People who develop severe coronavirus complications have raised levels of a specific protein in their blood, research suggests.
The infection is thought to be mild in four out of five cases, however, it can trigger a life-threatening disease called COVID-19.
To better understand why this occurs, scientists from across the UK analysed the blood of more than 500 mild and severe coronavirus patients, as well as that of swine flu victims and healthy volunteers.
Results suggest several inflammatory markers become elevated in the early stages of the coronavirus in those who later became critically ill.
The infection-fighting protein GM-CSF was specifically found to be 9.6 times higher in those who died with coronavirus.
Better understanding GM-CSF may help medics identify coronavirus cases who are at risk of becoming seriously ill.
It could also lead to "pinpointed" treatments that dampen the pathway behind GM-CSF, rather than broad-acting drugs that suppress the entire immune system.
The scientists analysed blood samples collected from 471 people hospitalised with the coronavirus across England, taken via the ISARIC4C study.
Blood was also sampled from 39 outpatients with a mild bout of the coronavirus, as well as stored vials taken from 20 people who died with swine flu during the 2009/10 outbreak.
All the samples were compared against the blood of 36 healthy volunteers, who did not have any respiratory infection.
Across all the samples, the scientists screened for 33 inflammatory markers.
They found increased clusters of markers that are associated with respiratory diseases – like the infection-fighting protein IL-6 – in both the mild and severe coronavirus patients, as well as those who died with swine flu.
Several markers were exclusively elevated among the mild and severe coronavirus patients, however, including those linked to general inflammation, swelling of blood vessel linings and increased blood clotting.
Only severe coronavirus patients had higher levels of GM-CSF, which rose in proportion to their complications.
The results, published in the journal Science Immunology, further show GM-CSF was on average 9.6 times higher in the patients who died with the coronavirus than the swine flu victims or healthy volunteers.
The protein typically became elevated within four days of the patient's coronavirus' symptoms emerging.
GM-CSF "appears to specifically mark out severe COVID-19 and may play a role in driving severe disease," said study author Dr Ryan Thwaites, from Imperial College London.
The protein is involved in the activation of immune cells called macrophages, which "mop up damaged material and are essential to the inflammatory process", according to co-author Professor Peter Openshaw, from Imperial College London.
"This particular pathway doesn’t appear to be activated in influenza, which superficially may resemble COVID quite closely," he added.
The study's older coronavirus patients showed higher levels of inflammation, however, age was not specifically linked to GM-CSF levels.
There was also no difference in GM-CSF between the male and female participants.
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GM-CSF is a form of infection-fighting proteins called cytokines. Since the coronavirus outbreak emerged, experts have thought so-called cytokine storms may be behind cases of severe illness.
A cytokine storm occurs when an excessive amount of the proteins are released due to the immune system over-reacting to an infection. This triggers inflammation that can severely damage healthy tissues and organs.
"Our new study shows there are many inflammatory markers raised in COVID-19, but these are more in the range of a 'response' than a 'storm'," said Dr Thwaites.
A cytokine storm tends to have a rapid onset, as seen in sepsis or toxic shock syndrome.
"The immune response very quickly turns on and goes out of control," said Dr Thwaites. "Clinically, that doesn't match COVID.
"A cytokine storm might not be a perfect fit."
Dr Thwaites added a "strong wind or gale" may be a more appropriate description.
Critically-ill coronavirus patients have routinely been given the steroid dexamethasone after a study released in June 2020 found the low-cost drug cut the risk of death among those on mechanical ventilators by a third.
The arthritis medication tocilizumab also suppresses cytokine function.
While the drugs save lives, dexamethasone in particular dampens the entire immune system. Serious side effects have not been widely reported, however, immune-suppressing medications can theoretically cause patients to catch other infections.
"There is a clearly a contribution of the immune system to the pathology of COVID-19, but it is more nuanced than that," said Dr Thwaites.
Some elements of the immune system cause damaging inflammation, while others try to clear the infection.
Future trials may help distinguish between these elements, pointing medics in the direction of more targeted drugs.
"Instead of giving a very broad-acting immunosuppressant treatment like steroids, we could give a pinpointed therapy that takes out the pathway causing harm while allowing the rest of the immune system to do its job," said Professor Openshaw.
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The scientists have stressed the frozen swine flu blood samples may have degraded over the past decade, causing some of the vials' protein markers to drop.
Coronavirus samples were not compared against seasonal flu due to the latter's rates being low in the UK. This has been put down to a high vaccine uptake and social distancing.
GM-CSF is not the only driver of severe coronavirus complications, with its presence alone also not indicating an increased risk of COVID-19, stressed the scientists.
Further research is therefore required before the blood marker could be used as a prognostic tool, they added.
Several therapies that target GM-CSF are in clinical trials, but not approved as a coronavirus treatment.
"This is another step forward in understanding this new disease," said co-author Dr Kenneth Baillie, from the University of Edinburgh.
"By studying patients with severe COVID-19 at large scale across the UK, we're building a clearer picture of lung disease in COVID-19.
"The lungs are being damaged by the patient's own immune system, rather than directly being damaged by the virus, and we can see specific signals in the immune system that might be responsible.
"Of course, clinical trials are needed before any change to the way patients are treated."