What is anaphylaxis, its clinical manifestations, pathophysiology, diagnosis, and management?

Anaphylaxis: Comprehensive Overview

Definition and Etiopathogenesis

Anaphylaxis is an acute, life-threatening systemic allergic reaction resulting from sudden release of mediators from mast cells and basophils, with IgE-mediated (anaphylactic) and non-IgE-mediated (anaphylactoid) mechanisms producing identical clinical presentations. 1

Mechanistic Pathways

• IgE-dependent mechanism: IgE antibodies bind and cross-link the high-affinity IgE receptor (FcεRI) on mast cells and basophils, triggering degranulation 1
• Non-IgE-dependent mechanisms: Direct mast cell activation or complement activation produces clinically identical reactions 2, 3
• Additional cellular involvement: Neutrophils, monocytes, macrophages, and platelets participate through mediators including complement components, cysteinyl leukotrienes, platelet-activating factor, IL-6, IL-10, and TNF-receptor 1 1

Common Triggers

• Adults: Medications and stinging insects are the leading triggers 1
• Children and adolescents: Foods (particularly peanuts, tree nuts, fish, shellfish, milk, eggs) and stinging insects predominate 1
• Unidentified triggers: Occur in up to 20% of cases (idiopathic anaphylaxis) 4
• Drug reactions: Affect up to 10% of the general population and 20% of hospitalized patients, with hypersensitivity reactions accounting for 10% of all adverse drug reactions 1

Clinical Manifestations

The more rapidly anaphylaxis develops after exposure, the more likely the reaction is severe and potentially life-threatening. 1

System-Specific Presentations

Cutaneous (90% of cases): 4

• Diffuse erythema, pruritus, urticaria, and/or angioedema 1
• Critical caveat: Skin manifestations may be delayed or absent in rapidly progressive anaphylaxis, particularly with cardiovascular collapse 1

Respiratory (40-60%): 4

• Upper airway: Dysphonia, stridor, laryngospasm, airway swelling 1
• Lower airway: Cough, wheezing, bronchospasm, shortness of breath 1

Cardiovascular (30-35%): 4

• Hypotension with or without syncope 1
• Tachycardia (typical), though bradycardia can occur due to Bezold-Jarisch reflex or in patients with conduction defects 1
• Cardiac arrhythmias 1
• Thready or unobtainable pulse 5

Gastrointestinal (25-30%): 4

• Nausea, vomiting, diarrhea, abdominal cramps 1
• Involuntary voiding 5

Neurological/Other:

• Altered level of consciousness (suggesting hypoxia) 1
• Lightheadedness, headache, feeling of impending doom 1
• Uterine cramps 1

Temporal Patterns

• Typical onset: Within minutes of allergen exposure, though reactions may develop >30 minutes later 1
• Biphasic reactions: Recurrence 1-72 hours (mean 11 hours) after resolution of initial episode, occurring in <1% to 20% of patients 1, 6
• Protracted anaphylaxis: May last up to 32 hours despite aggressive treatment 1

Pathophysiology

A characteristic feature of anaphylaxis is increased vascular permeability, allowing transfer of up to 50% of intravascular fluid into the extravascular space within 10 minutes, resulting in rapid hemodynamic collapse with minimal or absent cutaneous/respiratory manifestations. 1

Mediator Effects on Target Tissues

• Blood vessels: Vasodilation and increased permeability leading to hypotension 3
• Smooth muscle: Bronchospasm and gastrointestinal cramping 3
• Mucous glands: Increased secretions 3
• Nerve endings: Pruritus and pain 3

Key Mediators

• Histamine: Primary mediator causing immediate symptoms 3
• Lipid mediators: Leukotrienes and platelet-activating factor 3
• β-tryptase: Secreted in large amounts during mast cell degranulation 2

Diagnostic Plan

Anaphylaxis is a clinical diagnosis that must be made rapidly; confirmatory testing has poor sensitivity and should never delay treatment. 1

Clinical Diagnostic Criteria

The NIAID criteria (2006) provide a framework with 95% sensitivity and 71% specificity in emergency settings, though fulfilling criteria is NOT a prerequisite for epinephrine administration. 1

Initial Assessment Algorithm

1. Evaluate airway, breathing, circulation, and level of consciousness 1
2. Assess upper and lower airways: Dysphonia, stridor, cough, wheezing, shortness of breath 1
3. Cardiovascular examination: Blood pressure, heart rate, pulse quality 1
4. Skin examination: Erythema, pruritus, urticaria, angioedema 1
5. Gastrointestinal symptoms: Nausea, vomiting, diarrhea 1
6. Obtain exposure history: Setting and timing of symptom onset relative to potential triggers 1

Laboratory Testing

Serum tryptase levels (when diagnosis is unclear): 4

• Obtain at 1 hour and 2-4 hours after reaction onset 6
• Baseline sample at least 24 hours post-reaction 6
• Interpretation: Total tryptase to β-tryptase ratio ≤10 suggests anaphylaxis without systemic mastocytosis; ratio ≥20 suggests systemic mastocytosis 2
• Critical limitation: Proper timing is essential; tests are not helpful in acute management 7

Differential Diagnosis

Vasodepressor (vasovagal) reaction - most commonly confused with anaphylaxis: 1

• Urticaria absent
• Bradycardia (not tachycardia)
• Bronchospasm absent
• Blood pressure normal or increased
• Skin cool and pale (not flushed)

Other conditions to exclude: 1, 2

• Acute anxiety/panic attack/hyperventilation
• Myocardial dysfunction
• Pulmonary embolism
• Systemic mast cell disorders
• Foreign-body aspiration
• Acute poisoning
• Hypoglycemia
• Seizure disorder
• Hereditary angioedema
• Asthma exacerbation
• Flushing syndromes
• Scombroidosis
• Vocal cord dysfunction syndrome

Management

Epinephrine is the first-line, life-saving drug for anaphylaxis and should be administered promptly at the onset of apparent anaphylaxis; when in doubt, it is better to give epinephrine. 1, 5

Immediate Intervention Protocol

Step 1: Position and Assess 6

• Place patient supine or in Trendelenburg position to improve venous return 6
• Assess airway, breathing, circulation, level of consciousness 1
• Call for help and activate emergency medical services 1

Step 2: Administer Epinephrine Immediately 1, 5

• Dose: Aqueous epinephrine 1:1000 (1 mg/mL), 0.2-0.5 mL intramuscularly (0.01 mg/kg in children, maximum 0.3 mg) 1
• Route: Intramuscular injection into the lateral thigh (provides more rapid absorption and higher plasma levels than subcutaneous) 1
• Repeat: Every 5 minutes as necessary to control symptoms and increase blood pressure 1
• FDA indication: Emergency treatment of Type I allergic reactions including anaphylaxis 5

Step 3: Provide Oxygen and Establish IV Access 1

• Administer supplemental oxygen 6
• Establish intravenous access 7

Step 4: Volume Resuscitation 1, 6

• Crystalloids initially, then colloid volume substitutes in severe shock 7
• Rapid and adequate volume replacement is crucial 1, 6

Adjunctive Medications (ONLY after epinephrine)

H1-antihistamines: 1, 6

• Administer intravenously if possible 7
• Valuable in mild reactions; relieve itching and hives within 30-40 minutes 8
• Not a priority in acute management 6

Corticosteroids: 1, 6

• Given after adequate resuscitation to prevent protracted or biphasic reactions 7
• No immediate role in acute management 6

Inhaled β2-agonists: 6

• For persistent bronchospasm 6
• Consider IV bronchodilators if respiratory symptoms persist 6

Glucagon: 6

• For patients taking β-adrenergic receptor blockers: IV glucagon 1-2 mg 6

Refractory Anaphylaxis Management

Refractory anaphylaxis is defined as insufficient response after 10 minutes of sustained inadequate response despite appropriate epinephrine dosing and fluid resuscitation. 6

Protocol for refractory cases: 6

1. Re-evaluate after 10 minutes of standard treatment 6
2. Confirm adequate epinephrine dosing and volume resuscitation 6
3. Double the initial bolus dose of epinephrine 6
4. Start epinephrine infusion after three total bolus doses 6
5. Consider alternative vasopressors: vasopressin, norepinephrine, metaraminol, or phenylephrine 6
6. Consider extracorporeal life support where available 6

Observation Period

• Standard cases: Minimum 4 hours after symptom resolution 7, 4
• Severe reactions or risk factors for biphasic reaction: 6-12 hours observation 4
• Refractory anaphylaxis: Minimum 6 hours extended observation 6

Risk Factors for Severe or Fatal Anaphylaxis

• Cardiovascular disease 1, 6
• Asthma (especially severe, uncontrolled) 1, 7
• Older age 1, 6
• Peanut and tree nut allergy 4
• Drug-induced reactions 4
• Mast cell disorders 4
• Patients taking β-adrenergic blockers 7

Post-Acute Management

All patients who experience anaphylaxis require comprehensive follow-up care. 1

Essential components: 1, 6

• Education on anaphylaxis and risk of recurrence 1
• Trigger avoidance counseling (most effective treatment) 1
• Prescription of epinephrine auto-injector 1
• Training in self-administration of epinephrine 1
• Written emergency action plan 9
• MedicAlert identification jewelry 1, 10
• Referral to allergist-immunologist 1, 6

Indications for allergist referral: 1

• Doubtful or incomplete diagnosis
• Recurrent or difficult-to-control symptoms
• Need for identification of allergic triggers
• Candidate for desensitization or immunotherapy
• Requires daily preventive medications
• Requires intensive education on avoidance/management
• Complicated by comorbid conditions or concomitant medications

Common Pitfalls to Avoid

• Delaying epinephrine administration: Epinephrine should never be withheld while waiting for other interventions 1
• Assuming absence of skin findings rules out anaphylaxis: Up to 20% lack cutaneous manifestations, especially in rapidly progressive cases 1, 10
• Relying on antihistamines as primary treatment: Severe respiratory/cardiovascular symptoms can appear suddenly even after hives disappear 8
• Premature discharge: Biphasic reactions can occur up to 72 hours later 1, 6
• Subcutaneous instead of intramuscular epinephrine: IM route into lateral thigh provides superior absorption 1
• Failing to provide epinephrine auto-injector and education: Essential for preventing mortality in future episodes 1, 9