Pulmonary Alveolar Proteinosis Secondary to Hemophagocytic Lymphohistiocytosis and Juvenile Idiopathic Arthritis

Abstract

INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is rare in the pediatric population, yet similar to adult cases results in abnormal alveolar surfactant accumulation. Hemophagocytic lymphohistiocytosis (HLH) is characterized by macrophage hemophagocytosis of various cells and their precursors in the bone marrow and other tissues. Clinical symptoms include cytopenias, hepatosplenomegaly, and fever. HLH may be associated with malignancies, genetic, infectious or autoimmune diseases. We report a case of a patient with Juvenile Idiopathic Arthritis (JIA) and later onset of HLH who developed PAP. CASE PRESENTATION: A 7-year-old boy diagnosed with JIA at age four and HLH at age six, developed hypoxia and infiltrates on computed tomography (CT) at diagnosis of HLH. He was treated with multiple chemotherapeutic agents and systemic steroids resulting in remission of HLH and resolution of hypoxia. On later admission, he presented with a 1 day history of fever, chills, rash and increased ferritin level consistent with worsening HLH. Despite lack of supplemental oxygen requirement, he was tachypneic and easily fatigued with mild exercise. Pulmonary function tests showed severe progressive restrictive lung disease with a total lung capacity of 0.87L (60%) compared to 1.26 L (101%) from 18 months prior. CT of the chest showed bilateral nonspecific reticular nodular prominence. A lung biopsy demonstrated pulmonary alveolar proteinosis with evidence of chronic interstitial inflammation. Within days, he developed increasing dyspnea on exertion, but was still not hypoxic. Whole lung lavage was performed to optimize lung function in preparation for bone marrow transplantation, which yielded clinical and radiographic improvement. Subsequently, his course was complicated with pulmonary hemorrhage and acute respiratory failure requiring high frequency oscillatory ventilation and eventual extracorporeal membrane oxygenation (ECMO). Despite repeated whole lung lavages on ECMO, he was unable to transition to conventional ventilation and support was withdrawn. Autopsy confirmed diagnosis of PAP. DISCUSSIONS: Pulmonary alveolar proteinosis is a rare disorder in children with three recognized categories: congenital, idiopathic, and secondary. Congenital PAP is a disorder caused by genetic alterations in surfactant proteins and is treated with lung transplantation. Idiopathic PAP results from presence of an autoantibody and treatments include whole lung lavage and granulocyte macrophage colony-stimulating factor (GM-CSF). Secondary PAP can be associated with a multitude of diseases including infectious, hematologic, and autoimmune. Symptoms of secondary PAP include progressive exertional dyspnea, malaise and low-grade fever. Radiologic findings are generally worse than patient's symptoms. Bronchoalveolar lavage and biopsy yield definitive diagnosis. Pathologic findings include an abnormal accumulation of alveolar surfactant with a molecular structure similar, but not identical, to that of natural surfactant. Defective alveolar macrophage function impairs surfactant clearance. Treatment of the underlying disorder is necessary for curative treatment of secondary PAP. Pulmonary fibrosis is a typical finding late in the course of the disease. CONCLUSION: This patient has two potential causes for PAP: JIA and HLH. Pulmonary decline was not encountered prior to diagnosis of HLH leading us to believe HLH was reactivated causing secondary PAP. A literature review has shown rare adult cases, but no pediatric cases of PAP secondary to HLH. HLH is a disorder of macrophage activating system, while PAP can be a result of dysfunctional alveolar macrophages. Our report suggests PAP should be considered in patients with HLH and deteriorating lung function.