Table 1 Summary of European Respiratory Society statements on diagnosis, clinical management and treatment of pulmonary disease in α1-antitrypsin deficiency [10]

AATD and lung disease

• The clinical impact of AATD is highly variable. Heterogeneity in lung disease is only partly explained by exposure to known risk factors, such as cigarette smoke.

• Lung disease in AATD generally presents at a younger age than “usual” COPD and may be misdiagnosed as asthma.

• Although the patients’ clinical phenotype may vary they are more likely to have basal emphysema than patients with usual COPD.

• The WHO recommends all patients with a diagnosis of COPD or adult-onset asthma should be tested for AATD.

Laboratory diagnosis and hierarchy of testing

• The quantitative determination of AAT levels in blood is a crucial first test to identify AATD. Quantitative deficiency must be supported by qualitative tests to identify the genetic mutation(s) causing AATD.

• Protein phenotyping by isoelectric focusing identifies variants where AAT is present in the sample including the rarer variants F, I and P etc.

• Genotyping allows a rapid and precise identification/exclusion of S and Z alleles and other variants, where specific primers are available.

• Gene sequencing remains necessary for those cases where a null variant or a deficient variant other than Z or S is suspected.

• Testing of relatives of identified patients should be considered after appropriate counselling.

• Genetic testing should be carried out only after informed consent is given and in accordance with the

relevant guidelines and legislation.

Lung disease progression in AATD

• Annual measurement of lung function including post-bronchodilator FEV1 and gas transfer provides information about disease progression.

• Lung densitometry, as performed in observational cohort studies and randomised clinical trials is the most sensitive measure of emphysema progression.

• The correlation between change in lung density and any short-term change in measures of pulmonary function is weak. However, in the longer term, CT lung density decline correlates with reduction in FEV1 and health status.

• The role of CT in the follow-up of patients in routine clinical practice requires further validation.

The risk of lung disease in heterozygotes

• Never-smoking PiMZ subjects do not have an increased risk for COPD.

• Smoking PiMZ and PiSZ subjects have an increased risk of COPD compared to smoking PiMM subjects.

• The role of other heterozygotes remains unknown due to their rarity and potential ascertainment bias from measuring AAT in unusual cases of lung or liver disease.

Role and benefits of screening

• Most screening studies have been biased as they did not involve random population samples.

• Population-based screening studies provide less biased prevalence estimates of specific AATD protein and clinical phenotypes as well as valuable insights into the natural history of AATD.

• Neonatal screening has been shown to be effective in reducing the smoking rates for 18–20-year-olds compared to age-matched individuals.

• Screening may have negative psychological effects on parents and on mother–child bonding. However, these negative effects can be addressed by comprehensive genetic counselling and care provision at centres of excellence for AATD.

Augmentation therapy for AATD

• Several randomised clinical trials in severe AATD have shown intravenous augmentation therapy to reduce the progression of emphysema as assessed by CT densitometry.

• There is no evidence to support efficacy of AAT augmentation therapy in PiSZ, PiMZ or current smokers of any protein phenotype.

• Clinical trials have used fixed doses of AAT determined by body weight. Whether individualising dosage based on trough levels for each patient has any benefit requires confirmation.

Lung volume reduction surgery in AATD

• Surgical volume reduction and EBV placement may be considered in selected patients with AATD, but further studies are needed to confirm the role of such therapies.

• The optimal results of these techniques are obtained when a careful appraisal of risks and benefits are performed by a multidisciplinary team experienced in LVR and AATD.

Lung transplantation for emphysema associated with AATD

• The survival benefit of lung transplant in AATD patients is not clear.

• In general, patients with AATD have improved quality of life following lung transplantation.

• Referral timing, rate of decline in lung function, health status and social support differ from patient to patient, and will have an influence on the evaluation for transplant.

• The role of post-transplant augmentation therapy in particular needs to be explored.

New lines of research in AATD

• According to the European Council, management of patients with AATD should be supervised by reference centres of excellence at a national or regional level.

• The systematic collection of data concerning clinical characteristics and natural history of patients with AATD in national and international registries will enhance knowledge about the evolution of this disease and its optimal management.

• For many AATD individuals a respiratory service is the first point of diagnosis. The operational pathway includes varying assessments and follow-up depending on personalising the patients’ risk and defining the respiratory phenotype. Links to multidisciplinary teams will ensure the best quality of care.