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 IVhypersensitivity (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.

Hypersensitivity classification
Type I: Immediate Type II: Cytotoxic Type Type IV:
III: Immune Delayed (cell-
complex mediated)
Summary  Preformed IgE antibo  IgM and IgG  Antibodies bin Contact of
of dies coating mast antibodies bind to d to antigens antigen
pathophys cells and basophils are antigens on the cells of in circulation with presensit
iology crosslinked by contact particular tissue types  → Immune ized T
with free antigen complex form lymphocytes
 → Cell degranulation ation and  → Macrophag
and release deposition in eactivation and
 Hypersensitivity classification
Type I: Immediate Type II: Cytotoxic Type Type IV:
III: Immune Delayed (cell-
complex mediated)
 → Complement
of histamine and other particular inflammatory
inflammatory activation and lysis tissues reaction in
mediators or phagocytosis of cells → Inflammati tissue
on

 Allergic
Examples  Acute hemolytic  Arthus  Acute and
or anaphylactic transf transfusion reaction reaction chronic transp
usion reactions, e.g., Autoimmune  Polyarteritis lant rejection
in patients with IgA hemolytic anemia nodosa (PAN)  Contact
deficiency  Bullous pemphigoid  Poststreptoco dermatitis(e.g
 Anaphylaxis  Drug- ccal ., nickel,
 Drug induced neutropenia and glomerulonep poison ivy,
reactions (e.g., penicil agranulocytosis hritis, IgA cosmetics,
lin, muscle relaxants) Goodpasture nephropathy, rubber gloves)
 Food allergies (e.g., syndrome membranous  Drug reactions
nuts, shellfish, eggs,  Graves disease glomerulopath (e.g., Stevens-
soy, wheat)  Hemolytic disease of y, lupus Johnsonsyndr
 Insect the fetus and newborn nephritis ome, toxic
venom allergies (e.g., Immune  Serum epidermal
bee, wasp) thrombocytopenia (ITP) sickness necrolysis)
 Reactions to inhaled Hyperacute transplant  Serum  Graft-versus-
or other rejection sickness-like host disease
environmental allerge  Myasthenia gravis 
reaction(atypic Guillain-
ns (e.g., dust mites,  Pernicious anemia al without Barré
animal dander, pollen,  Pemphigus vulgaris circulating syndrome*
latex )  Rheumatic fever immune-  Hashimoto's
→ asthma, allergic complex thyroiditis*
rhinitis, atopy involvement) Mantoux tuber
 Systemic culin skin
lupus test for latent
erythematosu tuberculosis
s(SLE)  Multiple
sclerosis
 Rheumatoid
arthritis*
 Type
1 diabetes
mellitus*
 Hypersensitivity classification
Type I: Immediate Type II: Cytotoxic Type Type IV:
III: Immune Delayed (cell-
complex mediated)

* Autoantibodi
es 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 Ihypersensitivity, 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) →
 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)
 Pruritus
 Eosinophil and neutrophil chemotaxis induced by basophil and mast cell mediators
(→ eosinophilia)

Type I is first and fast.

Clinical findings
 Course
 Immediate reaction: allergic reaction within minutes of contact with antigen
 Late-phase reaction: occurs hours after immediate reaction
 Main symptoms: pruritus, edema, rash, rhinitis, bronchospasm, and abdominal
cramping
 Specific manifestations
 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 and 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 in the superficial dermis
  Angioedema: due to mast cell activation in the dermis and/or subcutaneous tissue
 Anaphylaxis

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.
 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
 Scratch test: comparable to prick test; a scratch (about 1 cm) is made and
the allergen subsequently applied
 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
 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 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 (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)
  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.

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!

Type II hypersensitivity reaction

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 overview of hypersensitivity reactions above).
 Distribution of disease: often limited to a particular tissue type
 Diagnosis may involve autoantibody testing (see antibody diagnosis of rheumatological
diseases) and the Coombs test.

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

 Opsonization → phagocytosis or complement activation
 Complement-mediated lysis
 Antibody-dependent cell-mediated cytotoxicity (NK cells or macrophages)

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 overview of hypersensitivity reactions 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

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
 Antivenom or antitoxin containing animal proteins or serum (→ “serum” sickness)
 Medications, most frequently antibiotics (penicillin, amoxicillin, cefaclor,
and trimethoprim-sulfamethoxazole)
 Infections: Hepatitis B virus
 Clinical features
 Fever
 Rash (urticarial or purpuric)
 Arthralgias, myalgia
 Headache, blurred vision
 Abdominal pain, diarrhea, nausea/vomiting
 Lymphadenopathy
 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
 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
 Localized swelling, erythema, hemorrhage
 Sometimes superficial skin necrosis within a few hours of booster vaccination
 Reaction peaks 12–36 hours later.
 Treatment:
 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 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
 T cell-mediated reaction

1. Sensitization: Antigen penetrates the skin → uptake by Langerhans cell → migration

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 → macrophageactivation and inflammatory
reaction in tissue
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)
 Nickel, cobalt, chromium
 Perfumes, soaps, cosmetics
 Latex or rubber gloves
 Topical medications: hydrocortisone, topical antibiotics (e.g., neomycin), benzocaine
 Course
 First contact with allergen → sensitization
 Repeated contact with allergen → development 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
 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

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

  Types
 Local drug reaction following topical application of drug; see allergic contact dermatitis
 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)
 Etiology
 Antiepileptic drugs (e.g., phenobarbital, carbamazepine, lamotrigine)
 Antibiotics (e.g. sulfonamide)
 Allopurinol
 Clinical features
 Fever
 Itching rash
 Facial edema
 Hepatomegaly
 Diffuse lymphadenopathy
 Often leads to multiorgan failure
 Laboratory tests
 Eosinophilia
 Thrombocytopenia
 Atypical lymphocytosis
 Treatment
 Drug withdrawal
 Symptomatic
 Prognosis: fatal in ∼ 10% of cases

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

Differential diagnoses

Nonallergic hypersensitivity
Pseudoallergy

 Definition: an IgE-independent reaction that is clinically indistinguishable

from type I hypersensitivity
 Etiology: radiocontrast media, narcotics, vancomycin, NSAIDs
 Pathophysiology
  Substances cause direct 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
 Symptoms are dose dependent.
 Urticaria, pruritus, edema, hypotension, or even symptoms of anaphylactic shock
 Diagnosis and treatment
 Minor reactions: Treat with avoidance of offending drug;
give antihistamines for pruritus or urticaria.
 Pseudoallergy with anaphylactic characteristics → See also anaphylaxis.

Infection-induced urticaria

 Etiology:
 Viral (e.g., rotavirus and rhinovirus) or bacterial infections (esp. Mycoplasma
pneumoniae and group A streptococcal pharyngitis).
 Parasitic infections (e.g., Anisakis simplex and Plasmodium falciparum)
 Pathophysiology: mast cell activation and subsequent release of histamine, most
likely IgE-independent
 Clinical presentation: See urticaria
 Diagnosis and treatment:
 Clinical diagnosis: based on physical examination and patient history
 Usually self-limited; antihistamines may be given for pruritus or urticaria