Soluble ST2 fails to reflect persistent endothelial dysfunction or symptoms in post-acute sequelae of COVID-19

Soluble ST2 (sST2), the circulating decoy receptor of interleukin-33 (IL-33), has been validated as a prognostic biomarker of disease severity and vascular injury during acute COVID-19. However, its relevance in the context of post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID) remains unclear.

We analyzed the association between plasma sST2 concentrations and clinical or vascular features in a prospective cohort of 137 long COVID patients (median age: 55 years; 49.6% male), encompassing 194 follow-up visits conducted 3 to 24 months after infection. Fatigue and dyspnea were systematically assessed, alongside full pulmonary function testing (PFTs), including diffusing capacity of the lung for carbon monoxide (DLCO). Plasma concentrations of sST2, VEGF-A, von Willebrand factor antigen (VWF: Ag) and circulating endothelial cells (CECs) were measured.

sST2 concentrations were significantly elevated in hospitalized patients during the acute phase of COVID-19 compared to healthy controls (P<0.001), but returned to baseline concentrations during the post-acute phase and remained stable across follow-up timepoints (3, 6, 12, and 24 months; P=0.11). sST2 was not associated with initial COVID-19 severity (P=0.13), nor with persistent symptoms including fatigue (P=0.11) or dyspnea (P=0.49), or with reduced DLCO (P=0.32) or abnormal PFTs (P=0.55). No correlation was found with VEGF-A, CECs, VWF: Ag, or D-dimers.

Although sST2 is a robust biomarker of acute COVID-19 severity, it does not reflect persistent endothelial dysfunction or symptom burden in long COVID. These findings suggest IL-33/sST2-independent mechanisms may underlie chronic vascular injury in PASC.