Anaphylaxis

Anaphylaxis is an acute, potentially fatal hypersensitivity reaction that is most often IgE mediated and can involve multiple organ systems. Diagnosis is based on the clinical presentation, but testing of tryptase, histamine, and other inflammatory markers can support the diagnosis. Newer laboratory tests that may assist in diagnosis include flow cytometry tests for expression of CD63 and CD203, markers of basophil activation. Referral to an allergist for allergen testing is recommended. Individuals with mastocytosis appear to be at increased risk for anaphylaxis; this should be considered when evaluating patients with possible 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

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
  • Gastrointestinal
    • Abdominal cramps
    • Diarrhea
    • Emesis
    • Nausea
  • Neurologic
    • Dizziness
    • Syncope
    • Seizures

ARUP Lab Tests

Primary Tests

Measure total tryptase to confirm mast cell activation in diseases such as mastocytosis, anaphylaxis, urticaria, and asthma

Not generally used acutely except when diagnosis is unclear; useful in prognosis of systemic mastocytosis

Measures total tryptase; does not distinguish between alpha and beta protein types

Samples should be collected between 15 minutes and 3 hours after event suspected to have caused mast cell activation

Aid in evaluation of patient with allergic signs and symptoms, such as anaphylaxis

May assist in diagnosing and monitoring of mast-cell activation disorders

Aid in evaluation of patient with allergic signs and symptoms, such as anaphylaxis

May assist in diagnosing and monitoring of mast-cell activation disorders

Aid in evaluation of patient with allergic signs and symptoms, such as anaphylaxis

May assist when diagnosing and monitoring mast-cell activation disorders or when evaluating histamine production over a longer time frame

Aid in evaluation of patient with allergic signs and symptoms, such as anaphylaxis

May assist when diagnosing and monitoring mast-cell activation disorders or when evaluating histamine production over a longer time frame

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS
Professor of Clinical Pathology, University of Utah
Chief, Division of Clinical Pathology, University of Utah and ARUP Laboratories
Chief Medical Officer and Director of Laboratories at ARUP Laboratories
Contributor

Slev

Patricia R. Slev, PhD
Associate Professor of Clinical Pathology, University of Utah
Section Chief, Immunology; Medical Director, Immunology Core Laboratory, ARUP Laboratories

References

Additional Resources