The definition of anaphylaxis

The term anaphylaxis is derived from Greek words for “against protection.” It was coined in over 100 years ago during some ill-fated experiments to immunize dogs to sea anemone venom. Instead of developing a tolerance, the dogs had progressively worsening reactions to the venom. This was the opposite of the intended protective effect and so anaphylaxis was named.  (Lieberman P, et al. Anaphylaxis –a practice parameter update 2015. Annals of Allergy, Asthma & Immunology 2015: 115(5), 341-384.)

 

The following were agreed upon a roundtable meeting for Anaphylaxis in Emergency Medicine, July 2011.

Working definition of anaphylaxis:

  • Anaphylaxis is a serious reaction that is rapid in onset and may cause death. It is usually due to an allergic reaction but can also be non-allergic.

Consensus statements:

  • The traditional mechanistic definition of anaphylaxis is not useful at the bedside.
  • Most acute episodes of anaphylaxis are managed by ED clinicians and not by allergists.
  • Anaphylaxis is underdiagnosed (and, hence, undertreated) in most pre-hospital care situations and EDs.
  • It is important for pre-hospital and emergency medicine providers to recognize that a patient can have anaphylaxis without shock.
  • Anaphylaxis causes significant morbidity and can be fatal.
  • Epinephrine should be the first-line treatment for all pre-hospital and ED patients with anaphylaxis.
  • There are no absolute contraindications to the use of epinephrine for anaphylaxis. Serious adverse effects are very rare when epinephrine is administered at the appropriate intramuscular doses for anaphylaxis.
  • Anaphylaxis is a long-term diagnosis, and management does not end with discharge from ED.
  • Outcomes data are needed.

Anaphylaxis has been defined several times with different criteria. I have selected definitions that I feel are demonstrative of the evolution of these criteria.  This list is not exhaustive.

The 2006 NIAID/FAAN criteria are the most frequently used to define patients to include in studies.  This data has also been validated with subsequent studies. (Sampson HA, et al. 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. J Allergy Clin Immunol 2006: 117(2), 391-397.)

Definitions and criteria of anaphylaxis
Year Source Definitions and statements Diagnostic criteria
1945 Cooke RA. Allergy in theory and practice. Philadelphia, PA: W. B. Saunders Company; 1945:5. Defined anaphylaxis as “A special of particular immunologic type of induced protein (or hapten) sensitivity in man or experimental animals and may properly be considered as a subdivision of allergy.”
1970s Nonspecific; in text of book “Anaphylaxis and hypersensitivity reactions” edited by M Castells Defined anaphylaxis as “a systemic, immediate hypersensitivity reaction caused by IgE-mediated immunologic release of mediators from mast cells and basophils.”

Defined anaphylactoid reaction as “a similar reaction without evidence of IgE involvement.”

 

1998 Joint Task Force on Practice Parameters Defined anaphylaxis as “immediate systemic reaction caused by rapid, IgE-mediated immune release of potent mediators from tissue mast cells and peripheral basophils.”

Defined anaphylactoid reaction as “reaction that mimic signs and symptoms of anaphylaxis, but are caused by a non-IgE mediated release of potent mediators from mast cells and basophils.”

2003 World Allergy Organization (WAO) Expanded definition of anaphylaxis to include immunologic events (with or without IgE) and non-immunologic (contrast, vibration, temperature, etc).

Recommended term “anaphylactoid reaction” be abandoned and term “nonallergic anaphylaxis” used instead.

2004 Brown, SGA. Clinical features and severity grading of anaphylaxis. Journal of Allergy and Clinical Immunology 2004: 114(2), 371-376. Recommended grading system for generalized hypersensitivity reactions. Grade 1: Mild

Skin and subcutaneous tissues only

Generalized erythema (redness/flushing), urticaria (hives), periorbital edema (swelling around eyes), or angioedema (swelling).

Can also be subdivided as with or without angioedema.

Grade 2: Moderate

Features suggesting respiratory, cardiovascular, or gastrointestinal involvement

Dyspnea (difficulty breathing), stridor, wheeze, nausea, vomiting, presyncope (dizziness/about to pass out), diaphoresis (sweating), chest or throat tightness, or abdominal pain.
Grade 3: Severe

Hypoxia (low blood oxygenation), hypotension (low blood pressure), or neurologic compromise

Cyanosis (turning blue), pulse oxygenation less than 92%, systolic blood pressure below 90 mm Hg (for adults), confusion, collapse, loss of consciousness, incontinence
2005 Sampson HA, et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol 2005; 115(3), 584-591. Recommended three specific scenarios that would identify anaphylaxis. Cautioned that these criteria are for classic anaphylaxis and may not cover non-immunologic anaphylaxis cases, such as exercise anaphylaxis.

Anaphylaxis is likely when any 1 of the 3 criteria are fulfilled.

1 Onset of illness within minutes to hours with involvement of:

Skin/mucosal tissue (hives, generalized itch, flush, swollen tips/tongue) and airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow)

Onset of illness within minutes to hours with involvement of:

Skin/mucosal tissue (hives, generalized itch, flush, swollen tips/tongue) and low blood pressure or associated symptoms (low muscle tone, fainting)

2 Onset of illness within minutes to hours with involvement of two or more of the following after exposure to known allergen for that patient:

History of severe allergic reaction

Skin/mucosal tissue (hives, generalized itch, flush, swollen tips/tongue)

 

Airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow)

Low blood pressure or associated symptoms (low muscle tone, fainting)

In suspected food allergy: gastrointestinal symptoms (crampy abdominal pain, vomiting)

3 Onset of low blood pressure within minutes to hours after exposure to known allergen for that patient:

For adults, systolic blood pressure less than 100 mm Hg or decrease from baseline by 30% or more

For children, low systolic blood pressure for age or decrease from baseline by 30% or more

 

 

2006 Sampson HA, et al. 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. J Allergy Clin Immunol 2006: 117(2), 391-397. Recommended three specific scenarios that would identify anaphylaxis. Cautioned that these criteria may only identify 95% of anaphylaxis cases.

 

Anaphylaxis is highly likely when any 1 of the 3 criteria are fulfilled.

These definitions have been used frequently to identify whether or not epinephrine is indicated to treat potential anaphylaxis.

 

These criteria have been validated, please refer to:

 

Campbell RL, et al. Evaluation of National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria for the diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol 2012; 129, 748-752.

1 Onset of illness within minutes to several hours with involvement of:

Skin/mucosal tissue (generalized hives, itching, flushing, swollen lips/tongue/uvula) and airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow, low blood oxygenation)

Onset of illness within minutes to several hours with involvement of:

Skin/mucosal tissue (generalized hives, itching, flushing, swollen lips/tongue/uvula) and low blood pressure or associated symptoms of end-organ dysfunction (low muscle tone/collapse, fainting, incontinence)

2 Onset of illness within minutes to several hours with involvement of two or more of the following after exposure to likely allergen for that patient:

 

History of severe allergic reaction

Skin/mucosal tissue (generalized hives, itching, flushing, swollen lips/tongue/uvula)

Airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow, low blood oxygenation)

 

Low blood pressure or associated symptoms of end-organ dysfunction (low muscle tone/collapse, fainting, incontinence)

Persistent gastrointestinal symptoms (crampy abdominal pain, vomiting)

3 Onset of low blood pressure within minutes to hours after exposure to known allergen for that patient:

 

For adults, systolic blood pressure less than 100 mm Hg or decrease from baseline by 30% or more

For children, low systolic blood pressure for age or decrease from baseline by 30% or more

2007 Kroigaard M, et al. Scandinavian clinical practice guidelines on the diagnosis, management and follow-up of anaphylaxis during anesthesia. Acta Anaesthesiol Scand 2007: 51, 655-670. Assign severity grades for anaphylaxis. Grade 1 Generalized skin symptoms: flushing, hives, possible angioedema
Grade 2 Moderate multiorgan involvement with skin symptoms, low blood pressure, tachycardia, airway reactivity (cough, difficulty breathing)
Grade 3 Severe life threatening multiorgan involvement that requires specific treatment: collapse, tachycardia or bradycardia, arrhythmias, bronchospasm. Skin symptoms may not be present.
Grade 4 Circulatory or respiratory arrest
Grade 5 Death due to a lack of response to cardiorespiratory resuscitation
2007 Ruggeberg JU, et al. Anaphylaxis: Case definition and guidelines for data collection, anaphylaxis, and presentation of immunization safety data. Vaccine 2007: 25, 5675-5684. Both defined anaphylaxis and attached diagnostic algorithm for “level of diagnostic certainty”, a measure of how confident a provider could be that anaphylaxis was the correct diagnosis.

 

Anaphylaxis was defined as “a clinical syndrome characterized by sudden onset AND rapid progression of signs and symptoms AND involving multiple (2 or more) organ systems as follows.”

Level 1 of diagnostic certainty

 

Highest level of certainty

One or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness)
One or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting)
Level 2 of diagnostic certainty

 

Moderate level of certainty

One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting)
One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more minor criterion involving one or more system besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)

 

One or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting) and one or more minor criterion involving one or more system besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)
One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more minor cardiovascular symptom (reduced peripheral circulation with at least 2 of 3 manifestations: tachycardia, capillary refill time >3 seconds without low blood pressure, decreased level of consciousness)
One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more minor respiratory symptom (persistent dry cough, hoarse voice, difficulty breathing without wheeze or stridor, sensation of throat closure, sneezing, stuffy nose)

 

One or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting) and one or more major dermatological symptom (hives or flushing, local or generalized) angioedema, generalized itching with rash) and one or more minor cardiovascular symptom (reduced peripheral circulation with at least 2 of 3 manifestations: tachycardia, capillary refill time >3 seconds without low blood pressure, decreased level of consciousness)
One or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting) and one or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) one or more minor respiratory symptom (persistent dry cough, hoarse voice, difficulty breathing without wheeze or stridor, sensation of throat closure, sneezing, stuffy nose)
Level 3 of diagnostic certainty

 

Low level of certainty

One or more minor respiratory symptom (persistent dry cough, hoarse voice, difficulty breathing without wheeze or stridor, sensation of throat closure, sneezing, stuffy nose) and one or more minor criterion involving two or more systems besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)

 

One or more minor cardiovascular symptom (reduced peripheral circulation with at least 2 of 3 manifestations: tachycardia, capillary refill time >3 seconds without low blood pressure, decreased level of consciousness) and one or more minor criterion involving two or more systems besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)
2010 Ring J, et al. History and classification of Anaphylaxis. Chem Immunol Allergy 2010: 95, 1-11. Assigned severity grade based upon worst symptom Grade 1 Skin (itching, flushing, urticaria, angioedema)
Grade 2 Skin (itching, flushing, urticaria, angioedema may or may not be present

GI (nausea, cramps)

Respiratory (stuffy nose, hoarseness, difficulty breathing, arrhythmia) Cardiovascular (increase of over 20 bpm, systolic blood pressure decreased by at least 20 mm Hg)

Grade 3 Skin (itching, flushing, urticaria, angioedema may or may not be present)

GI (vomiting, defecation)

Respiratory (swelling in airway, bronchospasm, turning blue)

 

Cardiovascular (shock)

Grade 4 Skin (itching, flushing, urticaria, angioedema may or may not be present)

GI (vomiting, defection)

Respiratory (respiratory arrest)

Cardiovascular (circulatory arrest)

2013 Ito K. Diagnosis of food allergies: the impact of oral food challenge testing. Asia Pac Allergy 2013: 3(1): 59-69. Identified severity of anaphylaxis based upon grade of most severe symptom. Grade 1

Per primary source, grade 1 is NOT considered anaphylaxis.

Skin (local itching, rash, hives, angioedema)

GI (oral itchiness, discomfort, lip swelling)

Respiratory (throat itchiness, discomfort)

Grade 2 Skin (systemic itching, rash, hives, angioedema)

 

GI (nausea, vomiting, diarrhea, transient colic)

Respiratory (mild nasal congestion, sneezing, single coughing)

Neurologic (loss of activity)

Grade 3 Skin (systemic itching, rash, hives, angioedema)

 

GI (repeated vomiting, diarrhea, persistent colic)

Respiratory (severe nasal congestion, repeated sneezing, continuous coughing, throat itching)

Cardiovascular (heart rate increased by 15 bpm or more)

 

Neurologic (anxiety)

Grade 4 Skin (systemic itching, rash, hives, angioedema)

 

GI (repeated vomiting, diarrhea, persistent colic)

Respiratory (choking sensation, hoarse voice, barking cough, difficulty in swallowing, wheezing, trouble breathing, turning blue)

 

Cardiovascular (arrhythmia, decreased blood pressure)

Neurologic (irritability, sense of impending doom)

Grade 5 Skin (systemic itching, rash, hives, angioedema)

GI (repeated vomiting, diarrhea, persistent colic)

 

Respiratory (respiratory arrest)

 

Cardiovascular (severe bradycardia, severe hypotension, cardiac arrest)

Neurologic (loss of consciousness)

7 Responses

  1. Mark June 19, 2016 / 3:35 am

    As you underscore, the 2006 “Consensus” criteria/definition of Anaphylaxis have been validated. The authors/experts called for their universal embrace, and the WAO, NIH, FDA, many other experts/authorities have followed suit. Some mastocytosis researchers have unsoundly deviated from Consensus recommendations in dictating discredited proposed criteria to exclude MCAD/S diagnosis — exclusions none advocate in readily diagnosing mediator afflictions w/ mastocytosis patients. But these are rogue positions at odds with Consenses of Anaphylaxis/ER experts and unrefuted scientific data on which these are soundly based. Why should we not embrace the “validated” Anaphylaxis Consensus and reject the rogue dictates from some powers that be in Masto-world seeking to impose their scientifically indefensible double standards to exclude comprehensively diagnosing the Systemic Mast Cell Disorders plaguing most of us?

  2. becca June 19, 2016 / 8:38 am

    re: anaphylaxis without shock.
    Can you define shock? Many of your criteria for anaphylaxis are what I thought was “shock,” especially low bp. So:
    Do you know why they define their concern only about a drop in “systolic” pressure?

  3. Donsnyder June 19, 2016 / 10:24 am

    Great review

  4. Tara June 27, 2016 / 4:17 pm

    Hi Lisa!

    Thank you so much for this detailed explanation. Is it common (or in your experience) for flushing to feel like a sunburn? When I flush, it feels exactly like a sunburn (red, burning, even slightly itchy) and occurs on my chest, back, and upper arms.

    • Lisa Klimas June 28, 2016 / 1:44 pm

      Yup, sure is. I get bright red especially under my chin, down my neck and across my chest. Sometimes gets itchy but I’m lucky (knock on wood) that it’s not terrible. If you can tolerate cold, putting an icepack on an itchy area often minimizes it pretty quickly.

      • Tara June 28, 2016 / 11:00 pm

        Great tip! Thank you 🙂

  5. Mark June 30, 2016 / 9:31 am

    What supports their assertion that most anaphylaxis is “allergic”? I wonder if true, it’s only because of food anaphylaxis in kids. The vast majority of severe reactions to drugs, radiocontrast, I gather “supplements”, are reportedly Anaphylactoid; presumably our many “idiopathic” episodes; most induced by physical stimuli.

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