The scientific community is all too familiar with the dangers an influenza pandemic could bring. The politicians and general public are starting to become aware of the issue as well; indeed, one can hardly open a newspaper or turn on the television without hearing about “bird flu.” So, what’s actually being done to prevent an influenza catastrophe? What are the issues? What can be done?

These are the questions that keep public health officials awake at night, because the answer is always that we’re not doing enough. While we may be resigned to the fact that a future pandemic can’t be completely prevented, the damage can be minimized. Today, I’ll begin discuss the problems we face, and the proposed solutions to counter them, when it comes to pandemic influenza preparedness.

The recognition of an influenza pandemic has the capacity to change the world overnight. It takes months to manufacture an influenza vaccine, and antivirals are in limited supply. In developing countries, they need not even worry about these: they will simply be out of their reach, due to the cost and limited availability that can be expected in the event of a pandemic. Foreign travel would be decreased, or halted. Domestic travel may be curtailed as well. And this is just for starters. A year-long (or, worst case scenario, multiple-year) pandemic could be a catastrophe like none we’ve seen in almost a century. Will it get to that? No one knows, but we need to prepare for that as one possibility.

The Good, The Bad, and The Ugly

Is this just more fear-mongering? The 2003 SARS experience is an instructive example. It showed how fast an infectious agent could globe-trot: once the virus emerged in China, it spread to five countries within 24 hours, and had reached every continent except Antarctica within a few months. Though the epidemic ended up being fairly small in terms of infections and fatalities (~8000 cases and 800 deaths), the financial impact was massive. In Canada, Toronto was the epicenter of the epidemic, as a traveler from Hong Kong began the wave of infection in that city that would go on to claim 43 lives and infect 438. The economic cost of this? An estimated $419 million to tourism alone; another $763 million on health care. The cost to the Asia-Pacific region has been tagged at the $40 billion mark; flights to the area decreased by 45% from the previous year. Keep in mind, these numbers are for a fairly small, fairly contained, 6-month epidemic. Influenza pandemics can last 12-36 months, and influenza is much more highly transmissible than the SARS coronavirus.

Due to both international travel and international trade, an influenza pandemic is necessarily an international issue. This may seem obvious, but when influenza response plans are made, they are all too often drafted to be specific to the community, the state, or the nation. This is all well and good, but unrealistic. Comprehensive preparedness needs to involve and coordinate all different levels, and many different types of entities. Specifically, it needs to involve those in the private sector as well as the public sector; currently, many companies have no plans in place should a pandemic occur, and many government plans don’t go far enough in collaborating with various companies whose assistance they may need in the wake of a pandemic. There are a number of repercussions that may hit industry heavily. Manufacturing of non-necessities and other “trivial” activities may be scaled back in order to conserve scarce resources. At the same time, production of critical goods–food, medicines, everyday items such as soap, gasoline, etc.–would need to be preserved with a diminished workforce and crippled supply chain. Our medical, military, and service positions (police, firefighters) may be weakened, due to not only illness/death in the ranks, but also because some will refuse to put themselves at further risk.

I mentioned developing countries earlier. In many areas, there are already governments in chaos, or on the verge of it. An influenza pandemic would serve to further de-stabilize these regions, as the government becomes increasingly helpless to assist their populace. This, in turn, can work to spread the pandemic further, as refugees flee into new areas, bringing their microbial stow-aways along with them.

Insights from mathematical models

They’re trite but true: “an ounce of prevention is worth a pound of cure;” and “knowledge is power.” Mathematical modelers work at the interface of math and biology in order to turn knowledge about infectious disease biology into targets for prevention. By tweaking the parameters and assumptions built into the model, they can see which variables have the greatest effect on outcome. 2 such analyses were published in the past 2 months, Strategies for containing an emerging influenza pandemic in Southeast Asia in September 8th’s Nature, and Containing pandemic influenza at the source in Science‘s August 12th issue. Both were focused on southeast Asia; both looked mainly at targeting antivirals to the at-risk population as a way to control the outbreak. They also looked at the effects of reducing the “social distance” between individuals (reducing their number of contacts), and the effect of quarantine. (See here for some cool supplemental movies that illustrate all this). Both determined that it should, in theory, be possible to contain a pandemic at its source, if the virus has a basic reproductive rate (R0) of below ~1.8; that is, each infected person infects less than an average of 1.8 others. These reports have led to an increased push by many world governments to stockpile one of these antiviral drugs, Tamiflu. I’ll discuss tomorrow the implications of and problems with this decision.

What about vaccines?

Clearly, an effective vaccine that could be produced well in advance of a potential or looming pandemic would be ideal. However, right now, that’s simply not possible. First, we don’t have the corporate backing. The number of companies willing and able to produce influenza vaccine has dropped off precipitously in the past 2 decades, from more than a dozen in 1980 to only a few in 2004. This is a pragmatic decision; the result of both mergers and a simple lack of profitability for the company. Vaccines are not big cash cows; indeed, they can potentially be drains. Vaccines are difficult to design and test, and with an increase in the anti-vaccine climate in the United States, it’s easy to see why some companies simply choose to avoid the issue. Flu vaccines are even more of a pain than other vaccines. Due to the frequent changes in the circulating influenza viruses, the vaccines must be made rapidly, increasing the risk of contamination or other mistakes. New batches need to be made every year, and can’t be banked for sale in subsequent years. Finally, the viruses need to be grown in live chicken eggs. This is particularly a problem with H5N1. I mentioned yesterday that this virus was nicknamed “chicken Ebola” due to the fact that it is highly lethal in chickens–and that includes chicken eggs. There have been some advances in growing the virus in eggs, but there’s no guarantee that, should we be facing a pandemic with this virus, the eggs could be cultivated fast enough to mass-produce a vaccine in time for it to have any effect on stemming the epidemic. What we need, badly, is 1) a cell culture-based method of vaccine production, getting rid of the eggs; and 2) a pan-influenza vaccine: one that works against all (or at least, most) strains of the virus. Work is being done on both of these, but it’s not something that’s going to ameliorate the situation for awhile yet.

Another concern involves the group targeted for vaccination. In typical years, those who are designated “high risk” have first dibs at the influenza vaccine in most areas. According to the CDC guidelines, these include:

1.) People at high risk for complications from the flu:
• People 65 years and older;
• People who live in nursing homes and other long-term care facilities that house those with long-term illnesses;
• Adults and children 6 months and older with chronic heart or lung conditions, including asthma;
• Adults and children 6 months and older who needed regular medical care or were in a hospital during the previous year because of a metabolic disease (like diabetes), chronic kidney disease, or weakened immune system (including immune system problems caused by medicines or by infection with human immunodeficiency virus [HIV/AIDS]);
• Children 6 months to 18 years of age who are on long-term aspirin therapy. (Children given aspirin while they have influenza are at risk of Reye syndrome.);
• Women who will be pregnant during the influenza season;
• All children 6 to 23 months of age;
• People with any condition that can compromise respiratory function or the handling of respiratory secretions (that is, a condition that makes it hard to breathe or swallow, such as brain injury or disease, spinal cord injuries, seizure disorders, or other nerve or muscle disorders.)

2.) People 50 to 64 years of age. Because nearly one-third of people 50 to 64 years of age in the United States have one or more medical conditions that place them at increased risk for serious flu complications, vaccination is recommended for all persons aged 50 – 64 years.

3.) People who can transmit flu to others at high risk for complications. Any person in close contact with someone in a high-risk group (see above) should get vaccinated. This includes all health-care workers, household contacts and out-of-home caregivers of children 0 to 23 months of age, and close contacts of people 65 years and older.

However, would these be the wisest people to target during a pandemic year? In typical years, if we plot the mortality as a function of age, we see a “U-shaped” curve: the oldest and youngest die at the highest rates. However, in pandemic years (1918 being the most dramatic example), we may see a “W-shaped” curve: the old and young still die, but those between the ages of ~15-40–the “young and healthy” who normally don’t have to worry about dying from influenza–also experience high mortality rates (see below):

Should we target this “middle” group for vaccination in the event of a pandemic? If so, and anticipating limited vaccine supplies, do we do it in addition to, or instead of, the other high-risk groups? These are questions that need to be addressed and ironed out long before a pandemic strikes.

Another approach is to target vaccination to those most likely to spread the virus, rather than to those most likely to die from it. A recent paper in The American Journal of Epidemiology suggests that vaccinating 3 and 4-year-olds may be the way to stem influenza outbreaks. Currently, children over 2 aren’t a target group for the vaccine; increasing coverage in the 3-18 age population may indirectly reduce overall mortality by reducing spread of the virus through the community.

What we need, like, yesterday

Even the best planning can fall through when the completely unexpected happens. As hard as we try to incorporate all kinds of variables and possible outcomes, sometimes you just can’t see an issue until it slaps you in the face. Despite many years of study, there are still too many unanswered questions about influenza. We need surveillance, surveillance, surveillance. We need better numbers about who the viruses are infecting, and where. We need to capture those asymptomatic infections, and examine as many viruses as we can at a molecular level to see how the virus is evolving. We need to sample as many animals as we can, to get a better handle on the ecology of the virus. We need to do this not only in Asia and the United States, but worldwide. We need to have incentives for companies to sink time and money into influenza vaccination research programs. We need additional anti-influenza drugs. We need better response plans at all levels. We need to figure out what to do with the surge of patients and, inevitably, corpses that will be a result of an influenza pandemic. We’ve recently seen the effects of a localized disaster on a community (and the effect of poor planning/response afterwards); during a pandemic, many of the largest cities in the U.S. would experience a shortage in hospital and morgue space. Even our supply of respirators would be overwhelmed. In the U.S., 75-80,000 of the 105,000 mechanical ventilators are in use at any given time for ordinary medical care. During influenza season, typical use increases to 100,000. Were a pandemic to strike, we may fall short by as many as several hundred thousand ventilators–and the situation is similar in all developed countries, so we can’t count on our allies to bail us out.

Depressed yet? All is not lost. There are some plans in place (whether they will be effective is another story…), and there are also steps you can take, as an individual, to prepare. More on that tomorrow.

Other posts in the series:

Day 1: History of Pandemic Influenza.

Day 2: Our adventures with avian flu.

More resources on pandemic influenza:

  • CIDRAP Pandemic influenza news
  • Infectious Disease Society of America (IDSA) Pandemic/Avian flu
  • CDC’s site on Avian flu
  • Flu wiki