Development of a Prediction Score for the Occurrence of Death or Lung Transplantation in Patients With Emphysema Secondary to Alpha-1-anti-tripsin Deficiency

Overview

Emphysema linked to alpha-1-antitrypsin deficiency (DAAT): towards a better prediction of risks Emphysema caused by alpha-1-antitrypsin deficiency (DAAT) is a rare genetic disorder that can lead to serious complications, such as the need for a lung transplant or death, affecting up to 15% of patients. The only specific treatment available is a weekly infusion of alpha-1-antitrypsin (IV-AAT), an expensive and burdensome therapy. Currently, there is no reliable model to predict the course of the disease in these patients. Our study, conducted in several French hospitals, aims to develop a prediction tool combining clinical, biological, functional data and advanced medical image analysis (lung CT). This model will make it possible to identify the most at-risk patients, in order to better adapt their care, anticipate transplant needs and avoid unnecessary treatments for low-risk patients. Ultimately, this approach could also improve access to care for patients who need it most, while optimizing health system resources.

Detailed description

Context. Emphysema secondary to alpha-1-anti-trypsin deficiency (AATD) is a genetic rare disease, but with pejorative events such as death or lung transplantation (LT) which affect up to 15% of patients. Aside from standard medical care for COPD management, the only specific treatment as augmentation therapy for severe AATD, is weekly intravenous alpha-1 antitrypsin (IV-AAT) which is still expensive and restrictive. Several prognostic scores for tobacco-related COPD have been developed but, none of them have been validated in AATD, neither have included quantitative chest CT imaging while they have been associated with mortality in emphysema. Therefore, we aim to develop a prediction model combining clinical, biological, functional and quantitative CT data (including radiomics) for mortality or LT to identify at-risk patients with emphysema secondary to AATD.

Methods: From several French hospitals, we'll conduct a multicenter retrospective study based on data collected in usual care among patients over 18-year-old, with an available chest CT. We'll collect clinical data (BMI, mMRC dyspnea scale), respiratory function parameters and quantitative imaging data (including radiomics) from the initial CT from AATD patients secondary to ZZ, Znull, ZMalton, Z and rare mutations. We'll then validate our results on an independent external database from the European AADT cohort (EARCO), with specific dedicated funding.

Perspectives: To develop a prediction model to identify the AATD patients at risk of clinical deterioration, defined by death or LT allowing for personalized care, in order to: 1. anticipate registration on the transplant list, 2. optimize overall management, including pharmacological (IV-AAT) and non-pharmacological management. 3. to avoid cost-prohibitive and constraining IV-AAT infusion for low risk patients For Health policy, finding a way to target high-risk patients may help a better access for IV-AAT to appropriate individuals.

Primary outcome measures

• Evaluation of vital status [Time frame: 5 years]
• Evaluation of transplantation status [Time frame: 5 years]

Eligibility criteria

• Inclusion criteria:

• diagnosed between 2010 and 2025
• in the pulmonology department
• diagnosis of emphysema and COPD secondary to alpha-1 antitrypsin deficiency ZZ, Znull, ZMalton, Z and rare mutations,
• emphysema according to the initial thoracic CT scan (+/- 12 months after diagnosis).
• Exclusion criteria:

• Age <18 years
• Patient opposed to the use of their data for research purposes
• Patient deprived of liberty by judicial decision
• Patient not affiliated with a social security scheme
• no CT scan available
• no lung function test available the year around CT scan

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

France · 4 centers

• Hospices Civils de Lyon — Bron
• CHU de Lille — Lille
• Hôpital BICHAT CLAUDE-BERNARD — Paris
• Bordeaux University Hospital — Pessac

Publications

• Ho ESY, Ellis PR, Kavanagh D, Subramanian D, Stockley RA, Turner AM. Proposal and Validation of the Minimum Clinically Important Difference in Emphysema Progression. Chronic Obstr Pulm Dis. 2025 Mar 27;12(2):109-116. doi: 10.15326/jcopdf.2024.0511. PMID 39933559
• McElvaney NG, Burdon J, Holmes M, Glanville A, Wark PA, Thompson PJ, Hernandez P, Chlumsky J, Teschler H, Ficker JH, Seersholm N, Altraja A, Makitaro R, Chorostowska-Wynimko J, Sanak M, Stoicescu PI, Piitulainen E, Vit O, Wencker M, Tortorici MA, Fries M, Edelman JM, Chapman KR; RAPID Extension Trial Group. Long-term efficacy and safety of alpha1 proteinase inhibitor treatment for emphysema caused PMID 27916480
• Stolk J, Stockley RA, Piitulainen E, Stoel BC. Relationship between Change in Lung Density and Long-Term Progression of Lung Function. Am J Respir Crit Care Med. 2015 Jul 1;192(1):114-6. doi: 10.1164/rccm.201502-0370LE. No abstract available. PMID 26131993
• Sieluk J, Levy J, Sandhaus RA, Silverman H, Holm KE, Mullins CD. Costs of Medical Care Among Augmentation Therapy Users and Non-Users with Alpha-1 Antitrypsin Deficiency in the United States. Chronic Obstr Pulm Dis. 2018 Nov 8;6(1):6-16. doi: 10.15326/jcopdf.6.1.2017.0187. PMID 30775420
• Gildea TR, Shermock KM, Singer ME, Stoller JK. Cost-effectiveness analysis of augmentation therapy for severe alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2003 May 15;167(10):1387-92. doi: 10.1164/rccm.200209-1035OC. Epub 2003 Feb 5. PMID 12574076
• Fraughen DD, Ghosh AJ, Hobbs BD, Funk GC, Meischl T, Clarenbach CF, Sievi NA, Schmid-Scherzer K, McElvaney OJ, Murphy MP, Roche AD, Clarke L, Strand M, Vafai-Tabrizi F, Kelly G, Gunaratnam C, Carroll TP, McElvaney NG. Augmentation Therapy for Severe Alpha-1 Antitrypsin Deficiency Improves Survival and Is Decoupled from Spirometric Decline-A Multinational Registry Analysis. Am J Respir Crit Care Me PMID 37624745

Identifiers

NCT: NCT07715617 · CHUBX 2024/85

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗