Critical care
treatments could be better suited to different subgroups. It’s already known, for example, that some patients experience a great deal of inflammation, whereas others’ immune systems are overwhelmed and suppressed.
That said, disparities within identified sepsis subphenotypes suggest the classifications could be age-dependent or subject to change over time. The complexities of critical care syndromes mean the relevance of individual biomarkers is difficult to interpret without insights into how they interact and are regulated.
“In the past, we’ve tended to use single biomarkers, like inflammation, and treat the patients with a high marker with [a matching] therapy,” says Anthony Gordon, the chair in anaesthesia and critical care at Imperial College London and a consultant in intensive care medicine based at St Mary’s Hospital, as well as another of O’Kane and Reddy’s co-authors. “But the body is more complex than that. We don’t need single biomarkers: we need signatures.” Thanks to advances in genomics, transcriptomics, proteomics and metabolomics, it is now possible to measure the profile of the RNA ‘signal molecules’ in the blood and see which patterns group together. “We’ve let these natural groupings come out in our data,” Gordon explains. Like Reddy, he points out that this enables a much freer, less biased approach. “Rather than us assume what it could be, you can measure many thousands of things and look for similar patients. There’s lots of evidence to suggest that different groups may respond to different treatments.”
Blood strokes
The whole field is at a very exciting stage. Until now, a huge amount of the work has been based on retrospective analysis, but researchers like Reddy, O’Kane and Gordon are spearheading a move to a more proactive, prospective approach in setting up their own critical care trials. This is also being made possible by further technological advances. For all the interest in the hypo and hyperinflammatory subphenotypes in ARDS, which have been seen across five randomised controlled trials, differentiating them is still a slow and laborious process. “We need to find ways to identify groups more practically, using less expensive tests,” Reddy explains. “Research lab tests are time- consuming and require expensive skills. That isn’t really feasible in a clinical hospital setting.” This is particularly the case in critical care, where patients are, by definition, very ill and may deteriorate further very quickly. Reddy and O’Kane are involved in the development of a point-of- care test for ARDS patients, which aims to be able to identify whether patients are hypo or hyperinflammatory. Gordon, meanwhile, is starting a new trial at Imperial to see if simple tests can be performed in the ICU itself so that the clinical team at
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The X-ray results of someone suffering from ARDS.
the bedside can immediately classify sepsis patients on the basis of their underlying biology. There are, of course, limits to how far this can go. “As we research this more and more, you may end up splitting people until the groups aren’t meaningful anymore,” Reddy points out. “At some level, everyone is their own phenotype.” But ultimately, this work should make it easier to recruit patients to targeted trials, and to develop more effective critical care therapeutics. At the moment, it’s yet to be established whether practitioners in the critical care unit should be treating syndromes, subgroups, or some combination of the two. The research community needs to coordinate and share data across multiple large and heterogeneous randomised controlled trials to determine which subphenotypes are reproducible, which are spurious and which overlap, as well as establishing their stability across different patient demographics.
“There’s lots of evidence to suggest that different groups may respond to different treatments.”
Anthony Gordon
It may never be clinically useful to observe that everyone’s different, but there’s clearly a case for more personalisation in critical care therapeutics. The pandemic has focused the world’s attention on the statistics coming out of its ICUs, but the wards exist to care for individuals. As the people that staff them well know, those aren’t clusters of symptoms behind all the tubing, but distinctive people. Adapting clinical resources to that fact could make all the difference. “All this research is essentially going to lead to a big change in how we classify disease in the ICU,” Reddy concludes. “I hope that if we can come up with more specific treatments, we may be able to enable patients to have a shorter stay or even avoid the ICU altogether.”
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