Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US. No medical therapies reduce mortality or slow disease progression, in part because COPD is a heterogeneous syndrome, which hinders the development of targeted therapies. The SPIROMICS study enrolled 2,982 participants into a 3-year longitudinal study of current and former smokers and never-smoking controls, phenotyping them clinically, radiographically and biologically to identify sources of heterogeneity in COPD. This new project will extend follow-up of participants enrolled in SPIROMICS, perform a bronchoscopy substudy and perform an exacerbation substudy to test three specific aims. The overarching premise underlying these aims is that COPD is a consequence of a heterogeneous group of molecular phenotypes that underlie distinct radiographic (anatomic) and clinical (physiologic) phenotypes; and that linking molecular phenotypes to specific radiographic and clinical phenotypes will identify key biological factors associated with disease exacerbation and progression.
The first aim i s to define the natural history of ?Smokers with symptoms despite preserved spirometry? and characterize the airway mucus abnormalities underlying this condition. Patients with this newly recognized condition do not meet current criteria for COPD but nonetheless have symptoms, exacerbation-like events, activity limitations and airway wall thickening and they may have a precursor condition to bona fide COPD.
The second aim i s to determine the radiographic precursor lesion(s) for emphysema, and identify the molecular phenotypes underlying progression of chronic bronchitis, radiographic airway disease and emphysema.
This aim will leverage several novel radiographic methods for measurement of lung disease and new approaches to phenotyping based on inflammatory pathways and the lung microbiome that we developed in SPIROMICS.
The third aim i s to advance our understanding of the biology of COPD exacerbations through analysis of predisposing baseline phenotypes, exacerbation triggers and host inflammatory response.
This aim will leverage RNA sequencing methods to simultaneously measure respiratory pathogens and the host inflammatory response in an exacerbation substudy. Our ultimate goal is to enable targeted approaches to COPD treatment and disease modification that are based on the heterogeneous biological pathways that underlie COPD progression and exacerbations.

Public Health Relevance

COPD is heterogeneous and the factors that contribute to disease progression and exacerbations are poorly understood. This study will investigate whether a newly described clinical condition (?Smokers with symptoms despite preserved spirometry?) progresses to COPD. This study will also investigate the mucus abnormalities, inflammatory pathways, and infectious processes that contribute to disease progression and exacerbations in heterogeneous patients with bona fide COPD. The ultimate goal will be to guide the development of therapeutics that target selected individuals with COPD based on their underlying biology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL137880-01
Application #
9365528
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Postow, Lisa
Project Start
2017-09-15
Project End
2022-05-31
Budget Start
2017-09-15
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Zeidler, Michelle R; Martin, Jennifer L; Kleerup, Eric C et al. (2018) Sleep disruption as a predictor of quality of life among patients in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS). Sleep 41:
Martinez, Fernando J; Han, MeiLan K; Allinson, James P et al. (2018) At the Root: Defining and Halting Progression of Early Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 197:1540-1551
Martinez, Carlos H; Li, Sara X; Hirzel, Andrew J et al. (2018) Alveolar eosinophilia in current smokers with chronic obstructive pulmonary disease in the SPIROMICS cohort. J Allergy Clin Immunol 141:429-432
Smith, Benjamin M; Traboulsi, Hussein; Austin, John H M et al. (2018) Human airway branch variation and chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A 115:E974-E981
Labaki, Wassim W; Xia, Meng; Murray, Susan et al. (2018) NT-proBNP in stable COPD and future exacerbation risk: Analysis of the SPIROMICS cohort. Respir Med 140:87-93
Curtis, Jeffrey L (2018) B Cells Caught in the Act: Class Switching to IgA in Lung Lymphoid Follicles in COPD. Am J Respir Crit Care Med :
Li, Xingnan; Ortega, Victor E; Ampleford, Elizabeth J et al. (2018) Genome-wide association study of lung function and clinical implication in heavy smokers. BMC Med Genet 19:134
Fawzy, Ashraf; Putcha, Nirupama; Paulin, Laura M et al. (2018) Association of thrombocytosis with COPD morbidity: the SPIROMICS and COPDGene cohorts. Respir Res 19:20
Han, MeiLan K; Tayob, Nabihah; Murray, Susan et al. (2018) Association between Emphysema and Chronic Obstructive Pulmonary Disease Outcomes in the COPDGene and SPIROMICS Cohorts: A Post Hoc Analysis of Two Clinical Trials. Am J Respir Crit Care Med 198:265-267
Han, MeiLan K; Quibrera, Pedro M; Carretta, Elizabeth E et al. (2017) Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med 5:619-626

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