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AFD - Differences In Virulence Between Closely Related H5N1 Strains

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  • AFD - Differences In Virulence Between Closely Related H5N1 Strains

    hat tip Michael Coston

    Differences In Virulence Between Closely Related H5N1 Strains

    # 6286

    One of the difficulties in determining the CFR (Case Fatality Rate) of the H5N1 virus (see The Great CFR Divide) is the fact that at least 20 distinct clades of the virus have so far been identified (with numerous variations among each clade), and that there appear to be differences in how they behave.
    `Clades’ are essentially branches on the virus’s family tree. Each new branch has a clearly identifiable lineage from its parental strain, but has mutated far enough away to become a new strain.
    TheWorld Health Organization’s report from October of 2011, Updated unified nomenclature system for the highly pathogenic H5N1 avian influenza viruses, identifies and updates the known clades of the H5N1 virus that have emerged since the detection of the A/goose/Guangdong/1996 H5N1 virus strain back in the mid 1990s.

    All of which means we are not watching just one H5N1 virus strain with pandemic potential, we are watching at least 20 genetically separate clades of the virus, with many minor variants of each clade thrown in the mix.
    And over time, it is expected that even more clades will emerge as the virus mutates and/or swaps genetic material with other viruses.
    To give you an idea of just how much the virus has diversified over the past 15 years, I’ve reproduced one of the WHO charts from in this report below.

    (click to load larger image)
    And among these different clades and strains (some of which have disappeared over the years), there appears to be a significant variation in its virulence, host range, and likely - transmissibility.
    Anecdotally, a look at the latest World Health Organization tally of known human H5N1 cases shows a wide spread in case fatality rates around the world.

    The latestglobal tally of human H5N1 cases from the WHO show 23 confirmed H5N1 infections for 2012, and 14 fatalities.

    In Bangladesh, of the 6 known cases, none have died, while in Cambodia 18 or 20 have succumbed to the virus. In Egypt, the CFR is running about 35%, while in Indonesia, it is nearly 83%.
    Although there are likely many factors involved in causing this disparity in CFR – including quality of, and delays in seeking medical care – it suggests that the H5N1 virus is more virulent in some regions of the world than in others.
    Which brings us to a study that recently appeared in the Journal Transboundary and Emerging Diseases that looked at two very similar H5N1 viruses of the same clade ( that produced widely varying pathogenicity in mice and ducks.
    Two Highly Pathogenic Avian Influenza H5N1 Viruses of Clade with Similar Genetic Background but with Different Pathogenicity in Mice and Ducks

    J. Hu, K. Zhao, X. Liu, X. Wang, Z. Chen, X. Liu
    Article first published online: 12 APR 2012
    DOI: 10.1111/j.1865-1682.2012.01325.x

    A number of genetic markers for virulence of avian influenza viruses (AIVs) in different hosts have been identified. However, we isolated two H5N1 AIVs, A/Chicken/Jiangsu/k0402/2010(CK/10) and A/Goose/Jiangsu/k0403/2010(GS/10) with similar genetic background, but most well-defined molecular markers for virulence in mammals and avian species were not found in both viral genomes.
    In addition, pathogenicity of this pair of viruses in different hosts remains unclear. Therefore, we evaluated their pathogenicity in chickens, mice, ducks and guinea pigs. Infection of CK/10 and GS/10 in chickens caused 100% mortality within 24 h.
    Mouse experiment showed that CK/10 was highly pathogenic (MLD<sub>50</sub> = 0.33 log<sub>10</sub> EID<sub>50</sub>), whereas GS/10 was avirulent (MLD<sub>50</sub> > 6.32 log<sub>10</sub> EID<sub>50</sub>).
    Interestingly, the virulence of CK/10 in ducks (DLD<sub>50</sub> = 3.83 log<sub>10</sub> EID<sub>50</sub>) was higher than that of GS/10 (DLD<sub>50</sub> = 7.7 log<sub>10</sub> EID<sub>50</sub>), which correlated with viral pathogenicity in mice. Although CK/10 and GS/10 showed distinct pathogenicity in mice, they both were lethal to guinea pigs, with CK/10 replicating to higher titres in airways than GS/10.
    Collectively, these findings suggest that AIVs with similar genetic backgrounds may exhibit distinct pathogenicity in specific hosts and that some unknown molecular markers for virulence may exist and need to be identified.
    With differences this great in the pathogenicity of two closely related H5N1 viruses, one might reasonably assume that even greater differences in host range, transmissibility, and virulence may exist between more dissimilar clades.
    Which just might help explain the `dueling studies’ problem, where some seroprevalence studies have shown a small but significant percentage of apparent asymptomatic H5N1 infections in exposed populations, while the majority have not.
    Granted, none of this brings us any closer to knowing the true CFR of the H5N1.

    But that may well be an impossible question to answer accurately, unless we first specify which strain, clade, or sub-clade of the virus we are talking about.

    Posted by Michael Coston at <a class="timestamp-link" href="" rel="bookmark" title="permanent link"><abbr class="published" title="2012-04-16T11:20:00-04:00">11:20 AM</abbr> 0 comments Links to this post
    Labels: CFR, H5N1

    EID Journal: Airport Screening For Pandemic Flu In New Zealand


    During the opening weeks and months of the 2009 H1N1 pandemic a number of countries worked to identify, and isolate, infected passengers arriving at their International airports in an attempt to prevent or slow the arrival of the pandemic virus to their nation.

    The reaction is a natural one; to deny entry to highly infectious carriers of pandemic influenza.
    And for some countries – particularly island nations like New Zealand and Japan, with no shared borders – it seems an attractive option.
    But is it practical?

    Prior to the pandemic many experts had expressed doubts - given the multi-day incubation period of influenza, the sensitivity of detection equipment, and the near certainty that some carriers will remain asymptomatic – that attempts to identify the infected based on fever, cough, or other outward signs of illness would prove successful.

    We’ve a new study published ahead of print in the May edition of the CDC’s EID Journal, that indicates that the mostly passive screening methods used at New Zealand’s airport were inadequate to slow the entry of pandemic flu into their country.
    Screening for Influenza A(H1N1)pdm09, Auckland International Airport, New Zealand

    Article Contents

    Michael J. Hale, Richard S. Hoskins , and Michael G. Baker

    Entry screening for influenza A(H1N1)pdm09 at Auckland International Airport, New Zealand, detected 4 cases, which were later confirmed, among 456,518 passengers arriving April 27–June 22, 2009. On the basis of national influenza surveillance data, which suggest that ≈69 infected travelers passed through the airport, sensitivity for screening was only 5.8%.
    Unlike some other countries in 2009, New Zealand did not employ thermal scanners, looking for arriving passengers or crew with elevated temperatures.

    (Thermal Imaging for SARS in 2003)

    The journal article describes their procedure as:
    Each unwell passenger and crew member was screened for influenza-like illness by a nurse and assessed by a medical officer if illness met the definition of a suspected case. Those whose illness met the case definition had nasopharyngeal swabs taken, were offered oseltamivir, and were sent home or to a facility for isolation. Reverse transcription PCR (RT-PCR) was used to confirm infection. Screening was escalated on April 29 to include all passengers arriving from other countries and stopped on June 22.
    After running the numbers, and coming up with a detection rate of less than 6%, the authors concluded that:
    The influenza A(H1N1)pdm09 screening program at Auckland International Airport had low sensitivity. This form of border screening is therefore unlikely to have substantially delayed spread of the pandemic into New Zealand in 2009.

    Limitations of influenza screening include the high proportion of asymptomatic infected travelers (5), incubation of infections acquired before or during a flight (3), reliance on self-identification, limitations of case definitions, and limitations of thermal scanning (6). Modeling data have shown that the ability of border screening to delay global pandemic influenza is closely linked to the effectiveness of the screening process or travel restriction used.

    To delay influenza spread by 1.5 weeks, border restrictions need to reduce imported infections by 90% (7). The entry screening program we describe does not meet these standards.
    As previously mentioned, other countries employed thermal scanners and far more strict interdiction techniques during the summer of 2009, yet their track record was not much better.

    In June of 2009, just as the pandemic was ramping up, I wrote Vietnam Discovers Passengers Beating Thermal Scanners, which looked at a Reuters report that a number of sick passengers flying into Ho Chi Minh City in Vietnam took fever reducers (Aspirin, Tylenol, etc) several hours prior to arrival in order to beat the thermal scanners.

    In December of 2009, in Travel-Associated H1N1 Influenza in Singapore, I wrote about a NEJM Journal Watch of a new study that has been published, ahead of print, in the CDC’s EID Journal entitled:
    Epidemiology of travel-associated pandemic (H1N1) 2009 infection in 116 patients, Singapore. Emerg Infect Dis 2010 Jan; [e-pub ahead of print]. Mukherjee P et al
    Travel-Associated H1N1 Influenza in Singapore

    Airport thermal scanners detected only 12% of travel-associated flu cases; many travelers boarded flights despite symptoms.
    One quarter of patients were symptomatic when they boarded flights; 15% developed symptoms during travel. Airport thermal scanners detected only 12% of patients overall and only 40% of those with symptomatic infection on arrival.
    And finally, in June of 2010 CIDRAP carried this piece on a study of thermal scanners in New Zealand in 2008 (before the pandemic) presented at 2010’s ICEID.
    Thermal scanners are poor flu predictors

    Thermal scanners for screening travelers do moderately well at detecting fever, but do a poor job at flagging influenza, according to researchers from New Zealand who presented their findings today at the International Conference on Emerging Infectious Diseases (ICEID) in Atlanta.

    The positive predictive value for fever was 1.5% for thermal scanners and 4.1% for tympanic thermometers. For influenza, the positive predictive value for the two techniques was 2.8%. None of the 30 passengers who tested positive for influenza had a tympanic temperature of 37.8&#176;C (100&#176;F) or higher, and only 2 had temperatures of at least 37.5&#176;C (99.5&#176;F). Three were asymptomatic. The group concluded that fever is a poor predictor of influenza, which limits the efficacy of thermal screening at entry points.

    Jul 13 ICEID abstracts (See Board 168)
    During the 1918 pandemic, when international travel was far less common, a few nations managed to block entry of the pandemic virus by imposing a strict quarantine of all arriving passengers.

    The four successful quarantines during the 1918 pandemic were in American Samoa (5 days' quarantine) and Continental Australia, Tasmania, and New Caledonia (all 7 days' quarantine).

    • The Spanish Flu did not reach American Samoa until 1920, and had apparently weakened, as no deaths were reported.

    • Australia's quarantine kept the influenza away until January of 1919, a full 3 months after the flu has swept New Zealand with disastrous effects.

    • Tasmania kept the flu at bay until August of 1919, and health officials believed they received an milder version, as their mortality rate was one of the lowest in the world.

    • By strictly enforcing a 7-day quarantine, New Caledonia managed to avoid introduction of the virus until 1921.

    Eventually, once the quarantines were lifted, the virus did make it to these isolated regions of the world.

    Areas that receive a small number of arrivals might be able to institute a quarantine system (see Can Island Nations Effectively Quarantine Against Pandemic Flu? ), but even then the ability to interdict infected travelers won’t be 100%.

    The author’s of today’s EID study summarize:
    Border screening might be conducted for reasons other than preventing or delaying an epidemic. It might provide public assurance and confidence that something is being done (14). The communication of health information and advice on how to seek treatment is consistently recommended as a pandemic prevention strategy (12,15) and is usually delivered as part of border screening programs. These benefits need to be balanced against the considerable resources used, opportunity cost (resources used for this activity and thereby unavailable for other activities), uncertain effectiveness, and inconvenience of border screening.
    To delay or prevent influenza entry at borders, influenza screening needs to be considerably more effective than the mostly passive program described here.
    Despite scant evidence showing that airport influenza screening would do very much to prevent or slow entry of a pandemic virus into a country, many governments may find it difficult not to at least be seen making the attempt.

    Which – if nothing else – will provide us with further evidence as to its efficacy (one way or the other) after the next pandemic is finished.