Compartmentalisation of immune responses in critical illness: does it matter?

Abstract

Critical illness is pragmatically defined as an acute illness resulting in organ dysfunction, necessitating organ support in specialised settings (intensive care units), to survive1. Despite current best care, ~30% of patients die within 30-days from onset of critical illness. Over the last 50-years, >500 randomised clinical trials (RCTs) involving common critical illnesses such as sepsis syndromes2, and acute respiratory distress syndrome (ARDS)3 have failed to show tangible benefit with pharmacological interventions, despite most of the interventions tested being grounded in detailed understanding of the biological mechanisms involved1. This lack of success is thought to arise from differences in biological features and in outcome risk between critically ill patients (i.e., loosely framed as heterogeneity). Hypotheses that are being pursued to improve the success of future RCTs include grouping patients based on observable clinical and or biological features (termed enrichment, vs sub-phenotyping)4, incorporate attributable risk of critical illness during trial design, innovative trial designs (adaptive RCTs), and redefine critical illness (such as treatable traits)5. In this editorial we explore another hypothesis: Compartmentalisation of immune responses during critical illness syndromes such as sepsis could explain the lack of benefit with immunomodulatory treatments?