eMedicine Specialties > Radiology > Chest

Alveolar Proteinosis

Author: Michael B Gotway, MD, Clinical Associate Professor of Diagnostic Radiology and Pulmonary/Critical Care Medicine, University of California at San Francisco School of Medicine; Consulting Staff, Scottsdale Medical Imaging, Ltd
Coauthor(s): Theodore J Lee, MD, Chief, Thoracic Radiology, San Francisco General Hospital; Assistant Professor of Clinical Radiology, University of California at San Francisco
Contributor Information and Disclosures

Updated: Dec 30, 2008

Introduction



Frontal chest radiograph from a patient with pulm...

Frontal chest radiograph from a patient with pulmonary alveolar proteinosis. This image demonstrates bilateral perihilar and infrahilar ground-glass opacity without evidence of mediastinal widening, pleural effusion, or adenopathy.

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Frontal chest radiograph from a patient with pulm...

Frontal chest radiograph from a patient with pulmonary alveolar proteinosis. This image demonstrates bilateral perihilar and infrahilar ground-glass opacity without evidence of mediastinal widening, pleural effusion, or adenopathy.


Frontal chest radiograph in a patient with pulmon...

Frontal chest radiograph in a patient with pulmonary alveolar proteinosis. This image reveals bilateral air-space opacity without evidence of effusion or mediastinal widening. A faintly reticular pattern is present, representing thickened, interlobular septa.

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Frontal chest radiograph in a patient with pulmon...

Frontal chest radiograph in a patient with pulmonary alveolar proteinosis. This image reveals bilateral air-space opacity without evidence of effusion or mediastinal widening. A faintly reticular pattern is present, representing thickened, interlobular septa.


High-resolution computed tomography scan (window ...

High-resolution computed tomography scan (window width = 1000 Hounsfield units [HU], level = -700 HU) in a patient with acute silicoproteinosis. This image demonstrates crazy paving, which refers to bilateral ground-glass opacity that is associated with marked interlobular septal thickening and a sharp nonanatomic demarcation between normal and abnormal lung.

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High-resolution computed tomography scan (window ...

High-resolution computed tomography scan (window width = 1000 Hounsfield units [HU], level = -700 HU) in a patient with acute silicoproteinosis. This image demonstrates crazy paving, which refers to bilateral ground-glass opacity that is associated with marked interlobular septal thickening and a sharp nonanatomic demarcation between normal and abnormal lung.


Background

Pulmonary alveolar proteinosis (PAP) is a rare, diffuse lung disease that is characterized by the alveolar and interstitial accumulation of a periodic acid-Schiff (PAS) stain-positive phospholipoprotein that is derived from surfactant.1,2,3 The lung architecture is otherwise normal, and any associated inflammation or fibrosis is limited in extent.4

For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

Related eMedicine topics:
Pulmonary Alveolar Proteinosis

Alveolar Proteinosis (Pediatrics: General Medicine)

Pulmonary Fibrosis, Idiopathic

Chronic Obstructive Pulmonary Disease and Emphysema

Lung, Nontuberculous Mycobacterial Infections

Pathophysiology

Pulmonary alveolar proteinosis (PAP) occurs in primary and secondary forms. Primary PAP is either idiopathic (90% of cases) or congenital (2% of cases) in origin, whereas secondary PAP occurs in association with various pathologies that may be grouped into the following 3 main categories:

  • PAP may be associated with hematologic malignancies, particularly chronic myeloid leukemia and lymphomas,5,6,7,8,9,10 and occasionally other solid organ malignancies.11 In the setting of hematologic malignancy, secondary PAP is commonly encountered in neutropenic patients.5
  • PAP may be associated with certain occupational exposures, particularly mineral dusts and fumes. Mineral dust exposures associated with PAP include aluminum dust,12 titanium dioxide,13,14 cement dust,15 fibrous insulation material,16 and nitrogen dioxide,17 among other fume or dust exposures,18 as reported in several studies. Such studies have noted the association of the development of PAP with certain exposures, but causality has not been proven. A condition that is histopathologically similar to PAP may be observed following the inhalation of silicon dioxide.19,20 In this circumstance, the resulting condition is termed acute silicoproteinosis, as described by Buechner and Ansari in 1969.19 At present, acute silicoproteinosis is quite rare, owing to the recognition of the pathogenesis of this syndrome and the institution of occupational precautions.
  • PAP may be associated with infections, including those caused by Nocardia,21 Mycobacterium tuberculosis,22,23 nontuberculous mycobacteria,24,25 cytomegalovirus,22,26 and fungal infections, such as histoplasmosis27 and cryptococcosis.28 PAP has also been described in patients with acquired immunodeficiency syndrome (AIDS),22,29,30 including AIDS patients with coincident Pneumocystis jiroveci pneumonia infection. Whether or not such infections are more prevalent in patients with PAP remains unclear.

Congenital PAP results from deficiency of surfactant protein B (SP-B)1,31,32 or abnormality of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor β chain.33,34,35 According to Ioachimescu and Kavuru, most cases of congenital PAP are transmitted in an autosomal recessive fashion.36

The pathophysiology that underlies idiopathic, or acquired, PAP is increasingly understood to result from defective surfactant clearance due to GM-CSF deficiency.2 Other mechanisms that may play a role in the development of PAP include the possibility that alveolar macrophage and type II pneumocyte clearance mechanisms become overwhelmed by the intra-alveolar accumulation of PAS-positive, surfactant-rich material or that surfactant itself is abnormal or defective in some fashion.

Dranoff and Mulligan developed an animal model in which mutant mice that lacked the gene for GM-CSF were affected by the alveolar accumulation of surfactant, similar to patients with PAP.35 The condition corrected when the respiratory epithelium of the mutant mice was reconstituted with the gene for GM-CSF. Data by Tchou-Wong et al further suggested that the condition in the mutant mice is similar, but not identical, to PAP in humans.37

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 that produces PAP in humans may be partly related to deranged expression of the gene for GM-CSF.2,24,38 Huffman et al 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.34

It has been recognized that anti-GM-CSF autoantibodies may be found in the circulation and lungs of patients with idiopathic PAP, but not in unaffected patients—raising the possibility that PAP is an autoimmune disease and suggesting that detection of GM-CSF antibody detection may have utility as a diagnostic test for PAP.39 Adult idiopathic PAP is currently regarded as an autoimmune disease that results from GM-CSF deficiency due to circulating autoantibodies.

These data not only indicate that GM-CSF plays a prominent role in normal surfactant metabolism but also imply that GM-CSF deficiency underlies the development of idiopathic PAP. In addition, available data suggest that GM-CSF deficiency is the result of neutralizing anti-GM-CSF antibodies rather than the result of GM-CSF receptor abnormalities or deficient GM-CSF production.40,41,42

Frequency

International

Pulmonary alveolar proteinosis (PAP) is a rare disease. The exact prevalence and incidence data are not clear, but an incidence of 1 case per 2 million people has been suggested by Shah et al,3 whereas an incidence of 0.37/100,000 and a prevalence of 37 cases per million people have been reported by Ben-Dov and colleagues.43 It is likely that underreporting of the disease results in an underestimation of the prevalence of PAP.

The prevalence of PAP may be decreasing, perhaps because of disease prevention that has resulted from the recognition that PAP is associated with certain industrial exposures. However, this perception could be an aberration that is 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

Before the introduction of therapeutic bronchoalveolar lavage (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.

  • In a study by Kariman et al with over 15 years of follow-up in their patients, spontaneous long-term disease remission was documented in 24% of cases.44 Other investigators noted spontaneous resolution in patients with PAP.45,46 However, such reports of spontaneous resolution of PAP have been complicated by the lack of long-term patient follow-up. In general, spontaneous resolution of PAP should be considered an exceptional circumstance.
  • Most patients improve after undergoing whole-lung lavage, and only a small proportion of patients require repeated episodes of lavage to restore functional status. In Kariman et al's study, 79% of patients responded favorably to pulmonary lavage.44 Shah et al indicated that fewer than 10% of patients with PAP fail to respond to whole-lung lavage.3 Seymour and Presneill's review of a number of published reports showed that the overall 5-year survival for patients from the time of diagnosis of PAP is higher for those who have undergone therapeutic lung lavage than for those who have not.2  The median duration of clinical benefit for therapeutic lung lavage has been reported to approach 15 months.
  • Seymour and Presneill reviewed data for 343 patients with PAP and found overall survival rates of 78.9% at 2 years, 74.7% at 5 years, and 68.3% at 10 years.2 Disease-specific survival exceeded 80% at 5 years.
  • The complications of PAP are primarily related to infections and relapse. Relapses are infrequent and are commonly treated with repeated BAL. Although relapses may occur shortly after the initial treatment, Wilson and Rogers documented relapses up to 18 years after the initial episode.45 Recurrence of PAP following double lung transplantation was reported by Parker and Novotny.47
  • Death due to PAP commonly occurs in the first year after the diagnosis and is usually the result of respiratory failure that has been induced by PAP; death by infection or unrelated etiologies in patients with PAP occurs less commonly.
  • According to Ioachimescu and Kavuru, complications that may be associated with whole-lung lavage treatment of patients with PAP include pneumothorax or pneumomediastinum, hypoxemia, pneumonia, sepsis, and adult respiratory distress syndrome (ARDS).36
  • Certain infections have also been suggested to be more prevalent in patients with PAP, including Nocardia21 and nontuberculous mycobacteria.24,25  Infections with nontuberculous mycobacteria usually do not reflect true infection and are more commonly the result of colonization or contamination. Whether or not infection with Nocardia species is truly more prevalent in patients with PAP is unclear. In general, pulmonary infection as a result of PAP is considered rare.
  • Several rare associations with PAP have been reported to exist, including interstitial fibrosis,24 bronchiectasis with amyloidosis,48 bronchogenic carcinoma, Fanconi anemia and psoriasis,49 and lymphocytic interstitial pneumonia.50 Respiratory failure related to PAP is rare.

Race

No particular racial predilection has been described. In a series by Goldstein et al of 24 patients from a single institution, all patients were white,51 and according to Seymour and Presneill, black patients account for approximately 17% of patients with PAP in North America.2

Sex

The male-to-female incidence rate is estimated to be 2-4:1.2

Age

Patients with pulmonary alveolar proteinosis (PAP) are typically aged 20-50 years (median age approximately 39 years), although the disease may affect anyone from newborns to persons older than 70 years. A report by Seymour and Presneill of 410 published cases of PAP identified a median patient age of 39 years at diagnosis.

Anatomy

In 1959, Sieracki et al documented a case of pulmonary alveolar proteinosis (PAP) in which the presence of lipoproteinaceous material within a supraclavicular lymph node was found.52 For all practical purposes, however, PAP is a disease that is limited to the pulmonary parenchyma.

Presentation

Almost one third of patients with pulmonary alveolar proteinosis (PAP) are asymptomatic. Symptomatic patients commonly present with dyspnea on exertion or slowly progressive shortness of breath. Pleuritic chest pain may also occur but is uncommon. Occasionally, a patient may complain of a nonproductive cough or a productive cough that consists of material sometimes described as gummy or chunky53 ; rarely, a material resembling casts of the bronchial tree may result from productive coughs. In addition, hemoptysis may occasionally be encountered.54

Generalized symptoms, such as malaise, fatigue, and weight loss, may be associated with PAP. Almost 50% of patients with PAP may have low-grade fever at the disease onset. Symptoms of progressive dyspnea or cough may be present for up to 7 months in 50% of patients with PAP; 25% of patients experience a more protracted presentation of 2 years or longer.36 Up to 75% of patients are smokers at the time of PAP presentation. Physical examination of the affected patients may reveal crackles and, rarely, digital clubbing or cyanosis.

Pulmonary function testing typically reveals restriction, with diminished total lung capacity and forced vital capacity. Often, the diffusing capacity of carbon monoxide is also reduced. In a study by Goldstein et al, the diffusion capacity of patients with PAP was disproportionately reduced relative to other pulmonary function parameters.51

Laboratory data have little utility in the evaluation of patients with PAP. Serum lactate dehydrogenase (LDH)55 and SP-A, SP-B, and SP-D1 may be elevated in patients with PAP. According to Takahashi et al, the mucinlike glycoprotein KL-6, which is produced in the lung, may also be elevated in patients with PAP, but these findings are usually not helpful in making the diagnosis of PAP, unless the measurement values of KL-6 are extremely high.56 Whether or not such values are useful in predicting the severity of PAP or monitoring disease activity is currently unknown. 

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 (ET) tube or segmental bronchoalveolar lavage (BAL) through a flexible fiberoptic bronchoscope, is recognized as the single best method for the treatment of PAP. Whole-lung lavage may be performed on both lungs in a sequential fashion during a single procedure or performed on each lung in separate procedures. Most commonly, whole-lung lavage is performed sequentially under general anesthesia for the bilateral lungs with use of a dual-lumen ET tube under close noninvasive monitoring, ideally with a multidisciplinary approach that involves pulmonary medicine and anesthesia. A single lung is lavaged at a time, typically with 500-1000 mL of warmed, sterile, normal saline until the lavage fluid return is clear. With some success,  Nagasaka  et al incorporated trypsin  to  the  BAL  fluid  for  an  added  proteolytic  effect.57

There are no explicitly published standardized indications for the performance of whole-lung lavage treatment for patients with PAP; however, according to Ioachimescu and Kavuru, common indications for whole-lung lavage in PAP patients include the following36 :

  • Dyspnea that impairs the activities of daily living
  • Arterial partial pressure of oxygen (PaO2) <60 mmHg
  • Shunt fraction >10-12%


According to Ioachimescu and Kavuru, after whole-lung lavage, the patient's forced vital capacity, total lung capacity, PaO2, exercise tolerance, and diffusing capacity all improve. In addition, the alveolar-oxygen gradient and shunt fraction decrease significantly after whole-lung lavage procedures.36

Other therapies that have occasionally been employed for the treatment of PAP include the use of corticosteroids, postural drainage, and intermittent positive-pressure breathing with aerosolized acetylcysteine, heparin, and saline. 

Another treatment direction for PAP has been granulocyte-macrophage colony-stimulating factor (GM-CSF) replacement or gene replacement therapy in patients with defects in surfactant protein B (SP-B) production. Such therapy offers the benefit of a focused treatment for PAP that directly targets the underlying derangement. Small observational trials of aerosolized GM-CSF therapy have been encouraging, showing symptomatic and physiologic improvement in the treated patients.

Rare forms of therapy for PAP include plasmapheresis, lung transplantation, and bone marrow transplantation.

Preferred Examination

Although computed tomography (CT) scan (in particular, high-resolution CT [HRCT] scan) findings of pulmonary alveolar proteinosis (PAP) are often characteristic, the diagnostic study of choice is fiberoptic bronchoscopy with bronchoalveolar lavage (BAL).

Gross inspection of the lavage fluid may reveal a characteristic milky-white appearance (see Image below and Image 15 in Multimedia). If the lavage fluid is allowed to settle, a more translucent supernatant will form with a denser, opaque white sediment beneath.



A tube showing the milky-white bronchoalveolar la...

A tube showing the milky-white bronchoalveolar lavage fluid from a patient with pulmonary alveolar proteinosis. Photo courtesy of Martha Warnock, MD.

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A tube showing the milky-white bronchoalveolar la...

A tube showing the milky-white bronchoalveolar lavage fluid from a patient with pulmonary alveolar proteinosis. Photo courtesy of Martha Warnock, MD.


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

Measurement of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) serum titers are a very promising diagnostic test for patients with PAP.58 There are data to indicate that the sensitivity of the anti-growth hormone (GH)-CSF assay for idiopathic PAP is 100%, with a specificity greater than 91%. When using a titer cut-off value of 1:400 or higher, the specificity of the assay improves to 100%. Furthermore, the anti-GM-CSF antibody titer correlates with PAP disease activity and may predict response to therapy with GM-CSF replacement.

Limitations of Techniques

Chest radiographs alone, while occasionally suggestive, are rarely diagnostic in patients with PAP. CT scanning, especially HRCT scanning, often displays findings that are characteristic of, though not pathognomonic for, PAP. Indeed, Johkoh et al include at least 15 different entities in the differential diagnosis for the characteristic HRCT scan findings (termed "crazy paving"; see CT Scan, Findings) of PAP.59 Fiberoptic bronchoscopy with BAL and transbronchial biopsy are sufficient for confirming the clinical diagnosis in most patients.

Differential Diagnoses

Acute Respiratory Distress Syndrome
Lung, Drug-Induced Disease
Pneumocystis (carinii) jiroveci Pneumonia
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)

More on Alveolar Proteinosis

Overview: Alveolar Proteinosis
Imaging: Alveolar Proteinosis
Follow-up: Alveolar Proteinosis
Multimedia: Alveolar Proteinosis
References
Further Reading
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References

  1. Brasch F, Birzele J, Ochs M, et al. Surfactant proteins in pulmonary alveolar proteinosis in adults. Eur Respir J. Sep 2004;24(3):426-35. [Medline]. [Full Text].

  2. Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: Progress in the first 44 years. Am J Respir Crit Care Med. July 2002;166:215-35. [Medline]. [Full Text].

  3. Shah PL, Hansell D, Lawson PR, et al. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax. Jan 2000;55(1):67-77. [Medline]. [Full Text].

  4. Mu XD, Nie LG, Wang GF, Que CL, Li HC. [Idiopathic pulmonary alveolar proteinosis: report of three cases and literature review]. Beijing Da Xue Xue Bao. Oct 18 2008;40(5):551-4. [Medline].

  5. Birsak CA, van Rossem RN, Nijhuis-Heddes JM, Maartense E. Pulmonary alveolar proteinosis: a complication in patients with hematologic malignancy. Neth J Med. May 2000;56(5):193-7. [Medline].

  6. Gacouin A, Le Tulzo Y, Suprin E, et al. Acute respiratory failure caused by secondary alveolar proteinosis in a patient with acute myeloid leukemia: a case report. Intensive Care Med. Mar 1998;24(3):265-7. [Medline].

  7. Ladeb S, Fleury-Feith J, Escudier E, et al. Secondary alveolar proteinosis in cancer patients. Support Care Cancer. Nov 1996;4(6):420-6. [Medline].

  8. Cordonnier C, Fleury-Feith J, Escudier E, Atassi K, Bernaudin JF. Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med. Mar 1994;149(3 Pt 1):788-94. [Medline].

  9. Hildebrand FL Jr, Rosenow EC 3rd, Habermann TM, Tazelaar HD. Pulmonary complications of leukemia. Chest. Nov 1990;98(5):1233-9. [Medline]. [Full Text].

  10. Lakshminarayan S, Schwarz MI, Stanford RE. Unsuspected pulmonary alveolar proteinosis complicating acute myelogenous leukemia. Chest. Mar 1976;69(3):433-5. [Medline]. [Full Text].

  11. Lugassy G, Michaeli J, Hurwitz N, et al. Pulmonary alveolar proteinosis associated with recurrence of Hodgkin's disease in the lung. Isr J Med Sci. Aug 1990;26(8):446-9. [Medline].

  12. Miller RR, Churg AM, Hutcheon M, Lom S. Pulmonary alveolar proteinosis and aluminum dust exposure. Am Rev Respir Dis. Aug 1984;130(2):312-5. [Medline].

  13. Keller CA, Frost A, Cagle PT, Abraham JL. Pulmonary alveolar proteinosis in a painter with elevated pulmonary concentrations of titanium. Chest. Jul 1995;108(1):277-80. [Medline]. [Full Text].

  14. Lee KP, Trochimowicz HJ, Reinhardt CF. Pulmonary response of rats exposed to titanium dioxide (TiO2) by inhalation for two years. Toxicol Appl Pharmacol. Jun 30 1985;79(2):179-92. [Medline].

  15. McCunney RJ, Godefroi R. Pulmonary alveolar proteinosis and cement dust: a case report. J Occup Med. Mar 1989;31(3):233-7. [Medline].

  16. McDonald JW, Alvarez F, Keller CA. Pulmonary alveolar proteinosis in association with household exposure to fibrous insulation material. Chest. Jun 2000;117(6):1813-7. [Medline]. [Full Text].

  17. Dawkins SA, Gerhard H, Nevin M. Pulmonary alveolar proteinosis: a possible sequel of NO2 exposure. J Occup Med. May 1991;33(5):638-41. [Medline].

  18. Friemann J, Pott F, Wilk KB, et al. Pulmonary alveolar proteinosis in rats after administration of quartz: its possible role in morphogenesis of lung cancer. J Cancer Res Clin Oncol. 1994;120(6):348-53. [Medline].

  19. Buechner HA, Ansari A. Acute silico-proteinosis. A new pathologic variant of acute silicosis in sandblasters, characterized by histologic features resembling alveolar proteinosis. Dis Chest. Apr 1969;55(4):274-8. [Medline].

  20. Heppleston AG. Animal model of human disease. Pulmonary alveolar lipo-proteinosis. Animal model: Silica-induced pulmonary alveolar lipo-proteinosis. Am J Pathol. Jan 1975;78(1):171-4. [Medline]. [Full Text].

  21. Martinez-Maldonado M, Ramirez de Arellano G. Pulmonary alveolar proteinosis, nocardiosis and chronic granulocytic leukemia. South Med J. Aug 1966;59(8):901-5. [Medline].

  22. Ruben FL, Talamo TS. Secondary pulmonary alveolar proteinosis occurring in two patients with acquired immune deficiency syndrome. Am J Med. Jun 1986;80(6):1187-90. [Medline].

  23. Reyes JM, Putong PB. Association of pulmonary alveolar lipoproteinosis with mycobacterial infection. Am J Clin Pathol. Oct 1980;74(4):478-85. [Medline].

  24. Bakhos R, Gattuso P, Arcot C, Reddy VB. Pulmonary alveolar proteinosis: an unusual association with Mycobacterium avium-intracellulare infection and lymphocytic interstitial pneumonia. South Med J. Aug 1996;89(8):801-2. [Medline].

  25. Owens MW, Kinasewitz GT, Gonzalez E. Sandblaster's lung with mycobacterial infection. Am J Med Sci. Jun 1988;295(6):554-7. [Medline].

  26. Ranchod M, Bissell M. Pulmonary alveolar proteinosis and cytomegalovirus infection. Arch Pathol Lab Med. Mar 1979;103(3):139-42. [Medline].

  27. Hartung M, Salfelder K. Pulmonary alveolar proteinosis and histoplasmosis: report of three cases. Virchows Arch A Pathol Anat Histol. Nov 28 1975;368(4):281-7. [Medline].

  28. Lee YC, Chew GT, Robinson BW. Pulmonary and meningeal cryptococcosis in pulmonary alveolar proteinosis. Aust N Z J Med. Dec 1999;29(6):843-4. [Medline].

  29. Tran Van Nhieu J, Vojtek AM, Bernaudin JF, et al. Pulmonary alveolar proteinosis associated with Pneumocystis carinii. Ultrastructural identification in bronchoalveolar lavage in AIDS and immunocompromised non-AIDS patients. Chest. Oct 1990;98(4):801-5. [Medline]. [Full Text].

  30. Israel RH, Magnussen CR. Are AIDS patients at risk for pulmonary alveolar proteinosis?. Chest. Sep 1989;96(3):641-2. [Medline]. [Full Text].

  31. Williams GD, Christodoulou J, Stack J, et al. Surfactant protein B deficiency: clinical, histological and molecular evaluation. J Paediatr Child Health. Apr 1999;35(2):214-20. [Medline].

  32. Wallot M, Wagenvoort C, deMello D, et al. Congenital alveolar proteinosis caused by a novel mutation of the surfactant protein B gene and misalignment of lung vessels in consanguineous kindred infants. Eur J Pediatr. Jun 1999;158(6):513-8. [Medline].

  33. Dirksen U, Nishinakamura R, Groneck P, et al. Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression. J Clin Invest. Nov 1 1997;100(9):2211-7. [Medline]. [Full Text].

  34. Huffman JA, Hull WM, Dranoff G, et al. Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice. J Clin Invest. Feb 1 1996;97(3):649-55. [Medline]. [Full Text].

  35. Dranoff G, Mulligan RC. Activities of granulocyte-macrophage colony-stimulating factor revealed by gene transfer and gene knockout studies. Stem Cells. 1994;12 Suppl 1:173-82; discussion 182-4. [Medline].

  36. Ioachimescu OC, Kavuru MS. Pulmonary alveolar proteinosis. Chron Respir Dis. 2006;3(3):149-59. [Medline]. [Full Text].

  37. Tchou-Wong KM, Harkin TJ, Chi C, et al. GM-CSF gene expression is normal but protein release is absent in a patient with pulmonary alveolar proteinosis. Am J Respir Crit Care Med. Dec 1997;156(6):1999-2002. [Medline]. [Full Text].

  38. Danel C, Israel-Biet D, Costabel U, et al. The clinical role of BAL in alveolar proteinosis. Eur Respir J. Sep 1990;3(8):950-1, 961-9. [Medline].

  39. Kitamura T, Tanaka N, Watanabe J, et al. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med. Sep 20 1999;190(6):875-80. [Medline]. [Full Text].

  40. Sánchez-Cuéllar S, García-Pérez FJ, Reina MT. Streptococcus pneumoniae Infection: Cause or Consequence of Pulmonary Alveolar Proteinosis?. Arch Bronconeumol. Nov 2008;44(11):645-646. [Medline].

  41. Suzuki T, Sakagami T, Rubin BK, Nogee LM, Wood RE, Zimmerman SL, et al. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med. Nov 24 2008;205(12):2703-10. [Medline].

  42. Martinez-Moczygemba M, Doan ML, Elidemir O, Fan LL, Cheung SW, Lei JT, et al. Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1. J Exp Med. Nov 24 2008;205(12):2711-6. [Medline].

  43. Ben-Dov I, Kishinevski Y, Roznman J, et al. Pulmonary alveolar proteinosis in Israel: ethnic clustering. Isr Med Assoc J. Oct 1999;1(2):75-8. [Medline].

  44. Kariman K, Kylstra JA, Spock A. Pulmonary alveolar proteinosis: prospective clinical experience in 23 patients for 15 years. Lung. 1984;162(4):223-31. [Medline].

  45. Wilson DO, Rogers RM. Prolonged spontaneous remission in a patient with untreated pulmonary alveolar proteinosis. Am J Med. May 1987;82(5):1014-6. [Medline].

  46. Haddad PG, Pankey GA. Pulmonary alveolar proteinosis: a case with spontaneous resolution. J La State Med Soc. Dec 1969;121(12):365-76. [Medline].

  47. Parker LA, Novotny DB. Recurrent alveolar proteinosis following double lung transplantation. Chest. May 1997;111(5):1457-8. [Medline]. [Full Text].

  48. Ganguli PC, Lynne-Davies P, Sproule BJ. Pulmonary alveolar proteinosis, bronchiectasis and secondary amyloidosis: a case report. Can Med Assoc J. Mar 4 1972;106(5):569 passim. [Medline].

  49. Steens RD, Summers QA, Tarala RA. Pulmonary alveolar proteinosis in association with Fanconi's anemia and psoriasis. A possible common pathogenetic mechanism. Chest. Aug 1992;102(2):637-8. [Medline]. [Full Text].

  50. Kaplan AI, Sabin S. Case report: interstitial fibrosis after uncomplicated pulmonary alveolar proteinosis. Postgrad Med. May 1977;61(5):263, 265. [Medline].

  51. Goldstein LS, Kavuru MS, Curtis-McCarthy P, et al. Pulmonary alveolar proteinosis: clinical features and outcomes. Chest. Nov 1998;114(5):1357-62. [Medline]. [Full Text].

  52. Sieracki JC, Horn RC Jr, Kay S. Pulmonary alveolar proteinosis: report of three cases. Ann Intern Med. Oct 1959;51:728-39. [Medline].

  53. Wang BM, Stern EJ, Schmidt RA, Pierson DJ. Diagnosing pulmonary alveolar proteinosis. A review and an update. Chest. Feb 1997;111(2):460-6. [Medline]. [Full Text].

  54. Lin FC, Chen YC, Chang SC. Clinical importance of bronchoalveolar lavage fluid and blood cytokines, surfactant protein D, and Kerbs von Lungren 6 antigen in idiopathic pulmonary alveolar proteinosis. Mayo Clin Proc. Dec 2008;83(12):1344-9. [Medline].

  55. Martin RJ, Rogers RM, Myers NM. PUlmonary alveolar proteinosis: shunt fraction and lactic acid dehydrogenase concentration as aids to diagnosis. Am Rev Respir Dis. Jun 1978;117(6):1059-62. [Medline].

  56. Takahashi T, Munakata M, Suzuki I, Kawakami Y. Serum and bronchoalveolar fluid KL-6 levels in patients with pulmonary alveolar proteinosis. Am J Respir Crit Care Med. Oct 1998;158(4):1294-8. [Medline]. [Full Text].

  57. Nagasaka Y, Takahashi M, Ueshima H, et al. Bronchoalveolar lavage with trypsin in pulmonary alveolar proteinosis. Thorax. Jul 1996;51(7):769-70. [Medline].

  58. Bonfield TL, Russell D, Burgess S, et al. Autoantibodies against granulocyte macrophage colony-stimulating factor are diagnostic for pulmonary alveolar proteinosis. Am J Respir Cell Mol Biol. Oct 2002;27(4):481-6. [Medline]. [Full Text].

  59. Johkoh T, Itoh H, Muller NL, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology. Apr 1999;211(1):155-60. [Medline]. [Full Text].

  60. Gale ME, Karlinsky JB, Robins AG. Bronchopulmonary lavage in pulmonary alveolar proteinosis: chest radiograph observations. AJR Am J Roentgenol. May 1986;146(5):981-5. [Medline]. [Full Text].

  61. Zontsich T, Helbich TH, Wojnarovsky C, et al. Pulmonary alveolar proteinosis in a child: HRCT findings before and after bronchoalveolar lavage. Eur Radiol. 1998;8(9):1680-2. [Medline].

  62. Rossi SE, Erasmus JJ, Volpacchio M, et al. "Crazy-paving" pattern at thin-section CT of the lungs: radiologic-pathologic overview. Radiographics. Nov-Dec 2003;23(6):1509-19. [Medline]. [Full Text].

  63. Marchiori E, Ferreira A, Muller NL. Silicoproteinosis: high-resolution CT and histologic findings. J Thorac Imaging. Apr 2001;16(2):127-9. [Medline].

  64. Moore EH, Webb WR, Muller N, Sollitto R. MRI of pulmonary airspace disease: experimental model and preliminary clinical results. AJR Am J Roentgenol. Jun 1986;146(6):1123-8. [Medline].

  65. McCook TA, Kirks DR, Merten DF, et al. Pulmonary alveolar proteinosis in children. AJR Am J Roentgenol. Nov 1981;137(5):1023-7. [Medline].

  66. Bonfield TL, Kavuru MS, Thomassen MJ. Anti-GM-CSF titer predicts response to GM-CSF therapy in pulmonary alveolar proteinosis. Clin Immunol. Dec 2002;105(3):342-50. [Medline].

  67. Claypool WD, Rogers RM, Matuschak GM. Update on the clinical diagnosis, management, and pathogenesis of pulmonary alveolar proteinosis (phospholipidosis). Chest. Apr 1984;85(4):550-8. [Medline].

  68. Conces DJ Jr, Tarver RD. Noninfectious and nonmalignant pulmonary disease in AIDS. J Thorac Imaging. Sep 1991;6(4):53-9. [Medline].

  69. Dee P, Suratt P, Winn W. The radiographic findings in acute silicosis. Radiology. Feb 1978;126(2):359-63. [Medline].

  70. Godwin JD, Muller NL, Takasugi JE. Pulmonary alveolar proteinosis: CT findings. Radiology. Dec 1988;169(3):609-13. [Medline].

  71. Green D, Criner GJ. Twenty-five-year follow-up of a patient treated with lung lavage for pulmonary alveolar proteinosis. N Engl J Med. Sep 24 1987;317(13):839-40. [Medline].

  72. Herman TE, Nogee LM, McAlister WH, Dehner LP. Surfactant protein B deficiency: radiographic manifestations. Pediatr Radiol. 1993;23(5):373-5. [Medline].

  73. Holbert JM, Costello P, Li W, et al. CT features of pulmonary alveolar proteinosis. AJR Am J Roentgenol. May 2001;176(5):1287-94. [Medline].

  74. Honda Y, Takahashi H, Shijubo N, Kuroki Y, Akino T. Surfactant protein-A concentration in bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis. Chest. Feb 1993;103(2):496-9. [Medline]. [Full Text].

  75. Kadota J, Nakamura Y, Iwashita T, et al. Pulmonary alveolar proteinosis with lung squamous cell carcinoma. Respir Med. Feb 1999;93(2):138-40. [Medline].

  76. Kronauer CM, Marincek B, Russi EW. Bilateral focal pulmonary densities. Chest. Dec 1989;96(6):1413-4. [Medline].

  77. Kuroki Y, Takahashi H, Chiba H, Akino T. Surfactant proteins A and D: disease markers. Biochim Biophys Acta. Nov 19 1998;1408(2-3):334-45. [Medline].

  78. Lee KN, Levin DL, Webb WR, et al. Pulmonary alveolar proteinosis: high-resolution CT, chest radiographic, and functional correlations. Chest. Apr 1997;111(4):989-95. [Medline].

  79. Masuda T, Shimura S, Sasaki H, Takishima T. Surfactant apoprotein-A concentration in sputum for diagnosis of pulmonary alveolar proteinosis. Lancet. Mar 9 1991;337(8741):580-2. [Medline].

  80. Mikami T, Yamamoto Y, Yokoyama M, Okayasu I. Pulmonary alveolar proteinosis: diagnosis using routinely processed smears of bronchoalveolar lavage fluid. J Clin Pathol. Dec 1997;50(12):981-4. [Medline]. [Full Text].

  81. Milleron BJ, Costabel U, Teschler H, et al. Bronchoalveolar lavage cell data in alveolar proteinosis. Am Rev Respir Dis. Dec 1991;144(6):1330-2. [Medline].

  82. Murch CR, Carr DH. Computed tomography appearances of pulmonary alveolar proteinosis. Clin Radiol. May 1989;40(3):240-3. [Medline].

  83. Pascual J, Gomez Aguinaga MA, Vidal R, et al. Alveolar proteinosis and nocardiosis: a patient treated by bronchopulmonary lavage. Postgrad Med J. Sep 1989;65(767):674-7. [Medline].

  84. Paul K, Muller KM, Oppermann HC, Nutzenadel W. Pulmonary alveolar lipoproteinosis in a seven-year-old girl. A follow- up over six years. Acta Paediatr Scand. Apr 1991;80(4):477-81. [Medline].

  85. Popovsky J, Reydman M, Abellera M, Stockfish H. Pulmonary Alveolar proteinosis. Lobar localization and surgical excision. Int Surg. Mar 1976;61(3):146-7. [Medline].

  86. Santamaria F, Parenti G, Guidi G, et al. Early detection of lung involvement in lysinuric protein intolerance: role of high-resolution computed tomography and radioisotopic methods. Am J Respir Crit Care Med. Feb 1996;153(2):731-5. [Medline].

  87. Schumacher RE, Marrogi AJ, Heidelberger KP. Pulmonary alveolar proteinosis in a newborn. Pediatr Pulmonol. 1989;7(3):178-82. [Medline].

  88. Seymour JF, Doyle IR, Nakata K, et al. Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis. Thorax. Mar 2003;58(3):252-7. [Medline]. [Full Text].

  89. Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. Dec 25 2003;349(26):2527-39. [Medline].

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Keywords

alveolar proteinosis, pulmonary alveolar phospholipoproteinosis, alveolar lipoproteinosis, PAP, surfactant protein, SP-B, granulocyte macrophage-colony stimulating factor, GM-CSF, bronchoalveolar lavage, BAL, whole-lung lavage, diffuse air-space disease

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Contributor Information and Disclosures

Author

Michael B Gotway, MD, Clinical Associate Professor of Diagnostic Radiology and Pulmonary/Critical Care Medicine, University of California at San Francisco School of Medicine; Consulting Staff, Scottsdale Medical Imaging, Ltd
Michael B Gotway, MD is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, Radiological Society of North America, and Society of Thoracic Radiology
Disclosure: Nothing to disclose.

Coauthor(s)

Theodore J Lee, MD, Chief, Thoracic Radiology, San Francisco General Hospital; Assistant Professor of Clinical Radiology, University of California at San Francisco
Theodore J Lee, MD is a member of the following medical societies: American Roentgen Ray Society, Radiological Society of North America, and Society of Thoracic Radiology
Disclosure: Nothing to disclose.

Medical Editor

Jeffrey A Miller, MD, Associate Professor of Clinical Radiology, University of Medicine and Dentistry of New Jersey; Associate Chief of Service, Department of Radiology, Veterans Affairs of New Jersey Health Care System
Jeffrey A Miller, MD is a member of the following medical societies: North American Society for Cardiac Imaging, Society for Health Services Research in Radiology, and Society of Thoracic Radiology
Disclosure: Nothing to disclose.

Pharmacy Editor

Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand
Disclosure: Nothing to disclose.

Managing Editor

John D Newell, Jr, MD, FACR, FCCP, FASER, Co-Director of Thoracic Imaging, UCDHSC; Director of Lung Imaging Center, Professor of Radiology and Professor of Medicine, Department of Radiology, University of Colorado Health Sciences Center, National Jewish Medical and Research Center; Univ. Colorado Hospital
John D Newell, Jr, MD, FACR, FCCP, FASER is a member of the following medical societies: American College of Chest Physicians, American College of Radiology, American Roentgen Ray Society, American Thoracic Society, Association of University Radiologists, Radiological Society of North America, and Society of Thoracic Radiology
Disclosure: Siemens Medical Grant/research funds Consulting; Forevision Technologies Ownership interest Consulting; Vida Corporation Ownership interest Board membership; TeraRecon Grant/research funds Consulting; eMedicine Honoraria Consulting

CME Editor

Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute
Robert M Krasny, MD is a member of the following medical societies: American Roentgen Ray Society and Radiological Society of North America
Disclosure: Nothing to disclose.

Chief Editor

Barry H Gross, MD, Professor, Department of Radiology, University of Michigan Medical School; Professor, University of Michigan Cancer Center
Barry H Gross, MD is a member of the following medical societies: American College of Chest Physicians, American College of Radiology, American Roentgen Ray Society, Association of University Radiologists, Michigan State Medical Society, Physicians for Social Responsibility, Radiological Society of North America, and Society of Thoracic Radiology
Disclosure: Nothing to disclose.

 
 
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