INTRODUCTION: Pulmonary venoocclusive disease (PVOD) is a rare disorder characterized by extensive and diffuse occlusion of the pulmonary veins by fibrous tissue that frequently results in a rapid progression to death. Etiology is uncertain, but factors including genetics, infection, thrombosis, autoimmune disease and exposures to toxins, such as chemotherapy, have been implicated in its development. Prognosis is generally poor with mortality near 100% at two years. Treatment with vasodilators has been advocated but may be complicated by the risk of worsening pulmonary edema. We report a case of PVOD treated successfully at one year with sildenafil monotherapy.
CASE PRESENTATION: A 53-year-old female with metastatic melanoma presented to the National Cancer Institute for an investigational therapy with tumor infiltrating lymphocytes (TIL). Treatment included high dose IL-2 followed by cyclophosphamide, fludarabine, total body irradiation, TIL cell infusion and CD-34+ stem cell infusion. The patient tolerated the treatment well and was discharged home. Four months later, the patient presented with 1 week of progressive exertional dyspnea. She had mild tachypnea but her physical exam was otherwise normal. A CXR, V/Q scan, HRCT scan of the chest, echocardiogram and a BNP level were normal. The 6 minute walk distance was 144 meters. On day 3 of the hospitalization, she became hypoxic at rest requiring oxygen. An echocardiogram was repeated and revealed an elevated pulmonary artery pressure (PAP) (tricuspid regurgitant (TR) jet of 3.5 m/s) and a normal left ventricle. A right heart catheterization was performed showing an elevated mean PAP and pulmonary vascular resistance that improved after 25 mg of sildenafil was administered. A lung biopsy was performed and was consistent with PVOD. Sildenafil therapy was continued at 25 mg three times daily and within two weeks supplemental oxygen was tapered and the patient had rapid and dramatic resolution of her resting dyspnea. Repeat echocardiogram after 3 months showed a TR jet of 2.8 m/s. One year later, the patient remained well on sildenafil 50 mg three times daily and had dyspnea and chest tightness only with exertion. The six minute walk was increased to 318 meters and the TR jet was reduced to 2.6 m/s. A right heart catheterization revealed exercise induced hemodynamic worsening associated with symptoms of chest tightness. Sildenafil was increased to 75 mg three times daily. Headaches were the only side effect of treatment and were well controlled with oral analgesics.
DISCUSSIONS: Treatment of PVOD presents a unique challenge because vasodilator therapy may result in arterial vasodilation without venous vasodilation increasing transcapillary hydrostatic pressure resulting in the formation of pulmonary edema. Optimal treatment is uncertain and mortality remains unacceptably high. In a recent randomized trial, sildenafil, a specific inhibitor of phosphodiesterase type 5, was shown to decrease PAP and increase 6 minute walk distance in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH associated with connective tissue disease. It has been proposed as a treatment for other forms of pulmonary hypertension but has only been used in the treatment of PVOD in one report as an adjunct to intravenous epoprostenol. We present a patient with biopsy proven PVOD who demonstrated persistent and significant hemodynamic and symptomatic improvement at one year during treatment with sildenafil.
CONCLUSION: Our experience suggests that sildenafil may have unique properties which are useful in the treatment of PVOD. The role of sildenafil in the treatment of PVOD should be evaluated in a clinical trial.
DISCLOSURE: Christopher Barnett, None.