Clinical Characteristics of 26 Human Cases of Highly Pathogenic Avian Influenza A (H5N1) Virus Infection in China

Self Cite

mentioning

confidence: 99%

Genesis and Dissemination of Highly Pathogenic H5N6 Avian Influenza Viruses

Yang

Zhu

et al. 2017

Self Cite

“…Some autopsy reports indicate that infection was limited to the respiratory and gastrointestinal tracts (9, 20), while others have isolated virus from the brain and gastrointestinal tract (21) or serum and cerebrospinal fluid (CSF) (22)(23)(24) or detected viral mRNA in the brain (21, 25). Measurements from blood samples taken early during the infectious period link severe disease outcomes with lymphopenia and hypercytokinemia (2,10,14,26), while the presence of high loads of negative-sense …”

mentioning

confidence: 99%

“…Fatal infection with H5N1 has been associated with acute respiratory distress syndrome (ARDS) (9)(10)(11), multiple organ failure (12)(13)(14)(15)(16)(17)(18), and encephalitis (19), but overall, few human autopsies have been conducted and it is difficult to determine the contribution of systemic infection to case fatality rates. Some autopsy reports indicate that infection was limited to the respiratory and gastrointestinal tracts (9,20), while others have isolated virus from the brain and gastrointestinal tract (21) or serum and cerebrospinal fluid (CSF) (22)(23)(24) or detected viral mRNA in the brain (21,25).…”

mentioning

confidence: 99%

“…However, some differences between the two species in response to H5N1 have been noted. Infected humans frequently show progression to ARDS, but neurological disease is rarely manifested (2,13,14,19,21,26,32,33), while detection of virus in the brain and neurological disease are common in ferrets experimentally infected by the total respiratory tract (TRT) route (34,35). H5N1 virus spread outside the respiratory tract in ferrets has enabled this model to be employed as a means to study the anatomical pathways of viral dissemination.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes

Edenborough

Lowther

Laurie

et al. 2016

Although avian H5N1 influenza virus has yet to develop the capacity for human-to-human spread, the severity of the rare cases of human infection has warranted intensive follow-up of potentially exposed individuals that may require antiviral prophylaxis. For countries where antiviral drugs are limited, the World Health Organization (WHO) has developed a risk categorization for different levels of exposure to environmental, poultry, or human sources of infection. While these take into account the infection source, they do not account for the likely mode of virus entry that the individual may have experienced from that source and how this could affect the disease outcome. Knowledge of the kinetics and spread of virus after natural routes of exposure may further inform the risk of infection, as well as the likely disease severity. Using the ferret model of H5N1 infection, we compared the commonly used but artificial inoculation method that saturates the total respiratory tract (TRT) with virus to upper respiratory tract (URT) and oral routes of delivery, those likely to be encountered by humans in nature. We show that there was no statistically significant difference in survival rate with the different routes of infection, but the disease characteristics were somewhat different. Following URT infection, viral spread to systemic organs was comparatively delayed and more focal than after TRT infection. By both routes, severe disease was associated with early viremia and central nervous system infection. After oral exposure to the virus, mild infections were common suggesting consumption of virus-contaminated liquids may be associated with seroconversion in the absence of severe disease. IMPORTANCERisks for human H5N1 infection include direct contact with infected birds and frequenting contaminated environments. We used H5N1 ferret infection models to show that breathing in the virus was more likely to produce clinical infection than swallowing contaminated liquid. We also showed that virus could spread from the respiratory tract to the brain, which was associated with end-stage disease, and very early viremia provided a marker for this. With upper respiratory tract exposure, infection of the brain was common but hard to detect, suggesting that human neurological infections might be typically undetected at autopsy. However, viral spread to systemic sites was slower after exposure to virus by this route than when virus was additionally delivered to the lungs, providing a better therapeutic window. In addition to exposure history, early parameters of infection, such as viremia, could help prioritize antiviral treatments for patients most at risk of succumbing to infection. Since the emergence of highly pathogenic avian influenza H5N1 in humans in 1997, outbreaks have occurred sporadically, primarily in populations associated with direct contact with sick birds (1-4). Currently, outbreaks occur in regions where H5N1 is endemic in migratory birds and where a large proportion of the population rear backyard poultry ...

“…Patients infected with H5N1 influenza virus developed mainly severe respiratory disease, characterized by fever, cough, shortness of breath, and pneumonia, that frequently progressed to acute respiratory distress syndrome (ARDS) and multiorgan failure (28,68,69). In fatal cases, the median time from onset to death was 9 to 10 days (1).…”

mentioning

confidence: 99%

Virulence Determinants of Avian H5N1 Influenza A Virus in Mammalian and Avian Hosts: Role of the C-Terminal ESEV Motif in the Viral NS1 Protein

Zielecki

Semmler

Kalthoff

et al. 2010

We assessed the prediction that access of the viral NS1 protein to cellular PDZ domain protein networks enhances the virulence of highly pathogenic avian influenza A viruses. The NS1 proteins of most avian influenza viruses bear the C-terminal ligand sequence Glu-Ser-Glu-Val (ESEV) for PDZ domains present in multiple host proteins, whereas no such motif is found in the NS1 homologues of seasonal human virus strains. Previous analysis showed that a C-terminal ESEV motif increases viral virulence when introduced into the NS1 protein of mouse-adapted H1N1 influenza virus. To examine the role of the PDZ domain ligand motif in avian influenza virus virulence, we generated three recombinants, derived from the prototypic H5N1 influenza A/Vietnam/1203/04 virus, expressing NS1 proteins that either have the C-terminal ESEV motif or the human influenza virus RSKV consensus or bear a natural truncation of this motif, respectively. Cell biological analyses showed strong control of NS1 nuclear migration in infected mammalian and avian cells, with only minor differences between the three variants. The ESEV sequence attenuated viral replication on cultured human, murine, and duck cells but not on chicken fibroblasts. However, all three viruses caused highly lethal infections in mice and chickens, with little difference in viral titers in organs, mean lethal dose, or intravenous pathogenicity index. These findings demonstrate that a PDZ domain ligand sequence in NS1 contributes little to the virulence of H5N1 viruses in these hosts, and they indicate that this motif modulates viral replication in a strain-and host-dependent manner.