To the Editor:
The article by Fragiadakis et al.1 is an interesting attempt in an everlasting quest to establish reliable markers for postsurgical recovery. The authors hypothesized that by testing presurgical immunologic parameters, individuals with expected delayed recovery can be identified. Whole blood was stimulated with several ligands aimed at mimicking an immunologic environment in blood during surgery followed by a correlational study linking the activation of several pathways to the psychosomatic measures of recovery (fatigue, pain, and functional impairment). In conclusion, the authors showed an impressive correlation between the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and studied clinical endpoints.
Activation of the immune system is often a nonspecific act. NF-κB is one of the most ubiquitous proteins activated by virtually any stressor or insult to the immune system. It would be expected that NF-κB–mediated pathway will be activated during surgery-induced stress. The study confirmed a pretty well-established link between psychosomatic markers of well-being and generalized systemic inflammatory response heralded by activation of NF-κB. However, the nature of the study precludes a final determination that suggested pathways are truly a cause, not a bystander, of the impaired recovery. Another important question is whether any manipulation lowering the activation of NF-κB benefits patients and speeds up postsurgical recovery? The authors also pointed out that most of the immunologic pathways are interconnected; thus, affecting one of them will have widespread consequences. Furthermore, how much can the activation of the immune system be decreased or increased by manipulation of NF-κB or Toll-like receptor (TLR) 4 system?2 The authors described a three- to five-fold difference between individuals with respect to the level of activation. Such a wide range of responses can affect statistical correlational analysis and suggests the high interindividual variability in response. It is unclear what the underlying causes of such differences are. Can polymorphism of TLR and several other cytokine receptors as described in previous literature play a role?3–5 It is unclear from the study how to modify these inflammatory responses to surgery from the perspective of an anesthesiologist. Investigation of different immunologic compounds in sepsis and other critical care grade of insults to the immune system failed to modify any outcomes. This is attributed at least partially to lack of sufficient fidelity in testing of the status of the immune system as well as lack of understanding how clinical interventions will affect incredibly convoluted and interdependent responses of the immune system to stress. Additionally, if polymorphism is to be blamed for the wide range of responses, our ability to affect these responses is very limited due to the underlying patient characteristics.
The stimulation used to activate samples of blood was lipopolysaccharide and several cytokines. Lipopolysaccharide should not be present in bloodstream during the elective “clean” surgery.6–8 It is also worth mentioning that the primary mediators of the activation are intracellular danger signals like adenosine, low pH, heat-shock proteins, or high-mobility group box protein 1.5 Some of these mediators share activation via TLR4/CD14 system, while some of them do not. Moreover, the concentration of lipopolysaccharide (1 μg/ml) was exceptionally high. At such concentration, activation of apoptosis is abundant, while other pathways mediated by lipopolysaccharide are less pronounced.9 Similar remarks can be made with respect to cytokine cocktail used for stimulation. Therefore, it should be concluded that the stimulation mixture used in the study is artificial and may never be seen during elective surgery.
Finally, testing of several psychosomatic variables is highly dependent on the preexisting psychologic makeup of patients. One would presume that at least some of the patients had significant physical impairment, pain, and fatigue. In the discussion, the authors identified this problem as a potential shortcoming of the study, and I want to further emphasize its importance.
The study by Fragiadakis et al. is a valuable resource. In previous work, they analyzed several data pertaining to activation of the immune system in the aftermath of the surgery. This study is a valuable addition, but their conclusions have to be taken with a grain of salt, considering the “artificial” stimulation regimen, correlational nature of the study, and the lack of long-term outcome data.
Support was provided solely from institutional and/or departmental sources.
The author declares no competing interests.