Angioedema

Angioedema is a self-limited, localized swelling of the dermis, subcutaneous tissues, and/or submucosal tissues caused by fluid leakage into the interstitial tissue. It is mediated by vasoactive substances and can be classified as histamine-mediated (often secondary to allergic reactions and NSAIDs), bradykinin-mediated (due to ACE inhibitor use or enzyme deficiencies), or unknown (idiopathic). Patients usually present with swelling of the eyelids, lips, and tongue. However, life-threatening laryngeal edema may occur, which requires immediate airway protection. Treatment generally consists of aggressive supportive care and avoidance of triggers, if applicable. In acute cases, histamine-mediated angioedema is treated with systemic glucocorticoids, antihistamines, and, if necessary, epinephrine for anaphylaxis. Bradykinin-mediated angioedema is treated with C1 inhibitor (C1-INH) concentrate, bradykinin-B₂-receptor antagonists, or kallikrein inhibitors.

Histamine-mediated angioedema (mast cell-mediated angioedema) ^[1][2]

• Direct mast cell activation
  • Non-IgE-mediated
  • Possible triggers: NSAIDs (most commonly aspirin) , opiates, radiocontrast media
• Allergic reactions
  • IgE-mediated
  • Possible triggers: food, insect bites/stings, antibiotics, latex, NSAIDs (less commonly), other allergens, physically-induced
  • Family history of atopy

Bradykinin-mediated angioedema ^[1][2]

• Hereditary angioedema (inherited C1 inhibitor deficiency )
  • Autosomal-dominant inheritance
  • Clinical manifestations in childhood or adolescence
  • Possible triggers: estrogen fluctuation (e.g., OCPs, hormone replacement, menstruation, ovulation, and pregnancy), infection (e.g., H. pylori), mental stress/fatigue, physical exertion, trauma, surgical and dental procedures, drugs (e.g., ACE inhibitors), and weather changes ^[3][4]
• Acquired angioedema: (acquired C1 inhibitor deficiency)
  • Presents in advanced or middle age (usually in or after the fourth decade of life)
  • Often associated with lymphoproliferative diseases and B-cell malignancies
• ACE inhibitor-induced (rarely ARB-induced): impaired bradykinin breakdown

Angioedema of unknown cause ^[1][2]

• Idiopathic angioedema
  • Recurrent episodes without known cause
  • Possible triggers: cold, heat, stress, and exercise
  • More commonly follows a histaminergic pattern
• Infections
  • More common in children
  • Possible triggers: common cold, streptococcal pharyngitis, urinary tract infections
• Drug-induced: calcium channel blockers, fibrinolytics, immunosuppressive agents (e.g., tacrolimus)

Common symptoms

• Facial edema (mouth, eyelids, tongue)
• Laryngeal involvement: dyspnea and inspiratory stridor; potentially life-threatening
• Possible swelling of extremities and urogenital area (e.g., hands, feet, scrotum)

Histamine-mediated angioedema

• Often associated with urticaria and pruritus
• Other associated with clinical findings of allergic reactions (see type 1 hypersensitivity reaction)
• Onset within 30 minutes to 2 hours of exposure and resolution over hours to days

Bradykinin-mediated angioedema

• Family history often present (hereditary angioedema)
• Abdominal symptoms : colicky abdominal pain, nausea/vomiting, diarrhea
• Angioedema of the extremities or trunk
• Not associated with urticaria or pruritus

References:^[5]

• Initial evaluation
  • The diagnosis is mainly based on history and clinical findings.
  • Flexible fiberoptic laryngoscopy should be performed if there is no clear obstruction but clinical suspicion of angioedema is high. ^[2]
• Further evaluation: indicated for follow-up or if the etiology is unclear ^[1][2]
  • Laboratory studies
    • Serum mast cell tryptase: increased in histamine-mediated angioedema
    • Evaluation of C1-INH deficiency in bradykinin-mediated angioedema (see table below)
  • Imaging: not routinely recommended
    • Neck x-ray or CT: may be used to rule out conditions that mimic angioedema, e.g., retropharyngeal abscess
    • Ultrasound or abdominal CT: may show bowel wall thickening

• Anaphylaxis is the most important differential diagnosis.

The differential diagnoses listed here are not exhaustive.

Emergency management ^[1][2][6]

• Evaluate for anaphylaxis: See anaphylaxis diagnostic criteria.
  • If there is concern for anaphylaxis:
    • Give IM epinephrine
    • Start aggressive supportive care (e.g., IV fluids, supplemental oxygen): See treatment of anaphylaxis for the full algorithm.
• Airway management
  • If airway compromise is present:
    • See airway management and ventilation in anaphylaxis.
    • Call anesthesia/otolaryngology for help.
    • Prepare for difficult airway with rescue devices and set up for surgical airway.
      • Awake fiberoptic intubation is preferred; RSI with paralytics should be avoided if possible.
      • A supraglottic airway (e.g., laryngeal mask) is not appropriate.
    • Only attempt unassisted intubation if the risk of death is imminent and there is no expert available.
• Stop any potential triggers: Remove potential exposures or offending medications (e.g., ACE inhibitors).

If airway compromise is suspected (stridor, wheezing, diminished air movement) or the patient is in shock, administer IM epinephrine immediately, start oxygen and IV fluids, and consider intubation to protect the airway. Once acute therapy has been initiated, the type and cause of angioedema should be determined.

Intubation is very risky in patients with angioedema and should only be performed by an expert. If there is no time for help, then preparation for the procedure must also include rescue devices and surgical airway equipment.

Case-based specific treatment ^[1][2]

• ABCs intact and no airway compromise: Proceed with histamine-mediated angioedema treatment.
• Poor response to repeated IM epinephrine administration: Consider bradykinin-mediated angioedema treatment.

Treatment of histamine-mediated angioedema and treatment of idiopathic angioedema

• Standard therapy
  • IV antihistamines: e.g., diphenhydramine
  • IV glucocorticoids: e.g., methylprednisolone
    • Positive response: Continue standard treatment.
    • Poor response: Consider bradykinin-mediated angioedema treatment.
• Idiopathic angioedema typically responds well to standard anaphylaxis treatment
• If the initial response to standard therapy is followed by progression to anaphylaxis : see treatment of anaphylaxis and acute management checklist for anaphylaxis.

Treatment of bradykinin-mediated angioedema and treatment of hereditary angioedema

• Administer one of the following targeted therapies:
  • Purified C1-INH concentrate (protein replacement)
    • Plasma-derived ^[1]
    • Recombinant
  • Kallikrein inhibitor: ecallantide
  • Bradykinin-B2 receptor antagonist: icatibant
• Second-line or suspected ACE inhibitor-induced etiology: fresh frozen plasma (FFP)

Epinephrine, glucocorticoids, and antihistamines are usually not effective in acute hereditary angioedema attacks! If these have been given empirically (e.g., for suspected anaphylaxis with airway compromise) and there is a poor response, then targeted therapy for bradykinin-mediated angioedema should be considered as the next step.

• Treat anaphylaxis if present at any time (see acute management checklist for anaphylaxis).
• Administer supplemental oxygen and perform basic airway maneuvers.
• Urgent anesthesia and/or ENT consult if the airway is compromised
• Prepare for a difficult airway and surgical airway as a backup.
• Administer case-based specific treatment.
  • If histamine-mediated angioedema is suspected or the etiology is unknown: Administer standard therapy with antihistamines and steroids.
  • If bradykinin-mediated angioedema is suspected: Administer targeted therapy with C1-INH protein replacement, ecallantide, or icatibant.
  • If an ACE inhibitor-induced etiology is suspected: Administer FFP.
• Remove potential exposures or offending medications (e.g., ACE inhibitors).
• Continuous telemetry and pulse oximetry (with or without capnography)
• ICU consult

General ^[2]

• Trigger avoidance (e.g., allergens, offending medications, environmental factors)
• Counseling on symptom recognition and instructions for when to return to the hospital
• Prespecified treatment action plans

Specific

• Hereditary angioedema ^[2][7]
  • Consider one of the following options for pharmacological prophylaxis:
    • Plasma-derived C1-INH concentrate: intravenous formulation OR subcutaneous formulation
    • Attenuated androgens: e.g., danazol
  • Follow-up with a hereditary angioedema specialist
• Histamine-mediated angioedema ^[2]
  • Epinephrine autoinjector for patients with anaphylaxis: prescription and directions for use
  • Follow-up with an allergist/immunologist for allergen immunotherapy as needed

1. Moellman JJ, Bernstein JA, Lindsell C, et al. A Consensus Parameter for the Evaluation and Management of Angioedema in the Emergency Department. Academic Emergency Medicine. 2014; 21 (4): p.469-484. doi: 10.1111/acem.12341 . | Open in Read by QxMD
2. Long B, Koyfman A, Gottlieb M. Evaluation and Management of Angioedema in the Emergency Department. Western Journal of Emergency Medicine. 2019; 20 (4): p.587-600. doi: 10.5811/westjem.2019.5.42650 . | Open in Read by QxMD
3. Zuraw B, Bingham CO III. An Overview of Angioedema: Clinical Features, Diagnosis, and Management. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/an-overview-of-angioedema-clinical-features-diagnosis-and-management.Last updated: July 21, 2015. Accessed: March 10, 2017.
4. Zotter Z, Csuka D, Szabó E, et al. The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency. Orphanet J Rare Dis. 2014; 9 (1): p.44. doi: 10.1186/1750-1172-9-44 . | Open in Read by QxMD
5. Banerji A, Riedl M. Managing the Female Patient with Hereditary Angioedema. Women's Health. 2016; 12 (3): p.351-361. doi: 10.2217/whe.16.6 . | Open in Read by QxMD
6. Craig T, Busse P, Gower RG, et al. Long-term prophylaxis therapy in patients with hereditary angioedema with C1 inhibitor deficiency. Annals of Allergy, Asthma & Immunology. 2018; 121 (6): p.673-679. doi: 10.1016/j.anai.2018.07.025 . | Open in Read by QxMD
7. Hahn J, Hoffmann TK, Bock B, Nordmann-Kleiner M, Trainotti S, Greve J. Angioedema - an interdisciplinary emergency. Dtsch Arztebl Int. 2017; 114 (29-30): p.489-496. doi: 10.3238/arztebl.2017.0489 . | Open in Read by QxMD
8. Herold G. Internal Medicine. Herold G ; 2014
9. Frank MM. Hereditary Angioedema. Hereditary Angioedema. New York, NY: WebMD. http://emedicine.medscape.com/article/135604-overview. Updated: July 27, 2016. Accessed: February 17, 2017.
10. Hereditary and Acquired Angioedema. http://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic,-autoimmune,-and-other-hypersensitivity-disorders/hereditary-and-acquired-angioedema. Updated: June 1, 2016. Accessed: February 17, 2017.
11. Cicardi M. Acquired C1 Inhibitor Deficiency: Clinical Manifestations, Epidemiology, Pathogenesis, and Diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/acquired-c1-inhibitor-deficiency-clinical-manifestations-epidemiology-pathogenesis-and-diagnosis.Last updated: August 29, 2016. Accessed: March 10, 2017.
12. Guyer AC, Banerji A. ACE Inhibitor-Induced Angioedema. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/ace-inhibitor-induced-angioedema.Last updated: June 4, 2015. Accessed: March 10, 2017.
13. Zuraw B, Bingham CO III. An Overview of Angioedema: Pathogenesis and Causes. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/an-overview-of-angioedema-pathogenesis-and-causes.Last updated: November 11, 2016. Accessed: March 10, 2017.
14. Li HH. Angioedema. In: Kaliner MA, Angioedema. New York, NY: WebMD. http://emedicine.medscape.com/article/135208. Updated: July 28, 2016. Accessed: March 10, 2017.
15. Cicardi M, Bruce Zuraw B, Saini S, Feldweg AM. Hereditary Angioedema: Treatment of Acute Attacks. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/hereditary-angioedema-treatment-of-acute-attacks.Last updated: August 29, 2016. Accessed: May 30, 2018.