Background: Avian influenza A viruses (AIVs) remain a global public health concern. Sporadic human infections continue to be reported, particularly in areas with frequent human-poultry contact. We report four cases of human infection with AIVs in Zhejiang Province that occurred between December 2021 and January 2024.

Method: Epidemiological investigations were carried out to collect detailed demographic information, underlying diseases, symptoms, hospital admission details, recent exposures to domestic poultry or wild birds, recent visit to wet markets. Samples from patients and their related environments as well as contacts were collected and detected. Epidemiological sources were also traced based on patient´s exposure history 10 days before symptom onset.

Results: The reported cases included two women aged 51 and 55 diagnosed with H5N6 infection in December 2021, a 33-year-old man identified in June 2022 as the first H10N3 case in Zhejiang Province and the second globally, and a 63-year-old woman from Anhui Province who became the world´s first documented case of coinfection with H10N5 and H3N2.All patients had a history of unprotected exposure to infected or contaminated poultry, primarily during cleaning and handling processes. Three of the patients responded well to antiviral treatment and recovered, whereas the patient with H10N5 coinfection died due to disease progression. Genomic analyses confirmed that all infections were AIVs, with no evidence of sustained human-to-human transmission.

Conclusion: These cases highlight the continued risk of AIVs spill-over into humans and emphasise the need for strengthened surveillance, improved poultry-handling protocols, and early detection to prevent future outbreaks.