Early plasma angiopoietin-2 is prognostic for ARDS and mortality among critically ill patients with sepsis.

Angiopoietin-2 (Ang-2) is associated with vascular endothelial injury and permeability in the acute respiratory distress syndrome (ARDS) and sepsis. Elevated circulating Ang-2 levels may identify critically ill patients with distinct pathobiology amenable to targeted therapy. We hypothesized that plasma Ang-2 measured shortly after hospitalization among patients with sepsis would be associated with the development of ARDS and poor clinical outcomes. To test this hypothesis, we measured plasma Ang-2 in a cohort of 757 patients with sepsis, including 267 with ARDS, enrolled in the emergency department or early in their ICU course before the COVID-19 pandemic. Multivariable models were used to test the association of Ang-2 with the development of ARDS and 30-day morality. We found that early plasma Ang-2 in sepsis was associated with higher baseline severity of illness, the development of ARDS, and mortality risk. The association between Ang-2 and mortality was strongest among patients with ARDS and sepsis as compared to those with sepsis alone (OR 1.81 vs. 1.52 per log Ang-2 increase). These findings might inform models testing patient risk prediction and strengthen the evidence for Ang-2 as an appealing biomarker for patient selection for novel therapeutic agents to target vascular injury in sepsis and ARDS.

A genome wide association study of chronic spontaneous urticaria risk and heterogeneity.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a dermatologic condition that is characterized by spontaneous, pruritic hives and/or angioedema that persist for six weeks or longer with no identifiable trigger. Anti-histamines and second line therapies such as omalizumab are effective for some CSU patients, but others remain symptomatic with significant impact on quality of life. This variable response to treatment and autoantibodies levels across patients highlight clinically heterogeneous subgroups. OBJECTIVE: We aimed to highlight pathways involved in CSU by investigating the genetics of CSU risk and subgroups. METHODS: We performed a genome-wide association study (GWAS) of 679 CSU patients and 4,446 controls and a GWAS of Chronic Urticaria (CU) index, which measures IgG autoantibodies levels, by comparing 447 CU-index low to 183 CU-index high patients. We also tested whether polygenic scores for autoimmune-related disorders associate with CSU risk and CU-index. RESULTS: We identified two loci significantly associated with disease risk. The strongest association maps to position 56 of HLA-DQA1 (P=1.69x10-9), where the arginine residue was associated with increased risk (OR=1.64). The second association signal colocalizes with expression-quantitative trait loci for ITPKB in whole blood (probabilitycolocalization=0.997). The arginine residue at position 56 of HLA-DQA1 was also associated with increased risk of CU-index high (P=6.15x10-5, OR=1.86), while the ITKPB association was not (P=0.64). Polygenic scores for three autoimmune-related disorders (hypothyroidism, type-1 diabetes, and vitiligo) are associated with CSU risk and CU-index (P<2.34x10-3, OR>1.72). CONCLUSION: This GWAS of CSU identifies two genome-wide significant loci and highlights the shared genetics between CU-index and autoimmune disorders.