Topics Raised by EMEA Member Organizations

This article is part of an extensive feature on the 2023 HAEi Regional Conference EMEA, published in Global Perspectives #2 2023

Members of the Scientific Committee presented on key topics of interest as identified by the EMEA region Member Organizations.

Diagnosing HAE – with and without labs by Associate Professor Jonny Peter

A/Prof. Peter outlined two main take-home themes from his talk. The first diagnosis saves lives. The second is that some basic biology can be really helpful for diagnosis.

In some countries, laboratory and genetic-based diagnosis is not readily available. A/Prof. Peter indicated that taking a good history and getting some clues can give you confidence that a person is unlikely to have HAE, saving time and money.

He showed the audience that only a tiny proportion of all angioedema patients coming to the emergency room have HAE. Where no laboratory test is available, clinical clues can be very helpful. One of these is time to resolution. An HAE attack generally takes longer to resolve than other types of angioedema.

If you take a careful history, you can see how it runs in families. The presence or absence of urticaria (that is hives or wheals on the skin), even a historical presence, is indicative.

Other medicines a person might have taken (such as ACE inhibitors and non-steroidal anti-inflammatory drugs) can trigger angioedema. Symptoms like wheezing, what A/Prof. Peter called ‘clinical clues’ can be informative and point away from an HAE diagnosis.

The value of C1 and C4 testing was stressed. If you have a normal C4 but are having an attack, it’s unlikely you have C1-inhibitor HAE. You may have another form, but the ‘common’ ones are excluded.

Moving beyond the simpler lab tests, A/Prof. Peter made clear that there can be problems in handling samples, some of which need to be kept frozen. Keeping samples frozen is even harder when tests need to be done in other countries due to a lack of capacity in one country.

Genetic testing should be accompanied by genetic counseling for those affected, A/Prof. Peter told the audience. ‘You need to understand the implications for your children and others in your family.’

A/Prof. Peter stressed the importance of clinical clues to make a presumptive diagnosis that can then be treated. If the treatment works, then, of course, the diagnosis can be confirmed.

His take-home message for the audience was: ‘Be an advocate for yourself. Look for clinical clues and get as familiar as you can with testing and diagnosis’.

Accessing medications (androgens, FFP, modern therapies) by Dr. Iman Nasr

Dr. Iman Nasr is from Oman. This country, she indicated, was the only one in the world, to begin with the letter ‘O’.

Dr. Nasr made clear that she understood there is sensitivity in her topic, but for many people across the world, there isn’t yet the access we would want to modern therapies. What then should be the treatment for these cases of HAE, she asked. In the long run, modern therapies must be the goal. However, she gave some guidance on treatment without modern therapies.

Dr. Nasr discussed the use of:

• Attenuated androgens (danazol, stanozolol)
• Antifibrinolytics (tranexamic acid)
• Fresh Frozen Plasma (FFP)
• Solvent/detergent plasma (SDP) – which is plasma processed with solvents to remove viruses

In the treatment of acute attacks, Dr. Nasr recommended SDP and FFP (if SDP not available).

For short-term prophylaxis, the recommended treatment depended on the scale of the surgical procedure. For minor manipulation, Dr. Nasr described the use of attenuated androgens and SDP/FFP. Tranexamic acid was not recommended by experts, but it may be preferable for children. By contrast, for major manipulation, Dr. Nasr presented that attenuated androgens plus SDP/FFP was preferred.

Specific recommendations for the use of attenuated androgens and antifibrinolytics in long-term prophylaxis, include routine monitoring for dose and outcomes.

In conclusion, Dr. Nasr made clear:

• Modern therapies are not available in many countries
• Other therapies exist, but efficacy, risks and side effects need to be kept in mind
• Treatment options, especially long-term prophylaxis, should be individualized in collaboration with the patient
• A treatment plan for patients with frequent attacks is necessary, as obtaining SDP/FFP can take time
• Understanding triggers for HAE attacks can help decide when short-term prophylaxis is needed

These medications, Dr. Nasr said: ‘I would love to think of them as a transition until modern medications become available’.

Medical emergencies – laryngeal attacks, how do they feel and what should you do by Dr. Fotis Psarros

Dr. Psarros told the audience that laryngeal attacks are a crucial medical emergency. Dr. Psarros described laryngeal attacks as rare, representing 1-4% of all attacks. However, he made clear that at least half of HAE patients will experience a laryngeal attack at least once in their lifetime. He also stressed that episodes can occur in children, the risk of misdiagnosis is high, and that suffocation can happen quickly due to the smaller airway.

Looking at factors linked to laryngeal attacks, Dr. Psarros highlighted intubation during general anesthesia, upper airway infections, mechanical trauma, ACE inhibitor drugs, and smoking.

Dr. Psarros clarified some of the most common symptoms of a laryngeal attack (in chronological order):

• Sensation of a lump in the throat
• Voice changes
• Cough dyspnea
• Fear of asphyxiation
• Inability to breathe, speak or cough

Dr. Psarros also described that patients may also use a near-universal sign of holding their throat between the thumb and index finger.

The importance of recognizing early symptoms, according to Dr. Psarros, is that it allows for attacks to be treated as early as possible, as time is of the essence. The later we treat, the more severe the attack.

If you suspect a laryngeal attack, please go immediately to the emergency department, Dr. Psarros stressed. A key reason for this is the ability to maintain a patient’s airway and save a patient’s life.

Summing up, Dr. Psarros said: ‘Patients must be informed and trained to recognize the main clinical symptoms. Always, always carry sufficient medicine as prescribed by your doctor. After a laryngeal attack, discuss with your doctor the possibility of long-term prophylaxis.’

HAE in women, children, pregnancy, family testing by Prof. Henriette Farkas

Professor Henriette Farkas is one of the co-chairs of the Scientific Committee for this meeting and a world-leading HAE expert.

Prof. Farkas told the audience that pregnancy and having a baby are wonderful things, and she always encourages her HAE patients to have children. However, she stated that these patients require special care. Changes in estrogen hormone levels during pregnancy can affect HAE.

Prof Farkas highlighted rare occasions where HAE is diagnosed during pregnancy but counseled care as C1-inhibitor level can decrease during pregnancy.

Speaking to birth control, Prof Farkas mentioned that contraception containing progestin is recommended and may lead to improved HAE. If you hope to become pregnant, Prof Farkas recommended stopping any attenuated androgens as these may cause harm to the unborn baby.

For treatment, Prof Farkas made clear that plasma-derived C1-inhibitor is the recommended first-line treatment during pregnancy and while breast-feeding, with limited data on other common treatments. Plasma-derived C1-inhibitor should also be available during complicated deliveries such as caesarians; and is also first line for long-term prophylaxis. Novel targeted therapies are available, but the data on the use of these in these patients is limited.

When considering children with HAE, Professor Farkas asked everyone to remember that children are not simply small adults. In half of cases, symptoms appear in childhood, most commonly between 10-12 years old. The frequency of symptoms can increase during adolescence. How children describe illness may also complicate diagnosis, such as ‘tummy ache’, which may be an indicator of an abdominal attack.

Prof Farkas recommended that teachers should be told about HAE as children may struggle to explain symptoms. Teachers and pediatricians can be given information and a treatment plan for self-administration.

When diagnosing children, genetic testing and C1/C4 inhibitor testing are used. Genetic testing can use a fingerprick of blood or from the umbilical cord. If HAE is known in the family, then genetic testing is the method she uses, as C1 and C4 inhibitor levels can be low under the age of one. C1/C4 inhibitor testing should therefore be repeated after one year.

In terms of treatment of attacks, three drugs are approved: plasma-derived C1-inhibitor, icatibant, and recombinant human C1-inhibitor. For short- and long-term prophylaxis, plasma-derived C1-inhibitor is recommended, although short-term prophylaxis is less frequently needed as children rarely undergo surgical procedures. Other long-term prophylaxis drugs available for children are available but may be limited in access in some countries, and also minimum ages.

In conclusion, Prof Farkas made clear that HAE patients may have a successful pregnancy, and children with HAE can live happy lives.

Taking part in clinical trials – what’s in it for patients? by Professor Vesna Grivcheva-Panovska

In the final requested talk, Prof. Vesna Grivcheva-Panovska was asked to speak on what she described as a subject very close to her heart, why should a patient take part in clinical trials.

She told the audience that clinical trials are the backbone of medical progress. They provide a structured way to evaluate new treatments, interventions and medical devices. Participants in clinical trials contribute directly to the advancement of medical science and the development of better therapies for their conditions. Prof. Grivcheva-Panovska explained that whenever a patient takes part in a trial, they are not just adding to the greater good but also helping themselves and their families.

Prof. Grivcheva-Panovska highlighted the following common questions asked about trials:

Safety

• Is the new treatment safe?
• What are the potential risks

Efficacy

• What are the benefits compared to what I’m already using?
• Why should I go into uncharted territory?

Unknowns

• What are the potential side effects?
• How would a clinical trial impact my daily life?

Ethics

• Is it ethical to participate?
• Will I be treated fairly?

Prof. Grivcheva-Panovska made clear that you should feel comfortable to ask and have all your questions answered before agreeing or not agreeing to take part. One important aspect to answer is: What’s in it for me? What’s in it for patients?

Often, clinical trials are the gateway to new treatments. You can expect expert care and close monitoring from a specialized medical team. For many people, the chance to contribute or give back to the HAE community is also an incentive to take part. People can often find their connection with their community can be strengthened by taking part and feel a sense of greater empowerment.

Ultimately, Prof. Grivcheva-Panovska stressed this is about the possibility of better outcomes. She invited people to consider some of the recent advances in cancer care and how glad those initial patients felt to be on a trial that ultimately kept them alive.

Prof. Grivcheva-Panovska made clear that it is important to learn as much as you can before taking part, and information will be available from your doctor and team, who will be able to answer your questions. Another source of impartial advice is HAEi, which provides updates on available trials. You can also research clinical trials on databases such as ClinicalTrials.org or clinicaltrialsregister.eu.

Summing up, Prof. Grivcheva-Panovska told the audience that clinical trials are a significant opportunity for patients to actively engage in their healthcare journey and also to help countless others in the future. Finally, she said: ‘Clinical trials have the potential to shape the future of the world. Please stay informed, stay engaged, and together we can make a difference.’