Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis

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.

PMID: 38384849
PMCID: PMC10879674
DOI: 10.1016/j.isci.2024.108835

Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis

Theodore G Liou et al. iScience. 2024.

. 2024 Jan 9;27(3):108835.

doi: 10.1016/j.isci.2024.108835. eCollection 2024 Mar 15.

Authors

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.

PMID: 38384849
PMCID: PMC10879674
DOI: 10.1016/j.isci.2024.108835

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.

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Conflict of interest statement

T.G.L., J.A.F., J.L.J., Y.L., K.A.P., and J.B.V. received other support from the CFF (CC132-16AD, LIOU14Y0, LIOU14P0) and the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) (R01 HL125520) and received support during the current study for performing clinical trials from Abbvie, Calithera Biosciences, Corbus Pharmaceuticals, Gilead Sciences, Laurent Pharmaceuticals, Nivalis Therapeutics, Novartis, Proteostasis, Savara Pharmaceuticals, Translate Bio, and Vertex Pharmaceuticals. F.R.A. received additional other support from the NHLBI/NIH (R01 HL125520), the National Science Foundation (EMSW21-RTG), and the Margolis Family Foundation of Utah. P.S.B. received other support from the CFF (Center and TDC grants) and the NHLBI/NIH (U01 HL114623) and received support for a clinical trial from Alcresta Therapeutics. B.A.C. received other support from the CFF (C112–12, C112-TDC09Y, 10063SUB, 41339154.s132P010379SUB) and received support for clinical trials from Genentech, Novartis, and Vertex Pharmaceuticals. C.L.D. received other support from the CFF (C004–11, C004-TDC09Y, DAINES11Y3) and from the Health Resources and Services Administration (T72MC00012). J.A.F. transitioned to become an employee of ICON plc, a clinical research organization involved in various trials pertinent to CF during the study and is now an employee of Vertex Pharmaceuticals; JAF, ICON, and Vertex had no direct involvement in performance of the study following the initial change in affiliation. T.H. received other support from the CFF (PACE, Center Grant) and received support for clinical trials from Celtaxsys and Vertex Pharmaceuticals. J.R.H. received other support from the NHLBI/NIH (HHSN268200900018C) and the Veterans Administration Healthcare System (I01 BX001533). J.L. received other support from the CFF (C017-11AF). C.N. received other support from the CFF (C138-12). P.R. received other support from the CFF (C003–12, C003-TDC09Y). S.D.S. received other support from the CFF (AQUADEK12K1, SAGEL11CS0, GOAL13K2, NICK13A0, SAGEL14K1, NICK15R0) and the NHLBI/NIH (U54 HL096458) and the NCATS/NIH (Colorado CTSA Grant Number UL1 TR002535). J.L.T.-C. received other support from the CFF (TDC) and the NHLBI/NIH (HL103801) and received support for clinical trials from Vertex Pharmaceuticals. K.N.O. was funded by the intramural research program of the NHLBI, NIH, during the study. Neither the project sponsors nor any sources of other support had direct roles in development and conduct of the study. None of the sponsors of clinical trials mentioned earlier participated in any way with this trial.

Figures

**Figure 1**
Directed acyclic graph of biomarkers and pulmonary exacerbation in CF The **heavy arrow** shows the key relationships targeted by study. **Thin unidirectional arrows** indicate either **Mediator** relationships (**top**) involving variables that are intermediate outcomes in causal pathways between biomarkers and exacerbations or **Confounder** relationships (**bottom**) involving variables associated with both biomarkers and exacerbations but not as intermediates. Mediators obscure biomarker-exacerbation relationships unless excluded from explanatory models. In contrast, confounders may introduce spurious associations between biomarkers and exacerbations unless some are included as model adjustments. Not all potential confounders and mediators are shown. **Individual biomarkers** included C reactive protein (**CRP**); **calprotectin**; extracellular newly identified receptor for advanced glycation end products binding protein (**ENRAGE**); granulocyte macrophage colony stimulating factor (**GMCSF**); high-mobility group box 1 protein (**HMGB1**); intracellular adhesion molecule 1 (**ICAM1**); interferon γ (**IFNγ**); interleukin (IL)-**1β, -5, -6, -8, -10, -17A**; matrix metallopeptidase 9 (**MMP9**); myeloperoxidase (**MPO**); neutrophil elastase (NE); proteinase 3 (**PR3**); **s100A8** and **s100A9**; soluble receptor for advanced glycation end products (**sRAGE**); secretory leukoprotease inhibitor (**SLPI**); thymus and activation regulation chemokine (**TARC**); tumor necrosis factor α (**TNFα**); and chitinase 3-like 1 protein (**YKL40**).

**Figure 2**
Kaplan-Meier plots exploring relationships of clinical factors with time to next pulmonary exacerbation Patients were stratified into evenly sized groups when possible in each Number at Risk legend for (A) 5-year prognostic risk score. (B) Number of pulmonary exacerbations in the year prior to enrollment. (C) Weight-for-age Z score. (D) FEV₁%. (E) CF-related diabetes status and (F) respiratory rate. Measurements and status were from the day of enrollment. Patients were followed until occurrence of the next pulmonary exacerbation and censored. Groups are unequal in size for number of prior exacerbations, diabetes and respiratory rate because those values are ordinal and do not allow more even distribution. Results of log rank tests are shown in each panel legend. See also Table S2.

**Figure 3**
Proportional hazards models of time to next exacerbation (A) Forest plots of hazard ratios with 95% confidence intervals derived from biomarker values as univariables adjusted for assay detection limits (gray) or assay detection limits and age and number of prior year pulmonary exacerbations as confounders (red). The upper 95% confidence limit for TARC adjusted by age and prior exacerbations is 6.80. (B) Graphical FDR analysis was applied to hazard ratios adjusted by age and exacerbations. Using the p values for each hazard ratio, we ranked the potential biomarkers and drew lines with slopes determined by the thresholds for false discovery (set to 0.1 and 0.2) divided by the number of potential biomarkers in the entire study. A biomarker falling below a threshold line has a fractional chance of being a true finding, which is greater than *1—FDR threshold* for that line. Once a biomarker is plotted above a threshold line, no biomarkers with a larger rank are considered to be below that threshold. ENRAGE falls below the FDR 0.1 line, whereas MPO is just above, hence the next eight are considered below the FDR 0.2 threshold and not below FDR 0.1.

**Figure 4**
Relationships between biomarkers and FEV₁% (A) Forest plots show linear regression model effect estimates and 95% confidence intervals for associations between inflammatory biomarkers adjusted for assay detection limits and FEV₁%. (B) FDR analysis shows nine biomarkers retain significance for associations with FEV₁%, three each at FDR < 0.001, FDR < 0.01, and FDR < 0.05. (C) Significance of hazard ratios of biomarkers when used in models with FEV₁% for time to next pulmonary exacerbation (**gray**) is reduced during testing and confirmation of FEV₁% as a mediator (**salmon**) even when adjusted by age and prior pulmonary exacerbations (**red**). (See Figure S2 for the results of FDR analysis of unadjusted bivariable models.) The order of biomarkers allows easier comparison with Figure 2A. (D) In mediation testing of FEV₁%, no biomarkers used as adjustments to FEV₁% for proportional hazards models of time to next pulmonary exacerbation clearly retain statistical significance after FDR analysis with FDR < 0.2.

**Figure 5**
Relationship between RAGE axis, protease-antiprotease imbalance, oxidant injury, and lung function Three pathways of injury with representative biomarkers shown contribute to reducing lung function. Sharp decreases in lung function are the most frequent indicator used by clinicians making a diagnosis of pulmonary exacerbation of CF.

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References

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Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis

Affiliations

Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

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Full Text Sources