Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial.

BACKGROUND: Interleukin (IL)-18 is a marker of inflammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatin was associated with benefit in patients with ARDS and high plasma IL-18. METHODS: In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvastatin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the effect on secreted IL-18 and IL-1ß compared. RESULTS: 511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥ 800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30-2.73]; p = 0.001). Allocation to simvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p = 0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated macrophage secretion of IL-18 and IL-1ß. CONCLUSION: In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this effect may be due to reduced inflammasome activation. These data suggest that baseline plasma IL-18 may allow a personalised treatment approach by identifying patients with ARDS who could benefit from simvastatin therapy.

Pharmacological treatments in ARDS; a state-of-the-art update.

Despite its high incidence and devastating outcomes, acute respiratory distress syndrome (ARDS) has no specific treatment, with effective therapy currently limited to minimizing potentially harmful ventilation and avoiding a positive fluid balance. Many pharmacological therapies have been investigated with limited success to date. In this review article we provide a state-of-the-art update on recent and ongoing trials, as well as reviewing promising future pharmacological therapies in ARDS.

Biological therapies in the acute respiratory distress syndrome.

INTRODUCTION: The acute respiratory distress syndrome (ARDS) is characterised by life-threatening respiratory failure requiring mechanical ventilation, and multiple organ failure. It has a mortality of up to 30 - 45% and causes a long-term reduction in quality of life for survivors, with only approximately 50% of survivors able to return to work 12 months after hospital discharge. AREAS COVERED: In this review we discuss the complex pathophysiology of ARDS, describe the mechanistic pathways implicated in the development of ARDS and how these are currently being targeted with novel biological therapies. These include therapies targeted against inflammatory cytokines, mechanisms mediating increased alveolar permeability and disordered coagulation, as well as the potential of growth factors, gene therapy and mesenchymal stem cells. EXPERT OPINION: Although understanding of the pathophysiology of ARDS has improved, to date there are no effective pharmacological interventions that target a specific mechanism, with the only potentially effective therapies to date aiming to limit ventilator-associated lung injury. However, we believe that through this improved mechanistic insight and better clinical trial design, there is cautious optimism for the future of biological therapies in ARDS, and expect current and future biological compounds to provide treatment options to clinicians managing this devastating condition.