Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19

Villa, Erica; Critelli, Rosina Maria; Lasagni, Simone; Melegari, Alessandra; Curatolo, A; Celsa, Ciro; Romagnoli, Dante; Melegari, Gabriele; Pivetti, Alessandra; Marco, Lorenza Di; Casari, Federico; Arioli, Dimitriy; Turrini, Fabrizio; Zuccaro, Valentina; Cassaniti, Irene; Riefolo, Mattia; Santis, Elena De; Bernabucci, Veronica; Bianchini, Marcello; Lei, Barbara; Maria, Nicola De; Carulli, Lucia; Schepis, Filippo; Gozzi, Chiara; Malaguti, Silvio; Buono, Mariagrazia Del; Brugioni, Lucio; Torricelli, Pietro; Trenti, Tommaso; Pinelli, Giovanni; Bertellini, Elisabetta; Bruno, Raffaele; Cammà, Calogero; D’Errico, Antonietta

doi:10.1182/bloodadvances.2020003736

Cited by 44 publications

(55 citation statements)

References 24 publications

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“… 21 Concentrations of circulating angiopoietin-2 and E-selectin were higher in patients requiring ICU admission, 22 and high concentrations at presentation 23 or increasing concentrations during admission were predictors of mortality. 24 Similar findings were observed in patients with ARDS unrelated to COVID-19, in which increasing concentrations of angiopoietin-2 and von Willebrand factor were associated with pulmonary vascular leak and increased ARDS severity. 25 The results of these biomarker studies together with our clinical observations could indicate that pulmonary capillary leak underlies the transition to a clinical ARDS phenotype, which can be targeted by imatinib.…”

Section: Discussionsupporting

confidence: 67%

“…The median duration of mechanical ventilation was 7 days (IQR 3-13) in the imatinib group and 12 days (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) in the placebo group (p=0•0080; table 3). In post-hoc analyses, we restricted the analysis to survivors only, and observed that the median duration of mechanical ventilation in the imatinib group was 7 days (3-12) compared with 12 days (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) in the placebo group (p=0•023). In patients admitted to the ICU, the number of ventilator-free days was 22 (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)…”

Section: Table 1: Baseline Characteristics and Demographic Variablesmentioning

confidence: 99%

“…In post-hoc analyses, we restricted the analysis to survivors only, and observed that the median duration of mechanical ventilation in the imatinib group was 7 days (3-12) compared with 12 days (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) in the placebo group (p=0•023). In patients admitted to the ICU, the number of ventilator-free days was 22 (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) in the imatinib group versus 9 days (0-23) in the placebo group (p=0•018; table 3).…”

Section: Table 1: Baseline Characteristics and Demographic Variablesmentioning

confidence: 99%

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

Aman

Duijvelaar

Botros

et al. 2021

The Lancet Respiratory Medicine

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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 pa...

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Section: Discussionsupporting

confidence: 67%

Section: Table 1: Baseline Characteristics and Demographic Variablesmentioning

confidence: 99%

Section: Table 1: Baseline Characteristics and Demographic Variablesmentioning

confidence: 99%

See 1 more Smart Citation

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

Aman

Duijvelaar

Botros

et al. 2021

The Lancet Respiratory Medicine

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“…In our patients with COVID-19, serum sFlt-1 was higher compared to controls, and the highest concentrations were associated with most severe disease course (i.e., the need for ICU admission). Although there are not many studies assessing the markers of endotheliopathy in COVID-19, the existing ones show the associations of such markers with disease severity [12,42,43]. However, to our knowledge, sFlt-1 has not been previously studied in COVID-19.…”

Section: Discussionmentioning

confidence: 91%

Diagnostic Significance of Serum Galectin-3 in Hospitalized Patients with COVID-19—A Preliminary Study

et al. 2021

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Severe coronavirus disease 2019 (COVID-19) is associated with hyperinflammation leading to organ injury, including respiratory failure. Galectin-3 was implicated in innate immunological response to infections and in chronic fibrosis. The aim of our preliminary study was the assessment of the diagnostic utility of serum galectin-3 in patients with COVID-19. The prospective observational study included adult patients admitted with active COVID-19 and treated in tertiary hospital between June and July 2020. The diagnosis was confirmed by the quantitative detection of nucleic acid of severe acute respiratory syndrome coronavirus 2 in nasopharyngeal swabs. Galectin-3 was measured by enzyme immunoassay in serum samples obtained during the first five days of hospital stay. We included 70 patients aged 25 to 73 years; 90% had at least one comorbidity. During the hospital stay, 32.9% were diagnosed with COVID-19 pneumonia and 12.9% required treatment in the intensive care unit (ICU). Serum galectin-3 was significantly increased in patients who developed pneumonia, particularly those who required ICU admission. Positive correlations were found between galectin-3 and inflammatory markers (interleukin-6, C-reactive protein, ferritin, pentraxin-3), a marker of endothelial injury (soluble fms-like tyrosine kinase-1), and a range of tissue injury markers. Serum galectin-3 enabled the diagnosis of pneumonia with moderate diagnostic accuracy and the need for ICU treatment with high diagnostic accuracy. Our findings strengthen the hypothesis that galectin-3 may be involved in severe COVID-19. Further studies are planned to confirm the preliminary results and to verify possible associations of galectin-3 with long-term consequences of COVID-19, including pulmonary fibrosis.

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“…Prior data published from our group and others have demonstrated that markers of endothelial activation/dysfunction such as Angpt-2 (23, 50), VEGFR-1 (50), E-selectin (50), P-selectin (51), thrombomodulin (52), VWF (53), and D-dimer (52), are elevated in sepsis, scale with disease severity, and in some cases may be predictive of survival. Previous studies suggest that circulating Angpt-2, thrombomodulin, and VWF levels are associated with adverse outcomes in COVID-19 (15,21,54). We expand this list to include E-selectin and P-selectin as well.…”

Section: Discussionmentioning

confidence: 99%

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

Schmaier¹,

Hurtado²,

Manickas-Hill³

et al. 2021

JCI Insight

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Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2-angiopoietin axis. Primary human endothelial cells treated with plasma from patients with severe COVID-19 upregulated expression of thromboinflammatory genes, inhibited expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from COVID-19 patients demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity and highest levels were associated with worse survival. These data highlight the disruption of Tie2-angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19.Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in

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Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19

Cited by 44 publications

References 24 publications

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

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

Diagnostic Significance of Serum Galectin-3 in Hospitalized Patients with COVID-19—A Preliminary Study

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

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