Sirolimus-induced secondary pulmonary alveolar proteinosis

Abstract

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome that is characterized by the accumulation of excess surfactant in the alveolar space, leading to impaired gas exchange. Sirolimus-induced PAP is an extremely rare entity that has only been described in the literature in a small number of case reports. We present a case of a 39-year-old female with acute lymphocytic leukemia who underwent stem cell transplant, complicated by graft-versus-host-disease (GVHD) involving the skin for which she was treated with steroids, photopheresis, sirolimus, and ruxolitinib. She was admitted to the intensive care unit (ICU) for acute on chronic hypoxic respiratory failure requiring intermittent mechanical ventilation. Computed tomography (CT) of the chest showed thickened inter- and intralobular septa with ground glass opacities and consolidation with a limited geographic pattern. Bronchoalveolar lavage fluid was stained with Periodic acid-Schiff (PAS), which was positive for extracellular proteinaceous material. Autoimmune studies including antibody levels for primary autoimmune pulmonary alveolar proteinosis (PAP) were negative. The patient was diagnosed with sirolimus-induced secondary PAP, and sirolimus was discontinued. A year later, she no longer required supplemental oxygen, and repeat CT imaging showed only faint residual disease. This is the only documented case of sirolimus-induced PAP in a stem cell transplant recipient and the first case reported in which the patient developed severe hypoxic respiratory failure requiring mechanical ventilation. In the right clinical context, PAP can be diagnosed with characteristic high resolution computed tomography (HRCT) findings, serum GM-CSF antibody levels, and bronchoscopy with bronchoalveolar lavage.

Fig. 1

Computed tomography (CT) scan of chest at the time of diagnosis. Imaging was performed on a GE medical systems scanner, and axial images were reformatted at 6mm slice thickness during administration of intravenous contrast (dFOV = 36 cm). CT scan shows dense bilateral thickened inter and intralobular septa, ground-glass opacification, and consolidation involving the right greater than the left lung. Other findings include a nonocclusive small right lower lobe posterior basal segment pulmonary embolism.

Fig. 2

Bronchoalveolar lavage showed a paucicellular specimen with abundant extracellular granular material (left panel, Papanicolaou stain, 400x magnification) that was Periodic acid-Schiff (PAS) positive; PAS-positive material is also present in pulmonary macrophages (upper right) (right panel, PAS stain, 400× magnification).

Fig. 3

High-resolution computed tomography (HRCT) scan obtained 7 months after discontinuation of sirolimus. Imaging was performed on a Siemens Multidetector scanner, in helical mode supine at suspended maximal inspiration with 1mm slice thickness. CT scan shows further decrease in diffuse ground glass attenuation with both intra- and interlobular septal thickening and essentially unchanged mild underlying pulmonary fibrosis.

Fig. 4

High-resolution computed tomography (HRCT) scan obtained 24 months after discontinuation of sirolimus. Imaging was performed on a Siemens 64-detector scanner, in helical mode supine at suspended maximal inspiration with 1mm slice thickness (dFOV = 30 cm). CT scan shows subtle residual areas of nodular groundglass predominating in the upper lobes.