Colorado Clinical and Translational Sciences Institute

INTRODUCTION: Answers to clinical and public health research questions increasingly require aggregated data from multiple sites. Data from electronic health records and other clinical sources are useful for such studies, but require stringent quality assessment. Data quality assessment is particularly important in multisite studies to distinguish true variations in care from data quality problems. METHODS: We propose a "fit-for-use" conceptual model for data quality assessment and a process model for planning and conducting single-site and multisite data quality assessments. These approaches are illustrated using examples from prior multisite studies. APPROACH: Critical components of multisite data quality assessment include: thoughtful prioritization of variables and data quality dimensions for assessment; development and use of standardized approaches to data quality assessment that can improve data utility over time; iterative cycles of assessment within and between sites; targeting assessment toward data domains known to be vulnerable to quality problems; and detailed documentation of the rationale and outcomes of data quality assessments to inform data users. The assessment process requires constant communication between site-level data providers, data coordinating centers, and principal investigators. DISCUSSION: A conceptually based and systematically executed approach to data quality assessment is essential to achieve the potential of the electronic revolution in health care. High-quality data allow "learning health care organizations" to analyze and act on their own information, to compare their outcomes to peers, and to address critical scientific questions from the population perspective.

A learning health system (LHS) integrates research done in routine care settings, structured data capture during every encounter, and quality improvement processes to rapidly implement advances in new knowledge, all with active and meaningful patient participation. While disease-specific pediatric LHSs have shown tremendous impact on improved clinical outcomes, a national digital architecture to rapidly implement LHSs across multiple pediatric conditions does not exist. PEDSnet is a clinical data research network that provides the infrastructure to support a national pediatric LHS. A consortium consisting of PEDSnet, which includes eight academic medical centers, two existing disease-specific pediatric networks, and two national data partners form the initial partners in the National Pediatric Learning Health System (NPLHS). PEDSnet is implementing a flexible dual data architecture that incorporates two widely used data models and national terminology standards to support multi-institutional data integration, cohort discovery, and advanced analytics that enable rapid learning.

BACKGROUND AND AIMS: Cirrhosis (CIR) occurs in 5-7% of cystic fibrosis (CF) patients. We hypothesized that alterations in intestinal function in CF contribute to the development of CIR. AIMS: Determine the frequency of macroscopic intestinal lesions, intestinal inflammation, intestinal permeability and characterize fecal microbiome in CF CIR subjects and CF subjects with no liver disease (CFnoLIV). METHODS: 11 subjects with CFCIR (6 M, 12.8 yrs ± 3.8) and 19 matched with CFnoLIV (10 M, 12.6 yrs ± 3.4) underwent small bowel capsule endoscopy, intestinal permeability testing by urinary lactulose: mannitol excretion ratio, fecal calprotectin determination and fecal microbiome characterization. RESULTS: CFCIR and CFnoLIV did not differ in key demographics or CF complications. CFCIR had higher GGT (59±51 U/L vs 17±4 p = 0.02) and lower platelet count (187±126 vs 283±60 p = 0.04) and weight (-0.86 ± 1.0 vs 0.30 ± 0.9 p = 0.002) z scores. CFCIR had more severe intestinal mucosal lesions on capsule endoscopy (score ≥4, 4/11 vs 0/19 p = 0.01). Fecal calprotectin was similar between CFCIR and CFnoLIV (166 μg/g ±175 vs 136 ± 193 p = 0.58, nl <120). Lactulose:mannitol ratio was elevated in 27/28 subjects and was slightly lower in CFCIR vs CFnoLIV (0.08±0.02 vs 0.11±0.05, p = 0.04, nl ≤0.03). Small bowel transit time was longer in CFCIR vs CFnoLIV (195±42 min vs 167±68 p<0.001, nl 274 ± 41). Bacteroides were decreased in relative abundance in CFCIR and were associated with lower capsule endoscopy score whereas Clostridium were more abundant in CFCIR and associated with higher capsule endoscopy score. CONCLUSIONS: CFCIR is associated with increased intestinal mucosal lesions, slower small bowel transit time and alterations in fecal microbiome. Abnormal intestinal permeability and elevated fecal calprotectin are common in all CF subjects. Disturbances in intestinal function in CF combined with changes in the microbiome may contribute to the development of hepatic fibrosis and intestinal lesions.

Dissemination and implementation (D&I) science is dedicated to studying how to effectively translate and apply research in real-world contexts. There has been increasing interest in health equity within the D&I field to ensure the equitable implementation of evidence-based programs/practices across a range of diverse populations and settings. At the same time, health equity researchers recognize the potential of D&I science to promote the more widespread dissemination, implementation, and sustainment of evidence-based interventions to address health inequities. The National Center for Accelerating Clinical and Translational Science Clinical and Translational Science Award (CTSA) Program has been a champion for community engagement and translational scholarship in its mission to improve individual and population health. The overall CTSA infrastructure and resources within and among CTSA hubs are well-equipped to facilitate a health equity focus to D&I across the phases of translational research. This paper proposes a framework that demonstrates the interaction and opportunities between health equity and D&I science and highlights how CTSAs can support and facilitate wider efforts in translational research with a focus on equitable D&I.

The Kaiser Permanente & Strategic Partners Patient Outcomes Research To Advance Learning (PORTAL) network engages four healthcare delivery systems (Kaiser Permanente, Group Health Cooperative, HealthPartners, and Denver Health) and their affiliated research centers to create a new national network infrastructure that builds on existing relationships among these institutions. PORTAL is enhancing its current capabilities by expanding the scope of the common data model, paying particular attention to incorporating patient-reported data more systematically, implementing new multi-site data governance procedures, and integrating the PCORnet PopMedNet platform across our research centers. PORTAL is partnering with clinical research and patient experts to create cohorts of patients with a common diagnosis (colorectal cancer), a rare diagnosis (adolescents and adults with severe congenital heart disease), and adults who are overweight or obese, including those with pre-diabetes or diabetes, to conduct large-scale observational comparative effectiveness research and pragmatic clinical trials across diverse clinical care settings.

OBJECTIVE: We sought to determine which of several simple indicators of emergency department crowding are most predictive of quality of care in 2 pediatric disease models: acute asthma and pain associated with long-bone fractures. METHODS: We performed a retrospective, cross-sectional study of patients 2 to 21 years old seen for acute asthma and patients 0 to 21 years old seen for acute, isolated long-bone fractures from November 1, 2007, to October 31, 2008, at a single, academic children's hospital emergency department. The main outcome measures were quality measures based on 3 asthma care-related processes-asthma score, β-agonist, and corticosteroid-and 2 fracture-related processes-analgesic and opioid analgesic. Good quality care was defined as receipt of an indicated process within 1 hour of arrival. Poor quality care was defined as nonreceipt or delayed receipt of an indicated process. Nine crowding measures were assigned based on conditions at each patient's arrival. We calculated the adjusted risk of receiving good quality care for each quality measure at 5 percentiles of crowding for each crowding measure. RESULTS: The asthma population included 927 patients, and the fracture population included 1229 patients. Among the 5 quality measures, we found rates of good quality care ranging from 23% to 64%. In adjusted models, we found an inverse association between crowding and quality. The 2 crowding measures with a consistently inverse association with the 5 quality measures across both populations were total patient-care hours and number arriving in prior 6 hours. Across the 10 models combining 1 of 2 key crowding variables with 1 of 5 quality measures, patients in the 2 populations were 0.40 (95% confidence interval, 0.27-0.55) to 0.78 (confidence interval, 0.71-0.85) times as likely to receive the indicated care process within 1 hour when each crowding measure was at the 75th than at the 25th percentile. CONCLUSIONS: Two measures of ED crowding are consistently associated with lower-quality asthma- and fracture-specific care in the ED for pediatric patients.

BACKGROUND: Limited consideration of clinical decision support (CDS) design best practices, such as a user-centered design, is often cited as a key barrier to CDS adoption and effectiveness. The application of CDS best practices is resource intensive; thus, institutions often rely on commercially available CDS tools that are created to meet the generalized needs of many institutions and are not user centered. Beyond resource availability, insufficient guidance on how to address key aspects of implementation, such as contextual factors, may also limit the application of CDS best practices. An implementation science (IS) framework could provide needed guidance and increase the reproducibility of CDS implementations. OBJECTIVE: This study aims to compare the effectiveness of an enhanced CDS tool informed by CDS best practices and an IS framework with a generic, commercially available CDS tool. METHODS: We conducted an explanatory sequential mixed methods study. An IS-enhanced and commercial CDS alert were compared in a cluster randomized trial across 28 primary care clinics. Both alerts aimed to improve beta-blocker prescribing for heart failure. The enhanced alert was informed by CDS best practices and the Practical, Robust, Implementation, and Sustainability Model (PRISM) IS framework, whereas the commercial alert followed vendor-supplied specifications. Following PRISM, the enhanced alert was informed by iterative, multilevel stakeholder input and the dynamic interactions of the internal and external environment. Outcomes aligned with PRISM's evaluation measures, including patient reach, clinician adoption, and changes in prescribing behavior. Clinicians exposed to each alert were interviewed to identify design features that might influence adoption. The interviews were analyzed using a thematic approach. RESULTS: Between March 15 and August 23, 2019, the enhanced alert fired for 61 patients (106 alerts, 87 clinicians) and the commercial alert fired for 26 patients (59 alerts, 31 clinicians). The adoption and effectiveness of the enhanced alert were significantly higher than those of the commercial alert (62% vs 29% alerts adopted, P<.001; 14% vs 0% changed prescribing, P=.006). Of the 21 clinicians interviewed, most stated that they preferred the enhanced alert. CONCLUSIONS: The results of this study suggest that applying CDS best practices with an IS framework to create CDS tools improves implementation success compared with a commercially available tool. TRIAL REGISTRATION: ClinicalTrials.gov NCT04028557; http://clinicaltrials.gov/ct2/show/NCT04028557.

Although pediatric research enjoyed significant benefits during the National Institutes of Health (NIH) doubling era, the proportion of the NIH budget devoted to the pediatric-research portfolio has declined overall. In light of this declining support for pediatric biomedical research, the Federation of Pediatric Organizations held a topic symposium at the 2009 Pediatric Academic Societies annual meeting as a forum for discussion of the past and future states of funding, the rationale for directing public funds toward the understanding of child health and disease, and new programs and paradigms for promoting child health research. This report of the symposium is intended to disseminate more broadly the information presented and conclusions discussed to encourage those in the child health research community to exert influence with policy makers to increase the allocation of national funding for this underfunded area.

OBJECTIVE: Barriers to executing large-scale randomized controlled trials include costs, complexity, and regulatory requirements. We hypothesized that source document verification (SDV) via remote electronic monitoring is feasible. METHODS: Five hospitals from two NIH sponsored networks provided remote electronic access to study monitors. We evaluated pre-visit remote SDV compared to traditional on-site SDV using a randomized convenience sample of all study subjects due for a monitoring visit. The number of data values verified and the time to perform remote and on-site SDV was collected. RESULTS: Thirty-two study subjects were randomized to either remote SDV (N=16) or traditional on-site SDV (N=16). Technical capabilities, remote access policies and regulatory requirements varied widely across sites. In the adult network, only 14 of 2965 data values (0.47%) could not be located remotely. In the traditional on-site SDV arm, 3 of 2608 data values (0.12%) required coordinator help. In the pediatric network, all 198 data values in the remote SDV arm and all 183 data values in the on-site SDV arm were located. Although not statistically significant there was a consistent trend for more time consumed per data value (minutes +/- SD): Adult 0.50 +/- 0.17 min vs. 0.39 +/- 0.10 min (two-tailed t-test p=0.11); Pediatric 0.99 +/- 1.07 min vs. 0.56 +/- 0.61 min (p=0.37) and time per case report form: Adult: 4.60 +/- 1.42 min vs. 3.60 +/- 0.96 min (p=0.10); Pediatric: 11.64 +/- 7.54 min vs. 6.07 +/- 3.18 min (p=0.10) using remote SDV. CONCLUSIONS: Because each site had different policies, requirements, and technologies, a common approach to assimilating monitors into the access management system could not be implemented. Despite substantial technology differences, more than 99% of data values were successfully monitored remotely. This pilot study demonstrates the feasibility of remote monitoring and the need to develop consistent access policies for remote study monitoring.

OBJECTIVE: To examine the impact of billing and clinical data extracted from an electronic medical record system on the calculation of an adverse drug event (ADE) quality measure approved for use in The Joint Commission's ORYX program, a mandatory national hospital quality reporting system. DESIGN: The Child Health Corporation of America's "Use of Rescue Agents-ADE Trigger" quality measure uses medication billing data contained in the Pediatric Health Information Systems (PHIS) data warehouse to create The Joint Commission-approved quality measure. Using a similar query, we calculated the quality measure using PHIS plus four data sources extracted from our electronic medical record (EMR) system: medications charged, medication orders placed, medication orders with associated charges (orders charged), and medications administered. MEASUREMENTS: Inclusion and exclusion criteria were identical for all queries. Denominators and numerators were calculated using the five data sets. The reported quality measure is the ADE rate (numerator/denominator). RESULTS: Significant differences in denominators, numerators, and rates were calculated from different data sources within a single institution's EMR. Differences were due to both common clinical practices that may be similar across institutions and unique workflow practices not likely to be present at any other institution. The magnitude of the differences would significantly alter the national comparative ranking of our institution compared to other PHIS institutions. CONCLUSIONS: More detailed clinical information may result in quality measures that are not comparable across institutions due institution-specific workflow, differences that are exposed using EMR-derived data.

PURPOSE: Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly. The role of systemic inflammation in AMD remains unclear specifically in patients with intermediate AMD (iAMD). We sought to determine whether systemic inflammation was associated with future iAMD progression. METHODS: Combinations of 27 circulating inflammatory markers including complement factors, cytokines, chemokines, and high-sensitivity C-reactive protein (hsCRP) were evaluated in iAMD patients recruited into a Colorado AMD registry. Systemic inflammatory markers were combined using principal component analysis. Risk factors for AMD progression were evaluated using Cox regression models. RESULTS: This study included 99 subjects with iAMD, 21 of which progressed to advanced AMD. Two principal components (PCs) were identified that contributed to the risk of progression to advanced AMD, after adjusting for age and bilateral reticular pseudodrusen. The strongest associated PC was explained largely by the pro-inflammatory cytokine TNFα and the anti-inflammatory IL1ra antagonist of IL1. The additional PC was largely explained by IL6, IL8, C3 and factor D in the positive direction and CRP, MCP1, factor B and factor I in the negative direction. CONCLUSION: When evaluated through multivariate analyses, combinations of biomarkers distinguished patients who did and did not progress to future advanced AMD. Increased risk could result from different combinations of analyte levels indicating a complex relationship rather than a simple increase in a few markers. This suggests that studying systemic inflammation in iAMD can provide insights into early pathologic events and potentially identify patients at highest risk for the development of severe AMD.

OBJECTIVES: Many clinical research data integration platforms rely on the Entity-Attribute-Value model because of its flexibility, even though it presents problems in query formulation and execution time. The authors sought more balance in these traits. MATERIALS AND METHODS: Borrowing concepts from Entity-Attribute-Value and from enterprise data warehousing, the authors designed an alternative called the Dimensional Bus model and used it to integrate electronic medical record, sponsored study, and biorepository data. Each type of observational collection has its own table, and the structure of these tables varies to suit the source data. The observational tables are linked to the Bus, which holds provenance information and links to various classificatory dimensions that amplify the meaning of the data or facilitate its query and exposure management. RESULTS: The authors implemented a Bus-based clinical research data repository with a query system that flexibly manages data access and confidentiality, facilitates catalog search, and readily formulates and compiles complex queries. CONCLUSION: The design provides a workable way to manage and query mixed schemas in a data warehouse.

Efforts to move community engagement in research from marginalized to mainstream include the NIH requiring community engagement programs in all Clinical and Translational Science Awards (CTSAs). However, the COVID-19 pandemic has exposed how little these efforts have changed the dominant culture of clinical research. When faced with the urgent need to generate knowledge about prevention and treatment of the novel coronavirus, researchers largely neglected to involve community stakeholders early in the research process. This failure cannot be divorced from the broader context of systemic racism in the US that has contributed to Black, Indigenous, and People of Color (BIPOC) communities bearing a disproportionate toll from COVID-19, being underrepresented in COVID-19 clinical trials, and expressing greater hesitancy about COVID-19 vaccination. We call on research funders and research institutions to take decisive action to make community engagement obligatory, not optional, in all clinical and translational research and to center BIPOC communities in this process. Recommended actions include funding agencies requiring all research proposals involving human participants to include a community engagement plan, providing adequate funding to support ongoing community engagement, including community stakeholders in agency governance and proposal reviews, promoting racial and ethnic diversity in the research workforce, and making a course in community engaged research a requirement for Masters of Clinical Research curricula.

Background: The field of Implementation science (IS) continues to evolve, and the number and type of IS capacity building Programs (ISCBPs) are in flux. These changes push the field to revisit the accepted IS competencies and to guide sustainment of ISCBPs. Our objectives were: (1) compare characteristics of current ISCBPs; (2) identify recommendations to support ISCBP sustainment; (3) measure how often ISCBPs address IS competencies; (4) identify novel and important IS competencies for the field. Method: This multi-method study included ISCBPs delivering structured, longitudinal IS training, excluding single courses and brief workshops. We used three complementary methods to meet our objectives. First, we identified ISCBPs via an internet search and snowball sampling methods. Second, we surveyed these ISCBPs to identify areas of program focus, types of trainees, IS competencies addressed, and recommendations to sustain ISCBPs. Third, we conducted a modified Delphi process with IS researchers/leaders to reach consensus on the IS competencies that were both important and novel as compared to the IS competencies published to date. Results: Among 74 eligible ISCBPs identified, 46 responded (62% response rate). Respondent ISCBPs represented diverse areas of focus (e.g., global health, cardiopulmonary disease) and trainee stages (e.g., graduate students, mid-career faculty). While most respondent ISCBPs addressed core IS methods, targeting IS competencies was less consistent (33% for nongraduate/non-fellowship ISCBPs; >90% for graduate/national ISCBPs). Our modified Delphi process identified eight novel and important IS competencies related to increasing health equity or the speed of translation. Recommendations to sustain ISCBPs included securing financial administrative support. Conclusions: Current ISCBPs train learners across varying career stages in diverse focus areas. To promote rigor, we recommend ISCBPs address specific IS competencies, with consideration of these eight novel/emerging competencies. We also recommend ISCBPs report on their IS competencies, focus area(s), and trainee characteristics. ISCBP programs need administrative financial support. Plain Language Summary: There is a limited workforce capacity to conduct implementation science (IS) research. To address this gap, the number and type of IS capacity building Programs (ISCBPs) focusing on training researchers and practitioners in IS methods continue to increase. Our efforts to comprehensively identify and describe ISCBPs for researchers and practitioners highlighted four implications for leaders of ISCBPs related to program sustainment and rigor. First, we identified a range of contextual characteristics of ISCBPs, including the research topics, methods, and IS competencies addressed, and the types of trainees accepted. Second, given the variability of trainee types and research, rigorous ISCBP programs should tailor the IS competencies and methods addressed to the skills needed by the types of trainees in their program. Third, the field of IS needs to periodically revisit the competencies needed with attention to the skills needed in the field. We used a consensus-building process with ISCBP leaders and other IS experts to expand existing IS competencies and identified eight important, novel IS competencies that broadly relate to promoting health equity and speeding the translation of research to practice. Finally, as more institutions consider developing ISCBPs, we identified factors needed to support ISCBP sustainment, including ongoing financial support. In addition to these implications for ISCBP leaders, there are also policy implications. For example, IS journals may enact policies to require manuscripts evaluating ISCBP performance to report on certain contextual characteristics, such as the IS competencies addressed and types of trainees accepted. The field may also consider developing an accreditation body to evaluate the rigor of ISCBP curricula.

The Colorado Healthy Heart Solutions program uses community health workers to provide health promotion and navigation services for participants in medically underserved, predominantly rural areas who are at risk for developing cardiovascular disease. A text messaging program designed to increase participant engagement and adherence to lifestyle changes was pilot tested with English- and Spanish-speaking participants. Preimplementation focus groups with participants informed the development of text messages that were used in a 6-week pilot program. Postimplementation focus groups and interviews then evaluated the pilot program. Participants reported a preference for concise messages received once daily and for positive messages suggesting specific actions that could be feasibly accomplished within the course of the day. Participants also consistently reported the desire for clarity in message delivery and content, indicating that the source of the messages should be easy to recognize, messages should state clearly when participants were expected to respond to the messages, and any responses should be acknowledged. Links to other websites or resources were generally viewed as trustworthy and acceptable, but were preferred for supplementary material only. These results may inform the development of future chronic disease management programs in underserved areas or augment existing programs using text messaging reinforcement.

The vision of precision medicine relies on the integration of large-scale clinical, molecular and environmental datasets. Data integration may be thought of along two axes: data fusion across institutions, and data fusion across modalities. Cross-institutional data sharing that maintains semantic integrity hinges on the adoption of data standards and a push toward ontology-driven integration. The goal should be the creation of query-able data repositories spanning primary and tertiary care providers, disease registries, research organizations etc. to produce rich longitudinal datasets. Cross-modality sharing involves the integration of multiple data streams, from structured EHR data (diagnosis codes, laboratory tests) to genomics, imaging, monitors and patient-generated data including wearable devices. This integration presents unique technical, semantic, and ethical challenges; however recent work suggests that multi-modal clinical data can significantly improve the performance of phenotyping and prediction algorithms, powering knowledge discovery at the patient- and population-level.

Background: It is not known whether sotrovimab, a neutralizing monoclonal antibody (mAb) treatment authorized for early symptomatic COVID-19 patients, is effective against the SARS-CoV-2 Delta variant to prevent progression to severe disease and mortality. Methods: 2021, using electronic health records from a statewide health system plus state-level vaccine and mortality data. We used propensity matching to select 3 patients not receiving mAbs for each patient who received outpatient sotrovimab treatment. The primary outcome was 28-day hospitalization; secondary outcomes included mortality and severity of hospitalization. Results: Of 10,036 patients with SARS-CoV-2 infection, 522 receiving sotrovimab were matched to 1,563 not receiving mAbs. Compared to mAb-untreated patients, sotrovimab treatment was associated with a 63% decrease in the odds of all-cause hospitalization (raw rate 2.1% versus 5.7%; adjusted OR 0.37, 95% CI 0.19-0.66) and an 89% decrease in the odds of all-cause 28-day mortality (raw rate 0% versus 1.0%; adjusted OR 0.11, 95% CI 0.0-0.79), and may reduce respiratory disease severity among those hospitalized. Conclusion: Real-world evidence demonstrated sotrovimab effectiveness in reducing hospitalization and all-cause 28-day mortality among COVID-19 outpatients during the Delta variant phase.

Abstract The COVID-19 pandemic has required many clinical and translational scientists and staff to work remotely to prevent the spread of the virus. To understand the impact on research programs, we assessed barriers to remote work and strategies implemented to support virtual engagement and productivity. A mixed-methods RedCap survey querying the remote work experience was emailed to Colorado Clinical and Translational Sciences Institute (CCTSI) scientists and staff in April 2020. Descriptive analyses, Fisher’s Exact tests, and content analysis were conducted. Respondents ( n = 322) were primarily female ( n = 240; 75%), 21–73 years old (mean = 42 years) with a PhD ( n = 139; 44%) or MD ( n = 56; 55%). Prior to COVID-19, 77% ( n = 246) never or rarely (0–1 day a week) worked remotely. Remote work somewhat or greatly interfered with 76% ( n = 244) of researchers’ programs and 71% ( n = 231) reported slowing or stopping their research. Common barriers included missing interactions with colleagues ( n = 198; 62%) and the absence of routines ( n = 137; 43%). Strategies included videoconferencing ( n = 283; 88%), altering timelines and expectations ( n = 180; 56%). Scientists and staff experienced interference with their research when they shifted to remote work, causing many to slow or stop research programs. Methods to enhance communication and relationships, support productivity, and collectively cope during remote work are available.

The gut microbiome in people living with HIV (PLWH) is of interest since chronic infection often results in long-term comorbidities. Metabolic disease is prevalent in PLWH even in well-controlled infection and has been linked with the gut microbiome in previous studies, but little attention has been given to PLWH. Furthermore, integrated analyses that consider gut microbiome, together with diet, systemic immune activation, metabolites, and demographics, have been lacking. In a systems-level analysis of predictors of metabolic disease in PLWH and men who are at high risk of acquiring HIV, we found that increased lipopolysaccharide-binding protein, an inflammatory marker indicative of compromised intestinal barrier function, was associated with worse metabolic health. We also found impaired metabolic health associated with specific dietary components, gut microbes, and host and microbial metabolites. This study lays the framework for mechanistic studies aimed at targeting the microbiome to prevent or treat metabolic endotoxemia in HIV-infected individuals.

BACKGROUND: Neutralizing monoclonal antibodies (mAbs) are authorized for early symptomatic COVID-19 patients. Whether mAbs are effective against the SARS-CoV-2 Delta variant, among vaccinated patients, or for prevention of mortality remains unknown. OBJECTIVE: To evaluate the effectiveness of mAb treatment in preventing progression to severe disease during the Delta phase of the pandemic and based on key baseline risk factors. DESIGN SETTING AND PATIENTS: Observational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from November 2020-October 2021, using electronic health records from a statewide health system plus state-level vaccine and mortality data. Using propensity matching, we selected approximately 2.5 patients not receiving mAbs for each patient who received mAbs. EXPOSURE: Neutralizing mAb treatment under emergency use authorization. MAIN OUTCOMES: The primary outcome was 28-day hospitalization; secondary outcomes included mortality and severity of hospitalization. RESULTS: Of 36,077 patients with SARS-CoV-2 infection, 2,675 receiving mAbs were matched to 6,677 not receiving mAbs. Compared to mAb-untreated patients, mAb-treated patients had lower all-cause hospitalization (4.0% vs 7.7%; adjusted OR 0.48, 95%CI 0.38-0.60) and all-cause mortality (0.1% vs. 0.9%; adjusted OR 0.11, 95%CI 0.03-0.29) to day 28; differences persisted to day 90. Among hospitalized patients, mAb-treated patients had shorter hospital length of stay (5.8 vs. 8.5 days) and lower risk of mechanical ventilation (4.6% vs. 16.6%). Relative effectiveness was similar in preventing hospitalizations during the Delta variant phase (adjusted OR 0.35, 95%CI 0.25-0.50) and across subgroups. Lower number-needed-to-treat (NNT) to prevent hospitalization were observed for subgroups with higher baseline risk of hospitalization (e.g., multiple comorbidities (NNT=17) and not fully vaccinated (NNT=24) vs. no comorbidities (NNT=88) and fully vaccinated (NNT=81). CONCLUSION: Real-world evidence demonstrated mAb effectiveness in reducing hospitalization among COVID-19 outpatients, including during the Delta variant phase, and conferred an overall 89% reduction in 28-day mortality. Early outpatient treatment with mAbs should be prioritized, especially for individuals with highest risk for hospitalization.