Viral Factors Associated With the High Mortality Related to Human Infections With Clade 2.1 Influenza A/H5N1 Virus in Indonesia

• Published in: Clinical infectious diseases Vol. 70; no. 6; pp. 1139 - 1146
• Main Authors: Pawestri, Hana A, Eggink, Dirk, Isfandari, Siti, Thanh, Tran Tan, Rogier van Doorn, H, Setiawaty, Vivi, de Jong, Menno D
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 03.03.2020
• Subjects: and Commentaries; Animals; Antiviral Agents - therapeutic use; Humans; Indonesia - epidemiology; Influenza A Virus, H5N1 Subtype - genetics; Influenza in Birds; Influenza, Human - epidemiology; Neuraminidase; Oseltamivir - therapeutic use; Indonesia; highly pathogenic avian influenza virus; mortality; H5N1; viral load; resistance
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/ciz328

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 reported, associated 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 fecal and blood samples from 180 patients with confirmed infection between 2005 and 2017. Mutations in the neuraminidase and M2 genes that confer resistance to oseltamivir and adamantanes were assessed. Fatal and nonfatal 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 viral RNA loads on admission. Furthermore, the prevalence of amantadine resistance–conferring M2 mutations increased over time, and viral loads were higher in patients infected with viruses that harbored these mutations. Compared to observations from other regions, viral RNA was detected more frequently in feces (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 related to clade 2.1 H5N1 infections in Indonesia. Detailed virological analyses of 180 Indonesian patients infected with avian influenza A/H5N1 virus point to potential differences in virulence and antiviral responses to oseltamivir that may explain the exceptionally high mortality related to these infections in Indonesia compared to other regions.