Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Medical Research Methodology
Published in: BMC Medical Research Methodology 1/2019

Open Access 01-12-2019 | Expectoration | Research article

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis

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

Published in: BMC Medical Research Methodology | Issue 1/2019

Login to get access

Abstract

Background

Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers.

Methods

We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation.

Results

From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies.

Conclusions

Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.
Appendix
Available only for authorised users
Literature
1.
Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168(8):918–51.CrossRef
2.
Sagel SD, Chmiel JF, Konstan MW. Sputum biomarkers of inflammation in cystic fibrosis lung disease. Proc Am Thorac Soc. 2007;4(4):406–17.CrossRef
3.
Mayer-Hamblett N, Aitken ML, Accurso FJ, et al. Association between pulmonary function and sputum biomarkers in cystic fibrosis. Am J Respir Crit Care Med. 2007;175(8):822–8.CrossRef
4.
Bonfield TL, Panuska JR, Konstan MW, et al. Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med. 1995;152(6 Pt 1):2111–8.CrossRef
5.
Sagel SD, Wagner BD, Anthony MM, Emmett P, Zemanick ET. Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis. Am J Respir Crit Care Med. 2012;186:857–65.
6.
Ramsey BW, Banks-Schlegel S, Accurso FJ, et al. Future directions in early cystic fibrosis lung disease research: an NHLBI workshop report. Am J Respir Crit Care Med. 2012;185(8):887–92.CrossRef
7.
Levy H, Kalish LA, Huntington I, et al. Inflammatory markers of lung disease in adult patients with cystic fibrosis. Pediatr Pulmonol. 2007;42(3):256–62.CrossRef
8.
Saavedra M, Hughes G, Sanders L, et al. Circulating RNA transcripts identify therapeutic response in cystic fibrosis lung disease. Am J Respir Crit Care Med. 2008;178(9):929–38.CrossRef
9.
Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol. 2001;153(4):345–52.CrossRef
10.
Buzzetti R, Alicandro G, Minicucci L, et al. Validation of a predictive survival model in Italian patients with cystic fibrosis. J Cyst Fibros Off J Eur Cyst Fibros Soc. 2012;11(1):24–9.CrossRef
11.
Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med. 1994;331(10):637–42.CrossRef
12.
Ramsey BW, Pepe MS, Quan JM, et al. Intermittent Administration of Inhaled Tobramycin in patients with cystic fibrosis. N Engl J Med. 1999;340(1):23–30.CrossRef
13.
Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA J Am Med Assoc. 2003;290(13):1749–56.CrossRef
14.
Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006;354(3):229–40.CrossRef
15.
Retsch-Bogart GZ, Quittner AL, Gibson RL, et al. Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest. 2009;135(5):1223–32.CrossRef
16.
Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663–72.CrossRef
17.
Boyle MP, Bell SC, Konstan MW, et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014;2(7):527–38.CrossRef
18.
Saiman L, Anstead M, Mayer-Hamblett N, et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2010;303(17):1707–15.CrossRef
19.
Fidler KJ, Hilliard TN, Bush A, et al. Mannose-binding lectin is present in the infected airway: a possible pulmonary defence mechanism. Thorax. 2009;64(2):150–5.CrossRef
20.
Hubeau C, Le Naour R, Abély M, et al. Dysregulation of IL-2 and IL-8 production in circulating T lymphocytes from young cystic fibrosis patients. Clin Exp Immunol. 2004;135(3):528–34.CrossRef
21.
Koller DY, Nething I, Otto J, Urbanek R, Eichler I. Cytokine concentrations in sputum from patients with cystic fibrosis and their relation to eosinophil activity. Am J Respir Crit Care Med. 1997;155(3):1050–4.CrossRef
22.
Merenmies J, Pihlaskari R, Laitinen J, Wartiovaara J, Rauvala H. 30-kDa heparin-binding protein of brain (amphoterin) involved in neurite outgrowth. Amino acid sequence and localization in the filopodia of the advancing plasma membrane. J Biol Chem. 1991;266(25):16722–9.PubMed
23.
Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285(5425):248–51.CrossRef
24.
Rowe SM, Jackson PL, Liu G, et al. Potential role of high-mobility group box 1 in cystic fibrosis airway disease. Am J Respir Crit Care Med. 2008;178(8):822–31.CrossRef
25.
Liou TG, Adler FR, Keogh RH, et al. Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis. PLoS One. 2012;7(8):e42748.CrossRef
26.
Gray RD, MacGregor G, Noble D, et al. Sputum proteomics in inflammatory and suppurative respiratory diseases. Am J Respir Crit Care Med. 2008;178(5):444–52.CrossRef
27.
Gray RD, Imrie M, Boyd AC, Porteous D, Innes JA, Greening AP. Sputum and serum calprotectin are useful biomarkers during CF exacerbation. J Cyst Fibros Off J Eur Cyst Fibros Soc. 2010;9(3):193–8.CrossRef
28.
Goldstein W, Döring G. Lysosomal enzymes from polymorphonuclear leukocytes and proteinase inhibitors in patients with cystic fibrosis. Am Rev Respir Dis. 1986;134(1):49–56.PubMed
29.
Nakamura H, Yoshimura K, McElvaney NG, Crystal RG. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J Clin Invest. 1992;89(5):1478–84.CrossRef
30.
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999;159(1):179–87.CrossRef
31.
Cox DR. Planning of experiments. New York: Wiley; 1958.
32.
Cox DR, Donnelly CA. Principles of Applied Statistics. 1st ed. Cambridge: Cambridge University Press; 2011.CrossRef
33.
Knapp EA, Fink AK, Goss CH, et al. The Cystic Fibrosis Foundation patient registry. Design and methods of a National Observational Disease Registry. Ann Am Thorac Soc. 2016;13(7):1173–9.CrossRef
34.
35.
36.
Rosenfeld M, Emerson J, Williams-Warren J, et al. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr. 2001;139(3):359–65.CrossRef
37.
Davison AC. Bootstrap Methods And Their Application. 1 edition. Cambridge; New York, NY, USA: Cambridge University Press; 1997.
38.
Davé SH, Tilstra JS, Matsuoka K, et al. Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis. J Leukoc Biol. 2009;86(3):633–43.CrossRef
39.
Mogayzel PJ, Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187(7):680–9.CrossRef
40.
Hilliard JB, Konstan MW, Davis PB. Inflammatory mediators in CF patients. Methods Mol Med. 2002;70:409–31.PubMed
41.
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377–81.CrossRef
42.
Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–7.CrossRef
43.
Quittner AL, Goldbeck L, Abbott J, et al. Prevalence of depression and anxiety in patients with cystic fibrosis and parent caregivers: results of the international depression epidemiological study across nine countries. Thorax. 2014;69(12):1090–7.CrossRef
44.
Kroenke K, Spitzer RL, Williams JBW. The PHQ-9. J Gen Intern Med. 2001;16(9):606–13.CrossRef
45.
Hayes M, Yaster M, Haythornthwaite JA, et al. Pain is a common problem affecting clinical outcomes in adults with cystic fibrosis. Chest. 2011;140(6):1598–603.CrossRef
46.
Roenneberg T, Wirz-Justice A, Merrow M. Life between clocks: daily temporal patterns of human Chronotypes. J Biol Rhythm. 2003;18(1):80–90.CrossRef
47.
48.
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81.CrossRef
49.
R Core Team. R: A language and environment for statistical computing [Internet]. Vienna, Austria: R Foundation for Statistical Computing; 2015. Available from: https://​www.​r-project.​org/​. Accessed 27 Mar 2019.
50.
51.
Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–43.CrossRef
52.
Liou TG, Jensen JL, Allen SE, et al. Improving performance in the detection and management of cystic fibrosis-related diabetes in the mountain west cystic fibrosis consortium. BMJ Open Diabetes Res Care. 2016;4(1):e000183.CrossRef
53.
Kelly MM, Keatings V, Leigh R, et al. Analysis of fluid-phase mediators. Eur Respir J Suppl. 2002;37:24s–39s.PubMed
54.
Smountas AA, Lands LC, Mohammed SR, Grey V. Induced sputum in cystic fibrosis: within-week reproducibility of inflammatory markers. Clin Biochem. 2004;37(11):1031–6.CrossRef
55.
Hector A, Jonas F, Kappler M, Feilcke M, Hartl D, Griese M. Novel method to process cystic fibrosis sputum for determination of oxidative state. Respir Int Rev Thorac Dis. 2010;80(5):393–400.
56.
Kelly MM, Leigh R, Carruthers S, et al. Increased detection of interleukin-5 in sputum by addition of protease inhibitors. Eur Respir J Off J Eur Soc Clin Respir Physiol. 2001;18(4):685–91.
57.
Cox DR. The regression analysis of binary sequences. J R Stat Soc Ser B Methodol. 1958;20(2):215–42.
58.
Cox DR. Regression models and life-tables. J R Stat Soc Ser B Methodol. 1972;34(2):187–220.
59.
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of the cystic fibrosis questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis. Chest. 2005;128(4):2347–54.CrossRef
Metadata
Title
Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis
Authors
Theodore G. Liou
Frederick R. Adler
Natalia Argel
Fadi Asfour
Perry S. Brown
Barbara A. Chatfield
Cori L. Daines
Dixie Durham
Jessica A. Francis
Barbara Glover
Theresa Heynekamp
John R. Hoidal
Judy L. Jensen
Ruth Keogh
Carol M. Kopecky
Noah Lechtzin
Yanping Li
Jerimiah Lysinger
Osmara Molina
Craig Nakamura
Kristyn A. Packer
Katie R. Poch
Alexandra L. Quittner
Peggy Radford
Abby J. Redway
Scott D. Sagel
Shawna Sprandel
Jennifer L. Taylor-Cousar
Jane B. Vroom
Ryan Yoshikawa
John P. Clancy
J. Stuart Elborn
Kenneth N. Olivier
David R. Cox
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medical Research Methodology / Issue 1/2019
Electronic ISSN: 1471-2288
DOI
https://doi.org/10.1186/s12874-019-0705-0

Other articles of this Issue 1/2019

BMC Medical Research Methodology 1/2019 Go to the issue

Research Article

Joint model robustness compared with the time-varying covariate Cox model to evaluate the association between a longitudinal marker and a time-to-event endpoint

Research article

The power of the group: comparison of interviews and group concept mapping for identifying patient-important outcomes of care

Research article

Machine learning in medicine: a practical introduction

Research article

Readiness assessment for pragmatic trials (RAPT): a model to assess the readiness of an intervention for testing in a pragmatic trial

Research article

Preventing bias from selective non-response in population-based survey studies: findings from a Monte Carlo simulation study

Research Article

Risk-adjusted CUSUM control charts for shared frailty survival models with application to hip replacement outcomes: a study using the NJR dataset