Host transcriptional analysis to improve the diagnosis of group A streptococcal pharyngitis

Current diagnostic methods used to evaluate patients with pharyngitis for the presence of group A Streptococcus (GAS) do not discriminate between acute infection and asymptomatic carriage, potentially resulting in overuse of antibiotics. We hypothesized that host response as measured by the transcriptomic profile of peripheral blood leukocytes could make this distinction, and could also distinguish between GAS and viral infection. We used RNA sequencing to generate whole blood transcriptomes from 37 children, including 10 with acute GAS pharyngitis, 5 with asymptomatic GAS carriage, 3 with adenoviral pharyngitis, 3 with pharyngitis of unknown etiology, and 16 asymptomatic children negative for GAS. Transcriptional profiles from children with symptomatic GAS, GAS carriage, symptomatic adenoviral pharyngitis, and controls were each distinct. Of 15,185 genes with analyzable sequence, 1357 (8.9%) were differentially expressed in the children with symptomatic GAS compared to those with asymptomatic carriage, and 1336 (8.8%) compared to symptomatic adenovirus infection. A panel of 13 genes distinguished between children with acute GAS and all others with 91% accuracy. The gene encoding CD177, a marker of neutrophil activation, had a 152-fold increase in expression in children with acute GAS, and is a potential diagnostic biomarker. We conclude that measurement of host response is highly promising to improve the diagnosis of GAS pharyngitis and could help limit unnecessary antibiotic use. One Sentence Summary This study demonstrates that analysis of host gene expression can improve the diagnosis of group A streptococcal pharyngitis, which will limit unnecessary antibiotic therapy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, Contract No. HHSN272201200005C. The Genome Technology Access Center is partially funded by National Cancer Institute Cancer Center Support Grant No. P30 CA91842 to the Siteman Cancer Center and by the Institute of Clinical and Translational Sciences/Clinical and Translational Sciences Award Grant No. UL1TR002345 from the NCCR, a component of NIH, and NIH Roadmap for Medical Research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Washington University Human Research Protection Office All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes RNA-seq raw data have been deposited in the NCBI (GEO) database, accession number GSE158163.