Abstract



Background

Since their emergence in Indonesia in 2005, 200 human infections with clade 2.1 highly pathogenic avian influenza A/H5N1 virus have been reportedassociated with exceptionally high mortality (84%) compared to regions affected by other genetic clades of this virus. To provide potential clues towards understanding this high mortality, detailed clinical virological analyses were performed in specimens from 180 H5N1 patients, representing 90% of all Indonesian patients and 20% of reported H5N1-infected patients globally.


Methods

H5N1 RNA was quantified in available upper- and lower respiratory tract specimens as well as faecal and blood samples from 180 patients reported between 2005 and 2017. Mutations in the neuraminidase and M2 genes that confer resistance to oseltamivir and adamantanes were assessed. Fatal and non-fatal cases were compared.


Results

High viral RNA loads in nasal and pharyngeal specimens were associated with fatal outcome. Mortality increased over time during the study period, which correlated with increasing admission viral RNA loads. Furthermore, the prevalence of amantadine resistance-conferring M2 mutations increased over time and viral loads were higher in patients infected with viruses harbouring these mutations. Compared to observations from other regions, viral RNA was detected more frequently in faeces (80%) and particularly in blood (85%), and antiviral responses to oseltamivir appeared less pronounced.


Conclusions

These observations confirm the association of viral load with outcome of human H5N1 infections and suggest potential differences in virulence and antiviral responses to oseltamivir that may explain the exceptionally high mortality of clade 2.1 H5N1 infections in Indonesia.