Why have clinical trials in sepsis failed? One potential answer is that the underlying assumptions about immune function in sepsis are mistaken.
What are the underlying assumptions?
The main assumption of immunomodulatory treatments for sepsis is that the observed host response is different from the optimal host response.
We have good reason to think that any individual’s measured cytokine or chemokine (e.g. IL-1β or TNF-α) is probably not optimal.
Because significant inter-individual variation exists for every trait. Logic dictates that there is no way that all of the different measurements that show variation in individuals in sepsis can be simultaneously optimal.
For most traits, it is unlikely that the non-optimality occurs is the same direction for all individuals.
Therefore, a second underlying assumption for sepsis immune treatments is that we know the direction of the non-optimality (usually involving an excessive inflammatory response). We also assume that patients will do better if we intervene in the opposite direction.
A third assumption is that intervening on a single biomarker will adjust host immune function in a way that increases fitness (in the biological sense). What if it doesn’t?
One fact that undermines the last assumption is that immunity relies on highly complex and interlinked regulation, characterized by compensation, and redundancy. In other words, interrupting TNFα function is likely to produce compensatory changes in other cytokines that might produce an equivalent functional result.
When we use medications in sepsis, are the compensatory effects and other pleiotropic changes in gene expression optimal or non-optimal? We don’t know.
Moreover, there is reason to believe that immune regulation is resistant to interference with any single immune signal.
Many pathogens have evolved ways to interfere with immune functions. These manipulations allow pathogens to establish an infection. One example is the inhibition of NF-kb and IL-8 in Pseudomonas aeruginosa pneumonia. Also read here and here and here (for more examples and a list of relevant references)
Host pathogen arms races have resulted in adaptations enhancing virulence in pathogens, and counter-adaptations in their hosts. An excellent example of this was observed in the iron-sequestering protein transferrin and Neisseira meningitidis, recently described in the New York Times.
Host-pathogen arms races might be responsible for immune system robustness that is resistant to inhibition of any one immune mediator. Hence, we observe complexity and redundancy in immune regulation.
The outcome of these co-evolutionary dynamics might yield functional results far closer to optimality than any single immune mediator. It would also create conditions resistant to “improvement” by blocking the endogenous host response. This last part, blocking the endogenous host response, typifies every failed anti-inflammatory treatment tried in humans thus far.
© Joe Alcock MD 2014