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Heart, Lung and Circulation (2014) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2014.02.014
ORIGINAL ARTICLE
Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study Qun Luo, MD1, Jiaxing Xie, MD1, Qian Han, MD1, Chunli Tang, MD, Xiaobo Chen, MD, Lulu Wu, MD, Rongchang Chen, PhD* Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital, Guangzhou Medical College, Guangzhou, China Received 12 September 2013; received in revised form 6 January 2014; accepted 19 February 2014; online published-ahead-of-print xxx
Background
To determine the prevalence of venous thromboembolism (VTE) in patients with connective tissue diseaserelated interstitial lung diseases (CTD-ILD) and idiopathic interstitial pneumonia (IIP) and to further evaluate associated risk factors. To also examine the diagnostic performance of the Wells score and the revised Geneva scores for diagnosing pulmonary embolism (PE) in ILD patients.
Method
Fifty-seven patients with CTD-ILD and IIP were prospectively enrolled. Plasma D-dimer was measured by ELISA. Deep-vein thrombosis (DVT) was examined by venous ultrasonography and PE by computed tomography pulmonary angiography. PE prevalence was further assessed by the Wells score and the revised Geneva score.
Results
VTE was diagnosed in 15 (26.3%, 15/57) patients. Bivariate analysis revealed that dyspnoea (OR 3.750, 95% CI 1.095-12.842, P=0.035), lower extremity oedema (OR 8.667, 95%CI1.814-41.408, P=0.007), palpitations (OR 4.75, 95%CI1.073-21.032, P=0.040), and positive D-dimer (OR 5.087, 95%CI 1.015-25.485, P=0.048) were associated with VTE. Using the Wells Score, 46 (80.70%), eight (14.4%) and three (5.26%) patients had a low, intermediate and high probability of PE, respectively, with seven (15.22%), three (37.5%) and two (66.67%) of the respective cases confirmed. By the revised Geneva score, 23 (40.35%), 32 (56.14%) and two (3.51%) patients had a low, intermediate and high probability of PE, respectively, with two (8.70%), nine (28.13%) and one (50.00%) of the respective cases confirmed. The AUC for the Wells score and the revised Geneva score was 0.7200.083 (CI 0.586 to 0.831) and 0.704 0.081 (CI 0.568 to 0.817), respectively.
Conclusion
VTE can be seen in approximately one fourth of patients with CTD-ILD or IIP and the Wells score and the revised Geneva score can be used for categorising PE risk.
Keywords
Venous thromboembolism Interstitial lung disease Pulmonary embolism Wells score Revised Geneva scores
*Corresponding author at: Guangzhou Institute of Respiratory Disease, 151 Yanjiang Road, Guangzhou, China. Tel.: +86-13902273260., Email: [email protected] 1
These authors contributed equally to this work.
© 2014 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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Introduction Interstitial lung diseases (ILDs) are a group of diffuse parenchymal lung disorders that afflict many patients worldwide. Idiopathic interstitial pneumonia (IIP) and connective tissue disease-associated ILD (CTD-ILD) are the most common forms of ILDs. Although the two conditions share similar clinical manifestations, radiographic findings and histopathologic appearance [1,2], they may have distinct outcomes, depending on the organs involved and complications [3]. Venous thromboembolism, which includes deep-vein thrombosis (DVT) and pulmonary embolism (PE), is initiated by endothelial injury of the venous system, and occurs as a result of disequilibrium between coagulation and fibrinolysis [4]. The incidence of venous thromboembolism is increased in CTD patients [5–7]. There are also several anecdotal case reports on the association of PE with IIP [8–13]; most of them came from Japan [9–12]. However, the prevalence of venous thromboembolism in patients with IIP and CTD-ILD has not been reported. PE could aggravate the symptoms of ILD, which may be mistaken for the acute exacerbation of ILD. The Wells score and the revised Geneva scores have been used in the diagnosis of PE, which assess patients with suspected PE based on three levels of probability using non-invasive tests [14]. However, there have not been reports on the use of Wells score and the revised Geneva score for diagnosing PE in ILD patients. In the current study, we sought to determine the prevalence of venous thromboembolism in patients with CTD-ILD and IIP and further to evaluate associated risk factors. We also examined the diagnostic performance of the Wells score and the revised Geneva scores for diagnosing PE in ILD patients.
Patients and methods Patients We prospectively enrolled patients with ILD (CTD-ILD and IIP) who were admitted to the ILD Center at Guangzhou Institute of Respiratory Diseases, Guangzhou, China, between January 1, 2011 and December 31, 2011. IIP was diagnosed according to the American Thoracic Society criteria [2,15,16]. CTDs were diagnosed as described elsewhere [17–23]. CTD-ILD was diagnosed if a subject had a definite diagnosis of CTD, developed respiratory symptoms and signs, and showed diffuse infiltrates or reticular nodules on chest high resolution computed tomography (HRCT) scan, and had no other pulmonary diseases. A subject was excluded from the analysis if 1) he or she failed to receive CTPA and lower-limb venous ultrasonography within 48 hours of admission; 2) he or she had renal failure (plasma creatinine>150 mmol/L); 3) he or she was allergic to intravenous contrast medium, 4) he or she was on anticoagulation therapy at admission; 5) he or she required invasive mechanical ventilation; 6) he or she was diagnosed as ILD other than IIP and CTD-ILD.
The study protocol was approved by the local institutional review board at the authors’ affiliated institution and informed consent was obtained from all study participants or their legal surrogates.
Patient evaluation Patient demographic and baseline data including age, sex, smoking, body mass index (BMI) and comorbid diseases were collected and routine blood chemistries and blood gas analysis were carried out. For D-dimer test, venous blood samples were collected without tourniquets and negative suction to avoid activation of coagulation ex vivo within 30 min after admission. The samples were stored at 80 8C for further testing. The plasma concentrations of D-dimer were measured using commercially available ELISA kits by the manufacturer’s instructions (Tianyou Scientific, Tianjin, China). In addition, autoantibodies including antinuclear antibodies, anti-myeloperoxidase antibodies and anti-PR3 antibodies were determined using commercially available kits.
Venous ultrasonography High definition B mode ultrasound imaging equipment was used with different probes according to the depth of the examined vessels. The inferior vena cava and iliac veins were examined with the patient supine or in the contralateral position, femoral veins and popliteal veins with the patient in a semi-upright position, and calf veins with the patient in a sitting position and both feet resting on a chair. The distal veins including the posterior tibial and peroneal veins, the gastrocnemius, and the soleal veins were also examined. All venous segments were examined over their entire length in the transverse or longitudinal axis. All ultrasound examinations were performed by vascular medicine specialists with at least 10 years of experience in vascular ultrasound imaging. Deep vein thrombosis was diagnosed with lack of compressibility of a deep vein and, for the iliac vein, in the absence of Doppler flow or direct visualisation of a thrombus.
Computed tomography pulmonary angiography CTPA images were obtained as part of standard care with 64 channel multi-detector equipment capable of 2.5 mm collimation with the following imaging parameters: detector width, 64 0.625 or 16 1.25 mm; section thickness, 1.25 mm; rotation time, 0.5 second; 120 kVp; and 380 mA. CT images were reconstructed with both standard soft-tissue and lung kernel algorithms. Two radiologists who were blind to patient data independently assessed PE on CTPA images by detecting the presence of an endoluminal central filling defect partially or completely occluding the pulmonary arteries.
Assessment of PE using the Wells score and revised Geneva score The prevalence of PE was further assessed in the lowprobability, intermediate-probability and high-probability categories as classified by the Wells score [24] and the revised
Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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Geneva score [25] by a clinician who was blind to the final diagnosis. The sensitivity, specificity and predictive values of both the Wells and Revised Geneva Scores were calculated.
Statistical analysis The Student t, one-way ANOVA, and Mann-Whitney U tests were used to compare continuous variables where appropriate. Difference among proportions was determined by Fisher’s exact test. Binary logistic regression model was used to identify independent predictors of venous thromboembolism. These factors were included in the multivariate analysis based on their clinical significance in the univariate analysis. The accuracy of the revised Geneva score and Wells score
was compared by the area under the curve (AUC) in receiver operating characteristic (ROC) analyses. Statistical analysis was performed by using the SPSS software (SPSS Inc., Chicago, IL) and MEDCALC software (Belgium).
Results Patient demographic and baseline characteristics A total of 77 consecutive patients with ILD (CTD-ILD and IIP) were screened for eligibility for the study. The study flow chart is shown in Fig. 1. Twenty patients were excluded
Figure 1 The study flowchart. Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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because of use of invasive mechanical ventilation or ICU admission (n=8), failure to provide informed consent (n=7) or other reasons (n=5). Fifty-seven patients were eligible for inclusion in the study. The demographic and baseline characteristics of these patients are shown in Table 1. They included 29 men and 28 women with a mean age of 61.35 11.00 (range, 30 to 81) years. Thirty patients were diagnosed with CTD-ILD and 27 patients were diagnosed with IIP. Among patients with CTD-ILD, one patient had systemic lupus erythematosus, three had subcutaneous sclerosis, four had rheumatoid arthritis, one had systemic sclerosis, 10 had polymyositis/dermatomyositis, one had mixed CTD, and 10 had undifferentiated CTD. Among patients with IIP, 19 patients had idiopathic interstitial fibrosis and eight had other IIPs.
Incidence of venous thromboembolism Venous thromboembolism was diagnosed in 15 (26.3%, 15/57) of our patients, including 12 cases diagnosed at admission and three cases diagnosed during the three months of follow-up. Three patients were diagnosed with deep-vein thrombosis of the lower extremity and 12 patients were diagnosed with pulmonary embolism. No patient had more than one venous thromboembolism event. Among patients with CTD-ILD, six (20%, 6/30) patients developed venous thromboembolism, including two patients with rheumatoid arthritis, one patient with systemic sclerosis, two patients with polymyositis/dermatomyositis and one patient with undifferentiated CTD. Among patients with IIPs, nine (33.3%, 9/27) patients developed venous thromboembolism, including seven patients with IPF and two patients with other IIPs (Fig. 2). There was no significant difference in the incidence of venous thromboembolism between patients with CTD-ILD and patients with IIPs (X 2 =1.303, P=0.254).
Characteristics of patients with venous thromboembolism We compared the demographic and baseline characteristics of patients with and without venous thromboembolism. The two groups were comparable in gender, BMI, lung functions and comorbidities (Table 2) while patients with venous thromboembolism were apparently older than those without the condition (mean age, 67.7 years vs. 59.1 years; P=0.014). Patients who developed venous thromboembolism had a noticeably higher smoking load (mean pack years, 19.66 vs. non-venous thromboembolism, 6.42; P=0.041). Moreover, significantly more patients with venous thromboembolism had dyspnoea, lower extremity oedema and palpitations than those without (P500 mg/L) than those without (42.9%, 18/42). Our bivariate analysis further revealed that dyspnoea (OR 3.750, 95%CI 1.095-12.842, P=0.035), lower extremity oedema (OR 8.667, 95%CI1.814-41.408, P=0.007), palpitations (OR 4.75, 95% CI1.073-21.032, P=0.040), and positive D-dimer (OR 5.087, 95%CI 1.015-25.485, P=0.048) were more likely
Table 1 Demographic and baseline characteristics of patients with CTD-ILD and IIPs. All patients No. of patients, n(%) CTD-ILD IIP
57(100) 30(52.6) 27(47.4)
Age, years Mean(SD)
61.35(11.00)
Range
30-81
Male gender, n(%)
29(50.9)
Smoking, pack-years Mean(IQT) Body mass index, kg/m2 25
9.91(15) 16(28.1)
Comorbidities Diabetes mellitus Hypertension Coronary heart disease Trauma/surgery Malignancies Immobilisation >7 days Dyspnoea (Recent onset or worsening)
5(8.8) 11(19.3) 8(14.0) 4(7.0) 1(1.8) 11(19.3) 21(36.8)
Lower limb oedema
8(14.0)
Haemoptysis
2(3.5)
Palpitations
8(14.0)
Pleuritic pain
3(5.3)
PaO2, mmHg Mean(IQT)
79.08(19.33)
PaCO2, mmHgz Mean(IQT)
37.44(4.26)
D-dimer, ng/mL 500
21(36.8)
> 500
36(63.2)
Lung function FVC%z Mean(SD)
65.94(23.37)
DLCO%z Mean(SD)
47.56(18.95)
Autoantibodies, U/mL Antinuclear antibody
58.77(56.20)
Mean(IQT) Anti-myeloperoxidase Mean(IQT) Anti-PR3
2.11(1.12)
Mean(IQT)
3.09(2.13)
CRP, mg/dL Mean(IQT)
1.92(2.41)
Data are expressed as n(%) unless otherwise specified. CRP, C-reactive protein; IIP, idiopathic interstitial pneumonias; CTD, connective tissue disease; ILD, interstitial lung disease; IQT, interquartile range.
Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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Table 2 Bivariate analysis of patients with or without venous thromboembolism. P
OR
95%CI
42(73.7) 59.1(11.61)
0.014
1.10
1.02-1.19
24(57.1)
0.12
2.67
0.78-9.17
19.66(30.00)
6.42(11.25)
0.041
1.038
1.002-1.075
6(40)
10(23.8)
0.317
2.133
0.609-7.472
VTE(%) 15(26.3) 67.67(5.62)
No. of patients Age, mean(SD) years
5(33.3)
Male gender Smoking, mean(IQT) pack-years Body mass index 25 kg/m2
Non-VTE(%)
Comorbidities Diabetes mellitus
2(13.3)
3(7.1)
0.369
2.608
0.322-21.131
Hypertension
3(20.0)
8(19.0)
0.906
0.912
0.195-4.265
Coronary heart disease Trauma/surgery
3(20.0) 0(0)
5(11.9) 4(9.5)
0.438 0.999
1.936 0.000
0.365-10.278 0.000
Malignancies
0(0)
0.000
1(2.4)
1.000
0.000
Immobilisation >7 days
1(6.7)
10(23.8)
0.236
0.243
0.023-2.517
Dyspnoea (Recent onset or worsening)
9(60)
12(28.6)
0.035
3.750
1.095-12.842
Lower limb oedema
6(40)
3(7.1)
0.007
8.667
1.814-41.408
Haemoptysis
1(6.7)
1(2.4)
0.458
2.929
0.172-49.996
Palpitations
5(33.3)
4(9.5)
0.040
4.750
1.073-21.032
Pleuritic pain PaO2, mean(IQT) mmHg
1(6.7) 35.34(5.83)
2(4.8) 38.55(8.41)
0.778 0.149
1.429 0.975
0.120-16.998 0.943-1.009
PaCO2, mean(IQT) mmHg
72.41(11.79)
80.622(20.16)
0.167
0.923
0.824-1.034
0.048
5.087
1.015-25.485
D-dimer > 500 ng/mL
13(86.7)
18(42.9)
Lung function FVC%, mean(SD)
76.45(11.79)
67.19(20.76)
0.58
1.01
0.98-1.05
DLCO%, mean(SD)
38.37(12.99)
49.28(17.21)
0.16
0.95
0.875-1.02
CRP, mean(IQT) mg/dL
3.43(6.12)
1.88(2.11)
0.102
1.166
Data are expressed as n(%) unless otherwise specified. CRP, C-reactive protein; IQT, interquartile range; OR, odds ratio; VTE, venous thromboembolism.
to associate with venous thromboembolism. Our multivariate analysis showed that age (OR 1.110 [CI, 1.013-1.217]), pack years of smoking (OR 1.054 [CI, 1.009-1.101]) and palpitations (OR 8.141 [CI, 1.403-47.223]) were independently associated with risk of venous thromboembolism (adj. OR 4.21, P=0.058) (Table 3).
Evaluation of the Wells score and the revised Geneva score The prevalence of PE in the low, intermediate and high pretest probability groups was assessed using the Wells score and the revised simplified Geneva score and is presented in
Table 4. Using the Wells Score, 46 (80.70%) patients had a low probability of PE; of these, seven patients (15.22%) had confirmed PE. Eight patients (14.04%) had an intermediate probability of PE; of these, three (37.50%) had confirmed PE. Three (5.26%) patients had a high probability of PE; of these, two (66.67%) had confirmed PE. According to the revised Geneva score, 23 (40.35%) patients had a low probability of PE; of these, two patients (8.70%) had confirmed PE. Thirty-two patients (56.14%) had an intermediate probability of PE; of these, nine (28.13%) had confirmed PE. Two patients (3.51%) had a high probability of PE; of these, one (50.00%) had confirmed PE. The AUC for the Wells score and the revised Geneva score were 0.7200.083 (CI 0.586 to 0.831)
Table 3 Multivariate analysis of risk factors for venous thromboembolism. ß
Wald
P
Odds ratio
95%CI
Age
0.094
5.142
0.026
1.110
1.013-1.217
Smoking, pack-years
0.042
4.315
0.019
1.054
1.009-1.101
Palpitations
2.097
5.465
0.019
8.141
1.403-47.223
Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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Table 4 Prevalence of pulmonary embolism in the three pretest probability groups as categorised by the Wells score and the revised Geneva score. Pretest probability
Patients(n=57)/
of PE
patients with PE(n=12) Wells
Revised
score
Geneva score
Low
43/4
23/2
Intermediate
11/6
32/9
3/2
2/1
High PE: pulmonary embolism.
and 0.704 0.081 (CI 0.568 to 0.817), respectively. The difference between the AUCs was not statistically significant (z=0.242, P=0.8085).
Discussion Substantial data [26] show that CTD is associated with a significantly increased incidence of venous thromboembolism. Accumulating epidemiological, clinical and experimental evidence reveals that an increased risk of venous thromboembolism is a feature of most CTDs [26], which may have different underlying causes in different CTDs [27]. Suppressed
fibrinolysis, increased procoagulant activity, and decreased anticoagulant activity impact on thrombotic responses, thus contributing to an increased risk of venous thromboembolism in CTDs [26,28]. To our knowledge, our study is the first to investigate the incidence of venous thromboembolism by firstline diagnostic tests (CTPA and ultrasonography) in patients with CTD-ILD and IIPs. Our study demonstrated that approximately one quarter (26.3%) of our patients developed venous thromboembolism. We further showed that several factors, including age, smoking pack years, and palpitations, are associated with increased risk of PE. Only a few studies have examined the relationship between venous thromboembolism and idiopathic pulmonary fibrosis. Two studies exploring the relationship between ILD and DVT or PE were based on autopsy findings or medical database. Using primary care data from the UK, Hubbard et al. [29] identified a cohort of 920 patients with idiopathic pulmonary fibrosis and found that the risk of DVT was greater in idiopathic pulmonary fibrosis than the general population. They did not exclude subjects with ILD whose causes were known. Using death certificate records in the USA, Sprunger et al. [30] found that the risk of venous thromboembolism in decedents with idiopathic pulmonary fibrosis was significantly greater than decedents in the background population, decedents with lung cancer or decedents with chronic obstructive lung disease. Compared with these two studies, the prospective design of this study allowed the detection of asymptomatic venous thromboembolism, especially PE in ILD patients.
Figure 2 Computed tomography pulmonary angiography (CTPA) of a patient diagnosed with IIPs. A–C: The mediastinal and lung window reveals filling defects in the right lower lobe pulmonary artery (arrow). B–D: Follow-up CTPA after treatment shows considerable improvement (arrow). Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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The diagnostic procedure based on D-dimer test, lowerlimb ultrasonography and CTPA in this study led us to characterise more precisely the symptoms and factors associated with the presence of venous thromboembolism in patients with ILD. The symptoms of venous thromboembolism, especially PE, are often confounded with respiratory symptoms in patients with ILD, which probably remain undetected and left untreated. On the contrary, the symptoms implicating venous thromboembolism such as haemoptysis, chest pain, and oedema of the lower limbs do not definitively indicate venous thromboembolism in our study group. In China, dyspnoea is the most frequent initial symptom of acute PE [31]. Although PE has always been suspected in patients presenting with dyspnoea or haemoptysis, dyspnoea in patients with ILD is mostly considered as pure PE. The elevation of plasma D-dimer levels (>500 ng/mL) was more frequent in patients with venous thromboembolism than those without, and elevated plasma D-dimer levels may be associated with increased risk of venous thromboembolism (OR5.087 95%CI 1.015-25.458), suggesting that plasma D-dimer levels may also serve as an important marker in screening venous thromboembolism in ILD patients. On the other hand, normal D-dimer levels were also observed in two patients with venous thromboembolism, who did not complain of dyspnoea or chest pain, with incomplete embolism observed in segmental pulmonary arteries, indicating that PE may still be considered in patients without abnormal plasma D-dimer levels and typical symptoms. In this study, we diagnosed patients with negative plasma D-dimer levels since CTPA was performed as a routine test, yet more evidence may be required to support CTPA, besides D-dimer, in the screening of PE in ILD patients. In our study samples, PE was observed in some patients identified as having low probability with the Wells score and revised Geneva score, indicating that a low probability Wells score and Geneva score could not rule out PE. Because the samples included in the present study differ from other studies, no patients in our study cohort had recent surgery. Only one patient had malignant disease. Haemoptysis is a frequent initial symptom of PE, but it was rarely seen in our subjects. As a result, a larger proportion of patients (80.7%) were categorised into the low clinical probability group when the Wells rule was applied. As the two scores are based on different criteria, most subjects in our study had an intermediate probability with the Wells score. Age and heart rate are taken into account only in the Geneva score. Moreover, the Wells score is not fully standardised due to the presence of a subjective criterion, the physicians’ judgment of whether ‘‘an alternative diagnosis is less likely than PE,’’ which was difficult in our group because the symptoms and signs of PE were rarely seen. Our study has limitations. Firstly, this was a single centre study and the number of patients was not large. Secondly, there are seven kinds of CTDs in our CTD-ILD patients. Different CTDs might have different incidences of venous
thromboembolism. Third, patients requiring invasive mechanical ventilation in the intensive care unit, who may have a higher incidence of venous thromboembolism, were not included in the study. In conclusion, our findings suggest that patients with idiopathic pulmonary fibrosis have a marked increase in the risk of venous thromboembolism, which should be considered during the routine care of these patients. Furthermore, these data suggest that future prospective trials should be conducted to examine the role of screening, anticoagulant prophylaxis, and treatment strategies for venous thromboembolism in ILD patients. Clinicians caring for patients with ILD should maintain a heightened awareness of the risks and lower the threshold for evaluating patients for possible venous thromboembolism.
Conflict of interest There is no conflict of interest.
Acknowledgement We would like to express our gratitude to Mei Jiang for her instructive suggestions and valuable comments on the statistics.
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Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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[12] Takeshita K, Shigihara T, Shimizu T, Sato N, Matsubara H, Nishio K, et al. Unilaterally dominant chronic idiopathic interstitial pneumonia complicated by pulmonary thromboembolism. Nihon Kokyuki Gakkai Zasshi 1999;37:948–52. [13] Eary JF, MC Fisher, MD. Cerqueira Idiopathic pulmonary fibrosis. Another cause of ventilation/perfusion mismatch. Clin Nucl Med. 1986; 11:396–399. [14] Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Bounameaux H, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006;144:165–71. [15] American Thoracic Society Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161:646–64. [16] Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788–824. [17] Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. [18] Lonzetti LS, Joyal F, Raynauld JP, Roussin A, Goulet JR, Rich E, et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 2001;44:735–6. [19] Bhambhani M. American Rheumatism Association (ARA) criteria for the classification of rheumatoid arthritis (RA). J Assoc Physicians India 1996;44:89. [20] Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554–8.
[21] Bohan A, Peter J. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–7. [22] Doria A, Ghirardello A, de Zambiasi P, Ruffatti A, Gambari PF. Japanese diagnostic criteria for mixed connective tissue disease in Caucasian patients. J Rheumatol 1992;19:259–64. [23] Mosca M, R Neri, S Bombardieri. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol. 1999;17:615–20. [24] Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:416–20. [25] Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Bounameaux H, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006;144:165–71. [26] Zo¨ller B, Li X, Sundquist J, Sundquist K. Autoimmune diseases and venous thromboembolism: a review of the literature. Am J Cardiovasc Dis 2012;2:171–83. [27] Ramagopalan SV, Wotton CJ, Handel AE, Yeates D, Goldacre MJ. Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study. BMC Med 2011;9:1. [28] Poredos P, Jezovnik MK. The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis. Int Angiol 2007;26:306–11. [29] Hubbard RB, Smith C, Le Jeune I, Gribbin J, Fogarty AW. The association between idiopathic pulmonary fibrosis and vascular disease: a population-based study. Am J Respir Crit Care Med 2008;178:1257–61. [30] Sprunger DB, Olson AL, Huie TJ, Fernandez-Perez ER, Fischer A, Solomon JJ, et al. Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease. Eur Respir J 2012;39:125–32. [31] National Project of the D and T. Treatment Strategies for Pulmonary [The clinical features of 516 patients with acute pulmonary thromboembolism]. Zhonghua Yi Xue Za Zhi. 2006; 86: p. 2161–2165.
Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
Heart, Lung and Circulation (2014) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2014.02.014
ORIGINAL ARTICLE
Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study Qun Luo, MD1, Jiaxing Xie, MD1, Qian Han, MD1, Chunli Tang, MD, Xiaobo Chen, MD, Lulu Wu, MD, Rongchang Chen, PhD* Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital, Guangzhou Medical College, Guangzhou, China Received 12 September 2013; received in revised form 6 January 2014; accepted 19 February 2014; online published-ahead-of-print xxx
Background
To determine the prevalence of venous thromboembolism (VTE) in patients with connective tissue diseaserelated interstitial lung diseases (CTD-ILD) and idiopathic interstitial pneumonia (IIP) and to further evaluate associated risk factors. To also examine the diagnostic performance of the Wells score and the revised Geneva scores for diagnosing pulmonary embolism (PE) in ILD patients.
Method
Fifty-seven patients with CTD-ILD and IIP were prospectively enrolled. Plasma D-dimer was measured by ELISA. Deep-vein thrombosis (DVT) was examined by venous ultrasonography and PE by computed tomography pulmonary angiography. PE prevalence was further assessed by the Wells score and the revised Geneva score.
Results
VTE was diagnosed in 15 (26.3%, 15/57) patients. Bivariate analysis revealed that dyspnoea (OR 3.750, 95% CI 1.095-12.842, P=0.035), lower extremity oedema (OR 8.667, 95%CI1.814-41.408, P=0.007), palpitations (OR 4.75, 95%CI1.073-21.032, P=0.040), and positive D-dimer (OR 5.087, 95%CI 1.015-25.485, P=0.048) were associated with VTE. Using the Wells Score, 46 (80.70%), eight (14.4%) and three (5.26%) patients had a low, intermediate and high probability of PE, respectively, with seven (15.22%), three (37.5%) and two (66.67%) of the respective cases confirmed. By the revised Geneva score, 23 (40.35%), 32 (56.14%) and two (3.51%) patients had a low, intermediate and high probability of PE, respectively, with two (8.70%), nine (28.13%) and one (50.00%) of the respective cases confirmed. The AUC for the Wells score and the revised Geneva score was 0.7200.083 (CI 0.586 to 0.831) and 0.704 0.081 (CI 0.568 to 0.817), respectively.
Conclusion
VTE can be seen in approximately one fourth of patients with CTD-ILD or IIP and the Wells score and the revised Geneva score can be used for categorising PE risk.
Keywords
Venous thromboembolism Interstitial lung disease Pulmonary embolism Wells score Revised Geneva scores
*Corresponding author at: Guangzhou Institute of Respiratory Disease, 151 Yanjiang Road, Guangzhou, China. Tel.: +86-13902273260., Email: [email protected] 1
These authors contributed equally to this work.
© 2014 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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Introduction Interstitial lung diseases (ILDs) are a group of diffuse parenchymal lung disorders that afflict many patients worldwide. Idiopathic interstitial pneumonia (IIP) and connective tissue disease-associated ILD (CTD-ILD) are the most common forms of ILDs. Although the two conditions share similar clinical manifestations, radiographic findings and histopathologic appearance [1,2], they may have distinct outcomes, depending on the organs involved and complications [3]. Venous thromboembolism, which includes deep-vein thrombosis (DVT) and pulmonary embolism (PE), is initiated by endothelial injury of the venous system, and occurs as a result of disequilibrium between coagulation and fibrinolysis [4]. The incidence of venous thromboembolism is increased in CTD patients [5–7]. There are also several anecdotal case reports on the association of PE with IIP [8–13]; most of them came from Japan [9–12]. However, the prevalence of venous thromboembolism in patients with IIP and CTD-ILD has not been reported. PE could aggravate the symptoms of ILD, which may be mistaken for the acute exacerbation of ILD. The Wells score and the revised Geneva scores have been used in the diagnosis of PE, which assess patients with suspected PE based on three levels of probability using non-invasive tests [14]. However, there have not been reports on the use of Wells score and the revised Geneva score for diagnosing PE in ILD patients. In the current study, we sought to determine the prevalence of venous thromboembolism in patients with CTD-ILD and IIP and further to evaluate associated risk factors. We also examined the diagnostic performance of the Wells score and the revised Geneva scores for diagnosing PE in ILD patients.
Patients and methods Patients We prospectively enrolled patients with ILD (CTD-ILD and IIP) who were admitted to the ILD Center at Guangzhou Institute of Respiratory Diseases, Guangzhou, China, between January 1, 2011 and December 31, 2011. IIP was diagnosed according to the American Thoracic Society criteria [2,15,16]. CTDs were diagnosed as described elsewhere [17–23]. CTD-ILD was diagnosed if a subject had a definite diagnosis of CTD, developed respiratory symptoms and signs, and showed diffuse infiltrates or reticular nodules on chest high resolution computed tomography (HRCT) scan, and had no other pulmonary diseases. A subject was excluded from the analysis if 1) he or she failed to receive CTPA and lower-limb venous ultrasonography within 48 hours of admission; 2) he or she had renal failure (plasma creatinine>150 mmol/L); 3) he or she was allergic to intravenous contrast medium, 4) he or she was on anticoagulation therapy at admission; 5) he or she required invasive mechanical ventilation; 6) he or she was diagnosed as ILD other than IIP and CTD-ILD.
The study protocol was approved by the local institutional review board at the authors’ affiliated institution and informed consent was obtained from all study participants or their legal surrogates.
Patient evaluation Patient demographic and baseline data including age, sex, smoking, body mass index (BMI) and comorbid diseases were collected and routine blood chemistries and blood gas analysis were carried out. For D-dimer test, venous blood samples were collected without tourniquets and negative suction to avoid activation of coagulation ex vivo within 30 min after admission. The samples were stored at 80 8C for further testing. The plasma concentrations of D-dimer were measured using commercially available ELISA kits by the manufacturer’s instructions (Tianyou Scientific, Tianjin, China). In addition, autoantibodies including antinuclear antibodies, anti-myeloperoxidase antibodies and anti-PR3 antibodies were determined using commercially available kits.
Venous ultrasonography High definition B mode ultrasound imaging equipment was used with different probes according to the depth of the examined vessels. The inferior vena cava and iliac veins were examined with the patient supine or in the contralateral position, femoral veins and popliteal veins with the patient in a semi-upright position, and calf veins with the patient in a sitting position and both feet resting on a chair. The distal veins including the posterior tibial and peroneal veins, the gastrocnemius, and the soleal veins were also examined. All venous segments were examined over their entire length in the transverse or longitudinal axis. All ultrasound examinations were performed by vascular medicine specialists with at least 10 years of experience in vascular ultrasound imaging. Deep vein thrombosis was diagnosed with lack of compressibility of a deep vein and, for the iliac vein, in the absence of Doppler flow or direct visualisation of a thrombus.
Computed tomography pulmonary angiography CTPA images were obtained as part of standard care with 64 channel multi-detector equipment capable of 2.5 mm collimation with the following imaging parameters: detector width, 64 0.625 or 16 1.25 mm; section thickness, 1.25 mm; rotation time, 0.5 second; 120 kVp; and 380 mA. CT images were reconstructed with both standard soft-tissue and lung kernel algorithms. Two radiologists who were blind to patient data independently assessed PE on CTPA images by detecting the presence of an endoluminal central filling defect partially or completely occluding the pulmonary arteries.
Assessment of PE using the Wells score and revised Geneva score The prevalence of PE was further assessed in the lowprobability, intermediate-probability and high-probability categories as classified by the Wells score [24] and the revised
Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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Geneva score [25] by a clinician who was blind to the final diagnosis. The sensitivity, specificity and predictive values of both the Wells and Revised Geneva Scores were calculated.
Statistical analysis The Student t, one-way ANOVA, and Mann-Whitney U tests were used to compare continuous variables where appropriate. Difference among proportions was determined by Fisher’s exact test. Binary logistic regression model was used to identify independent predictors of venous thromboembolism. These factors were included in the multivariate analysis based on their clinical significance in the univariate analysis. The accuracy of the revised Geneva score and Wells score
was compared by the area under the curve (AUC) in receiver operating characteristic (ROC) analyses. Statistical analysis was performed by using the SPSS software (SPSS Inc., Chicago, IL) and MEDCALC software (Belgium).
Results Patient demographic and baseline characteristics A total of 77 consecutive patients with ILD (CTD-ILD and IIP) were screened for eligibility for the study. The study flow chart is shown in Fig. 1. Twenty patients were excluded
Figure 1 The study flowchart. Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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because of use of invasive mechanical ventilation or ICU admission (n=8), failure to provide informed consent (n=7) or other reasons (n=5). Fifty-seven patients were eligible for inclusion in the study. The demographic and baseline characteristics of these patients are shown in Table 1. They included 29 men and 28 women with a mean age of 61.35 11.00 (range, 30 to 81) years. Thirty patients were diagnosed with CTD-ILD and 27 patients were diagnosed with IIP. Among patients with CTD-ILD, one patient had systemic lupus erythematosus, three had subcutaneous sclerosis, four had rheumatoid arthritis, one had systemic sclerosis, 10 had polymyositis/dermatomyositis, one had mixed CTD, and 10 had undifferentiated CTD. Among patients with IIP, 19 patients had idiopathic interstitial fibrosis and eight had other IIPs.
Incidence of venous thromboembolism Venous thromboembolism was diagnosed in 15 (26.3%, 15/57) of our patients, including 12 cases diagnosed at admission and three cases diagnosed during the three months of follow-up. Three patients were diagnosed with deep-vein thrombosis of the lower extremity and 12 patients were diagnosed with pulmonary embolism. No patient had more than one venous thromboembolism event. Among patients with CTD-ILD, six (20%, 6/30) patients developed venous thromboembolism, including two patients with rheumatoid arthritis, one patient with systemic sclerosis, two patients with polymyositis/dermatomyositis and one patient with undifferentiated CTD. Among patients with IIPs, nine (33.3%, 9/27) patients developed venous thromboembolism, including seven patients with IPF and two patients with other IIPs (Fig. 2). There was no significant difference in the incidence of venous thromboembolism between patients with CTD-ILD and patients with IIPs (X 2 =1.303, P=0.254).
Characteristics of patients with venous thromboembolism We compared the demographic and baseline characteristics of patients with and without venous thromboembolism. The two groups were comparable in gender, BMI, lung functions and comorbidities (Table 2) while patients with venous thromboembolism were apparently older than those without the condition (mean age, 67.7 years vs. 59.1 years; P=0.014). Patients who developed venous thromboembolism had a noticeably higher smoking load (mean pack years, 19.66 vs. non-venous thromboembolism, 6.42; P=0.041). Moreover, significantly more patients with venous thromboembolism had dyspnoea, lower extremity oedema and palpitations than those without (P500 mg/L) than those without (42.9%, 18/42). Our bivariate analysis further revealed that dyspnoea (OR 3.750, 95%CI 1.095-12.842, P=0.035), lower extremity oedema (OR 8.667, 95%CI1.814-41.408, P=0.007), palpitations (OR 4.75, 95% CI1.073-21.032, P=0.040), and positive D-dimer (OR 5.087, 95%CI 1.015-25.485, P=0.048) were more likely
Table 1 Demographic and baseline characteristics of patients with CTD-ILD and IIPs. All patients No. of patients, n(%) CTD-ILD IIP
57(100) 30(52.6) 27(47.4)
Age, years Mean(SD)
61.35(11.00)
Range
30-81
Male gender, n(%)
29(50.9)
Smoking, pack-years Mean(IQT) Body mass index, kg/m2 25
9.91(15) 16(28.1)
Comorbidities Diabetes mellitus Hypertension Coronary heart disease Trauma/surgery Malignancies Immobilisation >7 days Dyspnoea (Recent onset or worsening)
5(8.8) 11(19.3) 8(14.0) 4(7.0) 1(1.8) 11(19.3) 21(36.8)
Lower limb oedema
8(14.0)
Haemoptysis
2(3.5)
Palpitations
8(14.0)
Pleuritic pain
3(5.3)
PaO2, mmHg Mean(IQT)
79.08(19.33)
PaCO2, mmHgz Mean(IQT)
37.44(4.26)
D-dimer, ng/mL 500
21(36.8)
> 500
36(63.2)
Lung function FVC%z Mean(SD)
65.94(23.37)
DLCO%z Mean(SD)
47.56(18.95)
Autoantibodies, U/mL Antinuclear antibody
58.77(56.20)
Mean(IQT) Anti-myeloperoxidase Mean(IQT) Anti-PR3
2.11(1.12)
Mean(IQT)
3.09(2.13)
CRP, mg/dL Mean(IQT)
1.92(2.41)
Data are expressed as n(%) unless otherwise specified. CRP, C-reactive protein; IIP, idiopathic interstitial pneumonias; CTD, connective tissue disease; ILD, interstitial lung disease; IQT, interquartile range.
Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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Table 2 Bivariate analysis of patients with or without venous thromboembolism. P
OR
95%CI
42(73.7) 59.1(11.61)
0.014
1.10
1.02-1.19
24(57.1)
0.12
2.67
0.78-9.17
19.66(30.00)
6.42(11.25)
0.041
1.038
1.002-1.075
6(40)
10(23.8)
0.317
2.133
0.609-7.472
VTE(%) 15(26.3) 67.67(5.62)
No. of patients Age, mean(SD) years
5(33.3)
Male gender Smoking, mean(IQT) pack-years Body mass index 25 kg/m2
Non-VTE(%)
Comorbidities Diabetes mellitus
2(13.3)
3(7.1)
0.369
2.608
0.322-21.131
Hypertension
3(20.0)
8(19.0)
0.906
0.912
0.195-4.265
Coronary heart disease Trauma/surgery
3(20.0) 0(0)
5(11.9) 4(9.5)
0.438 0.999
1.936 0.000
0.365-10.278 0.000
Malignancies
0(0)
0.000
1(2.4)
1.000
0.000
Immobilisation >7 days
1(6.7)
10(23.8)
0.236
0.243
0.023-2.517
Dyspnoea (Recent onset or worsening)
9(60)
12(28.6)
0.035
3.750
1.095-12.842
Lower limb oedema
6(40)
3(7.1)
0.007
8.667
1.814-41.408
Haemoptysis
1(6.7)
1(2.4)
0.458
2.929
0.172-49.996
Palpitations
5(33.3)
4(9.5)
0.040
4.750
1.073-21.032
Pleuritic pain PaO2, mean(IQT) mmHg
1(6.7) 35.34(5.83)
2(4.8) 38.55(8.41)
0.778 0.149
1.429 0.975
0.120-16.998 0.943-1.009
PaCO2, mean(IQT) mmHg
72.41(11.79)
80.622(20.16)
0.167
0.923
0.824-1.034
0.048
5.087
1.015-25.485
D-dimer > 500 ng/mL
13(86.7)
18(42.9)
Lung function FVC%, mean(SD)
76.45(11.79)
67.19(20.76)
0.58
1.01
0.98-1.05
DLCO%, mean(SD)
38.37(12.99)
49.28(17.21)
0.16
0.95
0.875-1.02
CRP, mean(IQT) mg/dL
3.43(6.12)
1.88(2.11)
0.102
1.166
Data are expressed as n(%) unless otherwise specified. CRP, C-reactive protein; IQT, interquartile range; OR, odds ratio; VTE, venous thromboembolism.
to associate with venous thromboembolism. Our multivariate analysis showed that age (OR 1.110 [CI, 1.013-1.217]), pack years of smoking (OR 1.054 [CI, 1.009-1.101]) and palpitations (OR 8.141 [CI, 1.403-47.223]) were independently associated with risk of venous thromboembolism (adj. OR 4.21, P=0.058) (Table 3).
Evaluation of the Wells score and the revised Geneva score The prevalence of PE in the low, intermediate and high pretest probability groups was assessed using the Wells score and the revised simplified Geneva score and is presented in
Table 4. Using the Wells Score, 46 (80.70%) patients had a low probability of PE; of these, seven patients (15.22%) had confirmed PE. Eight patients (14.04%) had an intermediate probability of PE; of these, three (37.50%) had confirmed PE. Three (5.26%) patients had a high probability of PE; of these, two (66.67%) had confirmed PE. According to the revised Geneva score, 23 (40.35%) patients had a low probability of PE; of these, two patients (8.70%) had confirmed PE. Thirty-two patients (56.14%) had an intermediate probability of PE; of these, nine (28.13%) had confirmed PE. Two patients (3.51%) had a high probability of PE; of these, one (50.00%) had confirmed PE. The AUC for the Wells score and the revised Geneva score were 0.7200.083 (CI 0.586 to 0.831)
Table 3 Multivariate analysis of risk factors for venous thromboembolism. ß
Wald
P
Odds ratio
95%CI
Age
0.094
5.142
0.026
1.110
1.013-1.217
Smoking, pack-years
0.042
4.315
0.019
1.054
1.009-1.101
Palpitations
2.097
5.465
0.019
8.141
1.403-47.223
Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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Table 4 Prevalence of pulmonary embolism in the three pretest probability groups as categorised by the Wells score and the revised Geneva score. Pretest probability
Patients(n=57)/
of PE
patients with PE(n=12) Wells
Revised
score
Geneva score
Low
43/4
23/2
Intermediate
11/6
32/9
3/2
2/1
High PE: pulmonary embolism.
and 0.704 0.081 (CI 0.568 to 0.817), respectively. The difference between the AUCs was not statistically significant (z=0.242, P=0.8085).
Discussion Substantial data [26] show that CTD is associated with a significantly increased incidence of venous thromboembolism. Accumulating epidemiological, clinical and experimental evidence reveals that an increased risk of venous thromboembolism is a feature of most CTDs [26], which may have different underlying causes in different CTDs [27]. Suppressed
fibrinolysis, increased procoagulant activity, and decreased anticoagulant activity impact on thrombotic responses, thus contributing to an increased risk of venous thromboembolism in CTDs [26,28]. To our knowledge, our study is the first to investigate the incidence of venous thromboembolism by firstline diagnostic tests (CTPA and ultrasonography) in patients with CTD-ILD and IIPs. Our study demonstrated that approximately one quarter (26.3%) of our patients developed venous thromboembolism. We further showed that several factors, including age, smoking pack years, and palpitations, are associated with increased risk of PE. Only a few studies have examined the relationship between venous thromboembolism and idiopathic pulmonary fibrosis. Two studies exploring the relationship between ILD and DVT or PE were based on autopsy findings or medical database. Using primary care data from the UK, Hubbard et al. [29] identified a cohort of 920 patients with idiopathic pulmonary fibrosis and found that the risk of DVT was greater in idiopathic pulmonary fibrosis than the general population. They did not exclude subjects with ILD whose causes were known. Using death certificate records in the USA, Sprunger et al. [30] found that the risk of venous thromboembolism in decedents with idiopathic pulmonary fibrosis was significantly greater than decedents in the background population, decedents with lung cancer or decedents with chronic obstructive lung disease. Compared with these two studies, the prospective design of this study allowed the detection of asymptomatic venous thromboembolism, especially PE in ILD patients.
Figure 2 Computed tomography pulmonary angiography (CTPA) of a patient diagnosed with IIPs. A–C: The mediastinal and lung window reveals filling defects in the right lower lobe pulmonary artery (arrow). B–D: Follow-up CTPA after treatment shows considerable improvement (arrow). Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
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Prevalence of VTE and diagnostic performance
The diagnostic procedure based on D-dimer test, lowerlimb ultrasonography and CTPA in this study led us to characterise more precisely the symptoms and factors associated with the presence of venous thromboembolism in patients with ILD. The symptoms of venous thromboembolism, especially PE, are often confounded with respiratory symptoms in patients with ILD, which probably remain undetected and left untreated. On the contrary, the symptoms implicating venous thromboembolism such as haemoptysis, chest pain, and oedema of the lower limbs do not definitively indicate venous thromboembolism in our study group. In China, dyspnoea is the most frequent initial symptom of acute PE [31]. Although PE has always been suspected in patients presenting with dyspnoea or haemoptysis, dyspnoea in patients with ILD is mostly considered as pure PE. The elevation of plasma D-dimer levels (>500 ng/mL) was more frequent in patients with venous thromboembolism than those without, and elevated plasma D-dimer levels may be associated with increased risk of venous thromboembolism (OR5.087 95%CI 1.015-25.458), suggesting that plasma D-dimer levels may also serve as an important marker in screening venous thromboembolism in ILD patients. On the other hand, normal D-dimer levels were also observed in two patients with venous thromboembolism, who did not complain of dyspnoea or chest pain, with incomplete embolism observed in segmental pulmonary arteries, indicating that PE may still be considered in patients without abnormal plasma D-dimer levels and typical symptoms. In this study, we diagnosed patients with negative plasma D-dimer levels since CTPA was performed as a routine test, yet more evidence may be required to support CTPA, besides D-dimer, in the screening of PE in ILD patients. In our study samples, PE was observed in some patients identified as having low probability with the Wells score and revised Geneva score, indicating that a low probability Wells score and Geneva score could not rule out PE. Because the samples included in the present study differ from other studies, no patients in our study cohort had recent surgery. Only one patient had malignant disease. Haemoptysis is a frequent initial symptom of PE, but it was rarely seen in our subjects. As a result, a larger proportion of patients (80.7%) were categorised into the low clinical probability group when the Wells rule was applied. As the two scores are based on different criteria, most subjects in our study had an intermediate probability with the Wells score. Age and heart rate are taken into account only in the Geneva score. Moreover, the Wells score is not fully standardised due to the presence of a subjective criterion, the physicians’ judgment of whether ‘‘an alternative diagnosis is less likely than PE,’’ which was difficult in our group because the symptoms and signs of PE were rarely seen. Our study has limitations. Firstly, this was a single centre study and the number of patients was not large. Secondly, there are seven kinds of CTDs in our CTD-ILD patients. Different CTDs might have different incidences of venous
thromboembolism. Third, patients requiring invasive mechanical ventilation in the intensive care unit, who may have a higher incidence of venous thromboembolism, were not included in the study. In conclusion, our findings suggest that patients with idiopathic pulmonary fibrosis have a marked increase in the risk of venous thromboembolism, which should be considered during the routine care of these patients. Furthermore, these data suggest that future prospective trials should be conducted to examine the role of screening, anticoagulant prophylaxis, and treatment strategies for venous thromboembolism in ILD patients. Clinicians caring for patients with ILD should maintain a heightened awareness of the risks and lower the threshold for evaluating patients for possible venous thromboembolism.
Conflict of interest There is no conflict of interest.
Acknowledgement We would like to express our gratitude to Mei Jiang for her instructive suggestions and valuable comments on the statistics.
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Please cite this article in press as: Luo Q, et al. Prevalence of Venous Thromboembolic Events and Diagnostic Performance of the Wells Score and Revised Geneva Scores for Pulmonary Embolism in Patients with Interstitial Lung Disease: A Prospective Study. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2014.02.014
