Last updated: October 26, 2022
Summary
A hypersensitivity reaction (HSR) is an exaggerated and/or pathological immune response to exogenous or endogenous substances. HSRs are commonly classified into four types. Type I HSRs (e.g., food and pollen allergies, asthma, anaphylaxis) are immediate allergic reactions. Type II HSRs (e.g., autoimmune hemolytic anemia, Goodpasture syndrome) are cytotoxic; tissue-specific antibodies cause destruction of cells in these tissues. Type III HSRs (e.g., many vasculitides and glomerulonephritides) are immune complex-mediated; tissue damage is caused by antigen-antibody complex deposition. Type IV HSRs (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).
See also “Anaphylaxis” and “Drug hypersensitivity reactions.”
Overview
Stages
- Sensitization (immunology): initial asymptomatic contact with an antigen
- Effect: harmful immune response following subsequent antigen contact
Classification
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All four types of HSRs can be drug-induced.
Type I and IV HSRs most commonly manifest cutaneously. [7]
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 reaction
Overview
- Type I hypersensitivity reactions are referred to as “immediate reactions.”
- Antibody-mediated; include anaphylactic and atopic immune responses
- See “Hypersensitivity classification” for specific causes of type I hypersensitivity.
Pathophysiology
- 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 preformedIgE 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:
- ↑ Smooth muscle contraction → bronchospasm, abdominal cramping
- Peripheral vasodilation and ↑ vascular permeability → hypovolemia, hypotension
- Extravasation of capillary blood → erythema
- Fluid shift into the interstitial space → edema, pulmonary edema
- Pruritus
- 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-reactivity [8][9]
Examples
- Anaphylaxis; : pruritus, edema, rash, rhinitis, bronchospasm, and abdominal cramping
- Angioedema: due to mast cell activation in the dermis and/or subcutaneous tissue
-
Urticaria
(hives)
- 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 [10]
- Atopy
- Genetic predisposition to producing IgE antibodies against certain harmless environmental allergens (e.g., pollen, mites, molds, certain foods)
- Associated conditions: asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, food allergies
- Allergic conjunctivitis
- Allergic rhinitis
- Allergic asthma
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 [12]
- Approach
- Stop the following medications prior to
skin testing: [12]
- H1-antihistamines and β-adrenergic drugs: 5-days before testing
- Glucocorticoids: Timing depends on dose and duration of use.
- For drug hypersensitivity reactions (DHRs): Perform 4–6 weeks after both the resolution of initial symptoms and clearance of the suspected drug. [12]
- Stop the following medications prior to
skin testing: [12]
-
Description
- Small amounts of the following substances introduced into the skin:
- Suspected allergen
- Histamine-containing solution: positive control (always produces wheal)
- Saline: negative control (never produces wheal)
- Reaction should be measured:
- After 15–20 minutes for immediate reactions
- After 24 and 72 hours for nonimmediate reactions [13]
- Positive result [12]
- Allergen wheal size ≥ histamine control
- OR diameter of allergen wheal increases by > 3 mm [12]
- Small amounts of the following substances introduced into the skin:
- Modalities
- Skin prick test
- An allergen solution is applied through a skin prick (e.g., of the volar forearm).
- First-line test for immediate DHRs (safest and easiest) [2]
- Scratch test
- An allergen is applied to a scratch (∼ 1 cm) on the skin.
- Comparable to prick test
- Intradermal test
- Intradermal injection of small amounts of the allergen
- Can be used to diagnose immediate and nonimmediate HSRs [2][14]
- More sensitive than skin prick test; higher risk of false positives [12]
- May lead to anaphylaxis in IgE-mediated HSRs [12]
- Skin prick test
Hypersensitivity blood tests (in vitro)
- Tryptase
- Allergen-specific IgE test (sIgE)
- Total IgE levels (nonspecific)
- Often elevated in patients with allergic conditions
- Normal serum IgE levels do not exclude allergy.
-
Basophil activation test [14][15]
- Flow cytometry is used to measure basophil degranulation following exposure to allergens and controls.
- More precise than allergen-specific IgE test
- Less invasive and lower risk than provocation tests
- Is not widely available
Treatment
Treatment of type I hypersensitivity reactions depends on the cause of the reaction (see “Hypersensitivity classification” above).
- Drug reactions: Remove the offending drug.
- Emergency self‑management for patients with known allergic reactions
- Urticaria
- Avoid trigger (if known).
- H1-receptor blocker (e.g., cetirizine)
- Glucocorticoids
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 reaction
Overview
- 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 “Hypersensitivity classification” above).
- Distribution of disease: often limited to a particular tissue type
- Diagnosis may involve autoantibody testing (see “Antibody diagnosis of autoimmune diseases”) and the Coombs test.
Pathophysiology
IgM and IgG mistakenly bind to surface antigens of the cells in the body, which results in:
Type II is cy-2-toxicand consists of 2 components (antigenand antibody)
Examples
-
Hemolysis
- Acute hemolytic transfusion reaction
- Autoimmune hemolytic anemia
- Hemolytic disease of the newborn
- Systemic disorders
- Goodpasture syndrome
- Rheumatic fever
- Myasthenia gravis
- Graves disease
- Skin
disorders
- Bullous pemphigoid
- Pemphigus vulgaris
Type III hypersensitivity reaction
Overview
- 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 “Hypersensitivity classification” above).
- Distribution of disease: systemic
Pathophysiology
- 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
To remember Type III, think of three things stuck together: antigen + antibody + complement
Examples
- Vasculitis
- Nephropathy
- Poststreptococcal glomerulonephritis
- IgA nephropathy
- Membranous nephropathy
- Rheumatoid arthritis
- Hypersensitivity pneumonitis
- Systemic lupus erythematosus (e.g., lupus nephritis, hypertension, thrombosis)
- Serum sickness and serum sickness-like reactions
- Arthus reaction
Arthus reaction
Type IV hypersensitivity reaction
Overview
- Type IV hypersensitivity reactions are delayed and cell-mediated.
- See “Hypersensitivity classification” for the specific causes of type IV hypersensitivity.
- Clinical features, diagnostics, and treatment depend on the underlying etiology.
Pathophysiology
Compared to type I-III hypersensitivity reactions, which are antibody-mediated, type IV reactions are mediated by T cells. Type IV hypersensitivity reactions involve two major steps:
- 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)
- CD4+ T cells recognize antigens on antigen-presenting cells → release of inflammatory lymphokines cytokines (e.g., IFNγ, TNFα) → macrophagesactivation →phagocytosis of target cells
- CD8+ T cells recognize antigens on somatic cells → cell-mediated cytotoxicity → direct cell destruction
To remember the specifics of type IV hypersensitivity reaction, think of the 5 Ts: T cells, Transplant rejection, TB skin tests, “Touching” (contact) dermatitis, Terminal (last; delayed).
Examples
-
Severe cutaneous adverse reactions (SCAR)
- DRESS
- Stevens-Johnson syndrome (SJS)
- Toxic epidermal necrolysis (TEN)
- Acute generalized exanthematous pustulosis (AGEP)
- Exanthematous drug eruption: morbilliform rash on the trunk and proximal extremities
- Associated symptoms include pruritus and low-grade fever
- Typical onset 5-14 days after drug exposure
- Most commonly caused by antibiotics, e.g., “ampicillin rash” following ampicillin administration for infectious mononucleosis
- Resolves after discontinuation of the offending drug
- Allergic contact dermatitis: local drug reaction following topical application of drug
-
Skin tests
- Candida skin test (to test the immune function of T cells)
- Mantoux tuberculin skin test for latent tuberculosis
- Systemic disorders
- Hashimoto thyroiditis
- Multiple sclerosis
- Type 1 diabetes mellitus
Nonallergic hypersensitivity
Pseudoallergy
- Description: : an IgE-independent reaction that is clinically indistinguishable from type I hypersensitivity
- Etiology
- Radiocontrast media
- Narcotics
- Vancomycin, NSAIDs
- Pathophysiology
- Clinical features: urticaria, pruritus, edema, hypotension, or even symptoms of anaphylactic shock
- Diagnostics: clinical diagnosis
- Treatment
References
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