Over-reactive immune system kills young adults during pandemic flu

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Over-reactive immune system kills young adults during pandemic flu

Vanderbilt researchers have discovered how pandemic flu disproportionately kills

young adults. December 5, 2010.

On November 19, 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, " said, wiping his eyes.

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, 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.

" This looked every bit like that, " Rice recalled about H1N1 patients, including

, who piled into his intensive care unit in mid-September, 2009. " It

was impressive. These were as sick as any patients I had ever seen. We tried all

sorts of things, " Rice said.

Ultimately, Vanderbilt's ICU saw 49 adults with H1N1, most ages 25 to 45.

was one of 40 who survived.

But Polack wanted evidence beyond what he saw in patients in 2009. He asked

Joyce , M.D., professor of Pathology with VUMC, to look for evidence this

phenomenon may have happened during past flu pandemics. scanned

Vanderbilt's hand-penned autopsy ledgers, dating back to 1925. She was able to

locate tissue samples in Vanderbilt's tissue archive and extract half a dozen

slices of lung tissue from Nashville patients who died during the 1957 Hong Kong

flu pandemic.

Pediatric infectious diseases expert, , M.D., assistant professor

of Pediatrics, Microbiology & Immunology, and his lab found the signature for an

influenza infection in 4 of the 53-year-old samples, and were able to confirm

the lung tissues had high levels of C4d. These patients too had died from an

over-reactive immune response.

" C4d is part of the inflammatory cascade, and while it's really good at killing

organisms and protecting us, it's sort of the slash and burn approach, capable

of causing lots of tissue damage, " said.

But why did infants and the frail elderly escape this mechanism of death in the

H1N1 pandemic?

" We found in 2009, the elderly had good immunity because they had seen a very

similar virus sometime before 1957. Babies hadn't seen many viruses at all so

there was no trigger. It came down to the young adults – primed with an

ineffective response. Their bodies already had defenses against previous

influenza viruses that look like this one but weren't close enough, " Polack

said.

While the patient sample in the current study is relatively small: 75 patients,

including 23 who died in 2009, and 4 from 1957, investigators were able to show

that other theories, like dampening of interferon, or the triggering of an

inflammatory response called a " cytokine storm, " were not supported by the

evidence. Even the number of viruses present in a flu patient did not seem to

correlate with the severity of illness.

" It suggests this (immune over-reaction) is what happens with pandemic to make

young healthy adults seriously ill. There are other things that contribute to

threat, but this is one of the main things for this age group, " Polack said.

While many questions remain, one thing is clear: the H1N1 vaccine offers

protection. Patients who died were overwhelmingly unvaccinated. Many fell ill

before a vaccine was even available.

A study of genetics will be among the next steps to explain responses

experienced by people like . It may be possible to find out who is

susceptible to this over-reactive response so they can actively avoid exposure,

or receive a specific regimen of treatment. But until then, vaccination is the

best idea.

Provided by Vanderbilt University Medical Center

http://www.physorg.com/news/2010-12-over-reactive-immune-young-adults-pandemic.h\

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