Medical Professional Publications

Monitoring and Modulating Immune Function in Critically Ill Children

(From Pediatric Directions, Issue 40)

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Each year, more than 225,000 children in the U.S. are hospitalized following a traumatic injury, according to the Centers for Disease Control and Prevention. As if the damage from the trauma weren’t bad enough, studies have found that in some cases, the body’s immune system shuts down as a result of the injury, leaving patients at higher risk for hospital-acquired infections. When the immune system loss is severe or prolonged, the condition is called immunoparalysis—a potentially life-threatening problem.

What causes the immune system to fail in these cases is a mystery Mark Hall, MD, has spent nearly 15 years trying to solve. A critical care specialist and director of the Immune Surveillance Laboratory at Nationwide Children’s Hospital, Dr. Hall is painting a clearer picture of this phenomenon in pediatric patients —work that could redefine how physicians think about and treat immune dysfunction in critically ill patients. We asked Dr. Hall to explain the problem and his research.

What do scientists know about the link between traumatic injury and problems with immune function?
Our studies suggest that innate immune function, which is responsible for protecting the body by identifying and killing pathogens, can be impaired following critical injury, which we think is somehow linked to an innate immune cell called a monocyte. Monocytes recognize microbes such as bacteria, engulf and kill them, then display their remains on the cell surface with the aid of a class of receptors that include Human Leukocyte Antigen (HLA )-DR. Immune cells called lymphocytes detect these microbe remnants and activate the adaptive immune system, which allows the body to effectively battle the infection. In addition, activated monocytes should robustly produce the chemical tumor necrosis factor (TNF)-alpha. This pro-inflammatory cytokine, while harmful in excess, is important for making the local environment favorable for fighting infection.

For reasons we don’t yet fully understand, in some trauma patients, monocytes produce much less TNFalpha than they normally would when stimulated. Similarly, the monocytes can show reduced expression of HLA -DR molecules, which impairs the cell’s ability to activate lymphocytes. This state represents a form of immune suppression that places patients at high risk for new infection and death. Perhaps contrary to what one might think, this state can occur even in the presence of clinical signs and symptoms of hyperinflammation (fever, hemodynamic instability and capillary leak). We think that the monocytes are shutting themselves down in response to an overwhelming inflammatory stimulus and the system is unable to turn itself back on. Just why that happens is something we’re still investigating.

In the past, treatment of critical illness or traumatic injury has included an aggressive anti-inflammatory regimen to treat the kinds of symptoms you described. However, studies increasingly show that this approach isn’t working and can, in fact, further weaken immune function in some patients. Why does this happen?
Inflammation is a natural part of the body’s immune response to trauma and disease, but in many critically ill patients, the inflammatory response can rage out of control, causing organ failure. In the 1980s and 1990s, multiple therapies aimed at reducing inflammation reached phase III clinical trials in adults with severe sepsis and septic shock. Nearly all of these studies failed to demonstrate a survival benefit, suggesting that perhaps reducing inflammation is not the appropriate therapeutic goal in all cases.

We think it’s possible that an overactive inflammatory response may actually trigger a compensatory overactive anti-inflammatory response, or immunoparalysis. Since anti-inflammatory drugs also inhibit immune function, these medications may prevent the body from re-starting its immune system, perpetuating the state of immunoparalysis. Unfortunately, current clinical practice for critically ill patients does not include measurement of immune function. We believe that in these cases, it is essential to find out whether the patient’s immune system is functioning properly. If it is, anti-inflammatories may be able to do their job without causing further harm. But if the immune system isn’t working, anti-inflammatory therapies may not be the best course of action.

How can you measure immune function?
One of the major missions of our laboratory over the past decade has been the development and testing of protocols that allow for rapid, reliable measures of immune function in critically ill children. With the support of the National Institutes of Health and The Research Institute at Nationwide Children’s Hospital, we have evaluated TNF-alpha production capacity and other tests of immune function in hundreds of critically ill children across a broad range of diagnoses. We have also tested healthy children so that we can identify normal values for these assays. The result of this work is that we have been able to identify thresholds of immune function below which patients are at high risk for the development of new infection and death.

Among the most exciting parts of our immune monitoring program is the fact that we can provide same-day results, with our immune function testing taking about six hours to complete. In addition, these tests require only a very small amount of blood, so they are suitable for our smallest patients. The program has gained national and international attention, and we now provide test kits to researchers around the world for the study of immunoparalysis in a variety of patient conditions. Their work, along with studies in our lab, is answering a lot of questions about immunoparalysis, but there is still a lot we don’t know.

Is immunoparalysis reversible?
We believe it is, and to test that theory, we are conducting a phase IV clinical trial of a drug called GM-CSF, which was approved by the Food and Drug Administration in 1991 to stimulate white blood cell growth in bone marrow transplant patients. A number of small studies, mostly in adults, suggest the drug can reverse immunosuppression in critical illness, but ours is the first to study its use in pediatric trauma patients. In partnership with the Surgical Intensive Care Unit at The Ohio State University Wexner Medical Center, we plan to enroll more than 100 patients age 1 to 21 who are admitted to the ICU following a traumatic injury. We will measure immune function in these patients in the days following their injury. If a patient’s TNFalpha production capacity drops below a certain level, they will receive GM-CSF. The first step is to figure out what dose will effectively reverse critical injury-induced immune suppression. The next step will be to conduct a blinded, randomized, placebo-controlled clinical trial to see if improving immune function results in decreased risk for the development of new infection. If that trial is successful, it could move immune monitoring and modulation out of the research realm and closer to routine bedside care.

Does immunoparalysis only affect trauma patients? Or are these immune problems found in patients battling disease or other illness as well?
Immunoparalysis has been reported in patients with many types of conditions, ranging from influenza to major trauma to sepsis. Labs around the world are looking at the phenomenon from different angles. Here at Nationwide Children’s, we are working with a number of clinician scientists who are interested in measuring immune function in a variety of patient populations.

One study is looking at the role of red blood cell transfusion in immune suppression, and another is examining how cardiopulmonary bypass affects immune function. We are partnering with collaborators in the Center for Vaccines and Immunity in The Research Institute at Nationwide Children’s on research into gene expression in patients whose immune systems are suppressed by sepsis. We just enrolled our 100th participant in that project, and we have other studies under way to explore immune function in patients with influenza and respiratory syncytial virus. We also plan to expand our ongoing clinical trial to study the effectiveness of GM-CSF in other critically ill patients, such as those with sepsis.

When you began this work nearly 15 years ago,you were among the first to suggest that immunoparalysis in critically ill children was a problem. What’s different today?
Some things have changed, but some have stayed the same. In 2000, I gave my first national talk on the idea that immunoparalysis is associated with adverse outcomes in critically ill kids. It was a new idea then. Just this past January, I was asked to be part of a multi-expert panel at a Society of Critical Care Medicine Congress on immune monitoring and modulation in critical illness—which the organizers still considered a relatively new concept. The focus on anti-inflammatory therapies to reduce the proinflammatory response in critical illness has been quite persistent. The viewpoint that the anti-inflammatory response can be harmful is still gaining momentum.

That said, we have made progress. Studies of immunoparalysis from our lab and others have offered vital insight into immune function in the critically ill patient and the importance of considering immunotherapy alongside other therapies to prevent and treat secondary infection. While some patients will continue to require anti-inflammatory treatments, others may need therapies that augment the immune response. Work underway in labs such as ours will continue to investigate this phenomenon and the outcome, we hope, will be improved patient care.

Related publications
Mejias A, Hall MW, Ramilo O. Immune monitoring of children with respiratory syncytial virus infection. Expert Review of Clinical Immunology. 2013 May, 9(5):393-5. PMID: 23634732.

Mella C, Suarez-Arrabal MC, Lopez S, Stephens J, Fernandez S, Hall MW, Ramilo O, Mejias A. Innate immune dysfunction is associated with enhanced disease severity in infants with severe respiratory syncytial virus bronchiolitis. Journal of Infectious Diseases. 2013 Feb 15, 207(4):564-73. PMID: 23204162. Epub 2012 Nov 29.

Hall MW, Geyer SM, Guo CY, et.al. Innate immune function and mortality in critically ill children with influenza: a multicenter study. Critical Care Medicine. 2013 Jan, 41(1):224-36. PMID: 23222256.

Mark W. Hall, MDMark W. Hall, MD, is director of the Pediatric Critical Care Medicine Fellowship program, research director for Pediatric Critical Care Medicine, director of the Immune Surveillance Laboratory and a principal investigator in the Center for Clinical and Translational Research at The Research Institute at Nationwide Children’s Hospital. He also is an associate professor of pediatrics in the Division of Critical Care Medicine at The Ohio State University College of Medicine. He received his medical degree from the University of Virginia and completed a pediatrics residency at the Children’s Hospital of Pittsburgh, where he was chief resident, a fellow in pediatric critical care medicine and held the Charles Schertz Research Fellowship.

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