Imaging techniques in diagnosing acute pulmonary thromboembolism

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INTRODUCTION

Despite the presence of various treatment approaches, the global mortality rate from pulmonary thromboembolism (PTE) remains approximately 30%. In the United States, 100,000–180,000 people die annually from PTE and its complications [1]. According to the International Cooperative Pulmonary Embolism Registry, the overall 3-month mortality rate among patients with PTE is 45.1% [2], with mortality reaching 52.4% in high-risk patients and 14.7% in all other cases [3]. The mortality rate can be decreased to 2%–8% with appropriate treatment strategies [4]. In 95% of cases, PTE is caused by deep vein thrombosis of the lower extremities and thrombosis in the superior vena cava system in 2% [5].

The Framingham Heart Study found that PTE accounts for 15.6% of all in-hospital deaths. Particularly, hospital mortality was high among patients in medical wards: 82% of fatal PTE cases occurred in this group, compared with 18% among surgical patients [6]. In a study by Sukhanova et al. [7], PTE was the cause of death in 7.2% of autopsy cases in multidisciplinary hospitals.

In Russia, the PTE incidence ranges from 35 to 40 cases per 100,000 population, with a 30-day mortality rate of up to 6% following deep vein thrombosis. Furthermore, within 5 years, severe chronic thromboembolic pulmonary hypertension (CTEPH) following massive PTE leads to death in 10%–15% of patients [8].

In a study by Vertkin et al. [1], PTE was diagnosed postmortem in 14% of cases, with 1 in 10 patients undiagnosed during life. PTE accounts for >15% of fatal outcomes and is the most frequent cause of diagnostic discrepancy.

PTE is a common complication of various diseases, regardless of etiology or clinical characteristics. Therefore, early diagnosis and prompt treatment are crucial for improving prognosis [9]. Moreover, disease recurrence is observed in one-third of patients within 10 years after the initial PTE episode [10].

Notably, PTE is diagnosed antemortem in <70% of cases, highlighting the importance of clinical vigilance and timely use of diagnostic algorithms [1, 11].

DIAGNOSTIC ALGORITHM FOR SUSPECTED ACUTE PULMONARY THROMBOEMBOLISM

The most widely accepted procedure for managing patients with suspected acute PTE was identified by the European Society of Cardiology (ESC) in 2019. The clinical presentation of PTE is nonspecific and may mimic various conditions. Diagnosis begins with assessing the clinical probability of PTE using scoring systems that incorporate symptoms (e.g., dyspnea, cough, rales, etc.) and risk factors for thrombosis (e.g., age, surgery, medical history, etc.). The Wells and Geneva scores are the most commonly used tools, structured as two-level (PTE likely/unlikely) or three-level (low, intermediate, or high probability) scales. Based on these scores, patients with massive PTE and hemodynamic instability are categorized as high risk and should undergo evaluation per ESC guidelines (Fig. 1). In the absence of hemodynamic instability, the primary step in diagnostic decision-making is determining the clinical probability of PTE (Fig. 2) [12].

 

Fig. 1. Diagnostic algorithm for patients with suspected high-risk pulmonary thromboembolism presenting with hemodynamic instability. CT, computed tomography; CTPA, computed tomography pulmonary angiography; PTE, pulmonary thromboembolism; PA, pulmonary artery; RV, right ventricle; TTE, transthoracic echocardiography. Adapted from [12]. Published with permission from the copyright holder.

 

Fig. 2. Diagnostic algorithm for patients with suspected high-risk pulmonary thromboembolism without signs of hemodynamic instability. CTPA, computed tomography pulmonary angiography; PTE, pulmonary thromboembolism. Adapted from [12]. Published with permission from the copyright holder.

 

In a meta-analysis by Ceriani et al. [13], PTE prevalence was approximately 10% in the low-probability group, 30% in the intermediate group, and 65% in the high-probability group. Using the two-level model, the prevalence in the high- and low-risk groups was approximately 12%. Although the Wells and Geneva scores significantly facilitate the diagnostic process, PTE underestimation occurs in 1 of 8–10 patients [14]. For high-risk patients, radiographic confirmation is advised. However, in critical conditions, reperfusion therapy (e.g., thrombolysis and interventional or surgical treatment) may be initiated based on indirect evidence such as signs of right heart strain on echocardiography [12].

In patients with low or intermediate PTE probability, the next step is measuring the concentration of D-dimer, a fibrin degradation product. The specificity of this test decreases with age and falls below 10% in patients aged >80 years [15]. Consequently, increased D-dimer levels are not confirmatory for PTE; thus, they warrant further investigation. Moreover, increased D-dimer levels may be observed in conditions such as infection, inflammation, or bleeding, further limiting the test specificity [16]. Therefore, in cases of increased D-dimer or when clinical probability remains high despite normal levels, PTE should be confirmed.

Markers of Right-Sided Heart Dysfunction and Risk Stratification

The primary cause of death of patients with PTE is acute heart failure resulting from decompensated right-sided heart dysfunction. Therefore, risk stratification for adverse outcomes is based on criteria such as hemodynamic status, right heart dysfunction, and the degree of pulmonary artery obstruction determined by computed tomography pulmonary angiography (CTPA) [17]. Several scoring systems have been developed to simplify risk assessment, including the Qanadli score [18], Pulmonary Embolism Severity Index (PESI), and simplified PESI (sPESI) [19].

Acute right ventricular failure is a predictor of early mortality and requires immediate therapeutic intervention. In patients with massive PTE, acute right ventricular dysfunction, and systemic hypotension, the mortality rate reaches 32% [7].

PESI and sPESI are commonly used for patients with right ventricular failure to identify those at low or intermediate risk of adverse outcomes [19]. However, risk stratification in normotensive patients classified as having intermediate risk remains challenging.

Echocardiography is the primary diagnostic modality for right heart failure. Right ventricular dilation is observed in approximately 25% of patients with PTE [20]. The advantages of echocardiography include:

• Rapid application;
• No special patient preparation required;
• Repeatability for serial assessments.

Echocardiography is highly operator-dependent; this may cause variable results and complicate the differential diagnosis of right ventricular pathology, such as myocardial infarction. Thus, echocardiography alone is insufficient to exclude PTE in patients at low risk. Conversely, in cases of hemodynamic instability, which indicates high-risk PTE, this method is valuable for characterizing right heart changes and differentiating PTE from conditions such as cardiac tamponade, aortic dissection, and hypovolemic shock [20].

DIAGNOSTIC METHODS FOR PULMONARY THROMBOEMBOLISM

Computed Tomography Pulmonary Angiography

CTPA is the gold standard for diagnosing PTE [21]. According to the PIOPED II (Prospective Investigation of Pulmonary Embolism Diagnosis II) study, CTPA demonstrates a sensitivity and specificity of 83% and 96%, respectively [22]. CTPA should be performed in patients with high clinical probability, increased D-dimer levels, or hemodynamic instability to confirm or exclude the diagnosis. This diagnostic approach is classified as Class I¹ with Level A² evidence [23–30].

CTPA enables evaluation of structural abnormalities in the lungs and the extent of thrombotic involvement; however, it does not provide information on perfusion defects [12].

CTPA plays a key role in assessing hemodynamic disturbances in acute PTE to stratify patients based on fatal outcome risk. Hemodynamic classification in PTE is based on signs of right-sided heart dysfunction, thrombus density quantification, and pulmonary perfusion assessment [6, 31, 32].

However, CTPA has limitations in detecting emboli in segmental and subsegmental pulmonary arteries, often leading to delayed hospitalization and initiation of therapy in such cases [33].

CTPA is the preferred modality for differential diagnosis of PTE, as it confirms or excludes embolism and estimates the extent of vascular involvement and related complications and is beneficial for identifying alternative diagnoses with similar clinical presentations [34]. According to two large-scale clinical trials, suboptimal image quality due to motion artifacts or insufficient contrast opacification occurs in 5%–8% of CTPA cases [35, 36]. Its diagnostic value diminishes with decreasing caliber of affected pulmonary vessels [37, 38]. Furthermore, CTPA is less effective in diagnosing chronic PTE or complications such as CTEPH, where thrombotic material may be located more distally.

Ventilation-Perfusion Scintigraphy

Ventilation-perfusion scintigraphy (VQ scan) is a diagnostic method that combines the assessment of pulmonary microcirculation and initial evaluation of the bronchoalveolar structures and clinical probability of PTE. Ventilation scintigraphy reflects regional and segmental airflow and is performed using an inhaled aerosol containing technetium (100 MBq³ of ^99mTc aerosol), immediately followed by image acquisition. Perfusion scintigraphy is based on microembolization of the pulmonary microcirculation with ^99mTc-labeled radiopharmaceuticals, allowing for visualization of the vascular territory affected by occlusion in pulmonary arteries of any caliber. Combined evaluation of ventilation and perfusion patterns facilitates the differential diagnosis between PTE and bronchogenic pulmonary changes, such as pulmonary fibrosis and pneumonia [39].

Owing to the complexity and labor-intensive nature of the full protocol, a simplified procedure involving perfusion imaging alone, without the inhalation component, is often used.

An important advantage of VQ scan is its high predictive value; negative results in patients with low clinical probability and positive results in those with high probability are strongly informative [40]. The ventilation scan adds specificity, as areas of perfusion defects typically exhibit normal ventilation in cases of acute PTE [41, 42]. However, the test duration (approximately 20 minutes,) limits its use in urgent clinical scenarios.

A notable limitation is the lack of a universally accepted approach to the interpretation and evaluation of results. VQ scan is relevant for patients with high clinical probability of PTE who have contraindications to CTPA (e.g., history of anaphylaxis to contrast agents or significant decrease in glomerular filtration rate outside critical illness) or increased D-dimer levels. This modality offers diagnostic value in 30%–50% of patients with suspected PTE and remains the gold standard for assessing pulmonary perfusion, particularly suitable for serial follow-up due to its low effective radiation dose [20]. Nevertheless, in most patients with suspected PTE, scintigraphy yields intermediate or low probability results, which does not allow for definitive exclusion or confirmation of the diagnosis in real-world settings, necessitating further diagnostic steps [9].

Dual-Energy Computed Tomography Pulmonary Angiography

The concept of utilizing multiple energy levels in computed tomography was proposed over 40 years ago; however, its clinical implementation was long delayed because of the lack of appropriate technological infrastructure [44].

Dual-energy CTPA (DECT-PA) allows for tissue differentiation based on their distinct X-ray attenuation properties. This method enables the simultaneous acquisition of dual-energy images during the same contrast-enhanced phase. The technique involves scanning at two different tube voltage settings (typically 60–90 kV and 140–160 kV) under intravenous contrast administration, followed by the generation of perfusion maps [28].

Notably, DECT-derived images show a static distribution of iodine at a specific point (so-called pulmonary perfusion iodine maps) rather than reflect dynamic perfusion [44]. These perfusion images correlate with VQ scans and can display perfusion defects (Fig. 3) [45–47].

 

Fig. 3. Color iodine perfusion maps obtained using dual-energy computed tomography pulmonary angiography: a, perfusion defects in the right lower lobe and focal perfusion defect in the left lower lobe (white arrows); b, perfusion defect in the middle lobe and hypoperfused areas in segments S2 and S6 (white arrows). Published with permission from the copyright holder. © Federal State Autonomous Institution Medical Rehabilitation Center, 2018.

 

Iodine maps allow for differentiation between physiologic and pathologic perfusion changes. For example, hemodynamically significant vascular obstruction appears as wedge-shaped perfusion defects. Physiological hypoperfusion may be observed in areas of gravitational blood flow redistribution, along interlobar pleural fissures, or caused by artifacts from contrast media in the subclavian and superior vena cava, diaphragmatic motion, or cardiac pulsation. These perfusion defects have linear or crescentic shapes [27].

An important feature of DECT-PA is its ability to detect hypoperfusion in the absence of pulmonary infarction, distinguishing it from conventional CT. Typically, infarcted peripheral regions show wedge-shaped non-enhancing zones with parenchymal consolidation on lung window images. Areas of reduced enhancement on perfusion images in PTE without pulmonary infarction are identified without accompanying consolidation on lung window settings [28].

One of the less common complications of PTE is CTEPH. Assessing the congruence between perfusion defects and the anatomical location of occlusive–stenotic lesions in pulmonary arteries is critical when considering surgical or interventional management for patients with this complication [48].

A few studies have explored the use of inhaled xenon gas prior to DECT-PA to minimize ambiguity in interpreting findings when compared with conventional CTPA [26, 49]. In such protocols, patients inhaled 30% stable xenon for 80 s, followed by a scan 5 min later. With VQ scan, PTE was diagnosed based on a mismatch between perfusion and ventilation images. This approach demonstrated superior diagnostic performance compared to standard CTPA [49].

Thus, DECT-PA can simultaneously assess vascular alterations and pulmonary perfusion, enabling a comprehensive anatomical and functional evaluation [50]. Notably, the sensitivity and specificity of DECT-PA exceed those of traditional CTPA [49, 51].

Subtraction Computed Tomography Pulmonary Angiography

Another method for assessing the pulmonary microcirculation is subtraction CT pulmonary angiography with the subsequent iodine map generation. This technique involves subtracting non-contrast images from contrast-enhanced images, allowing for detailed visualization of the pulmonary vasculature. The patient undergoes two single-energy CT scans: one non-contrast and the other post-contrast. The average radiation dose is approximately 11.2 ± 4.7 mGy [52]. The non-contrast acquisition can be performed using a low-dose protocol to reduce radiation exposure. In several European and Asian medical centers, subtraction iodine imaging is used for diagnosing CTEPH. According to Shahin et al. [52], this method provides greater sensitivity for detecting iodine within the pulmonary parenchyma compared with dual-energy scanning. The default color scale for subtraction iodine maps ranges from 0 to 100 HU.⁴ Black areas represent complete perfusion defects, whereas dark blue regions indicate decreased perfusion (Fig. 4).

 

 

Fig. 4. Iodine perfusion maps obtained using subtraction computed tomography pulmonary angiography: a, wedge-shaped perfusion defects in the frontal view (white arrows); b, wedge-shaped perfusion defect in the sagittal view (white arrows). Published with permission from the copyright holder. © Federal State Autonomous Institution Medical Rehabilitation Center, 2018.

 

Comparative studies revealed promising results between multidetector and subtraction CTPA with iodine mapping, using lung scintigraphy findings as reference [25]. Subtraction imaging demonstrated superior diagnostic performance, with sensitivity and specificity of 95% and 84%, respectively, compared to 65% and 61% for single-energy CT without perfusion imaging [52].

False-positive and false-negative results account for approximately 2% of all studies. Retrospective data indicate that most discrepancies are due to interpretation challenges related to perfusion defect localization [25]. Artifacts from the contrast-filled superior vena cava or patient movement may appear as perfusion defects. In the frontal projection, they appear as black radial or horizontal bands extending beyond the pulmonary parenchyma to other structures such as the mediastinum, ribs, etc.

On vessel-enhanced images, pulmonary arteries appear with high contrast and decreased image noise, enabling improved identification of small-caliber vessels. On reconstructions highlighting the pulmonary parenchyma, the vessels appear as dark areas corresponding to the vascular territories of occluded arteries (Fig. 5).

 

Fig. 5. Subtraction images of lung parenchyma and vasculature: a, dark area in the right lung, visualized in sub-lung mode, indicating decreased pulmonary perfusion; b, filamentous pulmonary arteries, visualized in sub-VSL mode. Published with permission from the copyright holder. © Federal State Autonomous Institution Medical Rehabilitation Center, 2018.

 

Magnetic Resonance Imaging

The capabilities of magnetic resonance imaging (MRI) are underutilized in patients with PTE. MRI enables evaluating cardiac morphology and function and noninvasively measuring pulmonary blood flow using phase-contrast techniques without contrast administration.

Magnetic resonance pulmonary angiography (MRPA) is crucial in patients with CTEPH [19]. Challenges associated with this modality include artifacts related to respiration, patient movement, and nonuniform blood flow, which may require repeat scanning. MRPA should be performed in specialized centers with expertise in conducting the study and interpreting its results. Tsuchiya et al. [53] compared the diagnostic accuracy of MRPA and multidetector computed tomography and found similar levels of diagnostic effectiveness. This method is of particular interest in pregnant patients and those with intolerance to iodinated contrast agents. The sensitivity of contrast-enhanced, respiratory-synchronized MRI is approximately 73%, whereas non-contrast MRPA demonstrates a sensitivity and specificity of 67% and 100%, respectively [54].

The greatest diagnostic difficulty is noted in visualizing distal arterial branches and thrombi located along the vessel wall or in fragmented form. Dynamic contrast-enhanced MRI enables pulmonary microcirculation assessment (Fig. 6). In thrombotic occlusion, the vascular territory appears as an area with decreased vessel density and signal intensity. Several studies have confirmed the successful use of MRPA in detecting PTE among patients at intermediate or high risk, as determined by echocardiography [53, 54]. Consequently, MRPA is a viable alternative to VQ scan, also eliminating the need for iodinated contrast agents and reducing radiation exposure.

 

Fig. 6. Magnetic resonance pulmonary angiography findings: frontal projection shows dilated and distorted pulmonary arteries with mural contrast defects. Published with permission from the copyright holder. © Federal State Autonomous Institution Medical Rehabilitation Center, 2018.

 

CONCLUSION

PTE remains a critical and life-threatening condition in clinical practice. Diagnostic algorithms have been developed to facilitate timely diagnosis and prompt initiation of therapy. Currently, CTPA is the primary modality for confirming the diagnosis. However, it has several limitations, including:

• Contraindications to iodinated contrast media;
• Emboli localized in smaller pulmonary arterial branches;
• Delayed diagnosis, including progression to CTEPH.

In such scenarios, planar VQ scan is the primary modality for visualizing CTEPH, offering high sensitivity and specificity. Nonetheless, limited access to necessary equipment and trained personnel may hinder its widespread use in some clinical settings.

Moreover, it is important to note that in Russia, current diagnostic algorithms do not always consider variability in resource availability across healthcare facilities. Therefore, implementation of guideline-recommended diagnostic strategies may be challenging. In such cases, patients should be referred to specialized expert centers where advanced diagnostic modalities and highly qualified specialists are available.

Modern imaging modalities, including dual-energy and subtraction CTPA, and MRPA offer enhanced diagnostic capabilities for PTE. However, their availability varies by region and institution. This demonstrates the need to adapt diagnostic algorithms based on the actual technical capacities of individual healthcare facilities.

ADDITIONAL INFORMATION

Funding source. This article was not supported by any external sources of funding.

Disclosure of interests. The authors declare that they have no relationships, activities or interests (personal, professional or financial) with third parties (commercial, non-commercial, private) whose interests may be affected by the content of the article, as well as no other relationships, activities or interests over the past three years that must be reported.

Authors’ contribution. А.А Oganesyan, E.S. Pershina: collection and analysis of literary sources, writing and editing the article; V.E. Sinitsyn: analysis of literary sources, preparation and writing the article; E.A. Mershina: collection and analysis of literary sources, preparation and writing the article. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

¹ Class I recommendation: evidence supports that this diagnostic or therapeutic approach is beneficial and effective.

²Level of evidence A: data derived from multiple randomized clinical trials or meta-analyses.

³ Megabecquerel (MBq): unit of radioactivity in the International System of Units, equal to one million becquerels.

⁴ Hounsfield unit (HU): a quantitative scale for describing radiodensity in computed tomography imaging.

About the authors

Anait A. Oganesyan

Pirogov Municipal Clinical Hospital No. 1

Author for correspondence.
Email: talilen@mail.ru
ORCID iD: 0000-0003-1896-023X
SPIN-code: 6531-2957
Russian Federation, Moscow

Valentin E. Sinitsyn

Lomonosov Moscow State University

Email: vsini@mail.ru
ORCID iD: 0000-0002-5649-2193
SPIN-code: 8449-6590

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Moscow

Elena A. Mershina

Lomonosov Moscow State University

Email: Elena_Mershina@mail.ru
ORCID iD: 0000-0002-1266-4926
SPIN-code: 6897-9641

MD, Cand. Sci. (Medicine), Assistant Professor

Russian Federation, Moscow

Ekaterina S. Pershina

Pirogov Municipal Clinical Hospital No. 1

Email: pershina@mail.ru
ORCID iD: 0000-0002-3952-6865
SPIN-code: 7311-9276

MD, Cand. Sci. (Medicine)

Russian Federation, Moscow

References

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