Clinical Management of HAE

Clinical management of HAE is complex and includes avoiding potential triggers, short-term prophylaxis for exposure to known triggers, long-term prophylaxis for frequent attacks, and management of acute attacks.

• Treatment of acute attacks of HAE, which are dependent on the location of the attack
• Short-term prophylaxis for exposure to known triggers, such as dental procedures, surgeries, or childbirth, which are dependent upon the severity of the trigger (e.g., minor vs. major surgery)
• Long-term prophylaxis for patients with life-threatening, frequent, or life-altering attacks

Consider the severity of the disease. Frequent attacks involving the extremities or trunk are not as concerning as life-threatening attacks involving the airway or abdomen. Long-term prophylaxis may be necessary only for the latter group of patients. Patients who experience more than one episode of severe abdominal pain in a year or any head or neck swelling, may require prophylactic treatment that is maintained more than once a year (Gompels, et al. 2005).

Acute Attacks
Recommended emergency care for acute attacks currently includes the use of complement-1 esterase inhibitor protein (C1-INH) concentrates, where available. Fresh-frozen plasma (FFP), an increase in androgen dosing, or the use of antifibrinolytic medications, such as tranexamic acid or epsilon-aminocaproic acid (EACA), may be administered, where C1-INH is not available.

European guidelines base the C1-INH dosage amount on the location of the attack, with higher dosing for life-threatening laryngeal attacks. By contrast, the Canadian Algorithm calls for C1-INH dosing based on the patient’s body weight.

According to the European Consensus, symptoms should begin to resolve within 30 to 90 minutes with the use of C1-INH. If symptoms have not abated within two hours, the European Consensus recommends an additional dose of C1-INH concentrate and consideration of an alternative diagnosis.

The use of fresh frozen plasma (FFP) in HAE attacks can be helpful. In rare instances, however, FFP has been known to have unpredictable adverse effects and can even exacerbate attacks.

The risks of transmitting infection can be potentially high, since FFP is not pasteurized. This is in contrast to plasma products, which are pathogen-reduced using one or more steps to minimize potential transmission.

Treatment should be initiated as soon as possible in abdominal attacks to avoid pain and disruption of the patient's life. Pain medications may also be helpful during abdominal attacks.

Likewise, treatment of laryngeal attacks should be initiated as soon as there is evidence of such an attack (dysphagia, hoarse voice). At times, intubation or tracheotomy may be necessary for laryngeal attacks.

According to the European Consensus, the use of epinephrine may help treat the angioedema and hypovolemia of type I HAE, while the Canadian Algorithm notes that the early use of adrenaline may or may not be effective.

For attacks of the extremities, the Canadian Algorithm recommends a wait-and-see approach toward treatment, while the European Consensus recommends treatment of extremity or trunk attacks dependent on the patient. Where C1-INH is not available, the European Consensus notes that attenuated androgens, such as stanazolol or danazol, may be useful in such attacks. However, it should be noted that these medications increase production of C1-INH in the liver and may result in undesirable side effects:

• Virilization, including hair loss and male pattern baldness
• Prostatic hypertrophy and prostatic carcinoma
• Premature bone fusion in children leading to stunted growth
• Gynecomastia
• Voice changes
• Hepatic adenomas, hepatocellular carcinoma, and peliosis hepatis
• Aggravate cardiovascular disease by lowering levels of high-density lipoproteins (HDLs)

At times, some of these effects are irreversible.

Other androgens can be used in adult males. Six-month liver function tests, annual lipid profile, and biennial hepatic ultrasound are recommended follow-up for these patients (Gompels, et al. 2005).

Pain management, IV fluids, and supportive care may also be useful in acute attacks.

Short-term Prophylaxis
Short-term prophylaxis is generally limited to patients under unusual circumstances, particularly those about to undergo a surgical or dental procedure. Short-term prophylactic therapy may include C1 inhibitor concentrate (where available), attenuated androgens, or tranexamic acid. C1-INH infusions can be given 24 hours before the procedure or just prior to it. If antifibrinolytics or androgens are used, they are typically administered 5 days before the procedure and continued for 2 days afterward.

The Canadian guidelines differentiate short-term treatment based on whether a procedure is a mild manipulation, such as minor dental work, or a more major procedure, such as intubation or surgery.

The Europeans distinguish short-term therapy as first- or second-line treatment for all procedures.

Long-Term Prophylaxis
Prophylactic administration of antifibrinolytic agents (tranexamic acid or EACA) and/or synthetic attenuated androgens (danazol or stanazolol), has proved useful in reducing the frequency or severity of attacks.

Other androgens can be used in adult males (Gompels, et al. 2005). Note however that long-term use of danazol or stanazolol may result in virilization and arterial hypertension. Six-month liver function tests, annual lipid profile, and biennial hepatic ultrasound are recommended follow-up for these patients.

Alpha-alkylated androgens may also be used for prophylaxis at low dosage levels. Antifibrinolytic agents, such as epsilon-aminocaproic acid or tranexamic acid, can be used, though they have not been found to be as effective as the androgenic agents.

For patients with minor peripheral episodes, a milder approach to the level of treatment can be undertaken, such as a course of tranexamic acid before attenuated androgens.

Additional considerations in the treatment of patients with HAE include:

• Laryngeal edema: Depending on the symptoms and the sites of the angioedema, intensive support may be necessary, including the issuance of intravenous fluids. In cases of serious laryngeal edema causing respiratory obstruction, intubation or tracheotomy is appropriate.
• Monitoring of "trigger" medications: Because various medications, such as oral contraceptives, hormone replacement therapy, and ACE inhibitors, can contribute to the onset of attacks, medication history and selection should be carefully reviewed when treating patients with HAE attacks.
• Dental or surgical procedures: As mentioned above, short-term prophylaxis should be considered for patients scheduled to undergo a dental or surgical procedure.
• Pregnancy: During pregnancy, women are treated for pain relief (as needed). The European Consensus advises against the use of attenuated androgens during pregnancy and recommends that all prophylaxis be stopped prior to conception. The Consensus does allow the cautious use of tranexamic acid, if needed. C1-INH is recommended for the treatment of severe attacks, as prophylaxis prior to delivery, and in the delivery suite.
  The Canadian Algorithm concurs that long-term prophylaxis with androgens is contraindicated during pregnancy and lactation. However, it does allow for the short-term prophylactic use of danazol during the third trimester of pregnancy.  
• Hpylori infection: In a 1999 case report, eradication of H pylori infection in a patient with recurrent, acute HAE attacks, which were unresponsive to 800 mg of danazol daily, resulted in no further acute attacks and permitted a decrease in the daily maintenance dose of danazol to 400 mg (Nzeako, et al. 2001; Rais, et al. 1999).
  Those HAE patients infected with H pylori are more often symptomatic than those who are not infected. Eradication of H pylori or another infectious agent can help resolve symptoms (Heymann, 2006).

Note: Clinical research trials are currently underway for several new therapies, including recombinant human C1-INH, recombinant kallikrein inhibitor (DX-88), and bradykinin-2 receptor antagonist (Icatibant) and transgenic C1-INH (Rhucin).

Viral Safety of C1-Inhibitor Concentrate and Fresh Frozen Plasma
C1-inhibitor concentrate for C1-INH replacement is available in Canada and several European countries and is being studied in other countries, including the United States. Because this is a plasma-derived product, viral safety is a concern to all patients as well as the members of the patient care continuum. Several studies have confirmed the safety of multiple viral inactivation and reduction steps in the production of a C1-inhibitor concentrate, and no transmission of the human immunodeficiency virus, HCV or hepatitis G virus (HGV), has been observed in these studies (Kunschak M, et al. 1998) or in clinical usage of C1-INH.

Fresh-frozen plasma (FFP) is frequently used for HAE attacks due to the lack of other available approved treatments. The effectiveness of FFP has been sporadic, but it may be effective in the treatment of acute attacks and in short-term prophylaxis. However, use of FFP carries significant risks, including transfusion-related acute lung injury ([TRALI] 1 in 8000 with 10% fatalities), transfusion-associated circulatory overload ([TACO] 1 in 100-1000), and allergic-urticarial reactions (common and usually non-life threatening manifesting as localized erythema, hives, and pruritus and not usually accompanied by fever or any other severe symptoms). FFP also has an incidence of urticarial reactions of 1% to 3%. So while FFP is used for attacks when C1-INH is unavailable, it should not be considered acceptable as prophylactic treatment or where emergency treatment is foreseeable.

For more information about diagnosis and treatment of HAE see: