Hypersensitivity reactions

Last updated: November 20, 2023

Summarytoggle arrow icon

A hypersensitivity reaction (HSR) is an exaggerated and/or pathological immune response to exogenous or endogenous substances. HSRs are commonly classified into four types. Type I HSRs (e.g., food and pollen allergies, asthma, anaphylaxis) are immediate allergic reactions. Type II HSRs (e.g., autoimmune hemolytic anemia, Goodpasture syndrome) are cytotoxic; tissue-specific antibodies cause destruction of cells in these tissues. Type III HSRs (e.g., many vasculitides and glomerulonephritides) are immune complex-mediated; tissue damage is caused by antigen-antibody complex deposition. Type IV HSRs (e.g., TB skin tests, contact dermatitis) are delayed and cell-mediated and are the only HSRs that involve sensitized T lymphocytes rather than antibodies. In practice, many hypersensitivity syndromes are mixed reactions, meaning that they do not fit into a single reaction type. Nonallergic HSRs (e.g., pseudoallergies) are caused by mast cell activation and histamine release after the first exposure to a trigger substance (e.g., radiocontrast media).

See also “Anaphylaxis” and “Drug hypersensitivity reactions.”

Overviewtoggle arrow icon


  • Hypersensitivity reaction: an exaggerated and/or pathological immune response to foreign or self antigens [1]
  • 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 self-antigens
  • Drug hypersensitivity reaction: group of adverse drug effects that resemble an allergy (may be allergic or nonallergic) [2]



  • Traditionally categorized into four types based on immunological mechanisms
  • Reactions may be heterogeneous (i.e., syndromes do not fit into a single category). [1][2]
Hypersensitivity classification [3][4]
Summary of pathophysiology Examples
Type I: immediate
Type II: cytotoxic
Type III: immune complex

Type IV: delayed (T-cell mediated)

* Autoantibodies present

All four types of HSRs can be drug-induced.

Type I and IV HSRs most commonly manifest cutaneously. [7]

To remember the HSRs, think ACID: AAllergic/Anaphylactic/Atopic (Type I); CCytotoxic (Type II); IImmune complex deposition (Type III); DDelayed (Type IV).

Type I hypersensitivity reactiontoggle arrow icon



  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:
  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-reactive hypersensitivity [8][9]

  • 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


  • 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


Diagnostics [11]

Allergy-specific diagnostic testing should only be obtained in patients with a clinical history consistent with a HSR; it is not intended for screening purposes.

In vivo allergy skin tests [12]

  • Approach
  • Description
    • Small amounts of the following substances introduced into the skin:
      • Suspected allergen
      • Histamine-containing solution: positive control (always produces wheal)
      • Saline: negative control (never produces wheal)
    • Reaction should be measured:
      • After 15–20 minutes for immediate reactions
      • After 24 and 72 hours for nonimmediate reactions [13]
    • Positive result [12]
  • Modalities

Hypersensitivity blood tests (in vitro)


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

Preventative treatment (i.e., contact prevention and avoidance of offending agents) is the most effective form of management for allergies.

Allergen immunotherapy (desensitization)

  • Indication
  • 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) [17]
    • 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)

Type II hypersensitivity reactiontoggle arrow icon



IgM and IgG mistakenly bind to surface antigens of the cells in the body, which results in:

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


Type III hypersensitivity reactiontoggle arrow icon



  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 neutrophilscell deathinflammationvasculitis

To remember Type III, think of three things stuck together: antigen + antibody + complement


Arthus reactiontoggle arrow icon

Overview [18][19]


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

Differential diagnoses [19]

  • Injection site reaction unrelated to hypersensitivity
  • Abscess
  • Cellulitis
  • Shoulder injury related to vaccine administration

Diagnostics [18][19]


  • The reaction is self-limited.
  • Symptomatic relief of swelling (e.g., cold compresses, NSAIDs, limb elevation)


Evidence of vasculitis on histology differentiates between a true Arthus reaction and an injection site reaction unrelated to hypersensitivity. [19]

Type IV hypersensitivity reactiontoggle arrow icon



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)

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).


Nonallergic hypersensitivitytoggle arrow icon


Infection-induced urticaria

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Referencestoggle arrow icon

  1. Liang, et al. Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2018.
  2. Pool V, Mege L, Abou-Ali A. Arthus Reaction as an Adverse Event Following Tdap Vaccination. Vaccines. 2020; 8 (3): p.385.doi: 10.3390/vaccines8030385 . | Open in Read by QxMD
  3. Mandallaz et al.. Bird-egg syndrome. Cross-reactivity between bird antigens and egg-yolk livetins in IgE-mediated hypersensitivity. International Archives of Allergy and Applied Immunology. ; 87 (2): p.143-50.
  4. Relationship of Dust Mites and Crustaceans. Updated: July 13, 2013. Accessed: April 17, 2019.
  5. Luskin, Luskin. Anaphylaxis and Anaphylactoid Reactions: Diagnosis and Management. American Journal of Therapeutics. ; 3 (7): p.515-520.
  6. Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010; 126 (6 Suppl): p.S1-58.doi: 10.1016/j.jaci.2010.10.007 . | Open in Read by QxMD
  7. Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P. General considerations for skin test procedures in the diagnosis of drug hypersensitivity.. Allergy. 2002; 57 (1): p.45-51.
  8. Torres MJ, Romano A, Celik G, et al. Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America. Clin Transl Allergy. 2017; 7 (1).doi: 10.1186/s13601-017-0144-0 . | Open in Read by QxMD
  9. Demoly P, Adkinson NF, Brockow K, et al. International Consensus on drug allergy. Allergy. 2014; 69 (4): p.420-437.doi: 10.1111/all.12350 . | Open in Read by QxMD
  10. Ariza A, Mayorga C, Bogas G, et al. Advances and novel developments in drug hypersensitivity diagnosis. Allergy. 2020; 75 (12): p.3112-3123.doi: 10.1111/all.14603 . | Open in Read by QxMD
  11. Santos AF, Alpan O, Hoffmann H. Basophil activation test: Mechanisms and considerations for use in clinical trials and clinical practice. Allergy. 2021; 76 (8): p.2420-2432.doi: 10.1111/all.14747 . | Open in Read by QxMD
  12. Walls R, Hockberger R, Gausche-Hill M, Erickson TB, Wilcox SR. Rosen's Emergency Medicine 10th edition- Concepts and Clinical Practice E-Book. Elsevier Health Sciences ; 2022
  13. Fujita et al.. Mechanisms of allergen-specific immunotherapy. Clinical and translational allergy. 2012; 2 (2).doi: 10.1186/2045-7022-2-2 . | Open in Read by QxMD
  14. Dispenza MC. Classification of hypersensitivity reactions. Allergy Asthma Proc. 2019; 40 (6): p.470-473.doi: 10.2500/aap.2019.40.4274 . | Open in Read by QxMD
  15. Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. Elsevier Saunders ; 2015
  16. Murphy KM. Janeway's Immunobiology. Garland Science ; 2011
  17. Lum G, Szuflad P, D'Amarino M. A Patient With a Low IgA Level Requiring Transfusion During CABG Surgery. Lab Med. 2015; 36 (6): p.353-356.doi: 10.1309/1BTM2E2H81C9DVJN . | Open in Read by QxMD
  18. Latex Allergy. Updated: October 1, 2015. Accessed: March 9, 2017.
  19. Kanani A, Schellenberg R, Warrington R. Urticaria and angioedema. Allergy Asthma Clin Immunol. 2011; 7 (Suppl 1): p.S9.doi: 10.1186/1710-1492-7-s1-s9 . | Open in Read by QxMD

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