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The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic) acid analogs that competitively bind to the NA active site and potently inhibit enzyme activity have been synthesized and tested. Four NA inhibitors are now licensed in various parts of the world (zanamivir, oseltamivir, peramivir, and laninamivir) to treat influenza A and B infections. NA changes, naturally occurring or acquired under selective pressure, have been shown to reduce drug binding, thereby affecting the effectiveness of NA inhibitors. Drug resistance and other drawbacks have prompted the search for the next-generation NA-targeting therapeutics. One of the promising approaches is the identification of monoclonal antibodies (mAbs) targeting the conserved NA epitopes. Anti-NA mAbs demonstrate Fab-based antiviral activity supplemented with Fc-mediated immune effector functions. Antiviral Fc-conjugates offer another cutting-edge strategy that is based on a multimodal mechanism of action. These novel antiviral agents are composed of a small-molecule NA inhibitor and an Fc-region that simultaneously engages the immune system. The significant advancements made in recent years further support the value of NA as an attractive target for the antiviral development.

Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By desialylation, sialidase can modulate the functionality of the target compound and is thus often involved in biological pathways. Inhibition of sialidases with inhibitors is an important approach for understanding sialidase function and the underlying mechanisms and could serve as a therapeutic approach as well. Transition-state analogues, such as anti-influenza drugs oseltamivir and zanamivir, are major sialidase inhibitors. In addition, difluoro-sialic acids were developed as mechanism-based sialidase inhibitors. Further, fluorinated quinone methide-based suicide substrates were reported. Sialidase product analogue inhibitors were also explored. Finally, natural products have shown competitive inhibiton against viral, bacterial, and human sialidases. This Perspective describes sialidase inhibitors with different mechanisms and their activities and future potential, which include transition-state analogue inhibitors, mechanism-based inhibitors, suicide substrate inhibitors, product analogue inhibitors, and natural product inhibitors.

Influenza is a leading cause of community-acquired pneumonia (CAP), and results of influenza tests can direct therapy. However, among adults hospitalized with CAP, little is known about the frequency and timing of influenza testing, treatment, and their associations with outcomes.In patients with CAP, is testing for influenza associated with antiviral treatment and shorter antibiotic courses, and is early treatment associated with better clinical outcomes?This study included adults admitted with pneumonia in 2010 to 2015 to 179 US hospitals contributing to the Premier database. We assessed influenza testing and compared antimicrobial utilization and the outcomes of test-positive, test-negative, and untested patients. Associations of early antiviral treatment (oseltamivir) with 14-day in-hospital mortality, hospital length of stay, and cost were studied.Among 166,268 patients with CAP, 38,703 (23.3%) were tested for influenza, of whom 11.5% tested positive. Testing increased from 15.4% to 35.6% from 2010 to 2015 and was 28.9% during flu season (October-May) vs 8.2% in June to September. Patients testing positive for influenza received antiviral agents more often and antibacterial agents less often and for shorter courses than patients testing negative (5.3 vs 6.4 days; P .001). Influenza-positive patients receiving oseltamivir on hospital day 1 (n = 2,585) experienced lower 14-day in-hospital mortality (adjusted OR, 0.75; 95% CI, 0.59-0.96), lower costs (adjusted ratio of means, 0.88; 95% CI, 0.81-0.95), and shorter length of stay (adjusted ratio of means, 0.88; 95% CI, 0.84-0.93) vs patients receiving oseltamivir later or not at all (n = 1,742).Even during flu season, most patients with CAP in this study went untested for influenza. A positive influenza test result was associated with antiviral treatment, and early treatment was associated with lower mortality, suggesting that more widespread testing might improve patient outcomes.

The purpose of this study was to examine the in vivo activity of rosmarinic acid (RA) - a phytochemical with antioxidant, anti-inflammatory, and antiviral properties - against influenza virus (IAV). An antibody-based kinase array and different in vitro functional assays were also applied to identify the mechanistic underpinnings by which RA may exert its anti-IAV activity.We initially examined the potential efficacy of RA using an in vivo mouse model. A time-of-addition assay and an antibody-based kinase array were subsequently applied to investigate mechanism-of-action targets for RA. The hemagglutination inhibition assay, neuraminidase inhibition assay, and cellular entry assay were also performed.RA increased survival and prevented body weight loss in IAV-infected mice. In vitro experiments revealed that RA inhibited different IAV viruses - including oseltamivir-resistant strains. From a mechanistic point of view, RA downregulated the GSK3β and Akt signaling pathways - which are known to facilitate IAV entry and replication into host cells.RA has promising preclinical efficacy against IAV, primarily by interfering with the GSK3β and Akt signaling pathways.

The circulation of avian influenza A viruses in poultry is a public health concern due to the potential transmissibility and severity of these viral infections. Monitoring the susceptibility of these viruses to antivirals is important for developing measures to strengthen the level of preparedness against influenza pandemics. However, drug susceptibility information on these viruses is limited. Here, we determined the susceptibilities of avian influenza A(H5N1), A(H5N2), A(H5N8), A(H7N7), A(H7N9), A(H9N1), and A(H9N2) viruses isolated in Japan to the antivirals approved for use there: an M2 inhibitor (amantadine), neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, and laninamivir) and RNA polymerase inhibitors (baloxavir and favipiravir). Genotypic methods that detect amino acid substitutions associated with antiviral resistance and phenotypic methods that assess phenotypic viral susceptibility to drugs have revealed that these avian influenza A viruses are susceptible to neuraminidase and RNA polymerase inhibitors. These results suggest that neuraminidase and RNA polymerase inhibitors currently approved in Japan could be a treatment option against influenza A virus infections in humans.

H1N1 influenza has brought serious threats to people's health and a high socioeconomic burden to society. Oseltamivir, a kind of neuraminidase (NA) inhibitor, is the second-generation specific drug that is broadly used currently. However, H1N1 influenza viruses have exhibited oseltamivir resistance in the past decades, which might be a hidden danger. To understand the frequency and distribution laws of oseltamivir-resistant viruses, we conducted a thorough and deep analysis of the available NA protein sequences of H1N1 influenza viruses worldwide from 1918 to 2020. The differences and similarities before and after 2009 were also considered since the dominant viruses changed in this period. Results showed that 3.76% of H1N1 viruses harbored oseltamivir resistance currently. Among various significative mutations, H274Y had the highest frequency of 3.30%, while the frequencies of the other mutations were far below this whether before or after 2009. The oseltamivir resistance was mainly found in three hosts, humans, swine, and avian. Different mutation sites could exhibit different distributions in each host. Our results showed that the resistance level reached a peak during the 2007-2008 influenza season and then quickly decreased in 2009. The resistance also displayed a global distribution. The densely populated countries usually had a high resistance level. However, frequent significative mutations were also found in some small countries. Our findings indicated the necessity of monitoring oseltamivir resistance around the world. The study could provide a unique perspective toward the cognition of viruses and facilitate the future study of both pandemic and drug development.

Background Meta-analyses of individual patient data from randomized, controlled trials show that early oseltamivir treatment for influenza cut the risk of pneumonia and hospitalization by 44% and 63%, respectively. However, data on the effectiveness of inhaled zanamivir in preventing hospitalization and death are lacking. Methods This nationwide, population-based, cohort study included all outpatients treated with inhaled zanamivir or oral oseltamivir within 48 hours after a clinical diagnosis of influenza before and after the rollout of inhaled zanamivir as the first-line antiviral in Taiwan. The main outcome was influenza-related hospitalization or death within 14 days. Those who developed the outcome within 2 days were excluded from analyses. Propensity score stratification was used to control confounding from covariates. Results A total of 865 032 eligible influenza outpatients were included in the analysis. The risk of developing the main outcome (adjusted hazard ratio [aHR], 1.01; 95% confidence interval [CI], .96 to 1.06) did not differ between the inhaled zanamivir group (n = 595 897, 68.9%, the reference) and the oral oseltamivir group (n = 269 135, 31.1%). Prespecified analysis on high-risk subgroups further showed that inhaled zanamivir is not inferior to oral oseltamivir in either patients aged ≥65 years (aHR, 1.14; 95% CI: 1.05 to 1.25) or patients with chronic lung diseases (aHR, 1.23; 95% CI: 1.08 to 1.41). Conclusions Inhaled zanamivir is not inferior to oral oseltamivir as outpatient treatment in preventing influenza-related hospitalization or death for patients whose conditions do not require hospitalization within 2 days.

Immune thrombocytopenia (ITP) is a bleeding disorder caused by dysregulated B- and T- cell functions, which lead to platelet destruction. A well-recognized mechanism of ITP pathogenesis involves anti-platelet and anti-megakaryocyte antibodies recognizing membrane glycoprotein (GP) complexes, mainly GPIb/IX and GPIIb/IIIa. In addition to the current view of phagocytosis of the opsonised platelets by splenic and hepatic macrophages via their Fc γ receptors, antibodyinduced platelet desialylation and apoptosis have also been reported to contribute to ITP pathogenesis. Nevertheless, the relationship between the specific thrombocytopenic mechanisms and various types of anti-platelet antibodies has not been established. In order to ascertain such association, we used sera from 61 ITP patients and assessed the capacity of anti-platelet antibodies to induce neuraminidase 1 (NEU1) surface expression, RCA-1 lectin binding and loss of mitochondrial inner membrane potential on donors’ platelets. Sera from ITP patients with detectable antibodies caused significant platelet desialylation and apoptosis. Anti-GPIIb/IIIa antibodies appeared more capable of causing NEU1 surface translocation while anti-GPIb/IX complex antibodies resulted in a higher degree of platelet apoptosis. In ITP patients with anti-GPIIb/IIIa antibodies, both desialylation and apoptosis were dependent on FcγRIIa signaling rather than platelet activation. Finally, we confirmed in a murine model of ITP that destruction of human platelets induced by anti-GPIIb/IIIa antibodies can be prevented with the NEU1 inhibitor oseltamivir. A collaborative clinical trial is warranted to investigate the utility of oseltamivir in the treatment of ITP.

Objectives: The ALIC4E trial has shown that oseltamivir reduces recovery time while increasing the risk of nausea. This secondary analysis of the ALIC4E trial aimed to determine the gain in quality-adjusted life-years (QALYs) associated with adding oseltamivir to usual primary care in patients presenting with influenza-like illness (ILI). Methods: Patients with ILI were recruited during the influenza season (2015-2018) in 15 European countries. Patients were assigned to usual care with or without oseltamivir through stratified randomization (age, severity, comorbidities, and symptom onset). Patients' health status was valued with the EQ-5D and visual analog scale (VAS) for up to 28 days. Average EQ-5D and VAS scores over time were estimated for both treatment groups using one-inflated beta regression in children (-13 years old). QALY gain was calculated as the difference between the groups. Sensitivity analysis considered the value set to convert EQ-5D answers to summary scores and the follow-up period. Results: In adults, oseltamivir gained 0.0006 (95% confidence interval 0.0002-0.0010) QALYs, whereas no statistically significant gain was found in children (14-day follow-up, EQ-5D). QALY gains were statistically significant in patients aged >-65 years, patients without relevant comorbidities, or patients experiencing symptoms for

Oseltamivir phosphate (OS) is currently the most frequently used influenza antiviral drug. It moderates the course of influenza virus type A (IAV) infection, however, its impact on the induction of virus-neutralizing antibodies (VNAbs) is not understood in details. Here, we examined the influence of low (10 mg/kg) or high (60 mg/kg) doses of OS on the viral titer in lungs of BALB/c mice infected with 0.5 LD50 of IAV and on the level of VNAbs. Prophylactic application of OS (6 h before the infection) delayed the increase of viral titer in lungs with a lower peak in comparison to non-treated control mice. After therapeutic OS application (44 h after the infection), maximum of virus titer did not significantly change. However, the induction of VNAbs strongly decreased, to 16.7%-18.1% of the control, after preventive application of high OS dose. A minimal decrease of VNAbs titers was observed in groups of mice treated with low dose of OS applied therapeutically. They lowered to 91.1% / 14 or to 94.1% / 21 days post infection (p.i.) of VNAbs titers of non-treated control mice. In all other groups, levels of VNAbs titers dropped to 26.5-53.7% of those of non-treated mice. It should be noted that VNAbs titers were in direct proportion to maximal virus titers in mouse lungs of corresponding groups. In summary, after OS application the clinical symptoms of the disease were milder or non-observable in all OS-treated groups, but the lowering of VNAbs titers was dependent on the OS dose and interval between drug app-lication and the start of infection. Keywords: influenza A virus; Oseltamivir; prophylactic treatment; therapeutic treatment; virus-neutralizing antibodies.

Introduction Influenza epidemics are of higher risk at the extremes of life and in people with comorbidities. Effective vaccination prevents the occurrence of serious cases and decreases mortality. Objective To describe deaths from influenza with a history of timely vaccination, from the 2010 to the 2018 season in Mexico. Method Cross-sectional, descriptive study where the Influenza Epidemiological Surveillance System database was used. Results From 2010 to 2018, 65 vaccinated individuals died from influenza, from which 55% of cases (n = 36) were due to type A (H1N1), 51% (n = 33) were females, median age was 57 years, 21 % (n = 14) did not meet the operational definition of influenza-like illness or severe acute respiratory infection, 83% (n = 54) had at least one comorbidity, with the most common being diabetes mellitus and hypertension (32% each); 55% (n = 36) of deaths received antiviral treatment and only 8% (n = 5) had no comorbidities and received treatment with oseltamivir. Conclusions Deaths from influenza with timely vaccination represent a very low percentage of the totality. Vaccination against influenza has been a specific prevention strategy that decreases disease burden.

Background/ Aim: As the experience has increased regarding SARS-CoV-2 in time, treatment trends have changed since the beginning of the pandemic. This study aimed to compare the outcomes of different treatment modalities for inpatients in a tertiary pandemic hospital in Antalya, Turkey. METHODS: Individuals aged 18 years and above tested positive for SARS-CoV-2 in PCR with presenting COVID-related radiological findings, hospitalized for at least three days, and completed follow-up between March 15, 2020, and November 30, 2020, were included in the study. Patients? data were reviewed retrospectively. Seven treatment groups based on the single or combined use of hydroxychloroquine, oseltamivir, favipiravir, and remdesivir were formed and compared in terms of mortality, survival, length of hospital stay, need for intensive care, and mechanical ventilation. RESULTS: A total of 321 patients were included in the study. The length of hospital stay, the need for intensive care, and mechanical ventilation were lower in Group 1 (hydroxychloroquine) and Group 2 (hydroxychloroquine + oseltamivir) compared to the other groups (p

Influenza is an acute respiratory illness caused by the influenza A, B, and C viruses. It can occur in local outbreaks or seasonal epidemics, with possibility to spread worldwide in a pandemic when a novel strain with significant antigenic differences emerges. During the past years, several new drugs have become available, with different accessibility related to specific countries' approval. We have conducted a review of literature, analyzing the most recent data on efficacy and safety of drugs currently available to treat influenza, with a particular attention toward special populations. Efficacy and safety profile of neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, peramivir) and recently approved cap-dependent endonuclease inhibitor baloxavir marboxil are reported in literature, but still little information is available about special populations such as critically ill patients and patients with a history of chronic respiratory disease. Moreover, the emergence of strains with reduced or no susceptibility to current drugs is a matter of concern, suggesting the need of constant monitoring of viral variants.

The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 and has rapidly spread globally. As the confirmed number of cases has reached 83 million worldwide, the potential severity and the deadly complications of the disease requires urgent development of effective drugs for prevention and treatment. No proven effective treatment for this virus currently exists. Most of the antiviral discovery efforts are focused on the repurposing of approved or clinical stage drugs. This review highlights the small-molecule repurposed antiviral agents that are currently under investigation in clinical trials for COVID-19. These include viral polymerase and protease inhibitors remdesivir, galidesivir, favipiravir, ribavirin, sofosbuvir, tenofovir/emtricitabine, baloxavir marboxil, EIDD-2801, lopinavir/ritonavir; virus-/host-directed viral entry and fusion inhibitors arbidol chloroquine/hydroxychloroquine, chlorpromazine, camostat mesylate, nafamostat mesylate, bromhexine and agents with diverse/unclear mechanism of actions as oseltamivir, triazavirin, ivermectin, nitazoxanide, niclosamide and BLD-2660. The published preclinical and clinical data to date on these drugs as well as the mechanisms of action are reviewed.

Objective Maoto is a traditional Japanese Kampo formula used to treat influenza. However, clinical evidence for maoto has been limited to small-scale studies of its effect in alleviating symptoms. The present study evaluated whether or not the addition of maoto to a neuraminidase inhibitor was associated with a reduction in hospitalization following influenza. Methods Using the JMDC Claims Database, we identified outpatients

BACKGROUND: In our previous report on Turkish COVID-19 patients requiring intensive care, the 24 patients in a single ICU were elderly and mortality was high. We extended our analysis to include patients admitted to ten ICUs. OBJECTIVES: Report the demographics, clinical features, imaging findings, comorbidities, and outcomes in COVID-19 patients. DESIGN: Retrospective. SETTING: Intensive care unit. PATIENTS AND METHODS: The study includes patients with clinical and radiological confirmed or laboratory-confirmed COVID-19 infection who were admitted to ten ICUs between 15 March and 30 June 2020. MAIN OUTCOME MEASURES: Clinical outcomes, therapies, and death during hospitalization SAMPLE SIZE: 974, including 571 males (58%). RESULTS: The median age (range) was 72 (21–101) years for patients who died (n=632, 64.9%) and 70 (16–99) years for patients who lived (n=342, 35.2%) ( P P P =.013). Most (n=719, 73.8%) underwent invasive mechanical ventilation therapy. CONCLUSIONS: The majority of patients admitted to the ICU with a diagnosis of COVID-19 require respiratory support. LIMITATIONS: Although the Turkish Ministry of Health made recommendations for the treatment of COVID-19 patients, patient management may not have been identical in all ten units. CONFLICT OF INTEREST: None.

Antiviral treatment is recommended for all hospitalized children with suspected or confirmed influenza, regardless of their risk profile. Few data exist on adherence to these recommendations, so we sought to determine factors associated with influenza testing and antiviral treatment in children.Hospitalized children18 years of age with acute respiratory illness (ARI) were enrolled through active surveillance at pediatric medical centers in seven cities between 11/1/2015 and 6/30/2016; clinical information was obtained from parent interview and chart review. We used generalized linear mixed-effects models to identify factors associated with influenza testing and antiviral treatment.Of the 2299 hospitalized children with ARI enrolled during one influenza season, 51% (n = 1183) were tested clinically for influenza. Clinicians provided antiviral treatment for 61 of 117 (52%) patients with a positive influenza test versus 66 of 1066 (6%) with a negative or unknown test result. In multivariable analyses, factors associated with testing included neuromuscular disease (aOR = 5.35, 95% CI [3.58-8.01]), immunocompromised status (aOR = 2.88, 95% CI [1.66-5.01]), age (aOR = 0.93, 95% CI [0.91-0.96]), private only versus public only insurance (aOR = 0.78, 95% CI [0.63-0.98]), and chronic lung disease (aOR = 0.64, 95% CI [0.51-0.81]). Factors associated with antiviral treatment included neuromuscular disease (aOR = 1.86, 95% CI [1.04, 3.31]), immunocompromised state (aOR = 2.63, 95% CI [1.38, 4.99]), duration of illness (aOR = 0.92, 95% CI [0.84, 0.99]), and chronic lung disease (aOR = 0.60, 95% CI [0.38, 0.95]).Approximately half of children hospitalized with influenza during the 2015-2016 influenza season were treated with antivirals. Because antiviral treatment for influenza is associated with better health outcomes, further studies of subsequent seasons would help evaluate current use of antivirals among children and better understand barriers for treatment.

BACKGROUND Diagnosis and treatment of influenza patients are often provided across several medical specialties. We compared patient outcomes at an infectious diseases (ID), a rheumatology (Rheu) and a pulmonology (Pul) department. MATERIAL AND METHODS In this prospective observational multicenter study we included all influenza positive adults who were hospitalized and treated at flu isolation wards in three hospitals in Vienna during the season 2018/2019. RESULTS A total of 490 patients (49% female) with a median age of 73 years (interquartile range [IQR] 61-82) were included. No differences regarding age, sex and most underlying diseases were present at admission. Frequencies of the most common complications differed: acute kidney failure (ID 12.7%, Rheu 21.2%, Pulm 37.1%, p

Purpose The aim of this meta-analysis is to compare the clinical efficacy and safety of baloxavir with other anti-influenza agents or placebo in the treatment of influenza. Methods PubMed, Embase, Web of Science, Google Scholar, Scopus, CINAHL, Cochrane databases and clinical registration were searched from inception until February 15 2021 for relevant randomized controlled trials (RCTs). Only phase 3 RCTs evaluating the usefulness of baloxavir in the treatment of influenza were included. Results Three RCTs enrolling 3771 patients (baloxavir group, n = 1451; oseltamivir group, n = 1288; placebo group, n = 1032) were included. Compared with oseltamivir, baloxavir had an insignificantly shorter time to the alleviation of symptoms (mean difference [MD], −1.29 h; 95% CI, −6.80 to 4.21; I2 = 0%). In contrast, baloxavir had a significantly shorter time to the alleviation of symptoms than placebo (MD, −26.32 h; 95% CI, −33.78 to −18.86; I2 = 0%). Baloxavir was associated with a significant decline in influenza virus titers and viral RNA load compared to oseltamivir and placebo. Baloxavir was associated with a lower risk of any adverse events than oseltamivir (OR, 0.82; 95% CI, 0.69–0.98; I2 = 0%) and placebo (OR, 0.79; 95% CI, 0.66–0.96; I2 = 0%). Conclusions The findings of this meta-analysis suggested that baloxavir is superior to placebo in the treatment of influenza in both clinical outcome and virological response. Moreover, baloxavir was found to have a better virological response than oseltamivir and to be as effective as oseltamivir clinically. Compared with oseltamivir and placebo, baloxavir appears to be a relatively safe anti-influenza agent.

Background Influenza is associated with excess morbidity and mortality of individuals each year. Few therapies exist for treatment of influenza infection, and each require initiation as early as possible in the course of infection, making efficacy difficult to estimate in the hospitalized patient with lower respiratory tract infection. Using causal machine learning methods, we re-analyze data from a randomized trial of oseltamivir versus standard of care aimed at reducing clinical failure in hospitalized patients with lower respiratory tract infection during the influenza season. Methods This was a secondary analysis of the Rapid Empiric Treatment with Oseltamivir Study (RETOS). Conditional average treatment effects (CATE) and 95% confidence intervals were computed from causal forest including 85 clinical and demographic variables. RETOS was a multicenter, randomized, unblinded, trial of adult patients hospitalized with lower respiratory tract infections in Kentucky from 2009 through 2012. Adult hospitalized patients with lower respiratory tract infection were randomized to standard of care or standard of care plus oseltamivir as early as possible after hospital admission but within 24 h of enrollment. After randomization, oseltamivir was initiated in the treatment arm per package insert. The primary outcome was clinical failure, a composite measure including failure to reach clinical improvement within 7 days, transfer to intensive care 24 h after admission, or rehospitalization or death within 30 days. Results A total of 691 hospitalized patients with lower respiratory tract infections were included in the study. The only subgroup of patients with a statistically significant CATE was those with laboratory-confirmed influenza infection with a 26% lower risk of clinical failure when treated with oseltamivir (95% CI 3.2–48.0%). Conclusions This study suggests that addition of oseltamivir to standard of care may decrease clinical failure in hospitalized patients with influenza-associated lower respiratory tract infection versus standard of care alone. These results are supportive of current recommendations to initiate antiviral treatment in hospitalized patients with confirmed or suspected influenza as soon as possible after admission. Trial registration Original trial: Clinical Trials.Gov; Rapid Empiric Treatment With Oseltamivir Study (RETOS) (RETOS); ClinicalTrials.gov Identifier: NCT01248715 https://clinicaltrials.gov/ct2/show/NCT01248715

Purpose This study aimed to compare the safety and efficacy of clarithromycin-naproxen-oseltamivir combination therapy to that of oseltamivir therapy alone in hospitalized pediatric influenza patients. Methods This prospective, single-blind study included children aged 1–18 years hospitalized with influenza, in MacKay Children’s Hospital, Taiwan, between December 2017 and December 2019. The primary outcomes were the time to defervescence and decrease of the Pediatric Respiratory Severity Score (PRESS) during hospitalization. The secondary outcomes were serial changes in virus titers, measured using real-time polymerase chain reaction. Results Fifty-four patients were enrolled (28 in the control group and 26 in the combination group) in total. There were no differences in the patients’ baseline characteristics between the groups. The time to defervescence was significantly shorter in the combination group than the oseltamivir group (13.2 hours vs. 32.1 hours, p=0.002). The decrease in the virus titer from days 1 to 3 (log Δ13) was more pronounced in the combination group than the oseltamivir group. (39% vs. 19%, p=0.001). There were no differences in adverse effects such as vomiting, diarrhea, and abdominal pain during the study or within 30 days after antiviral therapy. Conclusion The clarithromycin-naproxen-oseltamivir combination group experienced a more rapid defervescence and a more rapid decline of influenza virus titer than the group treated with oseltamivir alone. Further consideration should be given to whether the overall benefits of combination therapy in hospitalized pediatric influenza patients outweigh the risks.

Author(s): Benjamin-Chung, Jade; Arnold, Benjamin F; Mishra, Kunal; Kennedy, Chris J; Nguyen, Anna; Pokpongkiat, Nolan N; Djajadi, Stephanie; Seth, Anmol; Klein, Nicola P; Hubbard, Alan E; Reingold, Arthur; Colford, John M | Abstract: BackgroundWe measured the effectiveness of a city-wide school-located influenza vaccination (SLIV) program implemented in over 102 elementary schools in Oakland, California.MethodsWe conducted a retrospective cohort study among Kaiser Permanente Northern California (KPNC) members of all ages residing in either the intervention or a multivariate-matched comparison site from September 2011 - August 2017. Outcomes included medically attended acute respiratory illness (MAARI), influenza hospitalization, and Oseltamivir prescriptions. We estimated difference-in-differences (DIDs) in 2014-15, 2015-16, and 2016-17 using generalized linear models and adjusted for race, ethnicity, age, sex, health plan, and language.ResultsPre-intervention member characteristics were similar between sites. The proportion of KPNC members vaccinated for influenza by KPNC or the SLIV program was 8-11% higher in the intervention site than the comparison site during the intervention period. Among school-aged children, SLIV was associated with lower Oseltamivir prescriptions per 1,000 (DIDs: -3.5 (95% CI -5.5, -1.5) in 2015-16; -4.0 (95% CI -6.5, -1.6) in 2016-17) but not with other outcomes. SLIV was associated with lower MAARI per 1,000 in adults 65n+nyears (2014-15: -13.2, 95% CI -23.2, -3.2; 2015-16: -21.5, 95% CI -31.1, -11.9; 2016-17: -13.0, 95% CI -23.2, -2.9). There were few significant associations with other outcomes among adults.ConclusionsA city-wide SLIV intervention was associated with higher influenza vaccination coverage, lower Oseltamivir prescriptions in school-aged children, and lower MAARI among people over 65nyears, suggesting possible indirect effects of SLIV among older adults.

Globally, there is a scarcity of effective treatments for SARS-CoV-2 infections (causing COVID-19). Repurposing existing medications may offer the best hope for treating patients with COVID-19 to curb the pandemic. IMU-838 is a dihydroorotate dehydrogenase inhibitor, which is an effective mechanism for antiviral effects against respiratory viruses. When used synergistically with oseltamivir, therapeutic effects have been observed against influenza and SARS-CoV-2 in rodents. The IMU-838 and Oseltamivir in the Treatment of COVID-19 (IONIC) trial is a randomised controlled trial that will investigate whether time to clinical improvement in patients with COVID-19 is improved following a 14-day course of IMU-838+oseltamivir versus oseltamivir alone.IONIC trial is an open-label study in which participants will be randomised 1:1 in two parallel arms: the intervention arm (IMU-838+oseltamivir) and the control arm (oseltamivir only). The primary outcome is time to clinical improvement; defined as the time from randomisation to a two-point improvement on WHO ordinal scale; discharge from hospital, or death (whichever occurs first). The study is sponsored by the University Hospitals Coventry and Warwickshire NHS Trust and funded by LifeArc.The IONIC protocol describes an overarching trial design to provide reliable evidence on the effectiveness of IMU-838 (vidofludimus calcium) when delivered in combination with an antiviral therapy (oseltamivir) (This study has been independently reviewed and approved by Wales Research Ethics Committee. In addition, required regulatory approvals were received from Medicines and Healthcare products Regulatory Agency.EudraCT 2020-001805-21, ISRCTN53038326, NCT04516915.

Oseltamivir phosphate is widely used to treat and prevent influenza, and is available in the form of capsules, powder for oral suspension, pediatric solutions, and granules. Because of the amino group, oseltamivir is easy to react with the excipients of the formulation to generate drug-excipient interaction impurities. In this research, two degradation products in a commercial oseltamivir phosphate powder for oral suspension due to interaction between API and citrate were investigated. They were characterized to be 3-((-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)carbamoyl)-3-hydroxypentanedioic acid and 2-(2-((-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)-2-oxoethyl)-2-hydroxysuccinic acid by MS and NMR, respectively. Furthermore, the formation mechanisms of these impurities were verified, and the method of analysis of covariance was used to assess the rate of impurities' degradation. HIGHLIGHTS: Two excipient interaction degradation products in commercial oseltamivir phosphate powder for oral suspension were studied and elucidated in detail via LC-MS/MS and NMR. The incompatibility risk of pH conditioners such as citrate and citric acid with formulations that contain an amino group was disclosed in this article. Analysis of covariance was demonstrated to assess the impact of various formulations and preparation techniques on the rate of impurity degradation.

The influenza A virus (IAV) is a highly contagious virus that causes pandemics and seasonal epidemics, which are major public health issues. Current anti-influenza therapeutics are limited partly due to the continuous emergence of drug-resistant IAV strains; thus, there is an unmet need to develop novel anti-influenza therapies. Here, we present a novel imidazo[1,2

Background Baloxavir marboxil (baloxavir) is a single-dose, oral antiinfluenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir vs neuraminidase inhibitors. Methods In this retrospective, observational, cohort study, we used real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was 1 October 2018 to 17 April 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. The primary end point was the incidence of hospitalization (days 2–14). Secondary end points included antibacterial use, secondary pneumonia, and additional antiinfluenza drug use. Results Compared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00–2.00]; risk difference [RD] and 95% CI, 0.06 [.01–.12]) and zanamivir group (RR, 1.85 [1.23–2.78]; RD, 0.11 [.02–.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [.82–.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21–2.38]) or antibacterial injection (RR, 1.67 [1.17–2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional antiinfluenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05–2.18], 2.84 [2.04–3.96], and 1.68 [1.35–2.10], respectively). Conclusions Baloxavir is an efficacious antiinfluenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir. Clinical Trials Registration University hospital Medical Information Network Clinical Trials Registry (UMIN000038159)., Baloxavir marboxil is a single-dose oral antiinfluenza drug with a novel mechanism of action. This real-world data study indicates that baloxavir marboxil may reduce hospitalization after influenza outpatient treatment compared with neuraminidase inhibitor treatment.

Background In a previous retrospective observational study, a 3-day regimen of oseltamivir as post-exposure prophylaxis (PEP) for preventing transmission of influenza in wards was shown to be comparable to 7- to 10-day regimens provided index cases were immediately separated from close contacts. In order to confirm the efficacy of a 3-day regimen, we started to conduct a prospective, multi-center, single-arm trial. Methods This study is a prospective, multi-center, single-arm study designed by the Sectional Meeting of Clinical Study, Japan Infection Prevention and Control Conference for National and Public University Hospitals. Index patients with influenza are prescribed a neuraminidase inhibitor and are discharged immediately or transferred to isolation rooms. The close contacts are given oseltamivir as 75 mg capsules once daily for adults or 2 mg/kg (maximum of 75 mg) once daily for children for 3 days as PEP. All close contacts are monitored for development of influenza for 7 days after starting PEP. Discussion A 3-day regimen of oseltamivir as PEP has advantages over 7- to 10-day regimens in terms of costs, medication adherence and adverse effects. Trial registration The Institutional Review Board of Hokkaido University Hospital for Clinical Research, 015-0518, registered on November 11, 2016. UMIN Clinical Trials Registry, UMIN000024458, disclosed on October 31, 2016. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000027881. Japan Registry of Clinical Trials, jRCTs011180015, disclosed on March 14, 2019. https://jrct.niph.go.jp/latest-detail/jRCTs011180015

Mild encephalopathy with reversible splenial lesion (MERS) is associated with a variety of infections and anti-epileptic drug withdrawal. Here we report the clinical characteristics of H1N1 influenza A-associated MERS based on our experience of four pediatric cases. A detailed retrospective analysis of four patients with H1N1 influenza A-associated MERS was performed at Guangzhou Women and Children’s Medical Center. All patients exhibited mild influenza-like illness and seizures. Three patients presented with a new-onset seizure with fever after 5 years of age. 75% patients had altered mental status. For all four patients, influenza A (H1N1) viral RNA was detected in throat swab specimens at least twice. Brain magnetic resonance images revealed similar ovoid lesions in the corpus callosum, mainly in the splenium and for one patient in the splenium and genu of the corpus callosum. Only one patient had an abnormal electroencephalogram tracing. Cells and protein in the cerebrospinal fluid were normal in all patients. All patients received oseltamivir and one patient received intravenous immunoglobulin. As a result, all patients fully recovered after 2 months and showed no neurologic sequelae at discharge. This case series provides insight towards clinical features of H1N1 influenza A-associated MERS.

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.

Influenza viruses exhibit considerable diversity between hosts. Additionally, different quasispecies can be found within the same host. High-throughput sequencing technologies can be used to sequence a patient-derived virus population at sufficient depths to identify low-frequency variants (LFV) present in a quasispecies, but many challenges remain for reliable LFV detection because of experimental errors introduced during sample preparation and sequencing. High genomic copy numbers and extensive sequencing depths are required to differentiate false positive from real LFV, especially at low allelic frequencies (AFs). This study proposes a general approach for identifying LFV in patient-derived samples obtained during routine surveillance. Firstly, validated thresholds were determined for LFV detection, whilst balancing both the cost and feasibility of reliable LFV detection in clinical samples. Using a genetically well-defined population of influenza A viruses, thresholds of at least 104 genomes per microlitre and AF of ≥5 % were established as detection limits. Secondly, a subset of 59 retained influenza A (H3N2) samples from the 2016–2017 Belgian influenza season was composed. Thirdly, as a proof of concept for the added value of LFV for routine influenza monitoring, potential associations between patient data and whole genome sequencing data were investigated. A significant association was found between a high prevalence of LFV and disease severity. This study provides a general methodology for influenza LFV detection, which can also be adopted by other national influenza reference centres and for other viruses such as SARS-CoV-2. Additionally, this study suggests that the current relevance of LFV for routine influenza surveillance programmes might be undervalued.

ImportanceOseltamivir therapy is recommended for all pediatric inpatients with influenza, particularly those with high-risk conditions, although data regarding its uptake and benefits are limited.ObjectiveTo describe temporal patterns and independent patient factors associated with the use of oseltamivir and explore patterns in resource use and patient outcomes among children hospitalized with influenza.Design, Setting, and ParticipantsThis multicenter retrospective cross-sectional study was conducted at 36 tertiary pediatric hospitals participating in the Pediatric Health Information System in the US. A total of 70 473 children younger than 18 years who were hospitalized with influenza between October 1, 2007, and March 31, 2020, were included.ExposuresHospitalization with a diagnosis of influenza.Main Outcomes and MeasuresThe primary outcome was the use of oseltamivir, which was described by influenza season and by hospital. Patient factors associated with oseltamivir use were assessed using multivariable mixed-effects logistic regression models. Secondary outcomes were resource use (including antibiotic medications, chest radiography, supplemental oxygen, positive pressure ventilation, central venous catheter, and intensive care unit [ICU]) and patient outcomes (length of stay, late ICU transfer, 7-day hospital readmission, use of extracorporeal membrane oxygenation, and in-hospital mortality), which were described as percentages per influenza season.ResultsAmong 70 473 children hospitalized with influenza, the median (IQR) age was 3.65 (1.05-8.26) years; 30 750 patients (43.6%) were female, and 39 715 (56.4%) were male. Overall, 16 559 patients (23.5%) were Black, 36 184 (51.3%) were White, 14 133 (20.1%) were of other races (including 694 American Indian or Alaska Native [1.0%], 2216 Asian [3.0%], 372 Native Hawaiian or Pacific Islander [0.5%], and 10 850 other races [15.4%]), and 3597 (5.1%) were of unknown race. A total of 47 071 patients (66.8%) received oseltamivir, increasing from a low of 20.2% in the 2007-2008 influenza season to a high of 77.9% in the 2017-2018 season. Use by hospital ranged from 43.2% to 79.7% over the entire study period and from 56.5% to 90.1% in final influenza season studied (2019-2020). Factors associated with increased oseltamivir use included the presence of a complex chronic condition (odds ratio [OR], 1.42; 95% CI, 1.36-1.47), a history of asthma (OR, 1.31; 95% CI, 1.23-1.38), and early severe illness (OR, 1.19; 95% CI, 1.13-1.25). Children younger than 2 years (OR, 0.81; 95% CI, 0.77-0.85) and children aged 2 to 5 years (OR, 0.83; 95% CI, 0.79-0.88) had lower odds of receiving oseltamivir. From the beginning (2007-2008) to the end (2019-2020) of the study period, the use of antibiotic medications (from 74.4% to 60.1%) and chest radiography (from 59.2% to 51.7%) decreased, whereas the use of oxygen (from 33.6% to 29.3%), positive pressure ventilation (from 10.8% to 7.9%), and central venous catheters (from 2.5% to 1.0%) did not meaningfully change. Patient outcomes, including length of stay (median [IQR], 3 [2-5] days for all seasons), readmissions within 7 days (from 4.0% to 3.4%), use of extracorporeal membrane oxygenation (from 0.5% to 0.5%), and in-hospital mortality (from 1.1% to 0.8%), were stable from the beginning to the end of the study period.Conclusions and RelevanceIn this cross-sectional study of children hospitalized with influenza, the use of oseltamivir increased over time, particularly among patients with high-risk conditions, but with wide institutional variation. Patient outcomes remained largely unchanged. Further work is needed to evaluate the impact of oseltamivir therapy in this population.

This study aims to explore the efficacy and safety of Lianhua Qingwen preparations combined with Oseltamivir in the treatment of influenza patients. PubMed, Cochrane Library, EMbase, SinoMed, CNKI, Wanfang, and VIP were searched for the randomized controlled trials(RCTs) involving the comparison between the influenza patients treated with Lianhua Qingwen preparations combined with Oseltamivir and those treated with Oseltamivir alone. Fever clearance time was taken as the primary outcome indicator. Clinical effective rate(markedly effective and effective), time to muscle pain relief, time to sore throat relief, time to cough relief, time to nasal congestion and runny nose relief, time to negative result of viral nucleic acid test, and adverse reactions were taken as the secondary outcome indicators. The data were extracted based on the outcome indicators and then combined. The Cochrane collaboration's tool for assessing risk of bias was used to evaluate the quality of a single RCT, and the grading of recommendations assessment, development and evaluations(GRADE) system to assess the quality of a single outcome indicator. RevMan 5.3 was employed to analyze data and test heterogeneity. Finally, 16 RCTs involving 1 629 patients were included for analysis. The Meta-analysis showed that Lianhua Qingwen preparations combined with Oseltamivir was superior to Oseltamivir alone in the treatment of influenza in terms of clinical effective rate(RR=1.16, 95%CI [1.12, 1.20], Plt;0.000 01), fever clearance time(SMD=-2.02, 95%CI [-2.62,-1.41], Plt;0.000 01), time to muscle pain relief(SMD=-2.50, 95%CI [-3.84,-1.16], P=0.000 2), time to sore throat relief(SMD=-1.40, 95%CI [-1.93,-0.85], Plt;0.000 01), time to cough relief(SMD=-1.81, 95%CI [-2.44,-1.19], Plt;0.000 01), time to nasal congestion and runny nose(SMD=-2.31, 95%CI [-3.61,-1.01], P=0.000 5), and time to negative result of viral nucleic acid test(SMD=-0.68, 95%CI [-1.19,-0.16], P=0.01). However, due to the low quality of the trials, the above conclusions need to be proved by more high-quality clinical studies. In addition, we still need to attach importance to the adverse reactions of the integrated application of Chinese and western medicines.

This study aims to obtain higher-level evidence by overviewing the Meta-analysis of Lianhua Qingwen preparations in the treatment of viral diseases including influenza, coronavirus disease 2019(COVID-19), and hand, foot and mouth disease(HFMD). CNKI, Wanfang, VIP, China Clinical Trial Registry(ChiCTR), PubMed, EMbase, Web of Science, and Cochrane Library were searched for the Meta-analysis about the treatment of viral diseases with Lianhua Qingwen preparations from the database establishment to April 1, 2022. After literature screening and data extraction, AMSTAR2 and the grading of recommendations assessment, development and evaluations(GRADE) system were used to assess the methodological quality and evidence quality, respectively, and then the efficacy and safety outcomes of Lianhua Qingwen preparations in the treatment of viral diseases were summarized. Thirteen Meta-analysis were finally included, three of which were rated as low grade by AMSTAR2 and ten as very low grade. A total of 75 outcome indicators were obtained, involving influenza, COVID-19, and HFMD. According to the GRADE scoring results, the 75 outcome indicators included 5(6.7%) high-level indicators, 18(24.0%) mediate-level indicators, 25(33.3%) low-level evidence indicators, and 27(36.0%) very low-level indicators.(1)In the treatment of influenza, Lianhua Qingwen preparations exhibited better clinical efficacy than other Chinese patent medicines and Ribavirin and had similar clinical efficacy compared with Oseltamivir. Lianhua Qingwen preparations were superior to other Chinese patent medicines, Oseltamivir, and Ribavirin in alleviating clinical symptoms. They showed no significant differences from Oseltamivir or conventional anti-influenza treatment in terms of the time to and rate of negative result of viral nucleic acid test.(2)In the treatment of COVID-19, Lianhua Qingwen preparation alone or combined with conventional treatment was superior to conventional treatment in terms of total effective rate, main symptom subsidence rate and time, fever clearance rate, duration of fever, time to fever clearance, cough subsidence rate, time to cough subsidence, fatigue subsidence rate, time to fatigue subsidence, myalgia subsidence rate, expectoration subsidence rate, chest tightness subsidence rate, etc. Lianhua Qingwen preparations no difference from conventional treatment in terms of subsiding sore throat, nausea, diarrhea, loss of appetite, headache, and dyspnea. In terms of chest CT improvement rate, rate of progression to severe case, cure time, and hospitalization time, Lianhua Qingwen alone or in combination with conventional treatment was superior to conventional treatment.(3)In the treatment of HFMD, Lianhua Qingwen Granules was superior to conventional treatment in terms of total effective rate, average fever clearance time, time to herpes subsidence, and time to negative result of viral nucleic acid test.(4)In terms of safety, Lianhua Qingwen preparations led to low incidence of adverse reactions, all of which were mild and disappeared after drug withdrawal. The available evidence suggests that in the treatment of influenza, COVID-19, and HFMD, Lianhua Qingwen preparations can relieve the clinical symptoms, shorten the hospitalization time, and improve the chest CT. They have therapeutic effect and good safety in the treatment of viral diseases. However, due to the low quality of available studies, more high-quality clinical trials are needed to support the above conclusions.

Pneumonia is a major cause of death in children aged under five years. As children with severe pneumonia have the highest risk of morbidity and mortality, previous studies have evaluated the additional benefit of adjunctive treatments such as oseltamivir, oral steroids, macrolides, and vitamin supplementation that can be added to standard antibiotic management to improve clinical outcomes. The study reviewed the evidence for the role of these additional treatments for children with severe pneumonia in low- and middle-income countries (LMICs).Four electronic databases were searched for English-language articles between 2000 to 2020. Systematic reviews (SRs) with meta-analyses, comparative cohort studies, and randomised controlled trials (RCTs) from LMICs that reported clinical outcomes for children with severe pneumonia aged between one month to 9 years who received adjunct treatment in addition to standard care were included. Risk of bias of included SRs was assessed using AMSTAR 2, and of individual studies using the Effective Public Health Practice Project (EPHPP) quality assessment tool for quantitative studies.Overall, the search identified 2147 articles, 32 of which were eligible, including 7 SRs and 25 RCTs. These studies evaluated zinc (4 SRs, 17 RCTs), Vitamin D (1 SR, 4 RCTs), Vitamin A (3 SRs, 1 RCT), Vitamin C (1 SR, 2 RCTs) and micronutrients (1 RCT). Most studies reported clinical outcomes of time to improvement, length of stay, and treatment failure (including mortality). No studies of oseltamivir, steroids, or macrolides fulfilling the inclusion criteria were identified. For zinc, pooled analyses from SRs showed no evidence of benefit. Similarly, a Cochrane review and one RCT found that Vitamin A did not improve clinical outcomes. For Vitamin D, an RCT evaluating a single high dose of 100 000 international units (IU) of vitamin D found a reduction in time to improvement, with 38%-40% documented vitamin D deficiency at baseline. However, two other studies of 1000 IU daily did not show any effect, but vitamin D status was not measured. For vitamin C, two studies found a reduction in time to symptom resolution in those with severe disease, with one reporting a shorter length of hospital stay. However, both studies were of weak quality. Most studies excluded malnourished children, and studies which included these children did not report specifically on the effect of micronutrients.This review found that adjunctive zinc and vitamin A, in addition to standard care, does not improve clinical outcomes in children with severe pneumonia in LMICs (strong evidence). However, a reduction in time to symptom resolution was reported with high dose vitamin D supplementation in children with documented vitamin D deficiency (strong evidence from one study) and vitamin C (weak evidence), although further research is needed, especially in underweight children.

Oseltamivir-resistant influenza viruses arise due to amino acid mutations in key residues of the viral neuraminidase (NA). These changes often come at a fitness cost; however, it is known that permissive mutations in the viral NA can overcome this cost. This result was observed in former seasonal A(H1N1) viruses in 2007 which expressed the H275Y substitution (N1 numbering) with no apparent fitness cost and lead to widespread oseltamivir resistance. Therefore, this study aims to predict permissive mutations that may similarly enable fit H275Y variants to arise in currently circulating A(H1N1)pdm09 viruses. The first approach in this study utilized

Influenza viruses cause significant morbidity and mortality worldwide but can be treated with antiviral drugs. In 2018, a highly effective antiviral drug, baloxavir marboxil, was licensed.

Introduction Health care professionals working in primary and specialized care typically search for medical information from Internet sources. In Finland, Physician’s Databases are online portals aimed at professionals seeking medical information. As dosage errors may occur when prescribing medication to children, professionals’ need for reliable medical information has increased in public health care centers and hospitals. Influenza continues to be a public health threat, with young children at risk of developing severe illness and easily transmitting the virus. Oseltamivir is used to treat children with influenza. The objective of this study was to compare searches for children’s oseltamivir and influenza diagnoses in primary and specialized care, and to determine if the searches could aid detection of influenza outbreaks. Methods We compared searches in Physician’s Databases for children’s oral suspension of oseltamivir (6 mg/mL) for influenza diagnoses of children under 7 years and laboratory findings of influenza A and B from the National Infectious Disease Register. Searches and diagnoses were assessed in primary and specialized care across Finland by season from 2012–2016. The Moving Epidemic Method (MEM) calculated seasonal starts and ends, and paired differences in the mean compared two indicators. Correlation was tested to compare seasons. Results We found that searches and diagnoses in primary and specialized care showed visually similar patterns annually. The MEM-calculated starting weeks in searches appeared mainly in the same week. Oseltamivir searches in primary care preceded diagnoses by −1.0 weeks (95% CI: −3.0, −0.3; p = 0.132) with very high correlation (τ = 0.913). Specialized care oseltamivir searches and diagnoses correlated moderately (τ = 0.667). Conclusion Health care professionals’ searches for children’s oseltamivir in online databases linked with the registers of children’s influenza diagnoses in primary and specialized care. Therefore, database searches should be considered as supplementary information in disease surveillance when detecting influenza epidemics.

Influenza A viruses (IAV), including the pandemic 2009 (pdm09) H1N1 or avian influenza H5N1 virus, may advance into more pathogenic, potentially antiviral drug-resistant strains (including loss of susceptibility against oseltamivir). Such IAV strains fuel the risk of future global outbreaks, to which this study responds by re-engineering Interferon-α2a (IFN-α2a) bioconjugates into influenza therapeutics. Type-I interferons such as IFN-α2a play an essential role in influenza infection and may prevent serious disease courses. We site-specifically conjugated a genetically engineered IFN-α2a mutant to poly(2-ethyl-2-oxazoline)s (PEtOx) of different molecular weights by strain-promoted azide-alkyne cyclo-addition. The promising pharmacokinetic profile of the 25 kDa PEtOx bioconjugate in mice echoed an efficacy in IAV-infected ferrets. One intraperitoneal administration of this bioconjugate, but not the marketed IFN-α2a bioconjugate, changed the disease course similar to oseltamivir, given orally twice every study day. PEtOxylated IFN-α2a bioconjugates may expand our therapeutic arsenal against future influenza pandemics, particularly in light of rising first-line antiviral drug resistance to IAV.