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

Abstract

BACKGROUNDThe 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).METHODSIn 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.RESULTSIn 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.CONCLUSIONSPediatric 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.FUNDINGNIH (K23HL-136688, R01-HL148054).

Keywords: Endothelial cells; Inflammation; Innate immunity; Proteomics; Pulmonology.

Figure 1. Study flowchart.

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.

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.

Figure 3. Correlation matrices on days 0, 3, and 7.

Most biomarkers demonstrated modest (|r| between 0.3 and 0.7) correlation.

Figure 4. Differences in biomarkers of inflammation, tissue injury, and DAMPs between PICU survivors and nonsurvivors on days 0 (n = 279), 3 (n = 266), and 7 (n = 207) of ARDS.

Values represent estimated levels (and 95% CIs) after biomarkers underwent log transformation and multivariable adjustment (age, ARDS etiology, immunocompromised status, initial PaO₂/FIO₂). The y axis shows differences in biomarker levels presented as a fold change; the x axis shows the P value. The dotted lines indicate a fold change = 1 (i.e., no difference; horizontal line) and the Bonferroni-corrected P value threshold (unadjusted P = 0.0025, Bonferroni-corrected P = 0.05; vertical line). This P value of the t statistic tests the hypothesis that the coefficient from the regression model differs from 0. Red dots depict biomarkers at unadjusted P < 0.0025; black dots represent those with unadjusted P > 0.0025.

Figure 5. Association between biomarker levels and trajectory over the first 7 days of ARDS with PICU mortality.

The β coefficients (and 95% CIs) are plotted for the association between the overall biomarker level in the first 7 days of ARDS (“status” in sTNFR1 example) and the trajectory (“trajectory” or status × time interaction term) with PICU mortality. In an effort to make meaningful comparisons between biomarkers, values are log transformed and standardized (set to mean = 0, SD = 1), and then adjusted for age, ARDS etiology, immunocompromised status, and initial PaO₂/FIO₂ in a multivariable mixed effects model. Red dots represent biomarkers with adjusted P < 0.05 with higher levels in nonsurvivors, blue dots represent biomarkers with adjusted P < 0.05 with lower levels in nonsurvivors, and black dots represent those with P > 0.05.

Figure 6. Unadjusted plasma biomarker levels between survivors (blue) and nonsurvivors (red) on days 0, 3, and 7 of ARDS.

Black bars are median values. Unadjusted Wilcoxon’s rank sum tests compare survivors and nonsurvivors on days 0, 3, and 7 (*P < 0.05, **P < 0.01, ***P < 0.001). Select biomarkers are shown, with the remainder in Supplemental Figure 4.

Figure 7. Association between biomarker levels and trajectory over the first 7 days of ARDS, with persistent ARDS (PaO₂/FIO₂ ≤ 200 on day 7) or persistent MODS (at least 2 nonpulmonary organ failures on day 7) restricted to patients who remained in the PICU until day 7 (n = 207).

The β coefficients (and 95% CIs) are plotted for the association between the overall biomarker level in the first 7 days of ARDS and the trajectory with persistent ARDS and persistent MODS. Biomarker levels are log transformed and standardized (set to mean = 0, SD = 1), and then adjusted for age, ARDS etiology, immunocompromised status, and initial PaO₂/FIO₂ in a multivariable mixed effects model. Red dots represent biomarkers with adjusted P < 0.05 with higher levels in nonsurvivors, blue dots represent biomarkers with adjusted P < 0.05 with lower levels in nonsurvivors, and black dots represent those with P > 0.05.