Immune perturbations in patients along the perioperative period: Alterations in cell surface markers and leukocyte subtypes before and after surgery
Introduction
Following surgery and trauma, changes in a myriad of immune indices are believed to impair host defense mechanisms, leaving the body susceptible to infections and dormant diseases (Angele and Faist, 2002). For instance, postoperative leukocyte expression levels of HLA-DR have been found to negatively correlate with sepsis (Ditschkowski et al., 1999, Haveman et al., 1999, Hershman et al., 1990, Schinkel et al., 1998). Additionally, an exaggerated and prolonged pro-inflammatory cytokine response was reported to contribute to multiple organ failure (MOF), (Hietbrink et al., 2006, Lin et al., 2000). Finally, the long-term appearance of cancer metastases has been linked to reduced cellular immunity in the postoperative period (Ben-Eliyahu, 2003).
Studies have reported several post-surgical alterations in numbers of circulating leukocyte subsets and in their activity: neutrophils, a first line of defense against invading organisms, increase in number after surgery, and release an oxidative burst (Smith et al., 2006). Lymphocyte numbers decrease (excepting B cells) (Franke et al., 2006), and their in vitro proliferation and cytokine secretion abilities are impaired (Angele and Faist, 2002, Hensler et al., 1997). Circulating monocytes express low MHC class II levels (Ayala et al., 1996, Zieren et al., 2000), possibly indicating reduced antigen presentation ((Flohe et al., 2004) but see (Hensler et al., 1997)). The Th1/Th2 cytokine balance has been reported to shift toward Th2 dominance, which limits Th1 pro-inflammatory reactions, and induces a relative paralysis of cellular immunity vis-à-vis of its targets (Hietbrink et al., 2006). It is now believed that the initial postoperative response is pro-inflammatory, contributing to immune activation at the site of injury. However, this pro-inflammatory response induces a systemic anti-inflammatory response that in turn causes suppression of cellular immunity. The anti-inflammatory response is thought to be adaptive in restricting inflammation to the site of injury, preventing inflammatory damage to tissue and organs and limiting undesirable systemic immune reactions toward newly exposed host determinants (Munford and Pugin, 2001).
It is unclear why the body promotes seemingly detrimental changes following surgery, including systemic immune suppression. Are they undesirable side-effects of the reaction to trauma, or do they have an adaptive value? We believe that although the above postoperative responses have evolved to promote survival or other adaptive processes following natural injury, some of them are maladaptive in the clinical setting of the operating room. Moreover, the unnatural setting of lesions induced during surgical procedures (sterile as opposed to natural infected injury) may contribute to impaired immune function after surgery. Last, unlike natural injury, patients awaiting surgery may already exhibit altered immune profiles as a result of the underlying disease, medication, and psychological stress (Lutgendorf et al., 2005, Lutgendorf et al., 2008). All of these factors were shown to alter metabolic and endocrine processes, and to cause a shift toward Th2 dominance and suppression of cellular immunity, which further contribute to the exaggerated postoperative immune suppression (Shakhar and Ben-Eliyahu, 2003; Ni Choileain and Redmond, 2006).
The aim of the current study was to provide a comprehensive view of immune responses, both before and following surgery, focusing on established and new indices relevant to postoperative immune suppression, and identifying preoperative perturbations that may contribute to postoperative effects. Our long-term goal is to promote the development of prophylactic measures against postoperative immune suppression, with minimal disturbance to beneficial postoperative responses. We therefore measured peripheral concentrations of leukocyte subtypes, as well as cell surface expression of MHC class II (HLA-DR) and the LFA-1 adhesion molecule (CD11a). In addition, we studied the cytokine network (specifically IL-10, IL-6, IL-12 and IFN-g) and natural killer (NK) cell activity. These indices were assessed each morning, before surgery and along the postoperative hospitalization period, and were compared to their levels in a non-operated control group. Various types of operations were studied, which were categorized as either ‘major’ or ‘minor–intermediate’ (minor and intermediate) surgeries. Although grouping different operations may mask or even cancel-out effects that are unique to a specific surgery, results that are manifested in multiple surgeries could be considered common and robust.
Importantly, in an attempt to assure that our measurements reflect the in-vivo status of the immune system, we analyzed fresh blood samples withdrawn no later than 5 h earlier (excluding approximately 20% of the samples that were taken in the evening and kept overnight), and conducted whole-blood assays that maintain the presence of autologous plasma factors, such as cytokines and hormones. Given the large scope of this study, and in order to allow an in depth evaluation and discussion of the results, the cytokine and NK cytotoxicity data have been published separately (Greenfeld et al., 2007). Last, the study was planned to accommodate technical and administrative constraints on blood sampling and analysis (see Section 2.3). These constraints are the result of using fresh samples and employing patients that were hospitalized for different surgeries and different durations (from 1 to 4 days). Thus, whereas all patients provided blood samples on the morning before surgery, and the great majority of them provided blood the morning after surgery, only 50% or less of the subjects provided blood samples on the evenings before and after surgery, and on the mornings of days 2, 3 and 4 after surgery. Our statistical approaches and deductions are therefore adapted to these constraints (see Section 2.6).
Section snippets
Patients and controls
Fifty-nine patients (age 53, SD 15) that provided multiple blood samples (all of which gave blood on the morning before surgery) were included in the study. Patients underwent various operations under general anesthesia, and were recruited from July to September 2005 in “Hasharon” and “Soroka” Hospitals, in Israel. Patients were recruited during the visit to the preoperative clinic by one of the attending anesthesiologists that participated in the study. Only patients of American Society of
Outliers and sample exclusion
In each of the indices tested, few outlier results (approximately 1–2% of the samples, ranking higher than 2 SD above the mean) were excluded from the analysis. These outliers are most likely technical measurement errors, as highly correlated indices within a subject were not exceptional. Because of a technical obstacle (plasma samples lost due to a freezer shutdown), plasma cortisol levels were measured only in 17 operated subjects and three controls (see Fig 1). Within these 17 patients, 9
Discussion
Our study aimed at depicting the immune profile of patients along the perioperative period, across various operation types. A specific objective was to characterize potential differences in preoperative immune status between patients prior to surgery and healthy controls. As detailed below, we found several surgery-related alterations in leukocyte subtype concentrations, a decrease in HLA-DR (MHC II) expression on lymphocytes and monocytes, and alterations in CD11a (LFA-1) expression, which
Acknowledgments
I. Bartal and S. Ben-Eliyahu were supported by NIH/NCI grant # CA73056. We thank the anonymous reviewers for their helpful comments.
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