Resurgence of Zoonotic Highly Pathogenic Avian Influenza A(H5N1) Virus in Cambodia
- kperry223
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New correspondance from Dr. Vijaykrishna Dhanasekaran on the New England Journal of Medicine, this correspondance investigates the resurgence of highly pathogenic avian influenza (HPAI) A(H5N1) virus infections in Cambodia after nearly a decade of no reported human cases.
To the Editor:
After a decade of no reported human cases, Cambodia faces a resurgence of highly pathogenic avian influenza (HPAI) A(H5N1) virus infections, with an overall mortality of 38%. Cases have occurred primarily in children and adolescents who were exposed to infected poultry (Figure 1). From February 2023 through August 2024, a total of 16 infections were detected through the long-standing national influenza-like illness and severe acute respiratory infection surveillance systems, both of which were strengthened by expanded laboratory-testing capacity that was developed during the coronavirus disease 2019 pandemic. All 16 patients reported exposure to sick or dead poultry, and outbreak investigations identified contemporary, genetically similar viruses in poultry collected in or around case households or from active, longitudinal surveillance of live-bird markets. Genomic sequencing revealed an avian origin for all the human infections, and sequences have been publicly shared through the Global Initiative on Sharing All Influenza Data (also known as GISAID).
Although most cases occurred in separate households, multiple infections occurred in four households. A father–daughter cluster initially suggested person-to-person transmission, but outbreak investigations by the Ministry of Health and the World Health Organization (WHO) revealed simultaneous onset of symptoms and direct contact with infected backyard poultry, which highlights poultry exposure as the most likely driver of these infections.
The initial cases, which occurred in February 2023 (Figure1), were caused by the regionally endemic A(H5N1) clade 2.3.2.1e (previously classified as 2.3.2.1c under WHO nomenclature), whereas subsequent cases were associated with a novel reassortant virus. The local clade 2.3.2.1e acquired genes from clade 2.3.4.4b and avian influenza viruses with low pathogenicity, most likely through wild birds or undetected poultry transmission, although limited genomic data preclude definitive source attribution . This reassortant virus has spread across the Greater Mekong Subregion, replacing earlier strains. Of note, this virus carries genomic signatures (e.g., PB2:E627K) that are linked to enhanced polymerase activity, virulence, and replication capacity in birds and mammals, which poses an increased potential risk to the poultry industry as well as an increased potential risk of zoonotic transmission.
This novel reassortment, genotype replacement, and resurgence in humans underscores the dynamic and unpredictable nature of HPAI A(H5N1) virus evolution, particularly in regions with dense poultry–human interfaces. The genetic landscape of HPAI is rapidly shifting. Since 2021, HPAI A(H5N1) viruses have expanded in host and geographic range, which has resulted in a heightened risk of zoonotic spillover. The outbreak in Cambodia highlights the need for One Health investments that integrate real-time surveillance, cross-sectoral data sharing, and genomic monitoring to mitigate pandemic risks.