PULMONARY ALVEOLAR PROTEINOSIS
Pulmonary alveolar proteinosis (PAP) is an uncommon disease characterized by ﬁlling of alveoli with a lipoproteinaceous material composed principally of the phospholipid surfactant and surfactant apoproteins. This amorphous material stains with periodic acid–Schiff (PAS) reagent. Impaired processing of surfactant by alveolar macrophages and diminished granulocyte macrophage-colony stimulating factor (GM-CSF) protein levels or function contributes to the pathogenesis of PAP. There is little inﬂammatory reaction in the surrounding lung, and the underlying lung architecture is preserved.
Three forms of PAP are recognized: acquired, congenital, and secondary. The vast majority of all cases of PAP (>90%) occur as a primary acquired disorder of unknown cause. The acquired form is seen in association with high-level dust exposures (e.g., silica, aluminum, or titanium), infection (e.g., Nocardia, Pneumocystis jiroveci, mycobacteria, and various endemic or opportunistic fungi), hematologic malignancies, and after allogeneic bone marrow transplantation for myeloid malignancies. The congenital form presents in the neonatal period and likely results from mutations in surfactant or the GM-CSF receptor gene. The secondary form develops in adulthood and is likely related to relative deﬁciency in GM-CSF and related macrophage dysfunction.
The typical age at presentation of an adult patient with PAP is 30 to 50 years, with a male predominance. Although some patients are asymptomatic, with only an abnormal chest radiograph at presentation, most patients have a cough (productive of mucoid or “chunky” gelatinous material) and dyspnea. In severely affected patients, constitutional symptoms of anorexia, weight loss, and fatigue appear. Physical examination may show tachypnea, cyanosis, crackles, tachycardia, and occasionally clubbing.
Laboratory abnormalities include polycythemia, hypergammaglobulinemia, and increased lactate dehydrogenase (LDH) levels. Elevated serum levels of lung surfactant proteins A and D (SP-A and SP-D) and several tumor markers (carcinoembryonic antigen [CEA], carbohydrate antigens sialyl Lewis-a [CA 19-9], and sialyl SSEA-1 [SLX]), have been found in broncho- alveolar lavage (BAL) and serum from some patients with PAP. Several serum biomarkers have been shown to correlate with disease severity, including LDH, SP-A, SP-D, Kerbs von Lungren 6 antigen (KL-6), and CEA.
A restrictive ventilatory defect is most common. Sometimes an isolated decrease in DLCO (diffusing capacity for carbon monoxide), often out of proportion to the degree of reduced lung volume, may be found. The most marked abnormality is a reduced Pao2, which may be profoundly lowered.
Chest radiographs show bilateral symmetric alveolar opacities located centrally in middle and lower lung zones, sometimes resulting in a “bat wing” distribution. Air bronchograms are rare. A thin lucent band may sharply outline the diaphragm and the heart consistent with sparing of the lung immediately adjacent to these structures. High-resolution computed tomography scanning (HRCT) reveals ground-glass opaciﬁcation that typically spares the periphery. In addition, thickened intralobular structures and interlobular septa in typical polygonal shapes may give the “crazy paving” appearance. Crazy paving is not speciﬁc for PAP because it has been observed in patients with the acute respiratory distress syndrome, lipoid pneumonia, acute interstitial pneumonia, drug-related hypersensitivity reactions, and diffuse alveolar damage superimposed on usual interstitial pneumonitis.
When PAP is suspected, ﬁberoptic bronchoscopy to obtain BAL and, if possible, transbronchoscopic biopsy is the appropriate next step. Video-assisted transthoracic biopsy is required in the occasional patient with negative BAL and transbronchoscopic biopsy results. Characteristic BAL ﬁndings of PAP include opaque or milky appearance caused by abundant lipoproteinaceous material; cytologic examination of BAL reveals alveolar macrophages engorged with PAS-positive material. Transbronchial and open lung biopsies reveal ﬁlling of the terminal bronchioles and alveoli with ﬂocculent and granular lipoproteinaceous material that stains pink with PAS stain.
The course of PAP is variable. The choice of treatment options for patients with PAP depends on the severity of symptoms and gas exchange abnormalities. For asymptomatic patients with little or no physiologic impairment (despite extensive radiographic abnormalities), a period of observation is recommended. For patients with severe dyspnea and hypoxemia, whole-lung lavage via a double-lumen endotracheal tube is recommended. The procedure should be done under general anesthesia. Only one lung is washed out at each session, and the contralateral lung receives oxygen as required. A few patients have improved after clearance of only one lung. Experimental therapy with GM-CSF has been used based on evidence that reduced GM-CSF effect contributes to PAP. Glucocorticoid therapy is not beneﬁcial.