Sections

Pediatric Angioedema

DDx

Diagnostic Considerations

A variety of other diagnostic possibilities should also be considered in children with possible angioedema.

For other discussions on angioedema, see the overview topics Acquired Angioedema and Hereditary Angioedema.

Cellulitis

Usually, this is caused by gram-positive bacterial infection. Pain and fever are common.

Erysipelas

This is caused by group A beta streptococci. Tenderness, fever, and redness are common.

Lymphedema

Chronic thickening of tissues occurs in lymphedema. This contrasts with the acute stretching of tissue observed in angioedema.

Collagen vascular disorders

Patients with systemic lupus erythematosus (SLE) or other collagen vascular disorders should have a history of systemic illness, indicating the presence of vasculitis. Laboratory findings reflect features of chronic inflammatory conditions.

Acute contact dermatitis

In acute contact dermatitis, the patient has a history of contact with sensitizing agents. The rash is always accompanied by intense pruritus.

Idiopathic scrotal edema in children

The etiology of this disorder is unknown, but swelling is limited to the scrotal area. Rarely, it causes systemic symptoms.

Rosenthal-Melkersson syndrome

In this rare neurologic disorder, recurrent facial edema, recurrent peripheral facial nerve palsy, and remarkable fissuring of the tongue are characteristic. Onset is in childhood or early adolescence.

Laryngeal swelling due to anaphylaxis

Most patients have a history of intense allergic diathesis. The anaphylaxis may be caused by ingestion of food, drugs, insect sting, or latex allergy. Idiopathic anaphylaxis, which is rare in children, may occasionally cause difficulty in the differential diagnosis.

Surgical abdomen

Severe pain caused by hereditary angioedema can be difficult to distinguish from conditions leading to surgical abdomen. The latter include intestinal obstruction and appendicitis. In addition, Crohn disease may cause chronic pain and diarrhea. History and physical examination should be helpful to distinguish those conditions with the aid of imaging studies.

Angioedema with eosinophilia

A total of 11 patients were reported from Japan. They were reported selectively in young females. The common features are angioedema with eosinophilia (eosinophil count of 7,839 +/- 6,008). Serum C-reactive protein and immunoglobulin E levels remained normal. They improved within 8 weeks, even without corticosteroid therapy.^[18]

Differential Diagnoses

Acute Urticaria
Cholinergic Urticaria
Chronic Urticaria
Contact Urticaria Syndrome
Cutaneous Manifestations of Cholesterol Embolism
Dermographism Urticaria
Pressure Urticaria
Solar Urticaria
Urticarial Vasculitis

Workup

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Patel NN, Patel DN. Hereditary angioedema with normal C1 inhibitor. Am J Med. 2008 Nov. 121(11):949-51. [QxMD MEDLINE Link].
Visy B, Fust G, Varga L, et al. Sex hormones in hereditary angioneurotic oedema. Clin Endocrinol (Oxf). 2004 Apr. 60(4):508-15. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol. 2010 Jul 28. 6(1):18. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link]. [Full Text].
Bork K. Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor. Allergy Asthma Clin Immunol. 2010 Jul 28. 6(1):15. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
Toklu Y, Sarac O, Berk S, Simsek S. Angioedema after intravitreal bevacizumab injection. Cutan Ocul Toxicol. 2012 Mar. 31(1):85-6. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Studdiford JS, Conniff KM, Trayes KP, Tully AS. Bedbug infestation. Am Fam Physician. 2012 Oct 1. 86(7):653-8. [QxMD MEDLINE Link].
Miller DG, Sweis RT, Toerne TS. Penile angioedema developing after 3 years of ACEI therapy. J Emerg Med. 2012 Aug. 43(2):273-5. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Busse PJ, Christiansen SC. Hereditary Angioedema. N Engl J Med. 2020 Mar 19. 382 (12):1136-1148. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Busse PJ, Christiansen SC, Riedl MA, Banerji A, Bernstein JA, Castaldo AJ, et al. US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema. J Allergy Clin Immunol Pract. 2021 Jan. 9 (1):132-150.e3. [QxMD MEDLINE Link]. [Full Text].
Epstein TG, Bernstein JA. Current and emerging management options for hereditary angioedema in the US. Drugs. 2008. 68(18):2561-73. [QxMD MEDLINE Link].
Longhurst H, Cicardi M, Craig T, Bork K, Grattan C, Baker J, et al. Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor. N Engl J Med. 2017 Mar 23. 376 (12):1131-1140. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link]. [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.
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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Media Gallery

The mechanism of angioedema resulting from C1-esterase inhibitor deficiency.
Angioedema secondary to ACE inhibitors

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Table 1. Drugs approved by FDA for routine prophylaxis of HAE attacks ^{[26, 27, 24, 25]}

Generic (Brand)	Population	Route	Mechanism
C1 inhibitor, plasma derived (Cinryze)	Aged 6 y and older	IV	Inhibits plasma kallikrein, coagulation factors Xlla, XIIf, and Xla, C1s, C1r, MASP-1, MASP-2, and plasmin
C1 inhibitor, plasma derived (Haegarda)	Aged 6 y and older	SC	Inhibits plasma kallikrein, coagulation factors Xlla, XIIf, and Xla, C1s, C1r, MASP-1, MASP-2, and plasmin
Lanadelumab (Takhzyro)	Adolescents and adults	SC	Kallikrein inhibitor
Berotralstat (Orladeyo)	Adolescents and adults	PO	Kallikrein inhibitor
Danazol	Adults and pediatrics (off-label)	PO	Androgen; mechanism unknown
Oxandrolone	Off-label	PO	Androgen; mechanism unknown
Methyltestosterone	Off-label	PO	Androgen; mechanism unknown
Aminocaproic acid (Amicar)	Off-label	PO	Inhibits plasminogen activation and plasmin activity
Tranexamic acid (Cyklokapron)	Off-label	PO	Inhibits plasminogen activation and plasmin activity

Table 2. Drugs approved by FDA for on-demand treatment of acute HAE attacks

Generic (Brand)	Population	Route	Mechanism
Ecallantide (Kalbitor)^{[28, 24, 25]}	Adolescents and adults	SC	Kallikrein inhibitor
Icatibant (Firazyr)^{[29, 30, 24, 25]}	Adults	SC	Bradykinin B2 antagonist
C1 inhibitor, recombinant (Ruconest)^{[31, 24, 25]}	Adolescents and adults	IV	Inhibits plasma kallikrein, coagulation factors Xlla, XIIf, and Xla, C1s, C1r, MASP-1, MASP-2, and plasmin
C1 inhibitor, plasma derived (Berinert)^{[32, 24, 25]}	Children and adults	IV	Inhibits plasma kallikrein, coagulation factors Xlla, XIIf, and Xla, C1s, C1r, MASP-1, MASP-2, and plasmin

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Pediatric Angioedema Differential Diagnoses

Diagnostic Considerations

Differential Diagnoses

References

Tables

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