Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis

Theodore G Liou; Natalia Argel; Fadi Asfour; Perry S Brown; Barbara A Chatfield; David R Cox; Cori L Daines; Dixie Durham; Jessica A Francis; Barbara Glover; My Helms; Theresa Heynekamp; John R Hoidal; Judy L Jensen; Christiana Kartsonaki; Ruth Keogh; Carol M Kopecky; Noah Lechtzin; Yanping Li; Jerimiah Lysinger; Osmara Molina; Craig Nakamura; Kristyn A Packer; Robert Paine 3rd; Katie R Poch; Alexandra L Quittner; Peggy Radford; Abby J Redway; Scott D Sagel; Rhonda D Szczesniak; Shawna Sprandel; Jennifer L Taylor-Cousar; Jane B Vroom; Ryan Yoshikawa; John P Clancy; J Stuart Elborn; Kenneth N Olivier; Frederick R Adler

doi:10.1016/j.isci.2024.108835

Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis

iScience. 2024 Jan 9;27(3):108835. doi: 10.1016/j.isci.2024.108835. eCollection 2024 Mar 15.

Authors

Theodore G Liou^{1

2}, Natalia Argel³, Fadi Asfour², Perry S Brown⁴, Barbara A Chatfield², David R Cox⁵, Cori L Daines⁶, Dixie Durham⁵, Jessica A Francis¹, Barbara Glover⁷, My Helms¹, Theresa Heynekamp⁸, John R Hoidal¹, Judy L Jensen¹, Christiana Kartsonaki⁹, Ruth Keogh¹⁰, Carol M Kopecky¹¹, Noah Lechtzin¹², Yanping Li¹, Jerimiah Lysinger¹³, Osmara Molina⁶, Craig Nakamura⁷, Kristyn A Packer¹, Robert Paine 3rd¹, Katie R Poch¹⁴, Alexandra L Quittner¹⁵, Peggy Radford³, Abby J Redway⁸, Scott D Sagel¹¹, Rhonda D Szczesniak¹⁶, Shawna Sprandel¹³, Jennifer L Taylor-Cousar^{14

17}, Jane B Vroom^{1

2}, Ryan Yoshikawa⁷, John P Clancy¹⁸, J Stuart Elborn¹⁹, Kenneth N Olivier²⁰, Frederick R Adler^{21

22}

Affiliations

¹ Adult Cystic Fibrosis Center, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah, 26 North Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
² Primary Children's Cystic Fibrosis Center, Division of Pediatric Pulmonology, Department of Pediatrics, University of Utah, 81 North Mario Capecchi Drive, Salt Lake City, UT 84113, USA.
³ Cystic Fibrosis Center, Phoenix Children's Hospital, 1919 East Thomas Road, Phoenix, AZ 85016, USA.
⁴ St. Luke's Cystic Fibrosis Center of Idaho, 610 W. Hays Street, Boise, ID 83702, USA.
⁵ Nuffield College, 1 New Rd, Oxford OX1 1NF, UK.
⁶ Division of Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, University of Arizona Health Sciences, University of Arizona, 1501 N. Campbell Avenue, Room 3301, PO Box 245073, Tucson, AZ 85724, USA.
⁷ Cystic Fibrosis Center, 3006 S. Maryland Pkwy, Suite #315, Las Vegas, NV 89109, USA.
⁸ Adult Cystic Fibrosis Program, Division of Pulmonary, Critical Care and Sleep Medicine, DoIM MSC10-5550, 1 University of New Mexico, Albuquerque, NM 87131, USA.
⁹ Clinical Trial Service Unit & Epidemiological Studies Unit and Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁰ Department of Medical Statistics, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
¹¹ Department of Pediatrics, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, 13123 East 16th Avenue, Aurora, CO 80045, USA.
¹² Division of Pulmonary and Critical Care and Sleep Medicine, Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Baltimore, MD 21205, USA.
¹³ Montana Cystic Fibrosis Center, Billings Clinic, 2800 10th Avenue N, Billings, MT 59101, USA.
¹⁴ Division of Pulmonary and Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
¹⁵ Behavioral Health Systems Research, Miami, FL 33133, USA.
¹⁶ Division of Biostatistics & Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁷ Division of Pulmonology, Department of Pediatrics, National Jewish Health, 1400 Jackson St, Denver, CO 80206, USA.
¹⁸ Former: Division of Pulmonary Medicine, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
¹⁹ School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Health Sciences Building, Lisburn Rd, Belfast BT9 7AE, UK.
²⁰ Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart Lung and Blood Institute, National Institutes of Health, 10 Center Drive MSC1454, Building 10-CRC, Room 1408A, Bethesda, MD 20892, USA.
²¹ Department of Mathematics, 155 South 1400 East, University of Utah, Salt Lake City, UT 84112, USA.
²² School of Biological Sciences, 257 South 1400 East, University of Utah, Salt Lake City, UT 84112, USA.

Abstract

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

Keywords: Health sciences; Medical specialty; Medicine; Omics; respiratory medicine.

Grants and funding

R01 HL125520/HL/NHLBI NIH HHS/United States