Alveolar Proteinosis

Background: Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by the alveolar and interstitial accumulation of a periodic acid-Schiff (PAS) stain-positive phospholipoprotein derived from surfactant.

 

Pathophysiology: PAP has been described as occurring in primary and secondary forms. Primary PAP is idiopathic, while secondary PAP occurs in association with various pathologies that may be grouped into the following 4 main categories:

 

  • PAP may be associated with hematologic malignancies, particularly chronic myeloid leukemia and lymphomas.

     

  • PAP may be associated with certain occupational exposures, particularly mineral dusts and fumes. Mineral dust exposures associated with PAP include aluminum dust, titanium dioxide, cement dust, fibrous insulation material, and nitrogen dioxide, as reported in several studies. A condition histopathologically similar to PAP may be observed following the inhalation of other inorganic dusts, particularly silicon dioxide. In this circumstance, the resulting condition is termed acute silicoproteinosis, as described by Buechner and Ansari.

     

  • In several studies, PAP has been associated with infections, including infection by Nocardia, Mycobacterium tuberculosis, nontuberculous mycobacteria, cytomegalovirus, and fungal infections, such as histoplasmosis and cryptococcosis. PAP also has been described by Ruben and Talamo in patients with AIDS, including AIDS patients with coincident Pneumocystis pneumonia infection.

     

  • PAP has been considered by some to be congenital in origin, resulting from a lysinuric protein intolerance (according to Parto et al) or deficiency of surfactant protein B (according to Wallot et al).
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    The pathophysiology underlying PAP remains unclear. Many studies suggest that the alveolar macrophage and type II pneumocyte clearance mechanisms are overwhelmed by the intra-alveolar accumulation of PAS-positive surfactant-rich material, implying that the deficient macrophage function is secondary.

    An animal model that closely resembles PAP has been developed by Dranoff and Mulligan. Mutant mice that lack the gene for granulocyte macrophage-colony stimulating factor (GM-CSF) are affected by alveolar accumulation of surfactant, similar to patients with PAP. The condition corrects when the respiratory epithelium of the mutant mice is reconstituted with the gene for GM-CSF. Recent data by Tchou-Wong et al further suggest that the condition in the mutant mice is similar, but not identical, to PAP in humans.

    Unlike in the mutant mice, GM-CSF messenger RNA (mRNA) can be found in the bronchoalveolar lavage (BAL) fluid of patients with PAP, implying that the defect producing PAP in humans may be partly related to deranged expression of the gene for GM-CSF. Huffman et al have suggested that the accumulation of phospholipoprotein within the air spaces in patients with PAP may be related to defective clearance of surfactant protein and lipid rather than overproduction.

     

    Frequency:

    • Internationally: PAP is a rare disease. Exact prevalence and incidence data are not clear, but an incidence of 1-2 cases per million has been suggested by Shah et al.
      Prevalence of PAP may be decreasing in recent years, perhaps because of disease prevention resulting from the recognition that PAP is associated with certain industrial exposures. However, this perception could be an aberration related to the presence of many well-trained pulmonologists in the private sector, which may limit academic center referral of PAP patients. No firm epidemiologic data are available to confirm this supposition.

    Mortality/Morbidity: Prior to the introduction of therapeutic BAL, PAP resulted in death in almost one third of patients. With the use of therapeutic BAL, the prognosis of patients with PAP has improved greatly, and disease-related mortality has virtually been eliminated.

    • Spontaneous long-term disease remission has been documented in 24% of cases in a series of patients followed over 15 years by Kariman et al. Other investigators also have noted spontaneous resolution in patients with PAP.

    • Most patients improve following whole lung lavage, and only a small proportion of patients require repeated episodes of lavage to restore functional status. In the study by Kariman et al., of the patients who completed long-term follow-up care, 79% responded favorably to pulmonary lavage. Fewer than 10% of patients with PAP fail to respond to whole lung lavage, as described by Shah et al.
    • Complications of PAP primarily are related to infections and relapse. Relapses are infrequent and commonly are treated with repeated BAL. Although relapses may occur shortly following initial treatment, relapses have been documented as many as 18 years after the initial episode by Wilson and Rogers. Recurrence of PAP following double lung transplantation has been reported by Parker and Novotny.
    • Several rare associations with PAP have been reported to exist, including interstitial fibrosis, bronchiectasis with amyloidosis, bronchogenic carcinoma, Fanconi anemia and psoriasis, and lymphocytic interstitial pneumonia. Respiratory failure related to PAP is rare.

    Race: No particular racial predilection has been described. In a recent series by Goldstein et al of 24 patients from a single institution, all patients were Caucasian.

    Sex: Male-to-female ratio is estimated to be 2-4:1.

    Age: Patients with PAP typically are aged 20–50 years, although the disease may affect anyone from newborns to persons older than 70 years.

    Anatomy: For all practical purposes, PAP is a disease limited to the pulmonary parenchyma. Sieracki et al have reported a single case documenting the presence of lipoproteinaceous material within a supraclavicular lymph node.

    Clinical Details: Almost one third of patients with PAP are asymptomatic. Symptomatic patients commonly present with dyspnea on exertion or slowly progressive shortness of breath. Pleuritic chest pain also may occur but is uncommon. Occasionally, a patient may complain of a nonproductive cough or a cough productive of material sometimes described as gummy or chunky, according to Wang et al. Rarely, a cough productive of material resembling casts of the bronchial tree may be encountered. Generalized symptoms, such as malaise, fatigue, and weight loss, may be associated with PAP. Almost one half of patients with PAP may have low-grade fever at disease onset.

    Physical examination may reveal crackles and, rarely, digital clubbing.

    Pulmonary function testing typically reveals restriction, with diminished total lung capacity and forced vital capacity. The diffusing capacity of carbon monoxide also is often reduced. In the study by Goldstein et al., the diffusion capacity was disproportionately reduced relative to other pulmonary function parameters.

    The treatment of PAP has evolved. Although surgical resection of PAP has been performed, pulmonary lavage, either whole lung lavage under general anesthesia through a double lumen endotracheal tube or segmental BAL through a flexible fiberoptic bronchoscope, is now recognized as the single best method for the treatment of PAP. Nagasaka et al have added trypsin to the BAL fluid for an added proteolytic effect, with some success. Future treatment directions include GM-CSF replacement or gene replacement therapy in patients with defects in surfactant protein B production, or bone marrow transplantation.

    Preferred Examination: While CT (in particular, high-resolution CT [HRCT]) findings of PAP often are characteristic, the diagnostic study of choice is fiberoptic bronchoscopy with BAL.

    Analysis of BAL fluid, among other suggestive findings, may demonstrate PAS-positive proteinaceous material, as well as elevated levels of surfactant proteins A and D. Light microscopy examination of BAL fluid may be adequate in most patients, but ultrastructural analysis with electron microscopy may provide a more confident diagnosis. Occasionally, tissue samples may be required for diagnosis, and, usually, transbronchial biopsy specimens are sufficient. Rarely, open lung biopsy may be needed.

    Limitations of Techniques: Chest radiographs alone, while occasionally suggestive, rarely are diagnostic in patients with PAP. CT, especially HRCT, often displays findings characteristic of, though not pathognomonic for, PAP. Indeed, the differential diagnosis of characteristic HRCT finding of PAP (termed crazy paving) includes at least 15 different entities, as described by Johkoh et al. Fiberoptic bronchoscopy with BAL and transbronchial biopsy is sufficient for diagnosis in most patients.

    DIFFERENTIALS

    Acute Respiratory Distress Syndrome
    Lung, Drug-induced Disease
    Pneumonia, Pneumocystis Carinii
    Pneumonia, Typical Bacterial
    Pulmonary Edema, Noncardiogenic
    Radiation Pneumonitis


    Other Problems to be Considered:

    Lipoid pneumonia
    Bronchioloalveolar carcinoma
    Hydrostatic pulmonary edema
    Diffuse infections (eg, Pneumocystis pneumonia, bacterial pneumonia, Mycoplasma pneumonia)
    Pulmonary hemorrhage
    Hypersensitivity pneumonitis
    Interstitial pneumonia (especially desquamative interstitial pneumonia)
    Bronchiolitis obliterans organizing pneumonia
    Chronic eosinophilic pneumonia
    Obstructive pneumonitis
    Diffuse alveolar damage (numerous etiologies)

     

    X-RAY

    Findings: The classic chest radiographic finding of PAP is bilateral symmetric air-space opacity, appearing either as ground glass or frank consolidation, with a perihilar or basilar predominance.

     

  • Air bronchograms are uncommon.

     

  • Radiographic opacities often are vaguely nodular and may be accompanied by fine linear opacities or reticulation. Serial radiographs may demonstrate persistence of this pattern over time, resulting in a more limited differential diagnosis of chronic air-space opacity.

     

  • Unlike in hydrostatic pulmonary edema, the mediastinum is not widened, the heart is not enlarged, and pleural effusions are not common.

     

  • Adenopathy is not a feature of the disease.

     

  • Atypical manifestations include a linear or reticular pattern unaccompanied by air-space opacity, lower lobe predominant consolidation, or poorly defined nodules as the primary radiographic manifestation of disease.
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    The differential diagnosis of PAP on chest radiographs includes all entities resulting in diffuse air space disease, such as hydrostatic and noncardiogenic pulmonary edema, diffuse infections (particularly Pneumocystis pneumonia), pulmonary hemorrhage, interstitial pneumonia, the diffuse form of bronchioloalveolar carcinoma, toxic lung injuries and hypersensitivity pneumonitis, eosinophilic pneumonia, drug or radiation-induced pulmonary disease, and lipoid pneumonia.

    Chest radiograph (as reported by Gale et al) and CT (as reported by Zontsich et al) findings of treated PAP also have been described.

     

  • Initial radiographs following BAL reveal increased opacity in the lobes in which BAL fluid was instilled; this opacity is transient, clearing in hours to a few days.

     

  • Following BAL, the washed lung gradually improves aeration. By 6 weeks after the BAL procedure, chest radiographs usually demonstrate improved aeration over preprocedure radiographs.

     

  • Rarely, in the course of resolution, new opacities may develop in either the washed lung or the contralateral side. Occasionally, these opacities are related to endobronchial obstruction, usually representing atelectasis. Areas of decreased lung opacity, representing hyperinflation, also may occur by the same mechanism.

     

  • Opacity in the contralateral lung may result from spillage of BAL fluid from the washed lung or atelectasis following the BAL procedure.

     

  • Complications of the BAL procedure, including pneumomediastinum and pneumothorax, may be evident on immediate postprocedure radiographs.
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    Degree of Confidence: Radiographic findings of PAP are not specific, and, as stated above, a large differential diagnosis must be considered. Similar to the case with other diffuse lung diseases, HRCT provides a more specific morphologic evaluation of the disease pattern and may provide a more limited differential diagnosis. HRCT also is useful for targeting the optimal site for tissue sampling.


    CAT SCAN

    Findings: Routine CT (7-10 mm collimation) may reveal bilateral areas of consolidation and reticulation in patients with PAP.

     

  • Occasionally, an underlying linear abnormality that represents thickened interlobular septa may be appreciated.

     

  • Disease distribution usually is bilateral and patchy.
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    HRCT is superior to both conventional CT and chest radiography in demonstrating morphologic characteristics of PAP.

     

  • Crazy paving is the characteristic finding of PAP on HRCT and consists of patchy, bilateral, geographic areas of ground-glass opacity associated with interlobular septal thickening. The disease is often distributed uniformly from lung apex to base. Interlobular septal thickening may be encountered more frequently in the lower lung zones. Although the ground-glass opacity in PAP is usually patchy, centrilobular nodules have been described in pediatric patients with PAP and recently depicted by Marchiori et al in adult patients with acute silicoproteinosis.

     

  • Although findings of the interlobular septa commonly are abnormal on pathologic specimens from patients with PAP, septa findings occasionally may be pathologically normal despite a thickened appearance on HRCT. This apparent septal thickening on HRCT presumably reflects the aggregation of PAS-positive lipoproteinaceous material immediately adjacent to the interlobular septa.

     

  • Abnormal pulmonary parenchyma classically is demarcated sharply from normal areas of lung, without a discernible anatomic boundary.
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    Pleural effusions and adenopathy are uncommon in PAP and should suggest superimposed infection or malignancy. Occasionally, pleural effusions may be encountered in uncomplicated cases of PAP shortly following bronchoalveolar lavage.

    Degree of Confidence: While the appearance of crazy paving is highly suggestive of PAP, it is not pathognomonic. Many other entities may present with a pattern similar to crazy paving on HRCT. The differential diagnosis of crazy paving includes hydrostatic pulmonary edema, diffuse alveolar damage from any number of causes, pulmonary hemorrhage, diffuse pulmonary infections (including Mycobacterium tuberculosis, Mycoplasma pneumoniae, and other bacterial pneumonias), the diffuse form of bronchioloalveolar carcinoma, adult respiratory distress syndrome, drug-induced pneumonitis, radiation pneumonitis, bronchiolitis obliterans organizing pneumonia, chronic eosinophilic pneumonia, obstructive pneumonitis, acute interstitial pneumonia, and lipoid pneumonia. In addition, atypical manifestations of PAP do occur. Do not expect all instances of PAP to present as crazy paving on HRCT.

    MRI

    Findings: Few data are available regarding the MRI appearance of PAP. Because of magnetic susceptibility effects and the short echo times of lung parenchyma, lung tissue is challenging to image with MRI.

    One study by Moore et al addressed the appearances of diffuse air-space disease on MRI and found that air-space opacity in PAP has a short T1 value, and this opacity demonstrated relatively little increased signal intensity with T2-weighted imaging. Presumably, the short T1 signal of PAP reflects the relative lack of water within the lipoproteinaceous material filling the air spaces in this disease.

    INTERVENTION

    Special Concerns:

    • In children, PAP may be divided into congenital and childhood forms, each differing from the other and from adult PAP in several respects.
      • Congenital PAP presents as severe unresponsive respiratory distress at birth and usually is fatal. Congenital PAP is believed to be the result of an autosomal recessive condition. It may be mistaken easily for severe hyaline membrane disease, although a more prolonged course can be a clue to the true diagnosis. PAP in older infants and children often presents as failure to thrive and recurrent infections. Patients often are immunocompromised, commonly with thymic alymphoplasia, diminished levels of immunoglobulin A, or other autoimmune diseases.
      • Generally, PAP in children often is more acute and severe than PAP in adults. Chest radiographic and HRCT findings in childhood forms of PAP are few but are likely similar to their adult counterparts. McCook et al have suggested that a miliarylike pattern is encountered more frequently in PAP in children than in adults, and that basilar predominant linear and reticular abnormalities may be observed more often on CT in children. Recent HRCT descriptions of childhood PAP by Zontsich et al suggest that a crazy-paving pattern may be seen in children as it is in adults.

    PICTURES
    Caption: Picture 1. Frontal chest radiograph from a patient with pulmonary alveolar proteinosis demonstrates bilateral perihilar and infrahilar ground-glass opacity without evidence of mediastinal widening, pleural effusion, or adenopathy.
    Picture Type: X-RAY
    Caption: Picture 2. Frontal chest radiograph in a patient with pulmonary alveolar proteinosis reveals bilateral air-space opacity without evidence of effusion or mediastinal widening. A faintly reticular pattern is present, representing thickened interlobular septa.
    Picture Type: X-RAY
    Caption: Picture 3. High-resolution CT (window width=1000 Hounsfield units [HU], level= -700 HU) in a patient with acute silicoproteinosis demonstrates the pattern termed crazy paving, which is bilateral ground-glass opacity associated with marked interlobular septal thickening with a sharp nonanatomic demarcation between normal and abnormal lung.
    Picture Type: CT
    Caption: Picture 4. Frontal chest radiograph in a patient with pulmonary alveolar proteinosis subsequently treated with bronchoalveolar lavage reveals bilateral symmetric air-space opacity without pleural effusion or mediastinal widening.
    Picture Type: X-RAY
    Caption: Picture 5. Chest radiograph following bronchoalveolar lavage demonstrates that the bilateral air-space opacity has improved. These opacities subsequently cleared completely, and the patient has remained in remission.
    Picture Type: X-RAY
    Caption: Picture 6. High-resolution CT (window width=1000 Hounsfield units [HU], level= -700 HU) in a patient with pulmonary alveolar proteinosis. The image reveals bilateral ground-glass opacity associated with septal thickening, consistent with the crazy-paving pattern.
    Picture Type: CT
    Caption: Picture 7. High-resolution CT (window width=1000 Hounsfield units [HU], level= -700 HU; same patient as Picture 4) performed after bronchoalveolar lavage reveals regression of ground-glass opacity, representing partial resolution of the disease.
    Picture Type: CT
    Caption: Picture 8. High-resolution CT (window width=1000 Hounsfield units [HU], level= -700 HU) in a patient with pulmonary alveolar proteinosis. Bilateral ground-glass opacity and interlobular septal thickening are present.
    Picture Type: CT
    Caption: Picture 9. High-resolution CT (window width=1000 hounsfield units [HU], level= -700 HU; same patient as Picture 8) reveals slight interval worsening of bilateral ground-glass opacity and interlobular septal thickening consistent with progression of pulmonary alveolar proteinosis.
    Picture Type: CT
    Caption: Picture 10. High-resolution CT (window width=1000 Hounsfield units [HU], level= -700 HU) in a patient with pulmonary alveolar proteinosis. The sharp demarcation between normal and abnormal lung parenchyma characteristic of the crazy-paving pattern is less conspicuous than usual, although it is evident in the anterior segment of the right upper lobe. Ground-glass opacity associated with interlobular septal thickening is the dominant finding on this study.
    Picture Type: CT
    Caption: Picture 11. Frontal chest radiograph in a patient with the diffuse form of bronchioloalveolar carcinoma. Bilateral hazy ground-glass attenuation is present, with normal mediastinal width and no pleural effusion. This appearance resembles alveolar proteinosis.
    Picture Type: X-RAY
    Caption: Picture 12. Axial CT (window width = 1500 Hounsfield units [HU], level = -600 HU) in a patient with the diffuse form of bronchioloalveolar carcinoma (same patient as picture 11). Note the presence of ground-glass opacity associated with septal thickening, resembling the crazy paving appearance of alveolar proteinosis. The space-occupying nature of the process (note that the left major fissure is bowed posteriorly) and the lack of the usually sharp, but nonanatomic, demarcation between normal and abnormal lung (best seen in the posterior right lung), are findings not characteristic of alveolar proteinosis and should suggest an alternate diagnosis.
    Picture Type: CT
    Caption: Picture 13. Axial CT (window width = 1000 Hounsfield units [HU], level = -700 HU) in a patient with diffuse pulmonary hemorrhage reveals diffuse bilateral ground-glass opacity associated with mild interlobular septal thickening. Similar to picture 12, the lack of the sharp demarcation between normal and abnormal pulmonary parenchyma, characteristic of crazy paving, suggests a diagnosis other than alveolar proteinosis. In addition, the septal thickening in alveolar proteinosis is usually more prominent.
    Picture Type: CT
    Caption: Picture 14. Axial CT (window width = 1000 Hounsfield units [HU], level =-700 HU) through the lower lobes in a patient with pulmonary edema reveals bilateral ground-glass opacity associated with smooth interlobular septal thickening. Although by definition these findings resemble crazy paving, the appearance is nevertheless quite distinct from alveolar proteinosis. Note also the absence of the sharp demarcation between normal and abnormal lung characteristic of crazy paving in alveolar proteinosis.
    Picture Type: CT