Use Of Neuraminidase Inhibitors Research Articles

The Use of Neuraminidase Inhibitors in Teenagers May Not Increase the Risk of Neuropsychiatric Adverse Events: A Nationwide Population-based Retrospective Study

Abstract Background: Pandemic influenza virus is a public health issue, and the neuraminidase inhibitors (NIs) “Oseltamivir” and “Zanamivir” are effective treatments. While teenagers use NIs, there are concerns regarding neuropsychiatric adverse events (NPAEs). Aim: We aimed to use the Taiwan National Health Insurance Research Database to identify the correlation between NPAEs and NIs use in teenagers aged 13–19 years. Methods: The final population between 2000 and 2015 included in this study was 3698 individuals, with 2287 individuals having received “Oseltamivir” and “Zanamivir” (study cohort group) and 9148 individuals not receiving “Oseltamivir” and “Zanamivir” (comparison cohort group). We initially used a multivariate Cox regression analysis during the tracking period to determine the cumulative incidence of NPAEs. Results: Our findings revealed no significant increase in the likelihood of developing NPAEs in the study group. The Kaplan–Meier survival curve demonstrated that individuals who received “Oseltamivir” and “Zanamivir” were not associated with statistically significantly increased NPAEs compared with controls (log-rank test, P = 0.724). Conclusion: No more risk in comparison of the normal population in our study, and the safety of “Oseltamivir” and “Zanamivir” is established treatments for influenza.

Influenza presentations and use of neuraminidase inhibitors by Australian general practice registrars: a cross-sectional analysis from the ReCEnT study

ObjectiveThis study aims to establish prevalence and associations of (1) influenza and influenza-like illness (IILI) presentations to Australian general practice (GP) registrars (trainees) and (2) the use of neuraminidase inhibitors...

Outcomes and Risk Factor Analysis of Plastic Bronchitis Among 321 Children with Influenza Pneumonia After Bronchoscopy Examination.

Plastic bronchitis (PB) is a rare and severe lung disease. It can be triggered by influenza virus infection, which is a common respiratory infection in children. Bronchoscopy can aid in the early detection and treatment of PB. However, the outcomes and risk for PB development in pediatric patients with influenza virus infection are not fully understood. Data from 321 children diagnosed with influenza virus pneumonia who underwent bronchoscopy examinations between 1st January, 2009 and 31st December, 2020 were retrospectively analyzed to assess the outcomes and risk factors associated with PB development. This study included 97 girls and 224 boys with influenza virus pneumonia with a median age of 42 months. Among them, 36 patients (11.2%) were categorized as having PB based on bronchoscopy findings. PB patients had significantly longer fever durations (p=0.010) and higher risks of developing severe conditions including respiratory failure (p<0.001), acute respiratory distress syndrome (p<0.001), and air-leak syndrome (p<0.001) compared to non-PB patients. Conventional treatment including the use of neuraminidase inhibitors and antibiotics did not differ between the PB and non-PB patients, but PB patients required more anti-inflammatory treatment (p=0.019) and ventilator support (p<0.001). Combined univariate and multivariate analyses suggested that radiographic findings, including mediastinal emphysema (p=0.012) and lung consolidation (p=0.012), as well as increased levels of neutrophils (p=0.026), aspartate aminotransferase (p=0.004), and lactate dehydrogenase (p<0.001), were identified as risk factors for PB development in patients with influenza virus pneumonia. Although PB patients required more intensive care and had longer hospital stays, they all recovered well after treatment. Influenza virus infection is linked to PB development in children. Identifying risk factors and early intervention such as bronchoscopy can improve the prognosis of children with PB.

Development of Digital Droplet PCR Targeting the Influenza H3N2 Oseltamivir-Resistant E119V Mutation and Its Performance through the Use of Reverse Genetics Mutants.

The monitoring of antiviral-resistant influenza virus strains is important for public health given the availability and use of neuraminidase inhibitors and other antivirals to treat infected patients. Naturally occurring oseltamivir-resistant seasonal H3N2 influenza virus strains often carry a glutamate-to-valine substitution at position 119 in the neuraminidase (E119V-NA). Early detection of resistant influenza viruses is important for patient management and for the rapid containment of antiviral resistance. The neuraminidase inhibition assay allows the phenotypical identification of resistant strains; however, this test often has limited sensitivity with high variability depending on the virus strain, drugs and assays. Once a mutation such as E119V-NA is known, highly sensitive PCR-based genotypic assays can be used to identify the prevalence of such mutant influenza viruses in clinical samples. In this study, based on an existing reverse transcriptase real-time PCR (RT-qPCR) assay, we developed a reverse transcriptase droplet digital PCR assay (RT-ddPCR) to detect and quantify the frequency of the E119V-NA mutation. Furthermore, reverse genetics viruses carrying this mutation were created to test the performance of the RT-ddPCR assay and compare it to the standard phenotypic NA assay. We also discuss the advantage of using an RT-ddPCR instead of qPCR method in the context of viral diagnostics and surveillance.

Flu-IV score: a predictive tool for assessing the risk of invasive mechanical ventilation in patients with influenza-related pneumonia

BackgroundThe need for invasive mechanical ventilation (IMV) is linked to significant morbidity and mortality in patients with influenza-related pneumonia (Flu-p). We aimed to develop an assessment tool to predict IMV among Flu-p patients within 14 days of admission.MethodsIn total, 1107 Flu-p patients from five teaching hospitals were retrospectively enrolled from January 2012 to December 2019, including 895 patients in the derivation cohort and 212 patients in the validation cohort. The predictive model was established based on independent risk factors for IMV in the Flu-p patients from the derivation cohort.ResultsOverall, 10.6% (117/1107) of patients underwent IMV within 14 days of admission. Multivariate regression analyses revealed that the following factors were associated with IMV: early neuraminidase inhibitor use (− 3 points), lymphocytes < 0.8 × 109/L (1 point), multi-lobar infiltrates (1 point), systemic corticosteroid use (1 point), age ≥ 65 years old (1 points), PaO2/FiO2 < 300 mmHg (2 points), respiratory rate ≥ 30 breaths/min (3 points), and arterial PH < 7.35 (4 points). A total score of five points was used to identify patients at risk of IMV. This model had a sensitivity of 85.5%, a specificity of 88.8%, and exhibited better predictive performance than the ROX index (AUROC = 0.909 vs. 0.594, p = 0.004), modified ROX index (AUROC = 0.909 vs. 0.633, p = 0.012), and HACOR scale (AUROC = 0.909 vs. 0.622, p < 0.001) using the validation cohort.ConclusionsFlu-IV score is a valuable prediction rule for 14-day IMV rates in Flu-p patients. However, it should be validated in a prospective study before implementation.

Противовирусная и антибактериальная терапия в лечении внебольничных пневмоний

Работа посвящена систематизации подходов к противовирусной и антибактериальной терапии в лечении внебольничных пневмоний. В настоящее время пневмония является основной причиной летальности среди всех инфекционных осложнений во всех возрастных группах и шестой ведущей причиной смерти у подобной категории больных старше 65 лет. Основным компонентом в комплексном лечении больных с гриппозной пневмонией, осложненной бактериальной инфекцией, является своевременное назначение адекватной антивирусной и антибактериальной терапии.Проведение антивирусной терапии следует начинать на раннем этапе заболевания, основываясь на клинической картине болезни, не дожидаясь лабораторного подтверждения гриппа, т.к. разброс чувствительности к экспресс-тестам может составлять от 10 до 70 %.Противовирусная терапия основана на использовании ингибиторов нейраминидазы, которые являются одними из основных препаратов для лечения вирусных пневмоний и гриппоподобных заболеваний как у взрослых, так и у детей. А проведение ранней эмпирической антимикробной терапии целесообразно у больных с признаками вирусного поражения легких при наличии у них сопутствующих гнойно-воспалительных процессов.

Role of etiotropic therapy in the treatment and prevention of influenza complications amidst the COVID-19 pandemic

Influenza remains one of the most common respiratory viral diseases with a high risk of complications. In the context of the COVID-19 pandemic, there is a possibility of simultaneous circulation of two viruses, which makes it necessary to conduct a differential diagnosis. Influenza and COVID-19 have common pathways of transmission of the pathogen and similar symptoms, so the optimal differential diagnosis is the use of test systems for both viruses. Against the background of influenza and COVID-19, complications from various organs and systems can develop. The article describes in detail the complications of influenza from the cardiovascular system. After infection with the flu virus, there is a 6-to 10-fold increase in the risk of acute myocardial infarction and a 3 - to 8-fold increase in the risk of stroke. COVID-19 is associated with arterial hypertension, diabetes mellitus, cardiac arrhythmias, myocarditis, high risk of acute myocardial infarction, and heart failure. The article presents the data of our own research, indicating that the transferred COVID-19 disease increases the risk of acute coronary syndrome, regardless of the presence of risk factors for cardiovascular events. Prevention of the development of influenza complications is the early administration of etiotropic antiviral therapy. Numerous studies confirm the effectiveness of the neuraminidase inhibitor oseltamivir in the treatment of influenza. The use of oseltamivir reduces the severity of clinical manifestations, reduces the duration of the disease, reduces the risk of complications and death. The most effective measure to prevent influenza and COVID-19 is specific immunization. In some cases, chemoprophylaxis can be used. The article discusses studies on the effectiveness of influenza chemoprophylaxis with the use of neuraminidase inhibitors.

Neonatal outcomes after neuraminidase inhibitor use during pregnancy: A meta-analysis of cohort studies.

Influenza infection poses a severe threat to pregnant mothers, and antiviral treatment is recommended. However, the safety of neuraminidase-inhibitor antiviral medications during pregnancy has not been well described. A systematic review and meta-analysis were performed to evaluate the adverse neonatal outcomes associated with exposure to neuraminidase inhibitors during pregnancy. The PubMed, Embase and Cochrane Library databases were searched to identify potential studies for inclusion. Nine cohort studies that estimated adverse neonatal outcomes associated with exposure to neuraminidase-inhibitor medication during pregnancy were included. Exposure to a neuraminidase inhibitor during pregnancy was not associated with an increased risk of congenital malformation (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.72-1.12, P = .341), low Apgar score (OR 0.96, 95% CI 0.77-1.2, P = .733) or preterm birth (OR 0.99, 95% CI 0.89-1.09, P = .771) compared with no exposure. However, exposure to a neuraminidase inhibitor was associated with a reduced risk of low birth weight (OR 0.79, 95% CI 0.68-0.92, P = .002) and giving birth to a small-for-gestational-age infant (OR 0.78, 95% CI 0.69-0.88, P < .001). Further analyses limited to oseltamivir exposure were consistent with the overall results. Exposure to neuraminidase-inhibitor medication during pregnancy does not appear to be associated with adverse neonatal outcomes. We recommend further studies to investigate this association, which will help clinicians determine whether to prescribe a neuraminidase inhibitor during pregnancy.

Neuraminidase inhibitor use in adults presenting to hospital with suspected influenza: A questionnaire-based survey of practice among hospital physicians

Abstract Background UK Public Health England (PHE) guidelines recommend the liberal use of neuraminidase inhibitors (NAIs) in hospitalised adults with suspected influenza and are aligned with international guidelines. NAI use is recommended to start as early as possible and empirical use is recommended whilst awaiting laboratory results. Current UK hospital physician knowledge, attitudes, and practises regarding the use of NAIs, and levels of adherence to guideline recommendations are not known. Methods This online, cross-sectional questionnaire-based survey of self-reported prescribing practice using clinical scenarios, was distributed to secondary care physicians involved in the assessment of adults presenting to hospital with suspected influenza. The primary outcome measure was adherence to PHE guidelines. Results There were 237 respondents to the survey. 157 (67%) of 233 respondents reported awareness of PHE guidelines. Adherence to guidelines in the clinical scenarios ranged from 56% (95% CI 49–63%) to 72% (95% CI 66–79%) with considerable variability between specialities (p = 0.0008). Not treating suspected cases was common as was withholding of NAIs whilst awaiting laboratory results, despite the acknowledgment of prolonged turnaround times. 73 of 220 (33%) respondents reported that concerns about NAI efficacy influenced their prescribing. Conclusions Concordance with national guidelines for the treatment of influenza is sub-optimal. Lack of guideline awareness and concerns over the effectiveness of NAIs are contributing factors. This study highlights a disparity between public health policy and clinical practice and suggests that strategies that promote rapid diagnostic testing and adherence to treatment guidelines are required. Study registration This study is registered with the ISRCTN:18249297.

Chinese expert consensus on the diagnosis and treatment of severely and critically ill patients with coronavirus disease 2019.

Chinese expert consensus on the diagnosis and treatment of severely and critically ill patients with coronavirus disease 2019.

Invasive pulmonary aspergillosis in immunocompetent patients hospitalised with influenza A-related pneumonia: a multicenter retrospective study

BackgroundIncreasing cases of pulmonary aspergillosis (IPA) in immunocompetent patients with severe influenza have been reported. Howevere, the risk factors for occurence and death are largely unknown.MethodsData of hospitalised patients with influenza A-related pneumonia (FluA-p) obtained from five teaching hospitals from 2031 to 2018, were reviewed. Univariate and multivariate logistical regression analyses were performed to determine the risk factors involved in the acquisition and 60-day mortality in IPA patients.ResultsOf the 693 FluA-p patients included in the study, 3.0% (21/693) were IPA patients with a 60-day mortality of 42.9% (9/21). Adjusted for confounders, a Cox proportional hazard model showed that IPA was associated with increased risk for 60-day mortality [hazard ratio (HR) 4.336, 95% confidence interval (CI) 1.191–15.784, p = 0.026] in FluA-p patients. A multivariate logistic regression model confirmed that age (odd ratio (OR) 1.147, 95% CI 1.048–1.225, p = 0.003), systemic corticosteroids use before IPA diagnosis (OR 33.773, 95% CI 5.681–76.764, p < 0.001), leukocytes > 10 × 109/L (OR 1.988, 95% CI 1.028–6.454, p = 0.029) and lymphocytes < 0.8 × 109/L on admission (OR 34.813, 95% CI 1.676–73.006, p = 0.022), were related with the acquisition of IPA. Early neuraminidase inhibitor use (OR 0.290, 95% CI 0.002–0.584, p = 0.021) was associated with a decreased risk for a 60-day mortality in IPA patients.ConclusionsOur results showed that IPA worsen the clinical outcomes of FluA-p patients. The risk factors for the acquisition and death were helpful for the clinicians in preventing and treating IPA.

Influenza management with new therapies.

Influenza represents a significant treatment burden to critical care services. A variety of treatment strategies exist, with more and more therapeutic avenues opening up as research progresses. We examined both pharmacological and supportive treatment strategies currently available to see how they might be applied in an ICU setting. Supportive care in Influenza centres around optimizing respiratory failure, particularly through well established and recognized ventilatory strategies. Noninvasive ventilation and high-flow nasal oxygen may have a limited role in selected patients under carefully monitored circumstances. Drug therapy exerts only a modest clinical effect and has been poorly studied in the critically ill, though there is some evidence to support the use of neuraminidase inhibitors (NAI) - particularly oseltamivir - as early as possible in this cohort. Newer agents have failed to demonstrate superiority over NAIs but may be useful options if the patient fails to respond or should resistant influenza strains emerge. Steroid therapy, in the absence of another indication, must be recommended against given the repeated trend towards increased mortality in this group. Influenza management is an evolving field of significant interest to any critical care provider. Currently, good respiratory supportive care and early enteral oseltamivir are the best supported treatment strategies. Further study in the intensive care setting will be needed before the use of novel agents can be recommended.

Etiotropic therapy and chemoprophylaxis of influenza with neuraminidase inhibitors

Influenza is a common respiratory infection caused by viruses of types A, B and C. Characteristic of influenza infection is the development of intoxication and damage to the epithelium of the mucous membrane of the upper respiratory tract, often the trachea. Complications of influenza occur in 10–15% of patients. Most often it is pneumonia, bacterial focal infections (sinusitis, otitis, urinary and biliary tract infections), activation of chronic infections (tuberculosis, rheumatism). In influenza infection, as in the treatment of any infectious disease, the greatest importance belongs to etiotropic therapy. The world health organization recommends the use of neuraminidase inhibitors for etiotropic treatment of influenza. Currently, 2 neuraminidase inhibitors are used in the Russian Federation - oseltamivir and zanamivir. Both of these drugs are included in the clinical guidelines approved by the Ministry of health of Russia. In the Russian pharmaceutical market, oseltamivir is represented including the domestic drug Nomides in several dosages of 75 mg, 45 mg, 30 mg, which allows it to be used in children from 3 years. Etiotropic drugs should be prescribed as early as possible from the moment of clinical manifestation of the disease, optimally - in the first 48 hours from the onset of the disease, without waiting for laboratory verification of the diagnosis. The advantages of etiotropic therapy are reducing the risk of complications, shortening the period of fever and other symptoms. It is equally important to reduce the incidence of secondary complications requiring antibiotics and hospitalizations due to influenza. Etiotropic drugs for influenza therapy, including nomides, are used to prevent influenza infection. It should be noted that chemoprophylaxis does not replace vaccination against influenza, but is an auxiliary method of preventing the disease.

Influenza A virus hemagglutinin mutations associated with use of neuraminidase inhibitors correlate with decreased inhibition by anti-influenza antibodies

BackgroundVaccination and the use of neuraminidase inhibitors (NAIs) are currently the front lines of defense against seasonal influenza. The activity of influenza vaccines and antivirals drugs such as the NAIs can be affected by mutations in the influenza hemagglutinin (HA) protein. Numerous HA substitutions have been identified in nonclinical NAI resistance-selection experiments as well as in clinical specimens from NAI treatment or surveillance studies. These mutations are listed in the prescribing information (package inserts) for FDA-approved NAIs, including oseltamivir, zanamivir, and peramivir.MethodsNAI treatment-emergent H1 HA mutations were mapped onto the H1N1 HA1 trimeric crystal structure and most of them localized to the HA antigenic sites predicted to be important for anti-influenza immunity. Recombinant A/California/04/09 (H1N1)-like viruses carrying HA V152I, G155E, S162 N, S183P, and D222G mutations were generated. We then evaluated the impact of these mutations on the immune reactivity and replication potential of the recombinant viruses in a human respiratory epithelial cell line, Calu− 3.ResultsWe found that the G155E and D222G mutations significantly increased viral titers ~ 13-fold compared to the wild-type virus. The hemagglutination and microneutralization activity of goat and ferret antisera, monoclonal antibodies, and human serum samples raised against pandemic A(H1N1)pdm09 viruses was ~ 100-fold lower against mutants carrying G155E or D222G compared to the wild-type virus.ConclusionsAlthough the mechanism by which HA mutations emerge during NAI treatment is uncertain, some NAI treatment-emergent HA mutations correlate with decreased immunity to influenza virus.

The selection pressure on the neuraminidase gene of influenza viruses isolated in Ukraine from 2009 to 2015

ABSTRACT A broad range of naturally occurring antigenic variants of the influenza virus is caused by its rapid evolutionary variability. The survival of viable influenza virus variants occurs through natural selection. The treatment of influenza infection with modern antiviral drugs – neuraminidase (NA) inhibitors – leads to the occurrence of mutations in the NA gene, which thereby result in the emergence of virus resistance to these drugs. The goal of this study was to determine the selection pressure on the NA protein of influenza viruses isolated in Ukraine from 2009 to 2015. The main method for assessing the selection pressure on proteins is to quantify the ratio of substitution rates at nonsynonymous (dN) and synonymous (dS) sites. With the help of this method, we showed that only a few codons in the NA gene were under positive selection resulting in mutations at the following sites: for influenza A viruses of the A(H1N1)pdm09 subtype – site 40, for viruses of the A(H3N2) subtype – sites 93 and 402, for Influenza B viruses of the B/Yamagata lineage – sites 74, 99, and 268, and for the viruses of the B/Victoria lineage – sites 358, 288, and 455. These sites are not associated with the NA active site, transmembrane domain, or the antigenic sites of this protein. We concluded that NA inhibitors are not a significant factor in the process of selection of the influenza viruses in Ukraine because the sites associated with the resistance of influenza viruses to NA inhibitors were not affected by positive selection. This finding could be explained by the limited use of NA inhibitors for the treatment of influenza infections in Ukraine.

Давление отбора на ген нейраминидазы вирусов гриппа, выделенных в Украине с 2009 по 2015 гг.

Большое разнообразие существующих в природе антигенных вариантов вируса гриппа вызвано его быстрой эволюционной изменчивостью. Отбор жизнеспособных вариантов вируса гриппа происходит за счет естественного отбора. Лечение гриппозной инфекции с помощью современных противовирусных препаратов – ингибиторов нейраминидазы (NA) – приводит к возникновению мутаций в гене NA, которые ведут к появлению резистентности вирусов к данным препаратам. Цель работы состояла в определении давления отбора на белок NA вирусов гриппа, выделенных в Украине в период с 2009 по 2015 год. Основным методом оценки эволюционного давления на белки является определение количественного соотношения частот замен в несинонимических (dN) и синонимических сайтах (dS). С помощью этого метода мы показали, что лишь некоторые кодоны в гене NA были под влиянием положительного отбора: для вирусов гриппа типа А подтипа A(H1N1)pdm09 – сайт 40, для вирусов подтипа A(H3N2) – сайты 93 и 402, для вирусов гриппа типа B разновидности B/Yamagata – сайты 74, 99 и 268, и для вирусов разновидности В/Victoria – сайты 358, 288 и 455. Указанные сайты не связаны ни с активным центром NA, ни с трансмембранным доменом, ни с антигенными сайтами. Ингибиторы NA не являются селективным фактором отбора вирусов гриппа в Украине, поскольку, сайты, ассоциированные с резистентностью вирусов гриппа к ингибиторам NA, не попали под влияние положительного отбора, что, вероятно, объясняется низким уровнем применения данных противовирусных препаратов в Украине.

967. Inhibition of Host Neuraminidase Increases Susceptibility to Invasive Pulmonary Aspergillosis

BackgroundInfluenza-associated aspergillosis (IAA) is an emerging fungal infection with high mortality and morbidity and the pathogenesis of this disease is not well understood. Interestingly, the number of IAA case reports has increased since the widespread use of neuraminidase inhibitors, such as oseltamivir in 2009. We set out to determine whether oseltamivir could contribute to the pathogenesis of IAA by modulating host responses.MethodsFirst, peripheral blood mononuclear cells (PBMCs) and neutrophils from healthy donors were stimulated with neuraminidase (NA)-treated A. fumigatus or were pre-exposed to NA prior to stimulation with Aspergillus conidia. In addition, PBMCs and neutrophils were pretreated with oseltamivir carboxylate prior to stimulation. Cytokines were measured from supernatants after 24 hours of incubation at 37°C. C57BL/6 and BALB/c mice were treated with oseltamivir prior to intranasal challenge with A. fumigatus. Immunosuppression was induced by corticosteroid or cyclophosphamide.ResultsWe demonstrate that Aspergillus treated with NA induced an enhanced immune response. Moreover, PBMCs and neutrophils treated with NA produced increased cytokine responses. Blocking NA in vitro with oseltamivir reduced Aspergillus-induced cytokine responses. Next we investigated the effects of blocking neuraminidase activity with oseltamivir in vivo. Immunocompetent mice and mice treated with corticosteroids showed increased mortality, lung fungal burden, and decreased cytokine production when treated with oseltamivir. These effects were not observed in cyclophosphamide-treated mice, suggesting that the effects of NA activity in anti-Aspergillus host defense acts mainly via myeloid cells.ConclusionOur results provide evidence that host neuraminidase activity is important for protective anti-Aspergillus immune responses. Treatment with oseltamivir, thus blocking host NA activity, in a setting of corticosteroid use might therefore increase susceptibility to Aspergillus infection. These results warrant further study on the role of neuraminidase and the effects of oseltamivir on susceptibility to invasive pulmonary aspergillosis during active influenza infection.Disclosures All authors: No reported disclosures.

Combined effect of anti-high-mobility group box-1 monoclonal antibody and peramivir against influenza A virus-induced pneumonia in mice.

Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti-inflammatory effect of anti-high-mobility group box-1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti-HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine-week-old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post-infection (dpi). The anti-HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti-HMGB1 mAb significantly improved survival rate whereas the anti-HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti-HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti-HMGB1 with conventional anti-influenza therapy might be useful against severe influenza virus infection.

Triple combination of FDA-approved drugs including flufenamic acid, clarithromycin and zanamivir improves survival of severe influenza in mice.

Seasonal influenza virus remains a common cause of mortality despite the use of neuraminidase inhibitors. This study evaluated the efficacy of a triple combination of zanamivir, clarithromycin and flufenamic acid (FFA) in the treatment of influenza virus A(H1N1) infection. An in vitro cell protection assay and a multiple-cycle growth assay showed that the antiviral activity of zanamivir was enhanced when combined with clarithromycin or FFA. A mouse challenge model was used here for the evaluation of the in vivo efficacy of the triple combination treatment. We found that mice receiving the triple combination of FFA, zanamivir, and clarithromycin had a significantly better survival rate than those receiving the double combination of zanamivir and clarithromycin (88% versus 44%, P = 0.0083) or zanamivir monotherapy (88% versus 26%, P = 0.0002). Mice in the FFA-zanamivir-clarithromycin triple combination group also exhibited significantly less body weight loss than those in the zanamivir-clarithromycin double combination group. There was no significant difference in the lung viral titers among the different groups from day 2 to day 6 postinfection. However, the levels of IL-1β, TNF-α and RANTES in the FFA-zanamivir-clarithromycin triple combination group were significantly lower than those in the zanamivir-clarithromycin double combination group, zanamivir monotherapy group, or solvent group on day 2 postinfection. Our findings showed that the FFA-zanamivir-clarithromycin triple combination improved the inflammatory markers and survival of severe influenza A(H1N1) infection in mice.

Trends of neuraminidase inhibitors use in children with influenza related respiratory infections.

Neuraminidase inhibitors are recommended for children hospitalized with influenza-related respiratory infections, and oseltamivir is the first choice of treatment in most situations. However, little is known regarding the recent trend in using neuraminidase inhibitors and their difference in health economy. The aim of this study was to reveal recent trends in neuraminidase inhibitor use and compare hospitalization costs across different treatment regimens. We retrospectively obtained the hospital discharge records of inpatients under 18 years of age with a diagnosis of influenza-related respiratory infections using a national inpatient database in Japan. We excluded patients with chronic medical conditions from the analyses. Multivariable mixed effects regression models were used to investigate the recent treatment trends and healthcare costs. We identified 27 771 inpatients with influenza-related respiratory infections. The proportions of neuraminidase inhibitor use increased from 62.6% in 2010 to 71.8% in2014 (Ptrend < 0.001). Correspondingly, the proportions of peramivir use showed an upward trend, ranging from 31.4% to 57.4% (Ptrend < 0.001). In contrast, proportions of oseltamivir and zanamivir use decreased from 26.1% to 12.1% and from 4.9% to 1.5%, respectively (Ptrend < 0.001). Laninamivir use did not change over the period. Total hospitalization costs were higher in the peramivir group than in the oseltamivir group (adjusted difference, $84.3; 95%CI, $70.7-$98.4). We observed an increasing trend in peramivir use and decreasing trends in use of oseltamivir and zanamivir. Treatment with peramivir required higher hospitalization costs.