Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long COVID from controls

Danilo Buonsenso; Nicola Cotugno; Donato Amodio; Giuseppe Rubens Pascucci; Gabriele Di Sante; Chiara Pighi; Elena Morrocchi; Alessandro Pucci; Giulio Olivieri; Nicole Colantoni; Lorenza Romani; Arianna Rotili; Alessia Neri; Rosa Morello; Michela Sali; Adriana Tremoulet; Francesca Raffaelli; Giuseppe Zampino; Paolo Rossi; Piero Valentini; Paolo Palma

doi:10.1038/s41390-025-03837-0

Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long COVID from controls

Pediatr Res. 2025 Jan 24. doi: 10.1038/s41390-025-03837-0. Online ahead of print.

Authors

Danilo Buonsenso^#¹, Nicola Cotugno^#^{2

3}, Donato Amodio^{2

3}, Giuseppe Rubens Pascucci^{2

4}, Gabriele Di Sante⁵, Chiara Pighi², Elena Morrocchi², Alessandro Pucci², Giulio Olivieri², Nicole Colantoni², Lorenza Romani⁶, Arianna Rotili², Alessia Neri², Rosa Morello⁷, Michela Sali^{8

9}, Adriana Tremoulet^{10

11}, Francesca Raffaelli⁹, Giuseppe Zampino⁷, Paolo Rossi^{3

12}, Piero Valentini⁷, Paolo Palma^{2

3}

Affiliations

¹ Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. danilobuonsenso@gmail.com.
² Clinical Immunology and Vaccinology Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
³ Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
⁴ Probiomics S.r.l., Via Montpellier 1, Rome, 00133, Italy.
⁵ Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy, University of Perugia, Rome, Italy.
⁶ Infectious Disease Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁷ Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
⁸ Department of Biotechnological, Basic, Intensivological and Perioperatory Sciences-Section of Microbiology, Università Cattolica del S Cuore, Rome, 00168, Italy.
⁹ Department of Laboratory and Infectivology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, 00168, Italy.
¹⁰ Department of Pediatrics & Kawasaki Disease Research Center, University of California San Diego (UCSD), San Diego, CA, USA.
¹¹ Rady Children's Hospital, San Diego, CA, USA.
¹² Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

^# Contributed equally.

PMID: 39849114
DOI: 10.1038/s41390-025-03837-0

Abstract

Background: Recent proteomic studies have documented that Long COVID in adults is characterized by a pro-inflammatory signature with thromboinflammation. However, if similar events happen also in children with Long COVID has never been investigated.

Methods: We performed an extensive protein analysis of blood plasma from pediatric patients younger than 19 years of age Long COVID and a control group of children with acute COVID-19, MIS-C, and healthy controls resulted similar for sex distribution and age. Children were classified as Long COVID if symptoms persisted for at least 8 weeks since the initial infection, negatively impacted daily life and could not be explained otherwise.

Results: 112 children were included in the study, including 34 children fulfilling clinical criteria of Long COVID, 32 acute SARS-CoV-2 infection, 27 MIS-C and 19 healthy controls. Compared with controls, pediatric Long COVID was characterized by higher expression of the proinflammatory and pro-angiogenetic set of chemokines CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a. A Machine Learning model based on proteomic profile was able to identify LC with an accuracy of 0.93, specificity of 0.86 and sensitivity of 0.97.

Conclusions: Pediatric Long COVID patients have a well distinct blood protein signature marked by increased ongoing general and endothelial inflammation, similarly as happens in adults.

Impact: Pediatric Long COVID has a distinct blood protein signature marked by increased ongoing general and endothelial inflammation. This is the first study studying and documenting proinflammatory profile in blood samples of children with long COVID. Long COVID was characterized by higher expression of the proinflammatory and pro-angiogenetic set of chemokines CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a. A proteomic profile was able to identify Long COVID with an accuracy of 0.93, specificity of 0.86 and sensitivity of 0.97. These findings may inform development of future diagnostic tests.