Equis ISSN 2398-2977

Anaphylaxis

Synonym(s): Allergic reaction hypersensitivity

Contributor(s): Cody Coyne, Graham Munroe, Jarred Williams

Introduction

  • Cause: immediate form of immune-mediated hypersensitivity initiated by the formation of antigen-antibody complexes. Classic examples include adverse drug reactions, insect hypersensitivity, food allergies, environmental antigen.
  • Signs: depending on site of exposure, subsequent reactions can manifest as severe systemic disease or local skin reactions. Systemic signs may include sudden death, urticaria, hypotension, sudden difficulty standing (CNS vascular hypotension), respiratory distress and colic; poor capillary refill time, abnormal mucous membrane color. Local signs may include multiple round elevated plaques of pitting dermal edema.
  • Treatment: needs to be rapid and includes epinephrine, glucocorticoids, large volumes of balanced polyionic fluid and administration of oxygen.

Pathogenesis

Etiology

Predisposing factors

General

  • History of prior exposure and reaction to an antigen.

Specific

  • Presendce of antigen.

Pathophysiology

  • Anaphylaxis is an immediate form of an immune-mediated hypersensitivity reaction.
  • Initiated by antigen-antibody complexes.
  • Antigen is bound to antigen-specific, cell-bound antibody and, depending on the site of interaction, the subsequent reactions can manifest as severe systemic disease or locally in the skin or elsewhere.
  • Accompanying disease states may include:
    • Allergic rhinitis.
    • Atopy.
    • Vasculitis Vasculitis.
  • Large antigens (>1000 Daltons) are only capable of cross-linking the Fab portions of surface-associated immunoglobulins that function as antigenic receptors. Smaller antigens have to combine with endogenous proteins to attain sufficient size.
  • Cross-linking results in cellular activation and initiation of the hypersensitivity reaction.
  • Classic anaphylactic hypersensitivity is associated with the production of IgE antibodies synthesized by Beta cells upon exposure to appropriate antigen.
  • The IgE has high-affinity binding to the surface receptors of mast cells and basophils via the Fc region of the antibody (homocytotropic, species specific). The Fab portion of the immunoglobulin is left exposed.
  • An antigen molecule can simultaneously bind to the Fab portions of 2 or more IgE molecules resulting in cellular stimulation.
  • Other antibody subclasses can → similar activation but are less significant because of their low-affinity binding to mast cells and basophils. Macrophages, eosinophils and platelets can also bind surface IgE but at a lower affinity.
  • Anaphylactic reactions may result in severe systemic reactions characterized by cardiovascular and respiratory compromise, or more commonly are localized as in urticaria.
  • Whether local or systemic reactions develop depends on the route of antigen exposure, type, quantity and site of mediator release, the response of the individual to mediators, and the activation requirements of the antigen.
  • Antigen characteristics and the cytokines that are produced following antigen interaction with T-cells determines the immunoglobulin isotype that is synthesized.
  • Usually IgE is transiently produced and subsequent interactions with the same antigen → formation of IgG antigen complexes that promote basophil degranulation and the release of histamine.
  • Histamine release promotes vasodilation, vascular collapse, vascular hypotension (shock); other endogenous mediators are also generated at higher than normal levels during anaphylactic reactions, including the prostaglandins in interleukins.
  • In some individuals there is an enhanced and persistent IgE response to low-dose antigen challenge and no or limited switching to IgG production. This may be genetically determined and related to differences in cytokine production (interleukin-4 (IL-4) and interferon-alpha (IFN-alpha)).
  • Additional alterations in allergic individuals may involve altered calcium homeostasis, neutrophil respiratory burst and accentuated other inflammatory responses.
  • Mast cells and basophils can be triggered to release their inflammatory mediators either immunologically or non-immunologically:
    • Immunological triggering: can occur in response to minute doses of antigen (allergen cross-links two or more IgE receptors on mast cell surface) but require prior exposure to this antigen → antigen-specific IgE synthesis. Alterations of the mast cell or basophil cell membrane by the signal from the antigen-antibody interaction triggers a cell-associated enzyme cascade.
    • Non-immunological triggering: occurs when the same cells are activated without direct antigen binding to surface IgE - 'anaphylactoid'. No prior exposure is required and clinically they are indistinguishable from immunologically triggered anaphylactic reactions.
    • Possible triggers include alternate complement pathway products C3a and C5a which may be stimulated by radiocontrast agents, certain complex polysaccharides, substance P, etc.
  • Other substances can directly induce mast cell and basophil degranulation, eg IL-3, hypertonic saline, NSAIDs, codeine Codeine phosphate, opiates.
  • There are three basic categories of inflammatory mediators of hypersensitivity:
    • Preformed within secretory granules (primary mediators), eg histamine, serotonin, IL 1-6, TNF-alpha, heparin, chondroitin sulfate, other enzymes including kallikrein, elastase, tryptase.
    • Synthesized on demand following cellular activation, eg leukotrienes, prostanoids and other cytokines.
    • Mediators derived from recruited cells or from the actions of the preformed or newly generated mediators on tissue or plasma components (secondary mediators), eg macrophage, neutrophil, eosinophil and platelet products.
  • The mediators that are released have multiple effects:
    • Increased vascular permability.
    • Constriction of smooth muscle.
    • Dilation of blood vessels (acute vasodilation → acute hypotension).
    • Stimulation of secretion of airway mucus, gastric acid and adrenal catecholamines.
    • Leukocytic chemo-attractants.
    • Activation of complement and coagulation cascades.
  • The clinical signs associated with mediator release vary but include combinations of:
    • Edema.
    • Urticaria.
    • Erythema.
    • Systemic hypotension (can be severe).
    • Tachypnea.
    • Dyspnea.
    • Colic.
    • Tachycardia.
    • Pruritus.
    • Mental dysfunction/disorientation/instability, secondary to severe acute CNS hypotension.

Timecourse

  • Immediate: within 20 min of exposure.

Diagnosis

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Treatment

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Prevention

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Olszewski M A, Robinson N E, Zhu F X, Zhang X Y & Tithof P K (1999) Mediators of anaphylaxis but not activated neutrophils augment cholinergic responses of equine small airways. Am J Physiol 276 (3 Pt 1), L522-529 PubMed.
  • Hanna C J, Eyre P, Wells P W & McBeath D G (1982) Equine immunology 2 - immunopharmacology - biochemical basis of hypersensitivity. Equine Vet J 14 (1), 16-24 PubMed.
  • Meagher D M (1976) Clinical evaluation and management of shock in the equine patient. Vet Clin North Am 6 (2), 245-255 PubMed.
  • Mansmann R A (1972) Equine anaphylaxis. JAVMA 161 (5), 438 PubMed.
  • McGavin M D, Gronwall R R & Mia A S (1972) Pathologic changes in experimental equine anaphylaxis. JAVMA 160 (12), 1632-1636 PubMed.


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