Anafilaksis

01Pathophysiology

Anaphylaxis is the prototypical type I (immediate) hypersensitivity reaction mediated by IgE antibodies. On first exposure to an allergen, the immune system generates allergen-bound IgE, which then coats the surface of mast cells and basophils via high-affinity FcεRI receptors. This is the sensitization phase, which is clinically silent.

On re-exposure, the allergen cross-links two or more surface-bound IgE molecules, triggering mast cell and basophil degranulation. This releases preformed mediators (histamine, tryptase, heparin) and newly synthesized mediators (leukotrienes C4/D4/E4, prostaglandin D2, platelet-activating factor). These mediators act on target tissues throughout the body, which is why anaphylaxis is a systemic reaction rather than a localized one.

Histamine acts on H1 receptors to cause vasodilation, increased vascular permeability, bronchoconstriction, and pruritus. It acts on H2 receptors to increase gastric acid secretion and contribute further to vasodilation. The combined effect of vasodilation and capillary leak produces distributive shock: intravascular volume shifts into the extravascular space, causing profound hypotension and tachycardia. This is why the patient looks flushed, swollen, and hypotensive all at once.

Leukotrienes (formerly known as slow-reacting substance of anaphylaxis) are the primary drivers of bronchospasm and mucus hypersecretion. They are far more potent bronchoconstrictors than histamine, which explains why wheezing and respiratory failure are often the lethal components of anaphylaxis.

Upper airway edema (laryngeal and pharyngeal angioedema) results from increased vascular permeability in the submucosa, leading to stridor and potential airway obstruction. This connects directly to why airway management and epinephrine are the immediate priorities.

Non-immunologic anaphylaxis (previously called "anaphylactoid reactions") occurs through direct mast cell activation without IgE involvement. Triggers include radiocontrast media, opioids, and vancomycin ("red man syndrome"). The clinical presentation and management are identical; the distinction is mechanistic, not therapeutic.

Biphasic anaphylaxis occurs in approximately 5 to 20% of cases, where symptoms recur 1 to 72 hours (most commonly 8 to 12 hours) after initial resolution without re-exposure to the allergen. This is attributed to the late-phase response driven by newly recruited inflammatory cells (eosinophils, basophils) and de novo mediator synthesis.

02Classification and Clinical Manifestation

Diagnostic Criteria (Any One of Three Scenarios)

Severity Grading

Organ System Manifestations

A critical teaching point: anaphylaxis can occur without skin findings in up to 10 to 20% of cases. When a patient presents with acute bronchospasm and hypotension after a known exposure but has no urticaria, this is still anaphylaxis until proven otherwise. Test writers use this to trap students who anchor on "must have hives."

03Diagnostic Workup

Anaphylaxis is fundamentally a clinical diagnosis. There is no single lab test that confirms or excludes it in real time. The diagnosis is made at the bedside by recognizing the acute onset of multisystem involvement following a plausible exposure. On exams, you will never need to "wait for labs" before treating. This is a diagnose-and-treat-simultaneously scenario.

The best initial step when anaphylaxis is suspected is to administer intramuscular epinephrine immediately. This is both diagnostic (response supports the diagnosis) and therapeutic. Do not delay treatment to order tests.

Serum tryptase is the most useful laboratory marker to support a diagnosis of anaphylaxis retrospectively. Tryptase is a protease stored in mast cell granules and released during degranulation. It should be drawn 1 to 3 hours after symptom onset for the best yield. A level greater than the baseline (or $>11.4\text{ ng/mL}>\; 11.4\; \backslash text\{\; ng/mL\}$ in a patient without known baseline) suggests mast cell activation. However, tryptase is often normal in food-induced anaphylaxis because food triggers tend to activate mucosal mast cells, which contain less tryptase than connective tissue mast cells. A normal tryptase never rules out anaphylaxis.

Plasma histamine rises within minutes but clears rapidly (half-life of about 1 minute in plasma), making it impractical in clinical settings. It is mentioned on exams primarily as a distractor or to test whether you understand its kinetics.

After the acute episode resolves, patients should be referred to allergy/immunology for trigger identification. Skin prick testing is the preferred modality, performed at least 4 to 6 weeks after the event (to allow IgE replenishment on mast cells). Serum allergen-IgE (previously called RAST testing) is an alternative when skin testing is contraindicated (e.g., dermatographism, inability to discontinue antihistamines).

04Management and Treatment

Step 1: Epinephrine. This is the single most important intervention and the answer to virtually every "next best step" question about anaphylaxis. Epinephrine is given intramuscularly in the anterolateral thigh (vastus lateralis), NOT subcutaneously, NOT intravenously (except in refractory shock), and NOT in the deltoid. The IM thigh route provides the fastest and most reliable absorption. The dose for adults is 0.3 to 0.5 mg of 1:1,000 concentration (equivalent to 1 mg/mL). For children, the dose is 0.01 mg/kg up to a maximum of 0.3 mg. This can be repeated every 5 to 15 minutes if symptoms persist or recur. There is no absolute contraindication to epinephrine in anaphylaxis, including in elderly patients, pregnant women, and those with cardiac disease.

Epinephrine works through alpha-1 receptor stimulation (vasoconstriction, increased peripheral resistance, reversal of hypotension, reduction of angioedema), beta-1 stimulation (increased heart rate and contractility), and beta-2 stimulation (bronchodilation, decreased mast cell mediator release). It addresses every pathophysiologic mechanism of anaphylaxis simultaneously, which is why nothing else substitutes for it.

Step 2: Positioning and supportive care. Place the patient supine with legs elevated to augment venous return. Patients who are vomiting or in respiratory distress should be kept in a position of comfort. Administer high-flow oxygen. Obtain IV access with two large-bore IVs and begin aggressive fluid resuscitation with normal saline (1 to 2 L for adults, 20 mL/kg boluses for children) for hypotension.

Step 3: Adjunctive therapies. Antihistamines (H1 and H2 blockers) are second-line agents. They help with cutaneous symptoms (urticaria, pruritus) but do NOT reverse hypotension or airway obstruction. They are never a substitute for epinephrine. Corticosteroids (methylprednisolone 1 to 2 mg/kg IV or equivalent) are traditionally given to prevent biphasic reactions, though recent evidence questions their efficacy for this purpose. Regardless, they remain part of standard protocols on exams. Nebulized albuterol is added for persistent wheezing that does not resolve with epinephrine alone.

Step 4: Refractory anaphylaxis. If the patient does not respond to two or three doses of IM epinephrine, transition to a continuous IV epinephrine infusion (1 to 4 mcg/min, titrated). Patients on beta-blockers may be refractory to epinephrine because beta-blockade prevents the beta-adrenergic effects of epinephrine. In these patients, glucagon is the rescue agent. Glucagon activates adenylate cyclase through a non-adrenergic pathway, producing inotropic and chronotropic effects independent of beta-receptors. The dose is 1 to 5 mg IV over 5 minutes, followed by an infusion of 5 to 15 mcg/min.

Step 5: Observation and discharge planning. All patients must be monitored for at least 4 to 6 hours for biphasic reactions. Patients with severe reactions, hemodynamic instability, or prior biphasic reactions should be observed for up to 24 hours. At discharge, every patient must receive a prescription for an epinephrine auto-injector, education on its use, a written anaphylaxis action plan, and a referral to allergy/immunology for trigger evaluation.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common trap with anaphylaxis questions is the student who delays epinephrine or substitutes another drug. Test writers will tempt you with diphenhydramine, IV steroids, or albuterol as the "next best step." These are all adjuncts. The answer to "what is the next best step in a patient with anaphylaxis" is always IM epinephrine unless the stem explicitly states it has already been given.

A closely related trap is the route of administration. The correct route is intramuscular in the anterolateral thigh, not subcutaneous, not intravenous (unless refractory), and not in the deltoid. If a vignette describes a patient who received "subcutaneous epinephrine" and is not improving, the answer is to give a proper IM dose.

Another common pitfall is the patient who presents with anaphylaxis without skin findings. Roughly 10 to 20% of anaphylaxis cases lack urticaria or flushing. A stem describing acute bronchospasm plus hypotension within minutes of eating shellfish is anaphylaxis, even without hives. Do not let the absence of cutaneous signs steer you away from the diagnosis.

Students also frequently miss the biphasic reaction concept. A patient who had an anaphylactic episode, was treated, improved, and then deteriorates 4 to 8 hours later without re-exposure is experiencing a biphasic reaction. This tests your understanding of why patients need prolonged observation and why corticosteroids are given.

The beta-blocker plus anaphylaxis scenario is a high-yield pearl. When a patient on a beta-blocker develops anaphylaxis refractory to epinephrine, the tested concept is recognizing that glucagon is the rescue agent. This bridges cardiology and allergy knowledge, which is exactly the kind of cross-disciplinary integration that exam writers favor.

Finally, know the distinction between anaphylaxis and hereditary angioedema. Both produce life-threatening airway swelling. The discriminating feature is that HAE presents with angioedema without urticaria, does not respond to epinephrine, and is associated with low C1-inhibitor levels. If the stem says "recurrent episodes of lip/tongue swelling, no hives, not responding to epinephrine," think HAE, not anaphylaxis.

The core competency being tested across anaphylaxis questions is your ability to recognize the syndrome rapidly, initiate epinephrine without hesitation, and manage the downstream complications (refractory shock, biphasic reaction, beta-blocker interference) with the correct pharmacologic logic.