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Researchers found that plasma biomarker sST2 independently predicts adverse clinical outcomes in diverse populations of patients with acute respiratory failure.

Plasma biomarker circulating soluble suppression of tumorigenicity 2 (sST2) independently predicts adverse clinical outcomes in diverse populations of patients with acute respiratory failure (ARF), according to a recent study published in Critical Care Medicine. 

ARF, a major driver of ICU admissions, is associated with significant in-hospital mortality and long-term complications, affecting both lung function and extrapulmonary organ dysfunction. Studies have identified distinct ARF sub-phenotypes characterized by differences in plasma biomarker levels; and sST2, a plasma biomarker and decoy receptor for the alarmin interleukin-33 (IL-33), has been implicated in poor clinical outcomes for patients with ARF.

Study author Georgios D. Kitsios, MD, PhD, of the University of Pittsburgh, and colleagues examined whether circulating sST2 levels could predict adverse clinical outcomes in diverse groups of patients who had ARF with various causes.

Measuring & Analyzing Plasma sST2 Levels

 The observational study involved 1,432 adult patients with ARF—863 without COVID-19 and 569 with COVID-19—in five independent cohorts. The patients in the non-COVID cohort were supported by invasive mechanical ventilation at enrollment. At enrollment among the COVID-19 cohort, 47% were supported by invasive mechanical ventilation, 49% by noninvasive oxygenation, and 4% by extracorporeal membrane oxygenation.

The researchers measured sST2 levels in plasma and lower respiratory tract (LRT) specimens and assessed for associations with ARF etiology, severity, organ dysfunction, systemic host response, sub-phenotypes, and 30-day mortality.

Results showed that plasma sST2 levels were higher for patients with non–COVID-related ARF than for patients with COVID-related ARF (P<0.05) and were notably elevated compared with LRT levels (>19-fold), with weak intercompartmental correlation.

“The weak correlation between plasma and LRT sST2 levels suggests a predominantly systemic source,” the authors noted.

In addition, the researchers found that elevated plasma levels of sST2were associated with extrapulmonary organ dysfunction and a hyperinflammatory sub-phenotype of ARF, but not with respiratory indices, including hypoxemia.

Furthermore, elevated plasma sST2 levels were independently associated with 30-day mortality across patient cohorts, adjusted for age, sex, and severity of illness. Longitudinal analysis with at least one follow-up sST2 measurement showed that at 30 days nonsurvivors consistently exhibited elevated sST2 levels from baseline through all follow-up points in the first 2 weeks of critical illness compared with survivors.

Precision Medicine Paradigm in Critical Care

“In summary, our study establishes circulating sST2 as an independent predictor of adverse clinical outcomes in diverse ARF populations, reflecting systemic dysregulation of host responses and extrapulmonary organ dysfunction,” the authors wrote. “Future research should focus on elucidating the cellular sources and triggers of sST2 secretion and exploring targeted modulation of the IL-33/ST2 axis (36), especially in reducing extrapulmonary organ failure. Such approaches could offer precise intervention points with limited off-target effects, potentially reducing inflammation without compromising host defense.”

The authors suggested that the discovery of novel biomarkers for early detection and monitoring of disease progression may result from a deeper understanding of the role of sST2 in the interplay between pulmonary and extrapulmonary organ dysfunction.

“By integrating these strategies into a multidisciplinary approach, we can advance toward a precision medicine paradigm in critical care, tailoring treatments based on the underlying pathobiology of the host response to lung injury,” they concluded.