Publish date: Posted on
Last updated: October 8, 2021
Keywords #
Histaminergic angioedema
hereditary angioedema
angiotensin converting enzyme inhibitor (ACEi)-induced angioedema
Diagnosis #
Angioedema is self-limited edema of subcutaneous and submucosal tissues resulting from increased microvasculature permeability in a circumscribed body area.[1] The localized increase in microvascular permeability can be attributed either to histamine or bradykinin-associated mechanisms. Sites commonly affected by angioedema are the skin/oral cavity/larynx and the gastrointestinal tract, all of which can require hospitalization depending on severity when presenting as either respiratory compromise or an acute abdomen, respectively.[1]
Initial evaluation of a patient presenting with angioedema should focus on vital conditions including level of consciousness/mental status, airway patency, hemodynamic stability and general severity. Once the patient is stable, a thorough diagnostic approach is critical to determine the underlying etiology and ensure appropriate treatment. Causes of edema such as anasarca, myxedema, superior vena cava syndrome and acute dermatitis should be ruled out.[2] Then, a careful history and physical examination should be performed to determine whether the angioedema is histaminergic (e.g. exposure to allergens, accompanying urticaria) or bradykinin-mediated (e.g. new ACEi prescription or family history of angioedema). Effective treatment is directed at the underlying etiology; histaminergic angioedema responds to therapies such as epinephrine, glucocorticoids and antihistamines whereas bradykinin-mediated angioedema is resistant to these measures but responsive to bradykinin interfering therapeutics.[3]
Hereditary angioedema (HAE) is similar to ACEi-induced angioedema in that it is caused by the accumulation of bradykinins but the underlying mechanism is different and due to genetic mutations. There are a number of genes implicated in HAE, but the most common form of HAE arises from mutation in the gene encoding C1-esterase inhibitor (C1INH) leading to low levels or non-functional C1INH.[6] HAE shows an autosomal dominant inheritance pattern and usually becomes apparent during the second decade of life.[6] Involvement is similar to ACEi-induced angioedema, with non-pitting subcutaneous edema that can involve the face, oral cavity, neck, gastrointestinal tract, extremities or genitals.[1] HAE can be distinguished from histaminergic angioedema by lack of urticaria/pruritus. Although erythema overlying edema may develop in HAE, the edematous plaques are not characteristically warm, painful, or pruritic as in histaminergic angioedema.[6]
Key Concepts #
- Angioedema is self-limited localized edema of subcutaneous and submucosal tissues due to increased microvascular permeability.
- Angioedema often presents as swelling of the skin/face, oral cavity and upper airway which can cause respiratory compromise.
- Angioedema can develop in the gastrointestinal tract, which can present with symptoms of an acute abdomen.
- Angioedema can be acquired or hereditary and histamine or bradykinin-mediated.
- Diagnosis is typically made by history and examination; in some patients, especially with bradykinin-mediated angioedema, complement studies can be helpful.
- First-line therapies for histaminergic angioedema are antihistamines, glucocorticoids and epinephrine; consider C1-inhibitor (C1INH), ecallantide, icatibant or fresh frozen plasma (FFP) for bradykinin-mediated angioedema.
Epidemiology #
The lifetime prevalence of angioedema and/or allergic reactions requiring medical care is approximately 25% in the United States, which results in over a million visits to emergency departments (ED) each year.[3] While the majority of angioedema episodes are allergic reactions, approximately 5000 visits to ED in the United States annually are attributable to hereditary angioedema.[3] As ACEi prescriptions continue to increase with growing rates of hypertension and heart failure, the prevalence of ACEi-induced angioedema episodes continues to increase substantially.[3]
Clinical Features #
- Angioedema is circumscribed, subepithelial non-pitting edema that may affect any skin or mucosal tissue and commonly affects lips, face and neck and/or oral cavity, larynx and the gastrointestinal tract.[1] Increased microvascular permeability causing angioedema typically lasts several hours to 1-2 days.[1]
- This disorder may be acquired or hereditary. Histaminergic angioedema is the most common type of the acquired form and may be accompanied by other manifestations of an allergic reaction such as pruritus, urticaria, and anaphylaxis. Symptoms typically occur within 60 minutes of allergen/triggering exposure and last 24-48 hours.[4] This reaction is mediated by mast cell and basophil activation.[1]
- ACEi-induced angioedema typically involves the face and upper aerodigestive tract with non-pruritic erythema that lasts 24-72 hours prior to spontaneous remission.[3]
The table below categorizes both the common and uncommon types of angioedema considering histamine-mediated versus bradykinin-mediated classification:
Histaminergic (allergic)
|
Bradykinin-mediated
|
Differential Diagnoses #
- Contact dermatitis
- Cellulitis
- Erysipelas
- Autoimmune disorders
- Superior vena cava syndrome
- Anasarca
- Myxedema
- Parasitic infections
- Hypothyroidism
- Cheilitis granulomatosa
Diagnostic Workup #
Angioedema is a clinical diagnosis based on localized swelling of the face, tongue, larynx, other body areas, and/or abdominal swelling/pain/discomfort without another reason for an acute abdomen.[3] Disorders that mimic or are known types of angioedema should be ruled out, including acute contact dermatitis, superior vena cava syndrome, generalized edema, hypothyroidism, dermatomyositis and others.[2]
Determining the underlying cause of angioedema can prove challenging, but a thorough clinical history often contributes important information. Allergen exposure with the presence of urticaria or anaphylaxis suggests histaminergic angioedema. Newly prescribed ACEi therapy points to possible ACEi-induced angioedema. A family history of angioedema with more widespread involvement including the abdomen is evidence of HAE. Furthermore, histaminergic angioedema characteristically has a more rapid onset (minutes) and lasts a shorter duration (12-24 hours) versus bradykinin-mediated angioedema with a more prolonged onset (hours) and longer duration (48-72 hours), important clinical clues as to underlying etiology.[1] Laboratory testing can be helpful to determine type of HAE or whether a patient has acquired angioedema. In these presentations, complement studies (C4, C1q, C1INH level, C1INH function) can be helpful in diagnosis.[3,6]
Treatment #
Treatment for angioedema should begin with airway management and circulatory support, if necessary. Patients who present to the ED with anaphylaxis and airway compromise should be stabilized accordingly with intubation and blood pressure support.
Histaminergic angioedema is treated with H1 antihistamines, glucocorticoids and epinephrine.[1,3] Epinephrine is not indicated if symptoms are non-life threatening and airway is not compromised.
If bradykinin-mediated angioedema is diagnosed, treat with C1INH, ecallantide, or icatibant.[3] There is evidence that FFP can help patients with ACEi-induced angioedema that are refractory to other treatments.[5] Glucocorticoids also can be helpful in patients with ACEi-induced angioedema.[1] Follow-up should be arranged with a primary care physician, immunologist or allergist depending on the suspected underlying cause of bradykinin-mediated angioedema for further management.
References #
- Depetri F, Tedeschi A, Cugno M. Angioedema and emergency medicine: From pathophysiology to diagnosis and treatment. Eur J Intern Med. 2019 Jan;59:8-13.
- Andersen MF, Longhurst HJ, Rasmussen ER, Bygum A. How Not to Be Misled by Disorders Mimicking Angioedema: A Review of Pseudoangioedema. Int Arch Allergy Immunol. 2016;169(3):163-70.
- Bernstein JA, Cremonesi P, Hoffmann TK, Hollingsworth J. Angioedema in the emergency department: a practical guide to differential diagnosis and management. Int J Emerg Med. 2017 Dec;10(1):15.
- Kanani A, Betschel SD, Warrington R. Urticaria and angioedema. Allergy Asthma Clin Immunol. 2018 Sep 12;14(Suppl 2):59.
- Dykewicz MS. Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management. Curr Opin Allergy Clin Immunol. 2004 Aug;4(4):267-70.
- Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001 Nov 12;161(20):2417-29.
- Nedelea I, Deleanu D. Isolated angioedema: An overview of clinical features and etiology. Exp Ther Med. 2019 Feb;17(2):1068-1072.