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Published online May 28, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61125-3
1
Association between adverse clinical outcome in human
disease caused by novel influenza A H7N9 virus and sustained
viral shedding and emergence of antiviral resistance
Yunwen Hu, Shuihua Lu, Zhigang Song, Wei Wang, Pei Hao, Jianhua Li, Xiaonan Zhang, Hui-Ling Yen, Bisheng Shi, Tao Li, Wencai Guan, Lei Xu,
Yi Liu, Sen Wang, Xiaoling Zhang, Di Tian, Zhaoqin Zhu, Jing He, Kai Huang, Huijie Chen, Lulu Zheng, Xuan Li, Jie Ping, Bin Kang, Xiuhong Xi,
Lijun Zha,Yixue Li, Zhiyong Zhang, Malik Peiris, Zhenghong Yuan
Summary
Background
On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe
respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus
remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients
with A/H7N9.
Methods
We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre
(SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir)
for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens
obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations
associated with resistance to neuraminidase inhibitors and their association with disease outcome.
Findings
All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further
deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral
treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three
patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent.
An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and
oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them,
wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292
dominated 9 days after start of treatment.
Interpretation
Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of
NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor
clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid
therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning.
Funding
National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning
Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National
Natural Science Foundation of China
Published online May 28, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61125-3
1
Association between adverse clinical outcome in human
disease caused by novel influenza A H7N9 virus and sustained
viral shedding and emergence of antiviral resistance
Yunwen Hu, Shuihua Lu, Zhigang Song, Wei Wang, Pei Hao, Jianhua Li, Xiaonan Zhang, Hui-Ling Yen, Bisheng Shi, Tao Li, Wencai Guan, Lei Xu,
Yi Liu, Sen Wang, Xiaoling Zhang, Di Tian, Zhaoqin Zhu, Jing He, Kai Huang, Huijie Chen, Lulu Zheng, Xuan Li, Jie Ping, Bin Kang, Xiuhong Xi,
Lijun Zha,Yixue Li, Zhiyong Zhang, Malik Peiris, Zhenghong Yuan
Summary
Background
On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe
respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus
remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients
with A/H7N9.
Methods
We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre
(SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir)
for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens
obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations
associated with resistance to neuraminidase inhibitors and their association with disease outcome.
Findings
All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further
deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral
treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three
patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent.
An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and
oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them,
wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292
dominated 9 days after start of treatment.
Interpretation
Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of
NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor
clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid
therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning.
Funding
National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning
Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National
Natural Science Foundation of China
Comment