Molecular Phenotyping of Sepsis and Differential Response to Fluid Resuscitation

Abstract

Rationale: Biological heterogeneity in critical illness syndromes, such as sepsis and acute kidney injury (AKI), has hindered development of effective therapies. In sepsis-associated AKI, two molecular sub-phenotypes (SP1 and SP2) have been identified with differing characteristics, outcomes and response to vasopressor treatment. It is unknown if these sub-phenotypes extend to all patients with sepsis, and whether they respond differently to fluid resuscitation strategy.

Methods: Patients enrolled in the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) clinical trial with plasma collected at study enrollment were classified into two sub-phenotypes using a previously validated parsimonious prediction model that included angiopoietin-1 and 2, and soluble tumor necrosis factor receptor-1. Kaplan-Meier estimates were used to test differences in outcomes and sub-phenotype by treatment interaction.

Measurements and main results: Among 1289 patients, we identified 1016 as SP1 and 273 as SP2. The risk of poor clinical outcomes was greater in SP2 relative to SP1 independent of demographics, comorbidities and illness severity scores. Patients with SP2, characterized by more severe endothelial injury and inflammation, had higher 28-day mortality with a liberal versus restrictive fluid strategy (41% vs 27%), while patients with SP1 had no difference (9% vs 9%) (p-value-for-interaction = 0.02). Furthermore, SP2 had fewer days free from ventilation, renal replacement therapy and vasopressors with a liberal compared to a restrictive resuscitation strategy.

Conclusion: Molecular sub-phenotypes previously identified in AKI are also identifiable in sepsis and respond differently to fluid resuscitation strategy. Future prospective identification of these sub-phenotypes could inform a precision-guided therapeutic approach in sepsis.

Keywords: acute kidney injury; endothelial dysfunction; sepsis; vasopressors; volume.