What is the pathogenesis of anaphylaxis?

Pathogenesis of Anaphylaxis

Core Mechanism

Anaphylaxis results from the sudden systemic release of mediators from mast cells and basophils, triggered by both immunologic and non-immunologic mechanisms that produce clinically identical presentations. 1

Immunologic Pathways

IgE-Mediated Mechanism (Allergic Anaphylaxis)

• IgE binding and cross-linking of the high-affinity IgE receptor (FcεRI) on mast cells and basophils is the primary immunologic mechanism in many cases of anaphylaxis 1
• This represents classic immediate hypersensitivity, with reactions beginning within minutes of antigen exposure 2
• Common triggers include drugs (particularly beta-lactam antibiotics), foods (nuts, peanuts, fish, shellfish), and Hymenoptera stings 2

Non-IgE-Mediated Mechanisms (Non-Allergic Anaphylaxis)

• Anaphylaxis can occur through immunologic mechanisms beyond IgE, including IgG antibodies and complement activation by immune complexes 1
• Direct mast cell activation can occur without antibody involvement through compounds acting directly on mast cell membranes (e.g., vancomycin, quinolone antibiotics, radiographic contrast media) 2
• Marked complement activation by plasma proteins can trigger mediator release 2
• Some patients with anaphylaxis have low or undetectable circulating allergen-specific IgE, indicating alternative pathways 1

Cellular Components Beyond Mast Cells

Anaphylaxis involves multiple cell types beyond mast cells and basophils, including neutrophils, monocytes, macrophages, and platelets 1. This broader cellular involvement explains the complexity and variability of anaphylactic presentations.

Mediator Release and Effects

Preformed Mediators

• Mast cells and basophils release preformed, granule-associated mediators, most notably histamine and tryptase 1, 3
• These mediators are released immediately upon cell activation 3

Newly Formed Mediators

• Lipid mediators are synthesized de novo, including cysteinyl leukotrienes (LTs) and platelet-activating factor 1
• Leukotrienes and platelet-activating factor contribute significantly to the pathophysiology 2

Cytokines and Chemokines

• Activated cells generate cytokines including IL-6, IL-10, and TNF-receptor 1, which amplify and sustain the reaction 1
• These mediators attract additional inflammatory cells to the area 3

Physiologic Consequences

Vascular Effects

• Mediators cause profound vasodilation and dramatically increased capillary permeability 3
• A characteristic feature is transfer of up to 50% of intravascular fluid into the extravascular space within 10 minutes, resulting in rapid hemodynamic collapse 4
• Intravascular volume redistribution is a critical component of anaphylactic shock 1

Cardiovascular Manifestations

• Cardiac output decreases from reduced coronary artery perfusion pressure and impaired venous return 1
• Local mediator release may cause coronary artery spasm 1
• Features of acute left or right ventricular failure may develop 1
• Myocardial ischemia with ECG changes is expected within minutes of severe anaphylactic shock 1

Respiratory Effects

• Smooth muscle contraction causes bronchospasm and upper airway angioedema 3
• Asphyxia may result from upper airway occlusion due to angioedema or bronchospasm with mucus plugging of lower airways 1
• Both processes may occur simultaneously, particularly in reactions to foods, latex, beta-lactam antibiotics, or aspirin 1

Other Target Organ Effects

• Mediators act on mucous glands, increasing secretions 2
• Nerve endings are stimulated, causing pruritus and pain 2
• Gastrointestinal smooth muscle contraction produces cramping and diarrhea 2

Amplification and Self-Limitation

• Positive feedback mechanisms amplify the reaction, explaining rapid progression 3
• Conversely, reactions can self-limit through endogenous regulatory mechanisms 3
• The more rapidly anaphylaxis develops, the more likely it is to be severe and potentially life-threatening 1, 4

Biphasic Reactions

Biphasic anaphylaxis represents recurrent mediator release occurring 1 to 72 hours after resolution of the initial episode, with estimates varying from <1% to 20% of patients 1. The mechanism underlying biphasic reactions remains incompletely understood but likely involves ongoing cellular activation and mediator synthesis.

Clinical Heterogeneity

Anaphylaxis is not a homogeneous process—the specific pathways, mediators, time course, and response to treatment depend on the trigger agent, its route and rate of administration, the nature of the patient's hypersensitivity, and patient-specific factors including comorbidities and medications (particularly beta-blockers and ACE inhibitors) 1. This explains why presentations range from isolated cardiovascular collapse to predominant respiratory failure to multisystem involvement.