scholarly journals Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS)

2019 ◽  
Vol 71 (5) ◽  
pp. 1186-1194 ◽  
Author(s):  
Rueshandra Roosenhoff ◽  
Vaughan Reed ◽  
Andy Kenwright ◽  
Martin Schutten ◽  
Charles A Boucher ◽  
...  
Keyword(s):  
Viral Load ◽  
Influenza A ◽  
Antiviral Treatment ◽  
Vaccination Status ◽  
Viral Clearance ◽  
Viral Rna ◽  
Baseline Viral Load ◽  
Influenza B ◽  
Resistance Mutations ◽  
Viral Burden

Abstract Background We studied the effect of age, baseline viral load, vaccination status, antiviral therapy, and emergence of drug resistance on viral shedding in children infected with influenza A or B virus. Methods Samples from children (aged ≤13 years) enrolled during the 7 years of the prospective Influenza Resistance Information Study were analyzed using polymerase chain reaction to determine the influenza virus (sub-)type, viral load, and resistance mutations. Disease severity was assessed; clinical symptoms were recorded. The association of age with viral load and viral clearance was examined by determining the area under the curve for viral RNA shedding using logistic regression and Kaplan-Meier analyses. Results A total of 2131 children infected with influenza (683, A/H1N1pdm09; 825, A/H3N2; 623, influenza B) were investigated. Age did not affect the mean baseline viral load. Children aged 1−5 years had prolonged viral RNA shedding (±1–2 days) compared with older children and up to 1.2-fold higher total viral burden. Besides, in older age (odds ratio [OR], 1.08; confidence interval [CI], 1.05–1.12), prior vaccination status (OR, 1.72; CI, 1.22–2.43) and antiviral treatment (OR, 1.74; CI, 1.43–2.12) increased the rate of viral clearance. Resistance mutations were detected in 49 children infected with influenza A virus (34, A/H1N1pdm09; 15, A/H3N2) treated with oseltamivir, most of whom were aged <5 years (n = 39). Conclusions Children aged 1−5 years had a higher total viral burden with prolonged virus shedding and had an increased risk of acquiring resistance mutations following antiviral treatment. Clinical Trials Registration NCT00884117.

scholarly journals Multiple Influenza A (H3N2) Mutations Conferring Resistance to Neuraminidase Inhibitors in a Bone Marrow Transplant Recipient

2014 ◽  
Vol 58 (12) ◽  
pp. 7188-7197 ◽  
Author(s):  
Alireza Eshaghi ◽  
Sarah Shalhoub ◽  
Paul Rosenfeld ◽  
Aimin Li ◽  
Rachel R. Higgins ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Therapy ◽  
Influenza A ◽  
Antiviral Treatment ◽  
Marrow Transplant ◽  
Viral Fitness ◽  
H3n2 Virus ◽  
Resistance Mutations ◽  
Depth Analysis ◽  
Resistant Strains

ABSTRACTImmunocompromised patients are predisposed to infections caused by influenza virus. Influenza virus may produce considerable morbidity, including protracted illness and prolonged viral shedding in these patients, thus prompting higher doses and prolonged courses of antiviral therapy. This approach may promote the emergence of resistant strains. Characterization of neuraminidase (NA) inhibitor (NAI)-resistant strains of influenza A virus is essential for documenting causes of resistance. In this study, using quantitative real-time PCR along with conventional Sanger sequencing, we identified an NAI-resistant strain of influenza A (H3N2) virus in an immunocompromised patient. In-depth analysis by deep gene sequencing revealed that various known markers of antiviral resistance, including transient R292K and Q136K substitutions and a sustained E119K (N2 numbering) substitution in the NA protein emerged during prolonged antiviral therapy. In addition, a combination of a 4-amino-acid deletion at residues 245 to 248 (Δ245-248) accompanied by the E119V substitution occurred, causing resistance to or reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir). Resistant variants within a pool of viral quasispecies arose during combined antiviral treatment. More research is needed to understand the interplay of drug resistance mutations, viral fitness, and transmission.

scholarly journals Non-Uniform and Non-Random Binding of Nucleoprotein to Influenza A and B Viral RNA

Viruses ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 522 ◽  
Author(s):  
Valerie Le Sage ◽  
Adalena Nanni ◽  
Amar Bhagwat ◽  
Dan Snyder ◽  
Vaughn Cooper ◽  
...  
Keyword(s):  
Influenza A ◽  
Gene Segment ◽  
Influenza Viruses ◽  
Viral Rna ◽  
Influenza B Virus ◽  
Viral Gene ◽  
Influenza B ◽  
Influenza A Viruses ◽  
Binding Profile ◽  
Random Manner

The genomes of influenza A and B viruses have eight, single-stranded RNA segments that exist in the form of a viral ribonucleoprotein complex in association with nucleoprotein (NP) and an RNA-dependent RNA polymerase complex. We previously used high-throughput RNA sequencing coupled with crosslinking immunoprecipitation (HITS-CLIP) to examine where NP binds to the viral RNA (vRNA) and demonstrated for two H1N1 strains that NP binds vRNA in a non-uniform, non-random manner. In this study, we expand on those initial observations and describe the NP-vRNA binding profile for a seasonal H3N2 and influenza B virus. We show that, similar to H1N1 strains, NP binds vRNA in a non-uniform and non-random manner. Each viral gene segment has a unique NP binding profile with areas that are enriched for NP association as well as free of NP-binding. Interestingly, NP-vRNA binding profiles have some conservation between influenza A viruses, H1N1 and H3N2, but no correlation was observed between influenza A and B viruses. Our study demonstrates the conserved nature of non-uniform NP binding within influenza viruses. Mapping of the NP-bound vRNA segments provides information on the flexible NP regions that may be involved in facilitating assembly.

Dual and Triple Infections With Influenza A and B Viruses: A Case-Control Study in Southern Brazil

2019 ◽  
Vol 220 (6) ◽  
pp. 961-968 ◽  
Author(s):  
Tatiana Schäffer Gregianini ◽  
Ivana R Santos Varella ◽  
Patricia Fisch ◽  
Letícia Garay Martins ◽  
Ana B G Veiga
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Clinical Symptoms ◽  
Antiviral Treatment ◽  
Influenza Virus Infection ◽  
H3n2 Virus ◽  
Influenza Surveillance ◽  
Influenza B Virus ◽  
Influenza B ◽  
Influenza A H1n1

Abstract Influenza surveillance is important for disease control and should consider possible coinfection with different viruses, which can be associated with disease severity. This study analyzed 34 459 patients with respiratory infection from 2009 to 2018, of whom 8011 were positive for influenza A virus (IAV) or influenza B virus (IBV). We found 18 cases of dual influenza virus infection, including coinfection with 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) and influenza A(H3N2) virus (1 case), A(H1N1)pdm09 and IBV (6 cases), A(H3N2) and IBV (8 cases), and nonsubtyped IAV and IBV (3 cases); and 1 case of triple infection with A(H3N2), A(H1N1)pdm09, and IBV. Compared with 76 monoinfected patients, coinfection was significantly associated with cardiopathy and death. Besides demographic characteristics and clinical symptoms, we assessed vaccination status, antiviral treatment, timeliness of antiviral use, hospitalization, and intensive care unit admission, but no significant differences were found between coinfected and monoinfected cases. Our findings indicate that influenza virus coinfection occurs more often than previously reported and that it can lead to a worse disease outcome.

scholarly journals The N-Terminal Extension of the Influenza B Virus Nucleoprotein Is Not Required for Nuclear Accumulation or the Expression and Replication of a Model RNA

1998 ◽  
Vol 72 (6) ◽  
pp. 5307-5312 ◽  
Author(s):  
Mark P. Stevens ◽  
Wendy S. Barclay
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Viral Rna ◽  
Nuclear Accumulation ◽  
Influenza B Virus ◽  
Virus Protein ◽  
Influenza B ◽  
Coding Region ◽  
B Virus ◽  
N Terminus

ABSTRACT The nucleoprotein (NP) of influenza B virus is 50 amino acids longer at the N-terminus than influenza A virus NP and lacks homology to the A virus protein over the first 69 residues. We have deleted the N-terminal 51 and 69 residues of the influenza B/Ann Arbor/1/66 virus NP and show that nuclear accumulation of the protein is unaffected. This indicates that the nuclear localization signal is not located at the extreme N terminus, as in influenza A virus NP. To determine if the N-terminal mutants could support the expression and replication of a model influenza B virus RNA, the genes encoding the subunits of the viral RNA-dependent RNA polymerase (PA, PB1, and PB2) were cloned. Coexpression of NP and the P proteins in 293 cells was found to permit the expression and replication of a transfected model RNA based on segment 4 of B/Maryland/59, in which the hemagglutinin-coding region was replaced by a chloramphenicol acetyltransferase gene. The expression and replication of the synthetic RNA were not affected by the replacement of NP with NP mutants lacking the N-terminal 51 or 69 residues, indicating that the N-terminal extension is not required for transcription or replication of the viral RNA. In addition, we report that the influenza B virus NP cannot be functionally replaced by type A virus NP in this system.

scholarly journals Predictors of Virological Failure and Time to Viral Suppression of First-Line Integrase Inhibitor–Based Antiretroviral Treatment

2020 ◽  
Author(s):  
Ashima Pyngottu ◽  
Alexandra U Scherrer ◽  
Roger Kouyos ◽  
Michael Huber ◽  
Hans Hirsch ◽  
...  
Keyword(s):  
Viral Load ◽  
Treatment Failure ◽  
Viral Suppression ◽  
Cox Regression ◽  
Baseline Viral Load ◽  
Resistance Mutations ◽  
First Line ◽  
Cd4 Counts ◽  
Cell Counts ◽  
The Impact

Abstract Background Integrase strand transfer inhibitors (InSTIs) are recommended for first-line treatment of persons with human immunodeficiency virus (HIV). We identified risk factors, including baseline minor InSTI resistance mutations, for treatment failure of InSTI-based regimens. Methods We studied time-to-treatment failure and time to viral suppression among 1419 drug-naive patients in the Swiss HIV Cohort Study. We performed Cox regression models adjusted for demographic factors, baseline HIV RNA/CD4 cell counts, AIDS-defining events, and the type of InSTI. In 646 patients with a baseline genotypic resistance test of the integrase, we studied the impact of minor integrase resistance mutations. Results We observed 121 virological failures during 18 447 person-years of follow-up. A baseline viral load ≥100 000 copies/mL (multivariable hazard ratio [mHR], 2.2; 95% confidence interval [CI], 1.3–3.6) and an AIDS-defining event (mHR, 1.8; 95% CI. 1.1–3.0) were associated with treatment failure. CD4 counts between 200 and 500 cells/µL (mHR, 0.5; 95% CI, .3–.8) and >500 cells/µL (mHR, 0.4; 95% CI, .2–.7) were protective. Time to suppression was shorter in lower viral load strata (mHR, 0.7; 95% CI, .6–.8) and in dolutegravir-based therapy (mHR, 1.2; 95% CI, 1.0–1.4). Minor resistance mutations were found at baseline in 104 of 646 (16%) patients with no effect on treatment outcome. Conclusions Factors associated with treatment failure on InSTI-based first-line regimen remained similar to those of older treatments, in particular high viral load and low CD4 counts.

Outcomes among critically ill adults with influenza infection

2021 ◽  
Author(s):  
Eitan Aziza ◽  
Jocelyn Slemko ◽  
Lori Zapernick ◽  
Stephanie W Smith ◽  
Nelson Lee ◽  
...  
Keyword(s):  
Critical Care ◽  
Antiviral Therapy ◽  
Critically Ill ◽  
Influenza A ◽  
Influenza Infection ◽  
Antiviral Treatment ◽  
Apache Ii ◽  
Apache Ii Score ◽  
Influenza B ◽  
Predictors Of Mortality

Background: Influenza infection is a major cause of mortality in critical care units. Methods: Data on critically ill adult patients with influenza infection from 2014 to 2019 were retrospectively collected, including mortality and critical care resource utilization. Independent predictors of mortality were identified using Cox regression. Results: One hundred thirty patients with confirmed influenza infection had a mean age of 56 (±16) years; 72 (55%) were male. Mean Acute Physiology and Chronic Health Evaluation (APACHE II) score was 22 (±9). One hundred eight (83%) patients had influenza A (46% H1N1pdm09, 33% H3N2); 21 (16%) had influenza B. Fifty-five (42%) patients had bacterial co-infection. Only 5 (4%) had fungal co-infection. One hundred eight (83%) patients required mechanical ventilation; 94 (72%), vasopressor support; 26 (20%), continuous renal replacement therapy (CRRT); and 11 (9%), extracorporeal membrane oxygenation. One hundred twenty one (93%) patients received antiviral therapy (median 5 d). Thirty-day mortality was 23%. Patients who received antiviral treatment were more likely to survive with an adjusted hazard ratio (aHR) of 0.15 (95% CI 0.04 to 0.51, p = 0.003). Other independent predictors of mortality were the need for CRRT (aHR 2.48, 95% CI 1.14 to 5.43, p = 0.023), higher APACHE II score (aHR 1.08, 95% CI 1.02 to 1.14, p = 0.011), and influenza A (aHR 7.10, 95% CI 1.37 to 36.8, p = 0.020) compared with influenza B infection. Conclusions: Among critically ill influenza patients, antiviral therapy was independently associated with survival. CRRT, higher severity of illness, and influenza A infection were associated with mortality.

Viral load dynamics in adult patients with A(H1N1)pdm09 influenza

2013 ◽  
Vol 142 (4) ◽  
pp. 753-758 ◽  
Author(s):  
J. Y. NOH ◽  
J. Y. SONG ◽  
S. Y. HWANG ◽  
W. S. CHOI ◽  
J. Y. HEO ◽  
...  
Keyword(s):  
Viral Load ◽  
Symptom Onset ◽  
Influenza A ◽  
Onset Time ◽  
Clinical Findings ◽  
Viral Clearance ◽  
Virus Infections ◽  
Hospital Visit ◽  
Viral Shedding ◽  
Respiratory Specimens

SUMMARYThe dynamics of influenza A viral load in respiratory samples collected from adult A(H1N1)pdm09 influenza patients were investigated. Three respiratory specimens were obtained every 2–4 days and clinical findings were recorded at the time each specimen was collected. A total of 105 serial specimens were collected from 35 patients. Viral clearance was more rapid in patients aged 15–29 years than patients aged 30–49 years (P < 0·01) or ⩾50 years (P < 0·01). Hospitalized patients showed slow viral clearance compared to outpatients (P < 0·01). Resolution of cough and headache was correlated with viral load reduction in respiratory specimens. Viral shedding was found in 17 patients (48·6%) 5 days after symptom onset. Time to hospital visit after symptom onset was significantly correlated with prolonged viral shedding (odds ratio 9·0, 95% confidence interval 1·56–51·87, P = 0·01). These findings will contribute to infection control aspects with respect to managing patients with influenza virus infections.

scholarly journals Analysis of influenza data generated by four epidemiological surveillance laboratories in Mexico, 2010–2016

2019 ◽  
Vol 147 ◽  
Author(s):  
L. Fernandes-Matano ◽  
I. E. Monroy-Muñoz ◽  
M. Bermúdez de León ◽  
Y. A. Leal-Herrera ◽  
I. D. Palomec-Nava ◽  
...  
Keyword(s):  
Influenza A ◽  
Public Health Problem ◽  
Vaccination Status ◽  
Epidemiological Surveillance ◽  
Molecular Diagnostic ◽  
Influenza B ◽  
Surveillance Systems ◽  
Global Public Health ◽  
Case Definitions ◽  
Influenza A H1n1

AbstractThe disease caused by the influenza virus is a global public health problem due to its high rates of morbidity and mortality. Thus, analysis of the information generated by epidemiological surveillance systems has vital importance for health decision making. A retrospective analysis was performed using data generated by the four molecular diagnostic laboratories of the Mexican Social Security Institute between 2010 and 2016. Demographics, influenza positivity, seasonality, treatment choices and vaccination status analyses were performed for the vaccine according to its composition for each season. In all cases, both the different influenza subtypes and different age groups were considered separately. The circulation of A/H1N1pdm09 (48.7%), influenza A/H3N2 (21.1%), influenza B (12.6%), influenza A not subtyped (11%) and influenza A/H1N1 (6.6%) exhibited well-defined annual seasonality between November and March, and there were significant increases in the number of cases every 2 years. An inadequate use of oseltamivir was determined in 38% of cases, and the vaccination status in general varied between 12.1 and 18.5% depending on the season. Our results provide current information about influenza in Mexico and demonstrate the need to update both operational case definitions and medical practice guidelines to reduce the inappropriate use of antibiotics and antivirals.

scholarly journals 2553. Individual Patient-Level Data Meta-Analysis of Live Attenuated and Inactivated Influenza Vaccine Effectiveness Among US Children, 2013–2014 Through 2015–2016

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S68-S68
Author(s):  
Jessie Chung ◽  
Brendan Flannery ◽  
Rodolfo Begue ◽  
Herve Caspard ◽  
Laurie Demarcus ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Influenza A ◽  
The United States ◽  
Vaccine Effectiveness ◽  
Vaccination Status ◽  
Influenza B ◽  
Rt Pcr ◽  
Current Season ◽  
Influenza A H1n1 ◽  
Vaccine Type

Abstract Background Quadrivalent live attenuated influenza vaccine (LAIV4) was not recommended for use in the United States for the 2016–2017 and 2017–2018 influenza seasons based on US observational studies of vaccine effectiveness (VE) from 2013–2014 to 2015–2016. We pooled individual patient data on children aged 2–17 years enrolled in 5 US studies during these 3 influenza seasons to further investigate VE by vaccine type. Methods Analyses included 17,173 children enrolled in the US Department of Defense Global Laboratory-based Influenza Surveillance Program, US Influenza Vaccine Effectiveness Network, Influenza Incidence Surveillance Project, Influenza Clinical Investigation for Children, and a Louisiana State University study. Participants’ specimens were tested for influenza by reverse transcription-polymerase chain reaction (RT-PCR), culture, or a combination of rapid antigen testing and RT-PCR. VE was calculated by comparing odds of vaccination with either inactivated influenza vaccine (IIV) or LAIV4 among influenza-positive cases to test-negative controls and calculated as 100 × (1 − odds ratio) in logistic regression models with age, calendar time, influenza season, and study site (random effect). Patients were stratified by prior season vaccination status in a subanalysis. Results Overall, 38% of patients (N = 6,558) were vaccinated in the current season, of whom 30% (N = 1,979) received LAIV4. Pooled VE of IIV against any influenza virus was 51% (95% CI: 47, 54) versus 26% (95% CI: 15, 36) for LAIV4. Point estimates for pooled VE against any influenza by age group ranged from 45% to 58% for IIV and 19% to 34% for LAIV4 during the 3 seasons (Figures 1 and 2). Pooled VE against influenza A(H1N1)pdm09 was 67% (95% CI: 62, 72) for IIV versus 20% (95% CI: −6, 39) for LAIV4. Pooled VE against influenza A(H3N2) was 29% (95% CI: 14, 42) for IIV versus 7% (95% CI: −11, 23) for LAIV4, and VE against influenza B was 52% (95% CI: 42, 60) for IIV and 66% (95% CI: 47, 77) for LAIV4. VE against influenza A(H1N1)pdm09 was lower for LAIV4 versus IIV across all strata of prior season vaccination (Figure 3). Conclusion Consistent with individual studies, our pooled analyses found that LAIV4 effectiveness was reduced for all age groups against influenza A(H1N1)pdm09 compared with IIV. This result did not vary based on prior vaccination status. Disclosures H. Caspard, AstraZeneca: Employee, Salary.

scholarly journals Development of oseltamivir and zanamivir resistance in influenza A(H1N1)pdm09 virus, Denmark, 2014

2017 ◽  
Vol 22 (3) ◽  
Author(s):  
Ramona Trebbien ◽  
Svend Stenvang Pedersen ◽  
Kristine Vorborg ◽  
Kristina Træholt Franck ◽  
Thea Kølsen Fischer
Keyword(s):  
Symptom Onset ◽  
Influenza A ◽  
Antiviral Treatment ◽  
Influenza Virus Infection ◽  
Resistance Testing ◽  
Antiviral Resistance ◽  
Resistance Mutations ◽  
Pdm09 Virus ◽  
Influenza A H1n1 ◽  
Two Samples

Antiviral treatment of immunocompromised patients with prolonged influenza virus infection can lead to multidrug resistance. This study reveals the selection of antiviral resistance mutations in influenza A(H1N1)pdm09 virus in an immunocompromised patient during a 6-month period. The patient was treated with two courses of oseltamivir (5 days and 2 months, respectively), with the first course starting at symptom onset, and subsequently zanamivir (2 months and 10 days, respectively). Respiratory samples were investigated by Sanger and next generation sequencing (NGS) and, for NGS data, low-frequency-variant-detection analysis was performed. Neuraminidase-inhibition tests were conducted for samples isolated in Madin-Darby canine kidney cells. In a sample collected 15 days after the end of the first treatment with oseltamivir (Day 20 post-symptom onset), oseltamivir resistance was detected (mutation H275Y with 60.3% frequency by NGS). Day 149 when the patient had almost completed the second zanamivir treatment, mixes of the following resistance mutations were detected; H275Y(65.1%), I223R(9.2%), and E119G(89.6%), accompanied by additional mutations, showing a more complex viral population in the long-term treated patient. Two samples obtained on Day 151 from bronchoalveolar lavage (BAL) and nasopharyngeal swab, respectively, showed different mutation profiles, with a higher frequency of antiviral resistance mutations in BAL. The results emphasise the importance of timely antiviral resistance testing both for treatment of individual patients as well as for preventive measures to control the development and transmission of antiviral resistant viruses.

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