What is Drug Hypersensitivity?
A drug hypersensitivity reaction (DHR) is an adverse effect of a drug that is mediated by the immune system [1.5.4]. It's different from a drug's predictable side effects or toxicity. These reactions are unpredictable and occur only in susceptible individuals [1.9.1]. While many people report drug allergies, true immunologically-proven allergies represent only about 5% to 10% of all adverse drug reactions [1.4.2]. The immune system mistakenly identifies a harmless drug, or a metabolite of the drug, as a threat. In response, it launches an attack that can manifest in numerous ways, affecting the skin, respiratory system, or multiple organs simultaneously. The skin is the most commonly affected organ in DHRs [1.6.4, 1.7.4].
The Gell and Coombs Classification: Four Types of Reactions
Drug hypersensitivity reactions are often categorized using the Gell and Coombs classification system, which describes four main types of immune responses [1.5.4].
Type I: Immediate (IgE-Mediated) Reactions
These are the fastest and often most severe reactions, occurring within minutes to a few hours of drug exposure [1.5.4]. They are mediated by Immunoglobulin E (IgE) antibodies, which bind to mast cells and basophils. Upon re-exposure to the drug, these cells release histamine and other inflammatory mediators [1.5.4, 1.8.4].
- Clinical Manifestations: Urticaria (hives), angioedema (swelling), bronchospasm, and in the most severe cases, anaphylaxis—a life-threatening reaction causing difficulty breathing, a sharp drop in blood pressure, and potential loss of consciousness [1.5.4, 1.6.2].
Type II: Cytotoxic Reactions
In Type II reactions, IgG or IgM antibodies are directed at a drug that has coated the surface of cells, such as red blood cells [1.5.4]. This targets the cell for destruction by the immune system.
- Clinical Manifestations: These reactions are variable in onset and can lead to conditions like drug-induced hemolytic anemia (destruction of red blood cells), neutropenia (low white blood cells), or thrombocytopenia (low platelets) [1.5.4, 1.10.3].
Type III: Immune Complex Reactions
These reactions occur when drug-antibody complexes (antigen-antibody pairings) are deposited in tissues like blood vessels, joints, and kidneys. This deposition activates the complement system, leading to inflammation and tissue damage [1.5.4].
- Clinical Manifestations: Symptoms typically appear one to three weeks after drug exposure and can include fever, rash, joint pain (arthralgia), and swollen lymph nodes, a syndrome known as serum sickness [1.5.4, 1.6.2]. Vasculitis (inflammation of blood vessels) can also occur [1.5.4].
Type IV: Delayed (T-Cell-Mediated) Reactions
Unlike the other types, Type IV reactions are not mediated by antibodies but by T-cells. They are delayed, typically occurring 2 to 7 days after exposure [1.5.4]. T-cells recognize the drug and release cytokines that cause inflammation and tissue damage [1.5.5].
- Clinical Manifestations: The most common manifestation is a maculopapular rash [1.5.4]. However, this category also includes severe cutaneous adverse reactions (SCARs) like Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN), which are rare but can be life-threatening [1.6.2, 1.9.2].
Common Drugs That Cause Hypersensitivity
While almost any drug can cause an allergic reaction, some classes are more frequently implicated than others [1.3.1, 1.4.3].
Antibiotics
- Penicillins and Related Drugs: This class, including penicillin, amoxicillin, and ampicillin, is the most common cause of drug allergies [1.3.1, 1.4.4, 1.4.5]. Although about 10% of people report a penicillin allergy, over 90% are not truly allergic upon evaluation [1.8.3]. True IgE-mediated reactions are rare, but can cause anaphylaxis [1.8.4].
- Sulfa Drugs (Sulfonamides): This class of antibiotics, such as sulfamethoxazole-trimethoprim (Bactrim), is another frequent cause of hypersensitivity [1.3.1, 1.10.4]. Reactions are most often delayed skin rashes, but severe conditions like SJS can also occur [1.10.1, 1.10.3]. Patients with HIV have a significantly higher risk of reacting to sulfa drugs [1.10.4].
Pain Relievers (NSAIDs)
Non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, ibuprofen, and naproxen are common triggers [1.3.2, 1.4.3]. NSAID reactions can be complex and are divided into different types:
- Cross-Reactive: The mechanism is often not truly allergic but related to the drug's inhibition of the COX-1 enzyme [1.9.1]. This can exacerbate underlying conditions, leading to NSAID-exacerbated respiratory disease (NERD) in patients with asthma or NSAID-exacerbated cutaneous disease (NECD) in those with chronic hives [1.9.2].
- Selective: These are true allergic reactions to a single NSAID, which can cause hives, angioedema, or anaphylaxis [1.9.2].
Other Notable Drug Classes
- Anticonvulsants: Medications used to treat seizures, such as carbamazepine, phenytoin, and lamotrigine, are well-known causes of severe delayed hypersensitivity reactions, including DRESS and SJS/TEN [1.3.5, 1.4.5, 1.5.5].
- Chemotherapy Agents: Platinum-based drugs (cisplatin, carboplatin) and taxanes are frequently associated with hypersensitivity [1.11.1, 1.11.4]. Reactions to platinum agents often occur after multiple cycles of therapy, suggesting a classic sensitization process, while taxane reactions can happen on the first or second infusion [1.11.1, 1.11.3].
- Anesthetics: Both local and general anesthetics can cause allergic reactions, although they are rare [1.3.2, 1.4.5].
- Radiocontrast Media: The dyes used in some imaging tests (like CT scans) can cause allergy-like (pseudoallergic) reactions that are not IgE-mediated but mimic them clinically [1.3.2, 1.5.4].
Comparison of Hypersensitivity Reaction Types
| Feature | Type I (Immediate) | Type II (Cytotoxic) | Type III (Immune Complex) | Type IV (Delayed) |
|---|---|---|---|---|
| Mediator | IgE Antibodies | IgG, IgM Antibodies | IgG, IgM Immune Complexes | T-Cells |
| Onset | Minutes to hours [1.5.4] | Variable [1.5.4] | 1 to 3 weeks [1.5.4] | 2 to 7 days, sometimes longer [1.5.4, 1.6.1] |
| Mechanism | Mast cell degranulation, histamine release [1.5.4] | Cell surface antigen binding, lysis [1.5.4] | Complex deposition, complement activation [1.5.4] | Activated T-cells release cytokines, inflammation [1.5.4] |
| Examples | Anaphylaxis, Urticaria, Angioedema [1.6.2] | Hemolytic Anemia, Thrombocytopenia [1.5.4] | Serum Sickness, Vasculitis, Drug Fever [1.6.2] | Contact Dermatitis, Maculopapular Rash, SJS/TEN [1.6.2] |
Diagnosis and Management
Diagnosis begins with a detailed clinical history, focusing on the timeline between drug administration and symptom onset [1.7.2, 1.7.4]. For immediate (Type I) reactions, skin testing (prick and intradermal) is the primary diagnostic tool, especially for penicillin [1.7.2, 1.8.3]. For delayed (Type IV) reactions, a patch test may be used [1.7.2, 1.7.4]. In some cases, a carefully supervised oral drug challenge is performed to confirm or rule out an allergy [1.7.2, 1.7.4].
The most critical management step is to stop the offending drug [1.6.1].
- Mild reactions like hives can be treated with antihistamines and sometimes corticosteroids [1.6.3].
- Severe reactions like anaphylaxis require immediate administration of epinephrine [1.7.4].
- Severe cutaneous reactions (SJS/TEN) require hospitalization and intensive supportive care [1.6.5].
If a patient must take a drug they are allergic to, a procedure called desensitization can be performed. This involves administering gradually increasing doses of the medication under close medical supervision to induce temporary tolerance [1.6.1, 1.10.4].
Conclusion
Drug hypersensitivity is a complex immune response that can be triggered by a wide range of medications, most notably antibiotics and NSAIDs. These reactions are classified into four types based on their underlying immunological mechanism, each with a distinct clinical presentation and timeline. Recognizing the signs of a reaction, identifying the culprit drug, and seeking prompt medical attention are essential for patient safety. Proper diagnosis through methods like skin testing can help clarify a patient's allergy status, preventing the unnecessary avoidance of first-line drugs and ensuring optimal treatment.
