Why flu can be fatal
Patients that become very ill after briefly recovering from a primary infection like flu may have an ‘immunological scar’, and intensive care treatments could be part of the problem
This year’s influenza season was Australia’s most severe since 2009.
And while many consider flu an annoying but relatively minor illness, it can kill. At least 121 related deaths were reported this year, and there were many more hospital admissions.
“Flu deaths are commonly caused by lower respiratory tract infections and pneumonia - a leading cause of death from infectious disease,” explains Professor Jose Villadangos from the University of Melbourne.
“The risk of pneumonia is particularly high for critically ill patients recovering from their first flu infection episode.
Stopping the flu before it takes hold
“After an initial severe infection, patients may be at high risk of contracting secondary infections and developing fatal pneumonia.”
Professor Villandangos, who is based jointly at the Bio21 Institute and the Peter Doherty Institute for Infection and Immunity, and his team discovered this is due to our immune systems being left paralysed by the initial infection.
Their research, which is published in Immunity, sheds light on why patients who survive a severe infection or physical inflammation, such as pneumonia caused by flu, may have compromised immune systems.
It raises questions about treatments inside Intensive Care Units (ICU) following acute infection, sepsis (inflammation) and even severe trauma.
“We have discovered that recovery from the viral infection leaves an ‘immunological scar’ that reduces the immune system’s capacity to launch protective responses against subsequent infections,” says Professor Villadangos.
Immunological paralysis
“We are not evolved to survive the level of inflammatory assault that would send a person to ICU. Modern medicine in ICU is the only reason we survive,” Professor Villadangos explains. “But this comes at a cost: the same processes that are normally at work to stop inflammation after the resolution of infection, ‘overshoot’ in ICU survivors, leaving them immunosuppressed.”
It means that as a person recovers from their primary infection, their immune cells are less able to activate their immune system.
“We have termed this phenomenon ‘immunological paralysis,” Professor Villadangos explains. “This new knowledge is changing our thinking about how best to manage patients after their infections.”
The research, which used tests in mice and observations in patients, was led by Professor Villadangos with Dr Antoine Roquilly, who is now based at the University Nantes in France.
Stopping the flu virus at the nose
To uncover the mechanism for the immunosuppression, the researchers measured the levels and activity of immune cells responsible for fighting infection.
They also looked at the levels of certain messenger molecules called cytokines and other factors that activate or suppress the immune system.
“We found that, following a primary infection, immune cells became ‘paralysed’ and unable to alert or activate the immune system to another invading pathogen threat,” says Dr Roquilly.
“Following a primary infection, the immune system essentially undergoes a reprogramming that can persist for weeks and cause immunosuppression, increasing susceptibility to further infections,” says Professor Villadangos.
Clinicians have traditionally blamed weakened immune barriers (such as the mucus membrane and lining of the lungs) for patients’ rapid descent back into severe illness after a brief, illusory recovery.
“That may be true, but our research suggests defective regeneration of the immune system means it happens more often and more severely,” he says.
The immunosuppression is similar to that experienced by organ transplant and blood cancer patients. “Crucially, they are sitting ducks for commensal flora – the everyday bacteria that we cope with easily when healthy – to become life threatening,“ explains Professor Villadangos.
Changing treatment
Managing patients after recovery from pneumonia or sepsis (an extreme response to an infection that is potentially life-threatening) is a balance between preventing new infections and managing inflammation.
“When our body is injured or invaded by pathogens, our immune system responds by releasing cytokines that stimulate an inflammatory response,” explains Villadangos.
The symptoms experienced during inflammation include heat, pain, redness, and swelling. This is due to cytokines being released by immune cells that increase blood flow through our arteries to allow them to quickly travel to the site of injury and infection to attack invaders and begin repairs.
During sepsis, it is not only the pathogen, but also inflammation that wreaks destruction in the body. Like a controlled-burn that has jumped containment lines, the body’s own immune cells go into overdrive.
The flu-hunters
To manage this risk, immunosuppressive drugs have become standard clinical practice. But these further lower the immune system’s already compromised ability to fight any secondary infection the patient may experience.
“We need to change our approach to treating people in ICU after severe infection,” says Professor Villadangos.
“The current focus is on dampening the immune system. While this is necessary to prevent organ damage by excessive inflammation, we also need to avoid establishing an ‘immunological scar’ that leaves patients susceptible to secondary pneumonia.”
Instead, the immune system can be supported to better fight secondary infections in sepsis patients.
“In these sorts of clinical situations there is always a balance between harnessing the powers of the immune system without unleashing its destructive forces.
We are now researching how we can use cytokines to reprogram the immune system to better respond to infections after acute inflammation, to translate these findings into the clinic,“ says Professor Villadangos.
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