Report from the 2nd MHH Patient Seminar „Alpha-1 Antitrypsin Deficiency“ at Hannover Medical School on August 24, 2024
At the beginning, Professor Dr. Sabina Janciauskiene from the Department of Pneumology and Infectious Diseases at Hannover Medical School (MHH), as scientific director of the event, and Marion Wilkens, board member of Alpha1-Deutschland e.V., welcomed the large number of guests. They also immediately expressed their gratitude to those who supported and made the event possible: Dr. Annegret Zurawski, clinic manager at MHH, for organizing and conducting the event; Inga Kwapniewska from the German Center for Lung Research (DZL) at MHH for her organizational support; the sponsors Grifols, CSL Behring, and Takeda for their financial support; and Linde for providing the oxygen.
The first presentation was given by Dr. Isabell Pink on the topic of "Bronchiectasis in AATD." Bronchiectasis refers to the widening and dilation of the bronchi, the airways between the trachea and the alveoli. Since AATD itself is a rare disease, its contribution to the overall incidence of bronchiectasis plays only a minor role, as can be seen from analyses of the corresponding European Bronchiectasis Registry EMBARC. However, studies based on the European Alpha-1 Registry EARCO have shown that a large proportion of individuals with the PI*ZZ variant of AATD exhibit bronchiectasis, usually in addition to pulmonary emphysema (27% of all Alphas have both).
Treatment for bronchiectasis initially focuses on the underlying condition, such as asthma or COPD, primarily with inhaled medications. Smoking cessation is also mandatory, and respiratory physiotherapy and measures to loosen secretions (e.g., using nebulizers) are helpful. However, these measures only alleviate symptoms and may prevent inflammation; the tissue changes themselves are irreversible.
The aforementioned deformities of the bronchi lead to the accumulation of mucus, which provides an ideal breeding ground for all kinds of pathogens. This often results in chronic bronchiectasis, a condition for which two of the following three criteria must be met for diagnosis:
- Cough on most days of the week
- Mucus production on most days of the week
- experienced exacerbations (su)
These chronic symptoms can sometimes develop into acute, crisis-like inflammatory processes, known as exacerbations. An exacerbation is suspected if at least three of the six key symptoms occur or worsen for at least 48 hours.
- Cough
- Ejection
- Discoloration in the sputum
- shortness of breath
- fatigue
- Coughing up blood
Fever, inflammation markers, and other clinical abnormalities can also support the diagnosis.
The therapy to be applied depends on the severity of the symptoms; it ranges from physiotherapeutic drainage of secretions to oral antibiotics and intravenous high-dose antibiotics as part of inpatient treatment.
Approaches to reducing the frequency of exacerbations depend on any identified triggers:
- If the self-cleaning function of the airways is impaired, it must be strengthened, e.g. through appropriate medication and targeted respiratory physiotherapy.
- In cases of bacterial infections, the aim is to permanently eliminate the relevant bacterial strains (e.g., Pseudomonas aeruginosa) through targeted antibiotic treatment; incidentally, patients with bronchiectasis and an acute Pseudomonas aeruginosa infection can currently (autumn 2024) apply to participate in a drug trial at [website address missing]. https://www.lungeninformationsdienst.de/klinische-studien/aktuelle-klinische-studien/non-cf-bronchiektasen/eradicate
- In cases of respiratory tract inflammation, therapy is based on the functional cause of the inflammation.
If the underlying cause is neutrophilic, a drug is now nearing the end of clinical trials: Brensocatib from Insmed. Phase 3, the comparison of efficacy with a placebo, has been successfully completed and largely evaluated: treatment with Brensocatib resulted in significantly fewer exacerbations during the observation period than in the placebo group, and the time to the first exacerbation was significantly prolonged; no serious adverse events were observed. The approval process has been initiated, so availability for patients is expected from 2026 onwards. It is anticipated that AATD patients with the corresponding clinical picture will also benefit from treatment with Brensocatib.
Following this positive outlook, in her subsequent presentation, "Living with AATM," Marion Wilkens, chairwoman of Alpha1-Germany, shared her life story with the audience: as a baby, she suffered from severe jaundice and failure to thrive, which, with today's knowledge, were already early signs of her illness. At 20, she was diagnosed with asthma, and it took another 20 years until she received an AATM diagnosis. Since then, her condition has been managed with regular lung and liver examinations, plenty of exercise, respiratory physiotherapy, and an adapted lifestyle. Among other things, she has been helped in coping with the illness by the wealth of information she has found, some of which she found readily available, and some of which she has gathered herself through her work with the association and presented in her talk. She emphasized once again the value of a large, well-informed, and mutually supportive community like the Alpha1 Germany association as a building block for successfully managing AATM, and then presented its structure and work in all its facets: regular events, self-help groups, information channels online and in print, free pulmonary exercise and memory training, and networking with organizations of doctors and patients (including internationally). All of this serves the goal of enabling those affected to live better lives with AATM.
The third presentation was given by Dr. Hinze on the topic of "Infections and Vaccination in AATD." He based his presentation on the recommendations of the nationwide Standing Committee on Vaccination (STIKO). While the primary goal is to avoid the infections in question and their often very unpleasant side effects, the aspect of preventing additional cardiovascular strain in patients with chronic pre-existing conditions and advanced age also plays a crucial role.
The following vaccinations are recommended:
- Pneumococci to prevent pneumonia (the vaccine is selected by the vaccinating doctor based on the individual's vaccination status)
- Respiratory syncytial virus (RSV) to prevent exacerbations; at the time of the presentation, cost coverage still had to be arranged individually with the respective payer, but in the long term, it is expected that health insurance companies will cover the costs for high-risk patients in late 2024.
- SARS-CoV2 (Covid-19)The vaccination should be boosted annually; after infection, the booster can be omitted for one year.
- Influenza (flu) as a high-dose vaccination for people over 60 years of age, also with regard to preventing the exacerbation of cardiovascular crises (heart attacks!).
- Herpes zoster (shingles) as an inactivated vaccine; even if there is a noticeable reaction to the first vaccination, the second vaccination should definitely be carried out after 2 to 6 months.
Dr. Mark Greer then gave a presentation on the topic of "Lung Transplantation in AATD." This procedure should be considered when lung function is largely lost and no further treatment options are available. However, transplantation is subject to a number of other prerequisites, including:
- Age
- body weight
- Compliance with the smoking ban
- no cancers
- no diseases of other vital organs
- psychological stability
- Ability/willingness to undergo rehabilitation
In addition to these objective criteria, assessments by the treating physicians also play a role, e.g.:
- a mortality risk above 50% within the next 2 years of life
- A survival probability of over 80% for the next 5 years of life after transplantation
If all these conditions are met, a patient can be considered for a lung transplant. This will then take place as soon as a suitable donor organ is available that is not needed for a patient with an even greater need for a transplant.
In the vast majority of cases, the patients' quality of life is significantly improved by the transplant, even though life afterwards differs significantly from life before: for example, medication must be taken regularly for life to prevent rejection of the new lung, and close monitoring by the transplant center remains necessary for years to come.
The success rate of lung transplants is constantly improving: half of all lung transplant recipients now survive the operation for more than 6.5 years.
Following this presentation, Prof. Dr. Sabina Janciauskiene addressed the question "Substitution – yes or no?", illustrating her points with reference to real-life case studies. She began by describing the mechanism of action of substitution therapy, which aims to compensate for the unbalanced activity of neutrophil elastase that leads to the breakdown of lung tissue. Alternatives to the common intravenous administration of AAT are currently under development: inhalation, transdermal administration, and the use of recombinant (i.e., biochemically produced) AATs. The latter is currently being tested in a clinical trial: this variant is metabolized more slowly by the body, potentially allowing for significantly longer treatment intervals, but it is also associated with a number of side effects.
With conventional replacement therapy using a weight-dependent dose, the treatment success for individual patients is sometimes difficult to predict, as examples from clinical practice demonstrate. Determining the dose based on the existing AAT level and other clinical parameters may offer advantages. Patients with poorer lung function than currently anticipated could also likely benefit from replacement therapy. However, no improvements have been observed in patients with bronchiectasis or asthma. The continuation of therapy after lung transplantation, on the other hand, remains controversial.
It is often overlooked that AATD can trigger a host of skin problems, often indirectly via AATD-related intestinal issues. These include, for example, acne, eczema, psoriasis, rosacea, urticaria, and dermatitis herpetiformis.
The final presentation of the day was given by Dr. Katja Deterding on the topic of "AATD from a Hepatologist's Perspective – New Treatment Options." She began by explaining that AATD involves an imbalance between AAT and neutrophilic elastase (NE), which can lead to the enzymatic destruction of lung tissue, resulting in pulmonary emphysema. This imbalance does not arise from insufficient AAT production in the liver, but rather from AAT being misfolded, causing it to polymerize into clumps or strands so large that they cannot leave the liver cells that produce them. This can lead to liver fibrosis, cirrhosis, or even liver cancer. While this process is particularly pronounced in individuals with the homozygous PI*ZZ variant, those with the heterozygous PI*MZ variant have more AAT entering the bloodstream, thus largely protecting the lungs, at least in non-smokers. However, in these patients, the risk of liver complications is significantly increased if chronic liver diseases are also present.
To detect and classify liver fibrosis, a liver tissue biopsy is the most reliable method, but also the one with the highest risk of adverse side effects. In contrast, measuring liver elasticity using FibroScan is free of side effects and therefore very suitable for monitoring disease progression. For monitoring alphas with the ZZ classification, the following are recommended:
- Annual liver function tests, possibly more frequent if taking potentially liver-damaging medications.
- Fibroscan every 3 years if the results are normal, otherwise more frequently (alternatively, the APRI value can be calculated from measured liver values; see also the link to an APRI calculator on the Alpha1 Germany website at [link to APRI calculator]). https://alpha1-deutschland.org/alpha-1-und-die-leber)
- Liver function test in advanced disease
- Cancer monitoring in advanced cirrhosis
- Even though liver and lung problems only very rarely occur together in ZZ patients, the lungs should be checked regularly even if abnormal liver findings are present.
Novel therapeutic approaches for AATM look like this:
- The intake of chemical agents is intended to correct the misfolding of AAT so that it passes from the liver into the blood in sufficient quantities to avoid burdening the liver with polymers and to adequately protect the lungs.
- By intervening in the genetic material (DNA) or in the copies of individual DNA segments necessary for the formation of proteins (i.e., based on RNA), the liver is to be made to produce "normal" AAT.
- Similarly, RNA-based interventions can downregulate the production of AAT, thereby allowing a liver burdened by AAT clumping to recover; a clinical trial of this approach has been underway in Germany for some time and is currently being expanded significantly, for which further study participants are being sought; interested parties can find further information, including the inclusion and exclusion criteria for participation, online at [website address]. https://global.theredwoodliverstudy.com/de-ch
This presentation concluded the second MHH patient seminar on "Alpha-1 Antitrypsin Deficiency." The large number of participants, the numerous questions and lively discussions with the speakers, and the intensive exchange of opinions among the attendees give them hope for further events in this seminar series.
Dr.-Ing. Heinz Stutzenberger
08.09.24
