ABSTRACT
The pathobiology of respiratory failure in COVID-19 consists of a complex interplay between direct viral cytopathic effects and a dysregulated host immune response. In a randomised clinical trial, imatinib treatment improved clinical outcomes associated with respiratory failure. Here, we performed longitudinal profiling of 6385 plasma proteins in 318 hospitalised patients to investigate the biological processes involved in critical COVID-19, and assess the effects of imatinib treatment. Nine proteins measured at hospital admission accurately predicted critical illness development. Next to dysregulation of inflammation, critical illness was characterised by pathways involving cellular adhesion, extracellular matrix turnover and tissue remodelling. Imatinib treatment attenuated protein perturbations associated with inflammation and extracellular matrix turnover. External RNA-sequencing data from the lungs of SARS-CoV-2 infected hamsters validated that imatinib exerts these effects in the pulmonary compartment. These findings implicate that the plasma proteome reflects alveolar capillary barrier disruption in critical COVID-19 which was attenuated with imatinib treatment.
Subject(s)
Adenocarcinoma, Bronchiolo-Alveolar , Severe Acute Respiratory Syndrome , Chronobiology Disorders , COVID-19 , Inflammation , Respiratory InsufficiencyABSTRACT
Background: Lung ultrasound (LUS) is a non-invasive method to detect and quantify pulmonary edema. However, it remains uncertain how components of the LUS examination should be aggregated into a score for quantifying pulmonary edema. We examined the diagnostic accuracy of various LUS scores with the extravascular lung water index (EVLWi) assessed with PiCCO in patients with moderate-to-severe COVID-19 ARDS. Methods: In this predefined secondary analysis of a multicenter randomized-controlled trial (InventCOVID), patients were included within 48h after intubation and underwent LUS and EVLWi measurement at two time points (first and fourth study day). EVLWi and ∆EVLWi were used as reference standard. Two 12-region scores (global LUS and LUS-ARDS), an 8-region anterior-lateral score and a 4-region B-line score were used as index tests. Pearson correlation was performed and the area under the receiver operating characteristics curve (AUROCC) for severe pulmonary edema (EVLWi>15mL/kg) was calculated. Results: 26 of 30 patients (87%) had complete LUS and EVLWi measurements at time point 1 and 24 of 29 patients (83%) at time point 2. The global LUS (r=0.54), LUS-ARDS (r=0.58) and anterior-lateral score (r=0.54) were significantly correlated with EVLWi, while the B-line score was not (r=0.32). ∆global LUS (r=0.49) and ∆anterior-lateral LUS (r=0.52) were significantly correlated with ∆EVLWi, while correlation of ∆LUS-ARDS (r=0.43) and ∆B-lines (r=0.32) did not reach statistical significance. AUROCC for EVLWi>15ml/kg was 0.73 for the global LUS, 0.79 for the anterior-lateral and 0.85 for the LUS-ARDS score. Conclusions: The global LUS, LUS-ARDS and antero-lateral score can quantify PiCCO-derived pulmonary edema measurements in COVID-19 ARDS. The LUS-ARDS score showed the highest diagnostic accuracy for severe pulmonary edema. Trial registration: ClinicalTrials.gov identifier NCT04794088, registered on 11 March 2021. European Clinical Trials Database number 2020-005447-23.
Subject(s)
COVID-19 , Pulmonary EdemaABSTRACT
Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fc{gamma} receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation while simultaneously minimizing inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.
Subject(s)
Thrombosis , COVID-19 , InflammationABSTRACT
Condition:
ARDS;Acute Respiratory Distress Syndrome;Covid19;Endothelial Dysfunction;Pulmonary EdemaIntervention:
Drug: Imatinib Mesylate intravenous solution;Drug: PlaceboPrimary outcome:
Change in extravascular lung water indexCriteria:
Inclusion Criteria:
- Age = 18 years;
- Moderate-severe ARDS, as defined by Berlin definition for ARDS (onset within 1 week of
a known clinical insult or new or worsening respiratory symptoms, bilateral opacities
not fully explained by effusions, lobar/lung collapse, or nodules, respiratory failure
not fully explained by cardiac failure or fluid overload and P/F ratio =200 mmHg with
PEEP =5 cmH2O), and intubated for mechanical ventilation.
- PCR positive for SARS-CoV2 within the current disease episode.
- Provision of signed written informed consent from the patient or patient's legally
authorised representative;
Exclusion Criteria:
- Persistent septic shock (>24h) with a Mean Arterial Pressure (MAP) = 65 mm Hg and
serum lactate level > 4 mmol/L (36 mg/dL) despite adequate volume resuscitation and
vasopressor use (norepinephrine > 0.2 µg/kg/min) for > 6 hours;
- Pre-existing chronic pulmonary disease, including:
- Known diagnosis of Interstitial Lung disease
- Known diagnosis of COPD GOLD Stage IV or FEV1<30% predicted
- DLCO <45% (if test results are available)
- Total lung capacity (TLC) < 60% of predicted (if test results are available);
- Chronic home oxygen treatment;
- Pre-existing heart failure with a known left ventricular ejection fraction <40%;
- Active treatment of haematological or non-haematological cancer with targeted immuno-
or chemotherapy, or thoracic radiotherapy in the last year;
- Currently receiving extracorporeal life support (ECLS);
- Severe chronic liver disease with Child-Pugh score > 12;
- Subjects in whom a decision to withdraw medical care is made (e.g. palliative
setting);
- Inability of the ICU staff to initiate IMP administration within 48 hours of
intubation;
- Known to be pregnant or breast-feeding;
- Enrolled in a concomitant clinical trial of an investigational medicinal product;
- White blood count < 2.5x109/l;
- Haemoglobin < 4.0 mmol/l;
- Thrombocytes < 50x109/l;
- The use of strong CYP3A4 inducers, including the following drugs:
- Carbamazepine, efavirenz, enzalutamide, fenobarbital, fenytoine, hypericum,
mitotaan, nevirapine, primidon, rifabutine, rifampicine;
ABSTRACT
For yet unknown reasons, severely ill COVID-19 patients often become critically ill around the time of activation of adaptive immunity. Here, we show that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyper-inflammatory response by human macrophages, which subsequently breaks pulmonary endothelial barrier integrity and induces microvascular thrombosis. The excessive inflammatory capacity of this anti-Spike IgG is related to glycosylation changes in the IgG Fc tail. Moreover, the hyper-inflammatory response induced by anti-Spike IgG can be specifically counteracted in vitro by use of the active component of fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk. One sentence summaryAnti-Spike IgG promotes hyper-inflammation.