Circulating proteins to predict COVID-19 severity.

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care.

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity.

Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10-10). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.

The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals.

INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

A randomized controlled trial of renin-angiotensin-aldosterone system inhibitor management in patients admitted in hospital with COVID-19.

BACKGROUND: Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection coronavirus disease 2019 (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes. METHODS: The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-to-treat principle. RESULTS: Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients' mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); P = .60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06-2.62]; P = .027); RAASi discontinuation increased brain natriuretic peptide levels (% change from baseline: +16.7% vs -27.5%; P = .024) and the incidence of acute heart failure (33% vs 4.2%, P = .016). CONCLUSION: RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased brain natriuretic peptide levels and may increase risk of acute heart failure; where possible, RAASi should be continued.

A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity.

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10-8), hospitalization (OR = 0.61, P = 8 × 10-8) and susceptibility (OR = 0.78, P = 8 × 10-6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.

A young man presenting with acute encephalopathy, hemiparesis, and headache.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare type of migraine. Correct diagnosis is challenging for emergency physicians (EPs) due to its variable clinical picture, as well as its lack of diagnostic biological markers. OBJECTIVES: To raise awareness among EPs regarding FHM's diverse clinical picture, and to highlight FHM's diagnostic criteria to facilitate an accurate and timely diagnosis of FHM in patients presenting to the emergency department (ED) with indicative symptomatology. CASE REPORT: A 24-year-old male student presented to the ED complaining of dizziness, general weakness, and blurred vision that had developed the previous night. The initial physical examination revealed drowsiness, slow speech production, and slight weakness with paresthesia in all limbs. Detailed communication with the patient's aunt revealed that he had experienced several similar attacks since the age of 12 years, and that there was also an extensive family history of the same symptoms. In addition, 2 h after arrival, the patient experienced severe throbbing headache, vomiting, severe dysphasia, and the weakness shifted to the right side. A computed tomography scan of the brain showed no anomalies. He was admitted with a tentative diagnosis of FHM. CONCLUSION: A diagnosis of FHM should be considered if the patient's clinical features include headache and weakness, with a family history of similar symptomatology. However, atypical symptoms of FHM may present as recurrent episodes of unexplained encephalopathy. Crucial elements for making an accurate and timely diagnosis of FHM include a detailed knowledge of weakness-related diseases and an ability to consider FHM in the differential diagnosis, as well as obtaining a thorough family history with repeated neurologic assessments.

Intervention to decrease emergency department crowding: does it have an effect on return visits and hospital readmissions?

STUDY OBJECTIVES: We evaluate the effect of a multifaceted intervention to decrease emergency department crowding on the incidence of return visits to the ED or a hospital ward. The intervention included increased emergency physician coverage, the designation of physician coordinators, and new hospital policies regarding laboratory, consultation, and admission procedures. METHODS: The incidence of return visits within 7 days of discharge was estimated in samples from 2 populations (ie, patients discharged from the ED and patients discharged from the hospital) and during a 12-month period before and a 12-month period after the implementation of the intervention. Return visits were categorized into the following groups: (1) scheduled or not and (2) related or not to initial visit. Logistic regression was used in subsamples to assess the effect of the intervention while controlling for potential confounders. By using information from the provincial medical services database, variation between the periods before and after implementation of the intervention in the incidence of return visits to any ED was compared between the study hospital and 2 external control hospitals. RESULTS: No difference was found in the incidence of return visits between the periods before and after implementation of the intervention, either for patients discharged from the ED (all returns: 11.0% versus 12.4%, 95% confidence interval on difference [CID] -1.5% to 4.3%; unscheduled-related returns: 6.5% versus 5.8%, 95% CID -2.8% to 1.6%) or the hospital (all returns: 6.8% versus 6.6%, 95% CID -2.5% to 2.1%; unscheduled-related returns: 4.2% versus 4.0%, 95% CID -2.0% to 1.7%). This lack of effect remained even after controlling for potential confounders. Variation between the periods before and after implementation of the intervention in the incidence of return to any ED was similar in the 3 hospitals examined. CONCLUSION: Our successful hospital intervention to decrease crowding reduced the mean length of stay for patients discharged from the ED from 13.8 to 5.9 hours, without resulting in increased return visits to the ED or hospital readmission.