key: cord-0818083-q6wy0bxn
authors: Kline, Jeffrey A.; Pettit, Katherine L.; Kabrhel, Christopher; Courtney, D. Mark; Nordenholz, Kristen E.; Camargo, Carlos A.
title: Multicenter registry of United States emergency department patients tested for SARS‐CoV‐2
date: 2020-11-12
journal: J Am Coll Emerg Physicians Open
DOI: 10.1002/emp2.12313
sha: 7adf658ac364952f4a6eb824efe34d518d13e177
doc_id: 818083
cord_uid: q6wy0bxn

This paper summarizes the methodology for the registry of suspected COVID‐19 in emergency care (RECOVER), a large clinical registry of patients from 155 United States (US) emergency departments (EDs) in 27 states tested for SARS‐CoV‐2 from March–September 2020. The initial goals are to derive and test: (1) a pretest probability instrument for prediction of SARS‐CoV‐2 test results, and from this instrument, a set of simple criteria to exclude COVID‐19 (the COVID‐19 Rule‐Out Criteria—the CORC rule), and (2) a prognostic instrument for those with COVID‐19. Patient eligibility included any ED patient tested for SARS‐CoV‐2 with a nasal or oropharyngeal swab. Abstracted clinical data included 204 variables representing the earliest manifestation of infection, including week of testing, demographics, symptoms, exposure risk, past medical history, test results, admission status, and outcomes 30 days later. In addition to the primary goals, the registry will provide a vital platform for characterizing the course, epidemiology, clinical features, and prognosis of patients tested for COVID‐19 in the ED setting.

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has impacted citizens internationally. As of October 12, 2020, there have been over 7 million infections and 215,000 deaths across the United States (US), with the number of cases growing. 1 diagnostic test availability and accuracy. 2, 4, 6, 7 In addition, the clinical picture of SARS-CoV-2 infection has a wide range of presenting symptoms, followed by a wide spectrum of associated complications and outcomes. [8] [9] [10] [11] [12] The emergency department (ED) is a key location for disease surveillance and collection of data to answer critically important questions about COVID-19 prediction, prognosis, and outcome. Furthermore, the ED is the catchment location for the population who may not have access to routine medical care and may use the ED exclusively for ondemand care and may be most threatened by this outbreak. Toward that goal, this report describes the methodology for the creation and execution of the registry of suspected COVID-19 in emergency care JACEP Open 2020;1:1341-1348. wileyonlinelibrary.com/journal/emp2 (RECOVER), a national registry of ED patients tested for severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2). The primary goals of this work involve the prediction of positive testing for SARS-CoV-2 and prognosis of patients with infection. RECOVER will also provide the platform for answering myriad other COVID-19 questions.

The RECOVER registry is the result of a grass-roots effort of a con- 

The registry is being completed by a network of 45 site investigators from 27 states listed in Figure 1 . Most of the sites are part of hospital systems, and as a result, data are derived from patients seen at 155 hospitals. The majority of hospitals are located in metropolitan areas, and ≈60% are community hospitals without residency programs.

The This form was pilot-tested at 19 sites before network-wide implementation. This pilot testing resulted in multiple changes to clarify fields, alter input ranges, and methods of questioning, and response options. As one example, this process resulted in adding more detail on timing of all tests relative to the index visit and results of antibody 

The primary outcomes were COVID-19 diagnosis and severe COVID- 19 . The criterion standard for COVID-19+ was a positive swab for SARS-CoV-2 nucleic acid by a molecular detection (rtPCR or other amplification technique) or positive convalescent sera for anti-SARS-CoV-2 IgM or IgG. 15, 16 We recognize the imperfect test sensitivity of the swab-based rtPCR and also serum antibody testing. 17 The

Timeline of eligibility and follow-up. The index visit refers to the first ED visit that occurred within the previous 14 days of SARS-CoV-2 testing. In many cases, the index visit is the same as the day of testing (day 0). All patients are followed for outcomes up to 30 days after the day of SARS-CoV-2 testing most pragmatic method to categorize patients as "clinically negative" 

Funding was derived from unrestricted internal monies from the

Medicine under the direction of the senior principal investigator (JAK).

The first defined aim of the study was to develop pragmatic criteria for a COVID-19 Rule Out Criteria-CORC rule that predicts an acceptably low probability of SARS-CoV-2 infection to forego testing. The general analytic strategy will encompass the use of logistic regression with positive SARS-CoV-2 testing as the primary outcome, and demographic, symptomatic, risk factors, vital signs, and past medical history as the predictor variables. The logistic regression coefficients will be used to create a pretest probability scoring system. To make the CORC rule widely applicable, the predictor variables will only include variables available in almost all cases at the bedside, including demographics, patient-reported exposure, vital signs, history of present illness, medications, past medical history, and findings from physical examination. The sample size estimate for the first aim was based on preliminary work done in March 2020, including a survey of 20 participating sites. We anticipated a SARS-CoV-2 positive rate between 8% to 66%, with an average of 31% (ie, 69% of testing negative). We also anticipated that ∼15% of the COVID-19 patients would have atypical presentations and ≈20% would go on to require mechanical ventilation or experience death, defining severe disease. Thus, a minimum sample size of 20,000 patients was anticipated to produce ≈6000 positive cases, including 600 with atypical features and 800 with severe disease. These samples would allow sufficient patients to derive pretest probability on a random sample of 10,000 patients using bivariate-multivariable approach and assuming a traditional 10:1 rule for the ratio of outcomes to predictors in a logistic regression equation; thus, this sample will allow inclusion of at least 25 predictor variables without significant overfit for atypical presentations. 18 The derived rule will be tested in the remaining independent sample.

Each site is asked to enroll at least 500 patients with a complete RED- 

The goal was to complete 20,000 forms within 6 months of study initiation (ie, September 2020). As of October 12, 2020, over 31,500 forms have been uploaded. The end of data collection is planned for October 16, 2020.

This registry is restricted to ED patients who received a SARS-CoV- Although registries can show associations, they have limited ability to establish causal inference. 19 

The RECOVER registry will provide data describing the presenting clinical characteristics and 30-day outcomes of over 30,000 US ED patients tested for SARS-CoV-2. This database will serve as a resource to create probabilistic tools for diagnosis and prognosis and to generate hypotheses about diverse aspects of the COVID-19 pandemic. 19 To our knowledge, this will be the largest and most geographically diverse registry of patients with suspected COVID-19 in emergency care. The

Steering Committee and the site investigators debated, discussed, and pilot-tested each question to ensure its scientific importance, clarity, or adequate explanation by "field notes," so that persons with modest research experience could complete them with minimal training.

This was essential, given the need for remote training and data entry. Although many prognostic criteria have been proposed, a recent systematic review of literature yielded an urgent need for high-quality diagnostic and prognostic data for COVID-19. 22 The authors note that "Of 541 papers that reported clinical characteristics, 295 were commentaries/expert opinions and 36 were case reports. There were no randomized clinical trials, 45 case series studies, 58 narrative reviews, 1 cohort study, and 5 systematic reviews." 22 The RECOVER registry may be unique because it includes ED patients who are both SARS-CoV-2 positive, as well as those who had suspected COVID-19, but who have negative diagnostic testing for SARS-CoV-2. This methodology specifically addresses the current critical need for a data set to derive and test-pretest probability and exclusionary rules for COVID- 19 , as has been done with many other diseases, notably pulmonary embolism. 23 The proposed CORC rule can be used to guide the decision whether to test or not, and assuming that accurate likelihood ratios can be produced for diagnostic tests for SARS-CoV-2, the pretest probability criteria derived from this work will allow an estimate of post-test probability. 6, 24 With upcoming influenza, respiratory syncytial, and other viral challenges approaching, the need for clinical criteria to exclude or estimate the probability of COVID-19 may increase.

Therefore, evidence-based pretest probability criteria, an exclusionary rule, and criteria to predict mild versus severe disease course, will be important to facilitate prudent decisions about the optimal and safe location of post ED care, timing of follow-up, or need for inpatient monitoring for clinical deterioration.

Finally, in terms of ancillary (hypothesis-generating) work, the RECOVER registry is a unique cooperative effort intended to be a public resource to address many other questions. As one example, the observation of increased risk of venous thromboembolism in critically ill patients with COVID-19 patients has particular concern in emergency care, because early anticoagulation may improve outcomes. [25] [26] [27] Opinions conflict about the use of empiric full-dose anticoagulation for patients with known or suspected COVID-19. [28] [29] [30] This debate is at least partly fueled by the lack of data to estimate the risk ratio for the short-term incidence of venous thromboembolism diagnosis after a positive SARS-CoV-2 test, compared with symptomatic patients who test negative for SARS-CoV-2 in the emergency care setting. 31, 32 The RECOVER registry will directly address that knowledge gap. For ancillary proposals, contributing sites in Figure 1 have first rights to submit for approval by the Steering Committee. After publication of the initial set of manuscripts, in approximately June, 2021, we will open the RECOVER registry to proposals from the general scientific community. Data access will be free of monetary charge, but will be subject to approval by the Steering Committee.

Defining the Epidemiology of Covid-19 -Studies Needed

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Comparison of molecular testing strategies for COVID-19 control: a mathematical modelling study

Making sense of mutation: what D614G means for the COVID-19 pandemic remains unclear

Diagnosing COVID-19 in the emergency department: a scoping review of clinical examinations, laboratory tests, imaging accuracy, and biases

Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection

Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

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Clinical characteristics of coronavirus disease 2019 in China

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COVID-19 testing: the threat of false-negative results

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Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease

Performance of VivaDiagTM COVID-19 IgM/IgG Rapid Test is inadequate for diagnosis of COVID-19 in acute patients referring to emergency room department

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Venous thromboembolism in hospitalized COVID-19 patients: systematic review

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The authors present this work on behalf of all site principal investigators in the RECOVER network. This work was made possible by the administrative oversite of Patti Hogan and Amanda Klimeck.

The authors declare no conflicts of interest.

JAK conceived the study, wrote the initial protocol, drafted the case report form, organized sites, obtained funding, collected data, and wrote, edited, and approved this manuscript. KLP assisted with drafting and revising of the case report form, organized sites, collected data, maintained the database, and edited and approved this manuscript.CK assisted with drafting and revising of the case report form, collected data, maintained the database, and edited and approved this manuscript. DMC assisted with drafting and revising of the case report form, collected data, maintained the database, and edited and approved this manuscript. KEN assisted with study design, data collection, manuscript preparation, and editing. CAC assisted with drafting and revising of the case report form, organized sites, collected data, maintained the database, and edited and approved this manuscript. All authors approved the submitted version of this manuscript. JAK takes the final responsibility of the article.