Big data reveals hidden subtypes of sepsis

by University of Pittsburgh

Sepsis is not a single syndrome, according to a University of Pittsburgh-led study in JAMA. Credit: Chris Konopack/UPMC

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.

28 may 2019--These findings, announced today in JAMAand 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. 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%.

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."

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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 

Pneumonia or sepsis in adults associated with increased risk of cardiovascular disease

Pneumonia or sepsis in adults that results in hospital admission is associated with a six-fold increased risk of cardiovascular disease in the first year, according to research published today in the European Journal of Preventive Cardiology. Cardiovascular risk was more than doubled in years two and three after the infection and persisted for at least five years.

10 aug 2017--"Severe infections in adulthood are associated with a contemporaneously raised risk of cardiovascular disease," said last author Professor Scott Montgomery, director of the clinical epidemiology group, Örebro University, Sweden. "Whether this raised risk persists for several years after infection is less well established."
This study examined if hospital admission for sepsis or pneumonia is associated with an increased risk of cardiovascular disease in the years following infection, and whether there is a period of particularly heightened risk.
The study included 236 739 men born between 1952 and 1956 who underwent extensive physical and psychological examinations at around age 18 years as part of compulsory military conscription assessments. The researchers obtained infection and cardiovascular disease diagnoses from a register that has recorded information on patients admitted to hospital since 1964. The men were followed from late adolescence into middle age (follow-up was completed in 2010).
The researchers analysed the associations between a first infection with sepsis or pneumonia that resulted in hospital admission with subsequent cardiovascular disease risk at pre-specified time intervals post-infection (0-1, >1-2, >2-3, >3-4, >4-5, and 5+ years after hospital admission for the infection).
During the follow-up period, a total of 46 754 men (19.7%) had a first diagnosis of cardiovascular disease. There were 9 987 hospital admissions for pneumonia or sepsis among 8 534 men who received these diagnoses.
The researchers found that infection was associated with a 6.33-fold raised risk of cardiovascular disease during the first year after the infection. In the second and third years following an infection, cardiovascular disease risk remained raised by 2.47 and 2.12 times. Risk decreased with time but was still raised for at least five years after the infection by nearly two-fold (hazard ratio 1.87).
Similar findings were observed for coronary heart disease, stroke, and fatal cardiovascular disease. The persistently raised risk could not be explained by subsequent severe infections.
"Our results indicate that the risk of cardiovascular disease, including coronary heart disease and stroke, was increased after hospital admission for sepsis or pneumonia," said lead author Dr Cecilia Bergh, an affiliated researcher at Örebro University. "The risk remained notably raised for three years after infection and was still nearly two-fold after five years."
When the researchers examined the relationship between other risk factors such as high blood pressure, overweight, obesity, poorer physical fitness, and household crowding in childhood, they found that infection was associated with the highest magnitude of cardiovascular disease risk in the first three years post-infection.
Professor Montgomery said: "Conventional cardiovascular risk factors are still important but infection may be the primary source of risk for a limited time."
The authors said the results point to a causal relationship, since cardiovascular disease risk is very high immediately after infection and reduces with time. Persistent systemic inflammation after a severe infection may play a role, as inflammation is a risk for cardiovascular disease. Most patients with sepsis or pneumonia recover but many still have high circulating inflammatory markers after the acute phase of the infection.
Professor Montgomery said: "Our findings provide another reason to protect against infection and suggest that there is a post-infection window of increased cardiovascular disease risk. We did not study any interventions that could be initiated during this period, but preventative therapies such as statins could be investigated."

More information: Bergh C, et al. Severe infections and subsequent delayed cardiovascular disease. European Journal of Preventive Cardiology. 2017. DOI: 10.1177/2047487317724009


Provided by European Society of Cardiology

Cytokine Levels in Sepsis Defy Conventional Wisdom

PITTSBURGH, Aug. 13 -- Fatal sepsis in hospitalized pneumonia patients is most likely to occur in the presence of high levels of certain proinflammatory and anti-inflammatory cytokines, investigators here found.
Overall, patients who died of severe sepsis had the highest cytokine levels, and patients without severe sepsis had the lowest levels, found Derek C. Angus, M.D., of the University of Pittsburgh, and colleagues, reported in the Aug. 13 issue of the Archives of Internal Medicine.
In particular, combined elevated levels of proinflammatory interleukin-6 and anti-inflammatory interleukin-10 conferred the highest mortality risk.
"We have, for the first time to our knowledge, described the systemic cytokine response to infection and severe sepsis in a large, multicenter inception cohort of subjects presenting to the [emergency department] with [community-acquired pneumonia]," said Dr. Angus, and colleagues.
"Our results show that this response is much longer in duration and much more heterogeneous than suggested by previous studies. Nevertheless, individuals with high circulating levels of both proinflammatory and anti-inflammatory cytokines had markedly increased risk of severe sepsis and death."
The authors noted that the results call into question previous interpretations of the inflammatory response to sepsis, at least as it applies to community-acquired pneumonia:
Systemic cytokine activation is common but not universal.
Cytokine concentrations had already peaked by the time patients presented to emergency departments, suggesting the classic cytokine cascade was already fully activated.
Cytokine activation did not increase with the onset of organ dysfunction.
Although cytokine concentrations were highest in patients who fared worse, differences between groups with different outcomes were modest.
For many patients, cytokine activation persisted throughout hospitalization, far longer than traditional models would suggest.
The findings' departure from those of prior investigations have "important implications for the development of future therapies," the authors concluded.
Severe sepsis is common and frequently fatal, and community-acquired pneumonia is the leading cause, the authors noted. Severe sepsis is often attributed to uncontrolled and unbalanced inflammation, but clinical data to support that viewpoint are scanty.
The researchers retrospectively reviewed records on 1,886 patients hospitalized with a diagnosis of community-acquired pneumonia through emergency departments at 28 academic and community hospitals. They defined severe sepsis as community-acquired pneumonia complicated by new-onset organ dysfunction, consistent with international consensus conference criteria.
Investigators measured plasma levels of tumor necrosis factor, IL-6, and IL-10 daily for the first week and weekly thereafter. The primary outcome measures were severe sepsis and 90-day mortality.
Hospital records showed that 583 (31%) patients developed severe sepsis, and 149 (26%) of these died. Systemic cytokine elevation occurred in 82% of all the patients with community-acquired pneumonia. The mean cytokine concentrations were highest at presentation. Levels declined rapidly over the first few days, but remained elevated throughout the first week, beyond resolution of the clinical signs of infection.
Patients with severe sepsis at presentation had significantly higher mean levels of IL-6, IL-10, and TNF compared with patients who did not have severe sepsis on day one (P<0.001). Additionally, septic patients with elevated cytokine levels had significantly higher levels compared with non-septic patients who had elevated cytokine levels at presentation (P=0.01 to P<0.001).
Among patients who had severe sepsis at any time during hospitalization, those who died within 90 days had significantly higher mean levels of IL-6 and IL-10 compared with levels among patients who were alive at 90 days (P=0.01). A separate analysis limited to patients with elevated cytokine levels showed that patients who died had significantly higher levels of IL-6 (P<0.001) and IL-10 (P=0.03).
IL-6 concentrations decreased rapidly from day one through day three but remained elevated throughout the first week. TNF levels were lower than those for IL-6 on day one and declined sharply over the next two days but remained elevated throughout the first week. More than half of all patients had normal levels throughout hospitalization. IL-10 concentrations also were lower at the outset compared with IL-6 and decreased even more precipitously from day one through day three. The authors reported that 64% of survivors and 42% of non-survivors had normal IL-10 levels throughout their hospitalization.
Although normal cytokine levels were common, only four fatal cases of severe sepsis (2.7%) were associated with undetectable cytokine concentrations. On the other hand, patients who fared well had some concentration of cytokines.
The authors reported no conflicts. The study was supported by the national Institute of General Medical Sciences, GlaxoSmithKline, and Diagnostic Products Corporation.Additional source: Archives of Internal MedicineSource reference: Kellum JA et al. "Understanding the inflammatory cytokine response in pneumonia and sepsis. Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study." Arch Intern Med 2007;167:1655-1663