Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome
Nadir Yehya, Thomas J. Booth, Gnana D. Ardhanari, Jill M. Thompson, L.K. Metthew Lam, Jacob E. Till, Mark V. Mai, Garrett Keim, Daniel J. McKeone, E. Scott Halstead, Patrick Lahni, Brian M. Varisco, Wanding Zhou, Erica L. Carpenter, Jason D. Christie, Nilam S. Mangalmurti
Nadir Yehya, Thomas J. Booth, Gnana D. Ardhanari, Jill M. Thompson, L.K. Metthew Lam, Jacob E. Till, Mark V. Mai, Garrett Keim, Daniel J. McKeone, E. Scott Halstead, Patrick Lahni, Brian M. Varisco, Wanding Zhou, Erica L. Carpenter, Jason D. Christie, Nilam S. Mangalmurti
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Clinical Research and Public Health Inflammation Pulmonology

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome

Abstract

BACKGROUND The molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODS In a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTS In 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONS Pediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDING NIH (K23HL-136688, R01-HL148054).

Authors

Nadir Yehya, Thomas J. Booth, Gnana D. Ardhanari, Jill M. Thompson, L.K. Metthew Lam, Jacob E. Till, Mark V. Mai, Garrett Keim, Daniel J. McKeone, E. Scott Halstead, Patrick Lahni, Brian M. Varisco, Wanding Zhou, Erica L. Carpenter, Jason D. Christie, Nilam S. Mangalmurti

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Figure 2

Clinical trajectories of ARDS severity (Berlin mild, moderate, severe), MODS, and hyper-/hypoinflammatory ARDS subphenotype (defined using a parsimonious algorithm of IL-6, IL-8, CCL3/MIP-1α, and ANG2) over the first 7 days.

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Clinical trajectories of ARDS severity (Berlin mild, moderate, severe), ...
Top: Berlin ARDS trajectories are stratified according to whether patients have mild (gray), moderate (blue), or severe (green) on day 0; on day 3, patients are again restratified according to whether ARDS has resolved (olive), or is mild (aqua), moderate (red), or severe (blue) according to Berlin criteria. Middle: MODS trajectories are stratified according to whether patients have at least 2 nonpulmonary organ failures (aqua) or not (olive) on day 0; on day 3, patients are restratified according to whether they have at least 2 nonpulmonary organ failures (red) or not (blue). Bottom: Day 0 hypo- (olive) and hyperinflammatory (aqua) ARDS trajectories, and day 3 hypo- (blue) and hyperinflammatory (red) ARDS subphenotype are similarly labeled. By day 7, 45 patients had been discharged alive from the PICU, and 27 had died. Note that these 27 nonsurvivors within 7 days of ARDS onset represent a subset of the total (n = 64) who died in the PICU.