Published ahead of print on January 18, 2007, doi:10.1164/rccm.200609-1354OC Am. J. Respir. Crit. Care Med., Volume 175, Number 8, April 2007, 822-828 A more recent version of this article appeared on April 15, 2007
Submitted on September 21, 2006 Association Between Pulmonary Function and Sputum Biomarkers in Cystic FibrosisNicole Mayer-Hamblett1*,1 Department of Pediatrics, University of Washington, Seattle, WA, USA; Children's Hospital and Regional Medical Center, Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle, WA, USA, 2 Department of Medicine, University of Washington, Seattle, WA, USA, 3 Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA, 4 Children's Hospital and Regional Medical Center, Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA, 5 Rainbow Babies and Children's Hospital and Case Western Reserve University School of Medicine, Cleveland, OH, USA, 6 Department of Pediatrics, University of Washington, Seattle, WA, USA * To whom correspondence should be addressed. E-mail: nicole.hamblett{at}seattlechildrens.org.
Rationale: Sputum biomarkers of infection and inflammation are noninvasive measures that enable quantification of the complex pathophysiology of cystic fibrosis (CF) lung disease. Validation of these biomarkers as correlates of disease severity is a key step for their application. Objectives: We constructed a large database from four multi-center studies to quantify the strength of association between expectorated sputum biomarkers and forced expiratory volume in one second (FEV1). Methods: FEV1 (range 25%-120% predicted) and quantitative data from expectorated sputum biomarkers including free neutrophil elastase, interleukin (IL)-8, neutrophils, Pseudomonas aeruginosa, and Staphylococcus aureus were obtained from 269 participants ages 9-54 from 33 centers. Cross-sectional and longitudinal statistical analyses were performed to estimate associations between the markers and FEV1, including the use of multivariable analyses. Results: Elastase was negatively correlated with FEV1 (correlation [r] = -0.35, 95% CI:-0.46,-0.22). On average, CF patients who differed in their elastase measurements by 0.5 log differed in their FEV1 values by 7.3% (95% CI: -9.7,-4.6). Neutrophil counts and IL-8 were also each negatively correlated. In a multivariable regression, elastase and neutrophil counts were able to explain the majority of variation in FEV1. Elastase was further shown to have a significant longitudinal association with FEV1, specifically a -2.9% decline in FEV1 (95% CI: -5.0,-0.9) per 1 log increase in elastase. Although correlated with FEV1, bacterial densities were unable to explain clinically meaningful differences in FEV1 within and across patients. Conclusions: These data support the role of sputum biomarkers as correlates of disease severity in a diverse CF population. Key words: cystic fibrosis; pulmonary function; sputum; infection; inflammation
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