Treatment and prognosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults

INTRODUCTION — Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH) is a rare condition that represents a subgroup of patients with pulmonary hypertension (table 1). In general, PVOD progresses rapidly such that early recognition and treatment of this entity is critical. PVOD and PCH are considered the same entity and for the purposes of this topic will be referred to as PVOD.

The approach to treating patients with PVOD varies from center to center. Our approach is reviewed in this topic. Issues related to the epidemiology, pathogenesis, clinical features, and diagnosis of PVOD as well as the diagnosis and management of pulmonary arterial hypertension are discussed separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

GENERAL PRINCIPLES — All patients with a clinical or histopathologic diagnosis of PVOD should be managed in centers with expertise in pulmonary arterial hypertension (PAH). Details regarding diagnosis of PVOD are provided separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Evaluation and approach to clinical diagnosis'.)

The approach used by most experts is based upon data derived from small case series of patients with PVOD-associated pulmonary hypertension as well as data extrapolated from larger randomized trials performed in patients with PAH. While considerable variation exists among centers, we suggest that the principles of managing patients with PVOD-associated pulmonary hypertension closely parallel that for patients with PAH (algorithm 1 and table 2). However, the clinician should be aware of important differences and potential harms of therapy that can occur in patients with PVOD (algorithm 2):

●General measures – Patients with PVOD should receive routine conventional therapies (eg, oxygen, diuretic, vaccination) but are thought to be at greater risk of alveolar hemorrhage such that, as a general measure, routine anticoagulation is avoided by some experts. (See 'Conventional therapies' below and 'Anticoagulants' below.)

●Advanced therapy – Patients with PVOD are at increased risk of developing pulmonary edema, respiratory failure, and even death from pulmonary hypertension-specific advanced therapy. While there is considerable variation in patient selection and agent administration, we administer trials of single agent advanced therapy to select patients with PVOD as a bridge to lung transplantation. Initial combination therapy is generally avoided in this population due to the increased potential for adverse effects. (See 'Pulmonary hypertension-specific therapy' below and 'Combination' below.)

●Lung transplantation – All patients with PVOD should be evaluated for lung transplantation as soon as the diagnosis is made since most patients progress rapidly, even while on therapy. (See 'Lung transplantation' below.)

GENERAL MEASURES

Conventional therapies — Similar to patients with pulmonary arterial hypertension (PAH), all patients with PVOD should exercise as tolerated, receive routine vaccinations, be counselled against smoking and pregnancy, and be treated with supportive measures including oxygen and diuretics, when indicated.

Evidence to support the use of these therapies is extrapolated from patients with other forms of pulmonary hypertension, which is discussed separately:

●Oxygen therapy when indicated (table 3) (see "Long-term supplemental oxygen therapy" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy')

●Diuretics (see "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy')

●Vaccinations (figure 1) (see "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy')

●Exercise (see "The benefits and risks of aerobic exercise" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy')

Details regarding the care of select populations including patients who are considering pregnancy or who are pregnant, patients who are planning to travel or be exposed to high altitude, and patients requiring surgery are discussed separately. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Special populations'.)

Anticoagulants — Anticoagulation is controversial in patients with PVOD. Many patients with precapillary pulmonary hypertension, particularly those in group 4 PAH and some in group 1 PAH (eg, idiopathic and drug-induced PAH) (table 1 and table 4), receive oral anticoagulants on the basis of observational studies suggesting benefit. However, because patients with PVOD may have a greater de novo risk of alveolar hemorrhage and no trials exist to show benefit in this population, some clinicians, including the author of this topic, avoid routine anticoagulation. In contrast, other experts do routinely anticoagulate when the risk of alveolar hemorrhage is assessed as low; in those cases, warfarin is typically used to target an International Normalized Ratio (INR) between 2 and 3. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

The avoidance of anticoagulants in this population by some experts is based upon one observational study that reported a higher percentage of hemosiderin-laden macrophages identified on bronchoscopy in eight patients with PVOD compared with eleven patients who had idiopathic PAH (40 versus 3 percent) [1]. Whether or not patients with PVOD have clinically relevant bleeding, as opposed to microscopic bleeding, and whether or not the risk is increased on anticoagulants remains unknown. PVOD is not an absolute contraindication to anticoagulation (eg, when administered for treatment of venous thromboembolism or atrial fibrillation). In our experience, small-volume hemoptysis may occur and usually does not require the discontinuation of anticoagulant therapy; however, we typically terminate anticoagulant therapy if more than 50 mL of blood are expectorated over a 24-hour period. (See "Evaluation of nonlife-threatening hemoptysis in adults".)

Avoid exposures — Patients should avoid or discontinue agents known to be associated with PVOD (eg, organic solvents and chemotherapy). (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Drugs and toxins'.)

PULMONARY HYPERTENSION-SPECIFIC THERAPY — Pulmonary arterial hypertension (PAH)-specific advanced therapy is treatment that is directed at the pulmonary hypertension itself, rather than an underlying cause (algorithm 2).

Indications — Patients with PVOD are at increased risk of developing pulmonary edema, respiratory failure, and even death from advanced therapy, with studies reporting rates of this complication ranging from 5 to 75 percent [2-5]. While some experts choose not to administer advanced therapy to this population, we suggest that cautious trials of single agent therapy may be administered as a bridge to lung transplantation in a select group of patients with PVOD who are fully informed of the risks. For patients who do not desire or are not appropriate candidates for lung transplantation, some experts, including the author of this topic, administer cautious trials of advanced therapy on a palliative basis since advanced therapy can be associated with improvement in functional class [6-8], though achievement of low-risk status, which is the goal for patients with PAH, is rare [6,9]. (See 'General principles' above and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Baseline risk assessment'.)

When advanced therapy is chosen, we suggest that it be administered using low doses of agent together with close monitoring and rapidly available treatment of pulmonary edema with oxygen and high dose diuretics; therapy can then be slowly escalated to the maximum tolerated dose. This preference is based upon our experience and that of others that suggest some benefit to this approach [10-12]. Trials of therapy should be given approximately 6 to 12 weeks before abandoning the approach. (See 'Prostanoids' below.)

Although patient selection for advanced therapy should be individualized, patients with PVOD who may benefit the most include:

●Patients who are severely ill (eg, World Health Organization [WHO] functional class IV (table 2), and/or those with markedly impaired cardiac index or refractory right ventricular failure) and need an urgent life-saving bridge to lung transplantation.

●Patients in whom the suspicion for a large component of precapillary pulmonary hypertension is high (eg, patients with atypical findings of PVOD during diagnostic evaluation) (table 4). (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Terminology' and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Evaluation and approach to clinical diagnosis'.)

Similar to patients with PAH (algorithm 1), the agent used for advanced therapy depends upon WHO functional class (table 2), individual patient preference, clinician and institutional experience, hemodynamics (table 4), and evidence of previous adverse effects with such therapy. Importantly, unlike patients with PAH, initial single agent therapy is preferred rather than combination therapy due to the likely increased risk of pulmonary edema from the latter. (See 'Combination' below.)

Assessing vasoreactivity — While vasoreactivity testing is recommended for patients with group 1 PAH (table 1 and algorithm 1) prior to the initiation of advanced therapy, its role in PVOD is less clear and it carries the risk of acute pulmonary edema. We typically don’t perform vasoreactivity testing because few patients with PVOD are vasoreactive [9,13] and are therefore rarely candidates for calcium channel blocker therapy.

On the rare occasion that vasoreactivity testing is performed, we use inhaled nitric oxide with limited exposure time and dose; one report suggested that less than 10 minutes of exposure to 10 ppm of inhaled nitric oxide was not associated with pulmonary edema in 24 patients with PVOD but was adequate to test for vasoreactivity [2]. Vasoreactivity testing using intravenous epoprostenol may carry the greatest risk of pulmonary edema [14]. Details regarding vasoreactivity testing are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients'.)

The proportion of patients with PVOD who are vasoreactive has been reported to range from 4 to 12 percent [9,13]. In our experience, those who develop significant pulmonary edema during testing often experience pulmonary edema with treatment. While some experts avoid advanced therapy in this population, others proceed cautiously with advanced agents, limited protocols, and aggressive pulmonary edema treatment readily available.

Minimizing the risk of pulmonary edema — Advanced therapy should not be administered in those with overt pulmonary edema.

The development of pulmonary edema in this population during the administration of advanced therapy is thought to be due to relatively greater pulmonary arteriolar vasodilation than associated pulmonary venodilation (advanced therapy does not have a rapid dilatory effect on pulmonary veins); pulmonary arteriolar resistance decreases while pulmonary venous resistance remains fixed, resulting in an increase in transcapillary hydrostatic pressure, which in turn results in the transudation of fluid from the vascular space to the alveolar space (ie, pulmonary edema).

To overcome this adverse effect, many experts initially use low doses of an advanced agent together with high dose diuretic and oxygen therapy; starting doses are unknown and should be individualized but one-half or lower of the recommended dose for non PVOD patients is appropriate (table 5). If tolerated, the dose is slowly increased (every one to two weeks) until a maximum tolerated dose is reached or an adverse effect is noted. In most studies, and in our experience, patients develop this side effect within hours or days such that monitoring should be vigilant during this period. Protocols vary among centers and should be tailored according to the institution and the individual being treated. This approach was best studied in patients taking prostanoids and is discussed below. (See 'Prostanoids' below and 'General principles' above.)

Treatment approach

WHO functional class I — Patients with PVOD and WHO functional class I symptoms, asymptomatic with ordinary activity, are rare [2,3,9]. Similar to patients with idiopathic pulmonary hypertension, patients with PVOD and WHO functional class I (table 2) require general measures only but do not require advanced therapy. However, they should be closely monitored every month for symptoms of disease progression and escalation of functional class. (See 'General measures' above.)

WHO functional class II and III

Agent selection — Patients with PVOD and WHO functional class II and III (table 2) require general measures and may be suitable for a trial of advanced therapy with an oral agent. However, in contrast to patients with idiopathic pulmonary arterial hypertension, we suggest that initial combination therapy be avoided in patients with PVOD due to the increased risk of adverse effects (see 'Combination' below). Agent selection is individualized and varies according to the institution, patient preference, and cost. Among the available oral agents, an endothelin receptor antagonist or a phosphodiesterase inhibitor may be appropriate. Experience with guanylate cyclase stimulators (eg, riociguat) or oral selective prostacyclin-receptor agonists has not been reported and thus they are not recommended. Rarely, patients with rapidly progressive disease and class III symptoms may be candidates for a cautious trial of intravenous epoprostenol. (See 'Endothelin receptor antagonists' below and 'Phosphodiesterase type 5 inhibitors' below and 'Prostanoids' below and 'Combination' below and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Endothelin receptor antagonists — Case reports describe hemodynamic improvements in patients with PVOD treated with the endothelin receptor antagonist (ERA), bosentan [2,15,16]. However, pulmonary edema has also been reported to occur as an adverse effect in up to one-third of treated patients. Endothelin receptor antagonists were the most common of the PAH specific therapies used in a large French series of confirmed or highly suspected PVOD patients, with 52 of 94 patients receiving an ERA alone or in combination with at least one other agent [9]. Data that support the role of endothelin receptor antagonists in patients with group 1 PAH are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Phosphodiesterase type 5 inhibitors — Hemodynamic improvement from PDE5 inhibitors in a limited number of patients with PVOD has been reported [17-21]; one patient developed pulmonary edema when bosentan, an ERA, was added to sildenafil therapy [20]. Data that support the role of PDE5 inhibitors in patients with group 1 PAH are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

WHO functional class IV — Patients with PVOD and WHO functional class IV (table 2) require general measures and may be candidates for prostanoid therapy, usually intravenous epoprostenol administered as a single agent. We also suggest that initial combination therapy be avoided in patients with PVOD due to the increased risk of adverse effects. (See 'Prostanoids' below and 'Combination' below.)

Prostanoids — Despite concerns with acute pulmonary edema, intravenous epoprostenol therapy has been administered to patients with severe PVOD as a bridge to lung transplantation [2,3,7,14,22]. As examples:

●In one report of twelve patients with severe PAH from PVOD, epoprostenol was infused at low doses which were incrementally titrated slowly over the following two to four months [7]. At initiation, all patients were aggressively treated with oral loop diuretics; the majority received oxygen supplementation (67 percent) and anticoagulation (92 percent) while a smaller proportion required a second diuretic and/or dobutamine for acute right ventricular failure. Eight patients also received dual therapy with bosentan. This regimen was associated with an improvement in hemodynamics (cardiac index, pulmonary vascular resistance), exercise capacity, and functional class in the majority of individuals treated (60 percent). At follow-up, several patients required adjustments of their diuretic regimen with only one case of reversible pulmonary edema noted. Two patients died and the remainder were successfully bridged to transplantation (median time from initiation of epoprostenol was 2.4 months).

●In a second study of eight patients, six with PVOD and two with PCH, a similar approach of epoprostenol and aggressive diuretic therapy when pulmonary edema was noted resulted in hemodynamic improvements and successful bridge to transplantation in 50 percent of the group [8].

●One case report of a patient, with a retrospective diagnosis of PVOD tolerated prostanoid therapy for more than 15 years [23], although this is rare in our experience.

Experience with other prostanoids including treprostinil or inhaled iloprost is even more limited but suggests a similar outcome to that with epoprostenol [21,24,25].

Detailed discussion of the value of prostanoid therapy in patients with group 1 PAH is provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Definition' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Refractory or progressive disease

Combination — Unlike patients with group 1 PAH who have WHO functional class II through IV, we recommend avoiding initiating combination therapy in patients with PVOD, due to the higher likelihood of inducing pulmonary edema. However, for those with progressive or refractory disease in whom single agent advanced therapy has been tolerated, the cautious introduction of a second or third agent may be appropriate as a bridge to transplant. Only a few cases have been reported that suggest potential application of combination advanced therapy including oral sildenafil and intravenous epoprostenol [18], bosentan and epoprostenol [7], bosentan and sildenafil [20], ambrisentan and tadalafil [26], inhaled nitric oxide and iloprost [25], PDE-5 inhibitor and treprostinil [21], and three class combination therapy [21].

LUNG TRANSPLANTATION — We refer all appropriate patients with PVOD to be evaluated for lung transplantation at the time of diagnosis since rapid progression is expected, even while on therapy. Although considered by most experts as the only effective therapy available for PVOD [27-29], the utility of lung transplantation is diminished by the fact that the average wait time in some parts of the United States exceeds the life expectancy associated with PVOD. As an example, one retrospective study of patient undergoing transplant reported that a higher proportion of patients with PVOD died while on the transplant waiting list for transplant when compared with patients with pulmonary arterial hypertension (23 versus 11 percent) [30]. (See "Lung transplantation: An overview".)

Single-lung, double-lung transplantation, and heart-lung procedures have both been performed, with possible recurrence of PVOD reported in only one patient [31-33]. Infection and the development of obliterative bronchiolitis remain major causes of morbidity and mortality in patients who undergo lung transplantation.

OTHER THERAPIES

Calcium channel blockers — For patients with PAH who demonstrate an acute vasodilator response on vasoreactivity testing, calcium channel blocker (CCB) therapy, usually long-acting nifedipine or diltiazem, is indicated. The value of CCB therapy in patients with PVOD is less clear since the great majority of case series of CCB therapy in patients with PVOD report a lack of improvement or the development of pulmonary edema (4 to 75 percent) [2-5]. Only one case report suggests sustained improvement with CCBs [4]. Due to the potential risk of CCB therapy with little chance of clinical benefit, we avoid use of CCB therapy in patients with PVOD, even those who are found to be acutely vasoreactive.

Immunomodulatory medications — We favor limited trials of immunomodulatory medications (eg, corticosteroids, antimetabolites) in a select group of patients with PVOD who also have prominent autoimmune features. This preference is based upon anecdotal responses that have occurred with immunomodulatory agents in this population, particularly in the context of limited treatment options [34-39]. Autoimmune conditions that are associated with PVOD are listed separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Autoimmune disorders'.)

However, the majority of patients with PVOD are not candidates for immunosuppressive therapy. One case series described the successful use of glucocorticoids and mycophenolate mofetil in three patients with inheritable and sporadic PVOD, with stabilization or improvement after institution of this combination immunosuppressant regimen [40]. This approach is not routinely recommended and we await further data.

For those in whom immunosuppression is trialed, the optimal agent is unknown. Specific regimens may vary depending upon the underlying associated autoimmune disease and occasionally when a pulmonary vascular response is noted, a second agent (eg, azathioprine) may be appropriate. We typically administer prednisone at doses of 0.75 to 1 mg/kg per day for four weeks and follow symptoms, radiographs, diffusing capacity, and the alveolar-arterial oxygen gradient. If a patient improves on this therapy, we slowly taper to the lowest tolerated dose for the maximum clinical benefit (usually 5 to 10 mg/day); a second agent may be added for a steroid-sparing effect. If no response is noted, then the medication is discontinued and an alternate agent may be tried. The selection of a second or alternate agent is usually determined by the underlying autoimmune disorder. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Glucocorticoids'.)

Our experience and that of experts suggest these drugs rarely palliate the symptoms of PVOD or affect the terminal nature of the condition. However, rare case reports suggest sustained improvement in select cases with autoimmune features. As examples, success has been reported in patients with Sjögren's disease [34], PVOD following hematopoietic stem cell transplantation [38], sarcoidosis [35], and mixed connective tissue disorders [36]. Despite reports of success, case reports of failure also have been published in patients with PVOD from autoimmune conditions [39].

Surgical or mechanical therapies — As a bridge to lung transplantation, atrial septostomy, lung assist devices, and extracorporeal membrane oxygenation (ECMO) have been used in rare cases of patients with severe PVOD [41,42]. Details of these mechanical therapies are provided separately. (See "Extracorporeal life support in adults in the intensive care unit: Overview" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Right-to-left shunt'.)

EXPERIMENTAL THERAPIES — A number of experimental agents, many of which have thrombolytic properties, have been proposed for use in patients with PVOD based upon evidence derived from patients with hepatic veno-occlusive disease (HVOD). However, due to lack of evidence and the rationale that acute thrombosis probably plays a smaller pathogenic role in PVOD than HVOD, we recommend against their use in patients who have PVOD except in the context of well-defined clinical trials. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Severe SOS'.)

Examples of such agents include:

●Defibrotide – Defibrotide, is a polydeoxyribonucleotide that has multiple effects on coagulation and fibrinolysis that may hasten resolution of thrombi [43-45]. Only one case report describes potential benefit in patients with PVOD associated with a chronic myeloproliferative disorder [45]. It has been approved by the US Food and Drug administration (orphan drug designation) for patients with HVOD [46].

●Kinase inhibitors – Imatinib and sorafenib are kinase inhibitors that have anti-angiogenesis effects and may promote vascular remodeling via non antithrombotic mechanisms. Animal studies and case reports suggest mixed outcomes in patients with PVOD, but no randomized clinical trials have been performed to validate their use [47-51]. While some studies report improved hemodynamics and exercise capacity with imatinib as an add-on therapy to epoprostenol [47,49,50], this effect has not been consistent [48,51]. In the largest observational series of imatinib use in PVOD, nine patients treated with imatinib were followed to death or transplantation and were also compared with seven patients who did not receive the drug. Mean survival was 1493.7 days, and those in the imatinib group experienced improvements in hemodynamics and brain natriuretic peptide values [52]. In another case report, sorafenib (but not imatinib) appeared to improve exercise tolerance [48].

PROGNOSIS — The prognosis of PVOD is poor, with studies reporting a one-year mortality of up to 72 percent [2,3,30,53,54]. Most patients die or require lung transplantation within two years of diagnosis and children with the disease progress more rapidly [55,56].

Rare cases may survive for longer. One case report described a patient on a prostanoid, an angiotensin converting enzyme inhibitor, warfarin, and oxygen who survived for more than 15 years beyond her diagnosis [23].

While not rigorously compared, small case series report that time to transplant or death is shorter in patients with PVOD compared with pulmonary arterial hypertension (PAH; 12 versus 42 months) [2]. Most patients die from progressive pulmonary hypertension resulting in respiratory failure, right heart failure, and circulatory collapse.

Rigorous outcome studies have not been performed in patients with PVOD on medical therapy. Therefore, the degree to which medical therapy favorably impacts outcomes is unknown. However, most experts agree that the impact of therapy is typically not profound with only rare case reports of survival beyond two years (eg, some patients with autoimmune disease) [34,36]. Similarly outcomes have not been studied following heart-lung or lung transplantation, and are assumed to be similar to those of other populations undergoing transplant. While recurrence is rare, one case report describes recurrence in a young man with PVOD [31]. (See "Heart-lung transplantation in adults", section on 'Prognosis' and "Lung transplantation: An overview", section on 'Outcomes'.)

Details regarding the prognosis and cause of death in patients with other types of pulmonary hypertension are provided separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

●Definition – Pulmonary veno-occlusive disease (PVOD) is a rare clinicopathologic syndrome that represents a subgroup of patients with pulmonary hypertension (PH) (table 1). In general, PVOD progresses rapidly such that treatment of this entity is critical. All patients with PVOD should be managed in centers with expertise in PH. PVOD and pulmonary capillary hemangiomatosis are considered the same entity and in this topic are referred to as PVOD. (See 'Introduction' above.)

●Principles of management – In patients with PVOD-associated PH, we suggest that the principles of management closely parallel those for patients with group 1 pulmonary arterial hypertension (PAH) (algorithm 1 and table 2 and algorithm 2) with some exceptions:

•Patients with PVOD, should be evaluated for lung transplantation as soon as the diagnosis is made, since rapid progression and high mortality rates are expected despite medical therapy.

•Patients with PVOD may be at increased risk of alveolar hemorrhage from routine anticoagulation and of pulmonary edema, respiratory failure, and death from advanced PAH-specific therapy, requiring additional precautions and monitoring on such therapies. (See 'General principles' above and 'Lung transplantation' above.)

●General measures – Patients with PVOD should exercise as tolerated, receive routine vaccinations, be counseled against smoking and pregnancy, and be treated with supportive measures including oxygen and diuretics, when indicated. (See 'General measures' above and 'Conventional therapies' above.)

For patients with PVOD, anticoagulant therapy is controversial. While some experts avoid routine anticoagulation in patients with PVOD based upon the greater de novo risk of alveolar hemorrhage and lack of data to support a benefit, other experts anticoagulate patients when the risk of alveolar hemorrhage is assessed as low; in those cases, we typically use warfarin and target an International Normalized Ratio (INR) between 2 and 3. (See 'Anticoagulants' above and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

●PAH-specific therapy indications – Indications for PAH-specific advanced therapy in patients with PVOD are uncertain. Treatment-associated risks, such as pulmonary edema and respiratory failure, are higher in this population, and patients generally progress rapidly despite such therapy. Patients most likely to benefit include those who are severely ill or those with a large precapillary component to their PH (table 4). (See 'Pulmonary hypertension-specific therapy' above and 'Indications' above and 'Minimizing the risk of pulmonary edema' above.)

●Treatment approach – For patients with PVOD awaiting lung transplantation or those who decline lung transplantation, we suggest the following approach to treatment which is based upon limited evidence of efficacy and the lack of therapeutic alternatives (Grade 2C):

•We initiate a cautious treatment trial with low doses of a single agent together with close monitoring and treatment of pulmonary edema with diuretic and oxygen. Advanced therapy should not be administered in those with overt pulmonary edema. (See 'Minimizing the risk of pulmonary edema' above.)

•Patient and agent selection is individualized and varies among experts and institutions. We select an agent for a treatment trial based upon World Health Organization (WHO) functional class (table 2). (See 'Assessing vasoreactivity' above.)

-Patients with PVOD and WHO functional class I are rare and do not require advanced therapy and should be closely monitored every month for symptoms of disease progression and escalation of functional class. (See 'WHO functional class I' above.)

-For patients with PVOD and WHO functional class II or III, we initiate a trial with an oral agent, either an endothelin receptor antagonist or a phosphodiesterase inhibitor. Patients with rapidly progressive disease and class III symptoms may be candidates for a trial of intravenous epoprostenol. (See 'WHO functional class II and III' above.)

-For patients with PVOD and WHO functional class IV, we use intravenous epoprostenol. (See 'WHO functional class IV' above.)

-Given limited long-term efficacy and increased risk of pulmonary edema, we avoid use of calcium channel blocker therapy in patients with PVOD, including in those with positive or neutral response to vasoreactivity testing.

•We do not initiate combination therapy. For those with progressive or refractory disease in whom single agent advanced therapy has been tolerated, the cautious introduction of a second or third agent may be appropriate, although this incrementally increases the risk of pulmonary edema.

●Other therapies – While the majority of patients with PVOD are not candidates for immunosuppressive medications (eg, corticosteroids, antimetabolites), we favor limited trials of prednisone (eg, 0.75 to 1 mg/kg/day for four weeks) in patients with PVOD who also have prominent autoimmune features. Atrial septostomy, lung assist devices, and extracorporeal membrane oxygenation (ECMO) may be used on a case-by-case basis in those with severe PVOD as a bridge to lung transplantation. (See 'Other therapies' above and 'Experimental therapies' above.)

●Prognosis – Patients with PVOD typically progress rapidly despite therapy, especially when compared with patients with group 1 PAH on therapy. Consequently, most patients die or require lung transplantation within two years of diagnosis. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Clardy, MD, who contributed to earlier versions of this topic review.