title: Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.
abstract: Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, we performed virological and immunological studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was associated with higher pharyngeal viral loads. We observed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex associated with mammalian adaptation and virulence. Our observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment.
authors.affiliation: Oxford University Clinical Research Unit, 190 Ben Ham Tu, Ho Chi Minh City, Vietnam. dejongmd@gmail.com
authors.forename: Menno D
authors.initials: MD
authors.lastname: de Jong
authors.forename: Cameron P
authors.initials: CP
authors.lastname: Simmons
authors.forename: Tran Tan
authors.initials: TT
authors.lastname: Thanh
authors.forename: Vo Minh
authors.initials: VM
authors.lastname: Hien
authors.forename: Gavin J D
authors.initials: GJ
authors.lastname: Smith
authors.forename: Tran Nguyen Bich
authors.initials: TN
authors.lastname: Chau
authors.forename: Dang Minh
authors.initials: DM
authors.lastname: Hoang
authors.forename: Nguyen Van Vinh
authors.initials: NV
authors.lastname: Chau
authors.forename: Truong Huu
authors.initials: TH
authors.lastname: Khanh
authors.forename: Vo Cong
authors.initials: VC
authors.lastname: Dong
authors.forename: Phan Tu
authors.initials: PT
authors.lastname: Qui
authors.forename: Bach Van
authors.initials: BV
authors.lastname: Cam
authors.forename: Do Quang
authors.initials: do Q
authors.lastname: Ha
authors.forename: Yi
authors.initials: Y
authors.lastname: Guan
authors.forename: J S Malik
authors.initials: JS
authors.lastname: Peiris
authors.forename: Nguyen Tran
authors.initials: NT
authors.lastname: Chinh
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity*; D007251:Influenza, Human / Q000097:blood* / Q000401:mortality* / Q000821:virology; D008875:Middle Aged; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D012367:RNA, Viral