What is Pulmonary Veno-Occlusive Disease (PVOD)?

Pulmonary Veno-Occlusive Disease (PVOD)

Pulmonary veno-occlusive disease (PVOD) is a rare and severe form of pulmonary hypertension characterized by progressive obstruction of small pulmonary veins and venules, leading to increased pulmonary vascular resistance, right heart failure, and premature death if left untreated. 1

Pathophysiology and Classification

PVOD is classified as a subgroup of pulmonary arterial hypertension (PAH) due to its pathological, clinical, and therapeutic differences from other forms of PAH. The disease involves:

• Progressive fibrous intimal proliferation primarily affecting pulmonary venules and small veins
• Obstruction of small pulmonary veins leading to increased pulmonary vascular resistance
• Development of chronic interstitial pulmonary edema
• Right ventricular failure as the disease progresses

PVOD may occur in idiopathic, heritable, or associated forms. Heritable forms have been linked to mutations in the bone morphogenetic protein receptor-2 (BMPR2) and EIF2AK4 genes. 1, 2

Clinical Presentation

Patients with PVOD typically present with:

• Dyspnea on exertion and fatigue (similar to idiopathic PAH)
• Digital clubbing (unusual in other forms of PAH)
• Bi-basal crackles on lung auscultation (unusual in other forms of PAH)
• Severe hypoxemia at rest
• Significantly reduced diffusion capacity for carbon monoxide (DLCO)
• Male predominance (unlike idiopathic PAH which has female predominance)
• History of tobacco exposure is common
• Lower body mass index compared to PAH patients 1, 3

Diagnostic Approach

The definitive diagnosis requires lung biopsy, but this is hazardous in patients with severe pulmonary hypertension. Therefore, diagnosis is typically established through a combination of:

Imaging

• High-resolution CT scan (investigation of choice) showing:
  • Subpleural thickened septal lines
  • Centrilobular ground-glass opacities (contrasting with panlobular distribution in IPAH)
  • Mediastinal lymphadenopathy
  • The presence of all three findings is 100% specific for PVOD in cases of PAH, with 66% sensitivity 1

Pulmonary Function Tests

• Severely reduced diffusion capacity (DLCO)
• Normal spirometry values (FEV1, FVC, TLC)

Arterial Blood Gas Analysis

• Severe hypoxemia at rest
• Lower PaO2 compared to other PAH forms

Bronchoscopy with Bronchoalveolar Lavage

• Elevated cell count
• Higher percentage of hemosiderin-laden macrophages
• Markedly elevated Golde score
• Can detect occult alveolar hemorrhage associated with PVOD 1

Hemodynamic Assessment

• Right heart catheterization shows:
  • Pre-capillary pulmonary hypertension
  • Normal pulmonary wedge pressure (PWP)
  • Normal left heart filling pressures
  • Vasoreactivity testing may precipitate acute pulmonary edema 1

Treatment Challenges

Patients with PVOD should be referred to a transplant center for evaluation as soon as the diagnosis is established, as lung transplantation is the only curative therapy. 1

Treatment considerations include:

• No established medical therapy exists specifically for PVOD
• PAH-specific vasodilators (especially prostanoids) must be used with extreme caution due to high risk of life-threatening pulmonary edema
• Approximately 43.8% of PVOD patients develop pulmonary edema when treated with PAH-specific therapies 3
• Supportive care includes:
  • Oxygen therapy
  • Diuretics
  • Cautious management of fluid balance

Management Recommendations

1. PVOD patients should only be managed at centers with extensive experience in pulmonary hypertension 1
2. If PAH-specific therapy is attempted:
   • Start at very low doses
   • Increase doses gradually
   • Monitor closely for development of pulmonary edema
   • Be prepared to discontinue therapy if pulmonary edema develops
3. Atrial septostomy may be considered but is usually limited by hypoxemia 1
4. For acute pulmonary edema management:
   • Position patient upright
   • Administer supplemental oxygen
   • Consider positive pressure ventilation
   • Use diuretics cautiously
   • Avoid excessive vasodilation 4

Prognosis

PVOD has a worse prognosis compared to other forms of PAH:

• Without therapeutic intervention, few patients survive more than two years
• Clinical outcomes are worse than those of PAH patients
• No reports of disease recurrence following lung transplantation 1, 5

Important Caveats

• Lung biopsy, while diagnostic, carries significant risk and is generally not recommended
• Misdiagnosis is common as PVOD can mimic idiopathic PAH or PH due to interstitial lung disease
• Inappropriate use of vasodilators can precipitate severe pulmonary edema
• Early recognition and referral for lung transplantation evaluation are crucial for survival 2, 6