Pulmonary artery aneurysms in Behçet disease

Pulmonary artery aneurysms (PAAs) are the most common type of pulmonary involvement in Behçet’s disease. However, the relationships between clinical features and prognosis have not been sufficiently evaluated. This article describes the results of a comprehensive review, revealing that PAAs have a predilection for hemoptysis manifestations, increased dimensions, right lower lobar location, multiplicity and concurrent intramural thrombus formation. Surgical intervention was needed in one third of patients. Patients with massive hemoptysis and PAA rupture warranted emergency operations. Conservatively treated patients were prone to PAA progression; interventional embolization was associated with higher risks of recurrence and reintervention for PAAs; and surgically treated patients exhibited the highest mortality rates. In conclusion, PAAs in Behçet’s disease are characterized by a predilection for hemoptysis manifestations, right lower lobar location, multiplicity, and concurrent intramural thrombus formation. Both the condition itself and the surgical operations it warrants are linked with high mortality due to PAA hemorrhage.


InTRoduCTIon
In Behçet's disease, pulmonary involvement is uncommon, with a prevalence of less than 5%. 1 Pulmonary artery aneurysms (PAAs) are the most common form of pulmonary involvement in Behçet's disease, followed by pulmonary artery thrombosis, pulmonary infarction and pulmonary parenchymal disorders. 2Thrombosis usually develops as a consequence of the underlying extensive vasculitis. 3,4 rrently, pulmonary artery aneurysms are the second most common type of arterial involvement in Behçet's disease, preceded by aortic aneurysms. 2emoptysis of varying degrees up to 500 ml was the most common symptom of PAAs, observed in 79%. 2,5 moptysis can sometimes be massive and lethal, when PAAs rupture into the adjacent bronchus. 6ther manifestations of PAA include cough, dyspnea and chest pain. 6ughes-Stovin syndrome is a combination of pulmonary artery thrombosis and aneurysms with peripheral thrombophlebitis and is considered an incomplete variant of Behçet's disease.Characterized by an association of multiple PAAs and peripheral venous thrombosis, Hughes-Stovin syndrome shares identical pulmonary manifestations with Behçet's disease. 7Thrombophlebitis, formation of large pulmonary and/or bronchial aneurysms and aneurysmal rupture leading to massive hemoptysis and death are the three phases of the clinical paradigm of Hughes-Stovin syndrome. 8][11] However, the relationships between the clinical features and prognosis have not been sufficiently evaluated and thus remain to be identified.This article presents a comprehensive literature review of the subject.

Search strategies
A comprehensive literature search was conducted on MEDLINE, Highwire Press and Google for the year range 1990-2013.The search terms included "Behçet's disease", "Hughes-Stovin syndrome" and "pulmonary artery aneurysm" or "pulmonary artery pseudoaneurysm".Data were extracted from the text, figures and/or tables, with details of the study population, demographics, duration of Behçet's disease, characteristics of PAAs, management strategies and pertinent indications, follow-up duration and main outcomes (survival, recurrence, complication, reintervention and mortality).definitions Severity of hemoptysis was defined as: mild <5 ml in 24 hours; moderate 5-600 ml/24 hours and massive >600 ml/24 hours, or 100 ml/<24 hours to 1000 ml/ several days, or >50 ml per expectoration, 12 and sudden recurrent massive hemoptysis was defined as life-threatening hemoptysis.Onset of action was defined as the time for the immunosuppressive agents to take effect (including symptom relief, decreased inflammatory mediators, reduced pulmonary or intracardiac thrombus and reduced PAA) after administration; and cure time was the time interval from drug administration to complete resolution of the PAA and pulmonary or intracardiac thrombus.

Statistical analysis
Quantitative data were presented as mean ± standard deviation with range and median values, and intergroup differences were compared using the unpaired t test.Frequencies were compared using Fisher's exact test.Univariate and multivariate analyses were conducted to evaluate predictive risk factors.Results with p<0.05 were considered statistically significant.
The indications for conservative treatment in severe patients were extensive PAA locations, 55,97 failed interventional embolization 95 and patient reluctance to undergo interventional embolization or surgical operations. 29,68,114 Hmatopoietic stem cell transplantation 86 and tumor necrosis factor-α plus infliximab 25 were indicated for patients refractory to conventional immunosuppressive therapy.Indications for interventional embolization included bilateral pulmonary artery involvement, 74 giant pulmonary artery pseudoaneurysm, 87 ruptured PAAs, 64 failed conservative treatment, 34 to avoid potential surgical complications 60 and patients' reluctance to undergo surgical operations. 72Patients with rapidly expanding pulmonary artery (pseudo)aneurysms 24,26,107 or with recurrent PAA following successful percutaneous embolization 24 usually warranted surgical operations; while patients with uncontrolled massive hemoptysis with impending PAA rupture often required an emergency operation. 55,59,106,110 A otal of 9 patients received intervention/surgery for the treatment of PAA on an urgent basis including 1 interventional embolization 41 and 8 open thoracic operations.24,35,55,85,110,115,118 In all 9 of these patients an urgent procedure was indicated for massive hemoptysis, and 4 (44.4%)patients of whom suffered from a PAA rupture.55,110,115,118 Patients were followed-up for 22.5±33.5 (range: Outcomes were reported for 175 patients and comparison of outcomes across different treatments revealed that conservatively treated patients were prone to suffer from PAA progression, that interventional embolization was associated with higher risks of recurrence and reintervention for PAAs, and that surgically treated patients had the highest overall and early mortality rates.However, there were no significant differences in late mortality between these three groups (Table 4).The time to death of surgically treated patients was much shorter than among conservatively treated patients (2.3±5.9 months vs. 7.8±6.4months, p=0.04650).There were 24 interventional procedures, 23 (95.8%) of which were elective including 1 (4.3%) postoperative death, while 1 (4.2%) was an emergency intervention and the patient survived.There were 26 surgical procedures, 21 (80.8%) of which were elective, including 9 (42.9%) deths; whereas 5 (19.2%) were emergency surgeries, including 3 (60%) deaths (c 2 =0.5, p=0.48953). Ten patientsuffered PAA rupture.Four of them had been managed conservatively, 4 had been managed surgically and 2 had been managed interventionally, with only 2 surgically-treated patients surviving, giving an overall survival rate of 20% and an emergency surgery survival rate of 50% (c 2 =5.0, p=0.08416).

dISCuSSIon
The pulmonary vasculitis seen in PAA associated with Behçet's disease is primarily located in the vasa vasorum.Histopathological observations revealed pulmonary vasculitis involving all layers of pulmonary arteries and veins, 3 resulting in thrombosis, stenosis, aneurysm formation and rupture.Mononuclear inflammatory cells, predominantly lymphocytes, are responsible for inflammatory infiltration in and around the vessel wall.Additionally, impaired natural killer cell activity and immune system dysregulation have also been observed in patients with Behçet's disease and pulmonary manifestations. 119Marked intimal thickening with degenerative changes in the medial layer from the lobar branches to the arterioles can explain hemoptyisis and PAA rupture. 120ronchopulmonary fistulas found during autopsies of patients who died of sudden hemoptysis 43 and in surgical specimens resected from patients with massive hemoptysis 10,110 were apparently the causative etiology of life-threatening hemoptysis.
Aneurysms may be single or multiple, unilateral or bilateral, saccular or fusiform, and may be located in the main pulmonary artery or lobar or segmental arteries. 2Pulmonary vasculitis in Behçet's disease may also result in thrombosis, stenosis or occlusion of lung vessels, but thrombosis rather than embolism was usually associated with PAAs. 121Other pulmonary problems seen in Behçet's disease patients, including pleural effusion and chylous pleural effusions, are the result of vascular complications. 11Focal hemorrhages or infarct areas can present in the lung parenchyma adjacent to the aneurysms. 120Thrombosed aneurysms cause ischemia and infarction in the pulmonary parenchyma. 6ulmonary artery aneurysms may manifest as hilar enlargement or round, lobulated opacities on chest radiographs. 16Computed tomography has largely replaced angiography as the diagnostic tool and magnetic resonance imaging can also be useful for diagnosis of PAAs, but appears to be less sensitive than computed tomography for diagnosis of small PAAs. 2 Erkan et al. 2 reported that PAAs are most often located in the right lower lobar arteries, followed by bilateral main pulmonary branches.Tunaci et al. 109 proposed that the pulmonary arteries of the lower lobe were the most common site of involvement, and a mural thrombus was observed in 85% of PAAs.Aneurysms were most frequently located in the lobar artery in the right lower lobe (35%), followed by the lobar artery in the left lower lobe (19%) and right main pulmonary artery (17%), and 33% of aneurysms had partial or total thrombus within the aneurysm itself. 109The present study showed similar results to those published by Tunaci et al. 109 Another important finding of Tunaci et al. 109 was complete or partial PAA resolution in response to immunosuppressive treatments: 76% of PAAs completely disappeared in 3-42 (mean: 21) months and 24% of PAAs regressed in 4-28 (mean: 17) months after treatment. 109It was reported that the largest aneurysm was 7 cm, 109 and the mean diameter of aneurysms was 2.3±1.1 cm. 122he present study, however, revealed much larger dimensions of PAAs with a mean diameter of 4.0 cm.In Behçet's disease, immunosuppressants should be the first line treatment of choice and provoke regression of the PAAs and associated thrombus in a majority of the patients. 21Pulse methylprednisolone followed by oral prednisolone is one routine regimen for Behçet's disease. 48,50,59 Mnthly intravenous cyclophosphamide 1 g, and azathioprine 2.5 mg/kg/day may also be employed. 88Tumor necrosis factor-neutralizing monoclonal antibody infliximab was an effective treatment for a case of potentially lethal PAA in Behçet's disease. 25wo patients with resistant PAA were treated with hematopoietic stem cell transplantation. 86Other tumor necrosis factor-a blockers, which include etanercept and adalimumab, would also be effective for the treatment of PAA in Behçet's disease patients. 77Pulmonary artery aneurysm patients with thrombophlebitis and/or pulmonary emboli who are on anticoagulants are at risk of massive bleeding and so anticoagulants should be used with great caution, especially in patients with hemoptysis. 76lternative management strategies to conservative treatment include surgical and transcatheter interventions.Diseased lung tissue resection is preferred to pulmonary artery reconstruction in surgical treatment of PAAs.Surgical treatment mostly consists of major anatomical resection rather than preserving lung tissue.Immediate operation for PAAs should be performed when systemic inflammation is under control after short-term immunosuppressive therapy. 21Patients with recurrent or massive hemoptysis, in particular patients with ruptured PAAs, warrant emergency surgery, which is often associated with very high mortality. 21ndovascular embolization has been shown to be effective at controlling PAA hemorrhage. 34The Amplatzer duct occluder is currently the most commonly used device for management of large aneurysms. 88It can be employed in most cases and recurrent PAAs may be curable with reintervention. 32ulmonary artery aneurysms were the major contributing factor to overall mortality from Behçet's disease. 121In the early years, short-term survival of patients with PAAs associated with Behçet's disease was only 50%. 3 A decade later, 5-year survival had increased to 62%. 4 The present study displayed an overall survival of 76.9% at a mean follow-up of 21.6 months.
The present study revealed that PAAs have predilections for hemoptysis manifestations, right lower lobar locations, multiplicity and concurrent intramural thrombus formation.Surgical intervention therapy is warranted in most of the patients.All these variables were shown to be predictive risk factors for higher mortality in PAAs.For refractory cases that respond poorly to conservative treatment, endovascular embolization and Amplatzer occluder device are good choices for PAA management.Hemorrhaging PAAs can also be controlled by pneumonectomy, lobectomy, pulmonary artery aneurysmectomy, or pulmonary arterial ligation, but these options may be associated with higher mortality compared with interventionally and conservatively treated patients.
The most important limitations of this review are related to the non-availability of numbers, locations and dimensions of the arteries involved by PAAs in a large proportion of the references cited.Further prospective studies with more detailed information of PAAs are essential if more precise conclusions are to be drawn.
In conclusion, PAAs in Behçet's disease are characterized by a predilection for hemoptysis manifestations, right lower lobar location, multiplicity and concurrent intramural thrombus formation.Both the condition itself and the surgical operations it warrants are linked with high mortality due to PAA hemorrhage.

Table 1 .
Comparison of symptoms of 47 hemoptysis patients and 43 patients free from hemoptysis.

Table 3 .
Surgical operations for pulmonary artery aneurysms in 26 patients.

Table 4 .
A comparison of the outcomes of 173 patients with pulmonary artery aneurysm: patients treated conservatively versus surgically versus interventionally.

Table 5 .
Odds ratios and 95% confidence intervals for multivariate regression analysis of risk factors predictive of mortality.