Journal article
Longitudinal Outcomes in PiMZ Alpha-1 Antitrypsin Deficient Individuals with Tobacco Smoking History from the SPIROMICS Cohort
Annals of the American Thoracic Society, Vol.22(7), pp.998-1008
07/2025
DOI: 10.1513/AnnalsATS.202411-1209OC
PMCID: PMC12254153
PMID: 40068143
Abstract
Reliable data about the natural history of lung function decline in alpha-1 antitrypsin (AAT) deficient Pi*MZ heterozygotes is largely missing. We hypothesized that, in adults with a tobacco smoking history, lung function deteriorates faster in Pi*MZ compared to Pi*MM genotype.
We identified 1856 Pi*MM and 79 Pi*MZ participants with ≥20 pack-years tobacco smoking history from the SPIROMICS cohort by DNA sequencing and followed them over a median of 4.8 years, comparing radiographic and clinical characteristics between the two groups over time using regression models.
Adjusted for age, sex, race, smoking pack-year history and smoking status, Pi*MZ participants had a lower baseline percent-predicted FEV1 (65.4% vs. 75.1%, difference 95% CI: -15.4%, -3.9%), more radiographic emphysema (<-950HU%: 12.9% vs. 7.8%, difference 95% CI: 2.8%, 7.5%) and non-significantly lower lung density. In the longitudinal analysis, the FEV1 annual rate of decline was similar in both groups over the course of the study (-34.5mL/year vs. -34.6mL/year for Pi*MZ and Pi*MM, difference 95%CI: -16.9,17.1mL/year). There were no significant differences between Pi*MZ and Pi*MM individuals in the annualized change in lung density, emphysema, patient-reported outcomes, exacerbations or survival. The proportion with faster FEV1 decline (annual loss ≥40mL) was similar in Pi*MZ and Pi*MM groups. In both groups, faster FEV1 decline was associated with more air trapping and small airway disease at baseline. In Pi*MZ only, faster decline was associated with higher blood eosinophil counts (310 vs. 220 cells/µL, difference 95% CI: 30, 140 cells/µL). In the subgroup analysis limited to a small number of, currently smoking participants, no significant differences in longitudinal outcomes were found.
Despite a lower FEV1 and more emphysema at enrollment, the longitudinal analysis did not demonstrate significantly greater lung function decline or lung density loss in Pi*MZ compared to Pi*MM participants with tobacco smoking history. Limited sample size and duration of longitudinal follow up constrain generalizability of our findings, thus prohibiting the conclusion that longitudinal trajectories did not differ between these groups. However, our results may suggest that earlier life events could be responsible for more extensive lung disease at enrollment in Pi*MZ compared to Pi*MM tobacco-exposed individuals.
Details
- Title: Subtitle
- Longitudinal Outcomes in PiMZ Alpha-1 Antitrypsin Deficient Individuals with Tobacco Smoking History from the SPIROMICS Cohort
- Creators
- Igor Barjaktarevic - University of California, Los AngelesRoxana Hixson - University of California, Los AngelesZian Zhuang - University of California, Los AngelesRussell G Buhr - University of California, Los AngelesVickram Tejwani - Cleveland ClinicR Graham Barr - Columbia UniversityLori A Bateman - University of North Carolina at Chapel HillSurya P Bhatt - University of Alabama at BirminghamEugene R Bleecker - Mayo Clinic in ArizonaChristopher B Cooper - University of California, Los AngelesJeffrey L Curtis - Michigan MedicineM Bradley Drummond - University of North Carolina at Chapel HillSpyridon Fortis - University of Iowa Hospitals and ClinicsAuyon J Ghosh - Upstate University HospitalMeiLan Han - Michigan MedicineNadia N Hansel - Johns Hopkins UniversityEric A Hoffman - University of IowaJill Ohar - Wake Forest UniversityFernando J Martinez - University of Massachusetts Chan Medical SchoolDeborah A Meyers - Mayo Clinic in ArizonaRobert Paine III - University of UtahCheryl S Pirozzi - University of UtahRobert Sandhaus - National Jewish HealthCharlie Strange - Medical University of South CarolinaDonald P Tashkin - University of California, Los AngelesJ Michael Wells - University of Alabama at BirminghamPrescott Woodruff - University of California, San FranciscoVictor E Ortega - Mayo Clinic in Arizona
- Resource Type
- Journal article
- Publication Details
- Annals of the American Thoracic Society, Vol.22(7), pp.998-1008
- DOI
- 10.1513/AnnalsATS.202411-1209OC
- PMID
- 40068143
- PMCID
- PMC12254153
- NLM abbreviation
- Ann Am Thorac Soc
- ISSN
- 2329-6933
- eISSN
- 2325-6621
- Publisher
- AMER THORACIC SOC
- Grant note
- National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute: HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C NIH/National Heart, Lung, and Blood Institute: U01 HL137880, U24 HL141762, R01 HL182622, R01 HL144718 AmgenAstraZeneca/MedImmuneBayerBellerophon TherapeuticsBoehringer-Ingelheim Pharmaceuticals, Inc.Chiesi Farmaceutici S.p.A.Forest Research Institute, Inc.GenentechGlaxoSmithKlineGrifols Therapeutics, Inc.Ikaria, Inc.MGC DiagnosticsNovartis Pharmaceuticals CorporationNycomed GmbHPolareanProterixBioRegeneron Pharmaceuticals, Inc.SanofiSunovionTakeda Pharmaceutical CompanyTheravance Biopharma and Mylan/Viatris
SPIROMICS was supported by National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C; NIH/National Heart, Lung, and Blood Institute grants U01 HL137880, U24 HL141762, R01 HL182622, and R01 HL144718; and contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan/Viatris. The funders had no influence on the decision to publish or the content of this manuscript. Drs. Buhr, Curtis, Fortis, and Paine are employees of the Veterans Health Administration. The findings and positions in this manuscript do not necessarily reflect those of the Department of Veterans Affairs or the U.S. Government.
- Language
- English
- Electronic publication date
- 03/11/2025
- Date published
- 07/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
- Record Identifier
- 9984800202002771
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