Anaphylaxis and Anaphylactoid Reactions

IgE-mediated (true anaphylaxis — requires prior sensitization)

• Foods: peanut, tree nuts, shellfish, fin fish, cow's milk, egg, wheat, sesame; leading cause in children and adolescents
• Drugs: beta-lactam antibiotics (most common drug cause), sulfonamides, platinum chemotherapeutics, monoclonal antibodies
• Hymenoptera venom: bee, wasp, yellow jacket, fire ant; parenteral route means faster, more severe reactions than ingested allergens
• Latex, allergen immunotherapy injections, and alpha-gal (galactose-α-1,3-galactose) sensitization after tick bite — the classic delayed (3–6 hour) anaphylaxis after red meat

Non-IgE / direct mast cell activation (anaphylactoid — no sensitization needed)

• Opioids, vancomycin, fluoroquinolones, neuromuscular blockers: direct mast cell degranulation (MRGPRX2 receptor); vancomycin infused rapidly gives red man syndrome
• Iodinated radiocontrast and NSAIDs/aspirin (COX-1 inhibition shunting arachidonate to leukotrienes)
• Complement-mediated: blood products, IgA-containing products in IgA-deficient patients, dialysis membranes (C3a/C5a)
• Bradykinin-mediated ACE inhibitor angioedema is a mimic, not mast cell disease — no urticaria, no pruritus, poor response to epinephrine
• Physical/idiopathic: exercise-induced, cold-induced, and truly idiopathic anaphylaxis

Non-modifiable risk factors

• Prior anaphylaxis (strongest predictor), atopic disease, and clonal mast cell disorders (systemic mastocytosis, elevated baseline tryptase) — a favorite stem detail alongside venom anaphylaxis
• Age extremes: older adults have higher fatality from cardiovascular comorbidity; adolescents from food triggers and risk-taking behavior

Modifiable risk factors (what examiners want you to change)

• Asthma, especially poorly controlled: the single biggest driver of fatal food anaphylaxis
• Beta blockers and ACE inhibitors: blunt compensatory catecholamine response and epinephrine efficacy; reactions are more severe and refractory
• Delayed epinephrine or no autoinjector: the leading modifiable cause of death; the AAAAI/ACAAI Joint Task Force practice parameter emphasizes prescribing epinephrine autoinjectors with an action plan and allergy referral
• Cofactors amplifying a borderline exposure: exercise, alcohol, NSAIDs, acute infection, menstruation, sleep deprivation

• IgE-mediated activation in anaphylaxis: Allergen cross-links preformed IgE on the surface of tissue mast cells and circulating basophils, triggering rapid degranulation and release of preformed mediators (histamine, tryptase, heparin) and de novo synthesis of newly generated mediators (leukotrienes, prostaglandins, thromboxane, platelet-activating factor)

• Non-IgE-mediated activation in anaphylactoid reactions: Direct mast cell/basophil degranulation occurs via complement fragments (C3a, C5a), opioids, NSAIDs, contrast agents, and direct physical stimuli, producing identical clinical manifestations without prior sensitization or IgE involvement

• Systemic pathophysiology: Released mediators cause vasodilation (hypotension), increased vascular permeability (angioedema, shock), bronchoconstriction (respiratory compromise), enhanced gastric acid secretion, and increased platelet aggregation and coagulation activation; histamine acts primarily on H1 and H2 receptors while leukotrienes (LTC4, LTD4, LTE4) are potent bronchoconstrictors and vasodilators; platelet-activating factor causes platelet activation and further mediator release

• Biphasic and protracted reactions: In some cases, a second wave of symptoms occurs 1-72 hours after initial resolution due to newly synthesized mediators and recruitment of additional inflammatory cells (eosinophils, neutrophils); protracted anaphylaxis may require prolonged treatment and observation

• Cutaneous manifestations (most common, 80-90% of cases): Urticaria and pruritus appearing within seconds to minutes, often with characteristic flushing and erythema; angioedema of lips, tongue, face, and potentially airway involvement; these skin findings may be the only presenting feature in mild cases but often coexist with more severe systemic symptoms

• Respiratory symptoms (40-60% of cases): Dyspnea, stridor (suggesting laryngeal edema), wheezing (bronchospasm), sensation of throat tightness, hoarseness, cough, and respiratory distress; respiratory involvement indicates moderate to severe anaphylaxis and risk of airway obstruction

• Cardiovascular manifestations (10-45% of cases, more common in older patients): Hypotension, syncope, shock, arrhythmias, myocardial ischemia, and cardiac arrest; "anaphylactic shock" represents distributive shock from profound vasodilation and increased vascular permeability; some patients present with cardiac anaphylaxis manifesting primarily as chest pain, arrhythmias, or MI with minimal skin findings

• Gastrointestinal symptoms: Nausea, vomiting, abdominal cramping, diarrhea, and dysphagia; these occur due to mast cell degranulation in the GI tract and increased intestinal permeability

• Neurological manifestations: Anxiety, sense of impending doom, confusion, headache, seizures (in severe cases); anxiety is both a symptom and a contributing factor (catecholamine sensitivity)

• Clinical pearl: Patients may present with only respiratory or cardiovascular symptoms without significant cutaneous findings—do not exclude anaphylaxis based on absence of urticaria; this variant is more common in food-induced anaphylaxis and carries higher mortality risk

• Clinical diagnosis is paramount: Anaphylaxis is diagnosed clinically based on rapid onset (minutes) of symptoms involving ≥2 body systems (skin, respiratory, cardiovascular, GI) OR hypotension/shock in a patient with known allergen exposure; diagnosis should not be delayed for testing, and treatment should begin immediately on clinical suspicion

• Serum tryptase measurement: Elevated mast cell tryptase (>11.4 ng/mL, though baseline levels vary) drawn within 15 minutes to 3 hours of symptom onset supports the diagnosis of mast cell-mediated anaphylaxis; tryptase is particularly useful in confirming IgE-mediated anaphylaxis and distinguishing from anaphylactoid reactions, though absence does not exclude anaphylaxis; anaphylactoid reactions typically show normal or minimally elevated tryptase

• Serum specific IgE testing and skin prick testing: Performed after acute episode resolves (not acutely) to identify specific allergen triggers; useful for confirmation and for patient education/avoidance strategies; skin testing has good sensitivity but variable specificity

• Diagnostic criteria (NIAID/FAAN): Anaphylaxis is likely if any one of three criteria are met: (1) acute onset with involvement of ≥2 systems, (2) hypotension/shock after known allergen exposure, or (3) specific allergen exposure with ≥2 typical symptoms; these criteria help standardize diagnosis across settings

• Important consideration: Anaphylactoid reactions are clinically indistinguishable but occur without prior sensitization and may have lower tryptase levels; the distinction may be difficult acutely and does not change management

• First-line: Intramuscular epinephrine (0.3-0.5 mg of 1:1000 solution IM in lateral thigh): Administer immediately at first clinical suspicion—this is the only treatment that addresses the underlying pathophysiology by activating alpha-adrenergic receptors (vasoconstriction, reduced angioedema) and beta-adrenergic receptors (bronchodilation, increased cardiac contractility, mast cell stabilization); may repeat every 5-15 minutes if symptoms persist or recur; IM administration (deltoid or lateral thigh) is preferred over IV due to lower risk of adverse effects and adequate efficacy; delay in epinephrine administration is a major cause of fatal anaphylaxis

• Positioning and oxygen: Place patient supine with legs elevated (unless vomiting/respiratory distress) to promote cerebral perfusion; establish IV access and begin normal saline infusion for fluid resuscitation in hypotensive patients; administer supplemental oxygen to maintain SpO2 >90%

• H1-receptor antagonist (antihistamine): Administer diphenhydramine 25-50 mg IV/IM or cetirizine 10 mg PO; antihistamines provide adjunctive benefit by blocking histamine-mediated symptoms (pruritus, urticaria) but do not replace epinephrine and should never be used as monotherapy; onset is slower than epinephrine (15-30 minutes)

• H2-receptor antagonist: Add famotidine 20 mg IV or ranitidine 50 mg IV to block H2-mediated effects (gastric acid hypersecretion, flushing); provides synergistic benefit with H1 blockade

• Corticosteroids: Administer methylprednisolone 125 mg IV or equivalent to reduce biphasic reactions and protracted anaphylaxis; corticosteroids do not treat acute anaphylaxis and have no role in initial management but help prevent recurrence of symptoms within 72 hours

• Beta-2 agonist for bronchospasm: Use albuterol inhaled or IV if bronchoconstriction is prominent and not responsive to epinephrine; ipratropium may provide additional benefit in severe cases

• Vasopressors for refractory hypotension: If hypotension persists after epinephrine and fluids, consider IV epinephrine infusion (0.1 mcg/kg/min titrated) or other vasopressors (dopamine, norepinephrine); requires intensive

Airway and respiratory (emergencies)

• Laryngeal edema with complete airway obstruction: mediator-driven mucosal edema in a non-distensible supraglottic space; signaled by stridor, hoarseness, "lump in the throat," tongue/uvular swelling. Intubate early — swelling progresses and the airway becomes unobtainable; be prepared for cricothyrotomy
• Refractory bronchospasm/respiratory failure: leukotriene- and histamine-mediated smooth muscle constriction plus mucus plugging; signaled by silent chest, rising PaCO2, exhaustion. Highest risk in asthmatics

Cardiovascular (emergencies)

• Distributive shock and cardiac arrest: massive vasodilation plus capillary leak can shift a large fraction of intravascular volume into the interstitium within minutes; arrest rhythm is more often PEA/asystole than ventricular fibrillation / pulseless VT, so per AHA ACLS emphasis on high-quality CPR and epinephrine plus aggressive volume
• Kounis syndrome (allergic acute coronary syndrome): mast cell mediators cause coronary vasospasm or plaque destabilization; signaled by chest pain with ST changes and troponin rise despite normal or near-normal coronaries
• "Empty ventricle" syndrome: abruptly sitting or standing a hypovolemic anaphylaxis patient collapses venous return and can cause sudden death — a documented reason the supine position is stressed

Course-related

• Biphasic reaction: recurrence hours after apparent resolution; signaled by return of urticaria, wheeze, or hypotension during observation. Risk is higher with severe initial presentation or delayed/repeated epinephrine dosing, which drives the AAAAI/ACAAI recommendation for individualized observation before discharge
• Hypoxic-ischemic brain injury after prolonged hypoxemia or arrest

Treatment-related

• Expected epinephrine effects: tremor, palpitations, anxiety, headache — never a reason to withhold the drug
• IV bolus/dosing error (giving the 1:1,000 ampule IV instead of IM): hypertensive crisis, tachyarrhythmia, myocardial ischemia — the classic iatrogenic harm
• Accidental digital injection from an autoinjector: vasospastic finger ischemia
• Fluid resuscitation excess: pulmonary edema, especially in HFrEF or renal failure
• Diphenhydramine: sedation and confusion that mask deterioration; anticholinergic delirium in elders

• The single best next step is always IM epinephrine into the anterolateral thigh — before IV access, before antihistamines, before steroids, before labs. There is no absolute contraindication in anaphylaxis; pregnancy, coronary disease, and advanced age are not exceptions (AAAAI/ACAAI Joint Task Force). The vastus lateralis is chosen for its bulk and blood flow, giving faster peak levels than deltoid or subcutaneous routes.
• The classic distractor is IV diphenhydramine or IV steroids as the initial step. Antihistamines treat itch and hives only; glucocorticoids act over hours through gene transcription. Neither reverses vasodilation, capillary leak, or bronchospasm.
• No urticaria does not exclude anaphylaxis. Hypotension or bronchospasm minutes after a bee sting or a beta-lactam dose is enough (NIAID/FAAN criteria).
• Refractory anaphylaxis in a patient on a beta blocker: unopposed alpha stimulation with blocked beta receptors. Give glucagon, which raises cAMP downstream of the beta receptor and bypasses the blockade.
• Serum tryptase must be drawn within a few hours of onset, and a normal value never overrides the clinical diagnosis; a persistently elevated baseline tryptase points to systemic mastocytosis or a clonal mast cell disorder.
• The association examiners love: alpha-gal — a lone star tick bite produces IgE against galactose-α-1,3-galactose, causing anaphylaxis 3–6 hours after eating red meat. The delay is the tell.
• Angioedema without urticaria or pruritus that ignores epinephrine is bradykinin-mediated: ACE inhibitor angioedema or hereditary angioedema (C1 inhibitor deficiency, low C4). Management is airway protection plus C1-esterase inhibitor, icatibant, or ecallantide — not epinephrine and antihistamines.
• Discharge is part of the answer: two epinephrine autoinjectors, a written action plan, trigger avoidance counseling, and allergy/immunology referral; venom immunotherapy is the one trigger with durably curative desensitization.