Angioedema

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, face (picture (Angio-oedema)); may also occur on the limbs (e.g. backs of the hands), 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))
  • Physical urticarias (pressure, vibration, heat or cold) (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
  • Angioedema may be the first symptom of an anaphylactic reaction (Anaphylaxis).
  • 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

  • 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)
  • 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).

Workup

  • Inflammation parameters (CRP, basic blood count with platelet count), as necessary for differential diagnosis, to exclude infection
  • In the case of recurring attacks (can be performed in the interim):
    • 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
    • Serum C1 esterase inhibitor, C1 esterase inhibitor biological activity, C3 and C4 (if hereditary angioedema is suspected)

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: for adults 0.3–0.5 mg i.m. (0.01 mg/kg if patient weighs < 50 kg), repeated every 10–20 min, as necessary. See Anaphylaxis (Anaphylaxis).
  • 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 life-threatening ACE inhibitor-induced angioedema, in addition to the aforementioned treatments, also spesific therapies for HAE (e.g. C1 inhibitors) have been used.
  • For hereditary angioedema, specific treatment (Hereditary angioedema (HAE) and ACE inhibitor-induced angioedema)

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

1. Powell RJ, Leech SC, Till S et al. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy 2015;45(3):547-65.  [PMID:25711134].
2. Moellman JJ, Bernstein JA, Lindsell C et al. A consensus parameter for the evaluation and management of angioedema in the emergency department. Acad Emerg Med 2014;21(4):469-84.  [PMID:24730413]
3. Sánchez-Borges M, Asero R, Ansotegui IJ et al. Diagnosis and treatment of urticaria and angioedema: a worldwide perspective. World Allergy Organ J 2012;5(11):125-47.  [PMID:23282382]
4. Hébert J, Boursiquot JN, Chapdelaine H et al. Bradykinin-induced angioedema in the emergency department. Int J Emerg Med 2022;15(1):15.  [PMID:35350995]
5. Caballero T, Baeza ML, Cabañas R et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part II. Treatment, follow-up, and special situations. J Investig Allergol Clin Immunol 2011;21(6):422-41; quiz 442-3.  [PMID:21995176]
6. LoVerde D, Files DC, Krishnaswamy G. Angioedema. Crit Care Med 2017;45(4):725-735.  [PMID:28291095]
7. Stoldt J, Cox C, Matusz E. Tranexamic acid use in the setting of ACE inhibitor induced angioedema. Am J Emerg Med 2022;(55):230.e3-230.e4.  [PMID:35105472]
8. Zuberbier T, Aberer W, Asero R et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy 2018;73(7):1393-1414.  [PMID:29336054]
9. Bernstein JA, Cremonesi P, Hoffmann TK et al. Angioedema in the emergency department: a practical guide to differential diagnosis and management. Int J Emerg Med 2017;10(1):15.  [PMID:28405953]
10. Riha HM, Summers BB, Rivera JV et al. Novel Therapies for Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Systematic Review of Current Evidence. J Emerg Med 2017;53(5):662-679.  [PMID:28939396]
11. Lawlor CM, Ananth A, Barton BM et al. Pharmacotherapy for Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Systematic Review. Otolaryngol Head Neck Surg 2018;158(2):232-239.  [PMID:29112487]
12. Zuberbier T, Abdul Latiff AH, Abuzakouk M et al. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy 2021 Sep 18. doi: 10.1111/all.15090  [PMID:34536239]
13. Jeon J, Lee YJ, Lee SY. Effect of icatibant on angiotensin-converting enzyme inhibitor-induced angioedema: A meta-analysis of randomized controlled trials. J Clin Pharm Ther 2019;44(5):685-692.  [PMID:31290163]

Copyright © 2023 Duodecim Medical Publications Limited.