A new study finds that interleukin-3 (IL-3), an inflammatory factor most associated with allergic reactions, appears to have an important role in the overwhelming, life-threatening immune reaction called sepsis.
Harvard Medical School investigators at Massachusetts General Hospital report that IL-3 is essential to the development of sepsis in a mouse model of the condition. They also discovered that IL-3 levels in human patients with sepsis are higher in those at greater risk of dying.
"Sepsis is an extremely dangerous condition that claims up to a half million lives in the U.S. every year and millions worldwide," said Dr Filip Swirski, HMS associate professor of radiology at Mass General and senior author of the study. "Our study shows that, in response to infection, IL-3 promotes the production of inflammatory monocytes and neutrophils—immune cells that are sources of the so-called cytokine storm that underlies sepsis."
Sepsis occurs when the immune system overreacts to an infection or injury, producing excessive levels of cytokines, signaling molecules that attract immune cells. Elevated levels of those cells secrete more cytokines, and this cytokine "storm" recruits even more immune cells, fueling a vicious cycle. Instead of stopping the initial infection, immune factors attack the body's tissues and organs, causing organ failure and death.
Many aspects of the mechanism behind sepsis are poorly understood. IL-3 is known to contribute to the production and proliferation of several types of white blood cells – including those that produce factors involved in the cytokine storm – leading Swirski's team to investigate IL-3’s potential involvement in sepsis.
First, they showed in a mouse model of sepsis that the absence of IL-3 both prevented the development of sepsis and reduced the production of sepsis-associated immune cells and cytokines. They also found that injecting IL-3 into mice in which expression of the factor had been knocked out restored their susceptibility to sepsis. Blocking the interaction between IL-3 and its receptors on immune cells reduced the production of sepsis-associated factors.
A search for the source of sepsis-inducing IL-3 revealed that it was produced by innate response activator B cells in the spleen, thymus and lymph nodes, cells that were first identified by Swirski's team in a 2012 paper. Those cells, called IRA B cells, also produce the growth factor GM-CSF. Without IRA B cell-derived GM-CSF, animals in which sepsis was induced died faster and in greater numbers than control animals.
But while GM-CSF protected against sepsis in the earlier study, IL-3 generated by the same cell population increased production of inflammatory cytokines that aggravate sepsis in the current investigation – an observation that reflects the delicate balance of immune reactions required to defend against infection without inflicting the damage that leads to sepsis.
To confirm that results observed in their mouse model reflect what could happen in human patients, the researchers analysed blood samples from 60 sepsis patients involved in a previous study and found that IL-3 levels during the first 24 hours after the onset of sepsis were higher in patients who eventually died. The investigators prospectively measured levels of IL-3 and monocytes in another group of 37 patients being treated for sepsis, finding that the onset of sepsis was accompanied by a rapid increase in cytokine levels and that patients with the highest IL-3 levels were most likely to die.
"Questions have been raised about how well mouse models of sepsis mirror the human disease, but our study shows that the role of IL-3 we discovered in mice is also important in human patients," Swirski said. "Since even seemingly healthy people have some level of IL-3 in their blood, it will be important to investigate whether those with higher levels are at greater risk of sepsis and other complications of infection and whether targeting IL-3 and the pathways it controls could be a treatment for sepsis."
"Overall we need a better understanding of what IL-3 does in sepsis and in other infectious and noninfectious diseases," Swirski said. "We currently are investigating whether IL-3 is involved in what is called the suppressive phase of sepsis, which can follow the initial inflammatory phase and put patients at risk of developing secondary infections."
Other sepsis research has found that for survivors of sepsis, the hospital door often looks like a revolving one. And many of the conditions that send them back to a hospital bed should be preventable.
The finding suggests a need for better post-hospital care for sepsis patients, to avoid re-admissions that drive up costs and interfere with recovery. The results could help medical teams customise care to the special risks that sepsis survivors face – and do the same for other conditions too.
The researchers, from the University of Michigan Medical School, made their findings using detailed data from 2,600 survivors of sepsis, a critical illness that shuts down internal organs in response to a major infection. They compared those patients with the same number of patients who went to the hospital for other acute illnesses.
In both groups, about 42% of patients ended up back in the hospital within three months of going home. But when the researchers looked closely at what sent them back, differences began to emerge.
Patients who had survived sepsis were significantly more likely to get readmitted for a condition that could possibly have been prevented or treated early to avoid a hospital stay. They were especially more likely to end up back in the hospital due to a second bout of sepsis, or kidney or lung failure. They also had more hospitalisations linked to infections, including in the lungs, skin and soft tissue as well as systemic sepsis.
Digging deeper into these differences could lead to customised ways of estimating each patient’s risk of preventable conditions before they leave the hospital, the researchers say. That could guide their health care providers to spot symptoms earlier and intervene before they get bad enough to need another hospital stay.
"Many of these conditions can be managed if the patient can get in to see a doctor at the start of the illness, meaning that we potentially avoid hospitalisation," says Dr Hallie Prescott, the lead author of the new paper and a critical care physician at the U-M Health System. "We need to assess their vulnerability and design a better landing pad for patients when they leave the hospital, and avoid the second hit that derails recovery."
Prescott and her colleagues, who have studied many aspects of sepsis and post-sepsis care, included in their analysis the range of relatively common conditions that experts call "ambulatory care sensitive". For these, the care provided at doctor’s visits can make a major difference in how well the patient does overall, and how well they avoid the hospital.
But since sepsis patients face specific risks, for instance due to their weakened kidneys or swallowing weakness related to the breathing tubes used in intensive care units. So the researchers also included conditions that aren’t common among the general population – but arise more often in sepsis survivors. In all, nearly 42% of the re-admissions among sepsis survivors were due to preventable conditions, using the expanded definition the team adopted. Nearly half of those readmissions were due to illnesses that are not on the usual list of ambulatory care sensitive conditions.
"Getting on the right medications and diet, receiving counselling on infection risks and signs, and having kidney function tested more often could be examples of post-hospital interventions that sepsis survivors could benefit more from," says Prescott.
The new research also shows the power of "big data" in finding subtleties that might not otherwise be visible, says Prescott. Harnessing this kind of analysis, and crafting tools that can personalise risk calculations, will be crucial to reducing unnecessary hospital stays – and avoiding the costs that come with them. Such "big data" can be used to target the right preventive medicine to each individual patient, rather than asking overwhelmed primary care physicians to do everything to everybody. Developing such precision medicine tools is one of the focus areas for Prescott's current research.
[link url="http://hms.harvard.edu/news/eyeing-storm-sepsis"]Harvard Medical School material[/link]
[link url="http://www.sciencemag.org/content/347/6227/1260.abstract?sid=b674344e-f723-41ce-bd92-44cff5fe5e23"]Science abstract 1[/link]
[link url="http://hms.harvard.edu/research/paper-chase?pcq=22245738&destination=research/paper-chase%3Fpcs%3D1%26pcq%3Dswirski%26pci%3D"]Science abstract 2[/link]
[link url="http://www.uofmhealth.org/news/archive/201503/stopping-revolving-door-study-finds-sepsis-survivors-return"]University of Michigan Health System material[/link]
[link url="http://jama.jamanetwork.com/article.aspx?articleid=2190975"]JAMA abstract[/link]