key: cord-0734933-7mu1hx79 authors: Neumann, Gabriele; Kawaoka, Yoshihiro title: Quo Vadis Influenza? date: 2021-12-03 journal: China CDC Wkly DOI: 10.46234/ccdcw2021.254 sha: e39181e7fb99a7a6865c3bdf47e157c1fac5f2b7 doc_id: 734933 cord_uid: 7mu1hx79 The number of influenza virus detections declined tremendously after the emergence and worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); an effect most likely caused by non-pharmaceutical interventions to slow the spread of SARS-CoV-2. Recent data suggest that influenza virus detection has slightly increased in parts of the world, perhaps owing to the relaxation of social distancing measures. the substantial decline in influenza virus detection rates. First and foremost, non-pharmaceutical intervention strategies including social distancing; travel restrictions; closure of schools, universities, and many public and commercial offices; mask wearing; and improved hand hygiene may have curbed the spread of influenza viruses. In addition, viral interference, whereby innate immune responses to a viral infection can affect infection by a second virus (11) (12) (13) (14) have been discussed as a potential mechanism that might explain the low rates of influenza virus circulation in human populations during the SARS-CoV-2 pandemic. However, several studies have demonstrated that influenza viruses can replicate in animals or cells co-or sequentially infected with SARS-CoV-2 (15) (16) (17) , suggesting that viral interference may not be the major reason for the low influenza virus detection rate during the SARS-CoV-2 pandemic. Interestingly, the decline in detection rates differs among human respiratory viruses. Human coronaviruses, parainfluenza viruses, human metapneumoviruses, respiratory syncytial virus, and adenoviruses have all been detected at very low rates since the outbreak of the SARS-CoV-2 pandemic, whereas rhinoviruses have been detected more frequently (4-5,18), perhaps because of their lower sensitivity to alcohol and detergents compared to other enveloped human respiratory viruses. These findings lead to interesting questions about the similarities and differences among human respiratory viruses regarding their transmission mode and the most effective mitigation strategies. Many of the influenza viruses isolated in 2020 and 2021 originate from the (sub)tropical regions of the world, where the year-round circulation of influenza viruses (believed to be a consequence of climate and behavioral factors) may have supported low-level influenza virus transmission in communities during the SARS-CoV-2 pandemic. Approaching the influenza virus season in the Northern hemisphere, combined with less restrictive non-pharmaceutical interventions in parts of the world due to increasing SARS-CoV-2 vaccination rates, it will be interesting to see whether influenza viruses make a comeback as major human respiratory pathogens. The latest WHO Influenza Update (19) showed that of 307,999 specimens tested worldwide, 2,199 were positive for influenza viruses, resulting in a detection rate of 0.7%. While this worldwide detection rate is still much lower than prior to the SARS-CoV-2 pandemic, it may suggest increasing influenza virus activity compared to 2020. In particular, parts of Asia (including India and Nepal) have recently experienced increased influenza activity with the number of influenza virus-positive specimens reaching about 50% of the numbers reported before the pandemic ( Figure 1) ; moreover, China has experienced low levels of B/Victoria virus circulation in 2021 ( Figure 1) . The massive reduction in the number of circulating human influenza viruses likely created a substantial genetic bottleneck. In fact, the influenza A and B viruses isolated in 2020 and 2021 fall into a limited number of (sub)clades, while other (sub)clades have virtually disappeared, although viruses of these (sub)clades may still be circulating at low levels. Most noticeably, influenza B viruses of the Yamagata lineage have been detected at very low levels; for example, of 1,176 influenza B viruses reported in the last WHO Influenza Update (19), only one belonged to the In summary, we are currently experiencing an extraordinary event in human influenza virus epidemiology and evolution during which the virus has experienced extreme pressure that may result in major genetic bottlenecks that could shape influenza virus evolution for years to come. With the expected comeback of human influenza virus infections in the ensuing years, which may be fueled by a waning of immune responses in previously exposed people and an increasing number of infants and toddlers who are naïve to influenza viruses, much can be learned about the evolution and spread of influenza viruses in humans. Timeline: WHO's COVID-19 response Reported cases and deaths by country or territory Where has all the influenza gone? The impact of COVID-19 on the circulation of influenza and other respiratory viruses Where have all the viruses gone? Disappearance of seasonal respiratory viruses during the COVID-19 pandemic Changes in influenza and other respiratory virus activity during the COVID-19 pandemic -United States Decreased influenza activity during the COVID-19 pandemic -United States World Health Organization. Influenza update N° 376 World Health Organization. Influenza update N° 350 World Health Organization. Influenza update N° 385 World Health Organization. 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Influenza Other Respir Viruses World Health Organization. Influenza update N° 406 Acknowledgments: Susan Watson.