Efficacy and safety of intravenous imatinib in COVID-19 ARDS: a randomized, double-blind, placebo-controlled clinical trial.

PURPOSE: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. RESULTS: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). CONCLUSIONS: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

Atrial inflammation and microvascular thrombogenicity are increased in deceased COVID-19 patients.

BACKGROUND: Histopathological studies have shown inflammation, cardiomyocyte injury, and microvascular thrombosis in the ventricular myocardium of patients with coronavirus disease 2019 (COVID-19). However, although atrial dysfunction is common in COVID-19, little is known about histopathological changes in the atria of the heart. We therefore analyzed inflammation, cardiomyocyte injury, and microvascular thrombogenicity in the atria of deceased patients with COVID-19. METHODS: Atrial tissue was obtained from autopsied COVID-19 (n=16) patients and control patients (n=10) and analyzed using immunohistochemistry. The infiltration of CD45+ leukocytes, CD3+ T lymphocytes, CD68+ macrophages, MPO+ neutrophils, and Tryptase+ mast cells were quantified as well as cardiomyocyte damage and microvascular thrombosis. In addition, Tissue Factor (TF) and Factor XII (FXII) were quantified as markers of microvascular thrombogenicity. RESULTS: The numbers of lymphocytes, macrophages, and neutrophils were significantly increased in the atrial myocardium and epicardial atrial adipose tissue of COVID-19 patients compared with the control group. This was accompanied by dispersed cardiomyocyte injury, the occasional presence of microvascular thrombosis, and an increased presence of TF and FXII in the microvascular endothelium. CONCLUSIONS: Severe COVID-19 induces inflammation, cardiomyocyte injury, and microvascular thrombosis in the atria of the heart.

Oxygen Consumption with High-Flow Nasal Oxygen versus Mechanical Ventilation- An International Multicenter Observational Study in COVID-19 Patients (PROXY-COVID).

The COVID-19 pandemic led to local oxygen shortages worldwide. To gain a better understanding of oxygen consumption with different respiratory supportive therapies, we conducted an international multicenter observational study to determine the precise amount of oxygen consumption with high-flow nasal oxygen (HFNO) and with mechanical ventilation. A retrospective observational study was conducted in three intensive care units (ICUs) in the Netherlands and Spain. Patients were classified as HFNO patients or ventilated patients, according to the mode of oxygen supplementation with which a patient started. The primary endpoint was actual oxygen consumption; secondary endpoints were hourly and total oxygen consumption during the first two full calendar days. Of 275 patients, 147 started with HFNO and 128 with mechanical ventilation. Actual oxygen use was 4.9-fold higher in patients who started with HFNO than in patients who started with ventilation (median 14.2 [8.4-18.4] versus 2.9 [1.8-4.1] L/minute; mean difference = 11.3 [95% CI 11.0-11.6] L/minute; P < 0.01). Hourly and total oxygen consumption were 4.8-fold (P < 0.01) and 4.8-fold (P < 0.01) higher. Actual oxygen consumption, hourly oxygen consumption, and total oxygen consumption are substantially higher in patients that start with HFNO compared with patients that start with mechanical ventilation. This information may help hospitals and ICUs predicting oxygen needs during high-demand periods and could guide decisions regarding the source of distribution of medical oxygen.

Concise Versus Extended Lung Ultrasound Score to Monitor Critically Ill Patients With COVID-19.

BACKGROUND: Lung ultrasound (LUS) can be used to monitor critically ill patients with COVID-19, but the optimal number of examined lung zones is disputed. METHODS: This was a prospective observational study. The objective was to investigate whether concise (6 zones) and extended (12 zones) LUS scoring protocols are clinically equivalent in critically ill ICU subjects with COVID-19. The primary outcome of this study was (statistical) agreement between concise and extended LUS score index evaluated in both supine and prone position. Agreement was determined using correlation coefficients and Bland-Altman plots to detect systematic differences between protocols. Secondary outcomes were difference between LUS score index in supine and prone position using similar methods. RESULTS: We included 130 LUS examinations in 40 subjects (mean age 69.0 ± 8.5y, 75% male). Agreement between concise and extended LUS score index had no clinically relevant constant or proportional bias and limits of agreement were below the smallest detectable change. Across position changes, supine LUS score index was 8% higher than prone LUS score index and had limits above the smallest detectable change, indicating true LUS score index differences between protocols may occur due to the position change itself. Lastly, inter-rater and intra-rater agreement were very good. CONCLUSIONS: Concise LUS was equally informative as extended LUS for monitoring critically ill subjects with COVID-19 in supine or prone position. Clinicians can monitor patients undergoing position changes but must be wary that LUS score index alterations may result from the position change itself rather than disease progression or clinical improvement.

Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. METHODS: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO2/FiO2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420. FINDINGS: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. INTERPRETATION: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government.

Evolution of Respiratory Muscles Thickness in Mechanically Ventilated Patients With COVID-19.

BACKGROUND: Given the long ventilation times of patients with COVID-19 that can cause atrophy and contractile weakness of respiratory muscle fibers, assessment of changes at the bedside would be interesting. As such, the aim of this study was to determine the evolution of respiratory muscle thickness assessed by ultrasound. METHODS: Adult (> 18 y old) patients admitted to the ICU who tested positive for SARS-CoV-2 and were ventilated for < 24 h were consecutively included. The first ultrasound examination (diaphragm, rectus abdominis, and lateral abdominal wall muscles) was performed within 24 h of intubation and regarded as baseline measurement. After that, each following day an additional examination was performed, for a maximum of 8 examinations per subject. RESULTS: In total, 30 subjects were included, of which 11 showed ≥ 10% decrease in diaphragm thickness from baseline; 10 showed < 10% change, and 9 showed ≥ 10% increase from baseline. Symptom duration before intubation was highest in the decrease group (12 [11-14] d, P = .03). Total time ventilated within the first week was lowest in the increase group (156 [129-172] h, P = .03). Average initial diaphragm thickness was 1.4 (1.1-1.6) mm and did not differ from final average thickness (1.3 [1.1-1.5] mm, P = .54). The rectus abdominis did not show statistically significant changes, whereas lateral abdominal wall thickness decreased from 14 [10-16] mm at baseline to 11 [9-13] mm on the last day of mechanical ventilation (P = .08). Mixed-effect linear regression demonstrated an association of atrophy and neuromuscular-blocking agent (NMBA) use (P = .01). CONCLUSIONS: In ventilated subjects with COVID-19, overall no change in diaphragm thickness was observed. Subjects with decreased or unchanged thickness had a longer ventilation time than those with increased thickness. NMBA use was associated with decreased thickness. Rectus muscle thickness did not change over time, whereas lateral abdominal muscle thickness decreased but this change was not statistically significant.

Extended Lung Ultrasound to Differentiate Between Pneumonia and Atelectasis in Critically Ill Patients: A Diagnostic Accuracy Study.

OBJECTIVES: To determine the diagnostic accuracy of extended lung ultrasonographic assessment, including evaluation of dynamic air bronchograms and color Doppler imaging to differentiate pneumonia and atelectasis in patients with consolidation on chest radiograph. Compare this approach to the Simplified Clinical Pulmonary Infection Score, Lung Ultrasound Clinical Pulmonary Infection Score, and the Bedside Lung Ultrasound in Emergency protocol. DESIGN: Prospective diagnostic accuracy study. SETTING: Adult ICU applying selective digestive decontamination. PATIENTS: Adult patients that underwent a chest radiograph for any indication at any time during admission. Patients with acute respiratory distress syndrome, coronavirus disease 2019, severe thoracic trauma, and infectious isolation measures were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Lung ultrasound was performed within 24 hours of chest radiograph. Consolidated tissue was assessed for presence of dynamic air bronchograms and with color Doppler imaging for presence of flow. Clinical data were recorded after ultrasonographic assessment. The primary outcome was diagnostic accuracy of dynamic air bronchogram and color Doppler imaging alone and within a decision tree to differentiate pneumonia from atelectasis. Of 120 patients included, 51 (42.5%) were diagnosed with pneumonia. The dynamic air bronchogram had a 45% (95% CI, 31-60%) sensitivity and 99% (95% CI, 92-100%) specificity. Color Doppler imaging had a 90% (95% CI, 79-97%) sensitivity and 68% (95% CI, 56-79%) specificity. The combined decision tree had an 86% (95% CI, 74-94%) sensitivity and an 86% (95% CI, 75-93%) specificity. The Bedside Lung Ultrasound in Emergency protocol had a 100% (95% CI, 93-100%) sensitivity and 0% (95% CI, 0-5%) specificity, while the Simplified Clinical Pulmonary Infection Score and Lung Ultrasound Clinical Pulmonary Infection Score had a 41% (95% CI, 28-56%) sensitivity, 84% (95% CI, 73-92%) specificity and 68% (95% CI, 54-81%) sensitivity, 81% (95% CI, 70-90%) specificity, respectively. CONCLUSIONS: In critically ill patients with pulmonary consolidation on chest radiograph, an extended lung ultrasound protocol is an accurate and directly bedside available tool to differentiate pneumonia from atelectasis. It outperforms standard lung ultrasound and clinical scores.

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.