Tools
Angioneurotic Edema
Introduction
Angioneurotic edema is a relatively common presentation in the emergency department (ED). It presents as unpredictable frequent edematous episodes of cutaneous and mucosal tissues such as lips, eyes, oral cavity, larynx, and gastrointestinal system (GIS). Urticaria (hives) and angioedema are part of a spectrum of allergic symptoms and occasionally have a non-allergic etiology. Laryngeal edema causing airway obstruction with the potentially fatal outcome if the diagnosis is late. In the early medical literature, it was initially named as ephemeral cutaneous nodosities, ephemeral congestive tumors of the skin, wandering edema, and giant hives.[1] After the year 2007, angioneurotic edema (ANE) was named as angioedema (AE) in the literature.
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
Angioneurotic edema can be classified into two main categories, such as allergic and non-allergic angioneurotic edema. Non-allergic angioneurotic edema can be subclassified into hereditary, i.e., C1-esterase-inhibitor deficiency (HANE), acquired (AANE), drug-induced and idiopathic ANE. Type 1 and 2 hereditary ANE are autosomal dominant disorders due to mutations in the gene encoding for C1-inhibitor.
Angiotensinogen converting enzymes inhibitors (ACEI), angiotensin-2 antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), oral contraceptive pills (OCPs), proton pump inhibitors (PPIs) and vaccines are common causes of drug-induced ANE. Acquired ANE can be caused by serious and/or chronic illnesses such as lymphoproliferative disorders, autoimmune disease, neoplastic conditions, and infections. ANE can be precipitated by any type of surgery, viral infection, exposure to heat and cold, pregnancy, minor trauma (e.g., dental work, tongue piercing), mental stress, and ingestion of certain foods.
Epidemiology
The lifetime prevalence of angioneurotic edema in the United States is approximately 25%, and there are more than one million ED visits yearly.[2][3] Italy published that 0.37% of all ED visits were diagnosed as angioedema, and a Canadian journal recently published that 1:1000 ED visits were related to angioedema.[4][5] UK survey discloses that 30% of patients with angioneurotic edema have visited the ED.[6]
Pathophysiology
The majority of angioneurotic edema cases (about 90%) are due to an allergic reaction that produces angioedema within minutes via eliciting a Type 1 hypersensitivity reaction (histaminergic mediated mast cells and basophil activation). In contrast, non-allergic angioneurotic edema by inhibiting bradykinin may not be seen for months. Bradykinin is a potent vasodilatory mediator. There is excessive production of bradykinin in ANE, which leads to swelling of the mucosa and submucosal swelling.
During the attack of ANE, plasma bradykinin levels increase sevenfold higher than normal.[7] In bradykinin-mediated angioedema, histamine mediators are not involved, as there is a lack of response to antihistamines. Pathogenesis of most HANE is the result of either deficiency of C1 inhibitor (C1-INH) (type 1 HANE) or dysfunction of C1-INH (type 2 HANE) or a combination. Type 2 HANE patients show normal C1INH levels. C1-INH, an acute-phase reactant, is a member of the "serpin" superfamily of serine protease inhibitors, which is essential in the regulation of plasma proteolytic systems, which are the complement system, coagulation system, and fibrinolytic system. C1-INH inhibits steps in the classical and lectin complement pathways, as well as of the intrinsic coagulation (contact system), fibrinolytic, and kinin-generating pathways. Within these different pathways, C1-INH inhibits several plasma proteases: C1r and C1s, mannose-binding lectin-associated serine proteases (MASP1 and MASP2), coagulation factor 12 (Hageman factor), coagulation factor 11, plasma kallikrein, and plasmin.[8][9]
Lack of C1-INH activates the contact system (kallikrein-kinin), which finally leads to the overproduction of bradykinin. Bradykinin causes vasodilation and increases vascular permeability. It also leads to the contraction of nonvascular smooth muscle and acts as the main mediator of the pathophysiology of HANE. As such, it prevents the activation of a cascade of proteins leading to the swelling called angioedema. In recent literature, a small but growing number of suspected pathogenic variants in genes for other proteins have been identified to explain the disease in some families, while the pathogenesis in other families remains unclear.
History and Physical
Detailed history taking, such as family and drug histories, is important in the evaluation of angioneurotic edema. For example, the use of ACEIs is important in diagnosing drug-induced ANE. ANE patients present with swelling of distensible tissues such as face, eyes, lips, mouth, throat, extremities, and genitalia. Some of the patients with angioneurotic abdominal edema can also present with colicky abdominal pain, vomiting, and abdominal distention due to bowel wall submucosal edema and intestinal obstruction.
Uvula or tongue swelling can be visualized directly on asking to open the mouth. However, it is advisable to do laryngoscopy to assess vocal cords. Airway concerns should be suspected in patients who present with hoarseness of voice, stridor, dysphonia, difficulty in breathing, and wheezing. The first step in airway assessment is assessing airway patency. In allergic ANE attacks, there may be itchy urticaria, skin rashes which appear as wheals on trunk and limbs, which may resolve spontaneously. Non-pitting edema may also be present in extremities.
Evaluation
Angioneurotic edema is diagnosed clinically, and the patient is stabilized acutely without waiting for blood investigations. Some routine blood investigations such as full blood count, renal function tests, and liver function tests can be ideally performed, but are unhelpful in establishing a diagnosis. If the ANE attack is due to an allergic reaction, mast cell tryptase levels may be elevated during the attack and can be compared with the convalescence stage. Complement levels C4 may be depleted during the HANE attack, which indicates a deficiency of C1 esterase inhibitor.[10]
Treatment / Management
Treatment of angioneurotic edema should be started as early as possible. Some of the HANE patients need airway intervention like intubation. HANE and AANE are bradykinin-mediated angioedema. They are often resistant to antihistamine, corticosteroids, and epinephrine which are useful drug treatments of histaminergic angioedema.[11] Hereditary angioedema attacks should be treated with C1 Inhibitor concentrate, ecallantide (kallikrein inhibitor), or icatibant (bradykinin-receptor antagonist).[12] (B3)
Icatibant is an effective home-based, on-demand treatment.[13] Before any high-risk procedure in high-risk patients, it is essential to give short-term prophylaxis.[1] Anesthetists must be aware of the guidelines for HANE and AANE.[14] C1 esterase inhibitor is the first-line long-term prophylaxis and androgens are used as second-line prophylaxis.[15] The majority of AANE cases are asymptomatic and respond to immunochemotherapy.[16]
Acute attacks can be treated with icatibant and C1 inhibitor concentrate (plasma-derived), and prophylaxis is with rituximab with or without chemotherapy and splenectomy.[17] Individuals with HANE are particularly susceptible to attacks with certain triggers, such as invasive medical procedures, (e.g., extensive dental work). Prior to these events, short term prophylaxis is recommended with plasma-derived C1 inhibitor concentrate, a short-term course of high dose therapy with attenuated androgens, or FFP.
In pregnancy, the recommended therapy is plasma-derived nano-filtered C1-inhibitor; however, in acute episodes, bradykinin receptor antagonist (icatibant) can be used as it is safe with no maternal and fetal adverse effects.[18][19] The plasma-derived C1 esterase inhibitor is safe and effective in pediatric patients below 12 years.[20] (B2)
In the pediatric population, the doses include 500 units (10-25 kg weighed patients), 1000 units, and 1500 units in patients weighing more than 25kg.[21] Icatibant is a well-tolerated medication in the pediatric group and might have a role in treating angiotensin-2 receptor blocker induced angioedema.[22] Patients with life-threatening orolingual angioedema who are treated with recombinant tissue plasminogen activator infusion, have a rapid response after using icatibant treatment.[23] Concurrent use of angiotensin-converting enzyme inhibitors with dipeptidyl peptidase-4 inhibitors should be monitored closely as dipeptidyl peptidase-4 is also a major enzyme in the degradation pathway of bradykinin like an angiotensin-converting enzyme.[24](A1)
Differential Diagnosis
Differential diagnosis includes anaphylaxis triggered by certain allergens resulting in the release of histamine from mast cells. Histamine release causes localized cutaneous reactions such as hives or urticaria that itch, as well as bowel wall mucosal edema, which can manifest as vomiting and abdominal pain. The systemic reaction can manifest as hypotension and tachycardia due to peripheral vessel dilatation and capillary leakage. These symptoms can be suppressed by the use of adrenaline, antihistamines, and steroids, which inhibit immunoglobulin production and reduce the recurrent chances of allergic attacks. Other differential diagnoses include cellulitis, contact dermatitis, lymphedema, erysipelas, and systemic lupus erythematosus.
Prognosis
An angioneurotic edema attack can occur at any point in time after the first exposure up to several times later. The time scale of hypersensitivity and resolution is unknown. ANE tends to recur in certain patients. Family screening plays a role in patients with possible HANE to identify susceptible families. Sudden death due to laryngeal edema is relatively common in HANE. The management strategy is to provide physician-supervised self-managed C1 esterase therapy-on-demand to terminate HANE attacks when the patient feels that needs to be given.[25]
Tranexamic acid, which presumably works on prostaglandin activation, has also been used as prophylaxis for HANE with some reduction in the frequency of attacks and, consequently, has been used in the acute event. However, studies have shown that it usually takes 24 to 72 hours for the resolution of symptoms.
Complications
Life-threatening complications can occur if angioneurotic edema is not treated emergently. Laryngeal edema can result in hypoxia, airway obstruction, and ultimately death. Failure to recognize potential airway difficulty can result in increased mortality and morbidity.
Deterrence and Patient Education
Patients should be advised to avoid precipitating causes of angioneurotic edema if known. Precipitant drugs should be discontinued if implicated and sought to be replaced with another medication in drug-induced ANE patients. ANE patients who have severe attacks requiring epinephrine should be discharged with EpiPen prescription. HANE patients should be referred to an immunologist and will need to be followed-up in an allergy clinic for a formal diagnosis.
Enhancing Healthcare Team Outcomes
Laryngeal edema should be managed emergently with highly skilled airway experts in the presence of anesthetist and ENT team. Difficult airway trolley with advanced airway equipment should be available while managing patients with angioneurotic edema attack. The surgical airway may be needed in patients with advanced glottic and supraglottic swelling, which makes it difficult to intubate with the oral route. An array of specialists, nursing staff, pharmacists are required to treat ANE. ANE requires high-quality interprofessional collaboration for good patient outcomes.
References
Maurer M, Magerl M, Ansotegui I, Aygören-Pürsün E, Betschel S, Bork K, Bowen T, Balle Boysen H, Farkas H, Grumach AS, Hide M, Katelaris C, Lockey R, Longhurst H, Lumry WR, Martinez-Saguer I, Moldovan D, Nast A, Pawankar R, Potter P, Riedl M, Ritchie B, Rosenwasser L, Sánchez-Borges M, Zhi Y, Zuraw B, Craig T. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update. Allergy. 2018 Aug:73(8):1575-1596. doi: 10.1111/all.13384. Epub 2018 Mar 12 [PubMed PMID: 29318628]
Bernstein JA, Moellman J. Emerging concepts in the diagnosis and treatment of patients with undifferentiated angioedema. International journal of emergency medicine. 2012 Nov 6:5(1):39. doi: 10.1186/1865-1380-5-39. Epub 2012 Nov 6 [PubMed PMID: 23131076]
Kelly M, Donnelly JP, McAnnally JR, Wang HE. National estimates of emergency department visits for angioedema and allergic reactions in the United States. Allergy and asthma proceedings. 2013 Mar-Apr:34(2):150-4. doi: 10.2500/aap.2013.34.3640. Epub [PubMed PMID: 23484890]
Bertazzoni G, Spina MT, Scarpellini MG, Buccelletti F, De Simone M, Gregori M, Valeriano V, Pugliese FR, Ruggieri MP, Magnanti M, Susi B, Minetola L, Zulli L, D'Ambrogio F. Drug-induced angioedema: experience of Italian emergency departments. Internal and emergency medicine. 2014 Jun:9(4):455-62. doi: 10.1007/s11739-013-1007-x. Epub 2013 Nov 9 [PubMed PMID: 24214335]
Level 2 (mid-level) evidenceFelder S, Curtis RM, Ball I, Borici-Mazi R. Prognostic factors in outcome of angioedema in the emergency department. Allergy and asthma proceedings. 2014 Sep-Oct:35(5):362-70. doi: 10.2500/aap.2014.35.3787. Epub [PubMed PMID: 25295803]
Level 2 (mid-level) evidenceJolles S, Williams P, Carne E, Mian H, Huissoon A, Wong G, Hackett S, Lortan J, Platts V, Longhurst H, Grigoriadou S, Dempster J, Deacock S, Khan S, Darroch J, Simon C, Thomas M, Pavaladurai V, Alachkar H, Herwadkar A, Abinun M, Arkwright P, Tarzi M, Helbert M, Bangs C, Pastacaldi C, Phillips C, Bennett H, El-Shanawany T. A UK national audit of hereditary and acquired angioedema. Clinical and experimental immunology. 2014 Jan:175(1):59-67. doi: 10.1111/cei.12159. Epub [PubMed PMID: 23786259]
Bork K, Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). The Journal of allergy and clinical immunology. 2007 Jun:119(6):1497-503 [PubMed PMID: 17418383]
Level 3 (low-level) evidenceMorgan BP. Hereditary angioedema--therapies old and new. The New England journal of medicine. 2010 Aug 5:363(6):581-3. doi: 10.1056/NEJMe1006450. Epub [PubMed PMID: 20818894]
Bracho FA. Hereditary angioedema. Current opinion in hematology. 2005 Nov:12(6):493-8 [PubMed PMID: 16217168]
Level 3 (low-level) evidenceBetschel S, Badiou J, Binkley K, Borici-Mazi R, Hébert J, Kanani A, Keith P, Lacuesta G, Waserman S, Yang B, Aygören-Pürsün E, Bernstein J, Bork K, Caballero T, Cicardi M, Craig T, Farkas H, Grumach A, Katelaris C, Longhurst H, Riedl M, Zuraw B, Berger M, Boursiquot JN, Boysen H, Castaldo A, Chapdelaine H, Connors L, Fu L, Goodyear D, Haynes A, Kamra P, Kim H, Lang-Robertson K, Leith E, McCusker C, Moote B, O'Keefe A, Othman I, Poon MC, Ritchie B, St-Pierre C, Stark D, Tsai E. The International/Canadian Hereditary Angioedema Guideline. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. 2019:15():72. doi: 10.1186/s13223-019-0376-8. Epub 2019 Nov 25 [PubMed PMID: 31788005]
Moellman JJ, Bernstein JA, Lindsell C, Banerji A, Busse PJ, Camargo CA Jr, Collins SP, Craig TJ, Lumry WR, Nowak R, Pines JM, Raja AS, Riedl M, Ward MJ, Zuraw BL, Diercks D, Hiestand B, Campbell RL, Schneider S, Sinert R, American College of Allergy, Asthma & Immunology (ACAAI), Society for Academic Emergency Medicine (SAEM). A consensus parameter for the evaluation and management of angioedema in the emergency department. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2014 Apr:21(4):469-84. doi: 10.1111/acem.12341. Epub [PubMed PMID: 24730413]
Level 3 (low-level) evidenceKatelaris CH. Acute Management of Hereditary Angioedema Attacks. Immunology and allergy clinics of North America. 2017 Aug:37(3):541-556. doi: 10.1016/j.iac.2017.04.002. Epub 2017 May 23 [PubMed PMID: 28687108]
Hide M, Fukunaga A, Maehara J, Eto K, Hao J, Vardi M, Nomoto Y. Efficacy, pharmacokinetics, and safety of icatibant for the treatment of Japanese patients with an acute attack of hereditary angioedema: A phase 3 open-label study. Allergology international : official journal of the Japanese Society of Allergology. 2020 Apr:69(2):268-273. doi: 10.1016/j.alit.2019.08.012. Epub 2019 Oct 28 [PubMed PMID: 31672405]
MacBeth LS, Volcheck GW, Sprung J, Weingarten TN. Perioperative course in patients with hereditary or acquired angioedema. Journal of clinical anesthesia. 2016 Nov:34():385-91. doi: 10.1016/j.jclinane.2016.05.010. Epub 2016 Jun 5 [PubMed PMID: 27687418]
Bekos C, Perkmann T, Krauth M, Raderer M, Lechner K, Jaeger U. Acquired C1 esterase inhibitor deficiency in lymphomas: prevalence, symptoms, and response to treatment. Leukemia & lymphoma. 2016 Sep:57(9):2033-6. doi: 10.3109/10428194.2015.1131273. Epub 2016 Jan 21 [PubMed PMID: 26795750]
Gobert D, Paule R, Ponard D, Levy P, Frémeaux-Bacchi V, Bouillet L, Boccon-Gibod I, Drouet C, Gayet S, Launay D, Martin L, Mekinian A, Leblond V, Fain O. A nationwide study of acquired C1-inhibitor deficiency in France: Characteristics and treatment responses in 92 patients. Medicine. 2016 Aug:95(33):e4363. doi: 10.1097/MD.0000000000004363. Epub [PubMed PMID: 27537564]
Fox J, Vegh AB, Martinez-Saguer I, Wuillemin WA, Edelman J, Williams-Herman D, Rojavin M, Rosenberg T. Safety of a C1-inhibitor concentrate in pregnant women with hereditary angioedema. Allergy and asthma proceedings. 2017 May 1:38(3):216-221. doi: 10.2500/aap.2017.38.4038. Epub [PubMed PMID: 28441992]
Farkas H, Kőhalmi KV, Veszeli N, Tóth F, Varga L. First report of icatibant treatment in a pregnant patient with hereditary angioedema. The journal of obstetrics and gynaecology research. 2016 Aug:42(8):1026-8. doi: 10.1111/jog.13003. Epub 2016 Apr 19 [PubMed PMID: 27093898]
Lumry W, Soteres D, Gower R, Jacobson KW, Li HH, Chen H, Schranz J. Safety and efficacy of C1 esterase inhibitor for acute attacks in children with hereditary angioedema. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2015 Nov:26(7):674-80. doi: 10.1111/pai.12444. Epub 2015 Aug 11 [PubMed PMID: 26171584]
Strassen U, Bas M, Hoffmann TK, Knopf A, Greve J. Treatment of angiotensin receptor blocker-induced angioedema: A case series. The Laryngoscope. 2015 Jul:125(7):1619-23. doi: 10.1002/lary.25163. Epub 2015 Feb 3 [PubMed PMID: 25646708]
Level 2 (mid-level) evidenceCraig TJ, Schneider LC, MacGinnitie AJ. Plasma-derived C1-INH for managing hereditary angioedema in pediatric patients: A systematic review. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2015 Sep:26(6):537-44. doi: 10.1111/pai.12425. Epub [PubMed PMID: 26111105]
Level 1 (high-level) evidenceLoudin M, Modiano N, Sallay S. Rapid Improvement of Pancreatitis Secondary to Hereditary Angioedema with C1 Inhibitor Administration. The American journal of medicine. 2016 Jul:129(7):e75-6. doi: 10.1016/j.amjmed.2016.02.045. Epub 2016 Apr 4 [PubMed PMID: 27056293]
Scott SI, Andersen MF, Aagaard L, Buchwald CV, Rasmussen ER. Dipeptidyl Peptidase-4 Inhibitor Induced Angioedema - An Overlooked Adverse Drug Reaction? Current diabetes reviews. 2018:14(4):327-333. doi: 10.2174/1573399813666170214113856. Epub [PubMed PMID: 28201967]
Peveling-Oberhag A, Reimann H, Weyer V, Goloborodko E, Staubach P. High-Concentration Liquid Prednisolone Formula: Filling a Therapeutic Niche in Severe Acute Attacks of Urticaria and Angioedema. Skin pharmacology and physiology. 2016:29(1):9-12. doi: 10.1159/000439032. Epub 2015 Oct 15 [PubMed PMID: 26465879]
Tourangeau LM, Castaldo AJ, Davis DK, Koziol J, Christiansen SC, Zuraw BL. Safety and efficacy of physician-supervised self-managed C1 inhibitor replacement therapy. International archives of allergy and immunology. 2012:157(4):417-24. doi: 10.1159/000329635. Epub 2011 Nov 25 [PubMed PMID: 22123229]