Waiting For The Next Flu To Drop

 

My 2012  Influenza Timeline Graphic

 

# 9991

 

Three years ago, with the 2009 H1N1 pandemic behind us, I wrote a blog called An Increasingly Complex Flu Field, where we looked at the growing number of novel flu threats that were beginning to appear on our radar. 

 

In addition to the venerable H5N1 virus, low path H9N2 and several LPAI H7 strains, I listed three up and coming `swine variant’ strains (H1N1v, H1N2v, H3N2v) that had recently jumped to humans, and were raising alarm bells (see CDC Teleconference & HAN Advisory On H3N2v).

 

Swine, like birds, are considered excellent `mixing vessels’ for influenza, and proved to the the crucible for the last (2009 H1N1) pandemic virus.  They are susceptible to a variety of influenza types, and when simultaneously infected by two different strains, are capable of producing a hybrid – or reassortant – virus.  

 

But as we’ve seen over the past few years, the number and variety of hosts for influenza reassortment go far beyond just pigs and birds.

 

Flu viruses can reassort in humans (see HK’s Dr. Ko Wing-man On Flu Reassortment Concerns), dogs (see Canine H3N2 Reassortant With pH1N1 Matrix Gene), and presumably in many other mammals (see Mixing Vessels For Influenza) including cats, seals, and even camels.

 

Over the past three years the number of newly emerged – or at least recently discovered – novel flu viruses has increased dramatically. Some of these viruses – like H5N6, H6N1, H7N9, and H10N8 – have already shown some limited ability to infect humans.

 

Others, like H5N8, H5N2, and H5N3 are related to viruses that can infect humans, but have not yet demonstrated the ability to do so.  Whether they will maintain that status quo is unknowable.

 

A partial list of influenza viruses of growing concern include:

 

I’ve purposefully excluded some recent influenza virus discoveries – like H17N10 and H18N11 found in bats, or the Novel Influenza C Virus In Bovines & Swine – because what little is known about these pathogens suggests they don’t pose a serious threat to human health at this time.

 

While most of the viruses I listed will likely never seriously threaten public health, this rapid increase in the number of pathogenic players is a concern. As they say, it only takes one.  And we’ve literally gone from watching a half dozen or so `novel’ flu viruses to having to keep track of nearly two dozen over the past three years.

 

The threat becomes even larger when you consider that each of these subtypes can have multiple clades, or genotypes.

 

• The H7N9 virus – which emerged in China in 2013, at last count (see Nature report), has produced at least 48 genotypes, spread across three major clades, and it is likely that constellation of H7N9 variants continues to expand.
• Likewise, H5N1’s evolution from 1996, when it emerged as clade 0, has spawned a constantly expanding family tree (albeit, not all of these incarnations continue to circulate)

 

So when we discuss a flu virus – like H5N1, H7N9 or H5N8 – we aren’t talking about a single, monolithic threat.  We are talking about an ever-expanding family of related viruses, which can vary considerably in their behavior and the threat they pose (see Differences In Virulence Between Closely Related H5N1 Strains).

 

The only real point we can draw from all of this is the number of potential influenza pandemic virus candidates has increased significantly over the past few years.

 

And with the geographic expansion of many of these viruses, the opportunities for them to interact with – an reassort with – other viruses, only increases. This is how North America ended up with two new HPAI H5 viruses (H5N2, H5N1 N/A) over the winter after the arrival of H5N8 in the Pacific Northwest last fall.   

 

It is certainly possible that – over time – additional reassorted H5 viruses will appear in the United States or Canada.   How they may end up affecting wild birds, poultry, or even humans is frankly . . .  unpredictable.

 

Three years ago, all eyes were on the emerging swine variant viruses (see A Variant Swine Flu Review), which caused more than 300 infections across the Midwest in 2012.  Although those viruses have receded from the headlines the past couple of summers, they haven’t gone away, and may surge again. 

 

These swine viruses are important because – unlike many of the avian strains – they belong to the H1, H2, and H3 HA types that have led to all of the known pandemics of the past 130 years.  

 

The progression of human influenza pandemics over the past 130 years has been H2, H3, H1, H2, H3, H1, H1 . . . .  and while that doesn’t prove that an H5 or an H7 virus couldn’t adapt to humans (or hasn’t in the past), it has led some researchers to wonder whether a non H1, H2, or H3 virus has the `right stuff’ to spark a pandemic (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).

 

This propensity for H1, H2, and H3 viruses to start human pandemics is another reason we keep our eyes on the H2N2 virus in birds (see H2N2: What Went Around, Could Come Around Again), H3N2 and H3N8 viruses canine viruses, the H3N8 seal virus, H2N2 and even H3N8 in horses (see Study: Dogs As Potential `Mixing Vessels’ For Influenza). 

 

But whether a repeat in the H1-H3 cycle, or a deviation into the more exotic avian virus realms, another influenza pandemic is considered all but inevitable.  

 

Two months ago (see WHO Warns On Evolving Influenza Threat) the World Health Organization advised:

 

Warning: be prepared for surprises

Though the world is better prepared for the next pandemic than ever before, it remains highly vulnerable, especially to a pandemic that causes severe disease. Nothing about influenza is predictable, including where the next pandemic might emerge and which virus might be responsible.

 

Given the growing number of candidate viruses in circulation, unlike the last interpandemic period, we may not have another three decades before the next pandemic appears.

Pregnancy, Flu and The Next Pandemic

Photo Credit – CDC

 

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During the 1918 pandemic an abnormally high number of pregnant women died from the influenza, and those that survived endured a very high miscarriage rate.  Again, during the much milder 1957 Asian Flu, pregnant women reportedly suffered disproportionately higher mortality rates than non-pregnant women of the same age.

 

Historical reviews of both events are available in a Perspective, written by 3 CDC physicians (Sonja A. Rasmussen,  Denise J. Jamieson, Joseph S. Bresee) and published in the CDC Journal of EID article, Pandemic Influenza and Pregnant Women in February of 2008.

True to form, the 2009 H1N1 pandemic saw similarly high rates of influenza complications among pregnant women, often with tragic results. 

 

• During the 2009 H1N1 pandemic,  pregnant women were six times more likely to be hospitalized than non-pregnant women (see Pregnancy & Flu: A Bad Combination).
• And in 2011, in BMJ: Perinatal Outcomes After Maternal 2009/H1N1 Infection we saw a study where pregnant women who were admitted to the hospital with an  H1N1 infection experienced a 3 to 4 times higher rate of preterm birth, 4 to 5 times greater risk of stillbirth, and a 4 to 6 times higher rate of neonatal death.

 

One problem with these studies has been they are often undertaken either in an ad hoc fashion in the midst of an influenza crisis, or are based on a retrospective look at the data.  While both can provide important clues, a more orderly and well planned study would likely provide better data.

 

To that end, researchers in the UK have already designed, and put into `hibernation’ until needed, the framework for just such a study, if and when the next influenza pandemic appears.   First a link to the Abstract (the entire document is available online), then I’ll be back with a bit more.

 

Planning for a cohort study to investigate the impact and management of influenza in pregnancy in a future pandemic.

Editors

Knight M, Brocklehurst P, O’Brien P, Quigley MA, Kurinczuk JJ.

Source

Southampton (UK): NIHR Journals Library; 2015 Mar.
Health Services and Delivery Research.

Excerpt

BACKGROUND:

Evidence from the 2009 A/H1N1 influenza pandemic demonstrated that pregnant women are particularly vulnerable to infection and at an increased risk of death. Active data collection through the UK Obstetric Surveillance System (UKOSS) about women admitted to hospital during the 2009 A/H1N1 pandemic was used to inform ongoing clinical guidance regarding the use of antiviral treatment for pregnant women and demonstrated that, in addition to an increased risk of maternal morbidity, influenza infection in pregnancy is associated with poor perinatal outcomes, including an increased risk of stillbirth and preterm birth. This evidence influenced the decision to offer routine influenza immunisation to pregnant women. Even in a non-epidemic period, pregnant women continue to die from influenza.

OBJECTIVE:

To establish, and then to put into hibernation, the study mechanisms needed to mount a rapid investigation of the impact of pandemic influenza in pregnancy in the event of a newly emerging pandemic strain.

DESIGN:

A new UKOSS cohort study was designed, based on the 2009–10 study, and following consultation with the Pandemic Flu Planning Group at the Royal College of Obstetricians and Gynaecologists and the UKOSS Steering Committee, to identify potential previously unanswered questions.

SETTING:

UK maternity units.

PARTICIPANTS:

All pregnant women admitted to hospital with influenza in a future pandemic.

MAIN OUTCOME MEASURES:

Management of pregnant women with influenza infection, intervention rates, treatment and pregnancy outcome for both the mother and fetus.

RESULTS:

The study was designed and approved by the UKOSS Steering Committee and then placed into hibernation for activation in the event of an influenza pandemic.

CONCLUSIONS:

Pregnant women, as a result of their changed immunological status, appear to be particularly susceptible to infection, including from influenza. The existence of the UKOSS enabled us to rapidly mount a study of pregnant women who were hospitalised with 2009 A/H1N1 influenza. Minor modifications to incorporate previously unanswered questions and our previous study enabled us to design, and then put into hibernation, a new study ready to investigate the impact and management of influenza in pregnancy, which is poised for activation in the event of a newly emerging pandemic strain. This will enable real-time data to be available on which to base rapid changes in clinical management as the as-yet-unforeseen pandemic unfolds. In the event of an influenza pandemic the study will be available to be immediately activated following expedited regulatory approvals.

 

 

We’ve known for a long time that influenza and pregnancy can endanger both the mother and unborn child’s life – and that holds true for both pandemic and seasonal influenza.

 

Over the past decade we’ve also seen a handful of studies tentatively linking prenatal exposure to influenza (or an influenza-like-illness) with a variety of child and adolescent development disorders (see Of Pregnancy, Flu & Autism).

 

Which explains why the CDC, the WHO, and other public health stress the importance of seasonal flu vaccination for pregnant women every year. 

Despite all of this evidence of harm from influenza - there remains reluctance among some pregnant women to get the shot. In part, due to the persistent anti-vaccine rhetoric on the internet and in the media - including unfounded claims that the 2009 H1N1 vaccine was responsible for `thousands’ of miscarriages. 

 

The science, however, overwhelmingly supports the safety of flu shots for pregnant women.

 

In October of 2011, in IDSA: Flu Vaccines In Pregnancy, we saw several studies presented at the 49th Annual Meeting of the Infectious Diseases Society of America (IDSA) reaffirming the benefits and safety of maternal vaccination.The CDC has synopsized these studies in:

 

Pregnancy and Influenza Vaccine Safety

 

In 2012, in BMJ: H1N1 Vaccination & Fetal Death Rates, we looked at a large cohort study of pregnant women in Demark that reassuringly finds no increase in miscarriage among those who received the 2009 H1N1 vaccine.  Results that mirrored another study  we saw in  Hong Kong: No Increase In Fetal Death Among Vaccine Recipients.

 

Ironically, while some seek to demonize the flu vaccine as causing fetal deaths, in October of 2011 in UK: Pregnancy And Swine Flu a study conducted at Oxford University by the National Perinatal Epidemiology unit found a strong link between infection with the 2009 `swine’ flu and an increased number of stillbirths.

 

Fetal deaths among women infected with the H1N1 virus were 5 times higher than normal.

 

While no drug or vaccine can claim to be 100% safe or benign, the evidence continues to show that flu vaccines are among the safest drugs available, and that most years they can provide decent protection against a serious and potentially deadly illness.

 

For pregnant women and their unborn children - the real risks come from influenza virus - not from the vaccine.

A Genetic Predisposition To Severe Flu Infection

Photo Credit – CDC PHIL

 

 

# 9874

 

Influenza can produce a wide spectrum of illness, ranging from mild or even asymptomatic presentation to severe and/or life threatening disease.  

 

Often we talk about `high risk’ patients – where their age and/or co-morbidities (COPD, Asthma, pregnancy, etc. ) can sometimes lead to a greater chance of complications, but there may be other factors at work as well. 

 

As we saw in the 2009 H1N1 pandemic, with seasonal flu, and with several strains of avian flu (H5N1, H7N9), young, otherwise healthy adults can be quickly overwhelmed by their infections.

 

For a number of years researchers have been looking for a hematological or genetic marker that would help predict which patients would be most likely to experience severe influenza.

 

In 2008, in the Journal of Infectious Diseases, we saw a study that suggested there might be a heritable susceptibility to death from the influenza virus:

Evidence for a heritable predisposition to death due to influenza.

Albright FS, Orlando P, Pavia AT, Jackson GG, Cannon Albright LA.  

 

While interesting, this study didn’t provide us with a smoking gene.

 

In 2009 (see The Best Defense) we inched a bit closer, with research from Harvard Medical School and the Howard Hughes Medical Institute, that identified the IFITM3 protein as capable of inhibiting the replication of influenza, and other viruses, such as West Nile and Dengue. 

 

We revisited the IFITM3 story again in early 2012, in Luck Of The Draw, when we looked at research from the Wellcome Trust Sanger Institute, that found that people who carried a particular variant of the IFITM3 gene - (SNP rs12252-C) - were more likely to be hospitalized with severe influenza

 

In 2013, a study by Professor Peter Doherty (see PNAS: Genetic Marker & Cytokine Levels Linked To Severity Of Human H7N9 Infection) linked IFITM3 CC gene variant (aka C/C Genotype)  to hypercytokinemia (aka a `Cytokine Storm’), and severe outcomes in H7N9 infections.

 

This genetic marker– while comparatively rare in Caucasians - is far more common in Han Chinese, and may (partially) account for some of the particularly high mortality rates we’ve seen with novel influenza’s in Asia. 

 

Fast forward to yesterday, and we get a study published in Science Express that identifies yet another (rare) genetic marker -  a mutation of the IRF7 gene -  linked to a lack of interferon production which can lead to a more severe influenza infection. 

 

Published Online March 26 2015

Science DOI: 10.1126/science.aaa1578

Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency

Michael J. Ciancanelli¹, Sarah X. L. Huang²,³,*, Priya Luthra⁴,*, Hannah Garner⁵,*, Yuval Itan¹, Stefano Volpi⁶,⁷, Fabien G. Lafaille¹, Céline Trouillet⁵, Mirco Schmolke⁴, Randy A. Albrecht⁴,⁸, Elisabeth Israelsson⁹, Hye Kyung Lim¹, Melina Casadio¹, Tamar Hermesh¹, Lazaro Lorenzo¹⁰,¹¹, Lawrence W. Leung⁴, Vincent Pedergnana¹⁰,¹¹, Bertrand Boisson¹, Satoshi Okada¹,¹², Capucine Picard¹,¹⁰,¹¹,¹³, Benedicte Ringuier¹⁴, Françoise Troussier¹⁵, Damien Chaussabel⁹,¹⁶,†, Laurent Abel¹,¹⁰,¹¹,†, Isabelle Pellier¹⁷,†, Luigi D. Notarangelo⁶,†, Adolfo García-Sastre⁴,⁸,¹⁸,†, Christopher F. Basler⁴,†, Frédéric Geissmann⁵,†, Shen-Ying Zhang¹,¹⁰,¹¹,†, Hans-Willem Snoeck²,³,†, Jean-Laurent Casanova¹,¹⁰,¹¹,¹⁹,²⁰,‡ 

Abstract

Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient’s leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient’s dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.

Some excerpts from the Rockefeller University press release follow:

 

Genetic mutation helps explain why, in rare cases, flu can kill

March 26, 2015 | Science News

(Excerpts)

The researchers scrutinized blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital. Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova discovered that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.

<SNIP>

Turning their attention to influenza, Michael J. Ciancanelli, a research associate and senior member of Casanova’s lab, and his colleagues sequenced all genes in the genomes of the young girl who survived her dangerous bout of the flu and her parents, looking for mutations that might explain her vulnerability. Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.

What emerged from their work was the finding that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon, a critical part of the body’s response to viral infections. “No other mutations could have explained her reaction to the influenza virus,” says Ciancanelli. “Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare.”

(Continue . . . )

 

In a separate press release from HHMI, in view of the likelihood that others care this or similar genetic factors, Dr. Casanova recommends that clinicians may want to consider including interferon alpha in the treatment of severe unexplained flu.

 

[ March 26, 2015 ]

Rare Genetic Mutations May Make Influenza Life-Threatening for Some

Summary

HHMI researchers identify a rare genetic mutation that tamps down immune response to influenza.

Highlights

• Why did the flu develop into a life-threatening infection in a two-year-old girl?
• HHMI researchers tried to identify the cause of the girl's severe response to influenza infection.
• They found that the girl carries a genetic mutation that affects production of natural antiviral molecules.

(Continue . . . )

WHO Warns On Evolving Influenza Threat

Credit NIAID

 

 

# 9762

 

The World Health Organization has issued a lengthy and strong statement on the emergence and proliferation of new subtypes of novel influenza around the world, and the potential risks they pose to global health.  Themes that are familiar to regular readers of this blog.

 

Helen Branswell has a report this evening summarizing the statement, and I’ve posted a link to it and a few excerpts.  I’ll have more to say about the specifics of this statement tomorrow.

 

 

The Canadian Press - ONLINE EDITION

Volatility of global patterns of novel flu viruses a source of concern: WHO

By: Helen Branswell, The Canadian Press

 

Follow the link to read the WHO statement in its entirety, where you’ll find specific discussions on the recent spike in H5N1 cases in Egypt (see WHO Releases Updated Egyptian H5N1 Numbers from earlier today), and China’s third winter wave of H7N9.

 

Warning signals from the volatile world of influenza viruses

February 2015

The current global influenza situation is characterized by a number of trends that must be closely monitored. These include: an increase in the variety of animal influenza viruses co-circulating and exchanging genetic material, giving rise to novel strains; continuing cases of human H7N9 infections in China; and a recent spurt of human H5N1 cases in Egypt. Changes in the H3N2 seasonal influenza viruses, which have affected the protection conferred by the current vaccine, are also of particular concern.

Viruses in wild and domestic birds

The diversity and geographical distribution of influenza viruses currently circulating in wild and domestic birds are unprecedented since the advent of modern tools for virus detection and characterization. The world needs to be concerned.

Viruses of the H5 and H7 subtypes are of greatest concern, as they can rapidly mutate from a form that causes mild symptoms in birds to one that causes severe illness and death in poultry populations, resulting in devastating outbreaks and enormous losses to the poultry industry and to the livelihoods of farmers.

Since the start of 2014, the Organisation for Animal Health, or OIE, has been notified of 41 H5 and H7 outbreaks in birds involving 7 different viruses in 20 countries in Africa, the Americas, Asia, Australia, Europe, and the Middle East. Several are novel viruses that have emerged and spread in wild birds or poultry only in the past few years.

Some of the outbreaks notified to OIE have involved wild birds only. Such notifications are indicative of the heightened surveillance and improved laboratory detection that have followed the massive outbreaks of highly pathogenic H5N1 avian influenza that began in Asia in late 2003.

Detection of highly pathogenic avian influenza viruses in wild birds signals the need for a close watch over poultry farms. Migratory waterfowl, immune to the disease, are known to spread avian viruses to new areas by quickly crossing continents along the routes of several flyways. These migratory waterfowl subsequently mix with local wild birds and poultry that then become infected.

<SNIP>

Warning: be prepared for surprises

Though the world is better prepared for the next pandemic than ever before, it remains highly vulnerable, especially to a pandemic that causes severe disease. Nothing about influenza is predictable, including where the next pandemic might emerge and which virus might be responsible. The world was fortunate that the 2009 pandemic was relatively mild, but such good fortune is no precedent.

WHO and its collaborating laboratories continue to help countries strengthen their alert, surveillance, and response capacities. A quality assurance program has been conducted by WHO since 2007 to maintain global influenza virus laboratory detection capacity, with panels of testing materials being provided free-of-charge to countries once or twice a year. To further capacity building in countries, particularly developing countries, nearly $17 million was provided in 2014 through the Pandemic Influenza Preparedness framework.

Virological research, which has done so much to aid the detection and understanding of novel viruses, assess their pandemic risks, and track their international spread, needs to continue at an accelerated pace.

More R&D is needed to develop better vaccines and shorten the production time. During a severe pandemic, many lives will be lost in the 3 to 4 months needed to produce vaccines.

An influenza pandemic is the most global of infectious disease events currently known. It is in every country’s best interests to prepare for this threat with equally global solidarity.

Unusual Presentation Of Parotitis With Seasonal Influenza

Credit Wikipedia

 

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The parotid glands are located on either side of the face, and are our largest salivary glands.   We don’t tend to notice them unless they become enlarged, usually due to a bacterial or viral infection.  

The classic cause of parotitis is the mumps virus, but other viruses (EBV & HIV), along with acute bacterial parotitis or Extrapulmonary Tuberculosis can cause inflammation of these glands, as well as some autoimmune diseases.

 

And sometimes, the etiology is unknown.

 

One common disease that isn’t usually associated with parotitis is influenza, although a few cases have been reported in the past (see Clinical Infectious Diseases Diagnosing Mumps: Don't Be So Sure).

A few weeks ago, the Chicago Department of Public Health issued an alert to local doctors to test for both influenza, and mumps, when diagnosing parotitis, as several unusual influenza-related cases had surfaced.

Background

Several Midwest state health departments, including Illinois, have received reports of parotitis in persons with lab-confirmed influenza. Parotitis is inflammation of one or both of the parotid glands, the major salivary glands in the oral cavity, and is an uncommon complication of influenza. The Illinois Department of  Public Health (IDPH) is working with other states and the Centers for Disease Control and Prevention  (CDC) in conducting an investigation into such reports. Information about persons with lab-confirmed  influenza who are diagnosed with parotitis is needed to understand the occurrence and further explore  characteristics of such cases.

 

Last night the CDC published an overview of the 2014-15 flu season, with the following comment on these parotitis cases.

What You Should Know for the 2014-2015 Influenza Season

(excerpt)

Is there any unusual disease activity going on this season?

Since December 2014, multiple states have notified CDC of laboratory-confirmed influenza infections in persons who have swelling of their salivary glands (a condition called ‘parotitis’). Of the cases of influenza infection with parotitis that have been reported to CDC, the majority have occurred in children with influenza A (H3) infection, and have resulted in mild illness. No deaths have been reported. CDC is currently investigating  the situation in order to understand the characteristics of patients and the occurrence of parotitis.

Parotitis is not a common symptom of influenza infection, although cases of parotitis with influenza infection have been reported in the past. Parotitis is much more commonly seen following infection with other pathogens such as the mumps virus. Symptoms of influenza infection include fever, chills, cough, sore throat, runny or stuffy nose, muscle or body aches, headache, fatigue (tiredness), and sometimes vomiting and  diarrhea (more common in children than adults).

 

As with several dozen EV-D68 related paralysis cases last year (see CIDRAP: Likely That Polio-like Illness & EV-D68 Are Linked), and a handful of reported Pediatric Neurological Complications during the 2009 H1N1 pandemic, this appears to be an infrequent (but far more benign) atypical side effect of infection.

A medical mystery for now, but one we’ll keep an eye on going forward.

Virology J: Human-like H3N2 Influenza Viruses In Dogs - Guangxi, China

 

# 9674

 

Influenza viruses are constantly evolving, and do so via two well established routes; Antigenic drift & Antigenic Shift (reassortment).

 

Antigenic drift causes small, incremental changes in the virus over time. Drift is the standard evolutionary process of influenza viruses, and often come about due to replication errors that are common with single-strand RNA viruses (see NIAID Video: Antigenic Drift).

 

Shift occurs when one virus swap out chunks of their genetic code with gene segments from another virus.  This is known as reassortment. While far less common than drift, shift can produce abrupt, dramatic, and sometimes pandemic inducing changes to the virus (see NIAID Video: How Influenza Pandemics Occur).

While most reassortant viruses fail to thrive, every once in a while a viable, and competitive new subtype will emerge.  As any virologist will tell you, while rare  – Shift Happens.

 

It has only been in the past few years that dogs have been viewed as potential important `mixing vessels’  for influenza – an evolutionary process that has traditionally been associated with birds and swine. 

 

But as we learn more about the host range (which includes humans, equines, swine, birds, bats, camels, and marine mammals) and the genetic diversity of influenza viruses (currently 18 hemagglutinin & 11 neuraminidase subtypes identified), we find a far more complex and intermingled ecology than previously envisioned. 

 

In years past we’ve looked at a number of species with at least theoretical potential to act as mixing vessels, including in  Mixing Vessels For Influenza & A Host Of Reservoirs.

 

Last summer, and particularly apropos for today’s blog -  in Study: Dogs As Potential `Mixing Vessels’ For Influenza - we looked at the ability of different influenza strains (canine, equine and human)  to infect, and replicate in, canine tracheal tissues. 

Last November, In A Dog & Cat Flu Review, we looked at (among other things) the emergence and evolution of avian H3N2 and equine H3N8 viruses in dogs, and just last week we saw reports that Korea has continued to find evidence of avian H5N8 infection in dogs.

 

So it isn’t a huge surprise that we find a study, published yesterday in the Virology Journal, that has isolated and identified what appears to be a human/swine combination H3N2 influenza virus in pet dogs from Guangxi, China.

 

Emergence of human-like H3N2 influenza viruses in pet dogs in Guangxi, China

Ying Chen^1*, Yan-Ning Mo¹, Hua-Bo Zhou², Zu-Zhang Wei¹, Guo-Jun Wang³, Qing-Xiong Yu¹, Xiong Xiao¹, Wen-Juan Yang¹ and Wei-Jian Huang¹ 

Virology Journal 2015, 12:10  doi:10.1186/s12985-015-0243-2

Published: 3 February 2015

Abstract (provisional)

Background After the 1968 H3N2 pandemic emerged in humans, H3N2 influenza viruses continuously circulated and evolved in nature. An H3N2 variant was circulating in humans in the 1990s and subsequently introduced into the pig population in the 2000s. This virus gradually became the main subtype of swine influenza virus worldwide. However, there were no reports of infections in dogs with this virus.

Findings  In 2013, 35 nasal swabs from pet dogs were positive for Influenza A virus by RT-PCR. Two viruses were isolated and genetically characterized. In the phylogenetic trees of all gene segments, two H3N2 canine isolates clustered with Moscow/10/99 and most H3N2 swine influenza viruses.

These results indicated that two H3N2 CIVs possessed high homology with human/swine influenza viruses, which at the same time exhibited some amino acid substitutions in NA, polymerase basic protein 1 (PB1), and nucleoprotein (NP), which probably were related to the interspecies transmission

.Conclusions These two viruses share the highest homology with swine H3N2, Moscow/99-like viruses, which indicated that these viruses might originate from swine viruses.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

While it doesn’t appear that these reassortant viruses have become well established in canine hosts, this adds to the growing body of evidence that dogs could serve as intermediate hosts – and potential mixing vessels – for a variety of non-canine influenza viruses.

Swine and poultry undoubtedly pose far larger reassortment risks, simply because they are natural hosts for influenza viruses, are often raised in large numbers and in close proximity with one another, and are often shipped long distances.

 

But as we’ve discussed previously, in China: Avian-Origin Canine H3N2 Prevalence In Farmed Dogs, in some parts of the world dogs are regarded as food  - not pets - and are raised under pretty much the same type of crowded conditions as other livestock, but apparently with even less oversight. 

China’s MOH introduced new regulations in 2013 requiring vaccinations and certificates of health for farmed dogs, but local reporting suggests widespread fraud or blatant disregard for these rules (see Yulin market dog safety not guaranteed - Reporter survey found that no regulations exist blank slaughter procedures).

While likely a minor player, all of this makes dogs a `wild card’ in the evolution and spread of new influenza reassortant viruses, and a host species worth keeping one eye on.

ECDC Influenza Season Risk Assessment

Credit ECDC – Week 3

 

# 9642

 

While North America’s flu season is already well underway (and in some regions has already peaked), seasonal flu is getting a later - but no less strenuous start - in Europe this year.  And as we’ve seen here in the United States, the predominant flu strain in Europe this season is a `drifted’ H3N2 virus, one which has reduced the effectiveness of this year’s vaccine.

This morning ECDC released an updated Rapid Risk Assessment and summary on this year’s flu season, and  Director Dr. Marc Sprenger  tweeted:

 

First a press release summary, with links to the Rapid Risk Assessment, and then I’ll be back with a few words on the CDC & ECDC’s strong recommendations for the use of antiviral medications.

 

More severe influenza season to be expected in Europe

28 Jan 2015

Medium or high rates of influenza intensity are likely to be observed in the vast majority of EU and EEA countries, concludes ECDC annual risk assessment on influenza for the remainder of the season. The number of severe cases of influenza as well as fatal outcomes especially among older people and other risk groups can be expected to rise.

Strenuous start of this influenza season

• Influenza activity in Europe started in week 50/2014 without a particular geographic progression, affecting the Netherlands, Sweden and England first, and then followed by Iceland, Malta and Portugal.
• Children between 0 and four years of age have been the most affected age group according to primary healthcare data in almost all reporting countries, similarly as in other seasons.
• Influenza-like illness and acute respiratory infections have been increasing in adults and older people in almost all countries.
• Most of the first affected countries report greater pressure on primary healthcare services during this season compared to the peak activity in previous season.
• Among the countries reporting hospitalised influenza cases, 34 fatal outcomes were reported, two thirds of these in the elderly.

Drifted A(H3N2) viruses dominant

• Subtype A(H3N2) viruses, known to cause more severe disease, are dominant in almost all reporting European countries.
• Majority of A(H3N2) viruses analysed are antigenically distinct from the A(H3N2) virus included in the vaccine for this season.
• Reduced vaccine effectiveness is expected as a result of this mismatch between the vaccine and the circulating influenza strains.

ECDC Director, Dr Marc Sprenger, said:
“We face an influenza season that could be more severe and exert bigger pressure on health care systems than in the last few years. As each year, ECDC undertakes a risk assessment early in the season, combining a multitude of data sources and aiming to inform and strengthen EU and EEA countries in their response to the influenza epidemics.”

How to protect oneself and others from the flu

• Self-isolation when sick, hand-washing and good respiratory hygiene as well as cough etiquette remain simple yet effective measures to protect from catching or passing on influenza.
• A lower overall vaccine effectiveness due to the circulation of drifted A(H3N2) viruses is expected, however, the vaccine may still reduce complications and severe outcomes associated with this subtype of influenza viruses.
• Influenza vaccine offers good protection against the circulating A(H1N1)pdm09 viruses.

Antivirals particularly important this season

• Treatment and post-exposure prophylaxis with antivirals protects the elderly and people in other risk groups against severe influenza illness.
• The circulating viruses are susceptible to antiviral drugs oseltamivir and zanamivir.

Dr Marc Sprenger emphasizes:

“In a season dominated by a drifted A(H3N2) strain of influenza viruses, more severe illness can be expected especially among older people and those in medical risk groups. It is therefore paramount that physicians across Europe consider treatment and post-exposure prophylaxis with antivirals especially for these patients.”

The annual ECDC risk assessment of seasonal influenza aims to provide an early description of seasonal influenza in the first affected countries and to inform public health decisions to be taken to reduce the burden of seasonal influenza in 2015 in Europe.

Read full risk assessment of seasonal influenza in the EU/EEA countries, 2014-2015

More information:

Flu News Europe: weekly influenza updates
Seasonal influenza on ECDC website
Influenza maps and graphs
Follow us on Twitter: @ECDC_Flu

 

 

In Europe, even more so than in the US, antiviral drugs have been excoriated in the press; often referred to as an expensive scam on the part of the government, purportedly in cahoots with `Big Pharma’.  In the past we’ve seen Tamiflu’s ®  value questioned by Cochrane meta-studies, some prestigious medical journals, conspiracy theorists, pundits, but most often, the tabloid press.

 

Admittedly, it hasn’t helped that for many years Tamiflu’s maker -  Roche Pharmaceuticals - has refused to release all of the testing data on their best selling antiviral drug, and we’ve seen some scare articles in the popular press suggesting adverse side effects to the drug.

 

With all of this baggage, you may be wondering why the ECDC, CDC , the UK’s PHE, and many other public health agencies continue to recommend the use of influenza antivirals for influenza. 

 

Last April, in Revisiting Tamiflu Efficacy (Again), I wrote at some length on the BMJ –  Cochrane Library review Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children – that examined a subset of the scientific literature and cast doubt on its effectiveness in treating influenza.

 

While I too lamented the lack of solid, well mounted Randomized controlled trials (RCTs) proving the effectiveness of Oseltamivir (particularly in high risk patients, or with novel flu strains), I listed a number observational studies that strongly support the effectiveness of Oseltamivir.

 

A few days later, the CDC issued their own response. I’ve posted the link and some excerpts below.  Follow the link to read their rationale in its entirety.

 

CDC Recommendations for Influenza Antiviral Medications Remain Unchanged

April 10, 2014 -- CDC continues to recommend the use of the neuraminidase inhibitor antiviral drugs (oral oseltamivir and inhaled zanamivir) as an important adjunct to influenza vaccination in the treatment of influenza. CDC’s current influenza antiviral recommendations are available on the CDC website and are based on all available data, including the most recent Cochrane report, about the benefits of antiviral drugs in treating influenza.

(Continue . . .)

 

Recommendations that were echoed a few months ago by Public Health England (see UK PHE: Revisiting Influenza Antiviral Recommendations), and that are supported by many studies I’ve written about previously, including:

 

Study: Antivirals Saved Lives Of Pregnant Women

BMJ: Efficacy of Oseltamivir In Mild H1N1

Study: The Benefits Of Antiviral Therapy During the 2009 Pandemic

The Lancet: Effectiveness Of NAI Antivirals In Reducing Mortality In Hospitalized H1N1pdm09 Cases

CID Journal: Under Utilization Of Antivirals For At Risk Flu Patients

 

For uncomplicated influenza in a healthy individual (essentially what the Cochrane studies looked at), antivirals probably offer little value.

 

But for severe influenza, or for people at risk of complications . . .

 

While not a cure, the preponderance of evidence shows that taking antivirals early can limit the severity and duration of symptoms – and for those patients  – that could help keep them out of the hospital, and even prove life saving.

‘Tis The Coronary Season

 

# 9471

 

If history is any gauge the three deadliest coronary days of the year will occur over the next two weeks; Christmas day, the day after Christmas, and New Year’s Day.   Events that are commonly called `Christmas Coronaries’ or `Hanukkah Heart Attacks’.

 

Fifteen years ago, a study looked at the rate of heart attacks in the United States, and found that Acute Myocardial Infarctions (AMIs) run as much 53% higher during the winter months than than during the summer.

 

Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction.

Spencer FA, Goldberg RJ, Becker RC, Gore JM.

 

While cold weather combined with strenuous physical activity (like clearing snow from sidewalks) has often been blamed for this spike, even in balmy Southern California, studies have shown a 33% increase in heart attacks over the holidays (see below).

When Throughout the Year Is Coronary Death Most Likely to Occur?

A 12-Year Population-Based Analysis of More Than 220 000 Cases

Robert A. Kloner, MD, PhD; W. Kenneth Poole, PhD; Rebecca L. Perritt, MS

Non-climate related factors – like over indulgence in food and alcohol, diminished activity levels, forgetting to take prescription medicines, and combined holiday stressors like shopping, running up debt, traveling, meal preparation, and the angst that comes from dysfunctional family gatherings are likely contributors to this yearly spike. 

 

But increasingly influenza and other respiratory infections have been linked to this seasonal increase in heart attacks.

 

In 2012, in Study: Influenza And Heart Attacks, we looked at research that appeared in the Journal of Infectious Diseases that suggested Influenza - and other acute respiratory infections - can act as a trigger for heart attacks. The same issue carried an editorial called Increasing Evidence That Influenza Is a Trigger for Cardiovascular Disease.

 

Influenza Infection and Risk of Acute Myocardial Infarction in England and Wales: A CALIBER Self-Controlled Case Series Study

Charlotte Warren-Gash, Andrew C. Hayward1, Harry Hemingway2, Spiros Denaxas2, Sara L. Thomas3, Adam D. Timmis5, Heather Whitaker6 and Liam Smeeth4

In 2010, in CMAJ: Flu Vaccinations Reduce Heart Attack Risk we saw what would turn out to be a controversial study (see Vaccine/Heart Attack Study Questioned) that strongly suggested that those over the age of 40 who get a seasonal flu vaccine each year may reduce their risk of a heart attack by as much as 19%.

 

Last year (October 2013), in JAMA: Flu Vaccine and Cardiovascular Outcomes, we looked at a meta-analysis of  5 published and 1 unpublished randomized clinical trials involving  6735 patients – that found among those who had previously had a heart attack, the receipt of a flu vaccine was linked to a 55% reduction in having another major cardiac event in the next few months.

 

So the idea that heart attacks may be linked to influenza infection is hardly new.

 

In late October of this year, the Texas Heart Institute published this article, suggesting that tens of thousands of cardiac deaths could be prevented if every high-risk cardiac patient got the flu shot each year.

 

Research Shows Flu Can Trigger Heart Attacks

Influenza vaccinations could prevent thousands of deaths from heart disease

People who are at risk of heart disease should receive the influenza vaccine every autumn. Research shows that influenza epidemics are associated with a rise in deaths from heart disease and that flu can actually trigger the heart attacks that result in death.

However, only about 60 percent of people in the U.S. who ought to have a flu vaccination actually have one, said Mohammad Madjid, MD, MSc, a senior research scientist at the Atherosclerosis Research Lab of the Texas Heart Institute.

(Continue . . . )

 

If their hypothesis is correct – given the expected reduced effectiveness of this year’s flu vaccine (see CDC HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus) and the rising tide of H3N2 influenza across the country – the next couple of weeks could prove very busy for the nation’s EMS crews and Coronary care units.

But regardless of the effectiveness of this year’s flu shot, and influenza’s effects on cardiovascular events, even on an `average day’ roughly 1,000 people suffer a Sudden Cardiac Arrest (SCA) in the United States.

 

This from the Heart Rhythm Association:

• Sudden Cardiac Arrest (SCA) is a leading cause of death in the United States, claiming more than 350,000 lives each year.
• Approximately 92% of those who experience sudden cardiac arrest do not survive.
• SCA kills more than 1,000 people a day, or one person every 90 seconds

 

What the people who witness these events do in the first few minutes can mean the difference between life and death for the stricken individual. Luckily, hands-only CPR (cardio-pulmonary resuscitation) is easier to do than ever before, and there are thousands of AEDs (automated external defibrillators) stationed in public venues across the nation.

 

With a little bit of training, you have the potential to save someone’s life.

 

While it won’t take the place of an actual class, you can watch how it is done on in this brief instructional video from the American Heart Association.  To learn how to use an AED, you can use this online training module  I wrote about in CPR Skills & AED Simulator.  A  CPR class only takes a few hours, can be fun, and is well worth the effort.  

 

To find a local CPR course contact your local chapter of the American Red Cross, the American Heart Association, or (usually) your local fire department or EMS can steer you to a class.

 

Of course, despite your best efforts, many SCA victims will not survive. It isn’t at all like on TV, where 75% of  recipients of CPR survive.  Even when cardiac arrests occur inside a hospital, the survival to discharge rate is less than 40%. Outside the hospital, the odds of seeing a good outcome are lower.

 

While there are no guarantee of success, early and coordinated action taken by bystanders (calling 911, starting CPR, using AED if available) can substantially improve the SCA’s chances of survival. 

 

For more on heart attacks, and CPR, you may wish to visit some of these earlier blogs.

 

Deadlier Than For The Male

Survivability Of Non-Shockable Rhythms With New CPR Guidelines

Fear Of Trying

NPM11: Early CPR Saves Lives

When Influenza Goes Rogue

Variability of Flu Seasons - Mash up from Multiple FluView Reports

 

# 9311

 

Most people are aware that over the past century we’ve seen 4 influenza pandemics; the 1918 Spanish Flu, the 1957 Asian Flu, 1968 Hong Kong Flu & the 2009 H1N1 pandemic. Of these, the 1918 pandemic was (by far) the worst, but each of the others exacted a heavy toll as well.

Less well known have been the `rogue’ flu years, when we saw something less than a pandemic, but something substantially worse than a typical flu season.

 

There is, of course, a good deal of variance between `normal’ flu seasons (see chart above), with significant jumps in P&I (Pneumonia & Influenza) mortality registered in the years 2000,  2003 and 2013, while 2012 was the mildest year for influenza in decades.

 

As a paramedic, I worked the `pseudo-pandemic’ of 1977, and I can attest that it had a big impact, even if it didn’t rise to the level of a global pandemic.  In that case, an old nemesis – H1N1 – which had disappeared 20 years earlier after the arrival of H2N2 in the 1957 pandemic, came back.

 

While the exact mechanism of that virus’ return isn’t known, the strain was so similar to one last seen in the 1950s that it has been postulated that it was the result of an accidental lab release in China or Russia (see PLoS ONe The Re-Emergence of H1N1 Influenza Virus in 1977 . . . ).  Hence, it was dubbed the `Russian Flu’.

Those over the age of 20 (I made the cut by 3 years), carried some immunity to the old H1N1 virus, but children and adolescents born after 1957 did not, and so they were the most susceptible to infection.  Emergency rooms were slammed, and while the impact was limited and most patients recovered, in some people’s books 1977 qualifies as a `pseudo-pandemic’ year . . . at least for kids.

H1N1’s impact went far beyond just what happened in 1977, for for the first time in our limited knowledge of influenza strains, we ended up having two seasonal influenza A strains in co-circulation; H3N2 and H1N1. Something that previously, had never been observed.

Another, less well remembered event, was the `Liverpool Flu’ of 1951, which for awhile, killed at a greater rate than did the Great Influenza of 1918.

 

For most of the world, 1951 was an average flu year.  The dominant strain of influenza that year was the so-called `Scandinavian strain', which produced mild illness in most of its victims. In fact, if you look at a graph of flu activity for the United States, running from 1945 to 1956, you'll see nary a blip.

 

But in December of 1950 a new strain of virulent influenza appeared in Liverpool, England, and by the end of the flu season, had spread across much of England, Wales, and Canada. This from an absolutely fascinating EID Journal article: Viboud C, Tam T, Fleming D, Miller MA, Simonsen L. 1951 influenza epidemic, England and Wales, Canada, and the United States.

 

The 1951 influenza epidemic (A/H1N1) caused an unusually high death toll in England; in particular, weekly deaths in Liverpool even surpassed those of the 1918 pandemic. . . . . Why this epidemic was so severe in some areas but not others remains unknown and highlights major gaps in our understanding of interpandemic influenza.

 

According to this study, the effects on the city of origin, Liverpool, were horrendous.

 

In Liverpool, where the epidemic was said to originate, it was "the cause of the highest weekly death toll, apart from aerial bombardment, in the city's vital statistics records, since the great cholera epidemic of 1849" (5). This weekly death toll even surpassed that of the 1918 influenza pandemic (Figure 1)

 

This extraordinary graph shows the excess deaths in Liverpool during this outbreak (red line),  while the black line shows the peak deaths during the 1918 pandemic.  This chart shows excess deaths by   A) respiratory causes (pneumonia, influenza and bronchitis) and B) all causes.

 

For roughly 5 weeks Liverpool saw an incredible spike in deaths due to this new influenza.   And it didn’t remain localized.  While it appears not to have spread as easily as the dominant Scandinavian strain, it managed to infect large areas of England, Wales, and Canada over the ensuing months.

 

Getting started relatively late in the flu season, this new strain never managed to spread much beyond UK and Eastern Canada.  Nor did it reappear the next flu season.  It vanished as mysteriously as it appeared.

 

Another example, but one that affected the transmissibility and not the virulence of the seasonal virus, occurred in 1947.  The so-called `vaccine failure’ year, when a new H1N1 virus swept quickly around the world.

 

In 1947 a new variant of the H1N1 virus appeared on military bases – first noticed in Japan – and quickly spread from there. While it produced a generally mild illness there were apparently low levels of immunity in the population (see EID Journal Influenza Pandemics of the 20th Century).  1947 is little remembered today, except by epidemiologists, because while widespread, this new flu strain produced few excess deaths.

.

And then there were the epidemics that might have been – but that for reasons unknown – didn’t happen.

 

In early 1976, after an absence of nearly two decades, a never-before-seen strain of H1N1 swine flu appeared at Ft. Dix, New Jersey – prompting a national emergency response for its expected return in the fall.  While that failed to happen (see Deja Flu, All Over Again), the following year we were blindsided by the `Russian’ H1N1 flu described above.

Why the 1976 H1N1 Swine flu fizzled out remains a mystery.

 

As we go into each year’s flu season, we are always presented with a  `Forrest Gump’ moment. We never quite know what we are going to get.

 

But we do know that even in a non-pandemic year, we can see tens of thousands of American lives lost due to influenza. Globally, we are talking hundreds of thousands. And that a season can start off mild and unassuming (like 1950) and end up as a raging epidemic. 

 

We also know that a flu season can affect different parts of the world differently.  We may very well see an H3N2-centric flu season this year in North America, but in Europe or Asia, they could easily see H1N1 instead.

 

While every year is a question mark, this year we have a number of additional variables at play. The first comes from the rise in the number of antigenically diverse H3N2 clades being reported around the world (see ECDC: Influenza Characterization – Sept 2014). 

 

Since this fall’s vaccine strains were selected last February, the `balance of power’ among flu H3N2 flu strains has begun to shift, and the H3N2 component for next year’s Southern Hemisphere flu shot has already been changed to meet the challenge of an emerging A/Switzerland/9715293/2013 (H3N2)-like virus. 

Complicating matters, last week it was announced that last year’s LAIV (Live Attenuated Influenza Vaccine)  –  aka FluMist nasal spray vaccine – was not effective against the H1N1(pdm) virus in children aged 2-8, and that it is likely to be ineffective this year as well.

 

And if all of this isn’t enough uncertainty, this year we are watching more novel flu strains than ever before;  H7N9, H5N1, H5N6, H5N2, H5N8, H5N3, H9N2 and H10N8 just to mention the biggest concerns.  You’ll find an excellent overview of these emerging avian flu threats in this weeks’ FAO-EMPRES Report On The Emergence And Threat Of H5N6.

 

As I’ve written here often , flu vaccines are considered very safe – and most years provide a moderate level of protection against influenza. While there are some questions regarding this year’s vaccine `match’ with circulating strains, some protection beats no protection any day of the week.

 

While the vaccine can’t promise 100% protection, it – along with practicing good flu hygiene (washing hands, covering coughs, & staying home if sick) – remains your best strategy for avoiding the flu (and other viruses) this winter.

 

Meanwhile, we have what is shaping up to be a fascinating year for studying all types of flu viruses.