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Stella G. Muthuri,1 Sudhir Venkatesan,1 Puja R. Myles,1 Jo Leonardi-Bee,1 Wei Shen Lim,2 Abdullah Al Mamun,3 Ashish P. Anovadiya,4 Wildo N. Ara ujo,5 Eduardo Azziz-Baumgartner,6 Clarisa B aez,7 Carlos Bantar,8 Mazen M. Barhoush,9 Matteo Bassetti,10 Bojana Beovic,11 Roland Bingisser,12 Isabelle Bonmarin,13 Victor H. Borja-Aburto,14 Bin Cao,15 Jordi Carratala,16 Mar ıa R. Cuezzo,17 Justin T. Denholm,18 Samuel R. Dominguez,19 Pericles A. D. Duarte,20 Gal Dubnov-Raz,21 Marcela Echavarria,22 Sergio Fanella,23 James Fraser,24 Zhancheng Gao,25 Patrick G erardin,26,27,28,29 Maddalena Giannella,30 Sophie Gubbels,31 Jethro Herberg,32 Anjarath L. Higuera Iglesias,33 Peter H. Hoeger,34 Matthias Hoffmann,35 Xiaoyun Hu,36 Quazi T. Islam,37 Mirela F. Jim enez,38 Amr Kandeel,39 Gerben Keijzers,40 Hossein Khalili,41 Gulam Khandaker,42 Marian Knight,43 Gabriela Kusznierz,44 Ilija Kuzman,45 Arthur M. C. Kwan,46 Idriss Lahlou Amine,47 Eduard Langenegger,48 Kamran B. Lankarani,49 Yee-Sin Leo,50 Rita Linko,51 Pei Liu,52 Faris Madanat,53 Toshie Manabe,54 Elga Mayo-Montero,55 Allison McGeer,56 Ziad A. Memish,57,58 Gokhan Metan,59 Dragan Miki c,60 Kristin G. I. Mohn,61,62 Ahmadreza Moradi,63,64 Pagbajabyn Nymadawa,65 Bulent Ozbay,66 Mehpare Ozkan,67 Dhruv Parekh,68 Mical Paul,69 Wolfgang Poeppl,70 Fernando P. Polack,71,72 Barbara A. Rath,73 Alejandro H. Rodr ıguez,74 Marilda M. Siqueira,75 Joanna Skre zt-Magierło,76 Ewa Talarek,77 Julian W. Tang,78,79,80 Antoni Torres,81 Selda H. T€ or€un,82 Dat Tran,83 Timothy M. Uyeki,84 Annelies van Zwol,85 Wendy Vaudry,86 Daiva Velyvyte,87 Tjasa Vidmar,88 Paul Zarogoulidis,89 PRIDE Consortium Investigators* Jonathan S. Nguyen-Van-Tam1 1Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK. 2Respiratory Medicine, Nottingham University Hospitals NHS Trust, Nottingham, UK. 3International Centre for Diarrhoeal Diseases, Research Bangladesh (ICDDRB), Dhaka, Bangladesh. 4Department of Pharmacology, Government Medical College and Sir Takhtsinhji General Hospital, Bhavnagar, Gujarat, India. 5University of Bras ılia, Bras ılia, DF, Brazil. 6Centers for Disease Control and Prevention, Atlanta, GA, USA. 7Ministerio de Salud de la Provincia de Buenos Aires, Buenos Aires, Argentina. 8Department of Infection Control, Hospital San Mart ın de Paran a, Entre R ıos, Argentina. 9Department of Medicine, King Saud Medical City, Riyadh, Saudi Arabia. 10Santa Maria Misericordia Hospital, Udine, Italy. 11Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia. 12Department of Emergency Medicine, University Hospital Basel, Basel, Switzerland. 13Institut de Veille Sanitaire, Saint-Maurice, France. 14Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico. 15Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. 16Department of Infectious Diseases, Hospital Universitari de Bellvitge, Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Red Espa~nola de Investigaci on en Patolog ıa Infecciosa, University of Barcelona, Barcelona, Spain. 17Ministerio de Salud de Tucum an, Tucum an, Argentina. 18Victorian Infectious Diseases Service and Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, Parkville, Vic., Australia. 19Department of Pediatric Infectious Diseases, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA. 20Universidade Estadual do Oeste do Parana ´, UNIOESTE, Cascavel, PR, Brazil. 21The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hashomer, Israel. 22Clinical Virology Laboratory, CEMIC University Hospital, Buenos Aires, Argentina. 23Section of Pediatric Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada. 24Paediatric Intensive Care Unit, Bristol Children’s Hospital, Bristol, UK. 25Department of Respiratory & Critical Care Medicine, Peking University People’s Hospital, Beijing, China. 26NICU/PICU, PFME, CHU Saint Pierre, Saint Pierre, La R eunion, France. 27CIC 1410 (CHU/Inserm/University of La Re ´union/URML-OI), CHU Saint Pierre, Saint Pierre, La Réunion, France. 28UMR PIMIT (CHU/Inserm/University of La Re ´union/IRD/CNRS), CYROI, Saint Denis – Reunion Island, Saint Denis, France. 29NICU/PICU CHU of La Re ´union, Groupe Hospitalier Sud Re ´union, Saint Pierre, La Re ´union, France. 30Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Maran ˜o ´n, Madrid, Spain. 31Department of Infectious Disease Epidemiology, Sector for National Health Documentation and Research, Statens Serum Institut, Copenhagen, Denmark. 32Section of Paediatrics, Division of Infectious Disease, Imperial College, London, UK. 33Epidemiology Research Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosı ´o Villegas, Mexico City, Mexico. 34Cath. Children’s Hospital Wilhelmstift, Hamburg, Germany. 35Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St. Gallen, St. Gallen, Switzerland. 36Peking Union Medical College Hospital, Beijing, China. 37Dhaka Medical College Hospital, Dhaka, Bangladesh. 38Departamento de Ginecologia e Obstetrı ´cia – UFCSPA, Preceptora da Reside ˆncia Me ´dica do Hospital Fe ˆmina, Porto Alegre, Brazil. 39Ministry of Health in Egypt, Cairo, Egypt. 40Gold Coast Hospital, Gold Coast, Qld, Australia. 41Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. 42National Centre for Immunisation Research and Surveillance (NCIRS), The Children’s Hospital at Westmead, University of Sydney, Sydney, NSW, Australia. 43National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. 44National Institute of Respiratory Diseases ‘Emilio Coni’ ANLIS “C. Malbran”, Santa Fe, Argentina. 45School of Medicine, University Hospital for Infectious Diseases, University of Zagreb, Zagreb, Croatia. 46Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong. 47Faculty of Medicine and Pharmacy, Mohammed V Military Teaching Hospital, Biosafety Level 3 and Research Laboratory, University Mohammed V-Souissi, Rabat, Morocco. 48Department of Obstetrics and Gynaecology, Stellenbosch University and Tygerberg, Stellenbosch, South Africa. 49Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. 50Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore. 51Helsinki University Hospital, Helsinki, Finland. 52Department of Infectious Diseases, The First Affiliated Hospital, China Medical University, Shenyang, China. 53Department of Pediatrics, King Hussein Cancer Center, Amman, Jordan. 54Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. 55Instituto de Medicina Preventiva de la Defensa, Capitan Medico Ramon y Cajal (IMPDEF), Ministerio de Defensa, Madrid, Spain. 56Toronto Invasive Bacterial Diseases Network, University of Toronto, Toronto, ON, Canada. 57Ministry of Health, Riyadh, Saudi Arabia. 58College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 59Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey. 60Military Medical Academy, Clinic for Infectious and Tropical Diseases, Belgrade, Serbia. 61Section for Infectious Diseases, Medical Department, and Department of Research and Development, Haukeland University Hospital, Bergen, Norway. 62Department of Clinical Science, The Influenza Centre, University of Bergen, Bergen, Norway. 63The Division of Ocular Immunology, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 64National Research Institute for Tuberculosis and Lung Disease, Massih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 65National Influenza Center, National Center of Communicable Diseases, Ministry of Health, Ulaanbaatar, Mongolia. 66Department of Pulmonary and Critical Care, Yuzuncu Yil University Medical Faculty, Van, Turkey. 67Clinic of Pediatric Neurology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey. 68Critical Care and Pain Perioperative, Critical Care and Trauma Trials Group, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK. 69Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel. 70Medical University of Vienna, Vienna, Austria. 71Department of Pediatrics, Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN, USA. 72Fundacion INFANT, Buenos Aires, Argentina. 73Division of Pneumonology-Immunology, Department of Pediatrics, Charite ´ University Medical Center, Berlin, Germany. 74Critical Care Department, Hospital Joan XXIII, IISPV, URV, CIBERES, Tarragona, Spain. 75Laboratory of Respiratory Viruses, Oswaldo Cruz Institute/Fiocruz, Rio de Janeiro, Brazil. 76Uniwersytet Rzeszowski, Rzeszo ´w, Poland. 77Department of Children’s Infectious Diseases, Medical University of Warsaw, Warsaw, Poland. 78Division of Microbiology/Molecular Diagnostic Centre, Department of Laboratory Medicine, National University Hospital, Singapore, Singapore. 79Alberta Provincial Laboratory for Public Health, University of Alberta Hospital, Edmonton, Canada. 80Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada. 81Hospital Clinic, University of Barcelona, IDIBAPS, CIBERES, Barcelona, Spain. 82Department of Pediatric Infectious Diseases, Istanbul Medical Faculty, Istanbul, Turkey. 83Division of Infectious Diseases, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Canada. 84Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. 85Department of Pediatric Intensive Care, VU University Medical Center, Amsterdam, The Netherlands. 86Division of Infectious Diseases, Department of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, AB, Canada. 87Lithuanian University of Health Sciences, Kaunas, Lithuania. 88General Hospital, Slovenj Gradec, Slovenia. 89Unit of Infectious Diseases, University General Hospital of Alexandroupolis, Democritus University Thrace, Dragana, Greece. Correspondence: Jonathan S. Nguyen-Van-Tam, University of Nottingham, City Hospital, DM, Room A28b, Clinical Sciences Building, Nottingham NG5 1PB, UK. E-mail: jvt@nottingham.ac.uk *List of PRIDE Consortium Investigators are in Appendix 1. For affiliations, please see Table S1. Múltipla - ver em notas Background The impact of neuraminidase inhibitors (NAIs) on influenza-related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1) pdm09 virus infection. Methods A worldwide meta-analysis of individual participant data from 20 634 hospitalised patients with laboratory-confirmed A (H1N1)pdm09 (n = 20 021) or clinically diagnosed (n = 613) ‘pandemic influenza’. The primary outcome was radiologically confirmed IRP. Odds ratios (OR) were estimated using generalised linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. Results Of 20 634 included participants, 5978 (29 0%) had IRP; conversely, 3349 (16 2%) had confirmed the absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0 83 (95% CI 0 64–1 06; P = 0 136)]. Among the 5978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR = 0 72 (0 44–1 17; P = 0 180)] or likelihood of requiring ventilatory support [adj. OR = 1 17 (0 71– 1 92; P = 0 537)], but early treatment versus later significantly reduced mortality [adj. OR = 0 70 (0 55–0 88; P = 0 003)] and likelihood of requiring ventilatory support [adj. OR = 0 68 (0 54– 0 85; P = 0 001)]. Conclusions Early NAI treatment of patients hospitalised with A (H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP, early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support.

BACKGROUND: The impact of neuraminidase inhibitors (NAIs) on Influenza-related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection. ----- METHODS: A worldwide meta-analysis of individual participant data (IPD) from 20,634 hospitalised patients with laboratory confirmed A(H1N1)pdm09 (n=20,021) or clinically diagnosed (n=613) 'pandemic influenza'. The primary outcome was radiologically confirmed influenza-related pneumonia (IRP). Odds ratios (OR) were estimated using generalized linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. ----- RESULTS: Among 20,634 included participants, 5,978 (29.0%) had IRP; conversely, 3,349 (16.2%) had confirmed absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0.83 (95%CI 0.64 - 1.06; p=0.136)]. Among the 5,978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR=0.72 (0.44-1.17; p=0.180)] or likelihood of requiring ventilatory support [adj. OR=1.17 (0.71-1.92; p=0.537)]; but early treatment versus later significantly reduced mortality [adj. OR=0.70 (0.55-0.88; p=0.003)] and likelihood of requiring ventilatory support [adj. OR=0.68 (0.54-0.85; p=0.001)]. ----- CONCLUSIONS: Early NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support.

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. 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. 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