key: cord-299888-ig0gy5e9
authors: Ooi, M.W.X.; Rajai, A.; Patel, R.; Gerova, N.; Godhamgaonkar, V.; Liong, S.Y.
title: Pulmonary thromboembolic disease in COVID-19 Patients on CT Pulmonary Angiography –Prevalence, pattern of disease and relationship to D-dimer
date: 2020-10-06
journal: Eur J Radiol
DOI: 10.1016/j.ejrad.2020.109336
sha: 
doc_id: 299888
cord_uid: ig0gy5e9

OBJECTIVES: To define the prevalence of pulmonary thromboembolic (PTE) disease diagnosed on CT pulmonary angiography (CTPA) in COVID-19 patients. To assess distribution of PTE and to evaluate for association between severity of COVID-19 disease, D-dimer values and incidence of PTE. METHODS: Patients with diagnosis of COVID-19 presenting to 5 different hospitals across Greater Manchester between 1(st) March 2020 and 30(th) April 2020 who had CTPA were included. CTPA images were evaluated for presence of PTE, distribution of PTE (in small and/or large vessels) and distribution of PTE within lungs with or without COVID-19 CT changes. Severity of COVID lung changes were graded. D-dimer values within 72 hours of CTPA were obtained. Statistical analyses were performed to evaluate for any significant association between variables. p values of ≤ 0.05 were regarded as statistically significant. RESULTS: A total of 974 patients presented across five hospital sites with COVID-19 infection. Eighty-four (n = 84) COVID-19 patients underwent CTPA. Of these, 38% (32/84) had PTE. PTE was seen in small vessels in 75% (24/32) and in lungs demonstrating COVID-19 changes in 72% (23/32). 84% (27/32) of PTE positive patients had disease severity of moderate or higher score (p = 0.005). D-dimer values were significantly higher (p ≤ 0.001) in PTE patients, median value in PTE group was 6441mcg/L(range219-90925). A D-dimer cut off value of 2247mcg/L provides sensitivity of 0.72 and specificity of 0.74. CONCLUSION: There is increased prevalence of PTE in patients with moderate to severe COVID-19 disease. D-dimer values may have potential in guiding anticoagulation therapy and prognostication.

3 analyses were performed to evaluate for any significant association between variables. p values of ≤ 0.05 were regarded as statistically significant.

A total of 974 patients presented across five hospital sites with COVID-19 infection. Eightyfour (n=84) COVID-19 patients underwent CTPA. Of these, 38% (32/84) had PTE. PTE was seen in small vessels in 75% (24/32) and in lungs demonstrating COVID-19 changes in 72% (23/32). 

There is increased prevalence of PTE in patients with moderate to severe COVID-19 disease. D-dimer values may have potential in guiding anticoagulation therapy and prognostication. Disseminated intravascular coagulopathy (DIC) has been reported in the majority of deaths from COVID-19 infection [1] . Pathogenesis of hypercoagulability in critically ill patients have been attributed to infection induced endothelial cell dysfunction [2] , increased blood viscosity and hypoxia induced transcription factor dependent signalling pathway [3, 4] . Heparin resistance has also been reported in COVID-19 patients [5] . The incidence of venous thromboembolic disease (VTE) in patients with severe COVID-19 pneumonia on intensive care unit (ITU) has been reported as 25% [6] . This compares with a VTE rate of 12.7% in ITU patients without COVID-19 [7] . Studies have also reported increased frequency of pulmonary thromboembolic disease (PTE) in COVID-19 patients. The incidence of pulmonary emboli in COVID-19 patients has been reported in the literature to be between 23-30% [8, 9] . There have also been reports of a strong correlation between D-dimer value and disease severity [9, 10] .

The aim of this study was to define the prevalence of PTE diagnosed on CT pulmonary angiography (CTPA) in COVID-19 patients and to assess the distribution of PTE within the lungs. We also sought to evaluate association between severity of COVID-19 disease graded on CT, D-dimer values and incidence of PTE.

J o u r n a l P r e -p r o o f curve was plotted to determine the ability of diagnosing PTE associated with different cut off points of D-dimer.

March and April 2020. Median age was 70 (range 19-101years), male to female ratio was 58:42. In 90% of these patients, diagnosis was based on positive RT-PCR swab, whilst in the remaining 10%, diagnosis was made on basis of strong clinico-radiological suspicion of COVID-

Eighty-six patients (8.8%) underwent CTPA. However, two patients were excluded from analysis due to having had incomplete CTPA examinations ( Figure 1 ). Only ten (10/84 examinations were performed in March. The remaining seventy-four examinations were performed in April.

The indications for CTPA requests in these patients can be seen on Table 2 ). The severity of disease was higher in the PTE positive group (p=0.005, Table 2 and Figure 2 (Tables 2 and 3 ).

In patients with PTE, 75% (24/32) of thromboembolus were observed within small vessels (subsegmental or smaller) and 25% (8/32) had thromboembolus within both small and J o u r n a l P r e -p r o o f larger vessels. There was no association between severity of disease and distribution of PTE (p=0.95, Table 4 ).

In 72% (23/32) of patients, PTE was observed in regions of lung demonstrating COVID-19 change. In the remaining 28% (9/32), PTE was observed in regions of lung without COVID-19 changes (Table 5 ). Over 70% of patients with disease severity 3 or more had PTE seen in diseased lungs, however, the difference was not statistically significant (p=0.2).

Sixty-three patients (25 in 

This study shows an increased prevalence of PTE in patients with more severe COVID-19

disease and demonstrates the role of D-dimer levels in this patient cohort. 

We did not find any statistically significant difference in gender nor age in patients with or without PTE (Table 2) . This is concordant with several other studies [14, 16] . However, this is in contrast to studies performed by Grillet et al [8] and Fauvel et al [17] , which found that males were statistically more likely to develop pulmonary emboli. It has also been reported in the literature that men tend to have more severe disease with COVID-19 infection than women [18] .

In our cohort, there is a significant correlation between incidence of PTE and severity of COVID-19 disease abnormality on CTPA imaging. This is consistent with published literature [12] , suggesting prothrombotic states in critically ill patients.

It is important to distinguish between pulmonary emboli and pulmonary thrombosis in situ (thrombi within diseased lung), because their pathogenesis and management are potentially different. In COVID-19 positive patients, pulmonary thrombosis in situ may develop as a consequence of vascular damage and thrombo-inflammation associated with the infection [19, 20] . The literature also suggests that whilst prophylactic low molecular weight heparin (LMWH) may be effective in preventing VTE, it may not be effective in preventing pulmonary thrombosis in situ [19] . In our cohort, the majority of patients had small vessel thrombosis within diseased lung. This may suggest pulmonary thrombosis in situ as a potential pathogenesis and thus a different treatment strategy will need to be considered.

A recent study on lung autopsy findings noted that alveolar microthrombi were 9 times more prevalent in patients who died from COVID-19 when compared to uninfected control lungs [21] . D-dimer levels were significantly higher in the PTE group compared with non-PTE group, as observed in other studies [14, 16, 17] . This is important as increased D-dimer levels have been associated with increased mortality [23] in adult patients with COVID-19.

A D-dimer value of 2247mcg/L was identified to provide a sensitivity of 72% and 74%, respectively, for development of PTE in our cohort of COVID-19 patients. This is similar to the D-dimer cut-off level in COVID-19 patients reported by Leonard-Lorant et al. [9] at 2660mcg/L and is much higher than the usual 500mcg/L cut-off point clinical teams use for the general population [24] . It is well published that acute infections can also cause a rise in D-dimer levels.

At the end of April, our institution published anticoagulation guidelines suggesting that any patient with suspected COVID-19 infection, high clinical suspicion of PTE and a D-dimer level between 500-3000mcg/mL should receive prophylactic dose LMWH and CTPA. This is in line with recommendations published in the Netherlands [25] . Before these guidelines were published, CTPA examinations for COVID-19 patients were mainly performed based on clinical suspicion ( Table 1) .

The limitations of this study include its retrospective nature and small sample size. An argument could be made that in the UK, there is a proportion of COVID-19 patients in the community (eg: nursing home residents) who were not sampled (for example, secondary to rapid deterioration before reaching the hospital). Our sample size is limited at this relatively early stage of the pandemic in the UK. Our findings should be validated in an adequately powered clinical study in the future. Ethnicity as a risk factor was not evaluated in this study.

Future studies looking into this would be useful considering there are increasing reports that Black and Ethnic Minority(BAME) population may be more severely affected by COVID-19

infections [26] . 

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 

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