Introduction
- 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
Pharmacology | |||||
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 |
Administration | IV | IV | Subcutaneous | Subcutaneously | IV |
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 | |
Conclusions
- 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
References
- 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.