- HAE results from a deficiency in quantity or function of C1 inhibitor (C1-INH) due to a genetic defect
- A rare, autosomal-dominant disorder that manifests in early childhood
- Swelling in HAE results from excess bradykinin production, which is a potent vasodilatory mediator
- Histamine and other mast cell mediators are not directly involved
- HAE attacks are classified as laryngeal, cutaneous, or gastrointestinal
- Laryngeal attacks are the least common but most serious due to possible airway obstruction
- Treatment involves airway management, empiric treatment, and targeted treatments
- Empiric treatment with antihistamines (e.x. IV diphenhydramine and famotidine), corticosteroids (IV methylprednisolone, dexamethasone)
i. While antihistamines are generally ineffective it is recommended to still do a trial of these medications
- IM epinephrine recommended for anaphylaxis, severe laryngeal edema, or respiratory distress
- Targeted treatment by C1-INH replacement, Bradykinin B2 receptor blocker, plasma kallikrein inhibitor
|Medication||C1-INH Concentrates (Berinert, Cinryze)||Conestat alfa (Ruconest)||Icatibant (Firazyr)||Ecallantide (Kalbitor)||Fresh Frozen Plasma (FFP)|
|Dose||20 units/kg over 10 min||50 units/kg over 5 min (max 4,200 units)||30 mg slow (may repeat every 6 hours (max 90 mg/day)||30 mg (may repeat one time within 24 hours)||2 units|
|Mechanism||CI-INH replacement||CI-INH replacement||Bradykinin B2 receptor antagonist||Plasma kallikrein inhibitor||CI-INH replacement|
|Onset||30-60 minutes||90 minutes||120 minutes||30 minutes to 4 hrs||2 to 4 hours|
|Adverse Effects||Headache, skin rash, injection site reactions, thrombotic events||Headache, injection site reactions, thrombotic events||Injection site reactions, increased transaminases, fever||Headache, fatigue, nausea, diarrhea, skin rash||Volume overload|
|Drug Interactions||Androgens, estrogens, and progestins may enhance effect||Androgens, estrogens, and progestins may enhance effect||May reduce the antihypertensive effect of ACEinhibitors||No significant interactions||Transfusion-related reactions, thrombotic events, hypocalcemia|
|Comments||Must be warmed to room temp Preferred therapy for children and in pregnancy||Must be warmed to room temp Maximum of 4200 units in 24 hrs||Indicated in patients > 18 years of age Caution in ischemic heart disease||BBW: Anaphylaxis (must be administered by a medical professional)||Monitor for volume 2nd line to other C1-INH therapies|
|Price Tag $||~ $3,500 per 500 units||~ $7,100 per 2,100 units||~ $2,000-4,000 per 10 mg||~ $6,000 per 10 mg||~ $ 55 per unit|
Jlpruitt@gmh.edu For educational purposes only
|Overview of Evidence|
|Author, year||Design/ sample size||Intervention & Comparison||Outcome|
|2017 Li||Randomized, double-blind, placebo- controlled (n=43)||IV recombinant human C1-INH (rhC1-INH) 50 units/kg (max of 4,200 units) or placebo to patients with a severe HAE attack||RhC1-INH significantly reduced the time to onset symptom relief (90 min vs 334 min) and also required less rescue therapy|
|2017 Farkas||Multicenter, openlabel, nonrandomized (n=32)||Pediatric patients (< 18 years old) received subcutaneous icatibant (0.4 mg/kg, max 30 mg)||Icatibant was well tolerated, injection-site reactions with erythema and swelling were most common (90.6% of patients)|
|2014 Riedl||Randomized, placebocontrolled (n=75)||IV rhC1-INH 50 units/kg (max of 4,200 units) or placebo||RhC1-INH significantly reduced the time to onset symptom relief (90 min vs 152 min) with no differences in adverse events|
|2011 Lumry||Randomized, double-blind, placebocontrolled (n=93)||Subcutaneous icatibant 30 mg or placebo||Icatibant significantly reduced median times in symptom severity reduction, the onset of symptom relief, complete symptom relief No difference in the incidence of adverse events|
|2010 Cicardi||Two randomized, double-blind trials (n=56, n= 74)||Subcutaneous icatibant 30 or placebo Subcutaneous icatibant 30 mg or PO tranexamic acid 3 gm||Icatibant significantly reduced time to complete symptom resolution compared to placebo and tranexamic acid|
|2010Levy||Randomized, double-blind, placebocontrolled (n=96)||Subcutaneous ecallantide 30 mg or placebo||Ecallantide significantly mean symptom complex severity score at 4 hours and treatment outcome score throughout 24 hours|
|2010 Cicardi||Randomized, double-blind, placebocontrolled (n=72)||Subcutaneous ecallantide 30 mg or placebo||Improvement in patient-reported treatment scores No difference in time to significant improvement or adverse effects|
- There is a lack of response to antihistamines and corticosteroids in HAE due to the underlying pathophysiology of the disease o While there is no proven benefit it is still recommended to give these agents in case there is an underlying allergic reaction occurring
- FFP is inexpensive but not routinely used in clinical practice for HAE
- Berinert is the preferred therapy in children < 12 year of age and pregnancy
- Recombinant human C1-INH, Icatibant and Ecallantide have provided evidence of safety and efficacy in HAE
- Craig TJ, et al. J Allergy Clin Immunol 2009;124:801-8.
- Zuraw BL, et al. N Engl J Med 2010; 363:513-22.
- Li HH, et al. Allergy Asthma Proc 2017;38(6):456.
- Farlkas H, et al. J Allergy Clin Immunol Pract. 2017;5(6):1671.
- Riedl MA, et al. Ann Allergy Asthma Immunol. 2014;112(2):163-169.
- Lumry WR, et al. Ann Allergy Asthma Immunol. 2011;107:529-37.
- Cicardi M, et al. N Engl J Med. 2010;363:532-41.
- Prematta M, et al. Ann Allergy Asthma. 2007; 98:383-8.
- Levy RJ, et al. Ann Allergy Asthma Immunol. 2010; 104:523-9.