Emerging concepts in the diagnosis and treatment of patients with undifferentiated angioedema

Histamine-mediated or allergic angioedema occurs through a type I IgE-mediated hypersensitivity immune response, which is largely mast cell-dependent. Genetically susceptible individuals with prior exposure to an offending allergen become “sensitized.” Sensitization occurs when the allergen is taken up by antigen-presenting cells (i.e., dendritic cells, macrophages, or B cells) and is broken down into small peptides (9–11 amino acids in length). The relevant peptides are then presented to the cell surface in conjunction with major histocompatibility class 2 (MHC2) antigens. This MCH2 peptide complex is recognized by T-helper lymphocyte receptors and a number of other co-stimulatory molecules, resulting in T-cell activation and the release of Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, that promote increased production of IgE and the differentiation and migration of eosinophils, in addition to many other functions leading to allergic inflammation. These cytokines also cause B lymphocytes to differentiate into plasma cells that produce specific IgE antibodies that specially recognize the original sensitizing antigenic peptide. These specific antibodies bind to high-affinity IgE receptors (FcεR-1) and can persist on these receptors for months or years. Upon re-exposure to the inciting agent, the allergenic peptide is recognized by the antigen-binding sites of the specific IgE antibodies bound to the high-affinity IgE receptors, leading to a series of chemical reactions that result in activation of the mast cell and the release of preformed and newly formed bioactive mediators (Figure 1) [4]. These mediators, such as histamine, can then bind to selective receptors (i.e., H₁ receptors) on the vascular endothelium, leading to vasodilation and increased permeability [4, 11].

Kinins are a group of pharmacologically active peptides that are released into body fluids and tissues following the enzymatic action of kallikreins on kininogens, which occurs through a complex proteolytic cascade of events called the kallikrein-kinin cascade (Figure 2). The kallikrein-kinin cascade, also referred to as the “contact activation pathway” or intrinsic pathway, is initiated when factor XII (Hageman factor) binds to damaged tissue, becoming activated through conversion to factor XIIa. Factor XIIa converts prekallikrein to plasma kallikrein, and these two proteins autoactivate each other through a positive feedback loop. Plasma kallikrein then cleaves high-molecular-weight kininogen (HMWK), thereby liberating bradykinin [12]. The binding of bradykinin to bradykinin β2 receptors induces vasodilation and increased endothelial permeability, yielding the characteristic signs and symptoms of an acute attack of angioedema [1, 13].

The prevalence of AAE is believed to be 1:100,000 to 1:500,000, and it primarily affects adults and the elderly. AAE results from a non-genetic C1-INH deficiency. Ten to fifteen percent of patients have an underlying lymphoproliferative disorder; therefore, screening these patients with blood tests and possibly bone marrow biopsy to exclude malignancy is recommended. Many of these patients may also have an autoantibody to C1-INH. Treatment of the underlying lymphoproliferative disorder and/or the C1-INH autoantibody can be curative [18].

Some of the classic signs associated with histamine-mediated angioedema are the “wheal and flare” reaction of the superficial layers of the skin and interstitial edema of underlying subcutaneous, mucosal, and submucosal layers of the skin [4]. These reactions therefore frequently manifest as pruritic hives with or without angioedema. Also of importance is the evanescent nature of these attacks in contrast to non-histamine-mediated angioedema. Acute attacks of urticaria and/or angioedema are typically self-limited; swelling typically lessens or resolves over the course of 24 h. Not infrequently, these reactions can be recurring, and when they persist for more than 6 weeks are considered chronic [5].

Although histamine-mediated attacks of angioedema most commonly occur in hyperallergic or atopic individuals (i.e., patients with allergic rhinitis, extrinsic asthma, or atopic dermatitis/eczema), attacks induced by a food or medication may be seen in the absence of atopy. In addition to acute swelling and edema, allergic angioedema always involves a recognizable trigger, most commonly insect stings, food, or medications [10].

Angioedema that is mediated by histamine typically responds to antihistamines (Table 1). Swelling can occur at any site of the body, but histamine-mediated angioedema has a predilection for the facial area, particularly the lips and periorbital area and, less commonly, the genitalia. Isolated allergic angioedema may involve the throat or larynx, resulting in dyspnea or stridor caused by laryngeal edema. In some instances, patients can progress to anaphylaxis, a potentially fatal systemic allergic reaction [4]. Anaphylaxic manifestations can include diffuse hives, angioedema, gastrointestinal symptoms, and hypotension. In its most severe form, loss of consciousness due to vascular collapse may occur [4]. Pulmonary symptoms, including hyperinflation, peribronchial congestion, submucosal edema, edema-filled alveoli, and eosinophilic infiltration are often noted during anaphylaxis [4]. Although these cases are responsive to antihistamine therapy, identifying a specific cause can be elusive. Often patients and/or physicians implicate a food or drug as the trigger without adequately proving cause and effect, which can lead to erroneous elimination of important medications or unnecessarily restrictive diets. Therefore, once stabilized, these patients should be evaluated by a physician experienced in the management of urticaria/angioedema to establish whether these reactions are secondary to a specific cause or are idiopathic, as the latter is often the case.

The most frequently encountered symptoms in HAE types I and II (HAE due to C1-INH deficiency) are skin edema, abdominal pain, and life-threatening laryngeal edema. Skin swelling occurs most commonly in the extremities and less frequently involves the face and other body sites. Abdominal attacks, which are also very prevalent in these patients, are caused by transient edema of the bowel wall and manifest with significant pain, vomiting, and diarrhea due to partial or complete intestinal obstruction, ascites, and hemoconcentration. In up to one-third of patients, erythema marginatum, which is a serpiginous erythematous non-pruritic rash, can manifest before the onset of an attack in patients with either type I or type II HAE; however, urticaria and pruritus are not typically associated with these two types of HAE (Table 1) [7, 10].

A recent analysis of 195 patients with HAE found that 54% experienced an average of more than 12 attacks per year; symptom-free years were rare, representing only 370 (6.5%) of the 5,736 patient-years included in the analysis [19]. Although clinical presentation varies, HAE types I and II often present during childhood (Table 1). Most patients experience progressive worsening of symptoms over several hours; these episodes can be quite protracted, lasting from 2 to 5 days without treatment [20].

ACEI-induced angioedema occurs in 0.1-0.7% of patients treated with these agents. The incidence of ACEI-induced angioedema appears to be highest (25%) during the first month of treatment [21] but can occur from months to years after the initiation of treatment. Less commonly, ACEI-induced angioedema has been associated with medications such as NSAIDs—via inhibition of the COX enzyme pathway leading to changes in prostaglandin synthesis [5, 11]—and alteplase [22]. Although rare, angioedema can also be induced by ARBs; for the most part, ARBs are considered safe for use by patients who have a history of ACEI-induced angioedema [21].

ACEI-induced angioedema is not associated with urticaria [8, 23] and most commonly involves the tongue, lips, and face [21]. ACEI-induced angioedema appears to be four to five times more common in African-American than in Caucasian individuals [21] owing to genetic polymorphisms in APP, a critical enzyme for metabolizing ACEIs.

The presentation of AAE is, broadly speaking, similar to that of HAE types I and II, with recurrent attacks of subcutaneous and/or submucosal swelling without urticaria. As mentioned, AAE is much less common than HAE, affecting approximately one-tenth as many patients. Clinical characteristics that differentiate this form of angioedema from HAE are older age (the typical patient is elderly) and the absence of a family history of angioedema [23].

A definitive diagnosis of histamine-mediated angioedema can be achieved through laboratory evaluation for markers of mast cell degranulation (elevated urine histamine and serum tryptase levels) (Table 2). Prick skin testing or serum-specific IgE assays may be appropriate if the history is suggestive of sensitization to a suspected allergen such as a food. If laboratory test results for urine histamine and serum tryptase levels are unavailable, the diagnosis relies on history and clinical presentation [21].

In patients with HAE Type III, the level and function of C1-INH are normal. The serum C4 level is also normal (Table 2) [8].

Because the clinical signs and symptoms of HAE types I and II are very similar, distinguishing between the two requires laboratory evaluation. In HAE type I, the serum C4 level is decreased during and between attacks, and the serum C1-INH level is decreased and sometimes undetectable. In HAE type II, the serum C4 level is decreased during and between attacks, while the serum C1-INH level is within normal limits or even increased, but C1-INH is functionally deficient (Table 2, Figures 4 and 5) [8]. Typically, in type II, the serum C2 level is also reduced during attacks, which may be helpful in making the diagnosis [8].

Patients who present with attacks of angioedema due to ACEIs will have normal levels of C4 and C1-INH (Table 2, Figure 5) [10]. Similarly, in IAE, C4 levels along with all other laboratory results are normal. IAE is primarily a diagnosis of exclusion (Table 2, Figures 4 and 5), In AAE, C4 levels and complement protein C1q are reduced; C3 levels may be low or normal (Table 2) [1].

The priority of the acute management of angioedema is airway maintenance. Intramuscular (IM) epinephrine may be used to control symptoms and sustain blood pressure during an anaphylactic reaction; it may be life-saving for patients with acute laryngeal edema or anaphylaxis [8]. Epinephrine 1:1,000 is administered IM 0.2-0.5 mg thigh (adults); 0.01 mg/kg (up to 0.03 mg) thigh (children). This dose can be repeated every 5–15 minutes, with close monitoring for signs and symptoms of toxicity [25].

The α-adrenergic, vasoconstrictive effect of epinephrine reverses peripheral vasodilation, which reduces angioedema and urticaria. The β-adrenergic properties of epinephrine cause bronchodilation, increase myocardial output and contractility, and suppress further mediator release from mast cells and basophils. It is important to note that epinephrine, administered in low concentrations (e.g., 0.1 mg/kg) is paradoxically associated with vasodilation, hypotension, and the increased release of inflammatory mediators. Because of the risk for potentially lethal arrhythmias, intravenous (IV) epinephrine 1:10,000 or 1:100,000 dilutions should be administered only during cardiac arrest or to patients who are profoundly hypotensive or have failed to respond to both IV volume replacement and multiple injections of epinephrine [25].

An important component of the acute management of anaphylaxis presented by severe histamine-mediated angioedema is volume expansion. The largest catheter possible should be inserted into the largest peripheral vein, and the rate should be titrated to pulse and blood pressure; infuse 1–2 l normal saline rapidly by IV in adults (5–10 ml/kg in the first 5 min), 30 ml/kg in the first hour in children [25].

Antihistamines act more slowly than epinephrine, have minimal effect on blood pressure, and should not be administered alone as treatment for anaphylaxis or acute allergic angioedema. Combined histamine-receptor blockade, with H₁ and H₂ blockers, is more effective than the use of H₁ agents alone. Diphenhydramine should be administered 25–50 mg IV (adults), 1 mg/kg IV up to 50 mg (children). Identical oral doses may be sufficient for milder episodes. Ranitidine should be administered 1 mg/kg (adults), 12.5-50 mg infused over 10 min (children) [25, 26].

Inhaled β2 agonists (e.g., albuterol) are helpful when bronchospasm resists epinephrine injections alone. Systemic corticosteroids are not sufficient to prevent the progression of anaphylaxis [25]. Although the use of a parenteral corticosteroid (IV methylprednisolone) provides a benefit in histamine-mediated angioedema, its therapeutic effect is not immediate.

For all types of angioedema, the priority of acute management is maintenance of airway patency. Because ACEI-induced angioedema does not involve histamine, antihistamines have not been found to be effective in either the acute or long-term management of these patients; similarly, corticosteroids are not effective for these conditions. Epinephrine should be considered to temporarily constrict permeable blood vessels. For patients who present with an acute attack of ACEI-induced angioedema, an immediate first step is discontinuation of the ACEI [6].

The mechanism underlying ACEI-induced angioedema (excess bradykinin) is similar to that underlying HAE. For that reason, agents shown to be effective in HAE, including the plasma kallikrein inhibitor ecallantide and the bradykinin receptor antagonist icatibant, are currently being investigated in clinical studies as treatments for acute ACEI-induced angioedema [27, 28]. Several small case studies have reported on the use of icatibant for the treatment of ACEI-induced angioedema [29‐31].

In May 2010, the third international conference on HAE was held in Toronto, Canada, where international consensus approaches for the diagnosis, treatment, and management of HAE were reviewed and updated. The consensus documents divide the therapy for patients with HAE into acute treatment, short-term prophylaxis, and long-term prophylaxis. The consensus recommends that HAE attacks be treated as early as possible [24]. Patients with HAE are unlikely to respond to antihistamines or corticosteroids. Epinephrine has low efficacy in HAE, but has been advocated for use early in the course of attacks Therapeutic agents available for the treatment of acute attacks of HAE are summarized in Table 3 [23, 32‐34]; see also the following discussion regarding differential availability of these agents.

C1-INH replacement therapy functions to restore the missing C1-INH in patients with HAE. Berinert is a human, plasma-derived, pasteurized form of C1-INH that was approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of acute abdominal, facial, and, more recently, laryngeal attacks of HAE in adult and adolescent patients [32]. C1-INH concentrate has been available in Europe for more than 20 years and is considered the standard of care for the treatment of HAE in many countries. Pasteurized and nanofiltered C1-INH is provided as a single-use vial that contains 500 units of C1 esterase inhibitor as a lyophilized concentrate. Each vial must be reconstituted with 10 mL of diluent (sterile water) provided. C1-INH concentrate must be administered using aseptic technique at a dose of 20 units per kilogram of body weight by IV injection (Table 3) [32, 37]. Recently, the FDA has approved self-administration of Berinert by patients.

In 2009, the FDA granted approval to ecallantide (Kalbitor), for the treatment of acute attacks of HAE in patients 16 years of age and older [33]. However, the European Union (EU) recently rendered a negative opinion regarding its approval. Ecallantide is a plasma kallikrein inhibitor that is effective against attacks of HAE at any anatomic location, including abdominal/gastrointestinal, laryngeal, and peripheral attacks (Table 3). Ecallantide binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMWK to bradykinin. By directly inhibiting plasma kallikrein, ecallantide reduces the conversion of HMWK to bradykinin and thereby treats symptoms that occur during acute episodic attacks of HAE.

Two randomized placebo-controlled trials demonstrated that a 30 mg subcutaneous dose of ecallantide significantly reduced the duration of symptoms in patients with HAE [38, 39]. The most commonly reported adverse events were headache (8%), nausea (5%), and diarrhea (4%) [38]. Because of the 2.9% incidence of anaphylaxis observed in clinical trials, the FDA has given ecallantide a black box warning, which requires the drug to be administered by a trained healthcare professional with emergency therapy readily available to treat an allergic reaction should one occur [33].

The bradykinin receptor blocker icatibant (Firazyr) (30 mg injected subcutaneously) is a synthetic, 10 amino acid, short-acting, and highly selective competitive bradykinin β2 receptor antagonist [34, 38, 40]. Three trials have examined the safety and efficacy of icatibant in HAE [41, 42]. These studies showed a decrease in median time to clinically significant symptom relief. This decrease was statistically significant in the For Angioedema Subcutaneous Treatment (FAST)-2 and FAST-3 trials [41, 42]. Adverse reactions consisted of injection site reactions in more than 90% of subjects, pyrexia, and elevated transaminase levels [41, 42]. No anaphylaxis was reported. Since bradykinin is thought to play a major role in the antihypertensive effect of ACE inhibitors, the icatibant package insert reports that any bradykinin β2 receptor antagonist has the potential to attenuate the antihypertensive effect of ACEIs [34].

Because certain treatment options may be licensed in some countries but not in others, the treatment of HAE differs across countries. Phase III clinical trials are ongoing in the US for specific agents, and the standard of care for the treatment of HAE will continue to evolve as data from these trials become available. Rigorous phase IV clinical trials will further delineate the long-term safety and efficacy of the differing treatments. Data from all trials will be used to update international and national HAE databases and registries [43].

Icatibant is approved for the treatment of acute attacks of HAE in the EU and the US. The recent FDA indication for icatibant allows patients with HAE aged 18 years or older to self-administer the medication [8, 43].

Another difference across countries regarding the treatment of HAE is the use of a recombinant C1-INH (conestat alfa, Rhucin), which is produced in transgenic rabbit milk. Recombinant C1-INH is currently under FDA review; in June 2010, the Committee for Medicinal Products for Human Use of the European Medicines Agency delivered a positive opinion on the use of recombinant C1-INH for the treatment of acute attacks in patients with HAE [43].

Regardless of the agent selected for acute attacks of HAE, the patient and/or healthcare provider needs to be able to differentiate the progression of an HAE attack from that of an allergic reaction, as there are many similar features, so that erroneous treatments are not provided and erroneous diagnoses are not made. Furthermore, patients trained to self-administer these agents should be advised that if they are experiencing facial, neck, and/or throat swelling, they should go to the closest emergency department for observation after taking their HAE medication.