Pediatric Angioedema Clinical Presentation
- Author: Shih-Wen Huang, MD; Chief Editor: Harumi Jyonouchi, MD more...
Hereditary angioedema is characterized by episodic attacks that generally last 1-4 days. Attacks typically involve the extremities, the abdomen, or the throat.
The extremities are the most common site of attacks. Swelling is usually brawny and is not associated with urticaria, pruritus, or pain.
Abdominal attacks are due to edema in the submucosa and serosa of the bowel wall and are often associated with nausea, vomiting, and severe pain, but not with diarrhea. Abdominal pain may resemble that of acute abdomen.
Episodes involving the throat are the most dangerous manifestation of angioedema. Edema of the upper airway may progress rapidly and result in asphyxiation.
Angioedema episodes may occur spontaneously or may be triggered by trauma, particularly the injection of an anesthetic (eg, in dental procedures, during tooth extraction), or even emotional stress. Approximately one half of patients with hereditary angioedema have attacks precipitated by trauma; interestingly, the other half do not.
In hereditary angioedema, initial manifestations occur in children at a median age of 4.8 years (range, 3-9.7 y). Angioedema attacks occur by age 13 in most hereditary angioedema cases and may increase in severity after puberty. Attacks occur more often with sex hormone fluctuation, with more severe symptoms associated with menses.
Only 25% of patients provide a positive family history. However, patients may have a family history of abdominal pain and unexplained diarrhea or of sudden death from asphyxia. In the past, the mortality rate for attacks involving the upper airways exceeded 25%. Patients live with the constant threat of life-threatening laryngeal obstruction.
The acquired form of angioedema (AAE1 or AAE2) may present like classic hereditary angioedema, except for the age of onset. Usually, this type of angioedema occurs in the fourth decade of life or later. Because it is an acquired defect, a family history is negative for angioedema.
The idiopathic form of angioedema may cause swelling anywhere in or on the body and may be accompanied by urticaria (hives).
Swelling due to nonhistaminergic angioedema (INAE) may occur anywhere, including the face, arms, legs, genitalia, throat, and abdomen, although abdominal symptoms are far less common than in those with hereditary angioedema. Furthermore, symptoms do not change with menstrual period or pregnancy.
Allergic angioedema may cause swelling, most often in the face and throat. Urticaria (hives) is often present. If the condition persists longer than 6 weeks, it is considered chronic idiopathic urticaria and is not a classic allergic reaction.
In patients with ACE-inhibitor–induced angioedema, swelling may occur just about anywhere, including the throat, face, lips, tongue, hands, feet, genitalia, and intestines. Urticaria (hives) is very rare in this form of angioedema. A recent report describes a patient who used ACE-inhibitors for 3 years who suddenly developed penile angioedema.
Three cases of small bowel angioedema were reported after the patients were given intravenous iodinated contrast media. It is most evident in the venous phase of the CT images. None of the patients would require specific treatment.
If a patient has urticaria-related angioedema, lesions appear as large swellings with indistinct borders around the eyelids and lips. They may also appear on the face, trunk, genitalia, and extremities. The face, hands, and feet are involved in 85% of patients; other areas are involved in 15%. As many as 50% of children with urticaria exhibit angioedema with swelling of the hands and feet.
Patients with hereditary angioedema have associated repeated attacks of swelling of extremities, face, and throat accompanied by abdominal pain. Edematous swelling of the skin is not accompanied with itching but causes an unpleasant sensation of distension within the involved lesion.
A generalized, nonpruritic skin rash (erythema marginatum) may be observed in 8% of children prior to the onset of an angioedema attack.
Angioedema manifests as a diffuse brawny swelling of the extremities in 75% of patients, abdominal pain in 52%, and swelling of the face and throat in 30%. Patients do not have typical urticarial wheals but exhibit targetlike lesions. Abdominal pain eventually becomes a major symptom in 93% of patients. Severe airway edema accounts for the almost 30% mortality rate in untreated patients.
Angioedema associated with ACE inhibitors affects fewer than 5% of patients taking these drugs. Affected patients experience episodic swelling of the lip or face, or tissue swelling on any part of the body; it is not usually accompanied by pruritus or pain.
Evidence of impaired sense of smell in hereditary angioedema has been reported. Using 3-stages Sniffin'-Sticks kit, Perricone et al observed a significant decrease in olfactory function observed in patients with hereditary angioedema compared with controls, as measured by threshold, discrimination, and identification (TDI) scores. Anosmia was present only in hereditary angioedema patients (3.3%). In addition, reduction of olfactory function in these cases seems to correlate with complement C4 and CH50 levels. This suggests that immune and genetic mechanisms might play a role in this defect.
Agostoni A, Aygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004 Sep. 114(3 Suppl):S51-131. [Medline].
Patel NN, Patel DN. Hereditary angioedema with normal C1 inhibitor. Am J Med. 2008 Nov. 121(11):949-51. [Medline].
Visy B, Fust G, Varga L, et al. Sex hormones in hereditary angioneurotic oedema. Clin Endocrinol (Oxf). 2004 Apr. 60(4):508-15. [Medline].
Cichon S, Martin L, Hennies HC, Muller F, Van Driessche K, Karpushova A. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet. 2006 Dec. 79(6):1098-104. [Medline].
Prieto A, Tornero P, Rubio M, Fernandez-Cruz E, Rodriguez-Sainz C. Missense mutation Thr309Lys in the coagulation factor XII gene in a Spanish family with hereditary angioedema type III. Allergy. 2009 Feb. 64(2):284-6. [Medline].
Duan QL, Binkley K, Rouleau GA. Genetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema. J Allergy Clin Immunol. 2009 Jan 27. [Medline].
Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol. 2010 Jul 28. 6(1):18. [Medline]. [Full Text].
[Guideline] Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010 Jul 28. 6(1):24. [Medline]. [Full Text].
Bork K. Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor. Allergy Asthma Clin Immunol. 2010 Jul 28. 6(1):15. [Medline]. [Full Text].
Kumar A, Khamkar K, Gopal H. Serum sickness and severe angioedema following rituximab therapy in RA. Int J Rheum Dis. 2012 Feb. 15(1):e6-7. [Medline].
Toklu Y, Sarac O, Berk S, Simsek S. Angioedema after intravitreal bevacizumab injection. Cutan Ocul Toxicol. 2012 Mar. 31(1):85-6. [Medline].
Tukenmez Demirci G, Kivanc Altunay I, Atis G, Kucukunal A. Allergic contact dermatitis mimicking angioedema due to paraphenylendiamine hypersensitivity: a case report. Cutan Ocul Toxicol. 2012 Sep. 31(3):250-2. [Medline].
Studdiford JS, Conniff KM, Trayes KP, Tully AS. Bedbug infestation. Am Fam Physician. 2012 Oct 1. 86(7):653-8. [Medline].
Miller DG, Sweis RT, Toerne TS. Penile angioedema developing after 3 years of ACEI therapy. J Emerg Med. 2012 Aug. 43(2):273-5. [Medline].
Hu XH, Gong XY, Hu P. Transient small bowel angioedema due to intravenous iodinated contrast media. World J Gastroenterol. 2012 Mar 7. 18(9):999-1002. [Medline]. [Full Text].
Huang SW. Results of an on-line survey of patients with hereditary angioedema. Allergy Asthma Proc. 2004 Mar-Apr. 25(2):127-31. [Medline].
Perricone C, Agmon-Levin N, Shoenfeld N, de Carolis C, Guarino MD, Gigliucci G, et al. Evidence of impaired sense of smell in hereditary angioedema. Allergy. 2010 Jul 22. [Medline].
Nakachi S, Inokuma S. Eleven cases of angioedema with eosinophilia treated in a single hospital in Japan. Allergol Int. 2012 Jun. 61(2):259-63. [Medline].
Cugno M, Zanichelli A, Bellatorre AG, Griffini S, Cicardi M. Plasma biomarkers of acute attacks in patients with angioedema due to C1-inhibitor deficiency. Allergy. 2009 Feb. 64(2):254-7. [Medline].
Kusuma A, Relan A, Knulst AC, et al. Clinical impact of peripheral attacks in hereditary angioedema patients. Am J Med. 2012 Sep. 125(9):937.e17-24. [Medline].
Jung M, Rice L. "Surgical" abdomen in a patient with chronic lymphocytic leukemia: a case of acquired angioedema. J Gastrointest Surg. 2011 Dec. 15(12):2262-6. [Medline]. [Full Text].
Sánchez-Borges M, Asero R, Ansotegui IJ, et al. Diagnosis and Treatment of Urticaria and Angioedema: A Worldwide Perspective. World Allergy Organ J. 2012 Nov. 5(11):125-147. [Medline].
Jaiganesh T, Hughan C, Webster A, Bethune C. Hereditary angioedema: a survey of UK emergency departments and recommendations for management. Eur J Emerg Med. 2012 Aug. 19(4):271-4. [Medline].
Epstein TG, Bernstein JA. Current and emerging management options for hereditary angioedema in the US. Drugs. 2008. 68(18):2561-73. [Medline].
Reshef A, Leibovich I, Goren A. Hereditary angioedema: new hopes for an orphan disease. Isr Med Assoc J. 2008 Dec. 10(12):850-5. [Medline].
Bernstein JA, Ritchie B, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz DS, et al. Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2010 Aug. 105(2):149-54. [Medline].
Riedl MA, Bernstein JA, Li H, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014 Feb. 112(2):163-169.e1. [Medline].
Cicardi M et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. Aug 2010. 363:523-31.
Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):532-41. [Medline]. [Full Text].
Lumry WR, et al. Results from FAST-3: A phase III randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant in patients with acute hereditary angioedema (HAE) attacks. American Academy of Allergy, Asthma, & Immunology Meeting. March 22, 2011; Abstract L2.
Zuraw BL et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. Aug 2010. 363:513-22.
Birjmohun RS, Kees Hovingh G, Stroes ES, et al. Effects of short-term and long-term danazol treatment on lipoproteins, coagulation, and progression of atherosclerosis: two clinical trials in healthy volunteers and patients with hereditary angioedema. Clin Ther. 2008 Dec. 30(12):2314-23. [Medline].
Zanichelli A, Badini M, Nataloni I, Montano N, Cicardi M. Treatment of acquired angioedema with icatibant: a case report. Intern Emerg Med. 2010 Aug 3. [Medline].
Herrmann G, Schneider L, Krieg T. Efficacy of danazol treatment in a patient with the new variant of hereditary angio-oedema (HAE III). Br J Dermatol. 2004 Jan. 150(1):157-8. [Medline].
[Guideline] Grattan CE, Humphreys F. Guidelines for evaluation and management of urticaria in adults and children. Br J Dermatol. 2007 Dec. 157(6):1116-23. [Medline].
Morgan BP. Hereditary angioedema--therapies old and new. N Engl J Med. 2010 Aug 5. 363(6):581-3. [Medline].