Title: Defining ARDS and sepsis sub-phenotypes: a re-analysis of two trials to inform stratified medicine approach with future trials
Funder: Department of Health and Social Care

Abstract: Background Acute Respiratory Distress Syndrome (ARDS) and sepsis are the two most common illnesses in the critically ill, with increasing incidence and high mortality. The ARDS and sepsis literature is replete with randomised controlled trials (RCTs) that show no difference between the intervention and standard care groups in the overall study population, despite promising pre-clinical data that a therapeutic effect from the intervention may exist. Recently, we completed four RCTs funded by the NIHR EME and RfPB programmes: simvastatin therapy in ARDS (HARP-2), vasopressin and steroids in septic shock (VANISH and VACS) and Levosimenden in septic shock (LeoPARDS) trial. The HARP-2 trial hypothesized that the immunomodulatory effects of statins would reduce pulmonary dysfunction, resulting in more ventilator free days. The VANISH and VACS trials hypothesised that vasopressin therapy and the immunomodulatory effects of corticosteroids would reduce shock duration, resulting in greater kidney-failure free days. The LeoPARDS trial tested the hypothesis that Levosimendan may improve outcomes in patients with sepsis. Indeterminate RCTs could result from the clinical and biological heterogeneity producing variation in treatment response. Identifying homogenous groups (sub-phenotypes) such as patients with certain clinical or biological features or treatment response characteristics is a research priority. This will inform future trial design by enriching patient populations likely to benefit the most from interventions. Hypotheses Sub-phenotypes exist in the overall population of patients with ARDS and sepsis, explaining the lack of average treatment effect in the overall population. Treatment responsive sub-phenotypes can be defined for statins in ARDS and steroids in septic shock. Investigating the effect of steroids and statins on biological mediators within the treatment responsive sub-phenotypes will help define their mechanism of action. Aims - To identify ARDS and septic shock sub-phenotypes using baseline characteristics, clinical data, cytokine, neutrophil and endothelial injury, organ specific marker profiles. - To identify treatment responsive sub-phenotypes in ARDS and septic shock. - To delineate mechanisms of action of statins in ARDS and hydrocortisone in septic shock using cytokine, neutrophil and endothelial injury, organ specific marker profiles. Methods First, we will assess how the treatment response varies by baseline risk deciles by generating baseline risk of death model using pre-randomisation clinical and biological data. Second, to delineate mechanisms of actions we will measure selected patterns of key cytokines driving neutrophil activation, lung endothelial and organ injury markers using stored serum samples from these RCTs. Ethical approval is in place to use the stored samples for proposed analysis. Then we will replicate the ARDS sub-phenotypes reported previously using latent class analysis (LCA) from the baseline samples collected in HARP-2 trial and generate septic shock sub-phenotypes using the same LCA approach in the three sepsis trials. We will then extend these analyses to identify treatment responsive sub-phenotypes in the respective cohorts. Finally, we will investigate the potential mechanism of action of the therapies within treatment responsive sub-phenotypes by testing the change over time in key treatment response variables of inflammation and organ injury.

Lay abstract: We study two common conditions affecting critically ill patients admitted to intensive care units, namely sepsis and ARDS. Both these conditions are triggered most often by the body’s response to infection and/or injury. This causes multiple organs of the body to fail. About a third of patients admitted to hospital with these two illnesses do not survive, despite intensive care management. Over the last two decades, doctors and scientists have tested numerous medical treatments for these two conditions. However, to date we do not have any specific treatment, especially medications that work in these conditions identified in clinical trials. One major reason for this lack of effective medical treatment is that patients with these conditions are very different to each other. Therefore, we hypothesised that we need to identify sub-groups of patients with these two illnesses, who are similar and likely to respond to treatments tested. This project tests the hypothesis that such patient sub-groups exist using information from trials that we already completed. This project also generates additional information using stored samples already collected from patients in these trials. This means that we do not inconvenience patients and keep the costs to a minimum. To test this hypothesis, we first assess how the severity of illness varies in the patients included within these two trials. Then we assess how the response to the two treatments tested in the trials varies with differences in severity of illness. To understand why and how patients respond to treatments tested in the trials, we will measure blood levels of illness indicators in ARDS and sepsis. We then use well-established statistical analysis methods to identify patient sub-groups in ARDS and sepsis using the principle of clustering of patients with similar features. Amongst these sub-groups of patients with similar features, we plan to identify those sub-groups of patients with ARDS who respond to statin treatment and patients with sepsis who respond to steroids. Finally, we investigate why this difference in response happens and how it could be predicted on admission day to target treatment to those who are likely to benefit the most. We have put together an expert group of clinicians, scientists and bio-statisticians to ensure our results are robust and inform future care of patients with these two serious illnesses.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM;RESPIRATORY