Drug reactions encompass all adverse events related to drug administration,
regardless of etiology.1 While adverse drug reactions
are common, only a small portion of these represent drug hypersensitivity,
defined as an immunologically-mediated response to a drug agent
in a sensitized patient. In turn, only a subset of drug hypersensitivity
reactions represent a true drug allergy, which refers specifically
to a reaction mediated by IgE.2 These distinctions
are important for optimal patient management, risk assessment, and
education of patients regarding specific drug reactions.
Drug reactions can be classified into immunologic and nonimmunologic
etiologies.3 The majority (75–80%)
of adverse drug reactions are due to predictable, nonimmunologic
effects. Drug reactions due to overdose, toxicity, pharmacologic
side effects, indirect side effects (ie, oral thrush with antibiotics),
or drug–drug interactions are included in this category.
The remaining 20% to 25% of adverse drug events
are due to unpredictable effects, which may or may not be immune
mediated. These unpredictable reactions are usually dose independent
and unrelated to the drug’s pharmacologic action. Immune-mediated
reactions constituting true drug hypersensitivity account for 5% to
10% of all drug reactions. Other causes of unpredictable
reactions include drug-direct mast cell stimulation (sometimes termed pseudoallergic).
Adverse drug reactions are a major cause of morbidity and mortality,
with antibiotics and NSAID agents being the most common offending drugs.
Drug exposure in the setting of concomitant inflammation from infection,
autoimmunity, or other systemic conditions may lead to increased
immunological reactivity to drug antigens. Individuals with chronic
medical conditions are often administered multiple therapeutic medications
and therefore may have more adverse drug effects due to increased
drug exposure. Variability in drug metabolism due to differences
in drug acetylation or haptenation rates is an important factor
for drug hypersensitivity. Although atopic patients do not have
a higher rate of sensitization to drugs, they are at increased risk
for serious allergic reactions.
A number of drug-related characteristics are important factors
for drug hypersensitivity. Drugs with greater structural complexity
(eg, proteins such as heterologous antisera, streptokinase, insulin,
and monoclonal antibodies) are more likely to be immunogenic. In
addition, drugs must have a sufficient molecular weight (> 1000
daltons) to be immunogenic in their native state. Most drugs have
a smaller molecular weight but become immunogenic by coupling with
carrier proteins, such as albumin, to form simple chemical (hapten)
carrier complexes.4 Topical, intramuscular, and
intravenous administration pose a higher risk of hypersensitivity reactions
than does the oral route of administration.
Drug hypersensitivity reactions should be considered in the differential
diagnosis of patients with allergic symptoms of anaphylaxis, urticaria,
and asthma, but also with serum sickness-like symptoms, skin rash,
fever, pulmonary infiltrates with eosinophilia, hepatitis, acute
interstitial nephritis, and lupuslike syndromes. Efforts should
be made to differentiate between immunological drug hypersensitivity
and other adverse drug reactions. Generally speaking, immune-mediated
drug hypersensitivity reactions pose a predictable, more serious
health risk with reexposure to a drug, whereas nonimmune drug reactions
tend to ...