Virological, Serological, and Antiviral Studies in an Imported Human Case of Avian Influenza A(H7N9) Virus in Taiwan

Lin, Pei-Yu; Chao, Tai‐Ling; Kuo, Shuenn‐Wen; Wang, Jann-Tay; Hung, Chien‐Ching; Lin, Hsiao‐Han; Yang, Zong-Yu; Ho, Shu-Yuan; Chang, Chun-Kai; Huang, Ming‐Bao; Chen, Hui-Hou; Chen, Yee‐Chun; Lai, Hong‐Shiee; Chang, Sui‐Yuan; Chang, Shan‐Chwen; Yang, Pan‐Chyr

doi:10.1093/cid/cit638

Cited by 41 publications

(29 citation statements)

References 17 publications

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“…Because the H7N9 virus is resistant to M2 blockers, patients have been treated with neuraminidase (NA) inhibitors (NAIs), among which oseltamivir is the most widely used. Notably, evidence for a therapeutic effect of oseltamivir treatment was reported in H7N9-infected patients during the 2013 outbreak (2)(3)(4)(5). In early 2015, the first imported H7N9 cases in North America were described in two travelers returning from China; both patients were given oseltamivir and eventually recovered from the disease (6).…”

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confidence: 99%

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Neuraminidase Mutations Conferring Resistance to Oseltamivir in Influenza A(H7N9) Viruses

Marjuki

Mishin

Chesnokov

et al. 2015

J Virol

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Human infections by avian influenza A(H7N9) virus entail substantial morbidity and mortality. Treatment of infected patients with the neuraminidase (NA) inhibitor oseltamivir was associated with emergence of viruses carrying NA substitutions. In the NA inhibition (NI) assay, R292K conferred highly reduced inhibition by oseltamivir, while E119V and I222K each caused reduced inhibition. To facilitate establishment of laboratory correlates of clinically relevant resistance, experiments were conducted in ferrets infected with virus carrying wild-type or variant NA genes recovered from the A/Taiwan/ 1/2013 isolate. Oseltamivir treatment (5 or 25 mg/kg of body weight/dose) was given 4 h postinfection, followed by twicedaily treatment for 5 days. Treatment of ferrets infected with wild-type virus resulted in a modest dose-dependent reduction (0.7 to 1.5 log 10 50% tissue culture infectious dose [TCID 50 ]) in nasal wash viral titers and inflammation response. Conversely, treatment failed to significantly inhibit the replication of R292K or E119V virus. A small reduction of viral titers was detected on day 5 in ferrets infected with the I222K virus. The propensity for oseltamivir resistance emergence was assessed in oseltamivir-treated animals infected with wild-type virus; emergence of R292K virus was detected in 3 of 6 ferrets within 5 to 7 days postinfection. Collectively, we demonstrate that R292K, E119V, and I222K reduced the inhibitory activity of oseltamivir, not only in the NI assay, but also in infected ferrets, judged particularly by viral loads in nasal washes, and may signal the need for alternative therapeutics. Thus, these clinical outcomes measured in the ferret model may correlate with clinically relevant oseltamivir resistance in humans. IMPORTANCEThis report provides more evidence for using the ferret model to assess the susceptibility of influenza A(H7N9) viruses to oseltamivir, the most prescribed anti-influenza virus drug. The information gained can be used to assist in the establishment of laboratory correlates of human disease and drug therapy. The rapid emergence of viruses with R292K in treated ferrets correlates well with the multiple reports on this NA variant in treated human patients. Our findings highlight the importance of the discovery and characterization of new antiviral drugs with different mechanisms of action and the use of combination treatment strategies against emerging viruses with pandemic potential, such as avian H7N9 virus, particularly against those carrying drug resistance markers.

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confidence: 99%

“…In the early stage of the 2013 outbreak, A/Taiwan/1/2013 (H7N9) virus (Taiwan/1) was recovered from a patient who underwent two courses of oseltamivir treatment (2,4). In a single isolate, we identified four virus variants differing by a single amino acid in the NA compared to the wild-type (WT) virus (22).…”

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confidence: 99%

Neuraminidase Mutations Conferring Resistance to Oseltamivir in Influenza A(H7N9) Viruses

Marjuki

Mishin

Chesnokov

et al. 2015

J Virol

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“…However, in October 2013 reports of new human H7N9 infections began to increase and, as of March 2014, more than 400 human infections leading to 115 deaths have been reported (2). Although the majority of human infections remain contained to mainland China, there have been imported cases confirmed in Taiwan, Hong Kong SAR, and Malaysia (3)(4)(5). There is no evidence that sustained human-to-human transmission is occurring, although the H7N9 viruses possess several key amino acid changes often associated with mammalian replication and transmission, heightening public health concerns (6)(7)(8).…”

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confidence: 99%

“…Patients infected with H7N9 viruses can exhibit severe and often lethal disease characterized by rapidly progressive pneumonia leading to acute respiratory distress syndrome and respiratory failure (4). Because of this, and its avian origin, the human H7N9 infections have been touted as an "H5N1-like" disease.…”

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confidence: 99%

Human H7N9 and H5N1 Influenza Viruses Differ in Induction of Cytokines and Tissue Tropism

Meliopoulos

Karlsson

Kercher

et al. 2014

J Virol

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Since emerging in 2013, the avian-origin H7N9 influenza viruses have resulted in over 400 human infections, leading to 115 deaths to date. Although the epidemiology differs from human highly pathogenic avian H5N1 influenza virus infections, there is a similar rapid progression to acute respiratory distress syndrome. The aim of these studies was to compare the pathological and immunological characteristics of a panel of human H7N9 and H5N1 viruses in vitro and in vivo. Although there were similarities between particular H5N1 and H7N9 viruses, including association between lethal disease and spread to the alveolar spaces and kidney, there were also strain-specific differences. Both H5N1 and H7N9 viruses are capable of causing lethal infections, with mortality correlating most strongly with wider distribution of viral antigen in the lungs, rather than with traditional measures of virus titer and host responses. Strain-specific differences included hypercytokinemia in H5N1 infections that was not seen with the H7N9 infections regardless of lethality. Conversely, H7N9 viruses showed a greater tropism for respiratory epithelium covering nasal passages and nasopharynx-associated lymphoid tissue than H5N1 viruses, which may explain the enhanced transmission in ferret models. Overall, these studies highlight some distinctive properties of H5N1 and H7N9 viruses in different in vitro and in vivo models. IMPORTANCEThe novel avian-origin H7N9 pandemic represents a serious threat to public health. The ability of H7N9 to cause serious lung pathology, leading in some cases to the development of acute respiratory distress syndrome, is of particular concern. Initial reports of H7N9 infection compared them to infections caused by highly pathogenic avian (HPAI) H5N1 viruses. Thus, it is of critical importance to understand the pathology and immunological response to infection with H7N9 compared to HPAI H5N1 viruses. We compared these responses in both in vitro and in vivo models, and found that H5N1 and H7N9 infections exhibit distinct pathological, immunological, and tissue tropism differences that could explain differences in clinical disease and viral transmission.

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“…Notably, no viral RNA could be detected in the serum specimens during the whole process, which did not fully corresponded with previous studies. Although Lin P et al also did not detect the viral RNA in a severe case [11], Hu Y et al reported that twelve out of fourteen H7N9-infected cases (86%) were positive in serum viral load test [8]. Based on the difference of admission, we believe that the viremia should be highly relevant with immunosuppression, which was mainly caused by the application of corticosteroid in Hu Y et al's study.…”

Section: Discussionmentioning

confidence: 71%

A case of human infection with avian Influenza A/H7N9 virus in Beijing: virological and serological analysis

Pan

Shi

Yang

et al. 2015

J Infect Dev Ctries

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This study described some essential viral and sera-characteristics of A/H7N9 virus infection in a 61-year old case patient. With the antiviral therapy and respiratory support, the patient showed a significant decrease of viral loads from 6.72 log 10 copies/mL to 0 in 22 days, and a correlated increase of serum hemagglutination inhibition titers during the same period. Phylogenetic analysis demonstrated that the isolated strain was highly homologous to previous strains isolated in the southeast of China. Drug resistance-associated R292K mutation became detectable 17 days after antiviral therapy, but no remarkable influence on the viral clearance was observed.

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Virological, Serological, and Antiviral Studies in an Imported Human Case of Avian Influenza A(H7N9) Virus in Taiwan

Cited by 41 publications

References 17 publications

Neuraminidase Mutations Conferring Resistance to Oseltamivir in Influenza A(H7N9) Viruses

Neuraminidase Mutations Conferring Resistance to Oseltamivir in Influenza A(H7N9) Viruses

Human H7N9 and H5N1 Influenza Viruses Differ in Induction of Cytokines and Tissue Tropism

A case of human infection with avian Influenza A/H7N9 virus in Beijing: virological and serological analysis

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