Can Use of Viral Load Improve Norovirus Clinical Diagnosis and Disease Attribution?

• Type of Material: Article
• Authors: Kayoko Shioda, Centers for Disease Control and Prevention; Leslie Barclay, Centers for Disease Control and Prevention; Sylvia Becker-Dreps, University of North Carolina; Filemon Bucardo-Rivera, National Autonomous University of Leon; Philip J. Cooper, Universidad Internacional del Ecuador Quitoto; Daniel C. Payne, Centers for Disease Control and Prevention; Jan Vinje, Centers for Disease Control and Prevention; Benjamin Lopman, Emory University
• Language: English
• Date: 2017-06-01
• Publisher: Oxford University Press Inc.
• Publication Version: Final Published Version
• Copyright Statement: © Published by Oxford University Press on behalf of Infectious Diseases Society of America 2017.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1093/ofid/ofx131
• Title of Journal or Parent Work: Open Forum Infectious Diseases
• Volume: 4
• Issue: 3
• Start Page: ofx131
• End Page: ofx131
• Grant/Funding Information: The following funding sources were put together for the study in Nicaragua: the Merck Investigator-Initiated Studies Program for laboratory analysis; the Thrasher Research Fund for field work; Grant 5K01TW008401-04 from the Fogarty International Center at the National Institutes of Health (to S. B.-D.); and NETROPICA (Grant 05-N-2010; to F. B.-R.).; Data and sample collection in Ecuador were funded by Wellcome Trust (Grant 088862/Z/09/Z; to P. C.).; This work was supported by an appointment to the Research Participation Program at the Centers for Disease Control and Prevention (CDC) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and CDC to (to K. S.).
• Keywords: cycle threshold; Association; Life Sciences & Biomedicine; United States; Children; Birth cohort; Gastroenteritis; norovirus; Microbiology; Diarrhea; Science & Technology; real-time PCR; receiver-operating characteristic analysis; Infectious Diseases; Infection; Rotavirus; Outbreaks; Immunology; Genetic susceptibility; attributable fractions
• Research Categories: Health Sciences, Immunology; Biology, Microbiology; Health Sciences, Epidemiology

Abstract

Background: Real-time reverse-transcriptase polymerase chain reaction (RT-PCR) is the state-of-the-art diagnostic for norovirus. Cycle threshold (Ct), an indicator of viral load, may be associated with symptomatic disease as well as demographic and outbreak characteristics. Methods: Data on (1) outbreak and sporadic cases and (2) asymptomatic controls in the United States and Latin America were analyzed. With multivariate regression models, we assessed relationships between various factors and Ct values, and we calculated odds ratios (ORs) for the presence of symptoms and attributable fractions of norovirus. Receiver-operating characteristic analysis was performed to define an optimal Ct cutoff to identify disease-causing infections. Results: Cycle threshold values were lower (ie, higher viral loads) among symptomatic cases (model-adjusted mean ± standard error: 25.3 ± 1.2) compared with asymptomatic controls (28.5 ± 1.4). Cycle threshold values were significantly different across age groups, norovirus genogroups, timing of specimen collection, outbreak settings, and transmission modes. Genogroup II (GII) Ct values were associated with presence of symptoms (OR = 1.1), allowing us to estimate that 16% of diarrheal disease was attributable to norovirus. The optimized Ct cutoff led to poor sensitivity and specificity for genogroup I and GII. Conclusions: Cycle threshold values were associated with host, pathogen, and outbreak factors. Cycle threshold values may not effectively distinguish disease-causing infection for individual patients, but they are useful for epidemiological studies aiming to attribute disease.