The most common presenting symptoms are exertional dyspnea and a decline in exercise tolerance. Other infrequent symptoms are cough, episodic hemoptysis, atypical chest pain, and palpitations.[16] In most cases, the diagnosis of CTEPH is established only in the later stages of the disease, when peripheral edema, dyspnea during exercise, dizziness, or syncopal episodes have already appeared.

During the early stages of CTEPH, physical examination of the patient may not reveal any notable findings. With the progression of pulmonary hypertension, a tricuspid regurgitation murmur, pedal edema, jugular venous distention, and other symptoms of right ventricular failure appear.

Classic signs of pulmonary hypertension that are present in CTEPH are an S4 gallop, a tricuspid regurgitant murmur, and a precordial right ventricular heave. The presence of pulmonary flow murmurs signaling turbulent flow across narrowed segments of large pulmonary arteries over lung fields is a unique finding in CTEPH. This finding gets described as subtle bruits, high pitched, blowing quality, accentuated on inspiration, and usually heard on holding breath.

Early diagnosis of chronic pulmonary thromboembolism is a challenging task due to nonspecific symptoms and delayed manifestation of the disease. Confirmation of the diagnosis requires a combination of imaging techniques such as echocardiography, Ventilation/perfusion scan (V/Q) scan, and CT pulmonary angiography.

Initial evaluation of a patient often includes Chest X-ray, which may be normal in the early stages of the disease. In later stages, Chest X-ray shows signs of pulmonary hypertension, cardiac chambers enlargement, and segmental oligemia with pleuroparenchymal scarring.[17] 

Transthoracic echocardiography is a primary diagnostic tool for the diagnosis of pulmonary hypertension, but it is not specific, as it cannot differentiate between acute and chronic PE.[18] 

V/Q scan has high sensitivity (90 to 100%) and specificity (94 to 100%) and is a first-line screening tool for diagnosing CTEPH.[19][20] Diagnostic criteria for CTEPH include mean pulmonary arterial pressure over 20 mm of Hg, pulmonary arterial wedge pressure under 15 mm of Hg, elevated pulmonary vascular resistance greater than 3 Woods units, and evidence of chronic pulmonary embolism on CT or V/Q scan.

Right heart catheterization with conventional pulmonary angiography is the gold standard in diagnosing CTEPH. Novel techniques such as dual-energy CT, dynamic contrast-enhanced MRI, and optical coherence tomography (OCT) are also valuable diagnostic tools and assist in the evaluation of patients with CTEPH.

The combination of different diagnostic tools can provide additional information and assist with differential diagnosis, planning treatment strategies, and assessing response to treatment.

Patients with CTEPH should be evaluated and treated in an experienced center by a specialized team of experts. All patients with suspected CTEPH should start on anticoagulation for at least three months. During this period, the disease can regress, and significant hemodynamic improvement or even full resolution of pulmonary hypertension may occur.  After this period, the diagnosis of CTEPH is considered to distinguish it from the subacute episode of PE. Then, upon completing the evaluation, CTEPH is confirmed, and the clinician can make clinical decisions regarding treatment strategy.

Treatment may be either surgical or medical therapy. 

Pulmonary endarterectomy (PEA) is a complex surgical intervention in selected operable patients. It results in the normalization of pulmonary hemodynamics, improves exercise capacity, and survival.[21] In general, motivated patients who consent to surgery, those with proximal thromboembolic burden, those with minimal comorbidities, and who have significant hemodynamic and ventilatory impairments from the disease benefit from the surgery.[22] 

The University of California, Sandiego (UCSD) proposed a classification of CTEPH, which helps in guiding the surgeons regarding the level of complexity and expertise needed for the treatment. With increasing complexity, the level of the category increases. Level 0 includes patients with no surgical evidence of chronic thromboembolic disease; level 1 denotes blockage at the level of main pulmonary arteries; levels 2, 3, and 4 show blockage at lobar, segmental, and subsegmental levels of pulmonary artery branching respectively.[23]

PEA removes obstructive and hardened thrombus and markedly improves the hemodynamic measures such as mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac output. Thus, reversing right ventricular remodeling with normalization of right-sided cardiac function.[24][25]  After PEA, the disorder persisted in 5% to 35% of the cases.[26]It is notable that, even after PEA, evidence suggests that patients need to be on lifelong anticoagulation to prevent further episodes of venous thromboembolism, thereby contributing to the prevention of worsening or recurrence of the disease. Compared to direct-acting oral anticoagulants, vitamin K antagonists are found to lower the risk of recurrent thromboemboli significantly.[27][27] 

More than 30% of the patients are inoperable, for whom pulmonary balloon angioplasty is a promising alternative.[28][29] Several ongoing, planned, and completed studies are the effect of balloon pulmonary angioplasty (BPA) on CTEPH patients. These include the EXPERT-BPA study, which is planned to observe the effect of the BPA on CTEPH patients at rest and during exercise at an international level, the International BPA Registry study- an ongoing prospective study to evaluate the efficacy and safety of BPA. A meta-analysis recently published in 2019 showed that BPA was superior to riociguat therapy in improving exercise intolerance and certain hemodynamic parameters.[30] BPA is known to cause general angioplasty complications like wire injury, vessel dissection, vessel rupture, and also complications specific to angioplasty in the lung area, including reperfusion pulmonary edema, pulmonary parenchymal bleeding, and hemothorax.[28]

Current guidelines recommend the use of anticoagulants, diuretics, and oxygen if needed for optimal medical treatment of CTEPH. Anticoagulation aimed at the prevention of in situ pulmonary artery thrombosis should be lifelong.

The medical treatment of CTEPH is based primarily on PAH-targeted therapy, which includes the use of endothelin receptors antagonists, phosphodiesterase type-5 inhibitors, and prostanoids. Among them, treprostinil and macitentan were extensively studied and proven to be beneficial in these patients.[14][31] Novel option in the treatment of CTEPH is riociguat, a guanylate cyclase stimulator, which is used primarily in patients that are ineligible for surgery or persistence of the disease after pulmonary endarterectomy.

CTEPH is a potentially curable disease, and clinicians should distinguish it from other conditions that cause the presence of thrombotic and fibrotic changes in the pulmonary arteries. First of all, a differential diagnosis with idiopathic pulmonary artery hypertension (IPAH) merits consideration.[32] On CT scan, IPAH has no thromboembolic material in pulmonary arteries or fibrotic obstructions but has significantly decreased segmental and subsegmental arteries. A key finding in IPAH is corkscrew-like pulmonary arteries, which represent the plexogenic arteriopathy.[33] Noninvasive test to differentiate between CTEPH and primary pulmonary hypertension is possible using Doppler Ultrasound. Pulmonary artery pressure waveforms differ significantly in a patient with CTEPH and IPAH with pulse pressure in CTEPH, usually being markedly larger.

Another differential diagnosis is the primary sarcoma of the pulmonary artery, which is a very rare disease with nonspecific symptoms that make it hard to differentiate from CTEPH. Sarcoma represents a solid lobulated mass in central pulmonary arteries on CT or MRI and has no response to anticoagulation treatment. Positron-emission tomography (PET-CT) with F-fludeoxyglucose can be performed to distinguish sarcoma from CTEPH.[34]

In rare cases, right heart failure with acute pulmonary thromboembolism can mimic CTEPH. In the case of acute thromboembolism, emboli form at an acute angle with pulmonary artery wall, while in CTEPH, that angle would be obtuse. Also, the right ventricle hypertrophy is less likely to be seen in acute PE.[35] 

Other differential diagnoses include thrombosis in situ, Takayasu arteritis, congenital proximal interruption of a pulmonary artery, tumor thrombus, Von Recklinghausen disease, and Osler-Weber-Randu disease.[36][37][38] 

Pulmonary endarterectomy (PEA) is proven to be the best option for improved survival rates for operable patients. According to a study from 2017, the five-year survival rate after PEA was found to be 70 to 80%.[39] Hemodynamic severity and systolic pulmonary artery pressure were significantly improved after PEA.[40] The period between the last pulmonary embolism episode and PEA is considered as a risk factor for in-hospital mortality, signifying the importance of timely diagnosis of CTEPH for a favorable outcome.

The long-term prognosis of CTEPH after surgical removal of thrombi currently is excellent.

CTEPH itself is a complication of chronic thromboembolism. If left untreated, it can lead to severe right heart failure, significant shortness of breath, decreased exercise tolerance, syncope, and eventually death with a three-year mortality rate estimated to be 90%.[41]

Patients of CTEPH should be educated well before discharge on medication adherence and follow up. In patients with multiple comorbidities, close follow up is very crucial as management of the concurrent medical conditions helps significantly improve the functional capacity of these patients. Physicians should assess patients who are about to travel by flight for possible need of oxygen requirement in-flight journey.

In the general population, measures are necessary against acute PE. Patients who have a prolonged hospital stay should be given appropriate anticoagulation during their visit. At the same time, they can also have inflatable compression devices or compression stockings for the prevention of clot formation. Individuals who travel frequently and have longer airplane time should make sure that they walk about every one to two hours or changing their seating positions regularly.

Chronic pulmonary thromboembolic hypertension is a rare, dangerous, but potentially curable, thromboembolic disease. The lack of predictable predisposing factors, including a prior medical history of acute pulmonary embolism, should not discourage CTEPH from being included in the differential diagnosis of patients with a progressive reduction in exercise tolerance.

Key points:

CTEPH should be considered in all patients with pulmonary hypertension, as this is the only cause of PH that is potentially curable.

V/Q scan is a first-line screening tool for diagnosing CTEPH.

Diagnostic criteria for CTEPH include mPAP greater than 20 mm of Hg, PAWP less than 15 mm of Hg, elevated pulmonary vascular resistance over 3 Woods unit, and evidence of chronic pulmonary embolism on CT/MRI or V/Q scan.

Current medical treatment for CTEPH includes PAH-targeted therapy and oral anticoagulation.

The surgical treatment of choice in CTEPH patients is pulmonary endarterectomy.

CTEPH is a difficult diagnosis, and the management is not straight forward; delays in treatment correlate with high mortality rates, and thus, management is best with an interprofessional team.

Given high morbidity and mortality and is a potentially curable condition, there should be a low threshold for suspicion of chronic pulmonary thromboembolism for patients presenting with pulmonary hypertension. As there are improved outcomes with surgical treatments, all the patients who are potential surgical candidates should undergo evaluation for surgical thromboendarterectomy. Also, physicians should be more aware of management options for patients who are not surgical candidates. Options include pulmonary balloon angioplasty, and PAH targeted medical therapy along with lifelong anticoagulation.

The primary care clinicians and nurses should educate patients before discharge on medication adherence and follow up. In patients with multiple comorbidities, close follow up is very crucial as management of the concurrent medical conditions helps significantly improve the functional capacity of these patients. If choosing pharmacotherapy, a board-certified pharmacotherapy specialty pharmacist should assist with the dosing and selection of drugs, especially the more novel agents. Clinicians and/or nurses should assess patients who are about to travel by flight for possible need of oxygen requirement in-flight journey.

In the general population, measures are necessary against acute PE. Patients who have a prolonged hospital stay should be given appropriate anticoagulation during their visit. At the same time, they can also have inflatable compression devices or compression stockings for the prevention of clot formation. Individuals who travel frequently and have longer airplane time should make sure that they walk about every one to two hours or changing their seating positions regularly. Close communication between the team members is vital to ensure that the patient is receiving the current standard of care. The interprofessional team, including clinicians, specialists, nursing, and pharmacists, all need to collaborate to implement these measures and advance positive outcomes in treating CTEPH. [Level V]