Influenza pandemic

An influenza pandemic is an epidemic of an influenza virus that spreads on a worldwide scale and infects a large proportion of the human population. In contrast to the regular seasonal epidemics of influenza, these pandemics occur irregularly, with the 1918 Spanish flu the most serious pandemic in recent history. Pandemics can cause high levels of mortality, with the Spanish influenza estimated as being responsible for the deaths of over 50 million people. There have been about three influenza pandemics in each century for the last 300 years. The most recent ones were the Asian Flu in 1957 and the Hong Kong Flu in 1968.
Influenza pandemics occur when a new strain of the influenza virus is transmitted to humans from another animal species. Species that are thought to be important in the emergence of new human strains are pigs, chickens and ducks. These novel strains are unaffected by any immunity people may have to older strains of human influenza and can therefore spread extremely rapidly and infect very large numbers of people. Influenza A viruses can occasionally be transmitted from wild birds to other species causing outbreaks in domestic poultry and may give rise to human influenza pandemics.
The World Health Organization (WHO) warns[when?] that there is a substantial risk of an influenza pandemic within the next few years[when?]. One of the strongest candidates is a highly pathogenic variation of the H5N1 subtype of Influenza A virus. As of 2006, prepandemic influenza vaccines are being developed against the most likely suspects which include H5N1, H7N1, and H9N2.Certain scholars and senior policy advisors argue that pandemic influenza represents a substantive threat to the international economy, to each nation's national security, and a challenge to international governance.On 11 June 2009, a new strain of H1N1 influenza was determined to be a global pandemic (Stage 6) by the World Health Organization after evidence of spreading in the southern hemisphere.

Influenza

Influenza, commonly known as flu, is an infectious disease of birds and mammals caused by an RNA virus of the family Orthomyxoviridae (the influenza viruses). In humans, common symptoms of influenza infection are fever, sore throat, muscle pains, severe headache, coughing, and weakness and fatigue.In more serious cases, influenza causes pneumonia, which can be fatal, particularly in young children and the elderly. Sometimes confused with the common cold, influenza is a much more severe disease and is caused by a different type of virus. Although nausea and vomiting can be produced, especially in children,these symptoms are more characteristic of the unrelated gastroenteritis, which is sometimes called "stomach flu" or "24-hour flu."
Typically, influenza is transmitted from infected mammals through the air by coughs or sneezes, creating aerosols containing the virus, and from infected birds through their droppings. Influenza can also be transmitted by saliva, nasal secretions, feces and blood. Infections occur through contact with these bodily fluids or with contaminated surfaces. Flu viruses can remain infectious for about one week at human body temperature, over 30 days at 0 °C (32 °F), and indefinitely at very low temperatures (such as lakes in northeast Siberia). Most influenza strains can be inactivated easily by disinfectants and detergents.Flu spreads around the world in seasonal epidemics. Three influenza pandemics occurred in the 20th century and killed tens of millions of people, with each of these pandemics being caused by the appearance of a new strain of the virus in humans. Often, these new strains result from the spread of an existing flu virus to humans from other animal species. When it first killed humans in Asia in the 1990s, a deadly avian strain of H5N1 posed a great risk for a new influenza pandemic; however, this virus did not mutate to spread easily between people.Vaccinations against influenza are most commonly given to high-risk humans in industrialized countries and to farmed poultry. The most common human vaccine is the trivalent influenza vaccine that contains purified and inactivated material from three viral strains. Typically this vaccine includes material from two influenza A virus subtypes and one influenza B virus strain.A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time and different strains become dominant. Antiviral drugs can be used to treat influenza, with neuraminidase inhibitors being particularly effective.

Spanish Flu (1918–1920)

The 1918 flu pandemic, commonly referred to as the Spanish flu, was a category 5 influenza pandemic caused by an unusually severe and deadly Influenza A virus strain of subtype H1N1.

The difference between the influenza mortality age-distributions of the 1918 epidemic and normal epidemics. Deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line).
The Spanish flu pandemic lasted from 1918 to 1919, although Price-Smith's data suggest it may have begun in Austria in the Spring of 1917. Older estimates say it killed 40–50 million peoplewhile current estimates say 50 million to 100 million people worldwide were killed. This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the Black Death , although the Black Death is estimated to have killed over a fifth of the world's population at the time , a significantly higher proportion. This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms.Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred." The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.
The Spanish flu pandemic was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%. Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old.This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that up to 1% of the world's population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.

The 1918 flu pandemic (commonly referred to as the Spanish flu) was an influenza pandemic that spread to nearly every part of the world. It was caused by an unusually virulent and deadly Influenza A virus strain of subtype H1N1. Historical and epidemiological data are inadequate to identify the geographic origin of the virus. Most of its victims were healthy young adults, in contrast to most influenza outbreaks which predominantly affect juvenile, elderly, or otherwise weakened patients. The flu pandemic has also been implicated in the sudden outbreak of Encephalitis lethargica in the 1920s.
The pandemic lasted from March 1918 to June 1920, spreading even to the Arctic and remote Pacific islands. It is estimated that anywhere from 50 to 100 million people were killed worldwide, or the approximate equivalent of one third of the population of Europe.An estimated 500 million people, one third of the world's population (approximately 1.6 billion at the time), became infected.
Scientists have used tissue samples from frozen victims to reproduce the virus for study. Given the strain's extreme virulence there has been controversy regarding the wisdom of such research. Among the conclusions of this research is that the virus kills via a cytokine storm (overreaction of the body's immune system) which explains its unusually severe nature and the concentrated age profile of its victims. The strong immune systems of young adults ravaged the body, whereas the weaker immune systems of children and middle-aged adults caused fewer deaths.

Asian Flu (1957–1958) Influenza A virus subtype H2N2

The "Asian Flu" was a category 2 flu pandemic outbreak of avian influenza that originated in China in early 1956 lasting until 1958. It originated from mutation in wild ducks combining with a pre-existing human strain. The virus was first identified in Guizhou. It spread to Singapore in February 1957, reached Hong Kong by April, and US by June. Death toll in the US was approximately 69,800. The elderly were particularly vulnerable.Estimates of worldwide The "Asian Flu" was a category 2 flu pandemic outbreak of avian influenza that originated in China in early 1956 lasting until 1958. It originated from mutation in wild ducks combining with a pre-existing human strain. The virus was first identified in Guizhou. It spread to Singapore in February 1957, reached Hong Kong by April, and US by June. Death toll in the US was approximately 69,800. Estimates of worldwide deaths caused by this pandemic varies widely depending on source; ranging from 1 million to 4 million, with WHO settling on "about 2 million".
Asian Flu was of the H2N2 subtype (a notation that refers to the configuration of the hemagglutinin and neuraminidase proteins in the virus) of type A influenza, and an influenza vaccine was developed in 1957 to contain its outbreak.
The Asian Flu strain later evolved via antigenic shift into H3N2 which caused a milder pandemic from 1968 to 1969.
Both the H2N2 and H3N2 pandemic strains contained avian influenza virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source (Belshe 2005)." deaths vary widely depending on source, ranging from 1 million to 4 million.

Influenza A virus subtype H3N2

Influenza A virus subtype H3N2 (also H3N2) is a subtype of viruses that cause influenza (flu). H3N2 viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains. H3N2 is increasingly abundant in seasonal influenza, which kills an estimated 36,000 pSeasonal influenza kills an estimated 36,000 people in the United States each year. Flu vaccines are based on predicting which mutants of H1N1, H3N2, H1N2, and influenza B will proliferate in the next season. Separate vaccines are developed for the northern and southern hemispheres in preparation for their annual epidemics. In the tropics, influenza shows no clear seasonality. In the past ten years, H3N2 has tended to dominate in prevalence over H1N1, H1N2, and influenza B. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 has increased from 1% in 1994 to 12% in 2003 to 91% in 2005.
Seasonal H3N2 flu is a human flu from H3N2 that is slightly different from one of last year's flu season H3N2 variants. Seasonal influenza viruses flow out of overlapping epidemics in East and Southeast Asia, then trickle around the globe before dying off. Identifying the source of the viruses allows global health officials to better predict which viruses are most likely to cause the most disease over the next year. An analysis of 13,000 samples of influenza A/H3N2 virus that were collected across six continents from 2002 to 2007 by the WHO's Global Influenza Surveillance Network showed that newly emerging strains of H3N2 appeared in East and Southeast Asian countries about 6 to 9 months earlier than anywhere else. The strains generally reached Australia and New Zealand next, followed by North America and Europe. The new variants typically reached South America after an additional 6 to 9 months, the group reportedeople in the United States each year.

2009 flu pandemic

The 2009 flu pandemic is a global outbreak of a new strain of influenza A virus subtype H1N1, identified in April 2009 and commonly referred to as swine flu, which infects and is transmitted between humans. It is thought to be a mutation—more specifically, a reassortment—of four known strains of influenza A virus subtype H1N1: one endemic in humans, one endemic in birds, and two endemic in pigs (swine). A June 17, 2009 update by the U.N.'s World Health Organization (WHO) states that "76 countries have officially reported 39,620 cases of influenza A(H1N1) infection, including 167 deaths".
The WHO officially declared the outbreak to be a pandemic on June 11, but stressed that the new designation was a result of the global spread of the virus, not its severity which can be mild, moderate, or severe. The WHO stated the pandemic appears to have "moderate severity" in comparatively well-off countries, however it is prudent to anticipate a bleaker picture as the virus spreads to areas with limited resources, poor health care, and a high prevalence of underlying medical problems.The case fatality rate (CFR) of the pandemic strain is estimated at 0.4% (range 0.3%-1.8%)
The virus typically spreads from coughs and sneezes or by touching contaminated surfaces and then touching the nose or mouth. WHO Director-General Margaret Chan says probably it will be September 2009 before the first doses of a vaccine for the 2009 flu pandemic strain will become available and even then, "there will be limited supply of vaccine".There is also concern that the virus could mutate later in the year and become more virulent and less susceptible to any vaccine developed to protect from an earlier strain. This concern is partly due to the memory of the 1918 flu pandemic, which is thought to have killed between 40 and 100 million people, and was preceded by a wave of milder cases in the spring.
Up until May 24, 2009 nearly 90% of reported deaths had taken place in Mexico. This has led to speculation that Mexico may have been in the midst of an unrecognized epidemic for months prior to the current outbreak, thereby showing a fatality rate that was much higher than it would have been if earlier cases had been counted. According to the US Centers for Disease Control and Prevention, the fact that the flu's infection activity is now monitored more closely may also help explain why more flu cases than normal are being recorded in many countries.

Influenzavirus A

This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics. The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

*H1N1, which caused Spanish flu in 1918, and the 2009 flu pandemic
*H2N2, which caused Asian Flu in 1957
*H3N2, which caused Hong Kong Flu in 1968
*H5N1, a current pandemic threat
*H7N7, which has unusual zoonotic potential
*H1N2, endemic in humans and pigs
*H9N2
*H7N2
*H7N3
*H10N7

Influenza virus B

This genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. The only other animals known to be susceptible to influenza B infection are the sealand the ferret. This type of influenza mutates at a rate 2–3 times lower than type A and consequently is less genetically diverse, with only one influenza B serotype.As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur

Influenzavirus C

This genus has one species, influenza C virus, which infects humans, dogs and pigs, sometimes causing both severe illness and local epidemics.However, influenza C is less common than the other types and usually only causes mild disease in children.

Signs and symptoms

Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from 38-39 °C (approximately 100-103 °F). Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worse in their backs and legs. Symptoms of influenza may include:
Body aches, especially joints and throat
Extreme coldness and fever
Fatigue
Headache
Irritated watering eyes
Reddened eyes, skin (especially face), mouth, throat and nose
Abdominal pain (in children with influenza B)
It can be difficult to distinguish between the common cold and influenza in the early stages of these infections,but a flu can be identified by a high fever with a sudden onset and extreme fatigue. Diarrhea is not normally a symptom of influenza in adults, although it has been seen in some human cases of the H5N1 "bird flu" and can be a symptom in children. The symptoms most reliably seen in influenza are shown in the table to the right.
Most sensitive symptoms for diagnosing influenza.
Symptom:
sensitivity
specificity
Fever
68-86%
25-73%
Cough
84-98%
7-29%
Nasal congestion
68–91%
19–41%

.
Sensitivity is the proportion of people having influenza who exhibit the symptom.
Specificity is the proportion of people not having influenza who do not exhibit the symptom.
All three findings, especially fever, were less sensitive in patients over 60 years of age.
Since anti-viral drugs are effective in treating influenza if given early (see treatment section, below), it can be important to identify cases early. Of the symptoms listed above, the combinations of fever with cough, sore throat and/or nasal conjestion can improve diagnostic accuracy.Two decision analysis studies suggest that during local outbreaks of influenza, the prevalence will be over 70% and thus patients with any of these combinations of symptoms may be treated with neuramidase inhibitors without testing. Even in the absence of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the prevalence is over 15%

Influenza treatment

Treatments for influenza include a range of medications and therapies that are used in response to disease influenza. Treatments may either directly target the influenza virus itself; or instead they may just offer relief to symptoms of the disease, while the body's own immune system works to recover from infection.
The two main classes of antiviral drugs used against influenza are neuraminidase inhibitors, such as zanamivir and oseltamivir, or inhibitors of the viral M2 protein, such as amantadine and rimantadine. These drugs can reduce the severity of symptoms if taken soon after infection and can also be taken to decrease the risk of infection. However, viral stains have emerged that show drug resistance to both classes of drug.

Symptomatic treatment

The United States authority on disease prevention, the Centers for Disease Control and Prevention (CDC), recommends that persons suffering from influenza infections:
*Stay at home
*Get plenty of rest
*Drink a lot of liquids
*Do not smoke or drink alcohol
*Consider over-the-counter medications to relieve flu symptoms
*Consult a doctor early on for best possible treatment
*Remain alert for emergency warning signs

Warning signs are symptoms that indicate that the disease is becoming serious and needs immediate medical attention. These include:
*Difficulty breathing or shortness of breath
*Pain or pressure in the chest or abdomen
*Dizziness
*Confusion
*Severe or persistent vomiting
In children other warning signs include irritability, failing to wake up and interact, rapid breathing, and a blueish skin color. Another warning sign in children is if the flu symptoms appear to resolve, but then reappear with fever and a bad cough.

Treatment

People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid using alcohol and tobacco and, if necessary, take medications such as paracetamol (acetaminophen) to relieve the fever and muscle aches associated with the flu. Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin during an influenza infection (especially influenza type B), because doing so can lead to Reye's syndrome, a rare but potentially fatal disease of the liver.Since influenza is caused by a virus, antibiotics have no effect on the infection; unless prescribed for secondary infections such as bacterial pneumonia. Antiviral medication can be effective, but some strains of influenza can show resistance to the standard antiviral drugs.
The two classes of antiviral drugs used against influenza are neuraminidase inhibitors and M2 protein inhibitors (adamantane derivatives). Neuraminidase inhibitors are currently preferred for flu virus infections since they are less toxic and more effective.The CDC recommended against using M2 inhibitors during the 2005–06 influenza season due to high levels of drug resistance.

Neuraminidase inhibitors
Antiviral drugs such as oseltamivir (trade name Tamiflu) and zanamivir (trade name Relenza) are neuraminidase inhibitors that are designed to halt the spread of the virus in the body.These drugs are often effective against both influenza A and B.The Cochrane Collaboration reviewed these drugs and concluded that they reduce symptoms and complications.Different strains of influenza viruses have differing degrees of resistance against these antivirals, and it is impossible to predict what degree of resistance a future pandemic strain might have.

M2 inhibitors (adamantanes)
The antiviral drugs amantadine and rimantadine block a viral ion channel (M2 protein) and prevent the virus from infecting cells.These drugs are sometimes effective against influenza A if given early in the infection but are always ineffective against influenza B because B viruses do not possess M2 molecules. Measured resistance to amantadine and rimantadine in American isolates of H3N2 has increased to 91% in 2005. This high level of resistance may be due to the easy availability of amantadines as part of over-the-counter cold remedies in countries such as China and Russia, and their use to prevent outbreaks of influenza in farmed poultry

Prognosis

Influenza's effects are much more severe and last longer than those of the common cold. Most people will recover completely in about one to two weeks, but others will develop life-threatening complications (such as pneumonia). Influenza, however, can be deadly, especially for the weak, old, or chronically ill. People with a weak immune system, such as people infected with HIV or transplant patients (whose immune systems are medically suppressed to prevent transplant organ rejection), suffer from particularly severe disease. Other high-risk groups include pregnant women and young children.
The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experience shortness of breath while they have the flu, and influenza may cause worsening of coronary heart disease or congestive heart failure. Smoking is another risk factor associated with more serious disease and increased mortality from influenza.
According to the World Health Organization: "Every winter, tens of millions of people get the flu. Most are only ill and out of work for a week, yet the elderly are at a higher risk of death from the illness. We know the worldwide death toll exceeds a few hundred thousand people a year, but even in developed countries the numbers are uncertain, because medical authorities don't usually verify who actually died of influenza and who died of a flu-like illness." Even healthy people can be affected, and serious problems from influenza can happen at any age. People over 50 years old, very young children and people of any age with chronic medical conditions are more likely to get complications from influenza, such as pneumonia, bronchitis, sinus, and ear infections.In some cases, an autoimmune response to an influenza infection may contribute to the development of Guillain-Barré syndrome. However, as many other infections can increase the risk of this disease, influenza may only be an important cause during epidemics. This syndrome can also be a rare side-effect of influenza vaccines, with an incidence of about one case per million vaccinations.

Mechanism for seasonal nature of influenza

The exact mechanism behind the seasonal nature of influenza outbreaks is unclear. Some proposed explanations are:
People are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person.
Cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles.
The virus may linger longer on exposed surfaces (doorknobs, countertops, etc.) in colder temperatures.
Vitamin D production from Ultraviolet-B in the skin changes with the seasons and affects the immune system.
Research in guinea pigs has shown that the aerosol transmission of the virus is enhanced when the air is cold and dry. The dependence on aridity appears to be due to degradation of the virus particles in moist air, while the dependence on cold appears to be due to infected hosts shedding the virus for a longer period of time. The researchers did not find that the cold impaired the immune response of the guinea pigs to the virus.
A recent research done by National Institute of Child Health and Human Development (NICHD) on influenza virus identified the virus as having "butter-like coating". The coating melts when it enters the respiratory tract. In the winter, the coating becomes a hardened shell; therefore, it can survive in the cold weather similar to a spore. In the summer, the coating melts before the virus reaches the respiratory tract.

Flu season

Flu season is a regularly re-occurring time period characterized by the prevalence of outbreaks of influenza. The season occurs during the cold half of the year in each hemisphere. Influenza activity can sometimes be predicted and even tracked geographically. While the beginning of major flu activity in each season varies by location, in any specific location these minor epidemics usually take about 3 weeks to peak and another 3 weeks to significantly diminish.Individual cases of the flu however, usually only last a few days. In some countries such as Japan and China, infected persons sometimes wear a surgical mask out of respect for others.

Cause

Three virus families, Influenzavirus A, Influenzavirus B, and Influenzavirus C are the main infective agents that cause influenza. During periods of cooler temperature, influenza cases increase roughly tenfold or more, resulting in the flu season. Despite higher prevalence of disease cases during the season, these viruses are transmitted amongst people all year round. They do not disappear and reappear.
Each annual flu season is normally associated with a major influenzavirus subtype. The associated subtype changes each year, due to mutational changes amongst viral populations, as well as the development of immunological resistance to last year's strain from previous infection and vaccination.

Seasonal variations

Influenza reaches peak prevalence in winter, and because the Northern and Southern Hemispheres have winter at different times of the year, there are actually two different flu seasons each year. This is why the World Health Organization (assisted by the National Influenza Centers) makes recommendations for two different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.
It is not clear why outbreaks of the flu occur seasonally rather than uniformly throughout the year. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Another is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The virus may also survive longer on exposed surfaces (doorknobs, countertops, etc.) in colder temperatures. Increased travel due to the Northern Hemisphere winter holiday season may also play a role.A contributing factor is that aerosol transmission of the virus is highest in cold environments (less than 5 °C) with low humidity.However, seasonal changes in infection rates also occur in tropical regions, and these peaks of infection are seen mainly during the rainy season.Seasonal changes in contact rates from school terms, which are a major factor in other childhood diseases such as measles and pertussis, may also play a role in the flu. A combination of these small seasonal effects may be amplified by dynamical resonance with the endogenous disease cycles. H5N1 exhibits seasonality in both humans and birds.
An alternative hypothesis to explain seasonality in influenza infections is an effect of vitamin D levels on immunity to the virus. This idea was first proposed by Robert Edgar Hope-Simpson in 1965. He proposed that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of vitamin D, which is produced in the skin under the influence of solar (or artificial) UV radiation. This could explain why influenza occurs mostly in winter and during the tropical rainy season, when people stay indoors, away from the sun, and their vitamin D levels fall.

Epidemic and pandemic spread

As influenza is caused by a variety of species and strains of viruses, in any given year some strains can die out while others create epidemics, while yet another strain can cause a pandemic. Typically, in a year's normal two flu seasons (one per hemisphere), there are between three and five million cases of severe illness and up to 500,000 deaths worldwide, which by some definitions is a yearly influenza epidemic.Although the incidence of influenza can vary widely between years, approximately 36,000 deaths and more than 200,000 hospitalizations are directly associated with influenza every year in the United States. Roughly three times per century, a pandemic occurs, which infects a large proportion of the world's population and can kill tens of millions of people (see history section). Indeed, one study estimated that if a strain with similar virulence to the 1918 influenza emerged today, it could kill between 50 and 80 million people.
New influenza viruses are constantly evolving by mutation or by reassortment. Mutations can cause small changes in the hemagglutinin and neuraminidase antigens on the surface of the virus. This is called antigenic drift, which slowly creates an increasing variety of strains until one evolves that can infect people who are immune to the pre-existing strains. This new variant then replaces the older strains as it rapidly sweeps through the human population—often causing an epidemic.However, since the strains produced by drift will still be reasonably similar to the older strains, some people will still be immune to them. In contrast, when influenza viruses reassort, they acquire completely new antigens—for example by reassortment between avian strains and human strains; this is called antigenic shift. If a human influenza virus is produced that has entirely new antigens, everybody will be susceptible, and the novel influenza will spread uncontrollably, causing a pandemic.In contrast to this model of pandemics based on antigenic drift and shift, an alternative approach has been proposed where the periodic pandemics are produced by interactions of a fixed set of viral strains with a human population with a constantly changing set of immunities to different viral strain.

Pandemics

The symptoms of human influenza were clearly described by Hippocrates roughly 2,400 years ago.Since then, the virus has caused numerous pandemics. Historical data on influenza are difficult to interpret, because the symptoms can be similar to those of other diseases, such as diphtheria, pneumonic plague, typhoid fever, dengue, or typhus. The first convincing record of an influenza pandemic was of an outbreak in 1580, which began in Russia and spread to Europe via Africa. In Rome, over 8,000 people were killed, and several Spanish cities were almost wiped out. Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of 1830–1833 being particularly widespread; it infected approximately a quarter of the people exposed.
The most famous and lethal outbreak was the 1918 flu pandemic (Spanish flu pandemic) (type A influenza, H1N1 subtype), which lasted from 1918 to 1919. It is not known exactly how many it killed, but estimates range from 20 to 100 million people.This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the Black Death. This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms. Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred." The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.
The 1918 flu pandemic (Spanish flu pandemic) was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%.Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old. This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that 2.5% to 5% of the world's population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years
The influenza viruses that caused Hong Kong flu. (magnified approximately 100,000 times)
Later flu pandemics were not so devastating. They included the 1957 Asian Flu (type A, H2N2 strain) and the 1968 Hong Kong Flu (type A, H3N2 strain), but even these smaller outbreaks killed millions of people. In later pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality compared to the Spanish Flu of 1918.

Infection in other animals

Influenza infects many animal species, and transfer of viral strains between species can occur. Birds are thought to be the main animal reservoirs of influenza viruses. Sixteen forms of hemagglutinin and nine forms of neuraminidase have been identified. All known subtypes (HxNy) are found in birds, but many subtypes are endemic in humans, dogs, horses, and pigs; populations of camels, ferrets, cats, seals, mink, and whales also show evidence of prior infection or exposure to influenza.Variants of flu virus are sometimes named according to the species the strain is endemic in or adapted to. The main variants named using this convention are: Bird Flu, Human Flu, Swine Flu, Horse Flu and Dog Flu. (Cat flu generally refers to Feline viral rhinotracheitis or Feline calicivirus and not infection from an influenza virus.) In pigs, horses and dogs, influenza symptoms are similar to humans, with cough, fever and loss of appetite. The frequency of animal diseases are not as well-studied as human infection, but an outbreak of influenza in harbour seals caused approximately 500 seal deaths off the New England coast in 1979–1980. On the other hand, outbreaks in pigs are common and do not cause severe mortality.

Bird flu

Flu symptoms in birds are variable and can be unspecific. The symptoms following infection with low-pathogenicity avian influenza may be as mild as ruffled feathers, a small reduction in egg production, or weight loss combined with minor respiratory disease.Since these mild symptoms can make diagnosis in the field difficult, tracking the spread of avian influenza requires laboratory testing of samples from infected birds. Some strains such as Asian H9N2 are highly virulent to poultry and may cause more extreme symptoms and significant mortality. In its most highly pathogenic form, influenza in chickens and turkeys produces a sudden appearance of severe symptoms and almost 100% mortality within two days.As the virus spreads rapidly in the crowded conditions seen in the intensive farming of chickens and turkeys, these outbreaks can cause large economic losses to poultry farmers.
An avian-adapted, highly pathogenic strain of H5N1 (called HPAI A(H5N1), for "highly pathogenic avian influenza virus of type A of subtype H5N1") causes H5N1 flu, commonly known as "avian influenza" or simply "bird flu", and is endemic in many bird populations, especially in Southeast Asia. This Asian lineage strain of HPAI A(H5N1) is spreading globally. It is epizootic (an epidemic in non-humans) and panzootic (a disease affecting animals of many species, especially over a wide area), killing tens of millions of birds and spurring the culling of hundreds of millions of other birds in an attempt to control its spread. Most references in the media to "bird flu" and most references to H5N1 are about this specific strain.
At present, HPAI A(H5N1) is an avian disease, and there is no evidence suggesting efficient human-to-human transmission of HPAI A(H5N1). In almost all cases, those infected have had extensive physical contact with infected birds.In the future, H5N1 may mutate or reassort into a strain capable of efficient human-to-human transmission. The exact changes that are required for this to happen are not well understood.However, due to the high lethality and virulence of H5N1, its endemic presence, and its large and increasing biological host reservoir, the H5N1 virus was the world's pandemic threat in the 2006–07 flu season, and billions of dollars are being raised and spent researching H5N1 and preparing for a potential influenza pandemic.

Swine flu

In pigs swine influenza produces fever, lethargy, sneezing, coughing, difficulty breathing and decreased appetite.In some cases the infection can cause abortion. Although mortality is usually low, the virus can produce weight loss and poor growth, causing economic loss to farmers. Infected pigs can lose up to 12 pounds of body weight over a 3 to 4 week period.Direct transmission of an influenza virus from pigs to humans is occasionally possible (this is called zoonotic swine flu). In all, 50 human cases are known to have occurred since the virus was identified in the mid-20th century, which have resulted in six deaths.
In 2009 a swine-origin H1N1 virus strain commonly referred to as "swine flu" caused the 2009 flu pandemic, but there is no evidence that it is endemic to pigs (i.e. actually a swine flu) or of transmission from pigs to people, instead the virus is spreading from person to person. This strain is a reassortment of several strains of H1N1 that are usually found separately, in humans, birds, and pigs.

Influenza research

Influenza research involves investigating molecular virology, pathogenesis, host immune responses, genomics, and epidemiology regarding influenza. The main goal of research is to develop influenza countermeasures such as vaccines, therapies and diagnostic tools.
The potential H5N1 pandemic has motivated a huge increase in flu research. At least 12 companies and 17 governments are developing pre-pandemic influenza vaccines in 28 different clinical trials that, if successful, could turn a deadly pandemic infection into a nondeadly pandemic infection. A vaccine that could prevent any illness at all from the not-yet-existing pandemic influenza strain will take at least three months from the virus's emergence until full-scale vaccine production could begin; with vaccine production hoped to increase until one billion doses are produced by one year after the virus is first identified.Improved influenza countermeasures require basic research on how viruses enter cells, replicate, mutate, evolve into new strains and induce an immune response. Solutions to limitations in current vaccine methods are being researched.
The Influenza Genome Sequencing Project is creating a library of influenza sequences that will help us understand what makes one strain more lethal than another, what genetic determinants most affect immunogenicity, and how the virus evolves over time.

Areas of current flu research

Before 2004, all previous highly pathogenic avian flu virus strains circulated only among domesticated poultry and by culling all of them in the area, the strains were made extinct. Previous HPAI strains only existed in domesticated birds. A wild bird's LPAI would mutate in a domestic flock into an HPAI strain, all domestic birds in the area would be killed, and the HPAI strain would no longer have any hosts and thus would no longer exist. This current HPAI H5N1 strain has turned out to be different. In October 2004 researchers discovered H5N1 is far more dangerous than previously believed because waterfowl, especially ducks, were directly spreading the highly pathogenic strain of H5N1. From this point on, avian flu experts increasingly referred to containment as a strategy that can delay but not prevent a future avian flu pandemic. Nonetheless, there is still hope it will mutate into some low pathogenic strain over time and no longer exist in its current high pathogenic set of strains. But as time as gone on, the hope has come to look less and less likely. The result is that billions of dollars every year are going to be needed in expenditures that would not be required if it did go away. Poultry farming is especially hard hit. How to best spend pandemic mitigation funds and poultry farming protection funds is a question that to be answered requires billions in flu research and new flu vaccine manufacturing factories.
Since it is not going away as was hoped, more data is needed to figure out how best to cope. So governments are funding a variety of studies from cell culture of flu viruses to H5N1 vaccination effectiveness to adjuvants to wild bird migration patterns to wild bird avian flu subtype distribution to poultry flu vaccination etc. The information being gathered is increasing the world's ability to keep H5N1 contained, limiting its speed and extent of mutation, and buying time for new flu vaccine manufacturing methods and factories to come on line so that when the next flu pandemic happens the death toll can be minimized.

Current major flu research contracts

The US federal government on May 4, 2006 awarded five-year contracts for "more than $1 billion to five drug manufacturers developing technology for speedier mass production of vaccines in the event of a pandemic" from the $3.8 billion pandemic preparedness bill passed in 2005. "The federal government says its goal is to be able to distribute a vaccine to every American within six months of a pandemic. Currently, flu vaccines are produced in specialized chicken eggs, but that technique does not allow for speedy mass vaccinations." The companies receiving the contracts were:
GlaxoSmithKline $274.8 million
MedImmune Inc $169.5 million
Novartis Vaccines and Diagnostics $220.5 million
DynPort Vaccine Company,LLC $41 million
Solvay Pharmaceuticals $298.6 million.The US government has purchased from Sanofi Pasteur and Chiron Corporation several million doses of vaccine meant to be use in case of an influenza pandemic from H5N1 and is conducting clinical trials on them. ABC News reported on April 1, 2006 that "Beginning in late 1997, the human trials have tested 30 different vaccines, all pegged to the H5N1 virus." "To address the H9N2 threat, NIAID contracted with Chiron Corporation to produce investigational batches of an inactivated vaccine, which will be evaluated clinically by NIAID early next year. For H5N1, Aventis-Pasteur and Chiron are both producing investigational lots of inactivated H5N1 vaccine preparations; additionally, DHHS has contracted with Aventis to produce up to 2 million doses to be stockpiled for emergency use, if needed, to vaccinate health workers, researchers, and, if indicated, the public in affected areas. Development and evaluation of a combination antiviral regimen against these potential pandemic influenza strains are also now under way..

Reverse genetics

A technique called reverse genetics allows scientists to manipulate the genomes of influenza viruses and to transfer genes between viral strains. The technique allows the rapid generation of seed viruses for vaccine candidates that exactly match the anticipated epidemic strain. By removing or modifying certain virulence genes, reverse genetics also can be used to convert highly pathogenic influenza viruses into vaccine candidates that are safer for vaccine manufacturers to handle

Cell culture

Another technique is use of cell cultures to grow vaccine strains; such as genetically engineering baculovirus to express a gene that encodes an influenza coat protein such as hemagglutinin or neuraminidase. "A recent NIAID-supported Phase II clinical trial of a vaccine produced by Protein Sciences Corporation using this strategy showed that it is well tolerated and immunogenic; the company is conducting further clinical evaluation of this product. Other new pathways for producing influenza vaccines include DNA-based approaches and the development of broadly protective vaccines based on influenza virus proteins that are shared by multiple strains." AVI Bio Pharma Inc. has evidence of inhibition of multiple subtypes of influenza A virus in cell culture with Morpholino oligomers from the results of their labs and four independent research laboratories. "The key finding here is that our NEUGENE(R) therapeutics continue to show efficacy against all strains of influenza A, including H5N1." Morpholinos conjugated with cell penetrating peptides have been shown effective in protecting mice from influenza A."Several companies are focusing on new vehicles for growing antigens, which are the bits of a virus or bacterium needed to spur a person's immune system to fight an infection. VaxInnate, a New Jersey-based biotechnology company, has reported success using E. coli bacteria, which can cause a sometimes-fatal infection but also can be used to grow vaccine ingredients when the harmful part of the bacterium is removed. Dowpharma, a unit of Dow Chemical, has been using different bacteria found in soil and water, P. fluorescens, which may make a higher volume of antigens more quickly than E. coli."A recent study has shown promise by a vaccine called FluBlOk, which is made in insect cells. This experimental vaccine, which focuses on hemagglutinin, would cut the production process by one to two months, as well as avoiding other pitfalls of chicken eggs."The Committee for Medicinal Products for Human Use (CHMP), which reviews applications for 27 EU countries, found that Novartis's Optaflu vaccine, given to more than 3,400 people during clinical studies, met the CHMP's immunogenicity criteria [...] Novartis has said that Optaflu is a subunit vaccine, meaning it contains individual viral proteins rather than whole virus particles. [...] Novartis said it anticipates applying for US licensing of its cell-based flu vaccine in 2008. The company has conducted phase 1 and 2 clinical trials of the vaccine in the United States and in July 2006 announced it would build a $600 million plant in Holly Springs, N.C., to make cell-culture flu vaccines. In May 2006 the US Department of Health and Human Services awarded Novartis a $220 million contract to develop cell-based flu vaccines, and Novartis has said the money would go toward the cost of the new facility. Depending on when its vaccine is approved by the Food and Drug Administration, the plant could begin production as early as 2011 and be ready for full production as early as 2012, with an annual output of 50 million doses of a trivalent vaccine, the company has said. In the event of a flu pandemic, the facility is designed to have the capacity to make up to 150 million monovalent (single strain) doses each year within 6 months of a pandemic declaration, Novartis said. Novartis' other cell-based vaccine production facility is in Marburg, Germany.

Pandemic flu vaccine planning

According to the US HHS (United States Department of Health & Human Services) Pandemic Influenza Plan Appendix F: Current HHS Activities last revised on November 8, 2005 :
Currently, influenza vaccine for the annual, seasonal influenza program comes from four manufacturers. However, only a single manufacturer produces the annual vaccine entirely within the U.S. Thus, if a pandemic occurred and existing U.S.-based influenza vaccine manufacturing capacity was completely diverted to producing a pandemic vaccine, supply would be severely limited. Moreover, because the annual influenza manufacturing process takes place during most of the year, the time and capacity to produce vaccine against potential pandemic viruses for a stockpile, while continuing annual influenza vaccine production, is limited. Since supply will be limited, it is critical for HHS to be able to direct vaccine distribution in accordance with predefined groups HHS will ensure the building of capacity and will engage states in a discussion about the purchase and distribution of pandemic influenza vaccine.
Vaccine production capacity: The protective immune response generated by current influenza vaccines is largely based on viral hemagglutinin (HA) and neuraminidase (NA) antigens in the vaccine. As a consequence, the basis of influenza vaccine manufacturing is growing massive quantities of virus in order to have sufficient amounts of these protein antigens to stimulate immune responses. Influenza vaccines used in the United States and around world are manufactured by growing virus in fertilized hens’ eggs, a commercial process that has been in place for decades. To achieve current vaccine production targets millions of 11-day old fertilized eggs must be available every day of production.
In the near term, further expansion of these systems will provide additional capacity for the U.S.-based production of both seasonal and pandemic vaccines, however, the surge capacity that will be needed for a pandemic response cannot be met by egg-based vaccine production alone, as it is impractical to develop a system that depends on hundreds of millions of 11-day old specialized eggs on a standby basis. In addition, because a pandemic could result from an avian influenza strain that is lethal to chickens, it is impossible to ensure that eggs will be available to produce vaccine when needed.
In contrast, cell culture manufacturing technology can be applied to influenza vaccines as they are with most viral vaccines (e.g., polio vaccine, measles-mumps-rubella vaccine, chickenpox vaccine). In this system, viruses are grown in closed systems such as bioreactors containing large numbers of cells in growth media rather than eggs. The surge capacity afforded by cell-based technology is insensitive to seasons and can be adjusted to vaccine demand, as capacity can be increased or decreased by the number of bioreactors or the volume used within a bioreactor. In addition to supporting basic research on cell-based influenza vaccine development, HHS is currently supporting a number of vaccine manufacturers in the advanced development of cell-based influenza vaccines with the goal of developing U.S.-licensed cell-based influenza vaccines produced in the United States.
Dose-sparing technologies. Current U.S.-licensed vaccines stimulate an immune response based on the quantity of HA (hemagglutinin) antigen included in the dose. Methods to stimulate a strong immune response using less HA antigen are being studied in H5N1 and H9N2 vaccine trials. These include changing the mode of delivery from intramuscular to intradermal and the addition of immune-enhancing adjuvant to the vaccine formulation. Additionally, HHS is soliciting contract proposals from manufacturers of vaccines, adjuvants, and medical devices for the development and licensure of influenza vaccines that will provide dose-sparing alternative strategies.

Vaccines

A vaccine probably would not be available in the initial stages of population infection. A vaccine cannot be developed to protect against a virus which does not exist yet, and the influenza virus capable of generating the next pandemic has not been identified yet. The Avian Flu virus H5N1 has the potential to mutate into a pandemic strain, but so do other types of flu virus. Once a potential virus is identified, it normally takes at least several months before a vaccine becomes widely available, as it must be developed, tested and authorized. The capability to produce vaccines varies widely from country to country; in fact, only 19 countries are listed as "Influenza vaccine manufacturers" according to the World Health Organization.It is estimated that, in a best scenario situation, 750 million doses could be produced each year, whereas it is likely that each individual would need two doses of the vaccine in order to become immuno-competent. Distribution to and inside countries would probably be problematic. Several countries, however, have well-developed plans for producing large quantities of vaccine. For example, Canadian health authorities say that they are developing the capacity to produce 32 million doses within four months, enough vaccine to inoculate every person in the country.
Another concern is whether countries which do not manufacture vaccines themselves, including those where a pandemic strain is likely to originate, will be able to purchase vaccine to protect their population. Cost considerations aside, they fear that the countries with vaccine-manufacturing capability will reserve production to protect their own populations and not release vaccines to other countries until their own population is protected. Indonesia has refused to share samples of H5N1 strains which have infected and killed its citizens until it receives assurances that it will have access to vaccines produced with those samples. So far, it has not received those assurances..
There are two serious technical problems associated with the development of a vaccine against H5N1. The first problem is this: seasonal influenza vaccines require a single injection of 15 μg haemagluttinin in order to give protection; H5 seems to evoke only a weak immune response and a large multicentre trial found that two injections of 90 µg H5 given 28 days apart provided protection in only 54% of people (Treanor 2006). Even if it is considered that 54% is an acceptable level of protection, the world is currently capable of producing only 900 million doses at a strength of 15 μg (assuming that all production were immediately converted to manufacturing H5 vaccine); if two injections of 90 μg are needed then this capacity drops to only 70 million (Poland 2006). Trials using adjuvants such as alum or MF59 to try and lower the dose of vaccine are urgently needed. The second problem is this: there are two circulating clades of virus, clade 1 is the virus originally isolated in Vietnam, clade 2 is the virus isolated in Indonesia. Current vaccine research is focused on clade 1 viruses, but the clade 2 virus is antigenically distinct and a clade 1 vaccine will probably not protect against a pandemic caused by clade 2 virus.

Anti-viral drugs

Many nations, as well as the World Health Organization, are working to stockpile anti-viral drugs in preparation for a possible pandemic. Oseltamivir (trade name Tamiflu) is the most commonly sought drug, since it is available in pill form. Zanamivir (trade name Relenza) is also considered for use, but it must be inhaled. Other anti-viral drugs are less likely to be effective against pandemic influenza.
Both Tamiflu and Relenza are in short supply, and production capabilities are limited in the medium term. Some doctors say that co-administration of Tamiflu with probenecid could double supplies.
There also is the potential of viruses to evolve drug resistance. Some H5N1-infected persons treated with oseltamivir have developed resistant strains of that virus.
Tamiflu was originally discovered by Gilead Sciences and licensed to Roche for late-phase development and marketing.

Public Response

*Social distance. By traveling less, working from home or closing schools there is less opportunity for the virus to spread.
*Respiratory hygiene. Populations should be repeatedly informed of the need for "respiratory hygiene" (covering mouth when coughing or sneezing, careful disposal of soiled tissues or other materials).
*Masks. No mask can provide a perfect barrier but products that meet or exceed the NIOSH N95 standard recommended by the World Health Organization are thought to provide good protection. WHO recommends that health-care workers wear N95 masks and that patients wear surgical masks (which may prevent respiratory secretions from becoming airborne).Any mask may be useful to remind the wearer not to touch the face. This can reduce infection due to contact with contaminated surfaces, especially in crowded public places where coughing or sneezing people have no way of washing their hands. The mask itself can become contaminated and must be handled as medical waste when removed.
*Hygiene. Frequent handwashing, especially when there has been contact with other people or with potentially contaminated surfaces can be very helpful. Alcohol-based hand sanitizers also kill both bacteria and viruses.
*Risk communication. To encourage the public to comply with strategies to reduce the spread of disease, "communications regarding possible community interventions [such as requiring sick people to stay home from work, closing schools] for pandemic influenza that flow from the federal government to communities and from community leaders to the public not overstate the level of confidence or certainty in the effectiveness of these measures."The Institute of Medicine has published a number of reports and summaries of workshops on public policy issues related to influenza pandemics. They are collected in Pandemic Influenza: A Guide to Recent Institute of Medicine Studies and Workshops and some strategies from these reports are included in the list above.

Phases

The World Health Organization (WHO) has developed a global influenza preparedness plan, which defines the stages of a pandemic, outlines WHO's role and makes recommendations for national measures before and during a pandemic.In the 2009 revision of the phase descriptions, WHO has retained the use of a six-phased approach for easy incorporation of new recommendations and approaches into existing national preparedness and response plans. The grouping and description of pandemic phases have been revised to make them easier to understand, more precise, and based upon observable phenomena. Phases 1–3 correlate with preparedness, including capacity development and response planning activities, while Phases 4–6 clearly signal the need for response and mitigation efforts. Furthermore, periods after the first pandemic wave are elaborated to facilitate post pandemic recovery activities.
The phases are defined below.In nature, influenza viruses circulate continuously among animals, especially birds. Even though such viruses might theoretically develop into pandemic viruses, in Phase 1 no viruses circulating among animals have been reported to cause infections in humans.
In Phase 2 an animal influenza virus circulating among domesticated or wild animals is known to have caused infection in humans, and is therefore considered a potential pandemic threat.
In Phase 3, an animal or human-animal influenza reassortant virus has caused sporadic cases or small clusters of disease in people, but has not resulted in human-to-human transmission sufficient to sustain community-level outbreaks. Limited human-to-human transmission may occur under some circumstances, for example, when there is close contact between an infected person and an unprotected caregiver. However, limited transmission under such restricted circumstances does not indicate that the virus has gained the level of transmissibility among humans necessary to cause a pandemic.
Phase 4 is characterized by verified human-to-human transmission of an animal or human-animal influenza reassortant virus able to cause “community-level outbreaks.” The ability to cause sustained disease outbreaks in a community marks a significant upwards shift in the risk for a pandemic. Any country that suspects or has verified such an event should urgently consult with WHO so that the situation can be jointly assessed and a decision made by the affected country if implementation of a rapid pandemic containment operation is warranted. Phase 4 indicates a significant increase in risk of a pandemic but does not necessarily mean that a pandemic is a forgone conclusion.
Phase 5 is characterized by human-to-human spread of the virus into at least two countries in one WHO region. While most countries will not be affected at this stage, the declaration of Phase 5 is a strong signal that a pandemic is imminent and that the time to finalize the organization, communication, and implementation of the planned mitigation measures is short.
Phase 6, the pandemic phase, is characterized by community level outbreaks in at least one other country in a different WHO region in addition to the criteria defined in Phase 5. Designation of this phase will indicate that a global pandemic is under way.
During the post-peak period, pandemic disease levels in most countries with adequate surveillance will have dropped below peak observed levels. The post-peak period signifies that pandemic activity appears to be decreasing; however, it is uncertain if additional waves will occur and countries will need to be prepared for a second wave.
Previous pandemics have been characterized by waves of activity spread over months. Once the level of disease activity drops, a critical communications task will be to balance this information with the possibility of another wave. Pandemic waves can be separated by months and an immediate “at-ease” signal may be premature.
In the post-pandemic period, influenza disease activity will have returned to levels normally seen for seasonal influenza. It is expected that the pandemic virus will behave as a seasonal influenza A virus. At this stage, it is important to maintain surveillance and update pandemic preparedness and response plans accordingly. An intensive phase of recovery and evaluation may be required.

WHO Pandemic Influenza Phases (2009)

Phase
Description

Phase 1
No animal influenza virus circulating among animals have been reported to cause infection in humans.

Phase 2
An animal influenza virus circulating in domesticated or wild animals is known to have caused infection in humans and is therefore considered a specific potential pandemic threat.

Phase 3
An animal or human-animal influenza reassortant virus has caused sporadic cases or small clusters of disease in people, but has not resulted in human-to-human transmission sufficient to sustain community-level outbreaks.

Phase 4
Human to human transmission of an animal or human-animal influenza reassortant virus able to sustain community-level outbreaks has been verified.

Phase 5
Human-to-human spread of the virus in two or more countries in one WHO region.

Phase 6
In addition to the criteria defined in Phase 5, the same virus spreads from human-to-human in at least one other country in another WHO region.

Post peak period
Levels of pandemic influenza in most countries with adequate surveillance have dropped below peak levels.

Post pandemic period
Levels of influenza activity have returned to the levels seen for seasonal influenza in most countries with adequate surveillance.

Government preparations for a potential H5N1 pandemic (2003-2009)

According to The New York Times as of March 2006, "governments worldwide have spent billions planning for a potential influenza pandemic: buying medicines, running disaster drills, [and] developing strategies for tighter border controls" due to the H5N1 threat.[T]he United States is collaborating closely with eight international organizations, including the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE), and 88 foreign governments to address the situation through planning, greater monitoring, and full transparency in reporting and investigating avian influenza occurrences. The United States and these international partners have led global efforts to encourage countries to heighten surveillance for outbreaks in poultry and significant numbers of deaths in migratory birds and to rapidly introduce containment measures. The U.S. Agency for International Development (USAID) and the U.S. Departments of State, Health and Human Services (HHS), and Agriculture (USDA) are coordinating future international response measures on behalf of the White House with departments and agencies across the federal government.Together steps are being taken to "minimize the risk of further spread in animal populations", "reduce the risk of human infections", and "further support pandemic planning and preparedness".Ongoing detailed mutually coordinated onsite surveillance and analysis of human and animal H5N1 avian flu outbreaks are being conducted and reported by the USGS National Wildlife Health Center, the Centers for Disease Control and Prevention, the World Health Organization, the European Commission, the National Influenza Centers, and others.

World Health Organization plan

The World Health Organization (WHO), believing that the world was closer to another influenza pandemic than it has been any time since 1968, when the last of the 20th century's three pandemics swept the globe, has developed a global influenza preparedness plan outlining the role of the WHO and recommendations for national measures before and during pandemics.

United States
"[E]fforts by the federal government to prepare for pandemic influenza at the national level include a $100 million DHHS initiative in 2003 to build U.S. vaccine production. Several agencies within Department of Health and Human Services (DHHS) — including the Office of the Secretary, the Food and Drug Administration (FDA), CDC, and the National Institute of Allergy and Infectious Diseases (NIAID) — are in the process of working with vaccine manufacturers to facilitate production of pilot vaccine lots for both H5N1 and H9N2 strains as well as contracting for the manufacturing of 2 million doses of an H5N1 vaccine. This H5N1 vaccine production will provide a critical pilot test of the pandemic vaccine system; it will also be used for clinical trials to evaluate dose and immunogenicity and can provide initial vaccine for early use in the event of an emerging pandemic."On August 26, 2004, Secretary of Health and Human Services, Tommy Thompson released a draft Pandemic Influenza Response and Preparedness Plan, which outlined a coordinated national strategy to prepare for and respond to an influenza pandemic. Public comments were accepted for 60 days.
In a speech before the United Nations General Assembly on September 14, 2005, President George W. Bush announced the creation of the International Partnership on Avian and Pandemic Influenza. The Partnership brings together nations and international organizations to improve global readiness by:
*elevating the issue on national agendas;
*coordinating efforts among donor and affected nations;
*mobilizing and leveraging resources;
*increasing transparency in disease reporting and surveillance; and
*building capacity to identify, contain and respond to a pandemic influenza.

On October 5, 2005, Democratic Senators Harry Reid, Evan Bayh, Dick Durbin, Ted Kennedy, Barack Obama, and Tom Harkin introduced the Pandemic Preparedness and Response Act as a proposal to deal with a possible outbreak.On October 27, 2005, the Department of Health and Human Services awarded a $62.5 million contract to Chiron Corporation to manufacture an avian influenza vaccine designed to protect against the H5N1 influenza virus strain. This followed a previous awarded $100 million contract to sanofi pasteur, the vaccines business of the sanofi-aventis Group, for avian flu vaccine.
In October 2005, President Bush urged bird flu vaccine manufacturers to increase their production.
On November 1, 2005 President Bush unveiled the National Strategy To Safeguard Against The Danger of Pandemic Influenza.He also submitted a request to Congress for $7.1 billion to begin implementing the plan. The request includes $251 million to detect and contain outbreaks before they spread around the world; $2.8 billion to accelerate development of cell-culture technology; $800 million for development of new treatments and vaccines; $1.519 billion for the Departments of Health and Human Services (HHS) and Defense to purchase influenza vaccines; $1.029 billion to stockpile antiviral medications; and $644 million to ensure that all levels of government are prepared to respond to a pandemic outbreak.On 6 March 2006, Mike Leavitt, Secretary of Health and Human Services, said U.S. health agencies are continuing to develop vaccine alternatives that will protect against the evolving avian influenza virus.The U.S. government, bracing for the possibility that migrating birds could carry a deadly strain of bird flu to North America, plans to test nearly eight times as many wild birds starting in April 2006 as have been tested in the past decade.On 8 March 2006, Dr. David Nabarro, senior U.N. coordinator for avian and human influenza, said that given the flight patterns of wild birds that have been spreading avian influenza (bird flu) from Asia to Europe and Africa, birds infected with the H5N1 virus could reach the Americas within the next six to 12 months."Jul 5, 2006 (CIDRAP News) – In an update on pandemic influenza preparedness efforts, the federal government said last week it had stockpiled enough vaccine against H5N1 avian influenza virus to inoculate about 4 million people and enough antiviral medication to treat about 6.3 million."

Canada
The Public Health Agency of Canada follows the WHO's categories, but has expanded them. The Avian Flu scare of 2006 prompted The Canadian Public Health Agency to release an updated Pandemic Influenza Plan for Health Officials. This document was created to address the growing concern over the hazards faced by public health officials when exposed to sick or dying patients.

Classification

Defining an epidemic can be subjective, depending in part on what is "expected". An epidemic may be restricted to one locale (an outbreak), more general (an "epidemic") or even global (pandemic). Because it is based on what is "expected" or thought normal, a few cases of a very rare disease may be classified as an "epidemic," while many cases of a common disease (such as the common cold) would not.

Endemic diseases
Common diseases that occur at a constant but relatively low rate in the population are said to be "endemic." An example of an endemic disease is malaria in some parts of Africa (for example, Liberia) in which a large portion of the population is expected to get malaria at some point in their lifetime.

Non-infectious disease usage
The term "epidemic" is often used in a sense to refer to widespread and growing societal problems, for example, in discussions of obesity or drug addiction. It can also be used metaphorically to relate a type of problem .

Factors stimulating new epidemics

Factors that have been described by to stimulate the rise of new epidemics include:

1.Alterations in agricultural practices and land use
2.Changes in society and human demographics
3.Poor population health (e.g., malnutrition, high prevalence of HIV)
4.Hospitals and medical procedures
5.Evolution of the pathogen (e.g., increased virulence, drug resistance)
6.Contamination of water supplies and food sources
7.International travel
8.Failure of public health programs
9.International trade
10.Climate change

Several other factors have also been mentioned in different reports.These include :

1.Reduced levels of biodiversity (e.g. through environmental destruction)
2.Bad urban planning .