Efficacy and #Safety of #Oseltamivir in #Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases, full page: (LINK). Abstract, edited.]

Efficacy and Safety of Oseltamivir in Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials 

Ryan E Malosh, PhD Emily T Martin, PhD Terho Heikkinen, MD W Abdullah Brooks, MD Richard J Whitley, MD Arnold S Monto, MD

Clinical Infectious Diseases, cix1040, https://doi.org/10.1093/cid/cix1040

Published: 23 November 2017




Oseltamivir has been used to treat children with influenza for nearly two decades, with treatment currently approved for infants 2 weeks of age or older, but efficacy and safety remain controversial. Newer randomized placebo controlled trials (RCT), not included in previous meta-analyses, can add to the evidence base.


We conducted a systematic review to identify RCTs of oseltamivir therapy in children. We obtained individual patient data and examined protocol-defined outcomes. We then conducted a two-stage, random effects meta-analysis to determine the efficacy of treatment in reducing the duration of illness, estimated using differences in restricted mean survival time (RSMT) by treatment group. We also examined complications and safety.


We identified 5 trials including 2561 patients in the intent to treat (ITT) and 1598 in the intent to treat infected (ITTI) population. Overall, oseltamivir treatment significantly reduced the duration of illness in the ITTI population (RMST difference -17.6 hours 95% CI: -34.7 to -0.62 hours). In trials that enrolled patients without asthma, the difference was larger (-29.9 hours 95% CI -53.9 to -5.8 hours). Risk of otitis media was 34% lower in the ITTI population. Vomiting was the only adverse event with a significantly higher risk in the treatment group.


Despite substantial heterogeneity in pediatric trials, we found that treatment with oseltamivir significantly reduced the duration of illness in those with influenza and lowered the risk of developing otitis media. Alternative endpoints may be required to evaluate the efficacy of oseltamivir in pediatric patients with asthma.

influenza, oseltamivir, children, meta-analysis

Issue Section: Major Article

© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Keywords: Seasonal Influenza; Antivirals; Oseltamivir.



#Severe #Respiratory #Illness Associated with #Rhinovirus during the #EVD68 #Outbreak in the #USA August – November, 2014 (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases, full page: (LINK). Abstract, edited.]

Severe Respiratory Illness Associated with Rhinovirus during the EV-D68 Outbreak in the United States, August – November, 2014 

Mila M Prill, Rebecca Dahl, Claire M MidgleyShur-Wern, Wang Chern,Xiaoyan Lu, Daniel Feikin,Senthilkumar K Sakthivel, W Allan Nix, John Watson, Susan I Gerber, M Steven Oberste

Clinical Infectious Diseases, cix1034, https://doi.org/10.1093/cid/cix1034

Published: 23 November 2017




In 2014, a nationwide outbreak of severe respiratory illness occurred in the United States, primarily associated with enterovirus D-68 (EV-D68). A proportion of illness was associated with rhinoviruses and other enteroviruses, which we aimed to characterize further.


Respiratory specimens from pediatric and adult patients with respiratory illness were submitted to CDC during August – November 2014. While initial laboratory testing focused on identification of EV-D68, the negative specimens were typed by molecular sequencing to identify additional enterovirus (EV) and rhinovirus (RV) types. Testing for other pathogens was not conducted. We compared available clinical and epidemiologic characteristics among patients with EV-D68 and RV species A-C identified.


Among 2629 typed specimens, 1012 were EV-D68 (39%) and 81 (3.1%) represented 24 other EV types; 968 were RVs (37%) covering 114 types and grouped into three human RV species (RV-A=446, RV-B=133, RV-C=389); and 568 (22%) had no RV or EV detected. EV-D68 was more frequently identified in patients presenting earlier in the investigation period. Among patients with EV-D68, RV-A, RV-B, or RV-C identified, the age distributions markedly differed. Clinical syndromes and ICU admissions by age were largely similar among those with EV-D68 and RV species.


RVs were commonly associated with severe respiratory illness, alongside EV-D68, during the nationwide outbreak. Clinical characteristics were largely similar among those with EV-D68, RV-A, RV-B, or RV-C. A better understanding of the epidemiology of RVs and EVs is needed to help inform development and use of diagnostic tests, therapeutics, and preventive measures.

respiratory disease, outbreak, rhinovirus, enterovirus, epidemiology

Issue Section: Major Article

Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Keywords: Rhinovirus; EV-D68; USA.


#ICU-treated #influenza A(#H1N1) pdm09 #infections more #severe post #pandemic than during 2009 pandemic: a retrospective analysis (BMC Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

BMC Infect Dis. 2017 Nov 21;17(1):728. doi: 10.1186/s12879-017-2829-3.

ICU-treated influenza A(H1N1) pdm09 infections more severe post pandemic than during 2009 pandemic: a retrospective analysis.

Ylipalosaari P1, Ala-Kokko TI2,3, Laurila J2,3, Ahvenjärvi L4, Syrjälä H5.

Author information: 1 Department of Infection Control, Oulu University Hospital, Box 21, FIN-90029, Oulu, OYS, Finland. pylipalo@gmail.com. 2 Department of Anesthesiology, Division of Intensive Care, Oulu University Hospital, FIN-90029, Oulu, OYS, Finland. 3 Medical Research Center, Research Group of Surgery, Anesthesiology and Intensive Care, University of Oulu, Oulu, Finland. 4 Department of Radiology, Oulu University Hospital, FIN-90029, Oulu, OYS, Finland. 5 Department of Infection Control, Oulu University Hospital, Box 21, FIN-90029, Oulu, OYS, Finland.




We compared in a single mixed intensive care unit (ICU) patients with influenza A(H1N1) pdm09 between pandemic and postpandemic periods.


Retrospective analysis of prospectively collected data in 2009-2016. Data are expressed as median (25th-75th percentile) or number (percentile).


Seventy-six influenza A(H1N1) pdm09 patients were admitted to the ICU: 16 during the pandemic period and 60 during the postpandemic period. Postpandemic patients were significantly older (60 years vs. 43 years, p < 0.001) and less likely to have epilepsy or other neurological diseases compared with pandemic patients (5 [8.3%] vs. 6 [38%], respectively; p = 0.009). Postpandemic patients were more likely than pandemic patients to have cardiovascular disease (24 [40%] vs. 1 [6%], respectively; p = 0.015), and they had higher scores on APACHE II (17 [13-22] vs. 14 [10-17], p = 0.002) and SAPS II (40 [31-51] vs. 31 [25-35], p = 0.002) upon admission to the ICU. Postpandemic patients had higher maximal SOFA score (9 [5-12] vs. 5 [4-9], respectively; p = 0.03) during their ICU stay. Postpandemic patients had more often septic shock (40 [66.7%] vs. 8 [50.0%], p = 0.042), and longer median hospital stays (15.0 vs. 8.0 days, respectively; p = 0.006). During 2015-2016, only 18% of the ICU- treated patients had received seasonal influenza vaccination.


Postpandemic ICU-treated A(H1N1) pdm09 influenza patients were older and developed more often septic shock and had longer hospital stays than influenza patients during the 2009 pandemic.

KEYWORDS: Critical care; Influenza; Outcome

PMID: 29162037 DOI: 10.1186/s12879-017-2829-3

Keywords: Seasonal Influenza; H1N1pdm09.


Presumed #Zika virus-related #congenital #brain #malformations: the spectrum of #CT and #MRI findings in #fetuses and #newborns (Arq Neuropsiquiatr., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Arq Neuropsiquiatr. 2017 Oct;75(10):703-710. doi: 10.1590/0004-282X20170134.

Presumed Zika virus-related congenital brain malformations: the spectrum of CT and MRI findings in fetuses and newborns.

Castro JDV1, Pereira LP1, Dias DA1, Aguiar LB1, Maia JCN1, Costa JIFD1, Castro ECM2, Feitosa FEL2, Carvalho FHC2.

Author information: 1 Universidade Federal do Ceará, Hospital Universitário Walter Cantídio, Setor de Radiologia, Fortaleza, CE, Brasil. 2 Universidade Federal do Ceará, Programa de pós-graduação em Saúde Pública, Departamento de SaúdeMaterno-Infantil, Fortaleza, CE, Brasil.




The new epidemic of Zika virus infection raises grave concerns, especially with the increasingly-recognized link between emerging cases of microcephaly and this infectious disease. Besides small cranial dimensions, there are striking morphologic anomalies in the fetal brain. Key anomalies include cortical developmental malformations and a peculiar distribution of pathologic calcifications. These potentially indicate a new pattern of congenital central nervous system infection.


Eight women underwent fetal MRI. Four infants also underwent postnatal CT. Five of the women underwent amniocentesis.


All neonates were born with microcephaly. On fetal MRI, ventriculomegaly, marked reduction of white matter thickness, severe sylvian fissure simplification, abnormal sulcation, and diffuse volumetric loss of cerebellar hemispheres were consistently seen. On postnatal CT, diffuse subcortical and basal ganglia calcifications were observed. The Zika virus was detected in two amniocenteses by polymerase chain reaction assays.


We hope to assist the medical community in recognizing the spectrum of encephalic changes related to congenital Zika virus infection.

PMID: 29166461 DOI: 10.1590/0004-282X20170134

Keywords: Zika Virus; Zika Congenital Infection.


Comparison of the Efficacy of #N9 #Neuraminidase-specific #mAbs against #Influenza A(#H7N9) Virus #Infection (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Comparison of the Efficacy of N9 Neuraminidase-specific Monoclonal Antibodies against Influenza A(H7N9) Virus Infection

Hongquan Wan{a}, Li Qi{b}, Jin Gao{a}, Laura K. Couzens{a}, Lianlian Jiang{a}, Yamei Gao{a}, Zong-Mei Sheng{b}, Sharon Fong{b}, Megan Hahn{a}, Surender Khurana{a}, Jeffery K. Taubenberger{b} and Maryna C. Eichelberger{a}⇑

Author Affiliations: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA{a}; Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA{b}



The fifth wave of A(H7N9) virus infection in China from 2016 to 2017 caused great concern due to the large number of individuals infected, the isolation of drug-resistant viruses and emergence of highly pathogenic strains. Antibodies against neuraminidase (NA) provide added benefit to hemagglutinin-specific immunity and may be an important contributor to the effectiveness of A(H7N9) vaccines. We generated a panel of mouse monoclonal antibodies (MAbs) to identify antigenic domains on NA of the novel A(H7N9) virus and compared their functional properties. Two major antigenic regions, i.e., the 250-loop and 370/400/430-loop domains, were identified. MAbs 1E8, 2F6, 10F4 and 11B2, which recognize these 2 antigenic domains, were characterized in depth. These 4 MAbs differ in ability to inhibit cleavage of small and large substrates (MU-NANA and fetuin, respectively) in NA inhibition assays. 1E8 and 11B2 did not inhibit NA cleavage of either MU-NANA or fetuin, 2F6 inhibited cleavage of fetuin alone, whereas 10F4 inhibited cleavage of both substrates. All 4 MAbs reduced the in vitro spread of viruses carrying either the wild-type N9 or N9 with antiviral-resistant mutations, but to different degrees. These MAbs have different in vivo effectiveness, 10F4 was the most effective in protecting mice against challenge with A(H7N9) virus, 2F6 was less effective and 11B2 failed to protect BALB/c mice at the doses tested. Our study confirms that NA-specific antibodies can protect against A(H7N9) infection, and suggests that in vitro properties can be used to rank antibodies with therapeutic potential.



The novel A(H7N9) viruses that emerged in China in 2013 continue to infect humans, with a high fatality rate. The most recent outbreak resulted in larger number of human cases than previous epidemic waves. Due to the absence of a licensed vaccine and emergence of drug-resistant viruses, there is a need to develop alternative approaches to prevent or treat A(H7N9) infection. We have made a panel of mouse monoclonal antibodies (MAbs) specific for neuraminidase (NA) of A(H7N9) viruses, some of these MAbs are effective in inhibiting viruses that are resistant to antivirals used to treat A(H7N9) patients. Binding avidity, inhibition of NA activity and plaque formation correlated with the effectiveness of these MAbs to protect mice against lethal A(H7N9) virus challenge. This study identifies in vitro measures that can be used to predict the in vivo efficacy of NA-specific antibodies, providing a way to select MAbs for further therapeutic development.



Address correspondence to Maryna C. Eichelberger, maryna.eichelberger@fda.hhs.gov

This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

Keywords: Avian Influenza; H7N9; Human; Monoclonal Antibodies.


#Antibodies directed towards #neuraminidase N1 control #disease in a mouse model of #influenza (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Antibodies directed towards neuraminidase N1 control disease in a mouse model of influenza

E.R. Job1,2, M. Schotsaert1,2, L.I. Ibañez1,2, A. Smet1,2, T. Ysenbaert1,2, K. Roose1,2, M. Dai4, C.A.M. de Haan4, H. Kleanthous3, T. U. Vogel3 and X. Saelens1,2#

Author Affiliations: 1 VIB-UGent Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; 2 Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium; 3 Sanofi Pasteur, Research North America, Cambridge, Massachusetts, USA; 4Virology Division, Department of Infectious Diseases & Immunology, Utrecht University, 3584CL Utrecht, The Netherlands



There is increasing evidence to suggest that antibodies directed towards influenza A virus (IAV) neuraminidase (NA) are an important correlate of protection against influenza in humans. Moreover, the potential of NA-specific antibodies to provide broader protection than conventional hemagglutinin (HA) antibodies has been recognized. Herein, we describe the isolation of two monoclonal antibodies, N1-7D3 and N1-C4, directed towards the N1 NA. N1-7D3 binds to a conserved linear epitope in the membrane distal, carboxy-terminal part of the NA and reacted with the NA of seasonal H1N1 isolates ranging from 1977 till 2007 the 2009 H1N1pdm virus as well as A/Vietnam/1194/04 (H5N1). However, N1-7D3 lacked NA inhibition (NI) activity and the ability to protect BALB/c mice against a lethal challenge with a range of H1N1 viruses. Conversely, N1-C4 bound to a conformational epitope that is conserved between two influenza subtypes, the 2009 H1N1pdm and H5N1 IAV and displayed potent in vitro antiviral activity mediating both NI and plaque size-reduction. Moreover, N1-C4 could provide heterosubtypic protection in BALB/c mice against a lethal challenge with 2009 H1N1pdm or H5N1 virus. Glutamic acid residue 311 in the NA was found to be critical for the NA binding and antiviral activity of monoclonal antibody N1-C4. Our data provide further evidence on cross-protective epitopes within the N1 subtype and highlight the potential of NA as an important target for vaccine and therapeutic approaches.



Influenza remains a world-wide burden to public health. As such the development of new and novel vaccines and therapeutics against influenza virus is crucial. Human challenge studies have recently highlighted the importance of antibodies directed towards the viral neuraminidase (NA) as an important correlate of reduced influenza-associated disease severity. Furthermore, there is evidence that anti-NA antibodies can provide broader protection than antibodies towards the viral hemagglutinin. Here we describe the isolation and detailed characterization of two N1 NA-specific monoclonal antibodies. One of these monoclonal antibodies broadly binds N1 type NAs and the second one displays NAI, in vitro and in vivo anti-viral activity against 2009 H1N1pdm and H5N1 influenza viruses. These two new anti-NA antibodies contribute to our understanding of the antigenic properties and protective potential of the influenza NA antigen.



#Corresponding author: Xavier Saelens. Email: xavier.saelens@vib-ugent.be

Copyright © 2017 American Society for Microbiology. All Rights Reserved.

Keywords: Influenza A; H1N1pdm09; H5N1; Monoclonal Antibodies; Animal Models.


Detecting Local #Zika Virus #Transmission in the Continental #USA: A Comparison of #Surveillance Strategies (PLoS Curr., abstract)

[Source: PLoS Currents Outbreaks, full page: (LINK). Abstract, edited.]

Detecting Local Zika Virus Transmission in the Continental United States: A Comparison of Surveillance Strategies

November 22, 2017 · Research Article

Authors: Steven Russell, Kyle Ryff, Carolyn Gould, Stacey Martin, Michael Johansson




The 2015-2017 Zika virus (ZIKV) epidemic in the Americas has driven efforts to strengthen surveillance systems and to develop interventions, testing, and travel recommendations. In the continental U.S. and Hawaii, where limited transmission has been observed, detecting local transmission is a key public health objective. We assessed the effectiveness of three general surveillance strategies for this situation: testing all pregnant women twice during pregnancy, testing blood donations, and testing symptomatic people who seek medical care in an emergency department (ED).


We developed a simulation model for each surveillance strategy and simulated different transmission scenarios with varying population sizes and infection rates. We then calculated the probability of detecting transmission, the number of tests needed, and the number of false positive test results.


The probability of detecting ZIKV transmission was highest for testing ED patients with Zika symptoms, followed by pregnant women and blood donors, in that order. The magnitude of the difference in probability of detection between strategies depended on the incidence of infection. Testing ED patients required fewer tests and resulted in fewer false positives than surveillance among pregnant women. The optimal strategy identified was to test ED patients with at least two Zika virus disease symptoms. This case definition resulted in a high probability of detection with relatively few tests and false positives.


In the continental U.S. and Hawaii, where local ZIKV transmission is rare, optimizing the probability of detecting infections while minimizing resource usage is particularly important. Local surveillance strategies will be influenced by existing public health system infrastructure, but should also consider the effectiveness of different approaches. This analysis demonstrated differences across strategies and indicated that testing symptomatic ED patients is generally a more efficient strategy for detecting transmission than routine testing of pregnant women or blood donors.

Funding Statement

This research was supported by the Centers for Disease Control and Prevention and MAJ received partial support from the Models of Infectious Disease Agent Study program (Cooperative Agreement 1U54GM088558). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Keywords: Zika; USA.