ECDC: Influenza Virus Characterisation, March 2018

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The ECDC  periodically publishes a review of recently isolated seasonal flu viruses in the EU they call an Influenza Virus Characterization Report.  Yesterday they published their 4th review of the 2017-18 influenza season, with data as of March of this year.

As we've discussed before, although there are currently 4 main categories of seasonal flu viruses (A/H1N1, A/H3N2, B/Yamagata and  B/Victoria), within each of these subtype/lineages there can be multiple variants and/or clades.

While influenza viruses are always evolving, in recent years - particularly with H3N2 subtype - we've seen the emergence of a number of new subclades, and (often subtle) amino acid changes that can make antigenic changes in the virus.

This not only complicates future vaccine virus selection - it can lower the effectiveness of the current vaccine - an all too familiar outcome over the past few years (see last October's ECDC: H3N2 Flu Vaccine Component Likely `Suboptimal').

While H1N1 has remained remarkably stable the past 9 years, requiring only one vaccine virus change since the 2009 pandemic - and influenza B viruses are typically slower to evolve than influenza A -  the same cannot be said for H3N2.

In February of 2017, in Eurosurveillance: Emergence Of A Novel Subclade Of Seasonal A/H3N2 - London, we saw a report of new subclade (3C.2a2) which followed the emergence of three earlier subclades in 2014'; one in subdivision 3C.2, 3C.2a, and two in 3C.3, 3C.3a and 3C.3b.

Today, via the ECDC's lastest characterization report, we learn that additional H3N2 subclades and genetic subgroups have now been identified, further complicating the field.

First the Executive summary, and then I'll have some specifics on the new subclades.

Influenza virus characterisation, March 2018
surveillance report
4 Jun 2018
Publication series: Influenza Virus Characterisation
Time period covered: 2017-2018 influenza season

European Centre for Disease Prevention and Control. Influenza virus characterisation, summary Europe, March 2018. Stockholm: ECDC; 2018.

This is the fourth report of the 2017–18 influenza season. The ECDC Influenza Virus Characterisations Reports are published periodically. The report provides an overview of the technical details of the circulating influenza viruses, such as antigenic and genetic properties, with a reference to the current vaccine strains. It also summaries the developments of the viruses since the last report, as well as the main developments for the ongoing season. The report is of special interest for influenza virologists and epidemiologists interested in the in-depth characterisation of influenza viruses.

Executive summary

This is the fourth report of the 2017–18 influenza season. As of week 13/2018, over 217 000 influenza detections across the WHO European Region have been reported. Types A and B viruses have been detected in the proportions 42% and 58%, respectively, with A(H1N1)pdm09 viruses now being slightly more prevalent than A(H3N2) (1:0.96), and B/Yamagata being significantly more prevalent than B/Victoria viruses (48.7:1). 

Twenty-nine EU/EEA countries have shared influenza-positive specimens with the London WHO CC, Crick Worldwide Influenza Centre (WIC), since week 40/2017, with 984 specimens having collection dates after August 2017. 

The 36 A(H1N1)pdm09 test viruses characterised antigenically showed good reactivity with antiserum raised against the 2017–18 vaccine virus, A/Michigan/45/2015. The 133 test viruses with collection dates from week 40/2017 genetically characterised at the WIC, as others from the WHO European Region with collection dates after 31 August 2017 deposited in GISAID (Global Initiative on Sharing All Influenza Data), all fell in subclade 6B.1, defined by HA1 amino acid substitutions S162N and I216T, the great majority with additional substitutions of S74R, S164T and I295V. 

Of 191 A(H3N2) viruses successfully recovered to date, only 32 (17%) had sufficient HA titre to allow antigenic characterisation by HI assay in the presence of oseltamivir. The majority of these 32 viruses were poorly recognised by antisera raised against the currently used vaccine virus, egg-propagated A/Hong Kong/4801/2014, in HI assays. Of the 225 viruses with collection dates from week 40/2017 genetically characterised at the WIC, 154 were clade 3C.2a (with 129 3C.2a2, 21 3C.2a3 and four 3C.2a4), 68 fell within clade 3C.2a1 (with two 3C.2a1a and 65 3C.2a1b) and three were clade 3C.3a. 

A single B/Victoria-lineage viruses was tested by HI and it reacted well with only one of the panel of post-infection ferret antisera; this antiserum was raised against tissue culture-propagated B/Norway/2409/2017, a virus with a deletion of two amino acids in HA1 (Δ162-163). Of the 29 viruses characterised genetically at the WIC with a collection date after week 40/2017, ten fell within clade 1A, and 19 fell within the subgroup carrying the HA1 double amino acid deletion.

A total of 45 B/Yamagata viruses were characterised antigenically and 98% reacted well (within fourfold of the homologous titre) with post-infection ferret antiserum raised against egg-propagated B/Phuket/3073/2013, the recommended vaccine virus for use in quadrivalent vaccines for the northern hemisphere 2017–18 and 2018–2019 seasons and for trivalent vaccines in the southern hemisphere 2018 season. The 180 viruses with collection dates from week 40/2017 genetically characterised

Influenza virus characterisation report, March 2018 - EN - [PDF-2.95 MB]

H3N2 viruses continue to be difficult to analyze antigenically due to variable agglutination of RBCs in laboratory testing, a problem we've been seeing for the past 4 years. From the PDF,  we've an excerpt on their characterization of the H3N2 subtype, including the addition of new subclades and new genetic subgroups.

Influenza A(H3N2) virus analyses

As described in many previous reports 2 , influenza A(H3N2) viruses have continued to be difficult to characterise antigenically by HI assay due to variable agglutination of red blood cells (RBCs) from guinea pigs, turkeys and humans, often with the loss of ability to agglutinate any of these RBCs. As was highlighted first in the November 2014 report 3 , this is a particular problem for most viruses that fall in genetic clade 3C.2a.

A number of the 278 A(H3N2) virus specimens with collection dates after week 40/2017, 24 of which were lysed specimens, are in process for antigenic and genetic characterisation (Table 2). However, of those successfully isolated to date (n = 191), as shown by positive neuraminidase activity, only 32 (17%) had sufficient HA activity in the presence of 20nM oseltamivir to allow antigenic analysis by HI assay.

Since the February 2018 report, no virus recovered, based on positive neuraminidase activity, retained sufficient HA activity to allow antigenic analysis by HI.

Phylogenetic analysis of the HA genes of representative A(H3N2) viruses from Europe with recent collection dates, after 31 August 2017 as available in GISAID, is shown in Figure 2.

Viruses in clades 3C.2a and 3C.3a have been in circulation since the 2013–14 northern hemisphere influenza season, with clade 3C.2a viruses predominating since the 2014–15 influenza season and continuing to predominate in recent months (Figure 2), but the HA gene sequences continue to diverge. New subclades and new genetic subgroups have been adopted. Amino acid substitutions that define these subdivisions and subclades are:

• 3C.2a: L3I, N144S (resulting in the loss of a potential glycosylation site), F159Y, K160T (in the majority of viruses, resulting in the gain of a potential glycosylation site) and Q311H in HA1, and D160N in HA2, e.g. A/Hong Kong/4801/2014;
• 3C.2a1: Those in clade 3C.2a plus: N171K in HA1 and I77V and G155E in HA2, most also carry N121K in HA1, e.g. A/Singapore/INFIMH-16-0019/2016;
• 3C.2a1a: Those in subclade 3C.2a1 plus T135K in HA1, resulting in the loss of a potential glycosylation site, and also G150E in HA2, e.g. A/Greece/4/2017;
• 3C.2a1b: Those in subclade 3C.2a1 plus K92R and H311K in HA1, e.g. A/England/74560298/2017;
• 3C.2a2: Those in clade 3C.2a plus T131K, R142K and R261Q in HA1, e.g. A/Norway/4465/2016;
• 3C.2a3: Those in clade 3C.2a plus N121K and S144K in HA1, e.g. A/Norway/4849/2016;
• 3C.2a4: Those in clade 3C.2a plus N31S, D53N, R142G, S144R, N171K, I192T, Q197H and A304T in HA1 and S113A in HA2, e.g. A/Valladolid/182/2017;
• 3C.3a: T128A (resulting in the loss of a potential glycosylation site), R142G and N145S in HA1 which defined clade 3C.3 plus A138S, F159S and N225D in HA1, many with K326R, e.g. A/Switzerland/9715293/2013.

The currently circulating viruses have HA genes that fall into genetic groups within clade 3C.2a, with the majority of recently circulating viruses in EU/EEA countries falling in subclade 3C.2a2. A sizable proportion had HA genes that fell into genetic group 3C.2a1b, and some also had HA genes that fell into other genetic subgroups. 

The location of A/Singapore/INFIMH-16-0019/2016 (3C.2a1), the A(H3N2) virus recommended for inclusion in vaccines for the southern hemisphere 2018 [2] and the northern hemisphere 2018–2019 influenza seasons [3], is indicated in Figure 2.

Although Europe saw more of a mixed bag of flu subtypes last winter (H1N1, H3N2, and Influenza B), North America has just come off its second H3N2 dominant flu season in a row. 

Normally, one would assume the odds now favor a switch back to H1N1 next fall due to an increased level of community immunity to H3N2 - and perhaps it will - but the emergence and continued spread  of so many H3N2 subclades makes things less certain.

Influenza has always been unpredictable, but as the number of viral players continues to grow, second guessing the flu has become increasingly difficult. All of which makes the development of a `universal flu shot' - even if it only covers seasonal strains - all the more important in the years to come.

For more on the challenges involved, you may wish to revisit J.I.D.: NIAID's Strategic Plan To Develop A Universal Flu Vaccine.

Supply Chain Of Fools (Revisited)

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Not quite 10 years ago, in Supply Chain Of Fools, we looked at growing concerns over our increasingly stretched, and fragile, supply chains and how they might fare during a pandemic or other disaster.

Eight months later, in the opening weeks of the 2009 H1N1 pandemic, we saw first hand how quickly the supply of masks and gowns can be depleted (see California Nurses Association Statement On Lack Of PPE and Nurses Protest Lack Of PPE’s) during a global health crisis. 

Fortunately, H1N1pdm did not turn out to be a particularly virulent strain, and so demand never came close to the HHS estimate that our nation would need 30 billion masks (27 billion surgical, 5 Billion N95) to deal with a major pandemic (see Time Magazine A New Pandemic Fear: A Shortage of Surgical Masks).

Since the vast majority of the gloves, gowns, and masks used by U.S. hospitals are now manufactured in places like China, Singapore, Malaysia, and Mexico - and are ordered in as needed rather than stockpiled - surge capacity during a health care crisis is very limited.

As a stopgap measure, in 2014's NIOSH: Options To Maximize The Supply of Respirators During A Pandemic we saw guidance designed to help Prolong Existing and Surge Capacity Supplies of Respirators during Infection with Novel Influenza A Viruses Associated with Severe Disease.

We saw a reprise of these PPE concerns in 2014 when two Ebola infected individuals entered the country, which touched off a nationwide effort to better prepare hospitals and employees to deal with highly contagious infections (see CDC: Best Practices On Procuring PPEs For Ebola Response).

But it isn't just gloves, gowns, and masks that will be in short supply.

IV bags, tubing, oxygen tubes, needles and syringes, and nearly all of our pharmaceutical drugs (including antibiotics & antivirals) . . .  essentially everything needed to run a hospital or pharmacy . . .  is either made overseas or is dependent on raw materials from other countries.

This past winter's moderately severe flu season was complicated by a nationwide shortage of saline IV bags  (see FDA Statement) - which we normally import from Puerto Rico - but which were in short supply after hurricane Maria knocked out the island's electrical grid.

In order to keep prices low, we've streamlined our production capabilities to match demand, we've created JIT (Just-in-Time) Inventory delivery systems to eliminate warehouse costs, and we've increasingly come to rely on high-tech professionals to keep everything running smoothly.

During `normal' times, this model works fairly well, although drug shortages continue to plague the medical industry (see current FDA list).  According to an FDA infographic, the reasons are many and varied.

Last week CIDRAP News published an article by Chris Dall called Report: Fragile supply chain causing antibiotic shortages, resistance threat
that paints a worrying picture.  A small excerpt follows:

In a white paper released today, the Dutch nonprofit Access to Medicine Foundation argues that a fragile global supply chain that's dependent on a small number of antibiotics manufacturers, along with a financially unstable economic model, are responsible for shortages of antibiotics on a global and national level. Because of these shortages, some patients in need of antibiotics are being treated with lower-quality medications that don't cure their infections and increase the risk of resistance.

        (Continue . . . )

In 2015 - after the slow response to the Ebola outbreak in West Africa -  a public-private partnership called the  Pandemic Supply Chain Network (PSCN) was created following the World Economic Forum annual meeting in Davos, in order to develop better ways to help ensure the delivery of goods during a pandemic. 

While a admirable initiative, how much impact this effort will have during a major pandemic or other crisis is unknown and untested.

Much will depend upon the perceived severity and speed of a pandemic threat.  During a particularly serious event, demand will likely quickly exceed existing manufacturing capacity.

Add in shipping delays dues to quarantines, border closings, or personnel loss - and the very real possibility of governments `nationalizing' factories or prioritizing their inventories for domestic use - and replenishment of supplies during a pandemic (or other crisis) is far from a sure thing.

During the relatively mild 2009 pandemic, we looked at shortages in OTC supplies as well (see UK: More Supply Chain Woes), where pharmacies in England reported a run on everything from surgical masks and thermometers, to antipyretics and anti-bacterial gels.


The US government does maintain a strategic national stockpile of PPEs, and many essential meds, including antivirals and antibiotics, but those supplies are finite, and might only last a few weeks in a severe pandemic (see Webinar: The Strategic National Stockpile).

While, for simplicity's sake, I've dealt only with the medical supply chain thus far, we could see similar shortages across a wide spectrum of goods and services; everything from food deliveries to local markets, to delivery of public utilities (water & electricity), to replacement parts for your car or computer.

And it isn't just a pandemic that could throw the global supply chain out of whack; large earthquakes or tsunamis in an important manufacturing area, regional conflicts, trade wars, solar storms and even cyber attacks (on the grid or Internet) could seriously disrupt manufacturing and/or delivery of goods.

Few people realize we barely escaped a grid down disaster six years ago (see NASA: The Solar Super Storm Of 2012). Last September, another major X-flare erupted just after it had passed around the limb of the sun, missing earth by only a few days (see USGS: Preparing The Nation For Severe Space Weather).

In 2014 a study was published suggesting the odds of earth being struck by one of these solar super storms is actually a lot higher than we’ve previously thought. From a NASA article:

In February 2014, physicist Pete Riley of Predictive Science Inc. published a paper in Space Weather entitled "On the probability of occurrence of extreme space weather events." In it, he analyzed records of solar storms going back 50+ years. By extrapolating the frequency of ordinary storms to the extreme, he calculated the odds that a Carrington-class storm would hit Earth in the next ten years.

His estimate: 12%.

The grid can also be taken down by other, more nefarious means, a topic explored by well known journalist Ted Koppel in his 2015 book called Lights Out: A Cyberattack, A Nation Unprepared, Surviving the Aftermath.

There are hours of interviews with Ted Koppel about his book on YouTube, including with PBS, Charlie Rose, and the following hour long discussion with the National Press Foundation. 

This is a topic we've looked at before (see The Lloyd’s Business Blackout Scenario) - and despite congressional committees and national GridEx preparedness drills - a new Congressional Research Service report warns that the US power grid remains vulnerable to attack.

Last year, in DHS: NIAC Cyber Threat Report - August 2017, we looked at a 45 page report addressing urgent cyber threats to our critical infrastructure that called for `bold, decisive actions'.

While our JIT Inventory economy is a modern marvel of logistics, statistics, and efficiency, it has a fatal flaw.  Everything has to work as designed, or it can unravel like a 3 dollar suit.

In 2005 Dr. Michael Osterholm, director of CIDRAP, likened a severe pandemic to an 18-month global blizzard, where nearly everything is shut down. Many will be without a paycheck, either due to their refusal to work and risk exposure, or because their jobs are simply no longer available (see Baby, it's Cold Outside).

More recently, in his 2017 book Deadliest Enemy (see my Review: Deadliest Enemy: Our War Against Killer Germs), Dr. Osterholm revisits the idea of our JIT economy, and writes:

Ironically, the ways we have organized the modern world for efficiency, economic development, and for enhanced lifestyle -- the largely successful attempts to transform the planet into a global village -- have made us more susceptible to the effects of infectious disease than we were in 1918.  

And the more sophisticated, complex, and technologically integrated the world becomes, the more vulnerable we will be to one disastrous element devastating the entire system.

While developing and distributing a safe and effective vaccine may seem like the most logical, and important step, to mitigate the next pandemic - finding a way to keep the lights on, and the infrastructure running well enough to deliver a vaccine or lifesaving medical assistance to the public - may be the bigger challenge. 

Collateral damage, not the infection itself, could prove to be the biggest killer during the next pandemic.

The inability to get routine or emergency medical treatment, or maintenance drugs (insulin, B/P or heart meds, antibiotics, etc.), or perhaps even sufficient food or potable water, could claim more lives than the virus.

While you and I cannot solve the big issues of trade, or strategic stockpiling, or JIT manufacturing, we can take steps to help ensure our families, and our businesses, have enough `extra' on hand to get through temporary interruptions in the supply chain. 

No, it wouldn't go very far during a worst case 18-month economic blizzard scenario, but if we see something less, it could make the difference between your family or business surviving the next big crisis (economically, or physically) or not.

Despite initiatives like the Pandemic Supply Chain Network, congressional reports like last year's DHS: NIAC Cyber Threat Report, and our nation's investment in The Strategic National Stockpile, we remain seriously unprepared to deal with a major pandemic or global crisis.

Last month, in the day-long Johns Hopkins Clade X exercise, a genetically altered Nipah virus (spliced onto a parainfluenza backbone) was the fictional  basis of a severe pandemic. 

Hopefully you've already taken the time to watch that 8 hour exercise.  But even if you haven't, I'd urge you to watch the 5 minute epilogue, which sums up the impact and is available on Youtube as a fictional news cast.

Even in this scenario, it's a toss up as to whether the virus - or cascading supply chain failures and collateral damage - ended up killing the most people.

While a vaccine against the next pandemic virus may be a long time coming, there are things we could be doing today -- as individuals, as business owners, as communities, and as nations - to better prepare so that we can keep the lights on, and life's necessities available, during the next pandemic. 

The only question is whether we can find the foresight, fortitude, and political will to do something substantial before the next crisis takes that opportunity away from us completely.

The `Other' Novel Flu Threat We'll Be Watching This Summer

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During the summer and early fall we normally see a drop off in the number of avian flu reports - at least in the temperate regions of the Northern Hemisphere - but in its place we often see a rise in human infections with swine variant flu viruses; H1N1v, H1N2v and H3N2v.

The CDC describes Swine Variant viruses in their Key Facts FAQ.

What is a variant influenza virus?

When an influenza virus that normally circulates in swine (but not people) is detected in a person, it is called a “variant influenza virus.” For example, if a swine origin influenza A H3N2 virus is detected in a person, that virus will be called an “H3N2 variant” virus or “H3N2v” virus.

Between 2005 and 2009, 1 or 2 cases were reported each year, although the real number is believed much higher. Most cases were mild, and indistinguishable from seasonal flu, and so very few cases were tested.

In 2010 that number jumped to 8, and in 2011 to 12.

The next year (2012), more than 300 cases were reported across 10 states (see CID Journal: H3N2v Outbreaks In United States – 2012) - nearly all associated with attendance at state and county fairs. Indiana reported the most cases (n=138), followed by Ohio (n=106). 

The actual number of swine-variant infections each year is unknown, but is believed to be much higher than reported. In 2013 we looked at a study (see CID Journal: Estimates Of Human Infection From H3N2v (Jul 2011-Apr 2012) that suggested the number of cases could be as much as 200 times higher. 

After 2012, things settled down for a few years, with only a handful of cases reported between 2013 and 2015. In 2016 that number rose to 22 cases, with 18 of those -  all fair attendees -  diagnosed with swine-variant H3N2v in two states; Michigan and Ohio during the month of August.

In October of 2016 the MMWR: Investigation Into H3N2v Outbreak In Ohio & Michigan - Summer 2016 revealed that 16 of the 18 cases analyzed belonged to a new genotype not previously detected in humans.

Last year (2017), the United States reported 67 human infections, once again mostly linked to agricultural exhibits at state and county fairs. This was the second highest yearly total reported since surveillance began in 2005, only surpassed by 2012.

Since the influenza subtypes that commonly circulate in swine (H1, H2 & H3) are also the same HA subtypes as have caused all of the human pandemics going back 130 years (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), when swine variant viruses jump to humans, it gets our attention.

Pigs are viewed as excellent `mixing vessels' for  influenza viruses, due to having both mammalian α2,6 receptor cells and avian-like α2,3 receptor cells, and having frequent contact with humans and birds. They are often infected with human seasonal flu, along with their own swine flu viruses.

While most swine variant infections have been mild or moderate, a couple of deaths have been reported since 2012, along with a number of hospitalizations. The CDC takes these zoonotic infections seriously, and their Influenza Risk Assessment Tool (IRAT) lists H3N2v as having moderate pandemic potential.

The problem of swine-variant infections extends far beyond the United States, with occasional reports of serious illnesses from Europe, Asia, and South America. Testing and surveillance is very limited, however, and we are far from having a complete picture. 

Two and a half years ago, Chen Hualan - director of China's National Avian Influenza Reference Laboratory - gave an interview to the Chinese News Agency Xinhua where she pegged the EA (Eurasian Avian-like) H1N1 swine virus (EAH1N1) as having perhaps the greatest pandemic potential of any of the novel viruses in circulation.

Avian-like H1N1 swine flu may "pose highest pandemic threat": study

WASHINGTON, Dec. 28 (Xinhua) -- The Eurasian avian-like H1N1 (EAH1N1) swine flu viruses, which have circulated in pigs since 1979, have obtained the ability to infect humans and may "pose the highest pandemic threat" among the flu viruses currently circulating in animals, Chinese researchers said Monday.

(Continue . . . )

Her comments came after the publication of her paper (see PNAS: The Pandemic Potential Of Eurasian Avian-like H1N1 (EAH1N1) Swine Influenza) by Hualan et al. that described the Prevalence, genetics, and transmissibility in ferrets of Eurasian avian-like H1N1 swine influenza viruses.

In June of 2016, in Sci Rpts: Transmission & Pathogenicity Of Novel Swine Flu Reassortant Viruses we looked at a study where pigs were experimentally infected with one of these Eurasian-Avian H1N1 swine influenza viruses and the 2009 H1N1pdm virus.

Researchers generated 55 novel reassortant viruses spread across 17 genotypes, demonstrating not only how readily EAH1N1 SIV can reassort with human H1N1pdm in a swine host, but also finding:

`Most of reassortant viruses were more pathogenic and contagious than the parental EA viruses in mice and guinea pigs'. 

A few months later, in EID Journal: Reassortant EAH1N1 Virus Infection In A Child - Hunan China, 2016, we reviewed the case report on a 30-month old child from Hunan Province, who was infected with one of these reassortant EAH1N1 - H1N1pdm viruses.   

While EAH1N1 is the prime swine-origin virus of concern in China, it isn't alone in that regard (see Front. Microbiol.: A Novel H1N2 Reassorted Influenza Virus In Chinese Pigs).

The emergence of novel swine viruses is truly a global concern, with new strains continuing to pop up in North America, South America, Europe and Asia.

Their ability to reinvent themselves through reassortment with human, avian, and swine viruses, the shipment of live pigs nationally and internationally, and the growth in the global pork industry in general, pretty much ensures this trend will continue.

While past performance is no guarantee of future results, as county and state fair season begins this month, we'll be watching for any signs of increased swine variant infections over the summer and fall.

Some additional past blogs include:

I&ORV: Triple-Reassortant Novel H3 Virus of Human/Swine Origin Established In Danish Pigs

Emerg. Microbes & Inf.: Pathogenicity & Transmission Of A Swine Influenza A(H6N6) Virus - China

EID Journal: Characterization of a Novel Human Influenza A(H1N2) Virus Variant, Brazil

J. Virol: Novel Reassortant Human-like H3N2 & H3N1 Influenza A Viruses In Pigs

Lastly, the CDC has published guidance documents for animal exhibitors, venues, and visitors to agricultural exhibits and sponsors a Public Health Youth Agriculture Education Program.

CDC FluView: 171 Pediatric Flu Related Deaths In 2017-2018 Season

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While influenza activity has dropped back to inter-seasonal levels in the Northern Hemisphere - the yearly flu season runs from October 1st to September 30th - and low level activity and delayed reporting means that the numbers in today's FluView report may continue to rise in the weeks and months ahead. 

Nevertheless, the 2017-18 flu season has been one for the record books, with an overall hospitalization rate in excess of 106.6 per 100,000 population. Comparisons with years prior 2010 are difficult because the method for collecting data has changed, but this is a modern record.

This flu season has also taken a heavy toll among pediatric patients, with a record matching (for a non-pandemic season) 171 flu-related fatalities, equaling the 2012-2013 season, which had set the record for the highest number of pediatric flu related deaths since record keeping began in 2004.

Since reporting became mandatory in 2004 yearly pediatric influenza deaths have ranged from a low of 35 during the 2011-2012 flu season to a high of 282 during the 2009—2010 H1N1 pandemic.

As tragic as the 2009 pandemic tally was, the CDC estimated that the number of pediatric deaths in the United States probably ranged from 910 to 1880, or anywhere from 3 to 6 times higher than reported.

Even during non-pandemic seasons, the CDC believes the officially reported numbers likely understate the true number of pediatric deaths due to influenza by half.  

In 2013, in Pediatrics: Influenza-Associated Pediatric Deaths, we looked at a study by Karen K. Wong et al. called Influenza-Associated Pediatric Deaths in the United States, 2004–2012 that analyzed the first 8 years of data on pediatric flu-related deaths. 

They reported the median age was 7 years, that 35% of children died before hospital admission, and of 794 children with a known medical history, 43% had no high-risk medical conditions.

A few months ago we looked at a new study (see Influenza-Associated Pediatric Deaths in the United States, 2010–2016), published in the journal Pediatrics, that looked at pediatric flu-related deaths during the next 6 post-pandemic flu seasons (2010–2016) and found the median age has dropped to 6 years, and the percentage of kids with no high-risk medical conditions had jumped to 50%.

While the flu shot isn't always as effective as we'd like - particularly in recent years against  H3N2 - it often works better in children, and the (quadrivalent) vaccine is usually far more effective against both H1N1 and Influenza B.

Less than a year ago, in Pediatrics: Study Shows Flu Shot Reduces Flu Related Pediatric Deaths By Half, we looked at another CDC study which found:

`. . . . flu vaccination reduced the risk of flu-associated death by half (51 percent) among children with underlying high-risk medical conditions and by nearly two-thirds (65 percent) among healthy children.'

Yesterday the CDC released the following statement on the record-matching pediatric flu-related death toll, which warns that due to delays in reporting, this year's number could climb higher.
 

CDC Reported Flu Deaths in Children Matches Seasonal High


June 1, 2018 – In CDC’s FluView report for the week ending June 1, 2018, two additional flu-related deaths in children were reported, bringing the total number this season to 171. This number matches the 2012-2013 season, which previously set the record for the highest number of flu-related deaths in children reported during a single flu season (excluding pandemics). Approximately 80% of these deaths occurred in children who had not received a flu vaccination this season. CDC recommends an annual flu vaccine for everyone 6 months and older. These deaths are a somber reminder of the importance of flu vaccination and the potential seriousness of flu. CDC experts have described the 2017-2018 season as a high severity season, with influenza-like-illness (ILI) remaining at or above baseline for 19 consecutive weeks, record-breaking flu hospitalization rates, and elevated pneumonia and influenza mortality for 16 weeks.

Since flu-related deaths in people younger than 18 years became nationally reportable in 2004, the number of deaths reported to CDC has ranged from 37 during the 2011-2012 season to 171 deaths during the 2012-2013 season. This excludes the 2009 H1N1 pandemic, when 358 pediatric deaths were reported to CDC during April 15, 2009, through October 2, 2010. The 2012-2013 season was similar to the current one in that influenza A(H3N2) viruses predominated overall. The severity of that season was characterized as moderate severity overall among children and adults, but high severity was reported among older adults. H3N2-predominant flu seasons are typically associated with more severe outcomes for both children and older adults.

While flu vaccination is recommended for everyone 6 months and older, certain people are known to be more vulnerable to serious flu-related complications, including children younger than 5 years (and especially those younger than 2 years) and children of any age with certain long-term health problems, such as asthma or other lung disorders, heart disease, or a neurologic or neurodevelopmental disorder.

Reported flu deaths in children this season are evenly split between boys and girls, and about half of these children are reported to have had a medical condition that placed them at high risk of developing serious flu complications. About 60% of these children died after admission to the hospital, while about 40% of children died at home or the emergency department. Most children died within 7 days of symptom onset. More information about reported flu deaths in children this season, and previous seasons, is available on FluView Interactive.

Data this season is similar to what has been previously reported, including in a recent CDC study published in the journal Pediatrics showing that half of flu-related deaths in children from 2010 to 2016 occurred in otherwise healthy children, only 22% of whom were fully vaccinated. The same study also showed antiviral treatment was only given in about half of all pediatric flu deaths. Nearly two-thirds of children died within seven days of developing symptoms. Over one-third died at home or in the emergency department prior to hospital admission.

While flu vaccine can vary in how well it works each season, a CDC study published in Pediatrics in 2017 showed that flu vaccination can be life-saving for children. The study, which looked at data from four flu seasons between 2010 and 2014, found that flu vaccination reduced the risk of flu-associated death by half (51 percent) among children with underlying high-risk medical conditions and by nearly two-thirds (65 percent) among otherwise healthy children.

As reporting of deaths in children can be delayed, it’s possible that additional flu-related deaths in children during the 2017-2018 season will be reported to CDC.

CDC Adds Two New Novel Viruses To Their IRAT List

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Yesterday the CDC released an updated  Influenza Risk Assessment Tool (IRAT) list of 16 novel flu subtypes/strains that currently circulate in non-human hosts, but that pose a potential threat to human health.  This latest update - the first since October 2017 - adds 2 new viruses to the watch list; both are North American H7N9 viruses.

Despite sharing the same HA/NA appellation as their more famous (and far more dangerous) Chinese counterpart - these North American H7N9 viruses are considered to currently pose a very low threat to human health.

Demonstrating how quickly the novel fluscape changes, of the 16 viruses currently being tracked, 13 have been either emerged or have been added to the list since 2011.

The IRAT list currently contains 14 avian flu viruses, 1 Canine flu (H3N2) and 1 swine-variant flu virus (H3N2v). Despite its length, this doesn't cover all of the potential pandemic flu viruses out there, only the ones of greatest concern.

The two new additions emerged in a multi-state outbreak in 2017 (see map below), which saw both LPAI and HPAI versions of a new North American H7N9 virus emerge.
 

The two new additions to the IRAT are described below:

H7N9: Low Pathogenic North American avian [A/chicken/Tennessee/17-007431-3/2017]

Surveillance conducted in March 2017 during the investigation of a highly pathogenic avian influenza (HPAI) A(H7N9) virus in commercial poultry in Tennessee revealed the contemporaneous presence of North American lineage low pathogenic avian influenza (LPAI) A(H7N9) virus in commercial and backyard poultry flocks in Tennessee and three other states. The outbreak in poultry appeared limited with no further detections in subsequent surveillance. There were no reports of human cases associated with this virus.

Summary:  A risk assessment this North American lineage LPAI A(H7N9) virus was conducted in October 2017. The overall IRAT risk assessment score for this virus falls into the low risk category (< 4). The summary average risk score for the virus to achieve sustained human-to-human transmission was in the low risk category (score 3.1).  The average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was between the low to low-moderate range (score 3.5). For a full report, click here[228 KB, 4 pages].

H7N9: High Pathogenic North American avian [A/chicken/Tennessee/17-007147-2/2017]

In March 2017, the U.S. Department of Agriculture (USDA) reported the detection of a highly pathogenic avian influenza (HPAI) A(H7N9) virus in 2 commercial poultry flocks in Tennessee. Full genome sequence analysis indicated that all eight gene segments of the virus were of North American wild bird lineage and genetically distinct from the lineage of influenza A(H7N9) viruses infecting poultry and humans in China since 2013. The outbreak investigation revealed that a related North American low pathogenic avian influenza A(H7N9) was circulating in poultry prior to the detection of the HPAI A(H7N9). There were no reports of human cases associated with this virus.

Summary:  A risk assessment this North American lineage HPAI A(H7N9) virus was conducted in October 2017. The overall IRAT risk assessment score for this virus falls into the low risk category (< 4). The summary average risk score for the virus to achieve sustained human-to-human transmission is in the low risk category (2.8). The summary average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was also in the low risk category (3.5). For a full report, click here[225 KB, 4 pages].

The full list of IRAT viruses (listed from highest risk to lowest) appears below:

The CDC uses two sets of criteria to evaluate novel viruses. One to estimate a virus's potential for sustained human-to-human transmission, and another to gauge it's potential for significant impact on public health.

While both of these new viruses fall very near the bottom of the list in terms of expected impact should they acquire human-to-human transmissibility, last October in EID Journal: Mammalian Pathogenesis & Transmission of Avian H7N9 Viruses - Tennessee 2017 we saw the results of lab experiments with these viruses.

While only mildly pathogenic in ferrets, with limited transmission observed in only 1 of 3 LPAI (and none of the HPAI) exposed animals - both viruses did replicate to a high titer in human bronchial epithelial cell lines.

Making them both viruses worth keeping track of.   

I'm a little surprised that the avian H7N2 virus which infected 400+ cats and a veterinarian in NYC in late 2016 hasn't made the list yet, but its day may yet come (see Influenza & Other Resp. Viruses.: Airborne & Fomite Detection of Avian H7N2 - NYC 2016).

For more background on the CDC's IRAT, you may wish to revisit CDC EID Journal: All About IRAT).

China MOA: H7N9 Confirmed At Liaoning Poultry Farm

Credit Wikipedia

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Based on the limited reporting we get out of China, last year's massive nationwide poultry vaccination campaign - using a newly developed H5 + H7 recombinant AI vaccine - appears remarkably successful, with only 4 human infections (3 H7N9, 1 H5N6) and a handful of poultry outbreaks announced since last October. 

In April we saw an H7N9 Outbreak In Ningxia Provice, while in March we saw Outbreaks Of HPAI H5N6 In Guangxi & H7N9 In Shaanxi.

Today we can add Liaoning Province to this short list of avian flu outbreaks, with the following (translated) announcement from China's MOA, after which I'll return with more on the use of poultry vaccines to control avian flu.

A H7N9 flu outbreak in poultry in Liaozhong District, Shenyang City, Liaoning Province, China

Time: 2018-05-31 

On May 22, a layer of hens raised by a farmer in Liaozhong District, Shenyang City, Liaoning Province experienced suspected avian flu symptoms, with 11,000 morbidities and 9,000 dead. On May 24, the Liaoning Provincial Center for Animal Disease Control and Prevention was diagnosed as suspected of the bird flu epidemic. On May 31, the national bird flu reference laboratory confirmed the epidemic was the H7N9 flu epidemic.

    After the outbreak of the epidemic, the local government did a good job in the handling of the epidemic in accordance with the relevant preplans and technical requirements for prevention and control. It had culled 8,000 diseased chickens and the same group of chickens, and conducted harmless treatment of all chickens in the epidemic site. At present, the epidemic has been effectively controlled.

While we don't have a genetic analysis, based solely on the reported mortality, this appears to have been an HPAI H7N9 outbreak.  LPAI H7N9 is normally asymptomatic in birds, including poultry.

Throughout the United States, and indeed, most of the world, the preferred method of controlling H5 and H7 avian flu outbreaks in poultry has been immediate quarantine and the culling of infected or exposed birds.

Since early in the last decade only a handful of countries have elected to go the vaccination route, with China, Indonesia, Egypt & Vietnam consuming nearly 99% of the world's poultry AI vaccines.

While we'll never know what would have happened had they not elected to go with vaccination, their track record hasn't been all that enviable.  H5 and H7 viruses remain endemic and a perennial problem in these countries after more than a dozen years of vaccine use.  

While it can be argued that these vaccines have saved millions of poultry from culling, have prevented financial ruin for farmers, and has lessened food instability in developing areas of the world, there has also been a downside. 

Poultry vaccines don’t always prevent disease – sometimes they only mask the symptoms of infection, and that can not only allow viruses to spread stealthily, it can also put human health at risk.

And as avian viruses evolve, poultry vaccines become increasingly less effective. Poor vaccine matches can then allow AI viruses to spread silently among flocks, to continue to reassort and evolve, and potentially lead to the emergence new subtypes of avian flu.

A few earlier blogs on that include:

Subclinical Highly Pathogenic Avian Influenza Virus Infection among Vaccinated Chickens, China).

Study: Recombinant H5N2 Avian Influenza Virus Strains In Vaccinated Chickens

EID Journal: Subclinical HPAI In Vaccinated Poultry – China

There are other factors in the creation of new avian subtypes, of course - including the bringing together of different bird species in live markets, the move to larger commercial poultry operations, and poor biosecurity - but vaccine-escape variant viruses appear to be significant driver as well.

While one hopes that the Chinese have hit a home run with their new poultry vaccine, a headline (see Vietnam: Thousands Of Vaccinated Chickens Die Of Suspected H5N1) from last August reminds us that pharmaceutical victories over rapidly evolving viruses and bacteria are often fleeting.

So we'll be watching for more signs of `breakthrough' events, such as the one reported above, in the months ahead.