Introduction:

GOLD 2023 defines Chronic Obstructive Pulmonary Disease (COPD) as a heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, expectoration and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction. Chronic Obstructive Pulmonary Disease (COPD) exerts a significant clinical, social and economic burden globally. The global prevalence of COPD oscillates around 12% of the general population. COPD currently ranks as the 3rd cause of mortality in the world (responsible for 3 million deaths), just behind CVDs.

Epidemiology of COPD and Pulmonary Thromboembolism:

COPD has multiple extrapulmonary manifestations including widespread systemic inflammation, osteoporosis and musculoskeletal degeneration, coronary artery disease and increased risk of venous thromboembolism (VTE). Pulmonary thromboembolism (PE), in particular, is a dreaded and often underdiagnosed entity causing significant mortality and morbidity among COPD patients. COPD patients are thought at increased risk for venous thromboembolism (VTE) because of immobilization, heightened systemic inflammation, cigarette smoking, and venous stasis. Postmortem studies in COPD have found pulmonary embolism (PE) in 28%-51% of cases. PE is diagnosed by computed tomography (CT) angiography in 25% of individuals presenting with an unknown etiology for a COPD exacerbation. VTE in COPD has prognostic implications. Prevalence of VTE in COPD has direct correlation with mortality and need for mechanical ventilation. One study found significantly higher 1-year mortality in COPD exacerbation with VTE (61.9% vs. 31.8%, p=0.013). Another study showed increased duration of hospitalization and need for mechanical ventilation.

A large cohort of unselected COPD patients showed that a history of VTE was associated with higher oxygen use, a lower 6-minute walk distance, a worse quality of life, a higher frequency of exacerbations, and a higher smoking history. Additionally, those with a history of VTE were older, heavier, and more likely to have multiple medical comorbidities. These findings were reported in a retrospective cross- sectional analysis comparing smokers with worse airflow obstruction to nonsmoking controls and smokers with no or mild airflow. The COPD patients were older (mean age 68 vs. 63 years), and had a higher frequency of heart failure (35.5% vs. 12.9%), and immobility (53.5% vs. 43.3%, all p<0.0001) compared to those without COPD.8 The COPD individuals were more likely to die in the hospital and within 30 days of the VTE diagnosis. Tillebrand et. al. found that in 25% of 211 patients with severe COPD exacerbations without an identifiable cause, the exacerbations were actually related to PEs.

COPD in Nepal and local scenario of VTE/PE in COPD:

COPD is the most prevalent non-communicable diseases (NCDs) in Nepal, with 12% prevalence in adults. In 2016, nearly one million Nepalese people were suffering from COPD, twice as many as in 1990. Although a large-scale study on VTE and PE among COPD patients in Nepal is lacking, we can safely assume that the prevalence of VTE and PE is fairly high. It is a sad fact that often such catastrophic events are undiagnosed, underdiagnosed and unreported. Looking at the number of COPD patients who die in the community and present as dead-on arrival to the hospital with history of sudden collapse, we can assume that many of these patients have a diagnosis of VTE/PE including cerebrovascular accidents (CVA) and acute coronary events.

Management of VTE/PE in COPD:

Acute PE in patients with Acute Exacerbation of COPD (AE of COPD) is usually difficult to diagnose clinically because the clinical manifestations of these two diseases are often similar. PE manifests as shortness of breath, chest tightness, chest pain, and hemoptysis, and is often accompanied by hemodynamic instability such as hypotension and hypoxia. COPD patients with PE are less likely to develop cough, dyspnea, and syncope, whereas COPD patients who are prone to developing PE complications are often associated with lower extremities thrombosis. In patients with AECOPD of unknown cause, pleural chest pain and heart failure are more strongly associated with PE, while symptoms of respiratory infection are less frequent. Patients with AECOPD combined with VTE had higher D-dimer but lower hemoglobin levels than those without VTE.

The eosinophil level can be used as a biomarker to predict the risk of all-cause mortality in hospitalized patients with COPD exacerbation, and thromboembolism occurs relatively commonly in patients with hypereosinophilic syndrome. Eosinophilia can lead to multiple arterial and venous thromboses. Catalytic cytotoxic proteins found in eosinophils, such as platelet-activating factor and eosinophilic peroxidase, cause and intensify inflammatory reactions, harm cells, encourage blood coagulation, and cause tissue damage. In addition, eosinophil cells can store tissue factors (TFs), which are believed to be the main initiator of blood clotting. Glucocorticoid provided effective short-term control of hypereosinophilia to delay thrombosis. The symptoms and signs of PE are nonspecific. Patients who experience dyspnea, chest discomfort, syncope, or hemoptysis-symptoms that characterize most COPD cases- should be closely watched for the possibility of PE. PE, however, can occasionally be identified while a patient is being examined for another illness or may present with no symptoms at all.

Elevated D-dimer can only be used to rule out a diagnosis; it does not confirm the diagnosis. Acute PE can be excluded if D-dimer <500 μg/L. By using the D-dimer test in conjunction with the Simplified Geneva Score pre-test, diagnostic accuracy can be increased. Studies have also shown that albumin (P = 0.0002) and RDW (P = 0.0446) significantly correlates with the occurrence of acute PE. The combined diagnosis of albumin and RDW had the highest sensitivity and specificity, and the threshold was ≤3 g/dL, and >14 g/dL, respectively. End-tidal carbon dioxide (ETCO2) is also a meaningful indicator for the diagnosis of PE. When PE is diagnosed with a cut-off value of 34 mmHg, PE can be appropriately and reliably excluded when combined with clinical likelihood. The “gold standard” for diagnosis is selective pulmonary angiography, while computed tomography (CT) pulmonary angiography is the recommended imaging technique for suspected PE. Direct diagnosis is possible through indications that correspond to deficiencies in the filling of the pulmonary arteries; indirect diagnosis is possible through signs such wedge-shaped pulmonary fields, banded densities or discoid pulmonary opacities, dilatation of the central pulmonary artery, and decreased or nonexistent distal vascular branches. The other modality like ventilation/ perfusion single-photon emission computed tomography (V/Q SPECT) can be used as well which is useful for diagnosing both acute and chronic PE, and can be diagnosed when more than one subsegment shows V/Q mismatches representing anatomic lung units.

The cornerstone of PE treatment is anticoagulation, which not only successfully inhibits thrombus formation and relapse but also has the ability to facilitate the fibrinolytic system’s disintegration, which breaks down blood clots. Anticoagulant medication should be initiated as soon as acute PE is clearly diagnosed. Currently, the first-line treatment for PE is direct oral anticoagulant (DOAC), which can also be used to treat PE and COPD together. In the acute phase of high-risk PE with hemodynamic instability, unfractionated heparin (UFH) anticoagulation, including intravenous injection and systemic thrombolysis, should be used right away. One surgical option in the event of thrombolysis failure or contraindication is pulmonary embolectomy. According to study by Hara et al., DOAC should a be administered following a single intravenous injection of UFH to high- risk PE patients with large thrombus. According to the findings, patients had lower hospital stay duration and a higher rate of pulmonary artery thrombosis reduction at three to six months following treatment than the patients in the traditional treatment group. For patients with high risk of PE, inferior vena cava (IVC) filter implantation is an effective therapy option. In a multi-center retrospective analysis, 440,370 hemodynamically stable AECOPD patients complicated by PE were included and the findings indicated that IVC therapy can lower the absolute risk of death in patients over 50 by 2.1%.The death rate for those over 80 years of age fell from 14.4% to 9.1%.

Conclusion:

When PE is added to AECOPD patients, the mortality rate rises and PE is thought to be an independent risk factor for a bad prognosis. However, PE is more likely to be misdiagnosed or disregarded in COPD patients due to comparable clinical symptoms. Consequently, early anticoagulant therapy becomes crucial to the management of AECOPD patients in order to prevent thrombosis. Oral anticoagulants have been utilized extensively in the treatment of COPD exacerbated by PE in recent years. There should be a high index of suspicion for VTE/PE in COPD patients admitted with acute exacerbations and there should be no delay in diagnosis. After the diagnosis of PE in COPD patients is confirmed, immediate treatment with anticoagulants should be commenced. More research and resources are required to address VTE/PE in COPD patients, particularly in low and middle-income nations like our own where the disease is incredibly and tragically common.

Dr. Sabin Chaulagain
MBBS, MD, Fellow in Endocrinology,
Diabetes & Metabolism, Department of
Internal Medicine, SMAH