What is the pathophysiology of pulmonary veno-occlusive disease (PVOD) in adults with a history of autoimmune diseases?

Pathophysiology of Pulmonary Veno-Occlusive Disease

Pulmonary veno-occlusive disease (PVOD) is characterized by widespread fibrous intimal proliferation and obstruction that occurs predominantly in pulmonary venules and small veins, leading to progressive increases in pulmonary vascular resistance, right ventricular failure, and premature death. 1, 2

Primary Vascular Pathology

The hallmark pathological feature is extensive occlusion of small pulmonary veins and venules with intimal and adventitial fibrosis. 2 This venous obstruction distinguishes PVOD from idiopathic pulmonary arterial hypertension (IPAH), where the primary pathology involves pulmonary arteries with plexiform lesions. 1, 2

• The disease involves microvascular remodeling with typical fibrous veno-occlusive lesions affecting postcapillary venules. 1, 3
• Large amounts of hemosiderin accumulate in alveolar macrophages and type II pneumocytes due to occult alveolar hemorrhage. 2
• Capillary vessels become engorged and prominent as part of the pathological process. 2

Secondary Arterial Changes

While the primary pathology targets veins, secondary changes occur in pulmonary arterioles:

• Pulmonary arterioles develop medial hypertrophy and intimal fibrosis as a consequence of elevated downstream venous pressures. 2
• Critically, plexiform lesions and fibrinoid arteritis are NOT present in PVOD, which distinguishes it from other forms of PAH. 2

Hemodynamic Consequences

Pulmonary artery wedge pressure (PAWP) remains almost invariably normal despite severe pulmonary hypertension because the pathological changes occur in small venulae that do not affect the larger pulmonary veins measured during catheterization. 1, 2

• This creates a paradoxical situation where patients have radiological and clinical evidence of pulmonary edema but normal left heart filling pressures. 1, 4
• Progressive obstruction of venous drainage leads to increased pulmonary vascular resistance and elevated pulmonary artery pressures. 3, 5
• The elevated resistance ultimately causes right ventricular hypertrophy and failure. 6

Pathophysiological Mechanisms Leading to Clinical Features

Chronic Interstitial Pulmonary Edema

The venous obstruction causes:

• Chronic interstitial pulmonary edema that explains the severe hypoxemia characteristic of PVOD (more severe than other PAH forms). 1
• Markedly reduced diffusion capacity for carbon monoxide (DLCO) due to thickened alveolar-capillary membranes from chronic edema. 1
• Radiographic findings of Kerley B lines, subpleural thickened septal lines, and centrilobular ground-glass opacities representing interstitial fluid accumulation. 1, 7

Occult Alveolar Hemorrhage

• Elevated venous pressures cause capillary stress failure leading to recurrent microscopic hemorrhage. 1
• This results in hemosiderin-laden macrophages detectable on bronchoalveolar lavage with elevated Golde scores. 1

Molecular Pathogenesis

Recent research has identified specific molecular mechanisms:

• Heritable PVOD involves bi-allelic mutations in the EIF2AK4 gene, which encodes a kinase involved in the integrated stress response (ISR). 1, 3
• The disease can be triggered by activation of protein kinase R (PKR) and the ISR pathway, leading to impairment of vascular endothelial junctional structure and barrier function. 6
• Environmental triggers include chemotherapy agents (particularly mitomycin C), organic solvents, and other toxins that activate stress response pathways. 3, 6
• Age-associated elevation of basal ISR activity and depletion of protein phosphatase 1 leads to prolonged eIF2 phosphorylation, explaining why older patients develop more severe disease. 6

Association with Autoimmune Diseases

In the context of connective tissue diseases (particularly systemic sclerosis):

• Pulmonary venous involvement occurs as part of the systemic vasculopathy characteristic of these conditions. 4, 7
• PVOD in systemic sclerosis patients shows the same pathological features as idiopathic PVOD, with obstruction of small pulmonary veins. 4
• HRCT signs of PVOD (lymph node enlargement, centrilobular ground-glass opacities, and septal lines) occur in 61.5% of systemic sclerosis patients with precapillary pulmonary hypertension. 7

Critical Pathophysiological Consequence: Vasodilator-Induced Pulmonary Edema

The unique pathophysiology of PVOD creates a life-threatening risk when pulmonary vasodilators are administered: 1

• Vasodilators dilate pulmonary arteries and increase blood flow into the pulmonary circulation. 1
• However, the obstructed venous outflow cannot accommodate increased flow, causing acute elevation of capillary hydrostatic pressure. 1
• This precipitates rapid-onset ("flash") pulmonary edema despite normal left heart pressures—a pathognomonic feature of PVOD. 1, 4, 7
• The risk of pulmonary edema correlates with the presence of radiographic signs of venous involvement on HRCT. 1, 7