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.

Tabs Content

Clinical Overview

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

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

Tryptase 0099173

Method: Quantitative Fluorescent Enzyme Immunoassay

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

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

Histamine, Whole Blood 0070037

Method: Quantitative Enzyme-Linked Immunosorbent Assay

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

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

Histamine, Plasma 0070036

Method: Quantitative Enzyme-Linked Immunosorbent Assay

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

Histamine, Urine 0070038

Method: Quantitative Enzyme Immunoassay

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

N-Methylhistamine, 24-Hour Urine 2011034

Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry/Colorimetry

Immunoglobulin E 0050345

Method: Quantitative ImmunoCAP® Fluorescent Enzyme Immunoassay

Medical Experts

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

Slev, Patricia R., PhD, Section Chief, Immunology; Medical Director, Serologic Hepatitis and Retrovirus and Immunology Core Laboratory; Co-Medical Director, Microbial Immunology, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson F, Bock A, Branum A, Brown SG, Camargo CA, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons E, Thomas S, Wood JP, Decker WW. Second symposium on the definition and management of anaphylaxis: summary report--second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006; 47(4): 373-80. PubMed
Muraro A, Roberts G, Simons ER. New visions for anaphylaxis: an iPAC summary and future trends. Pediatr Allergy Immunol. 2008; 19 Suppl 19: 40-50. PubMed
Simons ER, Ardusso LR, Bilò B, Dimov V, Ebisawa M, El-Gamal YM, Ledford DK, Lockey RF, Ring J, Sanchez-Borges M, Senna GE, Sheikh A, Thong BY, Worm M, World Allergy Organization. 2012 Update: World Allergy Organization Guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol. 2012; 12(4): 389-99. PubMed
Lieberman P, Camargo CA, Bohlke K, Jick H, Miller RL, Sheikh A, Simons ER. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol. 2006; 97(5): 596-602. PubMed
Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Rivas F, Santos AF, Zolkipli ZQ, Bellou A, Beyer K, Bindslev-Jensen C, Cardona V, Clark AT, Demoly P, Dubois AE, DunnGalvin A, Eigenmann P, Halken S, Harada L, Lack G, Jutel M, Niggemann B, Ruëff F, Timmermans F, Vlieg-Boerstra BJ, Werfel T, Dhami S, Panesar S, Akdis CA, Sheikh A, EAACI Food Allergy and Anaphylaxis Guidelines Group. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014; 69(8): 1026-45. PubMed
Bonadonna P, Pagani M, Aberer W, Bilò MB, Brockow K, Elberink O, Garvey L, Mosbech H, Romano A, Zanotti R, Torres MJ. Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper. Allergy. 2015; 70(7): 755-63. PubMed
Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, Bernstein JA, Burks W, Feldweg AM, Fink JN, Greenberger PA, Golden DB, James JM, Kemp SF, Ledford DK, Lieberman P, Sheffer AL, Bernstein DI, Blessing-Moore J, Cox L, Khan DA, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph C, Schuller DE, Spector SL, Tilles S, Wallace D. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. 2010; 126(3): 477-80.e1-42. PubMed
Simons ER, Ebisawa M, Sanchez-Borges M, Thong BY, Worm M, Tanno LK, Lockey RF, El-Gamal YM, Brown SG, Park H, Sheikh A. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organ J. 2015; 8(1): 32. PubMed

General References

Arnold JJ, Williams PM. Anaphylaxis: recognition and management. Am Fam Physician. 2011; 84(10): 1111-8. PubMed

Atkins D, Bock A. Fatal anaphylaxis to foods: epidemiology, recognition, and prevention. Curr Allergy Asthma Rep. 2009; 9(3): 179-85. PubMed

Ben-Shoshan M, Clarke AE. Anaphylaxis: past, present and future. Allergy. 2011; 66(1): 1-14. PubMed

Castells M. Diagnosis and management of anaphylaxis in precision medicine. J Allergy Clin Immunol. 2017; 140(2): 321-333. PubMed

Da Broi U, Moreschi C. Post-mortem diagnosis of anaphylaxis: A difficult task in forensic medicine. Forensic Sci Int. 2011; 204(1-3): 1-5. PubMed

Jones SM, Burks W. Food Allergy. N Engl J Med. 2017; 377(12): 1168-1176. PubMed

Liberman DB, Teach SJ. Management of anaphylaxis in children. Pediatr Emerg Care. 2008; 24(12): 861-6; quiz 867-9. PubMed

Sclar DA, Lieberman PL. Anaphylaxis: underdiagnosed, underreported, and undertreated. Am J Med. 2014; 127(1 Suppl): S1-5. PubMed

Simons ER, Sheikh A. Anaphylaxis: the acute episode and beyond. BMJ. 2013; 346: f602. PubMed

Tejedor-Alonso MA, Moro-Moro M, Múgica-García MV. Epidemiology of anaphylaxis. Clin Exp Allergy. 2015; 45(6): 1027-39. PubMed

Wood RA, Camargo CA, Lieberman P, Sampson HA, Schwartz LB, Zitt M, Collins C, Tringale M, Wilkinson M, Boyle J, Simons ER. Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States. J Allergy Clin Immunol. 2014; 133(2): 461-7. PubMed

Content Review:

February 2018

Last Update: October 2019

Anaphylaxis

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

ARUP Laboratories

ARUP Websites

ARUP Consult


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Anaphylaxis

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

ARUP Laboratories

ARUP Websites

ARUP Consult