Soluble ST2 fails to reflect persistent endothelial dysfunction or symptoms in post-acute sequelae of COVID-19 - 04/03/26

Le ST2 soluble ne reflète pas la dysfonction endothéliale persistante ni les symptômes du COVID long

Doi : 10.1016/j.pharma.2026.02.008

David M. Smadja ^a,^b,⁎ , Sven Günther ^a,^c, Jeanne Rancic ^a,^b, Alexandre G. Lellouch ^a,^b,^d,^e, Bertrand Renaud ^c, Jean-Luc Diehl ^a,^e, Aurélien Philippe ^a,^b

^a PARCC, Inserm, Université Paris-Cité, 75015 Paris, France

^b Service d’Hématologie Biologique, Hôpital Européen Georges-Pompidou, AP–HP, 75015 Paris, France

^c Service de Physiologie Respiratoire, Hôpital Européen Georges-Pompidou, AP–HP, 75015 Paris, France

^d Division of Plastic and Reconstructive Surgery, Cedars Sinai Hospital, Los Angeles, CA, United States

^e Service de Réanimation Médicale, Hôpital Européen Georges-Pompidou, AP–HP, 75015 Paris, France

^⁎ Corresponding author. Service d’Hématologie Biologique, Hôpital Européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France. Service d’Hématologie Biologique, Hôpital Européen Georges-Pompidou 20, rue Leblanc Paris 75015 France

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In corso di stampa. Prove corrette dall'autore. Disponibile online dal Wednesday 04 March 2026

Highlights

•	sST2 is elevated in acute COVID-19 but normalizes in long COVID cases.
•	No link found between sST2 and fatigue, dyspnea, or DLCO in PASC.
•	sST2 shows no correlation with VEGF-A or endothelial biomarkers.
•	The IL-33/sST2 axis is not involved in long-term vascular injury.
•	sST2 is ineffective as a biomarker for persistent COVID symptoms.

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Summary

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Il testo completo di questo articolo è disponibile in PDF.

Résumé

Objectifs

Le récepteur soluble ST2 (sST2), forme circulante du récepteur de l’IL-33, est un biomarqueur validé de la sévérité au cours de la phase aiguë de la COVID-19. Cette étude vise à explorer l’association entre les niveaux de sST2 et les phénotypes cliniques et/ou vasculaires du COVID long.

Méthodes

Nous avons analysé prospectivement 137 patients atteints de COVID long (âge médian : 55 ans ; 49,6 % d’hommes), représentant 194 visites entre 3 et 24 mois post-infection. Les patients ont bénéficié d’une évaluation clinique (fatigue, dyspnée), d’explorations fonctionnelles respiratoires (EFR) complètes incluant la capacité de diffusion du monoxyde de carbone (DLCO), ainsi que les dosages plasmatiques de sST2, VEGF-A, facteur von Willebrand antigène (VWF:Ag) et cellules endothéliales circulantes (CECs).

Résultats

Le sST2 était significativement élevé chez les patients hospitalisés pour COVID-19 aiguë comparé aux témoins sains ( p < 0,001), mais les concentrations revenaient à la normale lors du suivi et restaient stables entre 3 et 24 mois ( p = 0,11). Aucun lien n’a été retrouvé entre le sST2 et la sévérité initiale ( p = 0,13), ni avec la fatigue ( p = 0,11), la dyspnée ( p = 0,49), la DLCO réduite ( p = 0,32), ou les anomalies des EFR ( p = 0,55). Aucune corrélation significative n’était observée avec le VEGF-A, les CECs, le facteur von Willebrand antigène (VWF:Ag) ou les D-dimères.

Conclusion

Le sST2 ne reflète ni les symptômes persistants ni la dysfonction endothéliale du COVID long. L’axe IL-33/sST2 semble donc non impliqué dans les séquelles vasculaires prolongées, suggérant l’intérêt d’autres cibles biologiques.

Il testo completo di questo articolo è disponibile in PDF.

Keywords : Long COVID, PASC, sST2, Endotheliopathy, Biomarkers, COVID-19

Mots clés : COVID long, PASC, sST2, Endothéliopathie, Biomarqueurs, COVID-19