Pathogenesis and Clinical Manifestations of Anaphylaxis

Core Mechanisms and Immunologic Pathways

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, 2
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, 2, 3
Anaphylaxis can occur through immunologic mechanisms beyond IgE, including IgG antibodies and complement activation by immune complexes 4, 5, 6
Some patients with anaphylaxis have low or undetectable circulating allergen-specific IgE, indicating alternative pathways 1, 2, 3

Anaphylaxis involves multiple cell types beyond mast cells and basophils, including neutrophils, monocytes, macrophages, and platelets 1, 2, 3
Mast cells and basophils release preformed, granule-associated mediators, most notably histamine and tryptase 7
Lipid mediators are synthesized de novo, including cysteinyl leukotrienes (LTs) and platelet-activating factor 1, 2, 3
Activated cells generate cytokines including IL-6, IL-10, and TNF-receptor 1, which amplify and sustain the reaction 1, 2, 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 8
Intravascular volume redistribution is a critical component of anaphylactic shock 4, 5, 6
Cardiac output decreases from reduced coronary artery perfusion pressure and impaired venous return 4, 5, 6
Myocardial ischemia with ECG changes is expected within minutes of severe anaphylactic shock 4, 5, 6
Asphyxia may result from upper airway occlusion due to angioedema or bronchospasm with mucus plugging of lower airways 4, 5, 6
The more rapidly anaphylaxis develops, the more likely it is to be severe and potentially life-threatening 7, 8
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, 2, 3
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 4, 5, 6

Neutrophils are activated during acute anaphylaxis through both IgE-dependent and IgG-dependent pathways, contributing to the systemic inflammatory response, according to the American Academy of Allergy, Asthma, and Immunology 9
The complement system and neutrophils have been shown to be involved in anaphylaxis in human subjects, expanding our understanding beyond mast cells and basophils alone, as stated by the American Academy of Allergy, Asthma, and Immunology 9

Epinephrine remains the first-line treatment for anaphylaxis, regardless of the underlying cellular mechanism, as recommended by the American Academy of Allergy, Asthma, and Immunology 9 and supported by evidence from the American College of Allergy, Asthma, and Immunology 10