Pulmonary langerhans cell histiocytosis (PLCH) is a rare smoking-related interstitial lung disease. Pulmonary hypertension (PH) is a common complication, and is strongly associated with increased mortality. Our patient developed severe PH secondary to an unusual combination of pulmonary arteriopathy and pulmonary veno-occlusive disease (PVOD) associated with PLCH. The PH and the dyspnea improved with Bosentan therapy.
A 51 year old male with 60 pack year smoking history, presented with one year history of progressive exertional dyspnea, intermittent dry cough, and declining functional capacity. Physical examination was remarkable for decreased breath sounds bilaterally with diffuse end inspiratory fine crackles. Oxygen saturation was 89% and the PaO2 was 55 mm Hg on room air. Chest radiograph showed diffuse nodular interstitial opacities which were confirmed by high-resolution computed tomography that showed reticulonodular pattern with upper zone predominance. Pulmonary function testing revealed a mild combined obstructive and restrictive defect with a severe impairment in diffusing capacity at 40% of predicted suggesting pulmonary vascular disease. This was confirmed by an echocardiogram where the systolic pulmonary artery pressure was estimated at 98 mm Hg. Pulmonary embolism was not detected by perfusion lung scan or pulmonary angiogram. Hematologic, biochemical, and serologic tests were within the normal range. A right heart catheterization confirmed severe PH and there was no evidence of an intracardiac left-to-right shunt. Video assisted thoracoscopy with a wedge lung biopsy was performed which confirmed the diagnosis of PLCH with extensive interstitial fibrosis, medial hypertrophy and vascular intimal fibrosis with luminal obliteration consistent with PH and PVOD, respectively. The patient stopped smoking, treatment was started with prednisone and non-selective endothelin-1 blocker (Bosentan), and then the patient was referred to a lung transplantation center. Within 4 weeks, dyspnea on exertion improved. Pulmonary function tests and blood gases remained unchanged over 3 months. Right heart catheterization was repeated after 3 months of Bosentan therapy and demonstrated an important reduction of pulmonary artery pressure and pulmonary vascular resistance.
In the literature, pulmonary arteriopathy and PVOD have been described as possible causes of PH in PLCH. Our patient had severe PH out of proportion to ventilatory limitation, secondary to both pulmonary arteriopathy and PVOD. The normal pulmonary artery occlusion pressure (PAOP) in our patient could be explained by the exit of tributaries from the occluded vein proximal to the stenosis and their connection with non-occluded veins eventually reaching the left atrium. Treatment for PH in PLCH is not well established. A better understanding of the pathogenesis in PLCH is needed to appropriately treat the underlying PH. Variable degrees of fibrosis and distortion of the normal pulmonary architecture are often associated with advanced PLCH, with some histologic overlapping with idiopathic pulmonary fibrosis (IPF). Endothelin-1 may underlie the pathogenesis of lung fibrosis. Bosentan (non-selective endothelin-1 blocker) may have efficacy for the treatment of PH in advanced fibrotic phase of PLCH. A recent randomized control-blinded trial (BUILD-1) showed that Bosentan improved the quality of life and delayed time to death in IPF. However, pulmonary edema occurred in some patients with PVOD who were treated with oral Bosentan. Pulmonary arteriopathy contributes to the development of PH in PLCH. Prostacyclin induces relaxation of vascular smooth muscle by stimulating the production of cAMP and inhibits the growth of smooth-muscle cells. However, acute pulmonary edema occurred in some patients with PLCH who were treated with intravenous prostacyclin, due to the concomitant PVOD. This effect probably resulted from the increase in pulmonary blood flow in the setting of downstream vascular obstruction.
PLCH is often associated with severe PH and many new options for treatment are currently available but multicenter clinical trials are needed to develop an evidence-based approach.
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