CDC: Updated Interim Guidance On Handling & Treatment Of Novel Flu Infections

Photo Credit – Wikipedia

 

 

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Although HPAI H7N9 and HPAI H5N1 human infections remain almost exclusively an Asian or Middle Eastern problem, the potential for seeing an imported case (as we already have with two H7N9 & 1 H5N1 cases in Canada) certainly exists, as does the possibility of infection by one of the recently arrived (and reassorted) HPAI H5 viruses in North America.

This winter’s unprecedented H5N1 outbreak in Egypt, in particular, raises the risks of seeing cases here, and so the CDC has released new, updated (Interim) guidance on the handling of patients (and their contacts) who may have been exposed to, or infected by, novel influenza A viruses.

 

These new guidance documents essentially consolidate, and update, earlier individual guidance documents for the handling of H5N1 and H7N9 (see H7N9: Updated CDC Guidance For Antiviral Treatment and CDC Interim Guidance On Antiviral Chemoprophylaxis For Persons With Exposure To Avian Flu).

 

Wth the rapid expansion of novel avian flu types over the past two years it has become unwieldy and counter productive to maintain separate guidance documents for each subtype, when the advice is essentially the same across the board.

 

As these are long and detailed documents, I’ve only posted the links and the opening section of each. Clinicians will want to follow the links to read them in their entirety.

 

 

Interim Guidance on the Use of Antiviral Medications for Treatment of Human Infections with Novel Influenza A Viruses Associated with Severe Human Disease

Summary

This document provides guidance for antiviral treatment of human infection with novel influenza A viruses associated with severe human disease; these viruses currently include influenza A (H7N9) virus and highly pathogenic avian influenza A (H5N1) virus.¹

This guidance merges and replaces the previously posted guidance on the use of antiviral agents for treatment of human infections with avian influenza A (H7N9) and avian influenza A (H5N1). This antiviral treatment guidance is consistent with current CDC and World Health Organization (WHO) recommendations, and provides updated recommendations for treatment of novel influenza A infections associated with severe human disease in the United States.

This guidance reflects recently updated novel influenza A case definitions (see H7N9 case definitions and H5N1 case definitions).This guidance recommends antiviral treatment as soon as possible for all hospitalized cases of human infection with novel influenza A viruses associated with severe human disease, and for confirmed and probable outpatient cases.² Outpatient cases under investigation who have had recent close contact with a confirmed or probable case of human infection with a novel influenza A virus that can cause severe disease should receive antiviral treatment, whereas outpatient cases under investigation meeting only the travel exposure criteria for a case under investigation are not recommended to receive antiviral treatment. (For guidance on investigation of close contacts of confirmed or probable cases, see Interim Guidance on Follow-up of Close Contacts of Persons Infected with Novel Influenza A Viruses Associated with Severe Human Disease and the Use of Antiviral Medications for Chemoprophylaxis.)

These recommendations are based on expert opinion and available published and unpublished data on the treatment of infection caused by influenza viruses, including seasonal, pandemic, and novel viruses. This guidance will continue to be updated as additional information on virus transmissibility, epidemiology, and antiviral susceptibility patterns becomes available for novel influenza A viruses that cause severe disease.

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Interim Guidance on Follow-up of Close Contacts of Persons Infected with Novel Influenza A Viruses Associated with Severe Human Disease and on the Use of Antiviral Medications for Chemoprophylaxis

This document provides guidance for follow-up and antiviral chemoprophylaxis of close contacts of cases of human infection with novel influenza A viruses associated with severe human disease, which currently includes avian influenza A (H7N9) virus and highly pathogenic avian influenza A (H5N1) virus.¹ This guidance merges previously posted guidance on the use of antiviral agents for chemoprophylaxis of human infections with avian influenza A (H7N9) and avian influenza A (H5N1).

This interim guidance is based on expert opinion and currently available published and unpublished data for antiviral treatment and chemoprophylaxis of seasonal, pandemic, and novel influenza. These recommendations are based on the following considerations:

• Novel influenza A viruses have caused severe human disease and substantial mortality among detected cases to date.
• Limited, non-sustained human-to-human transmission cannot be excluded in some case clusters.
• Sufficient supplies of antiviral agents that are expected to be effective against novel influenza A viruses are available.

The public health goal of this interim guidance is to prevent further spread of novel influenza A viruses associated with severe human disease if there is introduction/travel of infected persons into the United States. It is specific to a scenario where there are sporadic cases associated with poultry exposure and possible limited, non-sustained human-to-human virus transmission.

This guidance will be updated as additional information on epidemiology and transmissibility becomes available for novel influenza A viruses causing severe human disease.

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CDC Interim Guidance For Testing For Novel Flu

 

Credit NIAID 

 

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While the risk to the public remains low, the importation this month of two cases of H7N9 into Canada from China, the ongoing outbreak of H5N1 in Egypt, and the recent introduction of HPAI H5 viruses via wild and migratory birds into North America are all reasons why doctors around the country need to be aware of the potential for seeing novel flu cases.

The HPAI H5 viruses currently circulating in North America have not been associated with human infection - but they are related to H5 viruses that have - and so they are deserving of extra scrutiny and vigilance.  

Last night the CDC published extensive interim guidelines on the handling of suspected novel flu patients for clinicians and public health entities, excerpts of which I’ve posted below:  They also published Interim Guidance on Influenza Antiviral Chemoprophylaxis of Persons Exposed to Birds with Avian Flu, which I will cover in my next blog.

 

 

Interim Guidance on Testing, Specimen Collection, and Processing for Patients with Suspected Infection with Novel Influenza A Viruses with the Potential to Cause Severe Disease in Humans

On this Page

• Background and Purpose
• Recommendations for Surveillance, Testing, and Investigation
• When Specimens Should Be Collected
• Infection Control when Collecting Specimens
• Preferred Respiratory Specimens
• Swabs
• Storing Clinical Specimens
• Shipping Clinical Specimens to State Public Health Laboratories
• Diagnostic Testing
• Testing at State Health Departments
• Antiviral Treatment
• Shipping Clinical Specimens to CDC

Background and Purpose

This document provides interim guidance for clinicians and public health professionals in the United States on appropriate testing, specimen collection and processing for patients who may be infected with novel influenza A viruses with the potential to cause severe illness in people. Examples of such viruses include Asian-lineage avian influenza A (H5N2), (H5N8), and (H5N1)¹ viruses, which were detected in wild and domestic birds in North America in December 2014 and January 2015; these viruses may have some or all of their genes from Asian avian influenza viruses, but for simplicity will all be referred to as “newly detected avian influenza A H5” viruses in this guidance document. Other newly detected avian influenza A H5 viruses also may have the potential to cause severe disease in humans. For a list of avian influenza A H5 virus infections identified in birds in the United States, and their locations, please see an update on avian influenza findings maintained by the US Department of Agriculture. CDC will update this guidance as additional information becomes available.

The appearance of newly detected avian influenza A H5 viruses in North America may increase the likelihood of human infection with these viruses in the United States. Because these newly identified avian influenza A H5 viruses are related to avian influenza A viruses associated with severe disease in humans (e.g., highly pathogenic Asian-lineage avian influenza A (H5N1) virus), they should be regarded as having the potential to cause severe disease in humans until shown otherwise. Other CDC guidance provides recommendations for influenza viruses known to be associated with severe disease in humans.

¹ The H5N1 virus isolated in the United States in January 2015 is a new mixed-origin virus (a “reassortant”) that is genetically different from the H5N1 virus found in several other countries (notably in Asia and Africa), which has caused human infections with high mortality. Although it is related to the H5N1 virus that has caused human infections with high mortality, the ability of this new reassortant H5N1 virus to cause severe disease is currently unknown.

Recommendations for Surveillance, Testing, and Investigation

Clinicians and public health personnel should consider the following recommendations for surveillance and testing:

1. Consider the possibility of infection with novel influenza A viruses with the potential to cause severe disease in humans in patients with medically-attended influenza-like illness (ILI) and acute respiratory infection (ARI) who have had recent contact¹ (<10 days prior to illness onset) with sick or dead birds in any of the following categories²:
   1. Domestic poultry (e.g., chickens, turkeys, ducks)
   2. Wild aquatic birds (e.g., ducks, geese, swans)
   3. Captive birds of prey (e.g., falcons) that have had contact with wild aquatic birds
2. If infection with a novel influenza A virus with the potential to cause severe disease in humans is possible, respiratory specimens should be collected with appropriate infection control precautions and sent to the state or local health department for immediate testing (see guidance below).
3. If infection with a novel influenza A virus with the potential to cause severe disease in humans is suspected, state health departments are encouraged to initiate a public health investigation with animal health partners and should notify CDC promptly.

¹ Contact may include: direct contact with birds (e.g., handling, slaughtering, defeathering, butchering, preparation for consumption); or direct contact with surfaces contaminated with feces or bird parts (carcasses, internal organs, etc.); or prolonged exposure to birds in a confined space.

² For questions or concerns about possible human infection in patients with exposures to birds not listed here, please contact CDC. Exposures that occur in geographic regions in the United States where newly detected avian influenza A H5 viruses have been identified are of most concern.

When Specimens Should Be Collected

The duration of shedding of novel influenza A viruses in humans is largely unknown, and there are currently limited data describing prolonged shedding of people infected with these viruses. Therefore, the estimated duration of viral shedding is based upon seasonal influenza virus infection. Specimens should be obtained for novel influenza A virus testing as soon as possible after illness onset, ideally within 7 days of illness onset. However, as some persons who are infected with seasonal influenza viruses are known to shed virus for longer periods (e.g., children and immunocompromised persons), specimens should be tested for novel influenza A virus even if obtained after 7 days from illness onset. Note that prolonged shedding of influenza virus in the lower respiratory tract has been documented for critically ill patients with highly-pathogenic avian influenza A H5N1 virus and avian influenza A H7N9 virus infections.

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The Lancet: H9N2’s Role In Evolution Of Novel Avian Influenzas

Schematic Diagram of Novel A(H7N9) Generation- Credit Eurosurveillance

 

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The three novel avian flu strains that currently worry scientists the most – H5N1, H7N9, and the recently observed H10N8 – all share several important features,  which we’ve discussed previously.

 

1. They all first appear to emanate from Mainland China
2. They all appear to have come about through viral reassortment in poultry
3. And most telling of all, while their HA and NA genes differ - they all carry the internal genes from the avian H9N2 virus

 

The avian H9N2 virus – unlike the H5 and H7 avian viruses – is not considered a `reportable’ disease by the OIE since it is viewed as a relatively stable LPAI (Low Pathogenic Avian Influenza), not prone to evolving into a more dangerous HPAI form.  It is, however:

 

1. Believed ubiquitous across much of Asia’s poultry population
2. Has occasionally infected humans (see Hong Kong: Isolation & Treatment Of An H9N2 Patient)
3. And is viewed as having at least some `pandemic potential’ (see H9N2: The Other Bird Flu Threat)

 

As the diagram at the top of this blog shows, the H7N9 virus is a combination (reassortment) of several different avian flu viruses – with six of its eight genes contributed by the H9N2 virus ( shown in green).  An evolutionary pathway similar to that followed by the H5N1 virus in the mid-1990s, and the recently emerging H10N8 virus in China.

Although categorized by their two surface proteins (HA & NA) Influenza A viruses have 8 gene segments (PB2, PB1, PA, HA, NP, NA, M1, M2, NS1, NS2).

Shift, or reassortment, happens when two different influenza viruses co-infect the same host swap genetic material.  New hybrid viruses may be the result of multiple reassortments, with gene contributions coming from several parental viruses.

 

In the past, we’ve looked at the propensity of the H9N2 virus to reassort with other avian flu viruses (see PNAS: Reassortment Of H1N1 And H9N2 Avian viruses &  PNAS: Reassortment Potential Of Avian H9N2) which have shown the H9N2 capable of producing `biologically fit’ and highly pathogenic reassortant viruses.

 

In 2010 (see Study: The Continuing Evolution Of Avian H9N2) we looked at computer modeling (in silica) that warned the H9N2 virus has been slowly evolving towards becoming a `more humanized’ virus.

 

All of which serves as prelude to a brief report appearing today in The Lancet, where Chinese researchers warn of the threat posed by the H9N2 virus, and call for prompt and bold action to prevent the `next pandemic virus’ from emerging from China’s poultry industry. 

 

The report is a short one, well worth reading,  and quite to the point. I’ve  only excerpted its conclusions (bolding mine).  Follow the link below to read it in its entirety.

 

 

Poultry carrying H9N2 act as incubators for novel human avian influenza viruses

Di Liu a, Weifeng Shi b, George F Gao a c 

(EXCERPT)

Although the contribution of H9N2 genes to infection in human beings needs to be determined, these genes probably enable H7N9 virus to survive and be transmitted within poultry, because dynamic reassortments of H7N9 with H9N2 genes have been observed,5 suggesting that H7N9 virus evolved in poultry to become a virus that infects human beings. Hence, reassortment between the prevalent poultry H9N2 viruses (providing genetic segments) and the influenza virus from wild birds could make the influenza evolve to adapt to domestic hosts. Poultry, especially in live markets, would have a pivotal role during the emergence of a novel influenza virus of avian origin.

 

Several subtypes of avian influenza viruses in poultry are capable of infecting human beings, and the next avian influenza virus that could cause mass infections is not known. Therefore, slaughter of poultry carrying H9N2—the incubators for wild-bird-origin influenza viruses—would be an effective strategy to prevent human beings from becoming infected with avian influenza.

 

We call for either a shutdown of live poultry markets or periodic thorough disinfections of these markets in China and any other regions with live poultry markets.

 

The shutdown of live poultry markets has been a stated goal by Chinese authorities for many years due to the H5N1 threat, but thus far, only limited (and usually temporary) shutdowns have been orchestrated. Despite pretty good evidence that the shutdown of live markets last spring helped quell China’s H7N9 outbreak (see The Lancet: Poultry Market Closure Effect On H7N9 Transmission), there remains strong public pressure to keep them open.

 

Even more problematic is their call to cull H9N2 infected chickens.  

 

As most infected poultry are asymptomatic, it would require extensive (and expensive) surveillance and testing just to identify these birds. And of course, given the likely incidence of the virus in Asian poultry,  the economic losses would be substantial. 

 

At least in China, the MOA (Ministry of Agriculture’s) policy has seemed to revolve around deflecting concerns over avian flu in their poultry supply, rather than addressing it in an organized and substantive manner (see  China’s MOA Disputes Poultry As Source Of H7N9 Infections). 

As we saw last year in  EID Journal: Predicting Hotspots for Influenza Virus Reassortment, China ranks as one of the globe’s top breeding grounds for new flu strains. Which makes the control of these emerging viruses in all the more important. 

 

For more on reassortment risks, you may wish to revisit:

 

Eurosurveillance:The Evolving Threat From New, Reassorted H7N9 Viruses

Lancet: Clinical & Epidemiological Characteristics Of A Fatal H10N8 Case

Viral Reassortants: Rocking The Cradle Of Influenza

Hong Kong Broadens Statutorily Notifiable Flu Definitions

 

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Amid the ever-expanding alphabet soup of novel flu combinations showing up in Asia, and around the world (think H5N1, H7N9, H10N8, H9N2, H7N7, H6N1 . . . the list goes on . . .) Hong Kong today has broadened their definition of what constitutes a `statutorily notifiable’ influenza.

In addition to scheduling the recently emerged H10N8 virus as a notifiable infection, the new regulation adds a generic "Novel influenza A infection" to include all subtypes of novel influenza infections in humans, regardless of whether it has been previously placed on the schedule.

According to well respected anthropologist and researcher George Armelagos of Emory University, we are entering the age of emerging and re-emerging infectious diseases, something he calls The Third Epidemiological Transition. As we saw yesterday, in The Global Reach Of Infectious Disease, this is a trend that public health agencies around the globe take very seriously.

 

As a result, public health agencies, and the regulations they work under, must become more nimble and proactive if these threats are to be contained. The following announcement comes from Hong Kong’s CHP.

 

Statutory notification of Novel influenza A infection

A spokesman for the Centre for Health Protection (CHP) of the Department of Health said today (February 17) that the Government will amend the Prevention and Control of Disease Ordinance (Cap 599) (the Ordinance) and its subsidiary legislation, the Prevention and Control of Disease Regulation (Cap 599A) (the Regulation), to include Novel influenza A infection as one of the statutorily notifiable diseases and specified diseases, and add influenza virus type A (subtype H10) as one of the scheduled infectious agents.

"Apart from the influenza viruses which can circulate among humans and cause seasonal influenza, many other influenza A viruses are found in birds and other animal species. Some of these animal viruses may, however, occasionally infect humans, causing disease ranging from mild conjunctivitis to severe pneumonia and even death. These are known as novel influenza viruses, against which the human population has low or no immunity," the spokesman explained.

Given the potentially unpredictable behaviour of novel influenza viruses and the fact that the majority of the population has no immunity against these viruses, vigilance and close monitoring is needed for Novel influenza A infection.

It is also foreseen that with frequent international travel, more imported human cases of Novel influenza A infections, such as influenza A (H6N1) or influenza A (H10N8) or other subtypes, may occur in Hong Kong, besides the five imported sporadic influenza A (H7N9) human infections detected so far locally.

Against this background, the Government has used the name "Novel influenza A infection" to include all subtypes of novel influenza infections in humans as a notifiable disease. The Government has also added subtype H10 to the various influenza virus type A as one of the scheduled infection agents, as human cases of influenza A (H10) infection detected so far have resulted in severe infection.

According to the amendments, "Influenza A (H2), Variant Influenza A (H3N2), Influenza A (H5), Influenza A (H7), Influenza A (H9)" will be repealed from the list of infectious diseases and replaced by "Novel influenza A infection" in Schedule 1 to the Ordinance; whereas "Influenza virus type A (subtype H2, H5 and H7)" will be repealed from the list of infectious agents and replaced by "Influenza virus type A (subtype H2, H5, H7 and H10)" in Schedule 2 to the Ordinance. Additionally, "Influenza A (H2), Influenza A (H5), Influenza A (H7), Influenza A (H9) or Swine Influenza" will be repealed from the list of specified diseases and replaced by "Novel influenza A infection" in Section 56 of the Regulation.

"The legislative amendments will be gazetted on February 21 with immediate effect. The amendments will make Hong Kong better prepared against the disease by facilitating early disease detection and implementation of appropriate public health measures if they are called for, depending on public health risk assessment," the spokesman said.

Medical practitioners are reminded to stay alert on cases of Novel influenza A infection and are required by law to notify the Director of Health of any suspected cases. Persons in charge of a laboratory are required to notify leakage of these viruses in the laboratory that may pose a public health risk.

"The CHP will issue letters to doctors and the medical laboratory sector to inform them of the relevant legislative amendments and the revised reporting criteria,"the spokesman said.

"In Hong Kong, the CHP has a sensitive laboratory surveillance system for influenza virus. The CHP conducts characterisation of all influenza virus isolates including antigenic and genetic analysis. Upon detection of any such cases, the CHP will conduct epidemiological investigation, contact tracing and other necessary control measures, to ascertain and contain the extent of transmission of infection," he said.

The spokesman reminded members of the public to observe good personal and environmental hygiene at all times to prevent influenza.

Ends/Monday, February 17, 2014
Issued at HKT 19:29
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The Expanding Array Of Novel Flu Strains

Photo Credit NIAID

 

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Not so very long ago, if someone spoke of `bird flu’, the understanding was they were talking about the H5N1 virus, which first appeared in Hong Kong in the mid-1990s.  Sure, there were other avian influenza viruses – mostly low pathogenic (LPAI) varieties – that usually resided quietly in wild birds and waterfowl. 

 

But H5N1, while only rarely jumping to humans, carried with it a staggering mortality rate (60% among known cases), and was considered the one to watch.

 

Along the way, we saw warning signs that other avian viruses might pose a threat, however.   In 2007, in It Isn't Just Bird Flu,  I wrote:

 

Other influenza viruses with pandemic potential exist out there, among them are H9N2, which infected two children in Hong Kong in 1999 and another in 2003, H7N7 which infected 89 people (1 death) in the Netherlands in 2003, and H10N7 which infected two infants in Egypt in 2004. 

Beyond Influenza we also watch for SARS, which broke out of China in 2003, and infected 8000 people worldwide, killing roughly 800.  SARS wasn't as easily transmitted as influenza, but it does have pandemic potential.  

 

Since then, the list of novel flu viruses that could  pose a public health threat has grown significantly, partly due to an increase in new reassortants, and partially due (I’m sure) to our ability to better detect new viruses.

 

Influenza A subtypes are categorized by two proteins they carry on their surface; their HA (hemagglutinin) and NA (neuraminidase). There are 17 known HA proteins, and 10 known NAs, making many different subtype combinations possible, although only a few are known to infect humans.

 

We also see variations within individual strains due to antigenic drift, which comes about when errors are made in the replication of the virus.  Over a period of a few hours, millions of copies of a virus can be produced in a single host, and invariably some of these copies are `flawed’, and contain amino acid substitutions somewhere in the virus’s genetic code.

 

Most of the time, these changes either do nothing, or make the virus less viable.  With millions of copies being generated, a few `duds’ hardly makes a difference to the virus, or the host.

 

But every once in awhile, out of millions of failures, a more biologically `fit’ virus will emerge.  One that replicates better than either its parents or its siblings - and if it is also easily transmissible - it can take off as a new, emerging variant or (if it is genetically distinct enough) as a new clade. 

 

And indeed, the  H5N1 virus continues to produce new clades, and variations within those clades. The result that we are not just looking at one H5N1 virus in circulation, but dozens – each on its own evolutionary journey.

 

Since the H5N1 virus was first identified in 1996 it has expanded into more than 20 different clades and subclades, and various versions of the virus now circulate in different parts of the world (see Differences In Virulence Between Closely Related H5N1 Strains).  You can see the evolution of the virus through 2011 in the chart below.

NOTE: Not all of these clades continue to circulate.

 

There are other H5 avian viruses of concern, including H5N2, H5N3, and the recently emerged H5N8 virus in Korea, which – for now, at least – only appears to infect poultry and wild birds.

  
Just about a year ago, the H7N9 virus appeared in China (although we did not learn of it until March 31st, 2013), a reassorted avian virus that owed much of its internal gene structure to the H9N2 virus.  Since then, it has spread across eastern China, and jumped to humans, at a remarkable rate.

 

Reassorted viruses come about when a host (bird, swine, human, etc) is infected with two different influenza viruses that swap genes and produce a biologically fit hybrid.

 

 

 

This process is called Antigenic Shift, and it can result in an abrupt change in the behavior of a virus.  While rare, as every virologist will tell you, Shift Happens.

 

This week alone we’ve seen published articles warning on the pandemic potential of the H10N8 virus, and a group of H6 avian viruses.  

 

On Wednesday, in Lancet: Clinical & Epidemiological Characteristics Of A Fatal H10N8 Case, we looked at a report on the first known human infection with this novel avian virus, where the authors cautioned, `The pandemic potential of this novel virus should not be underestimated.’

 

And yesterday, the Journal of Virology ran a report called H6 influenza viruses pose a potential threat to human health, issuing similar warnings.   CIDRAP NEWS summarized their findings last night in:

 

Study shows H6 avian flu may bind well to human cells

About a third of H6 avian flu strains tested were able to recognize human-type receptors, a sign that they may pose a threat to human health, according to a study yesterday in the Journal of Virology. The study also found that the strain replicated well in mouse lungs and transmitted fairly well among guinea pigs.

Chinese, Thai, and Japanese researchers, including Yoshihiro Kawaoka, DVM, PhD, who also has a lab at the University of Wisconsin, tested H6 viruses isolated from live-poultry markets in southern China from 2008 through 2011.

They found that, of 257 H6 strains tested, 87 (34%) recognized human-type receptors. Sequencing of 38 representative viruses revealed 30 different genotypes, "indicating that these viruses are actively circulating and reassorting in nature," the researchers wrote.

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And indeed, last May in Taiwan CDC Reports Human Infection With Avian H6N1, we saw the first known H6 human infection. 

 

So far, H10N8 and H6N1 have a minuscule track record when it comes to infecting humans, and so it is very difficult to gauge their true potential, particularly when you compare them to H7N9 and H5N1, which have infected hundreds of people.

Still, they bear watching.

 

Added to this rogues gallery of viral contenders, in the past year or so we’ve also looked at such unusual flu stories as:

 

Hong Kong: Isolation & Treatment Of An H9N2 Patient

China: Avian-Origin Canine H3N2 Prevalence In Farmed Dogs

mBio: A Mammalian Adapted H3N8 In Seals

PLoS Pathogens: New World Bats Harbor Diverse Flu Strains

 

And this is just a partial list, and doesn’t even touch on the swine varieties of influenza, or the constant evolution of seasonal flu strains.

While I can’t predict what any of these influenza viruses will do, it’s a pretty safe bet that we’re going to see more unusual flu viruses emerge over the next few years.

Admittedly, most will probably only pose a limited threat to humans.

 

But their emergence should inspire governments, agencies, businesses, organizations, and communities to dust off, update, and test their pandemic preparedness plans (see DNI: An Influenza Pandemic As A National Security Threat & Pandemic Preparedness: Taking Our Cue From The Experts).

 

Because, honestly,  it only takes one of these viruses to turn pandemic to ruin your entire day.

Taiwan CDC: Epidemiological Analysis Of Human H6N1 Infection

 

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Early in June of this year (see Taiwan CDC Reports Human Infection With Avian H6N1) we learned of the first known human infection with the avian H6N1 strain of influenza.  The patient was a 20-year-old female, diagnosed in May of this year, no doubt  picked up because of the heightened surveillance for H7N9 in Taiwan. 

Today, Taiwan’s CDC published an epidemiological analysis of that case in The Lancet Respiratory Medicine, which highlights the need to be prepared for known novel influenza threats (like H5N1, H7N9, H3N2v), but also for something emerging from out of left field (which is exactly what happened with the swine-origin H1N1 pandemic virus of 2009).

First a link and a short except from the Abstract, followed by the press release from Taiwan’s CDC.

 

Human infection with avian influenza A H6N1 virus: an epidemiological analysis

Sung-Hsi Wei*, Ji-Rong Yang*, Ho-Sheng Wu*, Ming-Chuan Chang*, Jen-Shiou Lin, Chi-Yung Lin, Yu-Lun Liu, Yi-Chun Lo, Chin-Hui Yang, Jen-Hsiang Chuang, Min-Cheng Lin, Wen-Chen Chung, Chia-Hung Liao, Min-Shiuh Lee, Wan-Ting Huang, Pei-Jung Chen, Ming-Tsan Liu, Feng-Yee Chang

Summary

(Excerpts)

Interpretation This is the first report of human infection with a wild avian influenza A H6N1 virus. A unique clade of H6N1 viruses with a G228S substitution of haemagglutinin have circulated persistently in poultry in Taiwan. These viruses continue to evolve and accumulate changes, increasing the potential risk of human-to-human transmission. Our report highlights the continuous need for preparedness for a pandemic of unpredictable and complex avian influenza

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Press Releases

Article describing world’s first case of human infection with avian influenza A(H6N1) virus confirmed in Taiwan to be published in international medical journal ( 2013-11-14 )

 

The Taiwan Centers for Disease Control (Taiwan CDC) announced an article describing the world’s first case of human infection with avian influenza A (H6N1) virus confirmed in Taiwan in June, 2013 had been submitted to The Lancet Respiratory Medicine by scientists working at Taiwan CDC. At the time of writing, this article has been accepted and will be published in the journal on November 14, 2013.

A genetic analysis of the avian influenza A (H6N1) virus isolated from this case shows that the virus is closest to that from poultry in Taiwan, suggesting that this virus originates from poultry in Taiwan. Notably, the virus had a G228S substitution in the haemagglutinin (HA) protein that might increase its ability to infect human cells. In addition, based on the sequences of the NA protein, the virus is susceptible to neuraminidase (NA) –inhibitors such as Oseltamivir and Relenza.

Taiwan CDC further explained that the case’s condition improved after administering antivirals and the case fully recovered after appropriate medical treatment.  Among the 36 close contacts of the case, none has been found to be infected with avian influenza A (H6N1) virus. Moreover, Taiwan CDC conducted enhanced influenza surveillance in patients that visit the 3 hospitals and 7 clinics located within the 8-km radius of the case’s residence for three months. A cumulative total of 178 influenza-like illness (ILI) specimens have been tested through this surveillance and none has been tested positive for avian influenza A (H6N1) virus. On the other hand, thus far in 2013, the contracted virology laboratories in the nation have tested a cumulative total of 6,985 respiratory specimens collected from the community and none has been tested positive for avian influenza A (H6N1) virus. Based on the results of the epidemiological investigation, the case presenting mild pneumonia is a sporadic case and testing of the close contacts of the case has not yielded any evidence of human-to-human transmission of this virus in the community. Both the health and agricultural authorities will continue to reinforce avian influenza surveillance in humans, poultry and the environment.

Taiwan CDC points out that avian influenza A (H6N1) virus is commonly found in poultry. No avian influenza A (H6N1) virus had been detected in humans till the world’s first case was confirmed in Taiwan.  To prevent avian-to-human transmission of avian influenza infections, Taiwan CDC advises poultry vendors to take relevant personal precautions and the general public to avoid unnecessary direct contact with poultry and birds or their droppings.  In addition, the public is also advised to practice good personal hygiene such as washing hands frequently and consuming only thoroughly cooked poultry and eggs to reduce the risk of infection.  If influenza-like illness symptoms or conjunctivitis develop, please put on a surgical mask, seek immediate medical attention and inform your doctor of your exposure history to birds/poultry, job contents and travel history. 

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Novel Viruses & Chekhov’s Gun

 

 

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Although the attribution is suspect, there is an old adage in literary circles – credited most often to Russian playwright Anton Chekhov – that if you show a gun hanging on the wall in the first act, it absolutely must go off by the third.

 

It is such a well used device, that I suspect it leads many people to believe we are on the brink of a pandemic every time a novel influenza virus is reported in humans.

 

Fortunately, emerging infectious diseases are not compelled to follow the dictums of modern literary convention. New flu viruses are constantly cropping up in humans, but only rarely do they portend a pandemic.

With headlines last month on a novel H3N8 `Seal flu’ with supposed pandemic potential, and several small clusters of H3N2v swine flu infections in the Midwest over the past few weeks, today seemed like a good day take a historical look at a few viral contenders that tried, and failed, to spark a pandemic.

Novel flu viruses are most likely to be zoonotic; jumping from another animal species to man, either directly, or through an intermediary host, or via reassortment. 

Over the past 100 years, we’ve seen four of these viral jumps spark a pandemic. The H1N1 pandemic of 1918, the H2N2 pandemic of 1957, H3N2 in 1968, and novel H1N1 in 2009.

But interspersed among these global pandemics have been numerous novel viruses that have infected humans and yet ultimately failed to produce a pandemic.

 

The most obvious example is the H5N1 virus, which first appeared 15 years ago in Hong Kong - and after a 5 year hiatus - returned in 2003.

 

Since that time has infected more than 600 people.

 

Yet despite morphing into more than 20 distinct clades, and spreading from Asia to Europe and the Middle East, this virus remains poorly adapted to human physiology and has (thus far) proved incapable of sparking a pandemic.

 

The caveat being, that this could change.

 

H5N1, like all flu viruses, is constantly evolving.  As long as it is out there, it poses a potential pandemic threat.

Similarly, we’ve seen scattered human infections by the H9N2 avian virus, and sporadic attempts by various strains of the H7 avian virus to jump to man.

 

• In 2003 an outbreak of H7N7 at a poultry farm in the Netherlands went on to infect at least 89 people. Most of the victims were only mildly affected, but one person died.
• In 2004 two people in British Columbia tested positive for H7N3 (see Health Canada Report) during an outbreak that resulted in the culling of 19 million birds.
• In 2006 and 2007 there were a small number of human infections in Great Britain caused by H7N3 (n=1)  and H7N2 (n=4), again producing mild symptoms.

 

But beyond these avian strains, we’ve seen human adapted flu viruses that have threatened – but ultimately failed – to spark a pandemic.

 

The first example comes from shortly after the end of WWII with what would become known as the `pseudo-pandemic’ or vaccine failure of 1947.

 

Fearing that crowded ships and barracks could give rise to a reprise of the 1918 pandemic, the United States Military  commissioned Dr. Thomas Francis of the University of Michigan and his protégé Jonas Salk to come up with a viable influenza vaccine in 1943.

 

Within a year a vaccine based on the 1934 and 1943 flu strains was in wide use in the military, and for several years the Francis/Salk vaccine worked well.

 

But in 1947, a new variant of the H1N1 virus appeared on military bases in Japan,and quickly spread from there infecting hundreds of millions around the globe (see 2002 PNAS article).

 

While it produced a generally mild illness, and few excess deaths, this new strain apparently had drifted enough antigenically to evade both the vaccine and community immunity acquired from earlier strains.

 

Had it been more virulent, the 1947 flu virus might well have been considered a pandemic.  Today it is barely remembered, except by virologists.

 

Four years later, a far more ominous flu strain made a brief appearance during the 1950-51 flu season.

 

For about six weeks, a highly virulent influenza erupted in Liverpool, England and then spread across the UK and to Eastern Canada.

 

For a time, it was as deadly as the 1918 pandemic.

This startling graphic comes from the March 16th, 1951 Proceedings of The Royal Society of Medicine – page 19 – and shows in detail the tremendous spike in influenza deaths in early 1951 over the (admittedly, unusually mild) 1948 flu season. 

 

The CDC's EID Journal  has a stellar account of this 1951 event, and is very much worth reading.

 

Viboud C, Tam T, Fleming D, Miller MA, Simonsen L. 1951 influenza epidemic, England and Wales, Canada, and the United States. Emerg Infect Dis [serial on the Internet]. 2006 Apr [date cited].

 

Despite its virulence, and obvious ability to spread efficiently from human-to-human, this virus died out as suddenly and mysteriously as it appeared.  

 

It remains a medical mystery.

 

Fast forward to  February 1976, and a young recruit at Ft. Dix, New Jersey fell ill and died from a virus that was later isolated and dubbed A/New Jersey/76 (Hsw1N1).

 

This swine-flu virus went on to infect more than 200 soldiers on the base, and caused severe respiratory disease in 13 of them. How and why it appeared in New Jersey remains unknown.

 

While the death rate was very low, this virus appeared to easily transmissible among humans. This led to the swine flu pandemic scare of 1976, which I chronicled several years ago in Deja Flu, All Over Again. 

 

The feared swine flu pandemic never materialized, and for reasons we cannot explain, the virus simply disappeared.

 

In the `close but no cigar’ category,  a year later we did see an epidemic - at least among children - with the return of the H1N1 virus after a 20 year absence. It was dubbed the `Russian Flu’, as it was believed to have escaped from a Russian research laboratory.

 

Given the limits of testing and surveillance, there have most certainly been other failed viruses – of which we are unaware – that simply `flu beneath our radar’. 

 

In recent years we’ve also seen a number of  non-flu viruses, such as the 2003 SARS outbreak, Clusters Of HEV68 Respiratory Infections, and various adenovirus outbreaks, that have produced illness and concerns, but no pandemic.

 

None of this tells us what will become of the H3N2v swine flu virus, or any of the other novel strains that are currently out there. Another pandemic will occur.  We just don’t know when, or from what source.

 

But it does provide some perspective.

 

While all pandemics are caused by novel viruses, not all novel viruses produce pandemics.

 

Emerging viruses deserve our attention and respect, and H3N2v is certainly no exception. In time, this variant virus may prove to be a significant public health threat.

 

But as we watch these myriad novel viruses crop up around the globe, it should provide some solace to remember: history shows us that in the world of emerging infectious diseases . . .

 

. . .  by the time act III comes along – we often find that Chekhov’s gun is loaded with blanks.

WHO Comment: Testing For Novel Flu Viruses

 

 

H3N2 influenza virions –CDC PHIL

# 6019

 

 

The recent detection of a handful of novel swine-origin influenza infections across four US states is a reminder that influenza viruses continue to mix and match and evolve, and that new (and potentially dangerous strains) can appear with little warning.

 

While the CDC states that these S-OIV trH3N2 viruses have yet to demonstrate an ability to spread efficiently among the human population - and therefore don’t currently pose a major public health threat - the concern is that over time they could obtain that capability.

 

So agencies like the CDC, the ECDC, the World Health Organization, and others are encouraging a heightened awareness and vigilance in the testing and reporting on any unusual (or un-subtypable) flu cases.

 

The following notice was posted on the WHO’s influenza page late yesterday (hat tip AlohaOR on the Flu Wiki).

 

 

 

WHO Comment on the importance of global monitoring of variant influenza viruses

19 December 2011

Human infections with variant influenza viruses

Recently, several human infections with variant influenza viruses currently thought to be circulating in swine populations have been reported. To date, epidemiological investigations have not revealed any onward transmission of these viruses outside of small clusters. Avian influenza H5N1 viruses also continue to cause infections in humans exposed to infected birds and contaminated environments especially in countries where the virus is considered endemic in poultry. Thus far, transmission of these variant viruses from animals to humans has only resulted in sporadic human cases or small clusters among close contacts, with no evidence of community level spread. These sporadic human cases and small clusters of human infection with variant influenza viruses are expected and are not considered unusual, and do not change WHO’s current assessment of pandemic risk.

 

However, because influenza viruses are unpredictable, they have the possibility to change and become more transmissible among humans as shown by the emergence of the influenza pandemic H1N1 virus in 2009. For this reason, continued monitoring of the occurrence of human infections with these viruses and characterization of the viruses themselves are critically important to assess their pandemic potential.

 

WHO reminds Member countries that it is an obligation under the International Health Regulations (IHR) to report to WHO all human cases of infection with influenza viruses that are not currently circulating seasonally in human populations (http://www.who.int/ihr/survellance_response/case_definitions/en/index.html), and to conduct epidemiological investigations around each case to identify or rule out any onward human-to-human spread which could indicate emergence of a more transmissible virus. WHO will continue to share information about variant influenza viruses with the international public health community in accordance with WHO's obligations under the IHR.

 

WHO also strongly recommends that all un-subtypable influenza A specimens should be immediately sent for diagnosis and further characterization to specialized laboratories or one of the six WHO Collaborating Centres for Reference & Research on Influenza (http://www.who.int/influenza/resources/documents/diagnostic_recommendations/en/index.html),

This is important for early identification of emerging viruses with the potential to threaten global public health.

 

 

It isn’t just the S-OIV trH3N2 virus that concerns health authorities. The H5N1 bird flu virus, avian H9N2, along with some H7 and H11 strains of avian influenza have all demonstrated some ability to infect humans. 

 

While none have yet managed to adapt well enough to human physiology to spread efficiently, the CDC and public health officials are obviously taking these novel virus detections seriously, and are encouraging enhanced global surveillance to track their evolution and spread.

 

It is too soon to know whether any of these new flu strains will take hold in the human population.

 

As I wrote in Pseudo Pandemics And Viral Interlopers it is certainly possible for new strains of influenza to appear and circulate among humans, without sparking a pandemic.

 

For now, we are in a watchful waiting mode; looking for signs that one of these novel viruses is getting better adapted to human physiology.

 

In the meantime, maintaining good flu hygiene this winter (washing/sanitizing your hands, covering coughs & sneezes, staying home when sick), and getting your seasonal flu shot, remain the best strategies to avoid getting sick during this flu season.

 

Update:  I noted shortly after posting this blog that Helen Branswell of the Canadian Press has an article on this WHO release as well.

 

Keep an eye out for new flu viruses: WHO

12/19/2011  | Helen Branswell, The Canadian Press

CDC Confirms 2 More Novel Flu Infections

 

H3N2 influenza virions –CDC PHIL

# 6001

 

 

The CDC announced today the detection of two new novel flu isolates; one in West Virginia (trH3N2) and another in Minnesota (A/H1N2).

 

The West Virginia virus isolate is described today by the CDC as being:

 

A novel influenza A (H3N2) virus with genes from swine, human, and avian lineages with the M gene from the 2009 H1N1 virus that was first identified in August 2011. Ten prior human infections with this virus in four other states have been confirmed.

 

This virus is distantly related to an H3N2 virus that circulated 20+ years ago, which may explain why those born after 1990 have made up vast majority of cases detected so far.

 

Earlier posts on those cases include:

 

Branswell On The New trH3N2 Flu Virus

CIDRAP: New Details In The trH3N2 Story

ECDC Risk Assessment On trH3N2 Cases In North America

CDC Update On Iowa trH3N2 Cases

 

The Minnesota isolate is an H1N2 virus that has been known to circulate in swine for some time, and is said to be similar to an H1N1 virus (A/New Caledonia /20/99-like) that circulated as recently as 2007.

In neither case did these patients have recent known contact with swine, and so these reports imply that low level human-to-human transmission may have taken place.

 

First stop, a notice in today’s (otherwise quiet) FluView week 48 Report, followed by some choice excerpts from the latest Have You Heard? statement from the CDC.

 

http://www.cdc.gov/flu/weekly/

Novel Influenza A Viruses:

Two human infections with novel influenza A viruses were detected in children from two states (Minnesota and West Virginia). One patient was infected with a novel influenza A (H1N2) virus and one patient was infected with a novel influenza A (H3N2) virus. Both patients have recovered from their illnesses. While both viruses are known to circulate in U.S. swine, there was no close contact with pigs reported preceding illness onset in either case. Both states have been investigating case contacts and sources of exposure, however, no additional confirmed cases have been detected at this time. Additional information on these cases can be found in the CDC Have You Heard posting.

 

CDC is required to report all cases of human infection with novel influenza viruses – including swine influenza viruses -- to the World Health Organization (WHO) as part of the International Health Regulations (IHR). Domestically, CDC reports these cases in this report and on its website. Early identification and investigation of human infections with novel influenza A viruses is critical to evaluate the extent of the outbreak and possible human-to-human transmission. Additional information on influenza in pigs and swine-origin influenza infection in humans can be found at http://www.cdc.gov/flu/swineflu/.

 

Below are some excerpts from today’s announcement (bolding & reparagraphing mine). Follow the link to read it in its entirety.

 

 

CDC confirms two human infections with novel influenza viruses

December 9, 2011 -- CDC has confirmed two cases of human infection with two different novel influenza A viruses in different states. Both patients have fully recovered. While the viruses infecting both patients have been found in U.S. swine and some of the prior human infections with these viruses have been associated with direct or close swine contact, there are no reports of direct or close contact with swine prior to illness onset in either of these cases. Laboratory testing at CDC has confirmed that both novel viruses are susceptible to the antiviral medications oseltamivir (Tamiflu®) and zanamivir (Relenza®).

<SNIP Narrative on 2 New Cases> 

 

Detection of Swine Influenza Infections in Humans

Human infections with novel influenza A viruses normally found in swine are rare events. Recently, however, the frequency of such detections has increased.

 

This could be occurring for a number of reasons, including one or more of the following factors:

 

First, laboratory methods for testing for these viruses in the United States were improved following the 2009 H1N1 pandemic. These improvements may be resulting in viruses being identified now that would have gone undetected previously.

 

Second, this could be due to increased surveillance in the United States for influenza at this time of year. CDC has requested that states analyze, and then send, their first influenza virus specimens of the season for seasonal influenza surveillance purposes. This practice, coupled with very low levels of seasonal flu activity at this time, could mean that sporadic novel influenza infections are more likely to be tested.

 

Third, it is possible that the increased frequency of detection of novel influenza viruses with swine origins identified by CDC represents a true increase in the number of such cases, possibly occurring from exposure to infected swine  or through subsequent, limited human-to-human transmission.

 

(Continue . . .)

 

 

While the CDC and public health officials are obviously taking these novel virus detections seriously, and are ramping up surveillance to track their spread, it is too soon to know whether any of these new flu strains will take hold in the human population.

 

As I wrote in Pseudo Pandemics And Viral Interlopers it is certainly possible for new strains of influenza to appear and circulate among humans, without sparking a pandemic.

 

Influenza is notoriously unpredictable.

 

For now, we are in a watchful waiting mode; looking for signs that one of these novel viruses is getting better adapted to human physiology.

 

In the meantime, maintaining good flu hygiene this winter (washing/sanitizing your hands, covering coughs & sneezes, staying home when sick), and getting your seasonal flu shot, remain the best strategies to avoid getting sick during this flu season.