Extremes of Interferon-Stimulated Gene Expression Associate with Worse Outcomes in the Acute Respiratory Distress Syndrome.
Acute Respiratory Distress Syndrome (ARDS) severity may be influenced by heterogeneity of neutrophil activation. Interferon-stimulated genes (ISG) are a broad gene family induced by Type I interferons, often as a response to viral infections, which evokes extensive immunomodulation. We tested the hypothesis that over- or under-expression of immunomodulatory ISG by neutrophils is associated with worse clinical outcomes in patients with ARDS. Genome-wide transcriptional profiles of circulating neutrophils isolated from patients with sepsis-induced ARDS (n = 31) and healthy controls (n = 19) were used to characterize ISG expression. Hierarchical clustering of expression identified 3 distinct subject groups with Low, Mid and High ISG expression. ISG accounting for the greatest variability in expression were identified (MX1, IFIT1, and ISG15) and used to analyze a prospective cohort at the Colorado ARDS Network site. One hundred twenty ARDS patients from four urban hospitals were enrolled within 72 hours of initiation of mechanical ventilation. Circulating neutrophils were isolated from patients and expression of ISG determined by PCR. Samples were stratified by standard deviation from the mean into High (n = 21), Mid, (n = 82) or Low (n = 17) ISG expression. Clinical outcomes were compared between patients with High or Low ISG expression to those with Mid-range expression. At enrollment, there were no differences in age, gender, co-existing medical conditions, or type of physiologic injury between cohorts. After adjusting for age, race, gender and BMI, patients with either High or Low ISG expression had significantly worse clinical outcomes than those in the Mid for number of 28-day ventilator- and ICU-free days (P = 0.0006 and 0.0004), as well as 90-day mortality and 90-day home with unassisted breathing (P = 0.02 and 0.004). These findings suggest extremes of ISG expression by circulating neutrophils from ARDS patients recovered early in the syndrome are associated with poorer clinical outcomes.
Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.|Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
Jerry A
JA
Nick
Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.
Silvia M
SM
Caceres
St Louis County Department of Public Health, Berkeley, Missouri, United States of America.
Jennifer E
JE
Kret
Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.
Katie R
KR
Poch
Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, Colorado, United States of America.
Matthew
M
Strand
Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, Colorado, United States of America.
Anna V
AV
Faino
Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America.
David P
DP
Nichols
Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.|Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
Milene T
MT
Saavedra
Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.|Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
Jennifer L
JL
Taylor-Cousar
Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
Mark W
MW
Geraci
Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
Ellen L
EL
Burnham
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, United States of America.
Michael B
MB
Fessler
Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
Benjamin T
BT
Suratt
Office of the Dean, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
Edward
E
Abraham
Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
Marc
M
Moss
Department of Medicine, National Jewish Health, Denver, Colorado, United States of America.|Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
Kenneth C
KC
Malcolm
D016022:Case-Control Studies; D002469:Cell Separation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D007372:Interferons / Q000494:pharmacology*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D016017:Odds Ratio; D012128:Respiratory Distress Syndrome / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome
D016898:Interferon-alpha; D007372:Interferons