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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
Authors: Muthuri, Stella G 
Venkatesan, Sudhir 
Myles, Puja R 
Leonardi-Bee, Jo 
Al Khuwaitir, Tarig S A 
Al Mamun, Adbullah 
Anovadiya, Ashish P 
Azziz-Baumgartner, Eduardo 
Báez, Clarisa 
Bassetti, Matteo 
Beovic, Bojana 
Bertisch, Barbara 
Bonmarin, Isabelle 
Booy, Robert 
Borja-Aburto, Victor H 
Burgmann, Heinz 
Cao, Bin 
Carratala, Jordi 
Denholm, Justin T 
Dominguez, Samuel R 
Duarte, Pericles A D 
Dubnov-Raz, Gal 
Echavarria, Marcela 
Fanella, Sergio 
Gao, Zhancheng 
Gérardin, Patrick 
Giannella, Maddalena 
Gubbels, Sophie 
Herberg, Jethro 
Iglesias, Anjarath L Higuera 
Hoger, Peter H 
Hu, Xiaoyun 
Islam, Quazi T 
Jiménez, Mirela F 
Kandeel, Amr 
Keijzers, Gerben 
Khalili, Hossein 
Knight, Marian 
Kudo, Koichiro 
Kusznierz, Gabriela F. 
Kuzman, Ilija 
Kwan, Arthur M C 
Amine, Idriss Lahlou 
Langenegger, Eduard 
Lankarani, Kamran B 
Leo, Yee-Sin 
Linko, Rita 
Liu, Pei 
Madanat, Faris 
Mayo-Montero, Elga 
McGeer, Allison 
Memish, Ziad A 
Metan, Gokhan 
Mickiene, Auksė 
Mikić, Dragan 
Mohn, Kristin G I 
Moradi, Ahmadreza 
Nymadawa, Pagbajabyn 
Oliva, Maria E 
Ozkan, Mehpare 
Parekh, Dhruv 
Paul, Mical 
Polack, Fernando P. 
Rath, Barbara A 
Rodríguez, Alejandro H 
Sarrouf, Elena B 
Seale, Anna C 
Sertogullarindan, Bunyamin 
Siqueira, Marilda M 
Skręt-Magierło, Joanna 
Stephan, Frank 
Talarek, Ewa 
Tang, Julian W 
To, Kelvin K W 
Torres, Antoni 
Törün, Selda H 
Tran, Dat 
Uyeki, Timothy M 
van Zwol, Annelies 
Vaudry, Wendy 
Vidmar, Tjasa 
Yokota, Renata T C 
Zarogoulidis, Paul 
Nguyen-Van-Tam, Jonathan S 
Issue Date: May-2014
Journal: The Lancet. Respiratory medicine 
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.
DOI: 10.1016/S2213-2600(14)70041-4
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