patients. 19 Drug sensitivity has been implicated in 4.3% of deaths and 5.6% of cerebral damage in cases of anesthetic mishaps reported in the United Kingdom. 25 The first step in properly diagnosing adverse drug reactions is to understand the different types that can occur. There are certain adverse drug reactions that may occur in all individuals. 20 These reactions include overdoses, which are toxic reactions caused by excessive doses or impaired excretion or metabolism of a medication. Side effects are undesirable but are potentially unavoidable because of the pharmacologic action of the particular medication, such as tremors with use of beta agonists. Secondary effects are undesirable effects that are unrelated to the primary pharmacologic action of the medication, such as oral candidiasis secondary to the use of inhaled steroids. Drug interactions involve the interaction of two or more drugs causing toxicity that otherwise would not be present, such as that seen with the terfenadine–erythromycin interaction. Other adverse drug reactions occur only in susceptible patients in an unpredictable manner. These include drug intolerance, which is caused by a lower threshold to the normal pharmacologic action of a particular medication, such as tinnitus seen at low doses of salicylates in selected patients; idiosyncratic reactions, which usually result from a genetically determined metabolic or enzyme deficiency that is not expressed under normal situations, such as hemolytic anemia occurring in patients with glucose-6-phosphate dehydrogenase deficiency after receiving an oxidant drug; drug allergies that by definition involve immunologic mechanisms such as IgE penicillin anaphylaxis; and pseudo-allergies, which are reactions that have similar clinical manifestations as allergic reactions but the mechanism has been proven not to involve effector immune cells (antibodies or sensitized T lymphocytes). Allergic drug reactions (involving immunologic mechanisms) account for approximately 5% to 10% of adverse drug reactions. 5 Properly diagnosing an offending medication as a cause of an adverse drug reaction is often difficult. Multiple medications are sometimes in use at the same time, and the clinical symptoms of adverse drug reactions may overlap with symptoms of the underlying disease. A common example is a patient who develops an exanthem. It is often unclear if the cutaneous reaction is related to the antibiotic prescribed or to the underlying infectious process. Our general lack of knowledge of the immunochemistry of drug metabolism and immunoreactive metabolites also greatly hampers our ability to accurately use diagnostic tests to evaluate allergic drug reactions. Except for penicillin and to a lesser degree anticonvulsant medications and sulfonamides, our understanding of the immunoreactive metabolites and immunochemistry of medications is quite limited. At times we employ tests for drug-specific immune responses, but we lack knowledge of the positive and negative predictive value of these as diagnostic tests. This lack of knowledge is understandable because there are only a few studies in which large numbers of patients with negative and positive diagnostic tests have been rechallenged with the suspected medication. Despite these difficulties, it is worth attempting to diagnose immunologic drug reactions. It is important to define the causal agent to help guide the selection and use of future medications for a given patient and to properly manage the present adverse drug reaction. Labeling a patient inaccurately allergic to a medication may cause the future use of less effective or more toxic medications as substitutes for the preferred medication.