Are immune-experienced mice better for sepsis research?

Why isn’t a laboratory mouse more like a human? There are several answers, beyond the differences in size and physiology between mice and humans, such as microbiome and immunological experience. Emory researchers led by Mandy Ford and Craig Coopersmith recently published a couple papers that aim to take those factors into account.

The goal is to make mouse immune systems and microbiomes more complex and more like those in humans, so the mice they can better model the deadly derangement of sepsis. So far, sepsis research in mice has been a poor predictor of clinical success. This aligns with work at the National Institutes of Health on “wildling” mice, which have microbes more like wild mice. (Lab Land likes noticing a trend that Emory researchers are part of.)

One Emory paper, in FASEB Journal, shows that mortality in a mouse model of sepsis varies according to the commercial facility where the mice came from. When the mice were allowed to live together and exchange microbes, mortality numbers evened out.

Another, published in JCI Insight, looks at mice that have more memory T cells than naïve mice, since adult humans have a high proportion of memory T cells in their immune systems. Other scientists have shown that sepsis leads to a wipeout of memory T cells, and probably vulnerability in defending against infection. Read more

Posted on August 22, 2019 by Quinn Eastman in Immunology Leave a comment

Predict the future of critical care in #STATMadness

Emory is participating in STAT Madness, a “March Madness” style bracket competition featuring biomedical research advances instead of basketball teams. Universities or research institutes nominate their champions, research papers that were published the previous year. It’s like “Battle of the Bands.” Whoever gets the loudest — or most numerous — cheers wins.

Please check out all 64 entries, follow the 2019 STAT Madness bracket and vote here:
https://www.statnews.com/feature/stat-madness/bracket/

Emory’s entry for 2019:
It’s like the “precogs” who predict crime in the movie Minority Report, but for sepsis, the deadly response to infection. Shamim Nemati and colleagues have been exploring ways to analyze vital signs in ICU patients and predict sepsis, hours before clinical staff might otherwise notice.

As landmark clinical studies have documented, every hour of delay in giving someone with sepsis antibiotics increases their risk of mortality. So detecting sepsis as early as possible could save thousands of lives. Many hospitals have developed “sniffer” systems that monitor patients for sepsis, but this algorithm tries to spot problems way before they become apparent.

As published in 2018 in Critical Care Medicine, the algorithm can predict sepsis onset—with some false alarms—four, eight, even 12 hours ahead of time. No algorithm is going to be perfect, but it was better than any other previous sepsis predictor. The technology is headed for additional testing and evaluation at several medical centers, as part of a project supported by the federal Biomedical Advanced Research and Development Authority (BARDA).

You can fill out a whole bracket or you can just vote for Emory. The contest will last several rounds. The first round began on Monday, March 4, and lasts until the end of the week. Before 10 am Eastern time Monday morning, there were already more than 5,000 brackets entered!

If Emory advances, then people will be able to continue voting for us starting on Friday. Emory’s first opponent is a regional rival, Vanderbilt University School of Medicine. We are on the upper left side of the bracket.

STAT News is a Boston-based news organization covering biomedical research, pharma and biotech. If you feel like it, please share on social media using the hashtag #statmadness.

Posted on March 4, 2019 by Quinn Eastman in Uncategorized Leave a comment

Life-saving predictions from the ICU

It’s similar to the “precogs” who predict crime in the movie Minority Report, but for sepsis, the deadly response to infection. That’s how Tim Buchman, director of the Emory Critical Care Center, described an emerging effort to detect and ward off sepsis in ICU patients hours before it starts to make their vital signs go haywire.

As landmark clinical studies have documented, every hour of delay in giving someone with sepsis antibiotics increases their risk of mortality. So detecting sepsis as early as possible could save lives. Many hospitals have developed “sniffer” systems that monitor patients for sepsis risk. See our 2016 feature in Emory Medicine for more details.

What Shamim Nemati and his colleagues, including bioinformatics chair Gari Clifford, have been exploring is more sophisticated. A vastly simplified way to summarize it is: if someone has a disorderly heart rate and blood pressure, those changes can be an early indicator of sepsis.* It requires continuous monitoring – not just once an hour. But in the ICU, this can be done. The algorithm uses 65 indicators, such as respiration, temperature, and oxygen levels — not only heart rate and blood pressure. See below.

Example patient graph. Green = SOFA score. Purple = Artificial Intelligence Sepsis Expert (AISE) score. Red = official definition of sepsis. Blue = antibiotics. Black + red = cultures. Around 4 pm on December 20, roughly 8 hr prior to any change in the SOFA score, the AISE score starts to increase. The top contributing factors were slight changes in heart rate, respiration, and temperature, given that the patient had surgery in the past 12hr with a contaminated wound and was on a mechanical ventilator. Close to midnight on December 21, other factors show abnormal changes. Five hours later, the patient met the Sepsis-3 definition of sepsis.

As recently published in the journal Critical Care Medicine, Nemati’s algorithm can predict sepsis onset – with some false alarms – 4, 8 even 12 hours ahead of time. No predictor is going to be perfect, Nemati says. The paper lays out specificity, sensitivity and accuracy under various timelines. They get to an AUROC (area under receiving operating characteristic) performance of 0.83 to 0.85, which this explainer web site rates as good (B), and is better than any other previous sepsis predictor. Read more

Posted on January 11, 2018 by Quinn Eastman in Heart, Immunology Leave a comment

2B4: potential immune target for sepsis survival

Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to infection.

2B4 is an inhibitory molecule found on immune cells. You may have heard of PD1, which cancer immunotherapy drugs block in order to re-energize the immune system. 2B4 appears to be similar; it appears on exhausted T cells after chronic viral infection, and its absence can contribute to autoimmunity.

In their new paper in Journal of Immunology, Mandy Ford, Craig Coopersmith and colleagues show that 2B4 levels are increased on certain types of T cells (CD4+ memory cells) in human sepsis patients and in a mouse model of sepsis called CLP (cecal ligation + puncture). Genetically knocking out 2B4 or blocking it with an antibody both reduce mortality in the CLP model. The effect of the knockout is striking: 82 percent survival vs 13 percent for controls.

How does it work? When fighting sepsis, 2B4 knockout animals don’t have reduced bacterial levels, but they do seem to have CD4+ T cels that survive better. CD4+ T cells, especially memory cells, get killed in large numbers during sepsis, and this is thought to contribute to mortality. Read more

Posted on September 26, 2017 by Quinn Eastman in Immunology Leave a comment

EHR data superior for studying sepsis

Are there more cases of a given disease because something is causing more, or because doctors have become more aware of that disease? A recent paper in JAMA tackles this question for sepsis, the often deadly response to infection that is the most expensive condition treated in US hospitals.

Researchers from several academic medical centers, including Emory, teamed up to analyze sepsis cases using two methods. The first is based on the ICD (International Classification of Diseases) codes recorded for the patient’s stay in the hospital, which the authors refer to as “claims-based.” The second mines electronic medical record (EHR) data, monitoring the procedures and tests physicians used when treating a patient. The first approach is easier, but might be affected by changing diagnosis and coding practices, while the second is not possible at every hospital. If you need your medical records for legal information, a notary must witness that the copy is the same as the original. Those who are looking to notarize their documents may consider searching for a notary near me online.

“This project was undertaken by several large, high quality institutions that have the ability to well characterize their sepsis patients and connect their EHR data,” says Greg Martin, MD, who is a co-author of the JAMA paper along with David Murphy, MD, PhD. The lead author, Chanu Rhee, MD, MPH, is from Brigham and Women’s Hospital, and the entire project was part of a Prevention Epicenter program sponsored by the Centers for Disease Control and Prevention. Read more

Posted on September 26, 2017 by Quinn Eastman in Immunology Leave a comment

Are you experienced?

Are you experienced? Your immune system undoubtedly is. Because of vaccinations and infections, we accumulate memory T cells, which embody the ability of the immune system to respond quickly and effectively to bacteria or viruses it has seen before.

Not so with mice kept in clean laboratory facilities. Emory scientists think this difference could help explain why many treatments for sepsis that work well in mice haven’t in human clinical trials.

Mandy Ford has teamed up with Craig Coopersmith to investigate sepsis, a relatively new field for her, and the collaboration has blossomed in several directions

“This is an issue we’ve been aware of in transplant immunology for a long time,” says Mandy Ford, scientific director of Emory Transplant Center. “Real life humans have more memory T cells than the mice that we usually study.”

Sepsis is like a storm moving through the immune system. Scientists studying sepsis think that it has a hyper-inflammatory phase, when the storm is coming through, and a period of impaired immune function afterwards. The ensuring paralysis leaves patients unable to fight off secondary infections.

In late-stage sepsis patients, dormant viruses that the immune system usually keeps under control, such as Epstein-Barr virus and cytomegalovirus, emerge from hiding. The situation looks a lot like that in kidney transplant patients, who are taking drugs to prevent immune rejection of their new organ, Ford says.

Ford’s team recently found that sepsis preferentially depletes some types of memory T cells in mice. Because T cells usually keep latent viruses in check, this may explain why the viruses are reactivated after sepsis, she says. Read more

Posted on August 24, 2016 by Quinn Eastman in Immunology Leave a comment

Pre-hospital recognition of severe sepsis

Severe sepsis, a consequence of the body’s response to infection, is a major cause of death in hospitals. The earlier that doctors recognize that a patient has sepsis, the earlier the patient can be treated with antibiotics, fluids and other measures, and the better the chance of survival.

That’s why critical care and emergency medicine researchers have been looking for ways to spot whether someone coming to the hospital might have sepsis, even before arrival.

At Emory, Carmen Polito, Jonathan Sevransky and colleagues recently published a paper in the American Journal of Emergency Medicine on an emergency medical services screening tool for severe sepsis. Polito and Sevransky are in the division of pulmonary, allergy, critical care and sleep medicine in the Department of Medicine. The tool was evaluated based on Grady emergency medical services data from 2011 and 2012.

“Sepsis is largely a face without a name in the EMS setting,” Polito says. “The goal of our study was to create a tool to assist EMS providers in naming this deadly condition at the point of first medical contact. Similar to other life-threatening, time-sensitive conditions like stroke and heart attack, naming sepsis is the first step in developing coordinated care pathways that focus on delivering rapid, life-saving treatment once the patient arrives at the hospital.”

Posted on June 16, 2015 by Quinn Eastman in Immunology Leave a comment

Test of megadose vitamin D in intubated critical care patients

Whether dietary supplementation with vitamin D is beneficial, in terms of preventing disease, has been controversial. However, vitamin D has been reported to increaseÂ immune cellsâ€™ production of microbe-fighting proteins. That’s why Emory doctorsÂ have been testing whether high doses of vitamin D couldÂ be helpful for critical care patients, who need to ward off infections.

The results of a small-scale clinical trial, presented in Denver this week at the American Thoracic Society meeting, suggest thatÂ high doses of vitamin D could decrease the length of hospital stays in critically ill patients with respiratory failure. Read more

Posted on May 21, 2015 by Quinn Eastman in Immunology Leave a comment

Staring (cell) death in the face: imaging agents for necrotic cells

DNA usually occupies a privileged place inside the cell. Although cells in our body die all the time, an orderly process of disassembly (programmed cell death or apoptosis) generally keeps cellular DNA from leaking all over the place. DNA’s presence outside the cell means something is wrong: tissue injury has occurred and cells are undergoing necrosis.

Researchers from the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University have devised a way to exploit the properties of extracellular DNA to create an imaging agent for injured tissue. Niren Murthy and Mike Davis recently published a paper in Organic Letters describing the creation of â€œHoechst-IR.â€ This imaging agent essentially consists of the DNA-binding compound Hoechst 33258 (often used to stain cells before microscopy), attached to a dye that is visible in the near-infrared range. A water-loving polymer chain between the two keeps the new molecule from crossing cell membranes and binding DNA inside the cell.

Posted on July 19, 2010 by Quinn Eastman in Uncategorized Leave a comment