ABSTRACT
Background and aims: Cerebral venous sinus thrombosis with thrombocytopenia syndrome (CVST-TTS) is a rare adverse effect of adenovirus- based SARS-CoV-2 vaccines. After the autoimmune pathogenesis of TTS was discovered, treatment recommendations were issued. The aim of this study was to evaluate if adherence to treatment recommendations was associated with lower mortality. Methods: TTS was defined according to the Brighton criteria. Cases from a prospective international CVT registry with symptom onset within 28 days of adenovirus-based SARS-CoV-2 vaccination were analysed. Treatment recommendations, following the International Society of Thrombosis and Haemostasis, included use of immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusions, unless needed for surgery. Results: Out of 178 CVT cases from 117 centres in 19 countries reported between March 29 and September 3, 2021, 95 patients fulfilled inclusion criteria. Five of 37 (14%), 13/25 (52%), and 29/33 (88%) of patients diagnosed in March, April, and from May onwards, respectively, were treated according to recommendations. Proportion of patients diagnosed in March, April, and from May onwards who received immunomodulation increased from 19/37 (51%) over 15/25 (60%) to 30/33 (90%), and the percentage of patients who were treated with heparins [26/37 (70%), 4/25 (16%), 1/33 (3%)] and platelet transfusion [15/37 (41%), 4/25 (16%), 7/33 (21%), respectively] decreased accordingly. Mortality of patients treated according to recommendations was 14/47 (30%, 95%CI 19-44%) compared to 28/48 (58%, 95%CI 44-71%) in patients not treated according to recommendations (OR 3.30, 95%CI 1.41-7.71). Conclusions: Over time, adherence to treatment recommendations improved, and mortality rate of patients with CVST-TTS decreased.
ABSTRACT
Balixafortide (POL6326) is a potent, selective inhibitor of the chemokine receptor CXCR4 currently in PhIII for treatment of advanced metastatic HER2-negative breast cancer patients in combination with eribulin (NCT03786094). Clinical proof-of-concept has been demonstrated in a PhI single arm dose-escalation trial (NCT01837095) Recently, CXCR4-positive lung 'bystander' T cells and neutrophils of Covid-19 patients were correlated with disease progression and fatal outcome1, 2. Consequently, CXCR4 inhibition has been suggested to have favourable effects on the prevention and treatment of acute respiratory distress syndrome and associated cytokine storm, lung fibrosis and unbalanced angiogenesis in the SARS-CoV-2 infected lung In vitro, balixafortide displayed a dose-dependent cell-protective effect in a SARS-CoV-2 induced cytopathic effect assay (CPE) in an EC50 range of 10 μM. Head-to-head comparison with remdesivir and time-of-virus addition studies suggest a different mode of action of balixafortide The activity of Balixafortide on SARS-CoV-2 infection was investigated in vivo in the free choice diet-induced obese hamster, a model that also develops nonalcoholic steatohepatitis and heart failure with preserved ejection fraction3. Balixafortide was subcutaneously administered 20mg/kg twice daily for 10 days after SARS-CoV-2 infection Upon balixafortide treatment, significantly less infectious SARS-CoV-2 particles were found on day 4 post infection, and a lower total viral load at day 10. Balixafortide statistically reduced CXCL10 gene expression (- 40% compared to vehicle) at day 4. Elevated CXCL10 in conjunction with IL-6 is a key feature in COVID-19 disease generating a vicious circle resulting in a cytokine storm. In addition, balixafortide treatment led to a marked reduction (-40% compared to vehicle) of ISG15 gene expression in the lung on day 10. Elevated free ISG15 is associated with immune pathology in viral infection. There was no loss in body weight compared to vehicle control and no balixafortide-related mortality suggesting that balixafortide is well-tolerated The data suggest a favourable dual activity of balixafortide based on the reduction of both, viral load and inflammatory driving factors of COVID- 19 disease.