Diving deep into patient data, researchers based at the University of Pittsburgh School of Medicine have uncovered four novel sepsis phenotypes. The phenotypes, shown to differ with respect to demographics, laboratory values, and patterns of organ dysfunction, appear to correlate with biomarkers and mortality. Overall, the newly characterized phenotypes emphasize that sepsis isn’t just one condition. Rather, sepsis comprises many conditions that could benefit from different treatments.

“For over a decade, there have been no major breakthroughs in the treatment of sepsis,” said Christopher Seymour, MD, an associate professor and researcher at the University of Pittsburgh. “The largest improvements we’ve seen involve the enforcing of ‘one size fits all’ protocols for prompt treatment.

“These protocols ignore that sepsis patients are not all the same. For a condition that kills more than six 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.”

Seymor is the first author of a paper (“Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis”) that appeared May 19 in JAMA. The article describes how the University of Pittsburgh team conducted a two-part study. In the first part, the team analyzed data from 63,858 patients in three observational cohorts: 20,000 University of Pittsburgh Medical Center (UPMC) patients recognized to have sepsis within six hours of hospital arrival from 2010 to 2012; 43,000 additional sepsis patients treated at UPMC between 2013 to 2014; and 500 pneumonia patients enrolled at 28 hospitals in the United States.

In the next part of the study, the team evaluated several recently completed international clinical trials that tested different promising therapies for sepsis—all of which had ended with unremarkable results.

Analysis of the first 20,000 UPMC patients revealed four distinct sepsis types:

  • 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%.

These findings were confirmed by analysis of the electronic health records of the subsequent 43,000 UPMC sepsis patients. The findings also held when the team studied rich clinical data and immune response biomarkers from the 500 pneumonia patients.

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 reexamined 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 the JAMA article’s senior author Derek Angus, MD, professor and chair of the University of Pittsburgh’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.”

“Concordance between clinical phenotypes and more computationally intensive transcriptomic endotypes could help identify subsets of patients most likely to benefit from particular immunomodulation strategies,” the authors of the JAMA article noted.

The article summarized the implications of the new findings as follows: “First, completed trials may have unrecognized heterogeneity in the treatment effects by clinical phenotype that were not apparent when analyzing (1) the entire cohort, (2) subgroups based on individual variables, or (3) stratification based on risk of death. Second, these proof-of-concept clinical phenotypes could be incorporated prospectively in future study designs that test new biologically active therapeutics.”

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