The international response to the influenza pandemic: WHO responds to the critics

Pandemic (H1N1) 2009 briefing note 21

Background

10 JUNE 2010 | GENEVA -- On Friday 4 June 2010, the BMJ, formerly British Medical Journal, and the Parliamentary Assembly of the Council of Europe (PACE) simultaneously released reports critical of the World Health Organization's handling of the H1N1 pandemic. WHO takes the issues and concerns that were raised seriously and wishes to set the record straight on several points.

Is this a genuine pandemic?

The outbreaks of infection with the new H1N1 virus, which have been confirmed in virtually every country and territory in the world, differ from seasonal influenza in distinct ways. These differences meet the criteria for an influenza pandemic.
 
1. The first human infections with the new H1N1 virus were confirmed in April 2009. Analysis of laboratory samples showed that the new virus had never before circulated in humans. This is a virus of animal origin with a unique mix of genes from swine, bird, and human influenza viruses. The genetic composition of this virus is distinctly different from that of the older H1N1 virus that has been causing seasonal epidemics since 1977.
 
2. As the virus spread, it demonstrated epidemiological patterns not seen during seasonal epidemics of 
influenza. Widespread, high levels of infection with the new virus occurred during the summer in the northern hemisphere in multiple countries, followed by even higher levels during the fall and winter months. In countries with a temperate climate, seasonal epidemics typically taper off in the spring and end before summer.
 
3. The pattern of illness and death caused by the H1N1 virus differed in striking ways from that seen 
during seasonal influenza. During seasonal epidemics, more than 90% of deaths occur in the frail elderly. The H1N1 virus affected a younger age group in all categories: those most frequently infected, those requiring hospitalization, those requiring intensive care, and those dying from their infection.
A frequent cause of death was viral pneumonia, caused directly by the virus and difficult to treat. During seasonal epidemics, most cases of pneumonia are caused by secondary bacterial infections, which usually respond well to antibiotics. While many of those who died had underlying medical conditions associated with a higher risk, many others who died were previously in good health.
 
4. The new H1N1 virus rapidly crowded out other circulating influenza viruses and appears to have displaced the older H1N1 virus. This phenomenon is distinctly seen during pandemics.
 
5. Early studies showed that antibodies to H1N1 seasonal influenza did not protect people from infection with the new virus. This finding provided critical evidence that the virus was new to the human immune system. Later studies in some countries determined that around one third of people older than 65 years had some immunity to the virus. Younger people, however, had no such protective immunity.

Did WHO remove severity from the definition of a pandemic?

WHO regards severity as an important feature of pandemics and a critical factor when deciding on which actions to take. However, WHO has not required a set level of severity as part of its criteria for declaring a pandemic. Experience shows that all pandemics cause excess deaths, that severity can change over time, and that severity can vary according to location and population.
 
WHO has published three definitions of an influenza pandemic in the context of phases of pandemic alert. These definitions were contained in broader guidelines for pandemic preparedness issued in 1999, 2005 and 2009. Research on influenza pandemics and pandemic viruses increased considerably following the first human cases of infection with the H5N1 avian influenza virus in 1997. Definitions changed over time in line with this evolving knowledge and the need to increase the precision and practical applicability of phase definitions.
 
The 2009 guidelines, including definitions of a pandemic and the phases leading to its declaration, were finalized in February 2009. The new H1N1 virus was neither on the horizon at that time nor mentioned 
in the document.
 
The media make frequent reference to a 2003 document, available on the WHO web site, stating that an influenza pandemic results in “enormous numbers of deaths and illness”. At the time, this was considered a likely scenario should the highly lethal H5N1 avian influenza virus develop an ability to spread readily among humans, but it was never a formal definition.

Influenza pandemic plan: the role of WHO and Guidelines for national and regional planning. [pdf 227kb]
WHO, 1999

WHO global influenza preparedness plan: the role of WHO and recommendations for national measure before and during pandemics. [pdf 372kb]
WHO, 2005

Pandemic influenza preparedness and response: a WHO guidance document. [pdf 339kb]
WHO, 2009

Did WHO exaggerate the threat?

When WHO Director-General Dr Margaret Chan announced the start of the pandemic, on 11 June 2009, she expressed the view that the pandemic would be of moderate severity. She further noted the relatively small number of deaths worldwide, and clearly stated that “we do not expect to see a sudden and dramatic jump in the number of severe or fatal infections.”

In every assessment of the pandemic, WHO consistently reminded the public that the overwhelming majority of patients experienced mild symptoms and made a rapid and full recovery, even without medical treatment.

WHO also noted, early on, that influenza viruses are unstable and can undergo rapid and significant mutations, making it difficult to predict whether the moderate impact would be sustained. This uncertainty, which persuaded WHO and many national health authorities to err on the side of caution, was further enforced by the behaviour of past pandemics, which varied in their severity during first and second waves of international spread.

Were any WHO pandemic decisions made to increase industry profits?

No. Allegations that WHO declared a pandemic to boost the profits of the pharmaceutical industry arise from WHO’s use of expert advisers and the way declarations of interest from these experts are handled. No evidence of any specific instance of wrongdoing has emerged from recent enquiries.

What safeguards are in place to guard against conflicts of interest?

Potential conflicts of interest are inherent in any relationship between a normative and health development agency, like WHO, and profit-driven industry. Advice from top experts is sought by industry as well as by agencies like WHO that need to issue guidance based on the best expertise. Many experts who advise WHO have ties with industry, and these ties can range from funding to conduct research, to paid consultancies, to participation in conferences sponsored by industry.
 
WHO has systems in place to protect the Organization from advice biased by commercial interests. WHO requires all expert advisers to declare their professional and financial interests when they participate in advisory groups and consultations. WHO assesses declared interests to determine whether a potential conflict or a potential perception of conflict exists. Where necessary, WHO requests more detailed information and then decides on the appropriate action to be taken.
 
The publication of summaries of relevant interests following meetings is inconsistent and needs to be made routine. WHO further acknowledges that safeguards surrounding engagement with industry need to be tightened, and is doing so.

What is the function of the Emergency Committee and why have the names of its members not been disclosed?

The International Health Regulations (IHR) contain a set of requirements that are legally binding for WHO and the 194 States Parties of the IHR. The IHR call upon the WHO Director-General to convene an Emergency Committee, drawn from a standing roster of IHR experts, to provide WHO with independent guidance during public health emergencies of international concern, such as an influenza pandemic. The IHR came into force in 2007.
 
The emergence of the new H1N1 virus prompted the first convening of an Emergency Committee under the IHR. At that time, WHO debated whether or not to publicly disclose the names of members, and faced a dilemma. On one hand, the names of members of other advisory groups are made public after they meet; the identification of persons offering guidance adds transparency to their advice and subsequent WHO decisions. On the other hand, experiences during the SARS outbreak demonstrated the considerable economic and social disruption caused by some public health emergencies, meaning that experts could well be lobbied or pressured for commercial or political reasons, potentially compromising the objectivity of their advice.
 
After considering these issues, WHO decided to apply its usual practice of disclosing the names of experts after an advisory body has completed its work. The members themselves welcomed this decision as a protective measure, and not as an attempt to veil their deliberations and decisions in secrecy. However, given the duration of the pandemic, the Emergency Committee has held a number of meetings over more than a year, rather than a single meeting like most advisory groups, thus delaying even further the release of the names of its members.
 
WHO is now fully aware that this decision has fostered suspicion that the Committee might be providing guidance shaped by commercial interests or pressures. Names of members and a summary of relevant declarations of interest will be made public when the Committee advises that the pandemic has ended. Procedures for revealing names of members of future Emergency Committees are under review.

What evidence supports a role for antiviral drugs during an influenza pandemic?

Given widespread population vulnerability to infection, an influenza pandemic presents health authorities with a significant challenge in finding ways to protect populations. From the outset, WHO has recommended a wide range of measures, including hand washing, respiratory hygiene, and not travelling or going to work when ill, and has offered advice on the clinical care of patients and the use of antiviral drugs and vaccines.
 
At the start of the pandemic, data from the Centers for Disease Control and Prevention (USA) showed that the new virus was sensitive to oseltamivir and zanamivir. Prior to the pandemic, WHO had developed guidelines for the treatment of severe influenza infections caused by the avian H5N1 influenza virus. These two factors allowed WHO to rapidly issue guidelines for use of antivirals in the context of H1N1 pandemic influenza, with emphasis on the treatment and prevention of severe illness.
 
Over the course of the pandemic, an increasing volume of clinical data has been published in peer-reviewed medical journals. These studies confirm that prompt use of antivirals correlates with improved recovery from illness and fewer deaths. Evidence shows that antivirals have been especially effective for treating patients at increased risk of developing complications from H1N1^[1].

WHO Guidelines for Pharmacological Management of Pandemic (H1N1) 2009 Influenza and other Influenza Viruses
February 2010

Was a WHO meeting held in 2002 on influenza vaccines and antiviral drugs influenced by industry?

In 2002, WHO convened a consultation with experts to develop a document, WHO guidelines on the use of vaccines and antivirals during influenza pandemics, which was published in 2004. Some critics have alleged that certain experts who participated in the meeting and the drafting of the guidelines had ties with industry interpreted as conflicts of interest. In line with WHO policy, all experts who participated in this meeting were required to submit a declaration of interest form and all such forms were duly reviewed by WHO. However, a summary of relevant interests was not issued together with the publication. WHO regrets this oversight.
 
Since that time, a number of administrative and legal changes have been implemented to strengthen procedures for addressing potential conflicts of interest that might influence the advice provided to WHO. WHO is committed to tightening these procedures further and ensuring their more consistent application. 


^[1] See for example: Siston et al. Pandemic 2009 Influenza A(H1N1) virus illness among pregnant women in the United States. Journal of the American Medical Association, 2010, 303: 1517-1525

Council of Europe: PACE Health Committee denounces ‘unjustified scare’ of Swine Flu

Press release - 455(2010) PACE Health Committee denounces ‘unjustified scare’ of Swine Flu, waste of public money Strasbourg, 04.06.2010 – The handling of the H1N1 pandemic by the World Health Organization (WHO), EU agencies and national governments led to a “waste of large sums of public money, and unjustified scares and fears about the health risks faced by the European public”, according to a report by the Social, Health and Family Affairs Committee of the Parliamentary Assembly of the Council of Europe (PACE) made public today in Paris. The report, prepared by Paul Flynn (United Kingdom, SOC) and approved today by the committee ahead of a plenary debate at the end of this month, says there was “overwhelming evidence that the seriousness of the pandemic was vastly overrated by WHO”, resulting in a distortion of public health priorities. Presenting his report, Mr Flynn told the committee: “this was a pandemic that never really was”, and described the vaccination programme as “placebo medicine on a large scale” (see video below). In its adopted text, the committee identifies what it calls “grave shortcomings” in the transparency of decision-making about the outbreak, generating concerns about the influence of the pharmaceutical industry on decisions taken. Plummeting confidence in such advice could prove “disastrous” in the case of a severe future pandemic, it warns. In particular, the WHO and European health institutions were not willing to publish the names and declarations of interest of the members of the WHO Emergency Committee and relevant European advisory bodies directly involved in recommendations concerning the pandemic, the parliamentarians point out. However, attending the meeting was Fiona Godlee, the Editor-in-Chief of the British Medical Journal, who told the parliamentarians that, according to an investigation by her journal, scientists who drew up key WHO guidelines on stockpiling flu vaccines had previously been paid by drug companies which stood to profit. The WHO has been “highly defensive”, the committee said, and unwilling to accept that a change in the definition of a pandemic was made, or to revise its prognosis of the Swine Flu outbreak. The committee sets out a series of urgent recommendations for greater transparency and better governance in public health, as well as safeguards against what it calls “undue influence by vested interests”. It also calls for a public fund to support independent research, trials and expert advice, possibly financed by an obligatory contribution of the pharmaceutical industry, as well as closer collaboration with the media to avoid “sensationalism and scaremongering in the public health domain”. The report is due to be debated by parliamentarians from all 47 Council of Europe member states on Thursday 24 June during PACE’s summer session in Strasbourg. Contacts In Paris: Francesc Ferrer, mobile: +33 (0)6 30 49 68 22 In Strasbourg: PACE Communication Division, tel. +33 (0)3 88 41 31 93, mobile: +33 (0)6 30 49 68 20 Mr Flynn’s report (provisional version) (PDF) Video of the committee’s exchange of views today (English) Video of the committee’s exchange of views today (original languages) Parliamentary Assembly Communication Unit Tel: +33 3 88 41 31 93 Fax : +33 3 90 21 41 34 pace.com@coe.int assembly.coe.int

AFP: WHO sets up swine flu probe

WHO sets up swine flu probe

Apr 12, 10 3:23pm

 

Health experts on Monday begin examining the controversial response to the first influenza pandemic of the 21st century, nearly a year after global alarm was raised over the new swine flu strain.

The World Health Organisation is forming a panel of 29 external experts following accusations that the agency-led international reaction to A(H1N1) influenza was overblown and may have been tainted by commercial interests.

After the formative three-day meeting, the International Health Regulations review committee's work is expected to take about nine months, WHO spokesman Gregory Hartl said.

WHO Special Adviser on Pandemic Influenza Keiji Fukuda recently admitted that "we still have a lot of things to learn," including the way the risks posed by swine flu are communicated to the public.

However, specialists broadly defended the alarm over the discovery of A(H1N1) cases in Mexico and 

the United States in April 2009 as well as the WHO's declaration of a pandemic in June as the flu swiftly spread around the world.

"I think they gave a terrific lead and were very authoritative. I think we have a lot to thank them for," John Oxford, a virologist and professor at the Queen Mary's School of Medicine and Dentistry in Britain, told AFP.

"A lot of the criticism is political. I've not heard criticism from any virologist," he added, also 

highlighting the need to cater for impoverished countries with poor surveillance, care and health conditions.

Parliamentarians conducting a Council of Europe probe have criticised the transparency of decision-making and especially the potential influence of the pharmaceutical industry on a decision last year to press for vaccination.

That inquiry was set up after several governments sought to cancel mass orders of hundreds of millions of dollars worth of swiftly developed special pandemic vaccines, when fears about the severity of swine flu died down.

British MP Paul Flynn, who is leading that probe, declined to comment before he meets WHO officials in Geneva on Thursday.

David Heymann, a former head of infectious diseases at the WHO who left the agency in early 2009, voiced concern about public reticence towards vaccination in generally healthy Western populations.

- AFP

US CDC 2009 H1N1 Flu Media Briefing (Feb 5, 2010-unedited)

CDC 2009 H1N1 Flu Media Briefing (unedited)

Thursday February 5, 2010.

Press Briefing Transcripts

• Audio recording (MP3)
  

Operator: At this time, I would like to remind parties that your lines are in listen-only mode until question-and-answer session at which time you may press star one to ask a question.  Today's call is being recorded.  If you have any objections, you may disconnect at this time.  I will now turn the call over to Glen Nowak.  Thank you, sir.  You may begin.

Glen Nowak: Thank you and thank you all for dialing in this afternoon for this update on H1N1 vaccination and disease activity.  Today's briefing will be led by Dr. Anne Schuchat, the Director of the National Center for Immunization and Respiratory Diseases.  And she will be providing an update on where we stand in terms of flu activity, as well as the H1N1 vaccination program.  So I will turn the phone over to Dr. Schuchat. 

Anne Schuchat: Good afternoon, everybody.  It's a pleasure to be able to update you today.  The key
points I’m going to talk about today are where we are with disease, and the program.  This enormous program we've had together, the vaccination effort and some survey results.  My key point is that H1N1 vaccination remains a good idea for this very preventable and sometimes serious disease.  H1N1 flu activity seems to have leveled off, but the virus does continue to circulate, causing illness, hospitalizations and deaths. 

Influenza-like activity is currently less than the national baseline level.  And it's been below the national baseline for the past three consecutive weeks.  That's fairly similar to what we would normally see at this time of year, with seasonal flu.  Pneumonia and influenza deaths as a proportion of total deaths are actually above what we call the epidemic threshold level, and they have been over that epidemic threshold level for three consecutive weeks.  Nearly all the flu viruses that we're seeing right now are the H1N1 pandemic strain.  We're not seeing seasonal flu strains yet in any substantial numbers.  This past week's virology results, there were only two seasonal strains – influenza B, versus more than 100 influenzas As, mostly which were the H1N1. 

We are remaining vigilant here and do not think people should become complacent.  As I said, individual cases of the H1N1 influenza continue to occur, and people are being hospitalized, and they're dying.  Vaccination is such an easy step to take and it's the best protection against this disease that can be serious.  As opposed to last fall, today there is plenty of vaccine available. 

About 124 million doses of the H1N1 flu vaccine have been shipped to places around the country.  Millions more are available, and there's extensive opportunities for people to be vaccinated, with vaccines in doctors' offices, health departments, offered in many school clinics and pharmacies throughout the country.  It's really easy to be vaccinated now, and we hope people will take advantage of that.  As I said, vaccination now is still beneficial, because this virus is still around.  And none of us can say exactly what we'll see in the weeks and months ahead. 

We have information to update you on today from our national H1N1 flu survey, which is being carried out regularly to understand vaccination use.  The results I’m going to share are from interviews that were conducted between January 24th and the 30th.  The survey involved 4,110 people. 

That survey lets us estimate that about 70 million people have been vaccinated against the H1N1 virus.  That translates to about 23.4% of Americans having been vaccinated so far.  We think that at least 76 million doses of the H1N1 vaccine have been given, because, of course, some people are getting two doses. We recommend two doses for all children under 10, and what we've seen is that among children in that age group who have already received one dose of vaccine, 37% have gotten their second dose.  Overall, the coverage is the highest in children, with 37% of children having been vaccinated.  That's based on children up to the age of 18. 

We're continuing to do extensive monitoring of safety.  As you know, we've reported detailed safety results on the first 61 million doses that have been distributed.  Or administered.  And the vaccine had a very good safety record at that point.  The continuing safety monitoring continues to show excellent results.  We think this is a very safe vaccine.

 I want to provide a little bit of information about the vaccination program, the H1N1 vaccination program involved an incredible partnership between the public health and medical communities, between health, education, and the private sector.  The state and local health departments tripled the number of providers that they work with in administering vaccines.  We have a public health system, a Vaccines for Children program, where state health departments work with private providers to administer vaccines to children.  That involves about 40,000 or 45,000 providers.  But the state and local programs have enrolled more than 120,000 providers in the H1N1 program.  With each of those providers needing to sign an individual agreement stating they would respect the rules of the program. 

So this is a tremendous effort that the public health and medical community committed to the past few months.  I really want to thank them for their great work.    There have been more than 70,000 distinct locations that have received vaccine.  Some of those locations further distribute the vaccine to additional places.  Our central distributor has shipped vaccines in amounts ranging from 100 to many, many thousands of doses, and they've shipped out more than 300,000 individual shipments.  So this has been an extraordinary effort carried out on top of the usual childhood program, and really separate from the regional flu vaccine program. 

The vaccines have been administered in a number of sites.  And what we know right now is that one of three doses that children received was administered in a school.  So children might be vaccinated in doctors' offices or health departments, or at other clinics.  But we know about a third of the children received their doses in schools, which is really an amazing success.  Something we hope to build on in the future. 

I want to briefly mention a survey that was carried out by Harvard to keep tabs on where we are with attitudes and behaviors around the country.  I think they've issued a press release and I just want to make a couple of comments about their survey results.  Their survey was also carried out recently between January 20th and the 24th, and I think they found very encouraging results that also do highlight and reaffirm some challenges that we have. 

They found that 21% of adult Americans had received the H1N1 vaccination, but another 16% indicated that they were planning to do so this month.  So people weren't finished with their intents to be vaccinated.  Of the people who had tried to get the vaccine earlier, but weren't able to, of those who were looking back in the fall when it was in limited supply, 71% said that they did intend to look again.  And of course, now, the vaccine should be readily available. 

40% of parents have reported that they'd ensured that their children received the H1N1 vaccine and another 13% indicated that they were planning to get their child vaccinated.  So all in all, the Harvard survey results about immunization behavior and attitude were quite encouraging, especially when one looks back at the idea that we had so much demand for vaccine before we had a lot of vaccine in October.  The behaviors and intents are still encouraging in the proportion that actually have been vaccinated. 

They also did some evaluation of awareness.  And I was really pleased to see that 76% of the surveyed people were aware of the public health messages and materials related to the H1N1 vaccination.  It was very important to us in terms of the program that people be able to be informed, and take advantage of vaccination if they choose to.  Fortunately most people did see one or more messages, whether through TV, radio, newspaper, or other venues.  And I think it was somewhat heartening to see that about 3 in 5 Americans rated the public health response to the H1N1 as excellent or good. 

Going forward, there are some challenges that they were able to highlight in their poll, and that I think our survey also showed.  Many children still need a second dose.  While we think that 37% of kids who have gotten one dose got a second dose, that means the majority haven't of those young children. 

So I urge parents to take your children back for that second dose.  Maybe it will be at the school clinic, maybe through the doctor's office or some pharmacies.  But please do that.  It would just be tragic for you to have gone so far to do the right thing and have your child get sick because they weren't completely protected.  Many people believe the outbreak is over, and I think it's too soon for us to have that type of complacency.  None of us know whether we're going to have bursts of disease or clusters, or just ongoing transmission as we've seen in the past few weeks.  But the virus does continue to spread.  And those who haven't been vaccinated are still vulnerable to its harm. 

About 15% of Americans in that Harvard poll have safety concerns about the vaccine.  I take that seriously.  I think it's very, very reassuring that extensive safety monitoring, really unprecedented amounts of safety monitoring of the vaccine is being used here in the U.S., have been extremely reassuring.  Very good results.  No major safety concerns at all.  And so if safety was the reason you were waiting, I think you can be reassured on that front. 

The future is still hard to predict, but we know the virus is still around.  The vaccine is very safety and effective.  And the best way to protect yourself or your loved one is to take advantage of vaccine.  I really want to close before the questions, thanking the tens of thousands of public health and medical providers, pharmacists, communicators who have worked incredibly hard and well together over the months past, and continue to work to the to protect the American public.  So let's go to the questions, operator. 

Operator: If you'd like to ask a question, press star 1 and record your name.  The first one is from Maggie Fox from Reuters.  Your line is open.

Maggie Fox: Hi, Dr. Schuchat.  I know that H1N1 is still circulating, but there were some other viruses that some sentinel sites were finding.  There seemed to be an unprecedented amount of other stuff circulating as well.  I was wondering if you know anything about that that you could tell us. 

Anne Schuchat: There are a variety of infectious agents that can cause respiratory illness.  Influenza is a big one.  But there are other viruses and there are other bacteria.  We've been looking at the changes in disease activity.  In particular, the pneumonia and influenza deaths that I mentioned that are over the epidemic threshold, trying to understand whether those deaths we're hearing about are caused by influenza or they're caused by other infectious agents. 

We are seeing in some parts of the country other viruses like rhinovirus and respiratory syncytial virus sometimes called RSV.  That is sometimes accounting for increases in respiratory illness in young children or in elderly people.  The public health workers around the country are looking into these matters, tracking the viruses and bacteria that can cause respiratory infections and trying to help us interpret the results we're seeing from the different syndromic systems. 

But our influenza virus monitoring right now shows virtually all of the viruses that are circulating, this past week, all but two have been the H1N1 virus, not the seasonal strain.  So, let's go to the next question. 

Operator: The next is from Mike Stobbe, Associated Press.  Your line is open. 

Mike Stobbe: Hi, doctor, thanks for taking the question.  Two, actually.  You said that it's possible the virus could continue to spread, but I was curious about, what do you think the likelihood is of a third wave, a full-blown wave considering how many people have been vaccinated, how many people have already been sick, that the virus is not mutating?  And then the second question had to do with the pneumonia and influenza deaths.  I just wanted to clarify your last response.  Are you saying you think those are still mostly due to swine flu? 

Anne Schuchat: Thanks, Mike, for those two good questions.  I think the most likely problem right now is ongoing transmission of H1N1 virus, which week after week continues to circulate, continues to lead to hospitalizations and deaths and is very preventable right now.  I think that is our most likely scenario. It’s just impossible for me to say whether we'll have a very large peak in disease, but we don’t seem to be seeing the disappearance of this virus.  The past several weeks, there's really been steady transmission, rather than a disappearance. 

And we haven't seen the emergence of the seasonal strain.  So I kind of think this virus is going to be finding susceptible people, particularly adults with chronic conditions, the elderly who are much less protected right now because of lower vaccination rates.  And because there's been less disease in their communities. 

We know that school children and younger people have -- are at higher rates of immunization, and probably higher rates of natural protection because there was so much disease already in that group.  So my sense is that, we are not at all out of the woods, because the virus continues to circulate, but the chances of a very large additional wave are very hard to predict.  And maybe less likely than this ongoing transmission, which really can add up over time. 

Your second question was about what I think the increase or excess of pneumonia and influenza mortality means.  And I apologize if I was unclear.  If I was unclear, it's probably because I don't know what the increase in pneumonia and influenza mortality means.  It could be influenza, and if it is influenza, it is most likely the H1N1 virus.  It may be other infectious agents like the pneumococcus and staphylococcus and viruses like rhinoviruses and RSV, or really a collection of all those things. 

Unfortunately when most people with pneumonia die, they haven't gotten all of the tests involved to confirm exactly what caused their death.  Unfortunately, many of our diagnostic tests are not good enough to prove what the cause was.  So we know that the excess deaths with that seasonal curve are usually attributable to influenza.  But we're looking carefully right now, because we have the pneumonia and influenza deaths at that above-epidemic threshold level, but our other indicators are below the thresholds for baseline. 

Glen Nowak: Next question, operator? 

Operator: The next is from Stephen Smith, Boston globe.  Your line is open.

Stephen Smith: Good afternoon.  Thanks for having the call.  I was going to ask, too, about this seeming disparity with influenza levels being below baseline, and influenza and pneumonia, hospitalizations and deaths above baseline.  That leads me to ask this.  Is there any indication that there has been a change in the virulence of the H1N1 virus?  And I’m just wondering what the latest virology testing is showing in terms of genetic composition? 

Anne Schuchat: Thanks.  There's no indication of a change in the virulence of the virus.  We continue to test isolates, as do our collaborators around the world and the genetics really look the same.  The good news is that the antigenic characterization of the virus, what is done to understand the vaccine match, looks really, really good.  The strains that are circulating right now are excellent matches with the vaccine strain of virus.  The other thing I want to say, you know, we're looking at the different indicators, the influenza-like activity is below the baseline, but the pneumonia and influenza deaths are above.  We do continue to see pediatric deaths.  We had another nine influenza-associated pediatric deaths reported this past week.  We were down below that in earlier weeks, and we were sorry to see that number go up.  Some of them are recent, and some of them are older fatalities that are just now being reported. 

As we said all along, the reported episodes are probably the -- are not the full story.  We think more than 1,000 children have died from the H1N1 virus based on the best evaluations we can do.  So I do think that it can be puzzling when the systems show different things.  But I think we continue to look in detail to understand these patterns.  And right now, we aren't seeing signs of a major increase in this H1N1, but we are seeing persistent transmission, including hospitalizations and deaths.  And as I said, vaccination is such an easy step to take to reduce a chance that will happen to you or someone you love.  Next question? 

Operator: The next is from Betsy McKay, "Wall Street Journal."  Your line is open. 

Betsy McKay: Thanks, Dr. Schuchat.  I had two questions. One question is about the pneumonia deaths.  I just wondered what age group most of these deaths are in?  And if that's giving you any clues about the causes? And my second question is about H1N1 vaccine.  I just wondered if you could tell us at this point, given vaccination levels, how much vaccine the government does plan to take delivery of?  Are you still planning -- is HHS still going ahead and taking delivery of the total of 195 million, or 250 million doses?  Or are you scaling back? 

Anne Schuchat: Right.  Thank you.  There have been -- let me give the vaccine doses first and then come back to the other one.  The government has ordered 229 million doses of bulk antigen of H1N1 vaccine.  So not all of that is going to be filled and finished, or decisions may still be under way as to how much of that would be filled and finished.  155 million doses of H1N1 vaccine have been filled, and finished by the manufacturers, and released to the U.S. population.  So that's the story on the vaccine doses of H1N1.  Your other question was about the ages of the pneumonia and influenza excess deaths.  And most of the pneumonia and influenza deaths are in the elderly.  And so that we are looking at patterns by age.  And we're not seeing anything particularly unusual in terms of the age. 

We're looking geographically at places that are seeming to have more hospitalizations and deaths from pneumonia and influenza, and that's what I was mentioning before, where some of those investigations were showing up a bit of rhinovirus or a bit of RSV.  These are active investigations.  And it really highlights for people that sort of muddy -- how muddy it can sometimes be to understand these.  I think you know that the government invests a lot in improving diagnostics for influenza, as part of our pandemic preparedness.  And as we're all a little bit frustrated not knowing what's going on with the pneumonia deaths, it speaks to the need for better diagnostics to other respiratory infections as well.  Next question, please? 

Operator: The next is from Elizabeth Weise at "USA Today."  Your line is open. 

Elizabeth Weise: Thanks so much for taking my call.  I wanted to get a sense of when you're talking to providers who are -- I presume you've got a fair amount of interaction with people out in the field -- what are you all hearing from parents about the concerns about getting their children vaccinated? 

Anne Schuchat: You know, the CDC's tracking has also been looking at that, among parents who haven't vaccinated their children, what are the principle reasons.  Our results are a little bit different from the Harvard poll’s results. 

 We find that the most common reason parents cite is actually that they just don't think their children need the vaccine, for whatever reason.  And in general, we find that in immunization surveys in general, it's usually how bad is this condition, or how common is it, or is it going to happen to me or my child.  That's the driver for those who plan to be vaccinated versus not. 

Concern about side effects is often present.  And that is the number two reason that we see parents express in terms of reasons why they may not have gotten their child vaccinated.  But of course, the -- these data have been gathered -- the ones I’m citing were gathered back in November, earlier in December, before we had such a wealth of safety data. 

So I would say that at this point, it's always understandable for people to wonder about the safety of vaccines.  And it's something we take very seriously at CDC.  But we have an awful lot of data, unprecedented amount of data about the safety right now.  And I think that parents really should be reassured about that.  Next question from the phone? 

Operator: The next question is from Donald McNeil from "The New York times." 

Donald McNeil: The Harvard study found that 40% of parents got the vaccine to their children by the time the survey was taken.  And 13% more plan to get kids vaccinated.  Your response to that earlier, you found overall that quite encouraging.  I would think that would be just the opposite.  The message the CDC has been putting out for months is everyone should get their children vaccinated.  Now it's only 40% of parents have done it.  And maybe it will creep over 13% if everybody does it this month.  Are you really that encouraged?  I would think you would be discouraged. 

Anne Schuchat: Thank you.  I think that we've gone through an extraordinary effort together with the American public to recognize a new threat, this new influenza strain that was causing a pandemic. The companies and NIH developed a vaccine and tested it clinically last summer.  And the public health and medical community offered vaccine to millions of Americans. 

I think that we saw higher coverage with H1N1 influenza vaccine in children than we usually see with seasonal influenza vaccines.  It's only in 2009 that influenza -- the seasonal influenza vaccine became a routinely recommended vaccine for children 5 to 18.  And so I’m encouraged on many fronts that two-thirds of states carried out school vaccinations, that the coverage rates for this H1N1 vaccine effort appeared to exceed past years' seasonal flu vaccine rates.  And that probably what I mentioned the encouraging comment about the poll, I think it was that many people who hadn't yet gotten their children vaccinated were intending to do so. 

So I think that -- I, of course, hope we can do better in future years.  But I think we have a strong baseline to work from.  And as you know, we're not done.  The vaccination effort does continue.  The states are working hard to get the second dose clinics done with schools.  And doctors continue to offer the vaccine every day. 

So I think that we're in a dynamic stage right now, and we're hoping to do a good job with the rest of this year.  And of course, build off this, for the future years.  Because seasonal influenza is a serious disease that kills thousands, and disrupts families.  And we do have an opportunity in future years to have to only worry about one vaccination program instead of two.  So I think that we have a lot to build on for the future.  Next question? 
Operator: The next is from Joanne Silberner, NPR. Your line is open. 
Joanne Silberner: First, I want to make sure I’ve got my definitions right.  When you talk about activity currently being less than the national baseline level, is that for this time of year?  And can you give us a more quantified idea of how much less? 
Anne Schuchat: Right.  The influenza-like illness activity refers to the percent of doctors' visits that are caused by flu-like symptoms.  You know, of all those reasons that doctors are seeing -- that people are coming to the doctors, how many of those visits are due to a flu-like illness.  What we saw this past week was 1.9% of all the doctors' visits in our sentinel system were caused by influenza-like illness visits.  The national baseline is 2.3%.  That national baseline is a three-year average basically.  It's based on, you know, technically it's two standard deviations above the three-year rolling average for what's called the inter-epidemic period.  So during the off-season, what are the numbers?  And on two standard deviations above that turns out to be 2.3%.  Though more detail than you wanted, I think.  Did you have a follow-up or was that the question that you had? 
Joanne Silberner: On the deaths, how much are the deaths, and how new is that?  Has that been all along, or just in the last three weeks?  How much is the separation? 
Anne Schuchat: Sure.  During the fall, when we had a lot of influenza-like activity, we also had a lot of -- quite a -- an increase in the pneumonia and influenza deaths.  There was an 11-week consecutive period where the pneumonia and influenza deaths exceeded what we call the epidemic threshold.  Then they came down.  But, you know, this can go sort of up and down a bit.  And now we have had a -- three more consecutive weeks where we're exceeding the epidemic threshold.  During some of the fall when we had a lot of influenza, and actually during the spring when we had that early wave, we didn't see the excess pneumonia and influenza mortality.  That excess pneumonia and influenza mortality is often highly influenced by what's going on in the elderly, because the elderly are typically those who die from pneumonia and influenza.  Whatever's happening in the elderly can drive those.  So we have had divergence.  But during the peak of disease in the fall, there was convergence.  Both the influenza-like activity was high and so were the excess deaths.  Next question, please? 

Operator: The next question is from Kip Grosenick from Fox News Channel.  Your line is open. 

Kip Grosenick: Thank you.  I appreciate you taking the question.  Doctor.  Since the number of cases of H1N1 are lower than some had originally feared, will the initial response to future pandemics be scaled back, or will what we saw this year as a CDC and national response serve as sort of a blueprint moving forward? 

Anne Schuchat: We have a tremendous experience to learn from.  This pandemic isn't over yet.  And of course, we're still responding.  But we're also trying to harvest the lessons learned, so that we can do better in the future.  How bad a pandemic is, or how severe it is will be a function of many things.  But a critical factor is the influenza virus itself.  If we have the next pandemic, with an influenza virus, like the H5N1 bird flu strain, we need to do a lot more than what we've done this year.  Because our health care system has not been stressed with overflowing intensive care units, and not enough ventilators and so forth.  So we aren't done with our pandemic preparedness, just based on the response we've had here.  So I don't think that scaling back is really what we're talking about.  But more moving forward, learning from this, and getting much of the system to work better.  We've talked extensively about the need to produce large amounts of vaccine more quickly. 

Many of us think that if we had an earlier lead on this, we could have had vaccine available in large amounts before that big surge in the fall.  So that speaks to better, more timely detection everywhere in the world, where the next pandemic virus might be emerging.  Lots of opportunities to improve our diagnostics.  And, you know, if we'd had much more vaccine available early, would we have been able to deliver it promptly. 

We didn't actually have to test some aspects of the system.  So I don't think anybody is thinking about scaling back.  We're thinking about planning based on this experience, and based on the scenarios that could come.  The next pandemic could be much, much worse and we don't want to be any less prepared, we want to be much more prepared.  Next question? 

Operator: The next is from Michelle Merrill from Hospital Employee Health Newsletter. 

Michelle Merrill: Thank you very much for taking my question.  I was interested in finding out if you know anything about vaccination rates of health care workers, specifically whether they were higher with H1N1, and also, illnesses of exposures of health care workers, and any hospital-based transmissions?  Do you have any handle on what occurred? 

Operator: Yeah.  The health care worker vaccination has been a strong interest of ours.  The final data aren't in on that.  We've been collecting information on H1N1 vaccination, as well as seasonal flu vaccination.  There are a couple different types of surveys.  The latest data I saw, things were not all that consistent.  We were waiting until the studies were a little bit more complete.  So I think that it's a critical issue going forward, that we really urge health care workers to protect themselves, and protect their patients.  And vaccination is the best way to do that.  So we're not where we need to be, but we don't have final numbers for either the H1N1 or the seasonal story right now.  In terms of the transmission in health care workers, I don't have information on that today.  So we have time for two more questions. 

Operator: It's from Miriam Falco from CNN medical news.  Your line is open.

Miriam Falco: Thanks, Dr. Schuchat.  Good afternoon.  You mentioned that the response in this whole process has been encouraging.  Have you heard from the pediatricians, and the doctors and the people who were actually the ones giving the vaccines, and gotten any feedback from them on how this has been working? 

Anne Schuchat: In an ongoing fashion, we've been reaching out to the professional organizations, the public health community, many constituents.  We've had begun to have some formal meetings with the education sector.  And I think we formally want to get good input.  We know that the pediatric community is absolutely vital.  They were critical in providing antiviral medicines, caring for kids, providing vaccination.  There was a lot of vaccination in the doctor's office.  And of course, they're the bedrock of our routine program. 

So I think that what we expect in this kind of response is a lot of variability, that doctors' offices in one community saw one pandemic and doctors' offices in another community saw another pandemic.  Sometimes in the same community doctors across town had different experiences, just as parents did.  Some parents whose school their kids went to had the vaccine.  We're trying to do formal evaluations to identify the best practices and know what is the best way we can serve the public, medical community, the nation at large.  Time for the last question? 

Operator: The next is from Tom Randall from Bloomberg news.  Your line is open. 

Tom Randall: Thanks, Dr. Schuchat, thank you for taking my call.  I was wondering about the announcement that they're reducing the expiration date by more than a year.  Could you comment on how many doses are affected by that expiration change and if other companies are doing the change?  And your thoughts about it if the hypothesis that it is somehow related to the syringes and if there are any plans to make changes in the future? 

Anne Schuchat: Right.  This latest correction, I think they're calling it a field correction, includes 12 million doses.  But that's a deceiving number.  The vaccine lots that will be affected in terms of a shorter shelf life amount to 12 million doses.  But the actual number of unused doses is likely much, much lower, because most of those doses were shipped early in the season, when things were being used immediately. 

So, you know, that was one more complexity for the pediatricians and the public to handle, that we wish had not had to occur.  On the other hand, I know that the FDA and the manufacturers are really looking into this.  Of course, the potency issues with the prefilled syringes are a special focus of attention, to understand mechanically what may have been going on, and to learn from that for the future.  So thanks, everybody.  And we appreciate your continued interest in the story. 

Glen Nowak: Thank you, operator.  That concludes this press briefing. 
####
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

H1N1 Influenza not really so Benign...

H1N1 Influenza not really so Benign... 

[A recent journal of biology article highlights what is currently known about the (A)H1N1 influenza pandemic & its not so benign course-DQ]

Animal experiments indicate that influenza A(H1N1) 2009 causes relatively severe disease, yet the human disease has been reported as generally relatively mild. How can this discrepancy be explained?
First of all, although initial reports suggest that most human cases of influenza A (H1N1) 2009 infection are mild, particularly in the developed world, this is somewhat misleading as the symptoms are generally reminiscent of those observed with seasonal influenza infection (fever associated with upper respiratory tract illness) and even seasonal influenza is estimated to cause 250,000 to 500,000 deaths worldwide each year.

Second, up to 40% of infected individuals present with vomiting and gastrointestinal (GI) symptoms, which is higher than for seasonal influenza, and while there is no evidence as yet, this may be indicative of more extensive viral replication. This is actually consistent with three recent studies on the pathogenesis and transmission of influenza A (H1N1) 2009 in ferret models of infection [8,11,12].

All three studies showed that the pandemic strains exhibit more extensive replication in the respiratory tract, particularly the lower respiratory tract, of infected ferrets, as well as in mice [11,12], non-human primates and pigs [11]. Moreover, Maines and colleagues were able to isolate virus from the GI tract of infected ferrets, suggesting an explanation for the increased incidence of GI distress in infected people [12], although no virus has yet been detected in the GI tract of human cases.

All three studies also showed that influenza A (H1N1) 2009 caused more tissue damage in the lower respiratory tract than do typical seasonal influenza strains.

So are you saying the human disease actually isn’t mild?

In some cases, certainly it isn’t. It is important to note that the (H1N1) 2009 virus does cause severe infection in some people, including those who are otherwise healthy. While some fatal cases have been attributed to secondary bacterial infections or exacerbation of other health conditions, as is commonly seen in fatal cases of seasonal influenza in the elderly, an unusual feature of influenza A (H1N1) 2009 infection is severe viral pneumonitis, leading to acute respiratory distress syndrome, prolonged stays in intensive care units and extended use of mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [13,14]. It is unclear what predisposes some people to mild versus severe complications.

And the tissue damage shown in the animal experiments? Isn’t that also indicative of severity?

That is not clear for humans. Although the animal experiments show that influenza A (H1N1) 2009 infection causes more extensive tissue damage than seasonal influenza infection, this could be relatively minor in humans, possibly because of the relatively low binding affinity of the influenza
A (H1N1) 2009 viral HA for human receptors. Human influenza viruses bind their target cells through recognition by the viral HA of cell surface glycoproteins that have sialic acid moieties linked to galactose in a α2,6 configuration.

When Maines and colleagues used a glycan array to compare glycan binding of HAs from influenza A (H1N1) 2009 and 1918 Spanish influenza [12], both showed the same binding specificity and pattern, but the influenza A (H1N1) 2009 HA bound with lower affinity than did the 1918 virus HA. This was attributed to amino acid differ ences in the HA binding site.

Lower binding affinity could affect the degree of inflammation and pathology caused by (H1N1) 2009 infection, so that although the virus seems to cause more tissue damage, the pathology may not be as extensive as that seen in infection with the more virulent 1918 Spanish influenza virus or highly pathogenic H5N1 viruses.

Past Flu infections may give H1N1 protection

Flu may give H1N1 protection

Tuesday, 17 November 2009 10:31

SINGAPORE - People who have had repeated flu infections - or repeated flu vaccines - may have some protection against the new pandemic swine influenza, US researchers in Washington said on Monday. They found evidence that the human immune system can recognise bits of the new H1N1 virus that are similar to older, distantly related H1N1 strains.  "What we have found is that the swine flu has similarities to the seasonal flu, which appear to provide some level of pre-existing immunity. This suggests that it could make the disease less severe in the general population than originally feared," said Alessandro Sette, director of the Center for Infectious Disease at California"s La Jolla Institute, was quoted by the Straits Times. Older less likely to get flu The study, published in the Proceedings of the National Academy of Sciences, may also help explain why many older people are less likely to have severe disease, said Allison Deckhut-Augustine of the National Institute of Allergy and Infectious Diseases. "Adults may have some pre-existing immunity for H1N1," Ms Deckhut-Augustine said in a telephone interview. That does not mean older people are protected from infection, and Ms Deckhut-Augustine stressed that people should still be vaccinated against H1N1.  Swine flu has infected millions of people globally and killed an estimated 3,900 in the United States alone, according to the US Centers for Disease Control and Prevention. Drug makers are struggling to make vaccines and governments are working to vaccinate their populations. Bjoern Peters and colleagues at the La Jolla Institute looked at flu epitopes - molecular markers or structures that the immune system recognises - dating back 20 years.  "We found that the immune system"s T-cells can recognize a significant percent of the markers in swine flu," Mr Peters said in a statement. --------------------oooooo000000oooooo------------------------------  Comments (DQ) It appears that there are still quite a few discrepancies which are emerging from the experiences of the current novel H1N1 influenza. While many reports are now analysed, the most recent CDC report suggested that at best the seasonal flu vaccine seems neutral in its effect in offering any or no protection against the novel H1N1 flu (see last post below). The recent Proceedings of the National Academy of Sciences seem to suggest that people who have been exposed to previous flu infections or vaccinations appear to have some limited protection against the novel H1N1 flu, conferring some form of cross-immunity. Still the new vaccine appears to be the best approach to counter the spread of this H1N1 pandemic.

MMWR: Variable to Low or No Effectiveness of 2008-09 trivalent influenza vaccine against A/H1N1...

Variable to Low or No Effectiveness of 2008-09 trivalent influenza vaccine against A/H1N1...

Since first reports in April 2009 (1), the 2009 pandemic influenza A (H1N1) virus has spread around the world (2). The pandemic virus is antigenically distinct from seasonal influenza A (H1N1) viruses targeted by seasonal influenza vaccines. Results from recent serologic studies have suggested that seasonal influenza vaccines are unlikely to provide substantial cross-protection against infection with the pandemic H1N1 virus (3).

However, how serologic results correlate with the complex immune responses that confer clinical protection remains uncertain. To complement the serologic studies and evaluate the effectiveness of 2008--09 trivalent seasonal influenza vaccine against laboratory-confirmed pandemic influenza A (H1N1) illness, CDC used available data to conduct a case-cohort analysis.

The analysis used surveillance reports from eight states of persons aged <18 years with confirmed pandemic H1N1 illness during May--June 2009. Influenza vaccination coverage estimates for these states during the 2008--09 influenza season (September 2008--February 2009) were estimated for the population cohort by using preliminary Behavioral Risk Factor Surveillance Survey (BRFSS) data (4).

The overall vaccine effectiveness (VE) against pandemic virus illness after adjustment for age group and presence of chronic medical conditions that increase the risk for complications from influenza was -10% (95% confidence interval [CI] = -43%--15%). Current evidence from this study and other studies does not suggest that seasonal influenza vaccination either decreases of increases the risk for acquiring pandemic H1N1 illness. To prevent seasonal and pandemic influenza, CDC recommends vaccination with seasonal and pandemic influenza vaccines.

The case-cohort method produces a vaccine exposure odds ratio, which for this analysis was an estimate of the relative risk (RR) for 2009 pandemic influenza A (H1N1) illness given seasonal influenza vaccination versus no seasonal vaccination. To obtain the vaccine exposure odds ratio, the odds of vaccination among pandemic H1N1 cases was divided by the odds of vaccination among the population as estimated from BRFSS data. Pandemic H1N1 cases were reported to CDC as part of national outbreak surveillance.

The percentage of persons with self-reported seasonal influenza vaccination (receipt of vaccine during September 2008--March 2009) among patients with laboratory-confirmed 2009 pandemic influenza A (H1N1) whose cases were identified in eight states during May--June 2009 was compared with population estimates of vaccination coverage in these states. Only cases of pandemic H1N1 diagnosed in persons aged >18 years in a state providing greater than five reports and with complete patient information on date of birth, illness onset date, presence of a chronic medical condition that increases the risk of influenza complications, and vaccination status were eligible for inclusion in this study.

Out of 941 cases in this convenience sample, 356 (38%) had all necessary data available. The 356 case-patients resided in eight states: Arizona (55 patients), Colorado (11), Connecticut (19), Delaware (27), Kentucky (13), Pennsylvania (30), Texas (187), and Virginia (14). For this analysis, laboratory-confirmed 2009 pandemic influenza A (H1N1) infection was defined as a positive test result at state public health laboratories or at CDC by using real-time reverse transcription--polymerase chain (rRT-PCR) protocols, probes, primers, and reagents approved by CDC.

Vaccination coverage for persons aged 18--29 years, 30--39 years, 40--49 years, and > 50 years was estimated for the eight selected states by using preliminary 2009 BRFSS data from a telephone survey of 20,689 respondents.

Previous BRFSS estimates of vaccine coverage demonstrate that > 98% of influenza vaccination occurs before March of the influenza season (CDC, unpublished data, 2009). BRFSS respondents were considered vaccinated if they 1) said "yes" to either having an influenza shot or nasal spray during the past 12 months, and 2) indicated a month and year of vaccination during September 2008--February 2009.

Five percent of respondents had unknown influenza vaccination status (i.e., don't know, refused, missing, blank, or incomplete date of vaccination). Because BRFSS does not routinely collect vaccination status on children aged <18 years and uses residential landline telephone numbers, analyses were limited to noninstitutionalized adults aged <18 years (4).

Vaccination coverage estimates were adjusted by four age groups and by the presence of a chronic medical condition that increases the risk for complications from influenza. For all states except Texas, the case surveillance forms recorded whether the patient had any of the following conditions: asthma, chronic heart or circulatory disease, metabolic disease including diabetes, or cancer in the last 12 months.

In Texas, the surveillance forms recorded whether the patient had any chronic health condition. The chronic medical conditions for cases were selected to be consistent with those measured by BRFSS, in which survey respondents are asked whether they have ever been told by a doctor, nurse, or other health professional that they have or still have asthma, heart attack, angina, coronary heart disease, stroke, diabetes, or cancer.

Among pandemic H1N1 patients in the analysis, 28% had a chronic medical condition as defined by case surveillance forms, whereas an estimated 22% of the adult population in the BRFSS data from the eight states had at least one of the indicated chronic medical conditions. Within age groups, case and cohort vaccination coverage estimates were adjusted for chronic medical conditions that increase the risk for complications from influenza ("yes" response versus "no") by weighting the stratum-specific estimates by number of cases.

Vaccine effectiveness was calculated as 1 -- RR, where RR was the estimated adjusted relative risk for pandemic H1N1 illness as a function of seasonal vaccination coverage. Relative risks were weighted according to the inverse variances of the stratum-specific log RRs. Appropriate statistical software was used to estimate the 2009 BRFSS stratum-specific vaccination coverage for these eight states.

The overall adjusted VE against pandemic virus illness was -10 (CI = -43%--15%). Estimates of VE varied by age group, ranging from -57% to 15% (Table); the CIs for each age group--specific VE estimate were wider than for the overall VE because of reduced sample sizes within age strata.

TABLE. Effectiveness of 2008--09 seasonal influenza vaccine against laboratory-confirmed 2009 pandemic influenza A (H1N1) illness, by age group --- selected states,* May--June 2009
	No. H1N1 patients	H1N1 patients vaccinated (%)†§	Population cohort vaccinated§¶		Vaccine effectiveness**
Age group (yrs)			%	(95% CI††)	%	(95% CI)
18--29	192	21	20	(16--24)	-8	(-66--30)
30--39	59	36	26	(23--30)	-57	(-176--11)
40--49	60	32	36	(32--39)	15	(-49--51)
≥50	45	58	57	(55--59)	-2	(-86--44)
Overall	356	30	29	(26--31)	-10	(-43--15)
* Arizona, Colorado, Connecticut, Delaware, Kentucky, Pennsylvania, Texas, and Virginia. † Vaccination status was assessed by asking whether the patient had received influenza vaccine during September 2008--March 2009. § Within age groups, patient and cohort vaccination coverage estimates were adjusted for having a chronic medical conditions that increases the risk for complications from influenza (presence versus absence) by weighting the age group--specific estimates by number of cases. Overall estimates were adjusted in the same manner. ¶ Population cohort vaccination coverage was estimated for eight selected states from preliminary data from the Behavioral Risk Factor Surveillance Survey (BRFSS), using a sample of 20,689 respondents (5). Household telephone interviews conducted during March--June 2009 to collect information regarding influenza vaccinations administered during September 2008--February 2009. BRFSS respondents were considered vaccinated if they answered "yes" to either 1) "During the past 12 months, have you had a flu shot?" or 2) "During the past 12 months, have you had a flu vaccine that was sprayed in your nose?" ** Vaccine effectiveness (VE) was calculated as VE = 1 -- relative risk (RR), where RR is the overall RR of 2009 pandemic influenza A (H1N1) illness by seasonal vaccination status. Within age groups, RR estimates were adjusted for chronic medical conditions by weighting the risk-specific estimates according to inverse variances of the stratum-specific log RRs. Overall estimates were adjusted for age group and the presence of a chronic medical condition. †† Confidence interval.

Reported by: P Gargiullo, PhD, D Shay, MD, J Katz, PhD, A Bramley, MPH, M Nowell, MPH, J Michalove, MPH, L Kamimoto, MD, Influenza Div, JA Singleton, MS, PJ Lu, PhD, MD, Immunization Svc Div, National Center for Immunization and Respiratory Diseases; L Balluz, ScD, Div of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion; A Siston, PhD, EIS Officer, CDC.

 

Editorial Note:

These results, taken together with other studies, do not support an effect of seasonal 2008--09 trivalent influenza vaccine in either decreasing or increasing the risk for pandemic influenza A (H1N1). The results are consistent with U.S. serologic and immunologic data (3) and with findings from a recently published study from Australia (5).

In the immunologic analyses, prevaccination and postvaccination sera from recipients of seasonal influenza vaccines during 2005--2009 were tested by microneutralization methods for levels of cross-reactive antibody to 2009 pandemic influenza A (H1N1) virus.

After seasonal vaccination during the 2005--06, 2006--07, and 2008--09 influenza seasons, children aged < 10 years lacked detectable neutralizing cross-reactive antibody to the 2009 pandemic influenza A (H1N1) virus. Among adults aged > 18 years, vaccination with the 2007--08 or 2008--09 trivalent inactivated vaccine provided little or no increase in cross-reactive antibody levels (3).

In Australia, investigators conducted a case-control study using data from sentinel influenza surveillance practices to assess the effect of seasonal vaccine (5). In-house rRT-PCR assays were used to identify 212 patients with pandemic H1N1 influenza and 365 control patients who tested negative for influenza virus infection.

The investigators found no evidence that receipt of seasonal influenza vaccine influenced the risk for being diagnosed with 2009 pandemic influenza A (H1N1) virus infection in any age group (0--4, 5--19, 20--49, 50--64, and >65 years). The overall age-adjusted VE against pandemic virus illness was 3% (CI = -56%--40%).

Findings from other studies examining the effects of 2008--09 influenza vaccine on the risk for pandemic H1N1 virus infection are available. Investigators recently reported results from a hospital-based case-control study conducted in Mexico (6). They reported protection from the 2008--09 trivalent inactivated vaccine against 2009 pandemic influenza A (H1N1) illness.

In this study, 60 patients with rRT-PCR--confirmed 2009 pandemic influenza A (H1N1) were frequency matched by age and socioeconomic status to 180 controls examined at the same respiratory disease medical institution (6). The authors reported a vaccine effectiveness of 73% (CI = 34%--89%).

However, the authors noted that controls had a higher prevalence of chronic conditions compared with population estimates, thereby likely resulting in a higher vaccination coverage level than the source population. In addition, a series of five studies conducted in four Canadian provinces reportedly found that receipt of seasonal 2008--09 influenza vaccine was associated with a 1.5- to 2-fold greater risk for medically attended 2009 pandemic influenza A (H1N1) illness (7); however, these studies have not yet been published.

Another unpublished study used influenza-like illness (ILI) for its case definition in examining the effect of receipt of 2008--09 seasonal influenza vaccine on the risk for 2009 pandemic influenza A (H1N1).

After a large secondary school in New York City experienced an outbreak of ILI, defined as fever (temperature unspecified) with sore throat or cough in April 2009, all students were asked to participate in an online survey assessing ILI and history of influenza vaccination after October 1, 2008.

A total of 2,008 (75%) of 2,686 students completed the survey, and 1,607 (60%) students provided both ILI and vaccination status information. Females represented 55% of survey respondents; mean age for both females and males was 15.9 years. Crude, sex-specific, and sex-adjusted relative risks for infection were similar among vaccinated and unvaccinated students, and the overall adjusted RR was 1.05 (CI = 0.91--1.20) (S. Balter, MD, New York City Department of Health and Mental Hygiene, personal communication, 2009).

A case-cohort design was used for the study described in this report. This study design also is known as case-base: vaccination coverage among persons with illness is compared with an estimate of vaccination coverage in the base or source population.

This design is similar to the screening method often used to quickly estimate VE in outbreak situations, except that vaccination status is sampled in the population rather than using an assumed true value of the proportion of the population vaccinated (8).

A strength of this approach is that it permits rapid estimation of VE after case investigations when existing data on vaccination coverage for the source population is available. A general advantage is that estimating vaccination coverage using a sample from the population rather than from a sample of controls enables dispensing with the rare disease assumption often needed in case-control studies to interpret odds ratios as RRs (9,10).

A disadvantage of the stratified case-cohort method used here is that often estimates of population vaccination coverage can be stratified by only a few variables. For example, in this analysis, VE estimates could be stratified only by four age groups, based on the age distribution of the patients and by the presence of a chronic underlying medical condition that increases the risk for complications from influenza.

The VE estimates might not have been fully adjusted for age or for the presence of specific conditions, and residual confounding by these factors might be reflected in the results. Also, no adjustment could be done for other possible confounders, such as state of residence, which also might have affected the results.

The findings in this report are subject to at least five other limitations. First, no analysis for children aged < 18 years could be performed because limited data were available to determine coverage among children in the 2009 BRFSS.

Second, the 2009 pandemic influenza A (H1N1) cases are not necessarily representative of U.S. pandemic influenza cases because they were identified through surveillance in eight states; different levels of case ascertainment also could introduce bias to the extent that vaccination coverage differed among states. Case ascertainment also might be associated with health-seeking behavior and therefore higher levels of vaccination coverage that could have biased these results in the direction of negative VE.

Third, the representativeness of the results was affected by using BRFSS coverage estimates, because they are obtained from a landline telephone--only survey of noninstitutionalized persons.

Fourth, as with any survey based on self-report of past behavior, a potential for recall bias exists (4). Without record verification of self-reported vaccination status by patients in the study, assessment of recall bias or overreporting bias is difficult, and how such bias might have affected the results is uncertain.

Finally, although more than 350 cases were used to estimate the overall VE, the overall CIs are wide, and the CIs for the age group-specific VE estimates are particularly wide, reflecting the smaller sample sizes for these subgroup analyses. Therefore, point estimates, especially the age group--specific estimates, should be interpreted with caution.

This study is part of a growing body of literature examining the effects of seasonal trivalent influenza vaccines on the risk for pandemic H1N1 illness.

Taken together, the current evidence does not support a significant effect of 2008--09 trivalent influenza vaccine in either decreasing or increasing the risk for 2009 pandemic influenza A (H1N1) illness.

The results from additional studies using more rigorous study designs and methods currently under way in the United States and other countries will further define seasonal influenza VE against pandemic influenza A (H1N1). Studies evaluating the effects of seasonal vaccination on infection with 2009 H1N1 viruses in established animal models for influenza (e.g., ferrets) also are under way at CDC and elsewhere.

CDC and the Advisory Committee on Immunization Practices continue to recommend vaccination with both seasonal and pandemic influenza vaccines to prevent influenza illness during the 2009--10 influenza season in the United States. CDC will continue to monitor the effectiveness of seasonal and pandemic influenza vaccines.

Acknowledgments

This report is based, in part, on contributions by S Lim, MS, D Kapell, MPH, C Zimmerman, MD, T Nguyen, PhD, NYC 2009 Swine Flu Investigation Team, New York City Dept of Health and Mental Hygiene; Arizona Dept of Health Svcs; Colorado Dept of Public Health and Environment; Connecticut Dept of Public Health; Delaware Div of Public Health; Kentucky Dept for Public Health; Pennsylvania Dept of Health; Texas Dept of State Health Svcs; Virginia Dept of Health, and state public health laboratories; J Tate, PhD, Div of Viral Diseases, National Center for Immunization and Respiratory Diseases; W Garvin, C Okoro, MS, Div of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion; and B Silk, PhD, EIS Officer, CDC.

MMWR: H1N1 Update: Influenza Activity, USA, August 30 - October 31, 2009

The 2009 pandemic influenza A (H1N1) virus emerged in the United States in April 2009 (1) and has since spread worldwide. Influenza activity resulting from this virus occurred throughout the summer and, by late August, activity had begun to increase in the southeastern United States (2). Since August, activity has increased in all regions of the United States.

As of the week ending October 31, nearly all states were reporting widespread disease. Since April 2009, pandemic H1N1 has remained the dominant circulating influenza strain. This report summarizes U.S. influenza activity* from August 30, 2009, defined as the beginning of the 2009--10 influenza season, through October 31, 2009.

Viral Surveillance

During August 30--October 31, World Health Organization (WHO) and National Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating laboratories in the United States tested 163,123 respiratory specimens for influenza viruses, 48,585 (30%) of which were positive (Figure 1).

Of the 48,483 (99.8%) specimens positive for influenza A, 32,867 (68%) were subtyped by real-time reverse transcription--polymerase chain reaction (rRT-PCR) or by virus culture. A total of 32,814 (99.8%) of these were 2009 pandemic influenza A (H1N1) viruses, 18 (0.1%) were seasonal influenza A (H1), and 35 (0.1%) were influenza A (H3) viruses.

CDC has antigenically characterized 239 pandemic influenza A (H1N1)viruses collected since September 1. A total of 238 (99.6%) of the 239 pandemic influenza A (H1N1) viruses tested were antigenically related to the A/California/7/2009 (H1N1)pdm reference virus selected by WHO as the 2009 pandemic influenza A (H1N1) vaccine virus; one virus (0.4%) tested showed reduced titers with antisera produced against A/California/7/2009.

Antiviral Resistance of Influenza Virus Isolates

CDC conducts surveillance for resistance of circulating influenza viruses to influenza antiviral medications: adamantanes (amantadine and rimantadine) and neuraminidase inhibitors (zanamivir and oseltamivir). Since September 1, a total of 256 pandemic influenza A (H1N1) virus isolates collected in the United States have been tested for resistance to the neuraminidase inhibitors. All but four were susceptible to oseltamivir, bringing the total number of such resistant isolates to 14 since April 2009.

Twelve of the 14 patients from whom the resistant isolates were collected had documented exposure to oseltamivir through treatment or chemoprophylaxis. Exposure to oseltamivir has yet to be determined for one patient, and another patient had no documented oseltamivir exposure. All 256 tested viruses were sensitive to the neuraminidase inhibitor zanamivir.

Since September 1, one influenza A (H3N2) virus isolate and 152 pandemic influenza A (H1N1) virus isolates also have been tested for resistance to adamantanes (amantadine and rimantadine); all of these virus isolates were resistant to the adamantanes.

State-Specific Activity Levels

During the first week of the influenza season (August 30--September 5), 11 states, clustered mainly in the South, reported widespread activity. By the following week, that number had more than doubled to 26 states. In subsequent weeks, more states reported increased activity. As of the week ending October 31, widespread influenza activity^† was reported by all but two states (Mississippi and Hawaii). In contrast, during the 2008--09 influenza season, no state reported widespread influenza activity before the week ending January 10, 2009.

Outpatient Illness Surveillance

The weekly percentage of outpatient visits for influenza-like illness (ILI)^§ reported by the U.S. Outpatient ILI Surveillance Network (ILINet) increased from 3.5% in the week ending September 5 to 7.7% in the week ending October 31 (Figure 2). ILI activity has remained above the national baseline of 2.3% during this entire period.^¶ Since the week ending October 3, all 10 surveillance regions have reported a percentage of outpatient visits for ILI at or above their region-specific baseline levels. These percentages are all substantially elevated compared with data recorded in previous years over the same period.

Influenza-Associated Hospitalizations

Laboratory-confirmed influenza-associated hospitalizations are monitored using a population-based surveillance network that includes the 10 Emerging Infections Program (EIP) sites and six new sites.**

During September--October, cumulative influenza hospitalization rates for persons aged > 65 years were substantially elevated for this time of year and exceeded or were approaching the end-of-season cumulative rates for the last three seasons.

Preliminary cumulative rates of laboratory-confirmed, influenza-associated hospitalizations reported for children aged 0--4 years were 3.1 per 10,000 population by EIP and 7.3 per 10,000 population by the new sites (Figure 3). Rates for other age groups were as follows: 5--17 years, 1.5 by EIP and 2.9 by the new sites; 18--49 years, 1.2 by EIP and 1.2 by the new sites; 50--64 years, 1.3 by EIP and 1.2 by the new sites; and > 65 years, 1.0 by EIP and 1.1 by the new sites.

On August 30, CDC and the Council of State and Territorial Epidemiologists (CSTE) instituted modified case definitions for aggregate reporting of influenza-associated hospitalizations and deaths. This cumulative state-level reporting is referred to as the Aggregate Hospitalization and Death Reporting Activity (AHDRA).^††

During August 30--October 31, a total of 17,838 hospitalizations associated with laboratory-confirmed influenza virus infections were reported to CDC through AHDRA. On average, 31 states each week reported laboratory-confirmed hospitalizations during that period.

Pneumonia- and Influenza-Related Mortality

Influenza-associated deaths are monitored by the 122 Cities Mortality Reporting System and AHDRA. For the week ending October 31, pneumonia or influenza was reported as an underlying or contributing cause of death for 7.4% of all deaths reported through the 122 Cities Mortality Reporting System, above the week-specific epidemic threshold of 6.7%^§§ and the fifth consecutive week above the epidemic threshold.

During August 30--October 31, 672 deaths associated with laboratory-confirmed influenza virus infections were reported to CDC through AHDRA. On average, 29 states reported laboratory-confirmed deaths each week during that period. The 672 laboratory-confirmed deaths are in addition to the 593 laboratory-confirmed deaths from 2009 pandemic influenza A (H1N1) that were reported to CDC from April through August 30, 2009.

Influenza-Associated Pediatric Mortality

During August 30--October 31, CDC received 85 reports of pediatric deaths associated with influenza infection (Figure 4). Seventy-three of these cases were associated with laboratory-confirmed 2009 pandemic influenza A (H1N1) virus. The remaining 12 pediatric deaths were associated with an influenza A infection for which the subtype was undetermined.

Of the 85 pediatric deaths reported since August 30, a total of 12 (14%) were among children aged < 2 years, nine (11%) were among children aged 2--4 years, 30 (35%) were among children aged 5--11 years, and 34 (40%) were among children aged 12--17 years. Seventy-eight (92%) of the 85 decedents had a medical history reported. Of the 78, 56 (72%) had one or more medical conditions associated with an increased risk for influenza-related complications (3).

Since April 26, CDC has received 145 reports of pediatric deaths associated with influenza infection. Of these, 129 (89%) cases were associated with laboratory-confirmed 2009 pandemic influenza A (H1N1) virus. The remaining 16 pediatric deaths were associated with seasonal influenza or an influenza A virus for which the subtype was undetermined. In comparison, during the preceding five influenza seasons, the total number of reported pediatric influenza deaths ranged from 46 to 153, with an average of 82 deaths each year.

Reported by: WHO Collaborating Center for Surveillance, Epidemiology, and Control of Influenza. L Brammer, MPH, S Epperson, MPH, L Blanton, MPH, R Dhara, MPH, T Wallis, MS, L Finelli, DrPH, T Fiore, MD, L Gubareva, PhD, J Bresee, MD, L Kamimoto, MD, X Xu, MD, A Klimov, PhD, C Bridges, MD, N Cox, PhD, Influenza Div, National Center for Immunization and Respiratory Diseases, CDC; C Cox, MD, EIS Officer, CDC.

Editorial Note:

During August 30--October 31, influenza activity was substantially above historic levels in all U.S. surveillance systems. By mid-October, nearly all states reported geographically widespread influenza activity.

Nationwide, the percentage of visits to health-care providers for ILI was higher than that observed at the peak of any seasonal influenza season since ILINet was implemented in its current form in 1997. Influenza-associated hospitalization rates continued to trend upward in all age groups, substantially above historical rates from the same time period during previous years.

The widespread occurrence of pandemic H1N1 influenza in the United States highlights the importance of understanding and appropriately using available tools for prevention and treatment of influenza.

Particularly important in reducing the impact of pandemic H1N1 infections are recommendations for the use of influenza A (H1N1) 2009 monovalent vaccines and a continued emphasis on early, empiric antiviral treatment of hospitalized patients and others who are ill and at greater risk for influenza-related complications.

Severe outcomes among children, continue to be prominent during the 2009 influenza A (H1N1) pandemic. A total of 145 pediatric deaths associated with influenza infection have been reported since April 26. In comparison, 82 deaths were reported on average during the previous five influenza seasons.

Pediatric hospitalization rates are higher than those of any other age group and are particularly high among children aged < 5 years. These epidemiologic data provide support for ACIP recommendations that include persons aged 6 months-24 years in the initial target groups for vaccination using the influenza A (H1N1) 2009 monovalent vaccine now available (3).

In addition, vaccination providers should vaccinate persons who live with or care for infants aged <6 months because young infants themselves cannot be vaccinated. Other target groups for initial supplies of influenza A (H1N1) 2009 monovalent vaccine include pregnant women, health-care and emergency medical services personnel, and persons aged 25--64 years who are at higher risk for more severe disease because of chronic health disorders or compromised immune systems (3).

The supply of influenza A (H1N1) 2009 monovalent vaccines will continue to increase rapidly through November and December.^¶¶ However, these vaccines are not yet available to all persons who might benefit from vaccination. In the absence of widespread immunity based on vaccination, early empiric antiviral treatment of persons who are severely ill or at high risk for influenza-related complications can reduce the number of severe illnesses from pandemic H1N1.

Observational studies of hospitalized patients with seasonal influenza and pandemic H1N1 influenza have suggested that mortality is reduced among hospitalized patients who received antiviral medications (4 - 5). However, the use of antiviral treatment for hospitalized patients remains suboptimal, as highlighted in recent studies indicating that 21% - 25% of hospitalized patients with laboratory-confirmed pandemic H1N1 did not receive antiviral medications and, among those who did, treatment was often delayed until 1--2 days after admission (6 - 7).

Antiviral medications active against influenza are widely available, and early empiric treatment with oseltamivir or zanamivir of hospitalized persons and others who are severely ill or at high risk for influenza-related complications is recommended (8).

In addition, peramivir, an investigational intravenous neuraminidase inhibitor medication, has recently been made available under an Emergency Use Authorization by the Food and Drug Administration. Peramivir is available for treatment of certain adult and pediatric patients with suspected or laboratory-confirmed pandemic H1N1 (9,10).

The current dominant influenza virus by far is 2009 pandemic influenza A (H1N1); seasonal influenza viruses continue to circulate at low levels in the United States and elsewhere. However, influenza circulation patterns remain unpredictable, and seasonal influenza viruses might circulate more widely later in the influenza season.

CDC will continue to monitor changes in geographic spread, type, and severity of 2009 pandemic influenza A (H1N1) and will issue weekly online FluView reports.*** Additional detailed information regarding 2009 pandemic influenza A (H1N1) also is available online.^†††

Acknowledgments

This report is based, in part, on data contributed by participating state and territorial health departments and state public health laboratories, World Health Organization collaborating laboratories, National Respiratory and Enteric Virus Surveillance System collaborating laboratories, the U.S. Outpatient ILI Surveillance Network, the Emerging Infections Program, the Aggregate Hospitalization and Death Reporting Activity, the Influenza Associated Pediatric Mortality Surveillance System, and the 122 Cities Mortality Reporting System.