Circulating RNA Transcripts Identify Therapeutic Response in Cystic Fibrosis Lung Disease

• Published in: American journal of respiratory and critical care medicine 2008-11, Vol.178 (9), p.929-938
• Main Authors: Saavedra, Milene T, Hughes, Grant J, Sanders, Linda A, Carr, Michelle, Rodman, David M, Coldren, Christopher D, Geraci, Mark W, Sagel, Scott D, Accurso, Frank J, West, James, Nick, Jerry A
• Format: Article
• Language: English
• Subjects: Acute Disease; Adult; Airway management; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anti-Bacterial Agents - therapeutic use; Antibiotics; B. Cystic Fibrosis; Biological and medical sciences; Biomarkers - blood; Chronic obstructive pulmonary disease, asthma; Clinical trials; Cohort Studies; Cystic fibrosis; Cystic Fibrosis - blood; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cytokines; Cytokines - blood; Female; Forced Expiratory Volume; Gene expression; Gene Expression Profiling - methods; Humans; Infections; Inflammation; Intensive care medicine; Leukocytes; Leukocytes - metabolism; Lung diseases; Male; Medical sciences; Oligonucleotide Array Sequence Analysis - methods; Patients; Pneumology; Polymerase chain reaction; Predictive Value of Tests; Prospective Studies; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA Precursors - blood; RNA Precursors - genetics; ROC Curve; Spirometry; Spirometry - methods; Variance analysis; Young Adult
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200803-387OC

Circulating leukocyte RNA transcripts are systemic markers of inflammation, which have not been studied in cystic fibrosis (CF) lung disease. Although the standard assessment of pulmonary treatment response is FEV(1), a measure of airflow limitation, the lack of systemic markers to reflect changes in lung inflammation critically limits the testing of proposed therapeutics. We sought to prospectively identify and validate peripheral blood leukocyte genes that could mark resolution of pulmonary infection and inflammation using a model by which RNA transcripts could increase the predictive value of spirometry. Peripheral blood mononuclear cells were isolated from 10 patients with CF and acute pulmonary exacerbations before and after therapy. RNA expression profiling revealed that 10 genes significantly changed with treatment when compared with matched non-CF and control subjects with stable CF to establish baseline transcript abundance. Peripheral blood mononuclear cell RNA transcripts were prospectively validated, using real-time polymerase chain reaction amplification, in an independent cohort of acutely ill patients with CF (n = 14). Patients who responded to therapy were analyzed using general estimating equations and multiple logistic regression, such that changes in FEV(1)% predicted were regressed with transcript changes. Three genes, CD64, ADAM9, and CD36, were significant and independent predictors of a therapeutic response beyond that of FEV(1) alone (P < 0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV(1). Circulating mononuclear cell transcripts characterize a response to the treatment of pulmonary exacerbations. Even in small patient cohorts, changes in gene expression in conjunction with FEV(1) may enhance current outcomes measures for treatment response.