Sepsis kills more than half a million people in the U.S. every year. A Harvard Chan student is untangling its secrets.
Katie McQuestion, a radiology technician in Kenosha, Wisconsin, was feeling perfectly healthy a week before she died from sepsis. She’d had her annual influenza vaccination but still came down with a nasty flu at the end of last December. The flu likely progressed to bacterial pneumonia. By New Year’s Day, her symptoms had catapulted from aches and chills to a dangerously low temperature and rapid heart rate. She was rushed to the emergency room. Twelve hours later, her parents received a phone call from the hospital: Their daughter had suffered a heart attack, her organs were failing, and there was nothing more that doctors could do. McQuestion, a newlywed, died at age 26.
Sepsis causes more than 500,000 deaths in the U.S. each year—more than prostate cancer, breast cancer, and AIDS combined. It develops when the immune system’s response to an infection cascades out of control. Cases are on the rise, and researchers are working to address the disorder’s many unanswered questions.
Rose Filoramo, PhD ’17, never expected to be one of those scientists. She entered the Harvard T.H. Chan School of Public Health three years ago with a Joseph D. Brain Fellowship in Environmental Health. A warm and articulate biologist with a big smile—who once considered a career in acting—Filoramo quickly developed a passion for studying the immune system. In her first two years of graduate study, she shifted her research focus from the immunological effects of environmental endocrine-disrupting compounds to those of naturally occurring hormones like estrogen and testosterone.
Now, working with adviser Lester Kobzik, professor in the Department of Environmental Health, she’s delving into an intriguing new question: Why do young, prepubertal children seem to have a natural resistance to dying from serious infections? This phenomenon was well documented during the deadly 1918 flu pandemic, during which children ages 5 to 14 were much less likely to die than the rest of the population, despite being infected at similar rates. The pattern also appears to apply to sepsis.
“Nearly 50 percent of people who develop sepsis die,” Filoramo says. “If we can figure out what is different in the regulation of children’s immune responses during sepsis, it could lead to the discovery of novel drug targets that could help adults better survive these lethal infections.”
According to Kobzik, “Any new treatment, even if it reduced mortality by only 10 percent, would save millions of lives a year worldwide.”
Immune System “Freakout”
Filoramo describes sepsis as an immune system “freakout.” During an infection, chemicals released by the immune system flood the bloodstream to ward off invaders. Normally, this process is very tightly controlled, producing only enough inflammation to kill the pathogens. The body then swiftly returns to normal. During sepsis, however, the infection causes a systemic inflammatory response far beyond what is “needed” to defend the body. This overly exuberant inflammation can lead to impaired blood flow and tissue damage.
If caught early, sepsis can be treated with antibiotics and intravenous fluids. But the disorder can be difficult to diagnose because its symptoms—such as fever and breathing difficulties—mimic other conditions like heart attack or acute pancreatitis. While antibiotic treatment can eliminate the offending pathogen, once the intense inflammatory response is set in motion, it can continue to wreak havoc on the body—lowering blood pressure and weakening the heart. No treatment currently exists for septic shock, the syndrome’s final stage, which can trigger multiple organ failure and death.
While it’s known that people who are older, or have compromised immune systems, are more at risk of developing and dying from sepsis, researchers don’t understand why common events like a playground scrape, appendicitis, or the insertion of an intravenous line cause some people’s immune systems to revolt.
“With sepsis—as with a lot of other diseases—the body goes into a state of chronic inflammation and can’t seem to return to a healthy homeostatic point,” Filoramo explains. “Even after people survive sepsis, their immune system can flip-flop from hyper-responsive to sluggish, making them vulnerable to secondary infections.” Sepsis cases have spiked in recent years, perhaps due in part to an aging population, the rise of antibiotic-resistant bacteria, and an increase in invasive medical procedures such as vascular catheters.
Kobzik, Filoramo’s adviser, praises her contributions to this vitally important area of research. “Rose brings in different perspectives and angles of biology to the project in a very coherent and well-informed way,” he says. “While I had already been looking at the central question of why children are less likely to die from infection, she initiated the work’s current focus, and it is proceeding very well.”
An “Aha” Moment
To observe the prepubertal protective effect in the lab, Filoramo injected mice with endotoxin, a substance found in the cell walls of certain bacteria. This creates a sterile model of sepsis—the body responds with the same overwhelming immune response, but without the added complexity of bacteria replicating in the body. After months of trial and error, experimenting with different dosages of endotoxin and observing their effects on the mice, she had a quietly satisfying “aha” moment last year. The postpubertal mice were dying at higher rates and their blood showed elevated levels of inflammatory proteins, compared with prepubertal mice. Filoramo describes these young mice as “looking a bit bedraggled, like you or me when we get the flu. But you could tell that they were going to get better.”
Filoramo believes it to be a novel finding. “No one is really looking at this question with sepsis and exploring it in the depth that our lab has,” she says. Now that she’s proven that the endotoxin model works, she will be conducting analyses to probe deeper into the differences in gene regulation between pre- and postpubertal mice. She will also be moving on to more complex models of sepsis using live bacteria. She is about a year away from publishing the findings, which she’ll continue to refine for her thesis.
Combining Theater and Science
Filoramo’s career course was set during a high school human physiology class. The inner workings of the body were so fascinating to her that she soon found she was asking more questions than her teacher could answer. He encouraged her to start looking things up on her own, which she did. Although she was active in theater in high school and college, and mulled becoming a professional actor, she ultimately decided that her future lay in biological research.
Her public speaking talents are coming in handy, however, as Filoramo embarks on a new passion: teaching. She recently served as a teaching assistant during a human physiology course for Harvard Chan graduate students and loved it—particularly when students came to her with their own challenging questions. She sees herself someday running a research lab at an undergraduate institution, teaching and mentoring students in their first research experiences.
Meanwhile, Filoramo will continue to explore perplexing questions about the immune system, focusing on sepsis, infectious disease, and chronic inflammation.
“The fact that we’re not sick all the time is kind of amazing,” Filoramo says. “The way that the body initiates and then shuts off the inflammatory response is really interesting to me. If we better understood the way inflammation is resolved, we could improve therapies for a lot of different diseases.”
But while these research questions intrigue her, she seems most inspired by the way that her research could provide a teaching opportunity for others.
“When I’m retired, I hope to have established a lot of good relationships with my former students. My goal is to have inspired them to go into research as well,” she says. “I believe that by making students feel confident that they can do this type of work, good teachers can recruit more young scientists to the field. There is always a need for new perspectives.”
— Amy Roeder is assistant editor of Harvard Public Health
Listen to our podcast Unraveling the mystery of sepsis, with Lester Kobzik and Rose Filoramo.
Photo: Kent Dayton/ Harvard Chan School