Hypersensitivity reactions

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.”

Definitions

• Hypersensitivity reaction: an exaggerated and/or pathological immune response to foreign or self antigens ^[1]
• 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) ^[2]

Stages

• Sensitization (immunology): initial asymptomatic contact with an antigen
• Effect: harmful immune response following subsequent antigen contact

Classification

• Traditionally categorized into four types based on immunological mechanisms
• Reactions may be heterogeneous (i.e., syndromes do not fit into a single category). ^[1][2]

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).

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

1. IgE is formed as a result of prior sensitization (i.e., previous contact with the antigen) and coats mast cells and basophils.
2. 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
3. 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
4. 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 ^[8][9]

• 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

Timing

• 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

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]
  • Differential diagnosis: See “Overview of annular skin lesions.”
• 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

Diagnostics ^[11]

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
  • A relatively specific marker of mast cell activation
  • Elevated levels indicate an increased risk of severe reactions.
• Allergen-specific IgE test (sIgE)
  • Indicated in patients with known allergic triggers and clinical symptoms
  • Preferable to skin testing in patients at high risk of anaphylaxis
  • Quantitatively assessed using enzyme-linked immunosorbent assay (ELISA)
• 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.
  • Severe reactions: emergency resuscitation; see “Management of anaphylaxis”
  • 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
  • Epinephrine autoinjectors, antihistamines, corticosteroids
  • Anaphylaxis emergency action plan
• Urticaria
  • Avoid trigger (if known).
  • H₁-receptor blocker (e.g., cetirizine or loratadine ) ^[16]
  • Glucocorticoids, e.g., prednisone or dexamethasone ^[16]

Preventative treatment (i.e., contact prevention and avoidance of offending agents) is the most effective form of management for allergies.

Allergen immunotherapy (desensitization)

• Indication
  • Documented IgE-mediated allergy (e.g., allergic rhinitis, allergic asthma, allergy to wasp or bee venom)
  • Significant symptoms and inadequate relief from symptomatic therapy and exposure prophylaxis
  • Significant symptoms despite symptomatic therapy and avoidance of the allergen
• Method
  • Only available for some allergens but can be quite effective
  • Application of specific antigen in subclinical dose (subcutaneous, mucosal)
  • Slow escalation of dose
  • Goal: ↑ production of IgG antibodies instead of excessive IgE production (isotype switching) ^[17]
  • Duration of treatment: at least 3 years
• Prognosis
  • Success in up to ⅔ of patients
  • Younger patients see comparatively more benefits.
  • Higher success rates in patients with sensitivity to only one allergen (monovalent) as opposed to patients with sensitivity to many allergens (polyvalent)

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:

• Cellular destruction
  • Antibody-dependent cell-mediated cytotoxicity (NK cells or macrophages)
  • Target cell opsonization → phagocytosis and/or complement activation
• Inflammation
  • Fc-receptor mediated immune cell activation
  • Antibodies bind to cellular surfaces → activation of the complement system
• Impaired cellular function
  • Antibodies bind to cell surface receptors → inhibition or activation of downstream signaling pathways → impaired cellular function

Type II is cy-2-toxic and consists of 2 components (antigen and 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

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

1. Antigen (e.g., the molecules of a drug in circulation) binds to IgG to form an immune complex (antigen-antibody complex)
2. 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
  • Polyarteritis nodosa
  • Drug-induced hypersensitivity 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

Overview ^[18][19]

• A local subacute type III hypersensitivity reaction.
• Typically caused by vaccination against tetanus and/or diphtheria. ^[19]

Pathophysiology

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

Clinical features

• Cutaneous small-vessel vasculitis ^[19]
• Localized swelling, erythema, hemorrhage
• Occasional superficial skin necrosis a few hours after booster vaccination
• The reaction typically peaks after 12–36 hours.

Differential diagnoses ^[19]

• Injection site reaction unrelated to hypersensitivity
• Abscess
• Cellulitis
• Shoulder injury related to vaccine administration

Diagnostics ^[18][19]

• Increased tetanus and diphtheria antibody levels in the serum support the diagnosis.
• Consider skin biopsy to rule out differential diagnoses. ^[19]

Treatment

• The reaction is self-limited.
• Symptomatic relief of swelling (e.g., cold compresses, NSAIDs, limb elevation)

Prevention

• 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.

Evidence of vasculitis on histology differentiates between a true Arthus reaction and an injection site reaction unrelated to hypersensitivity. ^[19]

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:

1. T cell sensitization: skin penetration by the antigen → uptake of the antigen by Langerhans cell → migration to lymph nodes → formation of sensitized T lymphocytes
2. 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, TNF α) → macrophages activation → 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

Pseudoallergy

• Description: : an IgE-independent reaction that is clinically indistinguishable from type I hypersensitivity
• Etiology
  • Radiocontrast media
  • Narcotics
  • Vancomycin, NSAIDs
• Pathophysiology
  • 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
• Treatment
  • Minor reactions
    • Avoidance of offending drug
    • Antihistamines for pruritus or urticaria
  • Pseudoallergy with anaphylactic characteristics: See “Anaphylaxis.”

Infection-induced urticaria

• Etiology
  • Viral infections (e.g., rotavirus and rhinovirus)
  • Bacterial infections (e.g., Mycoplasma pneumoniae, group A streptococcal pharyngitis)
  • Parasitic infections (e.g., Anisakis simplex infection from eating raw fish and Plasmodium falciparum)
• Pathophysiology: mast cell activation and subsequent release of histamine, most likely IgE-independent
• Clinical features: See “Urticaria.”
• Diagnostics: clinical diagnosis based on physical examination and patient history
• Treatment
  • Usually self-limited
  • Antihistamines may be given for pruritus or urticaria.

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