Increased Plasma Levels of Danger-Associated Molecular Patterns Are Associated With Immune Suppression and Postoperative Infections in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Abstract

IntroductionDanger-associated molecular patterns (DAMPs) can elicit immune responses and may subsequently induce an immune-suppressed state. Previous work showed that increased plasma levels of DAMPs are associated with immune suppression and increased susceptibility toward infections in trauma patients. Like trauma, major surgical procedures, such as cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC), are also thought to cause profound DAMP release. Furthermore, the incidence of postoperative infections in these patients, ranging from 10 to 36%, is very high compared to that observed in patients undergoing other major surgical procedures. We hypothesized that the double hit of surgical trauma (CRS) in combination with HIPEC causes excessive DAMP release, which in turn contributes to the development of immune suppression. To investigate this, we assessed DAMP release in patients undergoing CRS-HIPEC, and investigated its relationship with immune suppression and postoperative infections.MethodsIn 20 patients undergoing CRS-HIPEC, blood was obtained at five time points: just before surgery (baseline), after CRS, after HIPEC, at ICU admission, and 1 day after surgery. Circulating levels of DAMPs [heat shock protein (HSP)70, high mobility group box (HMGB)1, S100A12, S100A8/S100A9, nuclear (n)DNA, mitochondrial (mt)DNA, lactate dehydrogenase (LDH), a marker of unscheduled cell death], and cytokines [tumor necrosis factor (TNF)α, IL-6, IL-8, IL-10, macrophage inflammatory protein (MIP)-1α, MIP-1β, and MCP-1] were measured. The extent of immune suppression was determined by measuring HLA-DR gene expression and ex vivo leukocytic cytokine production capacity.ResultsPlasma levels of DAMPs (maximum fold increases of HSP70: 2.1 [1.5–2.8], HMGB1: 5.9 [3.2–9.8], S100A8/S100A9: 3.6 [1.8–5.6], S100A12: 2.6 [1.8–4.3], nDNA 3.9 [1.0–10.8], LDH 1.7 [1.2–2.5]), and all measured cytokines increased profoundly following CRS-HIPEC. Evidence of immune suppression was already apparent during the procedure, illustrated by a decrease of HLA-DR expression compared with baseline (0.5-fold [0.3–0.9]) and diminished ex vivo pro-inflammatory cytokine production capacity. The increase in HMGB1 levels correlated with the decrease in HLA-DR expression (r = −0.46, p = 0.04), and peak HMGB1 concentrations were significantly higher in the five patients who went on to develop a postoperative infection (p = 0.04).ConclusionCRS-HIPEC is associated with profound DAMP release and immune suppression, and plasma HMGB1 levels are related with the occurrence of postoperative infections in these patients.

Monocytic HLA-DR expression kinetics in septic shock patients with different pathogens, sites of infection and adverse outcomes

“…Due to small sample sizes in subgroups, the absence of a statistical difference cannot rule out the presence of an association. Finally, approximately 60% of the patients in our cohort underwent a surgical intervention, which can impact mHLA-DR expression [28].…”

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy

“…These components potentially influence drug response. Second, HIPEC is nearly always preceded by CRS which induces cytokine production that could also influence drug response. Third, intrapatient interlesion heterogeneity may provide an additional level of complexity that is not modelled in the present organoid collection.…”

Postoperative pain pathophysiology and treatment strategies after CRS + HIPEC for peritoneal cancer

“…Both surgical injuries and subsequent infections could cause inflammatory nociceptive pain after CRS + HIPEC treatment. This is especially significant in patients with complications [11,12]. High levels of serum danger-associated molecular patterns (DAMPs), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) have been identified in patients after CRS + HIPEC treatment.…”

“…DAMPs could induce the local accumulation and activation of macrophages, which releases interleukin-1β (IL-1β), TNF-α, and other proinflammatory cytokines. All these cytokines could affect peripheral and central pain sensitization [11,12].…”

“…These alternations can lead to neuroinflammation, DNA damage, and axonal degeneration. Peripheral neuropathy is initiated by the accumulation [11,12] Peripheral sensitization [13] Prostaglandin E 2 , cytokines, nerve growth factor, and substance P. DAMPs, TNF-α, IL-6, IL-8, IL-10.…”