2018 Human Coronavirus in Hospitalized Children with Respiratory Tract Infections_ A Nine-year-long, Population-based St

Accepted Manuscript The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: . MAJOR ARTICLE Title: Human Coronavirus in Hospitalized Children with Respiratory Tract Infections: A Nine- year-long, Population-based Study from Norway Authors: Inger Heimdal1, Nina Moe1,2, Sidsel Krokstad3, Andreas Christensen1,3, Lars Hsien Skanke1,2, Svein Arne Nordb1,3 and Henrik Dllner1,2 Affiliations: 1Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), and Department of 2Pediatrics and 3Medical Microbiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway Correspondence: Henrik Dllner, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7006 Trondheim, Norway henrik.dollnerntnu.no, +47-47667169 (phone), +47-72573801 (fax) Downloaded from by Chapman University Library user on 14 November 2018 Accepted Manuscript 2 Brief summary: During a nine-year long period, human coronaviruses (HCoV) OC43, NL63, HKU1 and 229E occurred at similar rates in hospitalized children with respiratory tract infections and asymptomatic controls, but infected children had higher genomic loads, supporting a causal role in infection. Downloaded from by Chapman University Library user on 14 November 2018 Accepted Manuscript 3 ABSTRACT Background: The burden of Human Coronavirus- (HCoV) associated respiratory tract infections (RTIs) in hospitalized children is poorly defined. We studied the occurrence and hospitalization rates of HCoV over nine years. Methods: Children from Sr-Trndelag County, Norway, hospitalized with RTIs and asymptomatic controls, were prospectively enrolled from 2006 to 2015. Nasopharyngeal aspirates were analyzed with semi-quantitative polymerase chain reaction (PCR) tests for HCoV subtypes OC43, 229E, NL63 and HKU1, and 13 other respiratory pathogens. Results: HCoV was present in 9.1% (313/3458) of all RTI episodes: 46.6% OC43, 32.3% NL63, 16.0% HKU1 and 5.8% 229E. Hospitalization rates for HCoV-positive children with lower RTIs were 1.5 and 2.8 per 1,000 <5 and <1 years of age, respectively. The detection rate among controls was 9.4% (60/639). Co-detections occurred in 68.1% of the patients and 73.3% of the controls. In a logistic regression analysis, high HCoV genomic loads (cycle threshold <28 in PCR- analysis) were associated with RTIs (OR = 2.16, P = .032) adjusted for relevant factors. Conclusions: HCoVs occurred in one out of 11 hospitalized children with RTIs and asymptomatic controls. A high HCoV genomic load was associated with RTI. HCoVs are associated with a substantial burden of RTIs in need of hospitalization. Downloaded from by Chapman University Library user on 14 November 2018 Accepted Manuscript 4 Keywords: Human Coronaviruses, children, hospitalization rates, respiratory tract infections, asymptomatic controls INTRODUCTION Human Coronaviruses (HCoV) are commonly detected in nasopharyngeal aspirates (NPAs) from children with respiratory tract infections (RTIs). They were first described in the 1960s as agents of the common cold 1-3. Recently, HCoV has obtained renewed interest, due to both more sensitive diagnostic methods and increased attention towards HCoV after the SARS outbreak in 2002, thereby resulting in the identification of new HCoV subtypes 4-7. Six species of HCoV infects humans: OC43, 229E, SARS, NL63, HKU1 and MERS. While SARS and MERS are feared for their potential for severe illness and pandemics 8, the other subtypes have traditionally been associated with milder upper RTIs. In children, however, HCoV may also cause lower respiratory tract infections (LRTIs) in need of hospitalization 9-12, but only a few population-based reports have precisely estimated the risk of HCoV-associated hospitalizations 13-16. OC43, NL63, 229E and HKU1 are distributed worldwide 17-19, and their detection frequency varies 15, 19-21. Some studies found similar 21-23, or even lower 24, detection rates of HCoV among hospitalized children compared to controls. Nonetheless, long-term studies of HCoV are rare, and most previous studies lack the inclusion of asymptomatic controls. Hence, the significance of HCoV detections in children with LRTIs, the seasonality and the overall burden of HCoV in hospitalized children remains poorly defined. Downloaded from by Chapman University Library user on 14 November 2018 Accepted Manuscript 5 To address these needs, we used data from a nine-year-long prospective population-based survey of children admitted to St. Olavs Hospital in Norway. Our primary aim was to determine the occurrence of HCoV detections in children hospitalized with RTI and the hospitalization incidence rates for HCoV-associated LRTIs in children. To help evaluate the role of HCoV in RTIs, we compared the presence an