Real threat of pandemic flu makes influenza draft plan a page turner

Practical, ethical questions dog vaccine, antivirals

The danger of the next influenza pandemic has become so crystal clear and ever present that the recently released federal pandemic influenza plan has become something of a page turner among the normally dry reading requirements of the infection control professional. The draft document by the Department of Health and Human Services (HHS) is being reviewed by many as if it may have to be implemented all too soon.1

"There isn’t any doubt, the pandemic influenza proposed plan could not have come at a better time," says William Schaffner, MD, chairman of the department of preventive medicine at Vanderbilt University Medical Center in Nashville, TN.

"It is commanding the serious attention of health care professionals and their academic and scholarly organizations. If it had come at a quieter time, people might have put it [aside]. But with avian flu looming, I think that this will compel attention and get everyone engaged in the process. That’s a good thing," Schaffner notes.

Like an engine trying to start, avian influenza sputters up annually in Asia and threatens to complete the genetic reassortment necessary to unleash a pandemic flu strain on a susceptible planet. The virus has found its way from birds to humans but, so far, has been unsuccessful in mutating into an easily transmissible strain. However, the grim consensus is a spark eventually will fire and a new pandemic strain will appear for the first time since 1968.

"We’re pretty concerned," says Scott Harper, MD, a medical epidemiologist in the influenza branch at the Centers for Disease Control and Prevention (CDC). "These warnings keep raising their heads. We have had these [recurring threats] since 1997; but this time, the geographic spread of disease is so immense that control measures have to be looked at carefully and differently. For instance in Hong Kong, in 1997, that was a very closed, defined population, and you could go in and cull all of the birds and know that you had gotten rid of the problem for the time being. But now the disease is so widespread in the bird population in Asia, culling is going to be part of the solution; but it is not going to be the only answer."

In addition, there was a recent ominous report that pigs in China have been infected with the H5N1 avian strain, setting up the classic mixing vessel scenario where bird and human strains reassort within and emerge from swine.

"I guess that result was anticipated; but now that is has been documented, it raises our level of anxiety somewhat," Schaffner continues. "Every influenza expert says, It is not a matter of whether; it is a matter of when [pandemic flu will emerge].’ You can’t predict the when, which makes it especially unsettling. As I see it, the pandemic plan and the investment that we have to make in it is kind of crudely analogous to buying an insurance policy on your home. It’s one of those things you hope you never have to use, but you would be unwise not to have it."

Similarly, a recently reported vaccine manufacturing problem that may affect supplies of the 2004-2005 flu vaccine only underscores how important vaccine production will be during a pandemic, Schaffner says. "[That also] comes around at the right time.

"It provides another stimulus for people to look at the pandemic plan very seriously. One of the elements of the plan has to do with trying to enhance the number of manufacturers of influenza vaccine and to diversify the way influenza vaccine is actually created so that you have cell-based mechanisms as well as egg-based mechanism for the development of vaccines," he adds.

The sheer size of an influenza pandemic is somewhat difficult to imagine, but it would certainly dwarf the considerable chaos and concern caused by severe acute respiratory syndrome (SARS).

"In past pandemics, influenza viruses have spread worldwide within months and are expected to spread even more quickly given modern travel patterns," the HHS plan states. "Pandemic viruses also have the ability to infect, within a year, one-third or more of large populations and lead to tens of millions of deaths."

How bad would it be for hospitals? Schaffner, who is about as experienced a hand as you can find in infection control, considered that question and offered a realistic assessment.

"Three or four years ago, every hospital in the city of Nashville was full in the middle of the flu season," he says. "In pandemic flu, it would be much worse. Hospitals have had some taste of this but have not been stressed to the degree of severity. Most hospitals have some experience with the regular annual outbreaks of influenza, some of which are more severe than others. But if you’re really talking about pandemic influenza, we’re in deep trouble, because the health care facilities of entire communities are going to be completely dedicated to taking care of people seriously ill with influenza."

Schaffner and colleagues have partially rolled out their facility pandemic/disaster plan when severe community flu outbreaks began straining hospital beds and resources.

"Last year, we had a sudden onslaught over a period of a week of early influenza," Schaffner recalls. "All of sudden, we had this big pressure on beds, the hospital was full, and we began to see patients back up in the emergency room who needed admission. We actually activated phase I of our bioterrorism/disaster response plan, got the group together, and discussed what to do," he notes.

The hospital put into effect a program to review the status of every patient who was in the hospital during the course of one morning, then attempted to promptly discharge every patient who did not absolutely need to be in the hospital.

"We discharged a fair number of people, therefore we were able to admit people from the emergency room," Schaffner adds. "We did not have to move into phase II of our plan, which was to cancel elective admissions, discharge a lot [more] people, designate certain wards as influenza wards. We thought of it at the time as a fire drill, as an exercise that taught us a lot about how our planning might actually work in real life."

While incoming patients will be one considerable problem, the prospect of controlling influenza transmission within hospitals during a pandemic is equally daunting.

The HHS plan notes that nosocomial influenza outbreaks are more likely to occur during a pandemic because of the large number of patients, staff, and visitors who will be infected. There will be difficulties implementing optimal infection control practices due to increased patient loads, staff shortages, and use of nonroutine or volunteer staff. Schaffner says he is doubtful standard infection control measures for influenza (i.e., droplet isolation precautions) will be that effective in a pandemic situation.

"Aside of vaccination, I have never been convinced that what we do during influenza season substantially inhibits the spread of influenza in the hospital," Schaffner says. "We will go to vaccination if possible, use of chemoprophylaxis if possible, and then obsessive attention to hand washing. I think we might go to things such as limiting visitors in order to curtail the spread of influenza within hospitals. It’s going to be very serious because I think conventional infection control is relatively ineffective when you’re dealing with an infection that can be spread [so easily]. This infection can be transmitted for 24 hours or even longer before anyone becomes ill so you can have a completely well person in your institution who is a transmitter. That can be a health care worker, a patient, or a visitor."

Antivirals and vaccine development 

Given the infection control challenges, it is understandable why planners have placed so much emphasis on rapid vaccine development and the use of antivirals. The latter likely will be the primary defense in the interim between pandemic emergence and vaccine development. Given that, some think the plan has insufficient detail on exactly how antivirals are going to be produced and distributed.

"The plan is a work-in-progress document," says Arnold Monto, MD, professor of epidemiology in the school of public health at the University of Michigan in Ann Arbor. "We need to flesh it out, and one of the things that concern me greatly is the issue of stockpiling of antivirals. With vaccines, we know there will be delays. There are scientific problems plus logistic problems. With the antivirals, there are only logistic problems. We know that the antivirals, particularly oseltamivir, would work. It is only a question of how much we are going to have available."

Use of antiviral prophylaxis has been up to 70% to 90% effective in preventing symptomatic influenza infection caused by susceptible strains, if prophylaxis is begun before exposure to influenza, the HHS plan states. Also, treatment with one class of agents, neuraminidase inhibitors, has been shown to decrease severe complications such as pneumonia and bronchitis and to reduce hospitalizations. Limitations of prophylaxis and therapy include drug availability, logistics of delivery to priority groups, side effects, potential development of resistance, and cost, the plan notes.

"Given the limited supply, prophylaxis should be limited to those who are supporting the goal of maintaining . . . public safety, providing critical response capacity, and other essential public health services," the HHS plan explains. "Target groups, to be defined by state health departments, might include frontline health care workers, public health personnel, those who provide essential community safety services, workers culling influenza-infected animals, and those involved in influenza vaccine manufacture who are at greatest risk of exposure."

Current discussions indicate antivirals may be gathered in push packages ready for rapid dispersal such as antibiotics in the Strategic National Stockpile, Harper says. As antivirals are dispensed and used, the race to develop a pandemic vaccine will be critical. The plan estimates it will require six to eight months to produce a vaccine once the pandemic strain emerges. Avian virus is so lethal to poultry that is has been called the "chicken Ebola," but he says scientists will still be able to use chicken eggs in vaccine development.

"The vaccine that is produced will almost certainly be done in chicken eggs," Harper adds. "The way that is done is taking a virus and using some reverse genetic procedures to develop a virus that is similar antigenically, but it does have the same pathogenic characteristics so that you can grow that virus in eggs. Just this sort of procedure is under development right now with this current H5 strain."

Using cell-based culture technology to develop vaccine without chicken eggs is a goal for the future, but "if we had a pandemic that started in the next six to 12 months, that would not be a major technology used to develop the vaccine. It would be the reverse genetic process," he explains.

Once the first lots of vaccine are available, there likely will be much greater demand than supply. Vaccine will need to first be targeted to priority groups that will be defined on the basis of several factors.

These may include: the risk of occupational infections/transmission (e.g., health care workers); the responsibilities of certain occupations in providing essential public health safety services; impact of the circulating pandemic virus on various age groups; and heightened risks for people with specific conditions, according to the HHS. In other words, tough choices will have to be made, particularly when supplies of antivirals and vaccine are both scarce.

"Under our current concept of vaccine distribution, the emphasis has always been on individual protection of those persons at highest risk of the complications of influenza," Schaffner says.

"Well, it could be argued that in a pandemic circumstance, the people who should be at initial consideration for getting the vaccine might be public safety, police, and fire as opposed to the frail and elderly. There is going to be discussion about that. Likewise, let’s say we have a certain stock of neuraminidase inhibitors. Should the drug be used principally for treatment of the very sick, or should it be used as prophylaxis of people who are providing essential services?" he asks.

Indeed, it is best to have these difficult discussions now; and by soliciting comment, the HHS has decided not to simply impose a plan from on high, Schaffner notes.

"These are issues that are difficult both pragmatically and ethically," he adds. "If there is a pandemic, they won’t be resolved to everyone’s satisfaction. There is no perfection here; this is a very elaborate coping mechanism."


1. Department of Health and Human Services. Pandemic Influenza Response and Preparedness Plan. Web site: