Avian influenza is a slightly misleading term, as influenza is among the natural infections found in birds. The term avian influenza used in this context refers to zoonotic human infection with an influenza strain that primarily affects birds.
Influenza virus is an orthomyxovirus—an enveloped, segmented, negative-sense RNA virus. Influenza virus has 3 strains—A, B, and C. (For additional information on influenza, see Medscape's Influenza Resource Center.) Avian influenza is caused by influenza A virus, which has 8 RNA segments. Avian influenza is a potential and unpredictable threat to humans because of the segmented nature of the genome.
The serotypes of influenza A virus are identified based on the hemagglutinin (H) and neuraminidase (N) proteins; 16 H serotypes and 9 N serotypes have been identified. For example, one currently circulating strain is designated as H3N2. The strain previously considered the greatest threat was H5N1, mostly because of the high associated mortality rate (up to 60%) in infected humans. H5N1 infections have decreased substantially in recent years, and the most recent avian influenza of note is H7N9, first described in China in 2013.
These serotypic differences result in much of the species specificity due to differences in the receptor usage (specifically sialic acid, which binds to hemagglutinin and which is cleaved by neuraminidase when the virus exits the cell).
The immune response to these antigens is responsible for most host protection. The viral RNA polymerase lacks error-checking mechanisms and, as such, the antigenic drift from year to year is sufficient to ensure a significant susceptible host population. However, the segmented genome also has the potential to allow re-assortment of genome segments from different strains of influenza in a co-infected host.
Although all strains of influenza A virus naturally infect birds, certain strains can infect mammalian hosts such as pigs and humans. The re-assortment of an avian strain with a mammalian strain may produce a chimeric virus that is transmissible between mammals; such mutation products may contain hemagglutinin and/or neuraminidase proteins that are unrecognizable to the immune systems of mammals. This antigenic shift results in a much greater population of susceptible individuals in whom more severe disease is possible.
Such an antigenic shift can cause a pandemic, 4 of which have occurred in recorded history. The most striking pandemic occurred in 1918, when the Spanish influenza (H1N1) resulted in approximately 50 million deaths worldwide. Others included the pandemics of 1957 (H2N2) and 1968 (H3N2); smaller outbreaks occurred in 1947, 1976, and 1977. The fact that H3N2 is still circulating without causing an ongoing pandemic highlights the importance of herd immunity. The most recent pandemic was in 2009, caused by a swine-origin influenza of the H1N1 serotype.
Avian influenza has low-pathogenic (LPAI) and highly pathogenic (HPAI) strains. H5N1 is typically a highly pathogenic virus in birds, resulting in severe disease and death. This strain has drawn more attention than other HPAI strains because of ongoing reports of bird-to-human transmissions that result in severe disease in the human host. Recently, some evidence has indicated that H5N1 may cause fewer symptoms in ducks, making them a potential reservoir for infection and spread by migratory flocks.  A reassorted H5N1 virus has been reported in the United States among wild birds but is not considered a threat to humans.
Several confirmed cases of human infection with LPAI strains (H7N2 in the United Kingdom and the US states of Virginia and New York; H7N7 in the Netherlands, H9N2 in China and Hong Kong) have been reported. In 2004, one outbreak of an HPAI H7N3 in Canada resulted in mild human disease.  In early 2009, a recombinant H1N1 influenza consisting of a mix of swine, avian, and human gene segments spread rapidly around the world, but it was a low-pathogenicity strain.
H5N1 was first reported to cause severe human disease in 1997 in an outbreak among infected chickens on Hong Kong Island. The outbreak was successfully contained with the slaughter of the entire local chicken population (around 1.5 million birds). However, 18 human cases were reported, of which 6 resulted in death.  Since then, H5N1 has been found in chickens, ducks, and migratory fowl throughout Asia and is now spreading west through Europe and North Africa. Human cases are following the route of the avian spread, but H5N1 has also been found in dead birds in several countries without any reported human cases (eg, the United Kingdom, Germany; see image below).
The latest H7N9 outbreak started in China in 2013 and was initially described in 126 people. Smaller numbers of cases have been reported since, mostly involving direct contact with domestic birds. To date, the total number of cases is over 600, with over 100 deaths. One case was imported to Canada in January 2014. Cases have been reported in China as recently as June 2015.
To date, avian influenza remains a zoonosis, with no sustained human-to-human transmission. Family clusters have been reported but appear to be almost always related to common exposures; however, limited human-to-human spread through close proximity could not be officially ruled out. In September 2004, one case in Thailand probably involved daughter-to-mother transmission; the mother died. 
The pathophysiology of avian influenza differs from that of normal influenza. Avian influenza is still primarily a respiratory infection but involves more of the lower airways than human influenza typically does. This is likely due to differences in the hemagglutinin protein and the types of sialic acid residues to which the protein binds. Avian viruses tend to prefer sialic acid alpha(2-3) galactose, which, in humans, is found in the terminal bronchi and alveoli. Conversely, human viruses prefer sialic acid alpha(2-6) galactose, which is found on epithelial cells in the upper respiratory tract. One group has reported that ex vivo cultures of human tonsillar, adenoidal, and nasopharyngeal tissues can support replication of H5N1 avian influenza. 
Although this results in a more severe respiratory infection, it probably explains why few, if any, definite human-to-human transmissions of avian influenza have been reported; infection of the upper airways is probably required for efficient spread via coughing and sneezing. Many are concerned that subtle mutation of the hemagglutinin protein through antigenic drift will result in a virus capable of binding to upper and lower respiratory epithelium. The 1918 pandemic strain was so lethal partially because the receptor utilization of the hemagglutinin differed from that of other strains, and H5N1 has that potential to acquire that same biology through mutation.
Differences in the PA, NP, M1, NS1, and PB2 genes tend to correlate with human strains of influenza, including human infections with avian influenza.  The functional role of these genetic markers has yet to be determined but likely involves replication enhancement and immune suppression.
Unlike with human influenza, most deaths associated with avian influenza have been due to primary viral pneumonia, with no evidence of secondary bacterial infection.
United States statistics
Normal influenza results in approximately 200,000 hospitalizations and 36,000 deaths annually in the United States, with the peak season in the winter months.  However, no cases of avian influenza in humans have been reported in the United States although avian influenza has been identified in some wild birds in a few states in the US in 2014 and 2015.
As of August 27, 2015, 844 cases of H5N1 had been reported worldwide, with 449 deaths.  Most cases have been in eastern Asia; some cases have been reported in Eastern Europe and North Africa. Underreporting has been a concern, particularly in China, but the prevailing attitude about the need to suspect, test, and report cases of avian influenza is growing. There have been 631 reported cases of H7N9 influenza, mostly from China, with other cases in Taiwan, Malaysia, Hong Kong, and Canada (2 imported cases).
Although the risk remains largely theoretical, the ease of global travel emphasizes the possibility of international spread. The risks have been highlighted recently with the rapid spread of a low-pathogenicity H1N1 swine-origin influenza in early 2009. The risk of a successful recombination event occurring between swine-origin H1N1 and a pathogenic avian influenza cannot be easily assessed. A mutation in avian influenza that rendered it permissive for sustained human-to-human transmission without affecting its pathogenicity in humans could be extremely dangerous.
The image below depicts the countries where avian influenza has been reported.
The extraordinarily high mortality rate of avian influenza (>60% for H5N1; approximately 30% for H7N9) is worrying and reasonably accurate. There have been very few instances of seropositive individuals without clinical signs of infection. In most instances, the policy is to test exposed individuals around an outbreak (human and avian). Therefore, a large population of exposed but untested people is unlikely.
Race appears to be a factor only to the extent that geographic differences in the rate of HPAI among birds and the degree of bird-to-human contact are significant.
In Egypt, 90% of fatalities due to avian influenza have involved women, a pattern that has not been readily apparent elsewhere.  Most cases of H7N9 have been reported in men.
Avian influenza has the highest case-fatality rate among persons aged 10-39 years. Unlike seasonal influenza, which disproportionately affects very young and very old individuals, young adults make up a large proportion of the avian influenza cases.
Fifty percent of reported cases have been in people younger than 20 years. Forty percent of cases involve persons aged 20-40 years.
In Egypt, avian influenza has been associated with a relatively low mortality rate, which seems to be associated with a high rate of infection in young children (<10 y); as of May 2009, the mortality rate in this subpopulation has been zero. The significance and reproducibility of these findings remains to be seen. 
The prognosis of confirmed human cases of avian influenza is related to the degree and duration of hypoxemia. The cases to date have exhibited a 60% mortality rate. The risk of mortality depends on the degree of respiratory disease rather than the bacterial complications (pneumonia).
Little evidence regarding the long-term effects of disease among survivors is available.
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