Biomarkers of coagulation, endothelial function and fibrinolysis in criticallyill patients with COVID-19: A single centre prospective longitudinal study

Background: Immunothrombosis and coagulopathy in the lung microvasculature may lead to lung injury and disease progression in COVID-19. We aim to identify biomarkers of coagulation, endothelial function, and fibrinolysis that are associated with disease severity and may have prognostic potential. Aims: To identify biomarkers of coagulation, inflammation, and fibrinolysis that may predict clinical course and outcome of COVID-19 patients. Methods: We performed a single-center prospective study of 14 adult COVID-19(+) ICU patients who were age and sex-matched to 14 COVID-19(-) ICU patients, and healthy controls. Daily blood draws, clinical data, and patient characteristics were collected. Ten biomarkers of interest were subjected to linear discriminant analysis (LDA) to explore the discriminatory ability of biomarkers for COVID-19 status. Linear repeated measures mixed models were used to screen biomarkers for associations with mortality. Selected biomarkers were further explored and entered into an unsupervised longitudinal clustering machine learning algorithm to identify trends and targets that may be used for future predictive modelling efforts. Results: LDA identified high D-dimer as the strongest contributor in distinguishing COVID-19 status however D-dimer was not associated with survival. Variable selection identified clot lysis time, and antigen levels of soluble thrombomodulin (sTM), plasminogen activator inhibitor-1 (PAI-1), and plasminogen as biomarkers associated with death. Longitudinal multivariate k-means clustering on these biomarkers alone identified two clusters of COVID-19(+) patients -low (30%) and high (100%) mortality groups (Figure 1). Biomarker trajectories that characterized the high mortality cluster were higher clot lysis times (inhibited fibrinolysis), higher sTM and PAI-1 levels, and lower plasminogen levels. Conclusions: Longitudinal trajectories of clot lysis time, sTM, PAI-1, and plasminogen may have predictive ability for mortality in COVID-19.

Quality of life among patients with primary biliary cholangitis during Canada's state of emergency response to COVID-19

Background: Canadian provinces initiated states of emergency (SoE) between March 13 and March 23 2020 due to community transmission of COVID-19 We explore changes in self-reported quality of life (QoL) in patients with PBC early-on during SoE Methods: Patients with PBC from the Canadian Network for Autoimmune Liver disease who completed QoL questionnaires between July 2019 and June 2020 are included Questionnaires include the Short-Form 36 (SF-36), PBC-40, and Itch Numeric Rating Scale (iNRS) Measurements during SoE are after March 17 2020, date of SoE initiation in Ontario Measurements before Feb 1 2020 are pre-SoE Measurements between Feb 1 and March 16 2020 are excluded given growing societal concern during this time, but no formal SoE Analyses include mixed effects regressions of QoL scores with SoE as a binary variable Models are adjusted for duration of disease and age at diagnosis and employ random intercepts at clinic and patient level Results: 312 patients were included from Toronto (64%, n=198), Montreal (14%, n=43), Edmonton (7 7%, n=24), Ottawa (5 8%, n=18), Saskatoon (5 4%, n=17), and Kingston (3 8%, n=12) The majority of patients were female (93%, n=291), Caucasian (82%, n=256), and born in Canada (78%, n=242) Mean age was 58 6 years (SD 10 8), mean age at diagnosis was 49 3 years (SD 11 0), mean duration of disease was 9 0 years (SD 7 2), and 6 4% (n=20) had overlap with autoimmune hepatitis Patients had a mean of 1 3 (SD 0 5) repeated measures (maximum 3) 219 patients had measures pre-SoE and 128 had measurements during SoE Estimated mean SF-36 physical component scores were similar before and during the first 3 months of SoE (41.9 vs 40.7, p=0.16), as were SF-36 mental component scores (43 3 vs 43 5, p=0 91) When compared to average Canadian population SF-36 scores, patients with PBC had significantly worse scores before and during SoE (p<0 001 all comparisons) PBC-40 domain scores remained stable, with estimated mean values before and during SoE as follows: Symptoms 13 8 vs 14 2 (p=0 32), Fatigue 24 9 vs 25 0 (p=0 81), Cognitive 10 8 vs 11 1 (p=0 47), Socio-Emotional 25 4 vs 26 2 (p=0 20), Itch 4 7 vs 4.9 (p=0.44). There was a small but statistically significant increase in estimated mean iNRS score, from 2 4 pre-SoE to 3.3 during the first 3 months of SoE (p<0.001). Conclusion: Quality of life scores remained largely stable during the first three months of Canada's SoE SF-36 scores in patients with PBC were significantly worse than Canada's general population Analyses should be updated as Canada's SoE continues.

Differences in self-reported quality of life among patients with autoimmune hepatitis and primary biliary cholangitis during Canada's state of emergency response to COVID-19

Background: Between March 13th and March 22nd, 2020, a state of emergency (SoE) was declared across Canada due to transmission of COVID-19 We compare self-reported quality of life (QoL) changes between Autoimmune Hepatitis (AIH) and Primary Biliary Cholangitis (PBC) patients during the first 3 months of SoE. Methods: Patients with an AIH or PBC diagnosis from the Canadian Network for Autoimmune Liver disease with completed QoL surveys between July 2019 and June 2020 were included in the analysis Surveys completed after March 17th, 2020 were categorized as during SoE, and data prior to February 1st, 2020 were categorized as before SoE. Domain-specific QoL measurements included the Short-Form 36 (SF-36) and Itch Numeric Rating Scale (NRS) Multiple linear mixed effect regressions and estimated marginal means compared PBC and AIH scores before and during the SoE, adjusting for age at diagnosis, duration of disease, and site Results: Of the total 456 participants included in the analysis, 63 3% had PBC Participants included were from six liver clinics across Canada: Toronto (AIH= 131, PBC =186), Montreal (PBC = 39), Edmonton (AIH= 2, PBC = 24), Saskatchewan (AIH = 13, PBC =17), Ottawa (AIH = 8, PBC = 14), and Kingston (AIH = 12, PBC = 9) Females accounted for 86 2% (n=393) of the cohort, and 78 9% (n=360) of participants were Caucasian Medians for age at diagnosis and age at SoE were 49 2 years [IQR 37 8- 57 8] and 58 3 years [48 7-66 4], respectively AIH patients were on average 7 years younger than PBC patients There were 316 assessment completed before the SoE (65% PBC) and 185 during (62% PBC). There were no significant differences in estimated mean SF-36 Physical component between diseases across time (Pre: AIH= 40 9 vs PBC= 41 8, p =0.9 vs During: 43.1 vs 40.7, p=0.49). Similar findings were observed in the SF-36 Mental component pre-SoE (p=0 78) and post-SoE (p=0 9) Overall, QoL scores in AIH remained stable across time Both patients with AIH and PBC reported lower SF-36 scores compared to the general Canadian population (p<0 001) Longer disease duration and older age at diagnosis were associated with better SF-36 scores, regardless of SoE (p<0 001) Estimated mean NRS scores for PBC were significantly worse than AIH, both before SoE (AIH= 1 7 vs PBC=2 63, p<0 05) and during SoE (AIH = 2 26 vs PBC= 3 62, p<0 01) Conclusion: Physical and mental QoL components remain stable for both patients with AIH and PBC, and we observed expected differences in itch between diagnoses.