key: cord-0711311-a8d8coyt authors: Elberts, Samuel J.; Bateman, Ryan; Koutsoubis, Alexandra; London, Kory S.; White, Jennifer L.; Fields, J. Matthew title: The impact of COVID‐19 on the sensitivity of D‐dimer for pulmonary embolism date: 2021-08-23 journal: Acad Emerg Med DOI: 10.1111/acem.14348 sha: cd8e40bd1e7e674e652ff0d227fdc6a9d90d471d doc_id: 711311 cord_uid: a8d8coyt OBJECTIVE: This study seeks to evaluate the test characteristics of D‐dimer for pulmonary embolism (PE) in patients with a concurrent diagnosis of COVID‐19. We hypothesized that the sensitivity of D‐dimer for PE at current institutional cut points would be similar to those without COVID‐19. METHODS: This is a multicenter retrospective observational cohort study across five urban and suburban EDs in the same health care system. The electronic health record was queried for all computed tomography pulmonary angiography (CTPA) studies from December 1, 2019, to October 22, 2020. All ED patients who underwent CTPA had D‐dimer and COVID‐19 testing completed in a single encounter were included in the study. Baseline demographics were obtained. Test characteristics of D‐dimer for PE were calculated for patients with and without COVID‐19. Additionally, receiver operator characteristics (ROC) curves were constructed for two different D‐dimer assays. RESULTS: There were 1158 patient encounters that met criteria for analysis. Performance of D‐dimer testing for PE was similar between COVID‐19–positive and –negative patients. In COVID‐19–positive patients, the sensitivity was 100% (95% confidence interval [CI] = 87.6%–100%), specificity was 11.9% (95% CI = 7.9%–17.1%), and negative predictive value (NPV) was 100%. In COVID‐19–negative patients the sensitivity was 97.6% (95% CI = 91.5%–99.7%), specificity was 14.4% (95% CI = 12.1%–17%), and NPV was 98.3% (95% CI = 93.8%–99.6%). For assay 1 the area under the curve (AUC) for COVID‐19–positive patients was 0.76 (95% CI = 0.68–0.83), and for COVID‐19–negative patients, 0.73 (95% CI = 0.69–0.77). For assay 2, AUC for COVID‐19–positive patients was 0.85 (95% CI = 0.77–0.92), and for COVID‐19–negative patients, 0.80 (95% CI = 0.77–0.84). Inspection of the ROC curve for assay 1 revealed that 100% sensitivity was maintained up to a threshold of 0.67 FEU (fibrinogen equivalent units; from 0.50 FEU) with an increase in specificity to 29% (from 18.7%), and for assay 2, 100% sensitivity was maintained up to a threshold of 662 D‐dimer units (DDU; from 230 DDU) with an increased specificity to 59% (from 6.1%). CONCLUSION: Results from this multicenter retrospective study did not find a significant difference in sensitivity of D‐dimer for PE due to concomitant COVID‐19 infection. Further study is required to determine if PE can safely be excluded based on D‐dimer results alone in patients with suspected or proven COVID‐19 or if adjusted D‐dimer levels could have a role in management. Pulmonary embolism (PE) is an important cause of emergency department (ED) visits, accounting for approximately 0.08% of annual ED visits. 1 The current criterion standard diagnostic imaging modality for PE is the multidetector computed tomography pulmonary angiography (CTPA). Clinical decision rules and D-dimer assays help risk stratify patients with presentations concerning for PE and have helped reduce the number of unnecessary CT scans in this population. 2 COVID-19 has added new uncertainty to the role of D-dimer testing in the evaluation of PE. COVID-19 creates a hypercoagulable state, leading to the increased incidence of venothromboembolism (VTE) within this population. [3] [4] [5] [6] Research has demonstrated D-dimer levels have clinical utility as surrogate markers for disease severity in COVID-19 patients, with higher levels associated with poor prognosis. [7] [8] [9] [10] This has led to widespread adoption of screening COVID-19 patients with D-dimer levels in an attempt to characterize disease severity. Numerous cohort studies have shown an increased burden of thromboembolic disease in hospitalized patients with COVID-19, despite prophylactic anticoagulation, ranging from 2.6% to 8.9% of all hospitalized patients. 6 The D-dimer's role in workup for PE in the setting of COVID-19 has not been fully elucidated. Among patients with COVID-19, the additional presence of VTE is associated with higher D-dimer values than in COVID-19 patients without VTE, and higher cutoff values have been suggested when ruling out VTE. 11 The purpose of this study was to determine the test characteristics of D-dimer for diagnosing PE in ED patients with COVID- 19 . We hypothesized that the sensitivity of D-dimer for PE in ED patients with COVID-19 will be similar to those without COVID-19. This is a multicenter retrospective observational cohort study. The study was approved by the hospital institutional review board. Study design follows the standards for reporting diagnostic accuracy (STARD). 12 Records from two urban and three suburban EDs within the same hospital system were included in this study. One of the urban sites is a large tertiary hospital with an annual volume of 70,000 All final CTPA reports were reviewed by one of the three study personnel (two resident emergency medicine physicians and one third-year medical student) for presence or absence of acute PE, as reported by the attending radiologist, using a predetermined data abstraction method. Reviewers were blinded to the patient's clinical data except as contained in the radiology report. All emboli noted to be definitively chronic per the radiologist's report were considered negative studies. Studies were diagnostic if the report characterized the quality of the study to be sufficient to be read to the segmental arteries, otherwise they were considered non-diagnostic and re- The EHR was additionally queried for demographics including age, sex, race, and body mass index, as well as history of prior VTE, presence of hypercoagulable disorder, and presence of active malignancy, D-dimer values, and COVID-19 status. Additionally, in-hospital mortality is reported as a surrogate for severity of illness in each cohort. To calculate the primary outcome 2 Out of 3006 radiologist reports, 64 were nondiagnostic leaving 2954 cases ( Figure 1 ). Of these, 1584 did not have a D-dimer result and were thus excluded from the study. Another 212 were removed because the CT scan occurred greater than 24 h apart from D-dimer. Test characteristics of D-dimer to predict PE for all patients regardless of assay used was similar between patients with and without COVID-19 (Table 2 ). In COVID-19-positive patients, the sensitivity was 100% (95% CI = 87.6% to 100%), specificity was 11.9% (95% CI = 7.9% to 17.1%), and negative predictive value (NPV) was 100%. In COVID-19-negative patients the sensitivity was 97.6% (95% This study demonstrates that D-dimer is a valid tool for the assess- (9) 28 (12) 82 (9) In-hospital mortality 49 (4) 29 (12) 20 (2) Note: Data are reported as n (%) or mean (±SD). Recently, studies have shown that use of an adjusted D-dimer in certain subgroups improves specificity with minimal sacrifice of sensitivity. 21 We constructed an ROC curve to examine overall test performance. International data suggest that D-dimer levels are in- There are several limitations to the current study. The study is retrospective and therefore subject to biases typical of its study design. Finally, as with all studies, the reader should take note of the lower bounds of the 95% confidence intervals of the primary outcome. For example, the sensitivity of D-dimer for PE in COVID-positive patients was 100% but, due to sample size limitations, the lower bound of the 95% CI is 88%. Future studies or meta-analysis of similar studies are needed to further clarify the bounds of D-dimer performance. Results from this study support that D-dimer at baseline cutoffs can reliably exclude PE in the setting of COVID-19 in a large cohort of patients using two different assays and five different EDs. Furthermore, our results suggest that in this subpopulation, the threshold for a positive may be able to be raised for an increase in specificity without sacrificing sensitivity. Future prospective studies should focus on improving the specificity of D-dimer assays via prospective testing of cutoff thresholds in patients with COVID-19. The authors have no potential conflicts to disclose. 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