In-hospital survival of critically ill COVID-19 patients treated with glucocorticoids: a multicenter real-world data study.

The COVID-19 pandemic has posed a major challenge to healthcare systems globally. Millions of people have been infected, and millions of deaths have been reported worldwide. Glucocorticoids have attracted worldwide attention for their potential efficacy in the treatment of COVID-19. Various glucocorticoids with different dosages and treatment durations have been studied in patients with different severities, with a suitable dosage and treatment duration not yet defined. This study aimed to investigate whether in-hospital survival differs between critically ill patients treated with low-dose glucocorticoids, high-dose glucocorticoids or no glucocorticoids. All critically ill patients admitted to the intensive care unit of the Charité Hospital-Universitätsmedizin Berlin between February 2020 and December 2021 with COVID-19 pneumonia receiving supplemental oxygen were eligible to participate in this multicenter real-world data study. Patients were retrospectively assigned to one of three groups: the high corticosteroid dose (HighC) group (receiving 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), the low corticosteroid dose (LowC) group (receiving less than 6 mg parenteral dexamethasone or an equivalent corticosteroid dosage for ten days), or the no corticosteroid (NoC) group. Overall survival and risk effects were compared among groups within the total observation period, as well as at 35 days after the onset of COVID-19 symptoms. Adjusted multivariable Cox proportional hazard regression analysis was performed to compare the risk of death between the treatment groups. Out of 1561 critically ill COVID-19 patients, 1014 were included in the baseline analysis. In the survival study, 1009 patients were assigned to the NoC (n = 346), HighC (n = 552), or LowC group (n = 111). The baseline characteristics were balanced between groups, except for age, BMI, APACHE II score, SOFA and SAPS II. While the 35-day survival did not show any differences, a landmark analysis of the patients surviving beyond 35 days revealed differences between groups. The restricted mean survival time was 112 days in the LowC group [95% CI: 97 - 128], 133 days in the HighC group [95% CI: 124 - 141] and 144 days in the NoC group [95% CI: 121 - 167]. The multivariable-adjusted Cox proportional hazard analysis indicated that, regardless of age, sex, health status or invasive oxygenation, a low-dose treatment increased the hazard of death of critically ill COVID-19 patients by a factor of 2.09 ([95% CI: 0.99, 4.4], p = 0.05) and a high-dose corticosteroid treatment increased the risk by a factor of 1.07 ([95% CI: 0.53, 2.15], p = 0.85) compared to no treatment with glucocorticoids. The analysis reveals that corticosteroid treatment does not influence the survival of critically ill COVID-19 patients in the intensive care unit within 35 days. Our evaluations further suggest that regardless of ventilation status, the decision-making process for administering corticosteroid therapy should account for the individual severity of the illness.

[Data-driven intensive care: a lack of comprehensive datasets]. / "Data-driven-Intensivmedizin": Mangel an umfassenden Datensätzen.

Intensive care units provide a data-rich environment with the potential to generate datasets in the realm of big data, which could be utilized to train powerful machine learning (ML) models. However, the currently available datasets are too small and exhibit too little diversity due to their limitation to individual hospitals. This lack of extensive and varied datasets is a primary reason for the limited generalizability and resulting low clinical utility of current ML models. Often, these models are based on data from single centers and suffer from poor external validity. There is an urgent need for the development of large-scale, multicentric, and multinational datasets. Ensuring data protection and minimizing re-identification risks pose central challenges in this process. The "Amsterdam University Medical Center database (AmsterdamUMCdb)" and the "Salzburg Intensive Care database (SICdb)" demonstrate that open access datasets are possible in Europe while complying with the data protection regulations of the General Data Protection Regulation (GDPR). Another challenge in building intensive care datasets is the absence of semantic definitions in the source data and the heterogeneity of data formats. Establishing binding industry standards for the semantic definition is crucial to ensure seamless semantic interoperability between datasets.

Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood. METHODS: We performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1-2 h after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI. RESULTS: High-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs, and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar. CONCLUSIONS: The study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies.

Cocaine/Levamisole-Induced, Skin-Limited ANCA-Associated Vasculitis with Pyoderma Gangrenosum-like Presentation.

The use of levamisole as the most frequent adulterant of cocaine has merged in previously unknown toxicities, notably a disease entity called cocaine/levamisole-associated autoimmune syndrome (CLAAS). Clinically, CLAAS can manifest with diverse cutaneous and extracutaneous features sharing common laboratory findings (neutropenia, autoantibody patterns). We report the case of a cocaine-abusing female patient with relapsing episodes of painful ulcers, worsening and expanding over a three-year period. The case exhibited all features of a drug-induced, skin-limited, ANCA-associated vasculitis, evolving over time to PG-like findings. In both disease stages, the patient responded well to the cessation of cocaine exposure and systemic glucocorticosteroids. This case demonstrates the continuous nature of cutaneous CLAAS manifestations in a single patient. CLAAS has become a major public health issue in the at-risk group of cocaine users, and clinicians should be alert of this condition when treating cocaine users presenting with single or multiple skin ulcerations.

Critical Illness and Systemic Inflammation Are Key Risk Factors of Severe Acute Kidney Injury in Patients With COVID-19.

INTRODUCTION: Acute kidney injury (AKI) is an important complication in COVID-19, but its precise etiology has not fully been elucidated. Insights into AKI mechanisms may be provided by analyzing the temporal associations of clinical parameters reflecting disease processes and AKI development. METHODS: We performed an observational cohort study of 223 consecutive COVID-19 patients treated at 3 sites of a tertiary care referral center to describe the evolvement of severe AKI (Kidney Disease: Improving Global Outcomes stage 3) and identify conditions promoting its development. Descriptive statistics and explanatory multivariable Cox regression modeling with clinical parameters as time-varying covariates were used to identify risk factors of severe AKI. RESULTS: Severe AKI developed in 70 of 223 patients (31%) with COVID-19, of which 95.7% required kidney replacement therapy. Patients with severe AKI were older, predominantly male, had more comorbidities, and displayed excess mortality. Severe AKI occurred exclusively in intensive care unit patients, and 97.3% of the patients developing severe AKI had respiratory failure. Mechanical ventilation, vasopressor therapy, and inflammatory markers (serum procalcitonin levels and leucocyte count) were independent time-varying risk factors of severe AKI. Increasing inflammatory markers displayed a close temporal association with the development of severe AKI. Sensitivity analysis on risk factors of AKI stage 2 and 3 combined confirmed these findings. CONCLUSION: Severe AKI in COVID-19 was tightly coupled with critical illness and systemic inflammation and was not observed in milder disease courses. These findings suggest that traditional systemic AKI mechanisms rather than kidney-specific processes contribute to severe AKI in COVID-19.

[COVID-19 and acute kidney injury in the intensive care unit]. / COVID-19 und akute Nierenschädigung im Intensivbereich.

Acute kidney injury (AKI) is a frequent and severe complication in coronavirus disease 2019 (COVID-19) patients in the intensive care unit. The development of COVID-19 associated AKI is closely linked to the severity of the disease course. The main risk factor for kidney failure requiring kidney replacement therapy is the necessity for invasive ventilation, whereby the onset of renal failure is often closely associated with the timing of intubation. Additionally, the risk factors for a severe course of COVID-19 have been shown to also be risk factors for renal failure. AKI in COVID-19 shows a high mortality and in some patients leads to chronic kidney disease; however, full recovery of kidney function in survivors who need dialysis is not uncommon. With respect to prevention and treatment of renal failure associated with COVID-19, the same recommendations as for AKI from other causes are valid (Kidney Disease: Improving Global Outcomes, KDIGO bundles). Due to the large numbers of patients in the setting of overwhelmed resources, the availability of extracorporeal renal replacement procedures can become critical, especially since hypercoagulation is frequent in COVID­19. In order to avoid triage situations, in some centers acute peritoneal dialysis was used as an alternative to extracorporeal procedures.

A Yin and Yang in Epithelial Immunology: The Roles of the αE(CD103)ß7 Integrin in T Cells.

The proper function(s) of cell-surface receptors is crucial for the regulation of adaptive immune responses. One such receptor is the αE(CD103)ß7 integrin, whose history in science is closely linked with the evolution of our knowledge of immune regulation. Initially described as a marker of intraepithelial T-lymphocytes, this leukocyte integrin is now seen as a dynamically regulated receptor involved in the functional differentiation of some cytotoxic T cells as well as regulatory T cells, thus presumably contributing to the fine-tuning of immune reactions in epithelial compartments. In this brief overview, we delineate our current view on αE(CD103)ß7 in T-cell-mediated immune responses.

Integrin αE(CD103) Is Involved in Regulatory T-Cell Function in Allergic Contact Hypersensitivity.

Murine contact hypersensitivity (CHS) is a dendritic cell (DC)-dependent T-cell-mediated inflammation with CD8+ T cells as effectors and CD4+ T cells as regulators (Treg cells) that models human allergic contact dermatitis. The integrin αE(CD103) is expressed by some T-cell and DC subsets and has been implicated in epithelial lymphocyte localization, but its role in immune regulation remains enigmatic. We have identified a function for CD103 in the development of cutaneous allergic immune responses. CHS responses, but not irritant contact dermatitis, were significantly augmented in CD103-deficient mice in hapten-challenged skin. Phenotype and function of skin DCs during sensitization were normal, whereas adoptive transfer experiments revealed that the elevated CHS response in CD103-deficient mice is transferred by primed T cells and is independent of resident cells in recipient mice. While T-cell counts were elevated in challenged skin of CD103-deficient mice, the FoxP3 expression level of CD4+CD25+ Treg cells was significantly reduced, indicating impaired functionality. Indeed, Treg cells from CD103-deficient mice were not able to suppress CHS reactions during the elicitation phase. Further, CD103 on FoxP3+ Treg cells was involved in Treg retention to inflamed skin. These findings indicate an unexpected dichotomous functional role for CD103 on Treg cells by modulating FoxP3 expression.