Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study

Xin Wang, You Li, Katherine L O'Brien, Shabir A Madhi, Marc-Alain Widdowson, Peter Byass, Saad B Omer, Qalab Abbas, Asad Ali, Alberta Amu, Eduardo Azziz-Baumgartner, Quique Bassat, W Abdullah Brooks, Sandra S Chaves, Alexandria Chung, Cheryl Cohen, Marcela Echavarria, Rodrigo A Fasce, Angela Gentile, Aubree Gordon, Michelle Groome, Terho Heikkinen, Siddhivinayak Hirve, Jorge H Jara, Mark A Katz, Najwa Khuri-Bulos, Anand Krishnan, Oscar de Leon, Marilla G Lucero, John P McCracken, Ainara Mira-Iglesias, Jennifer C Moïsi, Patrick K Munywoki, Millogo Ourohiré, Fernando P Polack, Manveer Rahi, Zeba A Rasmussen, Barbara A Rath, Samir K Saha, Eric Af Simões, Viviana Sotomayor, Somsak Thamthitiwat, Florette K Treurnicht, Marylene Wamukoya, Lay-Myint Yoshida, Heather J Zar, Harry Campbell, Harish Nair, Respiratory Virus Global Epidemiology Network, Harish Nair, Harry Campbell, Xin Wang, You Li, Alexandria Chung, Manveer Rahi, Qalab Abbas, Asad Ali, Zulfiqar A Bhutta, Bushra Saeed, Sajid B Soofi, Mohammad Tahir Yousafzai, Anita K Zaidi, Alberta Amu, Elizabeth Awini, Eduardo Azziz-Baumgartner, Henry C Baggett, Sandra S Chaves, Nong Shang, Stephanie J Schrag, Marc-Alain Widdowson, Stefano Tempia, Quique Bassat, Miguel Lanaspa, Sozinho Acácio, W Abdullah Brooks, Amanda Driscoll, Maria Deloria Knoll, Katherine L O'Brien, Christine Prosperi, Abdullah H Baqui, Luke Mullany, Peter Byass, Cheryl Cohen, Anne von Gottberg, Orienka Hellferscee, Florette K Treurnicht, Sibongile Walaza, Doli Goswami, Mustafizur Rahman, Nicholas E Connor, Shams El Arifeen, Marcela Echavarria, Débora N Marcone, Noelia Reyes, Andrea Gutierrez, Ivan Rodriguez, Olga Lopez, David Ortiz, Nathaly Gonzalez, Angela Gentile, Maria Del Valle Juarez, Aubree Gordon, Clare Cutland, Michelle Groome, Shabir A Madhi, Marta C Nunes, Susan Nzenze, Terho Heikkinen, Siddhivinayak Hirve, Sanjay Juvekar, Natasha Halasa, Jorge H Jara, Chris Bernart, Mark A Katz, Ilan Gofer, Yonat Shemer Avni, Najwa Khuri-Bulos, Samir Faori, Asem Shehabi, Anand Krishnan, Rakesh Kumar, Ritvik Amarchand, Carmen L Contreras, Oscar de Leon, Maria R Lopez, John P McCracken, Herberth Maldonado, Antonio P Samayoa, Ana B Gomez, Marilla G Lucero, Leilani T Nillos, Socorro P Lupisan, Hanna Nohynek, Ainara Mira-Iglesias, Joan Puig-Barberà, Javier Díez-Domingo, Bradford D Gessner, Berthe-Marie Njanpop-Lafourcade, Jennifer C Moïsi, Haoua Tall, Patrick K Munywoki, Mwanjuma Ngama, D James Nokes, Saad B Omer, Dayna R Clark, Millogo Ourohiré, Sié Ali, Zabré Pascal, Bagagnan H Cheik, Mauricio T Caballero, Romina Libster, Fernando P Polack, Zeba A Rasmussen, Elizabeth D Thomas, Julia M Baker, Barbara A Rath, Patrick E Obermeier, M D Hassanuzzaman, Maksuda Islam, Mohammad S Islam, Samir K Saha, Pinaki Panigrahi, Anuradha Bose, Rita Isaac, David Murdoch, Pritish Nanda, Shamim A Qazi, Danielle Hessong, Eric Af Simőes, Viviana Sotomayor, Somsak Thamthitiwat, Malinee Chittaganpitch, Halima Dawood, Catherine Kyobutungi, Marylene Wamukoya, Abdhalah K Ziraba, Lay-Myint Yoshida, Keisuke Yoshihara, Duc-Anh Dand, Minh-Nhat Le, Mark P Nicol, Heather J Zar, Shobha Broor, Mandeep Chadha, Lola Madrid, Lionel Gresh, Angel Balmaseda, Guillermina Kuan, Niteen Wairagkar, Milagritos D Tapia, Stacey L Knobler, Alfredo Barahona, Ericka Ferguson, Brunhilde Schweiger, Xin Wang, You Li, Katherine L O'Brien, Shabir A Madhi, Marc-Alain Widdowson, Peter Byass, Saad B Omer, Qalab Abbas, Asad Ali, Alberta Amu, Eduardo Azziz-Baumgartner, Quique Bassat, W Abdullah Brooks, Sandra S Chaves, Alexandria Chung, Cheryl Cohen, Marcela Echavarria, Rodrigo A Fasce, Angela Gentile, Aubree Gordon, Michelle Groome, Terho Heikkinen, Siddhivinayak Hirve, Jorge H Jara, Mark A Katz, Najwa Khuri-Bulos, Anand Krishnan, Oscar de Leon, Marilla G Lucero, John P McCracken, Ainara Mira-Iglesias, Jennifer C Moïsi, Patrick K Munywoki, Millogo Ourohiré, Fernando P Polack, Manveer Rahi, Zeba A Rasmussen, Barbara A Rath, Samir K Saha, Eric Af Simões, Viviana Sotomayor, Somsak Thamthitiwat, Florette K Treurnicht, Marylene Wamukoya, Lay-Myint Yoshida, Heather J Zar, Harry Campbell, Harish Nair, Respiratory Virus Global Epidemiology Network, Harish Nair, Harry Campbell, Xin Wang, You Li, Alexandria Chung, Manveer Rahi, Qalab Abbas, Asad Ali, Zulfiqar A Bhutta, Bushra Saeed, Sajid B Soofi, Mohammad Tahir Yousafzai, Anita K Zaidi, Alberta Amu, Elizabeth Awini, Eduardo Azziz-Baumgartner, Henry C Baggett, Sandra S Chaves, Nong Shang, Stephanie J Schrag, Marc-Alain Widdowson, Stefano Tempia, Quique Bassat, Miguel Lanaspa, Sozinho Acácio, W Abdullah Brooks, Amanda Driscoll, Maria Deloria Knoll, Katherine L O'Brien, Christine Prosperi, Abdullah H Baqui, Luke Mullany, Peter Byass, Cheryl Cohen, Anne von Gottberg, Orienka Hellferscee, Florette K Treurnicht, Sibongile Walaza, Doli Goswami, Mustafizur Rahman, Nicholas E Connor, Shams El Arifeen, Marcela Echavarria, Débora N Marcone, Noelia Reyes, Andrea Gutierrez, Ivan Rodriguez, Olga Lopez, David Ortiz, Nathaly Gonzalez, Angela Gentile, Maria Del Valle Juarez, Aubree Gordon, Clare Cutland, Michelle Groome, Shabir A Madhi, Marta C Nunes, Susan Nzenze, Terho Heikkinen, Siddhivinayak Hirve, Sanjay Juvekar, Natasha Halasa, Jorge H Jara, Chris Bernart, Mark A Katz, Ilan Gofer, Yonat Shemer Avni, Najwa Khuri-Bulos, Samir Faori, Asem Shehabi, Anand Krishnan, Rakesh Kumar, Ritvik Amarchand, Carmen L Contreras, Oscar de Leon, Maria R Lopez, John P McCracken, Herberth Maldonado, Antonio P Samayoa, Ana B Gomez, Marilla G Lucero, Leilani T Nillos, Socorro P Lupisan, Hanna Nohynek, Ainara Mira-Iglesias, Joan Puig-Barberà, Javier Díez-Domingo, Bradford D Gessner, Berthe-Marie Njanpop-Lafourcade, Jennifer C Moïsi, Haoua Tall, Patrick K Munywoki, Mwanjuma Ngama, D James Nokes, Saad B Omer, Dayna R Clark, Millogo Ourohiré, Sié Ali, Zabré Pascal, Bagagnan H Cheik, Mauricio T Caballero, Romina Libster, Fernando P Polack, Zeba A Rasmussen, Elizabeth D Thomas, Julia M Baker, Barbara A Rath, Patrick E Obermeier, M D Hassanuzzaman, Maksuda Islam, Mohammad S Islam, Samir K Saha, Pinaki Panigrahi, Anuradha Bose, Rita Isaac, David Murdoch, Pritish Nanda, Shamim A Qazi, Danielle Hessong, Eric Af Simőes, Viviana Sotomayor, Somsak Thamthitiwat, Malinee Chittaganpitch, Halima Dawood, Catherine Kyobutungi, Marylene Wamukoya, Abdhalah K Ziraba, Lay-Myint Yoshida, Keisuke Yoshihara, Duc-Anh Dand, Minh-Nhat Le, Mark P Nicol, Heather J Zar, Shobha Broor, Mandeep Chadha, Lola Madrid, Lionel Gresh, Angel Balmaseda, Guillermina Kuan, Niteen Wairagkar, Milagritos D Tapia, Stacey L Knobler, Alfredo Barahona, Ericka Ferguson, Brunhilde Schweiger

Abstract

Background: Seasonal influenza virus is a common cause of acute lower respiratory infection (ALRI) in young children. In 2008, we estimated that 20 million influenza-virus-associated ALRI and 1 million influenza-virus-associated severe ALRI occurred in children under 5 years globally. Despite this substantial burden, only a few low-income and middle-income countries have adopted routine influenza vaccination policies for children and, where present, these have achieved only low or unknown levels of vaccine uptake. Moreover, the influenza burden might have changed due to the emergence and circulation of influenza A/H1N1pdm09. We aimed to incorporate new data to update estimates of the global number of cases, hospital admissions, and mortality from influenza-virus-associated respiratory infections in children under 5 years in 2018.

Methods: We estimated the regional and global burden of influenza-associated respiratory infections in children under 5 years from a systematic review of 100 studies published between Jan 1, 1995, and Dec 31, 2018, and a further 57 high-quality unpublished studies. We adapted the Newcastle-Ottawa Scale to assess the risk of bias. We estimated incidence and hospitalisation rates of influenza-virus-associated respiratory infections by severity, case ascertainment, region, and age. We estimated in-hospital deaths from influenza virus ALRI by combining hospital admissions and in-hospital case-fatality ratios of influenza virus ALRI. We estimated the upper bound of influenza virus-associated ALRI deaths based on the number of in-hospital deaths, US paediatric influenza-associated death data, and population-based childhood all-cause pneumonia mortality data in six sites in low-income and lower-middle-income countries.

Findings: In 2018, among children under 5 years globally, there were an estimated 109·5 million influenza virus episodes (uncertainty range [UR] 63·1-190·6), 10·1 million influenza-virus-associated ALRI cases (6·8-15·1); 870 000 influenza-virus-associated ALRI hospital admissions (543 000-1 415 000), 15 300 in-hospital deaths (5800-43 800), and up to 34 800 (13 200-97 200) overall influenza-virus-associated ALRI deaths. Influenza virus accounted for 7% of ALRI cases, 5% of ALRI hospital admissions, and 4% of ALRI deaths in children under 5 years. About 23% of the hospital admissions and 36% of the in-hospital deaths were in infants under 6 months. About 82% of the in-hospital deaths occurred in low-income and lower-middle-income countries.

Interpretation: A large proportion of the influenza-associated burden occurs among young infants and in low-income and lower middle-income countries. Our findings provide new and important evidence for maternal and paediatric influenza immunisation, and should inform future immunisation policy particularly in low-income and middle-income countries.

Funding: WHO; Bill & Melinda Gates Foundation.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Approaches for estimation of global influenza virus morbidity and mortality in children under 5 years We report the number of influenza virus episodes and the number of cases of influenza-virus-associated ALRIs, global influenza-virus-associated-ALRI hospitalisations, and global estimates of influenza-virus-associated ALRI deaths in hospital and overall deaths (in community). This figure summarises our approach for each outcome and also shows how they relate to each other. Global estimates of hospitalisations for influenza virus ALRI were estimated by applying hospitalisation rates to population estimates (2018). Influenza-virus-associated ALRI in-hospital deaths were estimated by combining in-hospital case fatality ratios (hCFRs) for cases and hospitalisations. The inflation factor was estimated using three approaches (appendix pp 20–26), and we determined to use the most conservative estimate to calculate the number of overall deaths (appendix pp 20–26). A detailed description of imputation is in the appendix (p 28). ALRI=d acute lower respiratory infection.
Figure 2
Figure 2
Flow diagram for selection of studies on seasonal influenza For multisite papers, the site-specific data were extracted where available and were analysed as one study; in this way 100 studies were extracted from 89 papers. One study could provide data on multiple outcomes among the same population; therefore the total number of studies was greater than the sum of studies by outcomes. RSV GEN=Respiratory Virus Global Epidemiology Network. IFV=influenza virus. ALRI=acute lower respiratory infection.
Figure 3
Figure 3
Location of included studies on influenza-virus-associated acute lower respiratory infection in children younger than 5 years

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Source: PubMed

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