key: cord-0684064-qqe331ok
authors: Whyte, Martin B.; Kelly, Philip A.; Gonzalez, Elisa; Arya, Roopen; Roberts, Lara N.
title: Pulmonary embolism in hospitalised patients with COVID-19
date: 2020-07-10
journal: Thromb Res
DOI: 10.1016/j.thromres.2020.07.025
sha: 3e9b5f2111cc51de166f88b1223c63d4d629a355
doc_id: 684064
cord_uid: qqe331ok

BACKGROUND: Coronavirus disease 2019 (COVID-19) is characterised by dyspnoea and abnormal coagulation parameters, including raised D-dimer. Data suggests a high incidence of pulmonary embolism (PE) in ventilated patients with COVID-19. OBJECTIVES: To determine the incidence of PE in hospitalised patients with COVID-19 and the diagnostic yield of Computer Tomography Pulmonary Angiography (CTPA) for PE. We also examined the utility of D-dimer and conventional pre-test probability for diagnosis of PE in COVID-19. PATIENTS/METHODS: Retrospective review of single-centre data of all CTPA studies in patients with suspected or confirmed COVID-19 identified from Electronic Patient Records (EPR). RESULTS: There were 1477 patients admitted with COVID-19 and 214 CTPA scans performed, of which n = 180 (84%) were requested outside of critical care. The diagnostic yield for PE was 37%. The overall proportion of PE in patients with COVID-19 was 5.4%. The proportions with Wells score of ≥4 (‘PE likely’) was 33/134 (25%) without PE vs 20/80 (25%) with PE (P = 0.951). The median National Early Warning-2 (NEWS2) score (illness severity) was 5 (interquartile range [IQR] 3–9) in PE group vs 4 (IQR 2–7) in those without PE (P = 0.133). D-dimer was higher in PE (median 8000 ng/mL; IQR 4665–8000 ng/mL) than non-PE (2060 ng/mL, IQR 1210–4410 ng/mL, P < 0.001). In the ‘low probability’ group, D-dimer was higher (P < 0.001) in those with PE but had a limited role in excluding PE. CONCLUSIONS: Even outside of the critical care environment, PE in hospitalised patients with COVID-19 is common. Of note, approaching half of PE events were diagnosed on hospital admission. More data are needed to identify an optimal diagnostic pathway in patients with COVID-19. Randomised controlled trials of intensified thromboprophylaxis are urgently needed.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), defined as coronavirus disease 2019 (COVID-19) is a global pandemic. The clinical features of COVID-19 include fever, cough, fatigue, muscle pain, diarrhoea, and pneumonia. Dyspnoea is seen in approximately one-fifth of patients 18.7%. [1] However, in a series from China, COVID-19 produced no radiographic or CT abnormality in 157 of 877 patients (17.9%) with non-severe disease [1] . Severe cases are characterised by acute respiratory distress syndrome, metabolic acidosis, septic shock, coagulation dysfunction, and organ failure. [2] [3] [4] In addition to immobility induced by malaise and dyspnoea, COVID-19 predisposes to systemic inflammation which has been reported to increase the risk for deep vein thrombosis (DVT) [5] , with PE seen in 16.7-47% of patients admitted to intensive care unit (ICU) [6] [7] [8] [9] despite the use of thromboprophylaxis .

Elevated D-dimer values were reported in up to 43% of patients with COVID-19 [10] , with higher values seen in patients with more severe disease [11, 12] . Therefore, in the context of COVID-19 infection, identifying who to investigate for co-morbid pulmonary embolism (PE) is highly challenging.

D-dimer is a continuous variable, reflecting increasing risk for PE [13] , and is used to further risk stratify patients with low pre-test probability -with imaging not required in those with negative Ddimer [14, 15] . Patients with PE and significantly raised D-dimers have been shown to be more often hypotensive, tachycardic, and/or hypoxemic [16] . The radiographic burden of pulmonary thrombotic disease may also be greater with high D-dimer values [17, 18] .

We therefore examined the clinical and radiographic characteristics of patients with COVID-19, who underwent pulmonary imaging for possible thrombotic disease. We report the incidence of PE and looked at the utility of D-dimer and Wells score in this patient cohort.

J o u r n a l P r e -p r o o f

This was a retrospective analysis of adult inpatients with suspected COVID-19, having imaging to codiagnose PE, at King's College Hospital, London, UK, with a high regional numbers of COVID-19 cases [19] . Data collection was from 3 rd March 2020 and concluded on 7 th May 2020. At our institution, patients with suspected PE undergo a two-level PE Wells score, with mandatory recording of allcomponents of the Wells score in the electronic request for PE imaging. Imaging is not undertaken for those considered 'PE unlikely' by the Wells rule (score <4) in conjunction with a D-dimer result below 500 ng/mL. Hospitalised patients were categorised as ICU patients or ward patients (if they were not transferred to ICU during hospitalisation). Weight based thromboprophylaxis was standard of care for all patients admitted with COVID-19 (in the absence of contraindication). Patients with weight <50kg receive enoxaparin 20mg once daily; weight 50-100kg, enoxaparin 40mg od; 100-150kg, enoxaparin 80mg once daily and >150kg, enoxaparin 120mg once daily. This was also the case in patients admitted to ICU with eGFR>30ml/min, with unfractionated heparin 5000 units twice daily given to those <100kg, increasing to three times daily in higher body weight. From 24 th April, intermediate dosing was utilised in ICU only (see Supplementary Table 1 ).

D-dimer was measured by a latex photometric immunoassay, with STA-Liatest. Values over 500ng/mL are considered positive; the intraassay CV at this value is 10%. The upper limit of reporting of D-dimer assay is 8000ng/mL, we obtained raw values for this study, where available. Fibrinogen was measured by the Clauss method, with STA-Fibrinogen. Prothrombin time (PT was measured by coagulation-based assay with STA NeoPTimal. All reagents were obtained from Diagnostica Stago (Asnières, France), with assays performed on the automated analyzer STA-R Evolution as per manufacturer's instruction (Diagnostica Stago). Detection of COVID-19 was from viral RNA isolated from nasopharyngeal swabs using reverse transcriptase polymerase chain reaction (rtPCR). Computed Tomography Pulmonary Angiogram (CTPA) was performed using a GE Discovery CT750HD (Chicago, Il, USA). The interval between D-dimer and CTPA was less than 48 hr.

Using the Electronic Patient Records (EPR; Allscripts Sunrise™, Chicago, Il), we collected data for vital signs (including the National Early Warning Score 2; NEWS2 [20] ), components of Wells score from the clinical notes (not the completed imaging request form), basic demographic data, laboratory values and imaging results (CTPA and venous ultrasonography, if performed). PE is most or equally likely was considered present in patients with a sudden unexplained clinical deterioration, eg without new changes on chest X-ray. If there was no documentation for a component of the Wells score, it was considered absent. In cases with no documentation in the EPR, a Wells score was not calculated. CT scans were requested by the treating clinician for suspected PE. The free text of EPR was reviewed for clinician entry stating whether COVID-19 was suspected. COVID-19 swab results were obtained from EPR. The date and time of CTPA request was extracted from the EPR. All laboratory and clinical variables were taken as the last values recorded before CTPA request.

The Wells score was calculated post hoc by the authors [21, 22] , using only data available in the clinical record at the time of CTPA request. PE was considered most, or equally likely where there was an unexplained deterioration in clinical status. Normality was determined by Kolmogorov-Smirnov test. Parametric and non-parametric distributed quantitative variables were compared using the Student's t-test and the Mann-Whitney U test, respectively. Categorical variables including gender, or presence of a venous thromboembolism (VTE) risk factor were compared using the chisquared test (two-tailed). Contingency tables were constructed to evaluate the accuracy of using the D-dimer level to diagnose PE, with CTPA as the gold standard. Receiver operating characteristics (ROC) curve analysis was performed and area under the curve (AUC) calculated.

The results are given as the mean ± standard error of mean (SEM), median (interquartile range), or number (percentage), wherever appropriate. A P value of <0.05 was considered statistically significant. Data analysis was made using SPSS Statistics for Windows, version 26 (IBM Corp, Armonk, New York, USA).

J o u r n a l P r e -p r o o f continued therapeutic anticoagulation for pre-existing comorbidities (eg atrial fibrillation). Four patients did not receive any anticoagulant prophylaxis due to a contraindication (active bleeding or severe thrombocytopenia). Data were unavailable for four patients for whom a paper prescription record was in use.

Wells score: The Wells score was no different between those with and without PE ( Table 1) Table 1 . (Table 1) , with higher values seen in those with PE in both the low and high pre-test probability groups (Fig 2) . The performance of the D-dimer assay to determine PE is shown as a receiver operating characteristic (ROC) curve (Fig 3) . 

This study of hospitalised patients showed that in patients with suspected or confirmed COVID-19, and clinical suspicion for PE, more than one-third of CTPA studies were positive for PE. This compares to the yield of CTPA of inpatients, prior to the COVID-19 epidemic, of 12 to 17 % [24] [25] [26] , and 18% in an ICU environment [25] . Most literature on the use of CTPA centres on over-utilisation, particularly if yields fall below 10% [24] [25] [26] . The high-yield from CTPA in our series raises the possibility of relative under-diagnosis of PE in patients with COVID-19. Neither the Wells score, nor NEWS2 (a marker of general illness severity), differentiated between positive and negative studies.

Of Wells score components, only the presence of symptoms or signs of DVT were significantly greater in PE, although only evident in just over a tenth of cases. Our data suggest that the D-dimer has a positive predictive value for thrombotic events of approximately 70% when values approach 5000 ng/mL. No D-dimer threshold had an adequate NPV to eliminate the need for diagnostic imaging. We found the overall proportion of patients with PE to be 5.4%, increasing to 16.2% in ICU patients. PE was diagnosed in 3.5% patients receiving ward-based care, similar to that reported in Italy and the Netherlands (6.6% and 3.3% respectively). [8, 9] The higher rate of PE in ICU patients is consistent with previous reports (16.7 -47%), albeit at the lower end. This may partly be explained by imaging requested on clinical suspicion, compared to some centres incorporating screening imaging. [6] [7] [8] [9] The use of EPR means that data capture of requests and results was very high. However, as with any retrospective dataset evaluation, selection bias is likely. CTPA request would more likely be made after high D-dimer results, making assessment of the performance of D-dimer challenging. We used the D-dimer value closest to the request for CTPA. Evolution of D-dimer values may occur during illness, and evaluation of serial measurement would be of interest in COVID-19 patients.

Retrospective calculation of the Wells score based on author evaluation of the notes up to the time of imaging request relies on accurate recording of comorbidities and clinical features within the notes. We adopted this approach as previous audit has demonstrated the Wells recorded is not consistently recorded with accuracy in the imaging request. [21] In our series, very few individuals had fibrinogen measured (outside of ICU) and we are therefore unable to determine the presence of DIC for most of the cohort. Tang et al, (2020) [12] highlighted that the majority of COVID-19 patients who died during hospital stay, fulfilled the criteria for disseminated intravascular coagulation (71.6 vs. 0.6% in survivors) although overall numbers were low (15 of 21 non-survivors, total cohort n= 182). Of note, other markers of DIC were not prevalent J o u r n a l P r e -p r o o f in our cohort (seven patients with platelets < 100x10 9 /l and 11 with PT prolonged >3 seconds). Apart from D-dimer, coagulation markers were not significantly associated with PE.

There is debate as to whether the PE seen in COVID-19 represents true 'thrombus embolisation' or whether this may be localised 'immunothrombosis'. [27, 28] 51% of cases in our cohort were limited to unilateral segmental/subsegmental vasculature. A minority of patients (9%) had DVT imaging performed, with DVT confirmed in 11/19 scans including seven patients with confirmed PE. Of note, the majority of events were proximal DVT (n=8). Of patients with both DVT and PE, only 1 had PE limited to the segmental vasculature with all others demonstrating more proximal thrombosis. We did not collect data on whether segmental/subsegmental PE were co-localised to areas with lung parenchymal disease.

All patients diagnosed with PE during hospitalisation had received at least weight-based thromboprophylaxis beforehand. Whilst this may raise concern regarding the efficacy of thromboprophylaxis, it should be noted that the overall only 5.4% of patients hospitalised with COVID-19 were diagnosed with PE. Furthermore, in our series, over half of all imaging occurred within the first 72 hours of admission (43% of positives) suggesting PE may develop earlier in the disease, prior to hospitalisation. We therefore caution against intensified thromboprophylaxis strategies outside ICU without further evaluation in randomised controlled trials.

In summary, we have found that the diagnostic yield of CTPA for PE in patients with confirmed or suspected COVID-19 is high. A high index of clinical suspicion for PE in patients with COVID-19 is

warranted. An optimal D-dimer threshold to exclude PE without imaging was not identified; further studies to optimise risk stratification of patients for PE imaging are welcomed. Randomised controlled trials to evaluate intensified thromboprophylaxis strategies are urgently needed. Addendum M.B.Whyte data acquisition, data analysis, manuscript writing; E.Gonzalez data acquisition, P.Kelly and R.Arya study conception and data analysis. L.N.Roberts data acquisition and analysis, study conception. All authors were involved in manuscript revision and approved the final version.

J o u r n a l P r e -p r o o f 

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