Influence of extracorporeal cytokine adsorption on hemodynamics in severe acute pancreatitis: Results of the matched cohort pancreatitis cytosorbents inflammatory cytokine removal (PACIFIC) study.

BACKGROUND: Outcome of severe acute pancreatitis (SAP) highly depends on the degree of systemic inflammation and organ failure. Although treatment approaches targeting the inflammatory cascade have failed in pancreatitis, recent studies suggest that extracorporeal cytokine adsorption effectively reduces concentrations of pro-inflammatory cytokines and potentially improves the outcome of sepsis. METHODS: Sixteen patients with SAP, presenting within 7 days upon onset of pain, an APACHE-II score of ≥10 and ≥1 marker of poor prognosis, received 2 consecutive 24-h treatments with CytoSorb® extracorporeal cytokine adsorption (intervention group). Hemodynamics, organ failure, and mortality were compared with an APACHE-II score-matched retrospective control group of 32 patients. RESULTS: The primary objective (20% decrease in the vasopressor dependency index or 20% increase in the cardiac index) was reached in 68.8% of the intervention and 28.1% of the control patients (p = 0.007), respectively. The cytokine adsorption significantly reduced IL-6 (-1998 pg/ml, p = 0.005) serum levels and resulted in stable CRP (p = 0.101) and decreased PCT (p = 0.003) levels in contrast to increased CRP (p = 0.014) and stable PCT levels (p = 0.695) in the control group. While mortality and improvement of respiratory failure were similar in both groups, renal failure significantly improved (change of KDIGO classification 72 h postcytokine adsorption [-1 vs. 0, p = 0.005]) and the SOFA score significantly decreased (day 5: -1.8 ± 2.0 vs. 1 ± 3.8, p = 0.013) in the intervention group. CONCLUSION: Cytokine adsorption might be an effective treatment option to stabilize hemodynamics in SAP. It decreases levels of the pro-inflammatory marker IL-6 and stabilizes organ function according to serial SOFA score assessments.

Convalescent plasma therapy in B-cell-depleted and B-cell sufficient patients with life-threatening COVID-19 - A case series.

OBJECTIVE: To investigate the effect of convalescent plasma therapy (CPT) on clinical courses of B-cell-sufficient and B-cell-depleted patients with life-threatening COVID-19. PATIENTS AND METHODS: In this case series, we retrospectively analysed clinical, laboratory and cardiopulmonary parameters of six patients with life-threatening COVID-19 receiving convalescent plasma (CP) as rescue therapy between April 11, 2020 to October 10, 2020. Clinical and laboratory parameters before and after transfusion were compared in two B-cell-depleted patients and four B-cell sufficient patients (control group). RESULTS: Both B-cell-depleted patients cleared SARS-CoV-2 virus and survived, while all other patients died within 14 days from intervention despite maximal therapeutic efforts. D-dimer levels increased in both cohorts subsequent to CPT. In control patients, mean Interleukin-6 increased and platelet levels decreased as opposed to decreasing and stable levels in B-cell-depleted patients, respectively. Control patients required increased doses of vasopressor compared to decreasing doses in B-cell depleted patients subsequent to CPT. PO2/FiO2 decrease was more pronounced and respiratory deterioration required postinterventional extracorporeal membrane oxygenation in two control patients. Transpulmonary thermodilution revealed a further increase of the Extravascular Lung Water Index upon CPT in control patients. CONCLUSION: Use of CP in late stages of life-threatening COVID-19 should be used with caution but may be beneficial in B-cell-depleted patients. Further studies are necessary to assess factors predicting potential therapeutic benefits as well as possible hazards.

Extracorporeal carbon dioxide removal with the Advanced Organ Support system in critically ill COVID-19 patients.

Disturbed oxygenation is foremost the leading clinical presentation in COVID-19 patients. However, a small proportion also develop carbon dioxide removal problems. The Advanced Organ Support (ADVOS) therapy (ADVITOS GmbH, Munich, Germany) uses a less invasive approach by combining extracorporeal CO2 -removal and multiple organ support for the liver and the kidneys in a single hemodialysis device. The aim of our study is to evaluate the ADVOS system as treatment option in-COVID-19 patients with multi-organ failure and carbon dioxide removal problems. COVID-19 patients suffering from severe respiratory insufficiency, receiving at least two treatments with the ADVOS multi system (ADVITOS GmbH, Munich, Germany), were eligible for study inclusion. Briefly, these included patients with acute kidney injury (AKI) according to KDIGO guidelines, and moderate or severe ARDS according to the Berlin definition, who were on invasive mechanical ventilation for more than 72 hours. In total, nine COVID-19 patients (137 ADVOS treatment sessions with a median of 10 treatments per patient) with moderate to severe ARDS and carbon dioxide removal problems were analyzed. During the ADVOS treatments, a rapid correction of acid-base balance and a continuous CO2 removal could be observed. We observed a median continuous CO2 removal of 49.2 mL/min (IQR: 26.9-72.3 mL/min) with some treatments achieving up to 160 mL/min. The CO2 removal significantly correlated with blood flow (Pearson 0.421; P < .001), PaCO2 (0.341, P < .001) and HCO 3 - levels (0.568, P < .001) at the start of the treatment. The continuous treatment led to a significant reduction in PaCO2 from baseline to the last ADVOS treatment. In conclusion, it was feasible to remove CO2 using the ADVOS system in our cohort of COVID-19 patients with acute respiratory distress syndrome and multiorgan failure. This efficient removal of CO2 was achieved at blood flows up to 300 mL/min using a conventional hemodialysis catheter and without a membrane lung or a gas phase.

Increased extravascular lung water index (EVLWI) reflects rapid non-cardiogenic oedema and mortality in COVID-19 associated ARDS.

Nearly 5% of patients suffering from COVID-19 develop acute respiratory distress syndrome (ARDS). Extravascular lung water index (EVLWI) is a marker of pulmonary oedema which is associated with mortality in ARDS. In this study, we evaluate whether EVLWI is higher in patients with COVID-19 associated ARDS as compared to COVID-19 negative, ventilated patients with ARDS and whether EVLWI has the potential to monitor disease progression. EVLWI and cardiac function were monitored by transpulmonary thermodilution in 25 patients with COVID-19 ARDS subsequent to intubation and compared to a control group of 49 non-COVID-19 ARDS patients. At intubation, EVLWI was noticeably elevated and significantly higher in COVID-19 patients than in the control group (17 (11-38) vs. 11 (6-26) mL/kg; p < 0.001). High pulmonary vascular permeability index values (2.9 (1.0-5.2) versus 1.9 (1.0-5.2); p = 0.003) suggested a non-cardiogenic pulmonary oedema. By contrast, the cardiac parameters SVI, GEF and GEDVI were comparable in both cohorts. High EVLWI values were associated with viral persistence, prolonged intensive care treatment and in-hospital mortality (23.2 ± 6.7% vs. 30.3 ± 6.0%, p = 0.025). Also, EVLWI showed a significant between-subjects (r = - 0.60; p = 0.001) and within-subjects correlation (r = - 0.27; p = 0.028) to Horowitz index. Compared to non COVID-19 ARDS, COVID-19 results in markedly elevated EVLWI-values in patients with ARDS. High EVLWI reflects a non-cardiogenic pulmonary oedema in COVID-19 ARDS and could serve as parameter to monitor ARDS progression on ICU.

Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis.

Mesenchymal stromal cells (MSCs) are crucial components of the bone marrow (BM) microenvironment essential for regulating self-renewal, survival, and differentiation of hematopoietic stem/progenitor cells (HSPCs) in the stem cell niche. MSCs are functionally altered in myelodysplastic syndromes (MDS) and exhibit an altered methylome compared with MSCs from healthy controls, thus contributing to disease progression. To determine whether MSCs are amenable to epigenetic therapy and if this affects their function, we examined growth, differentiation, and HSPC-supporting capacity of ex vivo-expanded MSCs from MDS patients in comparison with age-matched healthy controls after direct treatment in vitro with the hypomethylating agent azacitidine (AZA). Strikingly, we find that AZA exerts a direct effect on healthy as well as MDS-derived MSCs such that they favor support of healthy over malignant clonal HSPC expansion in coculture experiments. RNA-sequencing analyses of MSCs identified stromal networks regulated by AZA. Notably, these comprise distinct molecular pathways crucial for HSPC support, foremost extracellular matrix molecules (including collagens) and interferon pathway components. Our study demonstrates that the hypomethylating agent AZA exerts its antileukemic activity in part through a direct effect on the HSPC-supporting BM niche and provides proof of concept for the therapeutic potential of epigenetic treatment of diseased MSCs. In addition, our comprehensive data set of AZA-sensitive gene networks represents a valuable framework to guide future development of targeted epigenetic niche therapy in myeloid malignancies such as MDS and acute myeloid leukemia.