Anaphylaxis

Diagnosis

Indications for Testing

• Flushing, angioedema, pruritus, hives, shortness of breath, wheezing, nausea, vomiting, diarrhea, hypotension, oxygen desaturation, and cardiovascular collapse (Castells, 2017)
• Atypical – chills and fever that accompany reactions to chemotherapeutic drugs; pain that accompanies reactions to taxane or monoclonal antibodies (Castells, 2017)

Criteria for Diagnosis

• Diagnosis is based on one of the following three criteria (Lieberman; American Academy of Allergy, Asthma and Immunology [AAAAI]; the American College of Allergy, Asthma and Immunology [ACAAI], 2010)
  • Acute onset of a reaction, within minutes or hours, involving skin and/or mucosal tissue, plus
    • Respiratory compromise OR
    • Reduced blood pressure or signs of end-organ dysfunction
  • Two or more of the following after exposure to likely allergen for specific patient
    • Skin or mucosal tissue involvement
    • Respiratory compromise
    • Reduced blood pressure or related symptoms
    • Persistent gastrointestinal symptoms
  • Reduced blood pressure after exposure to known allergen

Laboratory Testing

• Tryptase (serum)
  • Increased serum levels may confirm diagnosis – elevations may occur in 62% of patients (Simons, 2013)
  • Specific but not sensitive for diagnosis (Castells, 2017)
  • Testing most informative 15-180 minutes after symptom onset
    • Increased concentration may persist for 4-6 hours
  • Normal levels do not rule out anaphylaxis
    • More common to have normal levels in food allergy anaphylaxis
  • Postmortem femoral vein sampling may be useful to confirm anaphylaxis as cause of death – must be within ≤1 hour of death
    • Not definitive, as myocardial infarction, trauma, or asphyxia may also cause increased tryptase level
• Histamine
  • Serum or plasma
    • Levels peak 5 minutes after onset of anaphylaxis and return to baseline within 30-60 minutes
      • Testing may not be feasible, as levels must be obtained at symptom onset
    • Basophil activation during clotting may cause artifactual elevation
  • Urine
    • Histamine metabolite (N-methylhistamine) is measured
      • Remains elevated in urine for many hours after anaphylaxis
      • Preferred specimen is 24-hour urine
    • Reflects overall levels of released histamine
• IgE allergen serum testing
  • Used to identify potential allergens to enable allergen avoidance or desensitization
  • Multiple allergen IgE testing (based on suspected allergens) may be appropriate
    • IgE panel tests include insect and bee venom, food, inhalant, and other allergens
• CD63 and CD203 expression by flow cytometry
  • ​Newer tests
  • Markers of basophil activation
• Testing to rule out mastocytosis
  • Mastocytosis should be considered and ruled out in severe anaphylaxis
  • Flow cytometry, serum IgE, baseline tryptase (ie, not during acute event), and KIT D816V mutation testing should be considered in addition to clinical evaluation (Bonadonna, 2015)

Differential Diagnosis

• Respiratory symptoms (eg, dyspnea, wheezing)
  • Asthma
  • Acute congestive heart failure
  • Chronic obstructive pulmonary disease (COPD)
  • Foreign body in airway
  • Pulmonary embolism
  • Vocal cord dysfunction syndrome
• Cutaneous symptoms
  • Alcohol-induced flush
  • Basophilic leukemia
  • Carcinoid tumor
  • Flush syndrome
  • Hereditary or acquired angioedema
  • Systemic mastocytosis
  • Urticarial vasculitis
• Cardiovascular symptoms (eg, hypotension, tachycardia)
  • Acute myocardial infarction
  • Toxin ingestion
  • Cardiogenic shock (eg, acute congestive heart failure)
  • Hypoglycemia
  • Hypovolemic shock
  • Panic attack
  • Pulmonary embolism
  • Septic shock
  • Thyrotoxicosis
  • Vasovagal response
• Neurologic symptoms (eg, syncope)
  • Acute poisoning
  • Anxiety/panic disorder
  • Hypoglycemia
  • Seizure disorder
  • Stroke
  • Psychosis

Background

Epidemiology

• Incidence
  • 50-103 cases/100,000 person-years (Tejedor-Alonso, 2015)
• Prevalence
  • 1.6% in general U.S. population (Wood, 2013)
• Age – all
  • Most deaths from anaphylaxis occur in teens and the elderly (Tejedor-Alonso, 2015)

Risk Factors

• Previous history of anaphylaxis
• Hives or urticaria following allergen exposure
• One or more comorbidities
  • Asthma, atopic eczema, allergic rhinitis
  • Mastocytosis

Pathophysiology

• Involves activated mast cell release of multiple substances – cytokines, histamine, tryptase, prostaglandins
  • Common triggers include food, drugs, insect stings, exercise, vaccines
• IgE-immediate hypersensitivity
  • Medications
    • Most common – penicillin and related antibiotics
  • Foods – most frequent cause of anaphylaxis
    • Most common foods – fish, shellfish, peanuts, tree nuts, soy, eggs, wheat, and milk
  • Insect venoms
• IgE independent
  • Cold, heat
  • Drugs – opioids, muscle relaxants, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors
  • Exercise
  • Radiocontrast media
• Interval between exposure and anaphylaxis onset depends on allergen
  • Food – 25-30 minutes after ingestion
  • Drugs – 10-20 minutes after administration
  • Insect stings – 10-15 minutes after sting
  • Blood or blood products in patients with IgA deficiency (no detectable level of IgA) – 10-20 minutes after administration
• Allergies that trigger anaphylaxis may change with time

Clinical Presentation

• Acute onset of illness
  • May have biphasic recurrence 6-8 hours after initial episode
• Respiratory
  • Lower airway
    • Bronchospasm
    • Dyspnea
    • Tachypnea
    • Wheezing
  • Upper airway
    • Laryngeal wheezing
    • Lip swelling
    • Rhinitis
    • Stridor
    • Tongue edema
• Cutaneous/mucosal tissue
  • Most common symptoms
    • Urticaria
    • Generalized pruritus without rash
    • Angioedema
    • Erythema/flush
    • Conjunctivitis
    • Rhinitis
• Cardiovascular
  • Hypotension
  • Tachycardia
  • Cardiac arrest
  • Angina
  • Cardiac arrhythmias
• Gastrointestinal
  • Abdominal cramps
  • Diarrhea
  • Emesis
  • Nausea
• Neurologic
  • Dizziness
  • Syncope
  • Seizures