ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cytokines and Soluble Mediators in Immunity

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1599982

This article is part of the Research TopicExploring the Immune Landscape of the Liver: Mechanisms in Health and DiseaseView all articles

Comprehensive Immune Profiling and Predictive Modelling of Paediatric Acute Hepatitis of Unknown Aetiology from a Spanish Cohort

Provisionally accepted
Eduardo  López-CollazoEduardo López-Collazo*Roberto  Lozano-RodríguezRoberto Lozano-RodríguezLoreto  HierroLoreto HierroMaría José  QuilesMaría José QuilesAlejandro  Pascual-IglesiasAlejandro Pascual-IglesiasVerónica  Terrón-ArcosVerónica Terrón-ArcosGema  MuñozGema MuñozEsteban  FraucaEsteban FraucaFrancisco  J CuetoFrancisco J CuetoCristina  CalvoCristina CalvoLaura  Córdoba-GarcíaLaura Córdoba-GarcíaJesús  Fernández-FelipeJesús Fernández-FelipeLaura  Hurtado NavarroLaura Hurtado NavarroJulia  del Prado-MonteroJulia del Prado-MonteroGonzalo  Sáenz de Santa María-DiezGonzalo Sáenz de Santa María-DiezDaniel  Arvelo-RosarioDaniel Arvelo-RosarioPaloma  JaraPaloma JaraCarlos  Del FresnoCarlos Del Fresno
  • University Hospital La Paz Research Institute (IdiPAZ), Madrid, Spain

The final, formatted version of the article will be published soon.

Introduction: Paediatric acute hepatitis of unknown aetiology (PAHUA) has emerged as a global health concern, yet its cause remains unidentified. This study characterises the clinical and immunological profiles of PAHUA to identify reliable immune biomarkers for accurate diagnosis.Methods: Samples from 24 PAHUA patients, 6 children with autoimmune hepatitis (AIH), and 13 healthy paediatric volunteers (HVs) were analysed. Immunophenotyping, soluble immune checkpoints (ICs) and cytokine profiling, and ex vivo immune responses were assessed using spectral flow cytometry. Clustering and logistic regression modelling were used to identify predictive biomarkers.Results: PAHUA cases frequently presented with gastrointestinal symptoms and liver damage preceding jaundice, with 59% progressing to paediatric acute liver failure (pALF). Adenovirus was detected in only 17.6% of PAHUA patients, suggesting it is unlikely to be the primary causative agent. Antibodies against the SARS-CoV-2 Spike protein were identified in 88.2% of PAHUA patients, as well as in AIH and HV groups, indicating prior exposure. Immunophenotyping, ICs and cytokine profiling, and ex vivo immune revealed distinct immune profiles between PAHUA and non-PAHUA individuals. Furthermore, clustering and logistic regression modelling identified potential predictive biomarkers, including the plasmatic ICs Gal-9 and sTim-3, alongside specific immune cell populations. Notably, a combined Gal-9 and sTim-3 model achieved an AUC of 1.000 in differentiating PAHUA patients from non-PAHUA individuals.Conclusions: Despite the limited cohort analysed, owing to the rarity of cases worldwide, our data provide valuable insights for an accurate, early, and minimally invasive diagnosis of PAHUA. These patients exhibit a distinct immunological profile, with ICs, particularly Gal-9 and sTim-3, showing strong potential as reliable biomarkers.

Keywords: Hepatitis, Unknown Aetiology, biomarker, Gal-9, sTim-3

Received: 25 Mar 2025; Accepted: 04 Jun 2025.

Copyright: © 2025 López-Collazo, Lozano-Rodríguez, Hierro, Quiles, Pascual-Iglesias, Terrón-Arcos, Muñoz, Frauca, Cueto, Calvo, Córdoba-García, Fernández-Felipe, Hurtado Navarro, del Prado-Montero, Sáenz de Santa María-Diez, Arvelo-Rosario, Jara and Del Fresno. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Eduardo López-Collazo, University Hospital La Paz Research Institute (IdiPAZ), Madrid, Spain

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