Pulmonary Veno-Occlusive Disease

Pulmonary veno-occlusive disease (PVOD) is one of the less commonly encountered causes of pulmonary hypertension. Some reports suggest that PVOD accounts for 5-20% of cases classified as idiopathic pulmonary arterial hypertension (PAH).[1, 2, 3] PAH remains an incurable disease that results in significant morbidity and mortality. (See Epidemiology, Treatment, and Medication.)

In the past, PVOD has been described by various terms, such as pulmonary venous sclerosis, obstructive disease of the pulmonary veins, or the venous form of primary pulmonary hypertension. As the name suggests, PVOD is a clinicopathologic entity characterized by occlusion or narrowing of the pulmonary veins and venules by sometimes loose, sometimes more dense and collagen-rich, fibrous tissue,[4] leading to clinical manifestations that are, in many ways, similar to PAH. (See Pathophysiology, Etiology, Presentation, and Workup.) However, owing to the differences in pathology and response to PAH-specific therapy, it was classified in a unique group 1 in the pulmonary hypertension classification in 2009.

Although the term pulmonary veno-occlusive disease was first used in the 1960s, the first case was described by Dr J. Hora in 1934 in a 48-year-old patient who died within one year of diagnosis with symptoms of right-sided heart failure.[5] Historically, the disease has been underdiagnosed, possibly because of lack of awareness by clinicians.

Regardless of the mechanism of injury, the end result in pulmonary veno-occlusive disease (PVOD) is constriction and/or occlusion of the pulmonary veins and venules. In the early stage, the occlusion may be from loose, edematous tissue, which later transforms into dense and sclerotic fibrous tissue. Eccentric intimal thickening is seen in the lobular septal veins and venules and, rarely, in the larger veins.[6] In addition, dilatation of lymphatics occurs.

The plexiform arterial lesions seen in patients with primary pulmonary hypertension, or idiopathic pulmonary arterial hypertension (PAH), are absent, although some arterial medial thickening may occur.[7] The alveolar capillaries become dilated and engorged from back-pressure and sometimes causes capillary proliferation, which mimics another similar disease, pulmonary capillary hemangiomatosis. Recanalization of veins may occur over time.[8] (See the image below.)

Medium-power photomicrograph (original magnification, X10; hematoxylin and eosin stain) demonstrates a fibrotic interlobular septum containing a vein with an occluded lumen (arrowhead). The occlusion is composed of dense, collagen-rich, fibrous tissue. Image courtesy of Thoracic Imaging Section, Department of Radiologic Pathology, Armed Forces Institute of Pathology.

The exact etiology of pulmonary veno-occlusive disease (PVOD) remains largely unknown. However, several indirect observations have led to many hypotheses regarding the etiology. One such hypothesis proposes that injury to the vessel walls leads to a cascade of humoral and mechanical events that eventually results in structural changes with the end result being widespread fibrotic venous constriction or occlusion.[9]

The following mechanisms for injury have been proposed:

• Immune mediated

• Infectious

• Genetic

• Toxic

• Radiologic

• Coagulopathic

Immune mediated

Either idiopathic autoimmune injury to venules or immune-mediated injury to venules related to viral or other environmental agents has been proposed as a mechanism for the development of PVOD. Cases have been reported in patients with other autoimmune clinical features.[10, 11]

Some cases of pulmonary hypertension in the setting of mixed connective disease and scleroderma, including the CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) variant, have been known to have a histopathology consistent with that of PVOD.[12, 13, 14]

Infectious

Various infections have been reported to be associated with PVOD. These include infections with viruses such as cytomegalovirus, Epstein-Barr virus, and measles virus.[15] One case has been reported with concomitant Toxoplasma infection. A few cases of PVOD in the setting of human immunodeficiency virus (HIV) infection have been reported.[16]

Genetic

Several cases of PVOD have been reported to occur in siblings, with a similar age of onset.[17, 18] These observations may indicate a genetic predisposition or common environmental exposures. A case of well-documented PVOD associated with a bone morphogenetic protein receptor protein type II (BMPR2) mutation has been reported suggesting a possible pathogenetic connection with idiopathic PAH or heritable PAH.[19]

Toxic

PVOD has been reported after the administration of various chemotherapeutic agents such as bleomycin, mitomycin, and carmustine (BCNU), similar to hepatic veno-occlusive disease.[20, 21] Other chemical exposures that have been linked to the development of PVOD include powdered cleaning products containing silica, soda ash, dodecyl benzyl sulfonate, and trichloro-s-triazinetrione.[22] PVOD seems to occur more commonly in bone marrow transplant recipients than in the general population.[23, 24]

Radiologic

Radiation exposure is a well-recognized cause of vascular injury. A case of PVOD that may be associated with previous mantle irradiation for Hodgkin lymphoma has been reported.[25] However, the presence of a prothrombotic state in malignancies, especially in adenocarcinomas, simultaneously with exposure to chemotherapeutic agents and radiotherapy precludes the establishment of a firm cause-and-effect relationship between malignancy and PVOD.

Coagulopathic

The association of some cases of PVOD with oral contraceptive use or pregnancy has lent some support to the theory that PVOD is related to coagulation disorders, but an absence of thrombosis in other organs may refute this notion.

In view of the underrecognition of pulmonary veno-occlusive disease (PVOD), the true incidence and prevalence of this condition is unknown. Many cases are treated as idiopathic pulmonary arterial hypertension (PAH). Estimates indicate, however, that 6% of patients clinically believed to have primary pulmonary hypertension may have evidence of PVOD at autopsy.[26] Depending on the cited series, the estimated prevalence of PVOD among patients clinically diagnosed with idiopathic PAH varies from 5-20%.[2]

An annual incidence of PVOD of 0.1-0.2 case per million persons in the general population has been suggested based on the incidence of primary pulmonary hypertension in the general population.[27, 28] Note, however, that such indirect estimates of a rare disease’s incidence may be imprecise.

Age-related demographics

The age at diagnosis ranges from eight weeks[29] to the seventh decade of life with most reported cases occurring in young adults. PVOD in siblings tends to have an early onset usually within the first three decades of life.

The prognosis in pulmonary veno-occlusive disease (PVOD) is grim. Most patients have a rapidly progressive course with most reported patients dying within two years of diagnosis without proper treatment.[30, 31] Currently available PAH therapies do not appear to have a profound effect on survival in patients with PVOD. (See Treatment and Medication.)

The presenting signs and symptoms of pulmonary veno-occlusive disease (PVOD) lack specificity. Most of the symptoms mimic other pulmonary and cardiac entities. The most common presenting symptoms are exertional dyspnea, fatigue, and cough. Sometimes, a respiratory tract infection–like illness may be identifiable preceding the diagnosis. Chronic cough (either productive or nonproductive) is present in some individuals.

In the later stages of PVOD, symptoms attributable to right ventricular failure, including chest pain and dizziness with exertion, abdominal pressure and tenderness secondary to hepatic congestion, and exertional syncope, may be noted. Hemoptysis with diffuse alveolar hemorrhage has been reported as a presentation.[32]

The suggestion of occult alveolar hemorrhage in bronchoalveolar lavage findings, however, is not uncommon.[33] Postural dyspnea or orthopnea may be reported by patients with PVOD but these findings are unusual among patients with primary pulmonary hypertension.

Physical examination findings may be normal in patients with early pulmonary veno-occlusive disease (PVOD) disease. As the disease progresses, findings attributable to pulmonary hypertension and right-sided heart failure supervene. These findings include jugular venous distention, a right ventricular heave, a loud pulmonic heart sound, pedal edema, and epigastric tenderness. Inspiratory crackles may be heard if pulmonary infiltrates are prominent.[34] Clubbing is an unusual feature,[35] but has been described. Sudden death has also been reported as a presenting feature of PVOD.[36]

PVOD, being a postcapillary process, leads to increased visceral pleural and pulmonary capillary pressures with transudation of fluid into the pleural space resulting in pleural effusions. Pleural effusions are very rare in patients with primary pulmonary hypertension.[37]

Pulmonary veno-occlusive disease (PVOD) should be suspected in patients who have been diagnosed with pulmonary arterial hypertension (PAH) but who have radiographic findings suggestive of left-sided heart failure. The diagnosis is based on clinical and radiographic findings. Surgical or transbronchial biopsy should not be performed secondary to the very high rate of complications, including death.

Most patients with PVOD present with progressive dyspnea upon exertion.[38] Often, right-sided heart failure is initially suspected (owing to edema, jugular venous distention, a loud P2 sound, and hypoxemia) or left-sided heart failure is considered (secondary to radiographic findings of bilateral pulmonary infiltrates and Kerley B lines).

When these patients are evaluated using echocardiography or right-sided heart catheterization, the diagnosis of pulmonary hypertension is confirmed but their wedge pressure (if the pulmonary artery catheter is properly wedged) is within normal limits. In summary, PVOD is currently recognized based on one of two sets of findings, as follows (see the Table below):

• The patient is diagnosed with pulmonary arterial hypertension (PAH) but a review of the chest radiograph and CT scan raises the suggestion of pulmonary edema.

• The patient is diagnosed with suspected pulmonary edema but echocardiography or right-sided heart catheterization reveals pulmonary hypertension.

Table. Distinguishing Pulmonary Edema From PVOD Based on Radiographic, Echocardiographic, and Heart Catheterization Data (Open Table in a new window)

Lab studies

Laboratory parameters are generally unremarkable and not helpful in the diagnostic workup, although microangiopathic hemolytic anemia, proteinuria, and elevations in serum immunoglobulin G and M concentrations have been reported. Note, however, that laboratory results are more abnormal in cases of PVOD associated with autoimmune disease. The level of brain natriuretic peptide is expected to be high in patients with overt right-sided heart failure.

Pulmonary function tests

The single-breath diffusing capacity for carbon monoxide (DLCO) is usually reduced in persons with PVOD. A restrictive ventilatory defect has also been reported in many cases. However, the decrease in DLCO is usually out of proportion to the degree of restrictive or obstructive abnormality.

An echocardiogram is an extremely useful initial noninvasive tool to assess right-sided pressures and to rule out left ventricular abnormalities and valvular heart disease.

The most common chest radiography finding in pulmonary veno-occlusive disease (PVOD) is the presence of interstitial infiltrates. Kerley B lines similar to those associated with pulmonary edema may be seen as a result of interstitial edema and enlargement of pulmonary lymphatic channels. Central pulmonary arteries may be enlarged, as in other causes of pulmonary hypertension, and scattered, patchy opacities may be present. Pleural effusion may be present and is mostly right sided. However, the absence of these radiographic abnormalities does not exclude the condition.[39]

CT scanning commonly reveals septal thickening and diffuse or patchy ground-glass opacities.[40] The presence of subpleural septal thickening (observed in 93% of cases) and diffuse, ill-defined, centrilobular ground-glass opacities (observed in 73% of cases) is highly suggestive of PVOD in patients with pulmonary hypertension. Other findings on CT scans include small nodules, dependent areas of consolidation, lymphadenopathy, and pleural effusions. The association of ill-defined nodules, septal thickening, and lymphadenopathy should raise the suggestion of a diagnosis of PVOD. (See the image below.)[41, 42]

Pulmonary veno-occlusive disease in a 43-year-old man. An axial computed tomography (CT) scan (lung window level) shows multiple septal lines (arrowhead) and a dilated central pulmonary artery (arrow). Image courtesy of Thoracic Imaging Section, Department of Radiologic Pathology, Armed Forces Institute of Pathology.

The ground-glass attenuation may result from alveolar septal thickening and epithelial hyperplasia. The central pulmonary veins and the left atrium are not enlarged, in contrast to patients with mitral stenosis, cor triatriatum, or left atrial myxoma.[43] Pericardial effusion may be present in patients with advanced right-sided heart failure. Enlarged pulmonary arteries resulting from pulmonary hypertension are almost universal.

This study may be helpful in ruling out chronic pulmonary thromboembolic disease, but it is rarely needed. A ventilation-perfusion scan is generally sufficient to clinically exclude significant or, more precisely, operable, chronic pulmonary thromboembolic disease.

A selective pulmonary artery angiogram in a patient with suspected pulmonary veno-occlusive disease (PVOD) offers very little additional clinically relevant information when ventilation-perfusion scan findings are normal or show a low probability for chronic pulmonary thromboembolic disease or in patients who are not suitable candidates for pulmonary thromboendarterectomy, even if they were diagnosed with chronic pulmonary thromboembolic disease.[44]

In patients with pulmonary veno-occlusive disease (PVOD), abnormal ventilation-perfusion scan findings are not unusual. The scan may reveal focal areas of hypoperfusion, which may lead to a misdiagnosis of chronic thromboembolic pulmonary hypertension. A high-probability ventilation-perfusion scan in a patient with pulmonary hypertension does not always indicate a proximal pulmonary arterial process.

The reported ventilation-perfusion scan findings have also included (1) diffuse, patchy distribution of tracer material without clear segmental or subsegmental defects and (2) a unilateral absence of perfusion due to severe, asymmetrical involvement. The type of defect may vary depending on the size and location of the involved veins.[45]

Interestingly, a clue to the diagnosis of pulmonary veno-occlusive disease (PVOD) is the inability to accurately measure the wedge pressure during cardiac catheterization. Multiple wedge pressure measurements or a distal wedge reading confirmed by a partial pressure of oxygen similar to arterial blood should be performed to determine the correct wedge pressure.

A correctly performed pulmonary capillary wedge pressure measurement generally reveals normal or decreased wedge pressure, despite the fact that the pulmonary capillary pressures (in the absence of a static blood column) are elevated. Occasionally, an elevated wedge pressure may be obtained, depending on the degree of venous occlusion and collaterals. This may occur because of the patency of the larger pulmonary veins.[27]

In PVOD, the use of a short-acting pulmonary arterial vasodilator, such as inhaled nitric oxide or intravenous epoprostenol or adenosine, during acute vasoreactivity testing may precipitate acute pulmonary edema. The edema results from increased transcapillary hydrostatic pressures in the setting of acute arterial vasodilation and preexisting venous occlusion. The development of pulmonary edema in response to a pulmonary vasodilator, therefore, is strongly suggestive of the diagnosis of PVOD.[46] This complication in association with the poor response of PVOD patients to PAH-specific therapy argues against vasodilator testing in patients in whom PVOD is strongly suspected.

The development of acute fulminant pulmonary edema, and even death, has been reported with infusion of even a very low dose of intravenous epoprostenol. Hence, great caution should be used in patients with suspected PVOD while administering intravenous epoprostenol.[47]

Bronchoscopy does not have a major role in the management of PVOD but it may be performed to rule out other lung diseases in cases of an atypical presentation. Hyperemia of the small airway mucosa with vascular engorgement in the form of bright red, longitudinal streaks has been reported. The trachea and main bronchi may be spared because the venous drainage of the central airways is into bronchial veins, which are not involved. Bronchoalveolar lavage may suggest chronic alveolar hemorrhage.

Transbronchial lung biopsy is contraindicated because of the presence of pulmonary hypertension and the risk of excessive bleeding.

Surgical lung biopsy in the presence of moderate or severe pulmonary arterial hypertension (PAH) is associated with a significant risk of morbidity and mortality. Although this is a somewhat controversial issue, a surgical lung biopsy in patients with suspected pulmonary veno-occlusive disease (PVOD) also carries a serious risk of morbidity and mortality, particularly in the setting of high pulmonary vascular pressure.[48] Moreover, the results of the biopsy rarely affect PVOD treatment.

Some experts who favor biopsy argue that it provides prognostic information that facilitates decision making with regard to the timing of lung transplantation listing. In the authors’ opinion, however, the risk of surgical lung biopsy outweighs the value and usefulness of the information obtained. Alternative means of assessment, such as CT scan findings and observation of the patient (to determine whether there has been a lack of improvement or continued clinical worsening despite specific PAH therapies), may be used to make decisions about the listing for and timing of lung transplantation.

Specific PAH therapies may be associated with a risk of pulmonary edema at any time during the therapy. Extreme caution should be used while administering intravenous or subcutaneous prostanoids and dose escalation should be relatively slow.

No well-structured, prospective clinical trials have been performed to evaluate the effect of various nonsurgical interventions on the outcome of pulmonary veno-occlusive disease (PVOD). Currently, the information gained from clinical trials involving other forms of pulmonary arterial hypertension (PAH) is extrapolated from clinical experience, case reports, and case series in order to choose various therapies. Patients with PVOD are best served at a pulmonary hypertension specialty center.

No general consensus has been reached on the choice of first-line therapy for persons with PVOD. However, because PAH therapies (eg, continuous intravenous prostacyclin) are poorly tolerated and are perceived to have only a marginal effect on outcome, patients are offered the option of lung transplantation whenever possible. In the absence of this surgery, most patients do not survive beyond 2-3 years after diagnosis.

Lung transplantation

Currently, lung transplantation is the only therapeutic option capable of significantly prolonging and improving the lives of patients with PVOD.[49] Single- and double-lung transplantation procedures have both been used. Recurrence after heart-lung transplantation was reported in one patient.[50]

The use of specific pulmonary arterial hypertension (PAH) therapies—eg, prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase-5 inhibitors—in patients with pulmonary veno-occlusive disease (PVOD) is controversial.

Initial reports described the development of acute fulminant pulmonary edema and death[51] in association with infusions of intravenous epoprostenol. A 2008 report comparing PVOD patients with or without PCH to idiopathic patients reported pulmonary edema in 7 of 16 PVOD patients with vasodilator therapy.[52] However, in patients who do not have the option of lung transplantation, PVOD results in death within a few months to years after diagnosis. Consequently, continuous intravenous epoprostenol has been tried in PVOD patients, very cautiously and with relatively slow-dose up-titration. This treatment was met with some success.[47]

Epoprostenol has been reported to have some beneficial effects on hemodynamics in patients with pulmonary veno-occlusive disease (PVOD) and it has been demonstrated to reverse the increased vasomotor tone in pulmonary venules.[53] However, no structured clinical trials are available to support the use of any specific PAH therapies in PVOD patients.

Presently, treatment must be individualized to the patient after discussing the risks and benefits from the sparse data available. Pulmonary edema may occur, acutely or months after initiation of therapy, with the use of vasodilators.[39]

In the absence of an obvious or potential contraindication, the American College of Chest Physicians recommends anticoagulation in patients with PAH.[54] It is not unreasonable to consider anticoagulation with warfarin (Coumadin) in PVOD patients if they have no contraindications (eg, history of significant hemoptysis). The target international normalized ratio (INR) is 1.5-2.5.

Long-term oxygen supplementation therapy should be used for hypoxemic patients with PVOD to keep their oxyhemoglobin saturation at greater than 90% at all times. This may result in symptomatic and subjective improvement. No direct good-quality evidence exists for speculation about the magnitude of benefit in terms of survival or exercise capacity in patients with PVOD.

Other therapies have been reported to have some role in pulmonary veno-occlusive disease (PVOD) management. However, their use is not widespread.

The role of immunosuppressive medications in the treatment of PVOD remains undefined but these agents may help a subset of patients with PVOD, particularly those with autoimmune features.[31]

A trial of corticosteroids may be considered following a chest radiograph and oxygen therapy. Although it does not change the course of the disease, corticosteroid treatment may provide symptomatic improvement.[55]

Most experimental interventions involve antithrombotic treatment with agents such as heparin, thrombolytic agents such as recombinant tissue plasminogen activator, antithrombin III concentrate in patients with a documented antithrombin III deficienc. Another drug, defibrotide, which is a polydeoxyribonucleotide derived from mammalian cells, is now approved in the United States for hepatic VOD in adults and children with renal or pulmonary dysfunction following HSCT. Currently, none of these therapies has any role in the treatment of patients with PVOD.

As previously stated, the prostaglandin epoprostenol, a vasodilator, has been reported to have some hemodynamic benefits in patients with pulmonary veno-occlusive disease (PVOD) and has been shown to reverse the increase in pulmonary venule vasomotor tone that occurs in this condition.[53] Nonetheless, the development of acute fulminant pulmonary edema and death have been reported with the infusion of intravenous epoprostenol, even at a very low dose. Therefore, this drug should be used with great caution in patients with suspected PVOD.

Class Summary

These agents have vasodilatory effects.

Epoprostenol (Flolan, Veletri)

Epoprostenol, an analogue of prostacyclin (PGI2), has potent vasodilatory properties, an immediate onset of action, and a half-life of approximately 5 minutes. In addition to its action as a vasodilator, epoprostenol also contributes to the inhibition of platelet aggregation and plays a role in the inhibition of smooth muscle proliferation.[46]

Long-term infusion of this drug improves the outcome in patients with primary pulmonary hypertension and in selected patients with secondary pulmonary hypertension. A short-term vasodilatory response appears to be unrelated because favorable impact on disease progression occurs with long-term therapy.

The dose is determined during a dose/effect study performed in the catheterization laboratory or the intensive care unit (ICU). The selected dose should produce maximum vasodilation with minimal systemic hypotension.

Class Summary

These agents prevent thromboembolic disorders.

Warfarin (Coumadin)

Warfarin interferes with the hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.

Tailor the dose to maintain an INR in the range of 2-3. The recurrence rate of deep venous thrombosis (DVT) and pulmonary embolism increases dramatically when the INR drops to below 2 and decreases when the INR is kept at 2-3. Serious bleeding risk (including hemorrhagic stroke) is approximately constant when the INR is 2.5-4.5 but rises dramatically when INR is over 5.

Procoagulant vitamin K–dependent proteins are responsible for a transient hypercoagulable state when warfarin is first started and when it is stopped. This phenomenon occasionally causes warfarin-induced necrosis of large areas of skin or of distal appendages. Heparin is always used to protect against this hypercoagulability when warfarin is started; however, when warfarin is stopped, the problem resurfaces, causing an abrupt, temporary rise in the rate of recurrent venous thromboembolism.

At least 186 different foods and drugs have been reported to interact with warfarin. Clinically significant interactions have been verified for a total of 26 common drugs and foods, including 6 antibiotics and 5 cardiac drugs. Every effort should be made to keep the patient adequately anticoagulated at all times because procoagulant factors recover first when warfarin therapy is inadequate.

Patients who have difficulty maintaining adequate anticoagulation while taking warfarin may be asked to limit their intake of foods that contain vitamin K. Foods that have moderate to high amounts of this vitamin include Brussels sprouts, kale, green tea, asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, liver, certain beans, soybean oil, soybeans, mustard greens, peas (black-eyed peas, split peas, chick peas), turnip greens, parsley, green onions, spinach, and lettuce.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone

Prednisone is an immunosuppressant used for autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. It has some role in the treatment of pulmonary veno-occlusive disease (PVOD), particularly when autoimmune features coexist with it.

Class Summary

These agents have immunosuppressive properties.

Azathioprine (Imuran, Azasan)

Azathioprine is an imidazolyl derivative of 6-mercaptopurine, and many of its biologic effects are similar to those of its parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and the liver. No azathioprine or mercaptopurine is detectable in urine 8 hours after administration.

Azathioprine antagonizes purine metabolism and inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. The mechanism through which azathioprine affects autoimmune diseases is unknown. The drug works primarily on T cells. It suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity test results are suppressed to a greater degree than are antibody responses.

Azathioprine works very slowly; it may require 3-6 months of trial prior to effect. Up to 10% of patients may have an idiosyncratic reaction to the drug, disallowing use. The white blood cell (WBC) count must not be allowed to drop below 3000/µL or the lymphocyte count be allowed to drop below 1000/µL. Azathioprine is available in tablet form for oral administration or in 100mg vials for intravenous injection.