Hereditary Angioedema: Rare but potentially deadly if not diagnosed correctly

However, lack of awareness and understanding among healthcare professionals and a lack of common indicators often result in HAE being confused with other angioedema-linked conditions such as an allergic reaction, resulting in unnecessary suffering, medical procedures and even death.

In a bid to raise awareness among healthcare professionals and members of the public, the Allergy and Immunology Unit at Groote Schuur Hospital and the UCT Lung Institute recently launched two landmark initiatives – the first virtual angioedema centre in Africa, and a 24/7 Angioedema Hotline offering information and advice to assist with diagnosis, treatment and management. In addition, they have started with a training programme for emergency medicine specialists, ER24 staff and ambulance drivers as HAE patients often present at the emergency room when having a severe attack. Sufferers are also advised to wear Medic Alert bracelets.

Driving these initiatives is Prof Jonny Peter, head of the Division Allergology and Clinical Immunology at Groote Schuur, UCT.

According to him, HAE appears to be greatly underdiagnosed in SA.

“With our population, we would expect about 2 000 cases across South Africa. Currently, we only have around 125 people on the HAE registry with no cases recorded in some provinces. That probably means that many HAE cases are being missed in South Africa with the angioedema presentations being incorrectly attributed to other causes than genetics,” says Prof Peter.

It’s in the family

An audit recently conducted in emergency rooms across the Cape Town Metro showed that on average, four patients with angioedema present at these units per week. While most cases are drug-related such as an allergy to anti-hypertensive drugs, genetic testing of some of these patients have identified at least two new HAE cases a year. Discovery of a new cases is often very rewarding when it leads to diagnosis in several members of the family.

Acute attacks are difficult to predict, and triggers vary from person to person. These triggers can include hormone fluctuations in women, stress, anxiety, having an operation or a dental procedure, some drugs such as ACE inhibitors, and even minor trauma such as a light bump on a hand or a leg.

Potentially fatal

Because most attacks are not life-threatening, only presenting with uncomfortable swelling of a limb that will subside without treatment in two to four days, patients often don’t seek medical attention until they have a serious episode. This could involve the gastrointestinal tract leading to abdominal pain and swelling, and in extreme cases, swelling of the larynx that can cause asphyxiation and death if medical assistance is not urgently accessed.

“One of the dangers is that you can have an attack the first time when you are 40 and unfortunately if the attack affects the larynx, it could be fatal,” Prof Peter warns.

In a study conducted in Brazil 1 433 people with HAE and 75 fatal events were evaluated. Only 10 of the 75 people who died of asphyxiation caused by an attack were given a diagnosis of HAE before their death.

While not much is known about the mortality rate in South Africa, Prof Peter says he is aware of around three deaths in the Atlantis area in Cape Town, one in Johannesburg, and one in the Eastern Cape where patients developed laryngeal swelling and failed to access care and treatment in time.

“The Johannesburg patient was diagnosed with HAE but didn’t seek treatment because she never had bad swellings. She developed swelling of the airway while driving to the airport and died six hours later.”

Attacks involving the gastrointestinal tract are the most challenging as these patients are often misdiagnosed as having other gastrointestinal disorders such as irritable bowel syndrome, appendicitis, pancreatitis and cholecystitis. These patients often endure years of unnecessary pain and even surgical procedures before they are eventually diagnosed with HAE, Prof Peter remarks.

According to him, all patients presenting with recurrent swellings at doctors’ rooms or health facilities should be tested for HAE.

“This is often difficult because affected patients presenting at emergency rooms are rarely seen by the same doctor. Because there is a lack of awareness about the condition, we always try to educate emergency doctors to ask about family history and recurrent swellings,” Prof Peter says, adding that more education, media attention and advocacy are needed to improve diagnosis across the country and in other African countries.

Diagnosis of HAE is confirmed if levels of complement C4 and C1 inhibitor are low and can be established with a quick, cheap blood test. Prof Peter stresses that it is vital to also test other family members once a new patient is diagnosed.

Advances in treatment

The availability of effective, targeted treatments has increased dramatically in the past 20 years and include therapies to manage acute attacks as well long-term prophylaxis to minimise the frequency and severity of attacks. Short-term prophylaxis that can be taken before a medical or dental procedure. In South Africa, the South African Health Products Regulatory Authority’s (SAHPRA) approval of the bradykinin B2-receptor antagonist, icatibant, in November last year is regarded as a major development in improving treatment for HAE in the country.

Given as a subcutaneous injection, icatibant is a B2-receptor antagonist that blocks the effect of bradykinin, the peptide that is responsible for the swelling. It has an onset of 60- 90 minutes, and it lasts for 6-7 hours.

Prof Peter stresses that treatment of HAE is completely different from allergy and that it should be a red flag to doctors to suspect HAE if treatment with antihistamines or adrenalin fails to work.

For more information about HAE testing, treatment and management or to get urgent assistance, phone the 24-hour Angioedema hotline 082 091 5684 or visit the virtual “Sinovuyo” Virtual Angioedema Centre at  https://aiu.haei.org/

Frequently Asked Questions

What is HAE and are there different types?

Hereditary Angioedema (HAE) is a rare genetic disorder characterised by recurrent, painful episodes of swelling of the skin or mucous membranes.  It can affect various body parts, including the hands, feet, face, abdomen (gastrointestinal tract), and larynx. The commonest kind is caused by a gene-defect in the C- 1-gene which leads to C1 inhibitor deficiency or dysfunction. The condition has an autosomal dominant inheritance pattern, meaning it will be found in every generation. It occurs equally between men and women and affects all race groups. In 20% of cases, it is caused by de novo mutations which will then be passed on to family members.

What are the main symptoms and at what age do they start presenting?

Symptoms can present at any age. Physical signs include swelling of the skin and mucous membranes affecting the face, hands, arms and legs, the gastrointestinal tract and the upper airway (larynx) and tongue.

What should trigger suspicion that it is not an allergy when a patient presents at a practitioner?

If the swelling is not accompanied by hives (urticaria), does not respond to treatment with antihistamines or corticosteroids, the patient has a history of recurrent swellings, and there is a family history of HAE, there should be a strong suspicion that it is Hereditary Angioedema and NOT an allergy.

How do you test for HAE?

There are three types of HAE which can be confirmed with quick and cheap blood tests that measure complement C-4 levels. These levels will always be low during an attack. If they are NOT low, there is a 99% certainty that it is not HAE. Family history is an important indicator and if HAE is established, family members must also undergo genetic testing.

What are the treatments for HAE?

Treatment involves managing acute attacks, and long-term prophylaxis to prevent or minimize the frequency and severity of attacks. Short-term prophylaxis should be taken before any medical procedure. The aim of acute treatment is to stop the progression of the oedema and relieve symptoms, particularly when the attack affects the larynx, face, tongue or gastrointestinal tract.

Treatment for acute attacks include:

• Icatibant, a bradykinin-2 receptor blocker, is the most convenient treatment that is now available in South Africa. It is a subcutaneous injection that can be self-administered and works within 60-90 minutes.
• Intravenous infusion of fresh or freeze-dried plasma (FFP) or recombinant C1-INH to replace the deficient C1-enzyme that is responsible for the swelling.  FFP is a cheap, effective and easily accessible option that has a 4–6-hour onset action. Most patients only need one unit of FFP.

Short and long-term prophylaxis

• Attenuated androgens (danazol) are beneficial especially for people with frequent and severe attacks. However, side-effects such as headache, depression and menstrual irregularities should be monitored.
• Oral kallikrein inhibitor (Berotralstat) that inhibits plasma kallikrein can reduce the frequency and severity of attacks.
• The antifibrinolytic drug tranexamic acid is used in some countries as prophylaxis but is not effective in all patients.

What is the prognosis of HAE?

If diagnosed, treated, and managed correctly, the prognosis is excellent. Prior to the development of the current available therapies, the mortality rate was 20-30%. Misdiagnosed and mismanaged, HAE can be fatal if the oedema affects the airway which could lead to asphyxiation.  Gastrointestinal attacks can lead to severe pain and even unnecessary surgery if not correctly diagnosed and treated.

Who do doctors refer to in South Africa if they suspect HAE?

There are allergists across the country that doctors can refer to. They can also contact the South African Angioedema Hotline 082 091 5684 or visit the Sinovuyo Angioedema support centre at Groote Schuur Hospital  https://aiu.haei.org/;  or https://haei.org/hae/faq/ or www.haei.org/southafrica. 

People can also contact the HAE support group, HAE South
Africa through Janice Strydom at at haeadvocacysa@gmail.com or call
her at 083 309 3569.