Clinical Report: Comparison of Plasma and Whole Blood Multiplex ddPCR for Sepsis

Overview

This prospective multicenter cohort study compared paired plasma and whole-blood multiplex droplet digital PCR (ddPCR) for pathogen detection in critically ill adults with clinically suspected sepsis. Both matrices complemented conventional blood culture, with broadly similar overall diagnostic performance.

Background

Sepsis is a major cause of morbidity and mortality among critically ill patients, making early and accurate pathogen identification important. Conventional blood culture is limited by low sensitivity, prolonged turnaround time, and reduced performance after antimicrobial exposure. Although ddPCR can provide rapid, sensitive pathogen detection, plasma-based testing may miss microbial DNA retained within blood cells. The study therefore examined whether whole blood provided additional diagnostic information.

Data Highlights

• Patients enrolled: 223

• Participating hospitals: 3

• Blood culture–positive patients: 62 (27.8%)

• Blood culture–negative patients: 161

• Additional definite sepsis cases supported by plasma ddPCR: 38 of 161 (23.6%)

• Additional definite sepsis cases supported by whole-blood ddPCR: 46 of 161 (28.6%)

• Plasma ddPCR sensitivity for clinically adjudicated sepsis: 87.1%

• Whole-blood ddPCR sensitivity for clinically adjudicated sepsis: 90.3%

• Candida detection among 16 detection events: 31.3% with plasma vs 87.5% with whole blood

• Approximate ddPCR laboratory workflow: 2–4 hours

Key Findings

• Plasma and whole-blood ddPCR identified additional clinically supported pathogens among patients with negative blood cultures.

• Overall diagnostic performance did not differ significantly between the 2 matrices.

• Whole-blood ddPCR detected 218 of 238 pathogen-detection events, compared with 193 for plasma ddPCR; this difference was not statistically significant.

• Whole-blood ddPCR detected the Candida genus significantly more frequently than plasma ddPCR, although only 16 Candida detection events were evaluated.

• Results for most bacterial pathogens were largely consistent between plasma and whole blood.

• Concordant positivity in both matrices was associated with higher procalcitonin and greater disease severity, but 28-day survival did not differ significantly across ddPCR detection patterns.

• ddPCR detected microbial nucleic acids rather than viable organisms and therefore could not independently establish active infection.

Clinical Implications

Plasma and whole-blood ddPCR may serve as adjuncts to conventional cultures when evaluating critically ill patients with suspected sepsis, particularly when blood cultures are negative. Whole blood may provide incremental value when fungal sepsis is suspected because it can retain cell-associated microbial DNA. However, matrix selection should reflect the suspected pathogen and clinical context. Positive findings require interpretation alongside cultures, imaging, laboratory results, and the overall clinical presentation.

Conclusion

Plasma and whole-blood ddPCR provided broadly comparable pathogen-detection performance and complementary information beyond conventional blood culture. Whole-blood ddPCR detected Candida more frequently in this cohort, but the limited number of fungal events makes this finding hypothesis-generating. Larger multicenter studies are needed to validate matrix-specific differences and determine how ddPCR should be integrated into diagnostic and antimicrobial-stewardship workflows.

Related Resources & Content

Plasma Versus Whole Blood Multiplex Droplet Digital PCR for Pathogen Detection in ICU Patients With Clinically Suspected Sepsis: A Prospective Multicenter Cohort Study — Wu Z, Wang X, Xia J, et al. International Journal of Infectious Diseases. 2026;171:109015. doi:10.1016/j.ijid.2026.109015.