Etiology

The natural reservoir for influenza A viruses is wild aquatic birds, such as ducks and geese. Most influenza A virus subtypes identified to date, including 18 hemagglutinin and 11 neuraminidase subtypes, have been identified among birds.[88] Influenza A(H17N10) and A(H18N11) viruses have been identified in bats.[88][89] Other animal species can also be infected by influenza A viruses, including pigs, marine mammals, horses, dogs, cats, and penguins.

Avian influenza A viruses can infect tissues of the respiratory and gastrointestinal tracts of birds, which have receptors with sialic acid bound to galactose by alpha-2,3 linkages.[26][90]

Asian lineage low-pathogenic avian influenza (LPAI) A(H7N9) virus was detected for the first time in humans in March 2013. Unlike highly pathogenic avian influenza (HPAI) A(H5N1), Asian lineage LPAI A(H7N9) virus is associated with asymptomatic or subclinical infection in birds, making surveillance of outbreaks in poultry difficult. Closely related gene sequences were found in A(H7N9) viruses obtained from wild ducks in South Korea in early 2011, although it is not clear precisely when genetic reassortment events occurred between different viruses to give rise to Asian lineage A(H7N9) virus detected in 2013.[6][29][91] In 2017, Asian lineage HPAI A(H7N9) virus was detected in human respiratory specimens, poultry, and environmental samples, indicating evolution from Asian lineage LPAI A(H7N9) virus during circulation among poultry.[2][42][92]

Other influenza A viruses are also subject to genetic reassortment. Previous pandemic viruses are believed to have emerged in human populations through mutation from a zoonotic reservoir virus (1918 H1N1); genetic reassortment between LPAI avian influenza A viruses and seasonal influenza A viruses (1957 H2N2, 1968 H3N2); and genetic reassortment between triple reassortant swine influenza A(H1N1) and other swine influenza A viruses (A[H1N1]pdm09).[93][94] A potential exists for Asian lineage A(H7N9) virus to undergo reassortment events with co-circulating seasonal influenza A viruses.

Pathophysiology

Like other influenza A viruses, the Asian lineage low-pathogenic avian influenza (LPAI) A(H7N9) virus binds to receptors bearing sialic acid residues. A(H7N9) viruses have been shown to attach to both human upper and lower respiratory tract epithelial cells,[95] facilitated by binding to alpha-2,6-linked sialic acid residues (the receptors to which human seasonal influenza viruses bind) and alpha-2,3-linked sialic acid residues (the common avian influenza A virus receptors). Alpha-2,3 receptors are primarily, but not entirely, distributed in the human lower respiratory tract, whereas alpha-2,6 receptors are the predominant receptor in the human upper respiratory tract. Ex vivo studies suggest that A(H7N9) virus is better adapted and replicates more efficiently than highly pathogenic avian influenza (HPAI) A(H5N1) virus in human respiratory tract tissues.[96] Unlike other avian influenza viruses, Asian lineage LPAI A(H7N9) virus binds to ciliated epithelial cells of the nasal concha, trachea, and bronchus, in addition to the expected avian pattern of binding to alveolar epithelial cells, alveolar macrophages, and club cells (also known as bronchiolar exocrine cells or Clara cells) in the terminal bronchioles. The binding patterns of examples of Asian lineage A(H7N9) viruses have also been studied ex vivo in tissues obtained from ferrets, macaques, mice, pigs, and guinea pigs; wider tissue tropism is seen overall compared with HPAI A(H5N1) virus. It should be noted that the binding pattern of Asian lineage LPAI A(H7N9) virus in ferret tissues is markedly different from binding patterns in human tissues, with only limited attachment of Asian lineage LPAI A(H7N9) virus to ferret tracheal and bronchial epithelial cells.[97] This may help explain, at least in part, why airborne transmission of Asian lineage LPAI A(H7N9) virus between ferrets appears to be possible but is inefficient,[34][98][99] but does not explain the apparent inefficient transmission between humans. Experimental infection of ferrets is associated with shedding of high titers of Asian lineage LPAI A(H7N9) virus for 6 to 7 days, and shedding is seen in pigs for 6 days. Transmission did not occur between infected pigs and naive pigs or ferrets in the same model.[99]

Mice infected with Asian lineage LPAI A(H7N9) virus isolated from infected humans experience induction pro-inflammatory cytokines in serum and lung secretions, and during early infection cytokine levels positively correlate with virus load in the lungs. However, Asian lineage LPAI A(H7N9) virus appears to be less pathogenic than HPAI A(H5N1) virus in mice.[100] Increased levels of pro-inflammatory cytokines and chemokines have been observed in serum obtained from patients in the acute phase of Asian lineage LPAI A(H7N9) virus infection.[35] Serum levels of interleukin (IL)-6 and inducible protein-10 (IP-10) may positively correlate with severity of illness.[101] Others have shown that levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid tend to be greater than levels in plasma and that patients with higher plasma levels of IL-6, IL-8, and macrophage inhibitory protein 1-beta (MIP-1-beta) were more likely to have more severe illness or fatal outcomes.[102] Similar to findings in seasonal and pandemic influenza,[103][104] Asian lineage LPAI A(H7N9) virus-infected patients with the interferon-induced transmembrane protein-3 (IFITM3) rs12252-C, complement decay-accelerating factor (CD55) rs2564978, and toll-like receptor (TLR3) rs5743313 genetic polymorphisms are more likely to have severe disease.[102][105]

In addition to detection in respiratory tract secretions, Asian lineage LPAI A(H7N9) virus RNA has been detected in blood, urine, and feces in fatal and nonfatal cases.[106][107] The virus has been detected in multiple extrapulmonary organs in mouse and ferret models, including in brain and cardiac tissue, but has not been detected in the small number of human cerebrospinal fluid samples that have been analyzed. Reactive hemophagocytosis has been reported at autopsy.[106] Whether human infection with Asian lineage HPAI A(H7N9) virus will result in increased extrapulmonary spread and clinical manifestations (e.g., central nervous system disease) compared with Asian lineage LPAI A(H7N9) virus infection is not yet known.

Avian influenza A viruses, including Asian lineage A(H7N9) virus, can potentially be transmitted to humans through different modalities.

  • Direct or close exposure to infected sick or dead poultry or poultry products is thought to be the major risk for transmission of avian influenza A viruses to humans, including Asian lineage A(H7N9).[7][55]

  • Inhalation of aerosolized material (e.g., poultry feces) containing infectious Asian lineage A(H7N9) virus is a possible route of transmission from poultry to humans.[108]

  • Self-inoculation of the mucous membranes after direct contact with material containing Asian lineage A(H7N9) virus (touching or cleaning infected birds), or indirect (fomite) contact transmission from surfaces contaminated with poultry feces or products containing Asian lineage A(H7N9) virus to mucous membranes, are other possible routes of transmission.[108]

  • Consumption of uncooked poultry products, including blood from infected birds, has been identified in field investigations of HPAI A(H5N1) outbreaks as a potential risk factor for infections in humans, but it remains uncertain as to whether A(H5N1) and other avian influenza A viruses can cause infections via the human gastrointestinal tract.[1][109]

  • The handling and preparation of infected uncooked meat may pose a greater risk, although quantified risk estimates are not available.

Classification

Pathogenicity

Avian influenza A virus strains are classified as low-pathogenic avian influenza (LPAI) or highly pathogenic avian influenza (HPAI) using criteria that include molecular analyses and assessment of pathogenicity in experimentally infected chickens. Notably, the terms LPAI and HPAI do not describe, or necessarily correlate with, the severity of illness caused by infection in humans.

  • Most avian influenza A viruses are LPAI viruses and cause asymptomatic infection or mild disease in infected poultry. LPAI H6N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N7, and H10N8 virus strains have infected humans causing disease ranging from conjunctivitis to nonfatal upper respiratory and lower respiratory tract disease, to severe lower respiratory tract disease and death (H7N9, H10N8).[15][16][17][18][19][20][21]

  • All HPAI viruses identified to date are of the H5 and H7 subtypes and can cause severe illness in poultry. HPAI virus infections in humans have ranged from asymptomatic to severe or fatal disease. Rare, sporadic human cases of HPAI virus infection have been detected, for example with H5N1, H5N6, H7N3, and H7N7 viruses, and have caused a wide spectrum of illness from conjunctivitis (including H7N3 and H7N7 viruses) to acute respiratory distress syndrome and fatal outcomes (such as H7N7 and H5N1 viruses).[22][23][24]

  • During 2013 to 2016, all human cases of A(H7N9) virus infection were caused by LPAI viruses. From February 2017, Asian lineage A(H7N9) viruses with genetic characteristics of HPAI were detected in 3 human cases, and environmental and poultry samples, in China.[2][25]

Virology

Asian lineage A(H7N9) is a reassortant virus that contains genetic material from other avian influenza A viruses. The LPAI form of Asian A(H7N9) virus was the first LPAI virus to cause a significant outbreak of severe and fatal illness in humans. The RNA segment encoding the hemagglutinin is derived from a Eurasian A(H7) avian virus found in ducks and the segment encoding the neuraminidase is similar to avian A(H11N9) and other avian A(H7N9) viruses, which may have infected migratory birds. Six internal RNA segments are closely related to A(H9N2) viruses isolated from poultry in China, and at least two subclades of LPAI A(H7N9) virus have been identified.[26][27]

Analysis suggests that multiple, sequential reassortment events occurred to form the novel Asian lineage LPAI A(H7N9) virus, probably taking place in ducks and chickens. The animal reservoirs for Asian lineage A(H7N9) virus that have infected humans have not been confirmed, but the virus has been detected in samples from domestic birds sold in live poultry markets in eastern and southern China.[5][28] Asian lineage LPAI A(H7N9) virus can infect chickens, ducks, quail, pigeons, and geese; experimentally infected quail can transmit Asian lineage LPAI A(H7N9) virus to other quail.[29] The virus replicated in ferrets, mice, and nonhuman primates following experimental infection. Although the virus has genetic markers of mammalian adaptation, Asian lineage LPAI A(H7N9) virus appears to be less transmissible than A(H1N1)pdm09 virus in a ferret model of infection and transmission.[26][27]

The Asian lineage LPAI A(H7N9) virus has demonstrated genetic and antigenic evolution since it emerged in 2013, which is not unexpected or unusual for influenza A viruses. Two main sub-lineages of the Asian lineage A(H7N9) LPAI virus have been described, demonstrating different geographical presence within China: the Yangtze River Delta sub-lineage and the Pearl River Delta sub-lineage.[3][30] Additionally, the detection of insertion mutations at the multi-basic cleavage site of the viral hemagglutinin gene, reported in February 2017, signified the emergence of an Asian lineage HPAI A(H7N9) virus.[2][3] The cleavage site of HPAI A(H5N1) viruses has been shown to be a virulence factor in mammals (including humans); by contrast, experimental induction of the HPAI cleavage site in an A(H3N2) virus did not increase virulence in a ferret model of infection. There is some evidence that HPAI A(H5N1) viruses may have reduced airborne transmissibility,[31][32] and are associated with a lower viral burden,[33][34] compared with LPAI A(H5N1) viruses. There is no evidence currently to suggest that the Asian lineage HPAI A(H7N9) virus is associated with increased severity of disease in humans, nor increased transmissibility from birds to humans or between humans, but additional studies and monitoring of this evolving virus are required.

Amino acid substitutions associated with reduced susceptibility to neuraminidase inhibitor antivirals have also been detected sporadically in Asian lineage A(H7N9) viruses,[35][36][37][38][39][40][41] including some of the more recently detected HPAI viruses.[2] For viruses where sequence analysis has been performed, the proportions with reduced susceptibility have been similar between different annual waves of Asian lineage A(H7N9) virus activity.[2][42] Genetic analysis of 83 recent Asian lineage A(H7N9) viruses identified amino acid substitutions associated with reduced susceptibility in three viruses: two with R292K and one with A246T (N2 numbering).[2] Viruses with the R292K amino acid substitution demonstrate resistance to oseltamivir and reduced susceptibility to zanamivir and peramivir.[37] Some isolates have demonstrated reduced susceptibility to oseltamivir but not to peramivir.[43] Although reporting of associated clinical data is incomplete, some viruses with reduced susceptibility appear to have emerged following or during use of neuraminidase inhibitors for treatment in the affected individuals.[42] Several amino acid substitutions that confer reduced susceptibility to neuraminidase inhibitors do not confer a virus fitness cost (i.e., replication of Asian lineage HPAI A(H7N9) virus is not reduced) in cell lines in vitro.[44] Sequencing data suggest that all Asian lineage A(H7N9) viruses are inherently resistant to adamantane antivirals (amantadine and rimantadine) because they all possess the S31N amino acid substitution.

It should be noted that the North American wild bird lineage HPAI A(H7N9) virus, detected in commercial poultry flocks in Tennessee, US, in March 2017, is genetically distinct from the Asian lineage A(H7N9) virus. North American wild bird lineage LPAI A(H7N9) virus has also been detected in poultry in the US; no human infections have been identified to date with either the HPAI virus or the LPAI A(H7N9) virus in the US. Other distinct LPAI A(H7N9) viruses were detected in wild birds prior to the emergence of Asian lineage A(H7N9) virus in 2013.[45]

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