Who dies of the flu?

Flu: everyone’s had it, and had it again. The virus rarely means more than temporary inconvenience – except sometimes, when it kills. Why? Researchers at Imperial have led an unprecedented bid to find out.

We’ve all been there. You get that achy feeling, bit of a chill, a cough. Not to panic, it’s probably just the flu. It will be over in a few days.

But sometimes it isn’t. The yearly winter flu epidemic kills 200,000–500,000 people worldwide. Most are very elderly. But every now and then a new strain of flu virus appears, to which many younger people have no immunity. This is a flu pandemic – and one circled the world in 2009.

It is thought to have killed 200,000 people worldwide that year. It initially hit the UK in two waves, in June and October, killing 474 people. In England alone it is estimated to have put 7,879 people in hospital, 1,700 of them in intensive care. The same virus hit Britain again during the winter flu season of 2010–2011, killing 602. In England 8,797 ended up in hospital, 2,200 in intensive care.

At the peak of that outbreak, one in five UK intensive care beds was occupied by flu patients fighting for their lives. In the three waves that hit Britain between 2009 and 2011, eight in ten of those who died were under 65; 107 were under 15.

“I’ve never seen anything like it,” says Dr Jake Dunning, a researcher and clinician working at the St Mary’s campus, who graduated in Medicine from Imperial in 2001. “There were so many people in their 30s and 40s in intensive care.” Conditions including asthma, or being obese or pregnant, can make flu worse – but frighteningly, says Jake, around a third of the severe cases of pandemic flu had no obvious reason to be so sick.

And yet at the same time, research also partly done at Imperial has found that three-quarters of the people who caught that same virus never knew it: they didn’t even get symptoms. So, two perfectly healthy people can catch exactly the same flu virus, and one dies while the other doesn’t even get sick. How are they different? It’s a question that matters for people caring for themselves and their families, and it also matters to governments planning for pandemics.

In April 2009, Professor Peter Openshaw, head of Imperial’s Centre for Respiratory Infection – which had begun operating just that year – realised there was a once in a lifetime chance to answer that question. Reports of a nasty new flu were coming out of Mexico. Everything pointed to it becoming the first flu pandemic since 1968.

It was frightening – no one knew how bad it might be. “Remember how uncertain we all were,” says Peter. “There were early reports of very severe cases. We didn’t know if this was The Big One.” A flu pandemic can be quite mild, or it can be like the one in 1918 that killed 1 to 2 per cent of those infected – or maybe even worse.

But it was also an opportunity to learn how to defend ourselves, by turning the big guns of modern medical research on a flu pandemic for the first time. In particular, says Peter, it can be easier to pick apart what makes some people sicker than others during a pandemic rather than in normal flu seasons. The latter involve several flu viruses, to which people have differing previous exposures and immunity, which affects whether and how badly they fall ill. But in a pandemic, many have no immunity to the new virus at all.

“We had a chance to see what happened with one infection operating in relatively virgin territory,” says Peter. With variations in viruses and immunity reduced, the inbuilt differences between people that determine who gets severely ill might stand out.

“Peter rang round different labs asking what studies we could do if this thing kicked off,” says Jake. Meanwhile the big UK research funding agencies – the Medical Research Council, the Department of Health, and the Wellcome Trust – called a meeting to discuss what research might be needed to face a pandemic. Peter proposed a collaborative effort to record medical histories and analyse samples from people hospitalised with the new flu, to see what made them unlucky.

The plan was to recruit several hundred hospitalised patients. To get that many before the pandemic wave or waves ended, they would have to work at several hospitals. Medical staff would record what other conditions they had that affect flu, their symptoms, treatments, and final outcomes.

And they would take samples: blood, nose and lung fluids, urine and faeces, both early and late in the disease and, with luck, after recovery. The samples would undergo a host of analyses for viruses and bacteria, immune reactions, gene sequences from patient and virus – even patients’ messenger RNA – to see what genes were turned on or off as they fought the infection.

Studies like this, combining data from symptoms and from genes in individual people, are surprisingly rare: clinicians and virologists often inhabit different worlds. It is just such a divide that the Centre for Respiratory Infections was meant to bridge. But first, they had to get their funding.

The proposal led by Peter was called Mechanisms of Severe Acute Influenza Consortium, MOSAIC, and it was the most ambitious project proposed at the funder’s meeting that day. “Initially there was some scepticism,” he says. In the end MOSAIC was granted £2.7 million by the Wellcome Trust. “At first we had only a restricted budget for 12 months, I guess because they thought we might not be able to do it.”

He understands the trepidation. The beast they were studying wasn’t waiting around: the first wave of the pandemic was over in July. A study this big normally takes a year to organise. The grant proposal went to the Wellcome Trust in late April. It got an unprecedented fast-track through scientific review and ethical approvals, and the grant was awarded in a record six months.

Normally that would be when managers started hiring staff, but MOSAIC had already been getting people and permissions in place for months. The first patient was recruited in December.

And then the second wave of the pandemic ended. It seemed like all the rush had been for nothing. A few patients were recruited and studied. But then the virus struck again the following winter, and the funders let the project continue. In the end, two-thirds of MOSAIC’s subjects came from that ‘third wave’. If the UK had not had one – and many countries didn’t – MOSAIC would have started too late to learn much. The lesson for future outbreaks? “The process was fast, but not fast enough for outbreaks like this,” says Peter.

As a result, the UK has invented a new concept in research management: hibernation. Eight research projects totalling more than £3 million and designed to track and understand a pandemic as it is happening are now being designed, approved, and organised. They range from assessing the effectiveness of treatments and the virus’s spread, to managing overstretched hospitals and communicating with the public. They will now wait – hibernate – until the next pandemic strikes.

Back in 2009, MOSAIC had other problems. Nine hospitals, in London and Liverpool, were involved, and each one needed different paperwork. Navigating such obstacles is an everyday job for Mary Cross, a research manager at Imperial. Even so, in its dash to capture the pandemic before it was over, MOSAIC encountered obstacles no one had realised were there.

The procedures required before the MOSAIC recruiting team could start asking patients to take part were different at each hospital. Some required staff to be tested for the antibiotic-resistant bacteria MRSA before they could work there collecting samples; some didn’t. A ‘research passport’ meant to allow researchers at any hospital access to any other was not, it turned out, recognised by all hospitals. Approvals that were supposed to take 48 hours took weeks.

There has been some improvement since MOSAIC, says Mary. Research approvals by hospitals are now more standardised, and in theory work during a severe pandemic will be excused from some of the requirements.

In 2009, she says, “we were working around the clock”. Besides the administrative nightmares, there was the simple, physical job of putting the right sample tubes, swabs, gloves and other equipment in bags for nurses to use with the next day’s patients. Although a senior administrator, Mary put in late nights helping clinical staff fill the bags. “It was all hands on deck.”

But studying a pandemic is, by definition, entering the unknown. “Usually you know how frequent a disease is, so you know how many hospitals over how much time you need to work in, to recruit enough patients,” says Mary. No one knew that for the 2009 pandemic.

In the end, MOSAIC recruited 255 patients with suspected flu, of whom only 172 actually had flu and not some other cause of flu symptoms. In terms of linking immune signalling chemicals called cytokines to severity, says Peter, it is the biggest study ever made. It showed what genes were turned on and off by different patients during the infection, and how the virus’s genes changed over time – and it uncovered some real surprises.

Jake was Clinical Research Fellow for the study. Mostly, he recalls, that meant racing across London between hospitals and laboratories with a special secure container for patient samples on his bicycle – the fastest way to get them through the London traffic. “The hard bit was cycling in the snow.” For eight weeks he got four hours’ sleep a night.

“We had to refine procedures as we went along,” says Jake, for instance asking nurses to record patient weight and height more routinely so the effect of obesity on severity could be tracked. “One legacy of MOSAIC is that we will be better prepared to do outbreak research the next time.”

In fact Jake and Peter are now part of a global research consortium, called ISARIC, and a European network called PREPARE, working to develop standard protocols for doing this kind of investigation anywhere. “As long as we all get the same standard, core clinical data and get the samples in the freezer, we can analyse them later, pool data, and really dissect a disease,” says Jake.

For MOSAIC, that analysis has now yielded a clutch of research publications to be published later in 2014. One exciting result has already come out. Researchers at the Sanger Institute near Cambridge discovered that a gene called IFITM3 codes for a protein that helps mice fight off the flu virus. The MOSAIC team looked at their severely ill patients – and sure enough, they were nearly 20 times more likely than the British public generally to carry a mutation of IFITM3 that didn’t fight flu so well.

But the final answer to the question of why some people become severely ill with flu and some don’t even have a cough must involve more than that one gene. “It will turn out to be a combination of unfortunate events,” says Peter. “The particular virus, the patient’s genes and immune response, maybe the bacteria that are also present.”

That’s hard to untangle even from exhaustive data on sick people, says Jake. But, he says, MOSAIC is being analysed with a clear focus on how it might improve the way patients are treated.

For example, it might give us a way to find people who are most at risk and prioritise them for pandemic vaccines or antiviral drugs. It may show us how to counter the unhelpful immune responses that can do much of the damage in flu, or how to shore up some people’s faulty defences, perhaps via the IFITM3 protein. We might learn how to boost immune reactions that limit the severity of disease even if we can’t prevent infection. We might learn which bacteria in our lungs are most likely to attack us the minute our defences are lowered by a flu virus, and devise ways to stop them.

“MOSAIC allowed us to put the whole picture together – the patient’s genes, the pathogen, the other pathogens that co-infect with it – and that’s never been done before,” says Jake.

But perhaps as important, it showed us how to do medical science in a new way, as Peter puts it, “in the teeth of a pandemic”. Besides teaching us about flu, MOSAIC revealed much about our systems for regulating research, and how those must evolve to let us grapple with the next pandemic. The doctors, researchers and administrators who made it happen all hope those lessons will be learned in time.

Debora Mackenzie is a science journalist who writes regularly for New Scientist and other publications. She specialises in writing about infectious disease, arms control, food production and complexity.

Words by Debora Mackenzie

Art by Craig Alan