Overview
- Immune system
- An integral system of cells and their products that recognizes, attacks, and destroys potentially harmful entities to the health of an individual
- Provides normal protective immune response against pathogens
- Hypersensitivity reaction
- A “hyper” or exaggerated immune response to what should be seen as harmless environmental antigens
- Types I, II, and III are immediate reactions occurring within 24 hours.
- Type IV reaction develops over several days.
- Type I hypersensitivity reaction (atopy/type I immediate hypersensitivity reaction): involves immunoglobulin E (IgE)-mediated mast cell and basophil degranulation on reexposure to an antigen
- Allergy: an abnormal adaptive immune response that may or may not involve antigen-specific IgE
Epidemiology and Etiology
Epidemiology
- Lifetime prevalence: 15% worldwide
- In the United States:
- Allergies are the 6th-leading cause of chronic illness.
- Asthma, a form of airway hyperresponsiveness, accounts for over 500,000 hospitalizations each year.
- Allergic diseases have increased over the past half-century, partly from lifestyle changes (improved hygiene → reduced exposure to allergens early in life) and pollution.
Etiology
- Genetic predisposition:
- No single dominant gene for allergy
- Certain genes involved in the specific immune response (FcεR1 [high-affinity IgE receptor], IL-4 [interleukin 4], and other cytokines; CD14 [cluster of differentiation 14], HLA-DR [human leukocyte antigen-DR], Th1/Th2 [T-helper 1 and 2 cells] differentiation) contribute to the development of allergies.
- Environment:
- Allergen exposure
- Increased air pollution
- Bacterial and viral infection
- Lifestyle: nutrition, hygiene, pet ownership
Pathophysiology
Sensitization stage
- Asymptomatic; 1st antigen exposure
- Allergen is recognized by antigen-presenting cells → presented to naive T cells → T cells differentiate into Th2 cells
- Th2 cells release interleukins (IL-4, IL-5, IL-13) → switches B cells to increase IgE antibody production → IgE antibodies bind to mast cells and basophils (via FcεRI receptors)
Reaction or effector stage
- Mast cells and basophils are now bound with antigen-specific IgE antibodies ready to respond on antigen re-exposure.
- Early-phase reaction:
- Occurs within minutes
- May be a local or systemic reaction
- IgE-bound mast cell and basophil degranulation releasing mediators cause symptoms
- Histamine: vasodilation, bronchial smooth muscle contraction, increased mucus secretion, increased vessel permeability
- Prostaglandin: pulmonary smooth muscle contraction, platelet aggregation
- Platelet-activating factor: platelet aggregation, vasodilation
- Leukotrienes: bronchial smooth muscle contraction, increased vessel permeability, mucus production
- Late-phase reaction:
- Occurs 4–12 hours later, peaking at 6–9 hours
- Eosinophils (predominant) and other leukocytes migrate to allergen-contaminated tissue
Causes
- Drugs (most commonly) (e.g., penicillin, cephalosporins, muscle relaxants, anesthetics)
- Medications cause the most allergy-related deaths.
- Food (e.g., nuts, shellfish, eggs, soy, wheat, cow’s milk)
- Insect venom (e.g., bee and wasp venom)
- Environmental allergens (e.g., dust mites, animal dander, pollen, grass, latex)
Pathophysiology of type 1 hypersensitivity:
1. Antigen-presenting cells (APC) recognize the allergen and presents to naive T cells
2. T cells differentiate into Th2 which release the interleukins.
3. Interleukins stimulate the B cells to produce IgE.
4. Antigen-specific IgE binds to mast cells and basophils.
5. Subsequent exposure to the same antigen leads to degranulation and release of mediators.
TCR: T cell receptor
Mast cells are involved in allergy. Allergies such as pollen allergy are related to the antibody known as IgE. Like other antibodies, each IgE antibody is specific; one acts against oak pollen, another against ragweed.
Image by Lecturio.Types of hypersensitivity
| Type I | Type II | Type III | Type IV |
|---|---|---|---|
| IgE-mediated hypersensitivity | IgG-mediated cytotoxic hypersensitivity | Immune complex-mediated hypersensitivity | Cell-mediated hypersensitivity |
| IgE is bound to mast cells via its fragment crystallizable (Fc) portion. When an allergen binds to these antibodies, crosslinking of IgE induces degranulation. | Cells are destroyed by bound antibody, either by activation of complement or by a cytotoxic T cell with an Fc receptor for the antibody (antibody-dependent cellular cytotoxicity). | Antigen-antibody complexes are deposited in tissues, causing activation of complement, which attracts neutrophils to the site. | Th1 cells secrete cytokines, which activate macrophages and cytotoxic T cells and can cause macrophage accumulation at the site. |
| Causes localized and systemic anaphylaxis; seasonal allergies including hay fever; food allergies, such as those to shellfish and peanuts; hives; and eczema. | Red blood cells are destroyed by complement and antibody during a transfusion of mismatched type or during erythroblastosis fetalis. | The most common forms of immune complex disease include glomerulonephritis, rheumatoid arthritis, and systemic lupus erythematosus. | The most common forms are contact dermatitis, tuberculin reaction, diabetes mellitus type I, multiple sclerosis, and rheumatoid arthritis. |
Type 1 hypersensitivity
Image: “Figure 1” by Phil Schatz. License: CC BY 4.0, edited by Lecturio.
Type 2 hypersensitivity
Image: “Figure 1” by Phil Schatz. License: CC BY 4.0, edited by Lecturio.
Type 2 hypersensitivity
Image: “Figure 1” by Phil Schatz. License: CC BY 4.0, edited by Lecturio.
Type 3 hypersensitivity
Image: “Figure 1” by Phil Schatz. License: CC BY 4.0, edited by Lecturio.
Type 4 hypersensitivity
Image: “Figure 1” by Phil Schatz. License: CC BY 4.0, edited by Lecturio.
Clinical Features
Localized allergic reaction
- Rashes or blisters in the skin, pruritus (hives, atopic dermatitis, eczema)
- Increased eye and nasal secretions, itching, sneezing (allergic rhinitis/hay fever, allergic conjunctivitis)
- Oropharyngeal mucosal edema (food allergies)
- Bronchospasm, wheezing (bronchial asthma)
- Gastrointestinal abnormalities such as abdominal pain, diarrhea, vomiting (food allergies)
Systemic reaction/anaphylaxis
- Anaphylaxis is a severe, life-threatening systemic hypersensitivity reaction occurring within minutes of exposure to an allergen.
- A medical emergency: fatal without immediate treatment!
- Rapid in onset but the course can be biphasic (symptoms seem to resolve then return 1–3 hours later with the same severity)
- Large quantities of inflammatory mediators released → rapid systemic vasodilation and vascular permeability → hypotension and extensive tissue edema → fluid in the lungs and constriction of airways → shortness of breath and lethal suffocation → cardiovascular collapse and loss of consciousness
- Treatment: immediate administration of epinephrine to reverse bronchoconstriction and vasodilation
| Anaphylactic symptoms | Effects of histamine |
|---|---|
| Rhinitis, conjunctivitis | Peripheral vasodilation, increased vascular permeability, increased mucus secretion |
| Erythema | Accumulation of blood in the capillary bed from vasodilation |
| Pulmonary edema, angioedema, hypotension | Fluid shift into the stroma from increased vessel permeability, vasodilation |
| Pruritus, urticaria, or hives | Fluid extravasation into dermis; increase trigger of skin sensory nerves (itch) |
| Bronchospasm, bronchoconstriction | Bronchial smooth muscle contraction, increased mucus secretion |
Diagnosis
Skin testing
- Advantages:
- Results available within 15–20 minutes
- Less costly
- Patients can see the reactions, which helps them understand their allergies.
- Contraindications:
- Recent anaphylactic event
- Medications that may interfere with testing (e.g., H1 and H2 blockers, tricyclic antidepressants, prednisone) or treatment of anaphylaxis (e.g., beta-blockers)
- Individuals with high risk of anaphylaxis (history of immediate anaphylaxis, uncontrolled asthma, significant cardiovascular disease, frail elderly, pregnant)
- Test methods:
- Skin prick test (positive test is a wheal ≥ associated histamine control or > 3 mm)
- Scratch test (rarely used)
- Intradermal method: injection of allergen into skin
In vitro testing
- Advantages:
- Does not pose a risk of allergic reaction, so suitable for high-risk individuals
- Not affected by patient medications
- Not reliant on skin condition
- Disadvantages:
- Expensive
- In case of total IgE level, low or normal levels do not exclude allergy status; inciting allergen is also not specified.
- Tests:
- Immunoassays for allergen-specific IgE: available for food, insect venom, environmental allergen, latex, drugs
- Total IgE level: Patients with allergic conditions often have higher levels, but the result does not indicate to which specific allergen.
Management
Localized reaction
- Avoid triggering allergen
- Patients need to wear a MedicAlert bracelet that notes the possibility of anaphylaxis.
- Therapeutic options:
- H1 blockers/antihistamines
- Inhaled bronchodilators (albuterol) and inhaled corticosteroids for asthma
- Intranasal glucocorticoids or intranasal mast cell stabilizer for allergic rhinitis
- Vasoconstrictor/antihistamine ophthalmic drops for allergic conjunctivitis (for short-term or episodic use)
- Oral glucocorticoids for systemic symptoms of an allergic reaction/asthma (for short-term use)
- Leukotriene receptor antagonist (montelukast) for asthma and allergic rhinitis
- Anti-IgE immunotherapy (omalizumab) for severe asthma
- Allergy immunotherapy (AIT)
- Desensitization or hypo-sensitization
- Subcutaneous or sublingual delivery
- Alters abnormal immune response
- Highly effective for allergic rhinitis/conjunctivitis and allergic asthma
Anaphylaxis
- Epinephrine 0.3–0.5 mg intramuscularly
- Dose can be repeated
- Decreases mortality rates significantly!
- Immediate intubation for impending airway obstruction
- If not intubated: oxygen support via facemask up to 10 L/min
- Intravenous fluids
- Albuterol inhalation for bronchospasm
- Refractory symptoms:
- Can add an inotropic agent (dopamine, norepinephrine)
- Atropine for any bradycardic episodes
- Glucagon for patients on beta-blockers who may not respond to epinephrine
- Adjunctive treatments:
- H1- and H2-receptor blockers
- Histamine antagonists
- H2-receptor blockers (decrease stomach acid production) potentiate effect of H1-receptor blockers
- Corticosteroid infusion
- H1- and H2-receptor blockers
