Op-Ed: Measuring the Impact of Pandemic H1N1 in “Years of Life Lost” still shows a Moderate Flu Burden

Pandemic H1N1 (pH1N1), as has been widely documented, has had a greater burden on younger populations. In a normal flu season, 90% of deaths are in persons over age 65. With pH1N1 the percentages have been nearly reversed with 88% of deaths occuring in persons under 65.

Overall pH1N1 has exibited low pathogencity, resulting in approximately 12,000 (estimated) deaths in the US. This is well below the widely quoted figure of 36,000 annual deaths from seasonal flu.

The World Health Organization (WHO) has described pH1N1 as a moderate” pandemic. Many flu experts have never been comfortable with qualitative terms such as “mild” or “moderate”, perhaps in part because they also minimize the import of the disease, and can dissuade publics from taking protective action.

Researchers from the National Institites of Health (NIH) have devised what they term is an “apples-to-apples” methodology to estimate the burden of disease on a population. The metric, termed “Years of Life Lost” (YLL), takes into account the age-distribution of disease-related deaths and extrapolates potential years of life lost across age groups. Expressed as a function, the higher the numbers of deaths, and the lower the mean-age of deaths, the higher is YLL.

NIH researchers describe the impact of pH1N1 as “significant.” By their YLL metric, the burden of p1N1 exceeds that of typical seasonal flu dominated by Influenza A H3N2 virus. NIH research suggests pH1N1 may have had a comparable burden to the (Hong Kong) flu of 1968 (also described as a relatively mild pandemic).

There perhaps is no perfect way to measure the scope, intensity, and duration of a disease outbreak. Numbers of deaths, for obvious reasons, is a metric that is intuitively understood, and of course makes for headlines and optics. While YLL provides a relatively simple metric to compare impacts across pandemics, the measure is still fundametally sensitive to numbers of deaths. Overall, YLL estimates still suggest a moderate burden of disease for pH1N1.

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CIDRAP: Study: In life-years lost, H1N1 pandemic had sizable impact
PLoS Currents: Preliminary Estimates of Mortality and Years of Life Lost Associated with the 2009 A/H1N1 Pandemic in the US and Comparison with Past Influenza Seasons

Research sheds new perspective on much-maligned 1976 swine flu (H1N1) vaccination campaign

A study published by scientists from the National Institutes of Health provides additional evidence that persons who received the 1976 vaccine may have immunity from pandeminc H1N1 (pH1N1).

Researchers evaulated immune responses in mice after exposing them to several H1N1 viruses (1918, 1940, 1976 and 2009) and found that prior infection with a 1976 H1N1 virus provided complete protection against pH1N1. Mice infected with either 2009 or 1940 seasonal H1N1 viruses showed partial protection from pH1N1.

Comment: A serologic study published in the New England Journal of Medicine (NEJM) indicated substantial pre-existing immunity to pH1N1 in adults aged 60 years and older (34%). pH1N1 immunity for younger adults aged 19-64 was estimated at six percent.

Using a stylized assumption that the 1976 H1N1 vaccine was evenly distributed by age and location, rough calculations suggest approximately seven percent of persons in the 19-64 year age group could have received the 1976 H1N1 vaccine. This is close to the NEJM estimate of preexisting immunity for that cohort.

Hence, the much-maligned 1976 swine flu vaccine appears to have afforded a degree of protection against pandemic H1N1.

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Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus

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H1N1 in Transition: La persistance de dénouements

As the traditional winter flu season peaks, pandemic H1N1 (pH1N1) activity in the USA remains at low ebb. Overall flu activity has remained below baseline for the last six weeks. Currently, pH1N1 is circulating at elevated (above baseline) levels in pockets of the southeastern and western regions of the country. Recent CDC estimates indicate that 11,690 Americans died from influenza and around 57 million have been infected with pH1N1.

H1N1 vaccine demand is perhaps at low ebb as well. As of 13 Feb, pH1N1 vaccine uptake was estimated around 86 million persons (97 million doses). Despite the safety record of pH1N1 vaccine, which parallels seasonal flu vaccine, surveys continue to indicate persistent public doubts concerning vaccine safety in general.

According to the World Health Organization, pH1N1 transmission persists at elevated levels in areas of Europe and Asia, but is otherwise at declining or low levels in the northern hemisphere. The most active areas of pH1N1 transmission are parts of Southeastern Asia (Thailand and Myanmar) and Eastern Europe (Russia, Bulgaria, Armenia and Moldova). In China, Influenza B is the predominant flu strain in circulation, accounting for 88% of influenza detected in surveillance.

Overall, pH1N1 remains treatable with antiviral medications, oseltamivir and zanamivir. Disagreement remains over the pathogenicity of oseltamivir-resistant mutations of pH1N1 (referred to as D222G/D225G). The Norwegian Institute of Public Health reported that the mutation was associated with 11 of 61 cases of severe illness and was not found in any mild cases. The Influenza Division at the US Centers for Disease Control and Prevention (CDC) countered that global H1N1 data do not show a clear association between the mutation and severe illness, and that the mutation proved fatal in three of eight cases in the USA.

Comment: A comparison of apples-to-apples appears needed. CDC contends the Norwegian data needs to control for covarying factors, such as underlying patient conditions. The three fatalities in the USA that had the mutation were patients treated at Duke University, all of whom had compromised immune systems; this association had not been highlighted in reporting. At most, the Norwegian data suggests an upper-bound on the incidence of this mutation in severe disease. Seasonal H1N1 influenza viruses are now completely resistant to oseltamivir and this is a likely evolutionary path for future pH1N1 mutations.

CDC Estimates of 2009 H1N1 Influenza Cases, Hospitalizations and Deaths in the United States, April 2009 – January 16, 2010
CIDRAP: CDC – Pandemic vaccine safety record still matches seasonal vaccine
CIDRAP: H1N1 mutation’s proposed link to severe illness debated
LATimes Health: Parents’ vaccination fears remain high
Reuters: Biggest swine flu regret for U.S.: vaccine chaos
WHO: Pandemic (H1N1) 2009 – update 90
WHO: Pandemic (H1N1) 2009 – update 90: Weekly Virological Surveillance Update
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Ferreting out pandemic H1N1 pathogenicity; Building a better mousetrap and H5N1 virus.

Thus far, H1N1 has exhibited moderate pathogenicity while proving efficient at transmission and replication. H5N1 by contrast is highly pathogenic, but has not evidenced capacity for sustained human-to-human transmission. This has been the human experience. It stands to reason, we would expect to see similar results when H1N1 is tested (in vivo) in other mammals.

No mice, ferrets or monkeys were harmed in the making of this post.

Vitamin World

CIDRAP: Study yields highly pathogenic avian, human flu virus mix
J Inf Disease: Severity of Pneumonia Due to New H1N1 Influenza Virus in Ferrets Is Intermediate between That Due to Seasonal H1N1 Virus and Highly Pathogenic Avian Influenza H5N1 Virus
J Virol: Pathogenesis of Pandemic Influenza A (H1N1) and Triple-Reassortant Swine Influenza A (H1) Viruses in Mice.
PNAS: Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence
UW Madison: A new, highly detailed study of the H1N1 flu virus shows that the pathogen is more virulent than previously thought


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Emergency departments see rise in Influenza-like Illnesses (ILI)

Recent article in CIDRAP reports that emergency room clinicians are noting an increase in influenza-like illnesses (ILI). Key excerpts are provided below.

Emergency departments see rise in flu-like illness
Feb 24, 2010 (CIDRAP News), Lisa Schnirring Staff Writer

Some of the nation’s emergency departments are noting increases in flu-like illness cases that appear to be pandemic H1N1, and colleges are reporting the first increase in flu-like illness since the end of November, but it’s not clear if these are early signs of a third pandemic flu wave.

CIDRAP: Emergency departments see rise in flu-like illness
ACHA Pandemic Influenza Surveillance
AP: Swine flu slows down in Washington state

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Seroprevalence study suggests substantial H1N1 immunity in the USA; Factors influencing future H1N1 waves include social clustering, atmospheric conditions and virus competition

University of Pittsburgh researchers estimate that 21% of the U.S. population (63 million persons) have been infected with H1N1, and has developed immunity.

The research used 846 anonymous, leftover blood samples drawn on hospital and clinic patients from the Pittsburgh area in the mid-November and early December 2009 timeframe. Stored serum samples from 100 healthy, young adults from 2008 were used as a control group.

In addition to pandemic H1N1 (A/California/7/2009), the researchers examined seroprevalences against other virus strains to include: A/Brisbane/59/2007 (a seasonal H1N1 virus), A/Denver/1/1957 (a pandemic H2N2 virus) and A/South Carolina/1/1918 (a pandemic H1N1 virus).

Seroprevalences against pandemic 2009 H1N1 influenza varied by age group, with children age 10-19 years having the highest seroprevalence (45%), and persons age 70-79 years having the lowest (5%). The baseline seroprevalence among control samples from 18-24 year-olds was 6%. Overall seroprevalence against pandemic H1N1 across all age groups was approximately 21%.”

The study provided indications of prexisting immunity among seniors exposed to the 1957/1918 pandemic strains as suggested by the high seroprevalences found.

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Given these findings, and taking in account H1N1 vaccination efforts (at least 70 million Americans have been vaccinated), the authors conclude “that further sustained viral (pandemic H1N1) transmission is not likely.”

That said, no one is ready to declare an end to the pandemic. According to a panel of experts polled by the Washington Post, influenza “transmission waxes and wanes, and outbreaks of novel pandemic strains occur in particularly unpredictable waves that depend on such variables as human behavior, atmospheric conditions and even competition from other microbes.”

The report further adds “even if there isn’t a third wave, the new H1N1 may well spell the end of one or more of the families of flu virus that have been circulating for decades . That’s what’s happened in previous pandemics, at least.”

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CIDRAP: Seroprevalence study shows 21% H1N1 infection rate
PLoS Currents: Seroprevalence Following the Second Wave of Pandemic 2009 H1N1 Influenza
Washington Post: Swine flu wanes, but experts say pandemic strain could reemerge

Breaking News: WHO Emergency Committee Signals No Post-Peak Phase for H1N1 Pandemic

The Associated Press relays the following report from London that concerns World Health Organization (WHO) deliberations on transitioning from the peak phase of the H1N1 pandemic (i.e. Level 6), which has lasted nine months.

According to the AP report, WHO’s “emergency committee met Tuesday and suggested it was “premature” to recommend downgrading the global flu outbreak. Swine flu cases have dropped dramatically in recent weeks in Western countries, but the virus has only recently hit Africa. The southern hemisphere is also bracing for another wave of illness in the next few months.”

By WHO protocol, any public announcement is embargoed until after the Director-General informs the 193 member states of the decision. Formal announcement is expected on 24 Feb at 1000 GMT.

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AP: WHO: Swine flu still hasn’t peaked
CIDRAP: Novel H1N1 Influenza (Swine Flu): H1N1 Flu Breaking News (23 Feb)

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H1N1 Transitions: FDA Selects Pandemic H1N1 for Inclusion in 2010-11 Seasonal Flu Vaccine

A US Food and Drug Administration vaccines panel voted to follow World Health Organization (WHO) recommendations to include pandemic H1N1 in the seasonal flu vaccine for 2010-2011. A/California/7/2009 (the pandemic strain) will replace A/Brisbane/59/2007 for the H1N1 component of the trivalent (three-strain) influenza vaccine.  FDA’s Vaccines and Related Biological Products Advisory Committee also voted to switch the A/H3N2 component of the seasonal trivalent vaccine from the 2007 Brisbane strain to a A/Perth/16/2009 virus, and also to retain a B/Brisbane/60/2008 strain for the influenza B component, as WHO had advised.

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CIDRAP: FDA selects pandemic H1N1 for 2010-11 seasonal flu vaccine
WSJ: FDA Panel Recommends Single Flu Vaccine

H1N1 in Transition: WHO to Decide Post-Peak Phase in H1N1 Pandemic; 2009 H1N1 Replaces Seasonal A H1N1 in Next Trivalent Influenza Vaccine

This week, the World Health Organization (WHO) Emergency Committee will advise on transition to a “post-peak” phase for the H1N1 pandemic. The current pandemic alert level is at Level 6.

The committee ruled out a “post-pandemic” phase because, in its view, H1N1 is not yet behaving like normal seasonal infuenza, and that future waves of H1N1 were possible. WHO’s decision will be made public at 1000 GMT on 24 Feb.

Meanwhile, H1N1 has peaked and is waning across the globe. Pockets of “active, but declining H1N1 transmission persist in southern/eastern Europe as well South/East Asia.” Influenza B virus is circulating at elevated levels in China, displacing H1N1. H3N2 is co-circulating at low levels in Asia and China. H1N1 is the predominant strain in the Americas; flu activity in the USA is below baseline.

Last week WHO also recommended that A(H1N1) 2009 replace seasonal (A)H1N1 in the 2010-2011 trivalent seasonal influenza vaccine. As summarized by CIDRAP, the specific WHO recommendations were:

  • H1N1 component: a strain similar to A/California/7/2009, replacing A/Brisbane/59/2007
  • H3N2 component: a strain similar A/Perth/16/2009, replacing A/Brisbane/10/2007*
  • B component: a strain similar to B/Brisbane/60/2008-like virus

* A/Wisconsin/15/2009 is a A/Perth/16/2009 (H3N2)-like virus and is a 2010 southern hemisphere vaccine virus.

Oseltamivir (Tamiflu) resistance in pandemic A(H1N1) 2009 viruses has been limited. However, WHO also noted “the majority of seasonal A(H1N1) viruses were oseltamivir resistant.” This resistance developed during the 2008-2009 flu season.

COMMENT: Flu watchers understandably keep an anxious eye on hot-zone countries like Indonesia, Vietnam and Egypt where H5N1 (avian flu) and H1N1 are in co-circulation, carrying potential for a pathogenic virus reassortment. The WHO report serves as a reminder that a reassortment between 2009 H1N1 and antiviral-resistant seasonal H1N1 viruses would also be an unwelcome development.

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CIDRAP: CDC flu barometers show level activity
CIDRAP: WHO picks pandemic strain for next seasonal flu vaccine
Reuters: WHO may declare post-peak pandemic phase next week
Reuters: WHO to decide new flu vaccine formula
WHO: Pandemic (H1N1) 2009 – update 88
WHO: Recommended viruses for influenza vaccines for use in the 2010-2011 northern hemisphere influenza season (PDF)