Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia

Menno D. De Jong, Cameron P. Simmons, Tran Tan Thanh, Vo Minh Hien, Gavin J.D. Smith, Tran Nguyen Bich Chau, Dang Minh Hoang, Nguyen Van Vinh Chau, Truong Huu Khanh, Vo Cong Dong, Phan Tu Qui, Bach Van Cam, Do Quang Ha, Yi Guan, J. S.Malik Peiris, Nguyen Tran Chinh, Tran Tinh Hien, Jeremy Farrar

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1203-1207
Number of pages5
JournalNature Medicine
Volume12
Issue number10
DOIs
Publication statusPublished - 1 Oct 2006

Cite this

De Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J. D., Chau, T. N. B., ... Farrar, J. (2006). Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nature Medicine, 12(10), 1203-1207. https://doi.org/10.1038/nm1477
De Jong, Menno D. ; Simmons, Cameron P. ; Thanh, Tran Tan ; Hien, Vo Minh ; Smith, Gavin J.D. ; Chau, Tran Nguyen Bich ; Hoang, Dang Minh ; Chau, Nguyen Van Vinh ; Khanh, Truong Huu ; Dong, Vo Cong ; Qui, Phan Tu ; Cam, Bach Van ; Ha, Do Quang ; Guan, Yi ; Peiris, J. S.Malik ; Chinh, Nguyen Tran ; Hien, Tran Tinh ; Farrar, Jeremy. / Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. In: Nature Medicine. 2006 ; Vol. 12, No. 10. pp. 1203-1207.
@article{f0ea1f1649154fc3975f74ca6d041fcb,
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.",
author = "{De Jong}, {Menno D.} and Simmons, {Cameron P.} and Thanh, {Tran Tan} and Hien, {Vo Minh} and Smith, {Gavin J.D.} and Chau, {Tran Nguyen Bich} and Hoang, {Dang Minh} and Chau, {Nguyen Van Vinh} and Khanh, {Truong Huu} and Dong, {Vo Cong} and Qui, {Phan Tu} and Cam, {Bach Van} and Ha, {Do Quang} and Yi Guan and Peiris, {J. S.Malik} and Chinh, {Nguyen Tran} and Hien, {Tran Tinh} and Jeremy Farrar",
year = "2006",
month = "10",
day = "1",
doi = "10.1038/nm1477",
language = "English",
volume = "12",
pages = "1203--1207",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "10",

}

De Jong, MD, Simmons, CP, Thanh, TT, Hien, VM, Smith, GJD, Chau, TNB, Hoang, DM, Chau, NVV, Khanh, TH, Dong, VC, Qui, PT, Cam, BV, Ha, DQ, Guan, Y, Peiris, JSM, Chinh, NT, Hien, TT & Farrar, J 2006, 'Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia' Nature Medicine, vol. 12, no. 10, pp. 1203-1207. https://doi.org/10.1038/nm1477

Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. / De Jong, Menno D.; Simmons, Cameron P.; Thanh, Tran Tan; Hien, Vo Minh; Smith, Gavin J.D.; Chau, Tran Nguyen Bich; Hoang, Dang Minh; Chau, Nguyen Van Vinh; Khanh, Truong Huu; Dong, Vo Cong; Qui, Phan Tu; Cam, Bach Van; Ha, Do Quang; Guan, Yi; Peiris, J. S.Malik; Chinh, Nguyen Tran; Hien, Tran Tinh; Farrar, Jeremy.

In: Nature Medicine, Vol. 12, No. 10, 01.10.2006, p. 1203-1207.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia

AU - De Jong, Menno D.

AU - Simmons, Cameron P.

AU - Thanh, Tran Tan

AU - Hien, Vo Minh

AU - Smith, Gavin J.D.

AU - Chau, Tran Nguyen Bich

AU - Hoang, Dang Minh

AU - Chau, Nguyen Van Vinh

AU - Khanh, Truong Huu

AU - Dong, Vo Cong

AU - Qui, Phan Tu

AU - Cam, Bach Van

AU - Ha, Do Quang

AU - Guan, Yi

AU - Peiris, J. S.Malik

AU - Chinh, Nguyen Tran

AU - Hien, Tran Tinh

AU - Farrar, Jeremy

PY - 2006/10/1

Y1 - 2006/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33749511112&partnerID=8YFLogxK

U2 - 10.1038/nm1477

DO - 10.1038/nm1477

M3 - Article

VL - 12

SP - 1203

EP - 1207

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 10

ER -