What is known about this topic?: Global human cases of zoonotic influenza A(H5N6) have increased significantly in recent years, primarily due to widespread circulation of clade 2.3.4.4b virus since 2020. Concurrent with this trend, sporadic human infections with clade 2.3.4.4h H5N6 avian influenza virus continue to occur. The high mortality rate associated with H5N6 virus infections has emerged as a critical public health concern.

What is added by this report?: Through comprehensive field epidemiological investigations and laboratory analyses, we identified the infection sources for these cases and conclusively ruled out human-to-human transmission. Genetic analyses revealed that while the virus maintains its avian host tropism, it has acquired mutations that may enhance human receptor binding affinity, viral replication capacity, pathogenicity, and neuraminidase inhibitor resistance.

What are the implications for public health practice?: The ongoing viral mutations increase the potential for H5 subtype avian influenza viruses to overcome species barriers and cause human epidemics. Enhanced surveillance strategies incorporating advanced technologies, such as metagenomic sequencing, are essential for early risk detection and management. Special attention should be directed toward cancer patients and immunocompromised individuals, who demonstrate increased susceptibility to avian influenza virus infections and require targeted prevention and control measures.