INTRODUCTION: Idiopathic pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by the accumulation of surfactant derived lipoproteinaceous material in alveoli. Defective clearance of surfactant, mediated by circulating antibodies against granulocyte macrophage colony-stimulating factor (GM-CSF), leads to impairment in gas exchange. In PAP, alveolar walls are typically normal or only slightly thickened by cellular infiltrate, and interstitial fibrosis is unusual. This condition has a variable clinical course, ranging from spontaneous resolution to death secondary to respiratory failure.
CASE PRESENTATION: We report the case of a 43-year-old Hispanic male with the diagnosis of PAP who developed interstitial pulmonary fibrosis multiple years after the onset of his disease. He was originally diagnosed at the age of 36 based on bronchoalveolar lavage, transbronchial biopsies, and the presence of elevated serum anti-GM-CSF antibodies. Over the course of multiple years, he underwent bilateral whole lung lavages every 6-8 months with transient improvement in symptoms and imaging. However, he subsequently had a significant symptomatic decline over a 12-month period despite continued whole lung lavages. No secondary infections were identified though he did have a remote history of infections with Aspergillus, Pseudomonas, and Staphylococcus. A chest radiograph revealed extensive reticular markings, and a high resolution chest computer tomography (CT) scan confirmed the presence of bibasilar subpleural reticulations and traction bronchiectasis, consistent with diffuse interstitial fibrosis. This was in contrast to a chest CT 2 years prior showing classic findings of PAP including ground glass opacities and “crazy paving”. The patient has been started on a trial of subcutaneous GM-CSF and is undergoing lung transplantation evaluation.
DISCUSSION: Interstitial fibrosis in PAP is exceedingly rare, though there have been a number of cases reported in the literature. The pathogenesis of fibrosis in PAP remains uncertain and it is unclear whether interstitial fibrosis is an end-stage process in the natural history of PAP. It has been postulated that complicating pulmonary infections with organisms such as Aspergillus, Nocardia, or Cryptococcus may result in fibrosis. Another theory proposes that the accumulation of surfactant components and cellular debris in alveoli and bronchioles may form large crystals and promote granulomatous reactions in the surrounding alveolar walls. This may result in enhanced inflammatory response that leads to interstitial fibrosis. Another possible route to interstitial fibrosis in PAP is, macrophage and giant cell response to lipid crystals, with resultant fibroblast stimulation. Treatment options for interstitial fibrosis in PAP are limited. GM-CSF offers some promising results in the symptomatic management of PAP, but not pulmonary fibrosis. PAP has been treated with double-lung transplantation when there has been progression of pulmonary fibrosis, but there is concern for recurrence of PAP in transplant lung.
CONCLUSIONS: This case illustrates the unique finding of advanced pulmonary fibrosis in a patient with longstanding PAP. Recognition of this rare but reported association is critical to the management of PAP, as lack of response to therapies such as whole lung lavage should query the development of fibrosis.
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DISCLOSURE: The following authors have nothing to disclose: Sharon De Cruz, Tisha Wang
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