Clinical and mutagenic spectrum of highly pathogenic avian influenza A(H5N1) clade 2.3.4.4B: a narrative review
DOI:
https://doi.org/10.2478/AMB-2026-0076Keywords:
Avian influenza A(H5N1) , Global Spread , Pathogenesis, MortalityAbstract
Abstract. Avian influenza A(H5N1) is a highly pathogenic virus causing significant outbreaks in birds and sporadic human infections since 1997. The virus is classified into various clades based on genetic characteristics, and recently, concerns have been raised over the risk of clade 2.3.4.4b becoming widespread and infecting humans. Since 1997, more than 1,000 infections with highly pathogenic avian influenza A(H5N1) virus among humans have been reported globally. Given ongoing A(H5N1) outbreaks in animals, understanding the frequency of A(H5N1) virus infections among asymptomatic persons can inform public health risk assessments and infection prevention guidance. We performed a literature search focusing on reported infections among humans with Highly Pathogenic Avian Influenza (HPAI). This study was conceived as a narrative review focusing on clade 2.3.4.4b H5N1, but was expanded to all reported H5Nx and other zoonotic subtypes (H5N6, H6N1, H7N9, H10N3) when clade-specific data were sparse. Although not a formal systematic review, the search, screening, and appraisal followed the PRISMA 2020 Checklist for search reporting where applicable.
References
World Health Organization. Assessment of risk associated with recent influenza A(H5N1) clade 2.3.4.4b viruses [Internet]. Geneva: World Health Organization; 2022 Dec 21 [cited 2025 Dec 10]. Available from: https://cdn.who.int/media/docs/default-source/influenza/avian-and-other-zoonotic-influenza/h5-risk-assessment-dec-2022.pdf?sfvrsn=a496333a_1&download=true
Agüero M, Monne I, Sánchez A, et al. Highly pathogenic avian influenza A(H5N1) virus infection in farmed minks, Spain, October 2022. Euro Surveill. 2023;28. doi:10.2807/1560-7917.ES.2023.28.3.2300001
Rijks JM, Hesselink H, Lollinga P, et al. Highly Pathogenic Avian Influenza A(H5N1) Virus in Wild Red Foxes, the Netherlands, 2021. Emerg Infect Dis. 2021;27:2960-2.
Lindh E, Lounela H, Ikonen N, et al. Highly pathogenic avian influenza A(H5N1) virus infection on multiple fur farms in the South and Central Ostrobothnia regions of Finland, July 2023. Euro Surveill. 2023;28(31):2300400.
Banyard AC, Bennison A, Byrne AMP, et al. Detection and spread of highly pathogenic avian influenza virus H5N1 in the Antarctic Region. Nat Commun. 2024;15(1):7433. doi:10.1038/s41467-024-51490-8
Lin S, Chen J, Li K, et al. Evolutionary dynamics and comparative pathogenicity of clade 2.3.4.4b H5 subtype avian influenza viruses, China, 2021-2022. Virol Sin. 2024;39:358-368.
Jahid MJ, Nolting JM. Dynamics of a panzootic: genomic insights, host range, and epidemiology of the highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b in the United States. Viruses. 2025;17:312. doi:10.3390/v17030312
Graziosi G, Lupini C, Catelli E, Carnaccini S. Highly pathogenic avian influenza (HPAI) H5 clade 2.3.4.4b virus infection in birds and mammals. Animals (Basel). 2024;14:1372.
Rather MA, Hassan A, Aman M, et al. Molecular and ecological determinants of mammalian adaptability in avian influenza virus. Infection. 2025. doi:10.1007/s15010-025-02529-5.
Briand FX, Souchaud F, Pierre I, et al. Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus in domestic cat, France, 2022. Emerg Infect Dis. 2023;29(8):1696-1698. doi:10.3201/eid2908.230188
Tumpey TM, Maines TR, Van Hoeven LN, et al. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science. 2007;315:655-659.
Lin TH, Zhu X, Wang S, et al. A single mutation in bovine influenza H5N1 hemagglutinin switches specificity to human receptors. Science. 2024;386:1128-1134. doi:10.1126/science.adt0180.
Paulson JC, de Vries RP. H5N1 receptor specificity as a factor in pandemic risk. Virus Res. 2013;178:99-113.
de Vries RP, Peng W, Grant OC, et al. Three mutations switch H7N9 influenza to human-type receptor specificity. PLoS Pathog. 2017;13:e1006390.
Tanner WD, Toth DJ, Gundlapalli AV. The pandemic potential of avian influenza A(H7N9) virus: a review. Epidemiol Infect. 2015;143(16):3359-3374. doi:10.1017/S0950268815001570
Eggink D, Spronken M, van der Woude R, et al. Phenotypic effects of substitutions within the receptor binding site of highly pathogenic avian influenza H5N1 virus observed during human infection. J Virol. 2020;94(13):e00195-20. doi:10.1128/JVI.00195-20
European Centre for Disease Prevention and Control. Current case definition for zoonotic influenza in humans [Internet]. Stockholm: ECDC; [cited 2025 Dec 10]. Available from: https://www.ecdc.europa.eu/en/infectious-disease-topics/avian-influenza/disease-information-avian-influenza/current-case
World Health Organization. WHO case definition for human infections with avian influenza A(H5) virus [Internet]. Geneva: World Health Organization; [date unknown] [cited 2025 Dec 10]. Available from: https://www.who.int/teams/global-influenza-programme/avian-influenza/case-definitions
Drehoff CC, White EB, Frutos AM, et al. Cluster of influenza A(H5) cases associated with poultry exposure at two facilities - Colorado, July 2024. MMWR Morb Mortal Wkly Rep. 2024;73(34):734-739. doi:10.15585/mmwr.mm7334a1
Uyeki TM, Milton S, Abdul Hamid C, et al. Highly pathogenic avian influenza A(H5N1) virus infection in a dairy farm worker. N Engl J Med. 2024;390:2028–9. doi:10.1056/NEJMc2405371
Castillo A, Fasce R, Parra B, et al. The first case of human infection with H5N1 avian Influenza A virus in Chile. J Travel Med. 2023;30(5):taad083. doi:10.1093/jtm/taad083
Pardo-Roa C, Nelson MI, Ariyama N, et al. Cross-species and mammal-to-mammal transmission of clade 2.3.4.4b highly pathogenic avian influenza A/H5N1 with PB2 adaptations. Nat Commun. 2025;16(1):2232. doi:10.1038/s41467-02557338-z
Ministerio de Salud, Gobierno de Chile. MINSAL informa primer caso humano de gripe aviar en Chile [Internet]. Santiago: Ministerio de Salud, Gobierno de Chile; 2023 [cited 2025 Dec 10]. Available from: https://www.paho.org/sites/default/files/2024-12/2024-dic-3-phe-alerta-influenzaaviaresp-final1_2.pdf
Zhang Y, Wu J, Lin Q, et al. Infection Tracing and Virus Genomic Analysis of Two Cases of Human Infection with Avian Influenza A(H5N6) – Fujian Province, China, April-May 2024. China CDC Wkly. 2025;7(3):107–112. doi:10.46234/ccdcw2024.274
Yu H, Jin K, Ding S, et al. Severe Avian Influenza A H5N1 Clade 2.3.4.4b Virus Infection in a Human with Continuation of SARS-CoV-2 Viral RNAs. Transbound Emerg Dis. 2024;2024:8819622. doi:10.1155/2024/8819622.
Zhang L, Liu K, Su Q, et al. Clinical features of the first critical case of acute encephalitis caused by the avian influenza A (H5N6) virus. Emerg Microbes Infect. 2022;11(1):2437–2446. doi:10.1080/22221751.2022.2122584.
Huang Z, Zhang R, Yao D, et al. Avian influenza A(H5N6) virus detected during live-poultry market surveillance linked to a human infection in Changsha, China, from 2020 to 2023. Arch Virol. 2025;170(5):96. doi:10.1007/s00705-02506280-y.
Mellis AM, Coyle J, Marshall KE, et al. Serologic Evidence of Recent Infection with Highly Pathogenic Avian Influenza A(H5) Virus Among Dairy Workers – Michigan and Colorado, June-August 2024. MMWR Morb Mortal Wkly Rep. 2024;73(44):1004–1009. doi:10.15585/mmwr.mm7344a3
Zhu S, Harriman K, Liu C, et al. Human Cases of Highly Pathogenic Avian Influenza A(H5N1) – California, September-December 2024. MMWR Morb Mortal Wkly Rep. 2025;74(8):127–133. doi:10.15585/mmwr.mm7408a1
Garg S, Reinhart K, Couture A, et al. Highly pathogenic avian influenza A(H5N1) virus infections in humans. N Engl J Med. 2025;392:843–54. doi:10.1056/NEJMoa2414610
Siddiqui E, Khalid M, Khan MS, et al. The Missouri H5 flu case: a call for strengthening public health preparedness. Ann Med Surg. 2025;87(1):33–35. doi:10.1097/MS9.0000000000002866
Oliver I, Roberts J, Brown CS, et al. A case of avian influenza A(H5N1) in England, January 2022. Euro Surveill. 2022;27(5):2200061. doi:10.2807/1560-7917.ES.2022.27.5.2200061
Zeng Q, Wang J, Zhang X, et al. Successful combinatorial therapy of sirolimus and neuraminidase inhibitors in a patient with highly pathogenic avian influenza A (H5N6) virus: a case report. Ann Transl Med. 2022;10(5):265. doi:10.21037/atm-22-704
Yu JL, Hou S, Feng YT, et al. Emergence of a young case infected with avian influenza A (H5N6) in Anhui Province, East China during the COVID-19 pandemic. J Med Virol. 2021;93(10):5998–6007. doi:10.1002/jmv.27179
He J, Duan J. First human case of avian influenza A (H5N6) in Yunnan province, China. SAGE Open Med Case Rep. 2015;3:2050313X15596484. doi:10.1177/2050313X15596484
Wei SH, Yang JR, Wu HS, et al. Human infection with avian influenza A H6N1 virus: an epidemiological analysis. Lancet Respir Med. 2013;1(10):771–778. doi:10.1016/S22132600(13)70221-2
Zhang J. H7N9 avian influenza with first manifestation of occipital neuralgia: A case report. World J Clin Cases. 2023;11(2):434–440. doi:10.12998/wjcc.v11.i2.434
He H, Wang H, Li X, et al. Successful management of refractory respiratory failure caused by avian influenza H7N9 and secondary organizing pneumonia: a case report and literature review. BMC Infect Dis. 2019;19(1):671. doi:10.1186/s12879019-4306-7
Luo H, Wang S, Yuan T, et al. Clinical characteristics from co-infection with avian influenza A H7N9 and Mycoplasma pneumoniae: a case report. J Med Case Rep. 2018;12(1):77. doi:10.1186/s13256-018-1583-5
Xie H, Zhou ZG, Jin W, et al. Ventilator management for acute respiratory distress syndrome associated with avian influenza A (H7N9) virus infection: A case series. World J Emerg Med. 2018;9(2):118–124. doi:10.5847/wjem.j.1920-8642.2018.02.006
Zhang ZH, Meng LS, Kong DH, et al. A Suspected Person-to-person Transmission of Avian Influenza A (H7N9) Case in Ward. Chin Med J. 2017;130(10):1255–1256. doi:10.4103/0366-6999.205849
Zhao Z, Luo S, Gao Y, et al. A case report of human infection with avian influenza H10N3 with a complex respiratory disease history. BMC Infect Dis. 2024;24(1):918. doi:10.1186/s12879-024-09830-y
World Health Organization. Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2003-2024 [Internet]. Geneva: World Health Organization; 2024 Dec 12 [cited 2025 Dec 10]. Available from: https://cdn.who.int/media/docs/default-source/2021-dha-docs/cumulative-number-of-confirmed-human-cases-for-avian-influenzaa(h5n1)-reported-to-who--2003-2024.pdf
Li F, Sun Z, Tao M, et al. Epidemiological characterization of human infection with H5N6 avian influenza. Front Public Health. 2024;12:1398365. doi:10.3389/fpubh.2024.1398365
Purcell R, Giles ML, Crawford NW, et al. Systematic Review of Avian Influenza Virus Infection and Outcomes during Pregnancy. Emerg Infect Dis. 2025;31(1):50–56. doi:10.3201/eid3101.241343
Sandhu S, Ferrante C, MacCosham A, et al. Epidemiological characteristics of human infections with avian influenza A(H5N6) virus, China and Laos: A multiple case descriptive analysis, February 2014-June 2023. Can Commun Dis Rep. 2024;50(1-2):77–85. doi:10.14745/ccdr.v50i12a09
Pan H, Zhang X, Hu J, et al. A case report of avian influenza H7N9 killing a young doctor in Shanghai, China. BMC Infect Dis. 2015;15:237. doi:10.1186/s12879-015-0970-4
Wang D, Tang G, Huang Y, et al. A returning migrant worker with avian influenza A (H7N9) virus infection in Guizhou, China: a case report. J Med Case Rep. 2015;9:109. doi:10.1186/s13256-015-0580-1
Titorenkov PT, Encheva MD, Gotseva AL. Respiratory infections in the XXI century: Challenges and changes. World J Adv Res Rev. 2024;23(3):1900–1906. doi:10.30574/wjarr.2024.23.3.2730
Gotseva A. Complications of Influenza. Medinfo, 2024;24(8):8-11
Krammer F, Schultz-Cherry S. We need to keep an eye on avian influenza. Nat Rev Immunol. 2023;23:267–268.
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