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This sponsored article describes emergency care for people with hereditary angioedema
Hereditary angioedema (HAE) is a rare autosomal dominant disorder, estimated to affect 1 in 50,000 people (Zanichelli et al 2016, Aygören-Pürsün et al 2018). There are around 1,000-1,500 people with HAE in the UK (NHS Commissioning Board 2013). It is primarily caused by mutations in the SERPING1 gene, resulting in deficient or dysfunctional C1 esterase inhibitor (C1-INH) and leading to excessive production of bradykinin (Longhurst and Bork 2019).
People with HAE have recurrent angioedema (swelling) lasting 2–5 days and involving mostly the extremities, face, tongue, airway, gastrointestinal tract (resulting in abdominal pain, nausea, vomiting and diarrhoea) and genitalia (Busse and Christiansen 2020, Longhurst and Bork 2019, Patel et al 2015).
Although relatively uncommon, laryngeal attacks can be fatal and up to 50% of people with HAE have experienced at least one such attack, risking life-threatening airway obstruction at some point in their lives (Busse and Christiansen 2020, Longhurst and Bork 2019).
Immediate treatment of swelling that can affect the airway is essential
It is essential for nurses and physicians to be aware of HAE in the emergency setting, as it can easily be mistaken as anaphylaxis or an allergic reaction. Because of the life-threatening nature of laryngeal attacks, rapid recognition and early definitive treatment is important (Bernstein et al 2017, Bork et al 2003, Longhurst and Bork 2019).
- RELATED: Management of hereditary angioedema
People with HAE attending the emergency department (ED) may or may not already know that they have a diagnosis of HAE (Busse and Christiansen 2020).
Where the diagnosis of HAE is known
People with a known diagnosis of HAE are likely to be under the care of a specialist service, have been provided with a letter from their specialist team, and have a supply of medication to treat their symptoms (Volans 2021) (EDs may also keep their own stock of medication to treat HAE). Such people should be given their treatment promptly, particularly if the swelling may affect their airway, as early treatment is associated with better outcomes and shorter attack duration (Iwamoto 2021). The person’s stock of medication should be replaced before discharge as well.
It is important to note that swelling in people with HAE does not respond to drugs typically used for allergic reactions such as adrenaline, antihistamines and corticosteroids (Bernstein et al 2017).
Where the diagnosis of HAE is unknown
In people where the diagnosis of HAE is not known, they may present with recurrent swellings to various parts of the body and may be persistent attenders with unexplained abdominal pain (Bernstein et al 2017, Longhurst and Bork 2019). Swelling to the abdomen and associated pain can be mistaken for an ‘acute abdomen’ (Rubinstein et al 2014).
A differential diagnosis of HAE should be considered, especially if there is any family history of HAE or unexplained swelling in the patient or their family (Bernstein et al 2017). It is important to rule out a medical history of connective tissue and lymphoproliferative disease and carry out a review of regular medication (Kaplan 2008).
Causes of angioedema
Angioedema can be caused by histamine or bradykinin (Bernstein et al 2017):
- Histamine-mediated angioedema is caused by mast cell degranulation. It can be associated with exposure to an allergen (such as food or wasp/bee stings) and has rapid onset. In severe cases, it can present with features of bronchospasm, rapid upper airway obstruction and hypotension. It can also occur spontaneously without a direct trigger. It may be accompanied by urticaria and itching, and responds well to treatment with adrenaline, steroids and antihistamines (Bernstein et al 2017, Longhurst and Bork 2019).
- Bradykinin-mediated angioedema is non-pitting, non-pruritic, is not associated with urticaria and often develops over a longer period of time (Longhurst and Bork 2019). Bradykinin-mediated angioedema can occur as a result of:
- HAE (Bernstein et al 2017)
- Acquired C1-INH deficiency, which is very rare, develops later in life, and is often associated with lymphoproliferative disorders or autoimmune disease (Aygören-Pürsün et al 2018, Bernstein et al 2017, Sobotkova 2021)
- Treatment with angiotensin-converting inhibitors (ACEi), which occurs more often in patients >40 years of age (Bernstein et al 2017).
HAE can be preceded by prodromal symptoms such as erythema marginatum (a non-itchy rash), fatigue, malaise, mood changes, joint or muscle pain, nausea, thirst and a tight prickling sensation in the skin (Busse and Christiansen 2020, Longhurst and Bork 2019).
Idiopathic angioedema can also occur and can be bradykinin-mediated or be secondary to non-specific mast cell activation (Belbézier 2020, Obtułowicz 2016).
In the presence of a suggestive history or family history of HAE, laboratory testing aids in diagnosis (Bernstein et al 2017). HAE is expected to have low C1-INH concentration and/or function with low C4 level results (Bernstein et al 2017). However, the results of these tests are unlikely to be available as part of an emergency assessment (Bernstein et al 2017). Therefore, it is essential that all patients attending the ED with angioedema be considered for referral to a specialist immunology/angioedema centre for follow-up after initial assessment and treatment (Bernstein et al 2017).
HAE is a rare but serious and often missed condition, caused by low or dysfunctional C1-INH (Longhurst and Bork 2019).
HAE should be considered in all patients presenting to the ED with (Bernstein et al 2017, Busse and Christiansen 2020, Longhurst and Bork 2019):
- Angioedema without urticaria
- Unexplained recurrent abdominal pain
- Unexplained cutaneous swelling
- A family history of HAE or unexplained swelling
- Angioedema unresponsive to Resuscitation Council UK algorithm medications
- Where there are other features to indicate a non-histaminergic cause
Furthermore, regular medications such as ACE inhibitors, non-steroidal anti-inflammatory drugs, and oestrogen-containing pill (for women) should be checked in patients presenting to the ED with these signs and symptoms (Bernstein et al 2017, Longhurst and Bork 2019).
Where to go for more information
Misdiagnosis contributes to diagnostic delay, unnecessary treatments/surgery and increases the risk of death. Increased awareness of HAE is crucial to avoid such delays (Longhurst and Bork 2019).
You can find out more information about HAE online at:
- KnowHAE.co.uk – an online educational resource sponsored by Takeda UK providing accurate information about the symptoms, treatment and ongoing management of HAE developed specifically for healthcare professionals working outside the field of immunology.
- HAE UK – a patient support group focusing on the needs of people with HAE and acquired angioedema and their families.
- Aygören-Pürsün E, Magerl M, Maetzel M et al (2018) Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies. Orphanet Journal of Rare Diseases. doi.org/10.1186/s13023-018-0815-5
- Belbézier A, Bocquet A, Bouillet L (2020) Idiopathic angioedema: current challenges. Journal of Asthma and Allergy. doi: 10.2147/JAA.S205709
- Bernstein JA, Cremonesi P, Hoffmann TK et al (2017) Angioedema in the emergency department: a practical guide to differential diagnosis and management. International Journal of Emergency Medicine
- Bork K, Hardt J, Schicketanz K et al (2003) Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Archives of Internal Medicine. doi: 10.1001/archinte.163.10.1229
- Busse PJ, Christiansen SC (2020) Hereditary angioedema. New England Journal of Medicine. doi: 10.1056/NEJMra1808012
- Iwamoto K, Yamamoto B, Ohsawa I et al (2021) The diagnosis and treatment of hereditary angioedema patients in Japan: a patient reported outcome survey. Allergology International
- Kaplan A (2008) Angioedema. World Allergy Organization Journal. doi.org/10.1097/WOX.0b013e31817aecbe
- Longhurst HJ, Bork K (2019) Hereditary angioedema: an update on causes, manifestations and treatment. British Journal of Hospital Medicine. doi.org/10.12968/hmed.2019.80.7.391
- NHS Commissioning Board (2013) Clinical Commissioning Policy: Treatment of Acute Attacks in Hereditary Angiodema (Adult)
- Obtułowicz K (2016) Bradykinin-mediated angioedema. Polskie Archiwum Medycyny Wewnętrznej. doi: 10.20452/pamw.3273
- Patel N , Suarez LD, Kapur S et al (2015) Hereditary angioedema and gastrointestinal complications: an extensive review of the literature. Case Reports in Immunology. doi.org/10.1155/2015/925861
- Rubinstein E, Stolz LE, Sheffer AL et al (2014) Abdominal attacks and treatment in hereditary angioedema with C1-inhibitor deficiency. BMC Gastroenterology
- Sobotkova M, Zachova R, Hakl R et al (2021) Acquired angioedema with C1 inhibitor deficiency: occurrence, clinical features, and management: a nationwide retrospective study in the Czech Republic patients. International Archives of Allergy and Immunology. doi.org/10.1159/000512933
- Volans A (2021) Hereditary angioedema. RCEM Learning
- Zanichelli A, Longhurst HJ, Maurer M et al (2016) Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting. Annals of Allergy, Asthma & Immunology. doi.org/10.1016/j.anai.2016.08.014
About the authors
This feature was developed with funding from Takeda UK Limited