Hypersensitivity Reactions Definition
Hypersensitivity reactions are objectively reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by normal individuals, representing overreactions of the immune system that can be immune-mediated (allergic) or non-immune-mediated (non-allergic). 1
Core Definition and Scope
Hypersensitivity reactions encompass a broad spectrum of adverse responses:
The fundamental definition states these are symptoms or signs objectively reproducible upon exposure to a specific stimulus at doses that normal individuals tolerate without issue 1
Allergic hypersensitivity specifically refers to reactions initiated by immune mechanisms, including IgE-mediated and T-cell mediated responses 2, 1
Non-allergic hypersensitivity involves reactions that produce similar clinical manifestations but occur through non-immune mechanisms, such as direct mast cell activation or pharmacologic effects 2, 3
Classification Framework
The Gell and Coombs classification divides immune-mediated hypersensitivity into four distinct types, all representing different forms of immune tolerance failure 1, 4:
Type I (IgE-mediated): Includes anaphylaxis and immediate allergic reactions occurring within 1 hour of exposure 1, 5
Type II (Cytotoxic): Characterized by antibody-mediated reactions such as hemolytic anemia and thrombocytopenia 1
Type III (Immune complex-mediated): Manifests as serum sickness and vasculitis 1
Type IV (T-cell mediated): Delayed reactions occurring more than 1 hour after exposure, including severe cutaneous adverse reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis 5, 6
Temporal Patterns
The timing of symptom onset provides critical diagnostic information:
Immediate reactions occur within 1 hour of drug administration and are typically IgE-mediated or result from direct mediator release 6, 7
Delayed reactions develop 1-6 weeks after drug initiation and are characteristically T-cell mediated 6, 7, 8
Most immune-mediated hypersensitivity reactions occur within several weeks of drug administration, distinguishing them from other adverse effects 7, 8
Mechanistic Considerations
Two primary pathways explain drug-induced hypersensitivity 6, 1:
Hapten-dependent pathway: Drugs or their metabolites bind to proteins, creating immunogenic complexes that trigger adaptive immune responses 6
Hapten-independent pathway: Direct T-cell activation through drug interaction with MHC-peptide or T-cell receptors without requiring metabolic conversion 6
The danger hypothesis proposes that immune responses to drug antigens require co-stimulatory signals (cytokines, cellular damage signals) to manifest as clinical hypersensitivity 6, 1
Clinical Manifestations
Hypersensitivity reactions present with diverse organ system involvement:
Cutaneous manifestations range from mild maculopapular rashes to severe blistering conditions affecting variable body surface areas 6
Respiratory symptoms include dyspnea, wheeze, bronchospasm, and stridor 2
Cardiovascular involvement presents as hypotension, tachycardia, or shock 2
Multi-system involvement with fever, eosinophilia, or organ dysfunction suggests severe reactions like DRESS syndrome 7
Important Caveats
Several critical distinctions must be recognized:
Not all adverse drug reactions are hypersensitivity reactions—many result from predictable pharmacologic effects rather than immune mechanisms 6
Pseudo-allergic reactions can mimic true hypersensitivity but occur through non-immune mechanisms like direct histamine release or bradykinin-mediated pathways 3
Multiple hypersensitivity types can occur simultaneously in the same patient, complicating diagnosis and management 4
Rechallenge with offending drugs can precipitate severe or fatal reactions, occurring much sooner than initial exposure 6