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Association between Pulmonary Function and Sputum Biomarkers in Cystic Fibrosis

¹ Department of Pediatrics, University of Washington, Seattle, Washington; ² Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Children's Hospital and Regional Medical Center, Seattle, Washington; ³ Department of Medicine, University of Washington, Seattle, Washington; ⁴ Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; ⁵ Department of Biostatistics, University of Washington, Seattle, Washington; ⁶ Rainbow Babies and Children's Hospital and Case Western Reserve University School of Medicine, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Nicole Mayer-Hamblett, Ph.D., Department of Pediatrics, University of Washington, 4800 Sand Point Way N.E., Box 5371, Seattle, WA 98105-0371. 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 multicenter studies to quantify the strength of association between expectorated sputum biomarkers and FEV_1.

Methods: FEV₁ (range, 25–120% predicted) and quantitative data on expectorated sputum biomarkers including free neutrophil elastase, IL-8, neutrophils, Pseudomonas aeruginosa, and Staphylococcus aureus were obtained from 269 participants (ages, 9–54 years) 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% confidence interval [CI]: –0.46, –0.22). On average, patients with CF 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

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject There are limited data from single-center studies supporting the association between sputum markers and clinical parameters in CF. Associations have yet to be described in a more diverse CF population from multiple centers. What This Study Adds to the Field Sputum biomarkers, including elastase, neutrophil counts, and IL-8, are correlates of disease severity in diverse populations of patients with CF.

 

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