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INTRODUCTION — Hereditary angioedema (abbreviated HAE throughout this review) is a rare autosomal dominant disorder characterized by recurrent episodes of well-demarcated angioedema without urticaria, which most often affects the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Although swelling resolves spontaneously in two to four days in the absence of treatment, laryngeal edema may cause fatal asphyxiation, and the pain of gastrointestinal attacks may be incapacitating or lead to unnecessary abdominal surgery. The most common forms of HAE (types I and II) are caused by deficiency or dysfunction in C1 inhibitor (C1INH-HAE) . There are other forms of the disorder in which C1INH is normal called hereditary angioedema with normal C1 inhibitor (HAE with normal C1INH), which are discussed separately. (See "Hereditary angioedema with normal C1 inhibitor".)
The evaluation and treatment of acute attacks of HAE in adults and children will be reviewed here. Other aspects of these conditions are discussed elsewhere:
GUIDELINES — Several guidelines and practice parameters concerning the treatment of HAE have been published [2-8]. The approach presented in this topic review is consistent with these guidelines. There is also a guideline for the management of gynecologic and obstetric issues in women with HAE, which includes treatment of acute angioedema during pregnancy . (See 'Pregnant women' below.)
OVERVIEW — Attacks of HAE are commonly categorized as laryngeal, gastrointestinal, or cutaneous. Laryngeal attacks are the least common but most dangerous type of attack because airway obstruction can progress to asphyxiation and death. More than one-half of all HAE patients experience a laryngeal attack at some point . Therefore, all patients should be educated about the early signs and symptom of laryngeal attacks, even if the individual has never experienced one. There should also be a specific plan for how the individual will access emergency treatment (see 'Laryngeal attacks' below). Gastrointestinal attacks can range from mild to severe, but usually resolve without serious complications unless the patient undergoes unnecessary surgical interventions because the disorder is not recognized as HAE . Cutaneous attacks are not associated with significant risk of serious complications or death but often cause substantial morbidity, as patients' lives can be significantly disrupted by repeated episodes.
In HAE, deficiency or dysfunction of C1 inhibitor (C1INH) leads to excessive production of the vasoactive mediator bradykinin, which leads to episodic increases in vascular permeability and angioedema. The bradykinin-mediated angioedema of HAE is fundamentally different from the angioedema that occurs with allergic reactions (which is mediated by histamine and other mast cell mediators), and it does not respond to epinephrine, antihistamines, or glucocorticoids. Instead, first-line therapies for HAE act by replacing C1INH or by blocking the production or function of bradykinin.
Equipping patients for emergency care — HAE is rare, and clinicians in emergency settings may not be familiar with the disease or its treatment. Therefore, as soon as a patient has been diagnosed with HAE, a plan for emergency care should be put in place, with particular focus on how the patient should seek care in the event of a laryngeal attack. Patients should be educated that any swelling involving the airway is potentially life-threatening and should be treated as an emergency. All patients should have a plan for accessing treatment rapidly. An important concept that has arisen with the availability of the newer therapies is that of a personalized care plan that takes into account the severity of disease, resources available, and the patient's values and preferences regarding the different therapies [6,7].
●When possible, clinicians or their representatives should communicate with the hospitals nearest to the patient's home to ensure that acute therapies are available .
●Patients should be equipped with a form that summarizes treatments for acute episodes of angioedema to assist in communication with emergency providers and ensure appropriate care (full-sized and wallet forms are provided) (form 1 and form 2).
●In some countries (not the United States), call centers have been established to provide 24-hour phone access to HAE expert clinicians who can be consulted for help with emergency treatment .
First-line therapies — There are several first-line therapies for acute treatment of episodes of angioedema in HAE which are summarized in the table and discussed in more detail below (table 1) (see 'First-line agents: Dosing, efficacy, and adverse reactions' below):
●C1 inhibitor (C1INH) concentrate, derived from human plasma (plasma-derived C1INH or pdC1INH) (see 'C1 inhibitor (plasma-derived)' below)
A clinical response should be evident within two hours with first-line therapies. No direct, head-to-head trials comparing these agents have been performed, and attempts to compare therapies indirectly are likely confounded by the multiple variables specific to each protocol . Each medication is discussed in detail below, including mechanism of action, dosing, availability, efficacy data, and adverse effects. (See 'First-line agents: Dosing, efficacy, and adverse reactions' below.)
Initiating treatment of acute attacks at home — Early treatment of HAE attacks has been shown to result in improved efficacy [14-16]. Initiating treatment at home (or other settings away from a medical environment) can decrease the delay between the onset of symptoms and time of treatment, and time to start of improvement and resolution of swelling are both significantly shorter when therapies can be given at home. All of the first-line therapies for HAE are likely to be effective if given in the first few hours of the angioedema attack (when the swelling is increasing). Most patients are willing and able to initiate treatment of acute attacks at home. The medications which can be given at home by the patient or by a nursing service on demand are:
●C1INH concentrate (plasma-derived or recombinant), which may be self-administered or given by a caregiver or nurse through a peripheral intravenous line at the first sign of symptoms . Practices regarding infusion by the patient versus infusion by a nurse in the home setting differ by country. (See 'C1 inhibitor (plasma-derived)' below and 'Recombinant C1 inhibitor' below.)
●Ecallantide, which is only available in the United States and is given as three subcutaneous injections. Although it is not approved by the US Food and Drug Administration (FDA) for self-administration because of a risk of hypersensitivity reactions, it can be given by a trained nurse in the patient's home. (See 'Kallikrein inhibitor (United States only)' below.)
While home treatment is preferred, the decision to prescribe therapies for acute treatment at home must be individualized. The clinician must consider each patient's situation, history of attacks, proximity to care, ability to self-administer medications, and preferences.
Second-line therapies — If none of the first-line therapies is available, other options for acute laryngeal and gastrointestinal attacks are solvent/detergent (S/D)-treated plasma (preferred because of lower risk of transmission of infectious diseases) or fresh frozen plasma (FFP) (table 2). (See 'Plasma' below.)
MANAGEMENT ISSUES FOR SPECIFIC TYPES OF ATTACKS
Laryngeal attacks — More than one-half of all HAE patients experience a laryngeal attack at some point . Airway angioedema can present as a sensation of throat swelling, change in voice quality, difficulty swallowing secretions, or difficulty breathing. Angioedema usually progresses over hours, although it can escalate precipitously. Intubation may become very difficult due to distortion of the anatomy of the upper airway. Features of laryngeal attacks and patterns of progression are reviewed separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Laryngeal attacks'.)
A first-line therapy (C1 inhibitor [C1INH], icatibant, or ecallantide) should be administered as early as possible in the attack (table 1). Patients who have first-line therapies at home and self-administer an initial dose should still seek medical care promptly, in case further intervention is required.
Airway management — Assessment and protection of the upper airway is the first and most important management issue in the patient with an acute attack involving any part of the airway, because none of the available therapies, including first-line agents, can be considered universally effective in all cases. In addition, these agents take time to work and the patient's airway must be protected in the interim.
Intubation should be attempted immediately if stridor and/or signs of respiratory arrest are present. A clinician trained in difficult airway management and able to perform tracheostomy should be summoned if possible, because failed attempts can lead to fatal obstruction. Emergent cricothyroidotomy may be required at this stage. (See "Emergency cricothyrotomy (cricothyroidotomy)".)
Once the patient is assessed and either intubated or deemed stable, additional treatment can be considered. Transfer to the intensive care unit should be arranged, unless the laryngeal angioedema responds promptly to treatment in a stable patient. Frequent and meticulous monitoring of airway status should continue throughout the course of the attack until complete resolution, and patients should not be discharged until all airway symptoms have resolved.
Gastrointestinal attacks — Gastrointestinal attacks present with varying degrees of gastrointestinal colic, nausea, vomiting and/or diarrhea, which result from bowel wall edema. Gastrointestinal attacks can range from mild to severe, but usually resolve without serious complications, unless patients undergo unnecessary surgical interventions because the disorder is not recognized . The clinical presentation and evaluation of gastrointestinal attacks is reviewed in more detail separately.(See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Gastrointestinal attacks'.)
When a patient with known or suspected HAE presents with gastrointestinal colic, the clinician must determine if the abdominal symptoms are actually due to angioedema or to an unrelated process. Patients who have had previous gastrointestinal attacks should be questioned carefully to ascertain if their current symptoms are similar to past episodes.
The clinical response to one of these first-line therapies can be valuable in distinguishing gastrointestinal attacks of HAE from other abdominal pathologies. With all of the first-line therapies, clinical response should be evident within two hours, keeping in mind that improvement is usually most prompt when the therapy is given in the first several hours of the episode (table 1). If given later in the attack, a slower, more gradual response may be seen. However, if there is no response at all two hours after the initial dose, then evaluation for other causes of abdominal symptoms should proceed.
If first-line therapies are not available, then management of gastrointestinal attacks is largely supportive. Alternatively, two units of plasma can be administered after reviewing the risk of disease transmission with the patient. Dosing is discussed below. (See 'Dosing' below.)
Rehydration and symptomatic therapy — Therapy to abort the attack is most important, but some patients with gastrointestinal attacks also require treatment for dehydration and pain, particularly if effective treatment was not given early in the attack. The following may be required:
●For dehydration – Intravenous rehydration with normal saline.
●For pain – Diclofenac, 100 mg orally (or 75 mg intravenously if vomiting) daily or tramadol, 50 mg orally or intravenously every four to six hours as needed (maximum 300 mg per day for five days) for adults.
●For severe pain – Parenteral narcotics, such as meperidine, 75 mg administered intramuscularly may be administered. However, as with any chronic disease, a small subset of patients may make inappropriate use of narcotics, although the vast majority do not.
●For gastrointestinal cramping – Butylscopolamine (not available in the United States), 20 mg intravenously every four to six hours as needed for adults.
Cutaneous attacks — Cutaneous attacks may involve any part of the body, including the extremities, torso, face, and genitalia. Many cutaneous attacks result in significant dysfunction, and patients may miss several days of school or work . Thus, consideration of treating early rather than waiting until swelling becomes more severe should be given. Acute therapies are less likely to provide relief when given late in an attack. However, the decision to treat obviously depends upon the availability of acute therapies (table 1).
FIRST-LINE AGENTS: DOSING, EFFICACY, AND ADVERSE REACTIONS — The medications used for acute treatment of episodes of angioedema in HAE are discussed in this section, with proposed mechanism of action, dosing, efficacy data, and side effects (table 1). An approach to using these medications to manage acute angioedema was presented previously. (See 'Overview' above.)
C1 inhibitor (plasma-derived) — C1 inhibitor (C1INH) concentrate, also known as C1 inhibitor concentrate (human) and C1 inhibitor replacement protein, is obtained from pooled human plasma (plasma-derived C1INH or pdC1INH). It is administered intravenously for treatment of acute attacks. Plasma-derived C1INH is the best studied first-line therapy for acute episodes of angioedema in patients with HAE. C1INH acts at several points in the pathways important in the generation of angioedema (figure 1). (See "Hereditary angioedema: Pathogenesis and diagnosis", section on 'Pathogenesis'.)
Two pdC1INH products are available: Cinryze (Shire) and Berinert or Berinert P (two names for the same product, CSL Behring). Plasma-derived products have been available for many years in the European Union, Canada, Japan, and Argentina and became available in the United States in 2008 to 2009 [2,19].
Dosing — The dosing of pdC1INH for treatment of acute episodes is based upon weight, and the recommended dose is 20 units/kg [20,21]. Each vial of drug contains 500 units of pdC1INH. Thus, doses for patients of different weight ranges are:
●Administer 1000 units if weight is ≤50 kg (110 pounds)
●Administer 1500 units if weight is >50 kg (>110 pounds) and ≤75 kg (165 pounds)
●Administer 2000 units if weight is >75 kg (>165 pounds) and ≤100 kg (220 pounds)
●Administer 2500 units if weight is >100 kg (>220 pounds)
Plasma-derived C1INH should be reconstituted, warmed to body temperature before administration, and given through a peripheral vein over 10 minutes. It can be administered at home by the patient, a caregiver, or a nurse or in a medical facility [22,23]. The solution must not be shaken, as this can cause denaturation of the protein. In an emergency, it can be given without prewarming. These therapies should be given as early as possible in the course of an attack. One study showed that patients treated within six hours of symptom-onset had shorter times to relief and resolution of symptoms compared with those treated later .
Stabilization or improvement in symptoms is usually seen within 30 minutes in laryngeal or gastrointestinal attacks . Fewer than 5 percent of attacks require a second dose . However, if symptoms initially improve but then start to recur or only partially improve, a second dose can be given after the first, and if symptoms are still worsening after the initial dose of pdC1INH, a second dose can be administered, particularly for attacks affecting the airway.
The US Food and Drug Administration (FDA) has not approved Cinryze for treatment of acute attacks (only for prophylaxis). However, there is no empiric reason to suspect that Cinryze would be less effective than the C1INH products used for years in Europe. The Cinryze dose approved in the European Union for acute attacks is 1000 units, with the possibility of another 1000 units if not improving. In the absence of trials to determine optimal dosing of Cinryze in acute attacks, either this dosing or weight-based dosing (described above) is acceptable.
Efficacy — The efficacy of pdC1INH for treatment of acute attacks of HAE was first reported in 1980 and has been well-demonstrated in randomized trials [20,27-32].
●A randomized trial of pdC1INH (Cinryze) for the treatment of acute attacks involved 68 patients, assigned to either 1000 units (with the possibility of another 1000 units after one hour based on clinician and patient assessment of need) of pdC1INH regardless of weight or placebo for nonlaryngeal attacks . The median time to onset of unequivocal relief (the primary endpoint) was two hours in the pdC1INH group compared with over four hours in the placebo group.
●A subsequent randomized trial of 125 patients with acute gastrointestinal or facial cutaneous attacks compared pdC1INH (Berinert) at doses of 10 units/kg or 20 units/kg with placebo . Patients were treated within five hours of the symptoms reaching moderate intensity. Median time to onset of relief was significantly shorter with the higher dose of pdC1INH (0.5 hours) compared with the lower dose of pdC1INH (1.2 hours) or placebo (1.5 hours).
●The effect of pdC1INH on laryngeal attacks was evaluated in a retrospective study comparing pdC1INH with conservative management in 193 episodes of laryngeal swelling . The mean duration of laryngeal edema was 15.3 hours in patients who received pdC1INH concentrate and 101 hours in those who did not. A subsequent nonrandomized trial also confirmed the efficacy of pdC1INH (Berinert) (20 units/kg) in patients with laryngeal edema .
An observational trial suggested that the response could be improved when patients were able to self-administer pdC1INH at home at the first sign of swelling (pdC1INH "on demand") . The patients in this study had disease that was refractory to prophylactic therapy with androgens, antifibrinolytics, or both. They reported initiation of relief in a mean of approximately 40 minutes after the onset of symptoms, as compared with about 2.5 hours when the patients were dependent on a health care facility for administration.
Plasma-derived C1INH is the preferred treatment for acute attacks in pregnant women with HAE [9,34-36].
Adverse effects — Adverse effects are unusual and include headache and fever. Rare allergic reactions to pdC1INH have been described, which presented as generalized itching, urticaria, and edema of the tongue and oral mucosa or as anaphylactic shock shortly after infusion [37,38].
A retrospective analysis of the FDA event reporting system database identified an association between thrombotic events and use of Cinryze, although no conclusions about causality or frequency could be made from the data . This is discussed in more detail elsewhere. (See "Hereditary angioedema: General care and long-term prophylaxis", section on 'Adverse effects'.)
Disease transmission is a theoretical risk of pdC1INH treatment, since it is obtained from pooled human plasma that has been pasteurized and nanofiltered. However, there have been no reported cases of viral transmission with the most extensively used preparation (Berinert P), despite the administration of over 100 million units [36,40-42]. The issue of disease transmission with C1INH products is discussed in more detail elsewhere. (See "Hereditary angioedema: General care and long-term prophylaxis", section on 'Use of specific agents'.)
There is no indication that "resistance" to pdC1INH develops with repeated use, at least in most patients. This was evaluated in a study of 18 patients treated for at least 15 attacks over a mean duration of 34 months . No decrease in time to relief of symptoms or interval between attacks was observed. However, rare patients have been reported who experience an increase in the frequency of attacks during periods in which pdC1INH was administered for treatment of acute attacks . These patients were not receiving pdC1INH for prophylaxis. Plasma-derived C1INH infusions remained successful in treating acute symptoms, although the frequency of attacks gradually increased over a period of years. The mechanism responsible for this paradoxical response is not known.
Recombinant C1 inhibitor — Recombinant human C1 inhibitor (rhC1INH, conestat alfa) (Ruconest in Europe and the United States, Rhucin in other countries) became available in Europe in 2011 and in the United States in 2014 . It is collected from the milk of transgenic rabbits [46-48]. Compared with the plasma product, rhC1INH has a similar protease inhibitory activity, but a shorter half-life. Thus, higher doses are required to achieve adequate plasma levels over a period of time sufficient to impact acute symptoms, compared with the plasma-derived product.
Dose — The recommended dose of rhC1INH for treatment of an acute attack of angioedema is 50 units/kg, rounded up to the nearest whole vial [49,50]. Some clinical trials used 50 to 100 units/kg, which was also safe. One vial contains 2100 units, so patients weighing ≤42 kg can receive one vial, and those weighing >42 kg can receive two vials. Patients generally do not require repeat dosing, although a second identical dose can be given if there is no improvement, for a maximum of 4200 international units per 24 hours. Relapse has not been reported [50,51]. The medication is a lyophilized powder that is reconstituted in sterile water, warmed to body temperature before administration, and given through a peripheral vein over five minutes. The patient should be observed during administration for signs or symptoms of an allergic reaction.
Effectiveness and adverse effects — In two similar randomized trials, patients received rhC1INH at doses of 100 units/kg, 50 units/kg, or placebo . The primary endpoint was the time to initial relief of symptoms, which was a median of 66 minutes (95% CI 61-122) with the higher dose, 122 (95% CI 72-136) minutes with the lower dose, and 495 (95% CI 245-520) minutes with placebo. At both doses, rhC1INH was well-tolerated. Side effects were uncommon and included headache, nausea, and diarrhea. A severe allergic reaction was reported during a phase I study in a normal volunteer with pre-existing rabbit allergy, hence the recommendation to screen patients for this. No postexposure antibody responses against the product have been detected .
In another randomized trial, 75 patients were treated with rhC1INH (50 international units/kg to a maximum of 4200 international units/treatment) or placebo . Median time to the beginning of symptom relief was 90 minutes (range 61 to 150 minutes) and 152 minutes (range 93 minutes to uncertain) in the groups receiving rhC1INH and placebo, respectively. Median time to minimal symptoms was 303 minutes in the rhC1INH group.
The possibility of serious arterial and venous thromboembolic events associated with off-label use of pdC1INH products has been reported in a specific non-HAE population, and because of that, such patients should be monitored during and after use . However, these complications were not seen in the randomized trials of Ruconest mentioned above [50,51].
Recombinant and plasma-derived C1INH have not been compared in head-to-head studies, and information about their relative risks and benefits is limited. A small series described the use of rhC1INH in patients with disease that was not fully responsive to pdC1INH and other therapies, with mixed results .
Bradykinin B2-receptor antagonist — Icatibant (Firazyr) is a synthetic bradykinin B2-receptor antagonist, which has been available in the European Union since 2008 and became available in the United States in 2011 (for patients 18 years of age and older) [54-56]. It is a synthetic polypeptide that is structurally analogous to bradykinin and acts by selectively and competitively antagonizing the bradykinin B2-receptor (figure 1). It is approved for treatment of acute attacks of angioedema in adults with C1INH deficiency.
Icatibant dose and administration — The dose of icatibant is 30 mg, given by slow subcutaneous injection/infusion because of the relatively large volume (3 mL) involved, preferably in the abdominal region . It can be self-administered.
Most patients require only one dose to treat symptoms adequately. However, if clinical response is inadequate, a second injection can be given after six hours, and a third injection can be given, if needed, after an additional six hours. A maximum of three doses within 24 hours is recommended.
Efficacy studies — The "For Angioedema Subcutaneous Treatment" (FAST-1 and FAST-2) trials were randomized, multicenter, phase III trials, in which 130 adults with C1INH deficiency were treated with icatibant for acute laryngeal, gastrointestinal, or cutaneous attacks of moderate-to-severe intensity . FAST-1 compared icatibant with placebo, and FAST-2 compared icatibant with oral tranexamic acid (TA). The primary endpoint was median time to onset of symptom relief. FAST-1 did not demonstrate a clear benefit of icatibant over placebo (2 hours versus 4.2 hours), but FAST-2 did (2 hours with icatibant versus 11 hours with TA). In a pooled analysis of the two trials, significantly more patients receiving icatibant had symptom relief within four hours compared with placebo or TA (73 versus 45 and 29 percent, respectively) . In addition, median time to near-complete symptom relief was significantly shorter with icatibant compared with placebo or TA (15, 21, and 36 hours, respectively).
In a third trial, FAST-3, 83 patients were randomly assigned to receive icatibant or placebo for moderate-to-severe attacks at any location . Icatibant significantly reduced median times to ≥50 percent reduction in symptom severity (2 versus 19.8 hours, primary endpoint), onset of primary symptom relief (1.5 versus 18.5 hours, secondary endpoint), or near-complete symptom relief (8 versus 36 hours) and provided a shorter time to initial symptom relief (0.8 versus 3.5 hours). For laryngeal attacks, median times to ≥50 percent reduction in symptom severity were 2.5 and 3.2 hours for icatibant and placebo, respectively. None of the patients receiving icatibant required rescue therapy before symptom relief occurred.
Adverse effects and precautions — Mild and transient pain at the injection site is the most common adverse reaction to icatibant. Other uncommon adverse effects include nausea, gastrointestinal colic, fever, asthenia, dizziness, increase in transaminases, and headache . Icatibant should be used with caution in patients with acute ischemic heart disease or unstable angina, since antagonism of the bradykinin B2-receptor can reduce coronary blood flow in animal models, and patients with these comorbidities were excluded from clinical trials .
Kallikrein inhibitor (United States only) — Ecallantide (Kalbitor, Dyax Corp) is a genetically-engineered recombinant plasma kallikrein inhibitor . This drug blocks the production of bradykinin by inhibiting plasma kallikrein (figure 1) [54,64-68]. Ecallantide was approved by the FDA in 2009 for the treatment of acute attacks of HAE in patients 12 years of age or older . It is only available in the United States .
Like pdC1INH, ecallantide is a first-line therapy for acute laryngeal angioedema (following airway protection) and for gastrointestinal attacks. It is occasionally used for severe cutaneous attacks. However, clinical experience with ecallantide is more limited.
Ecallantide should be administered by a clinician or a nurse equipped to manage anaphylaxis as well as severe angioedema related to HAE. Anaphylaxis and allergic reactions were reported in 2 to 3 percent of patients in clinical trials. (See 'Efficacy studies and safety' below.)
Ecallantide dosing and administration — Ecallantide is available in 1 mL vials of 10 mg each, and the adult dose is 30 mg. Injections should be given as three separate injections of 10 mg in the abdomen, upper arm, or thigh. The sites of injection should be anatomically distant from the area affected by the angioedema.
A second dose of 30 mg may be administered if symptoms persist. Based on limited information, the second dose could be given as early as 1 hour and up to 24 hours after the first dose.
Efficacy studies and safety — The efficacy of ecallantide was assessed in two randomized trials: EDEMA3  and EDEMA4 . In an analysis of the pooled data from these studies, 143 subjects were treated with either ecallantide or placebo . All types of attacks occurred (gastrointestinal, laryngeal, and cutaneous), with gastrointestinal attacks being the most common. Change from baseline mean symptom complex score (MSCS) at four hours after dosing was significantly greater in the ecallantide group compared with the placebo group (-0.97±0.78 and -0.47±0.71, respectively). The percentages of ecallantide- and placebo-treated patients with meaningful improvement at four hours were 70 and 38, respectively.
The leading safety issue is a risk of allergic reactions and anaphylaxis, which have been reported in 3 to 4 percent of patients receiving it subcutaneously in the clinical trials [70,71,73]. For this reason, ecallantide should be administered in a supervised setting by a medically-trained provider. Patients should be monitored carefully following administration, because some symptoms of anaphylaxis overlap with those of HAE (ie, angioedema, throat discomfort), and recognition of an allergic reaction may be challenging. In the available reports, anaphylaxis presented within one hour of administration as flushing, urticaria, pruritus, rhinitis, chest discomfort, pharyngeal or laryngeal edema, wheezing, and/or hypotension. Anaphylaxis has not been reported with the first dose when the drug is given subcutaneously. All episodes have responded to epinephrine and other appropriate treatments with no fatalities . Until more information is available, patients experiencing anaphylaxis or clear symptoms of hypersensitivity should not be given the drug again until evaluated by an allergy specialist. The mechanism responsible for these reactions has not been conclusively demonstrated, and the role of skin testing is not clear . However, some patients with hypersensitivity reactions have tolerated the drug upon graded challenge .
Cost of first-line therapies — All first-line therapies for acute attacks of HAE are costly. In the United States, the cost of one treatment with pdC1INH, ecallantide, or icatibant ranged from USD $5000 to 10,000 . In European countries, the cost of one treatment with pdC1INH, rhC1INH, or icatibant is about 1500 to 2000 euros.
PLASMA — Plasma is a second-line therapy in the treatment of acute laryngeal attacks and severe gastrointestinal attacks and should be used only if the therapies discussed above are not available. There have been no studies directly comparing plasma with C1 inhibitor (C1INH), ecallantide, or icatibant.
Plasma is available as solvent/detergent-treated plasma (S/D plasma) or fresh frozen plasma (FFP), and both are reported to be helpful. Guidelines recommend S/D plasma over FFP, when both are available, because S/D-treated plasma theoretically carries a lower risk of viral transmission compared with FFP. However, most of the case reports of HAE treatment used FFP. This is potentially relevant because S/D treatment removes some plasma components, and the effect on C1INH specifically has not been investigated. (See 'Effectiveness' below.)
Dosing — Two units of plasma are given initially. This dose can be repeated every two to four hours until there is clinical improvement. Once the attack begins to subside, further plasma is not usually required. If a patient has comorbid conditions that increase the risk for volume overload, then dosing of 10 to 15 mL per kg body weight is recommended instead, with monitoring of volume status and cardiopulmonary function .
Effectiveness — The efficacy of plasma in treating acute attacks has been suggested by case reports. No controlled trials have been performed [76-82]. The majority of reports used FFP because this was the leading therapy for acute attacks in the United States for many years. A review of the literature included 23 case reports in which FFP was used for treatment of acute attacks and revealed improvement in 22 cases . The time to first signs of improvement ranged from 30 minutes to 12 hours. No clinical improvement was noted in one case, and transient worsening of symptoms, followed by improvement, was reported in two cases. Plasma could theoretically exacerbate angioedema because it contains not only C1INH, but also substrate proteins (prekallikrein and high molecular weight kininogen) that could consume the available inhibitor and paradoxically worsen the angioedema, although this has been reported only rarely . Still, the clinician must monitor patients with airway angioedema carefully and be prepared to intubate if necessary.
Risks — The primary concern with plasma products is disease transmission, and the risks of this must be presented to the patient prior to each administration.
●Solvent/detergent treatment inactivates enveloped viruses (such as human immunodeficiency virus [HIV], human T lymphotropic virus [HTLV], and hepatitis B and C), but not prions or nonenveloped viruses (eg, hepatitis A, parvovirus).
●FFP does not undergo processing to remove infectious agents. However, it is obtained from single-donor units rather than pooled plasma, and each unit undergoes serologic testing for viral markers. The risk of infection for a unit of FFP is identical to that of whole blood, which is also obtained from single donors. This risk is summarized in the table and presented in more detail elsewhere (table 3). (See "Risk of HIV from blood transfusion" and "Epidemiology and transmission of hepatitis C virus infection".)
INEFFECTIVE THERAPIES — Therapies that are minimally effective or have no benefit at all in the treatment of acute angioedema in HAE include androgens, tranexamic acid (TA), and treatments for allergic (histaminergic) angioedema.
●Androgens and TA are therapies that prevent attacks of angioedema in HAE, but androgens have never been conclusively shown to be useful in acute treatment, and TA appears to be minimally effective . If first-line agents are not available, attacks are best managed with plasma products or supportive care. Preventative therapies for HAE are reviewed in detail elsewhere. (See "Hereditary angioedema: General care and long-term prophylaxis".)
●Epinephrine is effective in histaminergic (allergic) angioedema, but is not known to have any impact on the bradykinin-mediated angioedema of HAE. There are isolated case reports suggesting benefit from epinephrine in HAE attacks [85,86]. However, controlled studies would be needed to validate a true effect, since the angioedema of HAE resolves spontaneously with time.
●Glucocorticoids and antihistamines are NOT effective for angioedema associated with disorders of C1 inhibitor (C1INH) and should not be given once the diagnosis of a C1INH disorder has been made.
●A few studies have examined the effects of inhaled or injected heparin or heparin-like compounds in treating (and preventing) the symptoms of HAE attacks [87-89]. However, more data are needed before this therapy can be considered.
PREGNANT WOMEN — The preferred treatment of acute attacks of HAE in pregnant women is plasma-derived C1 inhibitor (pdC1INH), given at 20 units per kilogram, because there is extensive experience with the products that have been available in the European Union . Few data are available regarding the use of icatibant, ecallantide, or recombinant C1 inhibitor (rhC1INH) in this population.
CARE FOLLOWING ATTACKS — Following any acute attack, events leading up to the attack should be examined to determine if an identifiable trigger was present. Common triggers include the following :
●Regularly missing doses of prophylactic medication
●Running out of prophylactic medication
●Initiating interfering medications (such as estrogens or angiotensin-converting enzyme [ACE] inhibitors)
●Trauma, including iatrogenic interventions (dental work and other procedures)
●Physical exertion or fatigue
●Mental stress (although often not avoidable, some patients increase their prophylactic medications during stressful periods)
●Narcotic addiction (which can lead to increased complaints of abdominal pain)
Discussing common triggers with the patient directly after an event should help that individual avoid the same set of circumstances in the future. In addition, the clinician should review how and when the patient sought medical attention and whether the written plan of action was available and utilized. It has been the experience of the authors that such review sessions are consistently illuminating and critical to improving care.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary angioedema and other forms of nonhistaminergic angioedema".)
SUMMARY AND RECOMMENDATIONS
●Hereditary angioedema (HAE) is a condition characterized by recurrent episodes of angioedema affecting the upper airway, bowel wall, or skin, which typically last two to four days. The angioedema of HAE is mediated by bradykinin and does not respond to epinephrine, antihistamines, or glucocorticoids. Instead, first-line therapies for HAE act by replacing the C1 inhibitor (C1INH)that is deficient or dysfunctional in this disease or by inhibiting the production or function of bradykinin. (See 'Overview' above.)
●Because HAE is rare, clinicians in emergency settings may not be familiar with the disease or its treatment. Once the diagnosis has been established, it is helpful for patients to be equipped with a personalized form or wallet card containing information about the treatment of acute attacks, which can assist emergency providers (form 1 and form 2). In addition, call centers have been established in some countries to provide 24-hour access to HAE experts who can assist with emergency management. (See 'Equipping patients for emergency care' above.)
●First-line therapies for HAE and dosing of each agent are summarized in the table (table 1):
●More than 50 percent of all HAE patients experience a laryngeal attack at some point. The airway should be assessed immediately, because laryngeal swelling progress rapidly and can result in fatal asphyxiation. Those with respiratory distress or stridor may require intubation, because even the first-line therapies take approximately 30 minutes or more to begin working. An expert should manage the airway if possible. (See 'Laryngeal attacks' above and 'Airway management' above.)
●In areas of the world where first-line agents are available:
•For patients with a laryngeal attack of any severity, we recommend treatment with a first-line therapy (Grade 1A) (table 1). Choice of agent depends mainly upon availability, although pregnant women are preferentially treated with pdC1INH. (See 'Laryngeal attacks' above and 'Pregnant women' above.)
•For patients with moderate-to-severe gastrointestinal attacks or severe cutaneous attacks that will likely result in dysfunction or lost days from school or work, we suggest treatment with a first-line therapy (Grade 2B) (table 1). The choice of agent should be based upon availability. (See 'Gastrointestinal attacks' above and 'Cutaneous attacks' above.)
•Mild gastrointestinal attacks may be treated with symptomatic therapies and mild-to-moderate cutaneous attacks can be observed.
●If none of the first-line agents is available, then the approach to treatment depends upon the type and severity of attack:
•For patients with any laryngeal edema or moderate-to-severe gastrointestinal attacks, we suggest solvent-detergent (S/D)-treated plasma or, if not available, fresh frozen plasma (FFP) (Grade 2C) (table 1) (See 'Plasma' above.)
•For patients with cutaneous attacks not involving skin adjacent to the airway, we suggest no treatment (Grade 2C).
●After an acute attack, the events leading up to the attack should be reviewed to determine the factors that may have precipitated it. This evaluation is invaluable in helping patients and clinicians identify triggers that are important for that individual and devise strategies to avoid these triggers in the future. In addition, the clinician should review whether the patient was able to access care quickly and improve upon the care plan if necessary. (See 'Care following attacks' above.)
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