I am a faculty member here at the University of Washington and do my clinical work at the VA hospital. My area of research interest is in vaccine preventable diseases but predominantly influenza, influenza epidemiology, and influenza public policy, I currently serve on several national committees that deal with vaccine policy.

Influenza is unlike any of the other agents you may have heard about. This is an incredibly common infection that affects all age groups and all segments of the population. There is no life long immunity to influenza so we are all at risk. Ten to 20% of those who do not receive the influenza vaccine will get influenza this year. Influenza has the potential to cause enormous morbidity and mortality. That is what makes it a real threat to the public health. What I want you to understand is the impact of pandemic and inter-pandemic influenza.

We can go back through recorded history and find descriptions of diseases that were obviously influenza such as a description by Thomson in 1852: "began with a roughness of the jaws, small cough, …a strong fever with a pain of the head, back and legs….". This describes the 3 main elements of influenza: fever, cough, and myalgias." Influenza is a self limited illness so what makes it so significant is the association of influenza with excess mortality.

[Figure:  Excess Mortality]

This slide demonstrates the excess mortality that occurs during the winter months, a time when influenza outbreaks typically occurs. In 1882 there was an influenza pandemic, noted by the large spike in mortality. This graph also shows the tremendous increase in mortality associated with the well known pandemic of 1918. This pandemic killed more people in 6 months (20-40 million) from influenza than the 3 years of World War I. Pregnant women had mortality rates up to 50%. Tissue from deceased persons during this time was fortunately preserved and more recently evaluated by newer laboratory techniques to identify the 1918 strain as an H1N1 influenza type A.

If we look at the great influenza pandemics of the last hundred years there has been a gradual decrease in mortality rate mainly because we have better supportive care now. We have antibiotics for bacterial super infections; we have intensive care units, and a better understanding of the disease pathogenesis. If we look at most pandemics we see a typical U-shaped curve with the largest death rates in the very young and in people over the age of 70. This epidemiology is consistent for interpandemic influenza as well with 90% of the deaths in persons over the age of 70 years.

What is a pandemic?

Any pandemic is an epidemic on a large scale that involves most of the world. In the instance of the 1918 influenza pandemic there was the emergence of a novel influenza A virus in a susceptible population. The reservoirs for many of these influenza viruses exist in the animal population predominately avian species and pigs. Avian viruses have the capacity to reassort with human viruses to produce progeny that possess novel surface antigens with potential to spread to humans. The RNA segments of the virus can transfer RNA between species such as avian or pig flu and they are able to attach to human epithelial cells. If you get the right mix of antigens, you can get a pandemic. Because of this segmented genome you can have many viruses mixing together in certain animal reservoirs which can spread easily in a population. The additional factor is that a substantial proportion of the population has little or no antibody to the novel virus.

[Figure:  Schematic of Surface Antigens of Influenza A]

This slide shows the schematic of an influenza virus with the neuraminidase and hemagglutinin antigens present. Hemagglutinin is a center for attachment of the virus to human epithelial cells. If you block hemagglutinin with antibody or with vaccines you can prevent infections. The neuraminidase is also a surface protein which is important for the virus to spread from cell to cell. By blocking neuraminidase you cannot prevent infection but you can limit spread of the infection. Some of the newer antiviral medications are targeted at the neuraminidase antigens.

Humans have 3 hemagglutinins and 2 neuraminidase antigens that circulate, while birds have 14 hemagglutinins.

The next great pandemic was in 1957. If you compare the antigens circulating before 1957 were H1N1, in 1957 a new antigen H2N2 circulated. Since the H2N2 was new to the population there was a selective advantage for spread and infection rates. In 1968 there was another antigenic shift with the appearance of the H3N2 strain. This strain could be traced to the combination of avian and human antigens.

In 1977 the H1N1 viruses reemerged. These were identical to human epidemics strains from the 1950’s. Since 1977 we have had both H1N1 and H3N2 as well as influenza B strains circulating in the population. Influenza B viruses can cause severe epidemics but do not undergo the same degree of mutations therefore have not been associated with the pandemics.

In 1976 there was a small outbreak of influenza in a military camp. There was concern that this could turn into an epidemic similar to the magnitude of the 1918 pandemic. The US Public Health Service and the Center for Disease Control launched a mass immunization campaign. Unfortunately, there was a higher than expected incidence of Guillain Barre Syndrome related to the influenza vaccination. The expected epidemic of this "swine flu" strain never materialized but the fallout from the adverse vaccine effect has taken years to overcome.

In 1997 in Hong Kong there were 18 confirmed cases and 6 deaths from influenza due to a new avian influenza virus (H5N1). Fortunately this virus in extensive testing and epidemiological studies did not appear to spread from person-to-person. Each of the 18 cases had direct contact with poultry. Many of the chickens and other bird species however were ill with influenza and in an effort to control this outbreak there was a mass slaughter of chickens and other infected birds.

While this may have seemed like a drastic public health approach, there were no further cases in humans of this influenza strain in the ensuing months. Since 1997, there have been an additional 2 mass slaughters of chickens for viral strains H5N1 and H9N2 in Hong Kong.

What is needed for effective influenza control?

• Global surveillance is key. The CDC and the WHO collaborate to establish global influenza surveillance which tries to determine what the annual circulating viral strains will be. This includes human strains as well as key animal strains that are prevalent.
   
• Improvement in vaccine production methods. Current methods are somewhat archaic. Viruses need living tissue to grow and influenza virus is grown on embryonated hens’ eggs. After the surveillance designates which strains are likely to circulate, the next step is to grow the viruses for vaccine development every year. You can see that in an epidemic or pandemic situation we might not have the ability to have an appropriate vaccine in time before the virus has circulated the globe.
   
• We need improvements in vaccine delivery. It takes time to get the vaccine from the developers out to the community where it then needs to be distributed.
   
• Liability programs also need to be developed for vaccines produced in response to an epidemic. The 1977 swine flu and Guillian Barre Syndrome has made it difficult for the United States to undertake mass immunization campaigns.
   
• We need rapid communication, emergency preparedness, contingency vaccine and antiviral guidelines and plans.

[Figure:  Slide Seasonal Occurrence of Flu etc. . .]

This graph depicts the interpandemic period of circulating respiratory viruses from 1996-1999. Influenza can be seen to be a winter time disease which usually peaks in January. This is also true of the other respiratory viruses such as parainfluenza and respiratory syncytial virus.

[Figure:  Attack Rates]

shows the percentage of mortality attributable to pneumonia and influenza from 1996-2000.

Paul Gleason in a study on influenza in a community mapped out the time course of community illness in Houston. He showed the first effect you see is an increase in school age absenteeism. The children bring the disease home and this is followed by the parents becoming ill and increases in work place absenteeism. About this same time there are increases in emergency room visits and increase in hospitalizations for severe illness and secondary pneumonia infections. Death from influenza typically lags by about 2 weeks after the initial signs of outbreak hits an area.

[Figure:  Attack Rates of Children < 5]

Our study looked at the symptomatic attack rates during this interpandemic time period from 1974-1998. The rates are variable from year to year as are the viral strains predominant in the society. Children in general have higher attack rates than adults.

[Figure:  Influenza Attributable Events]

This slide shows the influenza attributable events. If you assume a 30% attack rate of influenza in children, then only a percentage of these children, or 6-14% of all children will be ill enough to warrant an outpatient visit.  This slide also shows that at least 1/2 or more of these children will receive a course of antibiotics. This of course is a concern for the overuse or perhaps misuse of antibiotics for influenza which is a viral infection.

[Figure:  Hospitalizations]

This slide shows that those severely affected from influenza requiring hospitalization follows a U-shaped curve where the very young and the very old are most susceptible. This information helps us to determine who should receive the influenza vaccination.

General considerations for a vaccine policy

• Vaccine should be well tolerated and safe to administer
   
• There should be supportive evidence of clinical effectiveness
   
• It should reduce or ameliorate the burden of disease. The disease we are vaccinated against should have a significant burden on society or serious morbidity and/or mortality
   
• It should be cost effective
   
• It should be successful at reducing the transmission which can be evaluated by epidemiology studies. Are we protecting the appropriate individuals which stop the spread of the disease in a community?

What are the recommendations for influenza vaccination?

Who Should Be Immunized?

• Persons at high risk for complications of disease.
   
• Persons over age 65 years
   
• Adults and children who have chronic pulmonary or cardiovascular disorders, including asthma
   
• Adults and children who require regular medical follow up for chronic diseases (such as diabetes, renal disease, HIV infection etc)
   
• Women who will be in the second or third trimester of pregnancy during influenza season.
   
• Residents of chronic care facilities or nursing homes regardless of age.
   
• Children aged 6 months to 18 years who are receiving long-term aspirin therapy.
   
• Who should be immunized? Persons at high risk of transmitting disease to others.
   
• Health care workers
   
• Household members, including children, of persons in high risk group
   
• Employees of chronic care facilities, assisted living facilities, or persons who provide home care to high-risk groups.

Who Should Not Be Immunized?

• Persons known to have anaphylactic hypersensitivity to eggs or other components of the vaccine
   
• Persons with acute febrile illnesses
   
• Caution in persons who have had previous Guillain Barre Syndrome

How efficacious is the influenza vaccine?

• In healthy children and adults: it is 70-90% effective in preventing culture confirmed influenza
   
• In the elderly: it is 30-70% effective in preventing hospitalization for pneumonia and influenza
   
• In the frail elderly: it is 30-40% effective in preventing illness, 50-60% effective in preventing hospitalizations, and 80% effective in preventing death.

A study by Potter et al looked at influenza vaccination of health care workers in long term care facilities. He took 1059 residents of 12 geriatric long-term care facilities in Glasgow. They were randomized for whether their health care workers were offered influenza vaccination or no vaccine. The primary outcome was patient mortality. There were equal numbers of vaccinated and unvaccinated persons. He showed a significant reduction in mortality which persisted over time in the long term facilities where the staff was vaccinated.

A study by Hurwitz et al looked at the importance of children in the transmission of influenza. He randomized 10 day care center. There were 127 children and 328 household contacts. He vaccinated 60 children for influenza and 67 children received hepatitis A vaccine. He showed that there was a difference in any respiratory illness, and a larger difference for respiratory illnesses with fever. The effectiveness showing a 16%-47% reduction of illness in the contact of the children who received the vaccines.

[Figure:  Monto Study]

Monto et al vaccinated 87% of the school children in Tecumseh, Michigan in 1970 and compared respiratory illness rates with a neighboring community which did not vaccinate their school aged children. They were monitoring for respiratory illnesses, not specific to influenza. They saw that in every single age group where the children were vaccinated there was a reduction of overall respiratory illness.

Reichart et al conducted a study measuring the effect of influenza vaccination in Japanese schoolchildren. From 1977 to 1987 influenza vaccine coverage rates were >80%. Coverage rates began to drop in the late 1980’s and early 1990’s. The numbers of monthly deaths in Japan were obtained for the years 1949-1999. The winter excess of mortality in Japan was sharply reduced from the mid-1970s to about 1992. The timing of these changes matched that of the Japanese Influenza Vaccination program. The conclusion from this study was that the vaccination of 80% of schoolchildren averted 30,000 deaths per year in the elderly.

[Figure:  Influenza Vaccine Coverage Rates]

This slide shows our goals for coverage among the high risk populations. We give about 80 million doses of influenza vaccine which is one of the highest influenza vaccine rates in the world but it still is less than one-third of the United States population.

Limitations of Vaccine:  What About Antiviral Medications?

• Vaccines do not prevent all influenza infections, is there a role for antiviral medications for treatment or prevention.
   
• Some suggested uses for antiviral medications are for prophylaxis in those at risk who are unable to be vaccinated; for people with immunodeficiency, for outbreak control and pandemics, and for treatment.

Limitations of Antiviral Medications:

• Patients in trials need to be treated usually within 48 hours for any significant benefit
   
• Participants in the studies were predominantly healthy young adults with uncomplicated influenza.
   
• There have been no head to head comparisons of the antiviral medications. The comparisons have been predominately between drug and placebo.

Amantadine and Rimantidine

• Interfere with replication cycle of influenza A viruses. They do not have effectiveness against influenza B
   
• 70-90% effective in preventing illness caused by influenza A when administered prophylactically to healthy adults.
   
• Can reduce the severity and duration of influenza A
   
• Inexpensive compared with newer agents
   
• Associated with adverse effects such as dizziness and other CNS effects
   
• Rapid development of resistance to both agents can occur

Neuraminidase Inhibitors: Oseltamivir and Zanamivir

• Have activity against influenza A and B
   
• Less frequent development of resistance
   
• Have not shown better efficacy than the older antivirals
   
• Much more expensive than amantidine
   
• Oseltamivir side effects include nausea and vomiting
   
• Zanamivir (inhaled) can cause bronchospasm and is contraindicated in anyone with significant COPD or asthma

In summary, influenza is a major cause of morbidity, mortality, and lost productivity worldwide. Influenza vaccine administration should remain the cornerstone of influenza control efforts. Pandemic preparedness plans should be multifaceted and include surveillance, prevention and communications components.

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© 2002 University of Washington Department of Health Services Box 357660, Seattle, WA 98195-7660 e-mail: carrieho@u.washington.edu