# Anaphylaxis - Recognition and Management

## Definition and Epidemiology

Anaphylaxis is an acute, potentially fatal, multisystem allergic reaction that demands immediate recognition and treatment. The lifetime prevalence is estimated at 1.6 to 5.1 percent, with incidence increasing globally across all age groups. Despite advances in awareness and management, the fatality rate remains approximately 0.3 to 0.7 per million population per year in the United States. The most common triggers differ by age: foods predominate in children, while medications and Hymenoptera stings are the leading causes in adults. Biphasic anaphylaxis, defined as a recurrence of symptoms 1 to 72 hours after initial resolution without re-exposure to the trigger, has been reported in 1 to 20 percent of episodes, with the majority of biphasic events occurring within 4 to 12 hours of the initial reaction.

## Diagnostic Criteria (2019 WAO Updated Criteria)

The 2019 World Allergy Organization updated diagnostic criteria provide a practical clinical framework for identifying anaphylaxis. The diagnosis is considered highly likely when one of two criteria is met. The first criterion requires acute onset of illness (developing over minutes to hours) with skin or mucosal involvement (urticaria, flushing, or angioedema) plus at least one of the following: respiratory compromise (dyspnea, wheezing, stridor, or hypoxemia), cardiovascular compromise (hypotension, collapse, or syncope), or severe gastrointestinal symptoms (crampy abdominal pain or vomiting), particularly following exposure to a non-food allergen. The second criterion is met when there is acute onset of hypotension, bronchospasm, or laryngeal involvement after exposure to a known or highly probable allergen, even in the absence of skin findings.

| Trigger Category | Common Agents | Age Predominance | Notes |
|-----------------|---------------|-----------------|-------|
| Foods | Peanut, tree nuts, milk, egg, shellfish, wheat, soy, sesame | Children | Most common trigger in pediatrics |
| Medications | Beta-lactams, NSAIDs, NMBAs, biologics | Adults | Leading cause in adults |
| Hymenoptera venom | Bee, wasp, hornet, yellow jacket, fire ant | Adults | 95-98% protection with VIT |
| Latex | Natural rubber latex | Healthcare workers | Declining with latex-free environments |
| Exercise | Exercise alone or food-dependent (omega-5-gliadin) | Young adults | Cofactors: NSAIDs, alcohol, heat |
| Idiopathic | No identifiable trigger | Any age | Rule out mastocytosis; may respond to omalizumab |

A critical teaching point is that cutaneous manifestations are absent in 10 to 20 percent of anaphylaxis episodes, and their absence absolutely does not exclude the diagnosis. Cardiovascular collapse without urticaria is particularly common in drug-triggered and venom-triggered anaphylaxis and in patients taking beta-blockers.

## Pathophysiology

### Immunologic Mechanisms

The pathophysiology of anaphylaxis is most commonly driven by IgE-mediated mechanisms, in which a multivalent allergen crosslinks specific IgE antibodies bound to FcepsilonRI on the surface of mast cells and basophils, triggering rapid degranulation. Common IgE-mediated triggers include foods (peanut, tree nuts, cow's milk, egg, shellfish, wheat, soy, and sesame), medications (beta-lactam antibiotics, nonsteroidal anti-inflammatory drugs, neuromuscular blocking agents, and biologic therapies), Hymenoptera venoms (bee, wasp, hornet, yellow jacket, and fire ant), latex, seminal fluid, and food-dependent exercise-induced triggers.

Non-IgE immunologic mechanisms can also produce anaphylaxis, including complement activation triggered by blood products or dialysis membranes and IgG-mediated reactions to agents such as dextran and infliximab. Non-immunologic anaphylaxis, formerly termed "anaphylactoid" reactions, results from direct mast cell activation without immunologic sensitization. Radiocontrast media, opioids, and vancomycin (producing Red Man syndrome) activate mast cells through the Mas-related G protein-coupled receptor X2 (MRGPRX2), which binds cationic peptides and small molecules. Non-immunologic triggers also include physical stimuli such as exercise, cold exposure, and idiopathic triggers.

### Mediator Effects

The clinical manifestations of anaphylaxis result from the combined effects of multiple mast cell and basophil mediators released simultaneously. Histamine produces vasodilation, increased vascular permeability, bronchoconstriction, and reflex tachycardia. Tryptase, a serine protease that peaks in serum 60 to 90 minutes after symptom onset, activates the complement and coagulation cascades. Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) cause potent bronchoconstriction, mucus hypersecretion, and coronary vasoconstriction. Platelet-activating factor (PAF) induces platelet aggregation and vasodilation, and notably, PAF serum levels correlate with the severity of anaphylaxis. The enzyme PAF acetylhydrolase (PAF-AH) inactivates PAF, and low levels of PAF-AH have been associated with severe and fatal anaphylaxis. Nitric oxide contributes to vasodilation and may explain the refractoriness to vasopressors seen in severe cases. The cardiovascular collapse of anaphylaxis represents distributive shock, characterized by profound vasodilation and capillary leak, which can clinically mimic hypovolemic shock due to the massive intravascular volume depletion from third-spacing of fluid.

<image>A human body diagram illustrating the multi-system manifestations of anaphylaxis. Organ systems highlighted with arrows and symptom descriptions: Skin (urticaria, flushing, angioedema, pruritus - noted as present in 80-90% of cases), Respiratory (laryngeal edema with stridor, bronchospasm with wheezing, rhinorrhea - shown with cross-section of edematous larynx), Cardiovascular (hypotension, tachycardia, arrhythmia, cardiac arrest - with ECG tracing showing tachycardia), GI (nausea, vomiting, abdominal cramping, diarrhea), Neurologic (dizziness, confusion, loss of consciousness). Central panel shows a mast cell releasing mediators (histamine, tryptase, PGD2, LTC4, PAF) with arrows to their target organs. Bottom note: "10-20% of anaphylaxis episodes present WITHOUT skin findings."</image>

## Acute Management

### Epinephrine - First-Line Treatment

| Parameter | Adult | Pediatric (<30 kg) |
|-----------|-------|-------------------|
| Epinephrine dose | 0.3-0.5 mg (1:1,000) IM | 0.01 mg/kg (max 0.3 mg) IM |
| Auto-injector | EpiPen 0.3 mg | EpiPen Jr 0.15 mg (15-30 kg) |
| Injection site | Anterolateral thigh | Anterolateral thigh |
| Repeat interval | Every 5-15 minutes PRN | Every 5-15 minutes PRN |
| IV fluid bolus | 1-2 L NS rapid bolus | 20 mL/kg NS bolus |
| Glucagon (beta-blocker) | 1-5 mg IV bolus, then 5-15 mcg/min | 20-30 mcg/kg (max 1 mg) |

Intramuscular epinephrine injected into the anterolateral thigh is the first and most critical intervention in anaphylaxis. The dose is 0.01 mg/kg of 1:1,000 (1 mg/mL) concentration, with a maximum of 0.5 mg in adults and 0.3 mg in children weighing less than 30 kg. Epinephrine auto-injectors are available in two doses: EpiPen 0.3 mg for patients weighing 30 kg or more and EpiPen Jr 0.15 mg for those weighing 15 to 30 kg. Doses may be repeated every 5 to 15 minutes if the clinical response is inadequate. The intramuscular route is strongly preferred over subcutaneous injection, as landmark pharmacokinetic studies by Simons and colleagues demonstrated that intramuscular injection achieves peak plasma epinephrine levels in approximately 8 minutes compared with 34 minutes for subcutaneous injection.

There are no absolute contraindications to the use of epinephrine in anaphylaxis. Its pharmacologic effects are mediated through alpha-1 adrenergic receptors (producing vasoconstriction and reducing mucosal edema), beta-1 adrenergic receptors (providing positive chronotropic and inotropic cardiac effects), and beta-2 adrenergic receptors (causing bronchodilation and, importantly, inhibiting further mast cell mediator release). Delayed administration of epinephrine is consistently identified as the most significant modifiable risk factor for fatal anaphylaxis.

### Second-Line Interventions

Patient positioning is an important but often underappreciated element of anaphylaxis management. Patients should be placed supine with the lower extremities elevated (Trendelenburg position) to maximize venous return and cardiac preload. Assuming an upright posture during anaphylaxis can precipitate empty ventricle syndrome and fatal pulseless electrical activity due to inadequate venous return to a vasodilated cardiovascular system. If respiratory distress precludes a supine position, a sitting position is acceptable. Patients who are vomiting should be placed in the recovery position, and pregnant patients should be positioned in the left lateral decubitus position to avoid inferior vena cava compression.

Aggressive intravenous fluid resuscitation with normal saline or lactated Ringer's solution is essential, given the massive intravascular volume depletion caused by capillary leak. Initial boluses of 1 to 2 liters in adults (20 mL/kg in children) should be administered rapidly, with severe distributive shock potentially requiring 5 to 7 liters of crystalloid. Supplemental oxygen should be delivered via high-flow non-rebreather mask, targeting oxygen saturation above 94 percent. Nebulized albuterol (2.5 to 5 mg) is indicated for bronchospasm not adequately responding to epinephrine. Nebulized epinephrine (2 to 5 mL of 1:1,000 solution) may be administered for upper airway edema and stridor.

### Adjunctive Medications

H1 antihistamines, such as diphenhydramine 25 to 50 mg intravenously or intramuscularly or cetirizine 10 mg orally, are useful adjuncts for treating urticaria and pruritus but must be understood as treating only cutaneous symptoms. They have no role in managing hypotension, airway compromise, or cardiovascular collapse. H2 antihistamines, such as famotidine 20 mg intravenously, may provide additive benefit for cutaneous symptoms when combined with H1 blockade.

Glucocorticoids, such as methylprednisolone 1 to 2 mg/kg intravenously or prednisone 1 mg/kg orally, have an onset of action of 4 to 6 hours and therefore play no role in acute resuscitation. Their theoretical benefit lies in potentially preventing biphasic reactions, though the evidence supporting this is weak and conflicting. Glucocorticoids are emphatically not a substitute for epinephrine.

Glucagon, administered as a 1 to 5 mg intravenous bolus followed by an infusion of 5 to 15 mcg/min, is specifically indicated for patients on beta-blockers who develop refractory hypotension. Its mechanism involves bypassing beta-receptor blockade by directly activating adenylate cyclase through the glucagon receptor. Vasopressors such as norepinephrine or vasopressin should be initiated for hypotension refractory to epinephrine and fluid resuscitation.

### Refractory Anaphylaxis

Refractory anaphylaxis is defined as an inadequate clinical response to 2 to 3 doses of intramuscular epinephrine and necessitates escalation to intravenous epinephrine infusion at 0.1 to 1 mcg/kg/min with continuous hemodynamic monitoring, preferably in an intensive care setting. Methylene blue, at a dose of 1 to 2 mg/kg intravenously over 5 minutes, has been reported in case series to reverse refractory vasodilation by inhibiting nitric oxide-mediated vasodilation, though evidence is limited to case reports. When anaphylaxis appears refractory to standard treatment, alternative diagnoses should be reconsidered, including acute cardiac events, tension pneumothorax, and aspiration.

<image>A step-by-step emergency management algorithm for anaphylaxis. Flow starts with "Suspected anaphylaxis" box at top. Step 1 (RED - immediate): Remove trigger, call for help, administer IM epinephrine (0.3-0.5 mg adult anterolateral thigh), position supine with legs elevated. Step 2 (ORANGE): Assess ABCs, provide high-flow O2, establish IV access, cardiac monitoring. Step 3: If persistent hypotension - IV NS 1-2L bolus; if bronchospasm - nebulized albuterol; if stridor - nebulized epinephrine. Step 4: Adjunctive - H1/H2 antihistamines, corticosteroids. Decision diamond: "Response to treatment?" If No: repeat IM epinephrine q5-15 min (up to 3 doses), then consider IV epinephrine infusion, vasopressors, glucagon (if on beta-blocker). If Yes: observe minimum 4-6 hours (longer if biphasic risk factors). Discharge box: prescribe epinephrine auto-injector x2, allergy referral, anaphylaxis action plan, consider tryptase if not drawn.</image>

## Post-Event Management

### Observation Period

All patients who have experienced anaphylaxis should be observed for a minimum of 4 to 6 hours after complete symptom resolution. Extended observation of 12 to 24 hours is warranted in patients who had a severe initial presentation, required multiple doses of epinephrine, have a history of prior biphasic reactions, have limited access to emergency care, or have comorbid asthma. Biphasic reactions may occur despite appropriate initial treatment, and unfortunately, no single reliable predictor has been identified. Risk factors for biphasic reactions include delayed initial epinephrine administration, severe initial episode, wide pulse pressure, unknown trigger, and drug-related triggers.

### Discharge Planning

At the time of discharge, patients must be prescribed a minimum of two epinephrine auto-injector devices, as approximately 10 to 20 percent of anaphylaxis episodes require a second dose. Proper auto-injector technique should be demonstrated and practiced. An individualized written anaphylaxis emergency action plan should be provided, and patients should be encouraged to obtain medical alert identification. Referral to an allergist-immunologist for definitive trigger identification is essential, and the patient should be counseled to strictly avoid the suspected trigger until a comprehensive evaluation is completed.

### Laboratory Confirmation

Serum tryptase is the most useful laboratory biomarker for confirming mast cell activation during anaphylaxis. Blood should ideally be drawn 1 to 2 hours after symptom onset (during the acute event) and again at baseline (more than 24 hours later). The consensus formula for interpreting the result defines a significant elevation as an acute tryptase level exceeding 1.2 times the baseline level plus 2 ng/mL. However, it is critical to recognize that tryptase may remain within normal limits in food-induced anaphylaxis, which tends to be more basophil-predominant, and in mild to moderate episodes. A persistently elevated baseline tryptase level exceeding 11.4 ng/mL should prompt evaluation for systemic mastocytosis or hereditary alpha-tryptasemia (caused by extra copies of the TPSAB1 gene). Plasma histamine peaks within 5 to 10 minutes and returns to baseline within 30 to 60 minutes, making it impractical to obtain in most clinical scenarios. Urinary mediator metabolites, including N-methylhistamine, 11beta-prostaglandin F2alpha, and leukotriene E4, are primarily used in research settings.

## Special Scenarios

### Exercise-Induced Anaphylaxis (EIA)

Exercise-induced anaphylaxis is an uncommon but clinically important entity in which physical exertion triggers anaphylaxis. A distinct subtype, food-dependent exercise-induced anaphylaxis (FDEIAnA), occurs exclusively when exercise follows ingestion of a specific food within 2 to 6 hours; neither the food alone nor exercise alone produces symptoms. Common trigger foods include wheat (with the allergenic protein omega-5-gliadin, designated Tri a 19), shellfish, celery, and tomato. Important cofactors that lower the threshold for reactions include concurrent NSAID use, alcohol consumption, extreme ambient temperatures, and high pollen counts during allergy season. Management centers on avoidance of eating for 4 to 6 hours before exercise in patients with food-dependent EIA, exercising with a partner, and always carrying epinephrine.

### Idiopathic Anaphylaxis

Idiopathic anaphylaxis is a diagnosis of exclusion rendered after comprehensive evaluation fails to identify a causative trigger. Disease frequency is classified as "frequent" when patients experience 6 or more episodes per year or 2 or more episodes within a 2-month period. Prophylactic treatment typically includes a prednisone taper (starting at 40 to 60 mg daily and gradually reduced over weeks) combined with H1 and H2 antihistamines. Omalizumab has shown promise for refractory cases. Importantly, all patients with idiopathic anaphylaxis should be evaluated for clonal mast cell disease, including testing for the KIT D816V mutation and baseline tryptase levels, as a proportion of patients initially classified as idiopathic will ultimately be reclassified as having systemic mastocytosis or mast cell activation syndrome. Many patients with idiopathic anaphylaxis eventually achieve sustained remission.

### Perioperative Anaphylaxis

Perioperative anaphylaxis occurs at an estimated incidence of 1 in 10,000 to 1 in 20,000 anesthesia episodes. The most common causative agents are neuromuscular blocking agents (NMBAs), accounting for approximately 60 percent of cases, followed by antibiotics, latex, chlorhexidine, and dyes such as patent blue. Among NMBAs, succinylcholine and rocuronium are the most frequently implicated, with the quaternary ammonium groups serving as the allergenic epitopes and cross-reactivity between NMBAs reaching 60 to 70 percent. Of note, sugammadex can reverse the neuromuscular effects of rocuronium and may bind the allergen itself, as suggested by case reports. Chlorhexidine is increasingly recognized as a perioperative allergen, present in central line dressings, surgical preparation solutions, and coated urinary catheters. Diagnosis requires measurement of intraoperative tryptase levels compared with baseline, followed by skin testing to suspected agents performed 4 to 6 weeks after the event, and specific IgE testing where validated assays are available.

## Key Clinical Pearls
- Epinephrine is the ONLY first-line treatment for anaphylaxis; there are NO absolute contraindications
- IM injection in the anterolateral thigh achieves peak plasma levels faster than SC injection (8 vs. 34 min)
- Antihistamines treat urticaria and pruritus only; they do NOT treat hypotension, airway obstruction, or shock
- Patients should NOT be placed upright during anaphylaxis: "empty ventricle syndrome" can cause fatal pulseless electrical activity
- Biphasic reactions occur in up to 20% of cases; observe patients for a minimum of 4-6 hours
- Normal tryptase does not exclude anaphylaxis, especially in food-triggered or mild episodes
- Baseline tryptase >11.4 ng/mL warrants evaluation for mastocytosis or hereditary alpha-tryptasemia (extra TPSAB1 copies)
- Always prescribe >=2 epinephrine auto-injectors at discharge; approximately 10-20% of episodes require a second dose

## References
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3. Simons FER, et al. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. *J Allergy Clin Immunol*. 2001;108(5):871-873.
4. Shaker MS, et al. Anaphylaxis - a 2020 practice parameter update, systematic review, and GRADE analysis. *J Allergy Clin Immunol*. 2020;145(4):1082-1123.
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