Secondary Pulmonary Alveolar Proteinosis Due to Sirolimus

Abstract

Introduction Pulmonary alveolar proteinosis (PAP) is a rare, progressive lung disease characterized by the accumulation of lipoproteinaceous material in alveoli due to impaired clearance by alveolar macrophages. Although most cases are due to the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, secondary PAP from immunodeficiency is described in solid organ recipients. We present a treatment conundrum in a heart transplant (OHT) patient with a history of graft rejection who develops secondary PAP while on sirolimus. Case Report A 63-year-old male 6 years post re-do OHT, initially transplanted for ischemic cardiomyopathy then re-do for antibody mediated rejection presented with new hypoxia requiring 2L O2. His immunosuppression regimen included myfortic, prednisone, sirolimus, and tacrolimus. A CT scan demonstrated central and basilar ground glass opacities with “crazy paving”. He underwent a bronchoscopy with bronchoalveolar lavage (BAL) showing 90% macrophages, negative cultures, and cytology with hemosiderin pigment and proteinaceous material. He was empirically placed on levofloxacin and weaned to room air. At 5-month follow-up a repeat CT re-demonstrated similar findings. Repeat BAL, performed for concern for PAP, was Periodic acid-Schiff (PAS) stain positive for proteinaceous material. Serum GM-CSF antibodies were absent and the patient was diagnosed with secondary PAP due to sirolimus. Given the patient's prior history of graft failure, his sirolimus dose was unchanged and he was treated with inhaled sargramostim. Summary PAP is a rare disease caused by disorders in surfactant homeostasis further divided into three distinct etiologies: autoimmune (90%), secondary (5-10%), and congenital (2%). Secondary PAP is due to functional impairment in alveolar macrophages from immunodeficiency and is well-described in kidney and lung transplant recipients. To our knowledge, this is the first case described in a heart transplant recipient. The prognosis of transplant-associated secondary PAP is difficult to establish due to the limited number of published cases, though resolution is typically observed 2-4 months after removal of the offending agent. We present a case treated with GM-CSF due to difficulties reducing immunosuppression. Pulmonary alveolar proteinosis (PAP) is a rare, progressive lung disease characterized by the accumulation of lipoproteinaceous material in alveoli due to impaired clearance by alveolar macrophages. Although most cases are due to the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, secondary PAP from immunodeficiency is described in solid organ recipients. We present a treatment conundrum in a heart transplant (OHT) patient with a history of graft rejection who develops secondary PAP while on sirolimus. A 63-year-old male 6 years post re-do OHT, initially transplanted for ischemic cardiomyopathy then re-do for antibody mediated rejection presented with new hypoxia requiring 2L O2. His immunosuppression regimen included myfortic, prednisone, sirolimus, and tacrolimus. A CT scan demonstrated central and basilar ground glass opacities with “crazy paving”. He underwent a bronchoscopy with bronchoalveolar lavage (BAL) showing 90% macrophages, negative cultures, and cytology with hemosiderin pigment and proteinaceous material. He was empirically placed on levofloxacin and weaned to room air. At 5-month follow-up a repeat CT re-demonstrated similar findings. Repeat BAL, performed for concern for PAP, was Periodic acid-Schiff (PAS) stain positive for proteinaceous material. Serum GM-CSF antibodies were absent and the patient was diagnosed with secondary PAP due to sirolimus. Given the patient's prior history of graft failure, his sirolimus dose was unchanged and he was treated with inhaled sargramostim. PAP is a rare disease caused by disorders in surfactant homeostasis further divided into three distinct etiologies: autoimmune (90%), secondary (5-10%), and congenital (2%). Secondary PAP is due to functional impairment in alveolar macrophages from immunodeficiency and is well-described in kidney and lung transplant recipients. To our knowledge, this is the first case described in a heart transplant recipient. The prognosis of transplant-associated secondary PAP is difficult to establish due to the limited number of published cases, though resolution is typically observed 2-4 months after removal of the offending agent. We present a case treated with GM-CSF due to difficulties reducing immunosuppression.