A rare case of everolimus-induced pulmonary alveolar proteinosis

Abstract

A 56-year-old woman underwent bilateral single sequential lung transplantation in 2008 for idiopathic pulmonary fibrosis. She initially had excellent graft function, with a forced expiratory volume in 1 second of 2.8 liters until 2012, at which time she developed a lower respiratory tract infection with human metapneumovirus. This infection was associated with mild acute cellular rejection (A1B1). Despite treatment with corticosteroids, she experienced an irreversible decline in lung function, with a new baseline forced expiratory volume in 1 second of 1.5 liters (bronchiolitis obliterans syndrome 2). A high-resolution computed tomography chest scan performed at this time was unremarkable, and no donorspecific antibodies were detected on Luminex testing. She was commenced on everolimus (0.25 mg once daily) to reduce the fibroproliferative response. In February 2015, she complained of a 1-month history of increasing exertional dyspnea and general malaise in the absence of a decline in lung function. She denied cough, sputum, or hemoptysis. Chest X-ray imaging demonstrated a subtle reticulonodular infiltrate that, in retrospect, had been present for almost 2 years. A high-resolution computed tomography chest scan demonstrated innumerable centrilobular nodules and areas of centrilobular ground glass (Figure 1). Interstitial septal thickening was noted in the right upper lobe peripherally. Fiberoptic bronchoscopy demonstrated white, mucoid secretions bilaterally. Bronchoalveolar lavage was negative on culture and cytopathologic analysis for bacteria, viruses, mycobacteria, fungi, and Pneumocystis. Transbronchial biopsy specimens showed that many of the airway spaces were expanded with serous fluid and foamy macrophages, but there was no evidence of acute cellular rejection (A0B0). Cytomegalovirus/C4d stains were negative. The everolimus trough level was 6.1 mg/liter. In the absence of a definitive diagnosis, she underwent a video-assisted thoracoscopic biopsy of the right lower lobe. The sample demonstrated abundant slightly eosinophilic material present in the alveolar spaces (Figure 2) associated with numerous foamy macrophages focally with cholesterol crystal-type clefts in keeping with a diagnosis of pulmonary alveolar proteinosis. The everolimus was stopped, which resulted in a clinical and radiologic improvement, and she currently remains well. Pulmonary alveolar proteinosis is a disorder in which lipoproteinaceous material accumulates within alveoli. The reported incidence is 1:300,000 persons in the United States. Pulmonary alveolar proteinosis occurs in 3 clinically distinct forms: congenital, secondary, and acquired. It is caused by defective signalling by the granulocytemacrophage colony-stimulating factor (GM-CSF) receptor resulting in defective clearance of surfactant lipoprotein from the alveolar space. This may be due to a genetic deficiency that results in the diminished expression or function of the α-subunit or β-subunit of the GM-CSF receptor or, more commonly, to autoantibodies against GMCSF. Progressive accumulation of proteinaceous material may impair gas exchange, resulting in hypoxemic respiratory failure and reduced host defences. Acquired pulmonary alveolar proteinosis may be due to inhalational exposure, hematologic cancers, immune deficiency, or medications. Whole-lung lavage has been reported to improve symptoms, oxygenation, radiology, and survival in patients with this condition. A case series associated GMCSF administration with improvement in oxygenation and quality of life in approximately 50% of acquired cases. Interstitial lung disease has been reported due to administration of mammalian target of rapamycin inhibitors. Pulmonary alveolar proteinosis has also been described as an adverse reaction to sirolimus, with 7 case reports to our knowledge, so an association with everolimus was not unexpected. A review of adverse events in a prospective, randomized 24-month trial of everolimus in renal transplantation (A2309) confirmed pulmonary alveolar proteinosis based on a bronchoscopic biopsy specimen in 1 patient. We present a patient with pulmonary alveolar proteinosis attributable to everolimus administration. In our patient, time to onset of symptoms was 3 years, although there was reticulonodular change evident on chest X-ray imaging for 2 years, which may have been the disease in evolution.