- Clinical science
Hypersensitivity reactions occur when the normally protective immune system responds abnormally, potentially harming the body. Various autoimmune disorders as well as allergies fall under the umbrella of hypersensitivity reactions, the difference being that allergies are immune reactions to exogenous substances (antigens or allergens), whereas autoimmune diseases arise from an abnormal immune response to endogenous substances (autoantigens). A symptomatic reaction only occurs in sensitized individuals, i.e., they must have had at least one prior asymptomatic contact with the offending antigen. Hypersensitivity reactions are commonly classified into four types. 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 reactions (e.g., TB skin tests, contact dermatitis) are delayed and cell-mediated and are the only hypersensitivity reaction that involves sensitized T lymphocytes rather than antibodies. Unlike true hypersensitivity reactions, which occur after sensitization, nonallergic hypersensitivity reactions (e.g., pseudoallergies) cause mast cell activation and histamine release after initial exposure to a trigger substance (e.g., radiocontrast media).
- Hypersensitivity reaction: a condition in which the normally protective immune system has a harmful effect on the body
- 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
- Sensitization: initial asymptomatic contact with an antigen
- Effect: harmful immune response following sensitization and subsequent antigen contact
- Types: Hypersensitivity reactions are classified into four types.
|Type I: immediate||Type II: cytotoxic||Type III: immune complex||Type IV: delayed (T-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)
- 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 above.
- 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 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.
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
- 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
- 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: , , , ,
- 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
- 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
- Tryptase in serum (a relatively specific marker of mast cell activation): if elevated → increased risk of severe reactions
- Indicated in patients with known allergic triggers and clinical symptoms
- Preferable to in vivo skin testing in patients in whom the risk of anaphylaxis is high with skin testing
- Total IgE
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 by removing 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
- 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!
Symptoms: acute onset (within minutes to hours of exposure to a likely antigen)
- Skin or mucous membranes: flushing, urticaria, pruritus, erythema, swelling of the eyelids, 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)
Treatment of anaphylaxis
- Withdrawal of offending agent if possible (e.g., in drug reactions)
- Airway: examination of airway and intubation if obstruction seems imminent
- Epinephrine IM
- Positioning: The patient should be placed in a recumbent/supine position with elevation of the lower extremities.
- O2 by facemask
- If the patient is hypotensive: volume replacement – normal saline 1–2 L IV rapid bolus
- Bronchospasm and no benefit of epinephrine: nebulized albuterol (salbutamol)
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 (e.g., 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 several 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 ) and the .
IgM and IgG bind to antigens on cells in the body mistakenly detected as foreign and cause:
- Complement activation and Fc-mediated immune cell activation
- Cellular lysis or phagocytosis
- Inhibition or activation of the downstream signaling pathways
Type II is cy-2-toxic.
- Type III hypersensitivity reactions are referred to as immune complex reactions and include many glomerulonephritides and vasculitides.
- 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:
- Clinical features
- Symptoms appear 1–2 weeks following initial exposure.
- They resolve within a few weeks of discontinuation.
- Treatment: stop the offending agent
- Prognosis: excellent once the offending drug is stopped or once the causative infection has resolved clinically
- 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)
- Prevention 
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.
4 Ts associated with the type IV hypersensitivity: T cells, Transplant rejection, TB skin tests, Touching (contact dermatitis).
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, TNF α) by presensitized T lymphocytes → macrophage activation and inflammatory reaction in the tissue
- One of the most common dermatological diagnoses
- Prevalence of ∼ 1–6%
- 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: at 48 hours and 4–5 days following initial application
- 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
Contact dermatitis due to poison oak, poison ivy, or poison sumac is the most likely cause in a patient presenting with itching, burning, red skin lesions arranged in a linear pattern appearing 24 hours after a camping trip.
Type IV drug reactions
- Local drug reaction following topical application of drug; see above
- Maculopapular or morbilliform (measles-like) drug eruption
DRESS syndrome (drug rash with eosinophilia and systemic symptoms syndrome; also known as drug-induced hypersensitivity syndrome): delayed hypersensitivity reaction to a drug (within 1–8 weeks following administration)
- Clinical features
- Laboratory tests
- 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
- 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 → First contact can already lead to anaphylactic shock.
- Clinical presentation
- Diagnosis and treatment
- Pathophysiology: mast cell activation and subsequent release of histamine, most likely IgE-independent
- Clinical presentation: see
- Diagnosis and treatment: