What is avian influenza?

Causes and symptoms

A group of RNA viruses causes influenza in birds. Most such viruses do not attack humans, although human influenza viruses were probably derived from bird influenza viruses. On the rare occasion that a bird flu strain achieves the ability to enter and reproduce in human cells, the human is unlikely to have effective defenses and the viral attack is likely to be severe. If the virus strain combines its ability to reproduce in humans and its highly pathogenic nature with the ability to transfer from human host to human host efficiently, then it is particularly dangerous. The most deadly human influenza pandemics
in history probably began this way. Public health officials have been concerned that the avian influenza A virus strain H5N1 might undergo such a transformation and initiate such a pandemic.

Influenza virus subtypes are named for two types of their surface proteins, hemagglutinin (sixteen subtypes) and neuraminidase (nine subtypes), and all have been identified in avian influenza viruses. Each different protein is assigned a number, so that H5 in H5N1 refers to the hemagglutinin that is assigned the number five. Similarly, N1 refers to the neuraminidase assigned the number one. Hemagglutinins are responsible for attachment of the virus to host cells and entry into those cells. After the production of new viruses in the cell, neuraminidases are used by the new viruses to break out of the cell.

Influenza viruses are notorious for their ability to change their surface antigens and thereby escape host defenses, which are dependent on recognition of those antigens. The H5 and N1 surface proteins characterize the subtype causing severe human disease (since 1997) and are also antigens targeted by host defenses. Both are displayed on the surface of the membranelike coat that surrounds the virus. The hemagglutinin (H5) is the primary target for cell defenses. If an organism has been exposed to a given hemagglutinin, then it will quickly produce antibodies that attach to that hemagglutinin, blocking the site that is normally used to attach to the organism’s cells. The virus is rendered harmless if it cannot attach to and enter a cell. If this is the organism’s first exposure to the specific hemagglutinin, however, then the response will not be as rapid. The host’s immune system will begin making antibodies against the new antigen, but they are made too slowly during this first exposure, and illness results. Most humans have had no exposure to H5 antigens and so
are unprotected against H5N1.

Symptoms of avian influenza in humans include the familiar set generally caused by flu viruses. Those symptoms—fever, loss of appetite, clogged sinuses, runny nose, muscle aches, and so forth—pass in three to five days with most influenza strains, and the victim recovers. With H5N1, however, other host systems—such as the circulatory, nervous, reproductive, and gastrointestinal systems—often become involved. In approximately 60 percent of human cases reported, death occurs, sometimes within a day of the onset of symptoms.

Treatment and Therapy

The major medical solutions to avian flu infection are medications and vaccination. Antiviral medications have been difficult to develop, and few effective drugs are available. Many of the drugs prescribed for viral infections are actually used to combat secondary infections by bacteria attempting to take advantage of the host’s weakened condition. Vaccine development against influenza viruses is also problematic. The vaccines target antigens on the surface of the viruses, and the viruses mutate and change their surface antigens so frequently that new vaccines must be developed almost every year to defend against the new strains of influenza. Given these difficulties and the fact that most influenza victims recover in three to five days without treatment, drugs and vaccines against influenza have often not been a high priority compared to those against more deadly diseases such as smallpox. Periodically, however, a particularly pathogenic influenza strain has developed, and effective treatment would have saved many lives. Because the H5N1 strain is feared for its potential to be one of those strains, scientists have sought to develop both drugs and vaccines against this virus.

Four medications that act against flu viruses are available, but the virus has quickly developed resistance to the older pair, amantadine and rimantadine. The H5N1 virus populations in Vietnam and other Southeast Asian countries are already resistant to these drugs. In those countries, the virus has been present in poultry, and occasionally in humans, a bit longer than elsewhere. Two newer drugs, oseltamivir and zanamivir, have shown effectiveness against H5N1, although the virus has sometimes been resistant to oseltamivir. The antiviral resistance of avian flu is being continuously monitored.

Progress in vaccine development has been encouraging, but no 100-percent proven vaccine is available. Even when a vaccine becomes ready for use, production of enough to meet the needs of a pandemic would be challenging. Stockpiling a vaccine in anticipation of a pandemic is possible, but the exact antigen against which it must be directed cannot be known until the virus is in the process of initiating the pandemic. Each year, experts predict the most likely antigens for an approaching flu season, and vaccines are produced in advance against those antigens. Should an influenza virus employ an antigen not anticipated by the experts, then the stockpiled vaccines would be worthless.

Vaccine production technology is also improving, but the improvements have not been fully implemented. In the standard technique, the antigenic virus to be used in the vaccine is grown in fertilized eggs—an expensive, slow, and inefficient method. Tissue culture techniques, in which the antigenic virus is grown in cells in artificial media, promise dramatic improvement in vaccine preparation once they are fully integrated into the production system.

Perspective and Prospects

The history of influenza can be traced much further back in time than the understanding of its cause. Reports describing epidemics and pandemics in which the victims showed symptoms of influenza go back to the early sixteenth century at least, but the first isolation of an influenza virus did not occur until 1933. The worst flu pandemic occurred in 1918 to 1919 (the Spanish flu), when twenty million to one hundred million people died of influenza. It was one of the deadliest diseases in history. Two more recent flu pandemics, the Asian flu (1957) and the Hong Kong flu (1968), were seriously disruptive, but not as deadly. All these pandemics were caused by influenza type A viruses, the type to which strain H5N1 and the other avian influenza viruses belong.

The concern over avian influenza type A H5N1 began in 1997 in Hong Kong, where poultry and humans came under attack. Three events associated with these infections captured the attention of epidemiologists, because together they suggested H5N1’s potential as the agent of an influenza pandemic. First, transmission occurred from poultry to humans. Second, H5N1 proved to be highly pathogenic, as six of the eighteen infected humans died. Third, there was some indication of human-to-human transfer of the virus. If the virus maintained its pathogenic nature and its ability to move from poultry to humans, and if it added the ability to transfer efficiently from one human to another, it would almost certainly initiate another deadly pandemic.

Between 1997 and 2006, a number of human cases of avian influenza type A were documented in a number of countries. Not all were the result of the feared H5N1 strain, but the other strains bear watching as well. Between 2004 and 2006, there were two hundred confirmed cases of human infection with H5N1, most in Southeast Asia (Vietnam, Cambodia, Indonesia, Thailand) but also in Egypt, Iraq, Azerbaijan, and Turkey. Since November 2003, more than six hundred people across fifteen countries in Asia, the Pacific, Europe, Africa, and the Middle East have been infected with H5N1; and more than half of those infected have died. No H5N1 infections have been documented in North America, but avian influenza virus type A H7N2 caused illness in New York, and H7N3 attacked poultry workers in Canada. No North American infection resulted in a human fatality. A new serious strain of avian influenza type A, H7N9, was discovered in China in March 2013. By early May 2013, more than 130 people had been infected, and just over 20 percent of those infected had died. There is concern over H7N9's ability to spread more easily to mammals than other strains of bird flu; health officials have been working on a vaccine against this strain. None of these infections have involved extensive or sustained human-to-human transmission, though a few restricted transfers between humans may have occurred. Most of the human infections were transferred from infected domestic poultry. Some may have been contracted from wild waterfowl (ducks and geese).

Human health is not the only concern regarding the H5N1 strain; there are agricultural and economic concerns as well. Poultry flocks can be destroyed by the virus. There were several poultry outbreaks around the world before 2006, in which an estimated 150 million barnyard birds either died as victims of the virus or were culled to remove the infection focus and prevent further spread of the virus. Although the governments involved often compensated individuals for their culled animals, the compensation was usually well below market value. This practice encourages farmers to hide infections that occur in their flocks, which slows the discovery of potential outbreaks and gives the virus a head start that it does not need. In addition, several governments were suspected of hiding avian flu outbreaks until they were impossible to conceal, in an attempt to protect their countries’ economic interests.

The role played by wild birds is an important piece of this puzzle as well. Wild birds, especially waterfowl, act as the reservoir for H5N1. The birds maintain the virus between epidemics. Waterfowl are known to carry the virus, release virus in their feces and oral secretions, and are usually not sickened by the virus infection. These characteristics of the reservoir indicate how easily a pandemic could start from a mutant virus in the reservoir. In Hong Kong in 2002 to 2003 and again in China in 2005, large numbers of wild birds were killed by the virus, emphasizing the virus’s tendency to mutate. Experts believe that it may take only a few mutations for the virus to gain the ability to successfully transfer between humans. If they are right, then the waterfowl reservoir is always just a step away from creating a pandemic virus strain.

Given their mobility, especially during migration, wild birds also appear to be good candidates for spreading the virus among countries and continents. However, investigations suggest that, while wild bird migration might play a role in viral geographic expansion, it is probably secondary to the role played by commercial poultry exchanges.

Avian influenza virus type A H5N1 has demonstrated its ability to transfer from wild birds to domestic poultry (and perhaps to humans), to decimate domestic poultry flocks, to be transferred from poultry to humans, and to be highly pathogenic for humans. It has not definitively demonstrated the ability to pass freely from one human to another, although the Centers for Disease Control and Prevention indicates that a limited amount of human-to-human cases may have occured. While for the most part, H5N1 cannot transmit effectively from person to person, if it were to add this last ability successfully to its arsenal, it would be a candidate to initiate a pandemic as deadly as the influenza pandemics of the past. The change required to introduce this ability to the H5N1 virus is not thought to be elaborate. A few simple mutations in the viral RNA might suffice.

Epidemiologists have one special concern, the potential for the H5N1 virus to use pigs for reassortment of its genes. In developing countries, pigs often share living space with chickens and other poultry. Humans often live adjacent to the animals or even share their living space. These associations are troubling because pigs host both human and bird flu viruses—for example, the H1N1 strain that caused a global pandemic between 2009 and 2010 was of swine origin, although the H1N1 virus is endemic to both birds and pigs—and the intimate association of the three species presents the two viral strains with the opportunity to invade the same pig. Together in the same host, they would be expected to exchange RNA strands. Some reassortments might produce a virus with the capability to transfer from human to human. There is no evidence that such a transformation has occurred. However, the possibility is real and the defenses (antiviral drugs and vaccination) are not in place and fully functional, so the concern is understandable.

Some investigators suggest, however, that the concern has been overblown. They point out that no H5 influenza strain has ever caused a pandemic and that successful pandemic-causing influenza strains attach to receptors in the upper parts of the human respiratory tract, while the receptors to which H5N1 viruses attach are in the lower reaches. Some skeptics also argue that if H5N1 went through the changes necessary to achieve efficient transfer among humans, it would invariably lose pathogenic potency in the process, thus minimizing its pandemic potential.

Governments and public health officials are between the proverbial rock and hard place. They would be criticized if they prepared for a threat that did not materialize, but more tragic results would occur if they failed to prepare and a pandemic broke out. Criticism for a perceived lack of preparation is already widespread. While another pandemic is probably inevitable, no one can know when it will materialize or what specific disease organism will be the cause, so there is no easy answer to their conundrum. For the long-term struggle against avian influenza, however, disease patterns in animal populations might be very helpful in predicting which threats have the potential to cause human pandemics and in otherwise understanding the viruses. This possibility calls for close coordination among students of wildlife, veterinary, and human disease. That coordination will not solve all the mysteries of influenza outbreaks but should aid in understanding them, and the influenza viruses will not be controlled until they are more thoroughly understood.

Bibliography:

"Avian Influenza A (H7N9) Virus." Centers for Disease Control and Prevention, Apr. 23, 2013.

"Avian Influenza A (H7N9) Virus." World Health Organization, May 10, 2013.

"Avian Influenza A Virus Infections in Humans." Centers for Disease Control and Prevention, June 21, 2012.

Beigel, John, and Mike Bray. “Current and Future Antiviral Therapy of Severe Seasonal and Avian Influenza.” Antiviral Research 78 (2008): 91–102.

"Bird Flu." MedlinePlus, May 2, 2013.

Carson-DeWitt, Rosalyn. "Avian Influenza." Health Library, Dec. 30, 2011.

Clark, Larry, and Jeffrey Hall. “Avian Influenza in Wild Birds: Status as Reservoirs, and Risks to Humans and Agriculture.” In Current Topics in Avian Disease Research: Understanding Endemic and Invasive Diseases, edited by Rosemary K. Barraclough. Washington, D.C.: American Ornithologists’ Union, 2006.

Davis, Mike. The Monster at Our Door: The Global Threat of Avian Flu. New York: New Press, 2005.

Green, Jeffrey. The Bird Flu Pandemic. New York: Thomas Dunne Books, 2006.

"Highly Pathogenic Avian Infleunza A (H5N1) Virus." Centers for Disease Control and Prevention, June 21, 2012.

"Information on Avian Influenza." Centers for Disease Control and Prevention, Apr. 12, 2013.

Sfakianos, Jeffrey N. Avian Flu. New York: Chelsea House, 2006.

Siegel, Marc. Bird Flu: Everything You Need to Know About the Next Pandemic. Hoboken, N.J.: John Wiley & Sons, 2006.

Wehrwein, Peter, ed. “Bird Flu: Don’t Fly into a Panic.” Harvard Health Letter 31, 8 (June, 2006): 1–3.