title: Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data.
abstract: BACKGROUND
  Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection.
  
  
  METHODS
  We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling.
  
  
  RESULTS
  We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each day's delay).
  
  
  CONCLUSIONS
  We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
authors.forename: Stella G
authors.initials: SG
authors.lastname: Muthuri
authors.affiliation: Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Venkatesan
authors.affiliation: Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
authors.forename: Puja R
authors.initials: PR
authors.lastname: Myles
authors.affiliation: Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Leonardi-Bee
authors.affiliation: Department of Medicine, King Saud Medical City, Riyadh, Saudi Arabia.
authors.forename: Tarig S A
authors.initials: TS
authors.lastname: Al Khuwaitir
authors.affiliation: International Centre for Diarrhoeal Diseases, Research Bangladesh, Dhaka, Bangladesh.
authors.forename: Adbullah
authors.initials: A
authors.lastname: Al Mamun
authors.affiliation: Department of Pharmacology, Government Medical College Bhavnagar, Gujarat, India; Sir Takhtsinhji General Hospital, Bhavnagar, Gujarat, India.
authors.forename: Ashish P
authors.initials: AP
authors.lastname: Anovadiya
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Azziz-Baumgartner
authors.affiliation: Ministerio de Salud de la Provincia de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Clarisa
authors.initials: C
authors.lastname: Báez
authors.affiliation: Santa Maria Misericordia Hospital, Udine, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bassetti
authors.affiliation: Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia.
authors.forename: Bojana
authors.initials: B
authors.lastname: Beovic
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St Gallen, St Gallen, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bertisch
authors.affiliation: Institut de Veille Sanitaire, Saint-Maurice, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bonmarin
authors.affiliation: National Centre for Immunisation Research and Surveillance, The Children's Hospital at Westmead, University of Sydney, Sydney, NSW, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Booy
authors.affiliation: Instituto Mexicano del Seguro Social, Mexico City, Mexico.
authors.forename: Victor H
authors.initials: VH
authors.lastname: Borja-Aburto
authors.affiliation: Medical University of Vienna, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Burgmann
authors.affiliation: Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Cao
authors.affiliation: Department of Infectious Diseases, Hospital Universitari de Bellvitge, Bellvitge Institute for Biomedical Research, L'Hospitalet de Llobregat, Red Española de Investigación en Patología Infecciosa, University of Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Carratala
authors.affiliation: Victorian Infectious Diseases Service and Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Denholm
authors.affiliation: Department of Pediatric Infectious Diseases, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Dominguez
authors.affiliation: Universidade Estadual do Oeste do Paraná, Cascavel, Brazil.
authors.forename: Pericles A D
authors.initials: PA
authors.lastname: Duarte
authors.affiliation: The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Dubnov-Raz
authors.affiliation: Clinical Virology Laboratory, CEMIC University Hospital, Galvan, Buenos Aires, Argentina.
authors.forename: Marcela
authors.initials: M
authors.lastname: Echavarria
authors.affiliation: Section of Pediatric Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fanella
authors.affiliation: Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, Beijing, China.
authors.forename: Zhancheng
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Neonatal Intensive Care Unit/Paediatric Intensive Care Unit, Centre Hospitalier Universitaire-Groupe Hospitalier Sud Réunion, Saint Pierre, Réunion, France; Centre for Clinical Investigation 1410, National Institute for Health and Medical Research/Centre Hospitalier Universitaire/Université de La Réunion, Saint Pierre, Réunion, France; Unité Mixte de Recherche "Processus Infectieux en Milieu Insulaire Tropical" Université de La Réunion/Centre Hospitalier Universitaire/National Institute for Health and Medical Research/Research and Development Institute -Cyclotron Réunion Océan Indien, Saint Denis, Réunion, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gérardin
authors.affiliation: Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Giannella
authors.affiliation: Department of Infectious Disease Epidemiology, Sector for National Health Documentation and Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gubbels
authors.affiliation: Section of Paediatrics, Division of Infectious Disease, Imperial College, London, UK.
authors.forename: Jethro
authors.initials: J
authors.lastname: Herberg
authors.affiliation: Epidemiology Research Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Mexico City, Mexico.
authors.forename: Anjarath L Higuera
authors.initials: AL
authors.lastname: Iglesias
authors.affiliation: Catholic Children's Hospital Wilhelmstift, Liliencronstr, Hamburg, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hoger
authors.affiliation: Peking Union Medical College Hospital, Beijing, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Dhaka Medical College Hospital, Dhaka, Bangladesh.
authors.forename: Quazi T
authors.initials: QT
authors.lastname: Islam
authors.affiliation: Departamento de Ginecologia e Obstetrícia, Universidade Federal de Ciências da Saúde de Porto Alegre, Preceptora da Residência Médica do Hospital Fêmina, Porto Alegre, Brazil.
authors.forename: Mirela F
authors.initials: MF
authors.lastname: Jiménez
authors.affiliation: Ministry of Health in Egypt, Cairo, Egypt.
authors.forename: Amr
authors.initials: A
authors.lastname: Kandeel
authors.affiliation: Gold Coast Hospital, Gold Coast, QLD, Australia.
authors.forename: Gerben
authors.initials: G
authors.lastname: Keijzers
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Khalili
authors.affiliation: National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Marian
authors.initials: M
authors.lastname: Knight
authors.affiliation: National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kudo
authors.affiliation: National Institute of Respiratory Diseases, 'Dr Emilio Coni', Santa Fe, Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kusznierz
authors.affiliation: University Hospital for Infectious Diseases, University of Zagreb, School of Medicine, Zagreb, Croatia.
authors.forename: Ilija
authors.initials: I
authors.lastname: Kuzman
authors.affiliation: Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, Hong Kong.
authors.forename: Arthur M C
authors.initials: AM
authors.lastname: Kwan
authors.affiliation: University Mohammed V-Souissi, Faculty of Medicine and Pharmacy, Mohammed V Military Teaching Hospital, Biosafety Level 3 and Research Laboratory, Rabat, Morocco.
authors.forename: Idriss Lahlou
authors.initials: IL
authors.lastname: Amine
authors.affiliation: Department of Obstetrics and Gynaecology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa.
authors.forename: Eduard
authors.initials: E
authors.lastname: Langenegger
authors.affiliation: Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Kamran B
authors.initials: KB
authors.lastname: Lankarani
authors.affiliation: Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Yee-Sin
authors.initials: YS
authors.lastname: Leo
authors.affiliation: Helsinki University Hospital, Helsinki, Finland.
authors.forename: Rita
authors.initials: R
authors.lastname: Linko
authors.affiliation: Department of Infectious Diseases, the First Affiliated Hospital, China Medical University, Shenyang, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Liu
authors.affiliation: King Hussein Cancer Center, Department of Pediatrics, Amman, Jordan.
authors.forename: Faris
authors.initials: F
authors.lastname: Madanat
authors.affiliation: Instituto de Medicina Preventiva de la Defensa, Capitan Medico Ramon y Cajal, Ministerio de Defensa, Madrid, Spain.
authors.forename: Elga
authors.initials: E
authors.lastname: Mayo-Montero
authors.affiliation: Toronto Invasive Bacterial Diseases Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Allison
authors.initials: A
authors.lastname: McGeer
authors.affiliation: Ministry of Health, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Memish
authors.affiliation: Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey.
authors.forename: Gokhan
authors.initials: G
authors.lastname: Metan
authors.affiliation: Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Auksė
authors.initials: A
authors.lastname: Mickiene
authors.affiliation: Military Medical Academy, Clinic for Infectious and Tropical Diseases, Belgrade, Serbia.
authors.forename: Dragan
authors.initials: D
authors.lastname: Mikić
authors.affiliation: Section for Infectious Diseases, Medical Department, and Department of Research and Development, Haukeland University Hospital, Bergen, Norway; The Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Kristin G I
authors.initials: KG
authors.lastname: Mohn
authors.affiliation: The Division of Ocular Immunology, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; National Research Institute for Tuberculosis and Lung Disease, Massih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Ahmadreza
authors.initials: A
authors.lastname: Moradi
authors.affiliation: National Influenza Center, National Center of Communicable Diseases, Ministry of Health, Ulaanbaatar, Mongolia.
authors.forename: Pagbajabyn
authors.initials: P
authors.lastname: Nymadawa
authors.affiliation: Department of Infection Control, Hospital San Martín de Paraná, Entre Ríos, Argentina.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Oliva
authors.affiliation: Dr Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Clinic of Pediatric Neurology, Ankara, Turkey.
authors.forename: Mehpare
authors.initials: M
authors.lastname: Ozkan
authors.affiliation: Critical Care and Pain Perioperative, Critical Care and Trauma Trials Group, School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Parekh
authors.affiliation: Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Mical
authors.initials: M
authors.lastname: Paul
authors.affiliation: Vanderbilt Vaccine Center, Department of Pediatrics, Vanderbilt University, Nashville, TN, USA; Fundacion INFANT, Buenos Aires, Argentina.
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Polack
authors.affiliation: Department of Pediatrics, Division of Pneumonology-Immunology, Charité University Medical Center, Berlin, Germany.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Rath
authors.affiliation: Hospital Joan XXIII, Critical Care Department, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Ciber De Enfermedades Respiratorias, Tarragona, Spain.
authors.forename: Alejandro H
authors.initials: AH
authors.lastname: Rodríguez
authors.affiliation: Ministerio de Salud de Tucumán, Tucumán, Argentina.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Sarrouf
authors.affiliation: Paediatric Intensive Care Unit, Bristol Children's Hospital, Bristol, UK; Bristol Children's Vaccine Centre, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Seale
authors.affiliation: Yuzuncu Yil University Medical Faculty, Department of Pulmonary Medicine, Van, Turkey.
authors.forename: Bunyamin
authors.initials: B
authors.lastname: Sertogullarindan
authors.affiliation: Laboratory of Respiratory Viruses, Oswaldo Cruz Institute/Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Marilda M
authors.initials: MM
authors.lastname: Siqueira
authors.affiliation: Uniwersytet Rzeszowski, Rzeszów, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Skręt-Magierło
authors.affiliation: Department of Emergency Medicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Stephan
authors.affiliation: Department of Children's Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Talarek
authors.affiliation: Division of Microbiology, Molecular Diagnostic Centre, Department of Laboratory Medicine National University Hospital, Singapore, Singapore; Alberta Provincial Laboratory for Public Health, University of Alberta Hospital, Edmonton, AB, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Julian W
authors.initials: JW
authors.lastname: Tang
authors.affiliation: Carol Yu Centre for Infection and Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Kelvin K W
authors.initials: KK
authors.lastname: To
authors.affiliation: Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Ciber De Enfermedades Respiratorias, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Torres
authors.affiliation: Department of Pediatric Infectious Diseases, Istanbul Medical Faculty, Istanbul, Turkey.
authors.forename: Selda H
authors.initials: SH
authors.lastname: Törün
authors.affiliation: Division of Infectious Diseases, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Dat
authors.initials: D
authors.lastname: Tran
authors.affiliation: Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Uyeki
authors.affiliation: Department of Pediatric Intensive Care, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: Van Zwol
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Alberta, Stollery Children's Hospital, Edmonton, AB, Canada.
authors.forename: Wendy
authors.initials: W
authors.lastname: Vaudry
authors.affiliation: General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.
authors.forename: Tjasa
authors.initials: T
authors.lastname: Vidmar
authors.affiliation: Departamento de Vigilância Epidemiológica, Secretaria de Vigilância em Saúde, Ministério da Saúde, Brasília DF, Brazil.
authors.forename: Renata T C
authors.initials: RT
authors.lastname: Yokota
authors.affiliation: Unit of Infectious Diseases, University General Hospital of Alexandroupolis, Democritus University Thrace, Dragana, Greece.
authors.forename: Paul
authors.initials: P
authors.lastname: Zarogoulidis
authors.affiliation: Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK. Electronic address: jvt@nottingham.ac.uk.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Nguyen-Van-Tam
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D002648:Child; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006760:Hospitalization; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D053139:Oseltamivir / Q000627:therapeutic use*; D058873:Pandemics; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D055815:Young Adult; D053243:Zanamivir / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir