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.
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).
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.
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.
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.
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.
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.
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.
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%.
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.
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.
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.
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.
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.
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.
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.
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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