Superinfections in critically ill COVID-19 patients - an association with Dexamethasone? (preprint)

BacgroundSuper-infections in COVID-19 patients with acute respiratory distress syndrome (ARDS) on mechanical ventilation were initially reported to be rare. Little is known of their incidence after dexamethasone was introduced as standard care. We aimed to determine the incidence and characteristics of superinfections in mechanically ventilated COVID-19 patients during the course of the COVID-19 pandemic, and explore the possible impact of the introduction of dexamethasone as standard therapy. MethodsIn this national, multi-center, observational, retrospective study we included patients ≥ 18 years admitted from March 1 st 2020 to January 31 st 2021 with polymerase chain reaction (PCR)-confirmed SARSCoV-2 infection treated with invasive mechanical ventilation. Data was collected from electronic health records. Patient characteristics, clinical findings, microbiology, length of stay and 90-day survival were examined with backwards stepwise multiple regression. Results155 patients (115 men, mean age 62 years, range 26-84 years) were included. 73 patients (47%) had a total of 101 superinfections where pneumonia dominated (70%). Superinfections were more commonly observed in patients receiving dexamethasone (67% vs 30%, p<0.0001), and in patients with pre-existing autoimmune disease (18% vs 5%, p<0.01). Invasive fungal infections were reported exclusively in dexamethasone-treated patients [9/72 (13%) vs 0/83 (0%), p<0.0001]. There was no difference in 90-day survival between patients with and patients without superinfections (64% versus 73%, p=0.238). In multiple regression analysis, superinfection was associated with dexamethasone use [OR 5.35 (2.62–11.35), p<0.001], pre-existing autoimmune disease [OR 4.90 (1.50–19.4), p=0.008] and higher lymphocyte count at the time of admission [OR 2.31 (1.23–4.86), p=0.009]. ConclusionIn critically ill COVID-19 patients receiving invasive ventilation, introduction of dexamethasone as standard of care was strongly and independently associated with superinfections. A focus on this complication is warranted when studying alternative anti-inflammatory therapy.

New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations (preprint)

Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.

Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19 (preprint)

ObjectiveTo test the hypotheses that blood concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients. MethodsForty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa). Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects. ResultsIn total, 21 % (n = 10) of the patients were admitted to an intensive care unit, whereas the overall mortality rate was 13 % (n = 6). Non-survivors had higher serum concentrations of NfL than patients who were discharged alive both in adjusted analyses (p = 2.6 x 10-7) and unadjusted analyses (p = 0.001). Serum concentrations of GFAp were significantly higher in non-survivors than survivors in adjusted analyses (p = 0.02). The NfL concentrations in non-survivors increased over repeated measurements, whereas the concentrations in survivors were stable. Significantly higher concentrations of NfL were found in patients reporting fatigue, while reduced concentrations were found in patients experiencing cough, myalgia and joint pain. ConclusionIncreased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.

Increased Interleukin-6 and Macrophage Chemoattractant Protein-1 are associated with Respiratory Failure in COVID-19 (preprint)

Background: In SARS-CoV-2 infection there is an urgent need to identify patients that will progress to severe COVID-19 and may benefit from targeted treatment.Objectives: Analyze plasma cytokines in COVID-19 patients and investigate their association with respiratory failure (RF) and treatment in Intensive Care Unit (ICU). Method: Hospitalized patients (n=34) with confirmed COVID-19 were recruited into a prospective cohort study. Clinical data and blood samples were collected at inclusion and after 2-5 and 7-10 days. RF was defined as PaO2/FiO2 ratio (P/F) <40kPa. Plasma cytokines were analyzed by a Human Cytokine 27-plex assay. Measurements and Results: COVID-19 patients with RF and/or treated in ICU showed overall increased systemic cytokine levels. Plasma IL-6, IL-8, G-CSF, MCP-1, MIP-1α levels were negatively correlated with P/F, whereas combinations of IL-6, IP-10, IL-1ra and MCP-1 showed the best association with RF in ROC analysis (AUC 0.79-0.80, p<0.05). During hospitalization the decline was most significant for IP-10 (P<0.001). Conclusion: Elevated levels of pro-inflammatory cytokines were present in patients with severe COVID-19. IL-6 and MCP-1 were inversely correlated with P/F with the largest AUC in ROC analyses and should be further explored as biomarkers to identify patients at risk for severe RF and as targets for improved treatment strategies.