TABLE 2

Comparison of recommendations from American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines (2003), US Alpha-1 Foundation guidelines (2016) and ERS statement (2017)

	ATS/ERS statement (2003) [1]	US Alpha-1 Foundation guidelines (2016) [13]	ERS statement (2017) [14]
Diagnostic tests	AAT serum levels should not be viewed in isolation Phenotyping or targeted genotyping may be utilised Phenotyping may be insufficient to detect rare variants and sequencing may be required	Targeted genotyping for S and Z alleles as a minimum Initial tests can be confirmed by phenotyping, quantitation of AAT serum levels and/or expanded targeted genotyping	Establishing AAT serum levels is a crucial first test, but must be supported by qualitative evidence of a mutation Phenotyping and genotyping can both be used to establish mutation(s) present Gene sequencing is necessary when a null or rare variant is suspected
Who should be tested?
Testing for index case	Emphysema with early onset (<45 years) or without recognised risk factors, e.g. smoking, or with basilar hyperlucency Bronchiectasis or liver disease with unknown aetiology Necrotising panniculitis and anti-proteinase 3-positive vasculitis Family history of emphysema, bronchiectasis, panniculitis or liver disease	COPD or unexplained bronchiectasis, regardless of age/ethnicity All individuals with liver disease of unknown aetiology All patients with granulomatosis with polyangiitis/necrotizing panniculitis	COPD or adult-onset asthma
Familial testing	Recommended for siblings of index cases with severe deficiency Should be discussed with offspring or distant relatives of individuals with severe deficiency, and siblings, offspring, parents and distant relatives of individuals with intermediate deficiency	Parents, sibling, offspring and extended family should be offered genetic counselling and testing AAT level testing alone is not recommended when testing family members	Test parents of index case only if a null gene is suspected Test partner of index case; if PIMZ is found, test offspring of index case Test sibling(s) of index case; if PIMZ is found, test partner of sibling(s), if further PI*MZ is found, test offspring of sibling(s)
Population screening	Screening of any age group should be discouraged; screening of active smokers with normal spirometry is not recommended
Monitoring	Full lung function testing at baseline and spirometry at yearly intervals Regular liver function testing requires investigation	Baseline and annual spirometry CT scan at baseline; serial CT scanning not recommended Monitor for liver disease annually: liver ultrasound and AST, ALT, GGT, albumin, bilirubin and INR	Importance of multidisciplinary approach highlighted Baseline: assess lung physiology and conduct routine liver function and blood tests Up to 3 months: reassess and collate data; monitor exacerbation diary, initiate smoking cessation Up to 6 months: assess full physiology, QoL assessment, routine blood tests 6–12 months: continue monitoring, initiate AAT therapy as appropriate FEV₁ and D_LCO are useful to monitor disease progression
AAT therapy utilisation
Recommended	Symptomatic individuals with FEV₁ 35–65% pred	Symptomatic individuals with FEV₁ ≤65% pred (strongest recommendation); treatment can be considered outside of this range	Symptomatic individuals (no FEV₁ range given)
Not recommended	PI*MZ individuals and current smokers	PI*MZ and current smokers Emphysema/ bronchiectasis without airflow obstruction	PIMZ, PISZ and current smokers

AAT: α₁-antitrypsin; COPD: chronic obstructive pulmonary disease; CT: computed tomography; AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: γ-glutamyltransferase; INR: international normalised ratio; QoL: quality of life; FEV₁: forced expiratory volume in 1 s; D_LCO: diffusing capacity of the lung for carbon monoxide