A Four-Gene Signature from Blood to Exclude Bacterial Etiology of Lower Respiratory Tract Infection in Adults

Unnecessary antibiotic use is a major driver of antimicrobial resistance, an urgent public health threat. There is an unmet need for improved diagnostics for identifying bacterial etiology in acute respiratory infection (ARI). Hospitalized adults with ARI underwent comprehensive microbiologic testing and those with definitive viral (n = 280), bacterial (n = 129), or mixed viral-bacterial infection (n = 95) had whole blood RNA sequencing. A hard-thresholded, mostly relaxed, LASSO-constrained logistic regression model was used to select a parsimonious gene set ( ITGB4, ITGA7, IFI27, FAM20A ) highly capable of discriminating any bacterial from nonbacterial infection (cross validated AUC = 0.90). The 4-gene signature was validated in two independent cohorts (AUC = 0.90–0.94). Thresholding the 4-gene risk score to yield 90% sensitivity to detect bacterial infection resulted in 71% specificity and 91% negative predictive value. This 4-gene signature defining the absence of bacterial ARI may supplement clinical judgement for management of antibiotics in ARI.