Towards Fixed Dosing of Tocilizumab in ICU-Admitted COVID-19 Patients: Results of an Observational Population Pharmacokinetic and Descriptive Pharmacodynamic Study.

BACKGROUND AND OBJECTIVE: In the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including survival in intensive care unit (ICU)-admitted coronavirus disease 2019 (COVID)-19 patients. Therefore tocilizumab has been added to many COVID-19 treatment guidelines. Because obesity is a risk factor for the development of severe COVID-19, concerns have been raised about overtreatment, as well as undertreatment, through weight-based dosing of tocilizumab. The currently applied dose of 8 mg/kg is based on the use of this drug for other indications, however it has not formally been investigated for COVID-19. In this study, the pharmacokinetics and pharmacodynamics of tocilizumab were investigated in ICU-admitted COVID-19 patients. METHODS: This was an open-label, single-centre, observational population pharmacokinetic and descriptive pharmacodynamic evaluation study. Enrolled patients, with polymerase chain reaction-confirmed COVID-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received intravenous tocilizumab 8 mg/kg (maximum 800 mg) within 24 h after admission to the ICU and received dexamethasone 6 mg daily as concomitant therapy. For evaluation of the pharmacokinetics and pharmacodynamics of tocilizumab, all time points from day 0 to 20 days after dose administration were eligible for collection. A nonlinear mixed-effects model was developed to characterize the population pharmacokinetic parameters of tocilizumab in ICU-admitted COVID-19 patients. Covariate analysis was performed to identify potential covariates for dose individualization. For the development of alternative dosing schedules, Monte Carlo simulations using the final model were performed. RESULTS: Overall, 29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and nonlinear clearance (CL) was developed and validated. Average CL was estimated to be 0.725 L/day, average volume of distribution (Vd) was 4.34 L, maximum elimination rate (Vmax) was 4.19 µg/day, and concentration at which the elimination pathway is half saturated (Km) was 0.22 µg/mL. Interindividual variability was identified for CL (18.9%) and Vd (21%). Average area under the concentration versus time curve from time zero to infinity of the first dose (AUCinf 1st DOSE) was 938 [±190] µg/mL*days. All patients had tocilizumab exposure above 1 µg/mL for at least 15 days. Bodyweight-based dosing increases variability in exposure compared with fixed dosing. CONCLUSIONS: This study provides evidence to support a fixed dose of tocilizumab 600 mg in COVID-19 patients. Fixed dosing is a safe, logistically attractive, and drug expenses saving alternative compared with the current 8 mg/kg recommendation.

Aging and Microglial Response following Systemic Stimulation with Escherichia coli in Mice.

Systemic infection is an important risk factor for the development cognitive impairment and neurodegeneration in older people. Animal experiments show that systemic challenges with live bacteria cause a neuro-inflammatory response, but the effect of age on this response in these models is unknown. Young (2 months) and middle-aged mice (13-14 months) were intraperitoneally challenged with live Escherichia coli (E. coli) or saline. The mice were sacrificed at 2, 3 and 7 days after inoculation; for all time points, the mice were treated with ceftriaxone (an antimicrobial drug) at 12 and 24 h after inoculation. Microglial response was monitored by immunohistochemical staining with an ionized calcium-binding adaptor molecule 1 (Iba-1) antibody and flow cytometry, and inflammatory response by mRNA expression of pro- and anti-inflammatory mediators. We observed an increased microglial cell number and moderate morphologically activated microglial cells in middle-aged mice, as compared to young mice, after intraperitoneal challenge with live E. coli. Flow cytometry of microglial cells showed higher CD45 and CD11b expressions in middle-aged infected mice compared to young infected mice. The brain expression levels of pro-inflammatory genes were higher in middle-aged than in young infected mice, while middle-aged infected mice had similar expression levels of these genes in the systemic compartment. We conclude that systemic challenge with live bacteria causes an age-dependent neuro-inflammatory and microglial response. Our data show signs of an age-dependent disconnection of the inflammatory transcriptional signature between the brain and the systemic compartment.

Lung ultrasound and computed tomography to monitor COVID-19 pneumonia in critically ill patients: a two-center prospective cohort study.

BACKGROUND: Lung ultrasound can adequately monitor disease severity in pneumonia and acute respiratory distress syndrome. We hypothesize lung ultrasound can adequately monitor COVID-19 pneumonia in critically ill patients. METHODS: Adult patients with COVID-19 pneumonia admitted to the intensive care unit of two academic hospitals who underwent a 12-zone lung ultrasound and a chest CT examination were included. Baseline characteristics, and outcomes including composite endpoint death or ICU stay > 30 days were recorded. Lung ultrasound and CT images were quantified as a lung ultrasound score involvement index (LUSI) and CT severity involvement index (CTSI). Primary outcome was the correlation, agreement, and concordance between LUSI and CTSI. Secondary outcome was the association of LUSI and CTSI with the composite endpoints. RESULTS: We included 55 ultrasound examinations in 34 patients, which were 88% were male, with a mean age of 63 years and mean P/F ratio of 151. The correlation between LUSI and CTSI was strong (r = 0.795), with an overall 15% bias, and limits of agreement ranging - 40 to 9.7. Concordance between changes in sequentially measured LUSI and CTSI was 81%. In the univariate model, high involvement on LUSI and CTSI were associated with a composite endpoint. In the multivariate model, LUSI was the only remaining independent predictor. CONCLUSIONS: Lung ultrasound can be used as an alternative for chest CT in monitoring COVID-19 pneumonia in critically ill patients as it can quantify pulmonary involvement, register changes over the course of the disease, and predict death or ICU stay > 30 days. TRIAL REGISTRATION: NTR, NL8584. Registered 01 May 2020-retrospectively registered, https://www.trialregister.nl/trial/8584.

Lung ultrasound findings in patients with novel SARS-CoV-2.

BACKGROUND: Over 2 million people worldwide have been infected with severe acute respiratory distress syndrome-coronavirus-2 (SARS CoV-2). Lung ultrasound has been proposed to diagnose and monitor it, despite the fact that little is known about the ultrasound appearance due to the novelty of the illness. The aim of this manuscript is to characterise the lung ultrasonographic appearance of critically ill patients with SARS-CoV-2 pneumonia, with particular emphasis on its relationship with the time course of the illness and clinical parameters. METHODS: Adult patients from the intensive care unit of two academic hospitals who tested positive for SARS-CoV-2 were included. Images were analysed using internationally recognised techniques which included assessment of the pleura, number of B-lines, pathology in the PLAPS (posterolateral alveolar and/or pleural syndrome) point, bedside lung ultrasound in emergency profiles, and the lung ultrasound score. The primary outcomes were frequencies, percentages and differences in lung ultrasound findings overall and between short (≤14 days) and long (>14 days) durations of symptoms and their correlation with clinical parameters. RESULTS: In this pilot observational study, 61 patients were included with 76 examinations available for analysis. 26% of patients had no anterior lung abnormalities, while the most prevalent pathological ultrasound findings were thickening of the pleura (42%), ≥3 B-lines per view (38%) and presence of PLAPS (74%). Patients with "long" duration of symptoms presented more frequently with a thickened and irregular pleura (32 (21%) versus 11 (9%)), C-profile (18 (47%) versus 8 (25%)) and pleural effusion (14 (19%) versus 3 (5%)), compared to patients with short duration of symptoms. Lung ultrasound findings did not correlate with arterial oxygen tension/inspiratory oxygen fraction ratio, fluid balance or dynamic compliance. CONCLUSION: SARS-CoV-2 results in significant, but not specific, ultrasound changes, with decreased lung sliding, thickening of the pleura and a B-profile being the most commonly observed. With time, a thickened and irregular pleura, C-profile and pleural effusion become more common findings. When screening patients, a comprehensive ultrasound protocol might be necessary.