Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS)

Rueshandra Roosenhoff, Vaughan Reed, Andy Kenwright, Martin Schutten, Charles A Boucher, Arnold Monto, Barry Clinch, Deepali Kumar, Richard Whitley, Jonathan S Nguyen-Van-Tam, Albert D M E Osterhaus, Ron A M Fouchier, Pieter L A Fraaij, Rueshandra Roosenhoff, Vaughan Reed, Andy Kenwright, Martin Schutten, Charles A Boucher, Arnold Monto, Barry Clinch, Deepali Kumar, Richard Whitley, Jonathan S Nguyen-Van-Tam, Albert D M E Osterhaus, Ron A M Fouchier, Pieter L A Fraaij

Abstract

Background: We studied the effect of age, baseline viral load, vaccination status, antiviral therapy, and emergence of drug resistance on viral shedding in children infected with influenza A or B virus.

Methods: Samples from children (aged ≤13 years) enrolled during the 7 years of the prospective Influenza Resistance Information Study were analyzed using polymerase chain reaction to determine the influenza virus (sub-)type, viral load, and resistance mutations. Disease severity was assessed; clinical symptoms were recorded. The association of age with viral load and viral clearance was examined by determining the area under the curve for viral RNA shedding using logistic regression and Kaplan-Meier analyses.

Results: A total of 2131 children infected with influenza (683, A/H1N1pdm09; 825, A/H3N2; 623, influenza B) were investigated. Age did not affect the mean baseline viral load. Children aged 1-5 years had prolonged viral RNA shedding (±1-2 days) compared with older children and up to 1.2-fold higher total viral burden. Besides, in older age (odds ratio [OR], 1.08; confidence interval [CI], 1.05-1.12), prior vaccination status (OR, 1.72; CI, 1.22-2.43) and antiviral treatment (OR, 1.74; CI, 1.43-2.12) increased the rate of viral clearance. Resistance mutations were detected in 49 children infected with influenza A virus (34, A/H1N1pdm09; 15, A/H3N2) treated with oseltamivir, most of whom were aged <5 years (n = 39).

Conclusions: Children aged 1-5 years had a higher total viral burden with prolonged virus shedding and had an increased risk of acquiring resistance mutations following antiviral treatment.

Clinical trials registration: NCT00884117.

Keywords: Influenza Resistance Information Study; influenza; pediatrics; resistance mutations; viral load.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Baseline viral RNA load of children infected with A/H1N1pdm09, A/H3N2, and influenza B virus. The mean baseline viral RNA load of children infected with A/H1N1pdm09 (A), A/H3N2 (B), and influenza B virus (C) are depicted as mean ± standard deviation. Influenza B virus was not detected in infants aged 6 months−1 year. Asterisks represent significant P values (*.05 < P < .01 and **.01 > P > .001).
Figure 2.
Figure 2.
Total viral RNA load of children infected with A/H1N1pdm09, A/H3N2, and influenza B virus. The total amount of viral RNA shedding in children infected with A/H1N1pdm09, A/H3N2, and influenza B virus was determined by calculating the area under the curve. Influenza B virus was not detected in infants aged 6 months−1 year. The bar graphs depict the mean ± standard deviation. Asterisks represent significant P values (*.05 < P < .01, **.01 > P > .001, ***P < .001).
Figure 3.
Figure 3.
Kaplan-Meier plots for time to viral RNA clearance of children infected with H1N1pmd09 (A), A/H3N2 (B), and influenza B virus (C). Censored patients are illustrated as plus signs. The median time to viral RNA clearance in each age group is depicted next to the Kaplan-Meier plots. Influenza B virus was not detected in infants aged 6 months−1 year. Asterisks represent significant P values (*.05 < P < .01 and **.01 > P > .001). Abbreviation: CI, confidence interval.

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Source: PubMed

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