Lotte M. C. Jacobs

Prehabilitation is an emerging preoperative strategy designed to optimise patients' functional capacity before surgery to improve postoperative outcomes. Previous studies have demonstrated its clinical benefit, including enhanced recovery and reduced postoperative complications. However, the mechanisms underlying these benefits remain poorly understood. This exploratory study investigates the potential effects of prehabilitation on pre- and postoperative immune function. This prospective study utilized data and material from a subgroup of patients participating in the F4S PREHAB trial, which is a stepped-wedge trial investigating the effects of multimodal prehabilitation prior to major surgery. In this substudy, patients undergoing elective bladder, oesophageal, or rectal cancer surgery between June 2022 and November 2023, were included. Immune function was assessed at baseline, following the prehabilitation or usual care period, and on postoperative day 1 (POD1) by examining ex vivo cytokine production capacity, plasma cytokine concentrations, and mHLA-DR expression. This substudy included 130 patients: 102 in the prehabilitation group and 28 in the control group. Following prehabilitation, ex vivo production of pro-inflammatory cytokines was reduced, while ex vivo production of the anti-inflammatory cytokine IL-10 was increased. Plasma concentrations of IL-6 and IL-10 were decreased following prehabilitation. On POD1, no significant differences in postoperative immune function were observed between the prehabilitation and control groups. This study suggests that multimodal prehabilitation influences basal immune function, leading to a less inflammatory state. However, as no significant differences in immune function were observed between prehabilitation and control groups on POD1, the impact of prehabilitation on postoperative immune function may be limited.

Background: Trauma is an important risk factor for the development of nosocomial infections. Immunological consequences of trauma in paediatric patients remains scarcely explored and associations between injury severity and immunosuppression, a decreased functionality of the immune system, have not yet been investigated in this population. Therefore, the aim of this study was to characterise the early effects of trauma and trauma severity on paediatric immune function, and to assess whether immune profiles differed between polytrauma patients who developed nosocomial infections and those who experienced an uncomplicated recovery. Methods: This prospective explorative cohort study was conducted at Radboud University Medical Center between January 2024 and June 2025. Three groups were included: controls (n=10), monotrauma patients (single fracture requiring acute surgery, n=9), and polytrauma patients (Injury Severity Score ≥ 16, n=10) aged 4–16 years. Immune function was assessed using blood samples at three timepoints: at the trauma scene (HEMS), at the emergency room (ER), and on post-injury day 1 (PID1). Immune outcomes included immune cell counts and functionality, plasma concentrations of damage-associated molecular patterns (DAMPs) and cytokines, and ex vivo cytokine production capacity upon whole blood stimulation with an endotoxin. Results: Inflammatory biomarkers were elevated already at the trauma scene, followed by compensatory mechanisms. Immunosuppression was already detected in the ER. Immune trajectories differed between poly- and monotrauma patients, with the latter showing a milder response. Polytrauma patients who developed nosocomial infections exhibited more profound immunosuppression. Immunosuppression was at least partially reversible ex vivo by co-stimulation with interferon-γ (IFN-γ). Conclusions: Paediatric traumatic injury rapidly elicits a robust immune response, particularly in cases of polytrauma, alongside compensatory mechanisms. Children who developed nosocomial infections showed more pronounced immunosuppression, which might be partially reversed with IFN-γ. Given the small sample size, these exploratory findings should be interpreted cautiously. Early immune monitoring may help identify paediatric trauma patients at increased infection risk who might benefit from immunomodulation. Trial registration: Medical Ethics Review Committee ‘METC Oost-Nederland’, file number 2023-16883.

Background: Major surgery elicits a complex immune response involving both systemic inflammation and innate immune suppression. These changes may contribute to postoperative infectious complications. This study aimed to determine whether perioperative immune activation and suppression patterns are associated with the development of postoperative infectious complications. Materials and methods: A pooled analysis of six prospective clinical studies was conducted to evaluate perioperative immune function in patients undergoing diverse surgical procedures. Immune monitoring included plasma danger-associated molecular pattern and cytokine concentrations, ex vivo cytokine production after lipopolysaccharide stimulation of whole blood, and proteomic profiling. Clinical outcomes included postoperative infections, pain scores, and quality of recovery. Results: A total of 487 patients were included. Danger-associated molecular patterns generally increased following surgery. All surgical procedures induced a stereotypical immune trajectory, characterized by early plasma interleukin (IL)-6 and IL-10 elevation and suppression of ex vivo tumor necrosis factor (TNF) and IL-1β production, most pronounced on postoperative day 1. Immune suppression persisted through POD3 in patients undergoing colorectal surgery, but resolved more quickly after breast surgery, a less invasive procedure. Patients who developed post-operative infections had higher plasma IL-6 and TNF concentrations on postoperative day 1 and attenuated ex vivo TNF production on postoperative day 3. Proteomic profiling confirmed IL-6 upregulation and identified consistent downregulation of multiple immune signaling proteins, including IFN-γ and chemokines involved in lymphocyte activation. Conclusion: Surgical injury initiates a coordinated immune response with early inflammation and delayed innate immune suppression. Failure to recover innate immune function by postoperative day 3 is associated with increased infection risk. Perioperative immune profiling may enable early risk stratification and inform targeted immunomodulatory strategies.

Original Article Postoperative innate immune function after minimally invasive transcervical esophagectomy (MICE) versus minimally invasive transthoracic esophagectomy (MIE) Lotte M. C. Jacobs, Luuk D. Drager, Leo A. B. Joosten, Lucas T. van Eijk, Merlijn Hutteman, Baukje van den Heuvel, Cornelis J. H. M. van Laarhoven, Michiel C. Warlé, Bastiaan R. Klarenbeek

Purpose: Post COVID-19 Condition (PCC) negatively impacts Health Related Quality of Life (HRQoL) and can persist for years after initial infection. This study examined long term HRQoL of COVID-19 survivors with PCC to explore whether and how HRQoL changes over time, and to determine which patient characteristics are associated with changes. Methods: COVID-19 survivors from the Dutch CORona Follow-Up (CORFU) study were prospectively followed for up to 3 years post-infection using self-report questionnaires. PCC was defined on presence of symptoms reported at the 2-year time point. Within-person change in EQ-5D-5L utility and EQ VAS scores were analyzed from the 2-year to the 3-year time point. Changes were described using summary statistics, and associations with patient characteristics were analyzed using multivariable linear regressions. Results: Among 158 participants that met PCC definition 2-years after infection, mean utility and EQ VAS change score was 0.01 (95%CI − 0.02,0.04), and 0.9 (95%CI − 1.6,3.4), respectively. Based on EQ utility change scores, 30% experienced a decrease, 32% an increase, and 37% no change. Similar distributions were observed for EQ VAS. Female sex was associated with decreasing utility scores. Increasing utility scores were associated with female sex of older age when compared to younger ones, and with people that initially reported social participation problems.. Conclusion: Individual changes in HRQoL within a year vary widely in the PCC population. Our findings suggest that certain subgroups of individuals with PCC are more vulnerable to prolonged declines in HRQoL.

Increasing evidence shows that postoperative innate immune dysregulation is associated with delayed recovery and infectious complications. The aim of this study was to compare the effects of general versus spinal anesthesia on innate immune function during and after total hip arthroplasty (THA). This comparative matched cohort study used data from two single-center randomized-controlled trials. Patients from the control group of the HIPPO study received general anesthesia and were matched to control patients from the MAGIC study who received spinal anesthesia in a 2:1 ratio (general(n = 18); spinal(n = 9)). Immune function was assessed by determination of ex vivo cytokine production capacity upon whole blood stimulation with E. coli lipopolysaccharides (LPS) and measurement of plasma cytokines and danger-associated molecular patterns (DAMPs). In the general anesthesia group, ex vivo cytokine production capacity of IL-1β was significantly lower shortly after induction (p = 0.02) and both IL-1β and IL-6 were significantly lower at the end of surgery compared to the spinal anesthesia group (p = 0.002 and p = 0.02, respectively). On postoperative day 1 (POD1), no differences were observed. Plasma cytokine concentrations did not differ between the spinal and general anesthesia group at most timepoints, except for IL-10 at the end of surgery (p = 0.04) and TNF on POD1 (p = 0.04), which were higher in the general anesthesia group. Plasma concentrations of DAMPs did not differ between the groups. General anesthesia has a transient impact on innate immune function in patients undergoing THA, but the clinical significance of anesthesia-induced innate immune dysregulation might be limited as no differences were observed on POD1. The HIPPO study (NCT05562999, date of registration 2022-10-03) and MAGIC study (NCT05723406, date of registration 2023-02-10) are registered at ClinicalTrials.gov.

Objective: To compare the effectiveness of low intra‐abdominal pressure (IAP) facilitated by deep neuromuscular block (NMB) to standard practice in improving the quality of recovery, preserving immune function, and enhancing parietal perfusion during robot‐assisted radical prostatectomy (RARP). Patients and Methods: In this blinded, randomised controlled trial, 96 patients were randomised to the experimental group with low IAP (8 mmHg) facilitated by deep NMB (post‐tetanic count 1–2) or the control group with standard IAP (14 mmHg) and moderate NMB (train‐of‐four 1–2). Recovery was measured using the 40‐item Quality of Recovery questionnaire and 36‐item Short‐Form Health survey. Immune function was evaluated by plasma damage‐associated molecular patterns, cytokines, and ex vivo lipopolysaccharide‐stimulated cytokine production. Parietal peritoneum perfusion was measured by analysing the recordings of indocyanine‐green injection. Results: Quality of recovery was not superior in the experimental group ( n = 46) compared to the control group ( n = 50). All clinical outcomes, including pain scores, postoperative nausea and vomiting, and hospital stay were similar. There were no significant differences in postoperative plasma concentrations of damage‐associated molecular patterns, cytokines, and ex vivo cytokine production capacity. The use of low IAP resulted in better parietal peritoneum perfusion. Conclusion: Despite better perfusion of the parietal peritoneum, low IAP facilitated by deep NMB did not improve the quality of recovery or preserve immune function compared to standard practice in patients undergoing RARP.

Background: Guidelines do not provide clear recommendations with regard to the use of low intra-abdominal pressure (IAP) during laparoscopic surgery. The aim of this meta-analysis is to assess the influence of low versus standard IAP during laparoscopic surgery on the key-outcomes in perioperative medicine as defined by the StEP-COMPAC consensus group. Materials and methods: We searched the Cochrane Library, PubMed, and EMBASE for randomized controlled trials comparing low IAP (<10 mmHg) with standard IAP (10 mmHg or higher) during laparoscopic surgery without time, language, or blinding restrictions. According to the PRISMA guidelines, two review authors independently identified trials and extracted data. Risk ratio (RR), and mean difference (MD), with 95% CIs were calculated using random-effects models with RevMan5. Main outcomes were based on StEP-COMPAC recommendations, and included postoperative complications, postoperative pain, postoperative nausea and vomiting (PONV) scores, and length of hospital stay. Results: Eighty-five studies in a wide range of laparoscopic procedures (7349 patients) were included in this meta-analysis. The available evidence indicates that the use of low IAP (<10 mmHg) leads to a lower incidence of mild (Clavien–Dindo grade 1–2) postoperative complications (RR=0.68, 95% CI: 0.53–0.86), lower pain scores (MD=−0.68, 95% CI: −0.82 to 0.54) and PONV incidence (RR=0.67, 95% CI: 0.51–0.88), and a reduced length of hospital stay (MD=−0.29, 95% CI: −0.46 to 0.11). Low IAP did not increase the risk of intraoperative complications (RR=1.15, 95% CI: 0.77–1.73). Conclusions: Given the established safety and the reduced incidence of mild postoperative complications, lower pain scores, reduced incidence of PONV, and shorter length of stay, the available evidence supports a moderate to strong recommendation (1a level of evidence) in favor of low IAP during laparoscopic surgery.

Introduction: Among its effect on virtually all other organs, COVID-19 affects the cardiovascular system, potentially jeopardizing the cardiovascular health of millions. Previous research has shown no indication of macrovascular dysfunction as reflected by carotid artery reactivity, but has shown sustained microvascular dysfunction, systemic inflammation, and coagulation activation at 3 months after acute COVID-19. The long-term effects of COVID-19 on vascular function remain unknown. Materials and Methods: This cohort study involved 167 patients who participated in the COVAS trial. At 3 months and 18 months after acute COVID-19, macrovascular dysfunction was evaluated by measuring the carotid artery diameter in response to cold pressor testing. Additionally, plasma endothelin-1, von Willebrand factor, Interleukin(IL)-1ra, IL-6, IL-18, and coagulation factor complexes were measured using ELISA techniques. Results: The prevalence of macrovascular dysfunction did not differ between 3 months (14.5%) and 18 months (11.7%) after COVID-19 infection (p = 0.585). However, there was a significant decrease in absolute carotid artery diameter change, 3.5% ± 4.7 vs. 2.7% ± 2.5, p—0.001, respectively. Additionally, levels of vWF:Ag were persistently high in 80% of COVID-19 survivors, reflecting endothelial cell damage and possibly attenuated endothelial function. Furthermore, while levels of the inflammatory cytokines interleukin(IL)-1RA and IL-18 were normalized and evidence of contact pathway activation was no longer present, the concentrations of IL-6 and thrombin:antithrombin complexes were further increased at 18 months versus 3 months (2.5 pg/mL ± 2.6 vs. 4.0 pg/mL ± 4.6, p = 0.006 and 4.9 μg/L ± 4.4 vs. 18.2 μg/L ± 11.4, p < 0.001, respectively). Discussion: This study shows that 18 months after COVID-19 infection, the incidence of macrovascular dysfunction as defined by a constrictive response during carotid artery reactivity testing is not increased. Nonetheless, plasma biomarkers indicate sustained endothelial cell activation (vWF), systemic inflammation (IL-6), and extrinsic/common pathway coagulation activation (FVII:AT, TAT) 18 months after COVID-19 infection.