Surveillance, vaccines, and infection control can curb influenza, which causes three to five million severe infections annually.

The many types of influenza virus infect anywhere from five to 30 percent of the world's population during a typical year. Most cases of flu are mild, primarily affecting the nasal passages, throat, and pharynx in the upper respiratory tract. But every year three to five million severe infections occur, generally in the lower respiratory tract. Influenza kills 250,000 to 500,000 people annually.<br />Influenza tends to get more attention in wealthier countries, where infants and individuals over age 65 are typically at greatest risk because of their lessened immunity and underlying health conditions. In developing countries, where so many other health problems compete for attention, influenza is sometimes overlooked-yet it imposes a heavy disease burden, especially among populations that are malnourished or immunocompromised. The flu virus can travel on inhaled airborne particles, sprayed droplets that are projected onto mucous membranes, or a contaminated hand that touches the nose or mouth. In temperate regions of both hemispheres, peak flu activity occurs in the winter season, while in the tropics, influenza occurs throughout the year.

Influenza can be caused by three major classes of RNA viruses grouped by their genetic characteristics. Influenza A and B are associated primarily with diseases in humans, while influenza C primarily infects animals.

These classes are further delineated by the nature of the two large proteins on the viral surface-hemagglutinin (HA) and neuraminidase (NA). There are 16 HA and nine NA subtypes, although relatively few cause human infection. The proteins largely define the behavior of viruses, which are named according to the combinations of protein they contain. For example, the influenza A viruses currently circulating in the human population include the subtypes H1N1 and H3N2.

Once an influenza virus has invaded the body and attached itself to cells lining the respiratory tract, it incubates for one to seven days before symptoms appear. An infected individual may be able to infect others prior to and during the symptomatic period. One study of the pandemic H1N1 virus showed that children and young adults remained infectious for ten days or longer, while individuals with compromised immune systems might be capable of infecting others for weeks. Influenza can survive for hours outside a human host, further aiding its capacity to spread.

Take a Closer Look

Influenza viruses can mutate swiftly-one million times faster than vertebrates can mutate-and can swap genetic components with other viruses. Many influenza viruses are believed to originate in the tropics before being exported to the more temperate northern and southern hemispheres, although this pattern is not fully understood.

In a process known as antigenic drift, the proteins on the surface of the flu virus make frequent minor changes in their genetic structure. The resulting new strains can evade the human defense system, even among populations previously infected by, or vaccinated with, a related strain.

At unpredictable intervals, flu viruses with the power to infect humans undergo antigenic shift, a more significant genetic alteration that typically results from a merger with viruses residing in reservoirs of poultry, water fowl, pigs, or other mammals. If the recombined virus is zoonotic, or capable of traveling from animal to human populations, humans are unlikely to have any immunity.

Influenza A and B viruses are subject to antigenic drift, while only influenza A undergoes antigenic shift. The H1N1 pandemic of 2009-10 is an example of a significant viral antigenic shift.

A pandemic is the widespread transmission of a pathogen to populations around the world. Influenza pandemics are inevitable but unpredictable, and they generally occur with the emergence of a virus that is either novel or has not circulated for many decades. Pandemic flu infects far more people than a typical seasonal flu, although the illness is not necessarily more severe.

Pandemics of the past: Three influenza pandemics occurred in the 20th century, each resulting from antigenic shifts in the influenza A virus.

The Spanish flu of 1918, believed to be the most devastating in human history, infected between one-third and one-half the world's population and killed tens of millions of people. Milder pandemics occurred in 1957, when Asian influenza killed two million people, and in 1968, when the Hong Kong influenza was responsible for one million deaths. The Spanish flu pandemic may have involved an avian virus that adapted to become able to infect humans directly, while the Asian and Hong Kong pandemics were caused by a reassortment of human and avian viruses. In each case, younger populations faced greater-than-usual risks, possibly because they had no exposure to earlier versions of the pathogen-individuals younger than 65 were 20 times more likely to die during one of these pandemics than they were during a normal flu season. Elderly populations, who are inherently more vulnerable, may have already built up some immunological protection and did not face special additional risks.

Spanish flu of 1918: The 1918 pandemic occurred in three waves around the world. After a first round of mild infections in the spring, the Spanish flu returned with deadly power in the late summer, causing acute lung inflammation and progressing rapidly to lethal pneumonia. A third wave in early 1919 was also deadly, although less so. Mortality data are inconsistent, but most sources estimate that between 20 and 50 million deaths occurred. Global population growth remained depressed for a decade afterward.

Researchers have called the Spanish flu "the mother of all pandemics" because the genetic structure of most subsequent influenza A viruses can be traced back to it. Many of today's efforts to prepare for a potential new pandemic consider the severity of that event in their calculations, although the vagaries of biology, coupled with today's ease of travel, access to health care, and improved nutrition, make extrapolation difficult.

Avian flu watch: Aware that other influenza pandemics are inevitable, public health officials around the world conduct surveillance in order to identify new viral strains as soon as possible. A strain of H5N1 avian influenza virus, first isolated in Asia in 2003, remains worrisome. As many as 150 million birds were culled to reduce transmission of the highly contagious virus, which is often fatal in domestic stocks of poultry, cats, and wild birds, but the virus nonetheless remains endemic in many parts of Asia.

To date, the H5N1 virus has had limited ability to cross the species barrier into human populations. From 2003 to May 2010, WHO reported fewer than 500 laboratory-confirmed human infections, although the death rate when infection does occur approaches 60 percent (and in Indonesia, 165 cases caused 136 deaths). Should the virus evolve to infect humans more readily, it could cause a devastating new pandemic.

On June 11, 2009, two months after two cases of a new strain of influenza A H1N1 were confirmed in the United States, WHO officially declared the first flu pandemic of the 21st century. By then, some 30,000 cases had been confirmed in 74 countries. Although the circulating virus was a novel combination of swine and avian influenza A viral strains, some components had circulated in the past, giving many adults born before 1956 a degree of immunity.

At-risk groups: The majority of infections have occurred among individuals with an age range of 12 to 17 years, but the groups at highest risk for complications have been the elderly, children under five, pregnant women, and individuals with chronic health problems. As in a more traditional flu season, severe respiratory distress and coinfection with bacterial pneumonia can develop. As of May 2010, 18,000 laboratory-confirmed deaths from the pandemic form of H1N1 had been reported. However, the total death toll is undoubtedly much higher, as most cases are not confirmed.

Are we prepared? H1N1 has been a test case for global preparedness. WHO guided international surveillance efforts, and many nations declared the pandemic a public health emergency. Among those nations was the United States, which released stockpiles of antiviral medication and protective equipment but did not choose to exert the federal authority to impose border controls or mandate that public facilities be closed.

The burden on many local health systems was significant, with spikes in the use of emergency rooms, hospitals, and outpatient care. Mexico, where the virus was first reported, estimated the cost of the outbreak at 57 billion pesos in 2009 (US$4.29 billion), primarily from lost tourism. An adequate vaccine supply was slow to become available: Near the end of 2009, WHO said it would have 200 million donated doses available to 95 countries that are home to one-third of the global population; by contrast, the U.S. had already purchased 250 million doses for its residents.

Because the symptoms caused by the H1N1 pandemic have been relatively mild, at least thus far, global response capacity was not fully tested. Nonetheless, even an outbreak of limited virulence strained public health resources.

Worldwide monitoring of influenza provides "best-guess" information about the viral strains most likely to cause disease in a given year, so that a timely vaccine can be manufactured and distributed (some components of the vaccine change every year). Surveillance is also essential for alerting public health authorities to illness surges so that they can act before a new, highly transmissible, or especially dangerous virus spreads in human populations.

Many surveillance strategies are available. These include case counts, based on specific laboratory tests and physician reports, monitoring domestic and wild animal populations, emergency room records, and even Google Flu Trends, which tracks regional patterns of online flu-related queries.

WHO's Global Influenza Surveillance Network, established in 1952, is the primary vehicle for a coordinated, worldwide tracking effort. As part of this network, designated National Influenza Centres at 134 institutions in 104 countries isolate and analyze some 175,000 viral samples every year and submit 2,000 of them to five WHO Collaboration Centers. These centers sequence the viruses to determine the extent and direction of their evolution away from previously identified genetic structures. Through FluNet, the network's web-based data collection and reporting tool, tables, maps, graphs and reports are available to the public.

Many countries with the highest burden of acute respiratory infections do not have their own National Influenza Centres because they lack the resources and technology to provide the necessary data. For example, of 46 countries in the WHO African region, only 18 have centers, and only 10 have the laboratory capacity to conduct sophisticated diagnostic testing.

Take a Closer Look

Vaccines: The best protection against influenza is a vaccine well matched to the viral strains in circulation in any given season. Once developed, access remains a challenge and coverage rates are generally low, especially in less-developed countries. The vaccine supply is never sufficient to reach all those who need it: Even without a pandemic, some 1.2 billion people around the globe are considered at high risk for flu, and many more are likely to be affected during a pandemic.

Only 900 million doses of vaccine can be produced worldwide, if all manufacturing facilities are operating at maximum capacity. More research is needed to overcome production bottlenecks, improve vaccine technology, and identify more efficient immunization strategies. Strengthening distribution systems and developing strategies to ensure more equitable access to limited vaccines are also essential, and manufacturers' liability concerns may need to be addressed.

Because the vaccine designed for the 2009-10 flu season did not confer protection against the H1N1 virus that emerged to cause a pandemic, a new vaccine had to be developed, licensed and distributed in the months after its appearance. With supplies scarce, public health agencies in many countries initially limited immunization to first-responders and other priority populations. By the end of 2009, the United States had purchased adequate supplies for most of its residents, but WHO, relying on donated vaccines, had only 200 million vaccine doses for 95 countries with one-third of the world's population.

Other prevention strategies: No vaccine confers 100 percent immunity-for example, a single dose of H1N1 vaccine generates a robust immune response in only 56 to 80 percent of adults 65 or older. Public education about hand-washing techniques and cough and sneeze safeguards is essential to preventing flu outbreaks or reducing the virus's spread in communities. In severe epidemics, the principles of social distancing, such as canceling public events and closing recreational facilities, may also be necessary. Compliance with proper infection-control procedures in health care settings limits spread among patients and staff, and prophylactic antiviral drugs may be appropriate for health care workers and others at high risk of complications.

Government mandates are another option for prevention. For example, some Asian countries have used quarantine and medical detention to curb H1N1 transmission-aggressive but controversial measures that appear to have slowed the spread of disease. Many other nations have developed pandemic preparedness plans, with containment strategies that include travel restrictions and prohibitions against mass gatherings.

Take a Closer Look

A class of antiviral therapies known as neuraminidase inhibitors, which include zanamivir (Relenza) and oseltamivir (Tamiflu), can reduce the severity of some types of influenza, but only if they are administered within 48 hours of the onset of illness. Treatment is generally recommended only for individuals at risk of complications and for those who have been hospitalized with flu symptoms, as the majority of the population can recover on its own.

Certain influenza strains have become resistant to an older class of antivirals known as adamantanes, and Tamiflu is no longer effective against a form of H1N1 influenza that circulates seasonally. While Tamiflu generally remained effective for the 2009 pandemic strain of H1N1, scattered reports of resistance raise concern. Even if Tamiflu does retain its effectiveness, supplies are limited: In 2009, only about 220 million doses were available around the world.

Global Impact

  • Worldwide, three to five million severe influenza infections occur annually, killing between 250,000 and 500,000 people. While influenza is a burden everywhere, it tends to be overlooked in developing countries, where inadequate laboratory facilities impede diagnoses, and other health challenges compete for attention.
  • Vaccines are the most effective strategy available for preventing influenza, but the wealthier nations dominate production, and worldwide capacity is limited to 900 million doses.
  • Many influenza viruses are resistant to antiviral therapies, and those that remain effective are not being manufactured in adequate volume.

Actions That Make a Difference

  • Rigorous surveillance can send an early warning signal about the emergence of new viral strains, providing a window of opportunity for control. Effective surveillance requires adequate resources and international cooperation.
  • Research is needed on more efficient ways to manufacture vaccines, distribution systems to poor countries should be strengthened, and more equitable access to a limited vaccine supply is essential.
  • Public education about hand-washing techniques, cough and sneeze safeguards, and limiting social contact are essential to curbing the spread of flu. In health care settings, compliance with proper infection control procedures is also crucial, so that infections do not spread from patient to health care worker to patient.
  • In severe epidemics, it may become necessary to use public policies that restrict public interaction and minimize the spread of infection.
  • New antiviral therapies are needed to counter growing drug resistance. For example, oseltamivir (Tamiflu) has largely lost its value against a seasonal form of H1N1. Tamiflu remains effective against the pandemic strain of H1N1 that arose in 2009, but production capacity should be increased from the 220 million doses currently available around the world.

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