Anaphylaxis

Meet the patient

A 34-year-old nurse is ten minutes past a wasp sting at a picnic. She is flushed, wheezing and drooling, her voice is thickening, her systolic pressure is 84, and she tells you she is going to die.^[1][6]

Two questions are now live and you have a minute to answer both: is this anaphylaxis? and what do you do in the next thirty seconds? Everything below exists to answer those two questions at consultant depth — recognise the criteria, drive adrenaline into the anterolateral thigh, lay the patient flat, and do not discharge until the biphasic clock has run.^[1][3]

What anaphylaxis is — and why a simple allergy is the wrong frame

Anaphylaxis is defined by the World Allergy Organization (WAO) and the international consensus (NIAID/FAAN, 2006; EAACI 2021; WAO 2020) as a serious, generalised or systemic hypersensitivity reaction that is rapid in onset (minutes to a few hours) and may cause death — typically by airway obstruction, bronchospasm, or distributive (vasodilatory) shock.^[1][3][4]

Three features separate anaphylaxis from a "simple" allergic reaction and decide when to give adrenaline:^[4]

1. Multisystem — simultaneous involvement of two or more organ systems (skin plus respiratory and/or cardiovascular is the classic pattern).
2. Acute onset and rapid progression — typically minutes after exposure, occasionally up to an hour or more for oral triggers.
3. Life-threatening — airway compromise, breathing difficulty, or haemodynamic collapse. ^[1]

The clinical task at the bedside is binary: does this meet the diagnostic criteria? If yes — give IM adrenaline now, do not wait for tests, do not wait for the rash to "develop", do not wait for the doctor. Anaphylaxis is the one diagnosis in medicine where a single IM injection given within seconds saves a life; delay by minutes is the strongest predictor of death.^[3]

Two pathophysiological routes to the same syndrome

Historically two overlapping categories were taught: ^[1]

• Immunologic (IgE-mediated) — the classic "anaphylactic" reaction. Re-exposure to an allergen (food, drug, venom, latex) cross-links allergen-specific IgE on the high-affinity FcεRI receptor of mast cells and basophils, triggering degranulation. Penicillin, peanut, bee venom are archetypes.
• Non-immunologic (non-allergic, formerly "anaphylactoid") — direct mast-cell activation without IgE. Examples: radiocontrast media, opioids, vancomycin (rapid infusion), cold, heat, exercise, physical triggers. Clinically identical; management is identical. The distinction has been dropped from modern guidelines because treatment is the same — call both "anaphylaxis".^[3][6]

A third category, immunologic non-IgE (e.g. IgG- or immune-complex-mediated, complement activation by blood products), produces an identical clinical picture.^[2]

The single trap that kills patients is delayed adrenaline: the median time to respiratory or cardiac arrest is 30 minutes for foods, 15 minutes for envenomations, and 5 minutes for iatrogenic (drug) reactions — minutes that are entirely preventable.^[11]

Three axes that change the plan — mechanism, time, trigger

Anaphylaxis is classified along three axes — mechanism, temporal pattern, and trigger — each of which changes management.^[3][6]

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Who dies of anaphylaxis — the factors that turn a reaction fatal

Anaphylaxis is common and becoming commoner. Lifetime prevalence is now estimated at 1.6 to 5 percent of the population in high-income countries, with an annual incidence around 50 to 112 per 100 000 person-years and rising, particularly in children and young adults.^[3][6] Despite its frequency, case-fatality is low — around 0.03 to 0.3 percent of episodes are fatal (about 0.3 deaths per million population per year) — because most episodes resolve with prompt adrenaline.^[6]

Risk factors for a SEVERE or FATAL reaction

The single most useful bedside question is not "is this anaphylaxis?" but "what makes this patient at risk of dying from it?" Three categories determine severity.^[1][3]

Other contributors: adolescent and young-adult age (risk-taking, delayed autoinjector use), previous severe reaction (severity tends to escalate on re-exposure), allergen dose and route (intravenous triggers are the fastest and most dangerous), exercise and other cofactors (NSAIDs, alcohol, heat, infection, menstruation), aerosolised allergen in closed spaces (e.g. airplane peanut exposure), delayed adrenaline administration, geographic isolation from healthcare, older age and frailty, and limited physiological reserve.^[1]

Cofactors ("augmentation factors")

Up to 30 percent of episodes involve a cofactor that converts a tolerable exposure into a life-threatening reaction. The classic triad is food PLUS exercise PLUS an NSAID. Cofactors include exercise, NSAIDs (aspirin, ibuprofen), alcohol, heat or cold, fever or infection, psychological stress, and menstruation. Recognising a cofactor matters because allergen avoidance alone may be insufficient — the patient must also avoid the cofactor.^[3]

Why the patient collapses — the mast-cell cascade in two waves

The IgE-mediated cascade

In sensitised individuals, the first exposure to an allergen generates allergen-specific IgE via B-cell class-switching driven by T-helper-2 (Th2) cytokines (IL-4, IL-13). This IgE binds the high-affinity FcεRI receptor on the surface of mast cells (in tissues) and basophils (in circulation), arming the cell. On re-exposure, the multivalent allergen cross-links adjacent IgE-FcεRI complexes, triggering the mast cell to degranulate within seconds and to synthesise de novo lipid mediators over minutes to hours.^[1][2]

The signalling cascade is: ^[1]

1. Allergen cross-links IgE on FcεRI → the immunoreceptor tyrosine-based activation motif (ITAM) of the beta and gamma chains is phosphorylated by Lyn (Src-family kinase).
2. Syk tyrosine kinase is recruited and activated → phosphorylates LAT and PLCγ.
3. PLCγ cleaves PIP2 → IP3 (releases intracellular calcium from ER) + diacylglycerol (activates PKC).
4. Calcium and PKC trigger SNARE-mediated fusion of secretory granules with the cell membrane → immediate release of preformed mediators (exocytosis within minutes).
5. Activation of cytosolic phospholipase A2 (cPLA2) liberates arachidonic acid from membrane phospholipids → 5-lipoxygenase forms leukotrienes (LTC4, LTD4, LTE4) and cyclooxygenase forms prostaglandin D2 (PGD2). These lipid mediators are synthesised de novo, peaking at 5 to 45 minutes and accounting for the protracted and recurrent features.^[2][6]

Mediators and what they do

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Why does the patient collapse? — the cardiovascular pathophysiology

The cardiovascular collapse of anaphylaxis is a distributive (vasodilatory) shock compounded by relative hypovolaemia:^[2]

• Histamine and PAF cause widespread arteriolar vasodilation (drop in systemic vascular resistance) — the same peripheral vasodilation that causes flushing.
• Increased vascular permeability (capillary leak) shifts up to 35 percent of intravascular volume into the interstitium within minutes, producing relative and absolute hypovolaemia.
• The venous capacitance bed dilates — venous return to the heart falls ("relative empty vena cava syndrome").
• The result is reduced preload, reduced cardiac output, hypotension, and cerebral hypoperfusion → syncope. ^[1]

This is why positioning matters so much: a patient who suddenly sits up or stands during anaphylaxis can lose the residual venous return, empty the right heart, and arrest within seconds — the "empty vena cava / empty heart syndrome". Lie them flat with legs raised.^[3]

The biphasic and protracted reactions

A biphasic reaction is a recurrence of symptoms after initial resolution WITHOUT re-exposure to the trigger. In a systematic review and meta-analysis of 27 observational studies (4114 patients with anaphylaxis, 192 with biphasic reactions), the median time of symptom onset was 11 hours (range 0.2 to 72 hours). Initial presentation with hypotension (pooled OR 2.18) and an unknown inciting trigger (pooled OR 1.72) increase the risk, while food as the inciting trigger decreases it (pooled OR 0.62); severe anaphylaxis and/or the need for repeated doses of epinephrine are also risk factors. Clinicians should tailor observation periods individually based on clinical characteristics.^[4][5]

The mechanism is incompletely understood but is thought to involve late-phase recruitment of eosinophils, basophils and neutrophils by cytokines (TNF-alpha, IL-6) released from mast cells, sustained leukotriene and PAF production, and continued antigen absorption from the gut. The biphasic reaction can be milder, equal to, or more severe than the index event.^[5]

Coagulation and the bradykinin contribution

Anaphylaxis activates coagulation (prothrombin fragments, D-dimer rise) and fibrinolysis, which can produce a transient procoagulant state and, in severe cases, disseminated intravascular coagulation contributing to collapse. In patients taking an ACE inhibitor, blockade of angiotensin-converting enzyme (which also degrades bradykinin) allows bradykinin accumulation, augmenting vasodilation and angioedema and rendering anaphylaxis more severe and more adrenaline-resistant.^[2]

The presenting picture — skin is common, airway and pressure are lethal

The clinical picture reflects multisystem mediator release. Onset is typically within minutes of exposure (food, drug, venom) but may be delayed by hours after an oral drug or, rarely, exercise-induced episodes. The faster the onset, the more severe the reaction.^[1][6]

By system and frequency

The skin is the commonest organ involved but is NOT a target for adrenaline — its presence or absence during treatment does not indicate whether adrenaline is working. Anaphylaxis can occur WITHOUT skin signs in 10 to 20 percent of cases (especially drug-induced, perioperative, or in children with food allergy) — never wait for a rash.^[1][3]

The patient's own description

A sense of impending doom ("I am going to die"), a metallic taste, tingling of the lips or palms, warmth spreading from the chest, palpitations, and itching of the palms, soles, scalp, or genitalia are classical prodromes that precede overt organ involvement by seconds to minutes.^[1]

Atypical presentations

• Elderly — comorbidity and medication (beta-blocker, ACE inhibitor, digoxin) attenuate or distort signs; tachycardia may be absent; the only sign may be sudden hypotension or collapse. A myocardial infarction can be precipitated by the catecholamine surge — distinguish from a primary cardiac event.^[2]
• Pregnant — uterine cramps and vaginal discharge may herald anaphylaxis; fetal distress manifests as fetal bradycardia; eclampsia and amniotic-fluid embolism are differentials.^[3]
• Beta-blocked patient — refractory hypotension and bradycardia; may not respond to adrenaline; give glucagon.^[4]
• Mastocytosis (systemic mast-cell disorder) — reactions with a sting or a drug that are severe, recurrent, and often lack skin signs; baseline tryptase is persistently elevated.^[3]
• Children — atypical features include sudden behavioural change (becoming clingy, quiet, or irritable), drooling, cyanosis, and collapse; skin features may be missed because children cannot describe itching.^[6]
• Idiopathic — no trigger; recurring episodes, often flushing and cardiovascular features; diagnosis of exclusion after full workup including mastocytosis.^[3]

The mimics — one discriminator each

The diagnosis is clinical and based on the NIAID/FAAN criteria, but several conditions mimic anaphylaxis and require different treatment. All should be considered in the collapsed or distressed patient.^[1][3]

A bedside glucose must always be checked in the collapsed patient (hypoglycaemia is a great mimic). When a comatose patient with a suspected allergic reaction arrives, also send a paracetamol and salicylate level if overdose is possible.^[1]

The bedside minute — NIAID or FAAN first, adrenaline now

A rapid, structured ABCDE assessment secures the diagnosis and the priorities. Anaphylaxis is a clinical diagnosis — the NIAID/FAAN criteria (2006) are reproduced verbatim below and are the bedside gold standard.^[4]

^{[1] [11]}

The WAO 2020 revision adds that anaphylaxis is also "highly probable" when an acute onset (minutes to hours) of skin/mucosal features occurs together with at least one of respiratory or cardiovascular features, even if a trigger is not immediately identifiable.^[3]

The bedside assessment

• Airway — assess for hoarseness, stridor, drooling, tongue/lip swelling. Laryngeal oedema progresses rapidly — prepare for early intubation if the voice changes or stridor develops.
• Breathing — respiratory rate, oxygen saturation, wheeze, recession, use of accessory muscles, ability to speak in full sentences. Peak flow if the patient can cooperate. Hypoxia is a late and dangerous sign.
• Circulation — pulse (rate and character), BP (both arms if possible), capillary refill, peripheral temperature. Tachycardia and hypotension indicate shock. Bradycardia is a late, pre-terminal sign — cardiac arrest is imminent.
• Disability — GCS, pupils, glucose. A falling GCS signals cerebral hypoperfusion.
• Exposure — fully expose to inspect for urticaria, angioedema, flushing, surgical or dental sites (perioperative), injection sites, insect stings. Look at the oropharynx. ^[1]

Position

Lie the patient flat with the legs elevated. Do not allow a symptomatic patient to sit or stand up — sudden postural collapse is a described fatal event; the pathway exception is the patient with respiratory distress, who may sit upright with legs extended and elevated; the vomiting patient is placed in the recovery position.^[7][8]

Tests come after treatment — tryptase is a retrospective tool

Anaphylaxis is a clinical diagnosis. Investigations are NEVER required before starting treatment, and waiting for results costs lives.^[1] Investigations serve three roles: (1) support the diagnosis retrospectively; (2) exclude mimics and co-pathology; (3) identify the trigger after recovery.

Acute investigations (during the reaction)

• Acute serum tryptase — the most useful laboratory test. Mast-cell tryptase (beta) is released during degranulation, peaks at 1 to 2 hours after onset, and returns to baseline by 6 to 8 hours. Take the first sample as soon as possible after treatment has started (ideally within 1 to 2 h of onset), a second at 2 to 4 hours (or within 4 h), and a baseline (convalescent) sample at least 24 hours after the reaction (or at the allergy clinic). A rise to greater than (1.2 × baseline) + 2 micrograms/L supports the diagnosis of anaphylaxis and helps distinguish it from non-mast-cell mimics (vasovagal, panic, mastocytosis alone).^[3][2]
• ECG — for any perioperative, drug-induced, or elderly patient; anaphylaxis can precipitate ischaemia and arrhythmia, and adrenaline can cause ST elevation and ventricular ectopy.
• Capillary glucose — exclude hypoglycaemia.
• Arterial or venous blood gas — hypoxia, hypercapnia, metabolic acidosis in severe shock; methaemoglobinaemia if suspected.
• FBC, U&E, lactate — basophilia (paradoxical) and haemoconcentration; lactate tracks shock severity.
• Cardiac troponin — if chest pain, elderly, or perioperative; rule out Kounis syndrome (allergic ACS).

Confirming the trigger (after recovery, NEVER during)

Allergy testing is performed at least 2 to 4 weeks after the episode (skin tests are falsely negative during the refractory period). Referral to an allergy specialist is mandatory for every patient admitted with anaphylaxis.^[3]

• Skin-prick test — to suspected foods, drugs (penicillin, neuromuscular blockers), venoms; prick-prick for fresh foods.
• Serum allergen-specific IgE (ImmunoCAP, RAST) — useful for penicillin, venom, selected foods; less sensitive for some drugs.
• Component-resolved diagnostics — distinguishes true allergy (e.g. Ara h 2 for peanut) from cross-reactivity; predicts severity and risk.
• Basophil activation test (CD63/CD203c flow cytometry) — useful for drug allergy (beta-lactam, NSAID, neuromuscular blocker) and venom.
• Drug provocation / oral food challenge — gold standard but only in a specialist setting with full resuscitation facilities.
• Serum tryptase at baseline — a persistently elevated baseline tryptase (over 11.4 micrograms/L or over 20 micrograms/L), especially with a history of severe reactions to insect venom, mandates workup for systemic mastocytosis / clonal mast-cell disorder (KIT D816V mutation, bone marrow biopsy).^[3]

Perioperative anaphylaxis — the investigation pathway

Perioperative anaphylaxis is investigated by the EAACI/ESAIC three-step pathway: (1) acute serum tryptase (immediately, 1 to 2 h, and 24 h baseline); (2) skin tests (prick and intradermal) 4 to 6 weeks later to all suspected agents — neuromuscular blockers (most common), antibiotics, chlorhexidine, latex, dyes (patent blue, isosulfan blue), colloids, opioids; (3) specific IgE and basophil activation tests for selected agents. Chlorhexidine is an increasingly recognised cause, found in mouthwash, skin prep, and lubricant gels.^[2]

The first 60 seconds — flat, adrenaline, oxygen

The resuscitation bundle is time-critical and delivered in parallel. The order of priorities is ABCDE; the single most important intervention is IM adrenaline into the anterolateral thigh.^[1][3]

1. Remove the offending allergen if still present — stop the drug infusion, remove the sting, do not give more of the suspected allergen.
2. Call for help — senior clinician, resuscitation team, anaesthetist.
3. Position — supine with the legs elevated; if respiratory distress is present, allow the patient to sit upright with legs extended and elevated; do not let a shocked patient stand.
4. Airway and breathing — optimise airway, breathing and cardiovascular resuscitation: supplemental oxygen, noninvasive or invasive positive-pressure ventilation as needed.
5. Circulation — IM ADRENALINE 0.01 mg/kg of 1:1000 (maximum single dose 0.5 mg) into the anterolateral thigh — this is FIRST and MOST IMPORTANT; there are no absolute contraindications. Repeat every 5 to 15 minutes for persistent anaphylaxis.
6. IV fluid resuscitation — establish IV access and give aggressive intravenous fluid resuscitation for patients in anaphylactic shock. ^[7][8]

Why IM adrenaline first? Immediate intramuscular administration into the anterolateral thigh is the recommended first-line route and is always safe even if the diagnosis is uncertain; inadvertent intravenous administration can cause serious cardiovascular complications such as coronary vasospasm and stress cardiomyopathy.^[6][17]

Why is adrenaline given BEFORE antihistamines and steroids? Epinephrine is the first-line pharmacotherapy for uniphasic AND biphasic anaphylaxis; antihistamines and corticosteroids are adjuncts that cannot replace epinephrine, and they are not reliable interventions to prevent biphasic anaphylaxis.^[4][10]

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Adrenaline first, everything else second — the stepwise ladder

Adrenaline (epinephrine) — the first-line drug

Adrenaline is a non-selective alpha- and beta-adrenergic agonist. The recommended first-line dose is 0.01 mg/kg of 1:1000 intramuscularly (maximum single dose 0.5 mg), and the maximum single dose may be repeated after 5 to 10 minutes if needed.^[7]

^{[7] [9] [10] [15]}

Epinephrine is administered every 5 to 15 minutes for persistent anaphylaxis (and every 5 minutes in life-threatening or refractory presentations). An IV adrenaline infusion should be prepared for patients with persistent anaphylaxis after two doses of IM epinephrine and initiated after the third dose, or earlier at the provider's discretion.^[8]

The weight-based equivalent 0.01 mg/kg IM (maximum single dose 0.5 mg) applies to children as well — useful when age is uncertain or the child is small/large for age. ^[7]

Adrenaline autoinjectors (discharge)

^{[9] [10]}

Prescribe an adrenaline autoinjector on discharge — guidelines recommend the availability of adrenaline autoinjectors for patients in the community — with structured, comprehensive training in its use for the patient and family.^[3][6]

IV fluids

The shock of anaphylaxis is distributive with relative hypovolaemia. Patients with severe anaphylaxis need IV access for fluid replacement and supplementary oxygen; those in anaphylactic shock need aggressive intravenous fluid resuscitation alongside intravenous epinephrine.^[8][10]

• Give aggressive intravenous fluid resuscitation for patients in anaphylactic shock, together with epinephrine — fluid resuscitation is part of the initial treatment bundle alongside airway protection and removal of triggering agents.^[2][8]
• Where an epinephrine infusion is unavailable, repeat IM epinephrine every 5 minutes together with the other ABC interventions while arranging rapid transfer to advanced resuscitative care.^[8]

Adjuncts (after adrenaline, never before)

• Antihistamine — histamine H1 and H2 antagonists are adjunct medications considered only after epinephrine administration.^[1]
• Corticosteroid — corticosteroids are adjuncts after epinephrine; antihistamines and/or glucocorticoids are NOT reliable interventions to prevent biphasic anaphylaxis, although premedication has a role in specific chemotherapy protocols and rush aeroallergen immunotherapy.^[1][4]
• Beta2 agonist — beta2 agonists are adjuncts considered after epinephrine (predominantly for bronchospasm).^[1]
• Glucagon — an adjunct for the beta-blocked patient refractory to adrenaline; registry data show second-line options including glucagon are rarely used in practice.^[1][12][13]
• Antihistamines and steroids are second-line only — they cannot replace adrenaline at any point.^[10]

Refractory anaphylaxis — escalation

Refractory anaphylaxis is defined as anaphylaxis unresponsive to treatment with at least two doses of adrenaline. Registry data show refractory anaphylaxis is associated with drug-induced anaphylaxis in particular and carries a high mortality rate.^[13]

• IV adrenaline infusion — after two ineffective intramuscular injections, an intravenous continuous infusion of epinephrine should be initiated promptly, combined with aggressive fluid resuscitation and, if necessary, second-line vasoactive drugs.^[8][13]
• Airway and breathing — optimise airway, breathing and cardiovascular resuscitation, including supplemental oxygen and noninvasive or invasive positive-pressure ventilation.^[2][8]
• Second-line agents — registry data list vasopressors (e.g. dopamine), methylene blue and glucagon as second-line treatment options for refractory anaphylaxis; in practice these were not used at all for the refractory cases identified — a treatment gap to recognise.^[13]
• Ongoing epinephrine — where no epinephrine infusion is available, repeat IM (or intranasal) epinephrine every 5 minutes while arranging rapid transfer to a setting equipped for advanced resuscitative care.^[8]

Observation after recovery — the biphasic trap

Every patient must be observed after recovery for a potential biphasic reaction — recurrence of anaphylaxis without re-exposure. In the largest meta-analysis the median time of biphasic symptom onset was 11 hours (range 0.2 to 72 hours); initial hypotension and an unknown trigger predict higher risk, while food-triggered reactions carry lower risk. Observation should therefore be tailored to the individual patient.^[5]

^{[1] [4]}

The AAAAI 2020 practice parameter keeps all patients under observation until symptoms have fully resolved, with education on risk of recurrence, trigger avoidance, self-injectable epinephrine, and allergist referral before discharge.^[4]

Discharge bundle

Every patient admitted with anaphylaxis must leave with:^[1][3][4]

1. An adrenaline autoinjector at the correct dose for weight — demonstrated to patient and family.
2. A written anaphylaxis action plan (an individualized anaphylaxis emergency plan).
3. Allergen avoidance advice specific to the trigger.
4. Adjunct medication advice — antihistamines and/or corticosteroids are NOT reliable to prevent biphasic reactions; their role is adjunctive only.
5. Allergist referral for investigation of the trigger and immunotherapy where indicated.
6. Structured, comprehensive training in recognising early signs and in autoinjector technique.
7. School/workplace policies that reflect anaphylaxis guidelines for children. ^[1][3][4]

Scenarios you will actually meet

Drug-induced anaphylaxis

Drugs are the leading cause of fatal anaphylaxis in adults. The commonest culprits: beta-lactam antibiotics (penicillin, cephalosporin), NSAIDs (ibuprofen, diclofenac, aspirin), neuromuscular blockers, radiocontrast media, chemotherapy (platinum, taxanes), monoclonal antibodies, proton-pump inhibitors, chlorhexidine, patent blue dye.^[1][2]

Beta-lactam anaphylaxis is IgE-mediated against the beta-lactam ring or its side chains. Cross-reactivity between penicillin and cephalosporin is now under 2 percent for second- and third-generation cephalosporins; aztremonam is safe, and meropenem can usually be given. A documented history mandates skin testing and, if needed, desensitisation or drug provocation in a specialist setting.^[1]

NSAID anaphylaxis is often non-allergic (cross-reactive COX-1 inhibition) — symptoms with one NSAID predict symptoms with all non-selective NSAIDs. Selective COX-2 inhibitors (celecoxib) are usually tolerated. A minority have a single-NSAID IgE allergy (tolerate other NSAIDs).^[6]

Perioperative anaphylaxis

Incidence 1 in 10 000 to 20 000 anaesthetics; mortality 3 to 9 percent. The leading triggers are, in order: neuromuscular blocking agents (rocuronium, suxamethonium, vecuronium — quaternary ammonium IgE), antibiotics (teicoplanin, beta-lactam, vancomycin), chlorhexidine, latex, dyes (patent blue, isosulfan blue), colloids, opioids.^[2]

Latex anaphylaxis has fallen sharply with latex-free policies but remains relevant in spina bifida, multi-surgery, and healthcare-worker patients. Chlorhexidine is the rising culprit — found in skin prep, mouthwash, lubricant gels, and urinary catheters.^[2]

Distinguishing features: sudden hypotension, bronchospasm, or cardiac arrest within minutes of induction, often without skin signs (under drapes, the patient is anaesthetised). Management is identical — stop suspected agents, call for help, IM adrenaline, IV fluids, oxygen; exclude other causes of intraoperative collapse (gas embolism, tension pneumothorax, hypovolaemia, high spinal). Send acute and 1 to 2 hour and 24 hour tryptase; refer to a specialist allergy clinic for the EAACI/ESAIC investigation pathway.^[2]

Food-induced anaphylaxis

The commonest cause of anaphylaxis in children and a leading cause in adults. Top triggers: peanut, tree nuts (cashew, walnut, hazelnut, almond), shellfish, fish, milk, egg, sesame, wheat, soy, mustard, kiwi. Peanut and tree nut cause the most severe and recurrent reactions. Onset is usually within minutes to 2 hours of ingestion.^[6]

Cofactor-augmented food anaphylaxis — exercise, NSAIDs, alcohol, heat, infection, or menstruation at the time of exposure converts a tolerable dose into a life-threatening reaction. Food-dependent exercise-induced anaphylaxis (FDEIA) is the archetype: anaphylaxis occurs only when the trigger food (often wheat, celery, shellfish) is followed by exercise within 4 to 6 hours.^[3]

Management is identical. Long-term: strict allergen avoidance, component-resolved diagnostics (e.g. Ara h 2 for peanut) to predict severity, oral immunotherapy (PALFORZIA for peanut) for selected patients, and two autoinjectors.^[6]

Venom anaphylaxis

Honeybee, wasp, yellow-jacket, hornet, fire-ant stings cause systemic reactions in 0.3 to 8.9 percent of adults; venom anaphylaxis accounts for a disproportionate share of anaphylaxis deaths (often older men with cardiovascular comorbidity).^[1]

Indications for venom immunotherapy (90 to 98 percent protective): any systemic reaction with more than just skin features in adults; any systemic reaction in children; a systemic reaction with a positive diagnostic test. Therapy is given for 3 to 5 years (lifelong in mastocytosis and high-risk patients).^[3]

Idiopathic anaphylaxis

No trigger identified after a full workup (about 20 percent of cases). Diagnosis of exclusion; workup must include mastocytosis (baseline tryptase, KIT D816V, bone marrow biopsy if indicated), hidden allergens (spices, uncommon foods), and mast-cell-activating syndromes. Management: autoinjectors, oral prednisolone and antihistamine prophylaxis (in refractory cases — now used less commonly), omalizumab (anti-IgE monoclonal) for refractory cases.^[3]

Exercise-induced and physical anaphylaxis

Exercise-induced anaphylaxis — anaphylaxis during or shortly after exercise; food-dependent (wheat, celery, shellfish, alcohol) or non-food-dependent; stop exercise at the first prodromal symptom. Cold-induced anaphylaxis (after cold water immersion) and cholinergic anaphylaxis (with sweating and a rise in core temperature) are rarer physical forms.^[6]

How the patient comes to harm — the preventable list

Other pitfalls:^[1][3][4]

• Treating the rash with antihistamine instead of giving adrenaline for airway/BP. The rash is harmless; airway and BP are not.
• Giving adrenaline subcutaneously — absorption is unreliable in shock; always IM into the thigh.
• Giving adrenaline IV as a first-line bolus — risk of arrhythmia and hypertensive crisis; IV bolus is for cardiac arrest or carefully titrated in refractory shock by experienced staff.
• Failing to repeat adrenaline at 5 minutes — one dose is often insufficient.
• Letting the symptomatic patient sit up to "feel better" — sudden fatal collapse.
• Discharging too early and missing the biphasic reaction.
• Forgetting the beta-blocker history — adrenaline will not work; glucagon is needed.
• Missing the mastocytosis diagnosis — a persistently elevated baseline tryptase is the clue.
• Not prescribing two autoinjectors at discharge.
• Confusing hereditary/acquired angioedema (bradykinin-mediated) with anaphylaxis — adrenaline does NOT work; the patient needs C1-inhibitor concentrate or icatibant. ^[1]

Who goes home, who stays — the biphasic clock decides

Case-fatality is low (0.03 to 0.3 percent of episodes), but because anaphylaxis is common, the absolute number of deaths is significant. Death is typically from asphyxia (airway obstruction) or cardiovascular collapse. Predictors of death: delayed adrenaline, asthma (especially uncontrolled), cardiovascular disease, mastocytosis, beta-blocker/ACE-inhibitor therapy, intravenous or oral drug triggers, adolescent/young-adult age.^[1][6]

Safe discharge criteria (after an uncomplicated reaction responding to one dose of adrenaline, no risk factors):^[3]

• Asymptomatic, kept under observation until symptoms have fully resolved; monitoring for four to 12 hours depending on risk factors;
• An adrenaline autoinjector prescribed with technique demonstrated;
• Written anaphylaxis action plan, allergen avoidance advice, and allergy clinic referral provided;
• A reliable carer/companion;
• Cofactors and high-risk features excluded. ^[1]

Admit or observe longer (overnight) for: two or more adrenaline doses, refractory anaphylaxis, airway involvement, asthma, cardiovascular disease, beta-blocker therapy, mastocytosis, pregnancy, elderly, poor social support, presentation at night, a history of biphasic reactions, a wide initial pulse pressure, or a high tryptase.^[3][5]

ICU admission for: refractory anaphylaxis needing an adrenaline infusion, ventilated patients, those with profound shock or cardiac arrest, and those needing vasopressors or ECMO.^[2]

Special populations — children, pregnancy, the beta-blocked

Children

Food is the dominant paediatric trigger — in a multicentre series of children aged 0 to 2 years, food caused 93 percent of reactions (cow's milk the single commonest food), with drugs a distant second at 3.7 percent.^[14] Children can present atypically, and anaphylaxis is not more severe in younger children, though age-specific symptoms vary.^[9] Adrenaline is weight-based: 0.01 mg/kg IM (maximum single dose 0.5 mg), and IM epinephrine into the anterolateral thigh is always safe even if the diagnosis is uncertain.^[6][7] Autoinjector bands: 0.1 or 0.15 mg under 15 kg; 0.15 mg under 25 kg; 0.3 mg at 25 kg or greater.^[9][10]

Children with a first anaphylactic reaction must be referred to an allergy specialist; guidelines recommend the availability of adrenaline autoinjectors in the community and school policies that reflect anaphylaxis guidelines.^[3] Biphasic reactions are well described in children — observe four to 12 hours depending on risk factors, with observation tailored to the individual patient.^[1][5]

Pregnancy

Anaphylaxis in pregnancy threatens both mother and fetus. The fetal effects of maternal hypotension — fetal bradycardia, distress, miscarriage, preterm labour — are more dangerous than adrenaline. Adrenaline is safe and MUST NOT be withheld; treat the mother first. Position in the left lateral tilt (or left lateral) to relieve aortocaval compression. IV fluids are given generously. After stabilisation, monitor the fetus (cardiotocography) and obstetric review.^[3]

Differentials in pregnancy include amniotic fluid embolism, eclampsia, pulmonary embolism, and septic shock. Common triggers in pregnancy: antibiotics (for cesarean prophylaxis), oxytocin, anaesthetic agents, latex.^[3]

Elderly

Reduced physiological reserve, ischaemic heart disease, hypertension, heart failure, and beta-blocker/ACE-inhibitor/digoxin therapy all increase the risk of severe and fatal anaphylaxis and of adrenaline-related complications (arrhythmia, ischaemia). Adrenaline is still first-line — do not withhold, but titrate carefully in the elderly with cardiac disease; monitor ECG continuously.^[2]

Beta-blocked patients

Beta-blockers were once considered relative or absolute contraindications in anaphylaxis, but current evidence shows minimal absolute risk of severe reactions and supports continuation in most patients, particularly when cardiovascular disease is present.^[12] In patients with heart disease, discontinuing or changing beta blockers and/or ACE inhibitors may pose a larger risk of worsened cardiovascular disease than the risk of severe anaphylaxis with continuation.^[9] For the beta-blocked patient refractory to adrenaline, glucagon may aid adrenaline-resistant cases.^[12]

Patients on ACE inhibitors

ACE also degrades bradykinin; ACE-inhibitor therapy augments bradykinin-mediated angioedema and vasodilation, making anaphylaxis more severe and adrenaline-resistant. Stop the ACE inhibitor and consider icatibant (bradykinin B2 antagonist) and C1-inhibitor concentrate in addition to standard therapy.^[2]

Mastocytosis (systemic / clonal mast-cell disorder)

Patients with systemic mastocytosis (especially KIT D816V mutation) have a markedly elevated mast-cell burden and a high risk of severe anaphylaxis (often venom-triggered), frequently without skin signs and often refractory. Baseline serum tryptase is persistently elevated (over 11.4 to 20 micrograms/L). Every patient with a baseline tryptase above the threshold after anaphylaxis — especially after a sting — should be referred for bone-marrow biopsy and management by an allergist and haematologist. Life-long venom immunotherapy is recommended for venom-triggered mastocytosis anaphylaxis. Adrenaline autoinjectors always; H1 + H2 antihistamine prophylaxis and mast-cell stabilisers (cromoglicate, omalizumab) in selected patients.^[3]

Evidence and the names that score marks

The two foundational diagnostic frameworks are the NIAID/FAAN criteria (Sampson 2006) — still widely taught and reproduced above — and the WAO 2020 criteria, which add that anaphylaxis is also highly probable when an acute skin/mucosal reaction occurs with at least one of respiratory or cardiovascular features (acknowledging the difficulty in identifying a trigger at first presentation).^[3][4]

The major current guidelines:^[3][4]

• EAACI 2021 update (Muraro et al., Allergy 2022) — the European consensus; recommends clinical criteria for diagnosis, blood sampling for later tryptase measurement, prompt IM adrenaline as first-line management, availability of adrenaline autoinjectors in the community, and structured, comprehensive training for people at risk.^[3]
• AAAAI/ACAAI 2020 practice parameter (Shaker et al., JACI 2020) — the US consensus; epinephrine is first-line pharmacotherapy for uniphasic AND biphasic anaphylaxis, antihistamines and/or glucocorticoids are not reliable to prevent biphasic anaphylaxis, and all patients are kept under observation until symptoms fully resolve, with education, self-injectable epinephrine training, and allergist referral.^[4]
• 2023 Joint Task Force practice parameter — highlights diagnostic criteria, age-specific symptom variation in young children, autoinjector dosing by weight (0.1/0.15 mg under 15 kg; 0.3 mg at 25 kg or greater), and caution before stopping beta-blockers/ACE inhibitors in heart disease.^[9]
• Anaphylaxis clinical care pathway 2026 (Dribin et al., JACI-IP) — operationalises the first five steps (remove allergen, position, IM/intranasal epinephrine every 5 to 15 min, ABC resuscitation with aggressive fluids, and IV epinephrine infusion prepared after two doses and initiated after the third).^[8]

Regional deltas

• Adrenaline autoinjector doses by weight — 0.15 mg for children under 25 kg and 0.3 mg for children 25 kg or greater and adults; the 2023 practice parameter adds 0.1 or 0.15 mg for children under 15 kg.^[9][10]
• Adult IM dose — the World Allergy Organization-recommended maximum single dose is 0.5 mg (0.01 mg/kg); a retrospective cohort found an initial 0.5 mg dose required fewer escalations of care than 0.3 mg in adults.^[15]
• Observation duration — four to 12 hours depending on risk factors, with observation tailored to the individual patient (median biphasic onset 11 h, range 0.2 to 72 h).^[1][5]
• Intranasal adrenaline — now incorporated into a published clinical care pathway: intranasal and intramuscular epinephrine are considered equally efficacious based on pharmacokinetic data, and providers may switch between routes.^[8]
• Perioperative culprits differ from ward culprits — the most common causes include neuromuscular blocking agents, antibiotics, antiseptics, and latex.^[16]

Controversies

• IV adrenaline bolus in non-arrested patients — risk of arrhythmia and ischaemia; reserved for refractory anaphylaxis under experienced supervision.
• Glucagon — increasingly recommended for beta-blocked patients, but evidence is largely from case series.
• Corticosteroids — modern trials have not demonstrated a reduction in biphasic reactions, yet they remain in most guidelines; the AAAAI 2020 parameter makes their use optional.^[4]
• Optimal observation time — the 4-to-6-hour (AAAAI) versus 6-hour (UK) debate, and whether observation is needed at all in low-risk patients.
• Visually-impaired or dexterity-limited patients and children — autoinjector design and education.

The mantra, and the memory devices

The mantra: remove the trigger, supine with legs raised, adrenaline into the anterolateral thigh, repeat at five- to fifteen-minute intervals, and watch for the second wave.^[7][8]

^{[7] [8] [11]}

• IM ADRENALINE 0.01 mg/kg (max 0.5 mg) into the anterolateral thigh — FIRST, before anything else; there are no absolute contraindications, and it is safe even when the diagnosis is uncertain.
• Repeat every 5 to 15 minutes for persistent anaphylaxis — and prepare an IV adrenaline infusion once two doses have failed.^[8]
• Position: SUPINE with legs elevated — allow the upright position only for respiratory distress.
• Anaphylaxis can occur WITHOUT skin signs in 10 to 20 percent of cases — do not wait for the rash.^[11]
• Antihistamines and steroids are ADJUNCTS — they cannot replace adrenaline.^[4][10]
• Serum tryptase reflects mast-cell degranulation — sample when the clinical diagnosis is not clear; a persistently raised baseline with severe reactions points to a mast-cell disorder.^[1]
• Beta-blocked patient refractory to adrenaline → GLUCAGON may aid adrenaline-resistant cases.^[12]
• Biphasic reaction — median onset 11 hours, range 0.2 to 72 hours — observe four to 12 hours, tailored to risk factors; discharge with an adrenaline autoinjector, an action plan, and an allergy referral.^[1][5]
• Refractory anaphylaxis (unresponsive to at least two adrenaline doses) → IV adrenaline infusion promptly, aggressive fluids, and second-line vasoactive drugs if necessary.^[13]
• Perioperative anaphylaxis — the most common causes include neuromuscular blocking agents, antibiotics, antiseptics, and latex.^[16]
• Vasovagal: bradycardia + pallor, NO rash; anaphylaxis: tachycardia + rash + airway.
• Median time to respiratory or cardiac arrest: 30 min (foods), 15 min (envenomation), 5 min (iatrogenic).^[11]
• Always ensure an adrenaline autoinjector (with training) on discharge. ^[3][6]

Ward-round test — three stems, a minute each

Stem 1 — the patient who will not respond to adrenaline (answer)ShowHide

A 68-year-old man on metoprolol for ischaemic heart disease collapses minutes after a dose of co-amoxiclav. He is hypotensive, bradycardic and flushed, and two doses of intramuscular adrenaline 0.5 mg have done almost nothing. What now? Model: This is beta-blocked anaphylaxis — he is refractory to two doses of adrenaline, which defines refractory anaphylaxis. In a beta-blocked patient refractory to adrenaline, glucagon may aid adrenaline-resistant cases. Continue oxygen, aggressive IV fluids and airway support, prepare an IV adrenaline infusion (prepared after two doses, initiated after the third), and send acute and baseline tryptase. The lesson the examiner wants: a refractory patient on a beta-blocker is not an adrenaline-resistant mystery — it is a named, treatable trap.^[8][12][13]

Stem 2 — collapse on induction, no rash in sight (answer)ShowHide

Three minutes after induction for an elective hernia repair the blood pressure is unrecordable and the peak airway pressure has doubled. There is no rash and the drapes hide the skin. What is the first suspect, and what do you send? Model: Treat as perioperative anaphylaxis — stop the suspected agents, call for help, give intramuscular adrenaline, fluids and oxygen, and exclude the surgical mimics. The most common causes include neuromuscular blocking agents, antibiotics, antiseptics and latex. The skin is unreliable here — skin findings are absent in 10 to 20 percent of anaphylaxis and this patient is draped; treatment should not be delayed in the absence of cutaneous findings. Send acute tryptase, a sample at 1 to 2 hours, and a baseline at 24 hours (blood sampling for later tryptase measurement is recommended), then refer for specialist allergy investigation.^{[2][3][11][16]}

Stem 3 — the patient who recovered and wants to leave (answer)ShowHide

A 25-year-old with a peanut reaction responded fully to one dose of adrenaline. An hour later she is asymptomatic with normal observations and is asking to go home. What is the safe plan? Model: Do not discharge yet. A biphasic reaction is recurrence without re-exposure, with median onset 11 hours and a range of 0.2 to 72 hours; initial hypotension and an unknown trigger raise the risk, and the need for repeated doses of epinephrine marks her out only if it happens. Observe four to 12 hours depending on risk factors, keeping her under observation until symptoms have fully resolved, and tailor the period to her clinical characteristics. Discharge with an adrenaline autoinjector, a written emergency action plan, allergen-avoidance advice, and allergist referral.^[1][4][5]

References17ShowHide

1. [1]Pflipsen MC, Vega Colon KM Anaphylaxis: Recognition and Management Am Fam Physician, 2020.PMID 32931210
2. [2]Ma M, Duncan D, Bartoszko J Perioperative anaphylaxis: an update on pathophysiology, diagnosis, and management Can J Anaesth, 2025.PMID 40244358
3. [3]Muraro A, Worm M, Alviani C, et al. EAACI guidelines: Anaphylaxis (2021 update) Allergy, 2022.PMID 34343358
4. [4]Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis J Allergy Clin Immunol, 2020.PMID 32001253
5. [5]Lee S, Bellolio MF, Hess EP, et al. Time of Onset and Predictors of Biphasic Anaphylactic Reactions: A Systematic Review and Meta-analysis J Allergy Clin Immunol Pract, 2015.PMID 25680923
6. [6]Anaphylaxis Allergy Asthma Clin Immunol, 2024.PMID 39654057
7. [7]Hearrell M Diagnosis and management of anaphylaxis J Food Allergy, 2020.PMID 39022137
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9. [9]Maddukuri C, Kartha N, Conway AE, Shaker MS Pearls for practice from the 2023 joint task force anaphylaxis practice parameter Curr Opin Pediatr, 2025.PMID 39254667
10. [10]Skamstrup K, Garvey LH, Bindslev-Jensen C, et al. Anaphylaxis in children and adults Ugeskr Laeger, 2020.PMID 33215594
11. [11]O'Neill R, Adeli C, San Miguel CE An Appy That Needs Epi: An Atypical Presentation of Anaphylaxis J Educ Teach Emerg Med, 2024.PMID 38344051
12. [12]Ellis AK, Linton S Beta-Blockers, Angiotensin-Converting Enzyme Inhibitors, and Anaphylaxis Immunol Allergy Clin North Am, 2026.PMID 41932748
13. [13]Francuzik W, Dölle-Bierke S, Knop M, et al. Refractory Anaphylaxis: Data From the European Anaphylaxis Registry Front Immunol, 2019.PMID 31749797
14. [14]Selmanoglu A, Haci IA, Koc FSM, et al. Clinical and Treatment Evaluation of Anaphylaxis in Children Aged 0-2 Years: Multicenter Study Pediatr Res, 2025.PMID 39558120
15. [15]Jackson CA Retrospective comparison between 0.3 mg and 0.5 mg dosing of intramuscular epinephrine for anaphylaxis Am J Emerg Med, 2026.PMID 41106150
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17. [17]Chavali A, Ramirez A, Haller C Coronary Vasospasm and Acute Cardiogenic Shock Following Intravenous Epinephrine Administration in Anaphylaxis: A Case Report Mil Med, 2026.PMID 42366883