Pathophysiological mechanisms of liver injury in COVID-19

The recent outbreak of coronavirus disease 2019 (COVID‐19), caused by the Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) has resulted in a world‐wide pandemic. Disseminated lung injury with the development of acute respiratory distress syndrome (ARDS) is the main cause of mortality in COVID‐19. Although liver failure does not seem to occur in the absence of pre‐existing liver disease, hepatic involvement in COVID‐19 may correlate with overall disease severity and serve as a prognostic factor for the development of ARDS. The spectrum of liver injury in COVID‐19 may range from direct infection by SARS‐CoV‐2, indirect involvement by systemic inflammation, hypoxic changes, iatrogenic causes such as drugs and ventilation to exacerbation of underlying liver disease. This concise review discusses the potential pathophysiological mechanisms for SARS‐CoV‐2 hepatic tropism as well as acute and possibly long‐term liver injury in COVID‐19

Duration of invasive mechanical ventilation prior to extracorporeal membrane oxygenation is not associated with survival in acute respiratory distress syndrome caused by coronavirus disease 2019

BACKGROUND: Duration of invasive mechanical ventilation (IMV) prior to extracorporeal membrane oxygenation (ECMO) affects outcome in acute respiratory distress syndrome (ARDS). In coronavirus disease 2019 (COVID-19) related ARDS, the role of pre-ECMO IMV duration is unclear. This single-centre, retrospective study included critically ill adults treated with ECMO due to severe COVID-19-related ARDS between 01/2020 and 05/2021. The primary objective was to determine whether duration of IMV prior to ECMO cannulation influenced ICU mortality. RESULTS: During the study period, 101 patients (mean age 56 [SD ± 10] years; 70 [69%] men; median RESP score 2 [IQR 1–4]) were treated with ECMO for COVID-19. Sixty patients (59%) survived to ICU discharge. Median ICU length of stay was 31 [IQR 20.7–51] days, median ECMO duration was 16.4 [IQR 8.7–27.7] days, and median time from intubation to ECMO start was 7.7 [IQR 3.6–12.5] days. Fifty-three (52%) patients had a pre-ECMO IMV duration of > 7 days. Pre-ECMO IMV duration had no effect on survival (p = 0.95). No significant difference in survival was found when patients with a pre-ECMO IMV duration of < 7 days (< 10 days) were compared to ≥ 7 days (≥ 10 days) (p = 0.59 and p = 1.0). CONCLUSIONS: The role of prolonged pre-ECMO IMV duration as a contraindication for ECMO in patients with COVID-19-related ARDS should be scrutinised. Evaluation for ECMO should be assessed on an individual and patient-centred basis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13613-022-00980-3

Inadequate Energy Delivery Is Frequent among COVID-19 Patients Requiring ECMO Support and Associated with Increased ICU Mortality

Background: Patients receiving extracorporeal membrane oxygenation (ECMO) support are at high risk for malnutrition. There are currently no general nutrition guidelines for coronavirus disease 2019 (COVID-19) patients during ECMO therapy. Methods: We conducted a retrospective analysis of COVID-19 patients requiring venovenous ECMO support at a large tertiary hospital center. Nutrition goals were calculated using 25 kcal/kg body weight (BW)/day. Associations between nutrition support and outcome were evaluated using Kaplan–Meier and multivariable Cox regression analyses. Results: Overall, 102 patients accounted for a total of 2344 nutrition support days during ECMO therapy. On 40.6% of these days, nutrition goals were met. Undernutrition was found in 40.8%. Mean daily calorie delivery was 73.7% of calculated requirements, mean daily protein delivery was 0.7 g/kg BW/d. Mean energy intake of ≥70% of calculated targets was associated with significantly lower ICU mortality independently of age, disease severity at ECMO start and body mass index (adjusted hazard ratio: 0.372, p = 0.007). Conclusions: Patients with a mean energy delivery of ≥70% of calculated targets during ECMO therapy had a better ICU survival compared to patients with unmet energy goals. These results indicate that adequate nutritional support needs to be a major priority in the treatment of COVID-19 patients requiring ECMO support

Use of the CytoSorb adsorber in patients with acute-on-chronic liver failure

Abstract CytoSorb is a hemoadsorptive column used to remove high concentrations of proinflammatory cytokines in septic shock. Data on CytoSorb application in acute-on-chronic liver failure (ACLF) is lacking. This retrospective observational study analyzed 21 ACLF patients admitted to ICUs at the Vienna General Hospital who received CytoSorb adsorber therapy between 2017 and 2023. Median ICU length of stay was 8 days (IQR: 3–13), the ICU survival rate was 23.8% (n = 5). Significant decreases in bilirubin (median peak: 20.7 mg/dL to median post-treatment: 10.8 mg/dL; − 47.8%; p < 0.001), procalcitonin (1.34 to 0.74 pg/mL; − 44.6%; p < 0.001), interleukin-6 (385 to 131 ng/mL; − 66.0%; p = 0.0182)—but also of platelets (72 to 31 G/L; − 56.9%; p = 0.0014) and fibrinogen (230 to 154 mg/dL; − 33.0%; p = 0.0297) were detected. ICU survivors had a trend towards a stronger relative decrease in bilirubin (− 76.1% vs. − 48.2%), procalcitonin (− 90.6% vs. − 23.5%), and IL-6 (− 54.6% vs. − 17.8%) upon CytoSorb treatment. Moreover, no serious CytoSorb-attributed complications were detected. In conclusion, use of CytoSorb adsorber in ACLF patients results in a significant decrease in bilirubin and proinflammatory cytokines, while platelets and fibrinogen were also lowered. Prospective trials are warranted to investigate the impact of CytoSorb on clinical outcomes of ACLF patients with high proinflammatory cytokine levels

Proposed Diagnostic Criteria and Classification of Canine Mast Cell Neoplasms: A Consensus Proposal

Mast cell neoplasms are one of the most frequently diagnosed malignancies in dogs. The clinical picture, course, and prognosis vary substantially among patients, depending on the anatomic site, grade and stage of the disease. The most frequently involved organ is the skin, followed by hematopoietic organs (lymph nodes, spleen, liver, and bone marrow) and mucosal sites of the oral cavity and the gastrointestinal tract. In cutaneous mast cell tumors, several grading and staging systems have been introduced. However, no comprehensive classification and no widely accepted diagnostic criteria have been proposed to date. To address these open issues and points we organized a Working Conference on canine mast cell neoplasms in Vienna in 2019. The outcomes of this meeting are summarized in this article. The proposed classification includes cutaneous mast cell tumors and their sub-variants defined by grading- and staging results, mucosal mast cell tumors, extracutaneous/extramucosal mast cell tumors without skin involvement, and mast cell leukemia (MCL). For each of these entities, diagnostic criteria are proposed. Moreover, we have refined grading and staging criteria for mast cell neoplasms in dogs based on consensus discussion. The criteria and classification proposed in this article should greatly facilitate diagnostic evaluation and prognostication in dogs with mast cell neoplasms and should thereby support management of these patients in daily practice and the conduct of clinical trials

CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in <i>KIT</i> D816V⁺ Neoplastic Mast Cells

In most patients with advanced systemic mastocytosis (AdvSM), neoplastic mast cells (MC) express KIT D816V. However, despite their disease-modifying potential, KIT D816V-targeting drugs, including midostaurin and avapritinib, may not produce long-term remissions in all patients. Cyclin-dependent kinase (CDK) 4 and CDK6 are promising targets in oncology. We found that shRNA-mediated knockdown of CDK4 and CDK6 results in growth arrest in the KIT D816V+ MC line HMC-1.2. The CDK4/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib suppressed the proliferation in primary neoplastic MC as well as in all HMC-1 and ROSA cell subclones that were examined. Abemaciclib was also found to block growth in the drug-resistant MC line MCPV-1, whereas no effects were seen with palbociclib and ribociclib. Anti-proliferative drug effects on MC were accompanied by cell cycle arrest. Furthermore, CDK4/CDK6 inhibitors were found to synergize with the KIT-targeting drugs midostaurin, avapritinib, and nintedanib in inducing growth inhibition and apoptosis in neoplastic MCs. Finally, we found that CDK4/CDK6 inhibitors induce apoptosis in CD34+/CD38− stem cells in AdvSM. Together, CDK4/CDK6 inhibition is a potent approach to suppress the growth of neoplastic cells in AdvSM. Whether CDK4/CDK6 inhibitors can improve clinical outcomes in patients with AdvSM remains to be determined in clinical trials

Haematologica / The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis

Systemic mastocytosis is a complex disease defined by abnormal growth and accumulation of neoplastic mast cells in various organs. Most patients exhibit a D816V-mutated variant of KIT, which confers resistance against imatinib. Clinical problems in systemic mastocytosis arise from mediator-related symptoms and/or organ destruction caused by malignant expansion of neoplastic mast cells and/or other myeloid cells in various organ systems. DCC-2618 is a spectrum-selective pan KIT and PDGFRA inhibitor which blocks KIT D816V and multiple other kinase targets relevant to systemic mastocytosis. We found that DCC-2618 inhibits the proliferation and survival of various human mast cell lines (HMC-1, ROSA, MCPV-1) as well as primary neoplastic mast cells obtained from patients with advanced systemic mastocytosis (IC50 <1 M). Moreover, DCC-2618 decreased growth and survival of primary neoplastic eosinophils obtained from patients with systemic mastocytosis or eosinophilic leukemia, leukemic monocytes obtained from patients with chronic myelomonocytic leukemia with or without concomitant systemic mastocytosis, and blast cells obtained from patients with acute myeloid leukemia. Furthermore, DCC-2618 was found to suppress the proliferation of endothelial cells, suggesting additional drug effects on systemic mastocytosis-related angiogenesis. Finally, DCC-2618 was found to downregulate IgE-mediated histamine release from basophils and tryptase release from mast cells. Together, DCC-2618 inhibits growth, survival and activation of multiple cell types relevant to advanced systemic mastocytosis. Whether DCC-2618 is effective in vivo in patients with advanced systemic mastocytosis is currently under investigation in clinical trials.(VLID)470085

Combined targeting of STAT3 and STAT5: a novel approach to overcome drug resistance in chronic myeloid leukemia

In chronic myeloid leukemia, resistance against BCR-ABL1 tyrosine kinase inhibitors can develop because of BCR-ABL1 mutations, activation of additional pro-oncogenic pathways, and stem cell resistance. Drug combinations covering a broad range of targets may overcome resistance. CDDO-Me (bardoxolone methyl) is a drug that inhibits the survival of leukemic cells by targeting different pro-survival molecules, including STAT3. We found that CDDO-Me inhibits proliferation and survival of tyrosine kinase inhibitor-resistant BCR-ABL1+ cell lines and primary leukemic cells, including cells harboring BCR-ABL1T315I or T315I+ compound mutations. Furthermore, CDDO-Me was found to block growth and survival of CD34+/CD38 leukemic stem cells (LSC). Moreover, CDDO-Me was found to produce synergistic growth-inhibitory effects when combined with BCR-ABL1 tyrosine kinase inhibitors. These drug-combinations were found to block multiple signaling cascades and molecules, including STAT3 and STAT5. Furthermore, combined targeting of STAT3 and STAT5 by shRNA and STAT5-targeting drugs also resulted in synergistic growth-inhibition, pointing to a new efficient concept of combinatorial STAT3 and STAT5 inhibition. However, CDDO-Me was also found to increase the expression of heme-oxygenase-1, a heat-shock-protein that triggers drug resistance and cell survival. We therefore combined CDDO-Me with the heme-oxygenase-1 inhibitor SMA-ZnPP, which also resulted in synergistic growth-inhibitory effects. Moreover, SMA-ZnPP was found to sensitize BCR-ABL1+ cells against the combination ‘CDDO-Me+ tyrosine kinase inhibitor. Together, combined targeting of STAT3, STAT5, and heme-oxygenase-1 overcomes resistance in BCR-ABL1+ cells, including stem cells and highly resistant sub-clones expressing BCR-ABL1T315I or T315I-compound mutations. Whether such drug-combinations are effective in tyrosine kinase inhibitor-resistant patients with chronic myeloid leukemia remains to be elucidated.(VLID)485768