Thursday, December 14, 2017

Netherlands: Wild Birds Detected With HPAI H5N6


Last Friday, in Netherlands Rijksoverheid: H5 Outbreak (Likely HPAI) In Biddinghuizen, we learned of a (now confirmed) HPAI outbreak in poultry in the Netherlands, affecting roughly 16,000 ducks.
The following day, from a report issued by the Wageningen Bioveterinary Research Institute, we learned that the virus was remarkably similar to a reassorted H5N6 virus which recently showed up in South Korea, Japan, and Taiwan.
Today, in an updated announcement on the Wageningen Bioveterinary Research Institute website, we learn that wild birds found dead along the shores of Lake Veluwe - several miles from the original poultry outbreak in Biddinghuizen - have now tested positive for this newly arrived reassorted H5N6 virus.

Bird flu in Biddinghuizen
published 14 december 2017

In Biddinghuizen (municipality Dronten, Flevoland) on December 8, 2017 at a company with duck meat bird flu detected by Wageningen Bioveterinary Research (WBVR). The virus is characterized as highly pathogenic H5N6. This company also ran last year as one of the first infected. In poultry farms within an area of ​​three kilometers of the infected farm WBVR found no new infections, became known on 11 December.

To prevent further spread of the virus, the infected farm has been cleared by the Dutch Food Safety Authority (NVWA). Involved a total of approximately 16,000 meat ducks. In the area of ​​one kilometer around the holding in Biddinghuizen are no other companies that need to be preventively cleared.
Highly pathogenic H5N6 virus

A first genetic analysis shows that the virus is not related to the zoonotic H5N6 strain circulating in Asia, where people can get sick.

  • The H5 is akin to the Influenza A virus subtype H5N8 highly pathogenic virus that is found in the Netherlands in 2016.
  • The N6 is related to low pathogenic viruses previously found in wild birds in Europe.
The H5N6 virus has been created by the exchange of genetic material, or reassortment. WBVR doing further research to gain further insight into the origin and genetic composition of this virus.

Wild birds with avian flu in Veluwe

On December 11, Wageningen Research Bioveterinary various wild birds (locations Hulshorst and Elburg) tested positive for bird flu. On December 13 it became clear that it also comes to H5N6 avian influenza.
No new infections in BiddinghuizenIn the area of ​​three kilometers around the infected holding are four other companies. The latter poultry sampled and analyzed by WBVR on bird flu. On 11 December it was announced that no new infections have been detected in these companies.

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EID Journal: Characterization Of A Feline Influenza A(H7N2) Virus


Almost exactly a year ago (Dec 15th, 2016) the New York City Health Department issued an unusual Statement On Avian H7N2 In Cats at a Manhattan animal shelter.
While cats are known to be susceptible to some novel  flu strains (see Catch As Cats Can) this outbreak was remarkable due to its size (initially involving 45 cats), its location (NYC), and the virus involved - a relatively uncommon avian LPAI H7N2 virus not reported in the United States in years. 
Over the Christmas holidays the story continued to escalate  when the NYC DOH released a statement announcing a mild Human H7N2 Infection in a veterinarian who was treating sick cats.  Additionally, more than 400 cats - across multiple facilities - were said to have been infected. 
Although the risk to human health was believed low, the Health Department offered guidance to those who have had contact with cats in these shelters, and urged people to avoid `nuzzling and close facial contact' with sick cats.
Human infection with LPAI H7N2 has only rarely been reported, with only a couple of cases  on record in the United States (in 2002 and 2003), and 4 people who were presumed to have been infected in the UK in 2007 following local outbreaks in poultry. In all cases, illness was described as mild and self limiting.

Last May, in J. Virology: Virulence Of A Novel H7N2 Virus Isolated From Cats In NYC - Dec 2016,  we saw a follow up report on the NYC outbreak, which found the H7N2 virus will require additional adaptation before it poses a substantial human health threat.   

A month ago, in EID Journal: Avian H7N2 Virus in Human Exposed to Sick Cats, we saw another study that found the human H7N2 virus bound to both α2,6-linked (mammalian) and α2,3-linked (avian) sialic acids, an important trait for any species jumping avian flu virus to acquire, although virulence remained low. 

Today we've a new analysis published in the EID Journal of the H7N2 virus isolated from cats.  As this is a lengthy and technical report, I've only posted a few excerpts.  Follow the link below to read it in its entirety.

Characterization of a Feline Influenza A(H7N2) Virus

Masato Hatta1, Gongxun Zhong1, Yuwei Gao1, Noriko Nakajima1, Shufang Fan1, Shiho Chiba, Kathleen M. Deering, Mutsumi Ito, Masaki Imai, Maki Kiso, Sumiho Nakatsu, Tiago J. Lopes, Andrew J. Thompson, Ryan McBride, David L. Suarez, Catherine A. Macken, Shigeo Sugita, Gabriele Neumann, Hideki Hasegawa, James C. Paulson, Kathy L. Toohey-Kurth, and Yoshihiro Kawaoka


During December 2016–February 2017, influenza A viruses of the H7N2 subtype infected ≈500 cats in animal shelters in New York, NY, USA, indicating virus transmission among cats. A veterinarian who treated the animals also became infected with feline influenza A(H7N2) virus and experienced respiratory symptoms. 

To understand the pathogenicity and transmissibility of these feline H7N2 viruses in mammals, we characterized them in vitro and in vivo. Feline H7N2 subtype viruses replicated in the respiratory organs of mice, ferrets, and cats without causing severe lesions. 

Direct contact transmission of feline H7N2 subtype viruses was detected in ferrets and cats; in cats, exposed animals were also infected via respiratory droplet transmission. These results suggest that the feline H7N2 subtype viruses could spread among cats and also infect humans. Outbreaks of the feline H7N2 viruses could, therefore, pose a risk to public health.


We assessed feline H7N2 subtype viruses isolated from infected cats during the outbreak for their replicative ability, pathogenicity, and transmissibility in mammals; in contrast to the findings recently published by Belser et al. (7), we detected productive infection of co-housed ferrets, although with low efficiency.
We also conducted extensive pathology and transmission studies in cats, and detected feline virus transmission via respiratory droplets to exposed cats. Our study provides additional data on the risk that the feline H7N2 subtype viruses pose to public health.



In our study, we demonstrated that a feline H7N2 subtype virus isolated during an outbreak in an animal shelter in New York in December 2016 replicated well in the respiratory organs of mice and ferrets but did not cause severe symptoms.
The efficient replication of the feline H7N2 subtype viruses in the respiratory organs of several mammals, combined with the ability of these viruses to transmit among cats (albeit inefficiently) and to infect 1 person, suggest that these viruses could pose a risk to human health. Close contacts between humans and their pets could lead to the transmission of the feline viruses to humans. To protect public health, shelter animals (where stress and limited space may facilitate virus spread) should be monitored closely for potential outbreaks of influenza viruses.
Our findings of mild disease in mice and ferrets are consistent with the recent report by Belser et al. (7) who studied the H7N2 subtype virus isolated from an infected veterinarian. We also assessed feline H7N2 virulence in cats and detected efficient virus replication in both the upper and lower respiratory organs of infected animals, whereas an avian H7N2 subtype virus was detected mainly in the nasal turbinates.
Belser et al. (7) reported that intranasal or aerosol infection of ferrets with the H7N2 virus isolated from the infected veterinarian did not result in the seroconversion of co-housed or exposed animals, although nasal wash samples from some of the co-housed ferrets contained low titers of virus; these findings may suggest limited virus transmission that was insufficient to establish a productive infection.
In contrast, we detected feline H7N2 virus transmission to co-housed ferrets in 1 of 3 pairs tested; this difference may be explained by the amino acid differences in the PA, HA, and NA proteins of the feline and human H7N2 isolates (Technical Appendix[PDF - 3.63 MB - 35 pages] Table 4) or by the small number of animals used in these studies. We also performed transmission studies in cats and detected feline H7N2 subtype virus transmission via direct contact and respiratory droplets. However, the group size used is a potential limitation of our study.
Cats are not a major reservoir of influenza A viruses, but can be infected naturally or experimentally with influenza viruses of different subtypes (23). Serologic surveys suggest high and low rates of seroconversion to seasonal human and highly pathogenic avian influenza viruses, respectively. Natural infections most likely result from close contact with infected humans or animals, and most of these infections appear to be self-limiting.
Few cases of human infections with influenza viruses of the H7 subtype were reported until 2013, and they typically caused mild illness; however, infection of a veterinarian with a highly pathogenic avian H7N7 virus had fatal consequences (24,25).
Since 2013, influenza viruses of the H7N9 subtype have caused more than 1,300 laboratory-confirmed infections in humans, with a case-fatality rate of ≈30%. Although the current H7N9 and feline H7N2 subtype viruses do not exclusively bind to human-type receptors and do not transmit efficiently among humans, the spread and biologic properties of these viruses should be monitored carefully.
Dr. Hatta is a senior scientist at the Influenza Research Institute at the University of Wisconsin, Madison, WI. His research focuses on identifying the molecular determinants of influenza virus pathogenicity, with particular emphasis on the pathogenicity of highly pathogenic influenza viruses.
As pointed out in earlier blogs on this event, avian H7N2 doesn't appear to be ready for prime time, but it has evolved considerably since its previous appearances in U.S. poultry nearly 15 years ago.
In last May's J. Virology study the virus reportedly replicated with increased efficiency in human bronchial epithelial cells over previous H7N2 strains tested, and were better adapted to using a lower pH for HA activation, similar to seasonal flu viruses.
While we tend to focus our attention on a small number of high profile novel viruses (H7N9, H5Nx, H9N2, etc.), influenza evolution an open field event.

Any number of viruses can play.

WHO Update & Risk Assessment: Diphtheria At Cox's Bazar, Bangladesh

Credit WHO


Just over a week ago, in WHO: Diphtheria Spreading Rapidly In Cox’s Bazar, Bangladesh, we looked at the growing health crisis among Rohingya refugees fleeing Myanmar (Burma). Relatively rare in the western world, in places where vaccination rates are low, Diphtheria remains a substantial public health threat - particularly to children.
While we normally just hear about sporadic cases, FluTrackers is has recently been following reports of a sizable outbreak in Indonesia (see Indonesia: 2017 Diphtheria) and earlier this year there were reports of an outbreak in Venezuela. 
As recently as 30 years ago, 100,000 cases were reported globally each year, but over the last decade that number has dropped to about 5,000. According to UNICEF, in recent years India and Madagascar have accounted for 84% of the world's cases.
Late yesterday the WHO posted the following update and risk assessment on the Cox's Bazar outbreak.

Diphtheria – Cox’s Bazar in Bangladesh

Disease outbreak news
13 December 2017

From 3 November 2017 through 12 December 2017, a total of 804 suspected diphtheria cases including 15 deaths were reported among the displaced Rohingya population in Cox’s Bazar (Figure 1). The first suspected case was reported on 10 November 2017 by a clinic of Médecins Sans Frontières (MSF) in Cox’s Bazar.

Source: Médecins Sans Frontières

Of the suspected cases, 73% are younger than 15 years of age and 60% females (the sex for one percent cases was not reported). Fourteen of 15 deaths reported among suspected diphtheria cases were children younger than 15 years of age. To date, no cases of diphtheria have been reported from local communities.

Public health response

Since August 2017, more than 646 000 people from neighbouring Myanmar have gathered in densely populated camps and temporary settlements with poor access to clean water, sanitation and health services. A multi-agency diphtheria task force, led by the Ministry of Health Family Welfare of Bangladesh, has been providing clinical and public health services to the displaced population. WHO has mobilized US$ 3 million from its Contingency Fund for Emergencies (CFE) to support essential health services in Bangladesh.

WHO is working with health authorities to provide tetanus diphtheria (Td) vaccines for children aged seven to 15 years, as well as pentavalent vaccines (diphtheria, pertussis, tetanus, Haemophilus influenzae type b, and hepatitis B) and pneumococcal conjugate vaccines (PCV) for children aged six weeks to six years. A list of essential medicines and required supplies to support the response is being finalized by WHO and partners.The Serum Institute of India has donated 300 000 doses of pentavalent vaccines for use in the response.

WHO risk assessment

The current outbreak in Cox’s Bazar is evolving rapidly. To date, all suspected cases have occurred among the displaced Rohingya population, who are living in temporary settlements with difficult and crowded conditions. The coverage of diphtheria toxoid containing vaccines among the displaced Rohingya population is difficult to estimate, although diphtheria outbreaks are an indication of low overall population vaccination coverage. Available vaccination data for Bangladesh indicates that the coverage of diphtheria toxoid containing vaccines is high. However, spillover into the local population cannot be ruled out. WHO considers the risk at the national level to be moderate and low at the regional and global levels.

WHO advice

WHO recommends timely clinical management of suspected diphtheria cases that is consistent with WHO guidelines consisting of diphtheria antitoxin, appropriate antibiotics and implementation of infection prevention and control measures. High-risk populations such as young children, close contacts of diphtheria cases, and health workers should be vaccinated on priority basis. A coordinated response and community engagement can reduce the risk of further transmission and help to control the outbreak. 

Nature: Lactobacillus casei Confers Broad Protection Against Influenza A Virus (in Mice)

Credit WIkipedia


One of the things you don't often see in this blog are the all-too-common claims made by the purveyors of certain foods, and supplements - or by media health writers with a rapidly approaching deadline - of the miraculous commonly available cures ignored by western medicine.
It isn't that I don't believe some foods or supplements could prove beneficial against specific medical problems, its just that most of these stories are - at best - anecdotal in nature, and provide little in the way of real evidence. 
These topics haven't been entirely verboten in this blog, since we looked at research back in 2010 (see Study: Probiotic Therapy Cuts VAP Risk) on the effects of daily probiotic therapy on people on long-term ventilator support. I've also written several blogs on studies that have looked at the benefits of Vitamin D (see Study: Vitamin D And The Innate Immune System.)
But as much as I'd like to believe there are safe, effective, over-the-counter cures for many serious medical conditions, most claims of this sort carry little if any supporting evidence.
However, when a serious study - funded by NIAID, the NIH, the DOD, etc. -  published in Nature's Scientific Reports, finds a potential protective effect against influenza from a common probiotic, it is worth a look.

The open-access (and at times technical) study from Georgia State University is called:
Article | Open
Heat-killed Lactobacillus casei confers broad protection against influenza A virus primary infection and develops heterosubtypic immunity against future secondary infection 
Yu-Jin Jung, Young-Tae Lee, Vu Le Ngo, Young-Hee Cho, Eun-Ju Ko, Sung-Moon Hong, Ki-Hye Kim, Ji-Hun Jang, Joon-Suk Oh, Min-Kyung Park, Cheol-Hyun Kim, Jun Sun & Sang-Moo Kang


Lactic acid bacteria (LAB) are the common probiotics. Here, we investigated the antiviral protective effects of heat-killed LAB strain Lactobacillus casei DK128 (DK128) on influenza viruses.

Intranasal treatment of mice with DK128 conferred protection against different subtypes of influenza viruses by lessening weight loss and lowering viral loads. Protection via heat-killed DK128 was correlated with an increase in alveolar macrophage cells in the lungs and airways, early induction of virus specific antibodies, reduced levels of pro-inflammatory cytokines and innate immune cells. 

Importantly, the mice that were protected against primary viral infection as a result of heat-killed DK128 pretreatment developed subsequent heterosubtypic immunity against secondary virus infection. For protection against influenza virus via heat-killed DK128 pretreatment, B cells and partially CD4 T cells but not CD8 T cells were required as inferred from studies using knockout mouse models. 

Our study provides insight into how hosts can be equipped with innate and adaptive immunity via heat-killed DK128 treatment to protect against influenza virus, supporting that heat-killed LAB may be developed as anti-virus probiotics.
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From Georgia State University we get the following press release, after which I'll return with more.
Lactic acid bacteria can protect against influenza a virus 
Date:December 13, 2017
Source:Georgia State University

Summary:Lactic acid bacteria, commonly used as probiotics to improve digestive health, can offer protection against different subtypes of influenza A virus, resulting in reduced weight loss after virus infection and lower amounts of virus replication in the lungs, according to a new study. 


Lactic acid bacteria, commonly used as probiotics to improve digestive health, can offer protection against different subtypes of influenza A virus, resulting in reduced weight loss after virus infection and lower amounts of virus replication in the lungs, according to a study led by Georgia State University.

Influenza virus can cause severe respiratory disease in humans. Although vaccines for seasonal influenza viruses are readily available, influenza virus infections cause three to five million life-threatening illnesses and 250,000 to 500,000 deaths worldwide during epidemics. Pandemic outbreaks and air transmission can rapidly cause severe disease and claim many more human lives worldwide. This occurs because current vaccines are effective only when vaccine strains and circulating influenza viruses are well matched.

Influenza A virus, which infects humans, birds and pigs, has many different subtypes based on hemagglutinin (HA) and neuraminidase (NA) proteins on the surface of the virus. There are 18 different HA and 11 different NA subtype molecules identified, which indicates numerous HA and NA influenza virus combinations. As a result, it's important to find ways to provide broad protection against influenza viruses, regardless of the virus strain.

Fermented vegetables and dairy products contain a variety of lactic acid bacteria, which have a number of health benefits in addition to being used as probiotics. Studies have found some lactic acid bacteria strains provide partial protection against bacterial infectious diseases, such as Streptococcus pneumoniae, as well as cold and influenza viruses.

This study investigated the antiviral protective effects of a heat-killed strain of lactic acid bacteria, Lactobacillus casei DK128 (DK128), a promising probiotic isolated from fermented vegetables, on influenza viruses.

Mice pretreated with DK128 intranasally and infected with influenza A virus showed a variety of immune responses that are correlated with protection against influenza virus, including an increase in the alveolar macrophage cells in the lungs and airways, early induction of virus specific antibodies and reduced levels of pro-inflammatory cytokines and innate immune cells. The mice also developed immunity against secondary influenza virus infection by other virus subtypes. The findings are published in the journal Scientific Reports.

"We found that pretreating the mice with heat-killed Lactobacillus casei DK128 bacteria made them resistant to lethal primary and secondary influenza A virus infection and protected them against weight loss and mortality," said Dr. Sang-Moo Kang, lead author of the study and professor in the Institute for Biomedical Sciences at Georgia State. "Our results are highly significant because mice pretreated with DK128 had 100 percent survival and prevention of weight loss.
This strain of lactic acid bacteria also equipped mice with cross-protective immunity against secondary lethal infection with influenza virus. Protection against influenza virus infection was not specific to a particular strain of influenza.

"Our study provides evidence that heat-killed lactic acid bacteria could potentially be administered via a nasal spray as a prophylactic drug against non-specific influenza virus infections."
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The idea of crafting an antiviral from a probiotic isn't all that crazy. After all, Tamiflu (tm) is made from shakimic acid derived from the Chinese star anise plant. 
But before anyone decides that eating kimchi or downing handfuls of probiotic capsules obviates the need for getting a flu vaccine, or taking antivirals when infected, the words `potential' and `potentially' loom large in this study. 
Not only was this research conducted on mice, there are questions remaining on what would be an effective dose and best delivery method for humans.

That said, this is fascinating research that could conceivably yield new and effective treatments (or preventatives) for flu down the road, and as such is well worth our attention.

The Lancet: Estimates Of Global Seasonal Flu Respiratory Mortality


Getting a decent handle on the annual incidence of - or mortality from - any illness or disease has always been daunting, and in truth, nearly all of the numbers you see quoted are rough estimates. As the chart above illustrates, only a fraction of cases - even in the most highly developed nations  - are ever tested and confirmed by public health officials.
Add to that ambiguity the fact that many diseases vary widely from year-to-year in severity, and many deaths may occur weeks or even months removed from an initial illness, and the best we can hope for is some kind of broad range.
For years, the mantra has been that seasonal influenza (excluding pandemic years) claims as many as 500,000 lives each year.  It's a very rough estimate.  But it is an easily remembered round number, and so it gets mentioned a lot.

Overnight a new study was published in The Lancet which attempts to refine that number - based on better surveillance numbers and new modeling - and finds that 500,000 mark is probably a substantial underestimate.

Their new estimate, however, is based strictly on respiratory-mortality, and that likely under-counts other influenza-associated causes of death (heart attack, stroke, etc.) that can occur in the weeks following infection (see Int. Med. J.: Triggering Of Acute M.I. By Respiratory Infection and Study: Flu Vaccine May Reduce Heart Attack Risk). 
It is, however, a start.
First, a press release on this study from the CDC, then a link to the Lancet Abstract.
Seasonal flu death estimate increases worldwide

Embargoed Until: Wednesday, December 13, 2017, 6:30 p.m. ET
Contact: Media Relations
(404) 639-3286

According to new estimates published today, between 291,000 and 646,000 people worldwide die from seasonal influenza-related respiratory illnesses each year, higher than a previous estimate of 250,000 to 500,000 and based on a robust, multinational survey.

The new estimate, from a collaborative study by CDC and global health partners, appears today in The Lancet. The estimate excludes deaths during pandemics.

“These findings remind us of the seriousness of flu and that flu prevention should really be a global priority,” says Joe Bresee, M.D., associate director for global health in CDC’s Influenza Division and a study co-author.

The new estimates use more recent data, taken from a larger and more diverse group of countries than previous estimates. Forty-seven countries contributed to this effort. Researchers calculated annual seasonal influenza-associated respiratory deaths for 33 of those countries (57 percent of the world’s population) that had death records and seasonal influenza surveillance information for a minimum of four years between 1999 and 2015. Statistical modeling with those results was used to generate an estimate of the number of flu-associated respiratory deaths for 185 countries across the world. Data from the other 14 countries were used to validate the estimates of seasonal influenza-associated respiratory death from the statistical models.

Poorest nations, older adults hit hardest by flu

Researchers calculated region-specific estimates and age-specific mortality estimates for people younger than 65 years, people 65-74 years, and people 75 years and older. The greatest flu mortality burden was seen in the world’s poorest regions and among older adults. People age 75 years and older and people living in sub-Saharan African countries experienced the highest rates of flu-associated respiratory deaths. Eastern Mediterranean and Southeast Asian countries had slightly lower but still high rates of flu-associated respiratory deaths.

Despite World Health Organization recommendations to use flu vaccination to help protect people in high-risk populations, few developing countries have seasonal flu vaccination programs or the capacity to produce and distribute seasonal or pandemic vaccines.

Global flu surveillance protects all nations, including U.S.

CDC works with global partners to improve worldwide capacity for influenza prevention and control. CDC has helped more than 60 countries build surveillance and laboratory capacity to rapidly detect and respond to influenza threats, including viruses with the potential to cause global pandemics.  These efforts, along with technical support, has helped some partners generate estimates of influenza-associated deaths, which contributed to this global effort.

Global surveillance also provides the foundation for selecting the viruses used to make seasonal flu vaccines each year. This helps improve the effectiveness of flu vaccines used in the United States. Global surveillance also is crucial to pandemic preparedness by identifying viruses overseas that might pose a human health risk to people in the United States.

“This work adds to a growing global understanding of the burden of influenza and populations at highest risk,” says CDC researcher Danielle Iuliano, lead author of The Lancet study. “It builds the evidence base for influenza vaccination programs in other countries.”

The study authors note that these new estimates are limited to flu-associated respiratory deaths and therefore may underestimate the true global impact of seasonal influenza. Influenza infection can create or exacerbate other health factors which are then listed as the cause of death on death certificates, for example cardiovascular disease, diabetes, or related complications. Additional research to estimate non-respiratory causes of flu-associated deaths are ongoing.
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Estimates of global seasonal influenza-associated respiratory mortality: a modelling study

A Danielle Iuliano, PhD'Correspondence information about the author PhD A Danielle IulianoEmail the author PhD A Danielle Iuliano, Katherine M Roguski, MPH, Howard H Chang, PhD, David J Muscatello, PhD, Rakhee Palekar, MD, Stefano Tempia, PhD, Cheryl Cohen, PhD, Jon Michael Gran, PhD, Dena Schanzer, MSc, Prof Benjamin J Cowling, PhD, Peng Wu, PhD, Jan Kyncl, MD , Li Wei Ang, MSc, Minah Park, MPH, Monika Redlberger-Fritz, MD, Hongjie Yu, MD, Laura Espenhain, MPHS, Prof Anand Krishnan, PhD, Gideon Emukule, PhD, Liselotte van Asten, PhD, Susana Pereira da Silva, MSc, Suchunya Aungkulanon, MSc, Udo Buchholz, MD, Marc-Alain Widdowson, VetMB
, Joseph S Bresee, MD 
Published: 13 December 2017


Estimates of influenza-associated mortality are important for national and international decision making on public health priorities. Previous estimates of 250 000–500 000 annual influenza deaths are outdated. We updated the estimated number of global annual influenza-associated respiratory deaths using country-specific influenza-associated excess respiratory mortality estimates from 1999–2015.

EMR-contributing countries represented 57% of the global population. The estimated mean annual influenza-associated respiratory EMR ranged from 0·1 to 6·4 per 100 000 individuals for people younger than 65 years, 2·9 to 44·0 per 100 000 individuals for people aged between 65 and 74 years, and 17·9 to 223·5 per 100 000 for people older than 75 years. We estimated that 291 243–645 832 seasonal influenza-associated respiratory deaths (4·0–8·8 per 100 000 individuals) occur annually. The highest mortality rates were estimated in sub-Saharan Africa (2·8–16·5 per 100 000 individuals), southeast Asia (3·5–9·2 per 100 000 individuals), and among people aged 75 years or older (51·3–99·4 per 100 000 individuals). For 92 countries, we estimated that among children younger than 5 years, 9243–105 690 influenza-associated respiratory deaths occur annually.

These global influenza-associated respiratory mortality estimates are higher than previously reported, suggesting that previous estimates might have underestimated disease burden. The contribution of non-respiratory causes of death to global influenza-associated mortality should be investigated.
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The old adage (attributed to George E. P. Box (18 October 1919 – 28 March 2013), Professor Emeritus of Statistics at the University of Wisconsin) is that:
“All models are wrong, but some models are useful.”
While there will undoubtedly be debate over the accuracy of these newest estimates - as well as over what constitutes an `influenza-associated death' -  the simple reality is that seasonal influenza is a substantial and largely under-appreciated cause of morbidity and mortality around the world.

Finding ways to reduce its burden - either through better, more efficient vaccines or by encouraging better flu hygiene - could save a great many lives.

Wednesday, December 13, 2017

EID Journal: Changing Geographic Patterns/Risk Factors For H7N9 In China

H7N9 Waves - Credit EID Journal


In addition to sparking the largest number of human avian flu infections on record (see above), wave 5 saw the emergence of new (HPAI & LPAI) strains of H7N9, along with impressive geographic spread to 8 new provinces in China.

Over the past few months we've seen an avalanche of new studies on H7N9, none of which are particularly reassuring:
J. Virology: Genesis and Spread of Newly Emerged HPAI H7N9 In China

J. Infect. Diseases: Human Clusters Of H7N9 In China - March 2013 to June 2015
Sci. Repts: Adaptation of H7N9 in Primary Human Airway Epithelial cells
Obviously worried, for the very first time, China's MOA Ordered An HPAI H7N9 Vaccine Deployed Nationwide This Fall.

Although H7N9 hasn't managed to adapt well enough to human physiology to transmit efficiently, the CDC's IRAT system ranks the newly emerged Yangtze River Delta lineage along with the original Pearl River Delta Lineage (see Updating the CDC's IRAT (Influenza Risk Assessment Tool) Rankings) at the top of their list of viruses with the greatest pandemic potential.
While  human infection during the first three waves was most often linked to exposure at, or through, live bird markets  -  and rarely from farms (see CDC: Risk Factors Involved With H7N9 Infection) - during the 4th and 5th wave that pattern began to change.
Today we've  a new study, published this week in the CDC's EID Journal, that looks at both the increasing geographic range, and shifting risk patterns, from the H7N9 virus in China.  I've only include some highlights, so you'll want to follow the link to read the study in its entirety.

When you return, I'll have a bit more.

Volume 24, Number 1—January 2018
Changing Geographic Patterns and Risk Factors for Avian Influenza A(H7N9) Infections in Humans, China
Jean Artois1, Hui Jiang1, Xiling Wang, Ying Qin, Morgan Pearcy, Shengjie Lai, Yujing Shi, Juanjuan Zhang, Zhibin Peng, Jiandong Zheng, Yangni He, Madhur S. Dhingra, Sophie von Dobschuetz, Fusheng Guo, Vincent Martin, Wantanee Kalpravidh, Filip Claes, Timothy Robinson, Simon I. Hay, Xiangming Xiao, Luzhao Feng, Marius GilbertComments to Author , and Hongjie YuComments to Author


The fifth epidemic wave of avian influenza A(H7N9) virus in China during 2016–2017 demonstrated a geographic range expansion and caused more human cases than any previous wave. The factors that may explain the recent range expansion and surge in incidence remain unknown. We investigated the effect of anthropogenic, poultry, and wetland variables on all epidemic waves. Poultry predictor variables became much more important in the last 2 epidemic waves than they were previously, supporting the assumption of much wider H7N9 transmission in the chicken reservoir. 
We show that the future range expansion of H7N9 to northern China may increase the risk of H7N9 epidemic peaks coinciding in time and space with those of seasonal influenza, leading to a higher risk of reassortments than before, although the risk is still low so far.

The third and fourth epidemic waves of avian influenza A(H7N9) human infections in China showed an apparent reduction in incidence compared to the spring 2013 and winter 2013–14 epidemic waves. However, during the winter of 2016–17, the incidence rose, growing to levels never observed before and reaffirming concerns of a pandemic threat posed by the H7N9 virus (1–3). Since 2013, more than 1,520 human cases of H7N9 virus infection have been reported, mostly located in eastern China, with a case-fatality rate ranging from 30% to 40% (4–6).


The geographic range expansion and increase in incidence of human cases in the fifth wave of H7N9 brings serious human health concerns. 

First, repeated human infection by avian influenza viruses increases the chances of virus recombination, mutation, or both leading to human-to-human transmission. 

Second, the provinces affected by earlier H7N9 epidemic waves do not have a strong seasonal influenza A peak in January and February (30) that matches the peak of H7N9 cases (Figure 3). 

 However, if the H7N9 virus continues to expand its range northward, in areas with a strong influenza A peak in January and February, there will be a higher chance of local coincidence of peaks of incidence between human cases of H7N9 and seasonal influenza A virus. 

This change may enhance the chances of coinfections that could lead to the emergence of reassortants with the capacity to transmit easily between humans. 

Third, the extent of the geographic range of the expansion is not yet fully known; in the absence of new measures, it may spread further within China and internationally through poultry value chains.

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Although the risks are difficult to quantify, the co-infection of a human with a seasonal (H1N1 or H3N2) virus and a novel virus like H7N9 is a concern since the potential for seeing a reassorted `hybrid' virus emerge cannot be ignored.

When the peak of the regular flu season concides with the peak (and increase) in human H7N9 cases, the odds of seeing co-infections rises. While viable reassortant viruses aren't detected often, we've a couple of examples to look at.
In the summer of 2013, in the Lancet: Coinfection With H7N9 & H3N2, we saw the first evidence of co-infection with the newly emerged H7N9 virus and a seasonal flu virus in a human host. The case involved a 15-year-old boy from China - while two influenza viruses were isolated from the same patient - no reassorted virus was detected. 

Once again, in 2014, we saw a report (see EID Journal: Human Co-Infection with Avian and Seasonal Influenza Viruses, China) of two H7N9 co-infections, one with H1N1pdm09, and the other influenza B. 

Upping the ante, in February of 2016, in EID Journal: Nosocomial Co-Transmission Of H7N9 & H1N1pdm09,  we looked at an EID Journal report on another H7N9 - H1N1pmd co-infection from 2014, with the added twist that both strains appear to have been nosocomially transmitted to an immunocompromised patient in a hospital ward in China. 

While a reassorted virus was not detected in either of these events, the risks of eventually seeing it happen are not zero. 
Of course, H7N9 doesn't necessarily have to reassort with a humanized flu virus in order to become a pandemic.  It could simply evolve - perhaps through limited serial transmission in the community - to a more human adapted pathogen.
For now, H7N9 appears to be laying low in China, and while just about everyone (myself included) doubt that happy situation will persist much longer, avian flu often confounds our expectations.

The only thing we can say with absolute certainty is that H7N9 continues to evolve, and that means we need to be prepared for surprises going forward.

Stay tuned.