Gene expression signatures identify pediatric patients with multiple organ dysfunction who require advanced life support in the intensive care unit

Abstract

Background: Multiple organ dysfunction syndrome (MODS) occurs in the setting of a variety of pathologies including infection and trauma. Some of these patients will further decompensate and require extra corporeal membrane oxygenation (ECMO) as a palliating maneuver to allow time for recovery of cardiopulmonary function. The molecular mechanisms driving progression from MODS to cardiopulmonary collapse remain incompletely understood, and no biomarkers have been defined to identify those MODS patients at highest risk for progression to requiring ECMO support. We hypothesize that molecular features derived from whole blood transcriptomic profiling either alone or in combination with traditional clinical and laboratory markers can prospectively identify these high risk MODS patients in the pediatric intensive care unit (PICU). Design/Methods: Whole blood RNA-seq profiling was performed for 23 MODS patients at three time points during their ICU stay (at diagnosis of MODS, 72 hours after, and 8 days later), as well as four healthy controls undergoing routine sedation. Of the 23 MODS patients, six required ECMO support (ECMO patients). The predictive power of conventional demographic and clinical features was quantified for differentiating the MODS and ECMO patients. We then compared the performance of markers derived from transcriptomic profiling including (1) transcriptomically imputed leukocyte subtype distribution, (2) relevant published gene signatures and (3) a novel differential gene expression signature computed from our data set. The predictive power of our novel gene expression signature was then validated using independently published datasets. Results: None of the five demographic characteristics and 14 clinical features, including The Pediatric Logistic Organ Dysfunction (PELOD) score, could predict deterioration of MODS to ECMO at baseline. From previously published sepsis signatures, only the signatures positively associated with patients mortality could differentiate ECMO patients from MODS patients, when applied to our transcriptomic dataset (P-value ranges from 0.01 to 0.04). Deconvolution of bulk RNA-Seq samples suggested that lower neutrophil counts were associated with increased risk of progression from MODS to ECMO (P-value = 0.03, OR=2.82 [95% CI 0.63 - 12.45]). A total of 28 genes were differentially expressed between ECMO and MODS patients at baseline (log2 fold change ≥ 1 or ≤ -1 with false discovery rate ≤ 0.2). These genes are involved in protein maintenance and epigenetic-related processes. Further univariate analysis of these 28 genes suggested a signature of six DE genes associated with ECMO (OR > 3.0, P-value ≤ 0.05). Notably, this contains a set of histone marker genes, including H1F0, HIST2H3C, HIST1H2AI, HIST1H4, and HIST1H1B, that were highly expressed in ECMO. A risk score derived from expression of these genes differentiated ECMO and MODS patients in our dataset (AUC = 0.91, 95% CI 0.79-0.1.00, P-value = 7e-04) as well as validation dataset (AUC= 0.73,95% CI 0.53-0.93, P-value = 2e-02). Conclusions: This study identified lower neutrophils and upregulation of specific histone related genes as a putative signature for deterioration of MODS to ECMO. This study demonstrates that transcriptomic features may be superior to traditional clinical methods of ascertaining severity in patients with MODS.

Pediatric Multi-Organ Dysfunction Syndrome: Analysis by an Untargeted “Shotgun” Lipidomic Approach Reveals Low-abundance Plasma Phospholipids and Dynamic Recovery Over 8-Day Period, a Single-Center Observational Study

“…Synthesized by neutrophils [48-50], LysoPS enhances efferocytosis (“to carry to the grave” [51]) of neutrophils by macrophages [52] during acute inflammation [53,54]. Neutrophil levels were lower and more like controls in patients that needed ECMO [55] and other studies have shown that neutrophil levels drop in the sickest patients as bone marrow activity becomes suppressed. This may lead to the lower levels of LysoPS.…”