Denise and Gary Palmer lost their 15-month-old daughter, Breanne, to complications of the flu in December of 2003. Breanne did not receive an influenza vaccination because her doctor said she should not get vaccinated due to an ear infection she had at the time; however, Denise said, “There is not a day that goes by that I don’t think about what if my daughter had been vaccinated against the flu? I believe had she been vaccinated she would still be alive today, and I would still be able to hear her laughter.”

As a mother who lost a daughter to the flu Denise knows just how harmful the influenza virus can be in a year where the virus is only considered to be a usual epidemic season. Here, she shares her thoughts on the potential of a pandemic: “I am very concerned about the possibility of a pandemic. An influenza pandemic occurred in 1918 where over 50 million people worldwide died and I believe it is only a matter of time before this happens again. Pandemics have occurred throughout history; it is not a question of if, rather it is a question of when. I read a report on the Centers for Disease Control and Prevention’s (CDC) Web site about the 1918 influenza pandemic, and the flu strains that are circulating today are direct descendants of the strain that killed so many during the pandemic. Our family has planned for a pandemic by going to the Web site www.flu.gov
and downloading the Pandemic Influenza Planning Guide. Using the guide, we have gathered supplies for the possibility of a pandemic. Most of the supplies recommended in the guide are things we should have on hand for emergencies anyway, and not just for a pandemic.”

Background Information

As previously discussed in the first chapter, when the hemagglutinin (HA) or neuraminidase (NA) proteins of the strain of virus circulating in the population are closely related to those seen in previous years, we have a typical epidemic season with approximately 10 percent of the population becoming infected with the virus. However, when the HA or NA proteins of the strain of virus circulating in the population are substantially different than seen in previous years then pandemics can occur. Pandemics are consistently associated with high infection rates with up to 40 percent of the population becoming infected and substantially greater numbers of people hospitalized and dying than in epidemic years. This is because only a relatively small percentage of people, if any, have immunity to this new virus.

The combination of a large number of susceptible people and a highly contagious virus are classic features of all pandemics. Pandemic virus enters into a community via one or more infected people. An ill person may infect two to five additional people during a pandemic as compared to approximately one other person during epidemic years. Once the pandemic strain is present it will spread throughout the community over one to two months. The spread of the virus occurs at different times around the world often over a several year period. These pandemic waves can start at any time of the year, but typically are most intense during the fall and winter seasons in temperate climates, while year round outbreaks can occur in tropical climates. During some pandemics seasonal influenza viruses have circulated during the same time period as the pandemic virus adding to the burden of disease.

Past Influenza Pandemics

Previous pandemics have been characterized by major changes in the genetic makeup of the virus, which results in higher attack rates due to the lack of immunity to the virus in large portions of the population. The absence of immunity is particularly common in children and young adults, while older adults may have partial immunity due to exposure to a related virus in a previous pandemic. This age-based difference in immunity to a pandemic strain of influenza virus is a likely reason that there is a shift in the mortality curve to younger age groups during some pandemics when compared to epidemic years. For example, exposure to A/H1 subtypes that circulated prior to 1873 may have offered some protection against disease in middle age and older adults during the 1918 pandemic where the highest mortality rate occurred in young adults.

During the past three centuries there have been at least 10 pandemics. A distinctive feature of pandemics is the rapid spread of disease worldwide typically taking between six to nine months. Three human influenza pandemics occurred in the 20th century, each resulting in illness in approximately 20 to 30 percent of the world population. The most severe previous pandemic occurred in 1918 and was due to an H1N1 influenza virus whose genetic sequence is substantially different than the H1N1 virus causing the 2009 pandemic strain. The 1918 pandemic killed greater than 50 million people worldwide, including many young. The 1957 and 1968 pandemics were due to H2N2 and H3N2 influenza strains, respectively (see Figure 4).

Subsequent to 1968 new viruses containing other HA types (e.g., H9) have caused disease in a limited number of humans, but until the occurrence of the novel influenza A (H1N1) strain these viruses have not been able to easily spread between people. In 1997 the avian H5N1 influenza virus was first detected and this virus is now widespread and endemic in various species of birds in Asia. However, human-to-human transmission has occurred only on rare occasion during the past decade and unless the H5N1 virus acquires the capacity to spread easily between humans, a pandemic due to this virus will not occur.

The 2009 Pandemic

The pandemic began in March 2009 in Mexico and is caused by a novel influenza A (H1N1) virus that had not been detected previously in any species. Pigs are known to act as a mixing vessel where strains of influenza virus from birds, pigs and humans can exchange and reassort genes and create a new triple reassortant virus that has genes that produce internal and external viral proteins from all three species. Up until the emergence of the novel H1N1 virus, other triple reassortant viruses had been circulating in pigs for over a decade and occasional transmission from pigs to humans occurred, but these strains had not gained the ability to spread between humans. The novel H1N1 strain differs from the other triple reassortant viruses in that it efficiently spreads between humans, but does not easily spread amongst pigs or between pigs and humans. It is this ability to easily pass from human to human that enabled this virus to cause the current pandemic. The specific genetic factors that enable the novel H1N1 virus to be transmitted among persons remain unknown at this time.

The novel H1N1 virus also differs substantially from the avian H5N1 virus that has been circulating amongst the bird population for over a decade and has caused concern that it might cause a pandemic. The avian H5N1 virus has no swine genetic material and does not easily spread between humans. While there have been over 400 confirmed human cases of H5N1 (with >50 percent mortality) the great majority of these have occurred in Asia in people who had direct contact with chickens in farms or outdoor poultry markets. The novel H1N1 virus is associated with a much lower mortality rate than the H5N1 virus.

The 2009 pandemic was associated with many of the common clinical findings noted with seasonal influenza. Greater than 90 percent of those who became ill had fever and cough. The incidence of gastrointestinal symptoms, including vomiting and diarrhea, varied in different populations (5 percent to 40 percent), but overall was more common than in most epidemic and pandemic years. During the 2009 pandemic the attack rate (the number of people who became ill due to the novel H1N1 virus) was much higher than with seasonal influenza (~30 percent versus ~10 percent, respectively). Therefore, even though the hospitalization rate and mortality rate were similar to what is seen in seasonal influenza, the number of people admitted to the hospital and dying was greater than normal because the attack rate was much higher.

In most years influenza virus can cause focal outbreaks of disease in the summer, but overall disease activity markedly decreases. This is thought to be due to the viability of the virus being better in the low humidity seen in the cooler months and also schools being closed for the summer. In contrast to most years, during the summer of 2009 the novel H1N1 virus continued to cause many outbreaks of disease throughout the northern hemisphere (e.g., in summer camps). During the first wave of disease (from March to August 2009) in the southern hemisphere where the winter season was approaching, both seasonal influenza virus and the novel H1N1 virus were co-circulating. However, the novel H1N1 virus soon became the dominant cause of infection and caused widespread disease. Many countries developed problems with outpatient facilities being overwhelmed with patients and their inpatient facilities having inadequate numbers of beds, particularly in the intensive care units. Additionally, there were shortages of healthcare workers due to illness, ventilators and supplies (e.g., masks). Similar to seasonal influenza, the 2009 pandemic infected mainly children and young adults, but unlike seasonal influenza most of the hospitalizations and deaths due to the novel H1N1 virus were in young people. The median age of patients with confirmed illness in various countries, including the U. S., was 12 years (Figure 5). The median age of hospitalized cases in the U.S. was 20 years (Figure 6); this was markedly different than what was seen with seasonal influenza (Figure 7). The median age of fatal cases was 37 years (Figure 8). This was markedly different than what was seen with seasonal influenza (Figure 7).

Worldwide hospitalization rates were reported to be one to 10 percent of those who developed clinical illness. Of those hospitalized in the U.S., 10 to 20 percent were admitted to the ICU and about 10 percent of hospitalized patients required mechanical ventilation for an average of nine days. The most frequent cause for admission to intensive care units during this pandemic was pneumonia due to the novel H1N1 virus itself. This is in contrast to other pandemics and seasonal influenza where most people died of secondary bacterial pneumonias due to S. aureus or S. pneumoniae. While secondary bacterial pneumonias were not the leading cause of death in the 2009 pandemic, these bacterial infections remained an important cause of hospitalization and deaths, particularly in children.

The risk for hospitalization and death was highest in those with underlying risk factors (Figure 9). Predisposing conditions that increased the risk that a person would require hospitalization or die were present in approximately 70 percent of those who died and included lung (including asthma), heart, diabetes, renal, liver, neurologic and blood diseases. Additional risk factors included pregnancy and possibly those with severe obesity.

Pregnant women were noted to be at much greater risk than the general population for hospitalization and deaths. This increased risk in pregnant women had also been noted in previous pandemics, particularly during the 1918 pandemic.

Antiviral Medicines

The emergence of resistance of H3N2 seasonal influenza viruses to the adamantanes (amantidine and rimantidine) and H1N1 seasonal viruses to one of the neuraminidase inhibitor, oseltamivir, during the past decade made it clear that reliance on antiviral drugs as the major weapon in preventing infections during a pandemic was fraught with hazard (see Chapter 3 for more information about antiviral drugs used to treat influenza).

As part of the worldwide pandemic planning process, approximately 220 million courses of oseltamivir (Tamiflu®, 10 capsules taken over five days) had been sold by Roche Pharmaceuticals since 2004 to various countries that, for the most part, put the drug in their stockpiles for treatment of people during the next pandemic. Roche licensed several other producers to make a generic version of the drug and this was estimated to increase the amount of oseltamivir that could be made to approximately 400 million courses per year. Additionally, in August 2009, regulatory agencies in many countries (e.g., the U. S. Food and Drug Administration [FDA]) increased the shelf life of oseltamivir from five to seven years, which meant that stockpiled drug whose expiration date was approaching could now be used during the current pandemic.

At the onset of the 2009 pandemic, oseltamivir was widely prescribed for both treatment and prophylaxis of the novel H1N1 virus. The initial recommendations included treatment with a neuraminidase inhibitor (oseltamivir or zanamivir) of hospitalized patients or those known to be at higher risk for seasonal influenza, since at that point there was very little known about the specific risk factors for severe outcome due to the novel H1N1 virus. Those recommended for treatment included hospitalized patients >65 or <five years of age, or those with certain underlying medical conditions. Prophylaxis with these same drugs was recommended for these same groups of people if they had exposure to a confirmed case.

During the summer of 2009 most circulating novel H1N1 virus remained susceptible to oseltamivir and zanamivir. However, a small number of patients with oseltamivir resistant H1N1 virus infections were reported. While these cases were not related to one another, the fact that the novel H1N1 virus had demonstrated the capacity to become resistant to oseltamivir was of concern. Additionally, information about what groups of people were at high risk for developing serious complications from this virus was also becoming clearer. Based on these factors on October 16, 2009 the CDC revised their recommendations as noted below so that only those at high risk for serious consequences from the novel H1N1 virus would be treated or receive prophylaxis with these antiviral agents:

• Antiviral prophylaxis should be used judiciously in order to decrease opportunities for development of antiviral resistance.

1. Prophylaxis for prevention of illness in healthy children or adults following exposure to ill persons is not indicated.
2. Antiviral prophylaxis may be considered for persons at higher risk from complications due to influenza. Careful observation for symptoms following an exposure combined with early treatment if symptoms develop could be an appropriate alternative to prophylaxis in some settings.

• Healthy patients with uncomplicated illness need not be treated with antivirals.
• Antiviral treatment with either oseltamivir or zanamivir is recommended for all patients with confirmed, probable or suspected cases of pandemic influenza A (H1N1) virus infection who are hospitalized or who are at higher risk for influenza complications (e.g., asthmatics).
• Isolation of ill persons, good hand and respiratory hygiene, and vaccination (when available) should be the cornerstones of strategies to prevent transmission of pandemic influenza A (H1N1) viruses.

Then on November 4, 2009, the CDC posted the following quick facts for clinicians on antiviral treatment:

Many 2009 H1N1 Patients Can Benefit from Antiviral Treatment
All hospitalized patients with suspected or confirmed 2009 H1N1 should receive antiviral treatment with a neuraminidase inhibitor – either oseltamivir or zanamivir. Moderately ill patients, especially those with risk factors for severe illness, and those who appear to be getting worse can also benefit from neuraminidase inhibitors.

No Risk Factors Does Not Mean No Antiviral Treatment
While antivirals are recommended for treatment of 2009 H1N1 in patients with risk factors for severe disease, some people without risk factors may also benefit from antivirals. In fact, 40 percent of children and 20 percent of adults who end up hospitalized with complications of 2009 H1N1 have no risk factors. Clinical judgment is always an essential part of treatment decisions.

Pandemic Vaccine

The CDC announced at the Advisory Committee on Immunization Practices (ACIP) meeting in June 2009 that 40 million doses of pandemic vaccine should be available in the U.S. by September 2009 – 120 million doses of vaccine would be available by October 2009 and 600 million doses would be available by March 2010 (enough to vaccinate everyone in the U.S. with two doses, if needed). This was a substantial increase from previous estimates. It was based on the fact that during the past decade the U.S. government had invested billions of dollars to increase the plant manufacturing capacity to make influenza vaccine, and, in addition, the government had contractual agreements to buy influenza vaccine from various influenza vaccine companies with manufacturing plants both inside and outside the U.S. Based on these revised estimates of vaccine availability, the CDC announced that there would be a specially called meeting of the ACIP to determine if the U.S. vaccine prioritization scheme, which had last been revised in 2008 would need to be changed.

The ACIP met on July 29, 2009 and decided to revise the 2008 vaccine prioritization scheme based on a number of assumptions, including:

1. The severity of illness and groups at higher risk for infection or complications will be similar to what has initially been observed during the onset of the 2009 pandemic.
2. The U.S. would have 120 million doses of pandemic vaccine ready for use by October 2009. Adequate supplies of licensed vaccine can be produced for everyone in the U.S. by February or March 2010.
3. Two doses of pandemic vaccine would be needed for protection.
4. Pandemic vaccine and seasonal vaccine availability will overlap and both will be recommended for many population groups.
5. Initial demand for vaccination would be about the same as for seasonal vaccine, but could increase quickly as community transmission increased.
6. Vaccine distribution would be timely, but there would still be mismatches between supply and demand at the local level.
7. Implementation of the pandemic vaccine program will pose many challenges.

The presumption that the amount of vaccine available would be substantially greater than previously predicted allowed many of the groups that were contained within priority tiers one to four in the 2008 scheme to now be included in the new first priority tier grouping created at the July 2009 ACIP  meeting. The criteria used to decide who would be placed in the top priority group were:

1. Severity of illness and risk for complications due to the novel H1N1 virus.
2. Likelihood of developing illness due to the novel H1N1 virus.
3. Contribution to overall burden of severe illness.
4. Protection of healthcare system functions.
5. Reduction of societal impact.
6. Potential for indirect protection of more vulnerable contacts.

Based on these parameters the following five groups, totaling 159 million people, were chosen to be in the first priority group (Figure 10). The specific groups and the reasons for putting them in the first priority tier is noted below:

Healthcare workers (HCWs; ~14 million people)

• Increased absenteeism of HCWs due to the novel H1N1 virus would reduce healthcare system capacity and quality.
• Infection of HCWs with novel H1N1 virus had already been reported.
• HCWs are a potential source of infection of their patients.

Pregnant women (~four million women)

• Higher risk of complications based on data from seasonal influenza, past pandemics and the current pandemic.
• Potential for protection of infants who cannot be vaccinated by preventing the mother from getting the disease and possibly by the transfer of their antibodies against the novel H1N1 virus to their infant while in the womb.

Household contacts and caregivers for children younger than six months of age (~five million people).

• Infants less than six months of age do not make antibodies to the vaccine.
• Young infants are at higher risk for influenza-related complications and hospitalizations.
• Immunizing everyone in the household to protect the infant is called “cocooning” and could decrease the chance that the infant develops influenza.

All children six months to 24 years of age (102 million people)

• This age group has the highest incidence of illness.
• Explosive outbreaks in schools are a prominent feature of the current pandemic.
• This age group is a major source of infection for the entire community.
• Illness of children keeps parents from being able to go to work.
• This age group has a higher incidence of hospitalizations compared to older age groups.

All adults 25 to 64 years of age with one or more of the following chronic conditions, including those effecting the lung (e.g., asthma), heart, blood, kidney, liver, and nervous system. Additional people at high risk include those with metabolic disorders (e.g., diabetes), immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus) and severe obesity (34 million people).

• Approximately 70 percent of those hospitalized with novel H1N1 virus infections had a medical condition that confers higher risk for influenza-related complications.

The ACIP also considered a smaller first priority group if the amount of vaccine available by October 2009 was substantially less than the 120 million doses that was predicted. In this scenario pregnant women, infant contacts, HCWs with direct patient contact with children five to 18 years of age with high risk conditions, and all children six months to four years of age remained in the highest priority group for a total of 42 million people. Healthy children five to 18 years of age and adult with high risk conditions and HCWs with no patient contact were removed from the first priority group.

By the middle of August it became clear that the novel H1N1 virus strain that was being used to make the vaccine was not growing as well as expected and therefore the CDC announced that they had scaled back the amount of vaccine that they thought would be available in October to 45 million doses. However, the CDC left it up to public health officials in each community to decide whether to scale back the first priority group from 159 to 42 million people based on the amount of vaccine they had available and the demand for the vaccine.

The Pandemic as of the end of October 2009

The history of pandemics shows that a second wave always follows the first wave and its impact is usually more severe. Both the WHO and CDC were concerned that the peak of the second wave in the northern hemisphere would occur in the early fall prior to the time that enough pandemic vaccine would be available in sufficient quantities for the first priority group – no less the entire population.

During the last week of August the WHO issued a briefing note called, “Preparing for the Second Wave: Lessons from Current Outbreaks.” The basis for this report was the information about the effect of the novel H1N1 virus on the southern hemisphere and the knowledge that large numbers of people in all countries remained susceptible to infection. Even if the current pattern of relatively mild illness continued, the impact of the pandemic during the second wave would worsen as larger numbers of people were infected. Larger numbers of severely ill patients requiring intensive care was felt to be the likely issue that would place a greater burden on health services, creating pressures that could overwhelm intensive care units and interfere with the provision of care for other diseases. During the winter season in the southern hemisphere a number of countries had viewed the need for intensive care as the greatest burden on health services. Some cities in these countries reported that nearly 15 percent of hospitalized patients required intensive care. The WHO warned that preparedness measures need to anticipate this increased demand on intensive care units, which could be overwhelmed by a sudden surge in the number of severe cases.

Some of these predisposing conditions that led to severe disease had become more prevalent in recent decades, thus increasing the pool of vulnerable people. WHO estimates that worldwide, more than 230 million people suffer from asthma, and more than 220 million people have diabetes. Hospitalizations and deaths from such conditions, precipitated by infection with the H1N1 virus, were another dimension of the pandemic’s impact.

Several preliminary studies also showed a higher risk of hospitalization and death among certain subgroups, including minority groups and indigenous populations in developing countries. In some studies, the risk in these groups was four to five times higher than in the general population. Although the reasons are not fully understood, possible explanations included lower standards of living and poor overall health status, including a high prevalence of conditions such as asthma, diabetes and hypertension.

Another concern was that widespread resistance of the novel H1N1 virus to the neuraminidase inhibitors could develop. While only a handful of pandemic viruses resistant to oseltamivir have been detected worldwide, the report of transmission of oseltamivir-resistant virus between two children in a summer camp in North Carolina increased this concern and intense monitoring continued through the WHO and CDC networks of laboratories.

So what should parents do to reduce the impact of the pandemic on themselves and their children? The most important steps you can take until the pandemic vaccine becomes widely available is to make sure that everyone follows good personal protective measures, including staying away from those who are ill, washing hands frequently, and using appropriate cough and cold etiquette. You should also have everyone in the family vaccinated with the seasonal influenza vaccine since there is a reasonable chance that both seasonal virus and the novel H1N1 virus may co-circulate this flu season. If someone in the family becomes ill with fever and respiratory symptoms then call your physician to seek advice. If the person who is ill is at high risk for serious disease your physician should recommend the use of antiviral medicine for treatment if the drugs can be given within the first 48 hours of symptoms. Distribution of the 2009 pandemic vaccine started in early October 2009 and should become widely available within the next few months. Everyone in your family should get vaccinated with both the pandemic and seasonal vaccines as soon as possible. Finally, you should remain up to date on the newest recommendations by consulting reliable information that can be found on www.flu.gov.

Chapter 4 Figures

Like many of the other children in their preschool, four-year-old Jessica Stein and her brother, Eric, developed a fever and cold symptoms in January 2002. A few days later, the children’s parents, Gary and Doris, felt that both Jessica and Eric had recovered so the children returned to school. Jessica, however, continued to exhibit signs of decreased energy and soon thereafter appeared to suffer a relapse. Her parents were concerned enough to call the doctor’s office. The nurse advised them not to bring her into the office since she likely had the same virus that remained widespread in their community, and the presence of her appetite indicated that she likely had a mild case. The nurse also instructed Gary and Doris to give Jessica plenty of fluids. However, Jessica’s condition did not improve. On Friday, February 1, 2002 Jessica’s breathing grew uneasy as she slept and her hands and feet felt slightly cool. Gary and Doris called their pediatrician again that night who advised them to take Jessica to the emergency room for what appeared to be dehydration. Sadly, Jessica died the next morning at the hospital from myocarditis (swelling of the heart), a complication that can occur due to influenza virus infection.

Annual deaths in the U.S. due to influenza far exceed the total of all other vaccine preventable diseases combined, with an average of 36,000 influenza-associated respiratory and circulatory deaths annually. Influenza-associated complications are also substantial with greater than 200,000 annual hospitalizations. Age-specific rates of death are greatest in those >65 years old, while children less than two years of age have the highest hospitalization rates. Furthermore, influenza virus infects about 10 percent of the population on a yearly basis resulting in millions of people seeking medical attention each year (see Chapter One for additional information about the impact of influenza on the U.S. and worldwide).

Influenza Vaccines: Use in Prevention of Influenza Disease

Getting an annual influenza vaccination is the best means available to help prevent the flu. Although drugs are available to treat the flu if given within 48 hours of onset of the illness, preventing the flu is clearly preferable to treating the disease. Methods of prevention include avoiding exposure to the virus, good hygiene and most importantly annual vaccination. While avoiding exposure to someone who is ill with any infectious disease is a great idea in theory, from a practical standpoint this is often difficult to achieve. This is particularly true for children who play a central role in the spread of influenza virus in a community. The rate of infection is particularly high in child care and school settings because children shed virus from their nose and throat in larger amounts and for approximately twice as long as adults, and in addition, children are less likely to use good hygiene practices such as hand washing.

Individuals remain susceptible to influenza disease even if they have previously been infected or been given the vaccine in years past. This is due to changes that occur in the surface proteins (hemagglutinin and neuraminidase) of the virus (see Chapter One for more information). The effectiveness of the vaccine is highest in years where the strains of the virus circulating in the community are well matched to the strains contained in the vaccine used that year. Three different types of influenza virus (A/H1N1, A/H3N2 and B) currently cause most of the influenza disease. On a yearly basis the specific strains of virus that are spreading throughout the world can undergo genetic changes in these external proteins so that the previous year’s vaccine may not be as effective. For this reason in February of each year the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) meet to determine the specific strain of each type of influenza virus H1N1, H3N2 and B that will go into the influenza vaccine for the upcoming season. They base their decision in large part on the strains of influenza virus that are present in Asia at that time. For example, during the 2008–2009 influenza season the H1N1 and B strains caused a great majority of disease in the U.S. The H1N1 strain circulating in the community was a very good match with the one in the vaccine, but the B strain circulating in the U.S. was not as good a match. This resulted in the vaccine being more effective against the H1N1 strain than the B strain during that influenza season.

Yearly immunization with influenza vaccine is routinely recommended by the CDC for children six months through 18 years of age. During most epidemic years, disease due to influenza virus peaks between December and March. However, in some years the peaks occur as early as October or November or as late as April. While it is optimal to get the vaccine early in the fall, vaccination as late as March can be protective. Although the number of people getting the vaccine has increased in recent years (Table 4), a much greater percentage of the population needs to be vaccinated before influenza will stop being the leading cause of vaccine-preventable deaths in the U.S.

Because the risk of hospitalization among pregnant women who develop influenza is three-fold higher than in non-pregnant women, the CDC recommends that all women receive the inactivated vaccine if they will be pregnant anytime during the influenza season. Immunization is also recommended for other adults who are at high risk for complications due to influenza virus (e.g., those with underlying heart and lung disease). Vaccinating adults who are in the same household or otherwise have close contact with children can offer further protection both for the adult as well as the child.

Types of Vaccines & Adverse Effects

There are currently two kinds of influenza vaccine available in the U.S. – a killed virus vaccine, also known as an inactivated virus vaccine that contains inactivated H1N1, H3N2 and B virus strains, and a live virus vaccine containing the same three virus strains. In the live virus vaccine the virus has been genetically altered so that the virus can grow at temperatures found in human nasal cavities (32-33 degrees C), but not at temperatures found in internal organs such as the lung (>37 degrees C), thereby eliminating the chance that the vaccine can cause the flu. The inactivated vaccine is given as a shot into a muscle, while the live vaccine is administered by spraying the vaccine into the nose. The inactivated vaccine is approved for children six months and older, and the live vaccine is approved for children two years and older. The inactivated vaccine is approved for use in healthy children and those with chronic illnesses such as asthma. Currently, the live vaccine is recommended only for healthy people between two to 49 years of age.

A large number of studies involving many thousands of children and adults indicate that these influenza vaccines are effective in preventing illness. Overall, the effectiveness of the vaccine averages 75 percent with a range of 50 to 95 percent in any given year. Studies suggest that the live vaccine is more effective than the killed vaccine in children five years of age or younger. In older children and adults the inactivated vaccine appears to be more effective.

Inactivated and live influenza vaccines can be given at the same time as other routinely recommended vaccines. Children less than nine years of age receiving influenza vaccine for the first time require two doses administered one month apart to produce a satisfactory immune response. However, older children and adults only need one dose of the vaccine to exhibit a good immune response to help protect them from developing the flu.

Influenza vaccines are associated with few adverse effects (side effects). With the inactivated vaccine low grade fever is most common in children younger than two years of age (10 to 35 percent of recipients), and occurs primarily six to 24 hours after vaccination. Local reactions are infrequent in children younger than 13 years of age, while they occur in approximately 10 percent of adolescents and adults. Those with severe allergic reactions to egg protein can experience, on rare occasion, a similar type of reaction to influenza vaccines.  Although influenza vaccines have been administered safely to such children after skin testing and desensitization (a method used where a physician specializing in allergic diseases gives small, but increasing amounts of the egg protein over a short period of time followed by the influenza vaccine, which prevents the allergic reaction from occurring), children and adults with this allergy generally should not receive influenza vaccines because of their risk of a serious reaction. Instead, there are drugs available that can be used as an alternative way to try and prevent influenza infection in this population. The inactivated vaccine contains gelatin and should generally not be used in those who are allergic to this protein. People who have a history of Guillain-Barre syndrome (a disease that results in weakness of muscles that starts in the legs and ascends upwards) should also not receive influenza vaccines.

The most common side effect of the live vaccine is nasal congestion. Many people make the assumption that the live virus vaccine can cause the flu, but the virus in the vaccine can only grow in the nose and not at body temperature. Furthermore, studies show that flu-like symptoms are no more common in those who received the vaccine versus those who did not.

Antiviral Medication: Treatment of Influenza Disease

There are two types of influenza antiviral drugs currently licensed in the U.S.: adamantanes (amantadine and rimantadine) and neuraminidase inhibitors (zanamivir [Relenza®] and oseltamivir [Tamiflu®]). These drugs can reduce the severity and shorten the length of influenza illness by approximately one day if treatment is started within 48 hours of onset of the person’s symptoms. These drugs also decrease the amount of influenza virus in the nose thereby reducing the chance that they will pass the virus to others. Treatment with antiviral therapy (i.e., medicines that kill the virus) should be considered for any child or adult at high risk for complications from influenza or for anyone with influenza in whom it may be useful to reduce the length of symptoms (Table 5). While the use of influenza vaccine is clearly the preferred method for preventing influenza, these drugs can also be used to prevent illness in an unvaccinated person who is exposed to someone with the flu (Table 6).

Amantadine and rimantadine are effective against some strains of influenza type A. These drugs are given by mouth and work by blocking the ability of the virus to reproduce. Some disadvantages of amantadine and rimantadine include: 1) emergence of resistance (i.e., the virus undergoes changes that results in the drug no longer being able to kill the virus), which is now seen in most strains of influenza A H3N2; 2) the inability of these drugs to kill any strains of influenza type B; and 3) the occurrence of reversible central nervous system (CNS) side effects, including nervousness, lightheadedness, difficulty with concentration and rarely, tremors or seizures.

The neuraminidase inhibitors, oseltamivir and zanamivir, work by interfering with the release of viral particles from the surface of infected respiratory tract cells. Oseltamivir is taken by mouth and is approved for use only in those who are one year of age or older. Zanamivir is a powder taken by inhaling it through a breath-activated device and is approved for use only in those who are seven years of age or older. Oseltamivir has been shown to reduce the frequency of serious complications such as bacterial pneumonia. Until recently these drugs were effective for the treatment of influenza type A or type B if given within 48 hours of the start of symptoms. However, the H1N1 strain of influenza A has become resistant to oseltamivir, but zanamivir still remains able to kill the virus. The safety and efficacy of zanamivir in patients with chronic lung disease have not been established; some patients with a history of asthma have experienced wheezing, so zanamivir is generally not recommended for patients with underlying airway disease. Oseltamivir is associated with nausea and vomiting in approximately 10 percent of recipients.

These drugs can also be helpful in preventing influenza. When determining who should get these antiviral medications for prevention of the flu, factors related to cost, compliance and potential side events should be considered. To be maximally effective as preventive agents, the drugs must be taken each day for the duration of influenza activity in the community. Using these drugs to help prevent influenza should not be considered a substitute for annual vaccination.

The recent occurrence of oseltamivir resistance among influenza A H1N1 virus strains presents challenges for selecting antiviral medications to treat and prevent influenza. It also provides additional reasons for clinicians to do rapid testing on patients for influenza virus infection. Due to this recent issue with resistance of H1N1 to oseltamivir interim guidelines have been provided by the CDC to health care workers for treatment or prevention of influenza in the U.S. If available, confirmatory testing with a rapid diagnostic test capable of distinguishing influenza disease caused by influenza H1N1 from H3N2 or influenza B virus can be used to guide treatment. In some circumstances treatment with both a neuraminidase inhibitor and an adamantane should be considered.

Educating About Flu

Prior to Jessica’s illness her parents did not think that the flu was serious enough to get their children or themselves vaccinated even though they had always made sure their children had received all their other immunizations. They thought at worst their children might develop a “bad cold” and that nothing could occur that modern science could not resolve. Since Jessica’s death, Gary and Doris not only make sure that everyone in their family gets an annual flu vaccine, but as board members of Families Fighting Flu they work tirelessly to help ensure that all parents are aware that influenza virus is a serious disease that can result in hospitalization and even death. Gary and Doris, along with the other members of the organization, spend a great deal of time educating the public about the importance of vaccinating children and other family members every year against this vaccine-preventable illness. As a result, their advocacy has been instrumental in getting the CDC to expand the influenza vaccination recommendations to include routine immunization of all children six months through 18 years of age, as well as all adults living in the same household.

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Tables 4, 5, & 6

Like many young parents, Alana Yaksich’s parents were unaware of the severity of the flu. They were unaware that the flu is capable of killing and is responsible for thousands of deaths each year in the United States and many more worldwide. They, like many others, labeled many of their family’s illnesses generically as “the flu” despite the fact that most of their illnesses were due to other causes. They also would have never guessed that they would lose their five-year-old daughter within 24 hours of taking her to the hospital because of the flu.

Alana was on the last day of an antibiotic for strep throat the morning she began feeling under the weather. She had a low-grade fever, 100 degrees, and felt a little tired. Her pediatrician said that she probably just had a cold or maybe she still had a touch of strep. Never was influenza suspected or diagnosed, nor was an anti-influenza drug offered at that time. That evening, Alana started vomiting, had a high fever of 106 degrees and was very lethargic. She was taken to the hospital by ambulance. Alana spent two to three hours in the emergency room where the physicians were unable to diagnose the cause of her illness, and she was admitted to the pediatric ICU. Within 24 hours Alana was diagnosed with encephalitis (inflammation) of the brain caused by influenza and her parents were told that there was little hope that she would survive. Alana died on February 3, 2003 from influenza.

Today the family feels very differently about the flu. They feel that had their pediatrician ever explained the potential severity of the flu and suggested the influenza vaccine, they would have more than likely had all of their children vaccinated. They also believe that had Alana been vaccinated, the odds would have heavily weighed in her favor to have not gotten the flu, or at least not have become severely ill. And, she could still be with them today.

Like the Yaksich family, other families make the mistake of categorizing “feeling under the weather” or a “mild cold” as the flu. However, this is often not the case. Influenza is a virus that can have much more serious implications.

The Impact of Influenza

Influenza virus causes seasonal epidemics of disease throughout the world (see Table 1 for more information on epidemic influenza). In the U.S., the vast majority of influenza cases usually occur between December and March (i.e., seasonal epidemic disease that occurs each year), with endemic (low level) disease being present throughout the year. Both daycare and school-age children play a central role in the spread of virus in a community, since they have high rates of infection

by shedding the virus at higher levels from their nose and throat and for longer periods of time than adults.

Influenza is the leading cause of vaccine-preventable death in the U.S. in children and adults. The impact of influenza in a typical year includes the following:

• Infects about 54 million people a year with the highest attack rate occurring in children;
• Results in more than 200,000 hospitalizations a year with the highest rate in children less than 24 months of age;
• Leads to about 36,000 deaths a year (~90% in the elderly); and

Table 1

• Costs about 12 billion dollars a year.

Infection with influenza virus causes more deaths every year in the U.S. than any other respiratory virus. Serious morbidity (complications due to the virus such as pneumonia) and mortality (death) can occur in any person. High-risk populations include the elderly, young children, pregnant women, and those with underlying chronic heart, lung, blood, kidney, metabolic and immunocompromising diseases. However, age-specific morbidity and mortality is greatest in those older than 65 years of age and children less than three years of age – both groups have the second highest hospitalization rates. Alana had none of these risk factors, yet she clearly developed serious morbidity (i.e., swelling of the brain) and this complication lead to her death. Unfortunately, morbidity and mortality due to influenza virus infection remain high despite the availability of vaccines and antiviral drugs to help prevent and treat influenza, and antibacterial agents to treat bacterial superinfections. Importantly, the majority of cases of influenza could be prevented if everyone received the vaccine annually.

Types of Influenza Viruses and Their Structure

There are three different types of influenza viruses (A, B and C). Essentially all of the disease that occurs in humans is due to types A or B. In any given year most of the cases of influenza are due to a particular strain of influenza A or B, but in some years more than one strain of influenza A or B can cause widespread disease.

Influenza is a virus whose structure is composed of a membrane envelope with two proteins attached to the outside of the membrane and six proteins contained internal to the membrane. While the internal proteins are genetically stable, the two external proteins are genetically unstable and change their genetic code on

Figure 1: Influenza Viral Structure. The hemagglutinin (HA) and neuraminidase (NA) are the unstable proteins on the outside of the influenza virus that allow it to change its structure on a yearly basis. The lipid envelope and the internal proteins do not change on a yearly basis.

a frequent basis (see Figure 1). The two external proteins are the hemagglutinin (HA), of which there are fifteen different types, and neuraminidase (NA), which has nine different types. All of these types of HA and NA have been found in at least one animal species, but to date only some of these types of HA and NA have caused disease in humans (see Figure 2). During the past century most of the disease that has occurred in humans has been due to viruses containing the H1N1 or H3N2 proteins.

The unstable HA and NA external proteins are what make the influenza virus so dangerous because they allow the virus to change its structure enough so that many people are infected multiple times with influenza viruses during their lifetime. When the HA or NA proteins of the strain of virus circulating in the population make an antigenic shift (or are substantially different), severe epidemics or pandemics can occur with high levels of excess morbidity and mortality (see Table 1 for more on pandemic influenza). During the 20th century, there have been three influenza pandemics, including one in 1918 that killed more than 500,000 people in the U.S. and 20 million people worldwide, many of whom were young adults. Mortality rates with the more recent pandemics of 1957 and 1968 were substantially less, in part due to the use of antibiotic therapy for secondary bacterial infections and more aggressive supportive care. These pandemics occur at irregular intervals and have the potential to be true public health emergencies. Interagency groups from the U.S. (Centers for Disease Control and Prevention [CDC]) and other countries (World Health Organization [WHO]) continue to develop contingency plans for the next pandemic. In a future chapter we will discuss pandemics in detail and what your family can do to prepare for them.

Figure 2: Hemagglutinin and neuraminidase subtypes. This chart shows the various subtypes of the hemagglutinin and neuraminidase proteins and the types of species they are known to infect.

What Can You Do to Protect Your Child?

There is a lot that parents can do to help protect their children from influenza. Alana’s parents allowed us to use her story to help illustrate the seriousness of influenza and to educate other parents about the various steps they can take to help protect their child from developing disease caused by this potentially lethal virus. Future chapters will be published on this Web blog that tell the stories of other families who have lost a child due to influenza, and discuss the symptoms and signs that may suggest your child actually has the flu, what tests are available for diagnosis, and what can be done to help prevent and treat this disease. We hope that you will find this information helpful, and we welcome your feedback about what else we can do to make our Web blog more helpful for you and your family.

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Next Chapter >

Growing up, Diane McGowan never got a flu shot. Her mother and sister both experienced severe allergic reactions to the vaccine due to their egg allergies, so in turn, Diane never got vaccinated. Diane would often come down with what felt like the flu, but always fully recovered from the illness. It was not until much later in life, when Diane suddenly lost her healthy 15-year-old son, Martin, to the flu that she learned of the seriousness of this viral illness, and the vital importance of getting vaccinated against the flu.

Martin was a happy, healthy teenager. On February 8, 2005, he took an afternoon nap before trying out for the high school baseball team. Diane noticed that he looked a little under the weather, but Martin insisted that he felt fine – there was no way he would miss the highly-anticipated tryouts. Martin attended the baseball tryouts, but was exhausted afterwards. He also complained that his legs hurt from running. When Martin got home, he watched TV for a little while and then went to bed.

The next morning at 2:30 a.m., Diane heard Martin vomiting in the bathroom. He had a fever of 102 degrees. Diane gave him some over the counter medicine and he went back to bed. Martin later awoke at 4:30 a.m. and began to vomit once again. The pain in his legs had also increased. In addition to giving Martin plenty of fluids, Diane tried easing the pain in his legs by giving him a warm bath and applying ointment to the area, but nothing seemed to work. As the aching in his legs became more severe, Diane called the doctor who suggested that Martin either come in for an appointment that afternoon or be taken to the emergency room. Diane knew it was serious when Martin asked to be taken to the emergency room.

When he arrived at the hospital, the ER doctor took his vital signs and did an initial evaluation. Martin had a high fever and appeared pale. Martin appeared dehydrated and fluids were administered through his vein. He continued to complain of severe muscle pain in his legs, which was noted on his physical examination. The physician ordered a rapid influenza test that came back positive. Muscle aches are a symptom that is common in those who have the flu, but in Martin’s case the muscles in his legs had swollen so much that the blood was having trouble circulating throughout his legs (a complication known as “compartment syndrome”). The doctor told his parents that they thought that Martin needed to be operated on as soon as possible to help decrease the pressure in his legs and thereby improve the blood flow.

Martin was taken into operating room that afternoon, but, sadly, during the surgery his heart stopped beating. Doctors attempted to revive him but they were unsuccessful. On February 9, 2005, Martin died of complications from influenza just 24 hours after his first symptom appeared. Martin had not been vaccinated against the flu.

Symptoms of the Flu

Because the common cold and the flu cause some of the same symptoms it can sometimes be difficult to tell the difference between these two different illnesses. Influenza is caused by a highly contagious viral infection of the respiratory tract (nose, throat, trachea and lungs). In general, the flu is worse than the common cold, and symptoms such as fever, body aches, extreme tiredness, and dry cough are more common and intense. Also, colds generally do not result in serious complications that can result in hospitalization and even death.

There are a number of symptoms and signs that commonly occur with the flu, which can help lead to the diagnosis:

•    Upper respiratory tract symptoms (runny nose, nasal congestion and cough)

•    Gastrointestinal (GI) symptoms (vomiting and/or diarrhea)*

•    Body aches*

•    Headache

•    High fever (>102 degrees)* – typically lasting three to four days

* Symptoms that Martin exhibited.

Symptoms of influenza will typically develop one to four days after being exposed to the virus, a time period also known as the incubation period. Most children with the flu exhibit two or more of the above symptoms and recover by day three or four after the onset of the illness. It is important to note that young children can shed virus several days before illness and can be infectious for 10 or more days after the onset of symptoms. Persons with severely impaired immune systems, typically caused by a disease or treatment such as cancer, may remain infectious to others for a longer period of time since the virus can be present in their nose for weeks or even months.

Below is a list of other symptoms associated with influenza that suggest a serious complication due to the virus or a secondary bacterial infection, may be present:

•    High fever (102 degrees) lasting more than four days

•    Drop in body temperature (hypothermia)

•    Not able to take in usual amount of fluids*

•    Bluish or gray skin color*

•    Severe muscle pain causing difficulty with walking*

•    Difficulty with breathing

•    Flu-like symptoms improve but then return with fever and worsening respiratory problems

•    Changes in mental status such as not waking up, not interacting or seizures

•    Worsening of underlying medical conditions (for example a child with well controlled diabetes who suddenly has trouble with their blood sugar level)

* Symptoms that Martin exhibited.

Influenza Complications

Body Aches

As mentioned, body aches is a symptom commonly associated with influenza. Typically, myositis (inflammation of the muscles) is associated with the sudden onset of moderate to severe muscle pain and tenderness, most often in the calves of both legs, and can result in the patient refusing to walk. However, in Martin’s case, the severity of muscle pain he experienced in his legs was evidence of a more serious complication of influenza. Martin suffered from severe inflammation of his muscles (a.k.a. myositis), which led to the development of a compartment syndrome. The syndrome caused swelling in his legs, constricting the normal blood flow in his veins and arteries. Martin’s physicians think that the intense running that he did the previous night during baseball tryouts may have worsened the problems with his leg muscles. Severe myositis is mainly associated with an infection due to influenza B, but can also occur with influenza A (see Chapter 1 for more information about the different types of influenza viruses).

Upper Respiratory Tract Problems

Influenza is often associated with ear infections that are due to the virus or a subsequent (i.e. secondary) bacterial infection. The influenza virus can also cause a breathing problem called croup, which occurs when the virus spreads from the nose and throat to the larynx and trachea (the structures between the nose and the lung).

Lower Respiratory Tract (Lung) Infections

Influenza virus can invade the lung causing pneumonia, but this is a relatively rare complication. A more common infection in the lung is due to a bacteria – the medical term used to describe this complication is “secondary bacterial pneumonia.” The bacteria that most commonly cause this complication are Staphylococcus aureus (staph) or Streptococcus pneumoniae (pneumoccocus). Bacterial pneumonia usually occurs as the patient recovers from the initial flu symptoms and no longer has a fever. When the bacterial lung infection develops, the patient’s fever returns and breathing problems occur, including an increased breathing rate and a worsening cough. Secondary bacterial pneumonias are the major cause of hospitalization and death associated with the flu. Secondary bacterial infections can also occur in the blood, but are less common than those that occur in the lung.

Central Nervous System Complications

The influenza virus or the associated secondary bacterial infections can also cause complications that affect the central nervous system, including:

•    viral or bacterial meningitis (infection of the lining of the brain);

•    viral encephalitis (infection of the brain);

•    encephalopathy (alterations in mental status without proof that it is caused by a virus or bacteria that has infected the brain); and

•    Reye’s syndrome (a condition of unknown cause that is associated with the use of aspirin and is characterized by abnormalities of the liver and brain swelling).

The 2003 – 2004 influenza season was particularly bad in children. During this time the Centers for Disease Control and Prevention (CDC) received an increased number of reports of children who had encephalitis or encephalopathy associated with influenza. The CDC conducted a national survey to explore this trend and documented 50 cases of influenza-associated encephalopathy in children. Surprisingly, the majority of cases (29) occurred in previously healthy children (Table 2).

Table 2: Cases of encephalopathy in children reported to the CDC during the 2003 – 2004 flu season (n=50)

Subsequent to the 2003 – 2004 influenza season the CDC declared influenza-associated encephalitis and encephalopathy reportable diseases. Studies are ongoing to better understand why certain children and adolescents develop these serious complications from influenza.

Other complications from influenza virus involving the heart, kidneys and bone marrow can occur on rare occasions.

Testing for Influenza

Physicians caring for a patient with possible influenza should take a thorough history. It is important that the physician determine if the patient’s family members recently experienced an illness associated with fever. The physician should also perform a physical examination and consider doing laboratory testing. A number of tests are available to diagnose influenza. A rapid influenza test using the patient’s nasal secretions can be conducted in a physician’s office; the results are available within 30 minutes. However, these rapid tests are more reliable in children than adults, because children have higher amounts of the influenza virus in their nose. Influenza can also be diagnosed by performing a nose or throat culture (swabbing the nose or throat and seeing if the virus can be grown in a test tube). However, cultures must be sent to an outside laboratory and it often takes three to seven days for the virus to grow in the test tube.

Antiviral Treatment

Antiviral treatment is available and effectively decreases the duration of influenza and the incidence of secondary bacterial infections if started within 48 hours of onset of symptoms. Further discussion of the treatment and prevention of influenza will be available in Chapter 3.

Influenza Outcomes

Table 3: Prior health status of those children who died from influenza during the 2003-2004 influenza season that were reported to the CDC (n= 153)

In the U.S. and other developed countries, the influenza virus causes the greatest number of annual deaths compared to any other infectious disease. Approximately 36,000 influenza-related deaths occur annually in the U.S. – a death toll greater than that from all other vaccine-preventable diseases combined. While the majority of influenza-associated deaths occur in the elderly, over the past five flu seasons more than 400 children have died from influenza and its complications, making influenza one of the two leading causes of vaccine-preventable deaths in children (Table 3). These cases of laboratory confirmed influenza are undoubtedly an underestimate of the actual number of cases that occurred. The average age of those children who died from influenza was five years (range 19 days – 17 years). Most of these children and adolescents had no underlying chronic condition. The majority of these children with and without chronic underlying illnesses had not been vaccinated against influenza.

In the U.S., influenza causes approximately 200,000 hospitalizations each year and 20,000 children under the age of five are hospitalized due to influenza each year. Children less than two years of age have the highest rates of hospitalization of all age groups, including the elderly. The rate of hospitalization is greater in those with underlying high-risk chronic conditions (e.g., asthma, diabetes), but a large number of children who are hospitalized do not have underlying chronic illnesses (Figure 3).

While hospitalizations are less common in older children, studies show that five to 15 percent of children and adolescents are seen in the

Figure 3: Hospitalizations due to influenza (per 10,000 population). Adapted from presentation at the CDC Advisory Committee on Immunization Practices, June 2000

outpatient setting each year because of the flu.  Additional consequences of influenza illness among children seen in outpatient clinics include unnecessary exposure to antibiotics for treatment of fever, missed school, missed work by parents, and the spread of influenza illness among family members and others.

Thank you to Diane for letting us tell Martin’s story to help educate others about the symptoms and complications associated with influenza. As we discussed, flu is a highly contagious respiratory illness and often develops quickly. Martin died of complications from influenza just 24 hours after his first symptom appeared. It is important to learn the symptoms and complications of influenza to better protect your family from this illness.

If you have questions or feedback for Dr. Abramson about this chapter, please write a comment in the field below.