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This study was undertaken to evaluate the reliability of pathogenic diagnoses based on multisite mNGS detection at the clinically suspected sites and to analyze the efficiency of plasma mNGS detection based on lymphocyte subset counts in patients with sepsis-associated lymphopenia. ABSTRACT A precise and efficient microbiological diagnosis is essential for sepsis. Metagenomic next-generation sequencing (mNGS) is a novel technique for the diagnosis of infectious diseases, but its current application in multisite sampling and interpretation remains controversial. Therefore, this study was undertaken to evaluate the reliability of multisite mNGS tests and the efficiency of plasma mNGS based on lymphocyte subset counts. A prospective observational study was performed on the intubated patients with sepsis-associated lymphopenia from January 2020 to February 2022. During the study period, data on 71 patients with sepsis-induced lymphopenia were collected. Among the 125 mNGS tests, 95 were positive for pathogens, whereas of the 166 conventional microbiological tests (CMTs), 91 were positive. The comparison showed that 38 patients (53.5%) had at least one matched pair of plasma mNGS and CMT results, while for multisite sampling, 47 patients (66.2%) had at least one. Lymphocyte subset analysis showed that T lymphocyte (577 ± 317 versus 395 ± 207, P = 0.005) and CD4+ T lymphocyte (333 ± 199 versus 230 ± 120, P = 0.009) counts were lower in the matched group. According to receiver operating characteristic (ROC) analysis, a CD4+ T lymphocyte count lower than 266 cells/mm3 was predictive of a match result. For sepsis-associated lymphopenia patients, we found that multisite mNGS tests showed a higher positivity rate. With plasma mNGS, a lower CD4+ T lymphocyte count predicted a better match result with CMT. The lymphocyte subset analysis may promote the clinical interpretation of mNGS results. IMPORTANCE This study was undertaken to evaluate the reliability of pathogenic diagnoses based on multisite mNGS detection at the clinically suspected sites and to analyze the efficiency of plasma mNGS detection based on lymphocyte subset counts in patients with sepsis-associated lymphopenia.