Neurofilament light increases over time in severe COVID-19 and is associated with delirium.

Neurological monitoring in sedated Intensive Care Unit patients is constrained by the lack of reliable blood-based biomarkers. Neurofilament light is a cross-disease biomarker for neuronal damage with potential clinical applicability for monitoring Intensive Care Unit patients. We studied the trajectory of neurofilament light over a month in Intensive Care Unit patients diagnosed with severe COVID-19 and explored its relation to clinical outcomes and pathophysiological predictors. Data were collected over a month in 31 Intensive Care Unit patients (166 plasma samples) diagnosed with severe COVID-19 at Amsterdam University Medical Centre, and in the first week after emergency department admission in 297 patients with COVID-19 (635 plasma samples) admitted to Massachusetts General hospital. We observed that Neurofilament light increased in a non-linear fashion in the first month of Intensive Care Unit admission and increases faster in the first week of Intensive Care Unit admission when compared with mild-moderate COVID-19 cases. We observed that baseline Neurofilament light did not predict mortality when corrected for age and renal function. Peak neurofilament light levels were associated with a longer duration of delirium after extubation in Intensive Care Unit patients. Disease severity, as measured by the sequential organ failure score, was associated to higher neurofilament light values, and tumour necrosis factor alpha levels at baseline were associated with higher levels of neurofilament light at baseline and a faster increase during admission. These data illustrate the dynamics of Neurofilament light in a critical care setting and show associations to delirium, disease severity and markers for inflammation. Our study contributes to determine the clinical utility and interpretation of neurofilament light levels in Intensive Care Unit patients.

Cardiac Safety of Imatinib for the Treatment of COVID-19: A Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial.

ABSTRACT: Although previous studies support the clinical benefit of imatinib regarding respiratory status in hospitalized patients with COVID-19, potential cardiotoxicity may limit its clinical application. This study aimed to investigate the cardiac safety of imatinib in COVID-19. In the CounterCOVID study, 385 hospitalized hypoxemic patients with COVID-19 were randomly assigned to receive 10 days of oral imatinib or placebo in a 1:1 ratio. Patients with a corrected QT interval (QTc) >500 ms or left ventricular ejection fraction <40% were excluded. Severe cardiac adverse events were monitored for 28 days or until death occurred. Electrocardiogram measurements and cardiac biomarkers were assessed repeatedly during the first 10 days. A total of 36 severe cardiac events occurred, with a similar incidence in both treatment groups. No differences were observed in the computer-generated Bazett, manually interpreted Bazett, or Fridericia-interpreted QTcs. No clinically relevant alterations in other electrocardiogram parameters or plasma high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations were observed. Similar findings were observed in a subgroup of 72 patients admitted to the intensive care unit. In the univariate and multivariable linear mixed models, treatment with imatinib was not significantly associated with QT interval duration, hs-cTnT, or NT-proBNP levels. In conclusion, imatinib treatment did not result in more cardiac events, QT interval prolongation, or altered hs-cTnT or NT-proBNP levels. This suggests that treatment with imatinib is safe in hospitalized patients with COVID-19 with a QTc duration of less than 500 ms and left ventricular ejection fraction >40%.

Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients.

BACKGROUND: Imatinib reduced 90-day mortality in hospitalised coronavirus disease 2019 (COVID-19) patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19 and what baseline biological profile moderates the effect of imatinib. METHODS: We undertook a secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxaemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the aforementioned method. RESULTS: 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin (Ang)-2/Ang-1 ratio, E-selectin, tumour necrosis factor (TNF)-α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers. Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (hazard ratio 0.30, 95% CI 0.10-0.92). CONCLUSIONS: The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes.

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial.

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.