Sepsis represents life-threatening organ dysfunction caused by a dysregulated host response to infection [
1], which potentially affects every organ system. Susceptibility to damage, repair, and residual sequelae varies markedly between both individuals and organs [
2], as do the risk for and outcomes from sepsis, which represent heterogeneity [
3]. Studying the temporal effects of sepsis on the immune system is challenging as numerous abnormalities differ between sepsis patients and within the same patient over time [
4]. Furthermore, the time between onset of infection to clinical presentation varies considerably, influenced by patient characteristics, infection site, pathogen virulence, and access to healthcare. While novel interventions are frequently discovered and tested, numerous trials are statistically negative [
3]. While these interventions may indeed be completely ineffective, it is perhaps more plausible that a benefitting subset is diluted by the overall lack of signal or even harm [
5]. Thus, reassessing our specialty’s approach to targeting the dysregulated immune system in sepsis is key.
Recently, Antonakos et al. [
6] replicated the often reported finding that persistent impaired ex vivo cytokine production of monocytes and lymphocytes stimulated with either lipopolysaccharide (LPS) or Pam3 seen in sepsis patients differs by survival status [
4,
7]. LPS is a conserved motif on Gram-negative bacteria. Pam3 is a Toll-like receptor agonist.
The
causal reasoning here and in similar studies is that impaired cytokine production is a therapeutically modifiable surrogate endpoint that can improve outcomes in sepsis. This reasoning has not helped so far in bringing new therapies to routine clinical use [
5]. In this editorial, I suggest that enhanced translation and smarter interpretation of the sepsis immunology knowledge base should derive
extreme immune phenotypes, clarify
biomarkers’ purpose, identify
surrogates in the causal pathway of
clinical outcomes, and define
treatable traits within sepsis cohorts (Table
1).
Table 1
Definitions of terminology
Extreme phenotypes | Subpopulations defined by extremes of clinical features and outcomes |
Biomarker | Characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention |
Clinical outcome | Characteristic that reflects how a patient feels, functions, or survives |
Surrogate outcome | Substitute for clinical endpoints (or outcome) and expected to predict clinical benefit or harm based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence |
Precision medicine | Refers to an approach for disease treatment and prevention that considers individual variability in genes, environment, and lifestyle |
Heterogeneity | The differences in the risk of developing sepsis, risk of suffering sepsis-related outcomes, and in treatment response |
Treatable traits | Selecting a patient population with a well-defined treatment response characteristic |