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Four novel sepsis phenotypes identified

DALLAS — A new study has identified four clinical phenotypes of sepsis that may allow more precise therapy and improve care of critically ill patients.

As part of the NIH-funded Sepsis Endotyping in Emergency Care (SENECA) project, researchers used computer algorithms to analyze 29 clinical variables found in the electronic health records of 20,189 patients at 12 hospitals in the University of Pittsburgh Medical Center health system recognized to have sepsis within 6 hours of hospital arrival from 2010 to 2012. The mean age of the patients was 64 years and mean maximum 24-hour Sequential Organ Failure Assessment (SOFA) score was 3.9.

Based on the algorithm, patients were clustered into four distinct sepsis types:

Alpha: This was the most common phenotype (33%) and included patients with the fewest abnormal laboratory tests, least organ dysfunction and lowest in-hospital mortality rate (2%).

Beta: This phenotype was found in 27% of patients and included those who were older and had the most chronic illnesses and renal dysfunction.

Gamma: This phenotype was found in 27% of patients and included those with elevated measures of inflammation and primarily pulmonary dysfunction.

Delta: This was the least common phenotype (13%) and included patients with more liver dysfunction and shock and the highest in-hospital mortality rate (32%).

Christopher W. Seymour, MD, MSc
Christopher W. Seymour
Credit: University of Pittsburgh

“These sepsis phenotypes can be identified at the time of patient presentation to the emergency department, and thus could be useful with regard to early treatment and enrollment in clinical trials,” Christopher W. Seymour, MD, MSc, associate professor in the department of critical care medicine and member of the Clinical Research Investigation and Systems Modeling of Acute Illness Center at University of Pittsburgh and UPMC Health System, and colleagues wrote.

The phenotype distributions were similar in a validation cohort of another 43,086 patients with sepsis enrolled at the 12 Pennsylvania hospitals from 2013 to 2014 (mean age, 67 years; mean maximum SOFA score, 3.6) and again when the researchers studied rich clinical data and immune response biomarkers from about 500 patients with sepsis due to pneumonia enrolled at 28 U.S. hospitals from 2001 to 2003 as part of the Genetic and Inflammatory Markers of Sepsis (GenIMS) study.

The research team then applied their findings to several recently completed clinical trials that tested different therapies for sepsis and all yielded unremarkable results. The ACCESS trial compared eritoran vs. placebo for severe sepsis and reported no benefit in 28-day mortality. The PROWESS trial compared activated protein C vs. placebo for severe sepsis and reported improved mortality but increased bleeding. The ProCESS trial compared early goal-directed therapy, an aggressive resuscitation protocol that includes a catheter to monitor blood pressure and oxygen and delivery of drugs fluids and blood transfusions vs. alternative resuscitation approaches for septic shock and reported no benefit in 60-day mortality.

When participants in the three aforementioned trials were classified by the four novel sepsis phenotypes, the researchers noted that “some trials may not have been failures.” For example, in the ProCESS trial, early goal-directed therapy was beneficial for patients classified as having the alpha phenotype and resulted in worse outcomes for the delta subtype.

“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 said in a press release. “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 other results, the researchers observed differences in distribution of the host-response biomarkers across the four phenotypes. Among 27 biomarkers measured, 23 were significantly different across phenotypes in at least one of the studies, according to the data. The researchers observed an increase in markers of inflammation and abnormal coagulation in patients with both the gamma and delta phenotypes.

Derek C. Angus, MD, MPH
Derek C. Angus
Credit: University of Pittsburgh

“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,” Derek C. Angus, MD, MPH, distinguished professor and the Mitchell P. Fink Endowed Chair in the department of critical care medicine at University of Pittsburgh and UPMC Health System, said in the release. “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.”

The data were presented at the American Thoracic Society International Conference and published simultaneously in JAMA.by Katie Kalvaitis

References:

Hill NS, et al. Poster P1155. Presented at: American Thoracic Society International Conference; May 17-22, 2019; Dallas.

Seymour CW, et al. JAMA. 2019;doi:10.1001/jama.2019.5791.

Disclosures: The research was funded by the NIH. Seymour reports he received personal fees from Beckman Coulter Inc. and Edwards Inc. Angus reports he received personal fees from and served as a consultant to Ferring Pharmaceuticals, Bristol-Myers Squibb, Bayer AG and Beckman Coulter Inc., owns stock in Alung Technologies and has patent applications pending for selepressin and proteomic biomarkers of sepsis in elderly patients. Please see the study for all other authors’ relevant financial disclosures.

DALLAS — A new study has identified four clinical phenotypes of sepsis that may allow more precise therapy and improve care of critically ill patients.

As part of the NIH-funded Sepsis Endotyping in Emergency Care (SENECA) project, researchers used computer algorithms to analyze 29 clinical variables found in the electronic health records of 20,189 patients at 12 hospitals in the University of Pittsburgh Medical Center health system recognized to have sepsis within 6 hours of hospital arrival from 2010 to 2012. The mean age of the patients was 64 years and mean maximum 24-hour Sequential Organ Failure Assessment (SOFA) score was 3.9.

Based on the algorithm, patients were clustered into four distinct sepsis types:

Alpha: This was the most common phenotype (33%) and included patients with the fewest abnormal laboratory tests, least organ dysfunction and lowest in-hospital mortality rate (2%).

Beta: This phenotype was found in 27% of patients and included those who were older and had the most chronic illnesses and renal dysfunction.

Gamma: This phenotype was found in 27% of patients and included those with elevated measures of inflammation and primarily pulmonary dysfunction.

Delta: This was the least common phenotype (13%) and included patients with more liver dysfunction and shock and the highest in-hospital mortality rate (32%).

Christopher W. Seymour, MD, MSc
Christopher W. Seymour
Credit: University of Pittsburgh

“These sepsis phenotypes can be identified at the time of patient presentation to the emergency department, and thus could be useful with regard to early treatment and enrollment in clinical trials,” Christopher W. Seymour, MD, MSc, associate professor in the department of critical care medicine and member of the Clinical Research Investigation and Systems Modeling of Acute Illness Center at University of Pittsburgh and UPMC Health System, and colleagues wrote.

The phenotype distributions were similar in a validation cohort of another 43,086 patients with sepsis enrolled at the 12 Pennsylvania hospitals from 2013 to 2014 (mean age, 67 years; mean maximum SOFA score, 3.6) and again when the researchers studied rich clinical data and immune response biomarkers from about 500 patients with sepsis due to pneumonia enrolled at 28 U.S. hospitals from 2001 to 2003 as part of the Genetic and Inflammatory Markers of Sepsis (GenIMS) study.

The research team then applied their findings to several recently completed clinical trials that tested different therapies for sepsis and all yielded unremarkable results. The ACCESS trial compared eritoran vs. placebo for severe sepsis and reported no benefit in 28-day mortality. The PROWESS trial compared activated protein C vs. placebo for severe sepsis and reported improved mortality but increased bleeding. The ProCESS trial compared early goal-directed therapy, an aggressive resuscitation protocol that includes a catheter to monitor blood pressure and oxygen and delivery of drugs fluids and blood transfusions vs. alternative resuscitation approaches for septic shock and reported no benefit in 60-day mortality.

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When participants in the three aforementioned trials were classified by the four novel sepsis phenotypes, the researchers noted that “some trials may not have been failures.” For example, in the ProCESS trial, early goal-directed therapy was beneficial for patients classified as having the alpha phenotype and resulted in worse outcomes for the delta subtype.

“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 said in a press release. “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 other results, the researchers observed differences in distribution of the host-response biomarkers across the four phenotypes. Among 27 biomarkers measured, 23 were significantly different across phenotypes in at least one of the studies, according to the data. The researchers observed an increase in markers of inflammation and abnormal coagulation in patients with both the gamma and delta phenotypes.

Derek C. Angus, MD, MPH
Derek C. Angus
Credit: University of Pittsburgh

“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,” Derek C. Angus, MD, MPH, distinguished professor and the Mitchell P. Fink Endowed Chair in the department of critical care medicine at University of Pittsburgh and UPMC Health System, said in the release. “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.”

The data were presented at the American Thoracic Society International Conference and published simultaneously in JAMA.by Katie Kalvaitis

References:

Hill NS, et al. Poster P1155. Presented at: American Thoracic Society International Conference; May 17-22, 2019; Dallas.

Seymour CW, et al. JAMA. 2019;doi:10.1001/jama.2019.5791.

Disclosures: The research was funded by the NIH. Seymour reports he received personal fees from Beckman Coulter Inc. and Edwards Inc. Angus reports he received personal fees from and served as a consultant to Ferring Pharmaceuticals, Bristol-Myers Squibb, Bayer AG and Beckman Coulter Inc., owns stock in Alung Technologies and has patent applications pending for selepressin and proteomic biomarkers of sepsis in elderly patients. Please see the study for all other authors’ relevant financial disclosures.

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