Key Points
- What has often been referred to as drug desensitization is more appropriately described as induction of drug tolerance. Induction of drug tolerance can involve immunoglobulin E (IgE) immune mechanisms, non-IgE immune mechanisms, pharmacologic mechanisms, and mixed or unknown mechanisms. All involve administration of incremental doses of the drug.
- Adverse drug reactions (ADRs) are commonly encountered in both inpatient and outpatient settings and result in major health problems in the United States. (C)
Definitions
- ADRs are broadly categorized into predictable and unpredictable reactions. (D)
- Unpredictable reactions are subdivided into drug intolerance, drug idiosyncrasy, drug allergy, and pseudoallergic reactions. (D)
- Drug intolerance is an undesirable pharmacologic effect that occurs at low and sometimes subtherapeutic doses of the drug without underlying abnormalities of metabolism, excretion, or bioavailability of the drug. (D)
- Drug idiosyncrasy is an abnormal and unexpected effect that is unrelated to the intended pharmacologic action of a drug. (D)
- Drug allergy reactions are immunologically mediated responses that result in the production of drug-specific antibodies, T cells, or both. (B)
- Manifestations of pseudoallergic (anaphylactoid) reactions mimic IgE-mediated allergic reactions, but they are due to direct release of mediators from mast cells and basophils and do not require a preceding period of sensitization. (B)
Classifications of Immunologically Mediated Drug Hypersensitivity Reactions
- Some drug allergic reactions may be classified by the Gell-Coombs classification paradigm of hypersensitivity (type I: IgE mediated; type II: cytotoxic; type III: immune complex; type IV: cell mediated), whereas others cannot be classified because of lack of knowledge of their immunopathogenesis or a mixed mechanism. (C)
- Allergic drug reactions may also be classified according to the predominant organ system involved (eg, cutaneous, hepatic, renal) or according to the temporal relationship to onset of symptoms (immediate, accelerated, delayed). (D)
- To some extent, the structural characteristics of drugs may permit predictions about the type of hypersensitivity reactions they are likely to cause. (C)
IgE-Mediated Reactions (Gell-Coombs Type I)
- IgE-mediated reactions may occur after administration of a wide variety of drugs, biologicals, and drug formulation agents, with the most common agents being antibiotics. (C)
Cytotoxic Reactions (Gell-Coombs Type II)
- Cytotoxic reactions are very serious and potentially life-threatening. (C)
- Immunohemolytic anemias have occurred after treatment with quinidine, α-methyldopa, and penicillin. (C)
- Positive direct and indirect Coombs test results in immunohemolytic anemia may reflect the presence of drug-specific IgG, complement, or an Rh determinant autoantibody. (C)
- Immune-induced thrombocytopenia may result from treatment with heparin, quinidine, propylthiouracil, gold salts, sulfonamides, vancomycin, and other drugs. (C) Platelet membrane damage is mediated mainly by drug-immune serum complexes, which are adsorbed onto platelet membranes. (C)
- Immune-mediated granulocytopenia is uncommon but may be induced by cytotoxic antibodies synthesized in response to a variety of drugs. (C)
Immune Complex Reactions (Gell-Coombs Type III)
- Immune complex (serum sickness) reactions were originally described with use of heterologous antisera, but they may also be caused by some small-molecular-weight drugs and monoclonal antibodies. (C)
- The chief manifestations of fever, rash, urticaria, lymphadenopathy, and arthralgias typically appear 1 to 3 weeks after starting an offending agent. (C)
- The prognosis for complete recovery from serum sickness is excellent.However, symptoms may last as long as several weeks. Treatment with systemic corticosteroids and histamine1 receptor antihistamines may be required. (C)
- Drug-induced immune complex disease may occur after exposure to heterologous proteins (eg, thymoglobulin) or simple drugs (eg, penicillin, procainamide, phenylpropanolamine). (C)
Cell-Mediated Reactions (Gell-Coombs Type IV)
- Contact dermatitis produced by topical drugs (eg, bacitracin, neomycin, glucocorticosteroids, local anesthetics, and antihistamines) and/or excipients contained in topical formulations is due to cell-mediated reactions. (C)
- It is postulated that Gell-Coombs type IV reactions are also responsible for some delayed cutaneous maculopapular eruptions due to oral antibiotics, such as amoxicillin and sulfonamides. (C)
- Patch testing at proper concentrations may successfully detect suspected contact allergens. (B)
- After avoidance is instituted, topical and/or systemic corticosteroids may be required for total clearing of the dermatitis (provided that these drugs were not the primary causes). (C)
Miscellaneous Syndromes
- Some drugs or classes of drugs are associated with characteristic syndromes that often do not conform to specific Gell-Coombs categories and sometimes are referred to as mixed drug reactions (ie, a mixture of immunologic mechanisms). (C)
- Many drugs, hematopoietic growth factors, cytokines, and interferons are associated with vasculitis of skin and visceral organs. (C)
- The Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a drug-induced, multiorgan inflammatory response that may be life-threatening. First described in conjunction with anticonvulsant drug use, it has since been ascribed to a variety of drugs. (C)
- Anticonvulsant hypersensitivity syndrome is mainly associated with aromatic anticonvulsant drugs and is related to an inherited deficiency of epoxide hydrolase, an enzyme required for the metabolism of arene oxide intermediates produced during hepatic metabolism. (B)
Phenytoin, carbamazepine, and phenobarbital are considered cross-reactive, but valproic acid, gabapentin, and lamotrigine are therapeutic alternatives. (C) Anticonvulsant hypersensitivity syndrome is slower in onset than DRESS and presents with skin nodules, plaques, and lymphadenopathy at times confused with lymphoreticular malignant tumors (ie, pseudolymphoma). (B) - Pulmonary manifestations of allergic drug reactions include anaphylaxis, lupus-like reactions, alveolar or interstitial pneumonitis, noncardiogenic pulmonary edema, and granulomatous vasculitis (ie, Churg-Strauss syndrome). Specific drugs are associated with different types of pulmonary reactions, such as bleomycin-induced fibrosis. (C)
- Drug-induced lupus erythematosus (DILE) can have systemic forms and predominantly cutaneous forms. Procainamide and hydralazine are the most frequently implicated drugs for systemic DILE, and antihistone antibodies are present in more than 90% of patients but occur less commonly with minocycline, propylthiouracil, and statins. (C)
- Drugs most commonly associated with cutaneous DILE include hydrochlorothiazide, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and systemic antifungal agents. Anti-Ro and
anti-SSA antibodies are usually present, whereas antihistone antibodies are much less frequent. (C) - The recognition of immunologically mediated, drug-induced granulomatous disease with or without vasculitis has increased in recent years. (C)
- Immunologic hepatitis may occur after sensitization to para-aminosalicylic acid, sulfonamides, and phenothiazines. (C)
- Erythema multiforme minor is a cell-mediated hypersensitivity reaction associated with viruses, other infectious agents, and drugs. It manifests as pleomorphic cutaneous eruptions, with target lesions being most characteristic. (C)
- There is no consensus on the distinction between erythema multiforme major and Stevens-Johnson syndrome (SJS). These disorders involve mucosal surfaces as well as the skin. (D)
- Use of systemic corticosteroids for treatment of erythema multiforme major or SJS is controversial. (D)
- Toxic epidermal necrolysis ([TEN], ie, Lyell syndrome) is distinguished from SJS by the extent of epidermal detachment. (D)
- Systemic corticosteroids are associated with increased mortality
when used for the management of advanced TEN. (C) Treatment with high-dose intravenous immunoglobulin is controversial. (D) - Manage TEN in a burn unit. (D)
- Serum sickness-like reactions caused by cephalosporins (especially cefaclor) usually are due to altered metabolism of the drug, resulting in reactive intermediates. (B)
- Immunologically mediated nephropathies may present as interstitial nephritis (such as with methicillin) or as membranous glomerulonephritis (eg, gold, penicillamine, and allopurinol). (C)
Other Classification Systems for Drug Allergy
- In addition to Gell-Coombs hypersensitivity reactions, there are a number of other mechanistic and clinical classifications for drug allergy. (C)
- The p-i concept (pharmacologic interaction with immune receptors) is a new classification of drug hypersensitivity in which a drug binds noncovalently to a T-cell receptor, which may lead to an immune response via interaction with a major histocompatibility complex receptor. (C)
- From a clinical standpoint, the most practical method of classifying drug reactions is by indicating the various tissue and organ systems affected. (D)
- The structural characteristics of drugs and biological products may permit predictions about what type of hypersensitivity reactions to expect from certain classes of therapeutic substances. (C)
Table 1. Drug Allergic Reactions and Syndromes
| Type | Clinical Manifestations | Examples of Causative Agents |
|---|---|---|
| IgE mediated | Urticaria, angioedema, bronchospasm, anaphylaxis | β-Lactam antibiotics, platinum-based chemotherapeutics, perioperative agents |
| Cytotoxic | Hemolytic anemia, thrombocytopenia, granulocytopenia | Penicillin, quinine, sulfonamides |
| Immune complex | Serum sickness | Penicillin, infliximab, thymoglobulin |
| Delayed type hypersensitivity | Contact dermatitis, exanthems | Neomycin, glucocorticoids, penicillin, sulfonamide antibiotics |
| Hypersensitivity vasculitis | Cutaneous or visceral vasculitis | Hydralazine, penicillamine, propylthiouracil |
| DRESS | Cutaneous, fever, eosinophilia, hepatic dysfunction, lymphadenopathy | Anticonvulsants, sulfonamides, minocycline, allopurinol |
| Pulmonary drug hypersensitivity | Pneumonitis, fibrosis | Nitrofurantoin, bleomycin, methotrexate |
| Systemic DILE | Arthralgias, myalgias, fever, malaise | Hydralazine, procainamide, isoniazid |
| Cutaneous DILE | Erythematous/scaly plaques in photodistribution | Hydrochlorothiazide, calcium channel blockers, ACE inhibitors |
| Drug-induced granulomatous disease | Churg-Strauss syndrome, Wegener’s granulomatosis | Propylthiouracil, leukotriene modifiers |
| Immunologic hepatitis | Hepatitis, cholestatic jaundice | Para-aminosalicylic acid, sulfonamides, phenothiazines |
| Blistering disorders | Erythema multiforme, SJS, TEN | Sulfonamides, cephalosporins, imidazole anticonvulsants, NSAIDs |
| Serum sickness-like reactions | Erythema multiforme, arthralgias | Cefaclor, cefprozil |
| Immunologic nephropathy | Interstitial nephritis, membranous glomerulonephritis | Penicillin, sulfonamides, gold, penicillamine, allopurinol |
Table 2. Classification of Adverse Reactions to Biologics
Type of Adverse Reaction and Example
- High dose
- Cytokine release syndrome
- Hypersensitivity
- Delayed infusion reactions
- Secondary immunodeficiency
- Tuberculosis with anti-TNF
- Autoimmunity
- SLE or vasculitis
- Atopic disorders
- Atopic dermatitis
- Cross-reactivity
- Acne from anti-epidermal growth factor receptor
- Nonimmunologic adverse effects
- Depression from interferons
Diagnosis and Assessment
Risk Factors
- The most important risk factors for drug hypersensitivity may be related to the chemical property and molecular weight of drugs. (C)
- Other drug-specific risk factors for drug hypersensitivity include the dose, route of administration, duration of treatment, repetitive exposure to the drug, and concurrent illnesses (eg, Epstein-Barr virus infection and amoxicillin rash). (C)
- Host risk factors for drug hypersensitivity include age, sex, atopy, underlying diseases (such as lupus erythematous and human immunodeficiency virus [HIV]), and specific genetic polymorphisms. (C)
Clinical Evaluation and Diagnosis of Drug Allergy
- The history should focus on previous and current drug use and the temporal sequence of events between initiation of therapy and onset of symptoms. (C)
- Physical examination should include all systems that could possibly account for the clinical presentation. (C)
- Cutaneous manifestations are the most common presentation for drug allergic reactions. Characterization of cutaneous lesions is important in regard to determining the cause, further diagnostic tests, and management decisions. (C)
- Numerous cutaneous reaction patterns have been reported in drug allergy, including exanthems, urticaria, angioedema, acne, bullous eruptions, fixed drug eruptions, erythema multiforme, lupus erythematosus, photosensitivity, psoriasis, purpura, vasculitis, pruritus, life-threatening cutaneous reactions such as SJS, TEN, exfoliative dermatitis, and DRESS. (C)
- Possible laboratory tests might include but are not limited to a chest x-ray examination, electrocardiography, a complete blood cell count with differential, sedimentation rate or C-reactive protein, autoantibody tests, and specific immunologic tests. (C)
- The most useful test for detecting IgE-mediated drug reactions caused by penicillin and many large-molecular-weight biologicals is immediate hypersensitivity skin testing. (B)
- Specialized immunologic tests are sometimes able to confirm the immunologic basis of drug-induced cytotoxic reactions. (B)
- Drug patch testing may be useful for certain types of cutaneous drug reactions—including maculopapular exanthems, acute generalized exanthematous pustulosis, and fixed drug eruptions—but generally is not helpful for SJS or urticarial eruptions. The lack of standardization of reagent concentrations may limit the clinical usefulness of drug patch testing. (B)
- Lymphocyte proliferation assays may have utility as retrospective indicators of cell-mediated drug reactions, but their positive and negative predictive values have not been determined and they are not available in most medical centers. (C)
- In complex cases where multiple drugs are involved without a clear-cut temporal relationship, a skin biopsy may be useful in suggesting a drug-induced eruption. However, there are no absolute histologic criteria for the diagnosis of drug-induced eruptions, and a skin biopsy may not definitively exclude alternative causes. (C)