CLN Article

The Mystery of Sepsis

As Research Advances, Challenges Remain

Genna Rollins

Blood cells and germs

Here's a question that has baffled clinicians and researchers for decades: is sepsis the result of an infection (a bug) or the immune system's response (the host)? Today's Morning Symposium, "Sepsis: Is It the Bug or Is It the Host?" cosponsored by the American Society for Microbiology, will address this question and challenge attendees to harness the latest understanding about this perplexing syndrome to improve care for sepsis patients.

The session's moderator, James Faix, MD, emphasized that despite considerable research and high-profile public awareness initiatives such as the Surviving Sepsis Campaign, not enough progress has been made in sepsis care. "The surviving sepsis campaign is not getting through," he said. "Fewer than a quarter of U.S. and European hospitals have adopted its best practice recommendations for treating patients with sepsis. Considering the mortality, this is a big deal and we need to have much more focus on it."

Faix is director of clinical chemistry and immunology and a clinical professor of pathology at Stanford University in Palo Alto, Calif. Joining him today will be Ellen Jo Baron, PhD, D(ABMM), professor emerita of pathology at Stanford and executive director of technical support at Sunnyvale, Calif.-based Cepheid, and Hector Wong, MD, a professor of pediatrics and director of critical care medicine at Cincinnati Children's Hospital Medical Center.

Inflammation Versus Immunosuppression

Though recognized since ancient times, sepsis still is incompletely understood and has no specific treatment. One of the early hypotheses was that it was an exaggerated version of the normal response to bacteria, especially endotoxin, a lipopolysaccharide in the cell walls of gram-negative bacteria. As a consequence, for many years, high-dose corticosteroids were an important component of treatment. However, the ineffectiveness of this approach coupled with further research painted a more nuanced picture of sepsis.

"We don't have good evidence of infection in many of the patients whom we know are septic," explained Faix. "And in the individuals who do succumb, the infections they have are not really all that dangerous. They're fairly innocuous bacteria."

A 1991 consensus conference defined sepsis as an infection plus two or more features of systemic inflammatory response syndrome (SIRS), such as altered body temperature, or elevated pulse or respiratory rate (see Box, below). A 2001 update of the definition emphasized that a documented infection need not be a condition for diagnosing sepsis if there is strong suspicion of the disease.

Definitions of Sepsis
Criteria for the Systemic Inflammatory Response Syndrome (SIRS)

Two or more of the following are required:
Body temperature >38°C or <36°C
Heart rate >90 beats/minute
Respiratory rate >20 breaths/minute (or arterial pCO2 <32 mmHg, indicating hyperventilation)
White blood cell count >12,000/mm3 or <4000/mm3 (or >10% immature forms)

Sepsis = Infection + SIRS
Severe Sepsis = Sepsis + Evidence of Organ Dysfunction

Note: The 2001 update to the definitions stress that documentation of infection may not be required for the diagnosis of sepsis if strong suspicion exists. Additional criteria, such as altered mental status, edema, hyperglycemia in the absence of diabetes, elevated C-reactive protein, or elevated procalcitonin are also included.

Today, it appears that sepsis may have two phases. Following an initial infection, the innate immune system mounts a pro—or even hyper—inflammatory response during which the patient has signs and symptoms of SIRS. This phase resolves in many patients, but others go on to develop severe sepsis and compensatory anti-inflammatory response syndrome, where organ dysfunction, particularly in the lungs, kidneys or liver, sets in. Here, immunosuppression rather than hyper-inflammation is the order of the day.

"We don't know what causes the multiple organ dysfunction, which is the way people with sepsis die," said Faix. "The other thing, and it's even more interesting and a focus of research, especially research looking at novel therapies, is the fact that immunosuppression is occurring at the same time. Whether the immunosuppression is related to the multiple organ dysfunction, we have no idea."

The Latest Research Findings

If the pathogenesis of sepsis remains incompletely understood, today's symposium will highlight some of the fascinating research that one day may fill the gaps in knowledge. Wong has been on the vanguard of sepsis research for the past decade, pursuing two lines of investigation. The first involves developing a multi-center, microarray-based genome-wide expression database of critically ill children with septic shock. This database, which uses systems biology and bioinformatics, has facilitated discoveries in four broad areas, including: gene expression-based subclasses of pediatric septic shock; novel therapeutic targets; potential stratification biomarkers; and potential diagnostic biomarkers.

Wong summed up his research as follows. "A major message is the concept of heterogeneity, that we need to start to think of sepsis not as a singular disease where one size fits all but as a syndrome that's very heterogeneous," he said. "We need to come up with diagnostic and stratification tools to be able to measure or quantify that heterogeneity or manage it."

This variability came through in Wong's database. After analyzing more than 6,000 differentially regulated genes, his team characterized three subclasses of sepsis, A, B, and C, and identified 100 class predictor genes having to do with T-cell receptor signaling, B-cell receptor signaling, glucocorticoid-receptor signaling, and peroxisome proliferator-activated receptor-α activation. The genes related to these signaling pathways generally were repressed in Subclass A patients, who also had the greatest severity of illness and highest mortality rate of the three subclasses.

A second line of investigation by Wong's team involves development of a pediatric sepsis biomarker risk model (PERSEVERE), which the researchers derived from 12 candidate serum protein biomarkers identified through the genome-wide expression database. "With this model we're able to assign within 24 hours a low- intermediate- or high-risk of mortality," explained Wong. "My bias is that this is potentially very powerful because it impacts many things, including changing the clinical team's perception of an individual patient. If somebody's deemed high risk, you're going to be more vigilant, allocate more resources, maybe try high-risk therapies."

Which Organism Is the Culprit?

While Wong's findings bode well for future clinical decision-making in sepsis care, Baron emphasized that clinicians still face challenges in addressing the infectious aspect of the disease. "The initial decision-making process with regard to antibiotics is so important. There are some good studies showing that for every hour you delay in having the right antibiotic on board with these patients, their risk of mortality increases pretty statistically significantly," she explained.

Baron also outlined some of the hurdles in quickly and correctly identifying not only the pathogens involved in a case of sepsis but also their resistance patterns. "The physiology of septicemia is that often there is less than one organism per milliliter of blood circulating throughout the body, but there are all these red cells, white cells, and other components in the blood," she said. "That means if you're trying to identify the pathogen directly from the blood you'll have to find the one or two organisms from about 10 milliliters. Then the pathogens have to be freed of all the other things in the blood and amplified in order to get enough of a signal to know what's there."

Even as researchers bear down on the many unknowns in sepsis, Faix urged laboratorians to do whatever they can to improve outcomes for sepsis patients. He personally has been very touched by the story of Rory Staunton, a 12-year old boy who died of severe sepsis on April 1, 2012, just 4 days after scraping his arm playing basketball. Clues in Rory's symptoms and test results were overlooked in his initial encounters with the healthcare system, and Faix hopes Rory's tragedy, published in the New York Times, will spur awareness and action regarding sepsis care. He plans to make that point today.

"I want our audience to go back to work and volunteer to help do something about identifying people at risk," he said. "Whatever they can do to help their hospital better identify patients who are at risk of developing severe sepsis, they should do."

Disclosures: The Cincinnati Children's Hospital Research Foundation and Dr. Wong have submitted patent applications for the biomarkers that go into PERSEVERE.