Over-reactive immune system kills young adults during pandemic flu

On November 19, Jason Martin returned to the Medical Intensive Care Unit (MICU) at Vanderbilt University Medical Center for the first time since he nearly died there during last year's H1N1 flu pandemic. The tall and burly Warren County, TN, ambulance worker – a 30-year-old, father of three young children – broke down and hugged some of the nurses he recognized.

"I got sick on September 12 and didn't come out of it for the next 20 days. I am just so grateful I came through," Martin said, wiping his eyes.

Martin was among the first wave of critically ill middle Tennesseans, hit hard by the H1N1 flu pandemic in late 2009. A hallmark of pandemic flu throughout history, including the H1N1 pandemic, has been its ability to make healthy young and middle-aged adults seriously ill and even kill this population in disproportionate numbers.

In a paper published Dec. 5 in Nature Medicine, Fernando Polack, M.D., the Cesar Milstein Associate Professor of Pediatrics at Vanderbilt, and colleagues in Argentina and Nashville provide a possible explanation for this alarming phenomenon of pandemic flu. The study's findings suggest people are made critically ill, or even killed, by their own immune response.

"Every time there is an influenza pandemic there is a large proportion of younger, or middle-aged adults who die. We have always explained these deaths, based on presumed virulence of virus, or getting bacterial infection at the same time. We now have vaccines and antibiotics, but still we see middle-aged individuals who die," Polack said.

Polack directs the INFANT Foundation, a research and clinical institute based in Buenos Aires, in close cooperation with Vanderbilt's Vaccine Center. In Argentina, he had a front row seat for the emergence of the H1N1 flu pandemic, which began in April 2009.

As the H1N1 virus burned its way northward through the southern hemisphere, Polack and his team went to work looking for evidence of a biomarker he had used before. A biomarker is a protein that can be measured in blood or tissue whose concentration reflects the severity or presence of some disease state.

"We have seen this before. Where non-protective antibody responses are associated with an immune-based disease in the lung," Polack said.

Polack has previously published evidence that a first-line immune response, primed by an imperfect antibody, can overreact in a violent and uncontrolled fashion. Patients die from lung damage inflicted by their own immune system. A molecule called C4d, a product of this biochemical cascade (the complement system), is a marker for the strength of the response.

In adults who died during the 2009 H1N1 pandemic, high levels of C4d in lung tissues suggest a massive, potentially fatal activation of the complement system.

Pulmonary and critical care physician, Todd Rice, M.D., assistant professor of Medicine at VUMC, has seen people killed by the "exuberant" and uncontrolled response of the immune system in other diseases – like sepsis.