What to do with pandemic flu - E&T Magazine

Posted: 10 Oct 2019 12:00 AM PDT

The UK government has designed a contingency plan in the event that a deadly disease wreaks havoc on the world. What needs to be done if, or when, the time comes?

If you had to sum up the national sentiment towards influenza - aka 'the flu' - in a single word, you'd be pushed to do better than 'glib'. Flu isn't serious. Not serious-serious. It's in the sweet-spot: serious enough to avoid a dreadful wedding no questions asked; not so serious that you're expected to spend those days bedridden or hospitalised. In 2015, a study by healthcare provider Benenden of 2,500 UK employers and employees found that 'flu' was the third most popular excuse for missing work after vomiting and diarrhoea. That's flu, to us in the UK: food poisoning, but a bit more dignified.

Why are we so glib about the flu? Maybe because, while we know it does kill people, by and large, it's 'other people'. Statistically, you're unlikely to have known someone who died from flu – let alone be claimed by it yourself. On average, flu and its complications kill about 600 people per year in the UK. Cancer, by comparison, kills around 450 people per day. There are outlying years where the flu mortality rate spikes: around 13,000 people in the UK died as a result of flu infection in the winter of 2008/09. But in both those same years, circulatory diseases killed 150-160,000 and cancer around 140,000. Even at its worst, seasonal flu doesn't hold a candle to the UK's most common causes of death.

Neither do we afford flu the same ghoulish glamour as more 'exotic' diseases. The 2013 West African Ebola epidemic killed nearly 11,500 people, mainly in Liberia, Sierra Leone and Guinea, but led to only one case in the UK: aid worker Pauline Cafferkey who fell ill on return from Sierra Leone and was treated at the Royal Free Hospital in London. In 2015, the media made the UK public armchair experts on the Zika virus, with public health warnings ahead of the 2016 Rio Olympics that the virus could cause birth defects in the babies of pregnant women visiting the games. In both cases, the risk to the UK population was vanishingly small.

That relegates flu to the status of seasonal nuisance –but viewing it that way puts us at odds with the UK Cabinet Office, responsible for the biennial publication of the National Risk Register. The NRR sorts and categorises potential threats to the UK over the next five years based on two criteria: how likely the event is to transpire, and how severe the impact would be if it did. In an assessment that includes catastrophic weather, critical infrastructure failure and large-scale chemical, biological and nuclear attacks, pandemic flu stands alone: not only is its occurrence, according to the 2017 NRR, a "high probability" – it also has the dubious honour of being the only civil emergency outside of a nuclear or biological terror attack to make the top tier in impact severity. It's luridly fitting that the NRR sets out its threats in tables that look like bingo cards: if you were to go all-in on the next existential threat to the UK, there is only one sensible place to put your money.

Influenza is monitored continuously all around the world. The data collected and collated by national health agencies and organisations such as the World Health Organization (WHO) informs the makeup of your annual flu jab. Vaccines for seasonal flu are cocktails: they offer protection against whichever strains of circulating influenza are deemed most likely to cause problems. These are strains of flu we understand.

Pandemic influenza, by contrast, is (usually) novel: a new flu virus to which few, if any, have immunity. Pandemic flu needn't be particularly deadly: the 2009 swine flu pandemic led to only 474 deaths in the UK, lower than the average mortality rate for seasonal flu. A pandemic flu like the 1918 Spanish Flu with a high mortality rate is the nightmare scenario, but to qualify the candidate flu virus needs to spread quickly and globally through populations with no immunity. To achieve this, the virus needs specific characteristics.

"The more we know, the more we recognise that flu can [come from] many different places in the world," says Derek Smith, professor of zoology at the University of Cambridge and a principal investigator at the Cambridge Infectious Diseases Research Centre. "It has to be a type of influenza that has not been seen or is not currently circulating in humans but is in some animal that humans are in contact with. Critically, the things that are host-specific – the environment that the virus finds itself in within that animal – have to be similar enough to the environment that it would find itself in within humans. The virus has to be able to replicate at a similar temperature. The receptors that the virus is using in the animal [have to be] similar to the receptors the virus would use in humans."

Certain parts of the developing world make for better pandemic start-points than others. More basic healthcare systems are, obviously, less likely to detect novel forms of influenza and effectively control their spread. A lack of education about disease and hygiene is another risk factor. Cultural differences can also have detrimental effects: in countries where animals are traditionally bought live from markets and slaughtered at home, people and livestock are in constant and unsanitary contact. Influenza viruses that are transmitted from animals to people are evolutionarily poorly suited to human hosts, usually necessitating large doses of a virus to cause infection.

Markets in China and South-East Asia, with crates of live birds and pigs arranged in cramped stacks, are hotbeds of disease. Even if the virus and its animal host is identified, these markets and the trade in infected animals may continue. In developed countries, infected livestock can be slaughtered en masse to control the spread. But if a country's swine and poultry farmers rely on their produce to live and cannot expect remuneration for their destruction, the trade in diseased animals will continue.

In most recent cases of animal-to-human transmission of influenza, the buck has (fortunately) stopped with the infected individual. A saving grace of these infections – however destructive they might be to the individual – is that while a virus may get a foothold in one human host, extra mutations and adaptations are normally required before that person can then become infectious to others. Once that happens, says Smith, that's when the global flu research community "drops everything".

Once a potential pandemic has been identified by a national health service or sentinel teams from organisations like WHO, information is disseminated as far and as quickly as possible. A global threat demands a global response. Collaboration is the flu-killer.

"An unusual event, like a pandemic about to start, is noticed epidemiologically first," says Smith. "Some hospital in some region suddenly has a bunch of people coming in with a particular related syndrome and, in many instances, the tests don't identify [their condition] as this virus or that virus, because it's a new virus.

"This happened in 2003 in Hong Kong with Severe Acute Respiratory Syndrome (SARS). Many of the people in the flu world were involved in the analysis of this virus at the time. [There were] daily teleconferences with scientists all over the world to investigate and share information in a very open way... It was just an absolutely fantastic, new level of collaboration and investigation. And though we'll never really know, that probably stopped a SARS pandemic.

"In the space of a small number of weeks, the causative virus was found, detection and the incubation period was figured out, people could be tested for SARS and then quarantined very effectively. The Chinese government built massive quarantine hospitals very quickly and stamped out the disease in humans. And that was because of this incredible science that was done very quickly and organised in this fantastic collaborative way."

Even with effective early detection and collaboration, the likelihood of pandemic flu slipping past the controls and arriving in the UK is high. This is an eventuality for which the UK prepares intensively. But deciding how to respond to pandemic flu infection adequately and proportionately when information on the virus is still forthcoming is a balancing act between under- and over-reaction.

"Something that the 2009 pandemic taught us is: you shouldn't assume things about flu, because you're likely to be wrong," says Ellen Fragaszy, senior research fellow at University College London's (UCL) Institute of Health Informatics. "Pandemic flu doesn't necessarily mean more cases. Pandemic flu doesn't necessarily have to mean more severe disease. Not every pandemic flu is like the 1918 pandemic flu.

"We need to be able to scale our pandemic response accordingly – so if it's a really bad pandemic we need to throw everything at it, but if it's not a worst-case scenario, we need to be able to scale and target our interventions and what we do in response so it's proportionate. And to do that, we need to have better methods of measuring and [the ability] to do that quickly."

Collecting and measuring data, as the UK learned in the 2009 pandemic, can be problematic. Influenza viruses are stealthy: while everybody thinks they know the symptoms well enough to decide whether what they have is the flu or just the sniffles, the vast majority of people don't realise that they can be infected and infectious while showing no symptoms whatsoever. This diagnostic blindspot, coupled with a general reluctance to consult a GP over things that don't 'feel' serious, leads to a model of flu surveillance Fragaszy refers to as 'The Iceberg'.

"With icebergs, you only see the tiny bit that sticks up above the water – but the vast majority of the iceberg is underneath and not visible," says Fragaszy. "People use this comparison a lot with flu, because if you draw a triangle on a page pointing up and draw horizontal lines across [to represent] the different outcomes for people who get infected, the bottom part of that triangle – the big part of the iceberg – is asymptomatic infections. The majority of people infected with influenza – both for seasonal flu infections and also during the 2009 pandemic – don't develop illness or symptoms. A lot of people don't realise this: most flu infections don't make people ill."

Managing public misconceptions around flu is a high-stakes problem. If the patients you need to see aren't convinced their illness is worth the effort of a doctor's appointment – or don't realise they're sick at all – persuading them to give their time requires you to convince them they are at higher risk than they think. But communicating the facts about a pandemic disease is a minefield. If you undersell the severity of the threat, consultations remain low. If you oversell, you risk a flood of patients – both the sick and the worried well – overwhelming doctors' surgeries and causing a diagnostic logjam. Deciding the public message requires incredible nuance. Worst-case scenario planning is common-sense practice – but if just one opportunistic news outlet decides to misrepresent or sensationalise the risk to public health, one sound bite or line from a report out of context could spark a panic.

"Trying to communicate [that] risk is quite difficult," says Fragaszy. "When people make these estimates – for instance, number of cases or number of deaths – early on when there's not very much data, they might come to an estimate and say, 'We think that there might be approximately this many cases, [but] there may be as many as 500,000 or as few as 2,500.' And the media will, often, go for the high number: 'It could be as high as 500,000!' Well, yeah, it might be – but most likely it's going to be a number in the middle."

After this initial phase of monitoring and containment, the next duty of the UK health services is disease management. By its own estimates, the UK government puts the time between detection of a novel influenza virus and the development of a vaccine at no less than four-to-six months. In the interim period, various forms of triage will be implemented based on what has been learned about the disease, with those at most risk, not necessarily of catching but of suffering most severely from the flu, being prioritised for treatment using emergency stockpiles of antiviral drugs.

Extra precautions will also be put in place to protect healthcare workers – who are not only at high risk of infection due to exposure to sick patients, but also of then passing the infection on – and workers in key industries necessary to maintain critical supply chains. Pandemic preparedness has a lot of moving parts: if medical staff are healthy but can't get to work, or arrive at work to find they're short of antiviral medications, the machine stops working.

These disruptions correlate directly with the severity of the pandemic, and this ties neatly into a final misconception about the dangers of pandemic flu: that modern medicine makes a disastrous outbreak impossible.

"Something as destructive as Spanish Flu is still a possibility today," the Cambridge Infectious Diseases Research Centre's Smith says, firmly. "In the laboratory, that virus is still one of the absolutely 'hottest', most virulent viruses that anybody works with in terms of flu. It's not [as simple as saying]: 'That was 100 years ago; today it wouldn't be a problem.' No. That is one mean motherf****r of a virus. If we saw that virus today, it would be ugly.

"It's possible that things could be uglier: the H5 viruses have infected something like 1,500 people that we know of since 1996, and they've killed about half of them. These are infections that aren't transmissible to other humans as far as we know, so this is not necessarily the virus as it would adapt to transmit to other humans. But [H5N1] has killed about half of the people that it's infected – and the half that it didn't kill... they don't skip out of the hospital. They are severely respiratorily compromised for an extended period – possibly for the rest of their lives."

Complacency is, as Smith tells it, a trap. It's easy to write off fatal cases of influenza that happen on the other side of the world as the result of poor healthcare provision. Indeed, that's a view that's enforced by the media coverage of those earlier, 'glamorous' diseases. The images of the aid worker tents in West Africa hastily erected to treat Ebola and the lone UK case at The Royal Free Hospital paint a compelling picture: horrible diseases do horrible things to people in the nebulous 'Over There'. When a disease wipes out a village in Africa or Asia, it's because its victims were lying side-by-side on metal cots, breathing the same stale air, shedding disease under the same canvas, waiting for the same drugs... if they ever arrived. The case of Pauline Cafferkey – who recovered from Ebola on return to a 'proper' hospital in the UK – seems to underline the conclusion that what kills these people isn't the disease itself, but a tragic lack of modern medical care.

That's a comforting, compelling narrative for people to internalise. It's also wrong and incredibly dangerous.

"There are plenty of people who died of H5 in intensive care, in hospitals with access to any antibiotic, access to any of the flu antivirals, being kept alive with artificial respiration and external oxygenation of the blood, with lots of doctors around them. They still died. And that's just the occasional person with H5. One of the reasons that a flu pandemic could potentially still be as nasty as what happened in 1918 has to do with the surge on the healthcare system. It's not going to be a trickle of people that come in who need intensive care beds. Flu pandemics happen quickly; the numbers ramp up quickly. And the number of intensive care beds, the number of respirators, the number of external oxygenation units... All that stuff would be very quickly exceeded in the case of a severe pandemic.

"What happened in 1918 is still a [possibility]. Nobody that I know writes off a scenario like 1918."

Pandemic flu 'preparedness', then, is something of a clumsy catch-all. One reassuring take-home from the 2009 pandemic and SARS is that a flu pandemic isn't necessarily some ruthlessly unstoppable force. Detection works. The framework for global collaboration is in place. But by its very nature, pandemic flu is a game of known unknowns. However prepared we are, it will always have the potential to surprise.

"If it was a really bad virus, it would be difficult to contain and deal with," says Fragaszy. "I don't think that would be because of a lack of preparation in the UK or internationally. The case fatality in some of the avian influenza viruses was over 50 per cent. That's really bad. Having said that, they're not circulating in humans, and it's quite possible that [if] they adapted to circulate in humans [the adapted strain] wouldn't be so severe. The 1918 pandemic didn't have a case fatality like that – it was high, but nothing like that.

"So we don't really know what [the next pandemic] could be like. That's why it's scary."

1918 pandemic

Spanish Flu

The 1918 influenza pandemic, often referred to as 'Spanish Flu', is commonly used as a worst-case scenario reference point in pandemic flu preparedness. Though its mortality rate was lower than some modern influenzas, the global death toll is loosely pegged at somewhere between 50 and 100 million deaths. The reason for this wide error margin is also one of the reasons that Spanish Flu became such a global scourge: at the time of the outbreak, flu was poorly understood and outbreaks in many countries simply weren't identified or recorded.

In Britain, the outbreak killed some 228,000 people. The Prime Minister of the day, David Lloyd George, was himself infected in September 1918. And yet a discussion of the disease in Parliament would not occur until October. At the time, flu and other infectious diseases were considered local matters outside the purview of government. It wasn't until 1919 – the height of the pandemic – that this approach was reviewed, and the Ministry of Health was founded.

Severe Acute Respiratory Syndrome