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
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.
“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
Severe sepsis, a consequence of the bodyâ€™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.
Thatâ€™s why critical care and emergency medicine researchers have been looking for ways to spotÂ whether someone coming to the hospitalÂ might haveÂ 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.
â€œSepsis is largely a face without a name in the EMS setting, â€œ Polito says. â€œThe 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.â€
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
Nature Medicine has a nice feature from Jeanne Erdmann highlighting the debate over how long donated blood can be stored. It sets the stage for two prospective clinical trials (RECESS and ABLE), which recently concluded but are still being analyzed. The trials were looking at how the age of stored blood affects patients undergoing cardiac surgery or in intensive care, respectively. Erdmann alsoÂ mentions that the NIHâ€™s Clinical Center already has tightened its standards for blood storage time.
Emory Blood Bank director John Roback and cardiologist Arshed Quyyumi have been participants in this debate, both theoretically and experimentally. In 2011, they proposed that depletion of the messenger molecule nitric oxide limits the benefits donated blood can provide to patients. In addition to nitric oxide depletion, the â€œstorage lesionâ€ is likely to include several changes, such as lysis of red blood cells, mechanical alterations in the remaining cells, and other chemical changes.
Since then, Emory research has shown that transfusion of donated blood more than three weeks old results in impaired blood vessel function in hospitalized patients, but in contrast, not in healthy volunteers. This informationÂ could allow doctors to prioritize fresher blood for patients with cardiovascular diseases.
Emory clinical nutrition expert Thomas Ziegler, MD, has a case report article in the Sept. 10 issue of the New England Journal of Medicine.
The case report describes a woman with diabetes who needed surgery because of loss of blood flow to abdominal organs. While she is in intensive care after surgery, it becomes clear that a feeding tube leading from her nose to her stomach is not working. That makes her a good candidate for parenteral nutrition, or bypassing the digestive system and delivering nutrients directly into her blood.
Malnutrition is common in patients who are critically ill and often worsens with prolonged hospitalization. Some patients can’t eat normal food or benefit from a feeding tube into the stomach.
Thomas Ziegler, MD, Director, Center for Clinical and Molecular Nutrition, Department of Medicine
Yet few well-designed clinical trials studying parenteral nutrition have been conducted, Ziegler writes. He also notes that there is considerable debate over when parenteral nutrition is appropriate during critical care and how to administer it.
Ziegler’s own research has shown the beneficial effects of the amino acid glutamine, which must be added fresh to feeding formulas, for some critical care patients.
Several of the questions Ziegler outlines in his article will be issues investigators at Emory’s new Center for Critical Care will tackle. Recently, Timothy Buchman, MD, PhD, joined Emory to lead the critical care team.
Posted on September 17, 2009