H. Shaw Warren, MD
When our bodies are attacked by foreign invaders such as bacterial or viral micro-organisms, we can count on our immune systems to martial their forces and fend off the attackers. In a small percentage of adults and children who are hospitalized, however, an infection can become so severe and the body’s natural defenses so overwrought, that it develops into a toxic condition called sepsis. Sepsis is the third leading cause of death behind cancer and heart disease.
“In its exuberance to protect its host, the immune system can go into overdrive and actually be as or more harmful than the microorganism itself,” says Dr. Warren. Fortunately, in most cases our immune systems have a sophisticated plan in place to fight foreign microbes. Any micro-organism—whether it’s a virus, fungus, or bacteria—that enters the body is greeted by a protective, inflammatory response by cells called macrophages. These cells have toll-like receptors (TLR) on their surface that act as the lookout, the eyes and ears, for unwelcome intruders like microorganisms. With the precision of a trained military intelligence officer, they detect an invader and transmit this information from the surface of the cell into the cell nucleus to activate genes that produce a cytokine response. These cytokine proteins leave the cell and act as chemical messengers to produce inflammation throughout the body. This primal attempt from our immune systems to protect ourselves can go awry. And its consequences can be deadly when sepsis is diagnosed.
Sepsis has been used as a catch-all term to define our host response to severe, overwhelming infection in the bloodstream. It can occur in patients with appendicitis, severe pneumonia or surgical infection from a routine operation. Characterized by decreased blood pressure, high fever, and kidney or lung damage or failure, almost half of adults who get sepsis won’t escape its deadly rampage. Because children’s growing bodies are more resilient, they have a better chance of surviving sepsis than adults.
In the Pediatric Intensive Care Unit at MassGeneral Hospital for Children, critically ill patients who develop sepsis often have been admitted with an acute infectious disease that presented with fever. Alternatively, they may have a chronic illness that presented with an acute episode accompanied by fever and secondary infection. While sepsis develops in a small percentage of pediatric admissions, the threat of its deadly consequences puts it at the forefront of pediatricians’ and pediatric specialists’ minds.
There is currently no magic bullet to treat sepsis. The current practice is to introduce an antibiotic regimen and drain the infection if there is an abscess. Dr. Warren has analyzed about thirty clinical trials over the past two decades that investigated a variety of pharmacologic solutions that were based upon blocking the overwhelming inflammatory response. Most of these trials have failed, perhaps in part because many of the patients included in the trials may or may not have met appropriate criteria for sepsis. One therapy, an anti-coagulant drug called activated protein C, has shown some promise although there can be severe side effects from the drug; additional controlled trials are needed to confirm that it works and to define who best should receive it.
Areas of focused inquiry
Dr. Warren believes much more can be done and has received National Institutes of Health funding for two basic research programs in his laboratory at Massachusetts General Hospital. “My laboratory’s goal is to understand how to treat severe infection—no matter what its source—so that patients can survive the desperate situation sepsis creates,” he says. Dr. Warren is engaged in basic molecular research to understand the inflammatory cascade that unfolds between our on-board cell fighters and the offensive bacterial intruder. His studies currently focus on an exclusive category of sepsis involving Gramnegative bacteria, which produces about half of known bacterial infections, including Escherichia coli, Klebsiella, Salmonella, Pseudomonas and others. Dr. Warren is investigating a molecule called endotoxin on the surface wall of Gram-negative bacteria that interacts with host toll-like receptor 4 (TLR4) on macrophage cells to produce the massive inflammation that defines sepsis. The goal is to block the endotoxin and reduce inflammation. He’s also studying other molecules called bacterial outer membrane proteins that activate cells through toll-like receptor 2 (TLR2) at the same cells.
He is struck by a not so simple catch-22: animals injected with recombinant cytokine proteins will die from overwhelming inflammation; however, cytokines are the very protein that offers up the alarm signal when a foreign substance or particle invades our body, producing the inflammatory response. Another challenge resides in the likelihood that more micro-organisms will continue to emerge, just as they’ve done in the past twenty years with Legionnaire’s disease, HIV, and SARS.
Dr. Warren also is the recipient of another NIH-funded grant to study why rodents are more resistant to infection than humans—in fact, over one thousand times more resistant. He suspects there is a set of proteins that reduces the rodents’ inflammatory response and seeks to identify them, understand how they’re activated and how they work. Whatever the source, Dr. Warren will study its application in humans with the hopes of identifying a drug to interact with cells to dampen the overwhelming inflammation in sepsis that occurs as a consequence of severe infection.
While there is much work to do, Dr. Warren is driven by the promise of helping thousands of children and adults who develop sepsis each year. “As we continue to discover what happens during the septic process, we’re that much closer to identifying a solution and that’s what drives us in our work every day,” he says.
H. Shaw Warren, MD, is associate professor of Pediatrics at Harvard Medical School and an attending pediatrician in the Pediatric Infectious Disease Unit at MassGeneral Hospital for Children. In 2002-2003, he served as invited professor at the Institute Pasteur in Paris, France, Unit of Cytokines and Inflammation. Dr. Warren is the recipient of numerous awards and grants from the National Institute of Health, including the National Research Service Award, the FIRST award and several subsequent and ongoing RO-1 research grant awards; as well as the Fulbright-Hays Senior Research Scholar. He has served on multiple hospital committees and authored numerous articles, chapters, reviews and editorials.
