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.
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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.
