Diagnosis: Pulmonary veno-occlusive disease
Comment: Although it is possible that the veno-occlusive disease is familial in this case, the type of pulmonary hypertension was not established in either the brother or the sister. The peribronchial thickening noted on the CT had another cause.
Pulmonary Veno-occlusive Disease (PVOD)
Introduction: Pulmonary hypertension has many causes, which are classified below (table). Although clinical features are similar for many of these, separation is important because treatment is quite specific; for example, tumor emboli may respond to chemotherapy, plexogenic pulmonary angiopathy responds to prostacyclin whereas veno-occlusive disease may not, embolectomy may reverse thromboembolic disease.
Table: Classification of Pulmonary Hypertension
Clinical features of PVOD: Patients present with dyspnea--sometimes paroxysmal, syncope, hypoxia, chest pain, signs of right heart failure, or occasionally hemoptysis . Often a prodrome of upper respiratory tract infection with fever, cough, and myalgias is elicited. When heart failure is severe, liver function tests may be abnormal. The sedimentation rate may be increased. DLCO may be reduced, sometimes markedly so . Most patients die within 2 years of onset of symptoms, but survival up to 7 years has been recorded . Sudden, unexpected death has been described , as has death 6 weeks after onset of symptoms . One patient died of acute pulmonary hemorrhage . In one study, patients with PVOD had a course similar to that of those with plexogenic arteriopathy. The median survival for 7 patients with VOD was 84 da .
Incidence and demographics: In a series of patients with primary pulmonary hypertension, 7/58 (12%) were found to have veno-occlusive disease . Patients range in age from 11 days to 67 years old. One third to one half of cases occur in children under age 16: both sexes are equally affected. In adults, men are affected more than women (2:1) .
Causes or associations: The condition may be idiopathic (cryptogenic) or have known causes or associations, which provoke a common reaction pattern. These are listed below.
* In a study of 39 deaths following bone marrow transplantation, 17 (44%) had PVOD that occurred in association with interstitial pneumonia, hepatic veno-occlusive disease, or both. The incidence of PVOD was low--2/14 (14%)--in patients with neither interstitial pneumonia nor hepatic VOD. Chemotherapy was incriminated, especially busulfan or cytoxan .
Radiographic changes: The diagnosis is not usually made on plain radiographs. Right ventricular hypertrophy and prominent pulmonary arteries that are pruned peripherally resemble the changes of plexogenic pulmonary angiopathy. Increased interstitial markings and Kerley B lines, which might suggest the diagnosis, may be interpreted as changes of heart failure. Pleural effusion may be present or absent.
HRCT, which is more helpful in suggesting the diagnosis, shows bilateral diffuse prominence of smooth septal lines as well as focal, centrilobular, ground-glass or nodular alveolar opacities. In one case, after a single lung transplant with diversion of 80% of blood flow to the donor lung, the CT scan of the native lung reverted to normal, indicating that the opacities were due to congestion and edema and not fibrosis . Results of a study of 10 patients with veno-occlusive disease are summarized below.
Summary of CT Changes in PVOD--10 patients [30,31]
Diagnosis: The combination of pulmonary hypertension and pulmonary edema with a normal pulmonary capillary wedge pressure in a patient without cardiac or mediastinal disease suggests the diagnosis. Attention of the details listed above on the CT scan and exclusion of other causes of pulmonary hypertension help to confirm the diagnosis. Open lung biopsy is necessary for definite diagnosis. Bronchoscopy may show "the entire bronchial tree to be swimming in a pool of blood"  or longitudinal red streaks in lobar and segmental bronchi . These findings reflect pulmonary venous obstruction and resulting diversion of blood to the bronchial veins. Although the diagnosis is usually made at autopsy, some patients are diagnosed during life .
Histologic changes: The principal feature is stenosis or occlusion of venules or veins by intimal fibrous tissue. Initially loose, the connective tissue eventually becomes dense and collagenized. However, intimal fibrosis also occurs as a part of aging in patients without pulmonary hypertension, as well as in cardiac or mediastinal causes of venous obstruction (see below). The origin of the fibrous tissue, whether an intimal proliferation or an organization of thrombus, is unclear. Thrombi occur , but whether they occur secondary to low flow in an obstructed vascular bed or represent the primary lesion is unknown, although fibrous septa crossing lumens favor recanalized thrombi. In PVOD, vein walls thicken and develop inner and outer elastic layers making them resemble arteries (arterialization). This finding suggests a primary vascular wall disease, as primary thrombosis would not be expected to cause thickening of the vessel wall. Lymphocytes have been described in and around affected vessels .
In about 50% of cases, arterial intimal fibrosis, luminal narrowing, and thrombosis occur to a degree similar to that in veins, suggesting that the arterial lesions are a part of the disease and not just secondary to venous narrowing .
Capillary changes are also important. In a study of a patient with drug-induced PVOD (mitomycin and 5-fluorouracil), casting of the lungs postmortem showed proliferation of large new capillaries adjacent to the original distorted small ones, suggesting that capillaries are also involved in the vascular narrowing . This capillary proliferation corresponds to the nodular collections of enlarged capillaries found in the present case.
Secondary changes include atherosclerosis in the pulmonary artery and small infarcts from arterial narrowing. Bleeding from congested vessels produces hemosiderosis. Collateral drainage via the bronchial veins, which empty into the proximal pulmonary vein, may produce bronchial mucosal hyperemia and hemorrhage. Finally, non-specific interstitial inflammation may accompany narrowed veins.
Non-specific changes found in any type of venous obstruction in the heart, mediastinum, or pulmonary veins may mimic the changes of VOD and include chronic interstitial congestion, edema, lymphatic dilation, progressive fibrosis of interlobular septa (Kerley B lines) and adjacent alveolar walls, intimal fibrosis of veins, and increased hemosiderin-filled alveolar macrophages. The result is so-called "brown induration" of the lung.
Summary of Primary Histologic Changes with Links to Radiographic Correlation
Summary of Secondary Histologic Changes with Links to Radiographic Correlation
Differential diagnosis, histologic
Therapy: Vasodilators [37-39], steroids , and other immunosuppressive therapies  have been tried with some success, but there are no controlled trials, and prolonged survival in some patients without therapy makes the interpretation of reported successes uncertain. Several acute deaths from pulmonary edema following prostacyclin infusion have been reported [30,40]. Anticoagulants are used as for patients with plexogenic arteriopathy.
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Table of Contents
Last revised 10/16/99
Copyright 1999 by Martha L. Warnock. All rights reserved.