Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Precision medicine in alpha-1 antitrypsin deficiency

  Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder of the SERPINA1 gene that can cause early-onset emphysema, bronchiectasis and progressive liver disease. People carrying the same variants may nevertheless follow very different clinical paths because smoking, occupational dust, infections, alcohol use, metabolic health and access to treatment also influence outcomes. Precision medicine in AATD therefore means integrating molecular diagnosis, longitudinal phenotyping and individual exposures rather than treating a serum concentration in isolation.

  The respiratory focus of APSR 2022, organised in connection with APSR and KATRD, is well suited to this approach. Australian clinicians face particular issues involving dispersed specialist services, long-distance travel and families separated across states, making coordinated diagnosis, surveillance and cascade testing essential to reducing preventable harm.

  Genetic risk is only the first layer

  Most clinically significant AATD involves PiZZ, PiSZ or null alleles, while other combinations produce mild, intermediate or protective phenotypes. Interpretation requires the quantitative serum AAT concentration, SERPINA1 genotyping, family history and clinical findings. A single measurement or genetic result cannot define prognosis, particularly when rare or incompletely detected variants are possible.

  Environmental exposure can substantially modify genetic risk. Tobacco smoke accelerates lung destruction, while occupational particles, bushfire smoke and recurrent respiratory infections can worsen airflow limitation. Likewise, alcohol, diabetes, obesity and viral hepatitis may increase hepatic risk in someone with a severe genotype. Personalised care must therefore address these modifiers alongside inherited risk.

  Building a reliable diagnostic pathway

  Testing should be considered in adults with COPD, unexplained chronic liver disease, persistent liver-enzyme abnormalities, bronchiectasis and relatives of an affected person. Symptom-based case-finding misses people before injury becomes apparent, while family-based screening can identify relatives whose genotype would otherwise remain unknown.

  Serum AAT is an acute-phase reactant, so a level measured during pneumonia or another inflammatory illness may appear less severe than the underlying deficiency. If clinical suspicion remains high, repeat phenotyping and confirmatory genotyping should follow standard laboratory protocols. Expanded sequencing or deletion analysis may be appropriate when routine testing does not explain a convincing family pattern.

  Once AATD is confirmed, clinicians should establish a baseline rather than waiting for symptoms to progress. This usually combines spirometry, diffusing capacity, liver biochemistry, platelet count and imaging or elastography according to the suspected phenotype. Referral pathways should also include genetic counselling, first-degree relative testing and documentation of smoking and occupational exposures.

  Stratifying patients by dominant clinical trajectory

  A practical assessment separates present organ damage from future risk. This prevents severe lung disease from distracting from hepatic surveillance, while ensuring that someone without current injury still receives prevention and regular reassessment.

  Profiles may overlap, and serial review is more informative than a single classification. The aim is to match monitoring and treatment intensity to the organs most likely to be affected, with patient preferences and access incorporated into each plan.

  Clinical profile	Main risks	Key assessment	Personalised management
  Lung-predominant disease	Early emphysema, bronchiectasis, frequent exacerbations	Spirometry, diffusing capacity, CT when indicated, oxygen assessment	Smoking cessation, vaccination, bronchodilators, pulmonary rehabilitation and selected augmentation therapy
  Liver-predominant disease	Steatosis, fibrosis, portal hypertension, cirrhosis	Liver enzymes, INR, platelets, elastography and ultrasound	Alcohol and metabolic risk management, cirrhosis surveillance and transplant assessment when needed
  Preclinical high-risk profile	Future lung or liver injury despite few symptoms	Serial lung and liver measures plus exposure review	Dust and smoke avoidance, vaccination, lifestyle intervention and timely family screening
  Discordant or complex profile	Symptoms or family history not matching initial results	Repeat phenotyping, expanded genetics and comorbidity review	Multidisciplinary reassessment with individually adjusted treatment

  Selecting disease-modifying treatment in Australia

  Alpha-1 antitrypsin augmentation remains relevant for selected people with severe deficiency and clinically significant lung disease. It does not reverse established cirrhosis and is not routinely appropriate for every carrier. In Australia, plasma-derived alpha-1 proteinase inhibitor is hospital-administered through specialist services and public funding arrangements, including the Life Saving Drugs Program for eligible patients. Infusion capacity, product supply and travel should be considered when assessing the real-world burden of treatment.

  Liver disease requires a different therapeutic pathway. Standard care includes alcohol-risk reduction, management of metabolic contributors, vaccination and cirrhosis-specific surveillance. Advanced disease may prompt referral to public transplant units in Melbourne, Sydney, Brisbane, Adelaide or Perth. The timing of referral should reflect trajectory rather than a single abnormal result, with hepatology involvement introduced early in uncertain cases.

  RNA interference and other liver-targeted strategies remain investigational rather than routine Australian care. Their availability through specialist trials may be valuable, but regulatory status, evidence quality and patient goals must be reviewed carefully. Personalised treatment remains grounded in established care while monitoring emerging options without compromising access to proven interventions.

  Connecting specialist knowledge to community care

  Australian prevention priorities are concrete. The national 1800 QUIT service supports smoking cessation, a critical intervention for almost every severe AATD phenotype. In New South Wales and Queensland, bushfire events add periods of intense particulate exposure, while agricultural and mining regions may involve silica, dust and diesel exhaust. These exposures should be recorded explicitly and managed alongside smoking-related risk.

  Medicare-covered pathology and specialist referrals support diagnosis, although family testing still requires coordinated counselling and follow-up. Telehealth can connect rural patients with metropolitan respiratory, liver and genetics services, while Aboriginal Medical Services can support culturally safe access and continuity. Electronic results and shared care plans are particularly valuable when relatives live in different states or receive care across public and private providers.

  A practical framework for Australian respiratory clinics

  A concise clinical checklist can reduce missed opportunities without replacing specialist judgement. It should connect initial suspicion with confirmatory testing, baseline phenotyping and family assessment.

  For diagnosis and risk assessment:

  • Request AAT quantification and SERPINA1 genotyping for patients with compatible lung or liver disease.
  • Repeat phenotyping when inflammation or discordant results could distort interpretation.
  • Record smoking, alcohol, occupational dust, infection history and relevant comorbidities.
  • Offer first-degree relatives genetic counselling and testing through an accessible pathway.

  Follow-up should combine serial clinical measurements with prevention, organ-specific treatment and regular reassessment of the original diagnosis.

  For ongoing management:

  • Use spirometry, liver markers and appropriate imaging to establish individual review intervals.
  • Coordinate pulmonary rehabilitation, vaccination, smoking cessation and cirrhosis surveillance.
  • Reassess augmentation against lung trajectory, infusion burden and patient goals.
  • Include transplant planning, reproductive counselling and cascade testing when clinically relevant.

  The next concrete step is for each respiratory service to adopt a one-page AATD testing, referral and family-cascade pathway linking respiratory medicine, hepatology, genetics and primary care.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)