Parsimonious immune-response endotypes and global outcome in patients with traumatic brain injury
Romit Samanta, Anne-Cécile Chiollaz, Edward Needham, John K. Yue, Adel Helmy, Elisa R. Zanier, Kevin Wang, Firas Kobeissy, Jussi P. Posti, Charlotte Summers, Geoffrey T. Manley, Andrew IR Maas, Olli Tenovuo, Jean-Charles Sanchez, David Menon, David K. Menon, Neeraj Badjatia, Ramon Diaz-Arrastia, Ann-Christine Duhaime, V Ramana Feeser, Shankar Gopinath, Ramesh Grandhi, Ruchira J. Ha, Dirk Keene, Christopher Madden, Michael McCrea, Randall Merchant, Laura B. Ngwenya, Richard B. Rodgers, David Schnyer, Sabrina R. Taylor, Ross Zafonte, Cecilia Ackerlund, Krisztina Amrein, Nada Andelic, Lasse Andreassen, Audny Anke, Gérard Audibert, Philippe Azouvi, Maria Luisa Azzolini, Ronald Bartels, Ronny Beer, Bo-Michael Bellander, Habib Benali, Maurizio Berardino, Luigi Beretta, Erta Beqiri, Morten Blaabjerg, Stine Borgen Lund, Camilla Brorsson, Andras Buki, Manuel Cabeleira, Alessio Caccioppola, Emiliana Calappi, Maria Rosa Calvi, Peter Cameron, Guillermo Carbayo Lozano, Marco Carbonara, Ana M. Castaño-León, Simona Cavallo, Giorgio Chevallard, Arturo Chieregato, Giuseppe Citerio, Hans Clusmann, Mark Steven Coburn, Jonathan Coles, Jamie D. Cooper, Marta Correia, Endre Czeiter, Marek Czosnyka, Claire Dahyot-Fizelier, Paul Dark, Véronique De Keyser, Vincent Degos, Francesco Della Corte, Hugo den Boogert, Bart Depreitere, Đula Đilvesi, Abhishek Dixit, Jens Dreier, Guy-Loup Dulière, Ari Ercole, Erzsébet Ezer, Martin Fabricius, Kelly Foks, Shirin Frisvold, Alex Furmanov, Damien Galanaud, Dashiell Gantner, Alexandre Ghuysen, Lelde Giga, Jagoš Golubović, Pedro A. Gomez, Benjamin Gravesteijn, Francesca Grossi, Deepak Gupta, Iain Haitsma, Raimund Helbok, Eirik Helseth, Jilske Huijben
Abstract
BACKGROUND: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. METHODS: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. FINDINGS: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. INTERPRETATION: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. FUNDING: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.