Immune System

Anaphylaxis: recognition and CCS-style management

Clinical Overview and When to Suspect Anaphylaxis

— Acute onset (minutes to hours) of skin/mucosal involvement plus respiratory compromise or hypotension/end-organ dysfunction

— Acute onset of ≥2 of: skin/mucosal symptoms, respiratory, cardiovascular, persistent GI symptoms — after likely allergen exposure

— Hypotension alone after exposure to a known allergen for that patient (SBP <90 or >30% drop from baseline)

— Hypotension + urticaria + wheeze shortly after a med, food, or sting

— Isolated hypotension in PACU after induction agents or antibiotics

— Recurrent "asthma exacerbation" tied to a specific food

— Biphasic recurrence 1–72 h (typically <12 h) after apparent resolution

Definition (NIAID/WAO 2020 criteria): Anaphylaxis is highly likely when any one of the following is met:

Epidemiologic triggers (adults): medications (β-lactams, NSAIDs, contrast, perioperative neuromuscular blockers), Hymenoptera stings, foods (peanut, tree nut, shellfish, sesame — now a labeled allergen in the US per FASTER Act), latex, exercise-induced, idiopathic

Pathophysiology snapshot: IgE-mediated mast cell/basophil degranulation → histamine, tryptase, leukotrienes, PAF → vasodilation, capillary leak, bronchoconstriction, mucus, cardiac depression. Non-IgE ("anaphylactoid," e.g., radiocontrast, vancomycin "red man" overlap, opioids) is managed identically.

When to suspect on Step 3:

CCS pearl: On a CCS case, the first three orders when anaphylaxis is suspected are IM epinephrine 0.3–0.5 mg (1 mg/mL) into anterolateral thigh, supine with legs elevated, and high-flow O₂ — order these before IV access, labs, or antihistamines. Delay in epinephrine is the strongest predictor of fatality.

Board pearl: Absence of urticaria does not rule out anaphylaxis — up to 10–20% lack cutaneous findings, especially in fatal cases.

Presentation Patterns and Key History

— Cutaneous (~85–90%): generalized urticaria, flushing, pruritus, angioedema (lips, periorbital, tongue)

— Respiratory (~70%): throat tightness, hoarseness, stridor, dyspnea, wheeze, cough, rhinorrhea

— Cardiovascular (~45%): lightheadedness, syncope, palpitations, chest pain, hypotension

— GI (~45%): crampy abdominal pain, vomiting, diarrhea — persistent GI symptoms count as an organ involvement criterion

— Neuro: sense of impending doom, confusion, seizure (from hypoperfusion)

— Exposure: new medication, food, sting, contrast, latex, exercise

— Prior reactions and severity; prior epinephrine use; time since last dose

— Co-factors that amplify reactions: NSAID use, alcohol, exercise, viral illness, menstruation, β-blocker or ACE inhibitor therapy

— Asthma history (strong predictor of fatal respiratory anaphylaxis)

— Mastocytosis or prior unexplained anaphylaxis → check baseline tryptase later

— Food-dependent exercise-induced anaphylaxis (FDEIA): wheat or shellfish + exercise within 4 h

— Galactose-α-1,3-galactose (alpha-gal) syndrome: delayed (3–6 h) anaphylaxis after mammalian meat in patients with Lone Star tick exposure

— Perioperative: rocuronium, succinylcholine, chlorhexidine, latex, antibiotics

Tempo: Symptoms typically begin within 5–30 minutes of exposure; IV drugs and stings act fastest, oral foods slower (up to 2 h). Faster onset → higher mortality risk.

Organ-system symptom clusters (frequency):

Critical history items to elicit (even mid-resuscitation, from family/EMS):

Special patterns:

Key distinction: A patient with isolated angioedema, no urticaria, no pruritus, often on an ACE inhibitor or with family history → think bradykinin-mediated angioedema (ACEi or hereditary C1-INH deficiency), which does not respond to epinephrine, antihistamines, or steroids — treat with icatibant, ecallantide, or C1-INH concentrate.

Physical Exam Findings and Hemodynamic Assessment

— Airway: lip/tongue/uvular swelling, drooling, muffled "hot potato" voice, stridor → impending obstruction

— Breathing: RR, accessory muscle use, diffuse wheeze, decreased breath sounds, SpO₂; silent chest = pre-arrest

— Circulation: tachycardia is typical; bradycardia is ominous (vagal or pre-arrest, especially with severe hypotension — the Bezold-Jarisch reflex). Narrow pulse pressure, cool clammy skin, capillary refill >2 s, mottling

— Disability: GCS, agitation, syncope

— Exposure: full skin survey — urticarial wheals, flushing, angioedema; check back, scalp, perineum

— SBP <90 (adult), MAP <65, or >30% drop from baseline

— SpO₂ <92% on room air, or any stridor

— Altered mental status

— Inspiratory stridor + no urticaria → consider foreign body, vocal cord dysfunction, epiglottitis

— Bilateral wheeze + clear hemodynamics → asthma exacerbation

— Flushing without urticaria + diarrhea + right-sided murmur → carcinoid

— Hypotension + bradycardia + AV block → check for β-blocker/CCB ingestion or inferior MI

Primary survey (ABCDE) — perform simultaneously with treatment:

Vital sign red flags:

Distributive shock physiology: Massive vasodilation + capillary leak (up to 35% intravascular volume shift in 10 minutes) → low SVR, low preload, often relatively preserved CO early, then myocardial depression. Warm shock initially, may become cold as it progresses.

Targeted exam clues to mimics:

CCS pearl: Reassess vitals every 5 minutes in CCS after each epinephrine dose. Document airway status verbally each time — failure to reassess airway is a common CCS scoring miss.

Board pearl: A patient on a β-blocker who is refractory to epinephrine — next agent is IV glucagon 1–5 mg bolus, then 5–15 mcg/min infusion (bypasses β-receptor blockade via direct adenylyl cyclase activation).

Diagnostic Workup — Initial Labs and Bedside Studies

— Continuous cardiac monitor, pulse oximetry, automated BP q5min

— 12-lead ECG: rule out ACS-mimic, identify Kounis syndrome (allergic ACS — coronary vasospasm or plaque rupture triggered by mast cell mediators)

— Capillary glucose: rule out hypoglycemia as syncope cause

— CBC, BMP, lactate: lactate >2 reflects tissue hypoperfusion; helps trend resuscitation

— Troponin if chest pain, ECG changes, or persistent hypotension

— VBG/ABG if respiratory distress — look for hypercapnia (impending failure) or metabolic acidosis

— Draw serum tryptase at 15 min–3 h after symptom onset (peaks ~60–90 min)

— Draw a baseline tryptase ≥24 h after full recovery for comparison

— Diagnostic rise: acute tryptase > (1.2 × baseline) + 2 ng/mL

— Elevated baseline (>11.4 ng/mL persistently) → evaluate for systemic mastocytosis or hereditary α-tryptasemia

— Tryptase is often normal in food-triggered anaphylaxis — a normal value does not exclude the diagnosis

— CXR only if focal findings, suspicion of aspiration, or differential includes pneumothorax/PE

— Avoid CT contrast acutely if contrast was the suspected trigger

Anaphylaxis is a clinical diagnosis — do not delay epinephrine for labs or imaging. Workup serves to (1) confirm in ambiguous cases, (2) exclude mimics, (3) prepare for ICU admission.

Bedside/initial orders (CCS sequence after epinephrine, O₂, IV access ×2 large-bore, monitor):

Tryptase (the key confirmatory lab):

Imaging:

Board pearl: Tryptase has a short window — the single most commonly missed lab in board stems is failing to draw it within 3 hours of the reaction.

Step 3 management: In a CCS ED case, advance the simulated clock by 15-minute increments initially; reassess airway, BP, and lung exam at each interval before ordering additional therapies.

Diagnostic Workup — Advanced and Outpatient Confirmatory Studies

— Unclear trigger

— Food, venom, latex, or drug triggers requiring future avoidance or desensitization

— Recurrent or idiopathic episodes

— Elevated baseline tryptase

— Skin prick testing (SPT): first-line for foods, venoms, many drugs; highly sensitive, modest specificity

— Intradermal testing: more sensitive for drug and venom allergy when SPT negative

— Serum-specific IgE (ImmunoCAP): useful when antihistamines cannot be stopped, severe eczema, dermatographism, or high-risk patients

— Component-resolved diagnostics: e.g., Ara h 2 for peanut, omega-5 gliadin for wheat/FDEIA, galactose-α-1,3-galactose IgE for alpha-gal

— Oral food challenge (gold standard) in a monitored setting when history and testing are discordant

— Skin testing for the five Hymenoptera venoms; if positive and systemic reaction → venom immunotherapy (VIT) reduces future systemic reaction risk from ~60% to <5%, continued for 3–5 years

— Penicillin SPT + intradermal → if negative, graded oral amoxicillin challenge (per AAAAI 2022); >95% of "PCN-allergic" patients can be de-labeled

— Perioperative anaphylaxis: refer to specialized allergy clinic for testing of all administered agents including chlorhexidine and dyes

Who needs allergy/immunology referral after the index event? Essentially all patients with confirmed or strongly suspected anaphylaxis — especially:

Specific allergen testing (performed ≥4–6 weeks after the event to allow mast cell repletion and IgE recovery):

Venom hypersensitivity workup:

Drug allergy evaluation:

Mast cell disorder workup: persistently elevated baseline tryptase (>8 ng/mL) → consider KIT D816V mutation testing, bone marrow biopsy if criteria met for systemic mastocytosis

Board pearl: Hereditary α-tryptasemia (TPSAB1 gene duplication) causes elevated baseline tryptase and amplifies anaphylaxis severity — increasingly tested.

Key distinction: Skin testing performed too early (<4 weeks) yields false negatives due to mast cell mediator depletion.

Risk Stratification and Management Logic

— Mild: skin and subcutaneous only (urticaria, angioedema, mild GI)

— Moderate: respiratory, cardiovascular, or persistent GI features without hypotension or hypoxia

— Severe: hypoxia (SpO₂ <92%), hypotension, neurologic compromise, or collapse

— Asthma (especially poorly controlled) — leading comorbidity in fatal food anaphylaxis

— Delay to epinephrine >30 minutes

— Upright posture during hypotension ("empty ventricle syndrome" — keep patient supine)

— β-blocker, ACEi, MAOI, TCA use

— Older age, cardiovascular disease

— Mastocytosis or elevated baseline tryptase

— Peanut, tree nut, seafood triggers; injected drugs

1. IM epinephrine anterolateral thigh — repeat every 5–15 min as needed

2. Position: supine, legs elevated (Trendelenburg) — do NOT sit up a hypotensive patient, sudden upright posture has caused arrest

3. High-flow O₂ via NRB, target SpO₂ ≥94%

4. IV access ×2 large-bore, rapid isotonic crystalloid bolus 1–2 L (20 mL/kg peds), repeat as needed; severe cases may need 4–8 L

5. Adjuncts only after epinephrine: H1 antihistamine, H2 blocker, glucocorticoid, inhaled β2-agonist for wheeze

6. Refractory → epinephrine infusion, vasopressors, glucagon (if on β-blocker), advanced airway

Severity grading (Brown criteria, useful framework):

Predictors of fatal or near-fatal course:

Management priority ladder (memorize the order):

CCS pearl: If a CCS patient remains hypotensive after 2 IM epinephrine doses, escalate to IV epinephrine infusion (0.1 mcg/kg/min, titrate) and move location to ICU. Do not keep redosing IM indefinitely.

Board pearl: There is no absolute contraindication to epinephrine in anaphylaxis — even in pregnancy, coronary disease, or elderly patients, the risk of withholding exceeds the risk of giving it.

Pharmacotherapy — First-Line Drug Regimen

— Adult IM dose: 0.3–0.5 mg of 1 mg/mL (1:1000) into anterolateral mid-thigh (vastus lateralis)

— Pediatric IM dose: 0.01 mg/kg, max 0.3 mg (0.5 mg in adolescents)

— Auto-injector strengths: 0.15 mg (15–30 kg), 0.3 mg (>30 kg)

— Repeat every 5–15 minutes as clinically indicated

— IV infusion for refractory shock: 0.1 mcg/kg/min, titrate to MAP ≥65; central line preferred but peripheral acceptable in emergency

— Mechanism: α1 (vasoconstriction, ↓mucosal edema), β1 (inotropy/chronotropy), β2 (bronchodilation, ↓mediator release)

— Adverse effects: anxiety, tremor, palpitations, transient hypertension, rarely arrhythmia or ischemia — these are not reasons to withhold

— H1 antihistamine: diphenhydramine 25–50 mg IV/IM or cetirizine 10 mg IV/PO (less sedating, increasingly preferred per 2023 practice parameter)

— H2 antagonist: famotidine 20 mg IV — modest additive effect for cutaneous symptoms

— Glucocorticoid: methylprednisolone 1–2 mg/kg IV or prednisone 50 mg PO — does not prevent biphasic reactions per current evidence; routine use is now de-emphasized but commonly still given in practice. Consider especially in asthmatics

— Inhaled β2-agonist: albuterol 2.5–5 mg nebulized for persistent bronchospasm after epinephrine

— IV fluids: NS or LR, 1–2 L bolus, repeat

— Glucagon 1–5 mg IV bolus then 5–15 mcg/min infusion if on β-blocker

— Vasopressin, norepinephrine if epinephrine infusion insufficient

— Methylene blue has been used in refractory vasoplegia (case-level evidence)

Epinephrine (the only life-saving agent — everything else is adjunctive):

Adjunctive agents (do not replace epinephrine, do not delay it):

Refractory cases:

Step 3 management: Update guidelines (2023 AAAAI/ACAAI) state antihistamines and steroids are second-line and must never delay or replace epinephrine. Stem answers that pick diphenhydramine first are wrong.

Procedures and Airway Management

— Stridor not improving after 1–2 epinephrine doses

— Progressive tongue, lip, or oropharyngeal angioedema

— Hypoxia despite high-flow O₂

— Altered mental status, exhaustion, or cardiac arrest

— Most experienced operator at the bedside

— Awake fiberoptic or video laryngoscopy preferred when angioedema present — distorted anatomy makes DL hazardous

— Smaller ETT (6.0–7.0 mm) anticipated due to mucosal swelling

— Have difficult airway cart, surgical airway kit (cricothyrotomy), and ENT/anesthesia backup present

— Avoid paralytics until confident intubation is achievable; ketamine-only induction preserves spontaneous breathing

— Apply nebulized epinephrine 5 mg as a temporizing measure for upper airway edema

— Cricothyrotomy is indicated for "can't intubate, can't oxygenate" in adults; needle cricothyrotomy + jet ventilation preferred in children <12

— Two large-bore peripheral IVs (18 g or larger); intraosseous access if delayed >90 seconds — fully acceptable route for epinephrine, fluids, and pressors

— Foley catheter if hemodynamically unstable to track UOP (target 0.5 mL/kg/h)

— Arterial line for continuous BP if on epinephrine infusion (do not delay infusion for it)

— Central venous access for prolonged vasopressor needs

— Severe, intubated, or pressor-requiring → ICU

— Moderate, resolved with single dose, low risk → observe 4–6 hours minimum (longer if asthmatic, biphasic risk factors, or initial severe presentation — up to 12–24 h)

Airway is the leading cause of anaphylaxis death — anticipate and act early; do not wait for frank failure.

Indications for immediate intubation:

Intubation strategy:

Surgical airway:

Vascular access:

Adjunctive procedures:

Disposition decisions:

CCS pearl: On CCS, order anesthesia consult early if angioedema progresses, even before failure — this scores positively for anticipatory management.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher case fatality rate — reduced cardiopulmonary reserve, polypharmacy

— β-blocker and ACEi prevalence is high → expect refractory reactions, lower threshold for glucagon and prolonged observation

— Baseline hypertension may mask "relative" hypotension — a "normal" BP of 110/70 in a chronic hypertensive may represent shock; use >30% drop from baseline criterion

— Greater risk of Kounis syndrome (allergic ACS) — obtain ECG and troponin liberally

— Increased risk of epinephrine-induced ischemia and arrhythmia, but still give epinephrine — IM route remains first-line; titrate IV infusions cautiously

— Pulmonary edema risk with aggressive fluid resuscitation — reassess lung exam after each 500–1000 mL bolus

— Epinephrine dosing is unchanged

— Famotidine: reduce dose by 50% if CrCl <50

— Cetirizine: reduce to 5 mg daily if CrCl <30

— Avoid contrast re-exposure when contrast was the trigger; if absolutely required, use iso-osmolar contrast, premedicate (methylprednisolone 32 mg PO 12 h and 2 h before, diphenhydramine 50 mg 1 h before), and have epinephrine at bedside — premedication does not eliminate risk

— Most acute anaphylaxis drugs are unaffected

— Avoid hepatically cleared sedatives during airway management if cirrhotic

— β-blockers → blunt epinephrine response → use glucagon

— ACEi → impaired bradykinin metabolism → more severe angioedema, often non-mast cell mediated

— MAOI/TCA → potentiate epinephrine effects → start at lower infusion rates

— α-blockers (e.g., tamsulosin) → may blunt epinephrine vasoconstriction

Elderly considerations:

Renal impairment:

Hepatic impairment:

Drug interaction red flags in older adults:

Step 3 management: Elderly patients with anaphylaxis should be observed at least 8–12 hours (vs 4–6 for low-risk adults) and have outpatient cardiology follow-up if troponin elevated or ECG changes occurred during the episode.

Board pearl: Discontinuing the ACEi after ACEi-induced angioedema is mandatory — switching within the class is not safe; ARBs carry lower but real risk.

Special Populations — Pregnancy and Pediatrics

— Epinephrine IM remains first-line — category C, but maternal hypoxia/shock is far more dangerous to the fetus than epinephrine

— Position: left lateral decubitus tilt (≥15°) to relieve aortocaval compression; do not place flat supine after 20 weeks gestation

— Fetal monitoring: continuous external fetal heart rate monitoring if >24 weeks; obstetric consult early

— Common triggers: β-lactams in labor (intrapartum GBS prophylaxis), latex, oxytocin, anesthetic agents

— Avoid diphenhydramine in late third trimester if delivery imminent (neonatal sedation); cetirizine and loratadine are safer chronically

— Glucocorticoids safe; methylprednisolone preferred (less placental transfer than dexamethasone/betamethasone)

— Most common triggers: foods (peanut, tree nut, milk, egg, sesame), insect stings

— Epinephrine IM 0.01 mg/kg (max 0.3 mg pre-adolescent, 0.5 mg adolescent), anterolateral thigh

— Auto-injectors: 0.1 mg (7.5–15 kg, newer device), 0.15 mg (15–30 kg), 0.3 mg (>30 kg)

— Fluid bolus 20 mL/kg isotonic crystalloid, repeat up to 60 mL/kg

— Hypotension definition is age-specific: SBP <70 + (2×age in years) for ages 1–10

— Tachycardia is a more reliable early sign than hypotension in children (hypotension is late)

— Biphasic reactions may be slightly more common in children — observe at least 4–6 h, longer if severe

— Two epinephrine auto-injectors prescribed; one to keep at school

— Anaphylaxis Action Plan (AAAAI template) signed by physician

— Stock undesignated epinephrine laws now active in all 50 states

Pregnancy:

Pediatrics:

School and daycare planning (critical Step 3 ambulatory point):

Step 3 management: Every pediatric anaphylaxis discharge requires: 2 EpiPens, written action plan, allergist referral, school plan update, and trainer device demonstration with caregiver before leaving the ED.

Board pearl: Early introduction of peanut (4–6 months) per LEAP trial / NIAID 2017 guidelines reduces peanut allergy by ~80% in high-risk infants.

Complications and Adverse Outcomes

— Recurrence of symptoms 1–72 hours after apparent resolution, without re-exposure

— Incidence: 0.4–20% (most studies ~5%); typically within 6–12 hours

— Risk factors: severe initial reaction, delayed or inadequate epinephrine, hypotension at presentation, wide pulse pressure, unknown trigger, need for >1 epinephrine dose

— Steroids do not reliably prevent it (recent meta-analyses)

— Kounis syndrome — allergic coronary vasospasm (type I) or plaque rupture (type II); presents with chest pain/ECG changes during anaphylaxis

— Arrhythmias (sinus tachycardia, AF, VT)

— Stress (Takotsubo) cardiomyopathy

— Epinephrine-related: transient hypertension, tachyarrhythmia, MI (rare)

— Asphyxia from upper airway obstruction (leading cause of food anaphylaxis death)

— Bronchospasm refractory to standard therapy (asthmatics)

— ARDS (rare, severe cases)

— Aspiration during vomiting or intubation

— Anoxic brain injury from prolonged hypoperfusion

— Seizures

— Subcutaneous epinephrine (slower, erratic absorption — do not use for anaphylaxis)

— Inadvertent IV bolus of 1 mg/mL epinephrine (10× overdose) → hypertensive crisis, MI, intracerebral hemorrhage — a sentinel safety event

— Volume overload from aggressive fluids, especially in elderly or HF patients

Biphasic anaphylaxis:

Protracted anaphylaxis: symptoms persist hours to days despite treatment — usually requires epinephrine infusion and ICU

Cardiovascular complications:

Respiratory complications:

Neurologic complications:

Renal/hepatic: acute kidney injury from prolonged shock

Iatrogenic complications:

Psychological: PTSD, food/medication avoidance anxiety, refusal of subsequent imaging requiring contrast

Mortality: ~0.5–2% in hospitalized anaphylaxis; majority from airway obstruction (food) or cardiovascular collapse (drugs, venom)

Board pearl: The single most common medication error in anaphylaxis is giving IV push 1:1000 epinephrine instead of IM — this is a tested patient-safety item.

CCS pearl: Always observe for biphasic reaction with continuous monitoring; do not discharge directly from a hallway bed.

When to Escalate Care — ICU, Consults, and Inpatient Triage

— Need for epinephrine infusion or other vasopressor

— Intubation or impending airway compromise (progressive angioedema, stridor)

— Persistent hypoxia after initial stabilization

— Refractory shock requiring multiple fluid boluses or glucagon

— Significant comorbidity (active asthma, CAD, HF, pregnancy with fetal distress)

— Suspected Kounis syndrome with elevated troponin

— Required >2 IM epinephrine doses for stabilization

— Moderate reaction now stabilized but with biphasic risk factors

— Comorbid asthma, β-blocker use, prior severe reactions

— Required IV epinephrine bolus or significant fluid resuscitation

— Mild–moderate reaction responding fully to single IM epinephrine

— Reliable patient with transportation, understanding, EpiPens in hand

— Allergy/immunology — for all confirmed cases, ideally before discharge or scheduled within 1–2 weeks

— Anesthesia/ENT — actively for airway concerns

— Cardiology — if chest pain, ECG changes, elevated troponin (Kounis)

— OB — any pregnant patient >20 weeks

— Pharmacy — for EpiPen training and medication reconciliation (remove triggering agents from allergy list, update EMR)

— Social work/case management — auto-injector cost/access barriers

— If facility lacks ICU, advanced airway capability, or pediatric expertise — arrange interfacility transfer only after airway secured and patient stabilized

— Trigger identified or "unknown"

— Severity grade

— Medications given with times

— Response and reassessment vitals

— Discharge medications and instructions

— Follow-up plan and consult arrangements

ICU admission criteria:

Step-down/telemetry admission:

ED observation (4–6 h minimum, up to 24 h):

Consults to place (CCS-style ordering):

Transfer criteria:

Disposition documentation checklist:

Step 3 management: A patient who required 2 epinephrine doses is not a candidate for early discharge — admit for observation at least 12–24 hours even if currently asymptomatic.

CCS pearl: "Update location to ICU" is an explicit CCS action — do it as soon as criteria are met; do not wait for a bed.

Key Differentials — Same-Category Allergic and Immune Mimics

— Skin-only manifestations, no respiratory, CV, or persistent GI involvement

— Treat with antihistamines; epinephrine not required

— Still requires trigger identification and allergy follow-up

— Bradykinin-mediated, not mast cell–mediated

— Asymmetric facial/oral/tongue swelling, no urticaria, no pruritus

— Can occur months to years after starting drug — recent initiation not required

— Higher incidence in Black patients (4–5×)

— Does NOT respond to epinephrine, antihistamines, or steroids (though often given empirically)

— Treat with icatibant (bradykinin B2 antagonist) or fresh frozen plasma; airway protection priority

— C1-inhibitor deficiency (type I) or dysfunction (type II); rare type III with normal C1-INH (HAE-FXII)

— Recurrent episodes of non-pruritic angioedema, abdominal pain attacks, family history

— Labs: low C4 (best screening test), low C1-INH level/function

— Acute: C1-INH concentrate, icatibant, ecallantide

— Chronic prophylaxis: lanadelumab, berotralstat, C1-INH infusions

— Recurrent flushing, urticaria, GI symptoms, hypotension

— Elevated baseline tryptase, KIT D816V mutation in mastocytosis

— Confirmed by ≥20% rise in tryptase from baseline during episodes

— Mimics anaphylaxis after eating improperly stored dark-meat fish (tuna, mahi-mahi, mackerel)

— Histamine produced by bacterial decarboxylation

— Multiple diners affected, flushing, peppery taste

— Treat with antihistamines; resolves quickly

Acute urticaria/angioedema without anaphylaxis:

ACE inhibitor–induced angioedema:

Hereditary angioedema (HAE):

Acquired C1-INH deficiency: associated with lymphoproliferative disorders; low C1q distinguishes from hereditary

Mast cell activation syndrome (MCAS) and mastocytosis:

Scombroid poisoning:

Key distinction: Isolated angioedema without urticaria or pruritus in a patient on an ACEi → assume ACEi-induced until proven otherwise; stop the ACEi permanently and avoid the entire class.

Key Differentials — Non-Allergic Mimics

— Bradycardia (vs tachycardia in anaphylaxis), pallor, diaphoresis

— No urticaria, no respiratory symptoms, no GI persistence

— Resolves with recumbency

— Fever, infection source, slower onset, no urticaria

— Lactate elevated, procalcitonin may be elevated

— Can coexist (sepsis-triggered urticaria is rare but reported)

— Crushing chest pain, ECG ST changes, troponin rise

— Kounis syndrome bridges this category — allergic-mediated MI

— Acute dyspnea, hypoxia, tachycardia, hypotension; no urticaria

— Pleuritic chest pain, unilateral leg swelling, risk factors

— D-dimer, CTPA

— Hyperventilation, normal SpO₂, paradoxical inspiratory vocal cord adduction

— Stridor confined to inspiration; resolves with rebreathing or distraction

— Flow-volume loop shows blunted inspiratory limb

— Flushing without urticaria, diarrhea, wheeze, right-sided valvular disease

— Elevated urinary 5-HIAA; chronic course punctuated by attacks

— Vancomycin infusion reaction ("red man") — rate-related histamine release, flushing of face/neck; slow infusion to >1 h, antihistamine premedication. Not IgE-mediated but treat severe forms identically to anaphylaxis

— Opioid-induced flushing/pruritus — direct mast cell degranulation, usually mild

— Niacin flush — prostaglandin-mediated; aspirin pretreatment helps

Vasovagal syncope:

Septic shock:

Cardiogenic shock / acute MI:

Pulmonary embolism:

Tension pneumothorax: unilateral absent breath sounds, tracheal deviation, hyperresonance, JVD

Foreign body aspiration: sudden onset, choking history, unilateral wheeze, no skin findings

Asthma exacerbation: wheeze without urticaria/angioedema/hypotension; though severe attacks can mimic

Panic attack / vocal cord dysfunction:

Carcinoid syndrome:

Pheochromocytoma: episodic HTN, headache, palpitations, diaphoresis; not flushing/urticaria

Drug effects:

Hypoglycemia: diaphoresis, tachycardia, altered mental status; check glucose early

Board pearl: Bradycardia with hypotension after exposure is more consistent with vasovagal than anaphylaxis — but late-stage anaphylaxis (Bezold-Jarisch) can cause bradycardia; clinical context decides.

Secondary Prevention and Discharge Plan

1. Two epinephrine auto-injectors (patient + spare/backup; one for school/work if applicable)

2. Anaphylaxis Action Plan (written, signed, illustrated — AAAAI template)

3. Medical alert bracelet recommendation

4. Allergy/immunology referral within 1–4 weeks

5. EMR allergy field updated with trigger and reaction type

— Demonstrate with trainer device; have patient/caregiver demonstrate back ("teach-back")

— "Blue to the sky, orange to the thigh" (EpiPen); newer devices have voice prompts

— Through clothing is acceptable; hold 3 seconds (EpiPen) or per device

— Call 911 immediately after use, even if symptoms resolve

— Check expiration date quarterly; replace before expiry

— Discuss cost-access — generic epinephrine auto-injectors, manufacturer assistance programs

— Food allergy: strict avoidance, read labels (FALCPA + 2021 FASTER Act includes sesame), restaurant disclosure cards, school 504 plan

— Venom allergy: venom immunotherapy ↓ future systemic reaction risk from ~60% to <5%; 3–5 years duration

— Drug allergy: EMR alert, MedicAlert, discuss desensitization protocols if drug essential (e.g., penicillin in pregnancy with syphilis, chemo agents)

— Idiopathic anaphylaxis: consider daily H1 antihistamine ± H2 blocker; omalizumab in refractory cases

— Alpha-gal: avoid mammalian meat and gelatin-containing products

— Switch β-blockers to alternatives if anaphylaxis history (when clinically feasible)

— Discontinue ACEi after ACEi-angioedema; consider ARB cautiously or avoid

— Optimize asthma control (ICS adherence, action plan)

Mandatory discharge prescriptions and items (all 5 must be checked off):

Auto-injector counseling (must be performed in person):

Trigger-specific prevention:

Modifiable risk factor optimization:

Vaccination notes: Egg-allergic patients can receive standard influenza and MMR vaccines per ACIP; PEG and polysorbate are rare COVID vaccine triggers — consult allergy for reaction history.

Step 3 management: Failure to prescribe two auto-injectors at discharge is a frequently tested error — single device prescriptions are inadequate because biphasic reactions and device failures occur.

Follow-Up, Monitoring, and Counseling

— Primary care: within 1–2 weeks for medication reconciliation, EpiPen technique check, psychosocial assessment

— Allergy/immunology: within 2–4 weeks, ideally; testing typically at 4–6 weeks post-event

— Cardiology: within 1–2 weeks if Kounis features or troponin elevation

— OB: routine prenatal schedule if pregnant; sooner if any fetal monitoring concerns

— Baseline serum tryptase ≥24 h after recovery; recheck in 4–6 weeks if elevated to evaluate for mast cell disease

— Annual EpiPen prescription renewal and technique review

— Annual reassessment of trigger avoidance plan, action plan updates

— Asthma control (ACT score, spirometry annually)

— Recognize early symptoms — itching of palms/soles, throat tightness, anxiety, "doom"

— Use epinephrine early and liberally — undertreatment is the most common error

— After auto-injector use: call 911, lie down with legs elevated, do not stand or walk

— Avoid identified triggers; cross-reactivities (e.g., peanut and tree nut co-allergy ~30%; latex–fruit syndrome: banana, avocado, kiwi)

— Cofactors (NSAIDs, alcohol, exercise, viral illness) lower the threshold

— Travel: carry auto-injectors in carry-on, doctor's letter, know local emergency numbers

— Inform schools, workplaces, friends, dating partners (food kissing transmission documented)

— Anxiety and food-avoidance behaviors are common

— Screen for PTSD symptoms; refer for CBT if functional impairment

— Pediatric patients: avoid excessive parental restriction; balance safety with normal development

— Generic epinephrine cost ~$10 vs branded EpiPen >$600 — discuss formulary options

— Stock epinephrine laws allow schools, restaurants, public spaces to maintain undesignated supply

— Document patient education in chart for medico-legal protection

Follow-up cadence:

Long-term monitoring parameters:

Patient/family counseling priorities:

Psychological support:

Health systems / value-based considerations:

CCS pearl: On a CCS outpatient anaphylaxis follow-up, sequential orders should be: review EpiPen technique → confirm allergist appointment scheduled → reassess medication list (remove β-blocker/ACEi if reasonable) → update problem list and allergy field.

Ethical, Legal, and Patient Safety Considerations

— Anaphylaxis is a life-threatening emergency — implied consent applies; do not delay epinephrine for consent

— Awake intubation in angioedema: if patient has decision-making capacity, brief discussion of risks; if obtunded or imminent failure, proceed under emergency exception

— Adolescent self-administration: mature minor doctrine generally permits adolescents to carry/use auto-injectors; coordinate with parents and schools

— Religious objections to blood products: typically not relevant in anaphylaxis but matters if FFP used for HAE; document and respect

— Drug-induced anaphylaxis: report to FDA MedWatch (especially for new agents, biologics, vaccines)

— Vaccine-related anaphylaxis: report to VAERS — legally mandated

— Document trigger, time of onset, all interventions with times, response, biphasic surveillance, discharge plan

— EMR allergy field must be updated before discharge — failure is a sentinel risk for repeat exposure

— Communicate with PCP via discharge summary including: trigger, severity, medications given, follow-up plan

— Medication reconciliation — ensure triggering drug removed from active list; communicate with all prescribers and the patient's pharmacy

— Inpatient handoffs: SBAR communication with explicit "anaphylaxis precaution" note

— Wrong-route epinephrine (IV 1:1000 instead of IM) is a "never event"

— Failure to carry/dispense auto-injector at discharge is a recurring malpractice issue

— Restaurant/school exposures despite known allergy — document patient education, action plan provision

— Latex allergy: alert all future care teams; OR scheduled as first case to minimize ambient latex

— Oral immunotherapy for food allergy carries real anaphylaxis risk — informed consent must include this clearly

— Penicillin de-labeling: shared decision-making, especially in pregnancy/oncology contexts

Informed consent edge cases:

Mandatory reporting and documentation:

Transition-of-care risks (Step 3 favorite):

Patient safety / sentinel events:

Ethical issues in research and desensitization:

Confidentiality: school notifications require parental consent; balance privacy with safety needs

Step 3 management: Any patient with anaphylaxis must have the allergy field updated in the EMR before discharge order is signed — this is a hardwired safety step and a common tested item.

High-Yield Associations and Rapid-Fire Facts

Epinephrine = the only first-line drug. Antihistamines, steroids, β2 agonists are adjunctive.

IM anterolateral thigh > IM deltoid > SC. Never use subcutaneous for anaphylaxis.

Tryptase: draw within 15 min–3 h; baseline ≥24 h after recovery; diagnostic rise = (1.2 × baseline) + 2.

β-blocker refractory anaphylaxis → glucagon.

ACEi angioedema: bradykinin-mediated, no urticaria, treat with icatibant, discontinue ACEi permanently.

HAE: screen with low C4; confirm with C1-INH level/function.

Biphasic reaction: occurs in ~5%, usually within 6–12 h; steroids do not reliably prevent.

FASTER Act (2021): sesame is the 9th US labeled allergen.

LEAP trial: early peanut introduction in high-risk infants ↓ allergy ~80%.

Alpha-gal syndrome: delayed (3–6 h) anaphylaxis to mammalian meat after Lone Star tick bite.

Scombroid: histamine in spoiled dark-meat fish; multiple diners; antihistamines suffice.

Kounis syndrome: allergic ACS — get ECG and troponin in chest pain during anaphylaxis.

Venom immunotherapy: ↓ systemic reaction risk from ~60% to <5%; 3–5 years duration.

Latex–fruit syndrome: banana, avocado, kiwi, chestnut.

Cross-reactivity: peanut–tree nut ~30%; shellfish (crustacean–mollusk) ~75%; egg–chicken low.

Cetirizine 10 mg IV is now FDA-approved (2019) for acute urticaria — less sedating than diphenhydramine.

Pregnancy: left lateral decubitus during resuscitation after 20 weeks gestation.

Pediatric hypotension: SBP <70 + (2×age yr); tachycardia is earlier sign than hypotension.

No absolute contraindications to epinephrine in anaphylaxis.

Two EpiPens prescribed at every discharge — never just one.

Wrong-route epinephrine (IV 1:1000) is a sentinel safety event.

Hereditary α-tryptasemia (TPSAB1 duplication): amplifies anaphylaxis severity.

Omalizumab: used in refractory idiopathic anaphylaxis and chronic spontaneous urticaria.

Board pearl: When a stem mentions "delayed reaction 4 hours after a steak dinner in a hunter," the answer is alpha-gal syndrome.

Board Question Stem Patterns

Stem 1 — "Pick the first action": Patient develops urticaria, wheeze, and BP 80/50 ten minutes after IV ceftriaxone. Best next step? → IM epinephrine 0.3–0.5 mg anterolateral thigh. Distractors: diphenhydramine IV (wrong — second line), methylprednisolone IV (wrong), IV epinephrine bolus 1 mg (wrong dose/route).

Stem 2 — "Refractory case": Anaphylaxis not improving after 2 IM epinephrine doses; patient on metoprolol. Next? → Glucagon 1–5 mg IV bolus.

Stem 3 — "Isolated angioedema on lisinopril": Tongue swelling, no urticaria, no pruritus, on ACEi 2 years. Best treatment? → Icatibant (and stop ACEi); not epinephrine alone.

Stem 4 — "Delayed reaction to red meat": Hunter in Virginia, anaphylaxis 4–6 h after hamburger. Diagnosis? → Alpha-gal syndrome; test galactose-α-1,3-galactose IgE.

Stem 5 — "Multiple diners affected": Family ill after tuna sushi — flushing, headache, diarrhea, peppery taste. → Scombroid poisoning; treat with antihistamines.

Stem 6 — "Confirmatory lab": Patient stabilized after anaphylaxis; what test confirms? → Serum tryptase within 3 hours, baseline 24 h later.

Stem 7 — "Pediatric discharge": 8-year-old after peanut anaphylaxis. Discharge plan must include? → Two epinephrine auto-injectors + written action plan + allergist referral + school notification.

Stem 8 — "Pregnant patient": 28-week pregnant, anaphylaxis to bee sting. Position? → Left lateral decubitus tilt; epinephrine IM 0.3 mg unchanged.

Stem 9 — "Recurrent angioedema, family history": Episodic non-pruritic swelling, abdominal pain attacks, mother with same. Screening test? → C4 level; confirm with C1-INH.

Stem 10 — "Biphasic": Patient discharged after mild reaction returns 8 h later with worsening symptoms. → Biphasic anaphylaxis; treat as new anaphylaxis, admit, observe ≥24 h.

Stem 11 — "Vancomycin reaction": Flushing during rapid infusion, no hypotension. → Slow infusion rate, antihistamine premedication ("red man" — not true anaphylaxis).

Stem 12 — "Patient safety": Nurse prepared to give IV push 1 mg epinephrine 1:1000. → Stop; correct route is IM; IV requires 1:10,000 dilution and infusion in shock.

Step 3 management: Look for the answer that prioritizes (a) early epinephrine, (b) correct route, (c) anticipatory airway, (d) comprehensive discharge bundle. Distractors lean on antihistamines, steroids, or sitting the patient up.

One-Line Recap

— Skin/mucosal involvement + respiratory or CV compromise

— ≥2 organ systems after likely allergen exposure

— Hypotension after known allergen

— IM epinephrine → supine with legs elevated → high-flow O₂ → IV fluids → adjuncts → reassess every 5 min → repeat epinephrine every 5–15 min as needed → escalate to infusion + ICU if refractory

— β-blocker refractory → glucagon

— ACEi angioedema → icatibant, stop ACEi forever

— Pregnancy >20 wk → left lateral tilt, epinephrine unchanged

— Pediatrics → 0.01 mg/kg IM, 20 mL/kg fluid boluses

— Alpha-gal → delayed reaction to mammalian meat, tick-mediated

— 2 epinephrine auto-injectors + trainer demonstration

— Written anaphylaxis action plan

— Allergy/immunology referral within 2–4 weeks

— EMR allergy field updated, medication reconciliation done

— Observation ≥4–6 h (longer if severe, asthmatic, biphasic risk, β-blocker use, or required >1 epinephrine dose)

The take-home: Anaphylaxis is a clinical diagnosis demanding immediate IM epinephrine 0.3–0.5 mg anterolateral thigh — antihistamines, steroids, and adjuncts come after; refractory cases need IV epinephrine, glucagon for β-blocker users, and ICU escalation; every survivor leaves with two auto-injectors, a written action plan, an allergist referral, and an updated EMR allergy field.

Recognition (≥1 of 3 criteria):

Acute management priority ladder:

Key special situations:

Discharge bundle (never skip any element):

Board pearl: The single most important number on this topic is zero — the acceptable delay between recognizing anaphylaxis and giving IM epinephrine. Every other intervention can wait; epinephrine cannot.