16th February 2025

Anaphylaxis and angioedema

Overview of anaphylaxis

Anaphylaxis is a severe type I (IgE-mediated) hypersensitivity reaction. Excessive release of histamine from mast cells and basophils results in the following features:

• Angioedema – non-pitting swelling of deep tissues such as eyelids, lips, tongue and airway
• Skin changes – urticarial rash, flushing (absent in 20% of cases)
• Respiratory – bronchospasm, stridor
• Cardiovascular – distributive shock

The patient may also have reduced consciousness and arrhythmias, including supraventricular tachycardia.

The commonest medications to cause anaphylaxis are: antibiotics (particularly penicillins and cephalosporins), chemotherapy agents, contrast media, NSAIDs and neuromuscular blocking agents.

Management of anaphylaxis

Immediate management

The latest Resuscitation Council guidelines (2021) emphasise the importance of an A-to-E approach with early adrenaline administration and prioritising repeated use of adrenaline over the administration of other drugs. Adrenaline is usually given as 0.5 mg IM repeated up to every 5 minutes. Alternatively, it can be given in 50 mcg boluses IV in experienced hands.

Intravenous crystalloid fluid resuscitation should be aggressive, with fluid requirements sometimes being up to 5 litres.

Nebulised salbutamol and ipratropium can be given if there is wheeze present. Antihistamines may be used to treat cutaneous symptoms following initial resuscitation. The routine use of corticosteroids is no longer advised, though they may be used if asthma plays a role in the presentation or for refractory cases.

Refractory anaphylaxis

This is where there is ongoing cardiorespiratory compromise after two doses of IM adrenaline. The most important ongoing management is to administer further adrenaline, preferably by IV infusion. Other possible treatments include:

• Nebulised adrenaline (1 mg in 5 ml) for airway obstruction
• Tracheal intubation
• IV salbutamol or aminophylline for persistent bronchospasm
• Corticosteroids

Further management and follow up

Five percent of patients experience a biphasic anaphylaxis reaction and, as such,, patients should be observed for 6-12 hours following resolution of symptoms.

Serum mast cell tryptase should be measured in any patient where anaphylaxis is considered. Ideally, three samples should be taken: the first as soon as feasible, the second 1-2 hours after onset and the third 24 hours after complete resolution. A normal tryptase level does not exclude anaphylaxis.

All patients should be educated about the condition and given an adrenaline auto-injector, which comes in doses of 150-500 mcg. They should be referred to a specialist allergy clinic for skin prick testing and follow up.

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