Composition of the immunoglobulin G glycome associates with the severity of COVID-19 (preprint)

A large variation in the severity of disease symptoms is one of the key open questions in COVID-19 pandemics. The fact that only a small subset of people infected with SARS-CoV-2 develop severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the IgG glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of inter-individual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine (GlcNAc) in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing. To our knowledge, this is the first study exploring IgG N-glycome variability in COVID-19 severity.

Central Nervous System thrombotic microangiopathy in COVID-19 patients: an intriguing hypothesis? (preprint)

Objectives: Neurological manifestations of COVID-19 disease are being increasingly recognized. A growing number of studies has been showing CNS abnormalities on brain imaging.Purpose is to describe brain imaging findings of a population of COVID-19 patients with neurological manifestations and peculiar abnormalities on susceptibility weighted imaging (SWI) sequences.Methods: we retrospectively evaluated imaging data from 50 patients affected by SARS-CoV-2 infection, who underwent a brain MRI because of neurological symptoms between March and June 2020.We focused on those presenting with abnormalities on brain MRI on SWI (positive MRI, P-MRI). We also carried out comparative investigations using patients without SWI abnormalities (negative MRI, N-MRI) as a control group. Non-parametric tests were used. A p-value < 0.05 was considered significant.Results: From 50 patients presenting with neurological symptoms, 10 patients showed brain abnormalities on SWI (P-MRI). Mean age in P-MRI group was 63±12 years; 7 were men. Six patients were admitted to Intensive Care Units (ICUs) and needed invasive ventilation support. P-MRI subjects showed lymphopenia and significantly higher levels of inflammatory markers such as CRP, IL-6, and fibrinogen. No significant differences were found in the coagulation profile. MRI showed diffuse SWI hypointense lesions mostly in occipital and temporal lobes, predominantly located at the grey-white matter junction. Genu and splenium of corpus callosum were involved in 8 of 10 patients. No restricted diffusion or enhancement was associated to SWI lesions.Conclusions: SWI abnormalities in patients with COVID-19 with neurological symptoms may reflect microvascular endothelial damage in the setting of a pro-inflammatory state.

Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support (preprint)

Background Severe COVID-19 is characterised by interstitial pneumonia and hyperinflammation, with elevated levels of pro-inflammatory cytokines, such as IL-6. Effective treatments are urgently needed, and IL-6 is a rational target to reduce hyperinflammation. Methods An observational, control cohort, single-centre study initiated at the Papa Giovanni XXIII Hospital in Bergamo, Italy included patients with COVID-19 confirmed by a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 RNA and interstitial pneumonia requiring ventilatory support. Patients were treated with either best supportive care and siltuximab or best supportive care alone. Propensity score matching was applied to minimise differences in baseline covariates between patient cohorts. The main outcome was mortality in siltuximab-treated patients compared with patients in the matched-control cohort. This study (Siltuximab in Severe COVID-19, SISCO) is registered with ClinicalTrials.gov, identifier NCT04322188. Findings Thirty patients received siltuximab, while 188 control patients received only best supportive care. Siltuximab-treated patients were matched to 30 control patients using the propensity score analysis of baseline covariates. The 30-day mortality rate was significantly lower in the siltuximab-treated than the matched-control cohort patients (HR 0.462, 95% CI 0.221-0.965); p=0.0399). The mean follow-up was 33.3 days (range 7-58 days) for the siltuximab-treated patients and 22.8 days (range 2-45 days) for the control cohort. Sixteen siltuximab-treated patients were discharged from hospital, four remained on mechanical ventilation, and 10 patients died. Interpretation Patients with rapidly progressing COVID-19 respiratory failure requiring ventilatory support may benefit from treatment with siltuximab to reduce mortality and cytokine-driven hyperinflammation associated with severe disease. These findings require validation in a randomised controlled clinical trial. Funding Papa Giovanni XXIII Hospital and the Italian Association for Cancer Research funded the study. EUSA Pharma supplied siltuximab, and provided funding for data collection, analysis, and development of the publication.