Immune modulation by personalized vs standard prehabilitation program before major surgery

Position du problème et objectif(s) de l’étude

Up to 30% of surgical patients experience delayed surgical recovery, resulting in a 145 billion-dollar socioeconomic burden in the US. Multi-modal prehabilitation programs (prehab) integrating exercise, nutrition, cognitive training and stress reduction have been recognized to safely improve patient surgical recovery. However, the lack of personalization in prehab regimens, particularly the absence of pathophysiologically-driven implementation, remains a major limitation that has reduced their effectiveness. Here, a high-dimensional mass cytometry (CyTOF) approach was employed to comprehensively and dynamically characterize the effect of two different prehab approaches on patients’ immune system before surgery.

Matériel et méthodes

Fifty-four patients requiring major abdominal surgery were included in a monocentric randomized trial (NCT04498208, IRB-57570). Patients were randomized to either standard (i.e. paper-based prehabilitation program with a customizable daily step goal, n = 27 patients) or personalized (i.e. personalized weekly remote coaching program tailored to the patient's abilities and progress encompassing exercise, nutrition, cognition and behavioral techniques, n = 27 patients) prehab 2 to 6 weeks prior to surgery. Cognitive and physical evaluations were performed at enrollment (i.e., before the start of the prehab program) and at the end of the prehabilitation program, shortly before surgery. Whole blood samples collected at enrollment and at the end of the program were analyzed using a 47-plex single-cell CyTOF immunoassay. The effect of standard and personalized prehab on 1096 innate and adaptive immune features was classified using a sparse machine learning modeling method (Stabl). Model performance was established using Monte-Carlo cross-validation, accounting for repeated sampling and quantified using the Area Under the Receiver Operating characteristic Curve (AUROC).

Résultats & Discussion

A multivariable model accurately classified patients’ immune system before and after personalized (AUROC of 0.884 [0.786,0.968], p-value=2.095e-06 (Mann-Whitney (M-W)-Utest)) but not standard (AUROC of 0.625 [0.475,0.777], p-value=1.168e-01 (M-W-Utest)) prehab. Major immune modifications induced by personalized prehab included dampened pERK1-2 signaling in classical monocytes and Myeloid Derived Suppressor Cells (MDSC) in response to IL-2, IL-4, and IL-6 stimulation, as well as reduced pCREB signaling in Th1 cells in favor of a lower basal inflammatory state. Immune changes aligned with significant clinical improvements after personalized prehab in wall squat test, timed-up-and-go test, 6 minutes walk test (6MWT), and quick mild cognitive impairment test. Patients in the personalized prehab group also had better post-operative outcomes than the standard prehab group with less severe complications graded with the Clavien-Dindo Classification (1[1,1] vs 1[1,2] respectively, p= 0.029, M-W U test). While standard prehab improved the 6MWT, no other clinical change was significant, and no model successfully classified immunome change.

Conclusion

Personalized prehab, but not standard prehab, successfully modulated both innate and adaptive immune responses in patients before surgery, aligning with improved physical and cognitive performance, as well as previous findings related to the prediction of post-operative complications. Tailoring prehab programs to individual patients based on such insights will be crucial for the development of more effective, data-driven interventions.

Auteurs

Amélie CAMBRIEL (1) , Amy TSAI (2), Maximilian SABAYEV (2), Julien HEDOU (2), Benjamin CHOISY (2), Elisabeth SHELTON (3), Kreeti SINGH (3), Jonas AMAR (4), Valentin BADEA (4), Serena BRUCKMAN (3), Ed GANIO (2), Jakob EINHAUS (2), Dorien FEYAERTS (2), Ina STELZER (2), Masaki SATO (2), Thomas BONHAM (2), Olivier LANGERON (5), Dyani GAUDILLIERE (2), Andrew SHELTON (3), Cindy KIN (3), Brice GAUDILLIERE (2), Franck VERDONK (6) - (1)Department Of Anesthesiology Perioperative And Pain Medicine, Stanford University;aphp, Hopital Saint Antoine, Dmu Dream, Department Of Anesthesiology And Critical Care, Ap-Hp, Paris, France, Stanford, États-Unis, (2)Department Of Anesthesiology Perioperative And Pain Medicine, Stanford University;aphp, Hopital Saint Antoine, Dmu Dream, Department Of Anesthesiology And Critical Care, Ap-Hp, Paris, France-Stanford (états-Unis), Stanford, États-Unis, (3)Department Of Surgery, Stanford University, Stanford, États-Unis, (4)Department Of Anesthesia, Pain And Perioperative Medicine, Stanford University, Stanford, États-Unis, (5)Département D'anesthésie Réanimation, Chu Brest,, Brest, France, (6)Aphp, Hopital Saint Antoine, Dmu Dream, Department Of Anesthesiology And Critical Care, Ap-Hp, Paris, France; Department Of Anesthesiology Perioperative And Pain Medicine, Stanford University, Paris, France

Orateur(s)

Daniel EL KHOURY (Paris)