Angioedema

Zachary Kuschner

Yue Ma

THE CLINICAL CHALLENGE

Angioedema is nonpitting edema that often involves orofacial, glossopharyngeal, and laryngeal structures and that can lead to airway obstruction and death. Angioedema accounted for approximately 100 000 emergency department (ED) during the period 2001 to 2009 with an age-adjusted death rate of approximately 0.6 per million per year in 2010.¹^,² The clinical challenge presented with angioedema is 2-fold: airway and medical management. Localized extravasation of fluid from the vascular compartment into surrounding subcutaneous and submucosal tissue caused by histamine or bradykinin release deranges airway anatomy, making intubation difficult. Furthermore, there are multiple underlying pathophysiologic causes of angioedema, each with unique therapies. Differentiation of various angioedema syndromes is critical to allow for pathology reversal and ease airway management.

PATHOPHYSIOLOGY

Angioedema is categorized by the underlying pathophysiologic mechanism that provoking the capillary leak state: either mast cell degranulation producing histamine, or the kallikrein-kinin system producing bradykinin. Increased capillary permeability in the mucosal, submucosal, and subcutaneous tissues allows extravasation of fluid into the extracellular space, causing the physical presentation of angioedema.

Histamine Mediated Angioedema (HMA)

Histamine-mediated angioedema (HMA) is a component of anaphylaxis, an allergic response at the severe end of a broad clinical spectrum of histamine-mediated allergic reactions. In HMA, as with less severe allergic reactions, intracellular storage vesicles within basophils and mast cells release histamine in response to cross-linking of immunoglobulin E (IgE) antibodies provoked by antigen binding. The effects of histamine may be either local or diffuse and can produce edema, bronchial smooth muscle constriction, increased airway sputum production, pulmonary edema, and vasodilatory shock. In the gastrointestinal tract, histamine increases smooth muscle contraction and acid secretion. Histamine stimulation of subcutaneous nerve endings produces urticaria and pruritis. A variety of non-IgE-mediated triggers, including, but not limited to, opiates, salicylates, cyclooxidase inhibitors, iodinated contrast, exercise, and cold temperature, may directly stimulate histamine release.

Bradykinin-Mediated Angioedema (BMA)

Bradykinin, an end-product of the kallikrein-kinin system, is an important component of the physiologic response to tissue injury. It induces smooth muscle relaxation, activates the complement system, and stimulates coagulation. Bradykinin is metabolized by angiotensin converting enzyme (ACE) and carboxypeptidase N, and its production is regulated at multiple steps by C₁-inhibitor (C₁-INH)—also known as C₁ esterase.

Hereditary angioedema (HAE) is an autosomal dominant deficiency of C₁-INH resulting in increased levels of C₁ protein and overall complement activity, as well as impaired clearance of bradykinin. Two predominant varieties of HAE exist: type 1 is characterized by decreased C₁-INH production and type 2 by production of incompletely effective C₁-INH protein. Acquired C₁-INH deficiency (acquired angioedema, AAE) can occur owing to use of ACE inhibitors. Less commonly, conditions that produce anti-C₁-INH antibodies such as malignancy, hepatitis B or C infection, or autoimmune disorders can cause AAE.

APPROACH/THE FOCUSED EXAM

Angioedema patients present with signs of nonpitting edema in the subcutaneous and submucosal regions of the body. Once the patient is deemed to be hemodynamically stable and has an intact airway, a detailed history and physical exam should differentiate angioedema from angioedema-like conditions (see differential diagnosis section) and HMA from BMA. Management of angioedema requires an accurate diagnosis of the form of angioedema.

Assessing Patient Stability

Signs of hemodynamic instability and airway compromise should be first assessed and treated. Clinicians should look for symptoms and signs of hoarseness, stridor, drooling, dysphagia, and odynophagia. An early flexible laryngoscopy should be performed promptly for airway assessment.

Medical History and Physical Exam

History taking should assess for any prodromal symptoms, symptom onset and duration, triggers of attack, trialed medications and their responses, personal or family history of angioedema, medication list (eg, angiotensin converting enzyme inhibitor [ACEI]), allergies, and a complete review of systems to assess all organ systems involved. Table 15.1 lists clinical features of the angioedema subtypes. Patients with HMA present with pruritic urticaria and typically report other allergic symptoms like flushing, wheezing, vomiting, and abdominal pain. By contrast, patients with BMA generally do not report pruritus, flushing, or wheezing but do frequently have abdominal pain.³ Patients with HMA develop symptoms within minutes of exposure and usually have rapid resolution with the treatment cocktail of epinephrine, corticosteroids, and antihistamine. BMA, in contrast, typically has a much slower course of onset and resolution.

Family history of angioedema can signify a subset of BMA, HAE. Patients with HAE present with recurrent episodes of cutaneous and submucosal swelling that frequently begin before age 20 years. In contrast, patients with acquired C₁-INH deficiency typically present during or after the fourth decade of life and do not have familial history.⁴

More than half of patients with AAE have an underlying autoimmune or lymphoproliferative disorder. It is therefore important to ask for a history of monoclonal gammopathy of uncertain significance (MGUS), chronic lymphocytic leukemia, non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, or autoimmune disorders such as systemic lupus erythematosus.⁴

The physical exam should focus on common sites affected: lips, tongue, pharynx, larynx, periorbital area, extremities, genitalia, and gastrointestinal system. It is important to assess for signs of urticaria to differentiate between HMA and BMA. Clinicians should be aware that mucosal swelling in angioedema can lead to temporary bowel occlusion, which can present as severe tenderness, guarding, and rebound tenderness of the abdomen; this can mislead physicians to seek surgical treatment for an acute abdomen.³

Laboratory Testing

Subtypes of angioedema can be diagnosed through laboratory testing of C1-INH and function, C4 levels, and C₁q levels obtained from blood samples (Table 15.2). However, in the emergency setting, diagnosis of angioedema is clinical, because laboratory results may take days or weeks to result.

TABLE 15.1 Clinical Features in Angioedema Subtypes

		Demographic	Onset	Symptom Duration	Prodromal Symptoms	Urticaria	Response to Antihistamine Treatment	Triggers of Attack
Histamine-mediated angioedema	Allergic	Any	<1-2 hr	12-24 hr	–	+	+	Food, environmental allergens, drugs or insect venom
Bradykinin-mediated angioedema	HAE	Female, less than 20 yr	Slow onset (hr)	48-72 hr/last up to 5 d	+ fatigue, malaise, mood changes, erythema marginatum, and joint/muscle pain	–	–	Trauma/medical procedures to the face, mouth or upper airway, stress, infection, estrogen (HAE with normal C1-INH)
	AAE caused by ACEi	African-American, Females	Immediate or delayed (up to 6 months since last drug taken)	48-72 hr	–	–	–	ACEi
	AAE caused by C1-INH deficiency	More than 40 yr	Slow onset	Depends on treatment for underlying disease	–	–	–	Associated with underlying lymphoproliferative disorder and autoimmune disease
AAE, acquired angioedema; ACEi, angiotensin-converting enzyme inhibitor; C1-INH, C1-inhibitor; HAE, hereditary angioedema.