Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions.

Mechanisms underlying severe coronavirus disease 2019 (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 scRNA-seq 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 angiotensin-converting enzyme 2 (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.

Plasma proteomics reveals tissue-specific cell death and mediators of cell-cell interactions in severe COVID-19 patients.

COVID-19 has caused over 1 million deaths globally, yet the cellular mechanisms underlying severe disease remain poorly understood. By analyzing several thousand plasma proteins in 306 COVID-19 patients and 78 symptomatic controls over serial timepoints using two complementary approaches, we uncover COVID-19 host immune and non-immune proteins not previously linked to this disease. Integration of plasma proteomics with nine published scRNAseq datasets shows that SARS-CoV-2 infection upregulates monocyte/macrophage, plasmablast, and T cell effector proteins. By comparing patients who died to severely ill patients who survived, we identify dynamic immunomodulatory and tissue-associated proteins associated with survival, providing insights into which host responses are beneficial and which are detrimental to survival. We identify intracellular death signatures from specific tissues and cell types, and by associating these with angiotensin converting enzyme 2 (ACE2) expression, we map tissue damage associated with severe disease and propose which damage results from direct viral infection rather than from indirect effects of illness. We find that disease severity in lung tissue is driven by myeloid cell phenotypes and cell-cell interactions with lung epithelial cells and T cells. Based on these results, we propose a model of immune and epithelial cell interactions that drive cell-type specific and tissue-specific damage in severe COVID-19.

Antipsychotic medication utilization in nonpsychiatric hospitalizations.

BACKGROUND: Although antipsychotics are used for treatment of delirium/agitation in hospitalized patients, their scope of use has not been investigated in a large, multicenter cohort. OBJECTIVE: To determine rates of use and hospital variation in use of antipsychotics in nonpsychiatric admissions. DESIGN, SETTING, PATIENTS: Cohort study of adult, nonpsychiatric admissions to 300 US hospitals contributing data to the Premier database, from July 1, 2009 to June 30, 2010. MEASUREMENTS: Antipsychotic exposure defined using pharmacy charges. Potentially excessive dosing defined using guidelines for long-term care facilities. RESULTS: Our cohort included 2,695,081 admissions (median age, 63 years; 56% female). Antipsychotic exposure occurred in 160,773 (6%) admissions; 102,148 (64%) received atypical antipsychotics, 76,979 (48%) received typical, and 18,354 (11%) received both. Among exposed admissions, 47% received ≥1 potentially excessive daily dose. Among the variables we analyzed, the strongest predictors of antipsychotic receipt were delirium (relative risk [RR]: 2.93, 95% CI: 2.88-2.98) and dementia (RR: 2.78, 95% CI: 2.72-2.83). After adjustment for patient characteristics, patients admitted to hospitals in the highest antipsychotic prescribing quintile were more than twice as likely to be exposed compared to patients admitted to hospitals in the lowest prescribing quintile (RR: 2.56, 95% CI: 2.50-2.61). This relationship was similar across subgroups of admissions with delirium and dementia. CONCLUSIONS: Antipsychotic medication exposure is common in nonpsychiatric admissions to US hospitals. The observed variation in antipsychotic prescribing was not fully explained by measured patient characteristics, suggesting the possibility of differing hospital prescribing cultures. Additional research and guidelines are necessary to define appropriate use of these potentially harmful medications in the hospital setting. Journal of Hospital Medicine 2016;11:543-549. © 2016 Society of Hospital Medicine.

Antipsychotic Use in Hospitalized Adults: Rates, Indications, and Predictors.

OBJECTIVES: To investigate patterns and predictors of use of antipsychotics in hospitalized adults. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PARTICIPANTS: Individuals aged 18 and older hospitalized from August 2012 to August 2013, excluding those admitted to obstetrics and gynecology or psychiatry or with a psychotic disorder. MEASUREMENTS: Use was ascertained from pharmacy charges. Potentially excessive dosing was defined using guidelines for long-term care facilities. A review of 100 records was performed to determine reasons for use. RESULTS: The cohort included 17,775 admissions with a median age 64; individuals could have been admitted more than once during the study period. Antipsychotics were used in 9%, 55% of which were initiations. The most common reasons for initiation were delirium (53%) and probable delirium (12%). Potentially excessive dosing occurred in 16% of admissions exposed to an antipsychotic. Of admissions with antipsychotic initiation, 26% were discharged on these medications. Characteristics associated with initiation included age 75 and older (relative risk (RR) = 1.4, 95% confidence interval (CI) = 1.2-1.7), male sex (RR = 1.2, 95% CI = 1.1-1.4), black race (RR = 0.8, 95% CI = 0.6-0.96), delirium (RR = 4.8, 95% CI = 4.2-5.7), dementia (RR = 2.1, 95% CI = 1.7-2.6), admission to a medical service (RR = 1.2, 95% CI = 1.1-1.4), intensive care unit stay (RR = 2.1, 95% CI = 1.8-2.4), and mechanical ventilation (RR = 2.0, 95% CI = 1.7-2.4). In individuals who were initiated on an antipsychotic, characteristics associated with discharge on antipsychotics were age 75 and older (RR = 0.6, 95% CI = 0.4-0.7), discharge to any location other than home (RR = 2.5, 95% CI = 1.8-3.3), and class of in-hospital antipsychotic exposure (RR = 1.6, 95% CI = 1.1-2.3 for atypical vs typical; RR = 2.7, 95% CI = 1.9-3.8 for both vs typical). CONCLUSION: Antipsychotic initiation and use were common during hospitalization, most often for delirium, and individuals were frequently discharged on these medications. Several predictors of use on discharge were identified, suggesting potential targets for decision support tools that would be used to prompt consideration of ongoing necessity.

Improving appropriateness of acid-suppressive medication use via computerized clinical decision support.

As part of the Choosing Wisely Campaign, the Society of Hospital Medicine identified reducing inappropriate use of acid-suppressive medication for stress ulcer prophylaxis as 1 of 5 key opportunities to improve the value of care for hospitalized patients. We designed a computerized clinical decision support intervention to reduce use of acid-suppressive medication for stress ulcer prophylaxis in hospitalized patients outside of the intensive care unit at an academic medical center. Using quasiexperimental interrupted time series analysis, we found that the decision support intervention resulted in a significant reduction in use of acid-suppressive medication with stress ulcer prophylaxis selected as the only indication, a nonsignificant reduction in overall use, and no change in use on discharge. We found low rates of use of acid-suppressive medication for the purpose of stress ulcer prophylaxis even before the intervention, and continuing preadmission medication was the most commonly selected indication throughout the study. Our results suggest that attention should be focused on both the inpatient and outpatient settings when designing future initiatives to improve the appropriateness of acid-suppressive medication use.