Circulating Bacteriophage DNA Distinguishes Staphylococcal Infection From Commensal Colonization

Bacteriophage sequences from cell-free DNA (cfDNA) in plasma can be used to diagnose bacterial pathogens during sepsis. Here, we hypothesize that plasma bacteriophage cfDNA can serve as a serological biomarker to monitor Staphylococcal periprosthetic joint infection (PJI).

Using a previously described computational pipeline, bacteriophage sequences were identified in cfDNA from plasma of three distinct patient cohorts: patients with a current Staphylococcal PJI, prior PJI, and no PJI. The overall phageome was described in all three cohorts, and the proportion of Staphylococcus bacteriophage was compared among the three cohorts. The presence of Staphylococcus bacteriophage as a binary variable was also analyzed for its diagnostic performance in identifying Staphylococcal PJI.

There were no differences in the distribution of bacterial cfDNA among the three cohorts (P = 0.597). The current PJI cohort had a significantly higher proportion of Staphylococcus bacteriophage compared to no PJI (median, 2.6 versus 0%, P = 0.013), and the prior PJI cohort had a significantly higher proportion of Staphylococcus bacteriophage compared to no PJI (median, 1.0 versus 0%, P = 0.049). Of note, there was no difference in proportion of Staphylococcus bacteriophage between current PJI and prior PJI (median, 2.6% versus 1.0%, P = 0.554). Staphylococcus bacteriophage was present in six of ten samples in current PJI, seven of 12 samples in prior PJI, and one of 13 samples in the no PJI groups. The presence of Staphylococcus bacteriophage had a sensitivity of 60% and specificity of 92% for a Staphylococcal PJI.

These findings suggest that plasma bacteriophage cfDNA offers a promising approach to detect and monitor Staphylococcal PJI. The persistence of these Staphylococcus bacteriophages in prior PJI may reflect subclinical infection or residual microbial DNA undetectable by standard culture-based diagnostics.