Evaluation of a New Clinical Endpoint for Moderate to Severe Influenza Disease in Children: A Prospective Cohort Study

Abstract

Background: A moderate to severe (M/S) influenza clinical endpoint has been proposed in children, defined as fever >39°C, otitis media, lower respiratory tract infection, or serious extrapulmonary manifestations. The objective of the study was to evaluate the M/S measure against clinically relevant outcomes including hospitalization, emergency room visits, antimicrobial use, and child/parental absenteeism.

Methods: We conducted a prospective observational study of children aged 6 months-8 years at the Children's Hospital Colorado emergency department (ED) and urgent care site during 2016-2017 and 2017-2018. Children with influenza-like illness (ILI) underwent influenza testing by polymerase chain reaction (PCR); children who tested positive and a subset of matched test-negative controls underwent follow-up at 2 weeks. The primary outcome was the proportion of children who were hospitalized. Secondary outcomes included recurrent ED visits, antimicrobial use, hospital charges, and child/parental absenteeism within 14 days.

Results: Among 1478 children enrolled with ILI, 411 (28%) tested positive for influenza by PCR. Of children with influenza illness, 313 (76%) met the M/S definition. Children with M/S influenza were younger (3.8 years vs 4.8 years), infected with influenza A (59% vs 44%), and more frequently hospitalized (unadjusted risk difference [RD], 6.3%; 95% confidence interval [CI], 2.1-10.4; P = .03) and treated with antibiotics (unadjusted RD, 13.3%; 95% CI, 4.3-22.4; P < .01) compared to those with mild disease.

Conclusions: Children with M/S influenza have a higher risk of hospitalization and antibiotic use compared with mild disease. This proposed definition may be a useful clinical endpoint to study the public health and clinical impact of influenza interventions in children.

Clinical trials registration: NCT02979626.

Keywords: absenteeism; antibiotics; clinical endpoint; hospitalization; influenza; influenza-like illness; severity.

© The Author(s) 2019. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT)–style flow diagram for children with influenza-like illness evaluated at the Children’s Hospital Colorado emergency department and affiliated urgent care, during the 2016–2017 and 2017–2018 influenza seasons.

Figure 2.

Proportion of children classified as having moderate to severe influenza by each clinical criterion during the 2016–2017 and 2017–2018 influenza seasons (n = 313).

Figure 3.

Forest plot demonstrating unadjusted risk difference among children with moderate to severe vs mild influenza during the 2016–2017 and 2017–2018 influenza seasons for primary and secondary outcomes of interest. Abbreviations: CI, confidence interval; ED, emergency department; RD, risk difference.