Finding the Optimal Screening Test for Periprosthetic Joint Infection: A Prospective Study.

BACKGROUND: No single test has demonstrated absolute accuracy in the diagnosis of periprosthetic joint infection (PJI). Serological markers are often used as screening tools to avoid unnecessary joint aspiration in cases with a low probability of infection. This study aimed to determine the utility of standard-of-care serological tests as a screening tool for PJI in patients undergoing revision arthroplasty. METHODS: This prospective study enrolled 502 patients undergoing revision hip or knee arthroplasty between May 2017 and August 2021. A PJI was defined using a modified definition of the 2018 International Consensus Meeting criteria. Plasma D-dimer, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fibrinogen were measured preoperatively. There were 82 patients undergoing reimplantation who were excluded. Additionally, 8 patients who had an inconclusive International Consensus Meeting score were also excluded. Of the 412 included patients, 317 (76.9%) underwent revision for aseptic failure, and 95 (23.1%) had PJI. Receiver operating characteristic curves were used to assess the diagnostic utility of each serological test. A pairwise comparison with Bonferroni correction was performed to determine whether the differences in areas under the curve (AUCs) between the tests were significant. Additional analyses were performed to find the threshold for each test that offered 100% sensitivity, allowing it to be the optimal screening test. RESULTS: All 4 serological markers, D-dimer (AUC 0.860, sensitivity 81.3%, specificity 81.7%), CRP (AUC 0.862, sensitivity 90.4%, specificity 70.0%), ESR (AUC 0.833, sensitivity 73.9%, specificity 85.2%), and fibrinogen (AUC 0.798, sensitivity 74.7%, specificity 75.4%), demonstrated comparable accuracy for the diagnosis of PJI (all P > .05). When maximizing sensitivity to 100%, D-dimer demonstrated the highest specificity (AUC 0.860, specificity 40.2%), outperforming ESR (AUC 0.833, specificity 3.3%), fibrinogen (AUC 0.798, specificity 2.3%), and CRP (AUC 0.862, specificity 0%). A plasma D-dimer level of ≥ 244 ng/mL was identified as the optimal cutoff for use as a screening test. CONCLUSIONS: Although plasma D-dimer demonstrated similar diagnostic accuracy as CRP, ESR, and fibrinogen, it outperformed all 3 aforementioned serological markers when used as a screening test for PJI. LEVEL OF EVIDENCE: Level II.

Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease which leads to significant morbidity and mortality from respiratory failure. The two drugs currently approved for clinical use slow the rate of decline in lung function but have not been shown to halt disease progression or reverse established fibrosis. Thus, new therapeutic targets are needed. Endothelial injury and the resultant vascular permeability are critical components in the response to tissue injury and are present in patients with IPF. However, it remains unclear how vascular permeability affects lung repair and fibrosis following injury. Lipid mediators such as sphingosine-1-phosphate (S1P) are known to regulate multiple homeostatic processes in the lung including vascular permeability. We demonstrate that endothelial cell-(EC) specific deletion of the S1P receptor 1 (S1PR1) in mice (EC-S1pr1-/-) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC-S1pr1-/- mice had increased and persistent vascular permeability compared with wild-type mice, which was strongly correlated with the amount and localization of resulting pulmonary fibrosis. EC-S1pr1-/- mice also had increased immune cell infiltration and activation of the coagulation cascade within the lung. However, increased circulating S1P ligand in ApoM-overexpressing mice was insufficient to protect against bleomycin-induced pulmonary fibrosis. Overall, these data demonstrate that endothelial cell S1PR1 controls vascular permeability in the lung, is associated with changes in immune cell infiltration and extravascular coagulation, and modulates the fibrotic response to lung injury.

Soluble Suppression of Tumorigenicity-2 Associates With Ventilator Dependence in Coronavirus Disease 2019 Respiratory Failure.

OBJECTIVES: We hypothesize that elevated soluble suppression of tumorigenicity-2 concentrations, a marker of pulmonary epithelial injury, reflect ongoing lung injury in acute hypoxemic respiratory failure due to coronavirus disease 2019 and associate with continued ventilator dependence. DESIGN: We associated serial plasma soluble suppression of tumorigenicity-2 levels and markers of systemic inflammation including d-dimer, C-reactive protein, and erythrocyte sedimentation rate with 30-day mortality and ventilator dependence. SETTING: Adult medical ICUs and general medicine wards at an academic teaching hospital in Boston, MA. PATIENTS: Adult patients with severe acute respiratory syndrome coronavirus 2 infection and acute hypoxemic respiratory failure admitted to the ICU (n = 72) and non-ICU patients managed with supplemental oxygen (n = 77). INTERVENTIONS: Observational study from April 25 to June 25, 2020. MEASUREMENTS AND MAIN RESULTS: ICU patients had a higher baseline body mass index and median soluble suppression of tumorigenicity-2, d-dimer, and C-reactive protein concentrations compared with non-ICU patients. Among ICU patients, elevated baseline modified Sequential Organ Failure Assessment score and log (soluble suppression of tumorigenicity-2) were associated with 30-day mortality, whereas initial Pao2/Fio2 and markers of systemic inflammation were similar between groups. Only log (soluble suppression of tumorigenicity-2) associated with ventilator dependence over time, with the last measured log (soluble suppression of tumorigenicity-2) concentration obtained on ICU day 11.5 (interquartile range [7-17]) higher in patients who required reintubation or tracheostomy placement compared with patients who were successfully extubated (2.10 [1.89-2.26] vs 1.87 ng/mL [1.72-2.13 ng/mL]; p = 0.03). Last measured systemic inflammatory markers, modified Sequential Organ Failure Assessment score, and Pao2/Fio2 were not different between patients who were successfully extubated compared with those with continued ventilator dependence. CONCLUSIONS: Plasma soluble suppression of tumorigenicity-2 is a biomarker readily measured in blood that can provide dynamic information about the degree of a patient's lung injury and real-time assessment of the likelihood of extubation success. Measures of systemic inflammation, illness severity, and oxygenation did not associate with ventilator outcomes.