Lieuwe D J Bos1,2, Brendon P Scicluna3,4, David S Y Ong5,6, Olaf Cremer7, Tom van der Poll3, Marcus J Schultz1,8. 1. 1 Intensive Care, Laboratory of Experimental Intensive Care and Anesthesiology. 2. 2 Department of Respiratory Medicine. 3. 3 Center of Experimental Molecular Medicine, and. 4. 4 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Infection and Immunity, Amsterdam University Medical Center, location Academic Medical Center, Amsterdam, the Netherlands. 5. 5 Department of Microbiology, Julius Center for Health Sciences and Primary Care. 6. 6 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, and. 7. 7 Intensive Care, University Medical Center Utrecht, Utrecht, the Netherlands; and. 8. 8 Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand.
Abstract
Rationale: Two biologic phenotypes of acute respiratory distress syndrome (ARDS) have been identified based on plasma protein markers in four previous studies. Objectives: To determine if blood leukocyte gene expression is different between the "reactive" and "uninflamed" phenotype. Methods: This is a new study adding blood leukocyte transcriptomics and bioinformatics analysis to an existing patient cohort of ARDS in patients with sepsis admitted to two ICUs during a 1.5-year period. Canonical pathway analysis was performed. Measurements and Main Results: A total of 210 patients with sepsis and ARDS were included, of whom 128 had a reactive and 82 an uninflamed phenotype. A total of 3,332/11,443 (29%) transcripts were significantly different between the phenotypes. Canonical pathway analysis showed upregulation of oxidative phosphorylation genes indicative of mitochondrial dysfunction (52% of genes in pathway). The uninflamed phenotype was characterized by upregulation of mitogen-activated protein kinase pathways. Conclusions: A third of genes are differentially expressed between biologic phenotypes of ARDS supporting the observation that the subgroups of ARDS are incomparable in terms of pathophysiology. These data provide additional support for biologic heterogeneity in patients with ARDS and suggests that a personalized approach to intervention focusing on oxidative phosphorylation is pivotal in this condition.
Rationale: Two biologic phenotypes of acute respiratory distress syndrome (ARDS) have been identified based on plasma protein markers in four previous studies. Objectives: To determine if blood leukocyte gene expression is different between the "reactive" and "uninflamed" phenotype. Methods: This is a new study adding blood leukocyte transcriptomics and bioinformatics analysis to an existing patient cohort of ARDS in patients with sepsis admitted to two ICUs during a 1.5-year period. Canonical pathway analysis was performed. Measurements and Main Results: A total of 210 patients with sepsis and ARDS were included, of whom 128 had a reactive and 82 an uninflamed phenotype. A total of 3,332/11,443 (29%) transcripts were significantly different between the phenotypes. Canonical pathway analysis showed upregulation of oxidative phosphorylation genes indicative of mitochondrial dysfunction (52% of genes in pathway). The uninflamed phenotype was characterized by upregulation of mitogen-activated protein kinase pathways. Conclusions: A third of genes are differentially expressed between biologic phenotypes of ARDS supporting the observation that the subgroups of ARDS are incomparable in terms of pathophysiology. These data provide additional support for biologic heterogeneity in patients with ARDS and suggests that a personalized approach to intervention focusing on oxidative phosphorylation is pivotal in this condition.
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