Characterization of viral genomic mutations in novel influenza A (H7N9)-infected patients: the association between oseltamivir-resistant variants and viral shedding duration
Since February 2013, human infections with the novel influenza A H7N9 virus have occurred in eastern China. It is important to detect mutations in viral genes and analyze the clinical features of patients and viral shedding duration related to neuraminidase inhibitor (NAI) resistance. We collected clinical specimens from 31 hospitalized H7N9 patients and sequenced NA, PB2, HA, and M gene fragments. Of the 31 identified patients, 7 (22.6%) carried the R292K substitution in NA, 30 (96.8%), 3 (9.7%), and 5 (16.1%) carried E627K, Q591K, and D701N mutations in PB2, respectively, and 2 (6.5%) carried both E627K and D701N mutations in PB2. All 26 identified patients harbored Q226L mutations and possessed only a single arginine (R) at cleavage sites in the HA and a S31N mutation in M2. Among 7 NA-R292K mutated patients, 3 died and 4 were discharged. There was no significant difference in the days that patients started oseltamivir treatment after symptom onset between NA-R292K mutant and NA-R292 wild-type patients (median days, 7 vs 6, P = 0.374). NA-R292K mutant patients had a significantly longer duration of viral shedding than NA-R292 wild-type patients after oseltamivir treatment (median days, 10 vs 5, P = 0.022). The mutation of R292K in NA conferring the potential ability of oseltamivir resistance resulted in prolonged viral duration and poor outcome and should be taken into consideration in the clinical management of infected patients.
KeywordsInfluenza A (H7N9) Mutation Neuraminidase (NA) Oseltamivir resistance Viral duration
We thank Prof. Kwok-Yung Yuen and Prof. Hong-Lin Chen in the State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, University of Hong Kong for their advice in study design, and Dr. Weifeng Liang (State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China) for help with the clinical data collection.
This work was supported by the China National Mega-Projects for Infectious Diseases (Grant Number 2017ZX10103008), the National Natural Science Foundation of China (Grant Numbers 81672014, 81600300 and 81702079), the Natural Science Foundation of Zhejiang Province (Grant Number LQ 15H100001), the Fundamental Research Funds for the Central Universities (Grant Number 2017QNA7016), and the General research projects of zhejiang education department (Y201738209).
Compliance with ethical standards
Conflict of interest
We declare that all authors have no conflict of interest.
This study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital of Zhejiang University.
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