Cell-free Deoxyribonucleic Acid: A Potential Biomarker of Chronic Periprosthetic Knee Joint Infection

Cobra, Hugo Alexandre de Araújo Barros; Mozella, Alan de Paula; Palma, Idemar Monteiro da; Salim, Rodrigo; Leal, Ana Carolina

doi:10.1016/j.arth.2022.07.002

Cited by 4 publications

(6 citation statements)

References 36 publications

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“…We found that three NET-related biomarkers, cf-DNA, H3Cit, and MPO, are increased in the synovial fluid of patients who have PJI. Previous studies have shown that there were higher levels of cf-DNA [4] and MPO [7] in the synovial fluid of patients with PJI. Such studies have identified the NETosis process as a potential source of both biomarkers; however, the occurrence of this process in PJI has not been addressed.…”

Section: Discussionmentioning

confidence: 99%

“…The sample size was determined based on a power analysis using the mean and standard deviation from a previous study on cf-DNA quantification [4] to obtain a power of 0.8 and alpha of 0.05. For the analysis, we used mean cf-DNA values of 122.5 ± 57.2 in the chronic PJI group and a mean of 4.6 ± 2.5 in the aseptic group, based on our previous study [3].…”

Section: Methodsmentioning

confidence: 99%

“…Other putative biomarkers for NETs are cell-free DNA (cf-DNA) and granule enzymes such as myeloperoxidase (MPO), which may have sources other than NET formation, such as cell death and degranulation [13,17]. Recently, cf-DNA [4] and MPO [7] have been shown to be increased in the synovial fluid of patients with chronic PJI. However, little is known about the NET release process (because of NETosis) in PJI.…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil Extracellular Trap-related Biomarkers Are Increased in the Synovial Fluid of Patients With Periprosthetic Joint Infections

de Sandes Kimura,

Mozella,

Cobra

et al. 2023

Clin Orthop Relat Res

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Background The diagnosis of periprosthetic joint infection (PJI) is a major challenge in clinical practice. The role of neutrophils in fighting infection has been increasingly understood, and one mechanism of action of these cells is neutrophil extracellular traps. However, little is known about this process in PJI. Questions/purposes (1) Are the biomarkers of neutrophil extracellular trap formation (citrullinated histone H3 [H3Cit], cell‐free DNA [cf-DNA], and myeloperoxidase [MPO]) increased in the synovial fluid of patients with PJI? (2) What is the diagnostic accuracy of biomarkers of neutrophil extracellular trap formation for PJI? Methods Between May 2020 and March 2021, 43 patients who underwent revision THA or TKA were enrolled in this study. Eleven patients were excluded and 32 patients were categorized into the PJI group (n = 16) or non-PJI group (n = 16) according to the 2018 Second International Consensus Meeting on Musculoskeletal Infection criteria. There were 15 men and 17 women in this study, with a median (range) age of 70 years (60 to 80 years). Twenty-seven patients had TKA and five had THA. We measured cf-DNA, MPO, and H3Cit in synovial fluid. The sensitivity, specificity, and receiver operating characteristic curve were calculated for each biomarker using the Musculoskeletal Infection Society criteria as the gold standard for diagnosis and considering a clinical surveillance of 2 years for patients in the non-PJI group. Results Patients with PJI had higher levels of synovial fluid cf-DNA (median [range] 130 ng/µL [18 to 179] versus 2 ng/µL [0 to 6]; p < 0.001), MPO (1436 ng/µL [55 to 3996] versus 0 ng/µL [0 to 393]; p < 0.001), and H3Cit (2115 ng/µL [5 to 2885] versus 3 ng/µL [0 to 87]; p < 0.001) than those in the non-PJI group. In receiver operating characteristic curve analyses, we observed near-perfect performance for all biomarkers evaluated, with an area under the curve of 1 (95% CI 0.9 to 1), 0.98 (95% CI 0.9 to 1), and 0.94 (95% CI 0.8 to 0.99) for cf-DNA, MPO, and H3Cit, respectively. The sensitivity for detecting PJI using synovial fluid was 100% for cf-DNA, 94% for MPO, and 88% for H3Cit. The specificity was 100% for cf-DNA and MPO, and 88% for H3Cit. Conclusion Our results show that neutrophils in the periprosthetic microenvironment release neutrophil extracellular traps as part of the bactericidal arsenal to fight infection. These results allow a better understanding of the cellular and molecular processes that occur in this microenvironment, enabling the design of more assertive strategies for identifying new biomarkers and improving the available ones. Novel studies are needed to define whether and how neutrophil extracellular trap-related biomarkers can be useful for diagnosing PJI. Level of Evidence Level II, diagnostic study.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neutrophil Extracellular Trap-related Biomarkers Are Increased in the Synovial Fluid of Patients With Periprosthetic Joint Infections

de Sandes Kimura,

Mozella,

Cobra

et al. 2023

Clin Orthop Relat Res

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“…In human studies, NET markers in SF were significantly increased in cases of septic arthritis compared to non-septic joint inflammation and osteoarthritis, 45 and also in people with chronic periprosthetic joint infection. 15 Direct visualization and quantification of NET release have been recommended as the gold standard method for NET assessment. 17 NETs can be visualized with immunofluorescence, using antibodies targeting specific proteins that make up NETs, including citrullinated histone 3 (Cit-H3) and MPO, and with concurrent staining of DNA.…”

Section: Full Scientific Reportmentioning

confidence: 99%

mentioning

confidence: 99%

Visualizing neutrophil extracellular traps in septic equine synovial and peritoneal fluid samples using immunofluorescence microscopy

Birckhead,

Das,

Tidd

et al. 2023

J VET Diagn Invest

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Septic synovitis and peritonitis are routinely diagnosed in horses based on clinical examination findings and laboratory assessment of synoviocentesis and abdominocentesis samples, respectively. Diagnosis is difficult in some cases because of an overlap in laboratory results for septic and non-septic inflammation. Neutrophil extracellular trap (NET) formation is part of the innate immune response against pathogens. Identifying and quantifying NETs, which have not been explored in clinical samples from horses with septic synovitis and peritonitis, to our knowledge, may be helpful in detecting infectious processes. Our main objective was to determine whether NETs could be visualized in septic equine synovial and peritoneal fluid cytology samples using immunofluorescence with antibodies against citrullinated histone H3 (Cit-H3) and myeloperoxidase (MPO). We analyzed 9 synovial and 4 peritoneal fluid samples. NET percentages were quantified using a simple counting technique, which is suitable for high-quality, well-preserved, and stained cytospin smears. NETs were evident in all septic samples and were absent in a non-septic sample; NETs were better visualized with Cit-H3 than with MPO immunolabeling. Overall, we believe that there is the potential for NETs and associated markers to be used to investigate and understand septic inflammation in horses.

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Bone and joint infection: past, present, and future

2024

Frontiers Research Topics

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Cell-free Deoxyribonucleic Acid: A Potential Biomarker of Chronic Periprosthetic Knee Joint Infection

Cited by 4 publications

References 36 publications

Neutrophil Extracellular Trap-related Biomarkers Are Increased in the Synovial Fluid of Patients With Periprosthetic Joint Infections

Neutrophil Extracellular Trap-related Biomarkers Are Increased in the Synovial Fluid of Patients With Periprosthetic Joint Infections

Visualizing neutrophil extracellular traps in septic equine synovial and peritoneal fluid samples using immunofluorescence microscopy

Bone and joint infection: past, present, and future

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