Idiopathic Pulmonary Arterial Hypertension and ...

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Pulmonary veno-occlusive disease (PVOD) is a rare disorder and can be misdiagnosed as idiopathic pulmonary arterial hypertension (iPAH). PVOD and iPAH.
Idiopathic Pulmonary Arterial Hypertension and Pulmonary Veno-occlusive Disease: Similarities and Differences David Montani, M.D.,1 Kristina Kemp, M.D.,1 Peter Dorfmuller, M.D., Ph.D.,1 Olivier Sitbon, M.D., Ph.D.,1 Ge´rald Simonneau, M.D.,1 and Marc Humbert, M.D., Ph.D.1

ABSTRACT

Pulmonary veno-occlusive disease (PVOD) is a rare disorder and can be misdiagnosed as idiopathic pulmonary arterial hypertension (iPAH). PVOD and iPAH often share a similar clinical presentation, genetic background, and hemodynamic profile. PVOD accounts for 5 to 10% of cases initially considered as iPAH. When compared with iPAH, PVOD is characterized by a higher male:female ratio, higher tobacco exposure, and lower PaO2 at rest, diffusing capacity for carbon monoxide (DLCO), and oxygen saturation nadir during the 6-minute walk test. High-resolution computed tomography (HRCT) of the chest may be suggestive of PVOD in the presence of centrilobular groundglass opacities, septal lines, and lymph node enlargement. Additionally, occult alveolar hemorrhage is associated with PVOD. Definitive diagnosis necessitates a surgical lung biopsy; however, this procedure is exceedingly high risk in this patient population and is generally not recommended. Therefore, a noninvasive diagnostic approach using HRCT of the chest, arterial blood gases, pulmonary function tests, and bronchoalveolar lavage may be helpful to detect PVOD. In contrast with iPAH, PVOD is characterized by an even poorer prognosis and the possibility of developing severe pulmonary edema with specific PAH therapy. Lung transplantation remains the treatment of choice, but cautious use of specific PAH therapy can be helpful in select patients while awaiting this intervention. KEYWORDS: Pulmonary arterial hypertension, pulmonary veno-occlusive disease, carbon monoxide diffusing capacity, computed tomography, alveolar hemorrhage

Pulmonary veno-occlusive disease (PVOD) is a rare disorder that is often misdiagnosed as idiopathic pulmonary arterial hypertension (PAH). Both conditions are severe and show evidence of pulmonary hypertension, which is characterized by elevated pulmonary artery pressure (25 mm Hg at rest) leading to right 1

Universite´ Paris-Sud 11, Centre National de Re´fe´rence de l’Hypertension Arte´rielle Pulmonaire, Service de Pneumologie et Re´animation respiratoire, Hoˆpital Antoine-Be´cle`re, Assistance Publique - Hoˆpitaux de Paris, Clamart, France. Address for correspondence and reprint requests: David Montani, M.D., Centre des Maladies Vasculaires Pulmonaires, Service de Pneumologie, Hoˆpital Antoine Be´cle`re, Assistance Publique– Hoˆpitaux de Paris, Universite´ Paris-Sud., 157 rue de la Porte de

heart failure and death.1,2 PVOD has very similar clinical and hemodynamic characteristics to idiopathic PAH, which poses the diagnostic confusion; but in terms of pathology, these conditions are more easily distinguished. The pulmonary vascular pathology of idiopathic PAH is defined by a major remodeling of Trivaux, 92140 Clamart, France (e-mail: [email protected]). Pulmonary Hypertension; Guest Editors, Marc Humbert, M.D., Ph.D. and Rajan Saggar, M.D. Semin Respir Crit Care Med 2009;30:411–420. Copyright # 2009 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-0029-1233310. ISSN 1069-3424.

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small precapillary pulmonary arteries with frequent plexiform and possible thrombotic lesions, whereas PVOD preferentially affects the small pulmonary veins frequently associated with capillary involvement.3,4 PVOD is characterized by a worse prognosis than idiopathic PAH, and the possibility of developing severe pulmonary edema with specific PAH therapy, justifying the importance of establishing a correct and early diagnosis. It has been hypothesized that idiopathic PAH and PVOD may represent two parts of the same disease spectrum, with lesions preferentially affecting precapillary vessels in PAH and postcapillary vessels in PVOD. Because of the differences in pathological assessment, in response to specific PAH therapy and in prognosis, PVOD is now more clearly identified as a unique subgroup of PAH, and this will likely be reflected in the future revised classification of the 4th World Symposium on pulmonary hypertension (Simonneau et al, personal communication).

PATHOLOGICAL ASSESSMENT In idiopathic PAH, the characteristic pathological abnormalities are represented by fibrotic and proliferative changes located in muscular arteries of less than 500 mm in diameter. Different compartments of the vessel may contribute to the thickening of the arterial wall, and hence various histological patterns may occur.3 They include isolated medial hypertrophy, concentric and eccentric nonlaminar intimal fibrosis, concentric laminar intimal fibrosis (also known as ‘‘onion-skin’’ lesions), and complex lesions.3 Thrombotic lesions, also known as in situ thrombosis, are a frequent pattern in different PAH subgroups. A peculiar entity within the pathological classification of vasculopathies in pulmonary hypertension is referred to as the complex lesion,3 associating plexiform lesions with dilation lesions. The former represents the most illustrious form of vascular change in PAH and was considered for a long time as a pathogno-

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monic feature of idiopathic PAH.5 However, this presumption has been revised, and it has been reported that plexiform lesions may occur in PAH associated with other conditions.3 Dilation lesions are usually found distally to plexiform lesions and correspond to thinwalled and congestive precapillary pulmonary vessels. Arteritis, including transmural inflammation and fibrinoid necrosis, may be sporadically present in severe pulmonary hypertension, whereas perivascular inflammatory infiltrate is frequently encountered in the range of diseased vessels. In PVOD, the observed postcapillary lesions affect septal veins and preseptal venules, and consist of loose, fibrous remodeling of the intima, which may occlude the lumens of pulmonary veins (Fig. 1A). Occult alveolar hemorrhage in bronchoalveolar lavage fluid may be evaluated using the Golde score and frequently occurs in patients displaying PVOD in contrast to idiopathic PAH where alveolar hemorrhage is classically absent.6 Interestingly, venous lesions and postcapillary obstruction in PVOD are commonly associated with capillary remodeling, including angiectasia and even capillary angioproliferation (Fig. 1B). A doubling or tripling of the alveolar septal capillary layers may focally be observed. Despite the constant occurrence of arterial lesions in the lungs of PVOD patients, complex lesions, as defined earlier, usually do not occur in the context of PVOD.3

EPIDEMIOLOGY AND RISK FACTORS As observed in idiopathic PAH, PVOD has been diagnosed throughout a very wide age range, from the first weeks of life to the seventh decade.7 With regard to sex distribution, PVOD occurs equally in men and women; whereas, idiopathic PAH has a clear female predominance.1,8–10 There is a clear and significant risk of developing PAH after anorexigen (fenfluramine derivatives) exposure, and it has been clearly demonstrated that PAH

Figure 1 Pulmonary vascular lesions in a patient suffering from pulmonary veno-occlusive disease (hematoxylin-eosinsaffron-staining). (A) Occluding intimal fibrosis in a preseptal venule. (B) Alveolar septa with capillary proliferation: several layers of capillary lumina are separating the alveoli. Note the intraalveolar siderin-laden macrophages.

IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION AND PULMONARY VENO-OCCLUSIVE DISEASE/MONTANI ET AL

associated with anorexigens shares a similar presentation and evolution as does idiopathic PAH.11–15 Montani et al recently reported a case of a PVOD in a patient with a history of fenfluramine exposure, suggesting a possible association between anorexigen exposure and PVOD.8 Chemical exposure has been suggested to influence the development of PVOD but is not considered as a risk factor of PAH. This association has been reported in isolated case reports; however, the two largest series of PVOD found no significant association with chemical exposure but did not include specific exposure history elicited by questionnaire.8,9 PVOD has been reported in association with various chemotherapy regimens, including bleomycin, BCNU and mitomycin16–19 and after bone marrow transplantation.20–27 In a recent series, we reported a higher tobacco exposure and an increased proportion of smokers in PVOD as compared with idiopathic PAH.8 Even if it has been previously demonstrated that tobacco exposure may contribute to pulmonary vascular injury,28,29 it is not clear why tobacco exposure would be a specific risk factor for PVOD and not for PAH.8 Because PVOD is a difficult-to-diagnose subgroup of a rare disease, the prevalence and incidence are difficult to evaluate. PVOD, without any associated conditions, is usually considered to represent 5 to 10% of histological cases where patients were initially diagnosed as ‘‘idiopathic’’ PAH.7 PVOD can also occur in conditions usually associated with pulmonary hypertension, including connective tissue diseases,30–32 sarcoidosis,33 pulmonary Langerhans cell histiocytosis,7,34,35 and more rarely HIV infection.36–38 As previously described in idiopathic PAH, Montani et al have shown that even in the absence of a diagnosed autoimmune disorder, PVOD shares a similar autoimmune background with idiopathic PAH and the presence of autoantibodies (antinuclear, antiphospholipid, or thyroid antibodies) were found in 30% and 33% in PVOD and idiopathic PAH, respectively.8

GENETICS When PAH occurs in a familial context, germline mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene are detected in 70% of cases; however, BMPR2 mutations can also be detected in 10 to 40% of apparently idiopathic PAH.39–41 The distinction between idiopathic and familial BMPR2 mutation carriers may in fact be artificial. Recent expert discussion pleads in favor of the term heritable PAH, and this should be reflected in the future revised classification of the 4th World Symposium on pulmonary hypertension (Simonneau et al, personal communication). Interestingly, some patients with a definite diagnosis of PVOD have been reported to carry a BMPR2 mutation,

suggesting a genetic risk factor in the development of PVOD.8,42–46 These reports suggest a possible role of the BMPR2 pathway in the development of PVOD and further emphasize the similarities between PVOD and PAH. As in heritable PAH, heritable PVOD may occur in the absence of BMPR2 mutation suggesting that other genetic risk factors may also be contributing to the disease process. These results support systematic screening for a possible familial history of pulmonary vascular disease and similar genetic counseling in both PAH and PVOD patients.

CLINICAL CHARACTERISTICS Idiopathic PAH and PVOD have very similar clinical presentations; therefore the differentiation between these two entities is difficult and the clinical exam is most often unhelpful. As in PAH, progressive dyspnea on exertion is the main symptom in PVOD, although often neglected by patients, leading to the frequent diagnostic delay. In PVOD, most of the patients have severe exertional dyspnea with a New York Heart Association (NYHA) functional class III or IV at the time of the diagnosis.8,9 Montani et al found no difference in NYHA functional class at diagnosis between patients displaying PVOD as compared with idiopathic PAH. Right-sided cardiac dysfunction and failure often complicate the more advanced stages of the disease and represent right ventricular failure due to the sustained pressure overload. Signs of right heart failure are frequently elicited on clinical examination. Cardiac auscultation reveals a prominent pulmonic component of the second heart sound and a systolic murmur of tricuspid regurgitation.9 Respiratory auscultatory crackles may occur in PVOD patients with predominant pulmonary infiltrates, but the precise prevalence is unknown.7,9 Pleural effusions have been suggested to be more frequent in PVOD; however, the studies focused on radiography with high-resolution CT of the chest show a similar proportion of pleural effusions in both diseases.8,9,47,48 Hemoptysis has been described in PVOD. However, in the recent study by Montani et al, hemoptysis was reported infrequently and equally in both idiopathic PAH and PVOD, confirming that alveolar hemorrhage in PVOD is generally occult.6,8 Clubbing and Raynaud’s phenomenon have been reported as clinical signs in PVOD, but this was not reproduced in our recent series because these signs remain rare and can also occur in idiopathic PAH.8

HEMODYNAMIC EVALUATION As for all patients with suspected PAH, hemodynamic evaluation is required in PVOD to confirm the diagnosis. Both idiopathic PAH and PVOD patients have

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Figure 2 Measurement of pulmonary capillary wedge pressure (PCWP) in pulmonary veno-occlusive disease (PVOD). PCWP is usually normal in patients with PVOD because the disease mostly affects small pulmonary veins, leading to an elevation of true pulmonary capillary pressure (Pc). PCWP is obtained after balloon inflation of a pulmonary arterial branch (1), and the pressure measured reflects the pressure at the end of the static column of blood (hatched) in a large vein (2), usually of a larger size than those vessels affected by PVOD. Pv, pressure in small pulmonary veins; Pa, pulmonary artery pressure. From Montani et al.50 With permission from European Respiratory Society Journals Ltd.

evidence of severe precapillary PAH with an elevated resting mean pulmonary arterial pressure (mPAP) of greater than 25 mm Hg with a pulmonary capillary wedge pressure (PCWP) of less than or equal to 15 mm Hg.2,49,50 When biopsy-proven idiopathic PAH patients were compared with a group with biopsy-proven PVOD in a recent large series, similar hemodynamic characteristics were observed with the exception of right atrial pressure, which was lower in PVOD.8 Case reports51 and case series6,8,9 demonstrated that PCWP is usually normal (