What are the predisposing factors and mechanisms for anaphylaxis?

Predisposing Factors and Mechanisms for Anaphylaxis

Predisposing Factors

Risk factors for severe or fatal anaphylaxis include cardiovascular disease, poorly controlled asthma, older age, β-adrenergic blocker therapy, and prior history of anaphylaxis. 1, 2

Patient-Specific Risk Factors

• Cardiovascular disease significantly increases risk of severe anaphylaxis and refractory anaphylaxis 1, 3, 2
• Asthma, particularly if severe or poorly controlled, substantially increases the risk of fatal reactions 1, 2
• Older age is associated with increased severity and refractory anaphylaxis 1, 3
• Prior history of anaphylaxis predisposes to recurrent severe reactions 2
• Atopic background increases overall risk 2

Medication-Related Risk Factors

• β-adrenergic blocker therapy increases severity of anaphylaxis and reduces epinephrine responsiveness 1, 2, 4
• Patients on β-blockers may require IV glucagon (1-2 mg) during refractory anaphylaxis 3
• Concurrent β-blocker therapy adversely affects response to standard management 4

Trigger-Specific Patterns

• Medications and stinging insects are the leading triggers in adults 1, 2
• Foods and stinging insects are most frequently implicated in children and adolescents 1, 2
• Shellfish is a common cause of anaphylactic episodes in adults 2
• Penicillin and other beta-lactam antibiotics are the most common drug triggers 5, 6

Mechanisms of Anaphylaxis

Anaphylaxis results from sudden systemic release of mediators from mast cells and basophils through both IgE-mediated and non-IgE-mediated pathways that produce clinically identical presentations. 7, 5

IgE-Mediated Pathway (Classical Anaphylaxis)

• IgE binding and cross-linking of the high-affinity IgE receptor (FcεRI) on mast cells and basophils is the primary immunologic mechanism 1, 7
• This triggers immediate degranulation and mediator release within minutes of antigen exposure 7, 5
• Common IgE-mediated triggers include drugs (particularly penicillin), foods (nuts, peanuts, fish, shellfish), and hymenoptera stings 5

Non-IgE-Mediated Pathways (Anaphylactoid Reactions)

• IgG antibodies and complement activation by immune complexes can trigger anaphylaxis 7
• Direct mast cell membrane activation occurs with agents like vancomycin, quinolone antibiotics, and radiographic contrast media 5
• Marked complement activation from plasma proteins can trigger reactions 5
• Some patients with anaphylaxis have low or undetectable circulating allergen-specific IgE, indicating alternative pathways 1, 7

Cellular Components Beyond Mast Cells

• Multiple cell types participate including neutrophils, monocytes, macrophages, and platelets 1, 7
• Neutrophils are activated through both IgE-dependent and IgG-dependent pathways during acute anaphylaxis 7
• The complement system and neutrophils contribute to the systemic inflammatory response 7

Mediator Release and Effects

Preformed mediators:

• Histamine and tryptase are released immediately from granules 7
• These act on blood vessels, mucous glands, smooth muscle, and nerve endings 5

Newly synthesized lipid mediators:

• Cysteinyl leukotrienes (LTs) are generated de novo 1, 7
• Platelet-activating factor contributes to vascular effects 1, 7, 5

Cytokines and amplification:

• IL-6, IL-10, and TNF-receptor 1 amplify and sustain the reaction 1, 7

Pathophysiologic Consequences

Vascular effects:

• Transfer of up to 50% of intravascular fluid into extravascular space within 10 minutes is a characteristic feature 1, 7
• This intravascular volume redistribution is critical to anaphylactic shock 7
• Increased vascular permeability allows rapid hemodynamic collapse with little or no cutaneous manifestations 1

Cardiovascular collapse:

• Cardiac output decreases from reduced coronary artery perfusion pressure and impaired venous return 7
• Myocardial ischemia with ECG changes is expected within minutes of severe anaphylactic shock 7

Respiratory compromise:

• Asphyxia may result from upper airway occlusion due to angioedema or bronchospasm with mucus plugging 7

Temporal Patterns and Clinical Heterogeneity

• The more rapidly anaphylaxis develops after exposure, the more likely it is to be severe and potentially life-threatening 1, 7
• Reactions typically begin within minutes of antigen exposure, though some develop >30 minutes after exposure 1, 5
• Biphasic anaphylaxis represents recurrent mediator release occurring 1 to 72 hours after resolution of the initial episode, affecting <1% to 20% of patients 1, 7
• Risk factors for biphasic reactions include severe initial presentation, need for >1 dose of epinephrine, and delayed epinephrine administration 1, 8, 9
• Protracted anaphylaxis may persist beyond 24 hours despite aggressive treatment 1, 4

Important Clinical Caveats

• 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 7
• Urticaria and angioedema may be delayed or absent in rapidly progressive anaphylaxis 1
• The absence of cutaneous symptoms does not rule out anaphylaxis 3