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1.
Euro Surveill ; 26(27)2021 07.
Article in English | MEDLINE | ID: covidwho-1577032

ABSTRACT

BackgroundInfluenza virus presents a considerable challenge to public health by causing seasonal epidemics and occasional pandemics. Nanopore metagenomic sequencing has the potential to be deployed for near-patient testing, providing rapid infection diagnosis, rationalising antimicrobial therapy, and supporting infection-control interventions.AimTo evaluate the applicability of this sequencing approach as a routine laboratory test for influenza in clinical settings.MethodsWe conducted Oxford Nanopore Technologies (Oxford, United Kingdom (UK)) metagenomic sequencing for 180 respiratory samples from a UK hospital during the 2018/19 influenza season, and compared results to routine molecular diagnostic standards (Xpert Xpress Flu/RSV assay; BioFire FilmArray Respiratory Panel 2 assay). We investigated drug resistance, genetic diversity, and nosocomial transmission using influenza sequence data.ResultsCompared to standard testing, Nanopore metagenomic sequencing was 83% (75/90) sensitive and 93% (84/90) specific for detecting influenza A viruses. Of 59 samples with haemagglutinin subtype determined, 40 were H1 and 19 H3. We identified an influenza A(H3N2) genome encoding the oseltamivir resistance S331R mutation in neuraminidase, potentially associated with an emerging distinct intra-subtype reassortant. Whole genome phylogeny refuted suspicions of a transmission cluster in a ward, but identified two other clusters that likely reflected nosocomial transmission, associated with a predominant community-circulating strain. We also detected other potentially pathogenic viruses and bacteria from the metagenome.ConclusionNanopore metagenomic sequencing can detect the emergence of novel variants and drug resistance, providing timely insights into antimicrobial stewardship and vaccine design. Full genome generation can help investigate and manage nosocomial outbreaks.


Subject(s)
Cross Infection , Influenza, Human , Nanopores , Antiviral Agents/therapeutic use , Cross Infection/diagnosis , Cross Infection/drug therapy , Drug Resistance , Drug Resistance, Viral/genetics , Humans , Influenza A Virus, H3N2 Subtype/genetics , Influenza, Human/diagnosis , Influenza, Human/drug therapy , Influenza, Human/epidemiology , Metagenome , Neuraminidase/genetics , Seasons , United Kingdom
2.
Int J Immunopathol Pharmacol ; 35: 20587384211063976, 2021.
Article in English | MEDLINE | ID: covidwho-1582484

ABSTRACT

The underlying cause of many complications associated with severe COVID-19 is attributed to the inflammatory cytokine storm that leads to acute respiratory distress syndrome (ARDS), which appears to be the leading cause of death in COVID-19. Systemic corticosteroids have anti-inflammatory activity through repression of pro-inflammatory genes and inhibition of inflammatory cytokines, which makes them a potential medical intervention to diminish the upregulated inflammatory response. Early in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the role of corticosteroids was unclear. Corticosteroid use in other indications such as ARDS and septic shock has proven benefit while its use in other respiratory viral pneumonias is associated with reduced viral clearance and increased secondary infections. This review article evaluates the benefits and harms of systemic corticosteroids in patients with COVID-19 to assist clinicians in improving patient outcomes, including patient safety. Dexamethasone up to 10 days is the preferred regimen to reduce mortality risk in COVID-19 patients requiring oxygen support, mechanical ventilation, or extracorporeal membrane oxygenation. If dexamethasone is unavailable, other corticosteroids can be substituted at equivalent doses. Higher doses of corticosteroids may be beneficial in patients who develop ARDS. Corticosteroids should be avoided early in the disease course when patients do not require oxygen support because of potential harms.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/drug therapy , Adrenal Cortex Hormones/adverse effects , Dexamethasone/adverse effects , Dexamethasone/therapeutic use , Humans , Hydrocortisone/adverse effects , Hydrocortisone/therapeutic use , Influenza, Human/drug therapy , Methylprednisolone/adverse effects , Methylprednisolone/therapeutic use , Prednisolone/adverse effects , Prednisolone/therapeutic use
3.
Rev Med Virol ; 31(6): e2234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1574124

ABSTRACT

The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Genetic Predisposition to Disease , Influenza, Human/immunology , Respiratory Syncytial Virus Infections/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Biological Variation, Individual , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Gene Expression , Humans , Immunity, Innate , Immunologic Factors/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/genetics , Influenza, Human/virology , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/immunology , Orthomyxoviridae/drug effects , Orthomyxoviridae/immunology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/immunology , SARS Virus/drug effects , SARS Virus/immunology , SARS-CoV-2/classification , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology
4.
Cell Rep ; 37(12): 110126, 2021 12 21.
Article in English | MEDLINE | ID: covidwho-1556413

ABSTRACT

Previous studies have shown that the high mortality caused by viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus primarily results from complications of a cytokine storm. Therefore, it is critical to identify the key factors participating in the cytokine storm. Here we demonstrate that interferon-induced protein 35 (IFP35) plays an important role in the cytokine storm induced by SARS-CoV-2 and influenza virus infection. We find that the levels of serum IFP35 in individuals with SARS-CoV-2 correlates with severity of the syndrome. Using mouse model and cell assays, we show that IFP35 is released by lung epithelial cells and macrophages after SARS-CoV-2 or influenza virus infection. In addition, we show that administration of neutralizing antibodies against IFP35 considerably reduces lung injury and, thus, the mortality rate of mice exposed to viral infection. Our findings suggest that IFP35 serves as a biomarker and as a therapeutic target in virus-induced syndromes.


Subject(s)
COVID-19/blood , COVID-19/drug therapy , Influenza, Human/blood , Influenza, Human/drug therapy , Intracellular Signaling Peptides and Proteins/blood , Animals , Antibodies, Neutralizing/administration & dosage , Biomarkers/blood , COVID-19/pathology , COVID-19/physiopathology , Disease Models, Animal , Humans , Inflammation/metabolism , Influenza, Human/pathology , Lung/metabolism , Lung/pathology , Macrophages/metabolism , Macrophages/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Patient Acuity , SARS-CoV-2/physiology
5.
Sci Rep ; 11(1): 13587, 2021 06 30.
Article in English | MEDLINE | ID: covidwho-1500741

ABSTRACT

Influenza is an important cause of severe illness and death among patients with underlying medical conditions and in the elderly. The aim of this study was to investigate factors associated with ICU admission and death in patients hospitalized with severe laboratory-confirmed influenza during the 2017-2018 season in Catalonia. An observational epidemiological case-to-case study was carried out. Reported cases of severe laboratory-confirmed influenza requiring hospitalization in 2017-2018 influenza season were included. Mixed-effects regression analysis was used to estimate the factors associated with ICU admission and death. A total of 1306 cases of hospitalized severe influenza cases were included, of whom 175 (13.4%) died and 217 (16.6%) were ICU admitted. Age 65-74 years and ≥ 75 years and having ≥ 2 comorbidities were positively associated with death (aOR 3.19; 95%CI 1.19-8.50, aOR 6.95, 95%CI 2.76-1.80 and aOR 1.99; 95%CI 1.12-3.52, respectively). Neuraminidase inhibitor treatment and pneumonia were negatively associated with death. The 65-74 years and ≥ 75 years age groups were negatively associated with ICU admission (aOR 0.41; 95%CI 0.23-0.74 and aOR 0.30; 95%CI 0.17-0.53, respectively). A factor positively associated with ICU admission was neuraminidase inhibitor treatment. Our results support the need to investigate the worst outcomes of hospitalized severe cases, distinguishing between death and ICU admission.


Subject(s)
Antiviral Agents/administration & dosage , Influenza, Human , Intensive Care Units , Aged , Aged, 80 and over , Female , Humans , Influenza, Human/drug therapy , Influenza, Human/mortality , Male , Middle Aged , Neuraminidase/antagonists & inhibitors , Pneumonia, Viral/drug therapy , Pneumonia, Viral/mortality , Retrospective Studies , Severity of Illness Index , Spain/epidemiology
6.
J Immunother Cancer ; 9(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1495513

ABSTRACT

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B cell malignancies have profound and prolonged immunodeficiencies and are at risk for serious infections, including respiratory virus infections. Vaccination may be important for infection prevention, but there are limited data on vaccine immunogenicity in this population. We conducted a prospective observational study of the humoral immunogenicity of commercially available 2019-2020 inactivated influenza vaccines in adults immediately prior to or while in durable remission after CD19-, CD20-, or B cell maturation antigen-targeted CAR-T-cell therapy, as well as controls. We tested for antibodies to all four vaccine strains using neutralization and hemagglutination inhibition (HAI) assays. Antibody responses were defined as at least fourfold titer increases from baseline. Seroprotection was defined as a HAI titer ≥40. Enrolled CAR-T-cell recipients were vaccinated 14-29 days prior to (n=5) or 13-57 months following therapy (n=13), and the majority had hypogammaglobulinemia and cellular immunodeficiencies prevaccination. Eight non-immunocompromised adults served as controls. Antibody responses to ≥1 vaccine strain occurred in 2 (40%) individuals before CAR-T-cell therapy and in 4 (31%) individuals vaccinated after CAR-T-cell therapy. An additional 1 (20%) and 6 (46%) individuals had at least twofold increases, respectively. One individual vaccinated prior to CAR-T-cell therapy maintained a response for >3 months following therapy. Across all tested vaccine strains, seroprotection was less frequent in CAR-T-cell recipients than in controls. There was evidence of immunogenicity even among individuals with low immunoglobulin, CD19+ B cell, and CD4+ T-cell counts. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B cell aplasia. However, relatively impaired humoral vaccine immunogenicity indicates the need for additional infection-prevention strategies. Larger studies are needed to refine our understanding of potential correlates of vaccine immunogenicity, and durability of immune responses, in CAR-T-cell therapy recipients.


Subject(s)
Cell- and Tissue-Based Therapy/methods , Hemagglutination Inhibition Tests/methods , Immunogenicity, Vaccine/immunology , Influenza, Human/drug therapy , Influenza, Human/immunology , Adolescent , Adult , Aged , Humans , Middle Aged , Prospective Studies , Young Adult
7.
Curr Med Chem ; 28(6): 1068-1090, 2021.
Article in English | MEDLINE | ID: covidwho-1445716

ABSTRACT

BACKGROUND: Influenza is a seasonal disease that affects millions of people every year and has a significant economic impact. Vaccines are the best strategy to fight this viral pathology, but they are not always available or administrable, prompting the search for antiviral drugs. RNA-dependent RNA polymerase (RdRp) recently emerged as a promising target because of its key role in viral replication and its high conservation among viral strains. DISCUSSION: This review presents an overview of the most interesting RdRp inhibitors that have been discussed in the literature since 2000. Compounds already approved or in clinical trials and a selection of inhibitors endowed with different scaffolds are described, along with the main features responsible for their activity. RESULTS: RdRp inhibitors are emerging as a new strategy to fight viral infections and the importance of this class of drugs has been confirmed by the FDA approval of baloxavir marboxil in 2018. Despite the complexity of the RdRp machine makes the identification of new compounds a challenging research topic, it is likely that in the coming years, this field will attract the interest of a number of academic and industrial scientists because of the potential strength of this therapeutic approach.


Subject(s)
Influenza, Human , Viral Proteins , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Influenza, Human/drug therapy , RNA-Dependent RNA Polymerase , Virus Replication
8.
Acta Med Acad ; 49(2): 130-143, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-1414828

ABSTRACT

In this review, we discuss the latest developments in research pertaining to virus-induced asthma exacerbations and consider recent advances in treatment options. Asthma is a chronic disease of the airways that continues to impose a substantial clinical burden worldwide. Asthma exacerbations, characterised by an acute deterioration in respiratory symptoms and airflow obstruction, are associated with significant morbidity and mortality. These episodes are most commonly triggered by respiratory virus infections. The mechanisms underlying the pathogenesis of virus-induced exacerbations have been the focus of extensive biomedical research. Developing a robust understanding of the interplay between respiratory viruses and the host immune response will be critical for developing more efficacious, targeted therapies for exacerbations. CONCLUSION: There has been significant recent progress in our understanding of the mechanisms underlying virus-induced airway inflammation in asthma and these advances will underpin the development of future clinical therapies.


Subject(s)
Anti-Asthmatic Agents/therapeutic use , Antiviral Agents/therapeutic use , Asthma/drug therapy , Respiratory Tract Infections/drug therapy , Virus Diseases/drug therapy , Adenovirus Infections, Human/drug therapy , Adenovirus Infections, Human/immunology , Adenovirus Infections, Human/physiopathology , Administration, Inhalation , Asthma/immunology , Asthma/physiopathology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Disease Progression , Humans , Influenza, Human/drug therapy , Influenza, Human/immunology , Influenza, Human/physiopathology , Interferon-beta/therapeutic use , Macrolides/therapeutic use , Omalizumab/therapeutic use , Paramyxoviridae Infections/drug therapy , Paramyxoviridae Infections/immunology , Paramyxoviridae Infections/physiopathology , Picornaviridae Infections/drug therapy , Picornaviridae Infections/immunology , Picornaviridae Infections/physiopathology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/physiopathology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/physiopathology , Virus Diseases/immunology , Virus Diseases/physiopathology
10.
Microbiol Spectr ; 9(2): e0025721, 2021 10 31.
Article in English | MEDLINE | ID: covidwho-1410327

ABSTRACT

Human-to-human transmission of viruses, such as influenza viruses and coronaviruses, can promote virus evolution and the emergence of new strains with increased potential for creating pandemics. Clinical studies analyzing how a particular type of virus progressively evolves new traits, such as resistance to antiviral therapies, as a result of passing between different human hosts are difficult to carry out because of the complexity, scale, and cost of the challenge. Here, we demonstrate that spontaneous evolution of influenza A virus through both mutation and gene reassortment can be reconstituted in vitro by sequentially passaging infected mucus droplets between multiple human lung airway-on-a-chip microfluidic culture devices (airway chips). Modeling human-to-human transmission of influenza virus infection on chips in the continued presence of the antiviral drugs amantadine or oseltamivir led to the spontaneous emergence of clinically prevalent resistance mutations, and strains that were resistant to both drugs were identified when they were administered in combination. In contrast, we found that nafamostat, an inhibitor targeting host serine proteases, did not induce viral resistance. This human preclinical model may be useful for studying viral evolution in vitro and identifying potential influenza virus variants before they appear in human populations, thereby enabling preemptive design of new and more effective vaccines and therapeutics. IMPORTANCE The rapid evolution of viruses, such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is challenging the use and development of antivirals and vaccines. Studies of within-host viral evolution can contribute to our understanding of the evolutionary and epidemiological factors that shape viral global evolution as well as development of better antivirals and vaccines. However, little is known about how viral evolution of resistance to antivirals occurs clinically due to the lack of preclinical models that can faithfully model influenza infection in humans. Our study shows that influenza viral evolution through mutation or gene reassortment can be recapitulated in a human lung airway-on-a-chip (airway chip) microfluidic culture device that can faithfully recapitulate the influenza infection in vitro. This approach is useful for studying within-host viral evolution, evaluating viral drug resistance, and identifying potential influenza virus variants before they appear in human populations, thereby enabling the preemptive design of new and more effective vaccines and therapeutics.


Subject(s)
Drug Resistance, Viral/genetics , Evolution, Molecular , Influenza A virus/drug effects , Influenza A virus/genetics , Lab-On-A-Chip Devices , Amantadine/pharmacology , Antiviral Agents/pharmacology , Benzamidines/pharmacology , Guanidines/pharmacology , Humans , Influenza, Human/drug therapy , Influenza, Human/transmission , Lung/virology , Microfluidics , Oseltamivir/pharmacology , SARS-CoV-2/genetics
11.
Pediatrics ; 148(4)2021 10.
Article in English | MEDLINE | ID: covidwho-1398985

ABSTRACT

This technical report accompanies the recommendations of the American Academy of Pediatrics for the routine use of the influenza vaccine and antiviral medications in the prevention and treatment of influenza in children during the 2021-2022 season. Influenza vaccination is an important intervention to protect vulnerable populations and reduce the burden of respiratory illnesses during circulation of severe acute respiratory syndrome coronavirus 2, which is expected to continue during this influenza season. In this technical report, we summarize recent influenza seasons, morbidity and mortality in children, vaccine effectiveness, vaccination coverage, and detailed guidance on storage, administration, and implementation. We also provide background on inactivated and live attenuated influenza vaccine recommendations, vaccination during pregnancy and breastfeeding, diagnostic testing, and antiviral medications for treatment and chemoprophylaxis.


Subject(s)
Influenza Vaccines , Influenza, Human/prevention & control , Antiviral Agents/therapeutic use , Breast Feeding , Child , Contraindications, Drug , Drug Resistance, Viral , Drug Storage , Female , Hospitalization , Humans , Influenza Vaccines/administration & dosage , Influenza Vaccines/adverse effects , Influenza, Human/drug therapy , Influenza, Human/epidemiology , Influenza, Human/mortality , Mass Vaccination , Risk Factors , United States/epidemiology , Vaccines, Attenuated/administration & dosage , Vaccines, Attenuated/adverse effects , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/adverse effects
12.
Viruses ; 13(7)2021 07 04.
Article in English | MEDLINE | ID: covidwho-1389550

ABSTRACT

Amino acids have been implicated with virus infection and replication. Here, we demonstrate the effects of two basic amino acids, arginine and lysine, and their ester derivatives on infection of two enveloped viruses, SARS-CoV-2, and influenza A virus. We found that lysine and its ester derivative can efficiently block infection of both viruses in vitro. Furthermore, the arginine ester derivative caused a significant boost in virus infection. Studies on their mechanism of action revealed that the compounds potentially disturb virus uncoating rather than virus attachment and endosomal acidification. Our findings suggest that lysine supplementation and the reduction of arginine-rich food intake can be considered as prophylactic and therapeutic regimens against these viruses while also providing a paradigm for the development of broad-spectrum antivirals.


Subject(s)
Amino Acids, Basic/pharmacology , COVID-19/drug therapy , Influenza A virus/drug effects , Influenza, Human/drug therapy , SARS-CoV-2/drug effects , A549 Cells , Amino Acids, Basic/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/complications , COVID-19/prevention & control , COVID-19/virology , HEK293 Cells , Humans , Influenza, Human/complications , Influenza, Human/prevention & control , Influenza, Human/virology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment/drug effects , Virus Replication/drug effects
13.
Sci Rep ; 11(1): 14295, 2021 07 12.
Article in English | MEDLINE | ID: covidwho-1387482

ABSTRACT

Methylene blue is an FDA (Food and Drug Administration) and EMA (European Medicines Agency) approved drug with an excellent safety profile. It displays broad-spectrum virucidal activity in the presence of UV light and has been shown to be effective in inactivating various viruses in blood products prior to transfusions. In addition, its use has been validated for methemoglobinemia and malaria treatment. In this study, we first evaluated the virucidal activity of methylene blue against influenza virus H1N1 upon different incubation times and in the presence or absence of light activation, and then against SARS-CoV-2. We further assessed the therapeutic activity of methylene blue by administering it to cells previously infected with SARS-CoV-2. Finally, we examined the effect of co-administration of the drug together with immune serum. Our findings reveal that methylene blue displays virucidal preventive or therapeutic activity against influenza virus H1N1 and SARS-CoV-2 at low micromolar concentrations and in the absence of UV-activation. We also confirm that MB antiviral activity is based on several mechanisms of action as the extent of genomic RNA degradation is higher in presence of light and after long exposure. Our work supports the interest of testing methylene blue in clinical studies to confirm a preventive and/or therapeutic efficacy against both influenza virus H1N1 and SARS-CoV-2 infections.


Subject(s)
COVID-19/drug therapy , Influenza, Human/drug therapy , Methylene Blue/pharmacology , Virus Inactivation/drug effects , Animals , COVID-19/genetics , COVID-19/virology , Chlorocebus aethiops , Humans , Influenza, Human/genetics , Influenza, Human/virology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Ultraviolet Rays/adverse effects , Vero Cells , Virus Inactivation/radiation effects , Virus Replication/drug effects , Virus Replication/radiation effects
14.
ACS Chem Biol ; 15(9): 2331-2337, 2020 09 18.
Article in English | MEDLINE | ID: covidwho-1387140

ABSTRACT

We report on using the synthetic aminoadamantane-CH2-aryl derivatives 1-6 as sensitive probes for blocking M2 S31N and influenza A virus (IAV) M2 wild-type (WT) channels as well as virus replication in cell culture. The binding kinetics measured using electrophysiology (EP) for M2 S31N channel are very dependent on the length between the adamantane moiety and the first ring of the aryl headgroup realized in 2 and 3 and the girth and length of the adamantane adduct realized in 4 and 5. Study of 1-6 shows that, according to molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations, all bind in the M2 S31N channel with the adamantyl group positioned between V27 and G34 and the aryl group projecting out of the channel with the phenyl (or isoxazole in 6) embedded in the V27 cluster. In this outward binding configuration, an elongation of the ligand by only one methylene in rimantadine 2 or using diamantane or triamantane instead of adamantane in 4 and 5, respectively, causes incomplete entry and facilitates exit, abolishing effective block compared to the amantadine derivatives 1 and 6. In the active M2 S31N blockers 1 and 6, the phenyl and isoxazolyl head groups achieve a deeper binding position and high kon/low koff and high kon/high koff rate constants, compared to inactive 2-5, which have much lower kon and higher koff. Compounds 1-5 block the M2 WT channel by binding in the longer area from V27-H37, in the inward orientation, with high kon and low koff rate constants. Infection of cell cultures by influenza virus containing M2 WT or M2 S31N is inhibited by 1-5 or 1-4 and 6, respectively. While 1 and 6 block infection through the M2 block mechanism in the S31N variant, 2-4 may block M2 S31N virus replication in cell culture through the lysosomotropic effect, just as chloroquine is thought to inhibit SARS-CoV-2 infection.


Subject(s)
Adamantane/pharmacology , Influenza A virus/drug effects , Influenza, Human/prevention & control , Ion Channels/antagonists & inhibitors , Molecular Probes/chemistry , Viral Matrix Proteins/antagonists & inhibitors , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/metabolism , Betacoronavirus/drug effects , Binding Sites , COVID-19 , Cells, Cultured , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Genetic Variation , Humans , Influenza A virus/chemistry , Influenza A virus/genetics , Influenza, Human/drug therapy , Kinetics , Molecular Probes/metabolism , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Protein Binding , SARS-CoV-2 , Structure-Activity Relationship , Virus Replication/drug effects
15.
JAMA Netw Open ; 4(8): e2119151, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1355856

ABSTRACT

Importance: Antiviral treatment of influenza is recommended for patients with influenza-like illness during periods of community cocirculation of influenza viruses and SARS-CoV-2; however, questions remain about which treatment is associated with the best outcomes and fewest adverse events. Objective: To compare the efficacy and safety of neuraminidase inhibitors and the endonuclease inhibitor for the treatment of seasonal influenza among healthy adults and children. Data Sources: Medline, Embase, and the Cochrane Register of Clinical Trials were searched from inception to January 2020 (the last search was updated in October 2020). Study Selection: Included studies were randomized clinical trials conducted among patients of all ages with influenza treated with neuraminidase inhibitors (ie, oseltamivir, peramivir, zanamivir, or laninamivir) or an endonuclease inhibitor (ie, baloxavir) compared with other active agents or placebo. Data Extraction and Synthesis: Two investigators identified studies and independently abstracted data. Frequentist network meta-analyses were performed; relative ranking of agents was conducted using P-score probabilities. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations criteria. Data were analyzed in October 2020. Main Outcomes and Measures: The time to alleviation of influenza symptoms (TTAS), complications of influenza, and adverse events (total adverse events, nausea, and vomiting). Results: A total of 26 trials were identified that investigated antiviral drugs at high or low doses; these trials included 11 897 participants, among whom 6294 (52.9%) were men and the mean (SD) age was 32.5 (16.9) years. Of all treatments comparing with placebo in efficacy outcomes, high-quality evidence indicated that zanamivir was associated with the shortest TTAS (hazard ratio, 0.67; 95% CI, 0.58-0.77), while baloxavir was associated with the lowest risk of influenza-related complications (risk ratio [RR], 0.51; 95% CI, 0.32-0.80) based on moderate-quality evidence. In safety outcomes, baloxavir was associated with the lowest risk of total adverse events (RR, 0.84; 95% CI, 0.74-0.96) compared with placebo based on moderate-quality evidence. There was no strong evidence of associations with risk of nausea or vomiting among all comparisons, except for 75 mg oseltamivir, which was associated with greater occurrence of nausea (RR, 1.82; 95% CI, 1.38-2.41) and vomiting (RR, 1.88; 95% CI, 1.47-2.41). Conclusions and Relevance: In this systematic review and network meta-analysis, all 4 antiviral agents assessed were associated with shortening TTAS; zanamivir was associated with the shortest TTAS, and baloxavir was associated with reduced rate of influenza-related complications.


Subject(s)
Antiviral Agents/therapeutic use , Dibenzothiepins/therapeutic use , Enzyme Inhibitors/therapeutic use , Influenza, Human/drug therapy , Morpholines/therapeutic use , Pyridones/therapeutic use , Triazines/therapeutic use , Zanamivir/therapeutic use , Adolescent , Adult , Child , Endonucleases/antagonists & inhibitors , Female , Humans , Influenza A virus/drug effects , Influenza, Human/virology , Male , Middle Aged , Network Meta-Analysis , Neuraminidase/antagonists & inhibitors , Randomized Controlled Trials as Topic , Seasons , Young Adult
16.
Emerg Infect Dis ; 27(7): 1953-1957, 2021 07.
Article in English | MEDLINE | ID: covidwho-1348448

ABSTRACT

Four cases of oseltamivir-resistant influenza A(H1N1)pdm09 virus infection were detected among inhabitants of a border detention center in Texas, USA. Hemagglutinin of these viruses belongs to 6B.1A5A-156K subclade, which may enable viral escape from preexisting immunity. Our finding highlights the necessity to monitor both drug resistance and antigenic drift of circulating viruses.


Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza, Human , Antiviral Agents/therapeutic use , Drug Resistance, Viral , Hemagglutinins , Humans , Influenza, Human/drug therapy , Neuraminidase , Oseltamivir/therapeutic use , Texas , Viral Proteins
17.
Antiviral Res ; 194: 105158, 2021 10.
Article in English | MEDLINE | ID: covidwho-1340541

ABSTRACT

It is more than 20 years since the neuraminidase inhibitors, oseltamivir and zanamivir were approved for the treatment and prevention of influenza. Guidelines for global surveillance and methods for evaluating resistance were established initially by the Neuraminidase Inhibitor Susceptibility Network (NISN), which merged 10 years ago with the International Society for influenza and other Respiratory Virus Diseases (isirv) to become the isirv-Antiviral Group (isirv-AVG). With the ongoing development of new influenza polymerase inhibitors and recent approval of baloxavir marboxil, the isirv-AVG held a closed meeting in August 2019 to discuss the impact of resistance to these inhibitors. Following this meeting and review of the current literature, this article is intended to summarize current knowledge regarding the clinical impact of resistance to polymerase inhibitors and approaches for surveillance and methods for laboratory evaluation of resistance, both in vitro and in animal models. We highlight limitations and gaps in current knowledge and suggest some strategies for addressing these gaps, including the need for additional clinical studies of influenza antiviral drug combinations. Lessons learned from influenza resistance monitoring may also be helpful for establishing future drug susceptibility surveillance and testing for SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , Influenza, Human/drug therapy , Animals , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Dibenzothiepins/pharmacology , Drug Resistance, Viral , Enzyme Inhibitors/pharmacology , Humans , Influenza, Human/virology , Knowledge , Morpholines/pharmacology , Neuraminidase/therapeutic use , Oseltamivir/pharmacology , Pyridones/pharmacology , SARS-CoV-2/drug effects , Triazines/pharmacology , Virus Replication/drug effects , Zanamivir/pharmacology
18.
Sci Rep ; 11(1): 14961, 2021 07 22.
Article in English | MEDLINE | ID: covidwho-1322501

ABSTRACT

Influenza and other respiratory viruses present a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as from COVID-19. A barrier to the development of effective therapeutics is the absence of a robust and predictive preclinical model, with most studies relying on a combination of in vitro screening with immortalized cell lines and low-throughput animal models. Here, we integrate human primary airway epithelial cells into a custom-engineered 96-device platform (PREDICT96-ALI) in which tissues are cultured in an array of microchannel-based culture chambers at an air-liquid interface, in a configuration compatible with high resolution in-situ imaging and real-time sensing. We apply this platform to influenza A virus and coronavirus infections, evaluating viral infection kinetics and antiviral agent dosing across multiple strains and donor populations of human primary cells. Human coronaviruses HCoV-NL63 and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for spike protein priming, and we confirm their expression, demonstrate infection across a range of multiplicities of infection, and evaluate the efficacy of camostat mesylate, a known inhibitor of HCoV-NL63 infection. This new capability can be used to address a major gap in the rapid assessment of therapeutic efficacy of small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/virology , Influenza, Human/virology , Microbial Sensitivity Tests/instrumentation , Microfluidic Analytical Techniques/instrumentation , Respiratory Mucosa/cytology , Bronchi/cytology , Bronchi/virology , COVID-19/drug therapy , COVID-19/virology , Cell Culture Techniques/instrumentation , Cell Line , Coronavirus/drug effects , Coronavirus Infections/drug therapy , Equipment Design , High-Throughput Screening Assays/instrumentation , Humans , Influenza A virus/drug effects , Influenza, Human/drug therapy , Respiratory Mucosa/virology , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/virology , SARS-CoV-2/drug effects
19.
Trials ; 21(1): 956, 2020 Nov 23.
Article in English | MEDLINE | ID: covidwho-1277966

ABSTRACT

INTRODUCTION: Influenza is an important public health problem, but data on the impact of influenza among homeless shelter residents are limited. The primary aim of this study is to evaluate whether on-site testing and antiviral treatment of influenza in residents of homeless shelters reduces influenza spread in these settings. METHODS AND ANALYSIS: This study is a stepped-wedge cluster-randomized trial of on-site testing and antiviral treatment for influenza in nine homeless shelter sites within the Seattle metropolitan area. Participants with acute respiratory illness (ARI), defined as two or more respiratory symptoms or new or worsening cough with onset in the prior 7 days, are eligible to enroll. Approximately 3200 individuals are estimated to participate from October to May across two influenza seasons. All sites will start enrollment in the control arm at the beginning of each season, with routine surveillance for ARI. Sites will be randomized at different timepoints to enter the intervention arm, with implementation of a test-and-treat strategy for individuals with two or fewer days of symptoms. Eligible individuals will be tested on-site with a point-of-care influenza test. If the influenza test is positive and symptom onset is within 48 h, participants will be administered antiviral treatment with baloxavir or oseltamivir depending upon age and comorbidities. Participants will complete a questionnaire on demographics and symptom duration and severity. The primary endpoint is the incidence of influenza in the intervention period compared to the control period, after adjusting for time trends. TRIAL REGISTRATION: ClinicalTrials.gov NCT04141917 . Registered 28 October 2019. Trial sponsor: University of Washington.


Subject(s)
COVID-19 , Homeless Persons , Influenza, Human , Antiviral Agents/adverse effects , Humans , Influenza, Human/diagnosis , Influenza, Human/drug therapy , Influenza, Human/epidemiology , Molecular Diagnostic Techniques , Point-of-Care Systems , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
20.
Nature ; 594(7862): 259-264, 2021 06.
Article in English | MEDLINE | ID: covidwho-1275936

ABSTRACT

The acute clinical manifestations of COVID-19 have been well characterized1,2, but the post-acute sequelae of this disease have not been comprehensively described. Here we use the national healthcare databases of the US Department of Veterans Affairs to systematically and comprehensively identify 6-month incident sequelae-including diagnoses, medication use and laboratory abnormalities-in patients with COVID-19 who survived for at least 30 days after diagnosis. We show that beyond the first 30 days of illness, people with COVID-19 exhibit a higher risk of death and use of health resources. Our high-dimensional approach identifies incident sequelae in the respiratory system, as well as several other sequelae that include nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain and anaemia. We show increased incident use of several therapeutic agents-including pain medications (opioids and non-opioids) as well as antidepressant, anxiolytic, antihypertensive and oral hypoglycaemic agents-as well as evidence of laboratory abnormalities in several organ systems. Our analysis of an array of prespecified outcomes reveals a risk gradient that increases according to the severity of the acute COVID-19 infection (that is, whether patients were not hospitalized, hospitalized or admitted to intensive care). Our findings show that a substantial burden of health loss that spans pulmonary and several extrapulmonary organ systems is experienced by patients who survive after the acute phase of COVID-19. These results will help to inform health system planning and the development of multidisciplinary care strategies to reduce chronic health loss among individuals with COVID-19.


Subject(s)
COVID-19/complications , SARS-CoV-2/pathogenicity , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/psychology , Cohort Studies , Databases, Factual , Datasets as Topic , Electronic Health Records , Female , Hospitalization/statistics & numerical data , Humans , Influenza, Human/diagnosis , Influenza, Human/drug therapy , Influenza, Human/physiopathology , Male , Outpatients/psychology , Outpatients/statistics & numerical data , Risk , Time Factors , United States , United States Department of Veterans Affairs
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