Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis.
Lung function, acute pulmonary exacerbations (APE), and weight are the best clinical predictors of survival in cystic fibrosis (CF); however, underlying mechanisms are incompletely understood. Biomarkers of current disease state predictive of future outcomes might identify mechanisms and provide tre...
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doaj-7843fedf4401419791f58102bfdfca2b2020-11-24T22:03:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0178e4274810.1371/journal.pone.0042748Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis.Theodore G LiouFrederick R AdlerRuth H KeoghYanping LiJudy L JensenWilliam WalshKristyn PackerTeresa ClarkHolly CarvethJun ChenShaunessy L RogersChristen LaneJames MooreAnne SturrockRobert PaineDavid R CoxJohn R HoidalLung function, acute pulmonary exacerbations (APE), and weight are the best clinical predictors of survival in cystic fibrosis (CF); however, underlying mechanisms are incompletely understood. Biomarkers of current disease state predictive of future outcomes might identify mechanisms and provide treatment targets, trial endpoints and objective clinical monitoring tools. Such CF-specific biomarkers have previously been elusive. Using observational and validation cohorts comprising 97 non-transplanted consecutively-recruited adult CF patients at the Intermountain Adult CF Center, University of Utah, we identified biomarkers informative of current disease and predictive of future clinical outcomes. Patients represented the majority of sputum producers. They were recruited March 2004-April 2007 and followed through May 2011. Sputum biomarker concentrations were measured and clinical outcomes meticulously recorded for a median 5.9 (interquartile range 5.0 to 6.6) years to study associations between biomarkers and future APE and time-to-lung transplantation or death. After multivariate modeling, only high mobility group box-1 protein (HMGB-1, mean=5.84 [log ng/ml], standard deviation [SD] =1.75) predicted time-to-first APE (hazard ratio [HR] per log-unit HMGB-1=1.56, p-value=0.005), number of future APE within 5 years (0.338 APE per log-unit HMGB-1, p<0.001 by quasi-Poisson regression) and time-to-lung transplantation or death (HR=1.59, p=0.02). At APE onset, sputum granulocyte macrophage colony stimulating factor (GM-CSF, mean 4.8 [log pg/ml], SD=1.26) was significantly associated with APE-associated declines in lung function (-10.8 FEV(1)% points per log-unit GM-CSF, p<0.001 by linear regression). Evaluation of validation cohorts produced similar results that passed tests of mutual consistency. In CF sputum, high HMGB-1 predicts incidence and recurrence of APE and survival, plausibly because it mediates long-term airway inflammation. High APE-associated GM-CSF identifies patients with large acute declines in FEV(1)%, possibly providing a laboratory-based objective decision-support tool for determination of an APE diagnosis. These biomarkers are potential CF reporting tools and treatment targets for slowing long-term progression and reducing short-term severity.http://europepmc.org/articles/PMC3416785?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Theodore G Liou Frederick R Adler Ruth H Keogh Yanping Li Judy L Jensen William Walsh Kristyn Packer Teresa Clark Holly Carveth Jun Chen Shaunessy L Rogers Christen Lane James Moore Anne Sturrock Robert Paine David R Cox John R Hoidal |
spellingShingle |
Theodore G Liou Frederick R Adler Ruth H Keogh Yanping Li Judy L Jensen William Walsh Kristyn Packer Teresa Clark Holly Carveth Jun Chen Shaunessy L Rogers Christen Lane James Moore Anne Sturrock Robert Paine David R Cox John R Hoidal Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis. PLoS ONE |
author_facet |
Theodore G Liou Frederick R Adler Ruth H Keogh Yanping Li Judy L Jensen William Walsh Kristyn Packer Teresa Clark Holly Carveth Jun Chen Shaunessy L Rogers Christen Lane James Moore Anne Sturrock Robert Paine David R Cox John R Hoidal |
author_sort |
Theodore G Liou |
title |
Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis. |
title_short |
Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis. |
title_full |
Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis. |
title_fullStr |
Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis. |
title_full_unstemmed |
Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis. |
title_sort |
sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
Lung function, acute pulmonary exacerbations (APE), and weight are the best clinical predictors of survival in cystic fibrosis (CF); however, underlying mechanisms are incompletely understood. Biomarkers of current disease state predictive of future outcomes might identify mechanisms and provide treatment targets, trial endpoints and objective clinical monitoring tools. Such CF-specific biomarkers have previously been elusive. Using observational and validation cohorts comprising 97 non-transplanted consecutively-recruited adult CF patients at the Intermountain Adult CF Center, University of Utah, we identified biomarkers informative of current disease and predictive of future clinical outcomes. Patients represented the majority of sputum producers. They were recruited March 2004-April 2007 and followed through May 2011. Sputum biomarker concentrations were measured and clinical outcomes meticulously recorded for a median 5.9 (interquartile range 5.0 to 6.6) years to study associations between biomarkers and future APE and time-to-lung transplantation or death. After multivariate modeling, only high mobility group box-1 protein (HMGB-1, mean=5.84 [log ng/ml], standard deviation [SD] =1.75) predicted time-to-first APE (hazard ratio [HR] per log-unit HMGB-1=1.56, p-value=0.005), number of future APE within 5 years (0.338 APE per log-unit HMGB-1, p<0.001 by quasi-Poisson regression) and time-to-lung transplantation or death (HR=1.59, p=0.02). At APE onset, sputum granulocyte macrophage colony stimulating factor (GM-CSF, mean 4.8 [log pg/ml], SD=1.26) was significantly associated with APE-associated declines in lung function (-10.8 FEV(1)% points per log-unit GM-CSF, p<0.001 by linear regression). Evaluation of validation cohorts produced similar results that passed tests of mutual consistency. In CF sputum, high HMGB-1 predicts incidence and recurrence of APE and survival, plausibly because it mediates long-term airway inflammation. High APE-associated GM-CSF identifies patients with large acute declines in FEV(1)%, possibly providing a laboratory-based objective decision-support tool for determination of an APE diagnosis. These biomarkers are potential CF reporting tools and treatment targets for slowing long-term progression and reducing short-term severity. |
url |
http://europepmc.org/articles/PMC3416785?pdf=render |
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