Discussion Alveolar Proteinosis

Introduction Intra-alveolar accumulation of lipid and proteinaceous material. Secondary to impaired clearance of surfactant by alveolar macrophage. Increased work of breathing Diminished surface area for gas diffusion Ultimately respiratory failure. Not associated with inflammation and lung architecture is typically preserved.

Introduction Frequency: 3.76 cases per million Race: no race predilection Sex: male/female: 2.65/1, 72% with smoking Non-smoker: no male predominance Age: peak:30~50y/o, median age at diagnosis: 39y/o

Etiology Congenital PAP Secondary PAP: unknown etiology Autosomal ressive pattern Mutation in the genes for (1) surfactant protein B or C, (2)beta chain of receptor for GM-CSF Secondary PAP: unknown etiology In association with lysinuric protein intolerance Inciting agents: aluminum, titanium, silicates, insecticides Acquired PAP: unknown etiology GM-CSF neutralizing autoantibody in serum and BAL fluid

Clinical symptoms Neonatal respiratory distress Dyspnea: Cough: Progressive respiratory failure and marked hypoxemia shortly after birth Prolonged ventilator dependence: slow resolution, persisting atelectasis, pneumonia Dyspnea: Most consistent finding in children and young adults 50~80% Cough: Occasionally with thick sputum or solid material 80%

Clinical symptoms Failure to thrive: More common in young children and infants Decreased level of activity and difficult feeding Uncommon symptoms: chest pain, fever, pneumothorax, hemoptysis

Lab studies Arterial blood gas analysis Low PaO2 Compensated respiratory alkalosis Latex agglutination test: 100% sensitivity, 98% specificity Pulmonary function test Mild restrictive pattern of lung disease Slightly diminished functional lung volumes Decreased DLCO

Bronchoalveolar lavage Milky or opalescent aspirate with large alveolar macrophage and increased lymphocytes Positive for PAS Elevated SP-A and SP-D Low level of SP-B

Lung biopsy The criterion standard for diagnosis Transbronchial biopsy: not enough tissue for diagnosis in children Pathologic finding: Granular, proteinaceous, fluid-filled alveolar spaces Cholesterol crystals are sometimes observed Alveolar structure is generally preserved Some thickening of interlobular septae EM: lamellar bodies and tubular myelin within the alveolar space Adds little to the diagnosis

Image--CXR Bilateral symmetric air-space opacity, ground-glass appearance perihilar or basilar predominance("bat wing" distribution) Air bronchograms are uncommon. No mediastinum widening, adenopathy, cardiomegaly, pleural effusions.

CXR

Image--CT scan Conventional CT: bilateral areas of consolidation and reticulation HRCT Crazy paving: patchy, bilateral, geographic areas of ground-glass opacity associated with interlobular septal thickening Interlobular septal thickening : more frequent in the lower lung zones

CT scan

Differential diagnosis Hemosiderosis Hypersensitivity pneumonitis Goodpasture syndrome Pulmonary alveolar microlithiasis Sarcoidosis Lymphoma Bronchioalveolar cell carcinoma

Treatment Mechanical ventilation Gene therapy necessary in children with congenital PAP Partial liquid ventilation (PLV) offers the advantage of lung lavage combined with ventilator support. Gene therapy Intravenous immunoglobulin (IVIG) and GM-CSF therapy

Treatment The mainstay of therapy in PAP is whole-lung lavage improved survival rates < 20 y/o: 58% response >40 y/o: 90% response Remove surfactant buildup or minimize the effect of macrophage dysfunction Other options: extracorporeal membrane oxygenation and lung transplantation

Mortality/Morbidity Neonate with congenital alveolar proteinosis With conventional therapy:100% Lung transplantation: 5-year survival rate:88±4% Pulmonary alveolar proteinosis: <5 y/o: 14±13% Children with late-onset disease: bets likelihood for survival

Prognosis Highly variable course with clinical and radiological episodes of exacerbation and remission 50% improvement/recovery 30% death

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