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. After the year 2007, angioneurotic edema (ANE) was named as angioedema (AE) in the literature.
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.
The lifetime prevalence of angioneurotic edema in the United States is approximately 25%, and there are more than one million ED visits yearly. 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. UK survey discloses that 30% of patients with angioneurotic edema have visited the ED.
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. 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.
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.
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.
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.
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. Hereditary angioedema attacks should be treated with C1 Inhibitor concentrate, ecallantide (kallikrein inhibitor), or icatibant (bradykinin-receptor antagonist).
Icatibant is an effective home-based, on-demand treatment. Before any high-risk procedure in high-risk patients, it is essential to give short-term prophylaxis. Anesthetists must be aware of the guidelines for HANE and AANE. C1 esterase inhibitor is the first-line long-term prophylaxis and androgens are used as second-line prophylaxis. The majority of AANE cases are asymptomatic and respond to immunochemotherapy.
Acute attacks can be treated with icatibant and C1 inhibitor concentrate (plasma-derived), and prophylaxis is with rituximab with or without chemotherapy and splenectomy. 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. The plasma-derived C1 esterase inhibitor is safe and effective in pediatric patients below 12 years.
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. Icatibant is a well-tolerated medication in the pediatric group and might have a role in treating angiotensin-2 receptor blocker induced angioedema. Patients with life-threatening orolingual angioedema who are treated with recombinant tissue plasminogen activator infusion, have a rapid response after using icatibant treatment. 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.
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.
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.
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.
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.
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.
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.
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