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Journal of Medical Virology Feb 2024Influenza virus is known to cause mild to severe respiratory infections and is also prone to genetic mutations. Of all the mutations, neuraminidase (NA) gene mutations...
Optimization of an allelic discrimination real-time RT-PCR assay for detection of H275Y oseltamivir resistance gene mutation among influenza A(H1N1)pdm09 patients from 2020 to 2022.
Influenza virus is known to cause mild to severe respiratory infections and is also prone to genetic mutations. Of all the mutations, neuraminidase (NA) gene mutations are a matter of concern, as most approved antivirals target this protein. During the 2020 influenza season, an emergence of mutation in the NA gene, affecting the binding of the World Health Organization (WHO)-recommended probes to the specific site of the NA gene, was reported by our group. As a result of this mutation, the WHO-recommended allelic discrimination real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay was unable to detect wild-type (H275) or mutant oseltamivir-resistant (Y275) strains of influenza A(H1N1)pmd09 viruses. In the current study, the WHO-recommended probes were redesigned according to the mutation in the probe binding site. Fifty undetermined samples (2020-2021) from the previous study were retested with the newly designed probes and found to be positive for H275 and/or Y275. The results obtained were similar to the Sanger sequencing results from the previous study, suggesting that the redesigned probes were efficient in discriminating between wild-type and mutant-type viruses. Furthermore, 133 samples from 2022, making a total of 183 samples (2020-2022), were tested using improved allelic discrimination real-time RT-PCR, and the overall prevalence rate of oseltamivir resistance in 2020-2022 was found to be 0.54%.
Topics: Humans; Oseltamivir; Influenza, Human; Antiviral Agents; Influenza A Virus, H1N1 Subtype; Reverse Transcriptase Polymerase Chain Reaction; Mutation, Missense; Viral Proteins; Drug Resistance, Viral; Mutation; Neuraminidase
PubMed: 38288882
DOI: 10.1002/jmv.29427 -
Influenza and Other Respiratory Viruses Jan 2024During the 2019 severe influenza season, New South Wales (NSW) experienced the highest number of cases in Australia. This study retrospectively investigated the genetic...
BACKGROUND
During the 2019 severe influenza season, New South Wales (NSW) experienced the highest number of cases in Australia. This study retrospectively investigated the genetic characteristics of influenza viruses circulating in NSW in 2019 and identified genetic markers related to antiviral resistance and potential virulence.
METHODS
The complete genomes of influenza A and B viruses were amplified using reverse transcription-polymerase chain reaction (PCR) and sequenced with an Illumina MiSeq platform.
RESULTS
When comparing the sequencing data with the vaccine strains and reference sequences, the phylogenetic analysis revealed that most NSW A/H3N2 viruses (n = 68; 94%) belonged to 3C.2a1b and a minority (n = 4; 6%) belonged to 3C.3a. These viruses all diverged from the vaccine strain A/Switzerland/8060/2017. All A/H1N1pdm09 viruses (n = 20) showed genetic dissimilarity from vaccine strain A/Michigan/45/2015, with subclades 6B.1A.5 and 6B.1A.2 identified. All B/Victoria-lineage viruses (n = 21) aligned with clade V1A.3, presenting triple amino acid deletions at positions 162-164 in the hemagglutinin protein, significantly diverging from the vaccine strain B/Colorado/06/2017. Multiple amino acid substitutions were also found in the internal proteins of influenza viruses, some of which have been previously reported in hospitalized influenza patients in Thailand. Notably, the oseltamivir-resistant marker H275Y was present in one immunocompromised patient infected with A/H1N1pdm09 and the resistance-related mutation I222V was detected in another A/H3N2-infected patient.
CONCLUSIONS
Considering antigenic drift and the constant evolution of circulating A and B strains, we believe continuous monitoring of influenza viruses in NSW via the high-throughput sequencing approach provides timely and pivotal information for both public health surveillance and clinical treatment.
Topics: Humans; Influenza, Human; Retrospective Studies; Herpesvirus 1, Cercopithecine; Influenza A Virus, H3N2 Subtype; New South Wales; Phylogeny; Hemagglutinin Glycoproteins, Influenza Virus; Influenza Vaccines; Australia; Seasons; Whole Genome Sequencing
PubMed: 38288510
DOI: 10.1111/irv.13252 -
Antiviral Research Feb 2024In this research, we employed a deep reinforcement learning (RL)-based molecule design platform to generate a diverse set of compounds targeting the neuraminidase (NA)...
In this research, we employed a deep reinforcement learning (RL)-based molecule design platform to generate a diverse set of compounds targeting the neuraminidase (NA) of influenza A and B viruses. A total of 60,291 compounds were generated, of which 86.5 % displayed superior physicochemical properties compared to oseltamivir. After narrowing down the selection through computational filters, nine compounds with non-sialic acid-like structures were selected for in vitro experiments. We identified two compounds, DS-22-inf-009 and DS-22-inf-021 that effectively inhibited the NAs of both influenza A and B viruses (IAV and IBV), including H275Y mutant strains at low micromolar concentrations. Molecular dynamics simulations revealed a similar pattern of interaction with amino acid residues as oseltamivir. In cell-based assays, DS-22-inf-009 and DS-22-inf-021 inhibited IAV and IBV in a dose-dependent manner with EC values ranging from 0.29 μM to 2.31 μM. Furthermore, animal experiments showed that both DS-22-inf-009 and DS-22-inf-021 exerted antiviral activity in mice, conferring 65 % and 85 % protection from IAV (H1N1 pdm09), and 65 % and 100 % protection from IBV (Yamagata lineage), respectively. Thus, these findings demonstrate the potential of RL to generate compounds with promising antiviral properties.
Topics: Animals; Mice; Humans; Oseltamivir; Antiviral Agents; Influenza, Human; Influenza A Virus, H1N1 Subtype; Artificial Intelligence; Viral Proteins; Drug Resistance, Viral; Influenza A virus; Influenza B virus; Neuraminidase
PubMed: 38280564
DOI: 10.1016/j.antiviral.2024.105818 -
Cureus Dec 2023Pulmonary embolisms (PEs) are potentially life-threatening emergencies that carry significant morbidity and mortality. Advances in treatment options and the safety of...
Pulmonary embolisms (PEs) are potentially life-threatening emergencies that carry significant morbidity and mortality. Advances in treatment options and the safety of existing procedures have effectively reduced the long-term and short-term effects of the condition. Therefore, it is important to make an early diagnosis so that treatment options can be thoroughly explored. The D-dimer is an important tool in the early diagnosis of PEs. It is especially useful in ruling out the diagnosis in patients with a low to moderate suspicion of the disease. We present a case of a 22-year-old male who presented with exertional dyspnea, congestion, and rhinorrhea for one day and was noted to have persistent hypoxia and tachycardia. The influenza test was positive, and he was started on oseltamivir. Due to persistent hypoxia, a CT pulmonary angiogram was ordered and revealed filling defects in the left lower lobe segmental vessels suggestive of PE, as well as multifocal multilobar bilateral ground-glass opacities. He was initially treated with a heparin drip and subsequently switched to eliquis. After a significant improvement in his hypoxia, he was discharged home for outpatient follow-up, including a hypercoagulable workup. This case demonstrates that despite the usefulness of the D-dimer as a diagnostic tool for PEs, it cannot solely or fully replace the full gamut of screening tools used to determine the risk of PE. Although rare, false-negative scores do occur; therefore, the tool should always be used in conjunction with other scoring systems, physician gestalt, and within the specific clinical context.
PubMed: 38264382
DOI: 10.7759/cureus.51045 -
Frontiers in Medicine 2023The occurrence of a co-infection involving four distinct respiratory pathogens could be underestimated. Here, we report the case of a 72-year-old woman who presented to...
The occurrence of a co-infection involving four distinct respiratory pathogens could be underestimated. Here, we report the case of a 72-year-old woman who presented to a community hospital with a cough productive of sputum as her main clinical manifestation. Antibody detection of common respiratory pathogens revealed potential co-infection with influenza A, influenza B, respiratory syncytial virus, and . We treated her with 75 mg oseltamivir phosphate administered orally twice daily for 5 days, 0.5 g azithromycin administered orally for 5 days, and 0.3 g acetylcysteine aerosol inhaled twice daily for 3 days. The patient showed a favorable outcome on the eighth day after early diagnosis and treatment. Since co-infection with these four pathogens is rare, we performed an extensive PubMed search of similar cases and carried out a systematic review to analyze the epidemiology, clinical manifestations, transmission route, susceptible population, and outcomes of these four different pathogens. Our report highlights the importance for general practitioners to be vigilant about the possibility of mixed infections when a patient presents with respiratory symptoms. Although these symptoms may be mild, early diagnosis and timely treatment could improve outcomes. Additionally, further research is warranted to explore the potential influence of SARS-CoV-2 infection on the co-occurrence of multiple respiratory pathogens.
PubMed: 38259842
DOI: 10.3389/fmed.2023.1325482 -
Current Pharmaceutical Biotechnology Jan 2024Important physiological changes are observed in patients with obesity, such as intestinal permeability, gastric emptying, cardiac output, and hepatic and renal function....
Important physiological changes are observed in patients with obesity, such as intestinal permeability, gastric emptying, cardiac output, and hepatic and renal function. These differences can determine variations in the pharmacokinetics of different drugs and can generate different concentrations at the site of action, which can lead to sub therapeutic or toxic concentrations. Understanding the physiological and immunological processes that lead to the clinical manifestations of COVID-19 is essential to correlate obesity as a risk factor for increasing the prevalence, severity, and lethality of the disease. Several drugs have been suggested to control COVID- 19 like Lopinavir, Ritonavir, Ribavirin, Sofosbuvir, Remdesivir, Oseltamivir, Oseltamivir phosphate, Oseltamivir carboxylate, Hydroxychloroquine, Chloroquine, Azithromycin, Teicoplanin, Tocilizumab, Anakinra, Methylprednisolone, Prednisolone, Ciclesonide and Ivermectin. Similarly, these differences between healthy people and obese people can be correlated to mechanical factors, such as insufficient doses of the vaccine for high body mass, impairing the absorption and distribution of the vaccine that will be lower than desired or can be linked to the inflammatory state in obese patients, which can influence the humoral immune response. Additionally, different aspects make the obese population more prone to persistent symptoms of the disease (long COVID), which makes understanding these mechanisms fundamental to addressing the implications of the disease. Thus, this review provides an overview of the relationship between COVID-19 and obesity, considering aspects related to pharmacokinetics, immunosuppression, immunization, and possible implications of long COVID in these individuals.
PubMed: 38258769
DOI: 10.2174/0113892010264503231108070917 -
Investigative Ophthalmology & Visual... Jan 2024Whether H1N1 infection-associated ocular manifestations result from direct viral infections or systemic complications remains unclear. This study aimed to...
PURPOSE
Whether H1N1 infection-associated ocular manifestations result from direct viral infections or systemic complications remains unclear. This study aimed to comprehensively elucidate the underlying causes and mechanism.
METHOD
TCID50 assays was performed at 24, 48, and 72 hours to verify the infection of H1N1 in human retinal microvascular endothelial cells (HRMECs). The changes in gene expression profiles of HRMECs at 24, 48, and 72 hours were characterized using RNA sequencing technology. Differentially expressed genes (DEGs) were validated using real-time quantitative polymerase chain reaction and Western blotting. CCK-8 assay and scratch assay were performed to evaluate whether there was a potential improvement of proliferation and migration in H1N1-infected cells after oseltamivir intervention.
RESULTS
H1N1 can infect and replicate within HRMECs, leading to cell rounding and detachment. After H1N1 infection of HRMECs, 2562 DEGs were identified, including 1748 upregulated ones and 814 downregulated ones. These DEGs primarily involved in processes such as inflammation and immune response, cytokine-cytokine receptor interaction, signal transduction regulation, and cell adhesion. The elevated expression levels of CXCL10, CXCL11, CCL5, TLR3, C3, IFNB1, IFNG, STAT1, HLA, and TNFSF10 after H1N1 infection were reduced by oseltamivir intervention, reaching levels comparable to those in the uninfected group. The impaired cell proliferation and migration after H1N1 infection was improved by oseltamivir intervention.
CONCLUSIONS
This study confirmed that H1N1 can infect HRMECs, leading to the upregulation of chemokines, which may cause inflammation and destruction of the blood-retina barrier. Moreover, early oseltamivir administration may reduce retinal inflammation and hemorrhage in patients infected with H1N1.
Topics: Humans; Endothelial Cells; Influenza A Virus, H1N1 Subtype; Influenza, Human; Oseltamivir; Retina; Inflammation
PubMed: 38252524
DOI: 10.1167/iovs.65.1.38 -
Drugs - Real World Outcomes Jun 2024Abnormal behavior after oseltamivir administration has been reported in the media; in 2007, the package insert for oseltamivir phosphate was revised to restrict its...
Trends in Anti-Influenza Drug Prescription and Adverse Drug Reaction Reporting After the Lifting of Oseltamivir Prescribing Restrictions in Pediatric Outpatients: An Ecological Study Using the MDV Analyzer And the Japanese Adverse Drug Event Report Database.
BACKGROUND
Abnormal behavior after oseltamivir administration has been reported in the media; in 2007, the package insert for oseltamivir phosphate was revised to restrict its administration to individuals aged over 10 years. However, in 2018, the age limitation specified in the package insert was removed. Here, we evaluated the trends in anti-influenza drug prescription and adverse drug reactions (ADRs) reported in pediatric outpatients after revising the oseltamivir package insert as an ecological study.
METHODS
Anti-influenza drug prescriptions for pediatric outpatients with influenza aged 0-19 years were downloaded from the acute Diagnosis Procedure Combination hospital databases using the MDV analyzer. ADR reports on anti-influenza drug prescription among patients aged 0-20 years in the Japanese Adverse Drug Event Report database were downloaded from the Pharmaceutical and Medical Devices Agency website. Data were collected during the 2016/2017 and 2019/2020 influenza seasons.
RESULTS
During the influenza epidemic season (January-March), the percentage of oseltamivir prescriptions for patients with influenza aged 10-19 years tripled after the revision of the oseltamivir package insert (9.3% during the 2016/2017 season and 29.2% during the 2019/2020 season); however, reports of abnormal behavior did not increase (two during the 2016/2017 season and none during the 2019/2020 season).
CONCLUSIONS
The number of oseltamivir-related ADR reports among minors over 10 years of age did not increase although the proportion of oseltamivir prescriptions increased after the revision of the oseltamivir package insert.
PubMed: 38236514
DOI: 10.1007/s40801-023-00414-x -
Revue Medicale Suisse Jan 2024The year 2023 saw the publication of several studies in various areas of infectious diseases. The administration of corticosteroids decreased mortality in severe... (Meta-Analysis)
Meta-Analysis
The year 2023 saw the publication of several studies in various areas of infectious diseases. The administration of corticosteroids decreased mortality in severe community-acquired pneumonia. Administration of doxycycline post-exposure prophylaxis reduced the risk of bacterial sexually transmitted infections at the risk of resistance selection. An herbal preparation decreased mortality in sepsis. A meta-analysis concludes that oseltamivir does not significantly reduce the risk of hospitalisation for influenza. Discontinuation of antibiotic prophylaxis during dental procedures in Sweden did not increase the incidence of viridans group Streptococcus endocarditis. Several studies have led to the introduction of RSV (Respiratory Syncytial Virus (RSV) vaccination. 2023 also saw the resurgence of invasive Group A Streptococcal infections, of which clinicians must be wary.
Topics: Humans; Communicable Diseases; Sepsis; Streptococcal Infections; Influenza, Human; Doxycycline
PubMed: 38231101
DOI: 10.53738/REVMED.2024.20.856-7.55 -
Archives of Virology Jan 2024Genetic reassortment of avian, swine, and human influenza A viruses (IAVs) poses potential pandemic risks. Surveillance is important for influenza pandemic preparedness,...
Genetic reassortment of avian, swine, and human influenza A viruses (IAVs) poses potential pandemic risks. Surveillance is important for influenza pandemic preparedness, but the susceptibility of zoonotic IAVs to the cap-dependent endonuclease inhibitor baloxavir acid (BXA) has not been thoroughly researched. Although an amino acid substitution at position 38 in the polymerase acidic protein (PA/I38) in seasonal IAVs reduces BXA susceptibility, PA polymorphisms at position 38 are rarely seen in zoonotic IAVs. Here, we examined the impact of PA/I38 substitutions on the BXA susceptibility of recombinant A(H5N1) viruses. PA mutants that harbored I38T, F, and M were 48.2-, 24.0-, and 15.5-fold less susceptible, respectively, to BXA than wild-type A(H5N1) but were susceptible to the neuraminidase inhibitor oseltamivir acid and the RNA polymerase inhibitor favipiravir. PA mutants exhibited significantly impaired replicative fitness in Madin-Darby canine kidney cells at 24 h postinfection. In addition, in order to investigate new genetic markers for BXA susceptibility, we screened geographically and temporally distinct IAVs isolated worldwide from birds and pigs. The results showed that BXA exhibited antiviral activity against avian and swine viruses with similar levels to seasonal isolates. All viruses tested in the study lacked the PA/I38 substitution and were susceptible to BXA. Isolates harboring amino acid polymorphisms at positions 20, 24, and 37, which have been implicated in the binding of BXA to the PA endonuclease domain, were also susceptible to BXA. These results suggest that monitoring of the PA/I38 substitution in animal-derived influenza viruses is important for preparedness against zoonotic influenza virus outbreaks.
Topics: Animals; Dogs; Humans; Swine; Influenza A virus; Oxazines; Pyridines; Influenza A Virus, H5N1 Subtype; Thiepins; Influenza, Human; Antiviral Agents; Orthomyxoviridae; Enzyme Inhibitors; Amino Acid Substitution; Endonucleases; Drug Resistance, Viral; Dibenzothiepins; Morpholines; Pyridones; Triazines
PubMed: 38216710
DOI: 10.1007/s00705-023-05958-5