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.

Interstitial Cystitis/Bladder Pain Syndrome's Correlations with Pregnancy and Neonatal Outcomes: A Study of a Population Database.

PURPOSE: Our objective was to evaluate the associations with interstitial cystitis during pregnancy using a United States inpatient database. MATERIALS AND METHODS: We conducted a retrospective cohort study utilizing the Nationwide Inpatient Sample database from the Healthcare Cost and Utilization Project. ICD-9 code number 595.1 was used to extract cases of chronic interstitial cystitis and these pregnancies were compared to pregnancies without chronic interstitial cystitis, using the Chi-squared test to evaluate nominal variables. A multivariate logistic regression model was subsequently used to adjust for statistically significant confounders (p value <0.05). RESULTS: There were 9,095,995 deliveries during the study period; 793 pregnant women were found to have chronic interstitial cystitis. When controlling for confounding effects in terms of pregnancy outcomes, the diagnosed group had a greater risk of developing pregnancy-induced hypertension (adjusted OR 1.57, 95% CI 1.21-2.05), preeclampsia (adjusted OR 2.06, 95% CI 1.47-2.87), preterm delivery (adjusted OR 1.63, 95% CI 1.23-2.17), preterm premature rupture of membranes (adjusted OR 2.18, 95% CI 1.25-3.79), chorioamnionitis (adjusted OR 2.05, 95% CI 1.24-3.37), delivery via cesarean section (adjusted OR 1.57, 95% CI 1.32-1.88), maternal infection (adjusted OR 2.19, 95% CI 1.40-3.43), and deep venous thromboembolism (adjusted OR 10.56, 95% CI 3.37-33.09). CONCLUSIONS: Interstitial cystitis diagnosis is associated with an increased risk of preeclampsia, preterm birth, and other adverse pregnancy outcomes in this database study. Prospective studies are required to confirm the findings of the correlation between interstitial cystitis and adverse pregnancy outcomes.

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.

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.