Pulmonary endarterectomy in patients with occlusive isolated pulmonary vasculitis

Isolated pulmonary vasculitis (IPV) is a subtype of localized, single-organ vasculitis that can be distinguished from systemic vasculitis with exclusive involvement of pulmonary arteries. It is a rare inflammatory disorder characterized pathologically by vascular destruction with cellular inflammation and manifested as pulmonary stenosis or occlusion [1]. The incidence and underlying cause of IPV remain unclear because it often mimics chronic thromboembolic pulmonary hypertension (CTEPH). The true diagnosis is based on surgical specimen biopsy and the exclusion of systemic involvement, rather than preoperative assessments based on clinical manifestations, laboratory tests, and imaging [2]. This infers a high likelihood of long-term underdiagnosis. The lack of effective therapies for IPV has been demonstrated by the limited evidence derived from case reports and short case series [3, 4].

Pulmonary endarterectomy (PEA), a surgical procedure that has undergone revisions over the past several decades, is the cornerstone of curative therapy for CTEPH, an obstructive illness that leads to precapillary pulmonary hypertension (PH) [5]. Although both IPV and CTEPH are categorized as the cause of group 4 PH with certain similarities in pathophysiological features, microstructures point to important differences [2]. However, experience with PEA in occlusive IPV is limited to isolated instances in different centers [6]. Whether PEA in IPV might perform as well as PEA in CTEPH remains debatable. In this study, we aimed to determine whether PEA is safe and effective in patients with occlusive IPV.

The current study found two important findings in patients who underwent PEA for obstructive IPV. First, PEA alone or with patch angioplasty is safe and feasible to relieve occlusion caused by IPV, and PEA combined with subsequent BPA might be a promising therapeutic option. Second, comprehensive treatment protocols after PEA, including medications beyond the conventional dosage regimen of corticosteroids, should be investigated to improve long-term outcomes.

Studies on IPV are limited; only a few studies, particularly those that focus on the use of PEA in patients with IPV, have been conducted [2‐4, 7]. However, because the PEA techniques for IPV are similar to those for CTEPH, previous results in patients with CTEPH were helpful as a point of comparison. Under skilled hands, PEA, which has been refined, assessed, and used as the gold standard treatment for individuals with CTEPH for decades, could be potentially curative and safe [8]. According to reports from the University of California-San Diego Medical Center where the PEA technique was pioneered and developed, perioperative mortality decreases from 20% in the early stages to 2%, with 5- and 10 year survival rates of 82% and 75%, respectively, which were significantly improved compared with those who did not receive PEA [8, 11]. Based on the most recent similar results from our center, which have become better over time, the perioperative death rate was 1.2% (2/171) in 2015, with a 10-year survival rate of 83.9% [10]. Similar to the prior CTEPH group, the majority of the patients in the current cohort did not have postoperative complications, including reperfusion pulmonary edema, pulmonary bleeding, delirium, or lung infection, regardless of whether an additional patch expansion of PA was performed. These advancements might be attributed to the accumulated surgical expertise gained during the learning curve, bloodless vision with deep hypothermic circulatory arrest, enhanced perfusion strategy, and integrated management in the cardiac critical care unit [10, 12].

Unfortunately, one patient died during the postoperative period while still in the hospital because of residual PH and right heart failure. As the peripheral portion of the arterial tree accounted for more than 80% of the pulmonary arterial compliance [13] and determined the normalization of pulmonary vascular resistance [14] following successful PEA, PEA limited to the major left PA was insufficient for this patient. In our experience, arteries in the IPV were more likely to be transmurally implicated and to exhibit circumferential artery wall fusion and thickening, which correlates to the widespread lymphocytic infiltration, whereas in CTEPH, inner layer alteration was predominantly observed [10]. The PEA in IPV has occasionally been technically challenging due to this anatomical difference, particularly when surgeons attempt to reach the lobar segmental PA and separate the intima. Therefore, recognition of residual PH and pulmonary vascular resistance in patients with severe PH who underwent partial PEA is important because they are adversely related to postoperative and long-term survival [14, 15]. In this aspect, early detection and treatment might ease PEA as the inflammation might extend outward and lead to irreversible vascular changes as the day progresses [3, 4].

The United States CTEPH Registry presented declines in median mPAP from 44 to 24 mm Hg and total pulmonary resistance from 9.4 to 4.4 Wood units after PEA [16]. In contrast to CTEPH, arterial circumferential constriction in pulmonary vasculitis seems to be rather common [17], which calls for additional PA augmentation. Our team selected patch angioplasty, which was performed in four of seven patients. Alternative techniques including bypass surgery and graft replacement have also been discussed. Surgical outcomes are satisfactory, with no deaths or significant complications [6]. In any case, using these intensive therapies is preferable to leaving the occlusive PA untreated or performing lung transplantation prematurely [14]. Apart from its role in restoring the pulmonary arteries, PEA plays a pivotal role in the diagnosis of IPV. Among the patients included in the current study, no evidence of any other autoimmune disease was detected prior to the PEA procedure. It is important to note that characteristic manifestations commonly associated with vasculitis, such as multiple organ involvement, aneurysms, ulcers, fever, and specific autoantibodies, were absent, rendering them inadequate to fulfill the diagnostic criteria for vasculitis like polyarteritis and Behcet's disease. The diagnosis of IPV is usually uncertain until confirmed through biopsy, which aligns with findings reported in the majority of published studies on IPV to date [2‐4].

BPA is another developing technique for restoring flow in stenotic PA in CTEPH and Takayasu arteritis [18, 19]. Two patients in this group tried interventional treatment for the first time before receiving PEA but were eventually deemed ineligible for BPA because their total PA occlusions were either not amenable to route pathway establishment or had an unfavorable risk–benefit ratio. This type of situation was first investigated by Gerges et al. [18]. The overall success rate for recanalization of 352 chronic total PA occlusions was 50% in the expert center, which was much lower than the success rate for coronary chronic total occlusions [20]. Thus, surgery with complete PEA offers several patients a chance to undergo further therapies. When PEA was successfully completed, a significant improvement in pulmonary perfusion on the BPA scan and relief of PH were observed in this study, consistent with previous reports [2, 4]. If numerous segmental involvements or recurrences develop, PEA might be a pivotal therapy in individuals with occlusive IPV before prospective BPA. Three individuals in our study agreed to undergo BPA for proximal or distal lesions. Now, their condition has stabilized.

Since IPV is typically speculated to be a progressive, relapsing disease, arterial restenosis is the most worrisome consequence of PEA. In the current study, the incidence of proximal restenosis of the treated PA within the 6 month follow-up period was high (3/6) for the first time. The amount of time before deterioration may vary significantly from months to years [2‐4]. Although active inflammation may have played an important role in this result, detecting such a process at an early stage may be challenging because of the frequent mismatch between symptoms, well-known inflammatory indicators, such as ESR and CRP, and imaging [6, 21]. The strategy of monitoring IPV needs to be investigated in further research, particularly focusing on depicting preoperative subclinical inflammation that largely determines surgical timing [22].

Medications are the cornerstone of treating IPV. It is well known that anti-inflammatory therapy is crucial in the treatment of vasculitis, as it can alleviate symptoms and reduce the risk of restenosis [23]. For patients with active vasculitis, immunosuppressive therapy should be initiated first, and the timing of surgery should be determined by a multidisciplinary team after the condition has improved [24]. However, due to the nonspecific symptoms that many IPV patients present with at the onset of the disease, such as cough, difficulty breathing, and chest pain, combined with the low incidence rate, a definitive diagnosis is often delayed [4]. The preoperative diagnosis of most reported IPV cases is uncertain, with CTEPH being more frequently considered [2, 4]. A definitive diagnosis is made after biopsy, and immunosuppressive therapy is initiated at that point. Therefore, there is a need to strengthen early detection of IPV. Additionally, there is currently no well-established medication protocol for IPV patients after PEA. Patients in our cohort were prescribed oral prednisolone 60 mg daily following surgery, in accordance with the maximum initial dose recommended by the European League Against Rheumatism for active large vessel vasculitis, with a subsequent slow tapering regimen [25]. However, major relapses still occur in certain individuals at random. According to a recent study by Yanartaş et al., azathioprine seems to have an additional beneficial effect in postponing IPV restenosis [2]. Furthermore, in clinical trials, combination therapy with biologic immunosuppressants has been used for patients who are steroid-resistant or experience relapse after steroid tapering [4, 26, 27]. Despite the urgent need, there is currently no definitive evidence to suggest that a specific medication or combination therapy is superior to others in terms of inflammation suppression in the treatment of IPV.

During the chronic course, PH develops in some IPV patients as a result of progressive vascular narrowing and remodeling. In this study, one patient received a combination of tadalafil and ambrisentan during the perioperative period, resulting in a substantial reduction in both mPAP and PVR following PEA. Apart from this case, no other patients received drugs approved for pulmonary arterial hypertension. In sporadic IPV cases, bosentan, sildenafil, and epoprostenol were also used and showed positive effects [28, 29]. However, relying solely on PH-specific medications for the treatment of PH secondary to IPV may be impractical. In a recent multicenter cohort study, PH-specific medications improved the hemodynamic status of patients with Takayasu's arteritis-associated PH but did not achieve normalization [30]. In a randomized trial conducted by Bhasin et al., early administration of sildenafil increased the extent of postoperative reduction in PA pressure in patients undergoing corrective surgery for ventricular septal defect, indicating that combining multiple treatment strategies may bring greater benefits [31].

This study had several limitations. First, this was a small cohort study. The absence of a comparison with the non-surgery group and the limited sample sizes weakens the results to a certain degree. However, to our knowledge, our study represents the major series of occlusive IPV treated with PEA at a single institution with mid-term follow-up and is the first to reveal the incidence of relapse after surgery, given the rarity of IPV. It provides valuable therapeutic opinion for occlusive IPV and highlights the necessity of optimizing management strategies. Second, data were retrospectively collected and analyzed, thereby introducing inherent bias, although all PEA and perioperative treatments were carried out by the same team. Furthermore, the follow-up time was not long enough to assess late vascular patency and other cardiovascular events.

In conclusion, the data from this series tentatively demonstrate that PEA is a feasible procedure for the treatment of occlusive IPV, with significant hemodynamic and symptomatic benefits. The combination of PEA and BPA may be a promising therapy for aggressive IPV with recurrence. However, management of long-term vascular patency still requires further improvement. Advanced monitoring strategies and immunosuppressants are potentially useful.