• Clinical science

Hypersensitivity reactions

Abstract

Hypersensitivity reactions are a group of conditions in which the immune system, which normally serves a protective role, has a harmful effect. Both allergies and many autoimmune disorders fall under the umbrella of hypersensitivity reactions, the difference being that allergies involve an immune reaction to common substances in the environment, whereas autoimmune diseases involve a direct immune reaction to tissues within the body. Hypersensitivity reactions are commonly classified into four types: Type I hypersensitivity reactions are immediate allergic reactions (e.g., food and pollen allergies, asthma, anaphylaxis). Type II hypersensitivity reactions are referred to as cytotoxic, as they involve antibodies that are specific to particular tissues within the body and cause destruction of cells in these tissues (e.g., autoimmune hemolytic anemia, Goodpasture syndrome). Type III hypersensitivity reactions are immune complex-mediated, with tissue damage caused by antigen-antibody complex deposition (e.g., many vasculitides and glomerulonephritides). Type IV hypersensitivity (e.g., TB skin tests, contact dermatitis) reactions are delayed and cell-mediated, and are the only hypersensitivity reactions that involve sensitized T lymphocytes rather than antibodies.

Overview

  • Definitions
    • Hypersensitivity reaction: a condition in which the immune system, which normally serves a protective role, has a harmful effect
    • 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 an antigen that is actually part of the body itself
  • Hypersensitivity reactions are classified into four types by Gell and Coombs.
Hypersensitivity classification
Type I: Immediate Type II: Cytotoxic Type III: Immune complex Type IV: Delayed (cell-mediated)
Summary of pathophysiology
  • Preformed IgE antibodies coating mast cells and basophils are crosslinked by contact with free antigen
  • Cell degranulation and release of histamine and other inflammatory mediators
  • IgM and IgG antibodies bind to antigens on the cells of particular tissue types
  • Complement activation and lysis or phagocytosis of cells
  • Contact of antigen with presensitized T lymphocytes
  • Macrophage activation and inflammatory reaction in tissue
Examples
* Autoantibodies present

Drugs can cause all four types of hypersensitivity reactions!

The hypersensitivity reactions can be memorized with the mnemonic ACID: A – Allergic/Anaphylactic/Atopic (Type I); C – Cytotoxic (Type II); I – Immune complex deposition (Type III); D – Delayed (Type IV)

References:[1][2][3][4][5][6][7][8]

Type I hypersensitivity reaction

Type I hypersensitivity reactions are referred to as immediate and include anaphylactic and atopic immune responses. For the specific causes of type I hypersensitivity, see the overview of hypersensitivity reactions above.

Pathophysiology

  1. IgE is formed as a result of prior sensitization (i.e., 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)

Type I is first and fast.

Cross-reactivity

  • Individuals with allergies may also react to substances that contain particles that are similar to the main antigen.
  • Examples
    • Pollen: various foods, depending on type of pollen allergy; affects 80% of people with allergies
    • Mites: seafood
    • Latex: exotic fruits (banana, avocado, kiwi)
    • Birds : egg yolk
    • Cat : pork

Clinical findings

Diagnostics

  • In vivo skin testing
    • General principle: Small amounts of allergens (e.g., pollen) are introduced into the skin to test for a local allergic reaction.
      • Higher sensitivity may be achieved with more invasive testing. However, the more invasive the test, the higher the risk of anaphylactic shock.
      • Test results are usually available after 20 minutes.
      • Evaluation: skin reddening and size of wheals
    • Skin prick test
      • Tiny amounts of various allergens are applied to the skin ; a lancet is then used to prick the surface of the skin so that extracts may enter.
      • Positive result: wheal equal to or larger than histamine control (or greater than 3 mm)
    • Scratch test: comparable to prick test; a scratch (about 1 cm) is made and the allergen subsequently applied
    • Intradermal test: intradermal injection of small amounts of the allergen on the back or arm
  • In vitro testing
    • IgE antibodies in serum detected by immunoassay
      • Total IgE: useful as a screening test for patients with probable allergic symptoms but no known allergen
      • Allergen-specific IgE:
        • Patients with known allergic triggers
        • Patients in whom the risk of anaphylaxis is high with skin testing
    • Tryptase in serum (a relatively specific marker of mast cell activation): if elevated → increased risk of severe reactions

Treatment

Treatment of type I hypersensitivity reactions depends on the etiology of the reaction (see the overview of hypersensitivity reactions above).

  • Urticaria: : avoid offending agent (if known), H1-receptor blocker (e.g., cetirizine), glucocorticoids
  • Drug reactions
  • Emergency (self‑) medication: Patients with known allergic reactions to food or insect venom, for example, may be provided with antihistamines, corticosteroids, and epinephrine auto-injectors for self-treatment (in patients at risk of anaphylaxis).
  • 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 allergen
    • Principle
      • Only available for some allergens but can be quite effective
      • Application of specific antigen in subclinical dose (subcutaneous, mucosal)
      • Slow escalation of dose
      • Goal: increased production of IgG antibodies instead of excessive IgE production (isotype switching)
      • 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)

Prevention

  • Breastfeeding: There is conflicting data regarding the beneficial effect of breastfeeding in preventing asthma and atopic dermatitis.

Contact prevention and avoidance of offending agents is the best treatment for allergies!

References:[9][10][11][12][13][14][15][16]

Anaphylaxis

Anaphylaxis describes a potentially life-threatening acute reaction, classically of the type I hypersensitivity type, involving the sudden release of mediators from mast cells and basophils. Anaphylaxis may lead to circulatory failure (distributive shock). Anaphylaxis-like symptoms may also be caused by a a pseudoallergic reaction (see pseudoallergy).

Antihistamines and glucocorticoids should be administered in anaphylaxis only after the initial dose of epinephrine IM!

In patients presenting with sudden-onset dyspnea, hoarseness, diffuse skin changes (urticaria), swelling of the face, and/or hypotension, consider anaphylaxis as a differential diagnosis, especially if they have recently been exposed to a known allergen!
References:[17][18][19][20]

Type II hypersensitivity reaction

Type II hypersensitivity reactions are referred to as cytotoxic and play a role in many classical autoimmune diseases.

Pathophysiology

  1. IgM and IgG bind to antigens on cells in the body mistakenly detected as foreign.
  2. Complement activation
  3. Cellular lysis or phagocytosis

Type II is cy-2-toxic.

References:[1][21]

Type III hypersensitivity reaction

Type III hypersensitivity reactions are referred to as immune complex reactions and include many glomerulonephritides and vasculitides.

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 neutrophilscell deathinflammationvasculitis

Serum sickness

  • Definition
    • Serum sickness is classically a type III hypersensitivity reaction appearing as a complication of antitoxin or antivenom administration.
    • Serum sickness-like reaction is much more common than actual serum sickness. Serum sickness-like reactions are:
      • Usually caused by medications
      • Of unclear pathogenesis
      • Reactions that are so clinically similar to classic serum sickness that they are not usually differentiated from it
  • Etiology
  • Clinical features
  • Course
    • Symptoms appear 1–2 weeks following initial exposure.
    • They resolve within a few weeks of discontinuation.
  • Treatment: stop offending agent
  • Prognosis: excellent once the drug responsible is stopped

Arthus reaction

Type III means three things stuck together: antigen + antibody + complement

References:[1][21][22][23][24][7]

Type IV hypersensitivity reaction

Type IV hypersensitivity reactions are referred to as delayed and cell-mediated. For the specific causes of type IV hypersensitivity, see the overview of hypersensitivity reactions above.

  • Clinical features, diagnostics, and treatment depend on the underlying etiology.

Pathophysiology

  1. Sensitization: Antigen penetrates the skinuptake by Langerhans cellmigration to lymph nodes and formation of sensitized T lymphocytes
  2. Eruption: Repeated contact with antigen → secretion of lymphokines and cytokines (e.g., FNγ, TNFα) by presensitized T lymphocytes macrophage activation and inflammatory reaction in tissue

Allergic contact dermatitis

  • Epidemiology
    • One of the most common dermatological diagnoses
    • Prevalence of ∼ 1–6%
  • Etiology
  • Course
    • First contact with allergensensitization
    • Repeated contact with allergendevelopment of rash after 12–48 hours
  • Rash
    • Intensely pruritic, erythematous, papular
    • Vesicles and serous oozing in severe cases
    • Can spread to other parts of the body through antigen transfer by the hands or in the circulation
  • Diagnosis
    • Diagnosis is based on clinical findings.
    • Patch test: testing for specific allergens in allergic contact dermatitis
      • Allergen is fixed on a patch and then attached to the arm or back.
      • Reaction is recorded at two times: The first assessment is after 48 hours, the second after 4–5 days.
      • Positive result: erythema, papules, and vesicles under the area of contact
      • “Angry back” reaction
        • A few strong positive reactions may cause other patch tests to be falsely positive in patients with “angry backs.”
        • Mechanism unknown
        • Separate, sequential testing of allergens is necessary in these patients.
  • Treatment
    • Avoidance of the allergen is the best treatment and preventative measure.
    • Acute phase

In a patient presenting with itching, burning, red skin lesions arranged in a linear pattern appearing 24 hours after a camping trip, contact dermatitis due to poison oak, poison ivy, or poison sumac is the likely cause.

Type IV drug reactions

Type IV is fourth and last (i.e., delayed)

References:[1][1][21][25][26][27][28][29][30][31][32][33]

Differential diagnoses

Nonallergic hypersensitivity

Pseudoallergy

Infection-induced urticaria

References:[34][35][36][37][38][39]

The differential diagnoses listed here are not exhaustive.