Influenza

Contributors

Introduction

Influenza is an acute viral infection with symptoms ranging from mild to severe depending on an individual's phenotype. This virus circulates worldwide and can affect any age group. Influenza is attributed to not only social and economic disruption, but also hundreds of thousands of deaths each year. With the recent 2009 swine flu pandemic, influenza has become a major priority for governments and health agencies. This module will touch on the history of influenza, its biological basis, interventions, surveillance, and determinants of influenza.

Learning Objectives

After successfully completing this section, the student will be able to:

1. Explain the basic structure of the influenza virus.
2. Discuss the origin of new influenza strains.
3. Explain the process of infection and replication of influenza viruses.
4. Outline the symptoms and complications of influenza infection.
5. Distinguish between pharmaceutical and non-pharmaceutical interventions to mitigate influenza epidemics and pandemics..
6. Discuss who should and who should not get vaccinated and the priorities for influenza vaccination if supplies of the vaccine are limited..
7. Descrive worldwide surveillance of influenza viruses.
8. Discuss the factors that influence the propogation of influenza epidemics.

Background

Influenza has the potential to become a worldwide epidemic and to affect large portions of the human population, with numerous consequences. Unlike seasonal influenza epidemics, pandemics occur irregularly and can spread quickly due to increased commerce and air travel. Also, unlike the average 36,000 deaths per year due to seasonal epidemics, pandemics can cause hundreds of thousands of deaths within the US alone. Characteristics and challenges of flu pandemics include rapid worldwide spread, health care systems that become overloaded, inadequate levels of medical supplies and manpower and economic and social disruption (Flu.gov, 2011). The figure below shows annual US mortality rates from various causes from 190900-1965. The enormous spike in deaths due to influenza and pneumonia in 1918 is impressive to say the least.

Source: https://www.learnodo-newtonic.com/spanish-flu-facts

Worldwide the great influenza of 1918 is believed to have caused at least 25-50 million deaths. Many believe it is inevitable that period influenza pandemics will continue to occur in the future. It is therefore imperative that we understand the causes and prepare for the next pandemic. 

The video below (2:37 min) provides a glimplse of the devastating effects of the 1918 pandemic.

Viruses are non-living. They must reproduce by entering an animal or plant cell (i.e., a host) and using the hosts cell's organelles energy and nutrients to synthesize copies of the viral proteins and viral genetic material (DNA or RNA). Once these components have been replicated they self-assemble to form new virus particles.

Anatomy of the Flu Virus

The influenza virus has a nucleic core with genetic material surrounded by a membrane bound protein coat consisting of four proteins:

• Hemagglutinin protein (H protein): the viral protein that enables it to attach to a host cell.
• Neuraminidase (N protein): an enzyme that cleaves sialic acid residues on hemagglutinin. This is essential for release of the progeny virus after the infected cell lyses.
• The M1 matrix protein
• The M2 ion channel

Within the Orthomyxoviridae family of RNA viruses there are A, B and C types of influenza viruses. The A and B viruses cause seasonal epidemics throughout the world, while the C virus only causes mild illnesses and is not thought to cause epidemics.

• Influenza A Viruses: Influenza A viruses are further subdivided into subtypes based on the surface proteins hemagglutinin (H) and neuraminidase (N), and strains. There are 16 hemagglutinin proteins and 9 neuraminidase proteins; subtypes of the viruses are designated by the proteins that are present, e.g., the H1N1 virus has the H1 and N1 proteins. Although many protein combinations are possible, the only strains of influenza A currently in humans are the H1N1, H1N2 and H3N2 viruses. Influenza A viruses affect humans, mammals and birds. Major epidemics have been due to substrains of the influenza A virus, including the 1918 Spanish flu, 1957 Asian flu, 1968 Hong Kong flu, 2004 Avian flu and the 2009 swine flu.
• Influenza B Viruses: Influenza B viruses are not divided into subtypes but are broken down into different strains. They infect humans, but are generally less severe than influenza A. It has the potential to cause human epidemics, but has yet to cause a human pandemic. Both influenza A and B mutate fast enough that immunity cannot be achieved. The annual influenza vaccine contains an influenza A H1N1 strain, an H3N2 strain and an influenza B strain.  
• Influenza C Viruses: The less common influenza C viruses infect only humans and pigs, have no subtypes and has yet to cause a major epidemic.

Infection and Replication

The specific steps that occur during infection with an influenza virus were summarized by Hate (Hate, 1999).

1. The H protein binds to sialic acid (on the glycoproteins and glycolipids of the host cell).
2. A conformation change in the host cell's membrane endocytoses the attached virus.
3. The virus sheds its membrane and releases its genetic material (RNA and enzymes) through a nucleocapsid.
4. The nucleocapsid travels through host cell's cytoplasm to the nucleus.
5. Once in the nucleus, the virus transcribes essential proteins for further replication.
6. The produced proteins synthesize the 8 positive RNA strands from the 8 negative RNA strands (Type C influenza viruses only have 7 strands).
7. The H, N, and complimentary proteins aggregate at the host's cell membrane and start conforming the membrane again to bud.
8. At least 8 newly reproduced RNA strands come to the protein bundling.
9. The N protein binds to the sialic acid receptors on the host cell's membrane which allows for the release of newly created influenza viruses

Transmission

Influenza has two predominant mechanisms of transportation: person-to-person and fomites.

• Person-to-person transmission— Influenza is spread person to person via infected droplets (CDC, 2011).  Droplets can come from sneezing, coughing, talking, or touching one's mouth.  The infected droplets have the ability to infect others as far as six feet away (CDC, 2011).
• Fomites transmission—Influenza can be transmitted through fomites also.  Fomites are inanimate objects such as doorknobs, tables, phones, ect.  Transmission can occur when influenza droplets surface on objects and people come in contact with them, entering the body via mouth, nose, or eye contact (CDC, 2011).

Symptoms and Complications

The influenza virus can have a wide range of symptoms varying from mild to severe. (Hunt, 2010).

• Fever (usually from 100.4° to 104° F)
• Headaches
• Myalglias (muscle aches and pains)
• Fatigue
• Cough
• Sore throat
• Congested nose
• Diarrhea and vomiting Pulmonary complications (Hunt, 2010)—following and caused by influenza infection
• Croup (primarily in children): coughing, trouble breathing, stridor [textbox—wheezing sound while taking breaths]
• Pneumonia (caused by primary influenza virus)

Secondary bacterial infection (usually Streptococcus pneumoniae, Staphylococcus aureus, Hemophilus influenza) can also occur.

Non-pulmonary complications of influenza include the following:

• Cardiac complications
• Encephalopathy:  Rare occurrence but influenza can cause subsequent brain disease.
• Reye's Syndrome:  Very rare disease that effects the liver and brain after the influenza infection.  Typically infects the young and has a case fatality rate of 40%.
• Guillain-Barre Syndrome: autoimmune disease that affects the central nervous system.  It follows a bacterial or viral infection such as the influenza virus. 

The Origin of New Flu Strains

Avian, Swine, and Human Interaction

New influenza strains of influenza virus arise continually as a result of two mechanisms that alter the genetic code in the viral RNA. These mechansims are referred to as genetic drift and genetic shift.

Genetic Drifts— Small changes in genetic material called point-mutations.  The antigenic proteins of influenza may be subject to the small mutations and not recognized by antibodies (Hunt, 2010). (Explain this more)

Genetic Shifts result from reassortment of genetic material between vastly different strains of influenza viruses.  (This needs to be explained much better.) This can involve the creation of new H and N proteins on the virus coat (Hunt, 2010).  If the new viral proteins are sufficiently different from pre-existing viral proteins, there may be limited immune recognition by humans. As a result, the majority, if not all, of the human population may be susceptible to the new viral form. In addition, reassortment may also result in a very virulent new strain. (Hunt, 2010).

All three organisms can be infected with influenza virus.  Pigs are susceptible to both human and avian virus strands.  They act as an intermediate step in combining avian, human, and swine influenza genetic material.  This occurs when pigs become infected with both human and avian virus.  The influenza RNA strands reassort while in the pig to form new combinations of avian, swine, and human strands.  In turn, these new influenza viruses could possible infect humans and have surface proteins (H and N proteins) not previously seen by the human immune system. 

Pandemic Influenza

In the last century there have been four main worldwide pandemics:

• 1918 Spanish Influenza—The worst of the know influenza pandemics was the 1918 pandemic, which was caused by an H1N1 strain. It killed at least 25-50 million people worldwide. More recent studies suggest that these are underestimates because of underreporting in the developing world and the inordinately high mortality in underdeveloped countries. There were at least 675,000 deaths in the United States alone. A disctintive feature of the 1918 pandemic was that mortality rates were very high for young adults between 20-40 years of age.
• 1957 Asian Influenza—The 1957 Asian flu (H2N2), originating in East Asia, was the first in which surveillance and vaccine production were implemented. This epidemic also had a "second wave" of infection in which first children and young adults were infected, followed by another wave of illness in the elderly. Approximately 69,800 people died in the United States.
• 1968 Hong Kong Influenza—The Hong Kong influenza of 1968 (H3N2) first arose in Hong Kong, and slowly spread to the United States, where those over 65 years of age were most likely to become infected. The virus returned again in 1970 and 1972. The mortality rate for the epidemic was 33,800. It is thought that prior immunity to the Asian flu virus and improved medical care and surveillance may have helped reduce the severity of illness in 1968.
• 2009 Swine Influenza—The more recent 2009 flu pandemic, commonly known as the swine flu although it doesn't infect pigs, first appeared in April 2009 in Mexico as a re-assortment of bird, swine and human flu viruses. Over 14,000 people died around the world, including 3,600 in North America.  A mass vaccination campaign was introduced in addition to the trivalent seasonal flu vaccines and by November 2009, over 65 million doses of vaccine had been distributed. By June 2010, the World Health Organization declared that the epidemic was over, although the swine flu strain is still present in the seasonality of influenza.

Source: New England Journal of Medicine, http://www.nejm.org/doi/full/10.1056/NEJMp058281

The Threat of Bird Flu

Are we prepared?

This is a 15 minute talk at TED.com given by Laurie Garrett. This talk initially focuses on the potential threat from H5N1, so called "bird flu," but her remarks then turn to the threat from pandemic flu in general, and she has incisive observations about "preparedness" for pandemic influenza.

Influenza Epidemics

Influenza epidemics are influenced by several factors:

• Population characteristics
• Pathogen characteristics
• Behavioral and lifestyle
• Environment                                                                                       

Population characteristics                                                  

How a specific population is characterized by immunization status, age composition, and the number of people in the population at higher risks all affected the factors of an influenza epidemic.

• Immunization Status - The higher amount of a defined population is immunized for the     influenza, the potential for an epidemic decreases.  A highly vaccinated population protects those individuals who are unable to be vaccinated by decreasing the odds of exposure to the influenza virus.  This process of protecting unvaccinated individuals with a larger immunized population is called herd immunity.
• Age Composition - Specific age groups are more at risk for influenza.  Adults who are older than fifty years are more at risk (American Lung Association, 2011).  Also, children from six months to eighteen years are at an increased risk for influenza (American Lung Association, 2011).  For example, a population with high amounts of these two groups could increase the likelihood of an epidemic.
• Higher Risk Populations - Certain individuals have a great potential to be susceptible to influenza, besides looking at age alone.  Pregnant women and individuals with chronic illnesses [insert rollover—asthma, chronic obstructive pulmonary disease, cardiovascular disease, and diabetes, ect.] are more susceptible (American Lung Association, 2011).  Furthermore, residents in long-term care facilities and those who work in these facilities are at an increased risk (American Lung Association, 2011).

Pathogen Characteristics

The latency period of influenza, the infectious period, mechanisms of transmission, and virulence of the influenza strand are considered the pathogenic [insert rollover—disease causing agent = pathogen] traits which are also determinants.

• Latency period - The latency period is the amount of time from initial infection to illness. Influenza has a latency period of about two days (World Health Organization, 2009). 
• Infectious period - The infectious period is the time an infected individual is contagious to other people.  For the influenza, a person is contagious one day before symptoms appear and up to five to seven days after becoming symptomatic (Centers for Disease Control and Prevention, 2011). 
• Mechanisms of Transmission - This pathogenic trait of influenza plays a vital determinant of infection.  Influenza is spread person to person via infected droplets (CDC, 2011).  Droplets can come from sneezing, coughing, talking, or touching one's mouth.  The infected droplets have the ability to infect others as far as six feet away (CDC, 2011).  Influenza can also be transmitted by fomites [insert rollover—transmission by touching inanimate objects such as tables or doorknobs].
• Virulence of influenza - Virulence refers to the severity of the pathogen and is usually measured by case fatality rates [insert rollover—number of deaths divided by the total number of cases of disease].  The higher the virulence, the more influential this determinant is for influenza, and the higher number of influenza cases. The seasonal flu causes on average 36,000 deaths in the United States (CDC, 2011).

Behavioral and Lifestyle

Behavioral and lifestyle characteristics include population density, economic/political factors, and personal behaviors.  These factors are more social depending on human interactions.

• Population density— In order for influenza to infect, it must have "something" to infect.  Less populated areas would not have a high risk of influenza.  However, highly crowded or urbanized locations increase the odds of exposure from person to person.
• Economic/political factors— Trade, travel, and wars are great examples of economic and political factors that influence determinants of influenza.  With the world more globalized than ever before, the possibility of influenza strands can be spread across the world with one international flight or shipping company.  Also, wars bring many nations together increasing exposures.  This was the case in the previously discussion influenza epidemic of 1918.
• Personal behaviors— These include the frequency and commonality of people's hygiene.  Influenza can be determined by if people wash their hands properly and cover their mouths while sneezing or coughing.  A group of people who practice bad hygiene would be more susceptible to influenza.

Environment

The environment and climate are the final factors that determine influenza infection.  In the northern hemisphere "flu season" primarily takes place during the winter months (CDC, 2011).  The influenza virus seems to flourish best in the cooler weather.  Flu season can start in October and span into April (CDC, 2011).  Below is a graph which depicts the frequency of visits to US outpatient facilities for influenza-like illness during the past several years. Note that the frequency generally begins climbing in the fall, peaks in mid-winter, and then declinces sharply. However, there is variability in the pattern, and the H1N1 pandemic that occurred in 2009-2010 was very unusually with a large spike in spring followed by a sharp decline that contiued throughout the winter.

Source: http://www.cdc.gov/flu/weekly/summary.htm/

Non-Pharmaceutical Interventions

Measures can be taken to reduce one's personal risk and the risk of transmitting the flu virus. These include voluntary household isolation and quarantine, social distancing, widespread adoption of respiratory hygience and hand washing, and targeted use of antiviral medications. These are summarized in the table below.

Pharmaceutical Interventions

Vaccination

The World Health Organization has developed a global surveillance program in which virus strains are collected by national flu centers around the world and samples of interest are sent to WHO's advanced laboratories for further assessment.

Every year, WHO suggests three virus strains (2 influenza A and 1 influenza B) to be included in each country's upcoming flu vaccine (FLU, 2011). Selection is based on circulation and ability to cause mass illness in the coming flu season. The chosen strains used to create the vaccine will provide protection against strains that are the same or related.

As indicated above, WHO only provides a recommendation for the upcoming flu vaccine and each country makes the final decision for their population. In the United States, the Food and Drug Administration (FDA) makes the final decision (FLU, 2011). The FDA has chosen A/California/7/2009 (H1N1)-like virus, A/Perth/16/2009 (H3N2)-like virus, and B/Brisbane/60/2008-like virus to be included in the 2011-2012 flu vaccine (CDC, 2011).

Two types of vaccines are manufactured for influenza:

• vaccines containing inactivated ("killed") influenza virus
• vaccines containing attenuated virus

Inactivated vaccine—consists of dead viruses that are given through injection. The three types of flu shots available are regular (>6 mo. of age), Fluzone High-Dose (>65 yrs. old) and intradermal (18-64 yrs. old) (CDC, 2011).

• The amount of antigen in Fluzone High-Dose vaccines is fourfold that of regular flu shots to increase the amount of antibodies for a more robust immune system (CDC, 2011).
• The intradermal flu vaccine has fewer antigens and is injected into the skin and not the muscle.
• Side effects that may result from a flu shot include: soreness, redness, swelling or toughness and itching (only from intradermal vaccine) of the punctured area, and low grade fever and aches (CDC, 2011).

Attenuated vaccine—also known as live attenuated influenza vaccine (LAIV), is available as a nasal-spray (FluMist). As indicated by its name, the virus within the vaccine is weakened and will not cause the recipient to get the flu. Individuals under the age of 2 and over 49, pregnant, have a chronic medical condition, a weakened immune system or take medications that weaken their immune system should not get the vaccine (CDC, 2011).

Unless there is a contraindication, everyone 6 months of age or older should get vaccinated. However, vaccination is particularly important in certain groups. The following table from the CDC provides a list of those who should be most strongly encouraged to get vaccinated and also provides a list of those in whom vaccination is contraindicated.

Who Should Get Vaccinated

• Pregnant women
• Children < 5, especially those between 6 months and 2 years of age
• Individuals > 50
• Individuals who are immunosuppressed or who have chronic medical conditions, including morbid obesity
• Individuals living in long-term care facilities
• Healthcare workers
• Individuals who are in contact with those who are at high-risk for complications or around children < 6 months old

Who Should Not Get Vaccinated

• Individuals allergic to eggs
• Individuals who have had a severe reaction to the Influenza vaccine
• Children < 6 months
• Individuals with moderate-to-severe illness with a fever
• Individuals who developed Guillain-Barre Syndrome after receiving the influenza vaccine

Prioritization of Vaccine

In the past, emphasis has been placed on vaccinating individuals in high risk categories and healthcare providers during vaccine shortages first. In addition, sub-prioritizing is conducted at the discretion of state and local health officials and healthcare providers (CDC, 2011).

In the state of Massachusetts, high risk categories and their order of priority are (MA Department of Public Health, 2004):

1. All children aged 6-23 months
2. Adults aged > 65 years
3. Persons aged 2-64 years with underlying chronic medical conditions
4. All women who will be pregnant during the influenza season
5. Residents of nursing homes and long-term care facilities
6. Children aged 6 month-18 years on chronic aspirin therapy
7. Health-care workers involved in direct patient care
8. Out-of-home caregivers and household contacts of children aged <6 months

In the case of a pandemic, prioritization is illustrated in the figure below from the CDC.

Title: Vaccination target groups, estimated populations, and tiers for severe, moderate and less severe pandemics as defined by the Pandemic Severity Index (PSI).

Persons in occupational groups not specifically targeted for vaccination in Moderate and Less Severe pandemics are targeted according to their age and health status in the general population.

 ; .

Source: http://www.flu.gov/images/reports/pi_vaccine_allocation_guidance.pdf

However, new information suggests that traditional prioritization of the elderly over healthy young adults and children during shortages of vaccine and pandemics should be reconsidered. Past research has revealed that children are high-transmitter groups (as cited in Miller et. al, 2008). This is most likely due to poor hygienic habits and minimal to no exercising of social distance when infected. Research findings have also suggested using children to create herd immunity as it is more effective to immunize a small group of children to protect the elderly than it is to immunize a very large group of the elderly (as cited in Miller et al, 2008; Radonovich, Bender, & Small, 2007). Consequently, because annual epidemics tend to hit school children first, there may be a rationale for vaccinating them first, rather than last. Overall, there is a greater potential to control the spread of influenza by vaccinating healthy young adults and children before the elderly. This is further illustrated by the following facts (Miller et. al, 2008; as cited in Miller et. al, 2008; Randonvich et. al, 2007):

1. Higher mortality rate in younger adults during pandemic seasons and a higher mortality rate in the elderly during interpandemic seasons
2. Lower vaccine efficacy in the elderly compared to young adults by 25%-50%
3. Lower mortality rate in the elderly during pandemics possibly due to "recycling of influenza viral antigens over time"
4. "Immunizing 70% of schoolchildren may protect the entire community"

Flu Vaccine Distribution in Massachusetts

In the state of Massachusetts, it is estimated that there will be a shortage of flu vaccine during the 2011-2012 flu season as a result of billion dollar budget cuts. Consequently, in the coming year state-supplied vaccines will be prioritized for children who are 6 months —18 years of age within identified cohorts and uninsured or underinsured adults who are at high-risk for complications if infected with the influenza virus (MASS, 2011).

Massachusetts recommends (MASS, 2011):

• Vaccinations take place as soon as vaccines become available
• Vaccinating as long as influenza virus is circulating within the community
• Providing end of the season flu shots to children < 9 years of age with their second dose of vaccine if only vaccinated once and travelers going to the Southern Hemisphere who did not get a flu shot at the beginning of the season

All licensed healthcare facilities are required to offer their employees free flu vaccinations according to state regulations within 105 CMR (MASS, 2011). To ensure yearly provision of state-supplied flu vaccine, all healthcare workers are required to report state-supplied vaccine usage to MDPH by the specified deadline (MASS, 2011). 

Monitoring Vaccine Safety

Through the Vaccine Adverse Event Report System (VAERS) and the Vaccine Safety Datalink (VSD) Project, the CDC, FDA, and their partners are able to monitor the safety of the current flu vaccine by identifying adverse events and health complications that take place following vaccination (CDC, 2011). The data provided is also a means for: monitoring pattern changes in known adverse events, assessing the safety of groups that are at high-risk for complications, identifying individuals with a greater risk for certain adverse events, and assessing the safety and effectiveness of vaccine lots [insert rollover—batch of vaccine] (CDC, 2011).

Antiviral drugs

These drugs are designed to treat infection and any associated complications of individuals infected with the influenza virus or serve as a form of prevention for non-infected individuals who are allergic to eggs, have developed Guillain-Barre Syndrome from exposure to the influenza vaccine or have a negative immune response to the vaccine.  They consist of Amantadine (Flumadine), Rimantadine, Zanamivir (Relenza), and Oseltamivir (Tamiflu).

• Amantadine & Rimantadine—are both adamantanes that were very effective against Influenza A. Recent experience with H3N2 and H1N1 strains has demonstrated the rapid development of drug resistance. Consquently, use of these agents for prophylaxis or treatment of routine cases is not recommended (CDC, 2011).
• Zanamivir & Oseltamivir—are both neuraminidase inhibitors that are effective against Influenza A and B. We are currently limited to these antivirals. Cases of resistance to these antivirals have taken place in both Influenza A and B strains in past years (CDC, 2011). However, the percentage of cases was low and the currently circulating strains are still susceptible to antivirals (CDC, 2011). CDC maintains an ongoing surveillance of resistant cases.

Surveillance for Infuenza

Surveillance in the United States and around the world is an important step in identifying possible influenza epidemics and classifying which influenza strains go into the yearly vaccines.  There are 136 national influenza centers in over 100 countries worldwide that conduct year-round surveillance of influenza, and all information on trends and strains are reported to five World Health Organization Collaborating Centers for Reference and Research on Influenza in the United States, the United Kingdom, Australia, Japan and China.

In the United States, the Epidemiology and Prevention Branch in the Influenza Division of the CDC deals with analyzing influenza activity every year. Over 80 laboratories in the United States and abroad provide information on virologic surveillance, including the total number of respiratory specimens tested and the number positive for influenza types A and B each week (Center for Disease Control and Prevention, 2011).  Hospitals and healthcare facilities also provide numerous influenza cases to the CDC, thereby providing up-to-date prevalence and incidence rates in all 50 states. Mortality and hospitalization surveillance track the number of influenza-related deaths and the number of patients admitted to hospitals with laboratory-confirmed influenza, respectively. Lastly, the surveillance system also tracks the geographic spread of influenza. All of this information is important in controlling influenza mutations, identifying strains for the yearly vaccinations and categorizing susceptible populations.

The figure below shows the percentage of visits to US outpatient facilities for influenza-like illness by month and shows how it varies during the year.

Source: http://www.cdc.gov/flu/weekly/summary.htm/

Syndromic surveillance uses indicators from individuals and populations before laboratory results and confirmed diagnoses to identify outbreaks and to monitor the health status of the community (Center for Disease Control and Prevention, 2011). This type of surveillance is important because it more up-to-date and often provides information quicker than a laboratory test can be completed.

Current weekly reports on influenza activity in the US can be found at http://www.cdc.gov/flu/weekly/, while worldwide reports may be accessed at http://www.who.int/influenza/gisrs_laboratory/flunet/en/.  Google Flu Trends uses aggregated search data to estimate influenza activity around the world - http://www.google.org/flutrends/

Informative Multimedia Tools

• Pandemic Flu Planning Checklist for Individuals and Families: http://www.flu.gov/individualfamily/checklist.html
• FLU I.Q. Widget http://www.flu.gov/individualfamily/about/index.html
• Weekly Influenza Surveillance Report http://gis.cdc.gov/grasp/fluview/main.html
• FLU Vaccination Finder http://www.flu.gov/whereyoulive/index.html
• Elements that destroy Influenza http://answers.flu.gov/categories/321
• Vaccine Flu Shot or Nasal Spray http://www.flu.gov/individualfamily/vaccination/index.html
• Emergency Warning Signs in Children & Adults http://www.flu.gov/individualfamily/about/h1n1/index.html

References

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