RESUMEN
IMPORTANCE: Recent evidence suggests a multilevel inflammatory syndrome as a driving factor in some of the most severely ill coronavirus disease 2019 patients with overlapping features to other hyperinflammatory or autoimmune diseases. Therefore, plasma exchange is considered as potential therapy in these patients. OBJECTIVES: We characterize the longitudinal therapeutic efficacy and safety profile of plasma exchange in critically ill patients with clinical and laboratory evidences of coronavirus disease 2019-related immunopathology. DESIGN SETTING AND PARTICIPANTS: A retropsective case-control study of critically ill coronavirus disease 2019 patients treated with plasma exchange at Heidelberg University Hospital between March and December 2020. Plasma exchange-treated patients were compared with coronavirus disease 2019 patients on standard therapy matched for age, gender, disease severity, and features of hyperinflammatory syndrome. MAIN OUTCOME AND MEASURES: Mortality rate and course of clinical and laboratory parameters in response to plasma exchange were assessed in coronavirus disease 2019 patients and in patients on standard care. A plasma volume of 50 mL per kg body weight or a maximum of 4 L was exchanged. RESULTS: In total, 28 critically ill coronavirus disease 2019 patients were treated with a median of three plasma exchange procedures per patient. No relevant complications occurred during plasma exchange therapy. Inflammatory and biochemical markers of end-organ damage and endothelial activation were significantly reduced following plasma exchange together with normalization of body temperature, improved pulmonary function, and reduced vasopressor demand. Most importantly, these improvements were maintained after the last plasma exchange. In contrast, no such effects were observed in the control group, although baseline clinical and laboratory parameters were comparable. Kaplan-Meier analysis showed improved 30-day survival in the plasma exchange group compared with the control group (67.9% vs 42.9%; p = 0.044). In a multivariable analysis, the hazard ratio for death was 0.27 (95% CI, 0.11-0.68; p = 0.005) with plasma exchange versus standard care. CONCLUSIONS AND RELEVANCE: Our data provide further evidence for plasma exchange as a novel therapeutic strategy in a subset of critically ill coronavirus disease 2019 patients by potentially reversing the complex coronavirus disease 2019 immunopathology. Randomized controlled trials are underway to confirm these positive results.
RESUMEN
TP63, an important epithelial developmental gene, has significant homology to p53. Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative DeltaNp63. We investigated the downstream mechanisms by which TAp63alpha elicits apoptosis. TAp63alpha directly transactivates the CD95 gene via the p53 binding site in the first intron resulting in upregulation of a functional CD95 death receptor. Stimulation and blocking experiments of the CD95, TNF-R and TRAIL-R death receptor systems revealed that TAp63alpha can trigger expression of each of these death receptors. Furthermore, our findings demonstrate a link between TAp63alpha and the mitochondrial apoptosis pathway. TAp63alpha upregulates expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of RAD9, DAP3 and APAF1. Of clinical relevance is the fact that TAp63alpha is induced by many chemotherapeutic drugs and that inhibiting TAp63 function leads to chemoresistance. Thus, beyond its importance in development and differentiation, we describe an important role for TAp63alpha in the induction of apoptosis and chemosensitivity.
