Anaphylaxis and angioedema in adults

• Anaphylaxis in adults is a rapidly developing systemic hypersensitivity reaction that can obstruct the airway, impair breathing or collapse the circulation, and it is treated first with intramuscular adrenaline into the outer thigh, repeated every five minutes if it persists. ^{[1] [2]}
• Skin signs such as hives, flushing or lip swelling are common but can be absent in about 10 to 20% of cases, so breathing or circulation problems after a likely allergen must be treated as anaphylaxis even without a rash. ^[2]
• Angioedema is a separate but overlapping problem: localised, non-pitting swelling of deeper skin or mucosa. It can be mast cell-mediated and accompany anaphylaxis, or bradykinin-mediated, as in ACE inhibitor-induced and hereditary angioedema, where antihistamines and adrenaline usually do not help. ^{[4] [6]}
• ACE inhibitor angioedema can present years after starting treatment, affects the face, tongue or larynx without hives, and needs airway-first management and permanent withdrawal of the drug. ^{[5] [6]}
• Hereditary angioedema is an autosomal dominant C1 inhibitor deficiency (type 1) or dysfunction (type 2) affecting about 1 in 50,000 people; attacks are bradykinin-mediated and are treated with C1 inhibitor concentrate, icatibant or ecallantide rather than antihistamines. ^[4]

By the end of this page you should be able to:

1. Define anaphylaxis and angioedema and tell mast cell-mediated from bradykinin-mediated disease.
2. Use the World Allergy Organization diagnostic criteria and recognise presentations without skin signs.
3. Identify common triggers in adults and the cofactors (beta-blockers, ACE inhibitors, alcohol, infection, exercise) that make reactions more severe.
4. Manage anaphylaxis step by step, including IM adrenaline doses, fluids, oxygen and adjuncts, and decide on observation after the event.
5. Manage ACE inhibitor-induced angioedema, including airway decisions and drug withdrawal.
6. Diagnose and outline the treatment of hereditary angioedema (HAE types 1 and 2), including on-demand and prophylactic therapies.

Anaphylaxis is a systemic, often rapidly progressive hypersensitivity reaction. In this topic the word anaphylaxis is used for any reaction that meets the diagnostic criteria in the "Diagnostic criteria" section, whatever the trigger. ^{[2] [3]}

The mast cell pathway releases histamine, tryptase and leukotrienes, producing the classical picture of hives, flushing, bronchospasm and hypotension. ^[2] The bradykinin pathway raises vascular permeability without mast cell activation. Both can threaten the airway, so the first minutes of assessment are the same for both: airway, breathing, circulation. ^{[1] [4]}

Anaphylaxis is related to, but broader than, allergic disease. It can be triggered by foods, venoms and drugs acting via IgE, but also by drugs and physical factors that activate mast cells directly or through complement, and occasionally no trigger is found at all (idiopathic anaphylaxis, roughly 6.5 to 35% of cases depending on the series). ^[2]

Anaphylaxis is common enough to matter and serious enough to kill. ^[2] Global incidence is estimated at 50 to 112 episodes per 100,000 person-years, and lifetime prevalence at 0.3 to 5.1%. ^[2] Fatal reactions are rare (an estimated 0.05 to 0.51 deaths per million people per year for drug anaphylaxis, 0.03 to 0.32 for food and 0.09 to 0.13 for venom) but most deaths are avoidable with earlier adrenaline. ^{[2] [4]}

• Triggers vary by age and region. Foods dominate in children and young adults; drugs and insect venoms are relatively more important with increasing age. ^[2]
• Cofactors matter. Beta-blockers and ACE inhibitors can make a reaction more severe; other cofactors include poorly controlled asthma, infection, exercise, alcohol and sleep deprivation. ^[2]
• ACE inhibitor angioedema occurs in about 0.7 to 1% of people taking these drugs. ^[6]
• Hereditary angioedema affects about 1 in 50,000 people worldwide. ^[4]

The three big groups are foods, insect venom and drugs. ^[2]

• Foods: peanuts and tree nuts, shellfish, fish, wheat, sesame, seeds; in southern Europe lipid-transfer-protein containing fruits are common. Patterns are regional and age-dependent. ^[2]
• Insect venom: bee and wasp, and other stinging insects by region. ^[2]
• Drugs: antibiotics (penicillins, cephalosporins), non-steroidal anti-inflammatory drugs, peri-operative agents (neuromuscular blockers, opioids, chlorhexidine, latex), biologics, radiocontrast media. ^[2]
• Peri-operative anaphylaxis and anaesthesia-related reactions are a distinct high-risk subgroup. ^[2]
• Idiopathic anaphylaxis is diagnosed when no trigger is found after investigation. ^[2]
• Some non-protein triggers act directly on mast cells (MRGPRX2-mediated), for example certain fluoroquinolones and neuromuscular agents. ^[2]

Bradykinin-mediated angioedema in adults is most often drug-induced, principally ACE inhibitors. ^{[4] [6]} Other drugs that can produce bradykinin-mediated swelling include angiotensin receptor blockers, gliptins, neprilysin inhibitors and tissue plasminogen activators. ^[4] Acquired C1 inhibitor deficiency (usually associated with lymphoma or monoclonal gammopathy) and hereditary angioedema are the other main bradykinin causes. ^{[4] [2]}

Risk factors for ACE inhibitor angioedema include older age, African or Caribbean ancestry, smoking, and prescription of the drug for cardioprotection rather than hypertension. ^[6] Swelling can first appear months or years after the drug is started. ^[6]

HAE-1 and HAE-2 are autosomal dominant disorders of the SERPING1 gene, which encodes C1 inhibitor (C1-INH), and they are estimated to affect 1 in 50,000 people globally. ^[4] In about 20 to 25% of patients there is a de novo mutation. ^[4] Attacks are precipitated by trauma (including dental and surgical procedures), emotional stress, infections, hormonal factors (oestrogen-containing contraceptives or hormone replacement), and ACE inhibitors, which are avoided in HAE. ^[4]

Anaphylaxis. In classical IgE-mediated anaphylaxis, allergen cross-links IgE on mast cells and basophils, releasing histamine, tryptase, leukotrienes and prostaglandins. ^[2] Vasodilation and fluid shifts produce hypotension and shock; bronchial smooth muscle contraction and mucosal oedema produce wheeze and stridor; increased vascular permeability in the skin produces urticaria and angioedema. ^[2] Other mechanisms (complement, direct mast cell activation, IgG-mediated) produce the same clinical picture, which is why anaphylaxis is a clinical diagnosis rather than a positive test. ^[2]

Bradykinin angioedema. C1 inhibitor normally restrains plasma kallikrein and factor XIIa, which generate bradykinin. ^[4] When C1 inhibitor is deficient or dysfunctional (HAE-1/2 or acquired C1-INH deficiency) or when ACE, the main bradykinin-degrading enzyme, is inhibited (ACE inhibitor angioedema), bradykinin accumulates, stimulating B2 receptors on vessels and producing swelling without histamine, urticaria or itching. ^{[4] [6]}

Why angioedema threatens the airway. Swelling of the tongue, lips, soft palate and larynx can progress over minutes to hours; the mechanism is not histaminergic in bradykinin disease, which is why airway skills matter more than drugs. ^{[4] [6]}

The onset is usually within minutes and almost always within a few hours of exposure. ^[2] Symptoms span several systems at once: ^[2]

• Skin and mucosa: generalised urticaria, flushing, pruritus, angioedema of lips, tongue, eyelids or face.
• Respiratory: nasal blockage or rhinorrhoea; throat tightness or dysphagia; hoarse voice or stridor; wheeze, cough, chest tightness; reduced peak flow; cyanosis; tachypnoea.
• Cardiovascular: lightheadedness, syncope or pre-syncope, hypotension, tachycardia, chest pain from reduced coronary perfusion.
• Gastrointestinal: nausea, vomiting, abdominal cramps, diarrhoea.

Severely ill patients may present with isolated respiratory or cardiovascular collapse, especially in fatal food anaphylaxis. ^[2] Skin signs are absent in about 10 to 20% of cases. ^[2] A guiding principle is that waiting for a rash wastes the window in which adrenaline is effective. ^{[1] [2]}

The Resuscitation Council UK recognition picture for an adult emphasises life-threatening ABC problems: hoarse voice or stridor; increased work of breathing, wheeze, fatigue, cyanosis or oxygen saturation below 94%; low blood pressure, shock, confusion or reduced consciousness. ^[1]

• Mast cell-mediated angioedema usually comes with hives, itching and often a recognisable allergic trigger; it responds to adrenaline and H1 blockers. ^[2]
• ACE inhibitor angioedema: localised, white, non-pitting swelling of the face, lips, tongue or larynx, without hives or pruritus, developing hours after a dose. ^[6] Gastrointestinal angioedema can present with colicky abdominal pain and diarrhoea. It is usually self-limiting after the drug is stopped. ^[6]
• Hereditary or acquired bradykinin angioedema: recurrent, often post-traumatic swelling of the extremities, face, genitalia, abdomen or upper airway; abdominal attacks cause cramping pain with nausea and vomiting and can be mistaken for an acute abdomen. ^[4]

The World Allergy Organization grading system distinguishes non-anaphylactic systemic reactions (grades 1 and 2) from anaphylaxis with lower airway, upper airway or cardiovascular involvement (grades 3 to 5). ^[2] In practice most UK and European guidance treats any airway, breathing or circulation problem as anaphylaxis requiring adrenaline. ^{[1] [3]}

The key division is between mast cell-mediated (often with hives, responds to adrenaline/H1 blockers) and bradykinin-mediated (no hives, no response). ^{[4] [6]} Do not anchor on the first explanation: in one specialist series, a substantial minority of patients referred with suspected ACE inhibitor bradykinin angioedema were found to have mast cell-mediated disease. ^[6]

• No laboratory test makes the diagnosis. ^[2]
• Mast cell tryptase: take a sample as soon as possible after treatment and a second sample 1 to 2 hours (and no later than 4 hours) from symptom onset; compare to a baseline sample at least 24 hours later. ^[2] In children tryptase is less often raised. ^[2]
• Consensus equation: a peak mature tryptase greater than 1.2 times baseline plus 2 micrograms per litre supports mast cell activation, but normal results do not exclude anaphylaxis. ^[2]
• Cardiac monitoring, ECG and chest X-ray when the presentation could be acute coronary syndrome or asthma.
• Airway observation as clinically indicated for laryngeal oedema.

Hereditary or acquired C1 inhibitor disease is diagnosed biochemically: C1-INH function, C1-INH protein concentration and complement C4. ^[4]

• HAE-1: low C1-INH function (under 50% of normal) and low C1-INH protein. ^[4]
• HAE-2: low C1-INH function (under 50% of normal) with normal or high C1-INH protein. ^[4]
• Acquired C1-INH deficiency (AAE): usually older onset with low C1q (low in about 75% of cases) and an underlying lymphoma or monoclonal gammopathy. ^[4]
• In patients with normal C1-INH levels and function but suspected HAE, genetic testing for known mutations (factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, HS3ST6) is recommended. ^[4]
• Testing should be repeated to confirm the diagnosis; C1-INH testing is performed infrequently and false results occur. ^[4]
• Close family members should be screened, because offspring have a 50% chance of inheriting the mutation. ^[4]

The diagnosis is clinical: any angioedema in a patient taking an ACE inhibitor, especially with facial, tongue or laryngeal swelling and no urticaria. ^[6] There is no confirmatory blood test; stopping the drug and observing whether swelling recurs after six months is part of the diagnostic reasoning. ^[6]

Anaphylaxis is a serious, usually rapid-onset systemic hypersensitivity reaction that may cause death; severe anaphylaxis can compromise the airway, breathing or circulation and may occur without skin features or shock. ^[2]

Anaphylaxis is highly likely when either criterion is met: ^[2]

1. Acute onset of illness (minutes to several hours) with simultaneous skin or mucosal involvement (generalised hives, pruritus, flushing, swollen lips, tongue or uvula) and at least one of: respiratory compromise (dyspnoea, wheeze/bronchospasm, stridor, reduced peak expiratory flow, hypoxaemia); reduced blood pressure or end-organ symptoms (collapse, syncope, incontinence); or severe gastrointestinal symptoms (severe crampy abdominal pain, repetitive vomiting), especially after non-food allergens.
2. Acute onset of hypotension, bronchospasm or laryngeal involvement after exposure to a known or highly probable allergen, even without skin changes.

Hypotension for adults is a fall in systolic blood pressure greater than 30% from baseline; for children under 10, below (70 mmHg + [2 x age in years]). ^[2]

These criteria are designed to capture rather than define anaphylaxis; they exclude neither evolving reactions nor severe single-system presentations after allergen exposure (for example isolated laryngeal oedema after a known allergen is still anaphylaxis). ^[2]

The EAACI anaphylaxis guideline (2021 update) keeps the NIAID/FAAN-style criteria and adds emphasis on blood sampling for later tryptase and on prompt intramuscular adrenaline as first-line treatment. ^{[3] [2]}

HAE is suspected on history (recurrent swelling, onset in childhood or adolescence, positive family history, abdominal or laryngeal attacks, poor response to antihistamines, corticosteroids or adrenaline, absence of wheals). ^[4] Confirmation is biochemical, as described above. ^[4]

There is no diagnostic test. The diagnosis is based on swelling in a patient taking an ACE inhibitor, its clinical pattern (no urticaria or pruritus, often facial or oropharyngeal), and absence of an allergic trigger. ^[6] Important alternatives are mast cell-mediated angioedema and HAE, which are commoner than often assumed. ^[6]

Secure the airway early, give high-flow oxygen (preferably 100%, non-rebreather), and position the patient as above. ^[2] Sitting may help a patient who is struggling to breathe, but sudden upright posture can precipitate or restart cardiovascular collapse. ^{[3] [2]}

Adrenaline is first-line for anaphylaxis in every major guideline cited here. ^{[1] [2] [3]} It acts on alpha-1 receptors (vasoconstriction, reducing mucosal oedema) and beta-2 receptors (bronchodilation), opposing all the principal mechanisms of anaphylaxis. ^[1] Give it intramuscularly into the anterolateral aspect of the middle third of the thigh as soon as ABC problems are recognised; inject through clothing if needed. ^{[1] [2]}

Additional adrenaline points that matter in an adult:

• Delays kill. IM adrenaline is under-used; give it whenever airway, breathing or circulation problems are present after a likely allergen. ^{[1] [2]}
• Repeat every 5 minutes until symptoms resolve or specialist care arrives. ^[1]
• Intravenous adrenaline is reserved for refractory anaphylaxis and must be given by specialists in a monitored setting (as an infusion, with standard safety cautions about boluses). ^[2]
• Patients on beta-blockers may respond poorly to adrenaline; parenteral glucagon is an option in such patients, with limited evidence. ^[2]
• Low-dose IV adrenaline infusions are used for refractory reactions in some national guidelines. ^[2]

• Crystalloid resuscitation for hypotension or shock: 500 to 1000 mL bolus in adults, 10 mL per kg in children, repeated according to response. ^{[1] [2]}
• Bronchodilators: inhaled beta-2 agonist (e.g. salbutamol) for bronchospasm. ^[2]
• Nebulised adrenaline may be used as an adjunct for laryngeal oedema or stridor after IM adrenaline, not a substitute for it. ^[2]
• Antihistamines (H1, and H2 where available) relieve urticaria and rhinitis but do not treat anaphylaxis; they are now third-line in some guidelines because they can distract from repeated adrenaline. ^[2]
• Corticosteroids are commonly used to prevent biphasic or protracted reactions, particularly with bronchospasm, but evidence for benefit in acute anaphylaxis is weak and possible harm is being debated; routine use is no longer automatic. ^[2]
• Observation: around half of biphasic reactions occur within the first 6 to 12 hours. ^[2] All patients need observation after recovery, longer after severe reactions or when more than one dose of adrenaline was required. ^{[1] [2]}

Longer-term management of anaphylaxis:

• Investigate the cause: an allergy-focused history, specific IgE testing or skin prick guided by that history, and (after the reaction) mast cell tryptase. ^[2]
• Prescribe two adrenaline auto-injectors for at-risk patients, with brand-specific training, a written action plan and a spare device at school or work. ^{[2] [3]}
• Control comorbidities, especially asthma, which is the main risk factor for fatal food anaphylaxis. ^[2]
• Refer after every anaphylaxis to a specialist allergy service for confirmation of the trigger, risk stratification and education. ^{[2] [3]}
• Patients on beta-blockers or ACE inhibitors should have their medicines reviewed: anaphylaxis on beta-blockers can be refractory, and ACE inhibitors worsen histamine release and are absolutely avoided in HAE. ^{[2] [4]}

The approach is airway first.

1. Assess the airway immediately. Swelling of the tongue, floor of mouth or larynx can progress rapidly. Early involvement of anaesthetics and otolaryngology, admission to a monitored setting, and preparation for a difficult airway is warranted. ^[6]
2. Stop the ACE inhibitor. Angioedema is a class effect, so all ACE inhibitors should be withdrawn and never reintroduced. ^[6]
3. Expect limited benefit from histamine-directed therapy. Antihistamines, corticosteroids and adrenaline, used for histaminergic angioedema, are generally ineffective for bradykinin-mediated ACE inhibitor angioedema, although they are sometimes given when the mechanism is unclear. ^[6]
4. Consider disease-specific therapy where available. The bradykinin B2 receptor antagonist icatibant (30 mg subcutaneously) is used off-label: in one randomized phase 2 trial in ACE inhibitor angioedema of the upper aerodigestive tract, median time to complete resolution was 8.0 hours with icatibant versus 27.1 hours with prednisolone plus clemastine. ^[5] Repeat dosing follows product licence and local protocol. Randomised evidence overall is mixed, so availability and local protocol determine use. ^{[5] [6]}
5. C1 inhibitor concentrate or fresh frozen plasma may reduce symptom duration in case reports but have not been tested in trials; fresh frozen plasma is a second-line option where C1 inhibitor is unavailable. ^[6]
6. Observe for 48 to 72 hours, the usual spontaneous resolution period, longer with airway involvement. ^[6]
7. Warn the patient and the record that angioedema can still occur up to six months after stopping the drug, and that all ACE inhibitors are contraindicated. ^[6]
8. Choose a replacement regimen. Angiotensin receptor blockers act outside the kinin-kallikrein system and may be considered when renin-angiotensin blockade is indicated, with specialist input. ^[6]

Principles, not patient-specific plans (candidates are selected and doses prescribed by specialists): ^[4]

• Treat every attack early. On-demand first-line options are intravenous C1 inhibitor (plasma-derived or recombinant), icatibant (30 mg subcutaneously) and (in the USA and parts of Latin America) ecallantide (30 mg subcutaneously, given by a healthcare professional). ^[4]
• Where these are unavailable, use solvent-detergent-treated plasma, then fresh frozen plasma. ^[4]
• Upper airway attacks are emergencies: give on-demand treatment and prepare early for intubation or surgical airway. ^[4]
• Short-term prophylaxis: before dental, surgical or medical procedures with upper airway trauma, give intravenous C1 inhibitor (commonly 1000 units or 20 units per kg). ^[4]
• Long-term prophylaxis is considered for frequent or severe attacks: plasma-derived C1 inhibitor (60 units per kg subcutaneously twice weekly), lanadelumab (300 mg subcutaneously every 2 weeks, extendable to every 4 weeks if well controlled) or berotralstat (150 mg orally once daily with food, 110 mg in some regions or in hepatic impairment). ^[4]
• Alternatives where first-line drugs are unavailable: attenuated androgens (danazol 100 mg every other day to 200 mg three times daily, with ceilings on long-term dose) or tranexamic acid (30 to 50 mg per kg daily, maximum 6 g daily), with appropriate monitoring and precautions. ^[4]
• Pregnancy and breastfeeding: C1 inhibitor concentrate is preferred; androgens are contraindicated in pregnancy. ^[4]
• Children: C1 inhibitor concentrate or icatibant for attacks; C1 inhibitor for long-term prophylaxis in children under 12. ^[4]
• Triggers: avoid oestrogen-containing contraceptives or hormone replacement, ACE inhibitors, androgen excess, and advise patients about trauma-related attacks. ^[4]

• Fatal anaphylaxis (airway obstruction or cardiovascular collapse) remains rare but is largely preventable with earlier recognition and adrenaline. ^[2]
• Biphasic anaphylaxis is a second wave of symptoms after initial recovery; around half occur within 6 to 12 hours and severe initial reactions and multiple adrenaline doses increase the risk. ^[2]
• ACE inhibitor angioedema: recurrence can occur up to six months after withdrawal, and severe swelling may require airway intervention. ^[6]
• HAE: asphyxiation from laryngeal attacks is the main preventable cause of death; untreated abdominal attacks cause severe pain and unnecessary surgery. ^[4]
• Mislabelling and recurrence: without identification and elimination of the trigger, recurrence rates over years are high.

Most patients recover fully from anaphylaxis when adrenaline is given promptly; fatal outcomes are associated with delayed adrenaline, poorly controlled asthma, cardiovascular disease, older age and severe triggers such as drugs and venom. ^[2] ACE inhibitor angioedema generally resolves within 48 to 72 hours after withdrawal, although recurrence before withdrawal is common. ^[6] In HAE, effective on-demand and prophylactic therapies have transformed outcomes, and long-term control is the realistic goal. ^[4]

• Identify and record the trigger (allergy clinic confirmation, written plan, medic-alert). ^{[2] [3]}
• Prescribe two adrenaline auto-injectors to every patient with biphasic, severe or community-based risk, with training by device brand and regular retraining. ^{[2] [3]}
• Avoid the trigger and plan for accidental exposure (label reading, restaurant and workplace plans). ^[2]
• Control asthma (target good control; it is the leading modifiable risk factor for fatal food anaphylaxis). ^[2]
• Screen and counsel relatives in HAE, with genetic or biochemical testing. ^[4]
• Never rechallenge a patient with a suspected anaphylaxis trigger without specialist supervision. ^[2]

• Older adults with cardiovascular disease are more likely to die from anaphylaxis and may be taking beta-blockers or ACE inhibitors; adrenaline is still first-line but the airway and ECG merit close attention. ^{[2] [4]}
• Pregnancy: anaphylaxis is treated as in any adult; place the patient on the left side in a semi-recumbent position to relieve aortocaval compression. ^[2]
• Patients on beta-blockers may respond poorly to adrenaline; glucagon is an option. ^[2]
• HAE in pregnancy: C1 inhibitor concentrate is preferred; androgens are contraindicated. ^[4]
• HAE in children: C1 inhibitor or icatibant for attacks; prefer C1 inhibitor for long-term prophylaxis under 12. ^[4]

• Adrenaline in the thigh is the intervention that saves lives and is available almost everywhere as an ampoule and syringe: train all clinical staff to draw up 0.5 mL of 1 mg per mL (500 micrograms) for an adult, repeat every 5 minutes. ^{[1] [2]}
• Where auto-injectors are unavailable or unaffordable, use an individualised emergency plan built around hospital-accessible adrenaline and education on when to seek care; device training by brand applies only where devices exist. ^[2]
• High-flow oxygen and crystalloid remain low-cost adjuncts. ^{[1] [2]}
• HAE-specific drugs are unavailable in many regions; the guideline explicitly encourages advocacy for diagnostics and therapies. Solvent-detergent plasma or fresh frozen plasma and tranexamic acid can be used when first-line agents are absent. ^[4]
• ACE inhibitor angioedema can be managed with airway skills, withdrawal of the drug and observation. ^[6]

• Anaphylaxis is a clinical diagnosis of acute airway, breathing or circulation problems after exposure; skin signs may be absent. ^[2]
• Intramuscular adrenaline in the anterolateral thigh is first-line: 500 micrograms for adults, repeated every 5 minutes. ^{[1] [2]}
• Antihistamines and corticosteroids are adjuncts at best; they do not replace repeated adrenaline. ^[2]
• Observe for biphasic reactions, around half of which occur within 6 to 12 hours, especially after severe reactions. ^[2]
• Discharge planning always includes two adrenaline auto-injectors where there is ongoing risk, training and referral. ^{[2] [3]}
• ACE inhibitor angioedema is bradykinin-mediated, presents without hives, often years after starting, and requires airway-first management and permanent withdrawal of all ACE inhibitors. ^{[5] [6]}
• Hereditary angioedema (1 in 50,000) is C1 inhibitor deficiency or dysfunction; C1 inhibitor concentrate, icatibant or ecallantide treat attacks, and C1 inhibitor, lanadelumab or berotralstat prevent them. ^[4]
• Mast cell tryptase taken early and at 1 to 2 hours, plus a baseline, helps confirm anaphylaxis when the diagnosis is uncertain. ^[2]

Allergy clinic referral, adrenaline auto-injector training, chronic spontaneous urticaria, asthma control, and hereditary angioedema family screening arise from this topic; MedGrasp topic links are not embedded until those pages are verified.