Bird Flu Redux?

Just as winter gives way to spring and the prospect of relief from runny noses and sore throats, ominous reports begin to emerge of a mysterious new flu-like illness against which there appears to be little immunity and no vaccine. In the spring of 1918, the first reports came from the Iberian peninsula, though the true origin of ‘Spanish’ flu most likely lay on the eastern seaboard of the United States. In the spring of 2009, it was the unexpected emergence of ‘Mexican’ flu that set pulses racing, prompting the World Health Organisation to declare a worldwide ‘pandemic’ of H1N1 swine flu (an announcement that many considered premature when the pandemic turned out to be far milder than expected).

This April, the ill wind is blowing from China where since 31 March twenty-three people have died of a mysterious new virus. ‘Mysterious’ because although scientists have ascertained it is a ‘triple reassortment’, containing flu genes from wild birds and ducks, it also contains a pair of mammalian genes. Yet, so far, no one has been able to explain how H7N9 acquired these mutations or where the virus ­– which, unusually, does not make birds ill – resides between human outbreaks. Adding to the concerns is the unusual profile of the victims ­: twice as many men have been infected as women and by far the majority of cases have been adults aged 60 and older – precisely the age group that usually enjoys a measure of protection because of their prior exposure to pandemic viruses.

So far, there have been 110 cases spread across eight provinces in eastern China. However, the vast majority of those cases have occurred in Shanghai, one of the most densely populated cities in the world, prompting one expert to speculate this may be an insidious new ‘urban influenza’. Then, last week there was the first case from outside China, when a 53-year-old Taiwanese man, who travelled to eastern China for work, fell ill. He is now seriously ill in hospital. Even more alarming is the fact that to date the virus has killed one in five of those it has infected. If that ratio remains constant, it would make the virus ten times as deadly as the Spanish flu, which had a mortality rate of about 2 percent and killed 50 million people worldwide.

So how worried should we be about H7N9? That is a question I recently put to Jeremy Farrar, the director of the Oxford University Clinical Research Unit in Ho Chi Minh City and one of the world’s leading bird flu experts. Over the past few weeks, Farrar has been working with the WHO and China’s Centers for Disease Control (CDC), coordinating the exchange of information in an effort to understand the virus and anticipate its next move. These efforts were given urgency last week by a study in Plos Pathogens and highlighted in Nature showing that eastern China is now one of the most ‘connected’ places in the world, with 70 per cent of the world’s population living within two hours of an airport linked to the outbreak regions by a direct flight or a single connection.

As Farrar told me en route to China ahead of the May Day holiday, one of the paradoxes of improved surveillance systems is that it increases the visibility of ‘emergence’ events inside China –  something that was not true ten years ago when the Chinese authorities tried to cover up the SARS outbreak in the hope of averting a panic.

As Farrar puts it: ‘We will see more of these type of events. [So] we need to be honest and try and communicate the uncertainty that exists and admit that we don’t know. And we must avoid the cynicism that I appreciate is natural after the [H1N1 swine flu] pandemic of 2009 thankfully turned out to be less severe than feared.’

Farrar, who takes over as director of the Wellcome Trust in October, says one of the challenges facing scientists is that ‘we are not very good at communicating uncertainty or dealing with risk’.  However, having witnessed at close quarters the havoc wrought by SARS in 2003 (the virus claimed the life of one of Farrar’s collaborators, the Italian scientist Carlo Urbani), and having followed the re-emergence of H5N1 bird flu in Vietnam in 2004, he is better qualified than most to give a considered response. So here, ‘in no particular order’, is Farrar’s list of ‘What makes the emergence of a novel influenza virus worrying’:

1:  The appearance in human populations of an avian/animal influenza virus not previously experienced in humans and with little/no immunity.

2:   Surveillance is made more difficult when the animal/avian species does not get sick with the infection – i.e. Ducks in H5N1, and poultry in H7N9, which makes tracking outbreaks by deaths in poultry difficult.  The continued circulating in the animal/avian reservoir obviously means more viruses and presumably increases the risk (numbers game) of novel reassortment or mutations more likely.

3:  Always a concern when avian viruses are allowed to co-circulate with mammalian populations whether that be pigs in jointly farmed areas, or humans as seems to be the case in H7N9.  In such circumstances there is the worry about the virus adapting to [the] mammalian environment or meeting with a human or pig with flu (dual infections) and the ‘avian’ virus reassorting with a ‘human’ one.

4:  Outbreaks in major cities obviously increase the risk of spreading within densely populated centres as opposed to less populated rural areas.  Such urban centres often act as transmission points for more widespread dissemination either via markets and spread of poultry bought from far and wide and distributed far and wide or via human movement nationally and internationally.

5:  The age spectrum of cases to date is potentially very important and suggests that across all the human ages seen there is infection/illness.  Often the elderly in these ‘novel’ influenzas have some degree of protection from presumed cross protection from all the other viruses they have seen in their lives to specific immunity to the virus in question.   So for the pandemic H1N1 the elderly were in fact partially protected, presumably by prior exposure to similar viruses.  H7N9 flu cases have been very very rare so all ages will be non-immune.

6:  The epidemics in huge cities makes surveillance even more difficult.   Shanghai and Beijing are home to 20+ million people each (and many wet markets).  Hospitals are full of people with community acquired pneumonia and it is not possible to diagnose everyone.  We do not know how much is being missed as you cannot do flu PCR on every single Chinese person being seen in these huge hospital;  the first case in Taiwan was negative on the first two diagnostic PCR tests.  We don’t know what how much virus there is in a person and how sensitive the tests.

7:  The presence of mild and moderate cases is a cause for worry. In H5N1 it was clearly very, very difficult to acquire infection [and] once you did it came with a very high mortality.  That is absolutely tragic for the individuals and the families but does mean that that virus also dies and is not passed on.   Transmissibility between avian/animals  for this H7N9 to humans seems very much easier; there have already been a lot of cases and all are jumps across the species barrier.  The presence of mild/moderate cases increases the risk of further adaptation to humans and increases the chance of H2H transmission.   The lack of mild/moderate H5N1 cases probably has helped save us from that adaptation.   The deaths in H5 are tragic but do prevent on going human adaptation and transmission.

8:  Intermittent use of anti-virals and increased use will inevitably increase the risk of resistance developing and vaccines remain at best 4-6 months away in the West and even longer in Asia and the rest of the world, even if and when a decision is made to shift seasonal flu production to this virus with all the worries about lack of seasonal flu vaccines.   We do not know how immunogenic an H7N9 vaccine will be.

9:  The first case outside China will have HUGE implications and surely can only be a matter of time. [On April 25, the Taiwan CDC confirmed H7N9 had been isolated in a 53-year old Taiwanese man who recently returned from eastern China].

10:   The virus currently seems to bind to deep lung tissues and hence cause severe disease.  If it acquired H2H [human to human] transmissibility that would probably have to change to allow transmission by droplet/coughing, but we do not know if by gaining transmissibility it would lose deep lung binding and hence cause less severe lung damage.  There may be a trade off between severity and transmissibility.

11:  The mild/moderate cases with no obvious avian exposure does suggest there may be existing H2H transmission if only limited and not sustained.

12:  Despite the great efforts in China we do not yet know the extent of this infection beyond the cases, clearly crucial knowledge about risk assessment for further spread.

13:  Chicken/poultry production has changed in China and Vietnam over the last 5 years.  Markets now supply poultry over a very wide geographical area rather than just to their local markets, hence the spread of any infected (but not sick) birds).  The finding of H7N9 in flying birds and wild birds also increases the risk of it being spread further.  At the moment it is not absolutely clear what the natural host of this is

14:  [The outbreak is] occurring outside the normal flu season…and therefore potentially not having to compete with seasonal flu viruses.

‘In short,’ Farrar concludes, ‘I think if you were to write down the … “what would I be worried about” in a new flu virus this would have many of the hallmarks. That does not mean it will lead on to a major epidemic or a pandemic… but it does mean we have to take it seriously.’

So there you have it: this may not be 1918 but it may not prove as mild as 2009 either.

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