Severe T cell hyporeactivity in ventilated COVID-19 patients correlates with prolonged virus persistence and poor outcomes

Coronavirus disease 2019 (COVID-19) can lead to pneumonia and hyperinflammation. Here we show a sensitive method to measure polyclonal T cell activation by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood. We report a clear T cell hyporeactivity in hospitalized COVID-19 patients that is pronounced in ventilated patients, associated with prolonged virus persistence and reversible with clinical recovery. COVID-19-induced T cell hyporeactivity is T cell extrinsic and caused by plasma components, independent of occasional immunosuppressive medication of the patients. Monocytes respond stronger in males than females and IL-2 partially restores T cell activation. Downstream markers of T cell hyporeactivity are also visible in fresh blood samples of ventilated patients. Based on our data we developed a score to predict fatal outcomes and identify patients that may benefit from strategies to overcome T cell hyporeactivity.Coronavirus disease 2019 (COVID-19) can lead to pneumonia and hyperinflammation. Here we show a sensitive method to measure polyclonal T cell activation by downstream effects on responder cells like basophils, plasmacytoid dendritic cells, monocytes and neutrophils in whole blood. We report a clear T cell hyporeactivity in hospitalized COVID-19 patients that is pronounced in ventilated patients, associated with prolonged virus persistence and reversible with clinical recovery. COVID-19-induced T cell hyporeactivity is T cell extrinsic and caused by plasma components, independent of occasional immunosuppressive medication of the patients. Monocytes respond stronger in males than females and IL-2 partially restores T cell activation. Downstream markers of T cell hyporeactivity are also visible in fresh blood samples of ventilated patients. Based on our data we developed a score to predict fatal outcomes and identify patients that may benefit from strategies to overcome T cell hyporeactivity

Quality of life, infection control, and complication rates using a novel custom-made articulating hip spacer during two-stage revision for periprosthetic joint infection

Introduction!#!Two-stage revision remains the gold standard treatment for most chronically infected and complex total hip arthroplasty infections. To improve patient outcome and reduce complication rates, we have developed a novel custom-made articulating hip spacer technique and present our short-term results.!##!Materials and methods!#!Between November 2017 and November 2019, 27 patients (mean age 70 years) underwent two-stage revision for periprosthetic joint infection of the hip using the articulating spacer design described here. We retrospectively analyzed spacer-related complications as well as rates for complication, infection control, and implant survivorship after final reimplantation. Furthermore, we prospectively collected patient-reported health-related quality of life (HRQoL) scores prior to spacer implantation, with the spacer and after reimplantation of the new prosthesis.!##!Results!#!An additional round of spacer exchange was performed in two patients (8.3%), persistent wound discharge was the reason in both cases. We had one (4.2%) spacer-related mechanical complication, a dislocation that was treated with closed reduction. After reimplantation, infection control was achieved in 96% with an implant survivorship of 92% after a mean follow-up time of 19 (range 7-32, SD 7.2) months. While the scores for VR-12 MCS, VAS hip pain and patient-reported overall satisfaction significantly improved after first stage surgery, the scores for WOMAC, UCLA and VR-12 PCS significantly improved after second stage surgery.!##!Conclusions!#!Our two-stage approach for periprosthetic joint infection shows high infection eradication and implant survivorship rates at short-term follow-up. Spacer-related complication rates were low, and we achieved high patient satisfaction rates and low pain levels already during the spacer period. To further simplify comparison between different spacer designs, we propose a new hip spacer classification system

Impact and Modification of the New PJI-TNM Classification for Periprosthetic Joint Infections

The comprehensive “PJI-TNM classification” for the description of periprosthetic joint infections (PJI) was introduced in 2020. Its structure is based on the well-known oncological TNM classification to appreciate the complexity, severity, and diversity of PJIs. The main goal of this study is to implement the new PJI-TNM classification into the clinical setting to determine its therapeutic and prognostic value and suggest modifications to further improve the classification for clinical routine use. A retrospective cohort study was conducted at our institution between 2017 and 2020. A total of 80 consecutive patients treated with a two-stage revision for periprosthetic knee joint infection were included. We retrospectively assessed correlations between patients’ preoperative PJI-TNM classification and their therapy and outcome and identified several statistically significant correlations for both classifications, the original and our modified version. We have demonstrated that both classifications provide reliable predictions already at the time of diagnosis regarding the invasiveness of surgery (duration of surgery, blood and bone loss during surgery), likelihood of reimplantation, and patient mortality during the first 12 months after diagnosis. Orthopedic surgeons can use the classification system preoperatively as an objective and comprehensive tool for therapeutic decisions and patient information (informed consent). In the future, comparisons between different treatment options for truly similar preoperative baseline situations can be obtained for the first time. Clinicians and researchers should be familiar with the new PJI-TNM classification and start implementing it into their routine practice. Our adjusted and simplified version (“PJI-pTNM”) might be a more convenient alternative for the clinical setting

Impact and Modification of the New PJI-TNM Classification for Periprosthetic Joint Infections

The comprehensive “PJI-TNM classification” for the description of periprosthetic joint infections (PJI) was introduced in 2020. Its structure is based on the well-known oncological TNM classification to appreciate the complexity, severity, and diversity of PJIs. The main goal of this study is to implement the new PJI-TNM classification into the clinical setting to determine its therapeutic and prognostic value and suggest modifications to further improve the classification for clinical routine use. A retrospective cohort study was conducted at our institution between 2017 and 2020. A total of 80 consecutive patients treated with a two-stage revision for periprosthetic knee joint infection were included. We retrospectively assessed correlations between patients’ preoperative PJI-TNM classification and their therapy and outcome and identified several statistically significant correlations for both classifications, the original and our modified version. We have demonstrated that both classifications provide reliable predictions already at the time of diagnosis regarding the invasiveness of surgery (duration of surgery, blood and bone loss during surgery), likelihood of reimplantation, and patient mortality during the first 12 months after diagnosis. Orthopedic surgeons can use the classification system preoperatively as an objective and comprehensive tool for therapeutic decisions and patient information (informed consent). In the future, comparisons between different treatment options for truly similar preoperative baseline situations can be obtained for the first time. Clinicians and researchers should be familiar with the new PJI-TNM classification and start implementing it into their routine practice. Our adjusted and simplified version (“PJI-pTNM”) might be a more convenient alternative for the clinical setting

Secondary hemophagocytic lymphohistiocytosis and severe liver injury induced by hepatic SARS-CoV-2 infection unmasking Wilson’s disease: Balancing immunosuppression

A 21-year-old woman was hospitalized due to coronavirus disease 2019 (COVID-19)-associated respiratory and hepatic impairment concomitant with severe hemolytic anemia. Upon diagnosis of secondary hemophagocytic lymphohistiocytosis, immunosuppression with anakinra and steroids was started, leading to a hepatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and viremia. Subsequent liver biopsy revealed virus particles in hepatocytes by electron microscopy and SARS-CoV-2 virus could be isolated and cultured. Immunosuppression was stopped and convalescent donor plasma given. In the differential diagnosis, an acute crisis of Wilson’s disease was raised by laboratory and genetic testing. This case highlights the complexity of balancing immunosuppression to control hyperinflammation versus systemic SARS-CoV-2 dissemination

Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non–COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment