Faculty Bibliography

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity. BACKGROUND: We find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections. TRANSLATIONAL SIGNIFICANCE: We develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.

Background/UNASSIGNED:The epidemiology of nosocomial bloodstream infections (NBSIs) in patients with coronavirus disease 2019 (COVID-19) is poorly understood, due in part to substantial disease heterogeneity resulting from multiple potential pathogens. Methods/UNASSIGNED:We identified risk factors for NBSIs and examined the association between NBSIs and mortality in a retrospective cohort of patients hospitalized with COVID-19 in 2 New York City hospitals during the height of the pandemic. We adjusted for the potential effects of factors likely to confound that association, including age, race, illness severity upon admission, and underlying health status. Results/UNASSIGNED:infections did not have an identifiable source and were not associated with common risk factors for infection by these organisms. Conclusions/UNASSIGNED:Pathogen species and mortality exhibited temporal differences. Early recognition of risk factors among COVID-19 patients could potentially decrease NBSI-associated mortality through early COVID-19 and antimicrobial treatment.

BACKGROUND/UNASSIGNED:Corticosteroids and tocilizumab have been shown to improve survival in patients who require supplemental oxygen from coronavirus disease 2019 (COVID-19) pneumonia. The optimal dose of immunosuppression for the treatment of COVID-19 acute respiratory distress syndrome (ARDS) is still unknown. OBJECTIVE/UNASSIGNED:The objective of this study was to evaluate the effectiveness and safety of high- versus low-dose corticosteroids with or without tocilizumab for the treatment of COVID-19 ARDS. METHODS/UNASSIGNED:This was a retrospective study of patients admitted to the intensive care unit (ICU) requiring mechanical ventilation who received high- versus low-dose corticosteroids with or without tocilizumab. The primary outcome was survival to discharge. Safety outcomes included infections and incidence of hyperglycemia. RESULTS/UNASSIGNED:= 0.01). The highest rate of a bacterial pneumonia was in patients who received high-dose corticosteroids with tocilizumab. CONCLUSIONS/UNASSIGNED:In critically ill patients with COVID-19 ARDS requiring mechanical ventilation, we found no difference in high- versus low-dose corticosteroids with regard to survival to hospital discharge. However, patients receiving only low-dose corticosteroids without tocilizumab did worse than the other groups. Larger prospective studies are needed to determine the optimal immunosuppression dosing strategy in this patient population.

MAIN OBJECTIVE:There is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic. STUDY DESIGN AND METHODS:University of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission. RESULTS AND SIGNIFICANCE:The 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months. CONCLUSIONS:Mortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528).

BACKGROUND:Guidelines recommend moderate to high-intensity statins and antithrombotic agents in patients with atherosclerotic cardiovascular disease (ASCVD). However, guideline-directed medical therapy (GDMT) remains suboptimal. METHODS:In this quality initiative, best practice alerts (BPA) in the electronic health record (EHR) were utilized to alert providers to prescribe to GDMT upon hospital discharge in ASCVD patients. Rates of GDMT were compared for 5 months pre- and post-BPA implementation. Multivariable regression was used to identify predictors of GDMT. RESULTS:In 5985 pre- and 5568 post-BPA patients, the average age was 69.1 ± 12.8 years and 58.5% were male. There was a 4.0% increase in statin use from 67.3% to 71.3% and a 3.1% increase in antithrombotic use from 75.3% to 78.4% in the post-BPA cohort. CONCLUSIONS:This simple EHR-based initiative was associated with a modest increase in ASCVD patients being discharged on GDMT. Leveraging clinical decision support tools provides an opportunity to influence provider behavior and improve care for ASCVD patients, and warrants further investigation.

BACKGROUND AND OBJECTIVE/UNASSIGNED:With the coronavirus disease 2019 (COVID-19) pandemic, rates of in-hospital antimicrobial use increased due to perceived bacterial and fungal coinfections along with COVID-19. We describe the incidence of these coinfections and antimicrobial use in patients hospitalized with COVID-19 to help guide effective antimicrobial use in this population. SETTING/UNASSIGNED:This study was conducted in 3 tertiary-care referral university teaching hospitals in New York City. METHODS/UNASSIGNED:This multicenter retrospective observational cohort study involved all patients admitted with COVID-19 from January 1, 2020, to February 1, 2021. Variables of interest were extracted from a de-identified data set of all COVID-19 infections across the health system. Population statistics are presented as median with interquartile range (IQR) or proportions with 95% confidence intervals (CIs) as indicated. RESULTS/UNASSIGNED:Among 7,209 of patients admitted with COVID-19, 663 (9.2%) had a positive culture from the respiratory tract or blood sometime during their initial hospital admission. Positive respiratory cultures occurred found in 449 (6.2%) patients, and 20% were collected within 48 hours of admission. Blood culture positivity occurred in 334 patients (4.6%), with 33.5% identified within 48 hours of admission. A higher proportion of patients received antimicrobials in the first wave than in the later pandemic period (82.4% vs 52.0%). Antimicrobials were prescribed to 70.1% of inpatients, with a median of 6 antimicrobial days per patient. Infection-free survival decreased over the course of hospitalization. CONCLUSIONS/UNASSIGNED:We detected a very low incidence of coinfection with COVID-19 at admission. A longer duration of hospitalization was associated with an increased risk of coinfection. Antimicrobial use far exceeded the true incidence and detection of coinfections in these patients.

In 2021, Delta has become the predominant SARS-CoV-2 variant worldwide. While vaccines effectively prevent COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occur. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contribute to increased rates of breakthrough infections compared to unvaccinated controls. Here, we show a steep and near complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25, its spike mutation S112L, and nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthroughs increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. Our data indicate a limited impact of vaccine escape in favor of Delta's increased epidemic growth in times of waning vaccine protection.

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity.

Objective/UNASSIGNED:The widespread deployment of electronic health records (EHRs) has introduced new sources of error and inefficiencies to the process of ordering medications in the hospital setting. Existing work identifies orders that require pharmacy intervention by comparing them to a patient's medical records. In this work, we develop a machine learning model for identifying medication orders requiring intervention using only provider behavior and other contextual features that may reflect these new sources of inefficiencies. Materials and Methods/UNASSIGNED:Data on providers' actions in the EHR system and pharmacy orders were collected over a 2-week period in a major metropolitan hospital system. A classification model was then built to identify orders requiring pharmacist intervention. We tune the model to the context in which it would be deployed and evaluate global and local feature importance. Results/UNASSIGNED:The resultant model had an area under the receiver-operator characteristic curve of 0.91 and an area under the precision-recall curve of 0.44. Conclusions/UNASSIGNED:Providers' actions can serve as useful predictors in identifying medication orders that require pharmacy intervention. Careful model tuning for the clinical context in which the model is deployed can help to create an effective tool for improving health outcomes without using sensitive patient data.

Importance/UNASSIGNED:Black and Hispanic populations have higher rates of coronavirus disease 2019 (COVID-19) hospitalization and mortality than White populations but lower in-hospital case-fatality rates. The extent to which neighborhood characteristics and comorbidity explain these disparities is unclear. Outcomes in Asian American populations have not been explored. Objective/UNASSIGNED:To compare COVID-19 outcomes based on race and ethnicity and assess the association of any disparities with comorbidity and neighborhood characteristics. Design, Setting, and Participants/UNASSIGNED:This retrospective cohort study was conducted within the New York University Langone Health system, which includes over 260 outpatient practices and 4 acute care hospitals. All patients within the system's integrated health record who were tested for severe acute respiratory syndrome coronavirus 2 between March 1, 2020, and April 8, 2020, were identified and followed up through May 13, 2020. Data were analyzed in June 2020. Among 11 547 patients tested, outcomes were compared by race and ethnicity and examined against differences by age, sex, body mass index, comorbidity, insurance type, and neighborhood socioeconomic status. Exposures/UNASSIGNED:Race and ethnicity categorized using self-reported electronic health record data (ie, non-Hispanic White, non-Hispanic Black, Hispanic, Asian, and multiracial/other patients). Main Outcomes and Measures/UNASSIGNED:The likelihood of receiving a positive test, hospitalization, and critical illness (defined as a composite of care in the intensive care unit, use of mechanical ventilation, discharge to hospice, or death). Results/UNASSIGNED:Among 9722 patients (mean [SD] age, 50.7 [17.5] years; 58.8% women), 4843 (49.8%) were positive for COVID-19; 2623 (54.2%) of those were admitted for hospitalization (1047 [39.9%] White, 375 [14.3%] Black, 715 [27.3%] Hispanic, 180 [6.9%] Asian, 207 [7.9%] multiracial/other). In fully adjusted models, Black patients (odds ratio [OR], 1.3; 95% CI, 1.2-1.6) and Hispanic patients (OR, 1.5; 95% CI, 1.3-1.7) were more likely than White patients to test positive. Among those who tested positive, odds of hospitalization were similar among White, Hispanic, and Black patients, but higher among Asian (OR, 1.6, 95% CI, 1.1-2.3) and multiracial patients (OR, 1.4; 95% CI, 1.0-1.9) compared with White patients. Among those hospitalized, Black patients were less likely than White patients to have severe illness (OR, 0.6; 95% CI, 0.4-0.8) and to die or be discharged to hospice (hazard ratio, 0.7; 95% CI, 0.6-0.9). Conclusions and Relevance/UNASSIGNED:In this cohort study of patients in a large health system in New York City, Black and Hispanic patients were more likely, and Asian patients less likely, than White patients to test positive; once hospitalized, Black patients were less likely than White patients to have critical illness or die after adjustment for comorbidity and neighborhood characteristics. This supports the assertion that existing structural determinants pervasive in Black and Hispanic communities may explain the disproportionately higher out-of-hospital deaths due to COVID-19 infections in these populations.