Early Diagnosis of a Rare Pulmonary Vascular Condition: The Need for a High Index of Suspicion, a Good Network, and the Right Tools

Abstract Pulmonary veno–occlusive disease (PVOD) is a rare and deadly form of pulmonary arterial hypertension (PAH), characterized by preferential venular involvement/obliteration. This leads to reduced diffusion capacity of the lung (DLCO), oxygen desaturation, and pathognomonic alterations at chest computed tomography (CT): mediastinal lymph node enlargement, centrilobular ground–glass opacities, smooth thickening of the interlobular septa. PVOD is generally a late diagnosis that may benefit of lung transplantation only: acute pulmonary edema may occur after initiation of PAH–specific treatment. We report the case of a middle–age man in whom PVOD diagnosis was obtained only within 6 months from onset of symptoms and despite the absence of obvious CT findings. Treatment with PAH–specific drugs resulted in clinical and hemodynamic benefit. A 57–year–old male triathlete started complaining exertional dyspnea since December 2022. In February 2023, acute and chronic pulmonary embolism, as well as intracardiac and intrapulmonary shunt were excluded. Chest CT did not reveal relevant significant abnormality. Lung volumes were normal but DLCO was severely reduced (40%). Echocardiography suggested a low probability of PH, and BNP was normal. Right ventricular dimensions and function were within normal limits (RVEDV 90 mL/m2, RVEF 53%). Cardiopulmonary exercise test showed a moderate reduction of exercise capacity, an exercise–induced oxygen desaturation and a marked exercise–induced hyperventilation. He was thus referred to our center to undergo right heart catheterization (RHC) and invasive CPET (table). Genetic testing excluded EIF2AK4 gene mutation. A presumptive diagnosis of sporadic PVOD was made. Treatment with macitentan 10 mg was started, and well–tolerated. Three months later, both hemodynamics and exercise capacity were nearly normalized (table). Further treatment escalation adding tadalafil 40 mg was discussed and started. After that, the patient reported additional symptomatic benefit with improved exercise tolerance. This case raises several considerations: i) we need a high index of suspicion and a network approach to obtain early diagnoses of rare pulmonary vascular diseases; ii) CPET can enhance the diagnostic suspicion; iii) a low threshold for RHC in patients with unexplained dyspnea might be considered; iv) an early diagnosis and treatment of PVOD with PAH–specific drugs in our case was associated with clinical improvement, despite their intrinsic risk.