Aetiology

The natural reservoir for nearly all influenza A viruses is wild aquatic birds (ducks, geese). Of the 18 haemagglutinin and 11 neuraminidase subtypes of influenza A viruses identified to date, nearly all (except for H17N10, H18N11 identified in bats) have been identified among birds.[73] Other animal species can also be infected by influenza A viruses, including pigs, cows, wild terrestrial and marine mammals, horses, dogs, cats, and bats.[74]​​​​ Highly pathogenic avian influenza (HPAI) A viruses can cause asymptomatic infection to fatal disease in wild birds and domestic poultry. HPAI A(H5N1) virus was first identified in Scotland in 1959. However, the progenitor HPAI A(H5N1) virus to all HPAI A(H5N1) viruses currently circulating among birds was identified in 1996 from an infected goose in southern China. 

Most human HPAI A(H5N1) cases are sporadic and associated with direct contact (e.g., touching) or very close exposure (within ≤1 metre [≤3 feet]) with sick or dead backyard poultry (usually chickens), and a seasonal variation observed in human cases parallels that of outbreaks in birds.[26][75][76][77]​​ However, other risk factors include visiting a live poultry market and prolonged, unprotected close contact with a symptomatic human HPAI A(H5N1) case.​[78][79][80]​​ Exposure to pond water in regions where HPAI A(H5N1) virus has been widespread among birds has also been suggested as a possible risk factor.[81] In some cases, a possible exposure risk was not identified, suggesting possible environmental exposure or close contact with an unknown infected person.[82] Clustering of HPAI A(H5N1) cases among genetically related family members suggests the potential for increased genetic susceptibility. However, human-to-human transmission remains rare.[83][84][85][86][87]​​ Rare nosocomial transmission has also been documented.[1][2][88]​​ There is no evidence of ongoing human-to-human transmission of HPAI A(H5N1) virus. As of May 2024, no evidence of human-to-human transmission of HPAI A(H5N1) virus has been reported since 2007. 

Avian influenza A viruses, including HPAI A(H5N1) virus, can potentially be transmitted to humans through different modalities.

  • Direct contact (touching) 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.

  • Inhalation of aerosolised material (e.g., poultry faeces) containing infectious HPAI A(H5N1) virus is a likely route of transmission from poultry to humans.

  • Self-inoculation of the mucous membranes after direct contact with material containing HPAI A(H5N1) virus (touching or cleaning infected birds) or indirect (fomite) contact transmission from surfaces contaminated with poultry faeces or products containing HPAI A(H5N1) virus to mucous membranes has also been hypothesised.

  • Consumption of uncooked poultry products, including blood from infected birds, has been identified as a potential risk factor in field investigations, but whether transmission can occur by primary HPAI H5N1 virus infection of the human gastrointestinal tract is unknown.

Transmission from mammals to humans may be possible, but it is thought to be rare. The first instance of likely mammal-to-human transmission was reported in Texas, US, in April 2024.[3]​ The person developed conjunctivitis as their only symptom after exposure to dairy cattle presumed to be infected with HPAI A(H5N1) virus.[43]​​​[44]​​ Other cases of transmission from dairy cattle have been reported in the US since then.

Experimental studies in ferrets have demonstrated that HPAI A(H5N1) virus can acquire traits that improve transmissibility via respiratory droplets, and thus increase the risk of human-to-human transmission.[89] They have also shown the potential for H5N1 viruses to cause infection after exposure to virus via the eyes.[90]​ Ferret studies using the A(H5N1) virus from a human case in the 2024-2025 dairy cattle outbreak suggest that the virus is not capable of spreading efficiently among people via respiratory droplets or fomites, but spreads efficiently between ferrets in direct contact.[91]​

Of the several amino acid substitutions associated with increased respiratory transmission in this mammalian model, some have been found in HPAI A(H5N1) viruses circulating among poultry.[92] The odds of spontaneous mutations resulting in improved transmissibility are very low.[93] A change in the current epidemiology of HPAI A(H5N1) human cases, including a large increase in epidemiologically related clusters or unrelated cases, could suggest increased transmissibility from viral mutations and increased pandemic potential.[94] However, investigations of a large increase in human HPAI A(H5N1) cases reported in Egypt during 2014-2015 attributed increased diagnostic testing of exposed people and not viral mutations as the likely cause of increased case detection.​[67][95]

Influenza A viruses are subject to genetic re-assortment. Previous pandemic viruses are believed to have emerged in human populations through mutation from a zoonotic reservoir (1918 H1N1), genetic re-assortment between low pathogenic avian influenza and seasonal influenza A viruses (1957 H2N2, 1968 H3N2), and genetic re-assortment between triple re-assortant swine influenza A (H1N1) and other swine influenza A viruses (2009 H1N1).[96][97]

Pathophysiology

The incubation period has been estimated to be between 2-10 days (mean 3.3 days, median 5 days), and the infectious period has been estimated to be between 5-13 days. However, there is very limited evidence available.[98]​

Highly pathogenic avian influenza (HPAI) A(H5N1) virus binds to receptors with sialic acids bound to galactose by alpha-2,3 linkages, which are primarily, but not entirely, distributed in the human lower respiratory tract.[99][100]​ Such receptors have also been reported in the human gastrointestinal tract.[101] In contrast, most seasonal influenza A and B viruses bind preferentially to receptors with sialic acids bound to galactose by alpha-2,6 linkages, which are primarily distributed in the human upper respiratory tract. Furthermore, specific structural conformation, not just receptor binding affinity, may be important in binding to receptors in the upper respiratory tract.[102] HPAI A(H5N1) virus obtained from human clinical samples with the ability to bind upper respiratory tract tissue has also been reported.[99][103]​ High and prolonged HPAI A(H5N1) viral replication in the lower respiratory tract induces pro-inflammatory cytokines and chemokines at much higher levels than with seasonal influenza A virus infection, resulting in pulmonary capillary leak, diffuse alveolar damage, and acute lung injury, and can lead to development of acute respiratory distress syndrome.[104][105]​ HPAI A(H5N1) viraemia has been reported in fatal cases, and dissemination of HPAI A(H5N1) virus to infect brain tissue; isolation from cerebrospinal fluid, gastrointestinal infection, and vertical transmission with evidence of virus in placenta and fetal lung cells have been documented.[28][105][106]​ Reactive haemophagocytosis has also been reported.[106]

Classification

Pathogenicity

Avian influenza A virus strains are classified as low pathogenic avian influenza (LPAI) or highly pathogenic avian influenza (HPAI) on the basis of molecular and pathogenicity criteria.

  • Most strains are LPAI viruses and cause asymptomatic infection or mild disease in infected poultry. LPAI H3N8, H6N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N3, H10N7, and H10N8 virus strains have infected humans causing disease ranging from conjunctivitis to non-fatal upper respiratory and lower respiratory tract disease, to severe lower respiratory tract disease and death (H3N8, H7N9, H9N2, H10N8).[4][5][6][7][8][9][10][11]​​​

  • HPAI strains identified to date are of the H5 and H7 subtypes and can cause severe illness in poultry. HPAI A virus infections in humans have ranged from asymptomatic to severe or fatal disease. Rare, sporadic human cases of HPAI A virus infection have been detected with H5N1, H5N6, H7N3, H7N7, and H7N9 viruses and have caused a wide spectrum of illness from conjunctivitis (H7N3, H7N7) to severe pneumonia, acute respiratory distress syndrome, and fatal outcomes (H5N1, H5N6, H7N7, H7N9).[12][13][14][15]​ Asian lineage HPAI H7N9 viruses were detected and reported in the People’s Republic of China for the first time in February 2017.

Antigenic structure (clades)

In 2014, the World Health Organization/World Organisation for Animal Health/Food and Agriculture Organization H5N1 Evolution Working Group published a revision to HPAI A(H5N1) virus nomenclature.[16] According to this revised nomenclature system, circulating HPAI A(H5N1) virus strains among birds are classified into numerous clades, and subdivided into subclades and lineages.[17][18]​​​​​ These antigenic changes have important implications for vaccine development. Clades that have infected humans include 0, 1, 2, and 7. HPAI A(H5N1) virus continues to cause rare, sporadic human infections, including fatal outcomes. Most human HPAI A(H5N1) virus infections since 2005 have been with clade 2 virus strains. HPAI A(H5N1) virus strains continue to evolve among infected birds through genetic reassortment and antigenic drift.[19]​

In 2023, clade 2.3.4.4b viruses were the predominant HPAI A(H5N1) virus strains circulating among wild birds worldwide, resulting in outbreaks in commercial and backyard poultry, with spillover to terrestrial and marine mammals, and rare human infections.[20]​​[21]​ Clade 2.3.4.4b is also responsible for the current outbreak in dairy cattle in the US and the associated human cases.[22]​​​[23][24]​​​

  • Genotype D1.1 has been detected in human infections associated with the current outbreaks in poultry and wild birds in the US and Canada, and genotype B3.13 has been detected in human infections associated with the current outbreaks in dairy cattle in the US.[25]

Other HPAI A(H5N1) virus strains, such as clade 2.3.2.1c viruses, are circulating among poultry in some areas of the world, and have also caused sporadic human infections.

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