Global burden of influenza-associated lower respiratory tract infections and hospitalizations among adults: A systematic review and meta-analysis
Authors: Lafond Kathryn E. , Porter Rachael M. , Whaley Melissa J. , Suizan Zhou , Ran Zhang , Aleem Mohammad Abdul , Thapa Binay , Sar Borann , Proschle Viviana Sotomayor , Peng Zhibin , Feng Luzhao , Coulibaly Daouda , Nkwembe Edith , Olmedo Alfredo , Ampofo William , Saha Siddhartha , Chadha Mandeep , Mangiri Amalya , Setiawaty Vivi , Ali Sami Sheikh , Chaves Sandra S. , Otorbaeva Dinagul , Keosavanh Onechanh , Saleh Majd , Ho Antonia , Alexander Burmaa , Oumzil Hicham , Baral Kedar Prasad , Huang Q. Sue , Adebayo Adedeji A. , Al-Abaidani Idris , von Horoch Marta , Cohen Cheryl , Tempia Stefano , Mmbaga Vida , Chittaganpitch Malinee , Casal Mariana , Dang Duc Anh , Couto Paula , Nair Harish , Bresee Joseph S. , Olsen Sonja J. , Azziz-Baumgartner Eduardo , Nuorti J. Pekka , Widdowson Marc-Alain ,   Global Respiratory Hospitalizations–Influenza Proportion Positive (GRIPP) Working Group
Published: March 2021

Background
Influenza illness burden is substantial, particularly among young children, older adults, and those with underlying conditions. Initiatives are underway to develop better global estimates for influenza-associated hospitalizations and deaths. Knowledge gaps remain regarding the role of influenza viruses in severe respiratory disease and hospitalizations among adults, particularly in lower-income settings.

Methods and findings
We aggregated published data from a systematic review and unpublished data from surveillance platforms to generate global meta-analytic estimates for the proportion of acute respiratory hospitalizations associated with influenza viruses among adults. We searched 9 online databases (Medline, Embase, CINAHL, Cochrane Library, Scopus, Global Health, LILACS, WHOLIS, and CNKI; 1 January 1996–31 December 2016) to identify observational studies of influenza-associated hospitalizations in adults, and assessed eligible papers for bias using a simplified Newcastle–Ottawa scale for observational data. We applied meta-analytic proportions to global estimates of lower respiratory infections (LRIs) and hospitalizations from the Global Burden of Disease study in adults ≥20 years and by age groups (20–64 years and ≥65 years) to obtain the number of influenza-associated LRI episodes and hospitalizations for 2016. Data from 63 sources showed that influenza was associated with 14.1% (95% CI 12.1%–16.5%) of acute respiratory hospitalizations among all adults, with no significant differences by age group. The 63 data sources represent published observational studies (n = 28) and unpublished surveillance data (n = 35), from all World Health Organization regions (Africa, n = 8; Americas, n = 11; Eastern Mediterranean, n = 7; Europe, n = 8; Southeast Asia, n = 11; Western Pacific, n = 18). Data quality for published data sources was predominantly moderate or high (75%, n = 56/75). We estimate 32,126,000 (95% CI 20,484,000–46,129,000) influenza-associated LRI episodes and 5,678,000 (95% CI 3,205,000–9,432,000) LRI hospitalizations occur each year among adults. While adults <65 years contribute most influenza-associated LRI hospitalizations and episodes (3,464,000 [95% CI 1,885,000–5,978,000] LRI hospitalizations and 31,087,000 [95% CI 19,987,000–44,444,000] LRI episodes), hospitalization rates were highest in those ≥65 years (437/100,000 person-years [95% CI 265–612/100,000 person-years]). For this analysis, published articles were limited in their inclusion of stratified testing data by year and age group. Lack of information regarding influenza vaccination of the study population was also a limitation across both types of data sources.

Conclusions
In this meta-analysis, we estimated that influenza viruses are associated with over 5 million hospitalizations worldwide per year. Inclusion of both published and unpublished findings allowed for increased power to generate stratified estimates, and improved representation from lower-income countries. Together, the available data demonstrate the importance of influenza viruses as a cause of severe disease and hospitalizations in younger and older adults worldwide.