Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.
Open accessAbstract
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.
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Infection with some influenza subtypes, such as H1N1 and H5N1, typically results in lymphopenia, which has been associated with higher viral load.
“Furthermore infection with some influenza subtypes, for instance H1N1 and H5N1, typically result in lymphopenia, a state of abnormally low levels of lymphocytes, which has been associated with higher viral load.”
From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as de Jong et al., 2006
de Jong et al. (2006) found that influenza infection caused lower levels of cytotoxic T cell lymphocytes, which would negatively affect acquired immunity.
“de Jong et al. (2006) found influenza infection caused lower levels of cytotoxic T cell lymphocytes, which would therefore negatively affect acquired immunity (de Jong et al., 2006; Cunha et al., 2009).”
From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as de Jong et al., 2006
Where lymphopenia occurs, studies have shown a corresponding increase in macrophages, supported by increases in IP-10, IL-8, IL-6, and MCP-1.
“Where lymphopenia occurs, studies have shown a corresponding increase in macrophages.”
From Secondary bacterial infections associated with influenza pandemics (2017) · cites this paper as de Jong et al., 2006
In a case study conducted in Ho Chi Minh City, Vietnam, comparing 18 people infected with H5N1 virus in 2004 and 2005 to 8 people infected with seasonal H1N1 influenza virus, elevated levels of MCP-1 (CCL2), IP-10 (CXCL10), MIG (CXCL9), and IL-8 were observed in H5N1 virus-infected patients who progressed to severe lung injury.
“In a case study conducted in Ho Chi Minh City, Vietnam, comparing 18 people infected with H5N1 virus in 2004 and 2005 to 8 people infected with seasonal H1N1 influenza virus, elevated levels of MCP-1 (known as CCL2), IFN-␥-inducible IP-10 (CXCL10), MIG protein (CXCL9), and IL-8 were observed in H5N1 virus-infected patients who progressed to severe lung injury (38).”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [38]
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- Authors
- de Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J. D., Chau, T. N. B., Hoang, D. M., Van Vinh Chau, N., Khanh, T. H., Dong, V. C., Qui, P. T., Van Cam, B., Ha, D. Q., Guan, Y., Peiris, J. S. M., Chinh, N. T., Hien, T. T., & Farrar, J.
- Affiliations
- Oxford University Clinical Research Unit (VN)
- Hospital for Tropical Diseases (VN)
- University of Hong Kong (HK)
- Children's Hospital 2 (VN)
- Venue
- Nature Medicine
- Published
- 2006-09-10
- Volume
- 12
- Issue
- 10
- Pages
- 1203-1207
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4333202
- OpenAlex
- W1996311210
- Cited by
- 1,858
- References
- 29
- Citations by year
- 2026: 37 · 2025: 59 · 2024: 50 · 2023: 55 · 2022: 87 · 2021: 115 · 2020: 140 · 2019: 74 · 2018: 64 · 2017: 85 · 2016: 85 · 2015: 90 · 2014: 128 · 2013: 129 · 2012: 110
- FWCI
- 70.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Wellcome Trust (074636/Z/04/Z)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Outbreaks Research
- Keywords
- H5N1 avian influenza, avian influenza, fatal outcome, viral load, cytokine storm, cytokine imbalance, chemokines, T cell depletion, mammalian adaptation, viral pathogenesis
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Flow Cytometry, Humans, Infant, Influenza, Human, Middle Aged, Molecular Sequence Data, RNA, Viral, T-Lymphocytes, Cytokines, Treatment Outcome, Influenza A Virus, H5N1 Subtype
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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