Indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2 activity and severe course of COVID-19.

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19.

Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fcγ receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation whereas simultaneously minimizing the inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike-induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.

Mechanical circulatory support in cardiogenic shock from acute myocardial infarction: Impella CP/5.0 versus ECMO.

BACKGROUND: Short-term mechanical circulatory support devices are increasingly used in cardiogenic shock after acute myocardial infarction. As no randomised evidence is available, the choice between high-output Impella or extra-corporeal membrane oxygenation (ECMO) is still a matter of debate. Real-life data are necessary to assess adverse outcomes and to help guide the treatment decision between the different devices. The purpose of this study was to compare characteristics and clinical outcomes of Impella CP/5.0 with ECMO support in patients with cardiogenic shock from myocardial infarction. METHODS: A retrospective, two-centre study was performed on all cardiogenic shock from myocardial infarction patients with Impella CP/5.0 or ECMO support, from 2006 until 2018. The primary outcome was 30-day mortality. Potential baseline imbalance between the groups was adjusted using inverse probability treatment weighting, and survival analysis was performed with an adjusted log-rank test. Secondarily, the occurrence of device-related complications (limb ischaemia, access site-related bleeding, access site-related infection) was evaluated. RESULTS: A total of 128 patients were included (Impella, N=90; ECMO, N=38). The 30-day mortality was similar for both groups (53% vs. 49%, P=0.30), also after adjustment for potential baseline imbalance between the groups (weighted log-rank P=0.16). Patients with Impella support had significantly fewer device-related complications than patients treated with ECMO (respectively, 17% vs. 40%, P<0.01). CONCLUSIONS: Patients treated with Impella CP/5.0 or ECMO for cardiogenic shock after myocardial infarction did not differ in 30-day mortality. More device-related complications occurred with ECMO compared to Impella support.

Reducing errors in the administration of medication with infusion pumps in the intensive care department: A lean approach.

BACKGROUND: Medication errors occur frequently and may potentially harm patients. Administering medication with infusion pumps carries specific risks, which lead to incidents that affect patient safety. OBJECTIVE: Since previous attempts to reduce medication errors with infusion pumps failed in our intensive care unit, we chose the Lean approach to accomplish a 50% reduction of administration errors in 6 months. Besides improving quality of care and patient safety, we wanted to determine the effectiveness of Lean in healthcare. METHODS: We conducted a before-and-after observational study. After baseline measurement, a value stream map (a detailed process description, used in Lean) was made to identify important underlying causes of medication errors. These causes were discussed with intensive care unit staff during frequent stand-up sessions, resulting in small improvement cycles and bottom-up defined improvement measures. Pre-intervention and post-intervention measurements were performed to determine the impact of the improvement measures. Infusion pump syringes and related administration errors were measured during unannounced sequential audits. RESULTS: Including the baseline measurement, 1748 syringes were examined. The percentage of errors concerning the administration of medication by infusion pumps decreased from 17.7% (95% confidence interval, 13.7-22.4; 55 errors in 310 syringes) to 2.3% (95% confidence interval, 1-4.6; 7 errors in 307 syringes) in 18 months (p < 0.0001). CONCLUSION AND RELEVANCE: The Lean approach proved to be helpful in reducing errors in the administration of medication with infusion pumps in a high complex intensive care environment.