Critical care
30– 40%
Mortality rate of patients suffering from ARDS.
The American Thoracic Society
This has really revolutionised asthma, and this looks to me like something we can emulate.” With Reddy, O’Kane is one of the co-authors of a recent article, entitled ‘Subphenotypes in critical care: translation into clinical practice’, in Lancet Respiratory Medicine outlining advances in identifying biomarker-driven subphenotypes of critical care syndromes, and detailing how they can be translated into clinical practice. Although previous trials have failed to identify good pharmacological interventions, Reddy explains that retrospective analyses have revealed new ways of classifying patient subgroups that have distinct mortalities and seem to respond distinctly to different therapies. In contrast to the current approach, Reddy, O’Kane and their colleagues have focused on identifying these subgroups not simply by clinical insult and symptoms, but through analysing patients’ blood, breath and more for biomarkers with a clear link to the biological mechanisms that underlie the development of critical care syndromes. “Biomarkers are less biased than clinical data,” Reddy explains. “Let’s say you want to look at temperature trajectories in sepsis: some patients do and some don’t get pyrexia, and that data is used to split the sepsis groups into different categories. But that kind of approach can be clinically biased. When you use biomarkers, you’re not applying your own preconceptions.”
“All our treatments at the moment are just around best supportive care. There’s no drug that changes the outcome of ARDS.”
Cecilia O’Kane
What’s more, identifying biomarkers makes it possible to predictively enrich clinical trials, thus amplifying the effects of potential treatments while reducing the statistical noise and the large required sample sizes that have bedevilled previous critical care studies. “If we find a subgroup that has a shared biology that could hint at a shared mechanism, we can recruit patients with that shared biology to a clinical trial,” Reddy continues. “We can target the group that we think is going to benefit.”
Breathless conditions
ARDS is a condition in which the lining of the lung gets damaged and starts leaking, causing fluid to fill the alveoli and restrict the patient’s ability to breathe. As Reddy puts it, “it’s probably more of a description or syndrome than a disease”, and develops in response to a number of direct and indirect clinical insults, ranging from pneumonia – including Covid pneumonia – to severe injuries, non-lung sepsis and abdominal infection. Importantly, patients almost always develop ARDS when they are already in hospital; it is rare for
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someone to have it at the time of admission, but one in five patients on a ventilator will develop it. “All our treatments at the moment are just around best supportive care,” says O’Kane. “There’s no drug that changes the outcome of ARDS. You can treat the underlying infection, but that doesn’t necessarily enable the lung to recover.” Or that, at least, has been the case to date; but there are biomarkers indicating that the patient cohort isn’t as homogeneous as was once thought. All patients have fluid-filled lungs, low oxygen levels and similar looking X-rays, but their blood samples are different. In particular, they show different signatures or markers of inflammation. Retrospective analysis of existing data sets shows hypoinflammatory and hyperinflammatory subgroups. More patients fall into the former, less inflamed group, and usually become less ill. The smaller number of patients in the second group tend to become more ill, spend longer on a ventilator, and are more likely to die. At the same time, however, patients in the second group respond better to certain treatments. “The hyper group did better with more aggressive fluid strategies, high positive end-expiratory pressure and more use of intravenous fluids, whereas those treatments seemed to increase mortality in patients with less inflammation,” explains Reddy. “This hints at a different underlying biology.” That’s just the start. There may well be other subgroups, or endotypes (a term used in precision medicine in asthma to identify a distinct biological mechanism of disease), within these two main subphenotypes, where specific pathways respond to inflammation in different ways. A trial some years ago, for instance, found that the drug simvastatin (which can improve the function of the lining of blood vessels) showed no overall improvement in ARDS, until O’Kane and her colleagues went back and looked specifically at the group with extreme inflammation, where simvastatin was associated with higher 28-day and 90-day survival rates. The observation has allowed some important predictive enrichment. “What we’re interested in doing now is characterising the patients early and treating the ones who are highly inflamed to see, prospectively, if simvastatin improves that cohort,” she says. Remarkably, other retrospective studies have shown that hyperinflammatory and hypoinflammatory subphenotypes also exist in cases of respiratory failure that don’t meet the criteria for ARDS. Perhaps it’s our understanding of the condition as a whole, as much as the subgroups that make it up, that needs tweaking.
Sepsis disparity
Sepsis is another term that covers a wide range of patients – in this case, people who have life- threatening organ failure as the result of infection – and where there’s evidence to suggest that different
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