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

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          Abstract

          Avian influenza A (H5N1) viruses cause severe disease in humans 1, 2 , 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 3, 4, 5 . Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity 6, 7, 8, 9 . 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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          The online version of this article (doi:10.1038/nm1477) contains supplementary material, which is available to authorized users.

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          Most cited references 28

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          Rapid and simple method for purification of nucleic acids.

          We have developed a simple, rapid, and reliable protocol for the small-scale purification of DNA and RNA from, e.g., human serum and urine. The method is based on the lysing and nuclease-inactivating properties of the chaotropic agent guanidinium thiocyanate together with the nucleic acid-binding properties of silica particles or diatoms in the presence of this agent. By using size-fractionated silica particles, nucleic acids (covalently closed circular, relaxed circular, and linear double-stranded DNA; single-stranded DNA; and rRNA) could be purified from 12 different specimens in less than 1 h and were recovered in the initial reaction vessel. Purified DNA (although significantly sheared) was a good substrate for restriction endonucleases and DNA ligase and was recovered with high yields (usually over 50%) from the picogram to the microgram level. Copurified rRNA was recovered almost undegraded. Substituting size-fractionated silica particles for diatoms (the fossilized cell walls of unicellular algae) allowed for the purification of microgram amounts of genomic DNA, plasmid DNA, and rRNA from cell-rich sources, as exemplified for pathogenic gram-negative bacteria. In this paper, we show representative experiments illustrating some characteristics of the procedure which may have wide application in clinical microbiology.
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            Avian influenza A (H5N1) infection in humans.

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              Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses.

              In 1997, an H5N1 influenza A virus was transmitted from birds to humans in Hong Kong, killing 6 of the 18 people infected. When mice were infected with the human isolates, two virulence groups became apparent. Using reverse genetics, we showed that a mutation at position 627 in the PB2 protein influenced the outcome of infection in mice. Moreover, high cleavability of the hemagglutinin glycoprotein was an essential requirement for lethal infection.
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                Author and article information

                Contributors
                dejongmd@gmail.com
                Journal
                Nat Med
                Nat. Med
                Nature Medicine
                Nature Publishing Group US (New York )
                1078-8956
                1546-170X
                10 September 2006
                2006
                : 12
                : 10
                : 1203-1207
                Affiliations
                [1 ]GRID grid.412433.3, ISNI 0000 0004 0429 6814, Oxford University Clinical Research Unit, 190 Ben Ham Tu, ; Ho Chi Minh City, Vietnam
                [2 ]GRID grid.414273.7, Hospital for Tropical Diseases, 190 Ben Ham Tu, ; Ho Chi Minh City, Vietnam
                [3 ]GRID grid.194645.b, ISNI 0000000121742757, Department of Microbiology, , State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, ; 21 Sassoon Road, Hong Kong SAR, China
                [4 ]Pediatric Hospital Number One, 2 Su Van Hanh, Ho Chi Minh City, Vietnam
                [5 ]Pediatric Hospital Number Two, 14 Ly Tu Trang, Ho Chi Minh City, Vietnam
                BFnm1477
                10.1038/nm1477
                4333202
                16964257
                © Nature Publishing Group 2006

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2006

                Medicine

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