PECSS: Pulmonary Embolism Comprehensive Screening Score to safely rule out pulmonary embolism among suspected patients presenting to emergency department

Pulmonary embolism (PE) is a common severe cardiovascular illness andcan be life-threatening if left untreated [1‐3]. However, clinical signs and symptoms have relatively low sensitivity and specificity in PE diagnosis [4, 5]. Current diagnosis of PE still relies on computed tomographic pulmonary angiography (CTPA), which is costly, time-consuming and exposes patients to extra radiation [6, 7]. Recent studies in North America showed that the detection rate of suspected PE is as low as 5% [8]. Therefore, it is of great importance to avoid excessive CTPA by considering ruling out PE using clinical pretest probability scores.

Commonly used clinical pretest probability, such as Wells score and Geneva score, combines clinical symptoms with predisposing risk factors of venous thromboembolism and classifies patients with suspected PE into distinct risk categories [9‐11]. In addition to clinical pretest probability score, plasma level of D-Dimer, which is often elevated in the presence of acute thrombosis due to simultaneous activation of coagulation and fibrinolysis, is also used to rule out PE [12, 13]. The combination of low pretest probability score and plasma D-Dimer level lower than 500 ug/L were used to rule out PE in an initial attempt, followed by age adjusted D-Dimer cutoff (500 ug/L for patients below 50 years, and age*10 ug/L for patients older than 50 years) and risk category specific D-Dimer cutoffs (1000 ug/L for patients with low pretest score, and 500 ug/L for patients with moderate pretest score) [14‐16]. Despite efforts in adjusting D-Dimer thresholds in different age groups and PE risk categories, specificities and negative predictive values of the PE rule out strategies are generally low, resulting in an overuse of CTPA among alternatively diagnosed patients with high plasma D-Dimer levels or moderate pretest probability score. What’s more, none of the current PE rule out strategies differentiate the failure rates across different PE severity grades, as major embolism and multiple embolisms require much more stringent diagnosis and treatment window than mild embolism [17].

In this investigation, we aim to develop a comprehensive PE pretest score that incorporates clinical indications in Wells score and other important clinical predictors to guide clinicians in assessing PE risk with improved screening performances. The proposed PE Comprehensive Screening Score (PECSS) is designed to optimize the rule out performance among patients with severe PE and to achieve excellent operating characteristics among patients with moderate and mild PE. PE severity grades were evaluated based on CTPA and validation of PECSS was conducted in an independent held-out data set.

Due to the difficulties of PE diagnosis in early clinical stage and emergency medical setting [18, 19], physicians often rely on excessive CTPA use to reduce the miss diagnosis rate of PE, especially for those with pulmonary artery embolism or multiple pulmonary arteriole embolism, which could lead to poor prognosis and high risk of death. To rule out PE among patients presenting to the emergency department, the PERC [20] rule required 8 objective criteria, including age (less than 50 years old), medical history and several empirical indicator of clinical signs and symptoms [21]. However, with the aging population and potential assessment bias introduced by attending physicians of various clinical experiences in PE diagnosis, the application of PERC rule in emergency medical setting is relatively limited [22, 23].

In this investigation, we developed and validated an objective and easy-to-use scoring system to safely rule out PE among patients presenting to the emergency department. The newly proposed Pulmonary Embolism Comprehensive Screening Score (PECSS) combined important clinical predictors with indicators in the Wells score and achieved excellent performances across all PE severity grades. Particularly, we found that patients with age > 65 years old, anhelation, less pain, abnormal blood pressure, in critical condition when admitted, higher levels of pro-BNP, CRP, UA, WBC, NEUT, MONO and ALT, and lower levels of HGB, ALB and creatinine were at increased risk for PE. Through a comprehensive grid searching algorithm, PECSS identified 7 clinical predictors (anhelation, abnormal blood pressure, pro-BNP > 1000 pg/mL, CRP > 30 mg/L, UA > 300 umol/L, in critical condition when admitted and age > 65 years), in addition to indicators in Wells score (VTE symptoms, no alternative diagnosis, HR > 100 beats/min, immobilication / surgery and previous PE/VTE), and assigned corresponding scores to each of the predictor. All of the clinical predictors were easy to obtain from medical records and rountine blood tests in emergency department setting.

Identification of these candidate clinical predictors were supported by previous studies. Conditions such as pulmonary main embolism can lead to obstructive shock, which is a possible cause of hypotension. Elevated blood pressure can be explained by PE associated symptoms or stress [24, 25]. Although a large number of studies have found pro-BNP as a biomarker for PE, optimal cut-off values are still inconsistent [26‐28]. In our study, we assigned 0.5 point to pro-BNP greater than 1000 ng/L in constructing PECSS and provided a reference for future research regarding the effect of pro-BNP on PE. Both CRP and UA are acute phase reactant, which are associated with increased risk of cardiovascular and cerebrovascular events [29‐33]. CRP has been shown to increase the tendency to thrombose through the mediation of interleukin 6 and monocyte chemoattractant protein 1 [34, 35]. Plasma level of UA can be used as a risk marker for thrombosis and prognostic stratification among PE patients [36, 37]. Therapies targeted at lowering UA are associated with reduced risk of major adverse cardiovascular events [38‐40].

To facilitate clinical application and further improve the screening performance, we incorporated plasma level of D-Dimer, which is often elevated in the presence of acute thrombosis, with PECSS. Optimal D-Dimer cutoff values were investigated in patients with low (PECSS \(\le\) 4), moderate (4 < PECSS \(\le\) 6) and high (PECSS > 6) PE risk. It turned out that D-Dimer only played a role in patients with moderate PE risk, where higher levels of plasma D-Dimer increased the pretest probability of PE. Therefore, patients with moderate risk (4 < PECSS \(\le\) 6) and low D-Dimer (D-Dimer \(\le\) 2.5 mg/L) could be safely ruled out of PE, whereas those with moderate risk (4 < PECSS \(\le\) 6) and high D-Dimer (D-Dimer > 2.5 mg/L) need to undergo CTPA before PE can be ruled out. D-Dimer were not expected to affect the decision of ruling out PE in patients with low and high pretest probability, since patients with low PECSS have very low risk of PE according to medical records and clinical symptoms where D-Dimer do not have enough clinical specificity, while those with high PECSS have high risk of PE such that they need to undergo CTPA regardless of their plasma D-Dimer level.

Screening performances of PECSS only, PECSS + D-Dimer, Wells only, Wells + D-Dimer were thoroughly compared in terms of failure rates across all PE severity grades, sensitivity, specificity, PPV and NPV. Compared to Wells only, PECSS only approach greatly reduced the failure rates in all PE severity grades (5.1% to 0, 16.5% to 2.2%, 16.0% to 0, and 9.6% to 0.5% in severe, moderate, mild and any PE, respectively). The huge improvement indicated that by including the additional seven clinical predictors chosen by variable selection and clinical meaningfulness, PECSS are able to identify patients with suspected PE risk more accurately and efficiently than Wells score. Although PECSS + D-Dimer and Wells + D-Dimer had similar performances in moderate and mild PE, PECSS + D-Dimer had three times lower failure rate in severe PE compared to Wells + D-Dimer (0.3% versus 0.9%). This is of particular clinical significance since servere PE consists of patients with pulmonary artery embolism or multiple pulmonary arteriole embolism and had the worst clinical prognosis [41‐44]. By improving the accuracy and effectiveness of pretest probability and targeting on the clinically beneficial patient population, the PECSS + D-Dimer would greatly reduce the mortality associated with PE. In terms of sensitivity and specificity, Wells score achieved the highest specificity, but at the cost of low sensitivity and NPV. PECSS had the highest sensitivity, while at the cost of low specificity and PPV. PECSS + D-Dimer had the best compromise between good sensitivity and specificity, and moderately high PPV and NPV. It should be noted that although PECSS had very high sensitivity, its specificity and positive predictive value were relatively low. This indicates that PECSS works well in identifying patients at high risk of PE, but relatively under-performs to rule out PE when patients are screened negative. PECSS + D-Dimer strategy improved upon PECSS only in terms of both specificity and positive predictive value.

Admittedly, our study has several limitations. Firstly, this is a single center study and generalization of the results require validation from multi-center set. Secondly, patients who were suspected of PE but did not undergo CTPA due to hemodynamic instability were not included in out study due to the uncertainty of their PE status. This would potentially lead to bias in applying PECSS and PECSS + D-Dimer approaches in the targeted patient population. Thirdly, radiological severity instead of clinical severity (such as hypotension, pulmonary hypertension, cardiac failure, and the need for oxygen therapy) were used when defining PE severity grades. However, they do not usually correlate perfectly with each other. Further, right ventricular dysfunction was not considered in defining the PE severity grades since echocardiography was missing for a large proportion of the study population. Although CTPA has been applied in right ventricular dysfunction, its reliability and accuracy cannot be guaranteed as echocardiography [17, 18]. Finally, our study is retrospective in nature, and therefore, causal relationships could not be established between clinical predictors in constructing PECSS and PE diagnosis.

In conclusion, in this study we developed a new pretest probability (PECSS) that is more comprehensive and accurate than the well established Wells score for PE diagnosis, and incorporated plasma level of D-Dimer with PECSS as a clinical instrument to rule out PE among suspected patients presenting to the emergency department. Both PECSS and PECSS + D-Dimer approaches showed excellent performances in reducing PE cases that were ruled out, and the advantages over Wells score and Wells + D-Dimer approaches were more pronounced among patients with severe PE, which would usually lead to worst prognosis and highest mortality. With PECSS and D-Dimer, PE diagnosis could be operated more efficiently without overuse of CTPA. Finally, all clinical predictors in PECSS are easy to obtain from medical records and routine blood tests, making PECSS a practical tool in emergency medical setting.