RT Journal Article
SR Electronic
T1 Alpha-1 antitrypsin deficiency: clarifying the role of the putative protective threshold
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2101410
DO 10.1183/13993003.01410-2021
A1 Alessandro N. Franciosi
A1 Daniel Fraughen
A1 Tomás P. Carroll
A1 Noel G. McElvaney
YR 2021
UL http://erj.ersjournals.com/content/early/2021/06/17/13993003.01410-2021.abstract
AB AATD is the only readily identifiable monogenic cause of COPD. To date the only condition-specific treatment for AATD-associated COPD is weekly administration of intravenous purified pooled human AAT (IV-AAT). Uncertainties regarding which AATD genotypes should benefit from IV-AAT persist. IV-AAT is costly and involves weekly administration of a plasma product. Much of the risk stratification has been centred around the long-accepted hypothesis of a “putative protective threshold” of 11 µM (0.57 g·L−1) in serum. This hypothesis has become central to the paradigm of AATD care, though its derivation and accuracy for defining risk of disease remain unclear.We review the literature and examine the association between the 11 µM threshold and clinical outcomes to provide context and insight into the issues surrounding this topic.We found no data which demonstrates an increased risk of COPD dependent on the 11 µM threshold. Moreover, an abundance of recent clinical data examining this threshold refutes the hypothesis. Conversely, the use of 11 µM as a treatment target in appropriate ZZ individuals is supported by clinical evidence, although more refined dosing regimens are being explored.Continued use of the 11 µM threshold as a determinant of clinical risk is questionable, perpetuates inappropriate AAT-augmentation practices, may drive increased healthcare expenditure and should not be used as an indicator for commencing treatment.Genotype represents a more proven indicator of risk, with ZZ and rare ZZ-equivalent genotypes independently associated with COPD. New and better risk assessment models are needed to provide individuals diagnosed with AATD with reliable risk estimation and optimised treatment goals.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Franciosi reports grants from Michael Smith Foundation for Health Research, outside the submitted work.Conflict of interest: Dr. Fraughen has nothing to disclose.Conflict of interest: Dr. Carroll has nothing to disclose.Conflict of interest: Dr. McElvaney reports grants from Grifols, personal fees from CSl Behring, personal fees from Takeda, personal fees from vertex, outside the submitted work.