There Are More Things in Heaven and Earth, Horatio, Than Are Dreamt of in Our Philosophy

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To the Editor:In the last century, medicine has made giant steps forward. Early recognition, treatment of the underlying infection, and organ support have resulted in a significant reduction in mortality and morbidity, at least in developed countries. Unfortunately, major advances in the treatment of critically ill patients with infection/sepsis have plateaued. It would seem logical to expect further improvements by either better treatment of infections or protection against the overzealous or exhausted immunologic reactions of the body. However, over 150 trials aimed at intervening with the immunologic response associated with sepsis have failed to improve patient survival. Fortunately, these efforts were not completely wasted since many of these interventions have proved to be powerful tools for the treatment of autoimmune diseases. In addition, advances in transplantation medicine have also shown that we are capable of manipulating immunology. Additionally, recent findings found that secondary infection was not a major cause of mortality in critically ill patients (1). Hence, perhaps these immunocentric hypotheses have proven to be more than often wrong, and we would be better focusing on other directions. When we consider the immune system as just one of the failing organs and compare it with, for example, the kidney or the lung, we get a different perspective. We can support it, we can replace it partially, but we can only buy time for recovery. And it is not the one and only explanation for morbidity and mortality (2). We therefore plea not to introduce a new acronym based on the immunocentric hypothesis for patients surviving the acute phase of critical illness as proposed in the article published in a recent issue of Critical Care Medicine by Mira et al (3). We simply do not understand the pathophysiology of prolonged critical illness, and a premature focus on the immune system is not helpful. It impairs our vision of other potential causal mechanisms. As in the past, we should look over the fence to see what we can learn from other terrains of medicines. Specifically, research dealing with multiple organ involvement in chronic lung, liver, or kidney failure could provide important new insights. Frailty, a concept in aging research, has also unexpected resemblances to chronic critical illness. Loss of interaction between organs, loss of circadian rhythms, mitochondrial dysfunction, neurohumoral dysfunction, endothelial responses, and programmed death of the organism (phenoptosis) are some of the potential mechanisms. The much discussed new definition of sepsis which is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection leaves room for a broader view (4). The host response includes the immune system but does not place it center stage. We should therefore move on and leave the beaten path.Jill Moser, PhD, Matijs van Meurs, MD, PhD, Jan G.

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