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  . Laboratory experiments suggest that virusinduced 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 Tlymphocyte 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
COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. Influenza H5N1 viruses cause severe and often fatal disease in humans that is characterized by fulminant pneumonia and multi-organ failure 1,2 . High replication efficiency, broad tissue tropism and systemic replication seem to determine the pathogenicity of H5N1 viruses in animals  . To examine the relevance of these viral properties in the context of human disease, we carried out virological analyses in respiratory and non-respiratory specimens of 18 previously healthy individuals with influenza H5N1 who were admitted to referral hospitals in Ho Chi Minh City during the years 2004 and 2005, of whom 13 died. (Table 1). For comparison, we studied eight patients who were hospitalized during the same period with human influenza H3N2 or H1N1. These patients presented earlier in the course of illness (Table 1), which may be explained by their origin from Ho Chi Minh City or neighboring provinces, in contrast with H5N1 patients who were mostly from more distant provinces.
Europe PMC Funders GroupDespite their presentation late in the course of illness, we were able to isolate virus from pharyngeal specimens of 12 of 16 H5N1-infected individuals (Table 2). Genetic characterization and phylogenetic analysis revealed that all viral strains were of the genotype Z, H5N1 sublineage of viruses prevalent in Vietnam, Cambodia and Thailand, as previously reported 10 . Pairwise comparison of all gene segments of viruses isolated from eight fatal and four surviving cases did not reveal unique amino acid changes in either group. No viruses contained Glu92 in the NS1 protein, which is associated with increased virulence of H5N1 viruses 6 , but all contained the recently reported PDZ-domain ligand ESEV 11 . An E627K substitution in the viral polymerase basic protein 2 (PB2), which is associated with adap...
BackgroundNew prophylactic and therapeutic strategies to combat human infections with highly pathogenic avian influenza (HPAI) H5N1 viruses are needed. We generated neutralizing anti-H5N1 human monoclonal antibodies (mAbs) and tested their efficacy for prophylaxis and therapy in a murine model of infection.Methods and FindingsUsing Epstein-Barr virus we immortalized memory B cells from Vietnamese adults who had recovered from infections with HPAI H5N1 viruses. Supernatants from B cell lines were screened in a virus neutralization assay. B cell lines secreting neutralizing antibodies were cloned and the mAbs purified. The cross-reactivity of these antibodies for different strains of H5N1 was tested in vitro by neutralization assays, and their prophylactic and therapeutic efficacy in vivo was tested in mice. In vitro, mAbs FLA3.14 and FLD20.19 neutralized both Clade I and Clade II H5N1 viruses, whilst FLA5.10 and FLD21.140 neutralized Clade I viruses only. In vivo, FLA3.14 and FLA5.10 conferred protection from lethality in mice challenged with A/Vietnam/1203/04 (H5N1) in a dose-dependent manner. mAb prophylaxis provided a statistically significant reduction in pulmonary virus titer, reduced associated inflammation in the lungs, and restricted extrapulmonary dissemination of the virus. Therapeutic doses of FLA3.14, FLA5.10, FLD20.19, and FLD21.140 provided robust protection from lethality at least up to 72 h postinfection with A/Vietnam/1203/04 (H5N1). mAbs FLA3.14, FLD21.140 and FLD20.19, but not FLA5.10, were also therapeutically active in vivo against the Clade II virus A/Indonesia/5/2005 (H5N1).ConclusionsThese studies provide proof of concept that fully human mAbs with neutralizing activity can be rapidly generated from the peripheral blood of convalescent patients and that these mAbs are effective for the prevention and treatment of H5N1 infection in a mouse model. A panel of neutralizing, cross-reactive mAbs might be useful for prophylaxis or adjunctive treatment of human cases of H5N1 influenza.
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BackgroundThe dominant viral etiologies responsible for acute respiratory infections (ARIs) are poorly understood, particularly among hospitalized children in resource-limited tropical countries where morbidity and mortality caused by ARIs are highest. Improved etiological insight is needed to improve clinical management and prevention.ObjectivesWe conducted a three-year prospective descriptive study of severe respiratory illness among children from 2 months to 13 years of age within the largest referral hospital for infectious diseases in southern Vietnam.MethodsMolecular detection for 15 viral species and subtypes was performed on three types of respiratory specimens (nose, throat swabs and nasopharyngeal aspirates) using a multiplex RT-PCR kit (Seeplex™ RV detection, Seegene) and additional monoplex real-time RT-PCRs.ResultsA total of 309 children were enrolled from November 2004 to January 2008. Viruses were identified in 72% (222/309) of cases, including respiratory syncytial virus (24%), influenza virus A and B (17%), human bocavirus (16%), enterovirus (9%), human coronavirus (8%), human metapneumovirus (7%), parainfluenza virus 1–3 (6%), adenovirus (5%), and human rhinovirus A (4%). Co-infections with multiple viruses were detected in 20% (62/309) of patients. When combined, diagnostic yields in nose and throat swabs were similar to nasopharyngeal aspirates.ConclusionSimilar to other parts in the world, RSV and influenza were the predominant viral pathogens detected in Vietnamese hospitalized children. Combined nasal and throat swabs are the specimens of choice for sensitive molecular detection of a broad panel of viral agents. Further research is required to better understand the clinical significance of single versus multiple viral coinfections and to address the role of bacterial (co-)infections involved in severe respiratory illness.
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