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Background: Distinguishing bacterial and viral respiratory infections is challenging. Novel diagnostics based on differential host gene expression patterns are promising but have not been translated to a clinical platform nor extensively tested. Here, we validate a microarray-derived host response signature and explore performance in microbiology-negative and coinfection cases. Methods: Subjects with acute respiratory illness were enrolled in participating emergency departments. Reference standard was an adjudicated diagnosis of bacterial infection, viral infection, both, or neither. An 87-transcript signature for distinguishing bacterial, viral, and noninfectious illness was measured from peripheral blood using RT-PCR. Performance characteristics were evaluated in subjects with confirmed bacterial, viral, or noninfectious illness. Subjects with bacterial-viral coinfection and microbiologically-negative suspected bacterial infection were also evaluated. Performance was compared to procalcitonin. Findings: 151 subjects with microbiologically confirmed, single-etiology illness were tested, yielding AUROCs 0•85–0•89 for bacterial, viral, and noninfectious illness. Accuracy was similar to procalcitonin (88% vs 83%, p = 0•23) for bacterial vs. non-bacterial infection. Whereas procalcitonin cannot distinguish viral from non-infectious illness, the RT-PCR test had 81% accuracy in making this determination. Bacterial-viral coinfection was subdivided. Among 19 subjects with bacterial superinfection, the RT-PCR test identified 95% as bacterial, compared to 68% with procalcitonin (p = 0•13). Among 12 subjects with bacterial infection superimposed on chronic viral infection, the RT-PCR test identified 83% as bacterial, identical to procalcitonin. 39 subjects had suspected bacterial infection; the RT-PCR test identified bacterial infection more frequently than procalcitonin (82% vs 64%, p = 0•02). Interpretation: The RT-PCR test offered similar diagnostic performance to procalcitonin in some subgroups but offered better discrimination in others such as viral vs. non-infectious illness and bacterial/viral coinfection. Gene expression-based tests could impact decision-making for acute respiratory illness as well as a growing number of other infectious and non-infectious diseases. Keywords: Biomarkers, Gene expression, Respiratory tract infections, Coinfection, Diagnosis, Precision medicine

Jehovah’s Witness patients pose a unique surgical challenge due to their refusal of transfusion of whole blood or major blood products. One of the surgical strategies is to offer the least invasive approach with the least likelihood of losing blood. In the context of surgical treatment of gastroesophageal reflux disease, endoluminal approaches such as transoral incisionless fundoplication represent an appropriate approach for Jehovah’s Witness patients. This patient is a devout Jehovah’s Witness who was troubled with gastroesophageal reflux disease for many years which was refractory to proton pump inhibitor therapy. Her standard preoperative workup showed that she was a candidate for transoral incisionless fundoplication. Surgery was performed by a transoral incisionless fundoplication certified surgeon and this patient was his second case. Patient had no immediate or long-term complications. She was successfully weaned off proton pump inhibitors. Transoral incisionless fundoplication is an appropriate option for Jehovah’s Witness patients with refractory gastroesophageal reflux disease. This case report shows that the procedure is safe and durable, even in the early stage of the physician’s learning curve.