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Observational Study
. 2023 Mar 29;23(1):188.
doi: 10.1186/s12879-023-08140-z.

Factors associated with viral RNA shedding and evaluation of potential viral infectivity at returning to school in influenza outpatients after treatment with baloxavir marboxil and neuraminidase inhibitors during 2013/2014-2019/2020 seasons in Japan: an observational study

Jiaming Li  1 , Keita Wagatsuma  2 , Yuyang Sun  2 , Isamu Sato  3 , Takashi Kawashima  4 , Tadashi Saito  5 , Yasushi Shimada  6 , Yasuhiko Ono  7 , Fujio Kakuya  8 , Nobuo Nagata  9 , Michiyoshi Minato  10 , Naoki Kodo  11 , Eitaro Suzuki  12 , Akito Kitano  13 , Toshihiro Tanaka  14 , Satoshi Aoki  15 , Irina Chon  2 , Wint Wint Phyu  2 , Hisami Watanabe  2 , Reiko Saito  2
Affiliations
Observational Study

Factors associated with viral RNA shedding and evaluation of potential viral infectivity at returning to school in influenza outpatients after treatment with baloxavir marboxil and neuraminidase inhibitors during 2013/2014-2019/2020 seasons in Japan: an observational study

Jiaming Li et al. BMC Infect Dis. .

Abstract

Background: This study assessed the differences in daily virus reduction and the residual infectivity after the recommended home stay period in Japan in patients infected with influenza and treated with baloxavir (BA), laninamivir (LA), oseltamivir (OS), and zanamivir (ZA).

Methods: We conducted an observational study on children and adults at 13 outpatient clinics in 11 prefectures in Japan during seven influenza seasons from 2013/2014 to 2019/2020. Virus samples were collected twice from influenza rapid test-positive patients at the first and second visit 4-5 days after the start of treatment. The viral RNA shedding was quantified using quantitative RT-PCR. Neuraminidase (NA) and polymerase acidic (PA) variant viruses that reduce susceptibility to NA inhibitors and BA, respectively, were screened using RT-PCR and genetic sequencing. Daily estimated viral reduction was evaluated using univariate and multivariate analyses for the factors such as age, treatment, vaccination status, or the emergence of PA or NA variants. The potential infectivity of the viral RNA shedding at the second visit samples was determined using the Receiver Operator Curve based on the positivity of virus isolation.

Results: Among 518 patients, 465 (80.0%) and 116 (20.0%) were infected with influenza A (189 with BA, 58 with LA, 181 with OS, 37 with ZA) and influenza B (39 with BA, 10 with LA, 52 with OS, 15 with ZA). The emergence of 21 PA variants in influenza A was detected after BA treatment, but NA variants were not detected after NAIs treatment. Multiple linear regression analysis showed that the daily viral RNA shedding reduction in patients was slower in the two NAIs (OS and LA) than in BA, influenza B infection, aged 0-5 years, or the emergence of PA variants. The residual viral RNA shedding potentially infectious was detected in approximately 10-30% of the patients aged 6-18 years after five days of onset.

Conclusions: Viral clearance differed by age, type of influenza, choice of treatment, and susceptibility to BA. Additionally, the recommended homestay period in Japan seemed insufficient, but reduced viral spread to some extent since most school-age patients became non-infectious after 5 days of onset.

Keywords: Baloxavir marboxil; Daily viral reduction; Influenza virus; Neuraminidase inhibitor; Viral RNA shedding.

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Conflict of interest statement

All other authors report no conflict of interest.

Figures

Fig. 1
Fig. 1
Flowchart
Fig. 2
Fig. 2
Comparison of influenza viral clearance by age, treatment, vaccination groups with or without PA variants. a and b; Age groups, c and d; treatment groups, e and f; influenza vaccination status, and g; emergence of PA variants. Emergence of PA variants was not analyzed for influenza B because of no detection. a–d were analyzed using Kruskal–Wallis test, and Bonferroni correction was applied as a post-hoc test for each pair; e–g were analyzed using Mann–Whitney test. The p-value or no significance in the upper right corner of each figure was determined using Kruskal–Wallis test or Mann–Whitney test. The p-value above the two connected groups in the figure was determined using Bonferroni correction. BA, baloxavir; LA, laninamivir; OS, oseltamivir; ZA, zanamivir; NS, not significant
Fig. 3
Fig. 3
Receiver operating characteristic curves for assessment of CPE using viral RNA shedding. A total of 690 samples from 345 patients with influenza A and 190 samples from 95 patients with influenza B, aged 6–18 years were analyzed. a, b Represent Influenza A and Influenza B, respectively
Fig. 4
Fig. 4
Changes in viral RNA shedding in patients with influenza A and B after treatment. a and e Patients treated with baloxavir; b and f, patients treated with laninamivir; c and g, patients treated with oseltamivir; d and h, patients treated with zanamivir. The red solid line in each figure represents the paired samples that showed potential infectivity in the second visit collected between 5 to 13th days after symptom onset in the patient. The cut-off value for viral RNA shedding in influenza A and B was 2.628 log10 copies/µL and 1.886 log10 copies/µL, respectively. The solid gray line represents those with negative potential infectivity below the cut-off. The vertical red dotted line represents the fifth day after symptom onset. The red numeric numbers represent the rate of positive infectivity in the upper part and the corresponding percentage in the lower part
Fig. 5
Fig. 5
Changes in viral RNA shedding in baloxavir-treated patients with or without PA variants. a Patients with PA variants after baloxavir treatment; b patients without PA variants after baloxavir treatment. The solid red line in each figure represents the paired samples that showed potential infectivity in the second visit collected between the 5th to 13th days after the patient's symptom onset. The cut-off value for viral RNA shedding in influenza A was 2.628 log10 copies/µL. The solid gray line represents those with negative potential infectivity below the cut-off. The vertical red dotted line represents the fifth day after symptom onset. The red numeric numbers represent the rate of positive infectivity in the upper part, and the corresponding percentage in the lower part
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