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

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

Danilo Buonsenso #  1 , Nicola Cotugno #  2   3 , Donato Amodio  2   3 , Giuseppe Rubens Pascucci  2   4 , Gabriele Di Sante  5 , Chiara Pighi  2 , Elena Morrocchi  2 , Alessandro Pucci  2 , Giulio Olivieri  2 , Nicole Colantoni  2 , Lorenza Romani  6 , Arianna Rotili  2 , Alessia Neri  2 , Rosa Morello  7 , Michela Sali  8   9 , Adriana Tremoulet  10   11 , Francesca Raffaelli  9 , Giuseppe Zampino  7 , Paolo Rossi  3   12 , Piero Valentini  7 , Paolo Palma  2   3
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Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long COVID from controls

Danilo Buonsenso et al. Pediatr Res. .

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.

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Conflict of interest statement

Competing interests: D.B. was been granted a non-competitive grant from Pfizer to study Long COVID in children, and has won a grant to study mRNA profile in children with PCC from Roche Italia and ESPID. The funding agencies did not play any role in study design nor in data interpretation. D.B. has participated in educational peer-to-peer programs on Long COVID organized by Pfizer and has participated as invited speaker in a sponsored session of COVID-19 vaccines in children at the ESPID conference in 2022. All the other authors declare no conflicts of interest. Ethics approval: The Long COVID cohort was enrolled as part of a larger, prospective, multidisciplinary follow-up study of children with SARS-CoV-2 infection, approved by the ethics committee of Fondazione Policlinico Universitario A. Gemelli IRCCS of Rome, Italy (Ethic approval ID4518, Prot0040139/21), and informed consent was provided. Written and informed consent was obtained from parents/caregivers and from children older than 5 years of age, according to local guidance of the ethic committees. SARS-CoV2, MIS-C and HC were enrolled from March to April 2020 at Bambino Gesù Children’s Hospital in Rome for the CACTUS (Immunological studies in Children AffeCTed by COVID and acUte reSpiratory diseases) (Prot. 2083_OPBG_2020). The study was approved by local ethical committee, and written informed consent was obtained from all participants or legal guardians as previously reported.

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