Integrated clustering of multiple immune marker trajectories reveals different immunotypes in severely injured patients
Authors: Bodinier Maxime , Peronnet Estelle , Llitjos Jean-François , Kreitmann Louis , Brengel-Pesce Karen , Rimmelé Thomas , Fleurie Aurore , Textoris Julien , Venet Fabienne , Maucort-Boulch Delphine , Monneret Guillaume ,   REALISM study group,   HCL, Arnal Sophie , Augris-Mathieu Caroline , Bayle Frédérique , Caruso Liana , Ber Charles-Eric , Ben-Amor Asma , Bellocq Anne-Sophie , Benatir Farida , Bertin-Maghit Anne , Bertin-Maghit Marc , Boibieux André , Bouffard Yves , Cejka Jean-Christophe , Cerro Valérie , Crozon-Clauzel Jullien , Davidson Julien , Debord-Peguet Sophie , Delwarde Benjamin , Deleat-Besson Robert , Delsuc Claire , Devigne Bertrand , Fayolle-Pivot Laure , Faure Alexandre , Floccard Bernard , Gatel Julie , Genin Charline , Girardot Thibaut , Gregoire Arnaud , Hengy Baptiste , Huriaux Laetitia , Jadaud Catherine , Lepape Alain , Leray Véronique , Lukaszewicz Anne-Claire , Marcotte Guillaume , Martin Olivier , Matray Marie , Maucort-Boulch Delphine , Meuret Pascal , Monard Céline , Moriceau Florent , Monneret Guillaume , Panel Nathalie , Rahali Najia , Rimmele Thomas , Truc Cyrille , Uberti Thomas , Vallin Hélène , Venet Fabienne , Tissot Sylvie , Zadam Abbès ,   bioMérieux, Blein Sophie , Brengel-Pesce Karen , Cerrato Elisabeth , Cheynet Valérie , Gallet-Gorius Emmanuelle , Guichard Audrey , Jourdan Camille , Koenig Natacha , Mallet François , Meunier Boris , Moucadel Virginie , Mommert Marine , Oriol Guy , Pachot Alexandre , Peronnet Estelle , Schrevel Claire , Tabone Olivier , Textoris Julien , Marcos Javier Yugueros ,   BIOASTER, Becker Jérémie , Bequet Frédéric , Bounab Yacine , Brajon Florian , Canard Bertrand , Collus Muriel , Garcon Nathalie , Gorse Irène , Guyard Cyril , Lavocat Fabien , Leissner Philippe , Louis Karen , Mistretta Maxime , Moriniere Jeanne , Mouscaz Yoann , Noailles Laura , Perret Magali , Reynier Frédéric , Riffaud Cindy , Rol Mary-Luz , Sapay Nicolas , Tran Trang , Vedrine Christophe ,   SANOFI, Carre Christophe , Cortez Pierre , de Monfort Aymeric , Florin Karine , Fraisse Laurent , Fugier Isabelle , PAYRARD Sandrine , Peleraux Annick , Quemeneur Laurence ,   ESPCI, Griffiths Andrew , Toetsch Stephanie ,   GSK, Ashton Teri , Gough Peter J. , Berger Scott B. , Gardiner David , Gillespie Iain , Macnamara Aidan , Raychaudhuri Aparna , Smylie Rob , Tan Lionel , Tipple Craig 
Published: July 2024

Abstract
Background
The immune response of critically ill patients, such as those with sepsis, severe trauma, or major surgery, is heterogeneous and dynamic, but its characterization and impact on outcomes are poorly understood. Until now, the primary challenge in advancing our understanding of the disease has been to concurrently address both multiparametric and temporal aspects.

Methods
We used a clustering method to identify distinct groups of patients, based on various immune marker trajectories during the first week after admission to ICU. In 339 severely injured patients, we initially longitudinally clustered common biomarkers (both soluble and cellular parameters), whose variations are well-established during the immunosuppressive phase of sepsis. We then applied this multi-trajectory clustering using markers composed of whole blood immune-related mRNA.

Results
We found that both sets of markers revealed two immunotypes, one of which was associated with worse outcomes, such as increased risk of hospital-acquired infection and mortality, and prolonged hospital stays. This immunotype showed signs of both hyperinflammation and immunosuppression, which persisted over time.

Conclusion
Our study suggest that the immune system of critically ill patients can be characterized by two distinct longitudinal immunotypes, one of which included patients with a persistently dysregulated and impaired immune response. This work confirms the relevance of such methodology to stratify patients and pave the way for further studies using markers indicative of potential immunomodulatory drug targets.

Graphical Abstract