Sepsis treatments wrong, by definition

Sepsis – a disproportionate immune response to infection that can result in multiple organ failures and death – is not a single condition, but many, new research reveals.

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Sepsis has long been a severe and life-threatening condition, and treatment protocols have changed little over decades. Here, Britain’s King George V is seen, in 1929, convalescing after beating it. Queen Mary of Teck looks on. Credit: Universal Images Group/Getty Images

The results, arising from an analysis of more than 63,000 patients, all of whom developed sepsis, indicate that current clinical approaches to treatment are seriously inadequate. They may also explain why several recent clinical trials testing new methods have failed.

The research was conducted by scientists led by Christopher Seymour of the University of Pittsburgh, US, and published in the journal JAMA.

“For over a decade, there have been no major breakthroughs in the treatment of sepsis; the largest improvements we’ve seen involve the enforcing of ‘one-size fits all’ protocols for prompt treatment,” Seymour says.

“But these protocols ignore that sepsis patients are not all the same. For a condition that kills more than 6 million people annually, that’s unacceptable.

“Hopefully, by seeing sepsis as several distinct conditions with varying clinical characteristics, we can discover and test therapies precisely tailored to the type of sepsis each patient has.”

Using a combination of statistical, machine learning, and simulation tools, the researchers combed through data relating to 20,000 past hospital patients who had developed sepsis within six hours of admission.

In particular, they looked for clusters of symptoms and patterns of organ dysfunction, then correlated them against biomarkers and mortality. 

The findings revealed not one discernible type of sepsis, but four, which the researchers label alpha, beta, gamma and delta. 

Alpha sepsis was the most common, affecting 33% of patients, and carried the lowest fatality rate, about 2%. At the other end of the scale, delta sepsis occurred in only 13% of patients, but had an in-hospital death rate of 32%.

To further test their discovery, Seymour and colleagues ran the same analysis on records for a further 43,000 patients, all of whom had been treated for sepsis between 2012 and 2014. The finding held.

Intrigued, the researchers then examined the results of a number of failed clinical trials that had tested sepsis-fighting methods. The outcome was revealing.

One five-year, multi-million-dollar trial using aggressive resuscitation techniques had been abandoned because it showed no clear benefit. However, Seymour’s team discovered that it had, in fact, been very beneficial for patients with alpha-type sepsis – although made things worse for those with the delta-type.

The findings, researchers say, point to a radical revamp of the way sepsis is defined and treated.

“Intuitively, this makes sense – you wouldn’t give all breast cancer patients the same treatment,” says co-author Derek Angus. 

“Some breast cancers are more invasive and must be treated aggressively. Some are positive or negative for different biomarkers and respond to different medications. 

“The next step is to do the same for sepsis that we have for cancer – find therapies that apply to the specific types of sepsis and then design new clinical trials to test them.”

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