What is angioedema

Angioedema is swelling underneath the skin caused by fluid leakage from blood vessels into the surrounding skin and tissue. Angioedema is usually a reaction to a trigger, such as a medication or something you’re allergic to. Angioedemais most often characterized by a sudden or come on gradually over a few hours of short-lived swelling of the skin and mucous membranes. Swelling caused by angioedema normally lasts a few days. All parts of your body may be affected but swelling most often occurs around the eyes, lips, mouth, tongue, extremities, and genitalia. In severe cases the internal lining of the upper respiratory tract and intestines may also be affected causing breathing difficulties, tummy (abdominal) pain and dizziness. The swelling may be accompanied by a raised, itchy rash called hives (urticaria), which are more superficial, while angioedema affects the deeper layers of skin.

Angioedema isn’t normally serious, but it can be a recurring problem for some people and can very occasionally be life-threatening if it affects your breathing.

Treatment can usually help keep the swelling under control.

Figure 1. Angioedema eyes

Figure 2. Angioedema lips

Figure 3. Angioedema tongue

Angioedema symptoms

Symptoms and signs of angioedema may vary slightly between the different types of angioedema but in general the main symptom of angioedema is swelling that develops below the skin’s surface:

• Marked swelling, usually around the eyes and mouth (lips and tongue)
• Throat, tongue, hands, feet and/or genitals may be affected too
• Skin may appear normal, i.e. no hives or other rash
• Swellings may or may not be itchy
• Swellings may be painful, tender or burning
• In severe angioedema swelling of the throat and/or tongue may make it difficult to breath
• Swelling of the lining of the intestinal tracts may cause gastrointestinal pain and cramps

Many people also have a raised, itchy rash called urticaria (hives). The rash will usually settle in a few days. Otherwise, the skin over the swelling may feel tight and painful but look normal.

Less common symptoms of angioedema include:

• difficulty breathing
• red, irritated eyes (conjunctivitis)
• tummy (abdominal) pain
• feeling sick
• diarrhea
• dizziness
• fainting

Some features specific to the different types of angioedema are listed below.

What causes angioedema

There are several different types of angioedema, each of which has a different cause. Angioedema can be classified into at least four types, acute allergic angioedema, non-allergic drug reactions, idiopathic angioedema, hereditary angioedema and acquired C1 inhibitor deficiency.

Whatever the cause of angioedema, the actual mechanism behind the swelling is the same in all cases. Small blood vessels in the subcutaneous and/or submucosal tissues leak watery liquid through their walls and cause swelling. This same mechanism occurs in urticaria but just closer to the skin surface.

Allergic angioedema

Allergic angioedema is often the result of an allergic reaction.

This is where the body mistakes a harmless substance, such as a certain food, for something dangerous. It releases chemicals into the body to attack the substance, which cause the skin to swell.

Angioedema can be triggered by an allergic reaction to:

• certain types of food – particularly nuts, shellfish, milk and eggs
• some types of medication – including some antibiotics, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen
• insect bites and stings – particularly wasp and bee stings
• latex – a type of rubber used to make medical gloves, balloons and condoms

Drug-induced angioedema

Some medicines can cause angioedema – even if you’re not allergic to the medication.

The swelling may occur soon after you start taking a new medication, or possibly months or even years later.

Medications that can cause angioedema include:

• angiotensin-converting enzyme (ACE) inhibitors, such as enalapril, lisinopril, perindopril and ramipril, which are used to treat high blood pressure
• ibuprofen and other types of NSAID painkillers
• angiotensin-2 receptor blockers (ARBs), such as andesartan, irbesartan, losartan, valsartan and olmesartan – another medication used to treat high blood pressure

Hereditary angioedema

Rarely, angioedema occurs because of a genetic fault that you inherit from your parents. If you have hereditary angioedema, you have a 50% chance of passing it on to your children.

The fault affects the gene responsible for the production of a substance called C1 esterase inhibitor. If you don’t have enough of this, the immune system can occasionally “misfire” and cause angioedema.

Symptoms of hereditary angioedema typically begin in childhood and worsen during puberty. On average, untreated individuals have an attack every 1 to 2 weeks, and most episodes last for about 3 to 4 days. The frequency and duration of attacks vary greatly among people with hereditary angioedema, even among people in the same family.

There are three types of hereditary angioedema, called types I, II, and III, which can be distinguished by their underlying causes and levels of a protein called C1 inhibitor in the blood ¹. The different types have similar signs and symptoms. Type III was originally thought to occur only in women, but families with affected males have been identified.

Hereditary angioedema is estimated to affect 1 in 50,000 people. Type I is the most common, accounting for 85 percent of cases. Type II occurs in 15 percent of cases, and type III is very rare ¹.

Hereditary angioedema causes

Mutations in the SERPING1 gene cause hereditary angioedema type I and type II. The SERPING1 gene provides instructions for making the C1 inhibitor protein, which is important for controlling inflammation. C1 inhibitor blocks the activity of certain proteins that promote inflammation. Mutations that cause hereditary angioedema type I lead to reduced levels of C1 inhibitor in the blood, while mutations that cause type II result in the production of a C1 inhibitor that functions abnormally. Without the proper levels of functional C1 inhibitor, excessive amounts of a protein fragment (peptide) called bradykinin are generated. Bradykinin promotes inflammation by increasing the leakage of fluid through the walls of blood vessels into body tissues. Excessive accumulation of fluids in body tissues causes the episodes of swelling seen in individuals with hereditary angioedema type I and type II.

Mutations in the F12 gene are associated with some cases of hereditary angioedema type III. This gene provides instructions for making a protein called coagulation factor XII. In addition to playing a critical role in blood clotting (coagulation), factor XII is also an important stimulator of inflammation and is involved in the production of bradykinin. Certain mutations in the F12 gene result in the production of factor XII with increased activity. As a result, more bradykinin is generated and blood vessel walls become more leaky, which leads to episodes of swelling in people with hereditary angioedema type III.

The cause of other cases of hereditary angioedema type III remains unknown. Mutations in one or more as-yet unidentified genes may be responsible for the disorder in these cases.

Inheritance Pattern

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Hereditary angioedema symptoms

The swelling may happen randomly, or it may be triggered by:

• an injury or infection
• surgery and dental treatment
• stress
• pregnancy
• certain medications, such as the contraceptive pill

How often the swelling occurs can vary. Some people experience it every week, while in others it may occur less than once a year.

Idiopathic angioedema

Angioedema without a clear cause is known as idiopathic angioedema.

One theory is that an unknown problem with the immune system might cause it to occasionally misfire.

Certain triggers may lead to swelling, such as:

• anxiety or stress
• minor infections
• hot or cold temperatures
• strenuous exercise

In very rare cases, the swelling may be associated with other medical conditions, such as lupus or lymphoma (cancer of the lymphatic system).

Angioedema diagnosis

If you have experienced angioedema for the first time, your doctor will try to work out what may have caused it.

There are several different causes of angioedema. It’s important to know what’s causing your symptoms, as this affects the treatment you’ll need.

There’s no single test to determine the cause of angioedema. Some of the checks and tests you may have are outlined below.

A detailed medical history is invaluable in diagnosing angioedema.

• Keep a diary of exposure to possible irritants
• Tell your doctor about all medications you take, including over-the-counter (OTC) drugs and herbal remedies (even if taking them irregularly)
• Any family history of skin rash, allergies

Skin prick testing may be performed to try and identify any allergens. If hereditary angioedema is suspected, blood tests to check for levels and function of specific complement blood proteins may be done.

Allergy tests

If your doctor thinks your symptoms may have been caused by an allergy, they may refer you to a specialist allergy or immunology clinic for further testing.

Tests you may have include:

• a skin prick test – your skin is pricked with a tiny amount of the suspected allergen to see whether there’s a reaction
• a blood test – a sample of your blood is tested to determine whether your immune system reacts to a suspected allergen

Blood test

If your doctor thinks your symptoms may be caused by a genetic fault (hereditary angioedema) you’ve inherited from your parents, they may refer you for a blood test.

The test checks the level of a substance called C1 esterase inhibitor in your blood. This substance is important in regulating the immune system.

A very low level of C1 esterase inhibitor would suggest you have hereditary angioedema affecting how much of this substance your body is able to produce.

Angioedema treatment

The swelling will usually get better by itself in a few days, but there are treatments that can help it settle faster and reduce the risk of it happening again.

Treatment of angioedema depends on the severity of the condition. Angioedema can usually be treated at home, although severe cases may need to be treated in hospital. In cases where the respiratory tract is involved the first priority is to secure the airway. Patients may need emergency hospital care and require intubation (placement of a tube in the throat to keep the airway open).

Allergic and idiopathic angioedema

Allergic angioedema and idiopathic angioedema are usually treated in a similar way as acute urticaria.

In many cases the swelling is self-limiting and resolves spontaneously after a few hours or days. In more severe cases where there is persistent swelling, itchiness or pain the following medications may be used:

• Subcutaneous adrenaline (epinephrine)
• Oral or intravenous corticosteroids
• Oral or injected antihistamines

Antihistamines and steroid medication

Your doctor may suggest taking antihistamines to reduce swelling when it occurs.

Antihistamines work by blocking the effects of histamine, one of the chemicals responsible for the swelling. Some types can be bought in pharmacies and supermarkets without a prescription.

Some antihistamines can make you feel drowsy, so it’s best to take non-drowsy medications such as cetirizine and loratadine if your symptoms occur during the day.

Some antihistamines can make you feel drowsy. Avoid driving, drinking alcohol or operating dangerous machinery if you experience this.

Other side effects of antihistamines can include:

• headaches
• a dry mouth
• a dry nose

If the swelling is severe, your doctor may prescribe a short course of steroid medication. This is a powerful medication that’s only used for short periods because it can have troublesome side effects.

Adrenaline auto-injectors

If you have a particularly serious allergy, you may be given adrenaline auto-injectors to use if you experience a severe allergic reaction (anaphylaxis).

There are several types of auto-injector, which are used in slightly different ways.

Chronic angioedema with chronic autoimmune or chronic idiopathic urticaria

Chronic angioedema with chronic autoimmune or chronic idiopathic urticaria is often difficult to treat and response to medication variable. The following treatment steps are recommended. Each step is added to the previous one if inadequate response is obtained.

• Step 1: non-sedating antihistamines, eg, cetirizine
• Step 2: sedating antihistamines, e.g., diphenhydramine
• Step 3: a) oral corticosteroids, e.g., prednisone
  • b) immunosuppressants eg, ciclosporin or methotrexate

Omalizumab, an anti-IgE monoclonal antibody, has been reported to be effective in some refractory cases of angioedema.

The goal of treatment for chronic angioedema is to reduce itch, swelling, tenderness and pain to a tolerable level to maintain function (e.g, at work, school, and during sleep).

Avoiding triggers

The best way to prevent an allergic reaction is to avoid the substance that you’re allergic to, may help reduce your chances of experiencing swelling, although this isn’t always easy or practical.

For example, if you’re allergic to a certain type of food, it can help to check the ingredients in food you buy and be careful when eating out.

Below is some practical advice that should help you avoid the most common allergens.

Food allergies

By law, food manufacturers must clearly label any foods that contain something that’s known to cause allergic reactions in some people. By carefully checking the label for the list of ingredients, you should be able to avoid an allergic reaction.

People with food allergies most often experience an allergic reaction while eating out at a restaurant. You can avoid this by:

• not relying on the menu description alone (remember, many sauces or dressings could contain allergens)
• communicating clearly with the waiting staff and asking for their advice
• avoiding places where there’s a chance that different types of food could come into contact with each other, such as buffets or bakeries
• let restaurant staff you know your dietary requirements, including how severe your food allergy or intolerance is
• always check what allergens are in the dish even if you have eaten it before, as recipes and ingredients can change

Remember, simple dishes are less likely to contain “hidden” ingredients. If you’re not sure about a dish, don’t risk it

House dust mites

One of the biggest causes of allergies are dust mites, which are tiny insects found in household dust. You can limit the number of mites in your home by:

• choosing wood or hard vinyl floor coverings instead of a carpet
• fitting roller blinds that can be easily wiped clean
• choosing leather, plastic or vinyl furniture instead of upholstered furniture
• cleaning cushions, soft toys, curtains and upholstered furniture regularly, either by washing (at a high temperature) or vacuuming
• using tested allergy-proof covers on mattresses, duvets and pillows
• using a vacuum cleaner fitted with a HEPA (high efficiency particulate air) filter, because it can trap more dust mites than ordinary vacuum cleaners
• regularly wiping surfaces with a damp, clean cloth – avoid dry dusting, as this can spread dust into the air

Concentrate your efforts of controlling dust mites in the areas of your home where you spend the most time, such as the bedroom and living room.

Pets

It’s not the pet fur that causes an allergic reaction. Instead, it’s flakes of their dead skin, saliva and dried urine.

If you can’t permanently remove a pet from the house, you could try:

• keeping pets outside as much as possible, or limiting them to a particular area of the house, preferably an area without carpet
• not allowing pets in bedrooms
• washing pets at least once a week
• regularly grooming pets outside
• regularly washing all bedding and soft furnishings on which a pet has lain
• using an air filter in rooms where you spend most of your time
• increase ventilation with fans, air-conditioning or by opening windows

If you’re visiting a friend or relative with a pet, ask them not to dust or vacuum on the day you’re visiting, as this will stir up the allergens into the air. Taking an antihistamine medicine about an hour before entering a pet-inhabited house can also help reduce your symptoms.

Mould spores

Tiny particles released by molds can cause an allergic reaction in some people.

You can help prevent this by:

• keeping your home dry and well-ventilated
• removing any indoor pot plants from your home
• not drying clothes indoors, store clothes in damp cupboards or packing clothes too tightly in wardrobes
• dealing with any damp and condensation in your home
• avoiding damp buildings, damp woods and rotten leaves, cut grass and compost heaps

Hay fever

Pollen allergies – more commonly known as hay fever – are caused when trees and grasses release pollen into the air. Doctors often call hay fever allergic rhinitis.

Different plants pollinate at different times of the year, so the months that you get hay fever will depend on what sort of pollen(s) you are allergic to. Typically, people are affected during spring (trees) and summer (grasses).

To help keep your hay fever under control, you can:

• check weather reports for the pollen count and stay indoors when it’s high, if possible
• avoid drying clothes and bedding outside when the pollen count is high
• wear wraparound sunglasses to protect your eyes
• keep doors and windows shut when possible
• shower and change your clothes after being outside
• avoid grassy areas, such as parks and fields – particularly in the early morning, evening or night, when the pollen count is highest
• if you have a lawn, try asking someone else to cut the grass for you
• Insect bites and stings

If you’ve ever suffered a bad reaction to an insect bite or sting, it’s important to take precautions to minimize your risk.

When you’re outdoors, particularly in the summer, you could:

• cover exposed skin
• wear shoes
• apply insect repellent
• avoid wearing strong perfumes or fragrances, as these can attract insects

Preventing severe allergies (anaphylaxis)

If you’re at risk of experiencing a severe allergic reaction (anaphylaxis), make sure you carry two adrenaline auto-injectors with you everywhere.

Wearing a MedicAlert or Medi-Tag medallion or bracelet can make others aware of your allergy in an emergency.

Consider telling your teachers, work colleagues and friends, so they can give you your adrenaline injection in an emergency, while waiting for an ambulance.

There are three types of auto-injector – EpiPen, Jext and Emerade – that are each slightly different.

It’s important to remember the following:

• carry an auto-injector at all times (if you have two, carry them both) – there should be no exceptions; you may also be advised to get an emergency card or bracelet with full details of your allergy and doctor’s contact details to alert others
• extremes of heat can make adrenaline less effective – so don’t leave your auto-injector in the fridge or your car’s glove compartment, for example
  check the expiry date regularly – an out-of-date injector will offer limited protection
• manufacturers offer a reminder service, where you can be contacted near the expiry date – check the information leaflet that comes with your medicine for more information
• don’t delay injecting yourself if you think you may be experiencing anaphylaxis, even if your initial symptoms are mild – it’s better to use adrenaline early and then find out it was a false alarm than delay treatment until you’re sure you’re experiencing severe anaphylaxis

If your child has an auto-injector, they will need to change over to an adult dose once they reach 30kg (approximately 4.5 stone).

Hereditary angioedema treatment

Hereditary angioedema can’t be cured, but medications can help prevent and treat the swelling.

Preventing swelling

Medications called danazol and oxandrolone can help reduce the chances of swelling occurring if you have hereditary angioedema.

These medicines boost the levels of C1 esterase inhibitor in your blood. Low levels of this substance are what causes the swelling.

Side effects of these medications can include:

• weight gain
• in women, excessive body or facial hair growth, deepening of the voice, irregular periods or absent periods
• depression
• high blood pressure
• liver problems

A medication called tranexamic acid may sometimes be used as an alternative, particularly in children and women. This causes fewer side effects, but may not be as effective in preventing swelling.

Treating swelling

Acute episodes of hereditary angioedema do not respond to adrenaline, antihistamine and corticosteroids. Most acute episodes of Type I and II hereditary angioedema are non life-threatening.

Two main treatments can be used to treat swelling caused by hereditary angioedema:

• icatibant – a medication given by injection that blocks the effects of some of the chemicals responsible for the swelling
• C1 esterase inhibitor replacement – a treatment given by injection that boosts the levels of C1 esterase inhibitor in your blood

Occasionally, C1 esterase inhibitor replacement may also be used shortly before surgery or dental treatment, as it can reduce the risk of these triggering swelling.

You may be given a supply of medication to keep at home and be taught how to give the injections yourself.

• The mainstay of emergency medical treatment is intravenous C1 inhibitor concentrate (a blood product).
• If this is unavailable, fresh frozen plasma can be infused, but this occasionally exacerbates the angioedema.
• Icatibant, a synthetic peptidomimetic drug and bradykinin B2 receptor antagonist, can be used in emergencies for the symptomatic treatment of acute attacks of hereditary angioedema in adults with C1-esterase-inhibitor deficiency. It was approved by the FDA in 2011. In New Zealand, it is available for home use on Special Authority application.
• Ecallantide is a potent and selective human plasma kallikrein inhibitor that is also indicated for the symptomatic treatment of hereditary angioedema, approved for use by the FDA in 2009. It is a protease that is responsible for liberating bradykinin from its precursor kininogen. Ecallantide has been reported to cause anaphylaxis in 4% of cases and thus has a black box warning in the USA.

The chance of an attack can be reduced with the following medications:

• C1 inhibitor concentrate infused an hour before a surgical procedure
• Anabolic steroids (stanazolol, oxandrolone and danazol) to increase circulating levels of normal functional C1 inhibitor. These have ‘male-like’ hormonal activity, so may cause weight gain, menstrual irregularities and virilism.
• Tranexamic acid has been used in pre-pubertal children and may be effective in Type III hereditary angioedema.

Drug-induced angioedema

If a certain medication you’re taking is thought to be responsible for your angioedema, your doctor will usually advise stopping it.

They can prescribe a different medication for you to take instead.

This is usually all that needs to be done. Tell your doctor if your symptoms continue or come back after switching medication.

1. Hereditary angioedema. https://ghr.nlm.nih.gov/condition/hereditary-angioedema[↩][↩]