Genetic Roadmap May Assist with Identifying Lower Respiratory Tract Infections

Acute respiratory infections still pose a significant clinical challenge in patients of all ages, carrying with them significant mortality and potentially contributing to the overuse of antibiotics as a result of misdiagnosis.

Now, researchers from the University of Rochester (NY) School of Medicine believe they have developed an effective genetic roadmap to assist in the identification and characterization of infections in the lower respiratory tract. Their findings were published on July 26, 2017 in Scientific Reports.

Despite the advent of novel diagnostics, “we still see a number of individuals who, in our minds, appear to be at pretty low risk for bacterial infection—with a clear chest x-ray and low white blood cell count—in whom doctors are prescribing antibiotics,” study coauthor Ann R. Falsey, MD, Interim Chief, Department of Medicine—Infectious Diseases at the University of Rochester Medical Center told Contagion^®. “Clearly, the need to rule out bacterial infection with some degree of certainty is very important. And to be clear, I’m not disparaging clinicians. A chest x-ray and lab tests aren’t always definitive, and when you have somebody ill enough to be in the hospital you don’t want to miss a bacterial infection.”

As Dr. Falsey and her colleagues note in their introduction, lower respiratory tract infections (LRTIs) are difficult to properly treat because “the precise microbial etiology is [often] unknown.” And, they write, although technologies such as polymerase chain reaction (PCR) enable the accurate diagnosis of respiratory viruses, they have not always led to a reduction in antibiotic use because clinicians remain concerned about bacterial coinfection. In fact, earlier research from the University of Rochester group suggests that as many as 30% of hospitalized adults with viral LRTI “have evidence of concomitant bacterial infection.”

For this more recent study, Dr. Falsey and her colleagues screened daily admissions logs at the University of Rochester Medical Center for a 6-month period in 2013 for adults with diagnoses of acute exacerbation of chronic obstructive pulmonary disease (COPD), bronchitis, asthma, influenza, viral syndrome, respiratory failure and congestive heart failure with infection, pneumonia or symptoms of wheezing, dyspnea, cough, sputum production, nasal congestion, sore throat, and/or hoarseness. Eligible patients were enrolled in the study within 24 hours of hospital admission, and researchers collected nose and throat swabs, sputum, urine, and blood for analysis. Only subjects with a microbiologic diagnosis and complete diagnostic testing were included in the study.

In all, 213 subjects were enrolled; of these, 100 had definitive microbiologic diagnoses and 94 had transcriptomic data passing quality control metrics. Among the 94 patients, the mean age was 61 years, and 92 patients had at least 1 chronic medical condition. Asthma exacerbation was the diagnosis in 17 of the subjects, while 25, 21, 23, and 8 were diagnosed with bronchitis, acute exacerbation of COPD, pneumonia, and bacteremia, respectively. Overall, 41 subjects were classified with “bacterial” infection (27 bacterial only and 14 mixed viral/bacterial) and 53 subjects were classified with “nonbacterial” infection (viral infection alone).

In subsequent genetic analysis, the University of Rochester team assessed the expression of 10 marker genes (BTN3A3, IFI27, RSAD2, KIAA1618, OAS2, IFIT3, IFI44, OASL, IFIT2, and PARP9) identified in earlier research to determine their ability “to distinguish bacterial from nonbacterial illness.” In all, they found that 8 of the 10 genes (IFI27, RSAD2, KIAA1618, OAS2, IFIT3, IFI44, OASL, and IFIT2) “demonstrated significant differences between groups” based on Wilcoxon Rank test at a false discovery rate (FDR) or q <.05. In addition, based on qPCR, they noted that all 10 demonstrated “significant difference between bacterial and nonbacterial groups” according to Wilcoxon Rank test, at a nominal P value&thinsp;of <.05—and that expression of all 10 is associated with nonbacterial infection.

In addition, the authors identified 141 genes “that are differentially expressed between subjects with bacterial versus nonbacterial infections,” with most having higher expression in subjects with bacterial infection. They identified reduced expression of these genes in study subjects with a clinical diagnosis of asthma and bronchitis, and increased expression in those with pneumonia and bacteremia (COPD yielded a mixed pattern).

Finally, the research team identified 3 pathways (lymphocyte, α-linoleic acid metabolism, IGF regulation) and 11 genes (ICAM1, ITGAL, ITGB2, PECAM1, IGFBP6, IGFBP2, CTSG, MMP2, ACOX3, FADS2, and PLA2G4A) with which they were able to construct a classifier for bacterial LRTIs with 90% sensitivity and 83% specificity.

“Our results are encouraging [but] this was a small study,” Dr. Falsey said. “We have to further refine our predictive genes; [however], if our results can be prospectively validated, we believe it can be a really promising approach for differentiating bacterial infections clinically.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.