Clinical Reviews in Allergy & Immunology

, Volume 51, Issue 2, pp 162–169 | Cite as

Angioedema Phenotypes: Disease Expression and Classification

  • Maddalena Alessandra Wu
  • Francesca Perego
  • Andrea Zanichelli
  • Marco Cicardi
Article

Abstract

Due to marked heterogeneity of clinical presentations, comprehensive knowledge of angioedema phenotypes is crucial for correct diagnosis and choosing the appropriate therapeutic approach. One of the ways to a meaningful clinical distinction can be made between forms of angioedema occurring “with or without wheals.” Angioedema with wheals (rash) is a hallmark of urticaria, either acute or chronic, spontaneous or inducible. Angioedema without wheals may still be manifested in about 10 % of patients with urticaria, but it may also occur as a separate entity. Several classifications of angioedema as part of urticaria were published over time, while a latest one, released in 2014 (HAWK group consensus, see below), provided a classification of all forms of “angioedema without wheals” distinct from urticaria, which will be the focus of the present review. At this time, the HAWK consensus classification is the best in terms of covering the pathophysiology, mediators involved, angioedema triggers, and clinical expression. According to this classification, three types of hereditary angioedema (genetic C1-INH deficiency, normal C1-INH with factor XII mutations, and unknown origin) and four types of acquired angioedema (C1-INH deficiency, related to ACE inhibitors intake, idiopathic histaminergic, and idiopathic non-histaminergic) are presented. We will review the distinctive clinical features of each phenotype in details.

Keywords

Angioedema Classification Phenotypes Hereditary Acquired Wheals Urticaria 

References

  1. 1.
    Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT (2010) The humanistic burden of hereditary angioedema: impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc 31:407–14CrossRefPubMedGoogle Scholar
  2. 2.
    Quincke H (1882) Uber akutes umschriebened hautodem. Monatshe Prakt Dermatol 1:129–131Google Scholar
  3. 3.
    Osler W (1888) Hereditary angio-neurotic oedema. Am J Med Sci 95:362–367CrossRefGoogle Scholar
  4. 4.
    Vestergaard C, Deleuran M (2015) Chronic spontaneous urticaria: latest developments in aetiology, diagnosis and therapy. Ther Adv Chronic Dis 6:304–13CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW et al (2014) The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 69:868–87CrossRefPubMedGoogle Scholar
  6. 6.
    Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K et al (2014) Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy 69:602–16CrossRefPubMedGoogle Scholar
  7. 7.
    Zuraw BL, Bork K, Binkley KE, Banerji A, Christiansen SC, Castaldo A et al (2012) Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel. Allergy Asthma Proc 33(Suppl 1):S145–56CrossRefPubMedGoogle Scholar
  8. 8.
    Nussberger J, Cugno M, Cicardi M (2002) Bradykinin-mediated angioedema. N Engl J Med 347:621–2CrossRefPubMedGoogle Scholar
  9. 9.
    Cugno M, Nussberger J, Cicardi M, Agostoni A (2003) Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol 3:311–7CrossRefPubMedGoogle Scholar
  10. 10.
    Defendi F, Charignon D, Ghannam A, Baroso R, Csopaki F, Allegret-Cadet M et al (2013) Enzymatic assays for the diagnosis of bradykinin-dependent angioedema. PLoS One 8, e70140CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cicardi M, Bergamaschini L, Zingale LC, Gioffre D, Agostoni A (1999) Idiopathic nonhistaminergic angioedema. Am J Med 106:650–4CrossRefPubMedGoogle Scholar
  12. 12.
    Du-Thanh A, Raison-Peyron N, Drouet C, Guillot B (2010) Efficacy of tranexamic acid in sporadic idiopathic bradykinin angioedema. Allergy 65:793–5CrossRefPubMedGoogle Scholar
  13. 13.
    Del Corso I, Puxeddu I, Sardano E, Geraci S, Breggia M, Rocchi V et al (2012) Treatment of idiopathic nonhistaminergic angioedema with bradykinin B2 receptor antagonist icatibant. Ann Allergy Asthma Immunol 108:460–1CrossRefPubMedGoogle Scholar
  14. 14.
    Colas C, Montoiro R, Fraj J, Garces M, Cubero JL, Caballero T (2012) Nonhistaminergic idiopathic angioedema: clinical response to icatibant. J Investig Allergol Clin Immunol 22:520–1PubMedGoogle Scholar
  15. 15.
    Montinaro V, Loizzo G, Zito A, Castellano G, Gesualdo L (2013) Successful treatment of a facial attack of angioedema with icatibant in a patient with idiopathic angioedema. Am J Emerg Med 31(8):1295.e5–6. doi:10.1016/j.ajem.2013.04.024 CrossRefGoogle Scholar
  16. 16.
    Bas M, Greve J, Stelter K, Bier H, Stark T, Hoffmann TK et al (2010) Therapeutic efficacy of icatibant in angioedema induced by angiotensin-converting enzyme inhibitors: a case series. Ann Emerg Med 56:278–82CrossRefPubMedGoogle Scholar
  17. 17.
    Bova M, Guilarte M, Sala-Cunill A, Borrelli P, Rizzelli GM, Zanichelli A (2015) Treatment of ACEI-related angioedema with icatibant: a case series. Intern Emerg Med 10:345–50CrossRefPubMedGoogle Scholar
  18. 18.
    Bas M, Greve J, Stelter K, Havel M, Strassen U, Rotter N et al (2015) A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med 372:418–25CrossRefPubMedGoogle Scholar
  19. 19.
    Blanch A, Roche O, Urrutia I, Gamboa P, Fontan G, Lopez-Trascasa M (2006) First case of homozygous C1 inhibitor deficiency. J Allergy Clin Immunol 118:1330–5CrossRefPubMedGoogle Scholar
  20. 20.
    Lopez-Lera A, Favier B, de la Cruz RM, Garrido S, Drouet C, Lopez-Trascasa M (2010) A new case of homozygous C1-inhibitor deficiency suggests a role for Arg378 in the control of kinin pathway activation. J Allergy Clin Immunol 126:1307–10 e3CrossRefPubMedGoogle Scholar
  21. 21.
    Bafunno V, Divella C, Sessa F, Tiscia GL, Castellano G, Gesualdo L et al (2013) De novo homozygous mutation of the C1 inhibitor gene in a patient with hereditary angioedema. J Allergy Clin Immunol 132(3):748–750.e3. doi:10.1016/j.jaci.2013.04.006 CrossRefPubMedGoogle Scholar
  22. 22.
    Pappalardo E, Cicardi M, Duponchel C, Carugati A, Choquet S, Agostoni A et al (2000) Frequent de novo mutations and exon deletions in the C1 inhibitor gene of patients with angioedema. J Allergy Clin Immunol 106:1147–54CrossRefPubMedGoogle Scholar
  23. 23.
    Zanichelli A, Arcoleo F, Barca MP, Borrelli P, Bova M, Cancian M et al (2015) A nationwide survey of hereditary angioedema due to C1 inhibitor deficiency in Italy. Orphanet J Rare Dis 10:11CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bork K, Meng G, Staubach P, Hardt J (2006) Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 119:267–74CrossRefPubMedGoogle Scholar
  25. 25.
    Bors A, Csuka D, Varga L, Farkas H, Tordai A, Fust G et al (2013) Less severe clinical manifestations in patients with hereditary angioedema with missense C1INH gene mutations. J Allergy Clin Immunol 131(6):1708–11. doi:10.1016/j.jaci.2012.11.015 CrossRefPubMedGoogle Scholar
  26. 26.
    Xu YY, Zhi YX, Yin J, Wang LL, Wen LP, Gu JQ et al (2012) Mutational spectrum and geno-phenotype correlation in Chinese families with hereditary angioedema. Allergy 67:1430–6CrossRefPubMedGoogle Scholar
  27. 27.
    Bygum A, Fagerberg CR, Ponard D, Monnier N, Lunardi J, Drouet C (2011) Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency. Allergy 66:76–84CrossRefPubMedGoogle Scholar
  28. 28.
    Lopez-Lera A, Cabo FS, Garrido S, Dopazo A, Lopez-Trascasa M (2013) Disease-modifying factors in hereditary angioedema: an RNA expression-based screening. Orphanet J Rare Dis 8:77CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Speletas M, Szilagyi A, Psarros F, Moldovan D, Magerl M, Kompoti M et al (2015) Hereditary angioedema: molecular and clinical differences among European populations. J Allergy Clin Immunol 135:570–3CrossRefPubMedGoogle Scholar
  30. 30.
    Andrejevic S, Korosec P, Silar M, Kosnik M, Mijanovic R, Bonaci-Nikolic B et al (2015) Hereditary angioedema due to C1 inhibitor deficiency in Serbia: two novel mutations and evidence of genotype-phenotype association. PLoS One 10, e0142174CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Martinez‐Saguer I, Gutowski Z, Andritschke K, Csuka D, Kőhalmi KV, Varga L, Farkas H (2015) Inter individual variations in symptom expression and clinical course in monozygotic twins with hereditary angioedema type I. In: Abstracts of the 9th C1-inhibitor deficiency workshop, Budapest, Hungary, 28–31 May 2015. J Angioedema, p 55Google Scholar
  32. 32.
    Leibovich I, Golander H, Somech R, Reshef A (2015) The relationship between premonitory signs and symptoms (“prodromes”) and the onset of hereditary angioedema attacks. In: Abstracts of the 9th C1-inhibitor deficiency workshop, Budapest, Hungary, 28–31 May 2015. J Angioedema, p 61Google Scholar
  33. 33.
    Suffritti C, Zanichelli A, Maggioni L, Bonanni E, Cugno M, Cicardi M (2014) High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency. Clin Exp Allergy 44:1503–14CrossRefPubMedGoogle Scholar
  34. 34.
    Grumach AS, Veronez CL, Cagini N, Stieber C, Nicolicht P, Constantino‐Silva RN, Gonçalves RF, Cordeiro E, Komninakis S, Cichon S, Pesquero JB (2015) Hereditary angioedema without c1 inhibitor deficiency: evaluation of 21 families. In: Abstracts of the 9th C1-inhibitor deficiency workshop, Budapest, Hungary, 28–31 May 2015. J Angioedema, p 63Google Scholar
  35. 35.
    Bork K, Wulff K, Witzke G, Hardt J (2015) Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations. Allergy 70(8):1004–12. doi:10.1111/all.12648 CrossRefPubMedGoogle Scholar
  36. 36.
    Zingale LC, Castelli R, Zanichelli A, Cicardi M (2006) Acquired deficiency of the inhibitor of the first complement component: presentation, diagnosis, course, and conventional management. Immunol Allergy Clin N Am 26(4):669–90CrossRefGoogle Scholar
  37. 37.
    Cicardi M, Zanichelli A (2010) The acquired deficiency of C1-inhibitor: lymphoproliferation and angioedema. Curr Mol Med 10:354–60CrossRefPubMedGoogle Scholar
  38. 38.
    Bouillet-Claveyrolas L, Ponard D, Drouet C, Massot C (2003) Clinical and biological distinctions between type I and type II acquired angioedema. Am J Med 115:420–1CrossRefPubMedGoogle Scholar
  39. 39.
    Schreiber AD, Zweiman B, Atkins P, Goldwein F, Pietra G, Atkinson B et al (1976) Acquired angioedema with lymphoproliferative disorder: association of C1 inhibitor deficiency with cellular abnormality. Blood 48:567–80PubMedGoogle Scholar
  40. 40.
    Jackson J, Sim RB, Whelan A, Feighery C (1986) An IgG autoantibody which inactivates C1-inhibitor. Nature 323:722–4CrossRefPubMedGoogle Scholar
  41. 41.
    Castelli R, Deliliers DL, Zingale LC, Pogliani EM, Cicardi M (2007) Lymphoproliferative disease and acquired C1 inhibitor deficiency. Haematologica 92:716–8CrossRefPubMedGoogle Scholar
  42. 42.
    Wu MA, Castelli R (2016) The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity. Clin Chem Lab Med 54:207–14PubMedGoogle Scholar
  43. 43.
    Castelli R, Wu MA, Arquati M, Zanichelli A, Suffritti C, Rossi D et al (2016) High prevalence of splenic marginal zone lymphoma among patients with acquired C1 inhibitor deficiency. Br J Haematol. doi:10.1111/bjh.13908 Google Scholar
  44. 44.
    Alsenz J, Lambris JD, Bork K, Loos M (1989) Acquired C1 inhibitor (C1-INH) deficiency type II. Replacement therapy with C1-INH and analysis of patients’ C1-INH and anti-C1-INH autoantibodies. J Clin Invest 83:1794–9CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Burkhart DG, Brown NJ, Griffin MR, Ray WA, Hammerstrom T, Weiss S (1996) Angiotensin converting enzyme inhibitor-associated angioedema: higher risk in blacks than whites. Pharmacoepidemiol Drug Saf 5:149–54CrossRefPubMedGoogle Scholar
  46. 46.
    Brown NJ, Ray WA, Snowden M, Griffin MR (1996) Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther 60:8–13CrossRefPubMedGoogle Scholar
  47. 47.
    Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J et al (2005) Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med 165:1637–42CrossRefPubMedGoogle Scholar
  48. 48.
    Miller DR, Oliveria SA, Berlowitz DR, Fincke BG, Stang P, Lillienfeld DE (2008) Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors. Hypertension 51:1624–30CrossRefPubMedGoogle Scholar
  49. 49.
    Makani H, Messerli FH, Romero J, Wever-Pinzon O, Korniyenko A, Berrios RS et al (2012) Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am J Cardiol 110:383–91CrossRefPubMedGoogle Scholar
  50. 50.
    Agostoni A, Cicardi M, Cugno M, Zingale LC, Gioffre D, Nussberger J (1999) Angioedema due to angiotensin-converting enzyme inhibitors. Immunopharmacology 44:21–5CrossRefPubMedGoogle Scholar
  51. 51.
    Campo P, Fernandez TD, Canto G, Mayorga C (2013) Angioedema induced by angiotensin-converting enzyme inhibitors. Curr Opin Allergy Clin Immunol 13:337–44CrossRefPubMedGoogle Scholar
  52. 52.
    Beltrami L, Zanichelli A, Zingale L, Vacchini R, Carugo S, Cicardi M (2011) Long-term follow-up of 111 patients with angiotensin-converting enzyme inhibitor-related angioedema. J Hypertens 29:2273–7CrossRefPubMedGoogle Scholar
  53. 53.
    Slater EE, Merrill DD, Guess HA, Roylance PJ, Cooper WD, Inman WH et al (1988) Clinical profile of angioedema associated with angiotensin converting- enzyme inhibition. JAMA 260:967–70CrossRefPubMedGoogle Scholar
  54. 54.
    Dean DE, Schultz DL, Powers RH (2001) Asphyxia due to angiotensin converting enzyme (ACE) inhibitor mediated angioedema of the tongue during the treatment of hypertensive heart disease. J Forensic Sci 46:1239–43CrossRefPubMedGoogle Scholar
  55. 55.
    Dobbels P, Van Overbeke L, Vanbeckevoort D, Hiele M (2009) Acute abdomen due to intestinal angioedema induced by ACE inhibitors: not so rare? Acta Gastroenterol Belg 72:455–7PubMedGoogle Scholar
  56. 56.
    Benson BC, Smith C, Laczek JT (2013) Angiotensin converting enzyme inhibitor-induced gastrointestinal angioedema: a case series and literature review. J Clin Gastroenterol 47(10):844–9. doi:10.1097/MCG.0b013e318299c69d CrossRefPubMedGoogle Scholar
  57. 57.
    Mansi M, Zanichelli A, Coerezza A, Suffritti C, Wu MA, Vacchini R et al (2015) Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients. J Intern Med 277:585–93CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Maddalena Alessandra Wu
    • 1
  • Francesca Perego
    • 1
  • Andrea Zanichelli
    • 1
  • Marco Cicardi
    • 1
  1. 1.Department of Biomedical and Clinical Sciences “Luigi Sacco”University of Milan, Luigi Sacco HospitalMilanItaly

Personalised recommendations