Anaphylaxis

• IgE-Mediated Sensitization and Cross-Linking: During initial antigen exposure, antigen-presenting cells process allergen and promote Th2 differentiation, driving B cells to produce IgE antibodies. These IgE molecules bind to high-affinity IgE receptors (FcεRI) on the surface of tissue mast cells and circulating basophils. Upon re-exposure, the antigen cross-links membrane-bound IgE molecules, triggering rapid calcium influx and immediate degranulation. This process is the hallmark of immediate hypersensitivity and explains the rapid onset (minutes) of clinical manifestations.

• Mediator Release and Cascade Activation: Cross-linked FcεRI activates a tyrosine kinase cascade (Lyn, Syk), leading to phospholipase C activation and increased intracellular calcium. Mast cells and basophils release preformed mediators stored in cytoplasmic granules—primarily histamine (causing vasodilation, increased vascular permeability, pruritus), tryptase (protease with inflammatory effects), and heparin (anticoagulant). Simultaneously, newly synthesized mediators are produced: leukotrienes (LTC₄, LTD₄, LTE₄) which are potent bronchoconstrictors and vasodilators; prostaglandins (PGD₂, PGE₂); and platelet-activating factor (PAF), which causes platelet aggregation and further mast cell activation. The kinetics of mediator release dictate biphasic reactions: early release (minutes) causes immediate symptoms, while continued synthesis can perpetuate symptoms or trigger biphasic reactions.

• Cardiovascular Collapse Mechanisms: Widespread vasodilation occurs through multiple mechanisms: histamine acts on H1 and H2 receptors on vascular smooth muscle causing relaxation; leukotrienes and PAF increase endothelial permeability through VE-cadherin disruption, leading to massive third-spacing of intravascular fluid. Myocardial depression occurs through direct effects of mediators (histamine, leukotrienes) on cardiac contractility and through loss of circulating volume. The combination produces profound hypotension, decreased coronary perfusion, dysrhythmias, and potential cardiogenic shock—the primary life-threatening mechanism in anaphylaxis. In patients with underlying coronary disease, anaphylaxis can precipitate acute myocardial infarction through mediator-induced coronary vasospasm and increased cardiac oxygen demand.

• Airway and Bronchial Reactivity: Leukotrienes are the most potent bronchoconstrictors released in anaphylaxis. Mast cells in respiratory epithelium and smooth muscle degranulate, releasing mediators directly. Increased vascular permeability in the larynx and pharynx causes angioedema and potential airway obstruction. In the bronchi and bronchioles, leukotrienes, histamine, and PAF trigger smooth muscle contraction and mucus hypersecretion. These effects combine to cause airway obstruction at multiple levels, ranging from laryngeal edema (upper airway) to diffuse bronchospasm (lower airway), both of which are immediately life-threatening.

• Cutaneous Manifestations: Histamine release causes mast cell-mediated vasodilation and increased vascular permeability in dermal and subdermal vessels, producing erythema, urticaria (wheal and flare reactions), and pruritus. These cutaneous signs, while often first-recognized, are actually less immediately life-threatening than cardiovascular or airway involvement.

• Biphasic Reactions: In 5–15% of cases, anaphylaxis can recur or worsen 1–12 hours after initial onset (mean 8 hours) without re-exposure. This occurs through continued synthesis and release of mediators from mast cells and basophils and recruitment of eosinophils and neutrophils. Biphasic reactions are more common in severe initial reactions and IgE-mediated food anaphylaxis. This mechanism explains why prolonged monitoring and continued epinephrine availability are essential even after apparent resolution.

• Foods (Most Common in Pediatrics): Peanuts and tree nuts (almonds, cashews, walnuts) are the leading food triggers overall and represent up to 50% of food anaphylaxis. Shellfish (shrimp, crab, lobster) cause anaphylaxis in 0.5–2.8% of the population with exposure. Fish, milk, eggs, and sesame are additional common culprits. Oral allergy syndrome (itching/swelling of lips/mouth with raw fruits/vegetables) can occasionally progress to true anaphylaxis. Food-dependent exercise-induced anaphylaxis occurs when exercise within 2–4 hours after eating a specific food (commonly wheat) triggers anaphylaxis; this involves both IgE-mediated and non-IgE mechanisms.

• Medications (Most Common in Adults, Especially Hospitalized): Beta-lactam antibiotics (penicillins, cephalosporins) are the most common drug cause, with true IgE-mediated anaphylaxis occurring in 1–3 per 10,000 exposures; cross-reactivity between penicillins and first-generation cephalosporins is ~1%, lower with third-generation cephalosporins. Angiotensin-converting enzyme (ACE) inhibitors rarely cause anaphylaxis but are uniquely associated with bradykinin-mediated angioedema (non-IgE mechanism), not true anaphylaxis. NSAIDs, particularly aspirin, can trigger reactions in aspirin-sensitive asthmatic patients through cyclooxygenase inhibition and leukotriene pathway upregulation (arachidonic acid shunting). Chemotherapy agents (especially taxanes like paclitaxel), monoclonal antibodies (rituximab, cetuximab, infliximab), and insulin cause IgE-mediated reactions in previously sensitized patients. Vancomycin causes direct mast cell degranulation (not IgE-mediated). Neuromuscular blocking agents used in anesthesia cause anaphylaxis in 1 per 4,500–20,000 anesthetics, particularly rocuronium and atracurium.

• Hymenoptera Venom (Bee, Wasp, Yellow Jacket Stings): Represent 40% of adult anaphylaxis. Risk is higher in individuals with occupational exposure (beekeepers) or those with multiple previous stings. Venom immunotherapy reduces risk of anaphylaxis from 60% (with history of sting anaphylaxis) to <5%, representing a major prevention strategy.

• Latex: Predominantly affects healthcare workers and patients with spina bifida (10–17% sensitization rate). Allergen exposure occurs through contact with gloves, catheters, or during surgical procedures. Cross-reactivity with certain fruits (banana, avocado, kiwi) occurs in ~30–50% of latex-allergic individuals due to homologous proteins.

• Exercise-Induced Anaphylaxis: Rare (0.002% of population), occurs within minutes to 30 minutes of vigorous exercise. Food-dependent exercise-induced anaphylaxis (FDEIA) requires both food ingestion and exercise. Proposed mechanisms include increased gut permeability from exercise, increased mast cell sensitivity to lower IgE cross-linking thresholds, and increased blood flow to skin. Affected individuals can tolerate the food at rest or exercise without food ingestion.

• Idiopathic Anaphylaxis: Occurs in 10–20% of anaphylaxis cases with no identifiable trigger despite thorough history and testing. Subdivided into mast cell-mediated (elevated baseline tryptase) and non-mast cell-mediated forms. More common in women and middle-aged adults. Evaluation should exclude systemic mastocytosis and clonal mast cell disorders (see Complications).

• Cofactors That Increase Risk: Beta-blockers reduce therapeutic epinephrine response and delay symptom resolution. ACE inhibitors may impair bradykinin degradation. Alcohol and NSAIDs may increase intestinal permeability. Menstrual cycle phase may influence food anaphylaxis severity in women. Underlying asthma is a risk factor for severe, fatal anaphylaxis. Atopy (personal or family history of allergic disease) increases overall anaphylaxis risk.

• Cutaneous Manifestations (>90% of cases): Urticaria with pruritus is often the first sign, appearing as erythematous papules and plaques typically on trunk and proximal extremities, often spreading rapidly. Angioedema (non-pitting, localized edema) affects lips, tongue, throat, hands, and genitals, distinguishable from urticaria by involvement of deeper dermis and subcutaneous tissue. Flushing with generalized erythema occurs from histamine-induced vasodilation. Pruritus without visible lesions can be severe, sometimes preceding urticaria. Notably, absence of cutaneous signs does not exclude anaphylaxis (occurs in ~10% of cases, particularly with food anaphylaxis), and isolated cutaneous involvement without systemic symptoms represents urticaria or angioedema, not true anaphylaxis.

• Respiratory Manifestations (Severe/Life-Threatening): Dyspnea develops from bronchospasm (lower airway) or angioedema (upper airway). Stridor indicates laryngeal edema and upper airway obstruction. Wheezing reflects bronchial smooth muscle constriction and is particularly prominent in patients with underlying asthma. Hoarseness or voice changes suggest laryngeal involvement. Throat tightness or sensation of lump in throat often precedes overt airway obstruction and warrants immediate evaluation. Patients may use accessory muscles, exhibit tachypnea, or have silent chest from severe bronchospasm (ominous sign). Respiratory manifestations account for ~40% of fatal anaphylaxis cases.

• Cardiovascular Manifestations (Most Life-Threatening): Hypotension (systolic <90 mmHg or >30% drop from baseline) occurs from peripheral vasodilation and fluid extravasation; can develop insidiously or precipitously. Syncope or presyncope reflects inadequate cerebral perfusion and is an ominous sign indicating severe systemic anaphylaxis. Chest pain or discomfort may represent anaphylaxis-induced coronary vasospasm and acute coronary syndrome, particularly in older patients or those with cardiac risk factors. Palpitations or dysrhythmias occur from direct mediator effects on myocardium and catecholamine surge from compensatory response. Shock develops with profound hypotension, tachycardia, cool/clammy skin, and altered mental status. Cardiovascular collapse is the primary mechanism of fatal anaphylaxis, accounting for ~45–50% of deaths.

• Gastrointestinal Manifestations: Nausea and vomiting are common, mediated by histamine and vagal stimulation. Abdominal cramping and pain result from visceral smooth muscle contraction and increased peristalsis. Diarrhea may develop from increased intestinal secretion and altered motility. Fecal incontinence can occur with loss of consciousness.

• Neuropsychiatric Manifestations: Anxiety or sense of doom frequently accompanies anaphylaxis, likely multifactorial (catecholamine surge, hypoxia, hypotension). Altered mental status, confusion, or loss of consciousness indicate severe hypoxia, hypotension, or both and demand immediate intervention.

• Physical Examination Findings: Hypotension with systolic <90 mmHg or mean arterial pressure <65 mmHg. Tachycardia (typically >100 bpm) from sympathetic compensation, though can be absent or paradoxical bradycardia in vasovagal subset. Tachypnea (>20 breaths/min) from hypoxia and compensatory hyperventilation. Generalized erythema and urticaria with edema. Angioedema of lips, tongue, pharynx. Stridor on auscultation (upper airway) or wheezing (lower airway). Altered mental status ranging from anxiety to unresponsiveness.

• Important Clinical Variants: Biphasic anaphylaxis involves recurrence of symptoms 1–12 hours after apparent resolution of initial reaction without re-exposure. Anaphylactic shock (cardiovascular-predominant) presents with profound hypotension with minimal cutaneous or respiratory symptoms; particularly associated with latex and medications. Laryngeal edema-predominant anaphylaxis can rapidly progress to complete airway obstruction without prominent systemic symptoms. Food-dependent exercise-induced anaphylaxis occurs only when exercise follows food ingestion by 2–4 hours; eating the same food at rest or exercising without food do not trigger reaction.

• Clinical Diagnostic Criteria: Anaphylaxis is highly likely when one of the following is satisfied within minutes to hours: (1) Acute onset of symptoms involving skin and/or mucosal tissue (e.g., generalized erythema, urticaria, pruritus, angioedema) plus involvement of at least one of: respiratory system, cardiovascular system, or severe gastrointestinal symptoms; (2) Two or more of the following occurring rapidly after exposure to a likely allergen: skin/mucosal changes, respiratory symptoms, cardiovascular symptoms, severe gastrointestinal symptoms, or persistent gastrointestinal symptoms with hypotension; (3) Hypotension after exposure to a known allergen (in children: systolic pressure <70 mmHg + [age in years × 2]; in adolescents/adults: systolic <90 mmHg). These criteria emphasize rapid onset (key distinguishing feature from other conditions) and multi-system involvement. Notably, absence of cutaneous signs does not exclude anaphylaxis.

• Serum and Tissue Tryptase: Beta-tryptase measurement (collected 15 minutes to 3 hours after symptom onset, ideally 30 minutes after epinephrine administration) has 50–80% sensitivity and >95% specificity for anaphylaxis. Normal value is <11.4 ng/mL; elevated tryptase (>20% above baseline or >11.4 ng/mL) supports diagnosis but is not required for diagnosis. Tryptase peaks at 3 hours post-onset. Levels correlate with severity but not specificity for cause. Baseline tryptase (obtained weeks later) helps identify patients at risk for systemic mastocytosis (see Complications). Mast cell tryptase is less

Immediate stabilisation (simultaneous, not sequential)

• Remove the trigger and call for help: stop the infusion/sting exposure; do not delay drug therapy to complete the history.
• Position: supine with the lower extremities elevated, unless vomiting or respiratory distress dictates sitting. Abrupt standing or sitting up can precipitate the empty ventricle syndrome and sudden death from loss of preload.
• Airway, breathing, circulation: high-flow oxygen, continuous cardiac and pulse-oximetry monitoring, and two large-bore IVs. Stridor, hoarseness, or tongue/oropharyngeal angioedema mandates early intubation by the most experienced operator, with a surgical airway (cricothyrotomy) set open at the bedside — waiting for progression risks an unintubatable airway.

First-line therapy

• Epinephrine (alpha-1/beta-1/beta-2 agonist): 0.3–0.5 mg of the 1 mg/mL concentration IM into the anterolateral thigh (vastus lateralis) in adults; 0.01 mg/kg (max 0.3 mg) in children. Repeat every 5–15 minutes as needed. Alpha-1 vasoconstriction reverses vasodilation and mucosal edema, beta-1 supports inotropy/chronotropy, and beta-2 produces bronchodilation and inhibits further mast cell degranulation. The AAAAI/ACAAI Joint Task Force anaphylaxis practice parameter and the World Allergy Organization state there is no absolute contraindication to epinephrine in anaphylaxis — delay is the strongest predictor of fatality.
• IV crystalloid: rapid isotonic boluses for hypotension, since massive capillary leak causes distributive plus hypovolemic shock.

Adjunctive (never a substitute for epinephrine)

• Inhaled beta-2 agonist (albuterol): for bronchospasm unresponsive to epinephrine.
• H1 antihistamine (cetirizine or diphenhydramine) ± H2 blocker (famotidine): relieve urticaria/pruritus only; no effect on airway or shock.
• Glucocorticoids (methylprednisolone): the current practice parameter no longer recommends them routinely, as they do not prevent biphasic reactions.

Refractory anaphylaxis

• Continuous IV epinephrine infusion, titrated with arterial monitoring; add norepinephrine or vasopressin for persistent shock.
• Glucagon: 1–5 mg IV for patients on beta-blockers, bypassing the blocked receptor via direct adenylate cyclase stimulation.

Disease-related — all time-critical

• Complete upper airway obstruction (emergency): laryngeal and supraglottic angioedema from capillary leak. Signalled by stridor, hoarseness, drooling, or a muffled "hot potato" voice; loss of stridor with rising work of breathing means near-total obstruction, not improvement.
• Refractory distributive shock (emergency): persistent hypotension despite repeated IM epinephrine and fluids, driven by profound vasoplegia plus third-spacing. Rising lactate and oliguria mark inadequate perfusion.
• Cardiac arrest (emergency): usually PEA or asystole from combined hypoxia and vasoplegia; treat per ACLS with prolonged aggressive volume resuscitation, since the arrest is preload-dependent.
• Kounis syndrome (allergic acute coronary syndrome): mediator-induced coronary vasospasm and plaque destabilisation. Signalled by chest pain with ischemic ECG changes and troponin elevation during the reaction — consistent with the coronary vasospasm mechanism described above.
• Biphasic reaction (emergency): recurrence hours after apparent resolution without re-exposure; the reason observation and autoinjector provision are mandatory.
• Hypoxic-ischemic encephalopathy: from prolonged hypoxia or hypoperfusion; persistent altered mentation after hemodynamic recovery is the red flag.

Treatment-related

• Epinephrine concentration/route error (emergency): giving the 1 mg/mL (1:1000) IM formulation as an undiluted IV bolus — instead of IM, or instead of a diluted/infused preparation — causes hypertensive crisis, ventricular arrhythmia, and takotsubo-like cardiomyopathy. For IV use in arrest the 0.1 mg/mL (1:10,000) preparation is used (1 mg IV per ACLS); for refractory anaphylaxis, epinephrine should be given as a titrated infusion, not a push. Signalled by sudden severe hypertension, headache, and wide-complex tachycardia.
• Expected epinephrine effects: tachycardia, tremor, pallor, anxiety — these are not a reason to withhold further doses.
• Antihistamine sedation: diphenhydramine-induced somnolence and anticholinergic delirium can be mistaken for hypoperfusion-related altered mental status.
• Glucocorticoid hyperglycemia and, in fluid-resuscitated patients with cardiac or renal disease, volume overload with new hypoxemia and crackles.

Longer-term

• Clonal mast cell disease: a persistently elevated baseline tryptase measured weeks after recovery, or recurrent idiopathic/Hymenoptera anaphylaxis, should prompt evaluation for systemic mastocytosis or hereditary alpha-tryptasemia.

• IM epinephrine into the anterolateral thigh is almost always the single best next step in a spontaneously circulating patient: it beats "secure the airway," "give IV fluids," "obtain tryptase," and "give diphenhydramine" in nearly every stem. Choosing an antihistamine or a steroid first is the classic wrong answer. Two exceptions: a patient already in cardiac arrest is managed per ACLS (IV/IO epinephrine, CPR), and a patient with complete upper airway obstruction needs simultaneous definitive airway management, including a surgical airway.
• There is no absolute contraindication to epinephrine in anaphylaxis — not pregnancy, not coronary disease, not advanced age. The AAAAI/ACAAI practice parameter frames delayed epinephrine as the chief modifiable cause of death.
• Beta-blocker on the medication list = the tested association: epinephrine-refractory hypotension and bradycardia should prompt glucagon IV, which raises cAMP downstream of the blocked beta receptor.
• Diagnosis is clinical; tryptase is confirmatory and retrospective. Peak levels occur within a few hours of onset, and a normal tryptase does not exclude anaphylaxis — especially in food-triggered cases.
• No hives does not mean no anaphylaxis. Hypotension after a known allergen alone satisfies criteria. Conversely, isolated urticaria with no other system involved is not anaphylaxis.
• The angioedema distractor: ACE inhibitor–induced and hereditary angioedema are bradykinin-mediated — no urticaria, no pruritus, often isolated lip/tongue/bowel swelling, and no response to epinephrine, antihistamines, or steroids. Management is airway protection plus C1-inhibitor concentrate or icatibant; hereditary cases may also receive ecallantide or fresh frozen plasma.
• Posture kills: standing or sitting a hypotensive patient up can cause the empty ventricle syndrome. Keep them supine with legs raised.
• Delayed anaphylaxis 3–6 hours after red meat in a patient with prior tick bites is alpha-gal syndrome (IgE to galactose-alpha-1,3-galactose, Lone Star tick).
• Every discharge needs two autoinjectors, a written action plan, trigger avoidance counselling, and allergy referral; Hymenoptera-triggered cases get venom immunotherapy.