Hypersensitivity reactions

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. 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 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).

See also “Anaphylaxis.”

• Definitions
  • 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
• Stages
  • 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.

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)

Overview

• Type I hypersensitivity reactions are referred to as “immediate reactions”; they are antibody-mediated and include anaphylactic and atopic immune responses.
• For the specific causes of type I hypersensitivity, see “Hypersensitivity classification” above.

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-reactivity ^[5][6]

• 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

Clinical findings

• Course
  • 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
• Specific manifestations ^[7]
  • Allergic conjunctivitis
  • Allergic rhinitis
  • Allergic asthma
  • 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
  • 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
  • Angioedema: due to mast cell activation in the dermis and/or subcutaneous tissue
  • Anaphylaxis can be caused by: ^[8]
    • Food (e.g. peanut allergy)
    • Drugs (e.g., sulfa allergy) ^[9]
    • Toxins (e.g., bee sting allergy)

Diagnostics ^[10]

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 allergen extracts may enter.
  • Positive result: wheal equal to or larger than histamine control (or > 3 mm)
• Scratch test
  • Comparable to prick test
  • A scratch (∼ 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 (blood tests)

• Tryptase in serum (a relatively specific marker of mast cell activation): Elevated levels indicate an increased risk of severe reactions.
• Allergen-specific IgE
  • 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
  • Quantitatively assessed using enzyme-linked immunosorbent assay (ELISA)
• Total IgE
  • Often elevated in patients with allergic conditions
  • Because normal levels of IgE do not exclude allergy, in vitro testing should not be used as a definitive test for allergy diagnosis.

Treatment

Treatment of type I hypersensitivity reactions depends on the etiology of the reaction (see “Hypersensitivity classification” above).

• Urticaria
  • Avoid offending agent (if known)
  • H1-receptor blocker (e.g., cetirizine)
  • Glucocorticoids
• Drug reactions
  • Mild reactions (mild urticaria/angioedema)
    • Remove offending drug
    • Monitoring ± antihistamines
  • Moderate reactions (more pronounced urticaria/angioedema)
    • Should be treated with withdrawal of the offending drug
    • Antihistamines ± glucocorticoids.
  • Severe reactions require emergency resuscitation (see “Anaphylaxis”).
• 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

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) ^[11]
  • 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.

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
  • Examples: acute hemolytic transfusion reaction, autoimmune hemolytic anemia, hemolytic disease of the newborn
• Inflammation
  • Fc-receptor mediated immune cell activation
  • Antibodies bind to cellular surfaces → activation of the complement system
  • Examples: Goodpasture syndrome, rheumatic fever
• Impaired cellular function
  • Antibodies bind to cell surface receptors → inhibition or activation of downstream signaling pathways → impaired cellular function
  • Examples: Graves disease, myasthenia gravis

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

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

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

Examples ^[12][13]

Serum sickness

• Definition: Serum sickness is a classic example of a type III hypersensitivity reaction, which usually develops as a complication of antitoxin or antivenom administration.
• Etiology
  • Antivenom or antitoxin containing animal proteins or serum (→ “serum” sickness), such as:
    • Equine anti-snake venom
    • Equine anti-spider venom
    • Equine or bovine anti-rabies antitoxin
    • Equine botulinum antitoxin
  • Medications most frequently antibiotics (e.g., penicillin, amoxicillin, cefaclor, trimethoprim-sulfamethoxazole)
  • Infections: Hepatitis B virus
• Pathophysiology: exposure to an antigen (e.g., antivenom, drug) → formation of antibodies → deposition of antibody-antigen complexes in tissue → activation of the complement cascade → tissue damage and systemic inflammation
• Clinical features: Symptoms appear 1–2 weeks following initial exposure (because antibodies take several days to form), and usually resolve within a few weeks after discontinuation of the offending agent.
  • Fever
  • Rash (urticarial or purpuric)
  • Arthralgias, myalgia
  • Lymphadenopathy
  • Hand edema
  • Headache, blurred vision
  • Abdominal pain, diarrhea, nausea/vomiting
  • Mucosal involvement is uncommon
• Subtypes and variants: serum sickness-like reaction
  • Epidemiology: much more common than actual serum sickness
  • Etiology: similar to that of serum sickness
    • Infections (e.g., hepatitis B, rabies)
    • Medications that can act as haptens (e.g., allopurinol, cephalosporins, penicillin).
  • Pathogenesis is unclear (likely not the result of a type III hypersensitivity reaction).
  • Clinical features: difficult to distinguish from classic serum sickness, as they both present similarly (see “Clinical features” above)
• Diagnostics: Urinalysis may show mild proteinuria.
• Treatment: Stop the offending agent.
• Prognosis: excellent once the offending drug is stopped or the causative infection has resolved clinically

Arthus reaction

• Definition: local subacute type III hypersensitivity reaction
• Etiology: vaccination against tetanus, diphtheria
• 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
  • Localized swelling, erythema, hemorrhage
  • Sometimes superficial skin necrosis a few hours after booster vaccination
  • Reaction peaks 12–36 hours later.
• Treatment
  • Reaction is self-limited.
  • Symptomatic relief of swelling (e.g., cold compresses, NSAIDs, limb elevation)
• Prevention ^[14][15]
  • After Arthus reaction to tetanus toxoid-containing vaccine: always observe a 10-year interval between tetanus toxoid-containing vaccines.
  • After Arthus reaction to diphtheria toxoid-containing vaccine: use of tetanus toxoid rather than Tdap vaccine

Other examples

• Vasculitis
  • Polyarteritis nodosa
  • Drug-induced hypersensitivity vasculitis
• Nephropathy
  • Poststreptococcal glomerulonephritis
  • Lupus nephritis
  • IgA nephropathy
  • Membranous nephropathy
• Hypersensitivity pneumonitis

Overview

• Type IV hypersensitivity reactions are referred to as delayed and cell-mediated.
• For the specific causes of type IV hypersensitivity, see “Hypersensitivity classification” above.
• 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

Allergic contact dermatitis

• Epidemiology
  • One of the most common dermatological diagnoses
  • Prevalence of ∼ 1–6%
• Etiology
  • Poison ivy, poison oak, poison sumac (urushiol-induced contact dermatitis)
  • Latex or rubber gloves
  • Nickel, cobalt, chromium
  • Perfumes, soaps, cosmetics
  • Topical medications: hydrocortisone, topical antibiotics (e.g., neomycin), benzocaine
• Pathophysiology
  • First contact with allergen → sensitization
  • Repeated contact with allergen → development of a rash after 12–48 hours
• Clinical features
  • 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: 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 ^[16]
      • 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.
• Differential diagnosis: See ”Irritant vs. allergic contact dermatitis.”
• Treatment
  • Avoidance of the allergen is the best treatment and preventative measure.
  • Acute phase
    • Mild to moderate cases: topical corticosteroids, oatmeal baths, soothing lotions (e.g., calamine), wet dressings (especially for oozing, crusting lesions), topical antihistamines
    • Severe cases: systemic corticosteroids, systemic antihistamines

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 “Allergic contact dermatitis” above.
• Maculopapular or morbilliform (measles-like) drug eruption (e.g., “ampicillin rash” following ampicillin administration for infectious mononucleosis)
• Stevens-Johnson syndrome and toxic epidermal necrolysis

DRESS syndrome (drug rash with eosinophilia and systemic symptoms syndrome; also known as drug-induced hypersensitivity syndrome) ^[17]

• Description: delayed hypersensitivity reaction to a drug (within 1–8 weeks following administration)
• Etiology
  • Allopurinol
  • Antiepileptic drugs (e.g., lamotrigine, phenytoin, carbamazepine)
  • Antibiotics (e.g., sulfonamide)
• Clinical features
  • Fever
  • Pruritic morbilliform rash
  • Facial edema
  • Hepatomegaly
  • Diffuse lymphadenopathy
  • Possible multiorgan failure
• Diagnostics: laboratory studies
  • Eosinophilia
  • Thrombocytopenia
  • Atypical lymphocytosis
• Treatment
  • Drug withdrawal
  • Symptomatic: Corticosteroids are often used, but their effects are disputed.
• Prognosis: fatal in ∼ 10% of cases

Other examples

• Skin tests
  • Candida skin test (to test the immune function of T cells)
  • Mantoux tuberculin skin test for latent tuberculosis
• Systemic disorders
  • Guillain-Barré syndrome
  • Hashimoto thyroiditis
  • Multiple sclerosis
  • Rheumatoid arthritis
  • 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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