Much Ado About the Flu

Health Officials Worry About Bird Flu, Vaccine Supply, and Pandemic Threat

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Cover Story - December 2005  


By  Erin Prather
Associate Editor  

For most people, fall is associated with leaves changing, football, and unpacking warm sweaters. However, physicians know the season arrives simultaneously with the appearance of an old foe - the influenza virus. With memories of last year's vaccine shortage still fresh in their minds and the threat of a worldwide spread of the current avian flu virus A (H5N1), physicians must diligently monitor this annual threat that can cause havoc not only for their patients, but also for themselves.

The U.S. Centers for Disease Control and Prevention (CDC) reports that every year more than 200,000 people are hospitalized with flu complications, and about 36,000 die from the virus. It says the best way to prevent the flu is for people to get a flu shot each fall.

But that's sometimes easier said than done.

Last year, Chiron Vaccines, a California-based biotechnology company that produces influenza vaccine, lost its license because of contamination problems at its England plant. Nearly 50 million doses were destroyed, causing a vaccine shortage that panicked the public.

In October this year, physicians who had not received all or most of their vaccine shipments complained to their local county medical societies, the Texas Medical Association, and state health officials. Currently only four companies are approved to produce flu vaccine in the United States. Manufacturers elected to stagger their deliveries in case of a possible shortage. Chiron's license was not reinstated until Oct. 12.

A September CDC bulletin said four manufacturers expect to provide influenza vaccine during the 2005-06 influenza season.

"Sanofi Pasteur, Inc., projects production of 60 million doses of TIV (trivalent inactivated influenza vaccine). Chiron Corporation projects production of 18-26 million doses of TIV. GlaxoSmithKline (GSK), Inc., whose license application was approved by the Food and Drug Administration on Aug. 31, 2005, projects production of 8 million doses of TIV. MedImmune Vaccines, Inc., producer of live attenuated influenza vaccine (LAIV), projects production of approximately 3 million doses. However, because of the uncertainties regarding production of influenza vaccine, the exact number of available doses and timing of vaccine distribution for the 2005-06 influenza season remain unknown," the September CDC bulletin said.

"The influenza vaccine came out and was produced as we expected it," said Lisa Davis of the Texas Department of State Health Services (DSHS) Immunization Branch. "Sanofi, a very large manufacturer, said it was going to ensure that its distributors staggered shipments according to the CDC's recommended high-risk groups. We predicted that physicians would receive 25 percent of their vaccine shipment in September, 25 percent by mid-October, and the rest in November. Unfortunately the staggering resulted in the false belief that there is a vaccine shortage. Next year we plan on working with organizations, like TMA, to communicate with physicians so that type of misconception does not happen again."

Ms. Davis also says many factors can play into when a physician's office receives its vaccine order. These include from what company the vaccine was ordered, when and how it was ordered, and whether it was ordered through a distributor or directly from the manufacturer.

"Any of these can have an affect," she said. "It's important that each year physicians check on their flu order, especially if there is a staff turnover. Often a nurse or office manager who ordered the vaccine in the past leaves and no one checks about ordering next year's supplies."

Because vaccine shortages occurred in three of the past five years, the CDC established a priority list for immunization of the elderly, infants, and other high-risk groups that expired on Oct. 24. The CDC said in late October that the vaccine supply is adequate and that everyone is eligible for immunization.

In a late October news briefing, federal health officials warned that the threat of a pandemic flu could spur the sale of fake versions of the antiviral drug oseltamivir (Tamiflu). Officials advised the public to seek the drug through their physicians to make sure they get the genuine product. 

"Never Seen Influenza Like This"  

In October, the CDC announced that researchers had successfully reconstructed the influenza virus A (H1N1) that caused the 1918-19 influenza pandemic. They confirmed that the 1918 strain originally developed in birds and had similarities to today's avian bird flu. Terrence Tumpey, a CDC research scientist who assembled the virus, demonstrated the 1918 virus's avian-like characteristics by injecting it in fertilized bird eggs. It killed the eggs, just like the avian bird flu does. Human-based strains don't kill fertilized bird eggs.

Even before these latest findings, CDC officials were troubled by the prospect of a worldwide influenza pandemic. The 1918-19 virus, also known as the Spanish flu, killed an estimated 20 to 50 million people worldwide, 500,000 of them in the United States. (See "The Killer Flu," March 2005 Texas Medicine , pages 19-22.)

In the book The Great Influenza: The Epic Story of the Deadliest Plague in History , author John M. Barry provides an account of one 1918 physician.

"He diagnosed the disease as influenza. But he had never seen influenza like this. This was violent, rapid in its progress through the body, and sometimes lethal. This influenza killed. Soon dozens of his patients - the strongest, the healthiest, the most robust people in the county - were being struck down as suddenly as if they had been shot."

Years later, in February 1957, the Asian flu A (H2N2) was identified in China. By June it had spread to the United States where it caused an estimated 70,000 deaths. The last pandemic flu also came from Asia. Named the Hong Kong flu A (H3N2), it was the least deadly, although it still killed 34,000 in the United States alone during the winter of 1968-69 . Many experts believe the next pandemic is not only inevitable, but also overdue.

The influenza virus's ability to slightly alter its structure has frustrated scientists for years and is the reason the influenza vaccine must be changed annually. There are two ways the influenza virus can change. The first is an "antigenic drift" that occurs through small changes in the virus over time. Antigenic drifts produce the new virus strains that may not be recognized by antibodies to earlier influenza strains.

The other change is called "antigenic shift." It is an abrupt, major change in the influenza A viruses, resulting in a new influenza virus that can rapidly infect humans because they have no immunity against it. The development of these new viruses is the kickoff of the world threat known as pandemic flu. This spring, the House Energy and Commerce Committee heard testimony from national health officials about reemergence of worrisome avian flu strain A (H5N1). The first known appearance of the strain occurred in Hong Kong during 1997. It infected 18 people and caused six deaths. By 2003 and early 2004, reoccurring poultry outbreaks occurred in eight other Asian countries. At one point, officials believed the avian flu had been controlled due to poultry slaughter, but more cases eventually emerged. By October 2005, the strain had struck 116 people, killing at least 60. There were also reports of infected birds in European countries.

"Identified cases within birds have now been found in at least a quarter of the globe," said committee member U.S. Rep. Michael C. Burgess, MD (R-Texas.) "There have been cases where the virus has moved from birds to other species, and humans have become infected. Nearly all have been due to direct contact with infected birds or infected surfaces. On occasion, there has been human-to-human transmission, but that has not occurred with any degree of ease. People in similar situations as those transmission cases have not become infected, so the virus has not mutated to where it can transfer from human to human easily. That's the step it has to take to trigger the onset of a world wide pandemic. The U.S. population has no immunity and therefore no protection against this strain should that happen."  

 Following the terrorist attacks of Sept. 11, 2001, the CDC required all states to develop a plan to address potential bioterrorism agents. One of the agents identified was influenza, because a pandemic could be started with the intentional release of an altered influenza strain. The CDC acknowledges that it won't take a terrorist; a pandemic originating from natural sources inevitably will occur.

DSHS developed its own pandemic influenza preparedness plan in 2002. It outlines strategies by which state and local health care systems can work together to reduce pandemic influenza-related morbidity, mortality, and social disruption. (See "Texas Prepares for Pandemic.") 

Barbara Quiram,  PhD, director of the USA Center for Rural Public Health Preparedness and an associate professor at the Texas A&M University School of Rural Public Health, has been actively involved with the plan's review.  

"Some individuals at both the federal and state levels think that one of these days the U.S. will be hit by a pandemic flu outbreak. A diverse committee has reviewed the Texas plan for different perspectives. Our role was to decipher its appropriateness in relation to rural health needs. Planning at both levels has included detailed strategies on how to immunize entire population groups and also how to distribute preventative medication in case of exposure," she said.  

Vaccine's Role in a Pandemic World

In a meeting with congressional and administration leaders last May, the Infectious Diseases Society of America (IDSA) said the United States is unprepared to respond to the next flu pandemic. 

Andrew T. Pavia, MD, chair of the IDSA Pandemic Influenza Task Force, said the 2004-05 vaccine shortage highlighted the fragility of the country's vaccine supply. "If this had been a pandemic year, we would have been in serious trouble. Now is the time to fix these problems and develop the ability to respond, before the pandemic strikes," he said.  

The Atlanta Journal-Constitution reported in October that "health officials at the local, state, and federal level are sounding alarms over the United States' lack of preparedness for a possible flu pandemic stemming from the spread of H5N1 avian influenza, which has already emerged in 14 countries and killed at least 61 people. The U.S. government's delayed response to Hurricane Katrina is further raising concerns about the country's ability to handle a widespread outbreak of deadly flu," it said.

"We are far from being able to do what we optimally could do to protect people," CDC Director Julie Gerberding, MD, told the newspaper. IDSA estimates vaccinating the U.S. population against pandemic flu might require 600 million doses of vaccine, possibly two doses per person. Even in a best-case scenario, the society predicts it would take four to six months to produce vaccine and stresses that the country needs greater production capability.

Dr. Burgess agrees, and says vaccine manufacturers' fear of potential lawsuits inhibits vaccine production. 

"Our liability system has not helped vaccine production. Congress needs to address that, so more manufacturers will be encouraged to go back into the vaccine business. It will become easier to manufacture vaccine once we move away from the egg-based system to a cell-based system. Until then it will definitely take several months to develop a vaccine against a pandemic."

Since 2003, the World Health Organization (WHO) has worked with laboratories in its influenza network to develop vaccines against A (H5N1). In August, Sanofi Pasteur announced that its vaccine produced positive results in the first round of testing in healthy adults. However, the amount of antigen needed for the vaccine is 180 mcg versus the 15 mcg given in annual flu shots. There also is a chance the vaccine might become less effective should the A (H5N1) virus mutate. Other companies threw their hats into the ring, especially when it became apparent governments would be willing to pay. 

Government officials have indicated that the military might be used in controlling an outbreak of the disease. Madisonville family physician Andrew Eisenberg, MD, a member of the TMA Council on Public Health and director of a FluMist pilot program in Leon County (see "The FluMist Experiment"), suggests additional development of local response mechanisms. 

"A lot of people are concerned because the government said that should a pandemic outbreak occur it would have the military step in. That may in fact be a viable solution, since they have the largest infrastructure. However, why not develop local response that incorporates a variety of people so if one link is missing it can still be done? And it can be done by people whom folks know and trust, instead of guys in army suits carrying guns. If we can distribute flu vaccination at the schools, why can't that same system be used to distribute antiviral medication if that's what's chosen to be the appropriate response?"

Dr. Quiram says the A&M School of Rural Public Health is working on a pandemic flu toolkit. Envisioned even before the latest avian flu reemergence, the toolkit will be Internet-based with articles, resources, links, and sample materials on how to talk to the media and educate the public. 

" We decided we would do this back in July. The very first thing we decided to work on was pandemic flu. However, we were actively involved with the public health response aspects of the two hurricanes and have not worked on the toolkit as much as we would like. It will be available nationally, we anticipate by May 2006."  

Dr. Burgess offers fellow physicians this advice on what they can do to prepare for a possible pandemic: " Remember what we learned with the SARS virus," he said. "The SARS outbreak was contained with no vaccines available or effective treatments because physicians, nurses, and other health professionals were aware of it and where it was located. Quarantine and watching for the disease really controlled how far it went. As a result, we didn't have an outbreak like they experienced in Toronto. Even without an effective treatment or vaccine for the virus, quarantine and epidemiology can really play a big role in containment."

Pandemic or not, Dr. Eisenberg adds that health care workers need to be immunized against seasonal influenza.

"Health care workers need to remember that they spread disease. Physicians need to be immunized; you want to set an example for the rest of your health care team. Make sure they all get immunized and provide it for them. Unfortunately, or sometimes fortunately, you can have a systematic infection with influenza. If you're not immunized and do have a systematic infection, you could potentially be spreading that infection to your patients. We are doing a tremendous disservice to our patients if we don't get immunized ourselves."

Erin Prather can be reached at (800) 880-1300, ext. 1385, or (512) 370-1385; by fax at (512) 370-1629.  


The FluMist Experiment

Leon County health officials are conducting a study focusing on an alternative vaccine to fight the flu. The FluMist Pilot Program seeks to develop a template for expedient, nondisruptive distribution of the FluMist vaccine among 700 students from kindergarten through 12th grade. Through a partnership of MedImmune Vaccines, Leon County health officials, and school nurses, students receive FluMist for free in their school cafeterias.

Program director Andrew Eisenberg, MD, says he anticipates the study, which was to begin Nov. 1, will show reduced school costs due to decreased absenteeism among students and faculty. He also cites recent research that vaccinating children could be more beneficial to preventing flu outbreaks than immunizing the elderly. 

"Studies have shown there is more bang for the buck by immunizing kids rather than high-risk groups. If the vaccine is universally in the school population, that has a greater impact than the traditional tiered system, which can be confusing, difficult to use, and may not work as well. Immunizing kids is better than immunizing adults. Not only does it demonstrate to kids the importance of vaccination, it promotes preventative health interventions over acute interventions."

Signed consent forms from parents are required before students can participate in the study. Students will not be given FluMist if they have asthma, diabetes, chronic conditions that require medication, or are allergic to eggs. Dr. Eisenberg says he hopes 90 to 100 percent of the students and faculty members will participate in the program.

"It will be difficult to tell in a mild flu year if the program made a difference. However if it's a bad influenza season, the school could potentially be an island of wellness among others that have much higher influenza incidents. FluMist may have a much broader protection against mismatched strains. The influenza virus could change mid-season and become a strain that vaccine shots are not very effective against," Dr. Eisenberg said.

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What to Do If the Avian Flu Shows Up in Your Office


An outbreak of the highly pathogenic avian influenza A (H5N2) among poultry on a farm in Gonzales County last year - the first in the United States in 20 years - prompted the U.S. Centers for Disease Control and Prevention (CDC) to alert physicians to steps they should take in evaluating patients who may be exposed to the illness. The outbreak was detected by routine state monitoring for avian influenza and eventually contained.

"There is no epidemiologic link between the H5N1 virus in Asia and the H5N2 virus in Texas," the CDC said. But, it added, physicians and other health care professionals should be alert for respiratory illness among persons who may have been exposed to infected poultry. It issued the following recommendations:

  • Persons who develop a febrile respiratory illness should have a respiratory sample (e.g., nasopharyngeal swab or aspirate) collected.
  • The respiratory sample should be tested by reverse-transcription polymerase chain reaction (RT-PCR) for influenza A, and if possible for H1 and H3. If such capacity is not available in the state, or if the result of local testing is positive, then the CDC should be contacted and the specimen should be sent to the CDC for testing. Virus isolation should not be attempted unless a biosafety level 3+ facility is available to receive and culture specimens. (Texas does have RT-PCR capability.)
  • Optimally, acute- (within one week of illness onset) and convalescent-phase (after three weeks of illness onset) serum samples should be collected and stored locally in case testing for antibody to the avian influenza virus should be needed.
  • Texas physicians who encounter a case of avian flu should report it immediately to the Texas Department of State Health Services Infectious Disease Division at (512) 458-7676. 



Texas Prepares for Pandemic

At the end of October, the Texas Department of State Health Services (DSHS) posted on its Web site a draft of the proposed Texas Pandemic Influenza Preparedness Plan for public review. Citing the current bird flu virus (H5N1) as a possible cause of the next pandemic flu, the plan lists these key points:

  • The target audiences for the plan are primarily regional and local health departments, hospital planners, and emergency management planners who will develop response plans. It serves as a guide to local planning, as well as delineating DSHS activities.
  • In general, experts estimate that an international outbreak (pandemic) due to a new hemagglutinin variation of influenza may have a 25-to-50-percent attack rate, meaning that between 5 and 10 million Texans could become infected.
  • The outbreak could kill between 75,000 and 250,000 Texans.
  • Two waves of pandemic influenza are predicted to occur. The second wave will strike about three to nine months after the first wave.
  • The next pandemic will require an estimated three weeks to three months to reach North America following international identification. In addition, experts believe the next pandemic will involve sustained transmission of highly pathogenic avian influenza. The DSHS plan discusses the H5N1 virus as the next pandemic influenza threat; however, the agency acknowledges that other novel viruses may emerge in the future.
  • Lessons learned from hurricanes Katrina and Rita demonstrate that special populations are at risk for accessing and using emergency services both in the private and public sectors. Pre-pandemic efforts must be made to identify special populations, as well as mechanisms to ensure community delivery resources exist or are considered.
  • During an influenza pandemic, the bulk of the vaccine will be distributed through the public sector, with federal and state governments controlling the purchase and distribution while the vaccine is in short supply. DSHS will establish mechanisms for allocating and distributing the vaccine. Vaccine will be used to vaccinate priority groups as defined by the DSHS/CDC guidelines.

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