Essentials

• May occur as an independent symptom or be associated with urticaria (Hives (urticaria)).
• Angioedema without urticaria is usually either associated with an underlying drug reaction or idiopathic.
• The treatment is symptomatic. If the triggering factor can be identified, it should be avoided.
• It is important to identify laryngeal oedema and patients requiring acute hospital treatment.
• Angioedema may be an anaphylactic symptom (Anaphylaxis).

Clinical picture and symptoms

• Sudden-onset circumscribed oedema of deeper skin structures and/or mucosa.
• The superficial skin is usually normal; there may be erythema.
• The duration of symptoms varies from less than a day to even up to 5 days.
• Typical sites include the lips, tongue, eyelids (picture (Swelling around the eye in an HAE patient)), face (picture (Angio-oedema)); may also occur on the limbs (e.g. backs of the hands; picture (Swollen hand of an HAE patient)), trunk or genital area (such as the testes).
• The oedema feels doughy on palpation, and there is no pitting.
• There is usually tingling and pain, less often itching. Oedema may occur without any other symptoms.
• There may be urticaria.
• Oedema in the upper respiratory tract (laryngeal oedema) may lead to sudden respiratory insufficiency and may be fatal.
• Symptoms of laryngeal oedema include a sensation of tight throat, voice change and respiratory difficulty.
• During the attack, there may be gastrointestinal oedema and other gastrointestinal symptoms; these may rarely be the sole symptoms of angioedema.

Causes

• Drugs (ACE inhibitors, ARBs, non-steroidal anti-inflammatory analgesics, possibly also other drugs)
• Association with urticaria, such as acute urticaria triggered by infections (Hives (urticaria))
• Idiopathic (e.g. autoimmune angioedema)
  • About 10% of chronic urticarias present only as paroxysmal angioedema without wheals.
• Allergic reactions: food allergies (Food allergy in adults) (oral allergy syndrome), allergy to Hymenoptera, latex allergy
• Physical urticarias (pressure, vibration, heat or cold) (Hives (urticaria))
• Hereditary angioedema (Hereditary angioedema (HAE) and ACE inhibitor-induced angioedema); very rare, with a prevalence of about 1:50,000

Diagnosis

• The diagnosis is based on clinical findings.
• It is important to exclude angioedema of the upper respiratory tract (e.g. laryngeal oedema) and to identify patients requiring emergency hospital treatment (with intubation available during treatment and monitoring).
• Clinical examination
  • Pharyngeal and oral mucosa (uvular oedema, mucosal oedema?); palpation of the neck
  • Auscultation of the neck; inspiratory stridor?
  • Respiratory rate (more than 25/min usually abnormal); does dyspnoea prevent speaking?
  • Pulse oximetry (< 92% clearly abnormal)
  • Exclusion of anaphylactic reaction: blood pressure, lung auscultation (bronchial obstruction?)
  • Hot erythema, ulcers or symptoms of infection do not indicate angioedema.
• Patient history
  • Development of the disease, medication, allergies, food, family history
  • Is there a temporal association with any drug (new drug started before the onset of the symptoms)?
• Angioedema due to ACE inhibitors or ARBs (Hereditary angioedema (HAE) and ACE inhibitor-induced angioedema) may have a sudden onset even after long-term use. Symptoms may continue for 1–6 months after withdrawing the medication.

Differential diagnosis

• Angioedema may be the first symptom of an anaphylactic reaction (Anaphylaxis).
• Angioedema associated with ACE inhibitor therapy or, more rarely, with other pharmacotherapy (Hereditary angioedema (HAE) and ACE inhibitor-induced angioedema).
• Very rare hereditary angioedema (HAE) (Hereditary angioedema (HAE) and ACE inhibitor-induced angioedema).
• Erysipelas or cellulitis (glowing, hot erythema, fever, chills) (Erysipelas and cellulitis); recurring erysipelas may also occur, for instance in the genital area
  • Incipient shingles (pain, erythema in the area of the dermatome, precisely restricted to one side of the median line, unilateral) (Herpes zoster)
• Acute allergic contact dermatitis (Allergic contact dermatitis) (itching, papules and vesicles on the skin, eczematous clinical picture, restricted to area of exposure to contact allergen)
• Local reaction to insect sting or bite (Insect stings and bites) (history of insect sting or bite, sting or bite mark and petechia in the centre of the oedema)
• Other conditions causing oedema
  • Oedema caused by hypoproteinaemia (e.g. nephrotic syndrome, enteropathies)
  • Myxoedema (in most cases associated with hypothyroidism)
  • Factors obstructing veins and/or lymph vessels (e.g. compression of superior vena cava)
  • Lymphoedemas
  • Macroglossia (acromegaly, amyloidosis, hypothyroidism, Melkersson–Rosenthal syndrome)

Workup

• Inflammation parameters (CRP, basic blood count with platelet count, SR), as necessary for differential diagnosis, to exclude infection
• In the case of recurring attacks (can be performed in the interim):
  • Serum C1 esterase inhibitor, C1 esterase inhibitor biochemical activity, C3 and C4 (if hereditary angioedema is suspected)
  • Targeted examination for IgE-mediated allergy (specific IgE antibodies, prick tests) if an allergic reaction (food allergy, for example) is suspected
  • If an autoimmune disease is suspected, thyroid tests TSH, free T4, TPO antibodies, as necessary, or other targeted examinations

Treatment

• In patients who are in a good general condition and have no risk factors or signs of upper respiratory tract obstruction, monitoring and symptomatic treatment, as necessary, may be sufficient.
• The triggering factor (e.g. drug) should be withdrawn, as far as possible, and a follow-up visit arranged, as necessary
  • If angioedema is suspected of being caused by an ACE inhibitor or ARB, this should be replaced by another antihypertensive drug, such as a calcium-channel blocker and/or diuretic. If the ACE inhibitor has been paused for 6 months and the patient has remained asymptomatic, an ARB can be tried based on case-by-case judgement, if this is necessary for the treatment.
• An antihistamine at 1–4 times the normal dose (1–2 tablets in the morning and in the evening, with sic! written in the prescription) for 1–2 weeks at a time
  • This is effective for urticaria (histaminergic angioedema), in particular.
  • However, antihistamines are often ineffective (so-called non-histaminergic angioedema, usually bradykinin-mediated).
• If the oedema is severe and disturbing, adults can be given oral glucocorticoids, such as prednisolone at a dose of 30–40 mg once daily (0.5 mg/kg in courses of 1–3 days), for example.
• In some cases, tranexamic acid may help, given at doses of 1–1.5 g 2–3 times daily for a few days (until angioedema subsides).
  • Tranexamic acid may increase tendency for venous thrombosis (Evaluation of thrombophilia); remember to investigate risk factors for thromboembolism.
• Analgesics, as necessary (if there is no sign of a reaction triggered by non-steroidal anti-inflammatory analgesics)
• Topical application of cold or a cooling gel may alleviate the symptoms.
• For treatment of hereditary angioedema (HAE) and ACE inhibitor-induced angioedema, see (Hereditary angioedema (HAE) and ACE inhibitor-induced angioedema).

If there are signs of upper respiratory oedema

• Emergency hospital care (transportation with intubation available); further treatment and monitoring in a unit with intubation and tracheostomy available.
• Adrenaline will reduce the oedema: 0.3–0.5 mg i.m. (0.01 mg/kg), repeated every 10–20 min, as necessary.
• For patients with hypoxaemia symptomatic treatment with oxygen
• Glucocorticoid i.v., such as a 40–80 mg bolus of i.v. methylprednisolone
• I.v. fluid administration (Ringer or NaCl)
• Causal treatment, as far as possible (such as withdrawal of ACE inhibitor)
• For hereditary angioedema, specific treatment (Hereditary angioedema (HAE) and ACE inhibitor-induced angioedema)
• For ACE inhibitor-induced angioedema that is unresponsive to treatment, the bradykinin receptor blocker icatibant has been used (off-label use for treatment of HAE).

Recurring angioedema

• Avoid the cause (drugs, allergies) as far as possible
• In idiopathic angioedema, it is worth trying regular prophylactic medication with an antihistamine. If the treatment does not work, it is suggestive of so-called non-histaminergic, i.e. usually bradykinin-mediated, angioedema.
• Prophylactic antihistamines: 1–4 times the normal dose (1–2 tablets every morning and evening), with the patient titrating the dose according to the response and symptoms
• For attacks, a glucocorticoid at doses of, for example, 30–40 mg once daily (0.5 mg/kg in courses of 1–3 days) and an oral antihistamine
• In severe cases, the patient may be prescribed a disposable adrenaline syringe for use as needed. Instructions for its use must be given to the patient and the family.
• Tranexamic acid may also be useful for attacks.

Specialist consultation

• For patients with respiratory tract obstruction, emergency hospital care and monitoring (preparedness for intubation and tracheostomy)
• Specialized care should be consulted if symptoms are persistent or severe (unit with special expertise in the treatment and diagnosis of angioedema)
• An allergologist should be consulted if allergy is suspected but its cause remains unclear.
• For hereditary angioedema, monitoring and treatment in a specialized care unit specializing in familiar angioedema

References