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

doi:10.1016/S2213-2600(14)70041-4

Review

. 2014 May;2(5):395-404.

doi: 10.1016/S2213-2600(14)70041-4. Epub 2014 Mar 19.

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

Stella G Muthuri¹, Sudhir Venkatesan¹, Puja R Myles¹, Jo Leonardi-Bee¹, Tarig S A Al Khuwaitir², Adbullah Al Mamun³, Ashish P Anovadiya⁴, Eduardo Azziz-Baumgartner⁵, Clarisa Báez⁶, Matteo Bassetti⁷, Bojana Beovic⁸, Barbara Bertisch⁹, Isabelle Bonmarin¹⁰, Robert Booy¹¹, Victor H Borja-Aburto¹², Heinz Burgmann¹³, Bin Cao¹⁴, Jordi Carratala¹⁵, Justin T Denholm¹⁶, Samuel R Dominguez¹⁷, Pericles A D Duarte¹⁸, Gal Dubnov-Raz¹⁹, Marcela Echavarria²⁰, Sergio Fanella²¹, Zhancheng Gao²², Patrick Gérardin²³, Maddalena Giannella²⁴, Sophie Gubbels²⁵, Jethro Herberg²⁶, Anjarath L Higuera Iglesias²⁷, Peter H Hoger²⁸, Xiaoyun Hu²⁹, Quazi T Islam³⁰, Mirela F Jiménez³¹, Amr Kandeel³², Gerben Keijzers³³, Hossein Khalili³⁴, Marian Knight³⁵, Koichiro Kudo³⁶, Gabriela Kusznierz³⁷, Ilija Kuzman³⁸, Arthur M C Kwan³⁹, Idriss Lahlou Amine⁴⁰, Eduard Langenegger⁴¹, Kamran B Lankarani⁴², Yee-Sin Leo⁴³, Rita Linko⁴⁴, Pei Liu⁴⁵, Faris Madanat⁴⁶, Elga Mayo-Montero⁴⁷, Allison McGeer⁴⁸, Ziad Memish⁴⁹, Gokhan Metan⁵⁰, Auksė Mickiene⁵¹, Dragan Mikić⁵², Kristin G I Mohn⁵³, Ahmadreza Moradi⁵⁴, Pagbajabyn Nymadawa⁵⁵, Maria E Oliva⁵⁶, Mehpare Ozkan⁵⁷, Dhruv Parekh⁵⁸, Mical Paul⁵⁹, Fernando P Polack⁶⁰, Barbara A Rath⁶¹, Alejandro H Rodríguez⁶², Elena B Sarrouf⁶³, Anna C Seale⁶⁴, Bunyamin Sertogullarindan⁶⁵, Marilda M Siqueira⁶⁶, Joanna Skręt-Magierło⁶⁷, Frank Stephan⁶⁸, Ewa Talarek⁶⁹, Julian W Tang⁷⁰, Kelvin K W To⁷¹, Antoni Torres⁷², Selda H Törün⁷³, Dat Tran⁷⁴, Timothy M Uyeki⁷⁵, Annelies Van Zwol⁷⁶, Wendy Vaudry⁷⁷, Tjasa Vidmar⁷⁸, Renata T C Yokota⁷⁹, Paul Zarogoulidis⁸⁰; PRIDE Consortium Investigators; Jonathan S Nguyen-Van-Tam⁸¹

Collaborators, Affiliations

Collaborators

PRIDE Consortium Investigators:
Maria De Lourdes Aguiar-Oliveira, Malakita Al Masri, Robed Amin, Wildo N Araújo, Elena Ballester-Orcal, Carlos Bantar, Jing Bao, Mazen M Barhoush, Ariful Basher, Edgar Bautista, Julie Bettinger, Roland Bingisser, Emilio Bouza, Ilkay Bozkurt, Elvira Čeljuska-Tošev, Kenny K C Chan, Yusheng Chen, Tserendorj Chinbayar, Catia Cilloniz, Rebecca J Cox, María R Cuezzo, Wei Cui, Simin Dashti-Khavidaki, Bin Du, Hicham El Rhaffouli, Hernan Escobar, Agnieszka Florek-Michalska, James Fraser, John Gerrard, Stuart Gormley, Sandra Götberg, Matthias Hoffmann, Behnam Honarvar, Jianmin Hu, Christoph Kemen, Gulam Khandaker, Evelyn S C Koay, Miroslav Kojic, Win M Kyaw, Leonard Leibovici, Hongru Li, Xiao-Li Li, Romina Libster, Tze P Loh, Deborough Macbeth, Efstratios Maltezos, Toshie Manabe, Débora N Marcone, Magdalena Marczynska, Fabiane P Mastalir, Mohsen Moghadami, Lilian Moriconi, Bulent Ozbay, Blaž Pečavar, Wolfgang Poeppl, Philippe G Poliquin, Mahmudur Rahman, Alberto Rascon-Pacheco, Samir Refaey, Brunhilde Schweiger, Fang G Smith, Ayper Somer, Thiago M L Souza, Payam Tabarsi, Chandrabhanu B Tripathi, Daiva Velyvyte, Diego Viasus, Qin Yu, Kwok-Yung Yuen, Wei Zhang, Wei Zuo

Affiliations

¹ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
² Department of Medicine, King Saud Medical City, Riyadh, Saudi Arabia.
³ International Centre for Diarrhoeal Diseases, Research Bangladesh, Dhaka, Bangladesh.
⁴ Department of Pharmacology, Government Medical College Bhavnagar, Gujarat, India; Sir Takhtsinhji General Hospital, Bhavnagar, Gujarat, India.
⁵ Centers for Disease Control and Prevention, Atlanta, GA, USA.
⁶ Ministerio de Salud de la Provincia de Buenos Aires, Buenos Aires, Argentina.
⁷ Santa Maria Misericordia Hospital, Udine, Italy.
⁸ Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia.
⁹ Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St Gallen, St Gallen, Switzerland.
¹⁰ Institut de Veille Sanitaire, Saint-Maurice, France.
¹¹ National Centre for Immunisation Research and Surveillance, The Children's Hospital at Westmead, University of Sydney, Sydney, NSW, Australia.
¹² Instituto Mexicano del Seguro Social, Mexico City, Mexico.
¹³ Medical University of Vienna, Vienna, Austria.
¹⁴ Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
¹⁵ 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.
¹⁶ Victorian Infectious Diseases Service and Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia.
¹⁷ Department of Pediatric Infectious Diseases, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁸ Universidade Estadual do Oeste do Paraná, Cascavel, Brazil.
¹⁹ The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
²⁰ Clinical Virology Laboratory, CEMIC University Hospital, Galvan, Buenos Aires, Argentina.
²¹ Section of Pediatric Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.
²² Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, Beijing, China.
²³ 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.
²⁴ Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
²⁵ Department of Infectious Disease Epidemiology, Sector for National Health Documentation and Research, Statens Serum Institut, Copenhagen, Denmark.
²⁶ Section of Paediatrics, Division of Infectious Disease, Imperial College, London, UK.
²⁷ Epidemiology Research Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Mexico City, Mexico.
²⁸ Catholic Children's Hospital Wilhelmstift, Liliencronstr, Hamburg, Germany.
²⁹ Peking Union Medical College Hospital, Beijing, China.
³⁰ Dhaka Medical College Hospital, Dhaka, Bangladesh.
³¹ Departamento de Ginecologia e Obstetrícia, Universidade Federal de Ciências da Saúde de Porto Alegre, Preceptora da Residência Médica do Hospital Fêmina, Porto Alegre, Brazil.
³² Ministry of Health in Egypt, Cairo, Egypt.
³³ Gold Coast Hospital, Gold Coast, QLD, Australia.
³⁴ Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
³⁵ National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁶ National Center for Global Health and Medicine, Tokyo, Japan.
³⁷ National Institute of Respiratory Diseases, 'Dr Emilio Coni', Santa Fe, Argentina.
³⁸ University Hospital for Infectious Diseases, University of Zagreb, School of Medicine, Zagreb, Croatia.
³⁹ Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, Hong Kong.
⁴⁰ University Mohammed V-Souissi, Faculty of Medicine and Pharmacy, Mohammed V Military Teaching Hospital, Biosafety Level 3 and Research Laboratory, Rabat, Morocco.
⁴¹ Department of Obstetrics and Gynaecology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa.
⁴² Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
⁴³ Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore.
⁴⁴ Helsinki University Hospital, Helsinki, Finland.
⁴⁵ Department of Infectious Diseases, the First Affiliated Hospital, China Medical University, Shenyang, China.
⁴⁶ King Hussein Cancer Center, Department of Pediatrics, Amman, Jordan.
⁴⁷ Instituto de Medicina Preventiva de la Defensa, Capitan Medico Ramon y Cajal, Ministerio de Defensa, Madrid, Spain.
⁴⁸ Toronto Invasive Bacterial Diseases Network, University of Toronto, Toronto, ON, Canada.
⁴⁹ Ministry of Health, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
⁵⁰ Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey.
⁵¹ Lithuanian University of Health Sciences, Kaunas, Lithuania.
⁵² Military Medical Academy, Clinic for Infectious and Tropical Diseases, Belgrade, Serbia.
⁵³ 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.
⁵⁴ 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.
⁵⁵ National Influenza Center, National Center of Communicable Diseases, Ministry of Health, Ulaanbaatar, Mongolia.
⁵⁶ Department of Infection Control, Hospital San Martín de Paraná, Entre Ríos, Argentina.
⁵⁷ Dr Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Clinic of Pediatric Neurology, Ankara, Turkey.
⁵⁸ Critical Care and Pain Perioperative, Critical Care and Trauma Trials Group, School of Clinical and Experimental Medicine, University of Birmingham, UK.
⁵⁹ Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
⁶⁰ Vanderbilt Vaccine Center, Department of Pediatrics, Vanderbilt University, Nashville, TN, USA; Fundacion INFANT, Buenos Aires, Argentina.
⁶¹ Department of Pediatrics, Division of Pneumonology-Immunology, Charité University Medical Center, Berlin, Germany.
⁶² Hospital Joan XXIII, Critical Care Department, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Ciber De Enfermedades Respiratorias, Tarragona, Spain.
⁶³ Ministerio de Salud de Tucumán, Tucumán, Argentina.
⁶⁴ Paediatric Intensive Care Unit, Bristol Children's Hospital, Bristol, UK; Bristol Children's Vaccine Centre, School of Clinical Sciences, University of Bristol, Bristol, UK.
⁶⁵ Yuzuncu Yil University Medical Faculty, Department of Pulmonary Medicine, Van, Turkey.
⁶⁶ Laboratory of Respiratory Viruses, Oswaldo Cruz Institute/Fiocruz, Rio de Janeiro, Brazil.
⁶⁷ Uniwersytet Rzeszowski, Rzeszów, Poland.
⁶⁸ Department of Emergency Medicine, University Hospital Basel, Basel, Switzerland.
⁶⁹ Department of Children's Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
⁷⁰ 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.
⁷¹ Carol Yu Centre for Infection and Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
⁷² Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Ciber De Enfermedades Respiratorias, Barcelona, Spain.
⁷³ Department of Pediatric Infectious Diseases, Istanbul Medical Faculty, Istanbul, Turkey.
⁷⁴ Division of Infectious Diseases, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁷⁵ Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
⁷⁶ Department of Pediatric Intensive Care, VU University Medical Center, Amsterdam, Netherlands.
⁷⁷ Division of Infectious Diseases, Department of Pediatrics, University of Alberta, Stollery Children's Hospital, Edmonton, AB, Canada.
⁷⁸ General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.
⁷⁹ Departamento de Vigilância Epidemiológica, Secretaria de Vigilância em Saúde, Ministério da Saúde, Brasília DF, Brazil.
⁸⁰ Unit of Infectious Diseases, University General Hospital of Alexandroupolis, Democritus University Thrace, Dragana, Greece.
⁸¹ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK. Electronic address: jvt@nottingham.ac.uk.

PMID: 24815805
PMCID: PMC6637757
DOI: 10.1016/S2213-2600(14)70041-4

Review

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

Stella G Muthuri et al. Lancet Respir Med. 2014 May.

. 2014 May;2(5):395-404.

doi: 10.1016/S2213-2600(14)70041-4. Epub 2014 Mar 19.

Authors

Collaborators

PRIDE Consortium Investigators:
Maria De Lourdes Aguiar-Oliveira, Malakita Al Masri, Robed Amin, Wildo N Araújo, Elena Ballester-Orcal, Carlos Bantar, Jing Bao, Mazen M Barhoush, Ariful Basher, Edgar Bautista, Julie Bettinger, Roland Bingisser, Emilio Bouza, Ilkay Bozkurt, Elvira Čeljuska-Tošev, Kenny K C Chan, Yusheng Chen, Tserendorj Chinbayar, Catia Cilloniz, Rebecca J Cox, María R Cuezzo, Wei Cui, Simin Dashti-Khavidaki, Bin Du, Hicham El Rhaffouli, Hernan Escobar, Agnieszka Florek-Michalska, James Fraser, John Gerrard, Stuart Gormley, Sandra Götberg, Matthias Hoffmann, Behnam Honarvar, Jianmin Hu, Christoph Kemen, Gulam Khandaker, Evelyn S C Koay, Miroslav Kojic, Win M Kyaw, Leonard Leibovici, Hongru Li, Xiao-Li Li, Romina Libster, Tze P Loh, Deborough Macbeth, Efstratios Maltezos, Toshie Manabe, Débora N Marcone, Magdalena Marczynska, Fabiane P Mastalir, Mohsen Moghadami, Lilian Moriconi, Bulent Ozbay, Blaž Pečavar, Wolfgang Poeppl, Philippe G Poliquin, Mahmudur Rahman, Alberto Rascon-Pacheco, Samir Refaey, Brunhilde Schweiger, Fang G Smith, Ayper Somer, Thiago M L Souza, Payam Tabarsi, Chandrabhanu B Tripathi, Daiva Velyvyte, Diego Viasus, Qin Yu, Kwok-Yung Yuen, Wei Zhang, Wei Zuo

Affiliations

¹ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
² Department of Medicine, King Saud Medical City, Riyadh, Saudi Arabia.
³ International Centre for Diarrhoeal Diseases, Research Bangladesh, Dhaka, Bangladesh.
⁴ Department of Pharmacology, Government Medical College Bhavnagar, Gujarat, India; Sir Takhtsinhji General Hospital, Bhavnagar, Gujarat, India.
⁵ Centers for Disease Control and Prevention, Atlanta, GA, USA.
⁶ Ministerio de Salud de la Provincia de Buenos Aires, Buenos Aires, Argentina.
⁷ Santa Maria Misericordia Hospital, Udine, Italy.
⁸ Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia.
⁹ Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St Gallen, St Gallen, Switzerland.
¹⁰ Institut de Veille Sanitaire, Saint-Maurice, France.
¹¹ National Centre for Immunisation Research and Surveillance, The Children's Hospital at Westmead, University of Sydney, Sydney, NSW, Australia.
¹² Instituto Mexicano del Seguro Social, Mexico City, Mexico.
¹³ Medical University of Vienna, Vienna, Austria.
¹⁴ Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
¹⁵ 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.
¹⁶ Victorian Infectious Diseases Service and Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia.
¹⁷ Department of Pediatric Infectious Diseases, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁸ Universidade Estadual do Oeste do Paraná, Cascavel, Brazil.
¹⁹ The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
²⁰ Clinical Virology Laboratory, CEMIC University Hospital, Galvan, Buenos Aires, Argentina.
²¹ Section of Pediatric Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.
²² Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, Beijing, China.
²³ 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.
²⁴ Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
²⁵ Department of Infectious Disease Epidemiology, Sector for National Health Documentation and Research, Statens Serum Institut, Copenhagen, Denmark.
²⁶ Section of Paediatrics, Division of Infectious Disease, Imperial College, London, UK.
²⁷ Epidemiology Research Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Mexico City, Mexico.
²⁸ Catholic Children's Hospital Wilhelmstift, Liliencronstr, Hamburg, Germany.
²⁹ Peking Union Medical College Hospital, Beijing, China.
³⁰ Dhaka Medical College Hospital, Dhaka, Bangladesh.
³¹ Departamento de Ginecologia e Obstetrícia, Universidade Federal de Ciências da Saúde de Porto Alegre, Preceptora da Residência Médica do Hospital Fêmina, Porto Alegre, Brazil.
³² Ministry of Health in Egypt, Cairo, Egypt.
³³ Gold Coast Hospital, Gold Coast, QLD, Australia.
³⁴ Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
³⁵ National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁶ National Center for Global Health and Medicine, Tokyo, Japan.
³⁷ National Institute of Respiratory Diseases, 'Dr Emilio Coni', Santa Fe, Argentina.
³⁸ University Hospital for Infectious Diseases, University of Zagreb, School of Medicine, Zagreb, Croatia.
³⁹ Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, Hong Kong.
⁴⁰ University Mohammed V-Souissi, Faculty of Medicine and Pharmacy, Mohammed V Military Teaching Hospital, Biosafety Level 3 and Research Laboratory, Rabat, Morocco.
⁴¹ Department of Obstetrics and Gynaecology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa.
⁴² Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
⁴³ Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore.
⁴⁴ Helsinki University Hospital, Helsinki, Finland.
⁴⁵ Department of Infectious Diseases, the First Affiliated Hospital, China Medical University, Shenyang, China.
⁴⁶ King Hussein Cancer Center, Department of Pediatrics, Amman, Jordan.
⁴⁷ Instituto de Medicina Preventiva de la Defensa, Capitan Medico Ramon y Cajal, Ministerio de Defensa, Madrid, Spain.
⁴⁸ Toronto Invasive Bacterial Diseases Network, University of Toronto, Toronto, ON, Canada.
⁴⁹ Ministry of Health, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
⁵⁰ Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey.
⁵¹ Lithuanian University of Health Sciences, Kaunas, Lithuania.
⁵² Military Medical Academy, Clinic for Infectious and Tropical Diseases, Belgrade, Serbia.
⁵³ 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.
⁵⁴ 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.
⁵⁵ National Influenza Center, National Center of Communicable Diseases, Ministry of Health, Ulaanbaatar, Mongolia.
⁵⁶ Department of Infection Control, Hospital San Martín de Paraná, Entre Ríos, Argentina.
⁵⁷ Dr Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Clinic of Pediatric Neurology, Ankara, Turkey.
⁵⁸ Critical Care and Pain Perioperative, Critical Care and Trauma Trials Group, School of Clinical and Experimental Medicine, University of Birmingham, UK.
⁵⁹ Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
⁶⁰ Vanderbilt Vaccine Center, Department of Pediatrics, Vanderbilt University, Nashville, TN, USA; Fundacion INFANT, Buenos Aires, Argentina.
⁶¹ Department of Pediatrics, Division of Pneumonology-Immunology, Charité University Medical Center, Berlin, Germany.
⁶² Hospital Joan XXIII, Critical Care Department, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Ciber De Enfermedades Respiratorias, Tarragona, Spain.
⁶³ Ministerio de Salud de Tucumán, Tucumán, Argentina.
⁶⁴ Paediatric Intensive Care Unit, Bristol Children's Hospital, Bristol, UK; Bristol Children's Vaccine Centre, School of Clinical Sciences, University of Bristol, Bristol, UK.
⁶⁵ Yuzuncu Yil University Medical Faculty, Department of Pulmonary Medicine, Van, Turkey.
⁶⁶ Laboratory of Respiratory Viruses, Oswaldo Cruz Institute/Fiocruz, Rio de Janeiro, Brazil.
⁶⁷ Uniwersytet Rzeszowski, Rzeszów, Poland.
⁶⁸ Department of Emergency Medicine, University Hospital Basel, Basel, Switzerland.
⁶⁹ Department of Children's Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
⁷⁰ 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.
⁷¹ Carol Yu Centre for Infection and Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
⁷² Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Ciber De Enfermedades Respiratorias, Barcelona, Spain.
⁷³ Department of Pediatric Infectious Diseases, Istanbul Medical Faculty, Istanbul, Turkey.
⁷⁴ Division of Infectious Diseases, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁷⁵ Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
⁷⁶ Department of Pediatric Intensive Care, VU University Medical Center, Amsterdam, Netherlands.
⁷⁷ Division of Infectious Diseases, Department of Pediatrics, University of Alberta, Stollery Children's Hospital, Edmonton, AB, Canada.
⁷⁸ General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.
⁷⁹ Departamento de Vigilância Epidemiológica, Secretaria de Vigilância em Saúde, Ministério da Saúde, Brasília DF, Brazil.
⁸⁰ Unit of Infectious Diseases, University General Hospital of Alexandroupolis, Democritus University Thrace, Dragana, Greece.
⁸¹ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK. Electronic address: jvt@nottingham.ac.uk.

PMID: 24815805
PMCID: PMC6637757
DOI: 10.1016/S2213-2600(14)70041-4

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.

Findings: 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).

Interpretation: We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection.

Funding: F Hoffmann-La Roche.

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Conflict of interest statement

Declaration of interests

Between October, 2007, and September, 2010, JSN-V-T did ad-hoc paid consultancy and lecturing for several influenza vaccine manufacturers (Sanofi Pasteur MSD, Sanofi Pasteur, GlaxoSmithKline, Baxter AG, Solvay, Novartis) and manufacturers of neuraminidase inhibitors (F Hoffmann-La Roche: oseltamivir [Tamiflu] and GlaxoSmithKline: zanamivir [Relenza]). He is a former employee of SmithKline Beecham (now part of GlaxoSmithKline), Roche Products (UK), and Sanofi Pasteur MSD, all before 2005. He has no outstanding interests related to shares, share options, or accrued pension rights in any of these companies. He is in receipt of current or recent research funding, related to influenza vaccination from GlaxoSmithKline and AstraZeneca and non-financial support (travel) from Baxter AG. His brother became an employee of GlaxoSmithKline in January, 2014. JL-B is Statistical Editor of the Cochrane Skin Group. PRM is the recipient of the unrestricted educational grant for research in the area of pandemic influenza from F Hoffman-La Roche, used to fund this work. She has also received travel grants from F Hoffman-La Roche and its subsidiaries to attend clinical seminars to present this work. RB has received financial support from CSL, Sanofi, GlaxoSmithKline, Novartis, Roche, and Wyeth to do research and present at scientific meetings. Any funding received is directed to an NCIRS research account at The Children’s Hospital at Westmead, NSW, Australia, and is not personally accepted by RB. All other named authors declare that they have no competing interests.

Figures

**Figure 1:. Study flow diagram**
*47 overlapping data; one onset of illness before March 1, 2009 (Mexico); nine missing data for key variables.

**Figure 2:. Survival by time to treatment**
HR=hazard ratio. NAI=neuraminidase inhibitor. *Cox regression shared frailty model (adjusted for treatment propensity and in hospital steroid or antibiotic use).

See this image and copyright information in PMC

Comment in

Study claiming Tamiflu saved lives was based on "flawed" analysis.
Kmietowicz Z. Kmietowicz Z. BMJ. 2014 Mar 18;348:g2228. doi: 10.1136/bmj.g2228. BMJ. 2014. PMID: 24646608 No abstract available.
Authors' reply to Mark Jones's second critique of the study by Muthuri and colleagues reported in The BMJ.
Myles PR, Leonardi-Bee J; PRIDE research consortium investigators. Myles PR, et al. BMJ. 2014 Apr 30;348:g3004. doi: 10.1136/bmj.g3004. BMJ. 2014. PMID: 24788389 No abstract available.
Authors' reply to Mark Jones's critique of the study by Muthuri and colleagues reported in The BMJ.
Myles PR, Leonardi-Bee J; PRIDE Research Consortium Investigators. Myles PR, et al. BMJ. 2014 Apr 30;348:g2990. doi: 10.1136/bmj.g2990. BMJ. 2014. PMID: 24788485 No abstract available.
Mark Jones's reply to Myles and Leonardi-Bee's response to his critique of their paper reported in The BMJ.
Jones M. Jones M. BMJ. 2014 Apr 30;348:g3001. doi: 10.1136/bmj.g3001. BMJ. 2014. PMID: 24788584 No abstract available.
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Fry AM. Fry AM. Lancet Respir Med. 2014 May;2(5):346-8. doi: 10.1016/S2213-2600(14)70068-2. Epub 2014 Mar 19. Lancet Respir Med. 2014. PMID: 24815800 No abstract available.
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Antes G, Meerpohl JJ. Antes G, et al. Lancet Respir Med. 2014 Jul;2(7):e10. doi: 10.1016/S2213-2600(14)70127-4. Epub 2014 Jun 16. Lancet Respir Med. 2014. PMID: 24948429 No abstract available.
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Jones M, Del Mar C, Hama R. Jones M, et al. Lancet Respir Med. 2014 Jul;2(7):e9-e10. doi: 10.1016/S2213-2600(14)70126-2. Epub 2014 Jun 16. Lancet Respir Med. 2014. PMID: 24948431 No abstract available.
Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality.
Leonardi-Bee J, Venkatesan S, Muthuri SG, Nguyen-Van-Tam JS, Myles PR; PRIDE research consortium. Leonardi-Bee J, et al. Lancet Respir Med. 2014 Jul;2(7):e10-2. doi: 10.1016/S2213-2600(14)70137-7. Epub 2014 Jun 16. Lancet Respir Med. 2014. PMID: 24948433 No abstract available.
Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality.
Wolkewitz M, Schumacher M. Wolkewitz M, et al. Lancet Respir Med. 2014 Jul;2(7):e8-9. doi: 10.1016/S2213-2600(14)70115-8. Epub 2014 Jun 16. Lancet Respir Med. 2014. PMID: 24948434 No abstract available.

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References

1. Donner B, Bader-Weder S, Schwarz R, Peng MM, Smith JR, Niranjan V. Safety profile of oseltamivir during the 2009 influenza pandemic. Pharmacoepidemiol Drug Saf 2011; 20: 532–43. - PubMed
1. Atkins CY, Patel A, Taylor TH Jr, et al. Estimating effect of antiviral drug use during pandemic (H1N1) 2009 outbreak, United States. Emerg Infect Dis 2011; 17: 1591–98. - PMC - PubMed
1. Chemaly RF, Ghosh S, Bodey GP, et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 2006; 85: 278–87 - PubMed
1. Chemaly RF, Torres HA, Aguilera EA, et al. Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study. Clin Infect Dis 2007; 44: 964–67 - PubMed
1. Hassan K, McGeer A, Green KA, et al. Antiviral therapy improves outcomes of influenza infections in patients requiring admission to intensive care. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, CA; Sept 12–15, 2009. V-537

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[1] Donner B, Bader-Weder S, Schwarz R, Peng MM, Smith JR, Niranjan V. Safety profile of oseltamivir during the 2009 influenza pandemic. Pharmacoepidemiol Drug Saf 2011; 20: 532–43. - PubMed

[2] Donner B, Bader-Weder S, Schwarz R, Peng MM, Smith JR, Niranjan V. Safety profile of oseltamivir during the 2009 influenza pandemic. Pharmacoepidemiol Drug Saf 2011; 20: 532–43. - PubMed

[3] Atkins CY, Patel A, Taylor TH Jr, et al. Estimating effect of antiviral drug use during pandemic (H1N1) 2009 outbreak, United States. Emerg Infect Dis 2011; 17: 1591–98. - PMC - PubMed

[4] Atkins CY, Patel A, Taylor TH Jr, et al. Estimating effect of antiviral drug use during pandemic (H1N1) 2009 outbreak, United States. Emerg Infect Dis 2011; 17: 1591–98. - PMC - PubMed

[5] Chemaly RF, Ghosh S, Bodey GP, et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 2006; 85: 278–87 - PubMed

[6] Chemaly RF, Ghosh S, Bodey GP, et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 2006; 85: 278–87 - PubMed

[7] Chemaly RF, Torres HA, Aguilera EA, et al. Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study. Clin Infect Dis 2007; 44: 964–67 - PubMed

[8] Chemaly RF, Torres HA, Aguilera EA, et al. Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study. Clin Infect Dis 2007; 44: 964–67 - PubMed

[9] Hassan K, McGeer A, Green KA, et al. Antiviral therapy improves outcomes of influenza infections in patients requiring admission to intensive care. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, CA; Sept 12–15, 2009. V-537

[10] Hassan K, McGeer A, Green KA, et al. Antiviral therapy improves outcomes of influenza infections in patients requiring admission to intensive care. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, CA; Sept 12–15, 2009. V-537

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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

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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

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