Drug resistence and NA gene characteristics of influenza virus A/H1N1(pdm09) studied in Shanghai during 2018-2019 / 上海预防医学

Objective A/H1N1(pdm09) viruses were the dominant strains in Shanghai during 2018-2019 influenza surveillance year.This study is to provide a scientific reference for clinical drug use by investigating the susceptibility of A/H1N1(pdm09) viruses to neuraminidase inhibitors(NAIs). Methods Sixty strains of A/H1N1(pdm09) viruses were randomly selected for testing the susceptibility and drug resistance to Oseltamivir and Zanamivir by means of neutaminidase inhibition and neuraminidase (NA) gene sequencing. Results The 60 epidemic strains all proved to be susceptible to Oseltamivir and Zanamivir and the susceptibility was not observed to be decreased or remarkably decreased.In genetic sequencing, NA was not observed to present amino acid mutation at the key sites and auxiliary sites in catalytic activity, which confirmed the results of the phototypic detection of neuraminidase inhibition. Conclusion The subtype influenza viruses A/H1N1(pdm09) circulating in Shanghai during 2018-2019 surveillance year are still sensitive to NAIs, which provides a scientific reference for clinical use of drugs.However, we monitored only a number of strains and think that the work monitoring antiviral susceptibility should be continued with the wide use of the drugs.

Infuenza and Patients with Chronic Diseases and Elderly

@#Influenza is a highly contagious viral illness characterized by fever, cough, headache and myalgia. The influenza virus is a segmented ribonucleic acid (RNA) virus that can infect both humans and animals, and the capacity for reassortment when multiple viruses infect the same cell has led – and will continue to lead – to the development of novel pandemic influenza A viruses. The disease is generally self-limiting, although complications and deaths can occur, particularly in children < two years of age, adults >65 years of age, pregnant women, and immunosuppressed individuals. Specific antiviral therapy is available, including oseltamivir in Singapore, and is recommended for severe disease as well as those with higher likelihood for developing complications from influenza. In addition to hand hygiene and respiratory etiquette, antiviral prophylaxis may reduce the impact and burden of influenza in household and institutional settings. However, the primary means for preventing influenza is via annual vaccination in those above the age of two years. The influenza vaccine, while having variable efficacy depending on antigenic matching with circulating viruses each year, is safe and cost-effective at the population level.

Perspectives of antiviral drugs used on influenza / 中华流行病学杂志

Antiviral drugs on influenza are important in the control program of influenza.Options for influenza treatment are currently limited to using the neuraminidase inhibitors (NAIs).Given limited effectiveness of NAIs and related resistance,there remains an urgent need for the development of influenza antiviral drugs that can improve the efficacy and provide low propensity of viral resistance.Several influenza-related antiviral drugs that are currently under the late-stage clinical trials all appear differently in the mechanism of action.It is hoped that when new antiviral drugs are licensed,care and outcomes of severe influenza cases will be improved.

Perspectives of antiviral drugs used on influenza / 中华流行病学杂志

Antiviral drugs on influenza are important in the control program of influenza.Options for influenza treatment are currently limited to using the neuraminidase inhibitors (NAIs).Given limited effectiveness of NAIs and related resistance,there remains an urgent need for the development of influenza antiviral drugs that can improve the efficacy and provide low propensity of viral resistance.Several influenza-related antiviral drugs that are currently under the late-stage clinical trials all appear differently in the mechanism of action.It is hoped that when new antiviral drugs are licensed,care and outcomes of severe influenza cases will be improved.

Research progress on drug-resistance of influenza virus to neuraminidase inhibitors / 中华临床感染病杂志

Influenza virus , the causative agent of influenza , has characteristics of fast transmission and strong infectivity, posing a major threat to public health .Currently, with widely use of the first-line antiviral neuraminidase inhibitors , drug-resistant strains have appeared and brought difficulties to the precaution and treatment of influenza .This article reviews influenza virus structural characteristics , drug-resistance mechanisms , resistance situation and detection methods of drug-resistant virus strains , aiming to provide a reference for future research on influenza virus drug-resistance and clinical medication .

Analysis of the Association between Neuraminidase Inhibitors and Neuropsychiatric Adverse Events Using Japanese Adverse Drug Event Report (JADER) / 医薬品情報学

There have been concerns that neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) cause neuropsychiatric adverse events (NPAEs).  We evaluated the number of relevant reports, reporting ratio, and reporting odds ratio (ROR) by using spontaneous reporting database, such as the Japanese Adverse Drug Event Report (JADER) (April 2004 to July 2014).  The RORs of oseltamivir, zanamivir, laninamivir, and peramivir were 11.8 (95% confidence interval (CI), 10.8-13.0), 47.0 (95% CI, 40.0-55.3), 9.5 (95% CI, 6.8-13.2), and 3.3 (95% CI, 2.1-5.1), respectively.  The lower limit of the ROR 95% CI of NPAEs of all neuraminidase inhibitors was ≥1.  We analyzed the association of age and gender with NPAEs in patients treated with oseltamivir using a logistic regression model.  The adjusted ROR of NPAEs was 66.9 (95% CI, 50.3-88.9) in male patients treated with osletamivir aged 10-19 years.  The adjusted RORs of NPAEs were increased in male and female patients under the age of 20 years.  Neuraminidase inhibitors including oseltamivir treatment could be associated with NPAEs.  Therefore, these drugs should be used carefully in clinical practice.

Genetic variation and drug resistance mutation of influenza virus during 2013-2014 in Beijing, China: A report of 37 cases / 解放军医学杂志

Objective To evaluate the evolutionary characteristics of H1N1 and H3N2 influenza A and B viruses, and investigate the drug-resistant mutation of influenza viruses to amantadine and neuraminidase inhibitors (NAIs) during 2013-2014 episode in Beijing. Methods RNA was extracted from pharyngeal or nasal swab samples from 37 influenza virus-infected patients and viral genotype/subgenotype were analyzed by real-time reverse-transcription polymerase chain reaction. All influenza A viruses were further directly sequenced for NA and M2 matrix protein (M2) genes, and all influenza B viruses were further sequenced for NA and hemagglutinin (HA) genes. The drug-resistant mutations and genetic evolution were analyzed by Vector NTI software and phylogenetic trees were plotted using Mega software. Results Influenza A viruses were identified in 29 patients, including 23 with H1N1 and 6 with H3N2 viruses. Influenza B viruses were identified in 8 patients. M2 gene of all 29 patients with influenza A virus infection were detected with S31N amantadine-resistant mutation. NAIs-resistant mutations were not detected in all 37 patients with influenza A and B virus infection. Phylogenetic analysis showed that HA genes from 5 influenza B virus strains were identified as the B-Yamagata lineage, while NA genes from the corresponding strains were identified as B-Victoria lineage. Conclusions Among Beijing Influenza B virus strains reassortants derived from B-Yamagata lineage and B-Victoria lineage were found.

A Case of Influenza Associated Fulminant Myocarditis Successfully Treated with Intravenous Peramivir / 감염과화학요법

We report the case of a patient with fulminant myocarditis caused by influenza A virus, who presented with acute-onset heart failure and cardiogenic shock and was treated successfully with single dose of intravenous peramivir and with pharmacologic hemodynamic support. A 45-year-old Korean woman presented to our emergency department (ED) with shortness of breath and an episode of seizure that developed abruptly 5 hours before she arrived in the ED. She had a history of recurrent epileptic seizure 25 years ago, but denied other specific medical illnesses. In the ED, she was hypoxemic (arterial partial pressure of oxygen, 59.8 mmHg on room air) and chest radiography revealed bilateral alveolar infiltrates. A rapid antigen test for influenza A virus was positive, and she was administered a single dose of peramivir (300 mg) intravenously. Five hours later, the patient's dyspnea had worsened and she was hypotensive (blood pressure, 86/53 mmHg), requiring norepinephrine infusion. Further evaluation disclosed an increased cardiac troponin I level of 1.36 ng/mL and a depressed left ventricular ejection fraction of 30%. Under the diagnosis of influenza A-associated myocarditis and cardiogenic shock, she was managed with continuous critical care in the intensive care unit. On day 3, the patient's dyspnea began to resolve and her ventricular function returned to normal. Real-time polymerase chain reaction assays for influenza viruses in serial nasopharyngeal aspirates were positive for influenza A (hH3N2) with a threshold cycle value of 27.39 on day 2, but these became negative by day 4. The patient recovered and was discharged on day 9 after admission. In conclusion, this case indicates that intravenous peramivir might be an effective antiviral agent for the treatment of severe influenza A virus infection.

<b>Development of A Decision Making Model for the Management of Influenza. A Proposal of Diagnostic Policy </b><b>Based on Phenomena and Therapeutics. </b> / 日本東洋医学雑誌

The management of influenza has dramatically changed since the introduction of the rapid influenza diagnostic test, or RIDT, and neuraminidase inhibitors (NI). However, it is still far from optimal due to low RIDT sensitivity and problems involving NI such as side effects and the potential emergence of resistant virus.Therefore, we developed a decision-making model for the management of influenza, which includes Kampo medicines in its strategies. First, the severity of patients is evaluated. If a patient is judged at severe or high-risk, intravenous NI would be the main component of treatment. If a patient has neither a severe condition nor is at high-risk, the patient would be asked to choose either NI or Kampo medicine. In the former, RIDT would be used if pretest probability was less than 50%, but it would not be used if it was more than 50%, based on the lack of influence on the post-test probability. For the latter, RIDT would be not used in general as Kampo targets “phenomena”, not the virus <i>per se</i>. This model enables us to optimize the use of RIDT by appropriately selecting patients based on the characteristics of RIDT, and by avoiding unnecessary tests and their misinterpretation.

Strategies for designing influenza neuraminidase inhibitors and research progress / 国际药学研究杂志

Nowadays, influenza is still a big threat to human health and could cause mass mortality during pandemic years. The viral surface protein, neuraminidase (NA), plays an important role in the life cycle of influenza virus and has been proved as the major antiinfluenza target. Since the X-ray crystal structure of NA was defined in 1983, the application of structure-based drug design and computational chemistry have greatly contributed to the development of NA inhibitors (NAIs). Till now, two antiinfluenza drugs zanamivir (Relenza) and oseltamivir (Tamiflu) are available. In this article, we will illustrate the strategies of NAIs' design according to the development of the two drugs and also present some recent progress in this field.

Expression and Application of Neuraminidase of Influenza Virus / 中国生物工程杂志

To simplify the preparation of neuraminidase in screening influenza neuraminidase inhibitors,the neuraminidase gene of H5N1 influenza A virus was optimized for high expression in mammalian cells and cloned into pcDNA4/TO vector. The recombinant plasmids were transfected into T-REx 293 cells to establish stable cell lines,in which the expression of neuraminidase was induced by tetracycline. Unlike from virions,the preparation of neuraminidase became conveniently and safely from these stable cell lines,which would facilitate developing high throughput assay to screen neuraminidase inhibitors. More than 3000 natural extracts and herbal components were screened in the study. Baicalin and baicalein were found to inhibit oseltamivir-sensitive and oseltamivir-resistant neuraminidase at similar level,furthermore,their anti-influenza activity was confirmed by plaque assay and virus inhibition assay.