Development and validation of clinical prediction models to distinguish influenza from other viruses causing acute respiratory infections in children and adults.

Danielle Vuichard-Gysin,Marek Smieja,Eleanor Pullenayegum,Pardeep Singh,Mark Loeb,Dominik Mertz,Eric Hy Lau

doi:10.1371/journal.pone.0212050

Abstract

Predictive models have been developed for influenza but have seldom been validated. Typically they have focused on patients meeting a definition of infection that includes fever. Less is known about how models perform when more symptoms are considered. We, therefore, aimed to create and internally validate predictive scores of acute respiratory infection (ARI) symptoms to diagnose influenza virus infection as confirmed by polymerase chain reaction (PCR) from respiratory specimens. Data from a completed trial to study the indirect effect of influenza immunization in Hutterite communities were randomly split into two independent groups for model derivation and validation. We applied different multivariable modelling techniques and constructed Receiver Operating Characteristics (ROC) curves to determine predictive indexes at different cut-points. From 2008–2011, 3288 first seasonal ARI episodes and 321 (9.8%) influenza positive events occurred in 2202 individuals. In children up to 17 years, the significant predictors of influenza virus infection were fever, chills, and cough along with being of age 6 years and older. In adults, presence of chills and cough but not fever were highly specific for influenza virus infection (sensitivity 30%, specificity 96%). Performance of the models in the validation set was not significantly different. The predictors were consistently found to be significant irrespective of the multivariable technique. Symptomatic predictors of influenza virus infection vary between children and adults. The scores could assist clinicians in their test and treat decisions but the results need to be externally validated prior to application in clinical practice.

Highlights

Upper respiratory tract viral infections pose a substantial burden to the healthcare system [1,2,3]
Fever was less frequently reported in adults than in children and the proportion of children with laboratory confirmed influenza that reported fever was higher than the proportion of influenza positive adults with fever (48.7% versus 19.4%, respectively) (Fig 1A and 1B.)
Reviewing clinical signs and symptoms in patients during the 2009 pandemic influenza A/H1N1 revealed that mild illness without fever occurred in 8–23% of infected patients whereas fever was the predominant symptom in hospitalized patients or was only a significant predictor of influenza A/H3N2 but not for influenza A/H1N1 [11, 27]

Summary

Introduction

Upper respiratory tract viral infections pose a substantial burden to the healthcare system [1,2,3]. The average annual direct and indirect medical costs have been estimated to be $3.2 billion and 8.0 billion US dollar, respectively [5]. Antigen-based rapid influenza diagnostic tests render results within minutes, are inexpensive and simple to apply. They are used as point-of-care diagnostic tests and show reasonable performance for ruling in influenza infection. Their value for test and treat decisions is still limited because of the rather low sensitivity requiring more expensive molecular assays to reliably exclude the diagnosis of influenza [7, 8]. For influenza negative test results, the US Centers for Disease Control and Prevention (CDC) algorithm to assist in clinical decisionmaking recommends to rely on clinical signs and symptoms as well as on epidemiological information to guide further management [9]

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