16th February 2025

Non-anaphylactic angioedema

Presentation 

Non-anaphylactic angioedema, which is primarily thought to be mediated by bradykinin excess, is compared to anaphylaxis below: 

Table 1 Anaphylactic versus non-anaphylactic angioedema

Classification

To differentiate between causes of non-anaphylactic angioedema, complement studies may be helpful. The classification is as follows:

Medication-induced: most commonly due to ACE inhibitors or angiotensin-II receptor blockers; also gliptins, sirolimus, tacrolimus and alteplase.

Hereditary angioedema (HAE): typically presents before age 20, usually with a family history. In type 1 HAE, there is a low level of the C1-inhibitor protein, whereas in type 2 HAE, there is a normal C1-inhibitor level, but the protein has reduced function.

Acquired angioedema: typically presents after age 40. Anti-C1-inhibitor antibodies may be found in plasma, and C1q levels are typically low. It may be caused by lymphoproliferative disorders (MGUS, haematological malignancy) or auto-immune disease.

Idiopathic: no other cause is found, and complement studies are normal.

Management of acute attacks

For severe episodes of non-anaphylactic angioedema, two specific drugs exist: ecallantide and icatibant. Both of these are given by subcutaneous injection and take 2-4 hours to work. 

Replacement of C1-inhibitor may also be given, especially in the hereditary forms of the disease. This can be achieved by giving either C1-inhibitor concentrate or fresh frozen plasma (FFP).

References

• Chapman SJ, Robinson GV, Shrimanker R, Turnbull CD, Wrightson JM. Oxford handbook of respiratory medicine. 4th ed. London, England: Oxford University Press; 2021
• Campbell RL, Ellis AK. Differential diagnosis of anaphylaxis in adults and children [Internet]. Kelso JM, editor. UpToDate. 2022 [cited 2022 Dec 9]. Available from: https://www.uptodate.com/contents/differential-diagnosis-of-anaphylaxis-in-adults-and-children
• Campbell RL, Kelso JM. Anaphylaxis: Emergency treatment [Internet]. Walls RM, editor. UpToDate. 2022 [cited 2022 Dec 9]. Available from: https://www.uptodate.com/contents/anaphylaxis-emergency-treatment
• Guyer AC, Banerji A. ACE inhibitor-induced angioedema [Internet]. Saini S, editor. UpToDate. 2022 [cited 2022 Dec 9]. Available from: https://www.uptodate.com/contents/ace-inhibitor-induced-angioedema
• Zuraw B, Farkas H. Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis [Internet]. Saini S, editor. UpToDate. 2022 [cited 2022 Dec 9]. Available from: https://www.uptodate.com/contents/hereditary-angioedema-epidemiology-clinical-manifestations-exacerbating-factors-and-prognosis
• Zuraw B, Farkas H. Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis [Internet]. Saini S, editor. UpToDate. 2022 [cited 2022 Dec 9]. Available from: https://www.uptodate.com/contents/hereditary-angioedema-due-to-c1-inhibitor-deficiency-pathogenesis-and-diagnosis
• Emergency treatment of anaphylactic reactions: Guidelines for healthcare providers [Internet]. Resuscitation Council UK. [cited 2022 Dec 9]. Available from: https://www.resus.org.uk/library/additional-guidance/guidance-anaphylaxis/emergency-treatment