Pandemic Influenza Due to the 2009 Novel H1N1 Virus
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.
- Prophylaxis for prevention of illness in healthy children or adults following exposure to ill persons is not indicated.
- 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:
- 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.
- 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.
- Two doses of pandemic vaccine would be needed for protection.
- Pandemic vaccine and seasonal vaccine availability will overlap and both will be recommended for many population groups.
- Initial demand for vaccination would be about the same as for seasonal vaccine, but could increase quickly as community transmission increased.
- Vaccine distribution would be timely, but there would still be mismatches between supply and demand at the local level.
- 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:
- Severity of illness and risk for complications due to the novel H1N1 virus.
- Likelihood of developing illness due to the novel H1N1 virus.
- Contribution to overall burden of severe illness.
- Protection of healthcare system functions.
- Reduction of societal impact.
- 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.
