Pulmonary Veno-Occlusive Disease


Background

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). [123PAH remains an incurable disease that results in significant morbidity and mortality. (See EpidemiologyTreatment, 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, [4leading to clinical manifestations that are, in many ways, similar to PAH. (See PathophysiologyEtiologyPresentation, 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. [5Historically, the disease has been underdiagnosed, possibly because of lack of awareness by clinicians.

Pathophysiology

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. [6In 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. [7The 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 magnificatiMedium-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.

Etiology

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. [1011]

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. [121314]

Infectious

Various infections have been reported to be associated with PVOD. These include infections with viruses such as cytomegalovirusEpstein-Barr virus, and measles virus. [15One 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. [1718These 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. [2021Other 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. [22PVOD seems to occur more commonly in bone marrow transplant recipients than in the general population. [2324]

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. [25However, 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.

Epidemiology

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. [26Depending 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. [2728Note, 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 [29to 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.

Prognosis

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. [3031Currently available PAH therapies do not appear to have a profound effect on survival in patients with PVOD. (See Treatment and Medication.)

CLINICAL PRESENTATION


History

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. [33Postural dyspnea or orthopnea may be reported by patients with PVOD but these findings are unusual among patients with primary pulmonary hypertension.

Physical Examination

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. [34Clubbing is an unusual feature, [35but 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

DDx

SECTIONS

Diagnostic Considerations

In a patient with significant pulmonary hypertension, the possibility of chronic pulmonary thromboembolic disease must be considered because it is one of the common and treatable causes of pulmonary hypertension. More common causes of pulmonary venous hypertension (eg, systolic or diastolic left-sided heart failure) and valvular heart disease (eg, mitral stenosis) should be considered as a part of the differential diagnosis before a diagnosis of pulmonary veno-occlusive disease (PVOD) is established.

Vascular remodeling similar to PVOD occurs in both pulmonary veins and arteries in conditions such as mitral stenosis and fibrosing mediastinitis. However, the structural changes in the veins are more prominent in PVOD than in these other two conditions and may therefore provide a morphologic approach to differentiation of these diseases. [25]

In some cases of PVOD, advanced parenchymal lung diseases (eg, sarcoidosis, interstitial lung disease, pneumoconioses) may be considered as diagnostic possibilities because of prominent interstitial changes seen on chest radiographs. However, the distinction between most forms of advanced interstitial lung disease from PVOD is relatively straightforward for most experts upon review of chest CT scans. Pulmonary capillary hemangiomatosis should also be considered in the differential diagnosis of PVOD.

Differential Diagnoses


TREATMENT & MANAGEMENT
ECTIONS

Approach Considerations

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. [49Single- and double-lung transplantation procedures have both been used. Recurrence after heart-lung transplantation was reported in one patient. [50]

Specific PAH Therapies

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 [51in 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. [52However, 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. [53However, 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. [54It 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.

Immunosuppressants, Steroids, and Antithrombotic Agents

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

MEDICATION


Medication Summary

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. [53Nonetheless, 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.

Vasodilators

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.

Anticoagulants

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.

Corticosteroids

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.

Immunosuppressants

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

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