Angioedema

Angioedema is the swelling of parts of the body; usually sudden but can occur over a long period of time. This can be triggered by allergic reactions and often affects the face, mouth, hands, feet and genitals. The most severe form of swelling will affect the throat/upper airways. This can be severe so early interventions and treatment are important.

Epidemiology

The WHO notes that angioedema and itchiness in response to allergies affect up to 20% of the US population. [1]
More than 40% of angioedema is idiopathic (caused by no obvious condition)
The rarest type of angioedema is hereditary angioedema with is caused by a genetic defect. Impacting 1 in every 50,000 people globally according to the Rare Diseases Advisor. [2]
Long-term idiopathic angioedema is more common in females than males
The NHS Inform site states that angioedema affects about 10-20% of people during their life. [3]

Source: DermNetNZ.org

Angioedema
Transient lip oedema due to angioedema

Source: DermNetNZ.org

Angioedema
Lip angioedema

Pathophysiology

Medical Student
- Can be split into 4 categories of angioedema; allergic, non-allergic, idiopathic and hereditary.
  - Allergic angioedema
    - Mast cell-mediated in more than 90% of cases with IgE-mediated reactions
    - This reaction is usually associated with urticaria and wheals.
    - Stimulants include allergens like dust, pollen, and certain foods [4,5]
  - Non-allergic angiodema
    - Caused by the angiotensin drug, ACE inhibitor (angiotensin-converting enzyme inhibitor). The incidence of drug-induced angioedema is rare.
    - ACE inhibitors increase the levels of bradykinin in the body as degradation is blocked. This causes drug-induced swelling as bradykinin increases vascular permeability and fluid extravasation. [6]
  - Idiopathic angioedema
    - Occurs without itchiness and wheals. The condition is chronic and has no identifiable cause. [4]
  - Heriditary angioedema
    - More than 150 genetic mutations in the C1 inhibitor gene on the 11th chromosome have been found to be associated with the condition.
    - 75% of the cases of hereditary angioedema follow an autosomal dominant pattern while 25% are caused by spontaneous genetic mutations [2]
Patients
- Can be split into 4 categories of angioedema; allergic, non-allergic, idiopathic (caused by no obvious condition) and hereditary (caused by a genetic defect).
  - Allergic angioedema
    - Controlled by cells that are triggered in allergic reactions.
    - This usually also causes itchiness, hives and redness.
    - Stimulants include factors like dust, pollen, and certain foods [4,5]
  - Non-allergic angiodema
    - Caused by a drug which is used to treat high blood pressure, heart diseases and heart failure called ACE inhibitors. This is rare.
    - ACE inhibitors increase the level of a substance that promotes blood vessel widening and fluid invasion. This causes swelling. [6]
  - Idiopathic angioedema
    - Occurs without itchiness and wheals. The condition is long-term and has no identifiable cause [4]
  - Heriditary angioedema
    - Caused by genetic mutations on a non-sex determining chromosome (a structure in the DNA storing part of the cell).
    - 75% of the cases of hereditary angioedema follow an autosomal (non-sex determining) pattern while 25% are caused by spontaneous genetic mutations [2]

Source: DermNetNZ.org

Angioedema
Lid angioedema

Source: DermNetNZ.org

Angioedema
Unilateral (one side) lid angioedema

Causes [3]

Allergens like dust, pollen
Certain foods such as shellfish, nuts, peanuts, eggs etc
Insect bites
Certain drugs such as ACE inhibitors, aspirin, penicillins
Genetics
Stress
Infections/ inflammation

Risk factors
- Older age
- ACE inhibitor use
- Cardiopulmonary disease history
- Smoking history
- History of hives or angioedema
- History of allergic reactions [7,8]
Presentations
- Asymmetric swelling
- Swelling of the upper airways/ throat can cause respiratory distress
- Stridor (high-pitched noise when breathing in) or wheeze (high-pitched noise when breathing out)
- Difficulty breathing
- Redness
- Itching
- Allergic angioedema can develop over minutes-hours
- Non-allergic angioedema can develop over hours- days (not associated with other symptoms of an allergic reaction)
- Gastrointestinal tract swelling can cause vomiting, abdominal pain and diarrhoea [4,9]

Source: Waikato District Health Board; DermNetNZ

Angioedema
Angioedema and facial urticaria (red rash)

Investigations [10]

Symptoms and medical history
Skin prick test- stimulate a reaction to different allergic substances by adding a drop of liquid to the skin and then piercing the skin. If a raised bump is seen, it is labelled an allergen.
Blood tests to check for the level of C1 inhibitor in the body. Low levels can indicate angioedema.
Genetic tests can search for mutations that reduce the level of C1 inhibitors
If these tests are inconclusive, idiopathic angioedema may be labelled as the cause of the symptoms.
If itchiness is not present and reoccurs without a clear cause or is present in family members, may consider hereditary angioedema.

Differential diagnosis
- Allergic contact dermatitis
- Connective tissue disease
- Endocrine disorders
- Parasitic disease (eg. insect bites)
- Tumor masses
- Drug hypersensitivity syndrome
- Anaphylaxis [11,12]

Source: DermNetNZ

Angioedema
Angioedema of the feet

Source: DermNetNZ

Angioedema
Angioedema of the right hand

Management [4]

Medical Students
- In emergency cases where the airways are swollen, securing an airway to make sure a stable flow of air is maintained.
  - Epinephrine or adrenaline can be given into-muscularly (in the muscle) or subcutaneously (under the skin) for cases of allergic angioedema. Treatment results in a rapid reduction of airway swelling.
  - Patients who have severe mast cell-mediated reactions should be advised to always carry a pre-filled, self-injecting syringe of epinephrine and oral antihistamines
- For allergic angioedema that involves mast cell mediation, symptoms can be relieved with:
  - The removal or avoidance of allergens
  - Histamine (H1) blockers (antihistamine)
  - Prednisolone for more severe reactions
  - Corticosteroids and antihistamines combinations given intravenously (IV)
- For non-allergic angioedema that involves bradykinin-mediated angioedema, symptoms can be relieved with:
  - Removal of ACE inhibitor usage that resolves about 24 to 48 hours after stopping the drug.
  - Endotracheal intubation is more likely to be needed in bradykinin-mediated angioedema. Treatment can result in a response time of over 30 minutes.
- For hereditary angioedema, treatment can include:
  - Fresh frozen plasma
  - C1 inhibitor concentrate
  - Ecallantide (which inhibits plasma kallikrein, required for the generation of bradykinin)
  - Icatibant (which blocks bradykinin)
- For idiopathic angioedema**:**
  - A high dose of a nonsedating oral antihistamine can be tried.
Patients
- In emergency cases where the airways are swollen, securing an airway to make sure a stable flow of air is maintained.
  - Epinephrine or adrenaline can be given into-muscularly (in the muscle) or subcutaneously (under the skin) for cases of allergic angioedema. Treatment results in a rapid reduction of airway swelling.
  - Patients who have severe allergic reactions should be advised to always carry a prefilled, self-injecting syringe of epinephrine and oral antihistamines
- For allergic angioedema that involves mast cell mediation, symptoms can be relieved with:
  - The removal or avoidance of allergens
  - Antihistamines (drugs used to relieve symptoms of allergies)
  - Prednisolone (a steroid) for more severe reactions
  - Corticosteroids and antihistamines combinations given intravenously (IV)
- For non-allergic angioedema, symptoms can be relieved with:
  - Removal of ACE inhibitor usage that resolves about 24 to 48 hours after stopping the drug.
  - Endotracheal intubation (tubes used to keep the airway open) is more likely to be needed in this type of angioedema. Treatment can result in a response time of over 30 minutes.
- For hereditary angioedema, treatment can include:
  - Fresh frozen plasma (a component of blood)
  - C1 inhibitor (protein) concentrate
  - Ecallantide (which stops a substance required for the generation of bradykinin)
  - Icatibant (which blocks bradykinin)
- For idiopathic angioedema
  - A high dose of an oral antihistamine

Source: DermNetNZ

Angioedema
Lip angioedema and urticaria

Source: American Academy of Allergy Asthma and Immunology

Angioedema
Lip angioedema

Complications [12]
- Tongue or throat swelling that can cause difficulty breathing
- Airway swelling, causing that can cause difficulty breathing

Myths behind Angiodema
- Angiodema is never dangerous
- Itching is always associated with angioedema
Questions you may want to ask your doctor
- How do I manage an episode of swelling?
- How did I know how severe my swelling episode is?
- What foods should I avoid with allergic angioedema?
- When should I call emergency services during an episode?
- Will I have to use alternative drugs if they trigger my swelling?
Support
- Hereditary Angioedema Association
- NHS inform
- nidirect.gov.uk