Mechanisms underlying severe COVID-19 disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNAseq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell type-specific intracellular death signatures, cellular ACE2 expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Postoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. The authors hypothesized that delirium would be a significant risk factor for postoperative cognitive dysfunction during follow-up. Methods This study used data from an observational study of cognitive outcomes after major noncardiac surgery, the Successful Aging after Elective Surgery study. Postoperative delirium was evaluated each hospital day with confusion assessment method–based interviews supplemented by chart reviews. Postoperative cognitive dysfunction was determined using methods adapted from the International Study of Postoperative Cognitive Dysfunction. Associations between delirium and postoperative cognitive dysfunction were examined at 1, 2, and 6 months. Results One hundred thirty-four of 560 participants (24%) developed delirium during hospitalization. Slightly fewer than half (47%, 256 of 548) met the International Study of Postoperative Cognitive Dysfunction-defined threshold for postoperative cognitive dysfunction at 1 month, but this proportion decreased at 2 months (23%, 123 of 536) and 6 months (16%, 85 of 528). At each follow-up, the level of agreement between delirium and postoperative cognitive dysfunction was poor (kappa less than .08) and correlations were small (r less than .16). The relative risk of postoperative cognitive dysfunction was significantly elevated for patients with a history of postoperative delirium at 1 month (relative risk = 1.34; 95% CI, 1.07–1.67), but not 2 months (relative risk = 1.08; 95% CI, 0.72–1.64), or 6 months (relative risk = 1.21; 95% CI, 0.71–2.09). Conclusions Delirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.

In this large, well-characterized cohort assessed at multiple timepoints, we observed an inflammatory signature of delirium involving elevated interleukin-6 at POD2, which may be an important disease marker for delirium. We also observed preliminary evidence for involvement of other cytokines.

Background/Objectives Preoperative frailty has been associated with poor postoperative outcomes after orthopedic surgery; however frailty measures have not been compared in this population. We applied the Frailty Phenotype (FP) and Frailty Index (FI) before major elective orthopedic surgery to categorize frailty status and assessed association with postoperative outcomes. Design Prospective cohort study. Setting Two tertiary hospitals in Boston, MA. Participants 415 patients aged ≥70 years undergoing scheduled orthopedic surgery enrolled in SAGES: Successful Aging after Elective Surgery (SAGES) Study. Measurements Preoperative evaluation included assessment of frailty using the FP and FI. We used the weighted kappa statistic to determine concordance between the 2 frailty measures and multivariable modeling to determine associations between each measure and postoperative complications, postoperative length of stay (LOS) >5 days, discharge to post acute (PAC) institutional care, and 30 day readmission. Results Frailty was highly prevalent (FP 35%, FI 41%). There was moderate concordance between the FP and FI (kappa=.42, 95% confidence interval (CI) .36,.49). When using FP, compared to the robust group, being pre-frail predicted higher risk of complications (RR 1.6, 95% CI 1.1,2.1) and PAC (RR 1.8, 95% CI 1.2,2.9);being frail predicted complications (RR 1.7, 95% CI 1.1,2.1), LOS >5 days (RR 3.1, 95% CI 1.1,8.8), and PAC(RR 2.3 95% CI 1.4,3.7). When using FI, being pre-frail predicted LOS > 5 days (RR 2.1, 95% CI 1.0,4.8), and PAC (RR 1.5, 95% CI 1.4,2.1) as did being frail (RR=1.9, 95% CI 1.4,2.5; and RR 3.1, 95% CI 1.4,6.8 respectively).. The other outcomes were not significantly associated with frailty status. Conclusion Both FP and FI predict postoperative outcomes after major elective orthopedic surgery, and should be considered for preoperative risk stratification.