Research progress on the clinical diagnosis and treatment of COPD with pulmonary embolism

WANG Li-fang, LI Qi,2,3, ZHOU Xiang-dong,2,3?

1. Department of Respiratory Medicine, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, China

2. Clinical Medical Center for Respiratory Diseases, Haikou 570100, China

3. Key Laboratory of Tropical Disease Control and Prevention, National Health and Health Commission of Hainan Medical University, Haikou 571199, China

Keywords:

ABSTRACT Chronic obstructive pulmonary disease (COPD) is one of the most common and important diseases leading to the death of elderly patients in the world at present.It is characterized by continuous airflow restriction and irreversible chronic airway obstruction, which can easily lead to a variety of complications and accompanying symptoms, greatly affecting the quality of life of individuals and increasing the economic burden of families and society.Pulmonary embolism(PE) is one of the complications of COPD, which can lead to pulmonary blood circulation and respiratory failure, with a high risk of death.However, because its clinical symptoms overlap with the symptoms of acute exacerbation of COPD and lack of specific clinical manifestations and laboratory tests, it is easy to be misdiagnosed and ignored, thus delaying the treatment of patients and affecting the prognosis.This article will elaborate on the clinical diagnosis and treatment of chronic obstructive pulmonary disease combined with pulmonary embolism, providing certain value for early identification of COPD combined with PE patients and the severity of the condition.

Chronic obstructive pulmonary disease (COPD), a common,preventable condition characterized by persistent respiratory symptoms and irreversible small gas flow limitation, is predicted to become the third leading cause of death worldwide by 2030[1,2].Acute exacerbation of chronic obstructive pulmonary disease(AECOPD) refers to the exacerbation of pre-existing respiratory symptoms, limitation of pulmonary function tests and activities,which are often triggered by infections (50%～70%), smoking, air pollution and environmental changes (10%), etc.and can still be caused by unknown causes in up to 30% of patients[3, 4].Venous thromboembolism (VTE), which includes deep vein thrombosis(DVT) and pulmonary embolism (PE), is the third most common cardiovascular disease[5].Pulmonary embolism can be caused by obstruction due to air, amniotic fluid, thrombus, and other causes of pulmonary hypertension, and it is mostly caused by thromboembolism, which further affects right heart function, with subsequent systemic venous congestion and even hemodynamic instability that is life-threatening, and if left untreated, the mortality rate can be as high as 20%～30%[6].Several studies have proved COPD as an independent risk factor for pulmonary embolism[7],but because respiratory symptoms of pulmonary embolism are highly consistent with AECOP, it is often easy to be ignored and misdiagnosed, and the time window of treatment is missed, which affects the prognosis of patients.Current clinical guidelines and treatment strategies for COPD with pulmonary embolism are still not agreed on, therefore, early recognition and diagnosis of COPD with PE is a current research priority.This paper illustrates the possible related and underlying mechanisms of COPD combined with PE, analyzes its clinical symptoms and diagnosis and treatment methods, and provides a certain reference value for the early recognition and treatment of COPD combined with PE.

1.Epidemiology of COPD with PE

COPD is a common disease, with approximately 6% of adults having COPD in most countries[8], and a population-based retrospective cohort study found that COPD patients were four times more likely to have PE than non COPD patients[7].In Korea, a prospective study found that PE accounted for approximately 5% of the etiologies of COPD exacerbations[9], and a Turkish study found that 1 / 4aecopd patient had PE[10].A meta-analysis found that the prevalence of PE in unexplained AECOPD was as high as 16.1%(95% CI, 8.3%～25.8%)[11].Whereas a recent study found that the overall prevalence of PE and DVT among patients with AECOPD was 11% (95% CI, 6%～17%) and 9% (95% CI, 6%～12%),respectively[12].At present, the number of patients with COPD in China is large, and the prevalence of young and middle-aged adults is high[13], the number of COPD patients is large and still on the rise,PE has a high risk of respiratory failure and circulatory failure, so early identification of COPD patients with pulmonary embolism and treatment is of great significance to humans.

2.Associated mechanisms of COPD with PE

The pathogenesis of PAH is complex and not fully elucidated, and it can be broadly divided into genetic susceptibility and acquired forms, all factors that can lead to slow venous flow, endothelial compromise, and hyperviscosity state of blood (Virchow’s three elements) may contribute to VTE formation[14].The related mechanisms and underlying factors of COPD complicated with PE can be found in Table 1.

Tab 1 Relevant mechanisms and potential factors of COPD complicated with PE

Most COPD patients are older and have their own disease that leads to progressive reduction in pulmonary function, easy to get shortness of breath after activity, decreased time of attempted self mobility, prolonged bed rest, and then short muscle contraction,resulting in slow venous flow and increased risk of DTV in the lower extremities.A study that collected 153 patients aged ＜ 45 years with early-onset CVD found that compared to controls, patients generally had higher levels of total cholesterol and low-density lipoprotein(LDL), triglycerides, but lower levels of HDL, had higher levels of factor VIII coagulant, homocysteine, anticardiolipin antibody IgM,and low lupus anticoagulant, demonstrating a genetic predisposition for COPD with PE[22].

In the systemic inflammatory state, not only the increased production of inflammatory substances injures the vascular endothelium, but also leads to the shedding and necrosis of airway epithelial cells, airway structure collapse and remodeling, causing hypoxemia, secondary erythrocytosis, blood hyperviscosity and so on[23].It is fully illustrated that most of the mechanisms are mutually affecting, inseparable and multifactorial.

3.Clinical manifestations of COPD with PE

AECOPD refers to the exacerbation of pre-existing respiratory symptoms in patients with COPD that requires the addition of pre-existing medication or the addition of additional therapy[13],whereas AECOPD is similar to PE in its clinical symptoms, which can be cough, sputum, shortness of breath, chest pain, hemoptysis,tachycardia, and so on, and is often difficult to identify especially when dyspnea appears.The classic clinical triad of ape is as follows:chest pain, hemoptysis, and dyspnea, but its clinical incidence is only 20%, and symptoms of pleuritis and heart failure are more common in patients with PE[10, 24], and PE can also present with syncope,asymmetric edema of both lower extremities, and other VTE related clinical manifestations.Chaudhary[25] suggested that patients with unexplained COPD exacerbations should be promptly screened for PE if they develop chest pain, hemoptysis, dyspnea, increased respiratory rate, tachycardia, and respiratory alkalosis.

4.Diagnostic approach to COPD with PE

4.1 CT imaging examination

CT pulmonary angiography (CTPA) has high sensitivity and specificity, and is currently the imaging method of choice[26].With the development of technology, it can be examined by dual source CT pulmonary vascular imaging (CT) with fast scanning speed, high resolution, and small radiation volume, while CTPA and DEPI (dual energy pulmonary perfusion imaging) images are obtained to more clearly show the type of PE thrombus, the site of embolization, the extent of embolization, and pulmonary blood perfusion[27], Because it is more difficult to detect minute thrombi distal to the pulmonary vessels by CTPA, this technique also increases the detection of PES below the pulmonary segment[28].The traditional means of diagnosing COPD with PE is through quantitative analysis of the pulmonary embolism index from CTPA images, and then Spearman correlation analysis between the pulmonary embolism index and each index of coagulation function and blood gas analysis.In the present study[29], spiral CT enhanced scan of 50 patients with COPD combined with PE diagnosed by pathological examination found that 47 patients were diagnosed with an accuracy rate of 94%, and there was no statistical difference with the traditional pathological examination, thus it can be seen that the use of spiral CT enhanced scan can also be used as a definitive method for COPD combined with PE.

4.2 D-Dimer

Plasma D-dimer is a specific degradation product generated after in vivo hydrolysis of thrombus components by plasmin, and when detected elevated D-dimer can suggest hypercoagulability,thrombosis, secondary hyperfibrinolysis, etc.[30].Some studies found[31] that the plasma D-dimer level in AECOPD complicated with PE group ＞ AECOPD group ＞ healthy group.Thus, it can be concluded that D-dimer can be used as a screening indicator for COPD complicated with PE, but the D-dimer pair is not highly specific for the presence of PE, and increasing age, tumor,pregnancy, systemic inflammation, trauma, surgery, etc., can make D-dimer higher[32].There are studies showing a higher negative predictive value of D-dimer, and adjusting the D-dimer cut-off value according to age is better for excluding PE in older patients[4].It follows that this method has a certain deficiency, but the sensitivity is greatly improved after combining clinical features, and it is of great significance for diagnosing COPD combined with PE.

4.3 PaCO2

D-dimer and partial pressure of carbon dioxide (PaCO2) are two risk factors for COPD combined with PE, therefore, PaCO2 detection is feasible in addition to D-dimer detection analysis.COPD with PE causes patients to be hyperventilated and have increased CO2 emission compared with patients with COPD alone[33].This conclusion was further validated by Tillie-Leblond[34] with 197 patients diagnosed.Because detection of D-dimer and PaCO2 has many advantages, such as simplicity, rapidity and accuracy, D-dimer combined with PaCO2 can be used as a primary screening tool for COPD combined with PE, and CTPA can be reviewed for those with excessive deviation of values.

4.4 Ultrasonography

Ultrasonography can assist in determining the presence or absence of lower extremity deep vein thrombosis and assessing cardiac function, and is often used in clinical diagnosis, assessment of efficacy, and follow-up because of its powerful advantages of being inexpensive and safe and noninvasive.Patients with PE are prone to high right heart burden and right heart dysfunction after thromboembolism of pulmonary arteries, which can be obtained by echocardiography.Specifically, atrial and ventricular chamber sizes, valve function, wall function, pulmonary artery pressure, and pulmonary artery internal diameter can be assessed.Echocardiography, although not directly diagnostic of pulmonary embolism, can assist in the identification of other causes of shock,such as left ventricular dysfunction, pericardial tamponade, and cardiomyopathy.When patients are critically ill and cannot undergo CTPA examination, bedside cardiac ultrasound can be used first to assess the right heart function and the presence or absence of thrombosis in the pulmonary artery end, which provides an important aid in the evaluation of suspected PE and curative effect[35].

4.5 V/Q imaging

V/Q imaging examination can also be used as one of the important examinations for the diagnosis of PE, whose typical imaging is perfusion defect.PE is highly suspected if the area above the segment is poorly perfused but well ventilated.The radiation volume of V / Q imaging is low, and it can be used as the first choice test for women in pregnancy, patients with renal dysfunction, and allergy to contrast media[14].Chronic PE can be excluded if there is no abnormality on V / Q imaging.It should be noted that there are many cases caused the imbalance of perfusion flow ratio of pulmonary ventilation, and the diagnosis and treatment need to be closely contacted.

4.6 Routine blood test

In recent years, most studies have found that multiple indicators in blood routine have diagnostic value for COPD combined with PE.Wang J[36] et al collected a retrospective analysis of 125 COPD patients and found that COPD patients with PE had significantly higher RDW-SD (standard deviation of red cell distribution width)and RDW-CV (coefficient of variation of red cell distribution width)than COPD patients without PE, and suggested that the higher the RDW-SD value, the higher the PE risk should increase.Consider possible association with systemic inflammatory response.Bia?as AJ[37] et al., in a study of 101 COPD patients, found that monocyte to large platelet ratio (MLPR) could assist in the diagnosis of comorbid PE, and MLPR had a high sensitivity of 100% (95% CI,79.6%～100%) and specificity of 85.7% (95%Ci, 75.9%～92.6%).It has been reported that eosinophilia is associated with exacerbations of COPD and mortality in AECOPD[38-41], but studies such as Yang[42] further confirmed that eosinophils would be increased in AECOPD patients and also found that AECOPD patients with PE had no further activation of eosinophils, so whether eosinophil count can be used as a diagnostic indicator for AECOPD patients with combined PE needs further study.

4.7 Other

Pulmonary angiographic examination, previously as the “ gold standard “ examination, can directly show the situation of pulmonary vascular embolism, but this project is technically demanding and invasive examination is prone to many complications, so it has been replaced by CTPA, and is currently mostly used clinically to assist surgical localization.NMR pulmonary angiography is not yet used as a routine test in clinics because it is expensive, the long operation time is not conducive to emergency patients, the sensitivity,resolution, and ease of operation do not exceed that of CTPA.

BNP, a hormone that regulates body fluid and electrolytes produced by stretch stimulation of the ventricular wall, is a marker of cardiac dysfunction, and PE causes pulmonary hypertension, and BNP can be synthesized and secreted in the presence of right heart dysfunction[43].Troponin T (cTnT) as a mIarker of myocardial injury is often accompanied by right heart dysfunction and damaged myocardium when PE occurs, it may be used for PE diagnosis prediction and risk assessment[44].Some authors found that the serum Il-38 level in COPD patients with PE was significantly lower than that in non PE patients [46.3 (33.1, 58.1) ng / L: 61.5 (46.6, 72.5)ng / l][45], considering that Il-38 may improve the thrombophilic status of AECOPD patients by inhibiting the inflammatory response.Nafady A[46] et al found that the expression of miRNA-145 was downregulated, while the expression of miRNA-126 was higher in COPD patients with PE, Peng L[47] et al found that the expression levels of miR-1233 and miR-134 were significantly upregulated in the serum of AECOPD patients with PE compared with patients with AECOPD and stable COPD.MicroRNAs (miRNAs), a class of non coding small molecules in eukaryotes, are involved in all processes of human growth and development, and microRNAs may damage vascular endothelial cells, impair plaque stabilization, and so on under the influence of multiple mechanisms, and then promote pulmonary vascular thrombosis[48].Inflammatory markers such as CRP, erythrocyte sedimentation rate, IL and PCT were also highly expressed in COPD patients with PE.

4.8 Risk assessment methods

Due to the high risk of COPD associated with PE in clinic,screening for PE is often necessary in AECOPD patients, but the“ gold standard “ CTPA assay is costly, and some patients have chronic renal failure prohibiting the use of contrast media, problems with the amount of ultra radiation, inapplicability of critically ill patients, incomplete basic facilities, and incomplete technology[49],there is an urgent need to find an easy and suitable initial screening method to improve the detection rate, early intervention, and reduce the occurrence of adverse outcomes in COPD patients.At present,the Wells, Geneva score and the revised Wells, Geneva score are commonly used in the clinic, and also investigators have proposed the Padua, Kaprini, Caprini, Years score, etc., to confer each score and delineate the degree of risk, according to the index grouping to decide whether to treat and the scheme of treatment.Analytical evaluation methods are presented in table Table 2.

Tab 2 Risk assessment methods

5.Clinical management

5.1 Prevention

Due to the high risk of PE, appropriate means of thromboprophylaxis should be taken for patients with COPD exacerbation, which is an independent risk factor for VTE[52].For COPD patients with reversible risk factors of VTE, such as surgery,trauma, hormone therapy patients, it is recommended to get out of bed as early as possible, drink water appropriately without contraindications, avoid blood viscosity, use elastic stockings appropriately for those with limited mobility, use of intermittent pressor pumps and other auxiliary lower limb venous return, and avoid medical manipulation of the lower limbs as much as possible.

5.2 Treatment

COPD with PE can lead to respiratory failure in patients and trigger cardiovascular disease, and for medium - to high-risk patients,immediately after diagnosis, anticoagulant therapy should be performed to improve lung ventilation and then save the patient’s life.Commonly used anticoagulants are unfractionated heparin(UFH), low molecular weight heparin (LMWH), fondaparinux,warfarin and DOACS (novel oral anticoagulants).Demonstrated[59]that 7-d treatment with LMWH combined with warfarin resulted in significantly greater therapeutic efficacy compared with LMWH alone.It follows that LMWH combined with warfarin is an effective treatment for COPD with PE, which can improve lung function and improve blood flow rate in patients.Immediate anticoagulation is indicated when there is no significant risk of bleeding, highly suspicious of acute PE, or confirmed PE, or if warfarin is chosen as long-term anticoagulant, using parenteral anticoagulants overlapping warfarin anticoagulation within 24 h with additional anticoagulant discontinuation after an INR index of 2～3[50].PE patients with clear reversible risk factors are anticoagulated for 3 months, and those whose risk factors persist after a 3-month anticoagulation course require continued anticoagulation, even lifelong anticoagulation.

Thrombolysis is recommended in high-risk patients with acute PE and no contraindications to thrombolysis, with the usual thrombolytic agents being rt-PA, urokinase, and streptokinase.There are data to suggest that thrombolysis or thrombolysis combined with anticoagulation has better efficacy than anticoagulation alone in medium - to high-risk patients[60], and is an effective treatment for COPD complicated by PE.Emergency interventional vascular procedures (catheter thrombus aspiration, balloon angioplasty,and stenting) should be performed in those with contraindications to thrombolysis or those with unstable blood flow.Patients with anticoagulated VTE do not require placement of an inferior vena cava filter, and one retrospective analysis found that vena cava filters reduce mortality by 2.1% in patients over 50 years of age with COPD complicated by PE and that patients over 80 years benefit more, with mortality rates decreasing from 14.4% to 9.1%.Pulmonary artery thrombectomy may be considered in patients with pulmonary trunk embolism who have failed previous therapies[54].

5.3 Prognosis

Early intervention and treatment of PE has been shown to reduce mortality by 2%～8% and to be as high as 20%～30% if no effective treatment is available[61].PESI score (Pulmonary Embolism Severity Index), sPESI score (simplified version) can be used to evaluate the prediction of 30 day mortality in patients with PE.Yamashita Y[62]et al suggested that sPESI = 0 points could be classified as low risk,and patients with sPESI greater than 1 point had significantly higher 30 day mortality.Bertoletti L[63] observed COPD patients initially diagnosed with VTE 3 months after discharge and found that the risk of recurrent VTE and fatal PE was higher, and COPD patients with PE had a higher risk of recurrent PE and fatal PE.So for COPD patients with PE, prognosis observation is extremely important, to add reexamination, clear whether recurrence and timely intervention treatment, can save more patients lives.

6.Summarize

PE exists with high recurrence and lethality, and up to 30%of autopsy reports of patients who died from COPD remain undiagnosed[63], so clinicians need to be highly alert to the occurrence of PE in patients with unexplained COPD exacerbation,especially in patients with clear risk factors, who present with chest pain, hemoptysis, and increased dyspnea.For COPD patients at high risk of PE, pulmonary embolism related score prediction should be performed first, and those with higher scores followed by CTPA examination to clarify whether combined with PE, avoiding patients exposed to a large amount of radiation.For communities and township settings with imperfect examination equipment and poor operation technique, the risk scoring system for pulmonary embolism can screen PE patients in a timely manner and make timely referral, avoid the occurrence of poorer outcomes, and greatly reduce mortality.At present, a large number of clinical studies are still needed to screen out easier and high predictive value risk assessment methods, and to discover the more sensitive and specific diagnosis means to improve the diagnosis rate and make the next treatment and prognosis benefit for patients.

Author contributions note: WANG Lifang: completed the collection and analysis of relevant literature data and the writing of the first draft of the paper; LI Qi: participated in analysis and assembly of literature data and guided paper writing; ZHOU Xiangdong:conceiver of the project and mentored paper writing; All authors have read and agreed to the final text.