- Clinical science
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.
- 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.
|Type I: Immediate||Type II: Cytotoxic||Type III: Immune complex||Type IV: Delayed (cell-mediated)|
|Summary of pathophysiology|
|* 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)
- IgE is formed as a result of prior sensitization (i.e., contact with the antigen) and coats mast cells and basophils.
- 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
Release of histamine and other mediators (e.g., prostaglandin, platelet-activating factor, leukotrienes, heparin, tryptase) →
- Increased smooth muscle contraction + peripheral vasodilation + increased vascular permeability (→ bronchospasm, abdominal cramping and rhinitis) → hypovolemia, hypoxia
- Extravasation of capillary blood (→erythema)
- Fluid shift into the interstitial space (→ edema, pulmonary edema)
- Eosinophil and neutrophil chemotaxis induced by basophil and mast cell mediators (→ eosinophilia)
Type I is first and fast.
- Individuals with allergies may also react to substances that contain particles that are similar to the main antigen.
- Immediate reaction: allergic reaction within minutes of contact with antigen
- Late-phase reaction: occurs hours after immediate reaction for a duration of 24–72 hours
- Main symptoms: pruritus, edema, rash, rhinitis, bronchospasm, and abdominal cramping
Atopy: genetic predisposition to producing IgE antibodies against certain harmless environmental allergens (e.g., pollen, mites, molds, certain foods)
- Associated conditions: conjunctivitis, , , and
- 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 in the superficial dermis
- : due to mast cell activation in the dermis and/or subcutaneous tissue
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.
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
- Tryptase in serum (a relatively specific marker of mast cell activation): if elevated → increased risk of severe reactions
Treatment of type I hypersensitivity reactions depends on the etiology of the reaction (see the reactions above).
- Urticaria: : avoid offending agent (if known), H1-receptor blocker (e.g., cetirizine), glucocorticoids
- Mild reactions (mild urticaria/angioedema); may be treated with withdrawal of the offending drug; and monitoring ± antihistamines.
- Moderate reactions (more pronounced urticaria/angioedema) should be treated with withdrawal of the offending drug and antihistamines ± glucocorticoids.
- Severe reactions require emergency resuscitation (see ).
- 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 ).
Allergen immunotherapy (desensitization)
- 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
- 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)
- 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!
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 (). Anaphylaxis-like symptoms may also be caused by a a pseudoallergic reaction (see ).
- Skin or mucous membranes: flushing, urticaria, pruritus, erythema, swelling of the eyelids, or angioedema
- Respiratory: nasal congestion, cough, sneezing, hoarseness, chest tightness, dyspnea (due to bronchospasm or laryngeal edema)
- Cardiovascular: hypotension, tachycardia, chest pain (myocardial ischemia due to hypoxia and hypotension)
- GI: abdominal pain, nausea, and vomiting (especially in food allergies)
Criteria for diagnosis
- Acute onset (within 1 hour of exposure)
- Likely exposure to an allergen
- Reduced blood pressure after exposure to a known allergen
Treatment of anaphylaxis
- Withdrawal of offending agent if applicable (e.g., in drug reactions)
- Airway: examination of airway and intubation if obstruction seems imminent
- Epinephrine IM 0.3–0.5 mg: simultaneous and prompt administration; three doses total if necessary
- Positioning: The patient should be placed in a recumbent/supine position with elevation of the lower extremities.
- O2: 8–10 L/min by facemask
- If patient is hypotensive: volume replacement – normal saline 1–2 L IV rapid bolus
- Bronchospasm and no benefit of epinephrine: nebulized albuterol (salbutamol) 2.5–5 mg in 3 mL saline
- Methylprednisolone 125 mg IV
- Continuous monitoring of blood pressure, heart rate, heart function, and pulse oximetry; urine output should also be monitored in hypotensive patients receiving resuscitation.
- See also “Emergency (self‑)medication” in above.
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!
Type II hypersensitivity reactions are referred to as cytotoxic and play a role in many classical autoimmune diseases.
- Clinical features, diagnostics, and treatment depend on the underlying etiology (see also above).
- Distribution of disease: often limited to a particular tissue type
- Diagnosis may involve autoantibody testing (see antibody diagnosis of rheumatological diseases) and the .
- IgM and IgG bind to antigens on cells in the body mistakenly detected as foreign.
- Complement activation
- Cellular lysis or phagocytosis
Type II is cy-2-toxic.
- Clinical features, diagnostics, and treatment depend on the underlying etiology (see also the above)
- Distribution of disease: systemic
- 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
- 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
- Clinical features
- 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
- Definition: local subacute type III hypersensitivity reaction
- Pathogenesis: antigen injected intradermally (e.g., immunization) → antibody formation → antigen-antibody complexes form in skin → local inflammation and possibly necrosis
- Trigger: vaccination against tetanus, diphtheria
- Clinical findings
- Reaction is self-limited.
- Symptomatic relief of swelling (e.g., cold compresses; , limb elevation, NSAIDs)
Type III means three things stuck together: antigen + antibody + complement
Type IV hypersensitivity reactions are referred to as delayed and cell-mediated. For the specific causes of type IV hypersensitivity, see the above.
- Clinical features, diagnostics, and treatment depend on the underlying etiology.
- T cell-mediated reaction
- Sensitization: Antigen penetrates the skin → uptake by Langerhans cell → migration to lymph nodes and formation of sensitized T lymphocytes
- Eruption: Repeated contact with antigen → secretion of lymphokines and cytokines (e.g., IFNγ, TNFα) by presensitized T lymphocytes → macrophage activation and inflammatory reaction in tissue
- One of the most common dermatological diagnoses
- Prevalence of ∼ 1–6%
- First contact with allergen → sensitization
- Repeated contact with allergen → development of rash after 12–48 hours
- 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.
- 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
- Local drug reaction following topical application of drug; see
- Maculopapular or morbilliform (measles-like) drug eruption
- Stevens-Johnson syndrome and toxic epidermal necrolysis
DRESS syndrome (drug rash with eosinophilia and systemic symptoms syndrome; also known as drug-induced hypersensitivity syndrome): delayed hypersensitivity reaction to a drug (within 1 to 8 weeks)
- Clinical features
- Laboratory tests
- Drug withdrawal
- Prognosis: fatal in ∼ 10% of cases
Type IV is fourth and last (i.e., delayed)
- Definition: : an IgE-independent reaction that is clinically indistinguishable from type I hypersensitivity
- Etiology: radiocontrast media, narcotics, vancomycin, NSAIDs
- Clinical presentation
- Diagnosis and treatment
- Pathophysiology: mast cell activation and subsequent release of histamine, most likely IgE-independent
- Clinical presentation: See
- Diagnosis and treatment:
The differential diagnoses listed here are not exhaustive.