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creation date: 2025-09-08 16:15
tags: Pathologies

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Anaphylaxis

Background

Definitions

Anaphylaxis refers to an acute, potential lethal, multi-system syndrome resulting from sudden release of mast cell and basophil-derived mediators into circulation.

In some definitions, the term “anaphylactoid reaction” has been used to describe IgE-independent incidents but as they are clinically indistinguishable, the term anaphylaxis is often used for both immunologic and nonimmunologic events.

Etiology

A number of causes can result in anaphylaxis. Most often, it occurs from immunologic reactions to foods, medications, and insect stings.

Rarer, it can be induced nonimmunologically by anything capable of producing sudden and systemic degranulation of mast cells or basophils. Examples of triggers are contrast medium and vancomycin.

Pathophysiology

In majority of cases, anaphylaxis involves immunoglobulin E (IgE). Interactions between environment and genetics may also contribute but are not well understood.

The generation of allergen-specific IgE involves genetic susceptibility, environmental exposures, and immune system regulation which will not be discussed in depth here. Regardless, sensitization to an allergen is a precursor to anaphylaxis.

The classical mechanism for IgE mediated anaphylaxis is described as follows:

1. Initiation by allergen (antigen) interacting with corresponding IgE bound to a receptor on mast cells and/or basophils. Some allergens can bind to multiple receptors which causes cross-linking - resulting in greater reactivity.
2. If signal is sufficient, the mast cell or basophil activates and degranulates
3. Preformed mediators (eg. histamine), enzymes (eg. tryptase), and cytokines (eg. tumour necrosis factor) are released
4. Additional mediator, cytokine, and enzymes are produced and additional inflammatory cells (especially eosinophils) are recruited
5. The allergic inflammation is propagated in a “chain reaction”

The manifestations of anaphylaxis result from the chemical mediators of the allergic reaction. This consist of the products of mast cells, basophils, and eosinophils, and components of the inflammatory pathways.

From mast cells and basophils:

• Histamine - localized release in skin causes urticaria; systemic release causes increase in heart rate, flushing and headache, and increase in pulse pressure, at low, moderate, and high plasma levels, respectively.
• Tryptase - abundant protease that activates complement, coagulation, and kallikrein-kinin contact pathways which can cause hypotension, angioedema, clotting, and clot lysis (which can cause disseminated intravascular coagulation)
• Platelet-activating factor - unclear role but may be associated with severity
• Nitric oxide - potent vasodilator which is implicated in hypotension (shock)
• Arachidonic acid metabolites - acts in numerous pathways to generate proinflammatory mediators that can cause bronchospasm, hypotension, erythema, and enhanced mast cell degranulation

Eosinophils may have proinflammatory effect through cytotoxic proteins but may also have anti-inflammatory effects through metabolism of vasoactive mediators.

Other factors present in circulation include those of the complement system, coagulation pathways, and the kallikrein-kinin contact system which concurrently activate during anaphylaxis.

The effect of the chemical mediators on target cells are mediated by cytokines which can influence the severity of anaphylaxis.

The onset of these effects occur over a period of minutes to hours following exposure to allergen. The time course is affected by:

• Route of entry (eg. injected allergen precipitate symptoms in seconds/minutes while ingested allergens occur in minutes to 1-2 hours)
• Type of allergen (eg. protein allergens have quicker onset than carbohydrates)

In cases of non-IgE-mediated anaphylaxis, mast cells are directly activated by the trigger.

Clinical Presentation

Signs & Symptoms

The exact presentation can vary based on mode of exposure. Anaphylaxis generally begins as a mild allergic reaction.

Manifestations by organ system include:
Cutaneous:

• Flushing
• Pruritis
• Urticaria
• Angioedema
  Respiratory:
• Nasal congestion
• Rhinorrhea
• Throat pruritis
• Laryngeal edema
• Stridor
• Choking
• Wheeze
• Cough
• Dyspnea
  Gastrointestinal:
• Cramping
• Abdominal pain
• Nausea
• Vomiting
• Diarrhea
  Cardiovascular:
• Dizziness
• Tachycardia
• Hypotension
• Hypotonia
  Neurologic:
• Anxiety
• Mental confusion
• Lethargy
• Seizures

Presentation of symptoms can also vary in terms of temporal patterns:

• Uniphasic (95%) - buildup of symptoms which peaks within hours and resolves spontaneously or after treatment
• Biphasic - Recurrence of symptoms following apparently resolution of initial episode with no additional exposure, typically within 12 hours after initial resolution
• Protracted - persistent reaction that lasts hours to days without clearly resolving
• Refractory - persistent anaphylaxis following three or more appropriate epinephrine dosing or initiation of IV epinephrine infusion
• Delayed - onset beginning hours (rather than minutes) after exposure; associated with alpha-gal syndrome (red meat allergy)

History & Physical Exam

Initial assessment should be rapid and any respiratory involvement should prompt aggressive treatment. Clinical vigilance for SIRS should be maintained.

Important elements of the history include:

• Known allergies and if there were exposure, and severity of past exposures
• Potential exposures if no known allergies

It should be noted that once stabilized, biphasic anaphylactic reactions should still be monitored for as they occur in 20% of cases.

Risk factors

Risk factors for developing anaphylaxis include:

• Genetic susceptibility
• Immune system regulation (impaired regulatory T-cell function lowers the threshold for mast cell and basophil activation)
• Exercise, alcohol, NSAIDs use, menstruation, and acute infection can lower threshold for anaphylaxis
• Comorbidities such as uncontrolled asthma and cardiovascular disease
• Older age
• Medications such as beta-blockers, ACE inhibitors, NSAIDs

Diagnosis

Criteria

Acute diagnosis

Diagnosis is made clinically based on signs and symptoms in addition to detailed description of antecedent activities/events.

Diagnosis can be made using either the NIAID/FANN diagnostic criteria or the WAO criteria.

NIAID/FANN criteria
Anaphylaxis is highly likely (Sn: 95-97%, Sp: 71-82%) if one of the following three criteria is met:

Criterion 1 - acute onset of illness (mins-hours) involving skin, mucosal tissue, or both and at least one of the following:

• Respiratory compromise
• Reduced blood pressure or associated symptoms and signs of end-organ malperfusion

Criterion 2 - two or more of the following that occur rapidly after exposure to a likely allergen for that patient:

• Involvement of skin-mucosal tissue
• Respiratory compromise
• Reduced blood pressure or associated symptoms/signs of end-organ malperfusion
• Persistent gastrointestinal symptoms and signs

Criterion 3 - reduced blood pressure after exposure to a known allergen for that patient:

• In adults, SBP <90 mmHg or >30% decrease from baseline
• In infants and children, SBP reduced by greater than 30% decrease from baseline or low SBP as defined:
  • Age 1 month to 1 year: <70 mmHg
  • Age 1 to 10 years: 70 + (2 $\times$ age) mmHg
  • Age 11 to 17 years: <90 mmHg

Note that these criteria are not strictly necessary, and epinephrine treatment is still indicated for. For example, a patient with known peanut allergy presenting with urticaria and flushing that developed following ingestion of peanut.

WAO criteria
This criteria is a simplified version of the NIAID/FANN criteria. This criteria is more novel but due to its lack of validation in large-scale studies, will not be discussed further here.

Confirmatory diagnosis

Confirmation of acutely diagnosed anaphylaxis or suspected anaphylaxis is done through allergist referral. This process includes:

• Detailed history including exposures, activities, chronology of events, and more
• Assessment of risk and comorbidities
• Review of laboratory results that may have been done at initial treatment
• Testing of allergen causes through allergen skin tests and/or elevated serum allergen-specific IgE levels

Work-up

Laboratory confirmation or workup is not required for anaphylaxis. However, some tests can be used to support the diagnosis:

• Serum tryptase
• Serum histamine

These tests have low sensitivity however, and thus cannot be used to rule out anaphylaxis. This may be used in follow-up evaluation though as results will not be available immediately.

Differential

There may be alternative diagnoses based on the presenting symptoms.

Important diagnoses not to miss are:

• Foreign body airway obstruction
• Pulmonary embolism (may present with dyspnea and other overlapping symptoms)
• Myocardial infarction

Other common alternative diagnoses include:

• Vasovagal syncope
• Panic/anxiety attack
• Acute asthma/COPD exacerbation
• Isolated urticaria-angioedema
• ACE-inhibitor induced angioedema
• Early sepsis
• Inherited C1-inhibitor deficiency (causes angioedema)

Red Flags / Complications

Management

Emergency Treatment

Initial Assessment and Management

Initial steps are often done simultaneously. If in a community setting, the patient should be brought to hospital via ambulance.

As soon as anaphylaxis is recognized, epinephrine should be administered.

Initial stabilization steps include:

• Assessment of airway, breathing, and circulation
• Administration of oxygen, via nonrebreather mask at 15 L/min or high-flow oxygen mask until no significant bronchospasm or upper airway obstruction is confirmed
• Removal of inciting cause if possible (eg. stopping infusion)
• Position patient (in cases of hypotensive, place patient in recumbent position; position pregnant patients on left to avoid IVC compression)
• Establish IV access
• Monitoring of BP, HR, respiratory rate, oxygen saturation

Epinephrine injection is the cornerstone of treatment and discussed below.

Assessment of the airway should be followed by consideration of airway interventions.

• Preparation for early intubation if there are airway involvement of significant edema in oral region
• Tracheal intubation should be performed if stridor or respiratory distress due to upper airway compromise is present
• Emergency cricothyroidotomy may be required if edema occludes glottic aperature

Fluid resuscitation should be performed on patients with hypotension or incomplete response to IM epinephrine. This consist of:

• Adult: 1-2L of crystalloid solution at most rapid flow rate possible
• Children: 20 mL/kg crystalloid solution in boluses over 5-10 minutes and repeated prn

Pharmacological Treatment

Epinephrine is administered intramuscularly in most settings and is preferred over IV due to faster response and greater safety.

Recommended dose is 0.01 mg/kg up to a maximum dose of 0.5 mg per single dose. Ampules of epinephrine are available as 1 mg/mL or 0.1 mg/mL. In 90% of cases, one dose is sufficient but if not, epinephrine can be repeated at 5-minute intervals or sooner if clinically needed.

In cases where IM injections are insufficient, IV infusion and then a slow IV bolus can be used (with differing dosing).

There are no absolute contraindications to epinephrine for anaphylaxis but some conditions such as cardiovascular diseases and certain antidepressant use may put the patient at higher risk of adverse event.

In patients taking beta-blockers who are refractory to epinephrine, glucagon can be administered: 1-5 mg slow IV bolus over 5 minutes, followed by infusion of 5-15 mcg/min titrated to effect. Note, rapid administration can induce vomiting.

Adjunctive agents may be used but no direct evidence support a benefit. These include:

• H1 and H2 antihistamines
• Bronchodilators
• Glucocorticoids

In refractory cases, other treatments may include:

• Other vasopressors (eg. vasopressin)
• Methylene blue
• Extracorporeal membrane oxygenation

Disposition

Duration of observation required varies based on severity with little consensus.

In simple cases such as a patient with uniphasic anaphylaxis responsive to one dose of epinephrine, observation for one hour following resolution of symptoms is typically sufficient.

In cases where biphasic reaction is suspected, further observation may be warranted. Risk factors for biphasic reactions include:

• Hypotension or severe respiratory compromise at presentation
• Multiple dose of epinephrine needed
• Delayed time to first epinephrine
• Unknown trigger

Discharge should consist of:

• Counselling for anaphylaxis emergency action plan
• Epinephrine prescription and instructions for use
• Instructions to follow up with allergist

Long-term Management

Long-term management consists of education and comorbidity management.

Education points include:

• Use of epinephrine (antihistamines and asthma inhalers insufficient)
• Preparation of treating recurrences including creating an action plan
• Medical identification with known causes of anaphylaxis

References

Tools / Guidelines

Additional Reading