Pulmonary Veno-Occlusive Disease (VOD)

Epidemiology

Relationship of Pulmonary Veno-Occlusive Disease to Other Similar Diseases

Pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis (see Pulmonary Capillary Hemangiomatosis, [[Pulmonary Capillary Hemangiomatosis]]), and idiopathic pulmonary arterial hypertension (IPAH) (see Idiopathic Pulmonary Arterial Hypertension, [[Idiopathic Pulmonary Arterial Hypertension]]) may all represent various points on a single spectrum of disease

Prevalence

Pulmonary veno-occlusive accounts for <10% of patients with unexplained pulmonary hypertension
About 6% of patients previously thought to have idiopathic pulmonary arterial hypertension actually have pulmonary veno-occlusive disease at autopsy

Age

Most cases occur in children and young adults (although can occur at any age)

Sex

Slight male preponderance in adult cases

Risk Factors

Pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, and idiopathic pulmonary arterial hypertension share similar risk factors
- Scleroderma (see Scleroderma, [[Scleroderma]])
- Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
- Use of Anorexigens

Etiology

Idiopathic Pulmonary Veno-Occlusive Disease

Accounts for most cases

Familial Pulmonary Veno-Occlusive Disease

Familial clustering of pulmonary VOD cases has been reported, similar to [[Pulmonary Capillary Hemangiomatosis]] and [[Idiopathic Pulmonary Arterial Hypertension]]
Mutations in BMPR2 have been reported in pulmonary VOD, similar to [[Familial Pulmonary Hypertension]] and [[Idiopathic Pulmonary Arterial Hypertension]]

Chemotherapy

Bleomycin (see Bleomycin, [[Bleomycin]])
Carmustine (see Carmustine, [[Carmustine]])
Cyclophosphamide (Cytoxan) (see Cyclophosphamide, [[Cyclophosphamide]])
Etoposide (see Etoposide, [[Etoposide]])
Gemcitabine (Gemzar) (see Gemcitabine, [[Gemcitabine]])
Mitomycin (see Mitomycin, [[Mitomycin]])

Other Drugs

Fenfluramine (see Fenfluramine, [[Fenfluramine]]): case reports

Connective Tissue Disease

Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis, [[Rheumatoid Arthritis]])
Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus, [[Systemic Lupus Erythematosus]])

Other

Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
Toxic Exposure
Bone Marrow Transplant/Stemm Cell Transplant (see Bone Marrow Transplant, [[Bone Marrow Transplant]])
Sarcoidosis (see Sarcoidosis, [[Sarcoidosis]]): case reports
Thoracic Radiation (see Radiation Pneumonitis and Fibrosis, [[Radiation Pneumonitis and Fibrosis]])

Physiology

Fibrous Obliteration of Small Pulmonary Veins and Venules (Post-Pulmonary Capillary Involvement): results in pulmonary venous hypertension

Pathology

Pathologic studies of pulmonary VOD and [[Pulmonary Capillary Hemangiomatosis]] are similar (suggesting overlap between these conditions): pulmonary hemosiderosis, interstitial edema, and lymphatic dilation, pulmonary arterial intimal fibrosis, and medial hypertrophy
- Intimal fibrosis and medial hypertrophy are similarly seen in [[Idiopathic Pulmonary Arterial Hypertension]]
Clinicopathologic study of 38 cases (15 autopsies, 15 surgical biopsies, 7 explants, and 1 pneumonectomy obtained from 35 patients) diagnosed as having either pulmonary VOD (n = 30) or [[Pulmonary Capillary Hemangiomatosis]] (n = 5) -> demonstrated signficant pathologic overlap between the diseases
- [[Pulmonary Capillary Hemangiomatosis]] was identified in 24 (73%) patients diagnosed as having pulmonary VOD, either as perivenular foci or diffuse involvement of the pulmonary parenchyma
- In 5 patients diagnosed with [[Pulmonary Capillary Hemangiomatosis]], 4 showed the venous and arterial changes characteristic of pulmonary VOD
  [Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol 2006;30:850-7]

Diagnosis

Arterial Blood Gas (ABG)

Hypocapnia (see Hypocapnia, [[Hypocapnia]])
Increased A-a Gradient Hypoxemia (see Hypoxemia, [[Hypoxemia]]): due to decreased cardiac ouptut, V/Q mismatch, and intrapulmonary shunt
- May be due to opened patent foramen ovale with intracardiac shunt

Pulmonary Function Tests (PFT’s)

Spirometry/Lung Volumes: normal (although mild restriction is occasionally seen)
DLCO: decreased (due to vascular and interstitial disease)
- However, DLCO may be increased during active diffuse alveolar hemorrhage

Exercise Test

Exercise Desaturation
VD/VT Ratio: normal-increased

Lung Biopsy

Controversial if this is necessary (but is usually diagnostic)
Fibrous intimal proliferation of small pulmonary veins and venules, acute or recanalized thrombi, hemosiderosis
EM: electron-dense deposits reported in one case

CXR Pattern

Enlarged PA’s with Typically Clear Lung Fields: occasionally mild interstitial infiltrates
Cardiomegaly
Kerley B Lines in Absence of Other Signs of Left-Sided Heart Failure: this is often the most useful diagnostic radiographic feature
Diffuse, Patchy Focal Alveolar Infiltrates: seen in cases with DAH (interstitial infiltrates appear with chronic or recurrent DAH)

Chest CT Pattern

Ground Glass Infiltrates
Interlobular Septal Thickening
Pleural Effusions
Enlarged Pulmonary Arteries

Ventilation/Perfusion (V/Q) Scan

Patchy Defects

Pulmonary Angiogram

Normal

Erythrocyte Sedimentation Rate (ESR)

May be elevated

Serology

Autoantibodies may sometimes be seen

CBC

Anemia (see Anemia, [[Anemia]]): iron deficiency with frequent DAH

EKG

Right Axis Deviation with Right Ventricular Hypertrophy: R in V1 >5, etc
Right Atrial Enlargement

Echo

RVE with Decreased LV Cavity Size
Abnormal Septum
Dependence on atrial systole for RV filling
Doppler: quantifies TR estimates right-sided pressures
Bubble Study: excludes intracardiac shunt (VSD/ ASD/ etc.): PFO is present in 20% of cases

Swan-Ganz (Pulmonary Artery) Catheterization

RA, RV-Sys, PA-Sys, PA-Dia: elevated
PA-Mean: elevated (may be severe)
PA-/SaO2: lack of “step-up” excludes intracardiac shunt
PCWP: usually normal, but may be elevated depending on site of venous involvement and depending on where catheter wedges in the lung (PCWP may be different at different site within the same patient)
- Normal (most cases): in cases where venules are involved site
- Elevated (some cases): in cases where large veins are involved site
CO: normal-decreased at rest (does not rise appropriately with exercise)
SVR: normal
PVR: elevated

Cardiac Catheterization

Useful to exclude intracardiac shunt
PFO may occur due to pulmonary HTN, but left-to-right shunt suggests congenital defect

Pleural Fluid

Transudative

Clinical Manifestations

General Comments

The clinical presentations of pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis (see Pulmonary Capillary Hemangiomatosis, [[Pulmonary Capillary Hemangiomatosis]]), and idiopathic pulmonary arterial hypertension (see Idiopathic Pulmonary Arterial Hypertension, [[Idiopathic Pulmonary Arterial Hypertension]]) are often indistinguishable, prior to autopsy
- However, in contrast to idiopathic pulmonary arterial hypertension, patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis have crackles and clubbing on examination, ground glass opacities, septal thickening, mediastinal adenopathy on chest CT, hemosiderin-laden macrophages on bronchoalveolar lavage, lower DLCO, and more severe hypoxemia

Cardiovascular Manifestations

Pulmonary Hypertension/Cor Pulmonale (see Pulmonary Hypertension, [[Pulmonary Hypertension]]) and Congestive Heart Failure, [[Congestive Heart Failure]])
- Symptoms/Signs of Cor Pulmonale
  - Dyspnea
  - Peripheral Edema
  - Syncope
- Symptoms/Signs of Pulmonary Venous Hypertension
  - Orthopnea
  - Paroxysmal Nocturnal Dyspnea
- Symptoms/Signs of Pulmonary Hypertension
  - Accentuated P2
  - RV heave

Pulmonary Manifestations

Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]]): due to pulmonary venous hypertension
- Cough
- Dyspnea
- Chest Pain
- Hemoptysis: may be initially absent, even after significant bleed
  - Usually, hemoptysis with pulmonary hypertension suggests a post-capillary lesion
- Pulmonary Infiltrates
- Absence of Renal or Other Systemic Involvement
Mediastinal Lymphadenopathy (see Mediastinal Mass, [[Mediastinal Mass]])
Transudative Pleural Effusion (see Pleural Effusion-Transudate, [[Pleural Effusion-Transudate]])

Rheumatologic Manifestations

Clubbing (see Clubbing, [[Clubbing]])
Raynaud’s Phenomenon (see Raynaud’s Phenomenon, [[Raynauds Phenomenon]]): occasionally present
Arthritis (see Arthritis, [[Arthritis]]): occasionally present

Treatment

Pulmonary Vasodilators

In histologically-proven pulmonary VOD (with or without [[Pulmonary Capillary Hemangiomatosis]])
- In response to pulmonary vasodilator therapy (mainly continuous intravenous epoprostenol, but also with bosentan and calcium channel blockers), 43.8% of the pulmonary VOD patients developed pulmonary edema
- Clinical outcome was worse with pulmonary VOD, as compared to cases with IPAH/anorexigens/familial pulmonary HTN
Vasodilators: may be useful in some cases
- Prostacyclin: may precipitate pulmonary edema (due to decrease in upstream PVR and increased CO: increased pulmonary blood volume with downstream vascular obstruction)

Lung Transplantation (see Lung Transplant, [[Lung Transplant]])

Corticosteroids (see Corticosteroids, [[Corticosteroids]])

May be effective in some bone marrow transplant-associated cases

Anticoagulation

Useful in some cases of pulmonary VOD (however, should be avoided in cases with diffuse alveolar hemorrhage)

Azathioprine (Imuran) (see Azathioprine, [[Azathioprine]])

Effective in some cases

Prognosis

Expected Survival: approximately 24 months
- May possibly be prolonged with vasodilator therapy)

References

Pulmonary veno-occlusive disease: another vascular disorder associated with human immunodeficiency virus infection? Arch Pathol Lab Med 1994;118:664-6
Pulmonary veno-occlusive disease in a HIV-infected intravenous drug abuser. Eur Respir J 1995;8:1982-4
High-resolution CT of the chest in four patients with pulmonary capillary hemangiomatosis or pulmonary venoocclusive disease. AJR Am J Roentgenol 1998;171:1321–4
Pulmonary veno-occlusive disease: a case series and new observations. Chest 2000;118:1671–9
Pulmonary veno-occlusive disease caused by an inherited mutation in bone morphogenetic protein receptor II. Am J Respir Crit Care Med 2003;167: 889-94
Pulmonary hypertension: CT of the chest in pulmonary venoocclusive disease. AJR Am J Roent- genol 2004;183:65–70
Pulmonary veno-occlusive disease and pulmonary capillary hemangi- omatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol 2006;30:850-7
Occult alveolar haemorrhage in pulmonary veno-occlusive disease. Eur Respir J 2006;27:108–13
Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol 2007;38:893–902
Pulmonary veno- occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore) 2008;87:220-33
Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction. Bone Marrow Transplant. 41(8), 677-686 (2008)
Pulmonary veno-occlusive disease. Eur Respir J 2009;33:189–200 [MEDLINE]