Specific or Nonspecific? There Is Very Little Light at the End of the Tunnel.

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 wellestablished 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 threeto five-fold difference between individuals with respect to the level of activation. Such a wide range of responses can affect statistical correlational analysis and Future research should continue to explore the important drivers of earnings differences for physicians beyond what we were able to examine in our study.