Why have several recent clinical trials of sepsis treatments failed?


Much like cancer, sepsis isn’t simply one condition but rather many conditions that could benefit from different treatments, according to the results of a University of Pittsburgh School of Medicine study involving more than 60,000 patients.

These findings, announced today in JAMA and presented at the American Thoracic Society’s Annual Meeting, could explain why several recent clinical trials of treatments for sepsis, the No. 1 killer of hospitalized patients, have failed.

Sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs.

“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,” said lead author Christopher Seymour, M.D., M.Sc., associate professor in Pitt’s Department of Critical Care Medicine and member of Pitt’s Clinical Research Investigation and Systems Modeling of Acute Illness Center. “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.

“Sepsis is not a diagnosis. It’s a phenomenon,” says John Marshall, a hospital intensivist at St. Michael’s Hospital in Toronto and a member of the team that generated the first modern consensus criteria defining sepsis in the early 1990s (2).

Sepsis as a phenomenon had been recognized long before that.

But millennia would pass before anyone began to understand what brought on the condition or how to treat it.

With the advent of germ theory in the 19th and early 20th centuries, physicians realized that some type of infection almost always accompanied cases of sepsis.

And by the middle of the 20th century, microbiologists and immunologists understood that many of the hallmarks of infectious diseases in general were caused not by the invading pathogen but by the body’s own immune response to it (3).

When our immune systems are fighting off an infection, we usually can tell that a war is being waged.

The inflammatory response that causes fever also summons specialized immune cells to hunt and kill the invading pathogens.

Virus-infected cells are programmed to kill themselves to prevent the release of more viruses.

The runny nose, itchy eyes, and stuffed sinuses that bring misery during a cold are the body trying to flush out pathogens.

On a microscopic level, signaling molecules that spur inflammation, such as IL-6 and NF-κB, can also cause problems with blood clotting and alter blood pressure (4).

Other messengers, such as TNF and IL-1, can damage nearby cells as they tackle invading pathogens.

The collateral damage from these battles makes us temporarily miserable but keeps us alive. Not so for sepsis patients.

By the 1970s and 1980s, it was becoming clear that a patient’s own immune system response to infection was also responsible for the high fever, plummeting blood pressure, and organ dysfunction that characterized sepsis (5).

The immune system seemed to be overzealous, ravaging the host before it could control the infection.

A flurry of new clinical trials began testing immunosuppressive drugs to try to damp down inflammation in sepsis patients.

In 1976, William Schumer of the University of Chicago treated septic patients with high doses of the steroid methylprednisolone or a placebo and found that the steroids reduced mortality from 39% to 11% (6).

Subsequent trials weren’t nearly as convincing, though, and researchers speculated that inadequate definitions of sepsis itself might be muddying the waters.

“When I started treating sepsis patients as a young physician in the early 80s, I couldn’t compare two papers because they defined sepsis differently,” says Deutschman.

To facilitate better studies, the American College of Chest Physicians and the Society of Critical Care Medicine assembled a group of physicians in 1991, including Marshall, to create a clearer definition of sepsis (2).

The new consensus criteria, published in 1992 in the journal Chest, differentiated the process of infection from the host response, noting that it was the host response that created sepsis, not the infection itself.

The team also noted the wide range of symptoms and outcomes that fell under the sepsis umbrella, and the difficulties this heterogeneity posed, both for understanding the molecular basis of the condition and developing better ways to treat it.

Unfortunately, these criteria were still overly broad, Marshall says.

Many hospitalized patients fit the description without having sepsis.

Even when correctly identified, sepsis patients remained an extraordinarily diverse group, yet the protocols would treat them all in the same way. Perhaps not surprisingly, treatment trials continued to fail.

Any hope of fighting sepsis would require a more fine-tuned analysis of the biochemical cascade that turned an ordinary response to infection into a life-threatening crisis.

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Object name is pnas.1803551115fig02.jpg

Sepsis is characterized by a complex interplay of both proinflammatory and antiinflammatory responses. In some cases, a hyperinflammatory phase can lead quickly to death (A). In others who are afflicted, compromised immune systems often result in little hyperinflammatory response but a strong antiinflammatory response (B). A third, theoretical scenario entails cycling between hyper- and hypoinflammatory responses, sometimes resulting in the development of a new, dangerous secondary infection (C). Reprinted from ref. 21, with permission from Elsevier.

Gene studies have provided further clues. In 2015, a genome-wide association study, or GWAS, uncovered different variants of the FER gene, involved in intercellular signaling, that was strongly associated with 28-day survival in sepsis patients (17).

A separate 2016 GWAS study identified three regions of the genome, which include two immune system genes, VPS13A and CRISPLD2, that also seemed to influence 28-day survival (18).

These underlying host differences interact with the infecting organism, which can lead to a range of organ dysfunctions and disease outcomes, according to Peter Pickkers, an intensive care physician at Radboud University in The Netherlands.

Still, he warns against getting too focused on any single factor or pathway

“There’s so much going on [in sepsis] that targeting just one pathway probably won’t have much of an effect,” Pickkers says.

Not only might sepsis involve multiple physiological pathways, Deutschman says, but treating such a heterogeneous condition is like tackling different diseases simultaneously.

“We treat sepsis like it’s this monolithic thing, and it’s really not,” he says.

“There are aspects of the immune system that look like they are overactive and others that look like they are underactive and some that don’t look like anything you’ve ever see anywhere else ever before.”

Currently, sepsis treatment consists primarily of helping patients weather the immunological storm rampaging through their bodies until they can recover on their own.

But one principle has become abundantly clear: The earlier doctors see the storm coming, the better the patient’s chances.

That’s why attention has increasingly turned to more sophisticated diagnostics in treating sepsis.

New diagnostics are analyzing host factors to help identify which parts of the immune system are over- or underactive.

Inflammatix, led by Timothy Sweeney, formerly of Stanford University, has created a tool that identifies the immune system genes switched on and off in response to infection to predict the likelihood sepsis will develop and the chances it will be severe.

This diagnostic has been through clinical trials and is currently waiting on US Food and Drug Administration (FDA) approval.

The Duke University laboratory of Dennis Ko, meanwhile, has identified a biomarker called methylthioadenosine that is involved in the body’s inflammatory response and at high levels is associated with high rates of fever-induced host-cell death, which can predict sepsis death (19).

Peña created Sepset Biosciences to refine a genetic and immunological signature of sepsis that can rapidly distinguish it from other illnesses with similar symptoms.

before embarking on clinical trials.

And in February 2017, the FDA approved SeptiCyte LAB from Seattle-based startup Immunexpress. The RNA-based blood test looks for particular immune biomarkers to distinguish sepsis from a systemic inflammatory syndrome with similar symptoms, providing results in about 4 hours (20).

The newest insights into the molecular biology of sepsis have not affected treatment protocols yet, but Deutschman and Marshall believe that understanding interactions between the disease-causing pathogen, host genetics, and the precise nature of the host’s immune response will yield better outcomes

What physicians need, Pickkers says, is not so much batteries of newer, better drugs (though he acknowledges they’ll likely play a role), but better ways to deploy existing ones.

“When you look at what we used to put patients with sepsis through, it was like torture,” he says, referring to the drugs used to increase the amount of blood pumped by the heart to above normal levels and the high settings on ventilators. “It may be that less is more.”

“These new approaches being investigated are the complete opposite of what we have been doing,” Pickkers concludes. “But I think in the next 5 to 10 years, we’ll see some breakthroughs.”

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.”

In the “Sepsis ENdotyping in Emergency Care” (SENECA) project, funded by the National Institutes of Health (NIH), Seymour and his team used computer algorithms to analyze 29 clinical variables found in the electronic health records of more than 20,000 UPMC patients recognized to have sepsis within six hours of hospital arrival from 2010 to 2012.

The algorithm clustered the patients into four distinct sepsis types, described as:

  • Alpha: most common type (33%), patients with the fewest abnormal laboratory test results, least organ dysfunction and lowest in-hospital death rate at 2%;
  • Beta: older patients, comprising 27%, with the most chronic illnesses and kidney dysfunction;
  • Gamma: similar frequency as beta, but with elevated measures of inflammation and primarily pulmonary dysfunction;
  • Delta: least common (13%), but most deadly type, often with liver dysfunction and shock, and the highest in-hospital death rate at 32%.

Dr. Christopher Seymour, of UPMC and the University of Pittsburgh School of Medicine, explains why sepsis is not just one disease and how we should treat it differently. Credit: UPMC

The team then studied the electronic health records of another 43,000 UPMC sepsis patients from 2013 to 2014.

The findings held. And they held again when the team studied rich clinical data and immune response biomarkers from nearly 500 pneumonia patients enrolled at 28 hospitals in the U.S.

In the next part of the study, Seymour and his team applied their findings to several recently completed international clinical trials that tested different promising therapies for sepsis – all of which had ended with unremarkable results.

When trial participants were classified by the four sepsis types, some trials might not have been failures.

For example, early goal-directed therapy (EGDT), an aggressive resuscitation protocol that includes placing a catheter to monitor blood pressure and oxygen levels, delivery of drugs, fluids and blood transfusions was found in 2014 to have no benefit following a five-year, $8.4 million study.

But when Seymour’s team re-examined the results, they found that EGDT was beneficial for the Alpha type of sepsis patients.

Conversely, it resulted in worse outcomes for the Delta subtype.

“Intuitively, this makes sense – you wouldn’t give all breast cancer patients the same treatment.

Some breast cancers are more invasive and must be treated aggressively.

Some are positive or negative for different biomarkers and respond to different medications,” said senior author Derek Angus, M.D., M.P.H., professor and chair of Pitt’s Department of Critical Care Medicine.

“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.”

More information: Christopher W. Seymour et al, Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis, JAMA (2019). DOI: 10.1001/jama.2019.5791

Journal information: Journal of the American Medical Association
Provided by University of Pittsburgh


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