Clinical outcome of lung transplantation for chronic thromboembolic pulmonary hypertension

Abstract

Background

Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension with a low incidence. Despite pulmonary endarterectomy(PEA) being the preferred treatment for CTEPH, for patients who failed medical therapy and who are not suitable candidates for PEA, lung transplantation (LT) is still the only effective treatment for end-stage CTEPH; however, there are currently very few reports on the efficacy of LT for CTEPH.

Methods

We retrospectively analyzed the clinical data of seven patients diagnosed with CTEPH between July 2019 and July 2021. The follow-up deadline was March, 2022.

Results

The mean age at admission was 54 ± 12 years. The average value of mean pulmonary artery pressure (mPAP) was 40 ± 5 mmHg. The mean preoperative oxygenation index(PaO2/FiO2) was 203 ± 56 mm Hg. After evaluation, one patient underwent left LT and the rest underwent bilateral LT. Three patients received intraoperative veno-venous extracorporeal membrane oxygenation (ECMO) support, and four patients received intraoperative veno-arterial ECMO support. The average postoperative mPAP was 19 ± 4 mmHg. The mean postoperative oxygenation index(PaO2/FiO2) was 388 ± 83 mmHg. There was a significant difference between the preoperative and postoperative mPAP and oxygenation index(PaO2/FiO2). All patients recovered well and were discharged 37 ± 19 days postoperatively. The mean follow-up duration was 19 ± 8 months. There was no recurrence of CTEPH.

Conclusions

LT is an effective treatment for end-stage CTEPH, which can improve cardiopulmonary function and quality of life and prolong survival. Patients who are unable to tolerate PEA should be considered for LT as early as possible when internal medicine failed.

Introduction

Chronic thromboembolic pulmonary hypertension (CTEPH), a type of class IV pulmonary hypertension (PH), is a secondary pulmonary vascular disease characterized by a progressive increase in pulmonary artery pressure [1]. The incidence of CTEPH has been reported to be 4 per 1 million adults [2]. The main pathogenesis is incomplete dissolution of the thrombus, which causes fibrosis, mechanization, and thickening of the vascular intima, resulting in increased pulmonary vascular resistance, increased pulmonary artery pressure, right ventricular dysfunction, and eventually death due to right heart failure or total heart failure [3]. This is the only type of PH that may be cured without lung transplantation (LT). At present, the medical treatment effect of CTEPH is limited, and PEA is the preferred treatment for CTEPH [4]. However, LT remains the only effective treatment for end-stage CTEPH with severe pulmonary dysfunction. There are very few reports on the efficacy of LT for CTEPH. We conducted a single-center retrospective analysis to describe our clinical experience of LT in patients with CTEPH. This study aimed to provide a reference for current treatment selection.

Methods

Patient selection and data collection

We collected and analyzed the clinical data of 7 patients with CTEPH who underwent LT at the Affiliated Wuxi People’s Hospital of Nanjing Medical University between July 2019 and June 2021. Data on preoperative conditions, operation-related conditions, and postoperative follow-up were collected. The diagnosis and treatment were based on the 2015 guidelines published by the European Society of Cardiology and the European Respiratory Society [1]. This study was conducted in accordance with the Declaration of Helsinki (revised in 2013) and approved by the Ethics Committee of the Affiliated Wuxi People’s Hospital of Nanjing Medical University (no. KY22062). Written informed consent was obtained from all patients or their agents.

Lung transplantation

Multidisciplinary experts evaluated patients for LT according to the 2006 International Society of Heart and Lung Transplantation guidelines [5]. Transplant organs were donated by volunteers [6], who were all assessed as brain dead. ABO blood types were matched between donors and recipients. A preoperative chest radiograph or computed tomography (CT) scan showed no lung infection or other lung diseases, and the oxygenation index(PaO2/FiO2) exceeded 300 mmHg. Single or double LT was performed according to donor lung and patient conditions. In general, when the recipient is frail and elderly or bleeds more than 3000 ml after unilateral LT, we consider only doing single LT. The need for intraoperative extracorporeal membrane oxygenation (ECMO) support depends on the oxygenation index(PaO2/FiO2), pulmonary artery pressure, and hemodynamic stability after 15 min of single-lung ventilation. In cases where percutaneous oxygen saturation perists below 90%, veno-venous ECMO is used when hemodynamics are stable, whereas veno-arterial ECMO is used when hemodynamics are unstable.

Postoperative management

All patients were transferred to the intensive care unit (ICU) after surgery, where they received mechanical ventilation, anti-rejection therapy (with tacrolimus, cyclosporine, and corticosteroids), and antibiotic treatment and were subjected to regular imaging, bronchoscopy, and blood gas analysis. All patients were followed-up every 3 months during the first year after discharge. After one year, patients were evaluated every six months, and annually after three years. The assessment included lung and other organ function, patient immunity, and infection status. In this study, the follow-up deadline was March 2022.

Statistical analysis

All data are presented as mean ± standard deviation and were analyzed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). The changes in the indices before and after the operation were analyzed using paired t tests in GraphPad Prism (San Diego, California, USA). Statistical significance was set at P < 0.05.

Results

Between July 2019 and June 2021, seven patients visited our hospital with CTEPH, one of whom was female. Six patients had pulmonary fibrosis. All patients experienced cough and dyspnea after activity. The mean age at admission was 54 ± 12 years. The cardiac function of cases 5 and 7 was assessed as New York Heart Association (NYHA) class III, and the others were assessed as NYHA class IV. Patients 2 and 5 had a history of venous thrombosis of the lower extremities. All patients received standard anticoagulant therapy for at least three months prior to admission. Patients 3 and 6 also took macitentan tablets and treprostinil injection, respectively, to lower pulmonary artery pressure. However, these treatments did not significantly improve the patients’ symptoms.

CT pulmonary angiography (CTPA) showed pulmonary thromboembolism at different sites (Fig. 1A-E), except in Case 6. Case 6 did not undergo a CTPA because the patient was unable to tolerate the procedure. Before admission, case 6 received ECMO support in another hospital due to continuous deterioration of oxygenation. Preoperative ECMO was performed for 32 days. Thus, pulmonary artery thrombosis in Case 6 was confirmed by postoperative pathology (Fig. 1F). In addition, echocardiography in all patients showed varying degrees of increased pulmonary arterial pressure. The mean pulmonary artery systolic and diastolic pressures were 62 ± 6 mmHg and 29 ± 5 mmHg, respectively, as measured by right heart catheterization. The average value of mean pulmonary artery pressure (mPAP) was 40 ± 5 mmHg. The mean preoperative oxygenation index(PaO2/FiO2) was 203 ± 56 mmHg. Preoperative details are presented in Table 1.

Fig. 1

(A-E) Computed tomography of pulmonary angiography in case 1 (A), case 3 (B), case 4 (C), case 5 (D) and case 7 (E). (F) HE staining of case 5. Scale: 4×. HE, hematoxylin and eosin

Table 1 Preoperative patient details

After evaluation, Case 4 underwent left LT and the rest underwent bilateral LT. Three patients received intraoperative veno-venous ECMO support, and four patients received intraoperative veno-arterial ECMO support. The mean cold ischemia times of the left and right lungs was 9 ± 3 and 10 ± 2 h, respectively. The median intraoperative blood loss was 914 ± 410 mL, and the median intraoperative blood transfusion was 1089 ± 886 mL. The mean pulmonary artery systolic and diastolic pressures after surgery were 27 ± 5 and 15 ± 3 mmHg, respectively. The mean mPAP was 19 ± 4 mmHg. The postoperative mPAP values were significantly lower than the preoperative mPAP values (Fig. 2A). The detailed intraoperative data are shown in Table 2.

Fig. 2

Comparison of preoperative and postoperative (A) mean pulmonary artery pressure and (B) oxygenation index(PaO2/FiO2). **P < 0.01;****P < 0.0001.

Table 2 Intraoperative patient details

All patients were transferred to the ICU for further treatment. Owing to poor respiratory function and oxygenation, Case 6 required mechanical ventilation and ECMO for 48 and 13 days after surgery, respectively. Other patients received mechanical ventilation for less than 3 days and ECMO for less than 2 days. The mean oxygenation index(PaO2/FiO2) was 388 ± 83 mmHg two or three days after tube extraction, which was significantly higher than that before surgery (Fig. 2B). All patients recovered well and were discharged 37 ± 19 days postoperatively. The patients continued to take immunosuppressant drugs after discharge and visited the hospital for regular check-ups. The mean follow-up duration was 19 ± 8 months. Echocardiography and CTPA performed 3 months postoperatively showed no abnormal pulmonary artery pressure or pulmonary embolism. During follow-up, there were some postoperative complications that improved after treatment, which were shown in Table 3, but there was no recurrence of CTEPH. Quality of life was significantly improved in all patients. Patients 6 and 7 received a second LT 1 and 2.5 years after the surgery, respectively, due to rejection. The postoperative details are shown in Table 3.

Table 3 Postoperative patient details

Discussion

PH comprises a group of clinical pathophysiological syndromes characterized by persistently elevated pulmonary vascular resistance caused by heterogeneous diseases and different pathogeneses. The latest clinical classifications of PH include pulmonary arterial hypertension, PH associated with left heart disease, PH associated with pulmonary disease or hypoxia, CTEPH, and PH due to unknown and/or multifactorial mechanisms [1]. PH associated with respiratory disease or hypoxia includes the PH associated with pulmonary fibrosis. Prolonged hypoxia in individuals with pulmonary fibrosis triggers the development of fibrotic lesions, resulting in subsequent alterations in cardiopulmonary vascular compliance. Ultimately, this cascade leads to cardiopulmonary vascular damage, culminating in PH and right heart failure, commonly referred to as pulmonary fibrosis-related PH.

It has been hypothesized that CTEPH is caused by pulmonary embolism, pulmonary artery lumen thrombosis, and fibrosis changes, causing pulmonary artery stenosis or even complete occlusion, resulting in increased pulmonary vascular resistance, and ultimately leading to PH and sometimes right heart failure[7; 8]. Some researchers believe that venous thrombosis can increase the risk of pulmonary fibrosis, especially in patients who have never received anticoagulant therapy [9]. Subtle and persistent thrombosis in pulmonary vessels can lead to or aggravate pulmonary fibrosis. At the same time, the microenvironment of pulmonary fibrosis is procoagulant and antifibrinolytic, which can cause or aggravate pulmonary embolism[10; 11]. Both factors can lead to PH as an independent factor. In this study, six patients had CTEPH associated with pulmonary fibrosis. In addition, lower-extremity venous thrombosis can cause dislodging and can cause or exacerbate pulmonary embolism, resulting in CTEPH. Two patients in our study had a history of venous thrombosis of the lower extremities.

The pathogenesis of chronic embolic pulmonary hypertension is not fully understood. It has a low incidence, poor prognosis, and high mortality. The 2 to 3 year survival rate is only 10 to 20% [1]. The treatment of CTEPH includes general therapy, drug therapy, and surgery. The effect of drug treatment is poor. PEA is the preferred treatment for chronic embolic pulmonary hypertension [12]. However, even in regions with access to a PEA centre, nearly 40% of CTEPH patients were deemed inoperable for PEA. Reasons for inoperability varied; they included: chronic thromboembolic disease of distal pulmonary arteries beyond the potential reach of PEA; the presence of significant coexisting conditions; and patient refusal to undergo surgery. In addition, 10–35% of patients who have undergone PEA experience either persistent or recurrent PH following surgery. All patients in this study had grade III to IV cardiac function and severe pulmonary dysfunction and were unable to tolerate pulmonary embolectomy[13; 14]. LT or combined cardiopulmonary transplantation should be considered for these patients.

This is one of the very few case series dedicated to lung transplant for CTEPH. In this study, patients were diagnosed and selected according to international guidelines. We found statistically significant changes in preoperative and postoperative indicators. Our results indicate that LT is an effective treatment for end-stage CTEPH, which can improve cardiopulmonary function, quality of life, and prolong the survival period. Patients who are unable to tolerate PEA should be considered for LT as early as possible when internal medicine failed. Owing to the low incidence and diagnosis rate of CTEPH, the number of cases in this study was small. Analysis of more cases is needed to confirm the efficacy, and we will continue to collect data for large-sample analysis.