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Pulmonary Veno-Occlusive Disease

Clinical, Functional, Radiologic, and Hemodynamic Characteristics and Outcome of 24 Cases Confirmed by Histology

Montani, David MD; Achouh, Lara MD; Dorfmüller, Peter MD, PhD; Le Pavec, Jérôme MD; Sztrymf, Benjamin MD; Tchérakian, Colas MD; Rabiller, Anne MD; Haque, Rehan MD; Sitbon, Olivier MD, PhD; Jaïs, Xavier MD; Dartevelle, Philippe MD; Maître, Sophie MD; Capron, Frédérique MD; Musset, Dominique MD; Simonneau, Gérald MD; Humbert, Marc MD, PhD

doi: 10.1097/MD.0b013e31818193bb
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Pulmonary veno-occlusive disease (PVOD) is defined by specific pathologic changes of the pulmonary veins. A definite diagnosis of PVOD thus requires a lung biopsy or pathologic examination of pulmonary explants or postmortem lung samples. However, lung biopsy is hazardous in patients with severe pulmonary hypertension, and there is a need for noninvasive diagnostic tools in this patient population. Patients with PVOD may be refractory to pulmonary arterial hypertension (PAH)-specific therapy and may even deteriorate with it. It is important to identify such patients as soon as possible, because they should be treated cautiously and considered for lung transplantation if eligible. High-resolution computed tomography of the chest can suggest PVOD in the setting of pulmonary hypertension when it shows nodular ground-glass opacities, septal lines, lymph node enlargement, and pleural effusion. Similarly, occult alveolar hemorrhage found on bronchoalveolar lavage in patients with pulmonary hypertension is associated with PVOD. We conducted the current study to identify additional clinical, functional, and hemodynamic characteristics of PVOD.

We retrospectively reviewed 48 cases of severe pulmonary hypertension: 24 patients with histologic evidence of PVOD and 24 randomly selected patients with idiopathic, familial, or anorexigen-associated PAH and no evidence of PVOD after meticulous lung pathologic evaluation. We compared clinical and radiologic findings, pulmonary function, and hemodynamics at presentation, as well as outcomes after the initiation of PAH therapy in both groups.

Compared to PAH, PVOD was characterized by a higher male:female ratio and higher tobacco exposure (p < 0.01). Clinical presentation was similar except for a lower body mass index (p < 0.02) in patients with PVOD. At baseline, PVOD patients had significantly lower partial pressure of arterial oxygen (PaO2), diffusing lung capacity of carbon monoxide/alveolar volume (DLCO/VA), and oxygen saturation nadir during the 6-minute walk test (all p < 0.01). Hemodynamic parameters showed a lower mean systemic arterial pressure (p < 0.01) and right atrial pressure (p < 0.05), but no difference in pulmonary capillary wedge pressure. Four bone morphogenetic protein receptor II (BMPR2) mutations have been previously described in PVOD patients; in the current study we describe 2 additional cases of BMPR2 mutation in PVOD. Computed tomography of the chest revealed nodular and ground-glass opacities, septal lines, and lymph node enlargement more frequently in patients with PVOD compared with patients with PAH (all p < 0.05). Among the 16 PVOD patients who received PAH-specific therapy, 7 (43.8%) developed pulmonary edema (mostly with continuous intravenous epoprostenol, but also with oral bosentan and oral calcium channel blockers) at a median of 9 days after treatment initiation. Acute vasodilator testing with nitric oxide and clinical, functional, or hemodynamic characteristics were not predictive of the subsequent occurrence of pulmonary edema on treatment. Clinical outcomes of PVOD patients were worse than those of PAH patients.

Abbreviations: BMPR2 = bone morphogenetic protein receptor II, CI = cardiac index, CT = computed tomography, DLCO = diffusing lung capacity of carbon monoxide, DLCO/VA = diffusing lung capacity of carbon monoxide/alveolar volume, FEV1 = forced expiratory volume in 1 second, HIV = human immunodeficiency virus, mPAP = mean pulmonary arterial pressure, mSAP = mean systolic arterial pressure, NO = nitric oxide, NYHA = New York Heart Association, PaCO2 = partial pressure of arterial carbon dioxide, PAH = pulmonary arterial hypertension, PaO2 = partial pressure of arterial oxygen, PCWP = pulmonary capillary wedge pressure, PVOD = pulmonary venoocclusive disease, PVRi = indexed pulmonary vascular resistance, SpO2 = pulse arterial oxygen saturation, TLC = total lung capacity, TPRi = indexed total pulmonary resistance, VC = vital capacity.

From Université Paris-Sud 11, UPRES EA 2705, Centre des Maladies Vasculaires Pulmonaires, Service de Pneumologie et Réanimation Respiratoire (DM, LA, P. Dorfmüller, JLP, BS, CT, AR, RH, OS, XJ, FC, GS, MH); and Service de Radiologie (SM, DM); Hôpital Antoine- Béclère, Assistance Publique-Hôpitaux de Paris, Clamart. Université Paris-Sud 11, UPRES EA 2705, Service de Chirurgie Thoracique, Centre Chirurgical Marie-Lannelongue (P. Dartevelle), Université Paris-Sud, Le Plessis-Robinson. Service d'Anatomie Pathologique (P. Dorfmüller, FC), Groupe Hospitalier Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.

Address reprint requests to: Marc Humbert, MD, PhD, Centre des Maladies Vasculaires Pulmonaires, Service de Pneumologie, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, 157 rue de la Porte de Trivaux, 92140 Clamart, France. Fax: 33 1 46 30 38 24; e-mail: marc.humbert@abc.aphp.fr.

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INTRODUCTION

Pulmonary arterial hypertension (PAH) is a severe condition, characterized by elevated pulmonary artery pressure leading to right heart failure and death39,44. Although pulmonary hypertension can be screened by Doppler echocardiography, a definite diagnosis of PAH requires right heart catheterization showing a mean pulmonary artery pressure (mPAP) >25 mm Hg at rest or >30 mm Hg during exercise and normal pulmonary capillary wedge pressure (PCWP)39,44. PAH is divided into several subcategories according to the 2003 World Symposium clinical classification of pulmonary hypertension: idiopathic PAH, familial PAH, PAH associated with different conditions (connective tissue diseases, congenital heart diseases, human immunodeficiency virus [HIV], portal hypertension, and exposure to drugs and/or toxins), and PAH associated with significant venous or capillary involvement21,44. This latter group mainly corresponds to pulmonary veno-occlusive disease (PVOD), an uncommon cause of PAH18,26,28,34,44. While pulmonary vascular pathology of idiopathic or familial PAH is characterized by a major remodeling of small precapillary pulmonary arteries (<200 μm) with typical plexiform and/or thrombotic lesions, PVOD preferentially affects the postcapillary venous pulmonary vessels and may include significant pulmonary capillary dilatation and/or proliferation26,34. The pathologic hallmark of PVOD is the extensive and diffuse occlusion of pulmonary veins by fibrous tissue18,26,28,34. Intimal thickening involves venules and small veins in lobular septa and, rarely, larger veins18,26,28,34. It is well accepted that a definite diagnosis of PVOD requires histologic analysis of a lung sample18,28. However, surgical lung biopsy is too invasive for these frail patients, emphasizing the importance of developing less invasive tools to obtain the diagnosis36,38.

Clinically, PVOD patients frequently present in a broadly similar fashion to patients with other forms of PAH, and PVOD accounts for 5%-10% of the histologic forms of cases initially thought to be "idiopathic". Application of this frequency to the incidence rate of idiopathic PAH yields an estimated incidence of 0.1 to 0.2 cases per million25,39. Germline mutations in the gene coding for the bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta family, are present in more than 70% of familial PAH cases and in 10%-40% of idiopathic, apparently sporadic, cases of PAH. Although a genetic risk factor for PVOD was suggested by several descriptions of cases of PVOD in siblings7,47, to our knowledge only 4 germline BMPR2 mutations in patients with PVOD have been previously described27. One of the main concerns with PVOD is the poor response to available therapies (calcium channel blockers, prostacyclin derivatives, endothelin receptor antagonists, and type 5 phosphodiesterase inhibitors) and the risk of pulmonary edema with continuous intravenous epoprostenol33,38. It is therefore crucial for clinicians to distinguish PVOD from other forms of PAH. In 2004, Resten et al38 described radiologic characteristics suggestive of PVOD on high-resolution computed tomography (CT) of the chest, including nodular ground-glass opacities, septal lines, and lymph node enlargement. In addition, PVOD is responsible for chronic elevation of pulmonary capillary pressure because it mainly affects the postcapillary vasculature, and thus promotes occult alveolar hemorrhage. Indeed, Rabiller and colleagues36 showed in 2006 that occult alveolar hemorrhage may be a characteristic feature of PVOD, as compared to idiopathic PAH affecting predominantly precapillary pulmonary arteries.

PVOD remains a poorly understood entity, and numerous questions remain about its epidemiology; risk factors; and clinical, functional, and hemodynamic characteristics. Due to the different outcomes of patients with PVOD, it is of major importance to better define the characteristics of this patient group to help physicians establish a better diagnostic approach to this form of PAH with predominant venous involvement, without invasive procedures such as lung biopsy. Previous studies have analyzed characteristics of the disease in series of patients irrespective of histologic confirmation of PVOD. Therefore, we conducted the current study to compare 2 groups of patients with gold-standard histologic diagnosis of PVOD and PAH (idiopathic, familial, or anorexigen-associated PAH), in order to better identify the clinical, functional, radiologic, and hemodynamic parameters indicative of PVOD.

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PATIENTS AND METHODS

Patients

We retrospectively reviewed 24 patients referred to the French Reference Center for Pulmonary Hypertension (Université Paris-Sud, Hôpital Antoine Béclère, Clamart, France) between 1991 and 2004 for management of pulmonary hypertension and in whom the diagnosis of PVOD was confirmed by histology. For our control group, we selected the first 24 patients with histologically confirmed plexiform lesions and the absence of predominant occlusive venopathy or capillary proliferation in the context of PAH (idiopathic, familial, or with a history of anorexigen exposure) diagnosed during the same period at our institution. Patients with PAH associated with other conditions (portal hypertension, connective tissue diseases, HIV infection, congenital heart diseases) were excluded from the study. Patients with chronic respiratory diseases defined as obstructive disease with forced expiratory volume in 1 second (FEV1) <60% or restrictive lung disease with total lung capacity (TLC) <60% were excluded from the study. Similarly, patients with pulmonary hypertension due to left heart diseases or chronic thromboembolic disease were excluded.

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Histologic Analysis

Hematoxylin-eosin-saffron staining was used in all histologic specimens to characterize pulmonary vascular abnormalities. The pathologic hallmark of pulmonary arteriopathy observed in PAH was defined as medial hypertrophy, intimal thickening, and plexiform lesions34. The pathologic hallmark of PVOD was defined as an extensive and diffuse obstruction of pulmonary veins and venules by intimal thickening, with either fibrosis, cellular proliferation, or muscularization6,9,34. Figure 1 shows characteristic pathologic findings found in patients with idiopathic, familial, or anorexigen-associated PAH (A, B, C) and PVOD (D, E, F), respectively. In the PVOD group, the histologic specimens were obtained by autopsy in 14 patients (58%), surgical biopsy in 3 patients (13%), and from explanted lung in 7 patients (29%). In the PAH group, histologic confirmation was obtained by autopsy in 9 patients (38%), surgical biopsy in 1 patient (4%), and from explanted lung in 14 patients (58%).

FIGURE 1

FIGURE 1

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Clinical and Functional Assessment

Routine evaluation at baseline included medical history and physical examination. Age at diagnosis, history of familial PAH, smoking habits, anorexigen use, occupational exposure, and associated diseases were recorded. Clinical assessment included modified New York Heart Association (NYHA) functional class24 at diagnosis; signs of right heart failure (defined by jugular vein distension, hepatojugular reflux, or lower extremity edema); Raynaud phenomenon; digital clubbing; body mass index; and history of hemoptysis, syncope, or near-syncope. A non-encouraged 6-minute walk test according to the American Thoracic Society recommendations3 was performed; the 6-minute walk distance and the lowest pulse arterial oxygen saturation (SpO2) were both recorded32,35. Arterial blood gases and lung function tests were performed: partial pressure of arterial oxygen (PaO2) and partial pressure of arterial carbon dioxide (PaCO2), FEV1, vital capacity (VC), FEV1/VC ratio, TLC, diffusing lung capacity of carbon monoxide (DLCO), and DLCO/alveolar volume (DLCO/VA) were recorded.

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Laboratory Assessment and BMPR2 Analysis

Antinuclear antibodies, antiphospholipid antibodies, and thyroid antibodies were recorded. Screening for BMPR2 mutations was performed as previously described22,23.

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High-Resolution CT of the Chest

All high-resolution CT scans of the chest performed in our center at diagnosis and before initiation of PAH-specific therapy were reviewed by 2 blinded experienced radiologists (S. Maitre, D. Musset). The presence of lymph node enlargement and pleural and pericardial effusion was recorded. Centrilobular ground-glass opacities and septal lines were rated on a scale according to the lung parenchymal extension: normal findings were those without ground-glass opacities or septal lines; mild to moderate abnormalities were findings involving less than two-thirds of the lung; and severe abnormalities were those involving more than two-thirds of the lungs.

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Hemodynamic Measurements

PAH was defined as mPAP >25 mm Hg with a normal PCWP <15 mm Hg. Hemodynamic evaluation by right heart catheterization was performed at baseline in all subjects according to our previously described protocol45. Cardiac output was measured by the standard thermodilution technique. The cardiac index (CI) was calculated as the cardiac output divided by the body surface area, and systolic index as the CI divided by cardiac frequency. The mean systolic arterial pressure (mSAP), mPAP, PCWP, right atrial pressure, and mixed venous oxygen saturation were recorded during right heart catheterization. The indexed total pulmonary resistance (TPRi) and indexed pulmonary vascular resistance (PVRi) were calculated as (mPAP)/CI and (mPAP-PCWP)/CI, respectively, and results were expressed as Wood units/m2. Baseline hemodynamic data and response to short-term vasodilator nitric oxide (NO) obtained through right heart catheterization were obtained for all subjects. A NO challenge (10 ppm for 5-10 min) was used; a positive acute response was defined as a decrease in mPAP >10 mm Hg compared to the baseline mPAP reaching a mPAP <40 mm Hg and a normal or increased cardiac output, as previously described24,46.

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Statistical Analysis

Statistical analysis was performed using Stat View version 5.0 (Abacus Concepts Inc., Berkley, CA). Data are presented as mean ± standard deviation unless stated otherwise. Comparisons between patients with PVOD and patients with PAH were assessed by Student t test and chi-square test. A p value ≤ 0.05 was considered statistically significant. We correlated the nadir SpO2 during the 6-minute walk test and functional parameters using linear regression.

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ILLUSTRATIVE CASE REPORT

Pulmonary Edema Developing With PAH-Specific Therapy in a PVOD Patient With Acute NO Response

We report the case of a 28-year-old pregnant woman at 31 weeks gestation, referred to the French National Center for Pulmonary Hypertension for the investigation of worsening dyspnea (Figure 2). The patient had no relevant personal or familial medical history. Upon initial history and examination, she had dyspnea on exertion NYHA functional class II, peripheral cyanosis, tachycardia, and a pulmonary systolic murmur. A pulmonary ventilation/perfusion scan did not show any evidence of pulmonary thromboembolic disease. Doppler echocardiography revealed pulmonary hypertension with an estimated systolic pulmonary pressure of 80 mm Hg. Right heart catheterization confirmed PAH with mPAP of 55 mm Hg, high PVRi of 12.8 U/m2, and a CI of 4.3 L/min/m2 with no elevation of PCWP (Figure 2, upper right). Inhaled NO testing (10 ppm) revealed an acute response to NO (Figure 2, upper left) with a fall in mPAP (mPAP = 32 mm Hg) and PVRi (PVRi = 6.1 U/m2) and normalization of the CI. Six-minute walk distance was 237 m with an oxygen desaturation of 85%.

FIGURE 2

FIGURE 2

Idiopathic PAH was diagnosed, and delivery was scheduled at 32 weeks gestation by cesarian section under rachianesthesia. The delivery was uncomplicated. Because of the acute response to NO, treatment with calcium channel blockers (diltiazem) was initiated after delivery under close surveillance in the intensive care unit. After 24 hours of treatment, the patient had acute respiratory distress with acute pulmonary edema (Figure 2, lower left and right, Chest X-ray before and after diltiazem), which progressively resolved after diuretics were initiated. Right heart catheterization was repeated, confirming the initial hemodynamic findings and in particular the acute response to NO. Acute pulmonary edema following the administration of vasodilator therapy suggested PVOD. A surgical biopsy was therefore performed in this patient, whose condition was good. Histopathologic examination of the pulmonary biopsy disclosed predominant lesions of the septal veins and hemosiderosis with no evidence of inflammation of the arterial walls or plexiform lesions, thus confirming the diagnosis of PVOD. In addition to conventional treatment (diuretics and supplemental oxygen, Coumadin), an endothelin receptor antagonist (bosentan) was introduced with no immediate complications. The patient was also listed for lung transplantation. After 6 months of treatment, the patient was admitted to the intensive care unit for acute respiratory distress secondary to another episode of pulmonary edema and right heart failure. She did not respond to diuretics or vasoactive therapy (dobutamine), and died 24 hours after admission.

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RESULTS

Demographic and Clinical Characteristics

Demographic and clinical characteristics of patients with PVOD (n = 24) and PAH (n = 24) are shown in Table 1. PVOD occurred equally in men and women, while PAH had a female predominance. Age, time to diagnosis, and history of familial PAH were similar in both groups. In adults older than 18 years, tobacco exposure was significantly higher in patients with PVOD than in patients with PAH (13.6 ± 16.9 in PVOD vs. 2.7 ± 5.1 packs/yr in PAH, p < 0.01), and an exposure higher than 10 packs/year was observed in 10/21 (47.6%) PVOD patients compared with 5/21 (23.8%) PAH patients (p < 0.05). Anorexigen use was reported significantly more frequently in PAH patients than in PVOD patients (33.3% and 4.2%, respectively, p < 0.01). History of occupational exposure, radiotherapy, or chemotherapy was not significantly different in the 2 groups. Two PVOD patients had a history of hemochromatosis without portal hypertension or liver cirrhosis. Clinical characteristics at diagnosis, including NYHA functional class, hemoptysis, Raynaud phenomenon, syncope, clubbing, and right heart failure, were similar in PVOD and PAH patients, except for a lower body mass index in PVOD patients (21.4 ± 5.6 vs. 25.6 ± 5.6, p < 0.05).

TABLE 1

TABLE 1

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Pulmonary Function Tests and 6-Minute Walk Tests

Results for pulmonary function tests and 6-minute walk tests are presented in Table 2. No significant difference was observed between PVOD and PAH patients for PaCO2, FEV1, FVC, FEV1/VC, and TLC. Conversely, PVOD patients had significantly lower PaO2, DLCO, and DLCO/VA compared with PAH patients (Figure 3). The baseline 6-minute walk distance was similar in PVOD and PAH patients, but the nadir SpO2 during the 6-minute walk test was significantly lower in PVOD patients. For patients with PVOD or PAH, the nadir spO2 during the 6-minute walk test correlated with DLCO/VA (R = 0.53, p= 0.005).

TABLE 2

TABLE 2

FIGURE 3

FIGURE 3

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Laboratory Assessment and BMPR2 Analysis

Detection of antinuclear, antiphospholipid, and thyroid antibodies was not different between the 2 groups. Germline BMPR2 mutations were identified in 2 cases of PVOD and 4 cases of PAH (Table 3).

TABLE 3

TABLE 3

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High-Resolution CT of the Chest

We analyzed 33 high-resolution CT scans of the chest performed in our center before initiation of specific therapy. Centrilobular ground-glass opacities, septal lines, and lymph node enlargement were significantly more frequent in patients with PVOD (all p < 0.05, Table 4, Figure 4). Distribution of the severity of centrilobular ground-glass opacities and septal lines confirmed a more severe lung parenchymal extension (all p < 0.05). Pericardial effusion was more frequent in PAH patients than in PVOD patients.

TABLE 4

TABLE 4

FIGURE 4

FIGURE 4

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Hemodynamic Characteristics

The hemodynamic characteristics of the 2 groups of patients are shown in Table 5. The main hemodynamic parameters, including mPAP, PCWP, CI, TPRi, and PVRi, were similar in PVOD and PAH patients (Figure 5). However, mSAP and right atrial pressure were lower in the PVOD group than in the PAH group (p < 0.01). PCWP was not more elevated in PVOD patients compared with PAH patients. Multiple recordings of PCWP did not show elevated PCWP in any territories. Only 1 patient in the PVOD group versus none in the PAH group responded favorably to acute NO testing according to the recent definition of NO responders (Figure 2)46.

TABLE 5

TABLE 5

FIGURE 5

FIGURE 5

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Risk of Pulmonary Edema With PAH-Specific Therapy in PVOD

All PAH patients received PAH-specific therapy according to published guidelines at the time of inclusion14,24. Most of these patients had severe PAH and received intravenous epoprostenol; none of them developed pulmonary edema (Table 6). In the PVOD group, two-thirds of the patients (16 patients, 66.7%) received PAH-specific therapy, including epoprostenol (n = 11), bosentan (n = 6), iloprost (n = 3) and calcium channel blockers (n = 2). Eight episodes of pulmonary edema (Figure 2) occurred in 7 PVOD patients (44%) (5 with epoprostenol, 2 with bosentan, and 1 with calcium channel blockers), with a median time between initiation of therapy and edema of 9 days (range, 1-240 d). All patients underwent acute vasodilator testing with NO, but no patient in either group developed pulmonary edema during acute testing.

TABLE 6

TABLE 6

We analyzed predictive factors for the development of pulmonary edema with chronic PAH therapies in the 16 treated PVOD patients. All clinical, functional, and hemodynamic characteristics were similar in PVOD patients with and without pulmonary edema (Table 7). As described in the case report above, 1 PVOD patient was an acute responder to NO during right heart catheterization with no evidence of acute pulmonary edema during the test. This patient subsequently experienced a marked clinical deterioration with calcium channel blockers, and developed acute pulmonary edema within 24 hours of initiation of therapy. She was then treated with bosentan, and pulmonary edema relapsed after 8 months of bosentan therapy (Figure 2). CT scans of the chest were available for 8 PVOD patients treated with PAH-specific therapies. It is noteworthy that 3 of these PVOD patients developed pulmonary edema with specific therapy, and all of them had an association of centrilobular ground-glass opacities and septal lines, compared with only 1 (20%) PVOD patient without pulmonary edema (Table 7).

TABLE 7

TABLE 7

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Evolution

Time from diagnosis or first symptoms to death or lung transplantation was significantly shorter in PVOD patients compared with PAH patients (Table 6). These findings were also significant when death or lung transplantation was analyzed separately, suggesting a worse prognosis in PVOD patients.

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DISCUSSION

PVOD is a rare form of PAH that remains a poorly understood entity. It is critically important to diagnose this condition rapidly for many reasons. Indeed, PVOD has been reported to have a worse prognosis than idiopathic, familial, or anorexigen-associated PAH, and death usually occurs within 2 years of the diagnosis18. Therefore, listing on a lung transplantation program is often necessary for eligible PVOD patients. In addition, these patients are at high risk of developing acute severe pulmonary edema with vasodilator therapy18,33, warranting precautions when using these agents in a patient with suspected PVOD. A diagnosis of PVOD is usually suspected when radiologic abnormalities are present in a patient with PAH (including ground-glass opacities with a centrilobular distribution, septal lines, and lymph node enlargement)38. However, these findings are not present in all cases, and they may be difficult to identify in the early stages of the disease10,38. We have recently shown that evidence of occult alveolar hemorrhage pleads in favor of PVOD36. However, this is not a specific sign of the disease, and, furthermore, fiberoptic bronchoscopy and bronchoalveolar lavage may be hazardous in these frail patients. The occurrence of pulmonary edema with PAH-specific therapy such as intravenous epoprostenol is highly suggestive of PVOD, but all patients do not develop pulmonary edema with these agents, and such a complication may be life-threatening and cannot be regarded as a diagnostic tool. In theory, confirmation of a PVOD diagnosis requires histologic analysis of a lung sample. However, lung biopsy should not be recommended in the management of PAH because of the risk of severe complications in these patients after surgery30. Therefore, it is of major importance to better describe the clinical, functional, and hemodynamic characteristics of PVOD patients, in order to propose the best management (including lung transplantation in eligible patients) and close monitoring when PAH therapy is initiated.

To our knowledge, previous reports on PVOD are limited to isolated case reports or small case series with no PAH control group18,28. The present study focuses on a large group of 24 patients with histologic confirmation of PVOD. We compared these patients with a control group of PAH patients with no histologic evidence of PVOD in an attempt to point out any distinguishing characteristics of PVOD.

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Epidemiology

As previously described5,18,48, no female predominance was observed in PVOD: the male:female ratio in our cohort of PVOD patients was 1. No difference was observed in the age range in PVOD patients compared with PAH patients18. Whereas the risk of PAH is increased by the use of certain anorexigens21, PVOD had not yet been reported after ingestion of anorexigens1. One of our patients had a history of anorexigen use, suggesting a possible association between anorexigen exposure and PVOD.

In the current study, we observed a higher tobacco exposure and an increased proportion of smokers (10 or more packs/year) in patients with PVOD compared with patients with PAH. This difference cannot be explained by the difference in the male:female ratio, since the increased tobacco exposure was observed in both sexes. One could hypothesize that smoke exposure may contribute to pulmonary vascular injury. Wright et al49,50 demonstrated an increased level of mediators that control vasoconstriction (endothelin-1), vascular cell proliferation (endothelin-1 and vascular endothelial growth factor), and vasodilation (endothelial NO synthase) in the pulmonary arteries of animals exposed to cigarette smoke. These authors found that smoke-exposed animals developed increases in pulmonary arterial pressure and increased muscularization of the small pulmonary arteries. Gene expression and protein levels of all 3 mediators were increased, and pulmonary arterial pressure correlated with both the levels of mediator production and the degree of arterial muscularization, suggesting a direct role of tobacco on pulmonary arteries51. An association between smoke exposure and PVOD has not yet been investigated, but our data suggest a possible link. It is interesting that an association has been reported between PVOD and pulmonary Langerhans cell granulomatosis, a pulmonary disease occurring almost exclusively in smokers13,16. Further studies are needed to confirm a link between tobacco exposure and PVOD.

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Clinical Features

In previous studies, it has been suggested that PVOD patients could have different clinical manifestations compared with those of PAH patients18,28. Clinical features like digital clubbing, syncope or near syncope, and hemoptysis have been reported more frequently in small series of patients with PVOD18,28. In the current cohort of PVOD patients, clinical characteristics (Raynaud phenomenon, syncope or near syncope, clubbing) were similar to those of PAH patients, suggesting that these clinical findings are nonspecific and may not help to distinguish PVOD from other forms of PAH. Hemoptysis could be expected to be more frequent in PVOD because of the evidence of chronic alveolar hemorrhage, but its frequency was similar to that observed in PAH, confirming the fact that alveolar hemorrhage is usually occult36.

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Genetic Features

We found a history of familial PAH in 1 patient with PVOD and a germline BMPR2 mutation in 2 other patients47. A genetic risk factor for PVOD has been previously suggested by several reports of PVOD occurring in siblings7,47. It is noteworthy that only 4 cases of BMPR2 mutation have been found in PVOD27, as far as we know. In the current study, we report 2 novel BMPR2 mutations in PVOD patients, emphasizing the possible role of the BMPR2 pathway in the development of PVOD and the similarities between the PVOD and PAH genetic backgrounds. These results support systematic screening for a possible familial history of pulmonary vascular disease and providing similar genetic counseling for PAH and PVOD patients29.

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Hemodynamic Characteristics

In the current study, both groups of patients had similar hemodynamic characteristics. Despite reports of elevated PCWP in cases of PVOD, hemodynamic parameters are in fact usually identical to those of PAH with a normal pulmonary artery wedge pressure18,36. This paradoxical normal wedge pressure is due to the fact that the disease process occurs in the small pulmonary septal veins with little or no obstruction of the larger pulmonary veins34,37. Therefore, when one measures pulmonary artery wedge pressure during right heart catheterization, the static column of blood produced is unaffected by the occlusion and reflects the normal pressure in the larger veins, not the elevated pressure in the capillaries37.

Acute vasodilator response during right heart catheterization has been reported in some PVOD cases. In idiopathic PAH, an acute vasodilator response can predict response to calcium channel blockers. Acute responders have proven to have an excellent long-term prognosis compared with nonresponders46. It is noteworthy that 1 patient with PVOD had an acute vasodilator response to NO, but this patient had a bad outcome with calcium channel blocker therapy and developed pulmonary edema within 24 hours after initiation of calcium channel blockers (see Case Report, Figure 2). This suggests that an acute vasodilator response in PVOD may not be predictive of a better prognosis, and that calcium channel blockers should not be recommended in patients with PVOD even if the acute vasodilator test is positive.

Pulmonary edema during acute vasodilator testing has been reported17,39,40. In the current study, an acute vasodilator test was realized in all patients. Although 7 PVOD patients subsequently developed pulmonary edema with long-term vasodilator therapy, we did not observe any acute pulmonary edema during the acute vasodilator test. This may be due to our technique, using inhaled NO during a short time (5-10 min). These results suggest that the NO acute test is safe even in PVOD patients, but the results could not predict the possible development of pulmonary edema with long-term PAH-specific therapy.

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Pulmonary Function Tests

Pulmonary function tests may help in the diagnostic approach to PVOD. We have confirmed a lower baseline PaO2 at rest in PVOD patients, which could indicate a possible PVOD in conjunction with radiographic findings. Pulmonary function tests analyzed during spirometry and plethysmography were similar in both groups. Reports of low DLCO in patients with PVOD and PAH have been published11,18. We documented a significantly more severe reduction in DLCO/VA in most of the patients with PVOD compared with the PAH group. In the current study, more than 80% of PVOD patients had a DLCO/VA lower than 55%, compared with 21% in PAH patients. Even though PVOD patients had lower PaO2 and DLCO/VA, their 6-minute walk distance was similar to that of the PAH patients. However, PVOD patients had a lower nadir SpO2 during the test. These findings suggest that noninvasive pulmonary function tests could be helpful to suggest PVOD in patients with low PaO2 at rest, low SpO2 during the 6-minute walk test, and a DLCO/VA <55%.

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Radiologic Findings

A diagnosis of PVOD is usually suspected when radiologic abnormalities (centrilobular ground-glass opacities, septal lines, and lymph node enlargement) are present in a patient with PAH10,38. The current study indicates that radiologic abnormalities were present at the time of PAH diagnosis, before initiation of PAH-specific therapies. Of note, the presence of 2 or more abnormalities on chest CT were highly associated with PVOD. In contrast, the absence of radiologic abnormalities could not rule out PVOD, highlighting the importance of a diagnostic approach, using several tests including high-resolution CT of the chest, pulmonary functional tests, and bronchoalveolar lavage whenever possible. In addition, the current data seem to indicate that the association of centrilobular ground-glass opacities and septal lines before the initiation of PAH-specific therapy might be more frequent in PVOD patients who subsequently developed pulmonary edema. However, this difference did not reach significance because of the small number of patients studied. Further studies are needed to evaluate the possible usefulness of high-resolution CT of the chest in predicting the occurrence of pulmonary edema with PAH-specific therapy in PVOD.

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Prognostic Factors

Some studies have reported a worse prognosis for PVOD compared with PAH, and have suggested that PVOD patients presented with worse baseline conditions. In the current study focusing on 2 severe populations of PVOD and PAH patients in whom a lung sample was available, prognostic factors of PAH, such as NYHA functional class, clinical signs of right heart failure at diagnosis, 6-minute walk distance, and baseline hemodynamics, were broadly similar in both groups, suggesting similar disease severity at diagnosis. Nevertheless, survival from diagnosis of this small PVOD population was significantly worse than that of PAH patients.

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Risk of Pulmonary Edema With PAH-Specific Therapies

Treatment data regarding PVOD are scant and conflicting. Continuous intravenous epoprostenol therapy has been shown to improve hemodynamics in PVOD8, but there are also reports of massive pulmonary edema and death after use of pulmonary vasodilators such as epoprostenol in PVOD patients18,33. While pulmonary vasodilators such as intravenous prostacyclin have established efficacy in the treatment of PAH4,45, benefits of these treatments in patients with PVOD are unclear. One of the proposed reasons for vasodilators not being effective in PVOD is that if the pulmonary arterioles dilate and the resistance of the pulmonary venules remains fixed, an increased transcapillary hydrostatic pressure may ensue and produce pulmonary edema. We describe 2 cases of pulmonary edema occurring after initiation of bosentan-for the first time, as far as we know-and the potential risk of this therapy in some patients with PVOD. It has been suggested that acute vasodilator testing could help detect PVOD patients at risk of pulmonary edema after initiation of PAH-specific therapies28. However the current results do not support this hypothesis. Therefore, any PAH-specific therapy should be used with great caution when diagnosis of PVOD is suspected.

Indeed, in the present cohort of histologically confirmed PVOD patients, among the 7 patients who developed pulmonary edema with PAH-specific therapy, none had developed pulmonary edema during acute testing with NO. Furthermore, none of the clinical, functional, or hemodynamic characteristics analyzed in the current study could predict the risk of pulmonary edema after initiation of epoprostenol, bosentan, or calcium channel blockers.

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Evolution

Survival rates of PVOD patients are considered worse than those of PAH patients43. One could argue that we might have selected more severe cases, since we retrospectively selected patients with a histologically proven diagnosis. However, this selection bias exists in both groups. We observed a worse evolution in PVOD patients, with a shorter time from diagnosis or first symptoms to death or transplantation in comparison with PAH patients.

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Management of PVOD at the French Reference Center for Pulmonary Hypertension

The algorithm for PVOD management at the French Reference Center for Pulmonary Hypertension is presented in Figure 6. We propose to use several noninvasive tools (arterial blood gases, pulmonary function tests, and DLCO measurement; high-resolution CT of the chest; bronchoalveolar lavage) to identify a subgroup of patients with high risk of PVOD. This noninvasive diagnostic approach will limit the requirement of high-risk invasive procedures such as lung biopsy in these frail patients.

FIGURE 6

FIGURE 6

If PVOD is suspected due to the presence of hypoxemia, low DLCO/VA, septal lines, centrilobular ground-glass opacities, lymph node enlargement, or occult alveolar hemorrhage, we propose to initiate basic therapy including oxygen, diuretics, and warfarin. Pathology specimens from PAH patients classically show pulmonary artery medial hypertrophy, eccentric intimal fibrosis, thrombosis in situ, and thrombi recanalization. As a result, anticoagulant therapy has become part of the conventional therapy for PAH. Nevertheless, only a few studies support anticoagulation in PAH. These studies are mostly retrospective or nonrandomized, and generally include a small number of patients with idiopathic PAH. Current recommendations propose warfarin therapy with an international normalized ratio (INR) between 1.5 and 2.5. Although the somewhat weak evidence is derived exclusively from the idiopathic PAH population, anticoagulation has been generalized to all patient groups, given the absence of contraindication. Special care in the application of anticoagulation is required with PVOD patients because of the frequency of occult alveolar hemorrhage, and anticoagulation is usually not indicated if there is a history of severe hemoptysis. In symptomatic PVOD patients, PAH-specific therapy can be proposed under close medical monitoring, and lung transplantation should be discussed for eligible patients.

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Study Limitations

The current study has several limitations, mainly related to its retrospective design. To avoid biases due to comorbid conditions or their treatments, we studied only patients with no associated diseases. However, one must be aware that PVOD can occur in patients with associated diseases including HIV infection12,19,41, bone marrow transplant42, connective tissue diseases9, sarcoidosis31, or histiocytosis X13,16,28. In addition, we excluded patients with histologic evidence of predominant pulmonary capillary hemangiomatosis, a condition characterized by localized capillary proliferation. These patients usually present like PVOD patients, and pulmonary edema with continuous intravenous epoprostenol has been described in these patients as well2,15,20,34. Lantuejoul and colleagues26 have shown that pathologic characteristics of pulmonary capillary hemangiomatosis were found in 73% (16/24) of PVOD patients, and inversely, pathologic characteristics of PVOD were found in 80% (4/5) of patients with pulmonary capillary hemangiomatosis. Similarities in pathologic features and clinical characteristics, and the possibility of pulmonary edema with PAH-specific therapy, suggest that these 2 conditions may overlap, and it has been suggested that pulmonary capillary hemangiomatosis could be a secondary angioproliferative process caused by postcapillary obstruction of PVOD rather than a distinct disease26. Because of our selection of histologically well-characterized PVOD, patients with predominant capillary involvement were excluded from the analysis. Finally, it is likely that we selected a subgroup of patients with more severe disease and a worse outcome than other patients might have, because we required histologic confirmation of PVOD and PAH, thus requiring lung transplantation or postmortem analysis of the lungs.

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Conclusion

In the current study, the first of its kind to our knowledge, we report a large cohort of patients with an established histologic diagnosis of PVOD. Our results indicate that these patients have some characteristic features that may help clinicians in a noninvasive approach to this disease. Of interest, tobacco exposure was more frequent in PVOD patients compared with PAH patients and thus may play a role in the pathophysiology of the disease. PVOD presents similarly to other forms of PAH, and its clinical signs and symptoms are largely nonspecific. Among other characteristics, PVOD patients had a significantly lower PaO2 and DLCO/VA. These features in the setting of severe PAH, when associated with radiographic abnormalities consistent with PVOD or occult alveolar hemorrhage, support the diagnosis of PVOD and may help to avoid high-risk surgical lung biopsies. PAH-specific therapies may lead to pulmonary edema and need to be used with great precaution in patients with PVOD. Acute vasodilator testing with NO during right heart catheterization seems to be safe but is not predictive of the subsequent development of pulmonary edema after initiation of PAH-specific therapy. None of the clinical, functional, or hemodynamic characteristics analyzed in the current study could predict the risk of pulmonary edema after initiation of epoprostenol, bosentan, or calcium channel blockers. In our cohort of patients with histologically confirmed PVOD, the disease prognosis seemed to be worse than the prognosis for PAH.

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