A hypersensitivity reaction (HSR) is an exaggerated and/or pathological immune response to exogenous or endogenous substances. HSRs are commonly classified into four types. (e.g., food and pollen allergies, asthma, anaphylaxis) are immediate allergic reactions. (e.g., autoimmune hemolytic anemia, Goodpasture syndrome) are cytotoxic; tissue-specific antibodies cause destruction of cells in these tissues. (e.g., many vasculitides and glomerulonephritides) are immune complex-mediated; tissue damage is caused by antigen-antibody complex deposition. (e.g., TB skin tests, contact dermatitis) are delayed and cell-mediated and are the only HSRs that involve sensitized T lymphocytes rather than antibodies. In practice, many hypersensitivity syndromes are mixed reactions, meaning that they do not fit into a single reaction type. Nonallergic HSRs (e.g., pseudoallergies) are caused by mast cell activation and histamine release after the first exposure to a trigger substance (e.g., radiocontrast media).
- Hypersensitivity reaction: an exaggerated and/or pathological immune response to foreign or self antigens 
- Allergy: an abnormal immunological response to an otherwise harmless environmental stimulus (e.g., food, pollen, animal dander)
- Autoimmune disease: an abnormal immunological response directed against self-antigens
- Drug hypersensitivity reaction: group of adverse drug effects that resemble an allergy (may be allergic or nonallergic) 
- antigen: initial asymptomatic contact with an
- Effect: harmful immune response following subsequent antigen contact
- Traditionally categorized into four types based on immunological mechanisms
- Reactions may be heterogeneous (i.e., syndromes do not fit into a single category). 
|Hypersensitivity classification |
|Summary of pathophysiology||Examples|
|Type I: immediate|| |
|Type II: cytotoxic|
|Type III: immune complex|
Type IV: delayed (T-cell mediated)
|* Autoantibodies present|
All four types of HSRs can be drug-induced.
Type I and IV HSRs most commonly manifest cutaneously. 
To remember the HSRs, think ACID: A – Allergic/Anaphylactic/Atopic (Type I); C – Cytotoxic (Type II); I – Immune complex deposition (Type III); D – Delayed (Type IV).
- Type I hypersensitivity reactions are referred to as “immediate reactions.”
- Antibody-mediated; include anaphylactic and atopic immune responses
- See “type I hypersensitivity.” for specific causes of
- IgE is formed as a result of prior sensitization (i.e., previous contact with the antigen) and coats mast cells and basophils.
- Subsequent encounter with antigen results in an IgE-mediated reaction by preformed IgE antibodies: free antigen binds to two adjacent IgE antibodies (crosslinking) → degranulation of cells
- Release of histamine and other mediators (e.g., prostaglandin, platelet-activating factor, leukotrienes, heparin, tryptase), leading to:
- Mast cell secretion of cytokines and other proinflammatory mediators → eosinophil and neutrophil chemotaxis → late-phase reaction → inflammation and tissue damage
Type I is Fast and Furious.
Cross-reactive hypersensitivity 
- Description: Individuals with allergies may also react to substances that contain particles that are similar to the main antigen.
Examples (primary allergen – cross-reactant allergen)
- Pollen – various foods (e.g., apple, hazelnut, carrot, kiwi, apricots, peaches)
- Mites – crustaceans
- Latex – exotic fruits (e.g., banana, avocado, kiwi)
- Bird dander – egg yolk
- Cat dander – pork
- Immediate reaction: allergic reaction within minutes of contact with the antigen
- Late-phase reaction: occurs hours after immediate reaction for a duration of 24–72 hours
- ; : pruritus, edema, rash, rhinitis, bronchospasm, and abdominal cramping
- : due to mast cell activation in the dermis and/or subcutaneous tissue
- Well-circumscribed, raised, pruritic, and erythematous plaques with a round, oval, or serpiginous shape
- Up to several centimeters in diameter (wheals)
- Caused by mast cell activation and degranulation in the superficial dermis → hyperpermeability of microvasculature → edema 
- Differential diagnosis: See “Overview of annular skin lesions.”
Allergy-specific diagnostic testing should only be obtained in patients with a clinical history consistent with a HSR; it is not intended for screening purposes.
In vivo allergy skin tests 
- Stop the following medications prior to skin testing: 
- For drug hypersensitivity reactions (DHRs): Perform 4–6 weeks after both the resolution of initial symptoms and clearance of the suspected drug. 
- Small amounts of the following substances introduced into the skin:
- Reaction should be measured:
- After 15–20 minutes for immediate reactions
- After 24 and 72 hours for nonimmediate reactions 
- Positive result 
- Skin prick test
- Scratch test
- Intradermal test
Hypersensitivity blood tests (in vitro)
- A relatively specific marker of mast cell activation
- Elevated levels indicate an increased risk of severe reactions.
- Allergen-specific IgE test (sIgE)
- Total IgE levels (nonspecific)
- Basophil activation test 
Treatment of type I hypersensitivity reactions depends on the cause of the reaction (see “ ” above).
Drug reactions: Remove the offending drug.
- Severe reactions: emergency resuscitation; see “”
- Moderate reactions (more pronounced urticaria/angioedema, fever, arrhythmia, bronchospasm): antihistamines with or without glucocorticoids
- Mild reactions (mild urticaria/angioedema, GI symptoms, tremor, palpitations, headache, cough): expectant management with or without antihistamines
- See “Drug hypersensitivity reactions."
- Emergency self‑management for patients with known allergic reactions
Preventative treatment (i.e., contact prevention and avoidance of offending agents) is the most effective form of management for allergies.
Allergen immunotherapy (desensitization)
- Type II hypersensitivity reactions, or “cytotoxic reactions,” are antibody-mediated and responsible for a number of autoimmune disorders.
- Clinical features, diagnostics, and treatment depend on the underlying etiology (see “” above).
- Distribution of disease: often limited to a particular tissue type
- Diagnosis may involve autoantibody testing (see “ ”) and the .
- Cellular destruction
- Impaired cellular function
- Type III hypersensitivity reactions, also referred to as immune complex reactions, are antibody-mediated.
- Clinical features, diagnostics, and treatment depend on the underlying etiology (see “” above).
- Distribution of disease: systemic
- Antigen (e.g., the molecules of a drug in circulation) binds to IgG to form an immune complex (antigen-antibody complex)
- Immune complexes are deposited in tissue, especially blood vessels → initiation of complement cascade → release of lysosomal enzymes from neutrophils → cell death → inflammation → vasculitis
- Systemic lupus erythematosus (e.g., lupus nephritis, hypertension, thrombosis)
- Serum sickness and serum sickness-like reactions
- Arthus reaction
- A local subacute type III hypersensitivity reaction.
- Typically caused by vaccination against tetanus and/or diphtheria. 
Intradermal antigen injection in a presensitized individual (previously exposed to the antigen, with preformed, antigen-specific IgG in the serum) → formation of antigen-antibody complexes in the skin → complement activation → local inflammation and possibly necrosis
- Localized swelling, erythema, hemorrhage
- Occasional superficial skin necrosis a few hours after booster vaccination
- The reaction typically peaks after 12–36 hours.
Differential diagnoses 
- Injection site reaction unrelated to hypersensitivity
- Shoulder injury related to vaccine administration
- Increased tetanus and diphtheria antibody levels in the serum support the diagnosis.
- Consider skin biopsy to rule out differential diagnoses. 
- The reaction is self-limited.
- Symptomatic relief of swelling (e.g., cold compresses, NSAIDs, limb elevation)
- Reaction to tetanus toxoid: Observe a 10-year interval between tetanus toxoid-containing vaccines.
- Reaction to diphtheria toxoid: Administer tetanus toxoid rather than Tdap vaccine.
- Type IV hypersensitivity reactions are delayed and cell-mediated.
- See “type IV hypersensitivity.” for the specific causes of
- Clinical features, diagnostics, and treatment depend on the underlying etiology.
- T cell sensitization: skin penetration by the antigen → uptake of the antigen by Langerhans cell → migration to lymph nodes → formation of sensitized T lymphocytes
- Presensitized T cell response (after repeated contact with the antigen)
- Severe cutaneous adverse reactions (SCAR)
- Exanthematous drug eruption: morbilliform rash on the trunk and proximal extremities
- Allergic contact dermatitis: local drug reaction following topical application of drug
- Skin tests
- Description: : an IgE-independent reaction that is clinically indistinguishable from type I hypersensitivity
- Substances cause direct (or complement-mediated in case of anaphylactoid reaction) mast cell activation and subsequent release of histamine not mediated by immunoglobulin.
- In contrast to true anaphylactic reactions, no sensitization to allergens is required (i.e., first contact can already lead to anaphylactic shock)
- Clinical features: urticaria, pruritus, edema, hypotension, or even symptoms of anaphylactic shock
- Diagnostics: clinical diagnosis
- Pathophysiology: mast cell activation and subsequent release of histamine, most likely IgE-independent
- Clinical features: See “
- Diagnostics: clinical diagnosis based on physical examination and patient history
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