Background Coronavirus disease (COVID‐19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), was first detected in Japan in January 2020 and has spread throughout the country. Previous studies have reported that viral interference among influenza virus, rhinovirus, and other respiratory viruses can affect viral infections at the host and population level. Methods To investigate the impact of COVID‐19 on influenza and other respiratory virus infections, we analyzed clinical specimens collected from 2244 patients in Japan with respiratory diseases between January 2018 and September 2020. Results The frequency of influenza and other respiratory viruses (coxsackievirus A and B; echovirus; enterovirus; human coronavirus 229E, HKU1, NL63, and OC43; human metapneumovirus; human parainfluenza virus 1, 2, 3, and 4; human parechovirus; human respiratory syncytial virus; human adenovirus; human bocavirus; human parvovirus B19; herpes simplex virus type 1; and varicella‐zoster virus) was appreciably reduced among all patients during the COVID‐19 pandemic except for that of rhinovirus in children younger than 10 years, which was appreciably increased. COVID‐19 has not spread among this age group, suggesting an increased risk of rhinovirus infection in children. Conclusions Rhinovirus infections should be continuously monitored to understand their increased risk during the COVID‐19 pandemic and viral interference with SARS‐CoV‐2.

The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza A and B virus infections in February 2018 in Japan. Because of the need to monitor influenza viruses for reduced susceptibility to this drug, we used two cell-based screening systems – a conventional plaque reduction assay and a focus reduction assay – to evaluate the susceptibility of influenza viruses to baloxavir. First, we generated a reference virus possessing an I38T substitution in the polymerase acidic subunit (PA), which is known to be associated with reduced susceptibility to baloxavir, and demonstrated the validity of our systems using this reference virus. We then determined the susceptibility of a panel of neuraminidase (NA) inhibitor-resistant viruses and their sensitive counterparts to baloxavir. No significant differences in baloxavir susceptibilities were found between the NA inhibitor-resistant and -sensitive viruses. We also examined seasonal influenza viruses isolated during the 2017–2018 influenza season in Japan and found that no currently circulating A(H1N1)pdm09, A(H3N2), or B viruses had significantly reduced susceptibility to baloxavir and none of the viruses possessed an amino acid substitution at PA residue 38. Use of a combination of methods to analyze antiviral susceptibility and detect amino acid substitutions is valuable for monitoring the emergence of baloxavir-resistant viruses.

In January 2019, two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA), which confers reduced susceptibility to baloxavir, were detected from epidemiologically unrelated hospitalised children in Japan. The viruses exhibited reduced susceptibility to baloxavir but were susceptible to neuraminidase inhibitors. Only one of the two children had been treated with baloxavir. An epidemiological analysis suggests possible transmission of the PA I38T mutant A(H3N2) virus among humans.

In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling. These viruses’ whole-genome sequences were identical, indicating human-to-human transmission. Influenza virus isolates should be monitored for baloxavir susceptibility.

The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza virus infection in Japan in February 2018. Two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA) were detected in baloxavir-treated children in December 2018. This mutation is known to confer reduced susceptibility to baloxavir, and the two mutant viruses exhibited 76- and 120-fold reduced susceptibility to baloxavir.