Last updated: October 26, 2022 SummaryA 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.” OverviewStages- Sensitization (immunology): initial asymptomatic
contact with an antigen
- Effect: harmful
immune response following subsequent
antigen contact
Classification
Hypersensitivity classification [3][4] |
---|
| Summary of pathophysiology
| Examples |
---|
Type I: immediate
| - Preformed IgE antibodies coating
mast cells and
basophils are crosslinked by contact with free
antigen.
- Cell degranulationresults in the release of
histamine and other inflammatory mediators.
| - Allergic or anaphylactic
transfusion reactions (e.g., in patients with
IgA deficiency)
[5]
- Anaphylaxis
- Drug reactions (e.g., penicillin, muscle
relaxants)
- Food allergies (e.g., nuts, shellfish, eggs, soy, wheat)
- Insect venom
allergies (e.g., bee, wasp)
- Reactions
to inhaled or other environmental allergens (e.g., dust
mites, animal dander, pollen, latex) → asthma,
allergic rhinitis,
atopy
[6]
|
---|
Type II: cytotoxic | -
IgMor
IgG antibodiesbind to
antigens on the
cells of particular tissue types.
- Complement
system activation and lysis or
phagocytosis of cells
- Antibody-dependent cell-mediated cytotoxicity (e.g., by
natural killer cells)
- Antibody interference with normal cell function
| - Destruction of cells
- Acute hemolytic transfusion reaction
-
Autoimmune hemolytic anemia
- Hemolytic disease of the fetus and newborn
- Immune thrombocytopenia
(ITP)
- Drug-induced
neutropenia and
agranulocytosis (e.g., caused by
methimazole, sulfasalazine,
trimethoprim/sulfamethoxazole)
- Pernicious anemia
- Inflammation
- Goodpasture syndrome
- Rheumatic fever
- Hyperacute transplant rejection
- Impaired cellular function
- Graves disease
- Bullous pemphigoid
- Pemphigus vulgaris
- Myasthenia gravis
|
---|
Type III: immune complex
| - IgG antibodies bind to circulating
antigens.
-
Immune complexformation and deposition in particular tissues
- Deposits in tissue activate the complement system and attract
neutrophils
- Neutrophilic lysis or
phagocytosis of cells
| - Serum sickness
-
Serum sickness-like reaction (atypical without circulating immune-complex involvement)
- Arthus reaction
- Drug-induced
hypersensitivity vasculitis
-
Hypersensitivity pneumonitis
- Polyarteritis nodosa
(PAN)
- Poststreptococcal glomerulonephritis
- IgA nephropathy
- Membranous
nephropathy
- Systemic lupus erythematosus
(SLE)
|
---|
Type IV: delayed (T-cell mediated) | - Contact of
antigen with presensitized
T lymphocytes
- Presensitized
CD4+ T cells recognize
antigens on
antigen-presenting cells → release of inflammatory
cytokines → activation of
macrophages
- Presensitized
CD8+ T cells recognize
antigens on somatic cells → cell-mediated cytotoxicity
| - Acute and chronic transplant rejection
- Graft-versus-host disease
-
Contact dermatitis (e.g.,
nickel, poison ivy, rubber
gloves, cosmetics)
- Mantoux tuberculin skin testfor
latent tuberculosis
- Candida skin test
- Drug reactions, including:
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
-
Drug reaction with eosinophilia and systemic symptoms
(DRESS)
- Multiple sclerosis
- Hashimoto's thyroiditis*
- Rheumatoid arthritis*
-
Type 1 diabetes mellitus*
| * Autoantibodies present
|
---|
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 reactionOverview
- 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]
-
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]
- 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]
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
TreatmentTreatment 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
reactionOverview- 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.
PathophysiologyIgM 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
reactionOverview-
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 reactionType IV
hypersensitivity reactionOverview- 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.
PathophysiologyCompared 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 hypersensitivityPseudoallergy- 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
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What type of hypersensitivity reaction is delayed?
Type IV hypersensitivity, often called delayed-type hypersensitivity, is a type of hypersensitivity reaction that takes several days to develop. Unlike the other types, it is not humoral (not antibody-mediated) but rather is a type of cell-mediated response.
Type I, II and III hypersensitivity reactions are known as immediate hypersensitivity reactions because they occur within 24 hours of exposure to the antigen or allergen.
Type I hypersensitivity is also known as an immediate reaction and involves immunoglobulin E (IgE) mediated release of antibodies against the soluble antigen. This results in mast cell degranulation and release of histamine and other inflammatory mediators.
What are Type 1 hypersensitivity reactions?
Type I hypersensitivities include atopic diseases, which are an exaggerated IgE mediated immune responses (i.e., allergic: asthma, rhinitis, conjunctivitis, and dermatitis), and allergic diseases, which are immune responses to foreign allergens (i.e., anaphylaxis, urticaria, angioedema, food, and drug allergies).
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