Host Transcriptomic Signatures for Early Diagnosis of Acute Respiratory Viral Infection in a University-based Index-Cluster Cohort

Background: Early and accurate identification of persons with a potentially infectious illness can be of critical importance. In order to elucidate the performance of host gene expression based diagnostic signatures in real-world cases of naturally-acquired respiratory viral infection we performed an Index-Cluster study in a population of 1290 University students from 2009-2015.

Methods: Following development of symptomatic URI in an Index Case (IC, n=311), their Close Contacts (CC, n=979) were serially sampled for 5 consecutive days and those that developed symptoms of URI were tested for the presence of viral pathogens and host peripheral blood gene expression patterns (by Affymetrix microarray and/or RT-PCR).

Results: We identified 210 individuals who developed symptomatic, viral PCR–positive URI, 42 of which were Close Contacts with dense pre-disease sampling. In total, we detected Influenza virus in 46 individuals, Parainfluenza in 41, Rhinovirus in 73, and other respiratory viruses in the remaining patients. We then developed and tested the performance of a diagnostic transcriptomic signature at the time of maximal symptoms for each subject (IC and CC), as well as on samples from the 2 days prior to maximal illness in each CC. In the initial analysis group, the transcriptomic signature performed with 88% accuracy at the time of maximal symptoms, and 87% and 70% accuracy on the two days prior, respectively.

Conclusion: The results of this study show that a unique study design is capable of identifying Close Contacts of Index Cases who are at increased risk of developing symptomatic URI in a timeframe useful for examining both early and late periods in the course of infection. Furthermore, analysis of the host genomic response demonstrates that expression levels of a host response gene signature are capable of diagnosing URI not only at the time of clinical presentation but days earlier, during the presymptomatic phase, and that this detection is accurate across a wide array of naturally-occurring viral infections. Thus, the host genomic response to viral URI following naturally–occurring transmission is robust and offers the potential provide the means for detection before typical clinical symptoms are apparent.