Oseltamivir Treatment Research Articles

Unique synergistic antiviral effects of Shufeng Jiedu Capsule and oseltamivir in influenza A viral-induced acute exacerbation of chronic obstructive pulmonary disease

BackgroundThe aim of the present study was to investigate the synergistic effects and interactive mechanisms of Shufeng Jiedu Capsule (SFJDC) combined with oseltamivir in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) induced by the influenza A virus (IAV). MethodsThe extraction of SFJDC was analyzed by UHPLC/ESI Q-Orbitrap Mass Spectrometry. Human bronchial epithelial cells were isolated from COPD (DHBE) bronchial tissues, co-cultured with IAV for 24 h, and were subsequently treated with SFJDC and/or oseltamivir. Cell viability was detected by MTT assay. A rat model of COPD with IAV infection was established and treated with SFJDC and/or oseltamivir. Interleukin (IL)-1β and IL-18 in serum and bronchoalveolar lavage fluid (BALF) were measured by ELISA. Additionally, mRNA and protein levels of NLRP3 inflammasome pathway were measured by quantitative real-time PCR and Western blotting, respectively. ResultsSFJDC and/or oseltamivir, at their optimal concentrations, had no significant cytotoxicity against DHBEs. The levels of NLRP3-inflammasome-associated components were significantly elevated after cells were inoculated with IAV, whereas the mRNA and protein levels of these components were significantly decreased after treatment with SFJDC and/or oseltamivir in vitro. Moreover, in vivo, the combination of SFJDC and oseltamivir improved survival rates, attenuated clinical symptoms, induced weight gain, alleviated lung damage, and significantly reduced IL-1β and IL-18 levels in serum and BALF, as well as reduced the expression levels of NLRP3-associated components and viral titers in lung homogenates. ConclusionSFJDC combined with oseltamivir treatment significantly attenuated IAV-induced airway inflammation and lung viral titers. Hence, our findings may provide a novel therapeutic strategy for IAV-induced respiratory infection.

High-Dose Dexamethasone (HD-DXM) Plus Oseltamivir Versus High-Dose Dexamethasone for Treatment of Adult Primary Immune Thrombocytopenia: Interim Analysis of a Prospective, Multicenter, Randomized, Controlled Trial

Introduction: Primary immune thrombocytopenia (ITP) is an acquired hemorrhagic disorder caused by immune-mediated platelet destruction and insufficient platelet production. As the first-line treatment of ITP, corticosteroids enable the recovery of platelet count in 60% to 80% of cases. However, a large proportion of patients would relapse during steroid tapering or withdrawal. Recently, sporadic studies reported successful treatment of ITP with oseltamivir which decreased platelet destruction through inhibition of platelet desialylation, a possible mechanism leading to Fc-independent platelet phagocytosis by hepatocytes. We hypothesize that corticosteroids and oseltamivir might complement each other in terms of mechanisms and induce a better response in ITP. Therefore, a prospective randomized controlled trial was conducted to compare the efficacy and safety of high-dose dexamethasone (HD-DXM) plus oseltamivir with HD-DXM monotherapy in adult ITP. Here we report the interim analysis of this study. Methods: From February 2016 to May 2018, 80 newly diagnosed treatment-naïve ITP patients from 5 tertiary medical centers in China were screened in the trial (NCT01965626). Dexamethasone was administered orally at 40 mg daily to both arms for 4 days (days 1 - 4). If platelet counts remained < 30 × 109/L or there were bleeding symptoms by day 10, another course of HD-DXM was given (days 11 -14). For the combination arm, oral oseltamivir was given concomitantly at a dosage of 75 mg twice daily for the first 10 days (days 1 - 10). The primary endpoints were initial response and sustained response (SR). Platelet counts should be confirmed on two separate occasions at least 7 days apart when defining responses (CR: platelet count ≥ 100×109/L and absence of bleeding; R: platelet count ≥ 30 × 109/L but < 100 × 109/L and at least a doubling of baseline and absence of bleeding). Initial responses were assessed by day 14. Responders underwent follow-up for at least 12 months or until relapse. Response lasting for at least 6 consecutive months without additional ITP-specific intervention was regarded as SR. Secondary endpoints included time to response (TTR), bleeding scores, duration of response and adverse events (AEs). Platelet transfusion was permitted in patients with severe bleeding symptoms and recorded. Requirements for any additional ITP-specific intervention were considered as treatment failure. Results: Fifty-nine patients were enrolled, of whom 28 were randomly to receive HD-DXM plus oseltamivir and 31 to HD-DXM monotherapy. Demographics and baseline characteristics were balanced between the 2 arms (Table 1). Results showed that HD-DXM plus oseltamivir achieved a higher incidence of initial response than HD-DXM alone at day 14 (82.1% vs. 58.1%, P = 0.045). At the end of 6 months, SR rate in the HD-DXM plus oseltamivir arm was higher than that in the HD-DXM monotherapy arm even though it did not reach statistical significance (42.8% vs. 25.8%, P = 0.167). Relapse-free survival in the HD-DXM plus oseltamivir arm was significantly improved compared with the HD-DXM monotherapy arm during follow-up period (HR 1.96, Log Rank P =0.043), as estimated by the Kaplan-Meier analysis. There was no statistical difference in median TTR between the two arms (P > 0.05). Bleeding was well controlled in both arms, with comparable post-treatment bleeding events (7.1% vs.19.3%, P> 0.05) and lower bleeding scores in the HD-DXM plus oseltamivir arm (0 vs. 0, P = 0.036). Incidence of AEs was similar between the 2 arms (P > 0.05). A slight increase in gastrointestinal reactions was observed in the HD-DXM plus oseltamivir arm but it did not reach statistical significance. Most of the AEs were mild to moderate (grade 1 to 2) and usually resolved spontaneously after medication was completed. No previously undescribed AEs was observed. Conclusions: The combination of HD-DXM with oseltamivir significantly improved the initial response in newly diagnosed ITP patients. However, due to the limitation of sample size, the conclusion of SR superiority can hardly be drawn at the moment. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Oseltamivir, a sialidase inhibitor which is extensively used in the treatment of or prophylaxis against influenza virus A and B. It has been reported that the treatment of oseltamivir could concomitantly increase platelet counts, which was independent whether influenza was diagnosed. Along those lines, several studies showed successful treatment of ITP patients with oseltamivir. We hypothesize that HD-DXM and oseltamivir might complement each other in terms of the mechanisms and achieve better response rates in ITP patients.

Gegen Qinlian Decoction Downregulates the TLR7 Signalling Pathway to Control Influenza A Virus Infection

Ethnopharmacological relevanceIn recent years, Gegen Qinlian decoction (GQD) has been applied to treat influenza virus infection, and its clinical effectiveness has been shown. However, the potential mechanism by which GQD acts on influenza A virus (IAV) has not been fully elucidated. Traditional Chinese medicine (TCM) formulas are well known to have multiple targets and effects. Our previous experiments examined the mechanism by which TCM can be used to treat influenza from the perspective of the influenza immune mechanism. Aim of the studyTo explore the possible mechanism by which GQD affects mice infected with the FM1 strain of influenza virus. Materials and MethodsForty-eight C57BL/6 mice were divided randomly into four groups: a normal control (NG) group, an IAV infection (VG) group, an IAV + oseltamivir (30.44 mg/kg) treatment (VO) group, and an IAV + GQD (9.74 g/kg) treatment (VQ) group. We also grouped forty-eight Toll-like receptor 7 knockout (TLR7−/−) mice in the same manner. The pulmonary mRNA expression of TLR7, myeloid differentiation factor 88 (MyD88), and nuclear factor (NF)-κB p65 was measured by RT-qPCR, and the pulmonary protein expression of TLR7, MyD88, and NF-κB p65 was measured by western blot. The proportions of T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cells were measured by flow cytometry. ResultsIAV infection led to low body weights and high viral load. Compared with those in the NG group, the mRNA expression levels of TLR7, MyD88, and NF-κB p65 in the VG group were upregulated (P < 0.05). However, the mRNA and protein expression levels of TLR7, MyD88, and NF-κB p65 were lower in the VO and VQ groups than in the VG group (P < 0.05). IAV infection led to increased proportions of Th1/Th2 and Th17/Treg cells in the VG group. In the VO and VQ groups, both Th2 and Th1 cell numbers were increased, resulting in a lower Th1/Th2 proportion than that in the VG group. ConclusionsGQD downregulated the expression of some key TLR signalling pathway factors. GQD also affected the differentiation of CD4+ T cells, thereby exerting a protective systemic effect on influenza virus infection. In conclusion, GQD activated a balanced inflammatory response in the host to limit immune pathological injury and improve clinical and survival outcomes.

Acute Macular Neuroretinopathy Associated with Acute Influenza Virus Infection

ABSTRACT Purpose: To describe a prospective case series of patients with acute macular neuroretinopathy (AMN) associated with acute influenza virus infection Methods: Patients who presented with acute macular neuroretinopathy associated with confirmed influenza virus infection were subject to a detailed clinical history, HLA typing and longitudinal ophthalmological and imaging examinations. Results: Four female patients aged 18 to 32 years were studied. They reported the onset of ocular symptoms between 2 and 5 days after the development of flu like symptoms. Three patients had confirmed acute influenza B infection, while the fourth had influenza A. OCT angiography only demonstrated abnormal choriocapillaris perfusion in 1 patient and early oral Oseltamivir treatment appeared not to affect the ophthalmic outcome in one patient. Conclusion: This is the first report of AMN associated with virologically confirmed acute influenza virus infection. Variation in HLA alleles do not appear to predispose patients to influenza associated AMN.

Influenza-associated mortality in hospital care: a retrospective cohort study of risk factors and impact of oseltamivir in an English teaching hospital, 2016 to 2017.

BackgroundEvidence of an oseltamivir treatment effect on influenza A(H3N2) virus infections in hospitalised patients is incomplete.AimsThis cohort study aimed to evaluate risk factors for death among PCR-confirmed hospitalised cases of seasonal influenza A(H3N2) of all ages and the impact of oseltamivir.MethodsParticipants included all 332 PCR-confirmed influenza A(H3N2) cases diagnosed between 30 August 2016 and 17 March 2017 in an English university teaching Hospital. Oseltamivir treatment effect on odds of inpatient death was assessed by backward stepwise multivariable logistic regression analysis.ResultsThe odds of death were reduced by two thirds (odds ratio (OR): 0.32; 95% confidence interval (CI): 0.11–0.93), in inpatients treated with a standard course of oseltamivir 75 mg two times daily for 5 days – compared with those untreated with oseltamivir, after adjustment for age, sex, current excess alcohol intake, receipt of 2016/17 seasonal influenza vaccine, serum haemoglobin and hospital vs community attribution of acquisition of influenza.ConclusionsOseltamivir treatment given according to National Institutes of Clinical Excellence (NICE); United States Centres for Disease Control and Prevention (CDC); Infectious Diseases Society of America (IDSA) and World Health Organization (WHO) guidelines was shown to be effective in reducing the odds of mortality in inpatients with PCR-confirmed seasonal influenza A(H3N2) after adjustment in a busy routine English hospital setting. Our results highlight the importance of hospitals complying with relevant guidelines for prompt seasonal influenza PCR testing and ensuring standard oseltamivir treatment to all PCR-confirmed cases of seasonal influenza.

Cold Weather Viruses.

1. Asif Noor, MD* 2. Theresa Fiorito, MD* 3. Leonard R. Krilov, MD*,† 1. *Department of Pediatrics, Children's Medical Center, NYU Winthrop Hospital, Mineola, NY 2. †Department of Pediatrics, State University of New York, Stony Brook School of Medicine, Stony Brook, NY * Abbreviations: AAP: : American Academy of Pediatrics Adv: : adenovirus CDC: : Centers for Disease Control and Prevention FDA: : Food and Drug Administration hMPV: : human metapneumovirus PCR: : polymerase chain reaction PIV: : parainfluenza virus RSV: : respiratory syncytial virus RV: : rhinovirus Clinicians must learn to identify viral infections in children during the winter months and must practice caution with the use of unnecessary medications in such cases. Recognition of the clinical pattern of viral infection (eg, bronchiolitis) in conjunction with judicious use of viral tests (either office-based immunoassays or newer molecular tests) may assist in epidemiological monitoring, cohorting patients in the hospital, withholding unnecessary therapies, and providing a definitive diagnosis. After completing this article, readers should be able to: 1. Review the epidemiological aspects and clinical signs and symptoms of common cold weather viruses. 2. Recognize situations in which viral testing is indicated. 3. Recognize situations in which treatment is indicated. In early November you are evaluating a 9-month-old boy born at 33 weeks of gestation. The infant presents with 2 days of fevers (101°F–102°F [38.3°C–38.8°C]), copious rhinorrhea, and 1 day of coughing with difficulty breathing. He is otherwise feeding well and has had adequate urination. His 4-year-older sister has an upper respiratory tract infection. On physical examination, the infant has a respiratory rate of 45 breaths/min without chest wall retractions. On auscultation there is good air entry with scattered rhonchi bilaterally. What is the most appropriate next step in management? 1. Obtain respiratory syncytial virus (RSV) and influenza antigen testing. 2. Obtain a chest radiograph to look for focal infiltrate. 3. Provide supportive care with nasal …

Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 feeding enhances humoral immune responses, which are suppressed by the antiviral neuraminidase inhibitor oseltamivir in influenza A virus–infected mice

Antiviral neuraminidase inhibitors, such as oseltamivir, zanamivir, and peramivir, are widely used for treatment of influenza virus infection. We reported previously that oseltamivir inhibits the viral growth cycle, ameliorates symptoms, and reduces viral antigen quantities. Suppressed viral antigen production, however, induces a reduction of acquired antiviral humoral immunity, and increases the incidence of re-infection rate in the following year. To achieve effective treatment of influenza virus infection, it is necessary to overcome these adverse effects of antiviral neuraminidase inhibitors. Feeding of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus (L. bulgaricus) OLL1073R-1 is reported to have immune-stimulatory effects on influenza virus infection in mice and humans. In the present study, we assessed the effect of feeding L. bulgaricus OLL1073R-1 yogurt cultures (YC) on local and systemic humoral immune responses, which were suppressed by oseltamivir treatment, in mice infected with influenza A virus. Yogurt culture (1.14 × 108 cfu/0.4 mL per mouse per day) or sterile water (vehicle) was administered by intragastric gavage for 35 d. At d 22, influenza A virus/Puerto Rico/8/34 (H1N1) (PR8; 0.5 pfu/15 μL per mouse) was instilled intranasally, followed immediately by oral administration of oseltamivir (50 μg/100 μL per mouse, twice daily) or 5% methylcellulose (100 μL/mouse) as a vehicle for 13 d. Titers of anti-PR8-specific IgG and IgA in serum and mucosal secretory IgA (S-IgA) and IgG in bronchoalveolar lavage fluid (BALF) were analyzed by ELISA at 14 d after infection. Oseltamivir significantly suppressed the induction of anti-PR8-specific IgG and IgA in serum and S-IgA and IgG in BALF after infection. Feeding YC mildly but significantly stimulated production of PR8-specific IgA in serum, S-IgA in BALF, and IgG in serum without changing the IgG2a:IgG1 ratio. We analyzed the neutralizing activities against PR8 in serum and BALF and found that oseltamivir also reduced protective immunity, and YC feeding abrogated this effect. The immune-stimulatory tendency of YC on anti-PR8-specific IgA and IgG titers in serum and BALF was also detected in mice re-infected with PR8, but the effect was insignificant, unlike the effect of YC in the initial infection.

Patterns of influenza B circulation in Latin America and the Caribbean, 2010-2017.

ObjectiveThere are limited published data about the circulation of influenza B/Victoria and B/Yamagata in Latin America and the Caribbean (LAC) and most countries have a vaccine policy that includes the use of the trivalent influenza vaccine. We analyzed influenza surveillance data to inform decision-making in LAC about prevention strategies, such as the use of the quadrivalent influenza vaccine.MethodsThere are a total of 28 reference laboratories and National Influenza Centers in LAC that conduct influenza virologic surveillance according to global standards, and on a weekly basis upload their surveillance data to the open-access World Health Organization (WHO) platform FluNet. These data include the number of specimens tested for influenza and the number of specimens positive for influenza by type, subtype and lineage, all by the epidemiologic week of specimen collection. We invited these laboratories to provide additional epidemiologic data about the hospitalized influenza B cases. We conducted descriptive analyses of patterns of influenza circulation and characteristics of hospitalized cases. We compared the predominant B lineage each season to the lineage in the vaccine applied, to determine vaccine mismatch. A Chi-square and Wilcoxan statistic were used to assess the statistical significance of differences in proportions and medians at the P<0.05 level.FindingsDuring 2010–2017, the annual number of influenza B cases in LAC was ~4500 to 7000 cases. Since 2011, among the LAC-laboratories reporting influenza B lineage using molecular methods, both B/Victoria and B/Yamagata were detected annually. Among the hospitalized influenza B cases, there were statistically significant differences observed between B/Victoria and B/Yamagata cases when comparing age and the proportion with underlying co-morbid conditions and with history of oseltamivir treatment (P<0.001). The proportion deceased among B/Victoria and B/Yamagata hospitalized cases did not differ significantly. When comparing the predominant influenza B lineage detected, as part of surveillance activities during 63 seasons among 19 countries, to the lineage of the influenza B virus included in the trivalent influenza vaccine used during that season, there was a vaccine mismatch noted during 32% of the seasons analyzed.ConclusionsInfluenza B is important in LAC with both B/Victoria and B/Yamagata circulating annually in all sub regions. During approximately one-third of the seasons, an influenza B vaccine mismatch was identified. Further analyses are needed to better characterize the medical and economic burden of each influenza B lineage, to examine the potential cross-protection of one vaccine lineage against the other circulating virus lineage, and to determine the potential impact and cost-effectiveness of using the quadrivalent vaccine rather than the trivalent influenza vaccine.

Oseltamivir Therapy Improves Survival in Critically Ill Patients with Severe Influenza

Background: We aimed to determine whether treatment with oseltamivir was associated with decreased mortality among patients admitted to intensive care units (ICUs) with severe influenza and whether early therapy (within 48 hours of symptoms onset) was associated with improved survival rates. Methods: This was a prospective observational study of patients with confirmed influenza who were admitted to 184 ICUs in Spain. The primary outcomes were to investigate the association of ICU mortality with oseltamivir therapy by comparing patients who are untreated (UT group) with those who are treated (all treated; AT group) and those in early treatment (ET) and late treatment (LT) groups. We also assessed the associations of both ET and LT with ICU mortality and compared the results. Findings: We enrolled 4,175 patients of whom 3,537 met the inclusion criteria. Most patients were diagnosed with influenza pneumonia (84·7%). When comparing the AT (n=3,439) and UT (n=98) groups, the former had higher survival after adjusting for severity and confounding factors (Hazard ratio [HR] 0·67; p=0·03). We included 3,388 patients to compare the ET and LT groups. In the multivariable analysis, ICU mortality was lower in the ET group, having an odds ratio of 0·7 (p=0·004). When propensity score matching was applied to a matched cohort (ET, n=790; LT, n=2,522), the ET group had lower ICU mortality (HR 0·78; p=0·008) compared with the LT group, even after a competing risks analysis (sub-HR 0·79; p=0·01). Interpretation: Oseltamivir treatment is associated with better survival rates in patients admitted to ICU with severe influenza, especially when initiated within 48 hours of illness onset. Funding Statement: SEMICYUC (Spanish Society of Critical Care) and Ricardo Barri Casanovas Foundation. Declaration of Interests: JSN-V-T has received research funding from F. Hoffman-La Roche for separate work. He is currently seconded to the Department of Health and Social Care, England (DHSC). The views expressed in this paper are those of the authors and not necessarily those of DHSC. CG-V has received the INTENSIFICACIO Grant- a grant supported by the Catalan Health Agency [PERIS (Pla estrategic de recerca i innovacio en salut – ‘Strategic Plan for Research and Innovation in HealthCare’)]. All other authors declare no competing interests. Ethics Approval Statement: The study was approved by the Joan XXIII University Hospital Ethics Committee (IRB#11809). All data were anonymised, allowing the requirement for informed consent to be waived.

Characterization of viral genomic mutations in novel influenza A (H7N9)-infected patients: the association between oseltamivir-resistant variants and viral shedding duration.

Since February 2013, human infections with the novel influenza A H7N9 virus have occurred in eastern China. It is important to detect mutations in viral genes and analyze the clinical features of patients and viral shedding duration related to neuraminidase inhibitor (NAI) resistance. We collected clinical specimens from 31 hospitalized H7N9 patients and sequenced NA, PB2, HA, and M gene fragments. Of the 31 identified patients, 7 (22.6%) carried the R292K substitution in NA, 30 (96.8%), 3 (9.7%), and 5 (16.1%) carried E627K, Q591K, and D701N mutations in PB2, respectively, and 2 (6.5%) carried both E627K and D701N mutations in PB2. All 26 identified patients harbored Q226L mutations and possessed only a single arginine (R) at cleavage sites in the HA and a S31N mutation in M2. Among 7 NA-R292K mutated patients, 3 died and 4 were discharged. There was no significant difference in the days that patients started oseltamivir treatment after symptom onset between NA-R292K mutant and NA-R292 wild-type patients (median days, 7 vs 6, P = 0.374). NA-R292K mutant patients had a significantly longer duration of viral shedding than NA-R292 wild-type patients after oseltamivir treatment (median days, 10 vs 5, P = 0.022). The mutation of R292K in NA conferring the potential ability of oseltamivir resistance resulted in prolonged viral duration and poor outcome and should be taken into consideration in the clinical management of infected patients.Electronic supplementary materialThe online version of this article (10.1007/s11262-019-01678-8) contains supplementary material, which is available to authorized users.

PB2025 ACUTE RESPIRATORY VIRAL INFECTIONS IN CHILDREN WITH ACUTE LEUKEMIA

Background:Although major advances have been made in the treatment of leukemia in recent years, infections that develop during treatment still cause significant morbidity and mortality in children with acute leukemias. The general approach in febrile neutropenia is to initiate empirical antibacterial therapy for possible bacterial infections and to add antifungal therapy when necessary. On the other hand, considering that viral respiratory infections are the most common cause of febrile infections in all children, one might expect that they are also among the possible causes of infections in children with acute leukemia.Aims:In this study, we aimed to investigate the frequency, etiology and clinical features of viral infections in children with acute leukemia.Methods:This single‐center retrospective study was conducted in children with diagnosis of acute leukemia in Dokuz Eylül University Pediatric hematology Clinic. Patients who presented with symptoms of respiratory tract infection and in whom positive causative viral agents were detected enrolled in the study. Respiratory virus panel including 20 respiratory viruses was studied by real‐time multiplex polymerase chain reaction analysis of nasopharyngeal aspirates.Results:A total of 201 samples of nasopharyngeal aspirates were sent from 84 patients between June 2011 and June 2018. At least one viral causative agent was detected in 108 samples that were sent from 55 patients. More than one nasophayngeal aspirate was positive in 28 of 55 (51%) patients at different times. Forty‐seven patients (91%) had acute lymphoblastic leukemia (ALL) and 8 (9%) had acute myeloid leukemia (AML). The median age at diagnosis was 52 months (5‐193). Infections were most common during the induction period (57%). The most common complaints during the infections were cough (74%), runny nose (68%) and fever (65%). The absolute neutrophil count was below 500 / mm3 in 55 (50%) of 108 incidents. The most frequently detected factors were human rhinovirus (48%), parainfluenza virus (14%), respiratory syncytial virus (RSV) (12%), influenza virus (10%) and adenovirus (10%). Blood culture‐proven bacterial infection was detected simultaneously in 23 (21%) and probable invasive aspergillosis was detected simultaneously in 7 (6%) of 108 incidents. All patients with influenza A received oseltamivir treatment. The clinical findings were completely resolved on the median 7th day (2‐20 days) after the onset of symptoms. Six patients required invasive/ noninvasive respiratory support, three of whom were followed up in the intensive care unit. Of the three patients in the intensive care unit, two had RSV and one had parainfluenza virus. Death occurred in one patient due to RSV pneumonia.Summary/Conclusion:In this study; one or more viral agents were detected in half of respiratory tract infections in patients with acute leukemia. Detection of viral agents in this patient group will enable the use of existing antiviral drugs such as oseltamivir, and will enable treatment and follow‐up more effectively. In addition, identification of a viral agent may help explain the clinical situation in febrile neutropenia cases where a bacterial /fungal agent cannot be detected and there is no response to empirical antibacterial/antifungal treatment.

Oseltamivir for the treatment of influenza in children and adolescents

IntroductionInfluenza is a generally a benign disease, but occasionally it can cause serious complications. There is controversy about the benefits of antiviral treatment. ObjectivesTo provide some recommendations on the treatment with oseltamivir in paediatric patients with influenza, based on the best data available and valid in our environment. MethodsThe Respiratory Infections Group of the Spanish Society of Paediatric Infectious Diseases carried out a review of the literature. The findings were analysed using the GRADE methodology, and recommendations were made. ResultsThe systematic use of diagnostic tests for influenza in the outpatient setting, or in the emergency room, in immunocompetent patients with a compatible clinical picture is not recommended. If the aim is to prevent serious events, the use of antivirals is not recommended for the vast majority of healthy and asthmatic patients with influenza or suspected seasonal flu. The systematic use of oseltamivir in patients admitted to hospital with influenza is not recommended. Oseltamivir treatment is recommended in any patients with influenza and pneumonia or severe illness, and critically ill patients, especially during the first 48h of illness. The treatment of patients with risk factors is recommended, considering their underlying disease. Influenza vaccination, together with basic isolation measures, continue to be the main tool in the prevention of influenza. ConclusionIn some situations, there are sufficient data to issue clear recommendations. In other situations, the data are incomplete, and only allows weak recommendations.

Effect of aloin on viral neuraminidase and hemagglutinin-specific T cell immunity in acute influenza

Background: Millions of people are infected by the influenza virus worldwide every year. Current selections of anti-influenza agents are limited and their effectiveness and drug resistance are still of concern.Purpose: Investigation on in vitro and in vivo effect of aloin from Aloe vera leaves against influenza virus infection.Methods: In vitro antiviral property of aloin was measured by plaque reduction assay in which MDCK cells were infected with oseltamivir-sensitive A(H1N1)pdm09, oseltamivir-resistant A(H1N1)pdm09, H1N1 or H3N2 influenza A or with influenza B viruses in the presence of aloin. In vivo activity was tested in H1N1 influenza virus infected mice. Aloin-mediated inhibition of influenza neuraminidase activity was tested by MUNANA assay. Aloin treatment-mediated modulation of anti-influenza immunity was tested by the study of hemagglutinin-specific T cells in vivo.Results: Aloin significantly reduced in vitro infection by all the tested strains of influenza viruses, including oseltamivir-resistant A(H1N1)pdm09 influenza viruses, with an average IC50 value 91.83 ± 18.97 μM. In H1N1 influenza virus infected mice, aloin treatment (intraperitoneal, once daily for 5 days) reduced virus load in the lungs and attenuated body weight loss and mortality. Adjuvant aloin treatment also improved the outcome with delayed oseltamivir treatment. Aloin inhibited viral neuraminidase and impeded neuraminidase-mediated TGF-β activation. Viral neuraminidase mediated immune suppression with TGF-β was constrained and influenza hemagglutinin-specific T cell immunity was increased. There was more infiltration of hemagglutinin-specific CD4+ and CD8+ T cells in the lungs and their production of effector cytokines IFN-γ and TNF-α was boosted.Conclusion: Aloin from Aloe vera leaves is a potent anti-influenza compound that inhibits viral neuraminidase activity, even of the oseltamivir-resistant influenza virus. With suppression of this virus machinery, aloin boosts host immunity with augmented hemagglutinin-specific T cell response to the infection. In addition, in the context of compromised benefit with delayed oseltamivir treatment, adjuvant aloin treatment ameliorates the disease and improves survival. Taken together, aloin has the potential to be further evaluated for clinical applications in human influenza.

Untargeted metabolomics analysis of the upper respiratory tract of ferrets following influenza A virus infection and oseltamivir treatment.

Influenza is a highly contagious respiratory disease that causes high global morbidity and mortality each year. The dynamics of an influenza infection on the host metabolism, and how metabolism is altered in response to neuraminidase inhibitor drug therapy, is still in its infancy but of great importance. We aim to investigate the suitability of ferret nasal wash samples for metabolomics-based analysis and characterization of influenza infections and oseltamivir treatment. Virological and metabolic analyses were performed on nasal wash samples collected from ferrets treated with oseltamivir or a placebo. Untargeted metabolomics was performed using a gas chromatography coupled withmass spectrometery(GC-MS) based protocol that comprised a retention time (RT) locked method and the use of a commercial metabolomics library. Ferret activity was reduced at 2-3 days post infection, which coincided with the highest influenza viral titre. The metabolomics data indicated a shift in metabolism during various stages of infection. The neuraminidase inhibitor oseltamivir created considerable downregulation of energy center metabolites (glucose, sucrose, glycine and glutamine), which generated high levels of branched amino acids. This further increased branched amino acid degradation and deregulation via glycerate-type intermediates and biosynthesis of fatty acids in oseltamivir-treated animals where abrogated weight loss was observed. Metabolomics was used to profile influenza infection and antiviral drug treatment in ferrets. This has the potential to provide indicators for the early diagnosis of influenza infection and assess the effectiveness of drug therapies.

Effect of Early Oseltamivir Treatment on Mortality in Critically Ill Patients With Different Types of Influenza: A Multiseason Cohort Study.

The available evidence on whether neuraminidase inhibitors reduce mortality in patients with influenza is inconclusive and focuses solely on influenza A/H1N1pdm09. We assessed whether early oseltamivir treatment (≤48 hours from symptom onset) decreases mortality compared to late treatment in a large cohort of critically ill patients with influenza of all types. The study included all adults with laboratory-confirmed influenza hospitalized in intensive care units (ICUs) in Greece over 8 seasons (2010-2011 to 2017-2018) and treated with oseltamivir. The association of early oseltamivir with mortality was assessed with log-binomial models and a competing risks analysis estimating cause-specific and subdistribution hazards for death and discharge. Effect estimates were stratified by influenza type and adjusted for multiple covariates. A total of 1330 patients were studied, of whom 622 (46.8%) died in the ICU. Among patients with influenza A/H3N2, early treatment was associated with significantly lower mortality (relative risk, 0.69 [95% credible interval {CrI}, .49-.94]; subdistribution hazard ratio, 0.58 [95% CrI, .37-.88]). This effect was purely due to an increased cause-specific hazard for discharge, whereas the cause-specific hazard for death was not increased. Among survivors, the median length of ICU stay was shorter with early treatment by 1.8 days (95% CrI, .5-3.5 days). No effect on mortality was observed for A/H1N1 and influenza B patients. Severely ill patients with suspected influenza should be promptly treated with oseltamivir, particularly when A/H3N2 is circulating. The efficacy of oseltamivir should not be assumed to be equal against all types of influenza.

Clinical indices and mortality of hospitalized avian influenza A (H7N9) patients in Guangdong, China.

Background:Six epidemic waves of human infection with avian influenza A (H7N9) virus have emerged in China with high mortality. However, study on quantitative relationship between clinical indices in ill persons and H7N9 outcome (fatal and non-fatal) is still unclear. A retrospective cohort study was conducted to collect laboratory-confirmed cases with H7N9 viral infection from 2013 to 2015 in 23 hospitals across 13 cities in Guangdong Province, China.Methods:Multivariable logistic regression model and classification tree model analyses were used to detect the threshold of selected clinical indices and risk factors for H7N9 death. The receiver operating characteristic curve (ROC) and analyses were used to compare survival and death distributions and differences between indices. A total of 143 cases with 90 survivors and 53 deaths were investigated.Results:Average age (Odds Ratio (OR) = 1.036, 95% Confidence Interval (CI) = 1.016–1.057), interval days between dates of onset and confirmation (OR = 1.078, 95% CI = 1.004–1.157), interval days between onset and oseltamivir treatment (OR = 5.923, 95% CI = 1.877–18.687), body temperature (BT) (OR = 3.612, 95% CI = 1.914–6.815), white blood cell count (WBC) (OR = 1.212, 95% CI = 1.092–1.346) were significantly associated with H7N9 death after adjusting for confounders. The chance of death from H7N9 infection was 80.0% if BT was over 38.1 °C, and chance of death is 67.4% if WBC count was higher than 9.5 (109/L). Only 27.1% of patients who began oseltamivir treatment less than 9.5 days after disease onset died, compared to 68.8% of those who started treatment more than 15.5 days after onset.Conclusions:The intervals between date of onset and confirmation of diagnosis, between date of onset to oseltamivir treatment, age, BT and WBC are found to be the best predictors of H7N9 mortality.

Frequency of Influenza-A-H1N1 in Patients with Community-Acquired Pneumonia Admitted to Loghman Hakim Hospital

Background: Here we assessed the incidence of Influenza-A-H1N1-related pneumonia in community-acquired pneumonia (CAP) at Loghman Hakim Hospital, Tehran, Iran. M aterials and Methods: In this prospective study from November 22, 2016, to June 21, 2017, patients with CAP and suspected to seasonal influenza were included. Rapid Antigen test and quantitative real-time PCR assay were performed on samples. P-value < 0.05 was considered significant. In addition, radiologic patterns of them were evaluated. R es ults: a total of 29 admitted CAP patients were suspected of seasonal influenza. Two cases out of them were positive for influenza by real-time PCR, similar to result of influenza rapid test. The most common finding in their chest X ray was consolidation in one lobe. None of them vaccinated against influenza. Only nine patients received empiric Oseltamivir treatment. The amount of irrational antibiotic administration was significant. C onclusion: Despite low statistical numbers, admitted influenza CAP patients did not have unusual symptoms and radiologic patterns. Other results in this study showed need for antibiotic stewardship program and better training about necessity of vaccination.

2501. Impact of Influenza A and B Infection on Stem Cell Transplant Patients During the 2017–2018 Season at a Single Center

BackgroundSeasonal influenza causes significant morbidity and mortality on HSCT recipient. The 2017–2018 influenza has been characterized in the United States by prolonged high rates of both influenza A (IAV) and B (IBV) and low vaccine effectiveness. The aim of this study was to assess the impact of both IAV and IBV during 2017–2018 influenza season on a cohort of stem cell transplant (SCT) recipients at Weill Cornell- NYP.MethodsWe reviewed charts of HSCT recipients that were diagnosed with influenza by PCR on nasopharyngeal swabs. Demographics, clinical and microbiological data, and outcomes were collected. The study was approved by Weill Cornell Institutional review board.ResultsFrom September 2017 to March 2018, 30 stem cell transplant recipient at NYP were diagnosed with influenza. IAV cases peaked in January (11 cases) while IBV infected-patients were equally distributed from December to March. Infected subject were more likely to be male (n = 20, 66.6%) with mean age of 57 ± 12 (IAV) vs. 59 + 11 (IBV). Nine patients had received auto SCT and 21 patient allo SCT. Most commons symptoms were cough (present in all patients), fever (28/30), nausea, dyspnea. Patient received oseltamivir (for 5 or 10 days) in 28/30 cases, with one patient developing resistance under treatment. Interestingly both IAV and IBV caused lower respiratory tract infection (LRTI, 7 cases) with severe pneumonia (IAV 1 cases, IBV 2 cases) and intubation. In two severe cases IV was detected in the BAL. 13 subjects (56%) with a URTI and 4 (43%) subjects with LRTI had not received the influenza vaccine for the season. Prolonged shedding of influenza on oseltamivir treatment was documented in 7 patients.ConclusionBoth IAV and IBV are serious threat in SCT population. Vaccination and oseltamivir are useful tools. Resistance testing should be considered in subjects with prolonged disease.Disclosures S. G. Jenkins, Merck: Grant Investigator, Grant recipient. M. J. Satlin, Hardy Diagnostics: Grant Investigator, Research support. Allergan: Grant Investigator, Grant recipient. Merck: Grant Investigator, Grant recipient. Biomerieux: Grant Investigator, Grant recipient. Achaogen: Consultant, Consulting fee. L. F. Westblade, Accelerate Diagnostics: Grant Investigator, Grant recipient. Biomerieux: Grant Investigator, Grant recipient. Allergan: Grant Investigator, Grant recipient. Merck: Grant Investigator, Grant recipient.

Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration

Severe influenza A virus infection causes high mortality and morbidity worldwide due to delayed antiviral treatment and inducing overwhelming immune responses, which contribute to immunopathological lung injury. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), was effective in improving clinical outcomes in patients with severe H1N1 infection; however, the mechanisms by which it attenuates acute lung injury have not been elucidated. Here, delayed oseltamivir treatment was used to mimic clinical settings on lethal influenza A (H1N1) pdm09 virus (pH1N1) infection mice model. We revealed that delayed oseltamivir plus sirolimus treatment protects mice against lethal pH1N1 infection by attenuating severe lung damage. Mechanistically, the combined treatment reduced viral titer and pH1N1-induced mTOR activation. Subsequently, it suppressed the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated secretion of interleukin (IL)-1β and IL-18. It was noted that decreased NLRP3 inflammasome activation was associated with inhibited nuclear factor (NF)-κB activation, reduced reactive oxygen species production and increased autophagy. Additionally, the combined treatment reduced the expression of other proinflammatory cytokines and chemokines, and decreased inflammatory cell infiltration in lung tissue and bronchioalveolar lavage fluid. Consistently, it inhibited the mTOR-NF-κB-NLRP3 inflammasome-IL-1β axis in a lung epithelial cell line. These results demonstrated that combined treatment with sirolimus and oseltamivir attenuates pH1N1-induced severe lung injury, which is correlated with suppressed mTOR-NLRP3-IL-1β axis and reduced viral titer. Therefore, treatment with sirolimus as an adjuvant along with oseltamivir may be a promising immunomodulatory strategy for managing severe influenza.

Oseltamivir in pregnancy and birth outcomes

BackgroundPrenatal exposure to influenza or fever is associated with risk of congenital malformations. Oseltamivir is used to treat influenza and to provide post-exposure prophylaxis. We examined the association between oseltamivir use during pregnancy and birth outcomes.MethodsThis was a nationwide registry-based prevalence study with individual level data linkage, in a setting of universal health care access. We included all recorded pregnancies in Denmark in 2002–2013, and used data from population registries to examine associations between dispensings for oseltamivir during pregnancy (first trimester, second/third trimester, none) and congenital malformations, foetal death, preterm birth, foetal growth, and low 5-min Apgar score. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using propensity score matching.ResultsThe study included 946,176 pregnancies. Of these, 449 had first-trimester exposure and 1449 had second/third-trimester exposure to oseltamivir. Adjusted ORs following first-trimester exposure were 0.94 (95% CI 0.49 to 1.83) for any major congenital malformation and 1.75 (95% CI 0.51 to 5.98) for congenital heart defects, based on 7 exposed cases. The association with congenital heart defects was present for etiologically implausible exposure periods and for known safe exposures. There was no evidence of an association between prenatal exposure to oseltamivir and any of the other birth outcomes assessed.ConclusionsThe study does not provide evidence of risk associated with oseltamivir treatment additional to that associated with influenza infection.