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Lancet Respir Med. 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.

Author information

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.

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.

PMID:
24815805
DOI:
10.1016/S2213-2600(14)70041-4
[Indexed for MEDLINE]
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