What is the pathophysiology of anaphylaxis and anaphylactic shock?

Pathophysiology of Anaphylaxis and Anaphylactic Shock

Core Immunologic and Non-Immunologic Mechanisms

Anaphylaxis results from sudden, massive systemic release of mediators from mast cells and basophils, triggered by both IgE-mediated immunologic pathways and direct non-immunologic mechanisms that produce clinically identical life-threatening presentations. 1

Primary Immunologic Pathways

• IgE-mediated mechanism: Cross-linking of high-affinity IgE receptors (FcεRI) on mast cells and basophils is the classic pathway, occurring when allergen binds to allergen-specific IgE antibodies already bound to these cells 1, 2
• Alternative immunologic pathways: IgG antibodies can activate neutrophils to produce histamine-like molecules, and immune complex formation can trigger complement activation, both leading to anaphylaxis without IgE involvement 1, 3
• Anaphylatoxin activation: Complement components (C3a, C5a) directly activate mast cells through non-IgE pathways 1, 3

Non-Immunologic Direct Activation

• Certain drugs (vancomycin, opioids, quinolone antibiotics) and radiographic contrast media directly degranulate mast cells without requiring prior sensitization or antibody involvement 4, 2
• Physical factors (exercise, cold exposure) can trigger mast cell activation through unclear mechanisms 2, 5

Cellular Components and Mediator Release

Cells Involved Beyond Mast Cells

• Multiple cell types participate: neutrophils, monocytes, macrophages, and platelets contribute to the systemic inflammatory cascade beyond the traditional mast cell/basophil paradigm 1, 6
• Complement system activation and neutrophil involvement expand the pathophysiology beyond simple mast cell degranulation 1

Mediator Categories and Timeline

Preformed mediators (released within 5 minutes):

• Histamine: causes vasodilation, increased vascular permeability, smooth muscle contraction; remains elevated 15-60 minutes 1, 7
• Tryptase: marker of mast cell activation 1, 2
• Carboxypeptidase A and proteoglycans (heparin, chondroitin sulfates) 2

Newly synthesized lipid mediators:

• Cysteinyl leukotrienes (LTC4, LTD4): potent bronchoconstrictors and increase vascular permeability 1, 4
• Prostaglandin D2: causes vasodilation and bronchoconstriction 2
• Platelet-activating factor (PAF): induces profound hypotension and bronchoconstriction 1, 4

Cytokines (amplify and sustain reaction):

• IL-6, IL-10, TNF-receptor 1 perpetuate the inflammatory cascade 1

Cardiovascular Pathophysiology Leading to Shock

Rapid Intravascular Volume Loss

The hallmark of anaphylactic shock is transfer of up to 50% of intravascular fluid into the extravascular space within 10 minutes due to massive increase in vascular permeability. 8, 1

• This profound fluid shift results from mediator-induced endothelial gap formation 1
• Hemodynamic collapse can occur rapidly with minimal or absent cutaneous/respiratory manifestations 8

Cardiac Dysfunction

• Decreased cardiac output results from two mechanisms: reduced coronary artery perfusion pressure and impaired venous return from intravascular volume depletion 1
• Myocardial ischemia with ECG changes is expected within minutes of severe anaphylactic shock, even in patients without underlying coronary disease 1
• Vascular smooth muscle relaxation from mediators causes profound vasodilation and distributive shock 4, 2

Hemodynamic Patterns

• Tachycardia is the rule in anaphylaxis as a compensatory response to hypotension 8
• Bradycardia can paradoxically occur due to the Bezold-Jarisch reflex (cardioinhibitory vagal response), particularly in patients with conduction defects or on sympatholytic medications 8, 9

Respiratory Pathophysiology

Upper Airway Obstruction

• Angioedema of the lips, tongue, uvula, and larynx causes mechanical obstruction 8
• Laryngeal edema with stridor represents life-threatening upper airway compromise 8

Lower Airway Involvement

• Bronchial smooth muscle contraction from histamine, leukotrienes, and PAF causes bronchospasm 4, 2
• Mucus hypersecretion and mucus plugging can lead to complete airway obstruction 1
• Asphyxia results from either upper airway occlusion or severe lower airway bronchospasm 1

Clinical Heterogeneity and Time Course

Onset and Progression

• The "rule of 2s": Reactions typically begin within 2 minutes to 2 hours after exposure to the trigger 2
• Rapid onset predicts severity: The more rapidly anaphylaxis develops after exposure, the more likely it is to be severe and life-threatening 8, 1
• Death from food-induced anaphylaxis can occur within 30 minutes to 2 hours of exposure 8

Reaction Patterns

Uniphasic reaction: Occurs immediately, resolves with or without treatment within minutes to hours, does not recur 8

Biphasic reaction:

• Recurrence of symptoms after apparent complete resolution of initial reaction 8, 9
• Occurs in 1% to 20% of anaphylaxis episodes (estimates vary widely) 8, 1
• Typically occurs ~8 hours after initial reaction but can occur up to 72 hours later (mean 11 hours) 8, 9
• Represents recurrent mediator release, not continuation of initial reaction 1

Protracted reaction: Anaphylaxis lasting hours to days (up to 32 hours) despite aggressive treatment 8

Refractory Anaphylaxis

• Defined as insufficient response after 10 minutes of appropriate epinephrine dosing and fluid resuscitation 9
• Occurs in approximately 4% of severe anaphylaxis cases 9
• Risk factors: cardiovascular disease, older age, severe initial presentation 9

Organ System Manifestations

Cutaneous (Most Common)

• Urticaria and angioedema are present in the majority of cases but may be delayed or completely absent in rapidly progressive anaphylaxis 8, 9
• Generalized flushing, pruritus, and erythema occur from histamine-induced vasodilation 8

Respiratory (Up to 70% of Cases)

• Dyspnea, wheeze, cough, stridor, choking sensation 8
• Reduced peak expiratory flow rate, hypoxemia 8

Cardiovascular

• Hypotension, syncope, circulatory collapse 8
• Tachycardia (or paradoxical bradycardia) 8
• Cardiac arrhythmias 8

Gastrointestinal (Up to 40% of Cases)

• Cramping abdominal pain, nausea, vomiting, diarrhea 8

Neurologic

• Altered mental status from hypoxia or hypotension 8, 1
• Feeling of impending doom, lightheadedness, headache 8

Patient-Specific Modifying Factors

Comorbidities Increasing Severity

• Asthma, especially poorly controlled, significantly increases risk of fatal anaphylaxis 8
• Cardiovascular disease increases risk of refractory anaphylaxis and cardiac complications 1, 9
• Mastocytosis or elevated baseline tryptase predisposes to more severe reactions 1

Medications Affecting Response

• Beta-adrenergic blockers: Increase severity of anaphylaxis, reduce epinephrine effectiveness, may cause paradoxical bradycardia 8, 7
• ACE inhibitors: Increase severity and reduce response to treatment 7
• These medications do not contraindicate epinephrine use but may require higher doses or alternative vasopressors 9

Summation Anaphylaxis

• Individuals may only develop anaphylaxis when allergen exposure coincides with infection, physical exercise, psychological stress, or certain medications 5
• This phenomenon likely explains many cases previously labeled "idiopathic anaphylaxis" 5

Critical Pathophysiologic Distinctions

Anaphylaxis is not a homogeneous process—the specific pathways, mediators, time course, and treatment response depend on the trigger agent, route and rate of administration, nature of the patient's hypersensitivity, and patient-specific factors including comorbidities and medications. 1