Aetiology

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Choc anaphylactique chez l’enfant et l’adultePublished by: Groupe de Travail Développement de recommmandations de première ligneLast published: 2020Anafylaxie bij kinderen en volwassenenPublished by: Werkgroep Ontwikkeling Richtlijnen Eerste Lijn (Worel)Last published: 2020

Exposure to allergen in pre-sensitised individuals is the cause of immune-mediated anaphylaxis. Common allergens include foods, drugs, and insect stings, but exercise with or without presence of an allergen may also be a trigger. Sometimes, a co-factor (such as a non-steroidal anti-inflammatory drug [NSAID], alcohol, or another food) is required to provoke food-associated and exercise-induced anaphylaxis.[24]

Approximately one third to one half of reactions are triggered by food. Ingestion, food aerosols (e.g., peanut particles produced during processing, airborne proteins associated with preparation of shellfish or egg powder used in bakeries) as well as handling of the food (e.g., peanuts, tree nuts, egg, milk, and fish) may trigger severe reactions. Food-associated, exercise-induced anaphylaxis occurs when a patient exercises within 2 to 4 hours after ingestion of a specific food (e.g., wheat, celery, shellfish, though possibly after ingestion of any food).[20]

While sensitisation to food proteins is the most common form of allergy to foods of both plant and animal origin, sensitisation to carbohydrate epitopes leading to allergic reaction to mammalian meat has been described. This form of food allergy involves sensitisation to the carbohydrate epitope galactose-alpha-1,3-galactose (alpha-gal). Alpha-gal is a carbohydrate moiety that is present on cells and tissues of all mammals except the higher order primates (including humans). Tick bites can lead to sensitisation of humans to alpha-gal, and subsequent ingestion of meat (e.g., beef, pork, lamb) leads to a delayed allergic reaction. The reaction typically occurs 3 to 6 hours after ingestion. Cross-reactivity with cetuximab has been reported (alpha-gal is present on the Fab portion of the cetuximab heavy chain).[25]

Insect stings with the Hymenoptera (wasps and bees) are commonplace globally, while ant stings and spider bites are limited to their geographical prevalence.[26]

Drug-induced anaphylactic reactions occur in the hospital setting and in the community. For adults, antibiotics, especially penicillin, and NSAIDs have been found to be common causes of medication-related anaphylaxis.​[21][22][23]

The risk of anaphylaxis after vaccine administration is low. A review of the Vaccine Safety Datalink estimated the risk of anaphylaxis after vaccination to be 1.31 per million doses.[27]

Anaphylaxis during anaesthesia in adults is most often due to reactions to neuromuscular-blocking agents, but may also be due to reactions to intravenous anaesthetics, opioid analgesics, NSAIDs, local anaesthetics, colloids, antibiotics, and latex.[28][29] In children anaphylactic reactions during anaesthesia are more often due to latex, which makes a latex-free environment crucial.[30]

Cases of anaphylaxis to human seminal fluid are rare; the majority are immunoglobulin E-mediated allergic reactions to plasma proteins. Skin testing using seminal fluid from the male partner and desensitisation have been described.

Pathophysiology

Allergens are introduced into the body by various routes: ingestion, inhalation, parenteral, or skin contact. On first exposure, a susceptible person forms immunoglobulin E (IgE) antibodies specific to the antigen presented. IgE antibodies attach to high-affinity Fc receptors on basophils and mast cells.

On subsequent exposure, binding of antigen to the IgE antibodies leads to bridging and triggers the degranulation of mast cells.

Understanding the causative mechanisms of anaphylaxis can help differentiate it from other forms of shock.

Anaphylaxis may be:

  • Immunologically mediated (the classic IgE-mediated hypersensitivity reaction)

    • Massive degranulation or release of pro-inflammatory and vasoactive mediators and cytokines from basophils and mast cells (histamine, prostaglandin D2, leukotrienes, platelet-activating factor, tryptase, nitric oxide, and eosinophil and neutrophil chemotactic factors)

    • These agents have diverse effects, causing symptoms in many organ systems

  • Non-immunologically mediated (non-IgE-mediated)

    • Some drugs, such as non-steroidal anti-inflammatory drugs, may trigger cell activation by altering arachidonic acid metabolism. Activation of complement, the complement peptides (anaphylatoxins) such as C3a and C5a, and their direct action on mast cells and basophils may lead to mediator release, producing symptoms indistinguishable from the classic IgE-mediated reaction[31]

  • Idiopathic.

Shock in anaphylaxis is usually caused by immune mediators, which:

  • Depress myocardial function directly

  • Cause vasodilation

  • Cause fluid to leak from capillary blood vessels.[32] Up to 50% of intravascular volume can shift to the extravascular compartment in minutes

    • Adrenaline (epinephrine) exerts effects on:

      • Alpha-1 receptors, causing peripheral vasoconstriction, which reduces hypotension and mucosal oedema. Therefore, blood pressure may be normal due to this compensatory mechanism increasing peripheral resistance

      • Beta-1 receptors, which increase the rate and force of cardiac contractions and reduce hypotension.

Airway obstruction is caused by:

  • Fluid leaking from capillary blood vessels and causing tissue swelling[32]

  • Altered smooth muscle tone resulting in bronchospasm and asthma

    • Adrenaline exerts effects on:

      • Beta-2 receptors, reducing inflammatory mediator release from mast cells and basophils and causing bronchodilation.[32][33]

Classification

Classification of anaphylaxis according to causative mechanism[2]

Immunological immunoglobulin E (IgE)-mediated reactions

  • Food

  • Airborne allergens

  • Latex

  • Venom

  • Medication

  • Alpha-gal

  • Food-dependent, exercise-induced anaphylaxis

  • Hormones

  • Seminal fluid

  • Radiocontrast media

Immunological non-IgE-mediated reactions

  • Immune aggregate

  • Intravenous immunoglobulin

  • Medication

  • Radiocontrast media

Non-immunological reactions

  • Opiates

  • Physical factors (e.g., exercise, cold, heat)

Idiopathic

  • Increased mast cell sensitivity/degranulation

  • Unrecognised allergens

Masqueraders

  • Munchausen's stridor

  • Vocal cord dysfunction

Allergic Diseases Resource Center classification[3]

The Allergic Diseases Resource Center makes a distinction between:

  1. Anaphylaxis: immunological, particularly IgE-mediated reactions

  2. Non-allergic anaphylaxis: clinically identical to anaphylaxis; however, not immunologically mediated.

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