Avian Influenza Literature Review

Avian influenza is a zoonotic infectious disease transmitting from poultry to humans. The first case reported was influenza (A)H5N1 in Hong Kong, 1997. Cases and deaths are rising worldwide and within the UK. The first UK case of H5N1 was confirmed on 26th October 2021, rising to 80 by 22nd February 2022, showing that H5N1 is becoming more prevalent, posing the threat of a pandemic mirroring the 1918 influenza pandemic. A phylogenomic analysis by Worobey, Han and Rambaut (2014) shows there are homologous sequences between avian influenza subtypes and H1N1, the subtype responsible for the 1918 pandemic, inferring it was likely to be of avian origin. The most common strains of avian influenza infecting humans are H7N9 with a mortality rate of 38% and reports of 682 cases of H5N1 as of 2013 with 384 deaths exhibiting a 59% mortality rate (Poovorawan, Pyungporn, Prachayangprecha and Makkoch, 2013). Human deaths are set to rise as strains of influenza A have built up resistance against several widely administered anti-viral drugs such as, the mutated strain of H7N9 is resistance to Oseltamivir (Sivanandy et al., 2019). Therefore, new and improved treatments are needed to reduce the severity of disease and deaths caused by avian influenza.

Influenza causes seasonal epidemics with up to 50,000 deaths yearly and is categorised into A, B, C and D with influenza A and B causing human disease. Avian influenza is caused by strains of A with 16 hemagglutinin (HA) subtypes and 9 neuraminidase (NA) subtypes (Tejus, Mathur, Pradhan, Malik and Salmani, 2021) for example, H7N9, H5N1, H3N2, H7N7 and H9N2. Influenza A has an envelope made up of three glycoproteins, HA, NA and M2 (matrix protein-2) (Sun, Ling, Yang and Sun, 2022). Antigenic shift results in a variety of mutations in these glycoproteins enabling the virus to evade host immunity, continue to replicate and spread within a population. Avian influenza is becoming more prevalent in the population due to several factors including a growing resistance to antiviral drugs.

The treatment for avian influenza involves antiviral drugs to prevent viral replication and reduce viral load and corticosteroids to reduce inflammation, treating the pain. However, corticosteroids cannot be used when secondary infections such as pneumonia are present as data shows this leads to prolonged symptoms and increased mortality (Sivanandy et al., 2019).

M2 inhibitors and neuraminidase inhibitors are the two commonly used treatments for influenza A however, strains of influenza A have built up resistance to the drugs resulting in poor prognosis if infected with a resistant strain. The drugs amantadine and rimantadine work by inhibiting the M2 ion channel in the viral envelope, rendering the virion unable to fuse with the host cell, preventing viral replication. Resistance to M2 inhibitors is reported in 35%-50% of adults and 27%-50% of children (Ison et al., 2021). Caused by a substitution in the M2 protein of a single amino acid, resistance results in viral replication and transmissibility being unaffected, rendering amantadine or rimantadine ineffective in up to half of those prescribed it. Neuraminidase inhibitors (NAI’s) such as Zanamavir, Oseltamivir and Peramivir prevent the release of new replicated virions by the host cell, reducing viral load. When administered within 48 hours of symptom onset NAI’s have been shown to reduce mortality rates (Ison et al., 2021). Resistance to NAI’s is due to a point mutation in both or either the HA gene or NA gene. The emergence of resistance to oseltamivir has been reported as up to 16% in children less than 5 years old however, season flu (H1N1) in 2008 and 2009 contributed to increased resistance to oseltamivir as the mutated, resistant strain spread globally.

Resistance occurs when drugs administered at normal dosage are no longer effective at reducing or destroying a microbe. It is caused by over usage due to no new drug development, non-specific usage treating multiple strains of influenza, seasonal, swine and avian, poor hygiene, incomplete treatment courses, incorrect prescriptions and over usage in agriculture resulting in the emergence of resistance genes within the virus leading to increased zoonotic diseases and transmission. Zoonotic diseases not only have a human cost but also an economic one. The 2004 avian influenza outbreak in Thailand resulted in 17 human cases, 12 deaths, 62 million chickens culled and cost an estimated $3 billion (Gilbert, Thomas, Coyne and Rushton, 2021).

Until recently M2 inhibitors and NAI’s were the only widely available drugs however, alternative treatments are in development targetting resistant strains of influenza A. Favipiravir (T-705) has an additional purine on the surface resulting in the virus recognising it as a purine nucleotide allowing T-705 to then inhibit RNA polymerase and viral replication. T-705 was approved in Japan, 2014 to treat influenza but has only been approved to treat Covid-19 in 2021 in a few countries such as India but is still in clinical trials globally for influenza (Sivanandy et al., 2019). Baloxavir marboxil was approved in 2018 to treat influenza by preventing viral RNA transcription by inhibiting the viral CEN (cap-dependent) endonuclease and ultimately stopping the virus replicating (Tejus et al., 2021). Human monoclonal antibodies that target the HA glycoprotein in the envelope, disrupting viral fusion were reported successful in and preventing replication by Turner et al. (2019). The resistance rates of newly developed drugs need to be monitored to ensure treatments are being developed at a rate to combat resistance and successful treat those strains who do mutate and gain resistance.

Only nine infectious viruses out of 219 known viral diseases are treatable with antiviral drugs. This paired with growing resistance to these drugs and the increasing cases of avian influenza worldwide there is an urgent need for the development of new drugs (Heida et al., 2021). Advancement in the development of an efficacious human vaccine for H7N9 which has a mortality rate of almost 40% was reported by Kim et al. (2020) however, it is yet to receive approval demonstrating progress but the need for further advancement and alternative treatments to tackle the growing resistance to anti-viral drugs.

References

Gilbert, W., Thomas, L.F., Coyne, L. & Rushton, J. (2021). Review: Mitigating the risks posed by intensification in livestock production: the examples of antimicrobial resistance and zoonoses. Animal, 15(2).

Heida, R., Bhide, Y., Gasbarri, M., Kocabiyik, O., Stellacci, F., Huckriede, A., Hinrichs, W., Frijlink, W. (2021). Advances in the development of entry inhibitors for sialic-acid-targeting viruses. Drug Discovery Today, 26(1).

Ison, M., Hayden, F., Hay, A., Gubareva, L., Govorkova, E., Takashita, E., McKimm-Breschkin, J. (2021). Influenza polymerase inhibitor resistance: assessment of the current state of the art - a report of the isirv Antiviral group. Antiviral Research, 194.

Kim, JI., Park, S., Bae, JY., Lee, S., Kim, J. et al. (2020). Glycosylation generates an efficacious and immunogenic vaccine against H7N9 influenza virus. PLOS Biology 18(12).

Poovorawan, Y., Pyungporn, S., Prachayangprecha, S., Makkoch, J. (2013). Global alert to avian influenza virus infection: from H5N1 to H7N9. Pathogens and global health, 107(5), 217–223.

Sivanandy, P., Xien, F., Kit, L., Wei, Y., En, K., Lynn, L. (2019). A review on current trends in the treatment of human infection with H7N9-avian influenza A. Journal of Infection and Public Health, 12(2), 153-158.

Sun, X., Ling, Z., Yang, Z., Sun, B. (2022). Broad neutralizing antibody-based strategies to tackle influenza. Current Opinion in Virology, 53.

Tejus, A., Mathur, A.G., Pradhan, S., Malik, S. & Salmani, M. (2021). Drug update - Baloxavir marboxil: Latest entrant into the arena of pharmacotherapy of influenza. Medical Journal Armed Forces India, 77.

Turner, HL., Pallesen, J., Lang, S., Bangaru, S., Urata, S., et al. (2019). Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains. PLOS Biology 17(2).

Worobey, M., Han, GZ. & Rambaut, A. (2014). A synchronized global sweep of the internal genes of modern avian influenza virus. Nature, 508(7495), 254-257.