Acute Kidney Injury in Critical Care COVID-19 Patients on Invasive Mechanical Ventilation: The Potential Preventive Role of Dexamethasone

Background. A high incidence of acute kidney injury (AKI) has been reported in COVID-19 patients in critical care units and those undergoing invasive mechanical ventilation (IMV). The introduction of dexamethasone as treatment for severe COVID-19 has improved mortality, but its effects in other organs remain under study. Methods. In this prospective observational cohort study, we evaluated the incidence of AKI in critically ill COVID-19 patients undergoing mechanical ventilation, and the association of dexamethasone treatment with the incidence, severity, and outcomes of AKI. The association between dexamethasone treatment and AKI was evaluated by multivariate logistic regression. The association of the combination of dexamethasone treatment and AKI on mortality was evaluated by Cox-regression analysis. Results. We included 552 patients. AKI was diagnosed in 311 (56%), of which 196 (63%) corresponded to severe (stage 2 or 3) AKI, and 46 (14.8%) received renal replacement therapy (RRT). Two hundred and sixty-seven (48%) patients were treated with dexamethasone. This treatment was associated to lower incidence of AKI (OR 0.34, 95%CI 0.22-0.52, p<0.001) after adjusting for age, body mass index, laboratory parameters, SOFA score, and vasopressor use. Dexamethasone treatment significantly reduced mortality in patients with severe AKI (HR 0.63, 95%CI 0.41-0.96, p=0.032). Conclusions. The incidence of AKI is high in COVID-19 patients under IMV. Dexamethasone treatment is associated with a lower incidence of AKI and a lower mortality in the group with severe AKI.

Systemic high-dose dexamethasone treatment may modulate the efficacy of intratumoral viral oncolytic immunotherapy in glioblastoma models

BackgroundIntratumoral viral oncolytic immunotherapy is a promising new approach for the treatment of a variety of solid cancers. CAN-2409 is a replication-deficient adenovirus that delivers herpes simplex virus thymidine kinase to cancer cells, resulting in local conversion of ganciclovir or valacyclovir into a toxic metabolite. This leads to highly immunogenic cell death, followed by a local immune response against a variety of cancer neoantigens and, next, a systemic immune response against the injected tumor and uninjected distant metastases. CAN-2409 treatment has shown promising results in clinical studies in glioblastoma (GBM). Patients with GBM are usually given the corticosteroid dexamethasone to manage edema. Previous work has suggested that concurrent dexamethasone therapy may have a negative effect in patients treated with immune checkpoint inhibitors in patients with GBM. However, the effects of dexamethasone on the efficacy of CAN-2409 treatment have not been explored.MethodsIn vitro experiments included cell viability and neurosphere T-cell killing assays. Effects of dexamethasone on CAN-2409 in vivo were examined using a syngeneic murine GBM model; survival was assessed according to Kaplan-Meier; analyses of tumor-infiltrating lymphocytes were performed with mass cytometry (CyTOF - cytometry by time-of-flight). Data were analyzed using a general linear model, with one-way analysis of variance followed by Dunnett’s multiple comparison test, Kruskal-Wallis test, Dunn’s multiple comparison test or statistical significance analysis of microarrays.ResultsIn a mouse model of GBM, we found that high doses of dexamethasone combined with CAN-2409 led to significantly reduced median survival (29.0 days) compared with CAN-2409 treatment alone (39.5 days). CyTOF analyses of tumor-infiltrating immune cells demonstrated potent immune stimulation induced by CAN-2409 treatment. These effects were diminished when high-dose dexamethasone was used. Functional immune cell characterization suggested increased immune cell exhaustion and tumor promoting profiles after dexamethasone treatment.ConclusionOur data suggest that concurrent high-dose dexamethasone treatment may impair the efficacy of oncolytic viral immunotherapy of GBM, supporting the notion that dexamethasone use should be balanced between symptom control and impact on the therapeutic outcome.

Dynamics of laboratory indicators against the background of antibacterial therapy regimens that included fluoroquinolones in the treatment of critically ill COVID-19 patients depending on their age and doses of hormonal drugs

The article provides a review of the literature on the dynamics of blood counts in patients with the new coronavirus di­sease 19 and provides data from our own researches. It was found that patients of all age groups on the background of fluoroquinolone and dexamethasone treatment demonstrated an increase in leukocyte count, and in people over 60 years of age, its increase to the highest levels was observed. Individuals under 60 compared to patients over 60 years who received only antibiotics with the inclusion of fluoroquinolones, without the use of dexamethasone, had a slightly lower level of lymphocytes (р > 0.05) at the beginning of hospitalization, but already from day 4 their growth was observed. At the same time, in people over 60 years old, on the contrary, indicators decreased. In patients under 60 years of age who received antibiotics with the inclusion of fluoroquinolones and 16 mg of dexamethasone during treatment, their gra­dual increase with normalization was observed; this did not happen when 8 mg were used. In patients over 60 years of age who received antibiotics with the inclusion of fluoroquinolones, 8 and 16 mg dexamethasone and who recovered, fluctuations were observed at reduced numbers with a slight tendency towards normalization, as it was observed in younger people. In patients over 60 who received antibiotics without the use of dexamethasone and died, there was a decrease in lymphocyte level during treatment. In people over 60 who recovered, greater fluctuations in the level of lymphocytes to normal values were observed when using 8 mg of dexamethasone, while against the background of 16 mg of dexamethasone, the former showed a decrease in their level with a tendency to increase. At the same time, those who died, on the contrary, had a more significant decrease without a tendency towards normalization. Among patients under 60 and over 60 who have recovered, the former have a more rapid decrease in the le­vel of granulocytes with a tendency to normalize. In people under 60 years of age, when 16 mg of dexamethasone were prescribed, a slightly faster decrease in granulocyte level was observed. Also, a tendency to a more rapid decrease in the level of granulocytes was observed in patients older than 60 years against the background of the use of 16 mg of dexamethasone. In the age group over 60 years old against the background of 16 mg of dexamethasone, those who recovered demonstrated a decrease in granulocytes, and those who died, on the contrary, their increase. In people older than 60 years who recovered, when using 8 mg of dexamethasone and antibiotics with the inclusion of fluoroquinolones in the treatment regimen, the level of band neutrophils was slightly higher than in people younger than 60 years, and a period of its normalization was longer. Against the background of 16 mg of dexamethasone, people over 60 years of age who recovered, had lower indicators of band neutrophils in the first three days and a longer period of their normalization compared to those under 60 years of age. Patients over 60 years old who died, in comparison with those who reco­vered, already from the beginning of hospitalization demonstrated higher levels of band neutrophils and their gradual increase, while those who recovered, on the contrary, had a decrease. In patients under 60 years of age who, in addition to antibiotics, received 8 mg of dexamethasone, in the first three days after hospitalization the level of C-reactive protein (CRP) was lower than in people over 60 years of age who recovered. In both groups of patients, a tendency towards a decrease in the level of CRP was observed. Recovered patients over 60 years of age who received fluoroquinolones and 16 mg of dexamethasone had hig­her CRP content in the first three days than younger patients, and almost the same rates as those who died at the age of 60 years and older. Patients over 60 years old and those who recovered against the background of the use of 16 mg dexamethasone, had a more rapid decrease in the level of CRP; at the same time, in those who died, its slower decrease was observed. Also, the dynamics of ala­nine aminotransferase, aspartate aminotransferase, urea, creatinine, glucose, creatine phosphokinase, lactate dehydrogenase was established depending on the doses of hormones, age and the consequences of the disease course.

Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2

Glucocorticoids are used widely on a long-term basis in autoimmune and inflammatory diseases. Their adverse effects include the development of hyperglycemia and osteoporosis, whose molecular mechanisms have been only partially studied in preclinical models. Both these glucocorticoid-induced pathologies have been shown to be mediated at least in part by oxidative stress. The transcription factor nuclear erythroid factor 2-like 2 (NRF2) is a central regulator of antioxidant and cytoprotective responses. Thus, we hypothesized that NRF2 may play a role in glucocorticoid-induced metabolic disease and osteoporosis. To this end, WT and Nrf2 knockout (Nrf2KO) mice of both genders were treated with 2 mg/kg dexamethasone or vehicle 3 times per week for 13 weeks. Dexamethasone treatment led to less weight gain during the treatment period without affecting food consumption, as well as to lower glucose levels and high insulin levels compared to vehicle-treated mice. Dexamethasone also reduced cortical bone volume and density. All these effects of dexamethasone were similar between male and female mice, as well as between WT and Nrf2KO mice. Hepatic NRF2 signaling and gluconeogenic gene expression were not affected by dexamethasone. A 2-day dexamethasone treatment was also sufficient to increase insulin levels without affecting body weight and glucose levels. Hence, dexamethasone induces hyperinsulinemia, which potentially leads to decreased glucose levels, as well as osteoporosis, both independently of NRF2.

Insights into standards of care: dexamethasone and antibodies against COVID-19 in hamster models

Rationale: In face of the ongoing SARS-CoV-2 pandemic, effective and well-understood treatment options are still scarce. While vaccines have proven instrumental in fighting SARS-CoV-2, their efficacy is challenged by vaccine hesitancy, novel variants and short-lasting immunity. Therefore, understanding and optimization of therapeutic options remains essential. Objectives: We aimed at generating a deeper understanding on how currently used drugs, specifically dexamethasone and anti-SARS-CoV-2 antibodies, affect SARS-CoV-2 infection and host responses. Possible synergistic effects of both substances are investigated to evaluate combinatorial treatments. Methods: By using two COVID-19 hamster models, pulmonary immune responses were analyzed to characterize effects of treatment with either dexamethasone, anti-SARS-CoV-2 spike monoclonal antibody or a combination of both. scRNA sequencing was employed to reveal transcriptional response to treatment on a single cell level. Measurements and main results: Dexamethasone treatment resulted in similar or increased viral loads compared to controls. Anti-SARS-CoV-2 antibody treatment alone or combined with dexamethasone successfully reduced pulmonary viral burden. Dexamethasone exhibited strong anti-inflammatory effects and prevented fulminant disease in a severe COVID-19-like disease model. Combination therapy showed additive benefits with both anti-viral and anti-inflammatory potency. Bulk and single-cell transcriptomic analyses confirmed dampened inflammatory cell recruitment into lungs upon dexamethasone treatment and identified a candidate subpopulation of neutrophils specifically responsive to dexamethasone. Conclusions: Our analyses i) confirm the anti-inflammatory properties and indicate possible modes of action for dexamethasone, ii) validate anti-viral effects of anti-SARS-CoV-2 antibody treatment, and iii) reveal synergistic effects of a combination therapy and can thus inform more effective COVID-19 therapies.

The DEXA-CORT trial: study protocol of a randomised placebo-controlled trial of hydrocortisone in patients with brain tumour on the prevention of neuropsychiatric adverse effects caused by perioperative dexamethasone

IntroductionThe synthetic glucocorticoid dexamethasone can induce serious neuropsychiatric adverse effects. Dexamethasone activates the glucocorticoid receptor (GR) but, unlike endogenous cortisol, not the mineralocorticoid receptor (MR). Moreover, dexamethasone suppresses cortisol production, thereby eliminating its MR binding. Consequently, GR overactivation combined with MR underactivation may contribute to the neuropsychiatric adverse effects of dexamethasone. The DEXA-CORT trial aims to reactivate the MR using cortisol to reduce neuropsychiatric adverse effects of dexamethasone treatment.Methods and analysisThe DEXA-CORT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients who undergo elective brain tumour resection treated perioperatively with high doses of dexamethasone to minimise cerebral oedema. 180 patients are randomised between treatment with either two times per day 10 mg hydrocortisone or placebo during dexamethasone treatment. The primary study outcome is the difference in proportion of patients scoring ≥3 points on at least one of the Brief Psychiatric Rating Scale (BPRS) questions 5 days postoperatively or earlier at discharge. Secondary outcomes are neuropsychiatric symptoms, quality of sleep, health-related quality of life and neurocognitive functioning at several time points postoperatively. Furthermore, neuropsychiatric history, serious adverse events, prescribed (psychiatric) medication and referrals or evaluations of psychiatrist/psychologist and laboratory measurements are assessed.Ethics and disseminationThe study protocol has been approved by the Medical Research Ethics Committee of the Leiden University Medical Center, and by the Dutch competent authority, and by the Institutional Review Boards of the participating sites. It is an investigator-initiated study with financial support by The Netherlands Organisation for Health Research and Development (ZonMw) and the Dutch Brain Foundation. Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numberNL6726 (Netherlands Trial Register); open for patient inclusion. EudraCT number 2017-003705-17.