Using Clinical Research Networks to Assess Severity of an Emerging Influenza Pandemic

Lone Simonsen, Elizabeth Higgs, Robert J Taylor, Deborah Wentworth, Al Cozzi-Lepri, Sarah Pett, Dominic E Dwyer, Richard Davey, Ruth Lynfield, Marcelo Losso, Kathleen Morales, Marshall J Glesby, Jozef Weckx, Dianne Carey, Cliff Lane, Jens Lundgren, INSIGHT FLU002 and FLU003 Study Groups, David Munroe, Claire Rappoport, Siegfried Schwarze, Bitten Aagaard, Dejan Adzic, Jesper Grarup, Patricia Herrero, Per Jansson, Marie Louise Jakobsen, Birgitte Jensen, Karoline B Jensen, Heidi Juncher, Jesper Kjær, Jens Lundgren, Paco Lopez, Amanda Mocroft, Mary Pearson, Begoña Portas, Caroline Sabin, Klaus Tillmann, Abdel Babiker, Nafisah Braimah, Yolanda Collaco-Moraes, Fleur Hudson, Ischa Kummeling, Filippo Pacciarini, Nick Paton, Michelle George, Merrie Harrison, Kathy Herman, Eric Krum, Gregg Larson, Ray Nelson, Kien Quan, Siu-Fun Quan, Cavan Reilly, Terri Schultz, Greg Thompson, Nicole Wyman, Anchalee Avihingsanon, Lara Cassar, Kanlaya Charoentonpuban, Sean Emery, Kobkeaw Laohajinda, Thidarat Jupimai, Isabel Lanusse, Alejandra Moricz, Ines Otegui, Kiat Ruxrungtham, Rose Robson, Elizabeth Finley, Fred Gordin, Adriana Sanchez, Michael Vjecha, John Baxter, Shawn Brown, Elodie Ghedin, Rebecca Halpin, Marie Hoover, Julia A Metcalf, Larisa Gubareva, Kathy Hancock, Jackie Katz, Alexander Klimov, Michael Shaw, Laura Barcan, Jorge Alberto Corral, Daniel Omar David, Hector Enrique Laplume, Maria Beatriz Lasala, Gustavo Daniel Lopardo, Marcelo H Losso, Sergio Lupo, Eduardo Warley, Mark Bloch, Dominic E Dwyer, Richard Moore, Sarah L Pett, Norman Roth, Tuck Meng Soo, Emanuel Vlahakis, Heinz Burgmann, Nathan Clumeck, Stephan De Wit, Eric Florence, Kabamba Kabeya, Jozef Weckx, Carlos Perez, Marcelo J Wolff, Jan Gerstoft, Jens D Lundgren, Lars Østergaard, Kai Zilmer, Johannes R Bogner, Norbert H Brockmeyer, Gerd Faetkenheuer, Hartwig Klinker, Andreas Plettenberg, Juergen Rockstroh, Christoph Stephan, Anastasia Antoniadou, Georgios Koratzanis, Nikolaos Koulouris, Vlassis Polixronopoulos, Helen Sambatakou, Nikolaos Vasilopoulos, Saulius Caplinskas, Alberto La Rosa, Fernando Mendo, Raul Salazar, Jorge Valencia, Elzbieta Bakowska, Andrzej Horban, Brygida Knysz, Francisco Antunes, Manuela Doroana, Nesri Padayatchi, David Dalmau, Eduardo Fernandez-Cruz, Jose Maria Gatell, Jesus Sanz Sanz, Vincent Soriano, Ploenchan Chetchotisakd, Kiat Ruxrungtham, Gompol Suwanpimolkul, Clifford L S Leen, Calvin Cohen, David L Cohn, Jack A DeHovitz, Wafaa El-Sadr, Marshall Glesby, Fred M Gordin, Sally Hodder, Norman Markowitz, Richard M Novak, Robert Schooley, Gary L Simon, Ellen Marie Tedaldi, Zelalem Temesgen, Joseph Timpone, Daniel Z Uslan, Barbara Heeter Wade, Laura Barcan, Jorge Alberto Corral, Daniel Omar David, Hector Enrique Laplume, Maria Beatriz Lasala, Gustavo Daniel Lopardo, Marcelo H Losso, Eduardo Warley, Dominic E Dwyer, Julian Elliott, Pam Konecny, John McBride, Sarah L Pett, Heinz Burgmann, Nathan Clumeck, Stephan De Wit, Philippe Jorens, Kabamba Kabeya, Marcelo J Wolff, Tak Chiu Wu, Jan Gerstoft, Lars Mathiesen, Henrik Nielsen, Lars Østergaard, Svend Stenvang Pedersen, Frank Bergmann, Johannes R Bogner, Norbert H Brockmeyer, Gerd Faetkenheuer, Hartwig Klinker, Juergen Rockstroh, Christoph Stephan, Anastasia Antoniadou, Georgios Koratzanis, Nikolaos Koulouris, Vlassis Polixronopoulos, Helen Sambatakou, Nikolaos Vasilopoulos, Anne Maagaard, Fernando Mendo, Raul Salazar, Elzbieta Bakowska, Andrzej Horban, Nesri Padayatchi, David Dalmau, Vicente Estrada, Eduardo Fernandez-Cruz, Hernando Knobel Freud, Rosa M Blazquez Garrido, Jose Maria Gatell, Jose Sanz Moreno, Jose Ramon Pano-Pardo, Jesus Sanz Sanz, Vincent Soriano, Ploenchan Chetchotisakd, Kiat Ruxrungtham, Gompol Suwanpimolkul, Brian J Angus, David R Chadwick, David Dockrell, Clifford L S Leen, Melanie Newport, Ed Wilkins, Harry Anderson Iii, Jason V Baker, David L Cohn, Jack A DeHovitz, Wafaa El-Sadr, Matthew S Freiberg, Fred M Gordin, Roy Gulick, David Gurka, Sally Hodder, Norman Markowitz, Richard M Novak, Armando Paez, Namrata Patil, Annette Reboli, Michael Sands, Robert Schooley, Gary L Simon, Zelalem Temesgen, Joseph Timpone, Daniel Z Uslan, Barbara Heeter Wade, Lone Simonsen, Elizabeth Higgs, Robert J Taylor, Deborah Wentworth, Al Cozzi-Lepri, Sarah Pett, Dominic E Dwyer, Richard Davey, Ruth Lynfield, Marcelo Losso, Kathleen Morales, Marshall J Glesby, Jozef Weckx, Dianne Carey, Cliff Lane, Jens Lundgren, INSIGHT FLU002 and FLU003 Study Groups, David Munroe, Claire Rappoport, Siegfried Schwarze, Bitten Aagaard, Dejan Adzic, Jesper Grarup, Patricia Herrero, Per Jansson, Marie Louise Jakobsen, Birgitte Jensen, Karoline B Jensen, Heidi Juncher, Jesper Kjær, Jens Lundgren, Paco Lopez, Amanda Mocroft, Mary Pearson, Begoña Portas, Caroline Sabin, Klaus Tillmann, Abdel Babiker, Nafisah Braimah, Yolanda Collaco-Moraes, Fleur Hudson, Ischa Kummeling, Filippo Pacciarini, Nick Paton, Michelle George, Merrie Harrison, Kathy Herman, Eric Krum, Gregg Larson, Ray Nelson, Kien Quan, Siu-Fun Quan, Cavan Reilly, Terri Schultz, Greg Thompson, Nicole Wyman, Anchalee Avihingsanon, Lara Cassar, Kanlaya Charoentonpuban, Sean Emery, Kobkeaw Laohajinda, Thidarat Jupimai, Isabel Lanusse, Alejandra Moricz, Ines Otegui, Kiat Ruxrungtham, Rose Robson, Elizabeth Finley, Fred Gordin, Adriana Sanchez, Michael Vjecha, John Baxter, Shawn Brown, Elodie Ghedin, Rebecca Halpin, Marie Hoover, Julia A Metcalf, Larisa Gubareva, Kathy Hancock, Jackie Katz, Alexander Klimov, Michael Shaw, Laura Barcan, Jorge Alberto Corral, Daniel Omar David, Hector Enrique Laplume, Maria Beatriz Lasala, Gustavo Daniel Lopardo, Marcelo H Losso, Sergio Lupo, Eduardo Warley, Mark Bloch, Dominic E Dwyer, Richard Moore, Sarah L Pett, Norman Roth, Tuck Meng Soo, Emanuel Vlahakis, Heinz Burgmann, Nathan Clumeck, Stephan De Wit, Eric Florence, Kabamba Kabeya, Jozef Weckx, Carlos Perez, Marcelo J Wolff, Jan Gerstoft, Jens D Lundgren, Lars Østergaard, Kai Zilmer, Johannes R Bogner, Norbert H Brockmeyer, Gerd Faetkenheuer, Hartwig Klinker, Andreas Plettenberg, Juergen Rockstroh, Christoph Stephan, Anastasia Antoniadou, Georgios Koratzanis, Nikolaos Koulouris, Vlassis Polixronopoulos, Helen Sambatakou, Nikolaos Vasilopoulos, Saulius Caplinskas, Alberto La Rosa, Fernando Mendo, Raul Salazar, Jorge Valencia, Elzbieta Bakowska, Andrzej Horban, Brygida Knysz, Francisco Antunes, Manuela Doroana, Nesri Padayatchi, David Dalmau, Eduardo Fernandez-Cruz, Jose Maria Gatell, Jesus Sanz Sanz, Vincent Soriano, Ploenchan Chetchotisakd, Kiat Ruxrungtham, Gompol Suwanpimolkul, Clifford L S Leen, Calvin Cohen, David L Cohn, Jack A DeHovitz, Wafaa El-Sadr, Marshall Glesby, Fred M Gordin, Sally Hodder, Norman Markowitz, Richard M Novak, Robert Schooley, Gary L Simon, Ellen Marie Tedaldi, Zelalem Temesgen, Joseph Timpone, Daniel Z Uslan, Barbara Heeter Wade, Laura Barcan, Jorge Alberto Corral, Daniel Omar David, Hector Enrique Laplume, Maria Beatriz Lasala, Gustavo Daniel Lopardo, Marcelo H Losso, Eduardo Warley, Dominic E Dwyer, Julian Elliott, Pam Konecny, John McBride, Sarah L Pett, Heinz Burgmann, Nathan Clumeck, Stephan De Wit, Philippe Jorens, Kabamba Kabeya, Marcelo J Wolff, Tak Chiu Wu, Jan Gerstoft, Lars Mathiesen, Henrik Nielsen, Lars Østergaard, Svend Stenvang Pedersen, Frank Bergmann, Johannes R Bogner, Norbert H Brockmeyer, Gerd Faetkenheuer, Hartwig Klinker, Juergen Rockstroh, Christoph Stephan, Anastasia Antoniadou, Georgios Koratzanis, Nikolaos Koulouris, Vlassis Polixronopoulos, Helen Sambatakou, Nikolaos Vasilopoulos, Anne Maagaard, Fernando Mendo, Raul Salazar, Elzbieta Bakowska, Andrzej Horban, Nesri Padayatchi, David Dalmau, Vicente Estrada, Eduardo Fernandez-Cruz, Hernando Knobel Freud, Rosa M Blazquez Garrido, Jose Maria Gatell, Jose Sanz Moreno, Jose Ramon Pano-Pardo, Jesus Sanz Sanz, Vincent Soriano, Ploenchan Chetchotisakd, Kiat Ruxrungtham, Gompol Suwanpimolkul, Brian J Angus, David R Chadwick, David Dockrell, Clifford L S Leen, Melanie Newport, Ed Wilkins, Harry Anderson Iii, Jason V Baker, David L Cohn, Jack A DeHovitz, Wafaa El-Sadr, Matthew S Freiberg, Fred M Gordin, Roy Gulick, David Gurka, Sally Hodder, Norman Markowitz, Richard M Novak, Armando Paez, Namrata Patil, Annette Reboli, Michael Sands, Robert Schooley, Gary L Simon, Zelalem Temesgen, Joseph Timpone, Daniel Z Uslan, Barbara Heeter Wade

Abstract

Background: Early clinical severity assessments during the 2009 influenza A H1N1 pandemic (pH1N1) overestimated clinical severity due to selection bias and other factors. We retrospectively investigated how to use data from the International Network for Strategic Initiatives in Global HIV Trials, a global clinical influenza research network, to make more accurate case fatality ratio (CFR) estimates early in a future pandemic, an essential part of pandemic response.

Methods: We estimated the CFR of medically attended influenza (CFRMA) as the product of probability of hospitalization given confirmed outpatient influenza and the probability of death given hospitalization with confirmed influenza for the pandemic (2009-2011) and post-pandemic (2012-2015) periods. We used literature survey results on health-seeking behavior to convert that estimate to CFR among all infected persons (CFRAR).

Results: During the pandemic period, 5.0% (3.1%-6.9%) of 561 pH1N1-positive outpatients were hospitalized. Of 282 pH1N1-positive inpatients, 8.5% (5.7%-12.6%) died. CFRMA for pH1N1 was 0.4% (0.2%-0.6%) in the pandemic period 2009-2011 but declined 5-fold in young adults during the post-pandemic period compared to the level of seasonal influenza in the post-pandemic period 2012-2015. CFR for influenza-negative patients did not change over time. We estimated the 2009 pandemic CFRAR to be 0.025%, 16-fold lower than CFRMA.

Conclusions: Data from a clinical research network yielded accurate pandemic severity estimates, including increased severity among younger people. Going forward, clinical research networks with a global presence and standardized protocols would substantially aid rapid assessment of clinical severity.

Clinical trials registration: NCT01056354 and NCT01056185

Figures

Figure 1.
Figure 1.
Map of International Network for Strategic Initiatives in Global HIV Trials influenza protocol patient intake sites. Blue markers indicate FLU002 outpatient sites and red markers indicate FLU003 inpatient sites.
Figure 2.
Figure 2.
A schematic representation of the pyramid modeling approach used to estimate the 2009 pandemic case fatality ratio among medically attended cases from probabilities of disease progression from International Network for Strategic Initiatives in Global HIV Trials outpatient (FLU002) and inpatient (FLU003) data. Modeling was also done for 18–64 and 65+ year age groups separately due to known differences in attack rates and preexisting immunity. Abbreviations: AR, all infected persons; CFR, case fatality ratio; ILI, influenza-like illness; MA, medically attended; P (D|H), probability of death given hospitalization; P (H|ILI) , probability of hospitalization given influenza-like illness.

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