Outcomes of influenza A(H1N1)pdm09 virus infection: results from two international cohort studies

Ruth Lynfield, Richard Davey, Dominic E Dwyer, Marcelo H Losso, Deborah Wentworth, Alessandro Cozzi-Lepri, Kathy Herman-Lamin, Grazyna Cholewinska, Daniel David, Stefan Kuetter, Zelalem Ternesgen, Timothy M Uyeki, H Clifford Lane, Jens Lundgren, James D Neaton, INSIGHT Influenza Study Group, James D Neaton, Bitten Aagaard, Alvaro H D Borges, Tina Bruun, Marius Eid, Per O Jansson, Marianne Jeppesen, Zillah Maria Joensen, Ruth Kjærgård, Birgit Riis Nielsen, Mary Pearson, Lars Peters, Brian Angus, Abdel Babiker, Rachel Bennett, Nafisah Braimah, Yolanda Collaco-Moraes, Adam Cursley, Fleur Hudson, Charlotte Russell, Kate Brekke, Alain DuChene, Michelle George, Merrie Harrison, Ray Nelson, Siu-Fun Quan, Terri Schultz, Nicole Wyman, Dianne Carey, David Courtney-Rodgers, Sean Emery, Pamela Findlay, Sarah L Pett, Rose Robson, Fred Gordin, Adriana Sanchez, Barbara Standridge, Michael Vjecha, John Baxter, Shawn Brown, Marie Hoover, Julia Metcalf, Ven Natarajan, Fatma Ba-Alawi, Jon Iredell, Jen Kok, Olga Anagnostou, Anastasia Antoniadou, Vicky Gioukari, Maria Kantzanou, Georgios Koratzanis, Nikolaos Koulouris, Vlassis Polixronopoulos, Helen Sambatakou, Giota Touloumi, Nikolaos Vasilopoulos, Taryn M Aulicino, Jason V Baker, Cindy Bardascino, John D Baxter, Beverly D Bentley, Mary Lee Bertrand, Ann B Brown, Calvin J Cohen, Shirley Cummins, Jack A DeHovitz, Nila J Dharan, Kimberly Jo Garrett, Joanne Grenade, Edie Gunderson, Kirsis Ham, Susan Holman, Valery Hughes, Audrey Lan, Karen McLaughlin, Raquel Nahra, Mary Jane Nettles, Kathleen Nuffer, Hannah B Olivet, Bola Omotosho, Armando P Paez, Marta Paez-Quinde, Namrata Patil, Hari Polenakovik, Rachel A Prosser, Nancy A Reilly, Paul F Riska, Stacey Rizza, Robert Schooley, Gary L Simon, Daniel J Skiest, Clemencia Solorzano, Nicole Swanson, Doug Thomas, Colleen Traverse, David E Uddin, Daniel Z Uslan, William M Vaughan, Barbara Wade, Cameron R Wolfe, Anchalee Avihingsanon, Kanlaya Charoentonpuban, Ploenchan Chetchotisakd, Thidarat Jupimai, Peeraporn Kaewon, Naphassanant Laopraynak, Opass Putcharoen, Kiat Ruxrungtham, Gompol Suwanpimonkul, Sasiwimol Ubolyam, Frank Bergmann, Christoph Boesecke, Johannes R Bogner, Norbert Brockmeyer, Christine Czaja-Harder, Rika Draenert, Gerd Fätkenheuer, Hartiwig Klinker, Tim Kümmerle, Clara Lehmann, Vera Müller, Andreas Plettenberg, Jürgen Rockstroh, Stefan Schlabe, Wolfgang E Schmidt, Dirk Schürmann, Gundolf Schüttfort, Ulrich Seybold, Christoph Stephan, Albrecht Stoehr, Klaus Tilmann, Susanne Wiebecke, Timo Wolf, Bente Baadegaard, Philippa Collins, Jan Gerstoft, Lene Hergens, Lene Pors Jensen, Zillah Maria Joensen, Bitten Konradsen, Gitte Kronborg, Iben Rose Loftheim, Henrik Nielsen, Lars Oestergaard, Court Pedersen, Svend Stenvang Pedersen, Yordanos Yehdego, Delene Assam, Mark Bloch, Nicky Cunningham, Sian Edwards, Julian Elliott, Jill Garlick, Philip Habel, Fiona Kilkenny, Patricia King, Helen Lau, Karen MacRae, John McBride, Richard Moore, Isabel Prone, Sue Richmond, Norm Roth, Tuck Meng Soo, Trina Vincent, Emanuel Vlakahis, Rachel Woolstencroft, Noemi Cabello, Javier Carbone, Eduardo Fernández Cruz, David Dalmau, Vincente Estrada, Patricia Herreiro, Hernando Knobel, Paco López, Rocío Montejano, José Sans Moreno, José Ramón Paño, Begoña Portas, Maria Rodrigo, Pilar Romero, Domingo Sánchez-Sendín, Vincente Soriano, Helen Mülle, Kerstin Kase, Kai Zilmer, Elzbieta Bakowska, Andrzej Jerzy Horban, Brygida Knysz, Karolina Pyziak Kowalska, Anna Zubkiewicz-Zarebska, Leslie Andry, Mireille Bielen, Nathan Clumeck, Eric Florence, Kabamba Kabeya, Jolanthe Sagaer, Jozef Weckx, David Chadwick, Jane Democratis, David Dockrell, Jamie Kitt, Stefan Kutter, Allison Leslie, Melanie Newport, Nellie Nkhoma, Richard Rye, Lynne Smart, Pauline Spence, Bala Subramanian, Damian Aguila, Laura Barcan, Laura Barcelona, Veronica Berdiñas, Pablo Bonvehi, Juan Pablo Caeiro, Veronica Cisneros, Ana Crinejo, Marina Delfino, Juan Ebenrstejin, Gustavo Lopardo, Pablo Lucchetti, Sergio Lupo, Laura Moreno Macias, Valeria Menendez, Alejandra Moricz, Gabriel Nieto, Laura Nieto, Marisa Sanchez, Pablo Sanchez, Mariana de Paz Sierra, Silvina Tavella, Elena Temporiti, Liliana Trape, Ines Vieni, Eduardo Warley, Diego Yahni, Abel Humberto Zarate, Heinz Burgmann, Selma Tobudic, Gladys Allendes, Jimena Flores, Rebeka Northland, Carlos Perez, Isabel Velasco, Marcelo Wolff, Man-Yee Chu, Tak-chiu Wu, Anne Maagaard, Carlos Benites, Raul Castillo, Romina Chinchay, Eva Cornelio, Maria Guevara, Luis Gutierrez, Alberto La Rosa, Yvett Pinedo, Juan Vega, David Munroe, Ruth Lynfield, Richard Davey, Dominic E Dwyer, Marcelo H Losso, Deborah Wentworth, Alessandro Cozzi-Lepri, Kathy Herman-Lamin, Grazyna Cholewinska, Daniel David, Stefan Kuetter, Zelalem Ternesgen, Timothy M Uyeki, H Clifford Lane, Jens Lundgren, James D Neaton, INSIGHT Influenza Study Group, James D Neaton, Bitten Aagaard, Alvaro H D Borges, Tina Bruun, Marius Eid, Per O Jansson, Marianne Jeppesen, Zillah Maria Joensen, Ruth Kjærgård, Birgit Riis Nielsen, Mary Pearson, Lars Peters, Brian Angus, Abdel Babiker, Rachel Bennett, Nafisah Braimah, Yolanda Collaco-Moraes, Adam Cursley, Fleur Hudson, Charlotte Russell, Kate Brekke, Alain DuChene, Michelle George, Merrie Harrison, Ray Nelson, Siu-Fun Quan, Terri Schultz, Nicole Wyman, Dianne Carey, David Courtney-Rodgers, Sean Emery, Pamela Findlay, Sarah L Pett, Rose Robson, Fred Gordin, Adriana Sanchez, Barbara Standridge, Michael Vjecha, John Baxter, Shawn Brown, Marie Hoover, Julia Metcalf, Ven Natarajan, Fatma Ba-Alawi, Jon Iredell, Jen Kok, Olga Anagnostou, Anastasia Antoniadou, Vicky Gioukari, Maria Kantzanou, Georgios Koratzanis, Nikolaos Koulouris, Vlassis Polixronopoulos, Helen Sambatakou, Giota Touloumi, Nikolaos Vasilopoulos, Taryn M Aulicino, Jason V Baker, Cindy Bardascino, John D Baxter, Beverly D Bentley, Mary Lee Bertrand, Ann B Brown, Calvin J Cohen, Shirley Cummins, Jack A DeHovitz, Nila J Dharan, Kimberly Jo Garrett, Joanne Grenade, Edie Gunderson, Kirsis Ham, Susan Holman, Valery Hughes, Audrey Lan, Karen McLaughlin, Raquel Nahra, Mary Jane Nettles, Kathleen Nuffer, Hannah B Olivet, Bola Omotosho, Armando P Paez, Marta Paez-Quinde, Namrata Patil, Hari Polenakovik, Rachel A Prosser, Nancy A Reilly, Paul F Riska, Stacey Rizza, Robert Schooley, Gary L Simon, Daniel J Skiest, Clemencia Solorzano, Nicole Swanson, Doug Thomas, Colleen Traverse, David E Uddin, Daniel Z Uslan, William M Vaughan, Barbara Wade, Cameron R Wolfe, Anchalee Avihingsanon, Kanlaya Charoentonpuban, Ploenchan Chetchotisakd, Thidarat Jupimai, Peeraporn Kaewon, Naphassanant Laopraynak, Opass Putcharoen, Kiat Ruxrungtham, Gompol Suwanpimonkul, Sasiwimol Ubolyam, Frank Bergmann, Christoph Boesecke, Johannes R Bogner, Norbert Brockmeyer, Christine Czaja-Harder, Rika Draenert, Gerd Fätkenheuer, Hartiwig Klinker, Tim Kümmerle, Clara Lehmann, Vera Müller, Andreas Plettenberg, Jürgen Rockstroh, Stefan Schlabe, Wolfgang E Schmidt, Dirk Schürmann, Gundolf Schüttfort, Ulrich Seybold, Christoph Stephan, Albrecht Stoehr, Klaus Tilmann, Susanne Wiebecke, Timo Wolf, Bente Baadegaard, Philippa Collins, Jan Gerstoft, Lene Hergens, Lene Pors Jensen, Zillah Maria Joensen, Bitten Konradsen, Gitte Kronborg, Iben Rose Loftheim, Henrik Nielsen, Lars Oestergaard, Court Pedersen, Svend Stenvang Pedersen, Yordanos Yehdego, Delene Assam, Mark Bloch, Nicky Cunningham, Sian Edwards, Julian Elliott, Jill Garlick, Philip Habel, Fiona Kilkenny, Patricia King, Helen Lau, Karen MacRae, John McBride, Richard Moore, Isabel Prone, Sue Richmond, Norm Roth, Tuck Meng Soo, Trina Vincent, Emanuel Vlakahis, Rachel Woolstencroft, Noemi Cabello, Javier Carbone, Eduardo Fernández Cruz, David Dalmau, Vincente Estrada, Patricia Herreiro, Hernando Knobel, Paco López, Rocío Montejano, José Sans Moreno, José Ramón Paño, Begoña Portas, Maria Rodrigo, Pilar Romero, Domingo Sánchez-Sendín, Vincente Soriano, Helen Mülle, Kerstin Kase, Kai Zilmer, Elzbieta Bakowska, Andrzej Jerzy Horban, Brygida Knysz, Karolina Pyziak Kowalska, Anna Zubkiewicz-Zarebska, Leslie Andry, Mireille Bielen, Nathan Clumeck, Eric Florence, Kabamba Kabeya, Jolanthe Sagaer, Jozef Weckx, David Chadwick, Jane Democratis, David Dockrell, Jamie Kitt, Stefan Kutter, Allison Leslie, Melanie Newport, Nellie Nkhoma, Richard Rye, Lynne Smart, Pauline Spence, Bala Subramanian, Damian Aguila, Laura Barcan, Laura Barcelona, Veronica Berdiñas, Pablo Bonvehi, Juan Pablo Caeiro, Veronica Cisneros, Ana Crinejo, Marina Delfino, Juan Ebenrstejin, Gustavo Lopardo, Pablo Lucchetti, Sergio Lupo, Laura Moreno Macias, Valeria Menendez, Alejandra Moricz, Gabriel Nieto, Laura Nieto, Marisa Sanchez, Pablo Sanchez, Mariana de Paz Sierra, Silvina Tavella, Elena Temporiti, Liliana Trape, Ines Vieni, Eduardo Warley, Diego Yahni, Abel Humberto Zarate, Heinz Burgmann, Selma Tobudic, Gladys Allendes, Jimena Flores, Rebeka Northland, Carlos Perez, Isabel Velasco, Marcelo Wolff, Man-Yee Chu, Tak-chiu Wu, Anne Maagaard, Carlos Benites, Raul Castillo, Romina Chinchay, Eva Cornelio, Maria Guevara, Luis Gutierrez, Alberto La Rosa, Yvett Pinedo, Juan Vega, David Munroe

Abstract

Background: Data from prospectively planned cohort studies on risk of major clinical outcomes and prognostic factors for patients with influenza A(H1N1)pdm09 virus are limited. In 2009, in order to assess outcomes and evaluate risk factors for progression of illness, two cohort studies were initiated: FLU 002 in outpatients and FLU 003 in hospitalized patients.

Methods and findings: Between October 2009 and December 2012, adults with influenza-like illness (ILI) were enrolled; outpatients were followed for 14 days and inpatients for 60 days. Disease progression was defined as hospitalization and/or death for outpatients, and hospitalization for >28 days, transfer to intensive care unit (ICU) if enrolled from general ward, and/or death for inpatients. Infection was confirmed by RT-PCR. 590 FLU 002 and 392 FLU 003 patients with influenza A (H1N1)pdm09 were enrolled from 81 sites in 17 countries at 2 days (IQR 1-3) and 6 days (IQR 4-10) following ILI onset, respectively. Disease progression was experienced by 29 (1 death) outpatients (5.1%; 95% CI: 3.4-7.2%) and 80 inpatients [death (32), hospitalization >28 days (43) or ICU transfer (20)] (21.6%; 95% CI: 17.5-26.2%). Disease progression (death) for hospitalized patients was 53.1% (26.6%) and 12.8% (3.8%), respectively, for those enrolled in the ICU and general ward. In pooled analyses for both studies, predictors of disease progression were age, longer duration of symptoms at enrollment and immunosuppression. Patients hospitalized during the pandemic period had a poorer prognosis than in subsequent seasons.

Conclusions: Patients with influenza A(H1N1)pdm09, particularly when requiring hospital admission, are at high risk for disease progression, especially if they are older, immunodeficient, or admitted late in infection. These data reinforce the need for international trials of novel treatment strategies for influenza infection and serve as a reminder of the need to monitor the severity of seasonal and pandemic influenza epidemics globally.

Trial registration: ClinicalTrials.gov Identifiers: FLU 002--NCT01056354, FLU 003--NCT01056185.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. FLU 002 flow diagram.
Figure 1. FLU 002 flow diagram.
Figure 2. FLU 003 flow diagram.
Figure 2. FLU 003 flow diagram.
Figure 3. Cumulative percentage of patients with…
Figure 3. Cumulative percentage of patients with death from any cause in FLU 003 according to location of enrollment.
The number of patients at risk at each timepoint are given below the graph.
Figure 4. Frequency distribution of number of…
Figure 4. Frequency distribution of number of days between onset of ILI symptoms and enrollment for patients in FLU 002 and FLU 003.

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