Response to Letter to the Editor: “Reframing Soluble ST2 as a Vascular Signal in Acute Respiratory Failure”

To the Editor:

We thank Ting and Chen for their thoughtful commentary(1) on our recent study examining plasma soluble ST2 (sST2) as a prognostic biomarker in acute respiratory failure (ARF).(2) Their insights underscore key translational questions and help frame the path toward clinical implementation.

We agree that inter-cohort variability in baseline sST2 levels merits deeper examination. Site-specific factors such as fluid administration, sedation practices, and timing of biospecimen collection are potential unmeasured confounders that may contribute to these differences. However, the consistent prognostic value of sST2 across five diverse patient cohorts, multiple assay platforms, and site-specific variations underscore the robustness of this biomarker.(2) Moving forward, it will be essential to establish clinically meaningful thresholds using rapid, point-of-care assays to enable real-time risk stratification in ARF.

We concur with the authors that the correlation between sST2 and angiopoietin-2 (Ang-2)—a well-established marker of endothelial dysfunction—suggests the possibility of a shared vascular origin. Ting and Chen note that prior studies have reported sST2’s dissociation from canonical inflammatory cytokines, suggesting a possible model of sST2 as a readout of biomechanical or endothelial stress. However, our probabilistic modeling revealed significant associations between sST2 and both endothelial markers (such as Ang-2) and immune-derived mediators (such as IL-8). Importantly, sST2 was enriched in patients with the hyperinflammatory ARF subphenotype and remained prognostic even after accounting for this classification, suggesting that it captures distinct and additive pathobiology. Moreover, we previously showed that sST2 levels are associated with circulating pathogen-associated molecular patterns, including microbial cell-free DNA(3) and β-D-glucan.(4) These findings support a model in which sST2 serves as an integrative biomarker, reflecting multiple convergent pathways that include vascular dysfunction, inflammatory activation, and cellular stress responses.

Importantly, sST2 remained persistently elevated in non-survivors over time.(2) This temporal pattern supports the role of sST2 as a dynamic indicator of ongoing systemic disease progression, rather than simply a static marker of baseline risk. Given that extrapulmonary organ failure remains the leading cause of death in hypoxemic ARF, the ability of sST2 to track systemic injury over time may offer a practical tool for early identification and ongoing monitoring of high-risk patients.

We also share Ting and Chen’s interest in the therapeutic potential of targeting the IL-33/ST2 axis. As a soluble decoy receptor, sST2 neutralizes IL-33 and may thereby inhibit its beneficial effects on vascular repair, epithelial integrity, and immune regulation.(5) Excessive sST2 could thus be maladaptive in ARF, blocking reparative IL-33 signaling when tissue recovery is critical. The therapeutic tractability of this pathway opens promising avenues for precision interventions.

In summary, we thank Ting and Chen for advancing this important discussion. sST2 remains a promising biomarker in ARF, likely reflecting multiple mechanisms. Further mechanistic and translational studies, including point-of-care assay validation and IL-33/ST2 therapeutic modulation, are warranted to clarify sST2’s role and enable precision targeting of patients at high risk for extrapulmonary organ dysfunction in ARF.